Autonomic consequences of spinal cord injury.

Autonomic Consequences of Spinal Cord Injury Shaoping Hou*1 and Alexander G. Rabchevsky2 ABSTRACT Spinal cord injury (SCI) results not only in motor and sensory deficits but also in autonomic dysfunctions. The disruption of connections between higher brain centers and the spinal cord, or the impaired autonomic nervous system itself, manifests a broad range of autonomic abnormalities. This includes compromised cardiovascular, respiratory, urinary, gastrointestinal, thermoregulatory, and sexual activities. These disabilities evoke potentially life-threatening symptoms that severely interfere with the daily living of those with SCI. In particular, high thoracic or cervical SCI often causes disordered hemodynamics due to deregulated sympathetic outflow. Episodic hypertension associated with autonomic dysreflexia develops as a result of massive sympathetic discharge often triggered by unpleasant visceral or sensory stimuli below the injury level. In the pelvic floor, bladder and urethral dysfunctions are classified according to upper motor neuron versus lower motor neuron injuries; this is dependent on the level of lesion. Most impairments of the lower urinary tract manifest in two interrelated complications: bladder storage and emptying. Inadequate or excessive detrusor and sphincter functions as well as detrusor-sphincter dyssynergia are examples of micturition abnormalities stemming from SCI. Gastrointestinal motility disorders in spinal cord injured-individuals are comprised of gastric dilation, delayed gastric emptying, and diminished propulsive transit along the entire gastrointestinal tract. As a critical consequence of SCI, neurogenic bowel dysfunction exhibits constipation and/or incontinence. Thus, it is essential to recognize neural mechanisms and pathophysiology underlying various complications of autonomic dysfunctions after SCI. This overview provides both vital information for better understanding these disorders and guides to pursue novel therapeutic approaches to alleviate C 2014 American Physiological Society. Compr Physiol 4:1419-1453, secondary complications. 2014.

Introduction Normal autonomic function is critically dependent on the interaction between supraspinal centers and spinal autonomic components. Descending neuronal projections from the brainstem and hypothalamus regulate sympathetic and parasympathetic activities at the spinal cord level (48, 104, 213). Traumatic spinal cord injury (SCI) interrupts connections between higher centers and the spinal cord, resulting not only in somato-motor and sensory deficits but also in autonomic dysfunctions. From an historical perspective, autonomic dysfunctions have not been the focus of basic or clinical research when compared to the amount of attention that “curing paralysis” has received. However, in recent decades autonomic disorders after SCI have drawn more investigations as researchers and clinicians began to pronounce their clinical priority. The disruption of descending autonomic pathways renders abnormalities in multiple organ systems including cardiovascular function, respiration, gastrointestinal (GI) function, micturition, sexual function, sudomotor activity, and thermoregulation. The symptoms often vary according to the level and severity of the injury. For instance, prominent cardiovascular dysfunction may arise when the spinal cord is completely injured above the sixth thoracic (T6) level. This is because most sympathetic preganglionic neurons (SPNs) in the thoracolumbar segments suddenly lose descending vasomotor

Volume 4, October 2014

control. However, incomplete SCI above this level with spared supraspinal vasomotor axons can compensatively maintain sympathetic activity (144, 169). Injury-induced elevations of growth factors and subsequent maladaptive intraspinal plasticity are relevant to the development of detrimental autonomic dysreflexia in the chronic stages of SCI (279, 357). On the other hand, adaptive plasticity helps to re-establish spinal bladder and urethral reflexes for partial recovery of micturition function. Ultimately, the disruption of descending regulatory pathways and subsequent neuronal denervation in spinal autonomic nuclei underlie autonomic dysfunction after SCI. The purpose of this comprehensive overview is to emphasize the consequences of SCI on autonomic functions including cardiovascular regulation as well as abdominal and pelvic visceral activities such as lower urinary tract and GI systems. In addition, thermoregulatory and sexual dysfunctions are * Correspondence

to [email protected] Cord Research Center, Department of Neurobiology & Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 2 Spinal Cord & Brain Injury Research Center, Department of Physiology, Chandler Medical Center, University of Kentucky, Lexington, Kentucky Published online, October 2014 (comprehensivephysiology.com) DOI: 10.1002/cphy.c130045 C American Physiological Society. Copyright 1 Spinal

1419

Autonomic Consequences of Spinal Cord Injury

discussed briefly in relation to cardiovascular and lower urinary tract dysfunctions, respectively. The influence of SCI on respiratory impairments has not been included since this has been reviewed comprehensively elsewhere (4, 191-194, 363). While we describe the symptoms of autonomic dysfunctions following SCI in humans, anatomical neural connections are schematically illustrated in rats since the majority of morphological data acquired from rodents is similar to human structures; differences between species are duly noted.

Cardiovascular Dysfunction Cardiovascular dysfunction often occurs after cervical or high thoracic SCI and basal hemodynamic disorders emerge in both acute and chronic stages postinjury. Presently, cardiovascular disturbances are the leading causes of morbidity and mortality in patients with chronic SCI (108, 252).

Neuroanatomical basis Under normal conditions, the balance between sympathetic and parasympathetic activities is controlled by supraspinal centers. In the cardiovascular system, sensory information originating from the heart and blood vessels is transmitted to the central nervous system (CNS) via afferent fibers; higher cardiovascular centers within the medulla oblongata regulate autonomic outflow consisting of sympathetic and parasympathetic innervations. Additionally, the medial prefrontal cortex, insula, hypothalamus, and cuneiform nucleus project to the medullary nuclei and modulate neuronal activity. Altogether, commanding neurons in the higher CNS distribute order unto autonomic efferent spinal neurons, which in turn act on peripheral organs to regulate blood pressure and heart rate (Fig. 1).

Afferent pathways Primary afferent pathways in the autonomic nervous system express various receptors localized in diverse organs or tissue types. Examples include arterial chemoreceptors and cardiopulmonary baroreceptors. These afferent fibers provide excitatory inputs to the nucleus tractus solitarius (NTS) in the brainstem. Baroreceptors in the aortic arch, carotid sinus, and coronary arteries detect changes in arterial pressure whereas chemoreceptors in the carotid bodies respond to the changes in partial pressure of oxygen and carbon dioxide in the blood. Parasympathetic baroreceptor afferent fibers ascend in the vagus and glossopharyngeal cranial nerves, providing inhibitory inputs to the NTS (94,102,206). As a major recipient of primary sensory cardiovascular information, the NTS precisely regulates hemodynamic performance.

Sympathetic and parasympathetic efferents The efferent pathways in both sympathetic and parasympathetic autonomic divisions are composed of two parts: preganglionic neurons in the CNS and postganglionic neurons

1420

Comprehensive Physiology

in the peripheral nervous system (PNS). Most blood vessels in the body are innervated only by the sympathetic nervous system. However, there are some regions in the body where blood vessels also receive parasympathetic innervation such as the genital cavernous tissue in which parasympathetic activation causes vasodilation. Critically, the heart receives both sympathetic and parasympathetic inputs. SPNs are mainly situated within the intermediolateral cell column (IML) in the lateral horn and gray commissure around the central canal at the T1-L2 spinal cord levels. Some SPNs are also present in the nucleus intercalatus (the gray matter between IML and central canal). Preganglionic sympathetic fibers exit via the ventral roots and terminate in the paravertebral ganglia of the sympathetic chain where postganglionic neurons are located. Heart sympathetic regulation arises from SPN projections exiting T1-T4 spinal cord segments. The cardiac preganglionic sympathetic fibers (T1-T4) synapse onto postganglionic neurons in the superior, middle cervical, and stellate ganglia (a part of the paravertebral chains of ganglia). The postganglionic neurons in these ganglia project efferent fibers to target organs: the heart, thoracic blood vessels, as well as vessels in the head and neck. In the mediastinum, postganglionic sympathetic fibers and preganglionic parasympathetic fibers join to form a plexus of mixed efferent nerves connecting to the heart. The postganglionic cardiac sympathetic fibers in this plexus approach to the base of heart along the surface of great vessels, distributing to various chambers as an extensive epicardial plexus. Sympathetic preganglionic fibers originating from T5-T9 spinal cord levels bypass the paravertebral ganglia and synapse onto postganglionic neurons in the celiac ganglion. These fibers project to the major arteries and organs in the abdomen and pelvis such as the stomach, liver, gallbladder, pancreas, and the small and proximal large intestine. Sympathetic preganglionic fibers originating from T10-L2 spinal cord levels mainly synapse onto postganglionic neurons in superior and inferior mesenteric ganglia. The latter extends fibers to the large intestine, other pelvic organs, and blood vessels. The postganglionic neurons supplying the lower extremities with inputs from SPNs are at the T10-L2 spinal cord levels, located in the lumbosacral sympathetic chain ganglia (109). The parasympathetic neurons projecting to the heart are located in the dorsal motor nucleus of the vagus (DMV) and the nucleus ambiguous in the medulla oblongata. The preganglionic fibers course through the vagus and glossopharyngeal nerves and synapse onto postganglionic neurons situated within the epicardium or the cardiac walls adjacent to the sinoatrial and atrioventricular node (205). The neurotransmitter acetylcholine (ACh) released at the nerve terminals is immediately hydrolyzed because these nodes are rich in cholinesterase, an enzyme that breaks down ACh (32, 318); thus, the effect of the vagal stimulus declines rapidly. Although the right and left vagal nerves project to different cardiac areas, their overlapping terminals mediate both depressed sinoatrial node and impeded atrioventricular conduction. Parasympathetic excitation decreases heart




Figure 1 Schematic diagrams illustrating sympathetic and parasympathetic control of the cardiovascular system. SPNs are mainly situated in the intermediolateral (IML) cell column of T1-L2 spinal cord segments. The heart receives both sympathetic and parasympathetic input; sympathetic regulation arises from T1-T4 spinal segments whereas parasympathetic innervation originates from the dorsal motor nucleus of vagus (DMV) and nucleus ambiguous (N. Ambiguous) in the medulla oblongata via the vagus and glossopharyngeal nerves, respectively. Sympathetic preganglionic fibers project to postganglionic neurons in the middle cervical ganglia which activate cardiac plexuses distributing to the heart and thoracic blood vessels. Otherwise, most peripheral vessels have sympathetic innervation but do not have parasympathetic input. Sympathetic preganglionic fibers projecting to the abdomen, pelvis, and lower body originate primarily from T5-L2 spinal levels and synapse onto postganglionic neurons within celiac ganglion, superior mesenteric, and inferior mesenteric ganglia prior to innervating major arteries and organs. The lower thoracic and lumbosacral sympathetic chain ganglionic neurons project fibers to lower body skin blood vessels. Parasympathetic neurons located in the sacral spinal cord innervate pelvic viscera and do not participate in cardiovascular regulation. CNIX, cranial nerve IX; CNX, cranial nerve X.

rate whereas sympathetic excitation increases heart rate and myocardial contractility. The action of sympathetic neurons innervating arterial vessels is to regulate peripheral resistance such that sympathetic excitation raises blood pressure. In general, sympathetic and parasympathetic nervous systems have


opposing effects on hemodynamics, adapted to various activities (Table 1). Additionally, parasympathetic neurons located in the sacral spinal cord innervate pelvic viscera. This part of parasympathetic system does not, however, participate in cardiovascular regulation.

1421



Table 1

Autonomic Neuronal Control of the Heart and Blood Vessels

Organs

Neural control

First neuron location

Peripheral nerve (N.)

Second neurotransmitter/ receptor in organs

Heart

Sympathetic

T1-T4

Cardio-pulmonary N.

NE/β1 -AR

Increase HR, contractibility, conduction velocity

Para-sympathetic

DMV N. Ambiguous

Vagus N. Glosso-pharyngeal N.

ACh/mAChR

Decrease HR, contractibility, conduction velocity

Sympathetic

T1-T4 T5-L2

Cardiac plexus Splanchnic N. N. from sympathetic chain

NE/α1 -AR, P2X

Tonic vasoconstriction

Vessels

Functions

DMV, the dorsal motor nucleus of Vagus; N. Ambiguous, Nucleus Ambiguous; NE, norepinephrine; ACh, acetylcholine; mAChR, muscarinic acetylcholine receptor; AR, adrenergic receptor; P2X, purinergic P2X receptors; HR, heart rate.

Supraspinal cardiovascular regulation Supraspinal descending pathways, originating from the brainstem and hypothalamus, control spinal sympathetic and parasympathetic outflow (48, 104, 213). Their activities are further modulated by the limbic system. It has been recognized that five main brain regions provide input to SPNs in the thoracolumbar spinal cord: the rostral ventrolateral medulla (RVLM), the rostral ventromedial medulla, the caudal raphe nuclei, the A5 region of brainstem, and the paraventricular nucleus (PVN) of hypothalamus (43, 50, 156, 204) (Fig. 2).

Figure 2 Supraspinal vasomotor pathways descend from the brainstem and hypothalamus. The original regions include the rostral ventrolateral medulla (RVLM), the rostral ventromedial medulla (RVMM), the caudal raphe nuclei (RN), the A5 region, and the paraventricular nucleus (PVN); presympathetic neurons in these nuclei project to sympathetic preganglionic neurons (SPNs) in the thoracolumbar spinal cord, regulating sympathetic outflow.

1422

In addition, neurons in other supraspinal regions including the locus coeruleus, arcuate nucleus, and cortex also project to autonomic nuclei in the spinal cord. These presympathetic nuclei contain neurochemically heterogenic neurons which must be organized cooperatively to achieve integrated action in regulating lower autonomic neurons (204). Neurons throughout the ventrolateral medulla are involved in sympathetic cardiovascular regulation. This region comprises several columns of neurons that extend rostrally to the pontomedullary junction and caudally to the spinal cord. The organization is roughly similar among all mammalian species. In the rat, RVLM neurons are on average 1.8 mm from the midline and their mediolateral extent is approximately 1 mm (302). Among supraspinal autonomic centers, the RVLM is considered to play a key role in regulating cardiovascular function. As the most thoroughly studied region in the medulla, neurons in the RVLM tonically activate spinal sympathetic neurons to maintain arterial pressure and heart rate (120, 126). Anatomical and physiological studies have demonstrated that neurons in the RVLM including the C1 group give rise to the main supraspinal vasomotor pathways (SVPs) (71, 157, 173, 262). Previous experiments reported the discrepancies of SVP localization within the spinal cord among different species. SVPs are mainly located in the dorsal aspect of the lateral funiculus in humans (104, 257), in extensive areas from ventral to dorsal aspects of the lateral funiculi in non-human primates (165), and between the dorsolateral sulcus and dental ligament in cats (196). In rodents, descending SVPs have been identified within the dorsolateral aspects of the spinal cord by using electrophysiological techniques (71,169,289) or neuronal tract tracing (144,157,324) (Fig. 3). The descending SVPs innervating spinal SPNs contain a diverse array of neurotransmitters including amino acids, catecholamines, and neuropeptides (Fig. 4). Supraspinal vasomotor inputs from the RVLM release glutamate and GABA. A significant portion of RVLM neurons expresses neuropeptide Y and preproenkaphalin mRNA (239, 322). The main neurotransmitter in the caudal raphe nuclei is serotonin




(A)

(B)

(C)

(D)

Figure 3

Biotinylated dextran amine (BDA) anterograde tracing reveals supraspinal vasomotor pathways originating from the rostral ventrolateral medulla (RVLM) in an intact rat. BDA (10% in distilled water, 1 μL/side) is injected bilaterally into the RVLM 3 weeks before perfusion. (A) Low magnification microphotograph of transverse section in the rostral medulla shows bilateral injection sites within the RVLM. (B-D) Representative photomicrographs demonstrate (B) the distribution of BDA-labeled fibers in an overview of the lower cervical spinal cord, which are mainly located in the (C) dorsolateral funiculus (DLF) and (D) ventral white matter (VWM). (C and D) Higher magnification of areas boxed in (B). Scale bars: 1.5 mm (A), 500 μm (B), 25 μm (C), and 50 μm (D). (With permission from Ref. 144.)

(5-HT). Some neurons in these nuclei express both glutamate and GABA based on mRNA expression of phosphate activated glutaminase, vesicular glutamate transporter (VGLUT) 2, and glutamic acid decarboxylase (323). Notably, a population of serotonergic neurons in the caudal raphe nuclei coexpress substance P (297). Major sources of catecholaminergic input to SPNs are C1 adrenergic neurons in the RVLM and noradrenergic neurons in the A5 region (156). They provide epinephrine/norepinephrine to elicit excitatory responses via α1 adrenergic receptor (AR) or inhibitory responses via α2 -AR by modulating potassium conductance in the SPNs (149). After complete spinal cord transection, neurotransmitters including glutamate, GABA, substance P, neuropeptide Y, and enkephalin persist in the IML caudal to the injury, indicating that spinal interneurons are responsible for their maintained expression (204).

Complications of cardiovascular dysfunction Interruption of communication between superior centers and the spinal cord leads to “spinal shock” in the acute injury phase. Spinal shock is a transitory suspension of motor and sensory functions and reflexes below the injury level (14, 33, 133). The concept of “neurogenic shock” in the


acute phase of SCI is distinguished from spinal shock. The key components of neurogenic shock are characterized by pronounced hypotension, persistent bradycardia, and hypothermia. These disorders are caused by the disruption of supraspinal vasomotor control, the lack of sympathetic activity, and unopposed parasympathetic tone via an intact vagus nerve (23, 171, 215, 288). In the first few minutes after experimental SCI, there is a pressor response elicited by a burst of sympathetic outflow and massive norepinephrine release from the adrenal glands, and this elicits parasympathetic reflexmediated bradycardia in various animal models (81, 256). In humans, transient hypertension and bradycardia/tachycardia develop at once, usually lasting about 3 to 4 min in response to the trauma of SCI (115). Following this immediate response to injury, there are decreases in sympathetic activity, cardiac output, as well as total peripheral blood vessel resistance, which comprises neurogenic shock (122).

Reduced resting arterial pressure and orthostatic hypotension Hypotension occurs in both acute and chronic phases after severe SCI, notably at higher spinal levels. It is regarded as secondary to a reduction in sympathetic activity below the

1423


Figure 4

Multiple neurotransmitters are involved in cardiovascular regulation. Supraspinal vasomotor pathways contain a diverse array of neurotransmitters including amino acids, catecholamines, and neuropeptides. Descending projections from the rostral ventrolateral medulla (RVLM) are glutamatergic or γ-aminobutyric acid (GABA)ergic whereas serotoninergic (5-HT) neurons are predominant in the caudal raphe nuclei (RN). C1 adrenergic neurons in the RVLM and noradrenergic neurons in the A5 region are major sources of catecholaminergic inputs to sympathetic preganglionic neurons, releasing epinephrine (adrenaline) and norepinephrine (NE). Additionally, some descending axons express substance P, enkephalin (Enk), and neuropeptide Y. Neurotransmitters in the spinal cord are comprised of glutamate (Glu), GABA, substance P, neuropeptide Y, and Enk.

injury. The acute hypotension is caused by loss of vasomotor tone and pooling of blood in the peripheral and splanchnic vasculature. The extent and severity of the low blood pressure and heart rate changes are associated with the level and severity of SCI; hypotension is not common in individuals with incomplete or mild SCI (171). The possible reason is the widely spread distribution pattern of bilateral descending SVPs in the spinal cord that usually spares axons in incomplete SCI, allowing them to maintain blood pressure at normal levels. Earlier studies which measured resting blood pressure of a large number of patients with complete SCI reported an inverse relationship between the level of SCI and blood pressure (100). Later, hemodynamic recordings in humans with complete cervical SCI showed decreased blood pressure, but in those with lower thoracic or lumbar injury the values were normal (222). Individuals with high level SCI are commonly prone to orthostatic hypotension when changing position from horizontal to upright, particularly in the acute recovery phase. Orthostatic hypotension is defined as a decrease in systolic blood pressure of more than 20 mmHg, or a fall in diastolic

1424


blood pressure of more than 10 mmHg for at least 3 min while positioned upright or during head-up tilt to 60◦ (101). Patients may complain of dizziness, nausea, light headedness, and a feeling of faintness but there is usually no loss of consciousness. Despite indeterminate mechanisms, the evidence indicates that factors involved in the occurrence of orthostatic hypotension include: (i) excessive venous pooling of blood in the organs and lower extremities due to reduced sympathetic activity and loss of reflexive vessel constriction below the injury level, (ii) loss of lower extremity muscle function for counteracting venous pooling, (iii) reduced plasma volume as a consequence of hyponatremia, an electrolyte disturbance in which the sodium ion concentration in the plasma is lower than normal, and (iv) cardiovascular deconditioning resulting from prolonged bed rest (103, 105, 359). Head-up tilt elicits an immediate initial fall in blood pressure. However, if the upright position is prolonged, blood pressure tends to recover partly, which is likely related to activation of the renin-angiotensin-aldosterone system (223). Renal baroreceptor excitation stemming from low pressure of renal blood perfusion results in renin release. Subsequently, renin promotes the production of peptide angiotensin II, a powerful direct-acting vasoconstrictor which also facilitates peripheral norepinephrine and adrenal aldosterone release. As a result, the activation of renin-angiotensin-aldosterone system raises blood pressure. In the absence of supraspinal influence the renal vasculature is shown to respond to an orthostatic stimulus with vigorous vasoconstriction, suggesting that the adaptation of blood pressure to the upright position may be correlated with spinal vasomotor reflexes acting on the splanchnic circulation (179). When orthostatic hypotension occurs, tachycardia typically happens as a consequence of enhanced sympathetic activity, but it is not sufficient to compensate for the systemic hypotension. Management and treatment of orthostatic hypotension consists of physical and pharmacological methods. Frequent postural changes to head-up position help to diminish symptoms. Avoiding rapid postural changes is effective to circumvent situations causing low blood pressure. In some cases, preventing postural-related venous pooling by using abdominal binders, thigh cuffs and lower limb elastic stockings are useful to reduce hypotension. Typically, individual SCI patients do not need drugs to deal with low blood pressure. If severe symptoms persist, a variety of drugs can be used such as vasoconstrictors ephedrine, α-AR agonist midodrine, dopamine receptor blocker domperidone, among others (225).

Cardiac dysrhythmias Sinus bradycardia is the most common symptom in patients in the acute stage of SCI. However, various other cardiac dysrhythmias may occur including cardiac arrest, sinus tachycardia, supraventricular tachycardia, and atrial fibrillation (198, 367). Persistent bradycardia, defined as mean heart rate for at least 1 day of < 60 beats/min, is reported in 100% of individuals with quadriplegia resulting from severe cervical



Autonomic dysreflexia after SCI

MAP (mmHg)

HR (bpm)

CRD

HR (bpm)

Intact

480 400 320 200 160 120 80 0

MAP (mmHg)

SCI (198). Primary cardiac arrest happens in approximately 16% of patients with severe lesions of the cervical spinal cord (198). Similar to the change of blood pressure following SCI, the development of acute cardiac dysrhythmias is also related to the severity of SCI at high levels (123, 150). The most pronounced altered heart rate parameters are manifested during the acute phase while cardiac performance can improve substantially in the more chronic injury stages (122). It has been reported that tracheal stimulation can provoke bradycardia and cardiac arrest in the acute stage of SCI, attributed to a vago-vagal reflex (99). In individuals with an intact spinal cord, stimulating the trachea elicits hypertension and tachycardia, a response dependent on supraspinal regulated sympathetic activity. By contrast, in patients with SCI, efferent cardiac parasympathetic nerve pathways remain intact while sympathetic regulation is impaired, which can cause unopposed vagal over-activity in response to tracheal stimulation, leading to bradycardia and cardiac arrest (373). The treatment of bradycardia with atropine to competitively antagonize cardiac muscarinic ACh receptors on target organs is only partially and transiently effective because of sympathetic deficiency. Low-dose isoproterenol, a β-AR agonist, is suggested to eliminate the sinus pause, a condition wherein the sinoatrial node ceases to generate electrical impulses to stimulate myocardial contractions (198). In rat models of cervical or high thoracic SCI, the mean arterial pressure is reduced whereas tachycardia usually occurs following the period of neurogenic shock, as a compensatory response to hypotension (144, 177, 189, 282).


1

2

CRD

560

3

T4-Tx

480 400 320 200 160 120

Min

80 0

1

2

3

Figure 5 Autonomic dysreflexia develops following SCI at cervical or high thoracic levels. During colorectal distension (CRD), mimicking noxious pelvic visceral stimuli, both mean arterial pressure (MAP) and heart rate (HR) increase slightly in intact F344 rats, indicative of escape/avoidance response. In T4-transected (T4-Tx) rats, however, CRD triggers a prominent rise in MAP accompanied by bradycardia, a typical symptom of autonomic dysreflexia, measured at 10 weeks postinjury. (Unpublished data, S. Hou.)

Autonomic dysreflexia Autonomic dysreflexia is a syndrome characterized by sudden episodic high blood pressure, typically accompanied by baroreflex-mediated bradycardia, in response to visceral or cutaneous stimuli below the level of spinal cord lesion (Fig. 5). It is commonly confined to individuals with SCI at the T6 level or higher with a 50% to 90% occurrence rate, although it has also been reported in patients with SCI from T8 to T10 levels (334). In patients with SCI below the T6 spinal level, supraspinal sympathetic innervation of vasculature including important splanchnic blood vessels is usually preserved; as a result, autonomic dysreflexia rarely occurs. Usually, the higher the level of spinal cord lesion, the more severe the hypertension in autonomic dysreflexia, which can result in debilitating headaches, seizures, strokes, and serious cases can cause cerebral and spinal subarachnoid hemorrhage, as well as pulmonary edema (316). This syndrome is typically triggered by noxious pelvic visceral stimulation in the form of colorectal or bladder distension; however non-noxious stimuli including gentle skin stroking or mild colon distension can also provoke it (160, 175, 200). The response in magnitude of blood pressure increase is more pronounced during noxious stimuli below the spinal cord lesion, compared to non-noxious stimuli (218).


The loss of supraspinal inhibitory modulation of spinal sympathetic neurons facilitates a massive discharge of SPNs which can give rise to profound alterations in vasomotor, pilomotor, and sudomotor activities. Autonomic dysreflexia is characteristic in chronic injury phases but it may occur any time following SCI. It is thought that acute autonomic hyperreflexia arises from the loss of bulbospinal sympathetic modulation rather than reorganization of intraspinal neural circuits (177, 178). Following SCI, the basal firing of the renal sympathetic nerve is greatly reduced and lower sympathetic activity persists, which can elicit significant changes in peripheral targets. However, if the activity is greatly increased by a vicsero-spinal-sympathetic reflex, alterations in vasculature and peripheral neurotransmitters contribute to a large hypertensive response. Injury-induced intraspinal plasticity in both pelvic primary afferents and propriospinal neurons are involved in the development of autonomic dysreflexia in the chronic stage. This was unveiled with experiments in rats. The profuse increase in growth factor expression stimulates progressive changes in calcitonin gene-related peptide (CGRP)+ unmyelinated (C) fiber structure and electrophysiology (39, 143, 181, 358). It has been documented that NGF-mediated aberrant

1425


Figure 6 Schematic illustrating reorganization of intraspinal circuits related to autonomic dysreflexia. SCI-induced elevation in spinal levels of nerve growth factor mainly contributes to the plasticity of pelvic visceral calcitonin gene-related peptide (CGRP)+ C-fiber afferents. The sensory arbors, in turn, are relayed by ascending propriospinal neurons to sympathetic preganglionic neurons (SPNs) in the thoracolumbar spinal cord to elicit autonomic dysreflexia, notably when the distal colon or bladder is distended.

sprouting of C-fiber afferents particularly into lumbosacral spinal segments, termination sites of pelvic visceral sensory axons, is associated with the severity of induced autonomic dysreflexia (44, 279). Subsequent plasticity of lumbosacral propriospinal dorsal gray commissural (DGC) neurons, which react to primary afferent sprouting, relays pelvic visceral sensations to SPNs in the rostral thoracolumbar spinal cord and elicits vasoconstriction-induced hypertension (142) (Fig. 6). These two intraspinal alterations coincide temporally with the occurrence of delayed increased severity of autonomic dysreflexia. At 7 days postinjury, autonomic dysreflexia presents weak responses to noxious stimuli, which correlates with transient atrophy of the denervated SPNs below the injury. When SPN morphologies begin to return to normal by 2 weeks following injury (178), the hypertensive response to noxious stimuli becomes significantly greater (229). Novel methodologies to detect spontaneous autonomic dysreflexia in experimental SCI rodents have been developed with telemetric monitoring techniques (282, 387). Together with colon or bladder distension models, the refined analytical tool using algorithms to detect spontaneous events represents a clinically relevant approach to evaluate pharmacological therapeutic intervention for autonomic dysreflexia. While some studies report that strain specificity is relevant to the incidence of autonomic dysreflexia in rats (190), more recent experiments indicate otherwise. Besides commonly used Wistar rats, Sprague-Dawley rats have been used to study autonomic dysreflexia (88, 208, 386), as well as inbred Fisher 344 rats that are advantageous for cell or tissue transplantation experiments (144). Inhibition of upper GI motility after SCI is typically considered to be a consequence of autonomic dysreflexia (92). Accordingly, an animal model of autonomic

1426


dysreflexia has been established by inducing gastric distension using an implanted catheter in rats with SCI (195). While most studies of SCI-induced autonomic dysreflexia have centered on the rat, a mouse model presumably creates potential genetic tools to investigate its pathophysiology (39, 153). Many studies in rodents have used spinal cord contusion or compression to mimic cardiovascular dysfunction in humans. Basal mean arterial pressure and heart rate are gradually exacerbated with increasing injury force (68, 229, 358). However, spinal cord contusion and clip compression often result in a rim of white matter sparing at the injury site (93), in which a partial preservation of SVPs helps to maintain basal cardiovascular parameters. Indeed, normal cardiovascular function can be sustained and autonomic dysreflexia may not develop if a critical threshold of vasomotor pathways is spared. In a recent study, hemodynamic consequences were compared in several types of SCI rat models with defined lesions at T4 level, including complete transection, dorsal hemisection, lateral hemisectioin, and dorsolateral funiculus transection (144). Only complete spinal cord transections caused disordered basal hemodynamics and colon distensioninduced autonomic dysreflexia. Thus, rats with complete T4transection provide a reliable model to investigate the pathophysiology and neuronal mechanisms of cardiovascular dysfunction.

Alterations in cardiovascular control after SCI Traumatic SCI interrupts descending vasomotor control. The parasympathetic cardiac pathways otherwise remain intact. In response to blood pressure changes in peripheral vessels, baroreflex-mediated parasympathetic activity brings about bradycardia and other cardiac arrhythmias. In contrast, incomplete injury above the T6 level or severe injury below the T6 level does not often generate disordered hemodynamics due to spared vasomotor axons which can retain sympathetic regulation of some splanchnic visceral bed. However, abnormal peripheral vasomotor responses can arise as a result of decentralized regulation of vascular tone. Although the mechanisms are partially known, cardiovascular problems after SCI are attributed to the following pathophysiological elements occurring in autonomic nuclei and circuits below the injury: (i) disruption of SVPs, (ii) atrophy of SPNs and reduced sympathetic activity, (iii) inappropriate synapse reorganization, and (iv) peripheral α-AR hyper-responsiveness.

Disruption of descending vasomotor pathways Under normal conditions, supraspinal epinephrine secreted from neurons in C1 region of the brainstem modulates the tonic discharge of SPNs to sustain sympathetic outflow within a normal range, while serotonin originating from the caudal raphe nucleus regulates cardiovascular function by increasing sympathetic activity (211, 217). Previous studies in animals reported that abolition of most serotonergic inputs decreases resting blood pressure (66). Anatomically,



(A)

(B)


(C)

the acute stage after SCI reduced sympathetic activity elicits an areflexic urinary bladder and a paralytic bowel, known as flaccid paralysis, which contributes to the low systemic arterial pressure. In combination with the depression of autonomic activity after deprival of supraspinal input, the atrophy of SPNs may attribute to sympathetic atonia and manifestation of “spinal shock.” Typically within a month or so of injury, a sympathetic excitatory response develops to exhibit autonomic dysreflexia (316). The re-establishment of SPN morphological appearance with time may be reflective of these changes. In rats, returning to normal dendritic arbors and somal sizes of SPNs in the chronic stage of SCI coincides with the stability and severity of autonomic dysreflexia (178).

Figure 7

Supraspinal serotonergic (5-HT) projections to sympathetic preganglionic neurons (SPNs) in the intermediolateral (IML) cell column are interrupted after SCI. (A) In an horizontal thoracolumbar section of intact spinal cord, 5-HT-immunolabeled axon bundles (red) extend into the IML, where Fluorogold (FG)-labeled SPNs (blue) are located. (B) Higher magnification of boxed region in (A) shows serotonergic axons in proximity to FG-labeled SPNs. (C) Four weeks after complete T4-transection, there is no 5-HT-immunolabeled axons in the IML below the lesion of spinal cord. Scale bars: 500 μm (A) and 100 μm (C). (Note: FG was 0.5% in distilled water 0.4 mL, intraperitoneal injection.) (Unpublished data, S. Hou.)

nearly all hypotension-sensitive SPNs are innervated by serotonergic fibers (238); abundant varicose brainstem-derived catecholaminergic fibers are found appose to hypotensionsensitive SPNs (238). Direct catecholaminergic or serotonergic innervation of SPNs is critical to maintain stimulated pressor responses brief and of limited magnitude when the spinal cord is intact (16, 130). Following SCI, medullary vasomotor centers no longer mediate efferent control of vasomotor tone (Fig. 7). Hypotension thus occurs due to reduced sympathetic activity of SPNs and lower plasma levels of catecholamine. In humans with complete SCI at high levels, orthostatic hypotension is frequently observed during postural position changes in addition to lower basal blood pressure (226).

Atrophy of SPNs and reduced sympathetic activity Spinal neurons undergo morphological changes after SCI. Previous studies have described structural changes at the injury site, such as neuronal death, axon demyelination, or cavitation (329). Although acute atrophy occurs in SPNs below the injury (178), the normal morphology of SPNs is gradually re-established. The initial atrophy of autonomic neurons could be a consequence of the loss of supraspinal control. In humans with SCI, preliminary comparisons of somal size of SPNs in the thoracic segments indicated a decrease in one case but no change in another case (170). Overall, sympathetic activity is reduced caudal to SCI level. Microneurographic recordings reveal sparse activity in sympathetic postganglionic axons below the injury of a human spinal cord (372). Plasma epinephrine and their urinary metabolites are decreased in the low-normal range immediately after SCI and remain at this level as long as there is no sensory or visceral stimulation below the injury (64). During


Intraspinal plasticity related to cardiovascular abnormality Following SCI the disinhibited SPNs are more sensitive to spinal afferent input. This is attributed to two factors: one is the loss of descending modulation and another is the more dominant influence of remaining spinal reflex circuits caudal to the injury. Reorganization of intraspinal circuits is likely to change the patterns of input to sympathetic neurons. The recording of renal sympathetic nerve activities suggested enhanced transmission through the spinal reflex circuits after spinal cord transection (214). Investigators proposed the concept that synaptic input to SPNs undergoes plasticity after SCI, resulting in replacement of synapses from supraspinal projections to interneuron inputs (356). This hypothesis is supported by the observation of re-established normal SPN dendritic arbor and somal size within 2 to 4 weeks after a transient degenerative retraction during the first week postinjury (178, 203). As pelvic primary afferents cannot act directly on thoracolumbar SPNs, injury-induced sprouting of propriospinal relay pathways is believed to be involved in the development of autonomic dysreflexia (Fig. 6) (142). In addition, prominent c-fos gene expression is localized to interneurons throughout the lumbosacral spinal cord in response to visceral pain only in rats with complete high thoracic SCI (142), indicating significant activation of local neural circuitry postinjury. However, electron microscopy suggests that the loss of approximately 50% to 70% of bulbospinal synaptic input to thoracic SPNs is not replaced by intraspinal inputs since the number of synapses from interneurons is not altered after injury (203). It is postulated that the new intraspinal influences on SPNs may be mediated by interneurons that have initially synapsed with sympathetic neurons instead of novel direct innervation (357). The sprouting of pelvic primary afferents following SCI is related to cardiovascular dysfunction. Unlike their somatic counterparts, pelvic visceral afferents are comprised of unmyelinated C-fibers and thinly myelinated Aδ-fibers, and they primarily terminate in the laminae I, II, and V, lamina X above the central canal, as well as the lateral gray matter. It has been shown that the density of CGRP+ afferent fibers increases at the lumbosacral spinal cord in spite of unchanged

1427


number of CGRP+ DRG neurons after SCI (143, 181). As described before, injury-induced elevation of nerve growth factor (NGF) in the spinal cord below the lesion arouses lumbosacral CGRP+ sensory afferent sprouting (39,181). Further manipulation of exogenous NGF gene expression in situ confirmed that the extent of increased CGRP+ afferent arbors correlates with the magnitude of autonomic dysreflexia (44). Propriospinal neurons then relay the information of sprouted pelvic primary afferents to the thoracolumbar SPNs to elicit autonomic dysreflexia when the distal colon or bladder is distended (279), as described above.


(172). Analgesia can be achieved by administration of paracetamol, coproxamol, or nonsteroidal anti-inflammatory drugs such as aspirin. For patients unresponsive to above therapies, regional or general anesthesia may successfully block sympathetic response. Antisympathetic drugs consist of ganglionic blockers and catecholaminergic antagonists, which often have immediate effects for responsive hypertension (122). A presynaptic calcium channel blocker, gabapentin (113,361), widely used for the treatment of neuropathic pain and epilepsy, is reported to alleviate both experimental spasticity and autonomic dysreflexia by eliminating a physiological link between these aberrant reflexes, impeding neurotransmission of noxious stimuli into the spinal cord (281, 282).

Peripheral α-adrenoceptor hyperresponsiveness Peripheral vascular below the level of SCI becomes hypersensitive to α-AR stimulants. In animal experiments, decentralization of postganglionic sympathetic neurons by cutting their preganglionic inputs results in hypersensitivity response to norepinephrine (148). In humans with quadriplegia and cervical SCI, enhanced pressor response to norepinephrine was observed (224). Thus, evidence from both animal and human studies suggests that peripheral α-AR hyper-responsiveness likely accounts for a significantly enhanced pressor response during autonomic dysreflexia. It is consistent with the fact that the level of plasma catecholamines is often reduced in individuals with high SCI (223, 300). However, assessing α-AR hyper-responsiveness (i.e., the pressor response) in vivo is complicated by the fact that able-bodied subjects and uninjured control animals have an intact baroreflex. The mechanism of this hypersensitivity is not completely elucidated. It could be a consequence of an increased number of receptors, abnormalities of postsynaptic coupling mechanisms or reduced presynaptic reuptake (330). Interestingly, some studies have challenged the concept of α-AR hypersensitivity by reporting no change in pressor response to norepinephrine in rats with complete cervical SCI (216, 268), suggesting that apparent enhanced sympathetic response may be caused by periodic episodes of SPN hyperactivity rather than denervation-related hypersensitivity. Other studies have otherwise shown that arterial and venous blood vessels from rats with more chronic SCI markedly increase nerve-evoked constrictions (290, 337), and the arterial vascular muscle is transiently supersensitive to α1 and α2 -AR agonists (338).

Therapeutic strategies for cardiovascular dysfunction after SCI Treatments for autonomic dysreflexia include the removal of triggering factors and providing antihypertensives and/or sympatholytic drugs based on internationally accepted Paralyzed Veterans of America recommendations on the management of autonomic dysreflexia (1). Avoidance of factors like colon impaction or bladder distension is effective in minimizing the occurrence of autonomic dysreflexia. Persistence of visceral stimuli maintains heightened sympathetic responses

1428

Techniques for functional assessments There are two methods for measuring blood pressure in experimental animals, one direct and the other indirect. Direct measurements can be achieved either with fluid-filled cannulae or the implantation of a telemetry probe whereas indirect monitoring of hemodynamics employs a tail cuff (187). Fluid-filled cannulae: In SCI animals, cardiovascular parameters can be measured using an arterial cannula implanted acutely. A fluid-filled cannula is inserted into the femoral or carotid artery tunneled subcutaneously and extruded through the back skin. The cannula is filled with heparin solution and can be maintained patent for at least 1 week with daily flushing. Animals implanted with cannulae should be housed singly to prevent chewing from cagemates. After the effects of anesthesia disappear on the second day, basal hemodynamic data and colon distension-induced autonomic dysreflexia can be monitored in gently restrained conscious animals by connecting the cannulae to a pressure transducer (44, 174, 177). This fluid-filled cannulae method provides high-resolution cardiovascular data with a relatively modest investment in equipment. However, it is difficult to preserve catheter patency without infection for repeated measurements over a long time. Thus, this approach is typically used as a terminal snapshot for hemodynamic recording in each animal (151). Telemetric acquisition and analysis system: To continuously monitor cardiovascular parameters, the wireless radiotelemetric system is a more refined tool to record hemodynamics in conscious, freely moving animals for long term. Animals undergo surgery to expose the femoral artery or descending aorta. The catheter of radio-telemeter with a pressure sensor on the tip is inserted into the artery. A small drop of tissue glue is applied to seal the artery lesion but the vessel remains patent for blood flow. The body of telemeter is secured and preserved inside the abdomen or subcutaneously. After 1 to 2 weeks, animals can receive spinal cord transection or contusion (125, 229, 282). During the recording, arterial pressure data is transmitted as a radiofrequency signal to a receiver under the cage. Recent telemetric analysis verified persistence of hypotension and tachycardia existing for a



long term period after complete SCI at high thoracic level in rats (144, 189, 282). Tail-cuff: The noninvasive blood pressure methodology utilizes a tail-cuff placed on the tail to occlude blood flow. Upon deflation, one of several types of noninvasive blood pressure sensors, placed distal to the occlusion cuff, can monitor blood pressure. An animal holder is needed to comfortably restrain the animal and create a low-stress environment. To monitor blood pressure with the tail-cuff, there must be adequate blood flow in the tail to acquire a blood pressure signal. By means of thermo-regulation, the animal dissipates heat through its tail and generates tail blood flow. Therefore, the body temperature is very important for accurate and consistent blood pressure measurements. If the room temperature is too cool (such as below 22◦ C), it may be difficult to obtain blood pressure signals due to reduced tail blood flow (187).

Thermoregulatory dysfunction The thermoregulatory function is mediated by the sympathetic nervous system and effectors including vasomotor, sudomotor and pilomotor structures. SCI interrupts supraspinal sympathetic pathways regulating body temperature below the injury, resulting in thermoregulatory difficulty. Consequently, patients are susceptible to alterations in core temperature in response to environmental temperature changes (232, 249, 276, 325). In addition, the disruption of afferent pathways from the peripheral temperature receptors causes transmission impairment of thermal information. Unlike noradrenergic characteristics in most sympathetic efferents, sudomotor efferents are cholinergic. The excitation of sudomotor fibers increases sweat gland secretion via muscarinic receptor activation. Pilomotor efferents innervating piloerector muscles are noradrenergic, whose excitation raise their associated hair to enhance insulation when the muscles contract. During exercise or heat exposure, skin blood flow in abled-bodies increases as a response of body temperature elevation triggered by vasodilation and sweating; with cold exposure, skin blood flow decreases via cutaneous vasoconstriction. However, in spinal cord-injured patients at high thoracic or cervical levels, this cutaneous blood flow adjustment as well as shivering and thermoregulatory sweating below the injury level is compromised (83). As a compensatory response, sweat glands above the injury level increase productivity but the patients remain at a high risk for heat illness in the period of exercise or heat stress (67, 369). The core temperature in individuals with SCI is lower than normal. Core temperature usually falls during the first week postspinal cord transection in rats but recovers to a certain extent with time (189). The substantial initiation of hypothermia probably results from decreased sympathetic activity due to sudden loss of supraspinal control in the period of spinal shock, whereas partial recovery of core temperature may be achieved by regaining sympathetic activity and recovery from spinal shock. Thermoregulatory dysfunction takes place in both acute and chronic phases of recovery. There are four



main thermoregulatory disability-associated symptoms after SCI: hypothermia, poikilothermia, acute hyperthermia, and exercise-induced hyperthermia (176). Similar to cardiovascular dysfunction, the severity of temperature instability is related to the SCI level. Individuals with higher level injury are anticipated to have more severe thermoregulatory disability (124, 229, 353). During autonomic dysreflexia, massive sympathetic discharge concurrently induces excessive sweating below the level of injury which often causes hypothermia through heat dissipation in the presence of thermoregulatory dysfunction (161). To assess thermoregulatory function following SCI, core temperature can be measured clinically or in SCI animals by using a rectal thermometer or telemetric blood pressure probes with a temperature channel. Cutaneous temperature can be recorded by skin thermometers in humans or infrared thermography in animals (151). In patients with SCI, thermoregulatory dysfunction should be considered as a diagnosis as long as other causes of fever have been ruled out. The treatments typically consist of behavioral and environmental strategies, such as changing the environment, posture, and the amount and type of clothing.

Lower Urinary Tract Dysfunction The lower urinary tract (LUT) consists of the bladder, urethra, internal urethral sphincter (IUS), and external urethral sphincter (EUS). The bladder wall is composed of smooth muscles, termed the detrusor, and is innervated by parasympathetic and sympathetic projections. The IUS, situated at the junction of the bladder neck and urethra, also consists of smooth muscles and receives autonomic control. The EUS is striated muscles controlled by somatic nerves from the sacral spinal cord. As somatic innervation is involved in LUT activity, micturition is normally under voluntary control. This distinguishes LUT from other autonomic visceral functions such as regulating blood pressure and digestion (19,188). The integration of autonomic and somatic efferent mechanisms within the spinal cord determines activities of urinary storage or voiding. Following SCI, interruption of efferent or afferent neuronal pathways causes abnormal bladder hyperreflexia, areflexic bladder, and/or detrusor-sphincter dyssynergia, all leading to impaired micturition.

Neuroanatomical basis A complex neural control system integrates reflexes for micturition between the brain and the spinal cord (19,73,84,188). Afferent projections convey sensory information from the bladder and urethral to the lumbosacral spinal cord which, in turn, is transmitted to the pontine micturition center (PMC) in the brainstem. Under modulation of the cerebral cortex, neurons in the PMC command efferent neurons in the spinal cord controlling LUT organs. Notably, sympathetic, parasympathetic, and somatic innervations are located in the lower

1429



DRG

T11-L2 (human) L1-L2 (rat)

SPNs IMG

Hy

po

Bladder

ga s

tric

n. Pelvic n.

Pelvic ganglion

IUS

DRG

Urethra S2-S4(human) L6-S1 (rat)

PPNs

.

al n

end Pud

Onuf’s N.

EUS

Sympathetic nuclei

Sympathetic nuclei

Onuf’s nuclei

Preganglionic projection Postganglionic projection

Preganglionic projection Postganglionic projection

Somatic efferent Sensory afferent

Figure 8 Neuronal control of the lower urinary tract (LUT). Primary sensory neurons are located in the dorsal root ganglia (DRG) at T11-L2 and S2-S4 spinal levels in humans (L1-L2 and L6-S1 in rats). Afferent fibers convey sensory information of LUT to the spinal cord via the hypogastric, pelvic, and pudendal nerves, respectively. Sympathetic and parasympathetic projections distribute to the bladder, urethra, and internal urethral sphincter (IUS). Sympathetic preganglionic neurons (SPNs) involved in LUT activity are situated in the lower intermediolateral (IML) cell column at T11-L2 levels in humans (L6-S1 in rats). The projections course through the hypogastric nerve to postganglionic neurons within inferior mesenteric ganglia (IMG). Sympathetic pathways have an important role in urinary continence by maintaining bladder relaxation and urethral contraction. Parasympathetic preganglionic neurons (PPNs), located at the S2-S4 spinal cord levels in humans (L6S1 in rats), extend fibers onto postganglionic neurons within pelvic ganglion via the pelvic nerve. Parasympathetic excitation elicits bladder contraction and urethral relaxation. Somatic efferents project from motoneurons in Onuf’s nucleus and join the pudendal nerve, innervating external urethral sphincter (EUS) muscles. n., nerve.

lumbar and sacral spinal cord. Their elaborate interactions result in effective urinary storage and/or voiding (Fig. 8).

Afferent pathways Afferent fibers carry sensory signals such as pressure, contraction, and noxious stimuli from the bladder, urethra or sphincter to the spinal cord via hypogastric, pelvic, and pudendal nerves (128, 155, 374). The somata of these afferent neurons are located in the T11-L2 and L6-S1 dorsal root ganglia (DRG) in rats but in the T11-L2 and S2-S4 DRG in humans. Pelvic nerve afferent pathways from the bladder project into Lissauer’s tract in the superficial dorsal horn and terminate in the region of the sacral parasympathetic nuclei and DGC. A similar distribution pattern is exhibited by pudendal afferent pathways from the urethra and urethral sphincter projecting to the sacral spinal cord (331). The interaction of afferent fibers with spinal autonomic nuclei is associated with the integration of visceral information and coordination of bladder and sphincter activity. The phenotypes of these afferents are small myelinated (Aδ) and unmyelinated (C) fibers. Both Aδ and C bladder afferents code for mechanoceptive and nociceptive information (53, 250). In some species, C-fiber bladder

1430

afferents are more specialized for inflammatory or noxious reactions (128). Approximately 70% of bladder afferent neurons in rats exhibit isolectin-B4 (IB4) binding and immunoreactivity for various neuropeptides including CGRP, substance P, vasoactive intestinal peptide (VIP), enkephalin, pituitaryadenylcyclase activating polypeptide (PACAP), tachykinins, galanin, and opioid peptides (163,212). Most C-fiber neurons contain CGRP and substance P, and CGRP is usually used to identify/characterize these type of fibers (21, 140).

Efferent pathways The LUT receives complex neural efferent control from the lumbosacral spinal cord: parasympathetic, sympathetic, and somatic innervations (Table 2). Normal micturition function depends on the coordination of their composite activities. Parasympathetic preganglionic neurons (PPNs) are situated in the lateral gray matter column of S2-S4 spinal cord levels in humans and the L6-S1 in rats, which extend axons onto postganglionic neurons in pelvic ganglia through the pelvic nerve. Cholinergic PPNs release ACh to activate postganglionic nicotinic receptors (154). Parasympathetic postganglionic nerves are also cholinergic, projecting to the



Table 2


Neuronal Control of the Lower Urinary Tract at Spinal Level

Neural control

Organs

Sympathetic

Bladder

First neuron location

Peripheral nerve (N.)

Second neurotransmitter

Receptor in organs

T10-L2 (human) L1-L2 (rat)

Hypogastric N.

NE

α1 -AR (neck) β3 -AR (dome)

Excitatory Inhibitory

α1 -AR

Excitatory

mAChR/P2X

Excitatory

IUS Para-sympathetic

Bladder

S2-S4 (human) L6-S1 (rat)

Pelvic N.

IUS Somatic

EUS

ACh/ATP

NO S2-S4 (human) L6-S1 (rat) (Onuf’s N.)

Pudendal N.

ACh

Effects and functions Bladder neck contraction, dome relaxation, Urethra contraction, Continence

Bladder contraction, Urethra relaxation, Voiding

Inhibitory nAChR

Excitatory

Striated muscle contraction, Continence

IUS, internal urethral sphincter; EUS, external urethral sphincter; ACh, acetylcholine; nAChR, nicotinic acetylcholine receptor; mAChR, muscarinic acetylcholine receptor; NE, norepinephrine; AR, adrenergic receptor; ATP, adenosine triphosphate; P2X, purinergic P2X receptors; NO, nitric oxide.

bladder and urethral smooth muscles, but their actions (in these two tissues) are different. Those projecting to the bladder secrete ACh and excite muscarinic receptors on the detrusor to induce contraction (86, 370). Adenosine triphosphate (ATP) is a cotransmitter released from parasympathetic postganglionic terminals, inducing a rapid onset of detrusor contraction (209). However, parasympathetic input to the urethra causes inhibitory effects by relaxing smooth muscles, at least partially through nitric oxide (NO) release (7, 333, 374). Together, the excitation of sacral parasympathetic efferents elicits bladder contraction by releasing ACh/ATP, but urethral relaxation via NO secretion. SPNs controlling bladder and urethra are present at the T11-L2 spinal cord levels in humans (L1-L2 levels in rats). Their projections extend through the hypogastric nerve to postganglionic neurons mainly within the inferior mesenteric ganglia, paravertebral ganglia, and pelvic ganglia. Cholinergic SPNs discharge ACh acting on nicotinic receptors on postganglionic neurons. Sympathetic postganglionic neurons are noradrenergic and their terminals release norepinephrine when excited (53,154,188), which produces inhibitory effects to relax the detrusor by activating β-AR on the bladder body wall. In contrast, it provokes excitatory effects to contract muscles in the bladder base and urethra via α-AR (7, 73). Thus, sympathetic pathways have an important role in urinary continence by maintaining bladder relaxation and urethral contraction. Somatic efferent pathways originate from the sacral spinal cord and participate in EUS muscle activity. These cholinergic motoneurons are located in the ventral horn region at the S2-S4 spinal levels in humans and L6-S1 in rats, termed Onuf’s nucleus (267). Retrograde neuronal tract tracing in rats identify two divisions of Onuf’s nucleus: a dorsomedial part and a ventrolateral part (231,254). The efferent fibers innervate the EUS and pelvic floor via the pudendal nerve, mediating striated muscle contraction by activating nicotinic receptors (84, 374). The connections between


somatic neurons in Onuf’s nucleus and autonomic neurons in the DGC have been unveiled using pseudorabies virus (PRV) transsynaptic tracing, suggesting possible integration mechanism of bladder and urethral reflexes at spinal levels (254). Therefore, coordinated activation between autonomic and somatic neuronal control provides a reciprocal role to maintain urinary storage and voluntary voiding.

Pontine Micturition Center PMC, also known as Barrington’s nucleus (Fig. 9), has been characterized anatomically as a small group of neurons located bilaterally in the pontine tegmentum, ventromedial to the rostral pole of locus coeruleus (19, 286). Electrical or chemical stimulation to PMC neurons induces bladder voiding, whereas bilateral lesions of this nucleus block intravesical pressure-induced reflexic voiding, suggesting their critical role in urinary bladder control (19, 263, 365). It is plausible that the PMC may act as an integration center to coordinate forebrain activity and micturition reflex (347). Neurons in Barrington’s nucleus receive bladder afferent information conveyed from the lumbosacral spinal cord as well as from the periaqueductal gray region (PAG). The PAG is an important relay station which receives sensory information of bladder fullness from the dorsal horn and projects to multiple brain sites involved in bladder storage (27, 80). In the rat, other regions connecting to the PMC include the pontomedullary tegmental field, the posterior hypothalamic region, Kolliker Fuse nucleus, raphe nuclei, NTS, parabrachial nucleus, nucleus paragigantocellularis, and cuneiform nucleus (84, 186, 345). Two separate regions within the rostral dorsolateral pons are related to micturition. One is the medial neurons (M-region) projecting to sacral parasympathetic nuclei and another is the more lateral neurons (L-region) that extend axons to sacral sphincteric motoneurons in Onuf’s nucleus (251). The main neurotransmitter in PMC projections is glutamate, which activates spinal PPN

1431



essential to maintain urinary continence until cortical arousal occurs to initiate a bladder contraction. Given the prevalence of incontinence disorders in individuals with SCI, further investigations are vital to determine detailed roles of CRF.

Supraspinal regulation

Figure 9

Schematic describing supraspinal control of micturition. Barrington’s nucleus (BN), located bilaterally in the pontine tegmentum, acts as an integration center coordinating forebrain activity and spinal micturition reflexes. BN neurons receive bladder afferent information from the lumbosacral spinal cord as well as from the nucleus tractus solitarii (NTS) and periaqueductal gray region (PAG), two important sensory relay stations. In BN, medial neurons (M-region) project to lumbosacral sympathetic or parasympathetic preganglionic neurons (SPNs and PPNs) innervating the bladder whereas lateral neurons (Lregion) prominently innervate sacral sphincteric motoneurons within Onuf’s nucleus (N.).

for bladder contraction (228). To relax EUS for micturition, a glycinergic or GABA-ergic inhibitory interneuron mediates PMC projections onto Onuf’s somatic motoneurons (29,307). In addition, neurons in Barrington’s nucleus also project to locus coeruleus in the brainstem and to spinal sympathetic nuclei (46, 342). Corticotropin-releasing factor (CRF) is a crucial neurohormone and neurotransmitter relevant to bulbospinal regulation of bladder reflex (Fig. 10). Neurons in Barrington’s nucleus (BN) prominently express CRF (343, 346). Immunolabeling revealed CRF+ axon terminals project to PPNs in the lumbosacral spinal cord (342). CRF provides inhibitory influence in the micturition circuits since blocking CRF effects at the spinal level increases the magnitude of Barrington’s nucleus-stimulated bladder contraction (271). This inhibitory role may result from direct actions on PPNs or antiexcitatory neurotransmitters in Barrington’s nucleus (271,347). It is

1432

Many populations of neurons in the brainstem and hypothalamus are related to the activity of micturition as revealed by transsynaptical labeling of PRV injected into the rat’s bladder wall, urethra and/or EUS (253, 254, 349). These areas include Barrington’s nucleus (PMC), medullary raphe nuclei (magnus and obscurus), locus coeruleus (LC), subcoeruleus, PAG, A5 noradrenergic region, medial parabrachial nucleus, PVN, reticularis gigantocellularis, and nucleus paragigantocellularis. Descending pathways from most of these regions are identified in the lumbosacral spinal cord. Neuronal tracers injected into Barrington’s nucleus label axon terminals in sacral PPNs and motoneurons within Onuf’s nucleus as described before. Immunolabeling indicates serotonergic axons from caudal raphe nuclei innervate spinal autonomic regions, as well as catecholaminergic axons derived from the locus coeruleus, subcoeruleus and A5 (41, 75, 76, 246, 254). Anterograde neuronal tract tracing reveals PVN neurons extending axons to lumbosacral SPNs and sacral PPNs in the spinal cord (139, 284, 388). Currently, it is unknown how these nuclei are connected to each other to coordinate urinary activity. Multiple neurotransmitters are involved in micturition control at supraspinal levels, including glutamate, GABA, and glycine (Fig. 11). The axon terminals of PMC neurons release glutamate, a critical excitatory transmitter acting on sacral PPNs, regulating bladder and urethral reflexes. Both NMethyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5mehyl-4-isoxazoleproprionic acid/kainite (AMPA) receptors mediate glutamatergic neurotransmission during micturition activity (227, 228, 384, 385). PMC neurons express CRF as described above. 5-HT, secreted from caudal raphe nucleiderived supraspinal projections, modulates sensory processing in the dorsal horn, and autonomic or motoneuron activity (41, 76). Parasympathetic and sympathetic nuclei as well as Onuf’s nucleus in the lumbosacral spinal cord receive serotonergic innervations in various mammalian species. In rats, the 5-HT1A receptor subtype is relevant to micturition control. Bladder and urethral reflexes are enhanced by administration of 5-HT1A receptor agonists, whereas the receptor antagonists reverse these effects in intact and chronically spinalized rats (54,75,332). Noradrenergic fibers projecting to lumbosacral parasympathetic and sympathetic nuclei mainly originate from the A5 region and locus coeruleus. Electrical stimulation of the locus coeruleus in anesthetized cats induces bladder contraction whereas destruction of noradrenergic neurons in this nucleus by delivering 6-hydroxydopamine (6-OHDA), a toxin for catecholaminergic neurons, renders a hypoactive bladder (379, 380). Adrenergic fibers arising from the C1 region provide input to autonomic nuclei in the




(A)

v

(B)

Figure 10 Corticotropin releasing factor (CRF) is a major neurotransmitter in Barrington’s nucleus (BN) neurons. (A) Bright field photomicrograph of a rat brain coronal section at the level of BN showing CRF-immunolabeled neurons (blue) and neurons that are retrogradely labeled with the tracer Fluorogold (FG) from the lumbosacral spinal cord (brown). Note that most neurons have the hybrid blue/brown color indicating that they are CRF neurons that project to the spinal cord (example indicated by arrow). The arrowhead points to a neuron that is CRF-labeled only. Dorsal is at the top and medial is to the right. V indicates the fourth ventricle. (B) A section at the level of lumbosacral spinal cord showing dense CRF immunoreactive terminal fields (blue) in the region of parasympathetic nuclei (arrows). The section is counterstained with Neutral Red (with permission from Ref. 347).

lumbosacral spinal cord. Recent studies have shown that α1 AR is critical in regulating bladder storage function (59,246). Ultimately, supraspinal noradrenergic and adrenergic pathways enhance the spinobulbospinal micturition reflex. In addition, tachykinin, substance P, enkephalin, VIP, and PACAP take part in supraspinal control of sacral parasympathetic or sympathetic nuclei (374). It is necessary to point out that supraspinal descending pathways may act directly on neurons controlling micturition or may excite inhibitory or excitatory interneurons to regulate bladder and urethral reflexes indirectly.

Cortical control

Figure 11

Supraspinal neurotransmitters involved in micturition control. Neurotransmitters including glutamate (Glu), γ-aminobutyric acid (GABA), and glycine participate in the activity of lower urinary tract. In addition, corticotropin-releasing factor (CRF) expressed by Barrington’s nucleus (BN) neurons, norepinephrine (NE), and adrenaline (epinephrine) released by neurons in the A5 and C1 regions, and serotonin (5-HT) expressed by the caudal raphe nuclei (RN) neurons act on bladder and urethral reflexes. It has been characterized that tachykinin, substance P, enkephalin (Enk), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) take part in the regulation of voiding or continence.


Although the circuits of suprapontine connections controlling bladder reflexes are less well defined, the voluntary control of micturition is thought to depend on the regulation of frontal cortex. Two cortical areas, the right dorsolateral prefrontal cortex and the anterior cingulate gyrus (ACG), are active during voiding as detected by PET scan in humans (28, 30). The ACG responds to bladder filling, storage, and withholding. The insular cortex participates in processing afferent information (121). Parts of the limbic system (hippocampal complex and amygdala) are also related to bladder control. The PAG and the preoptic area in hypothalamus show activity in concert with voluntary micturition (17). During the period of bladder filling, the activity increases in the PAG, midline pons and mid cingulate gyrus (13). Activity of the basal ganglia is rarely observed while micturition is inhibited due to impaired dopamine pathways in Parkinson’s disease. Hyperreflexic bladders emerge in monkeys treated with 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine, a toxin for dopaminergic neurons, to abolish dopaminergic pathways stemming from

1433


the substantia nigra (3). This hyperreflexic response can be suppressed by activation of dopamine D1 receptor (377,378). Presently, neurotransmitters relevant to cortical diencephalic mechanism for the PMC are comprised of ACh, dopamine, enkephalin, GABA, and glutamate (374).

Spinal interneurons Spinal interneurons are involved in processing afferent input as well as relaying supraspinal input to lumbosacral autonomic neurons and motoneurons. When PRV is injected into the bladder wall, urethra or EUS, retrogradely labeled interneurons are consistently present in the superficial dorsal horn (Lamina I, II), IML and DGC (349), where the spinal cord receives afferent inputs from LUT and autonomic neuronal dendrites are situated nearby. It indicates a prominent overlap of interneuronal pathways controlling various LUT organs. Some interneurons project rostrally to the brain whereas others make local connections relevant to segmental spinal reflexes. Under noxious or non-noxious stimulation of the bladder or urethra, interneurons processing afferent information express the immediate early gene, c-fos (24, 25). In the lumbosacral spinal cord, some interneurons are located immediately dorsal and medial to the parasympathetic nuclei. Both excitatory glutamatergic interneurons and inhibitory GABA-ergic or glycinergic interneurons exist to elicit postsynaptic currents in the preganglionic neurons. NMDA and non-NMDA receptors mediate glutamatergic excitatory potentials in these neurons (244, 245). The level of glutamic acid decarboxylase (GAD67), an enzyme in GABA synthesis, is decreased in the injured spinal cord. Hence, reduced GABA-ergic inhibition to autonomic neurons may be associated with the occurrence of bladder hyperreflexia (247). In essence, local spinal interneurons play an important role of controlling autonomic outflow for LUT activity.

Complications of micturition dysfunction after SCI Micturition dysfunction often occurs after SCI. All clinical problems manifest two impaired basic functions: bladder storage and emptying. The emergence and severity of this abnormality is dependent on the injury level and completeness. Despite anatomical or physiological changes within the spinal cord, the fundamental cause of disordered LUT function is the disruption of central neuronal pathways or the impairment of peripheral nerves controlling bladder and urethral reflexes. The loss of bulbospinal control and coordinated interaction between the autonomic and somatic nervous systems results in urinary bladder dysfunction termed “neurogenic bladder” (57, 352). The incidence of neurogenic bladder is exceptionally common after SCI and it may also develop in other CNS diseases including Parkinson’s disease, multiple sclerosis, and tumors (5, 269, 371). Such brain disorders cause hyperactive

1434


or uninhibited bladders, leading to incontinence. Voiding disability occurs when the local detrusor excitatory reflex pathways are interrupted or detrusor-sphincter dyssynergia takes place. In addition, an areflexic bladder can arise from (i) injury to the pelvic nerve or the sacral spinal cord, (ii) interruption of the bladder afferent pathways, and (iii) the acute stage of upper motor neuron injury (76, 374). Under normal conditions, the bladder retains urine as a fluid reservoir to a threshold and then voids completely. These two continuous activities are employed through coordinated contraction and relaxation of the bladder detrusor, urethra, and urethral sphincter under well-mannered neuronal control. All impairments of LUT dysfunction following SCI affect storage and emptying. Four main issues can account for these clinical problems: (i) inadequate or excessive detrusor function, (ii) inadequate or excessive sphincter function, (iii) detrusorsphincter dyssynergia, and (iv) impaired bladder sensation (201, 275). Bladder dysfunction is classified into two types: upper motor neuron injury and lower motor neuron injury, based on the level of SCI.

Upper motor neuron injury Bladder dysfunction is characterized as an upper motor neuron type if the injury occurs rostral to the sacral spinal cord and interrupts descending supraspinal micturition pathways. In the early stage following cervical or thoracolumbar spinal lesion, a phase of spinal shock presents itself immediately after SCI. During this period, the urinary bladder displays flaccid paralysis and an absence of reflex activity. However, urethral sphincter contraction recovers rapidly after injury. Thus, failure to void causes urinary retention which requires intermittent or continuous transurethral catheterization in humans or manual expression in rats to empty the bladder. Following the acute stage of SCI, reflexic detrusor activity reappears after 2 to 12 weeks in most patients (91). This is due to the development of involuntary detrusor reflex contraction in response to bladder filling or suprapelvic manual compression. In rats, partial bladder function recovery is defined by spontaneous involuntary micturition, and is established within 2 to 3 weeks postinjury. Local intraspinal plasticity including afferent C-fiber sprouting may be a neuronal basis underlying spinal reflexes. During this stage, increased detrusor tone or spasticity causes bladder hyperreflexia (Fig. 12). Upper motor neuron injury interrupts descending micturition pathways, which coordinate activities of bladder contraction and the suppression of the sphincter in normal conditions. As a result, simultaneous contraction of the bladder and spasticity of the striated external sphincter develops, known as detrusor-sphincter dyssynergia, leading to incomplete elimination of urine from the bladder. Together, complications of LUT dysfunction in patients with upper motor neuron injury include (i) bladder hyperreflexia, (ii) dysfunctional relaxation of the bladder neck, and (iii) detrusor-sphincter dyssynergia (76).




bladders and upper arm function typically void with intermittent catheterization for periodic emptying. With inadequate sphincter function, muscle contraction can be enhanced by using agonists of muscarinic cholinergic receptors to assist continence while β-AR agonists prevent detrusor spasticity (51).

cmH2O 30

Intact

0

60

SCI

30

0

Figure 12 Representative cystometry assessments in urethaneanesthetized intact and SCI rats. Rhythmic contractions elicit voiding (asterisks) in an intact rat when saline is infused into the bladder via a catheter inserted into the bladder dome. However, in a T10 spinal cord transected rat, multiple rhythmic contractions between adjacent expels do not result in voiding 3 weeks after injury, which is termed nonvoiding contractions (arrows) indicating hyperactivity of bladder. Notably, the SCI rat exhibits higher voiding amplitude compared to the intact during the assessment. (Unpublished data, S. Hou.)

Excessive detrusor pressure can be treated with cholinergic muscarinic receptor antagonists. Bladder hyperreflexia can also be decreased by chemically blocking C-fiber afferent neurotransmission with capsaicin or resiniferatoxin (vanniloids). To reduce excessive sphincter tone, α1 -AR blockade is used in pharmacological management of smooth muscle sphincter contraction (8). Surgical approaches to the spastic sphincter consist of sphincterotomy and pudendal nerve interruption (275).

Lower motor neuron injury When SCI occurs at or below the sacral level such as cauda equina (conus medullaris), motor neurons or sacral PPNs controlling the EUS and bladder are damaged. It results in an areflexic bladder and sphincters; the bladder becomes flaccid associated with inadequate striated external sphincter pressure. If SPNs at the L1/L2 spinal cord level are injured simultaneously, the contraction of internal smooth muscle sphincter is also decreased. Thus, the problems of both voiding and storage exist in lower motor neuron SCI (374, 375). An animal model of cauda equina/conus medullaris injury (lumbosacral ventral root avulsion) in rats has been established to mimic a complete or partial lesion to cauda equina, in which pharmacological intervention is applied to investigate urinary retention and impaired micturition reflex (54, 135). To increase voiding capacity, a cholinergic muscarinic receptor agonist, bethanecol, is used to stimulate detrusor contraction. Mechanical techniques of increasing intraabdominal pressure with the Crede maneuver facilitate bladder voiding. The most common approach to manage the spontaneous emptying of a flaccid bladder is the use of an indwelling catheter. Alternatively, those with reflexive


Detrusor-sphincter dyssynergia Under normal conditions, micturition is coordinated by activities of bladder detrusor and external striated urethral sphincter. When bladder detrusor muscle contracts, the muscle of EUS is relaxed. This synergic action expels the urine stored in the bladder. The disruption of connections between PMC and the sacral spinal cord often results in detrusor-sphincter dyssynergia (DSD). It is defined as a detrusor contraction concurrent with an involuntary contraction of the urethral striated sphincter which causes the failure to void (Fig. 13) (98, 162). DSD occurs typically in patients with high level spinal cord lesions and is uncommon in lower motor neuron injuries. In addition, DSD emerges in other neurological diseases including multiple sclerosis, acute transverse myelitis, and myelomeningocele (11, 107). With inability to empty the bladder, urodynamic studies are required to determine whether the impairment is caused by DSD or other disordered activities such as inadequate detrusor function and/or excessive sphincter actions. DSD prevents effective voiding and can render a noncompliant and thickwalled bladder, elevated retrograde pressure in the ureter and pelvis, autonomic dysreflexia, and terminal kidney failure. Without adequate treatment, more than 50% of male patients with DSD will develop severe complications. In women these complications are less common due to lower detrusor pressure (360). Current therapeutics are focused on decreasing abnormal contraction of EUS. Pharmacological interventions include baclofen and a glycine and GABA agonist which suppresses motoneuron or interneuron excitation in the spinal cord (47). α1 -AR antagonists can be used to relax smooth muscle in the bladder neck, as described above. Alternatively, bladder detrusor contraction may be reduced pharmacologically, or eliminated by using cholinergic muscarinic receptor antagonists. In this situation, the urine is typically voided through intermittent catheterization methods. Botulinum toxin, a presynaptic neuromuscular blocker, can induce reversible muscle weakness up to several months when injected intramuscularly (309). Different medical disciplines use the agent to treat mainly muscular hyperactivity. In urology, studies have demonstrated that botulinum-A toxin inhibits ACh release at the presynaptic cholinergic nerve terminals, decreases substance P and CGRP release in afferent nerves, and reduces the expression of transient receptor potential vanilloid subfamily 1 (TRPV-1), as well as purinergic receptor P2X expression in the bladder wall (65,111,315). Thus, botulinum-A toxin has been used to treat neurogenic detrusor overactivity, DSD, and motosensory urge. When the toxin is injected transurethrally or transperineally, it deceases

1435


100 Reflex void Bladder filling 0

EMG

Detrusor pressure (cmH2O)

(A) Infant


0 0

100 Bladder volume (mL)

200

Stop Start

100

Start

Voluntary void Bladder filling 0

EMG


(B) Adult

0 0

100

200

300

Bladder volume (mL)

Reflex void Bladder filling

0

Detrusor-sphincter dyssynergia

EMG


(C) Paraplegia patient 100

0 0

100

200

300

Bladder volume (mL)

Figure 13 Reflex voiding responses in an infant, a healthy adult and a paraplegic patient. Combined cystometry and sphincter electromyograms (EMGs recorded with surface electrodes), allow a schematic comparison of reflex voiding responses in (A) an infant and in (C) a paraplegic patient compared to voluntary voiding response in (B) a healthy adult. The abscissa in all recordings represents bladder volume in milliliters; the ordinates represent electrical activity of the EMG recording and detrusor pressure (the component of bladder pressure that is generated by the bladder itself) in cmH2 O. On the left side of each trace (at 0 mL), a slow infusion of fluid into the bladder is started (bladder filling). In (B) the start of sphincter relaxation, which precedes the bladder contraction by a few seconds, is indicated (“start”). Note that a voluntary cessation of voiding (“stop”) is associated with an initial increase in sphincter EMG and detrusor pressure (a myogenic response). A resumption of voiding is associated with sphincter relaxation and a decrease in detrusor pressure that continues as the bladder empties and relaxes. In the infant (A) sphincter relaxation is present but less complete. On the other hand, in the paraplegic patient (C) the reciprocal relationship between bladder and sphincter is abolished. During bladder filling, involuntary bladder contractions (detrusor overactivity) occur in association with external sphincter activity. Each wave of bladder contraction is accompanied by simultaneous contraction of the sphincter (detrusor-sphincter dyssynergia, DSD), hindering urine flow. Loss of the reciprocal relationship between the bladder and the sphincter in paraplegic patients thus interferes with effective bladder emptying (with permission from Ref. 98).

EUS amplitude, voiding pressure, and postvoid residual volume (106, 272). In 2000, botulinum-A toxin was first used to treat neurogenic bladder hyperactivity in spinal cord injured patients by injection into the bladder detrusor (303). It offers a new promising treatment strategy for SCI-induced urological dysfunctions (199). Now the toxin is FDA-approved for

1436

effective relief of “overactive” neurogenic bladders in the SCI population. While more costly per procedure, it often requires repeated injections only every 6 months after the neuromuscular junctions are re-established, and often obviates the need for traditional oral medications with undesirable side-effects.



Intraspinal plasticity related to partial recovery of LUT function SCI usually induces plasticity of intraspinal neuronal circuits below the lesion level. Following cervical or thoracic SCI (i.e., upper motor neuron injury), the bladder is initially areflexic during the period of spinal shock but then becomes hyperreflexic. Two underlying reasons may account for this pathophysiological change. Firstly, the loss of supraspinal descending regulation of lumbosacral autonomic neurons is critical. Another is the emergence of reorganized spinal micturition reflex pathways as a consequence of lesioninduced plasticity. However, the bladder does not empty completely due to excessive sphincter activity or dyssynergia between bladder detrusor and external sphincter muscle contractions.

Bladder afferents Normally, mechano-sensitive myelinated Aδ-fiber afferents convey information of bladder filling to activate micturition reflexes. Following high level SCI, mechano-insensitive unmyelinated C-fiber bladder afferents that usually do not respond to bladder distension become mechano-sensitive and participate in the afferent limb of the micturition reflex (128). At present, it is recognized that physiological properties of C-fiber afferents in the bladder switch after SCI, and this phenotypic change contributes to the development of bladder hyperreflexia. Bladder C-fiber afferent neurons synthesize and release various neuropeptides, including PACAP, CGRP, VIP, and tachykinins (substance P and neurokinin A). These neurons also express IB4 binding which is commonly used as a marker for ATP responsive sensory neurons (308). Changes in bladder afferent DRG neurons include (i) somal hypertrophy in L6-S1 DRG neurons, (ii) increased expression and afferent terminal expansion of PACAP, VIP, CGRP, IB4, and substance P containing primary afferent fibers in the spinal cord, and (iii) increase expression of nNOS, galanin, TrkA, and TrkB in bladder DRG neurons and in the region of the lumbosacral PPNs. In SCI rats, intrathecal administration of PAPAP or VIP enhances reflex bladder activity, whereas delivery of neurokinin-1 receptor antagonist blocks micturition reflexes (74, 152). The phenotypic change in bladder afferents after SCI may be mediated by a decrease in tetrodotoxin (TTX)-resistant and an increase in TTX-sensitive Na+ channel expression in DRG neurons (376). This is also reflected in the alteration of electrophysiological properties in DRG cells innervating the bladder which become larger in the chronic stage after SCI in rats (185). The action potentials in the majority of bladder afferent neurons change from high threshold TTXresistant type in the intact to low threshold TTX-sensitive type following injury (381). Additionally, bladder afferent neurons in the intact usually respond with only one or two action potentials (phase firing), whereas those in SCI animals exhibit multiple action potentials (tonic firing) (77).



Interneurons related to bladder function Many interneurons in the lumbosacral spinal cord play a role in bladder function. Some are related to the transmission of ascending bladder afferent information to higher centers, whereas other interneurons participate in the descending efferent control of bladder and sphincter activities. Such bladder and sphincter-related interneurons are mainly located in the dorsal gray matter and parasympathetic nuclei in the lumbosacral segments as revealed using transsynaptic PRV tracing or immediate early gene c-fos expression in response to bladder distension (254, 348). During first 3 weeks after birth, neonatal rats use a spinal bladder reflex pathway to elicit micturition when supraspinal descending projections from PMC have not grown and connected to target spinal neurons. Later, bladder function is controlled by newly established supraspinal pathways (spinobulbospinal micturition). In this circuit spinal interneurons might act as a component of a disynaptic parasympathetic reflex pathway mediating spinal bladder reflexes. In response to the interruption of supraspinal descending pathways, neuronal plasticity develops a spinal micturition reflex (10). Lumbosacral interneurons associated with bladder and sphincter activities may undergo physiological and structural changes from development to maturity (390). A similar mechanism of interneuron property transition occurs after SCI. By using patch clamp recordings, stimulating interneurons located dorsal to the PPNs in neonatal rats can elicit excitatory postsynaptic currents (EPSCs) in the PPNs (9, 245). In prepared spinal cord slices dissected from 1- to 2-week-old rats, amplitudes of interneuron-invoked EPSCs are large and constant. However, in slices from 3 week old rats, in which supraspinal micturition control has begun to be established, induced EPSCs decrease to 50% in amplitude. Remarkably, transection of 1- to 2-weekold rat spinal cords prevents the reduction of interneuron invoked EPSC amplitudes that occurs in 3 week of age (10). Two possibilities may account for bladder reflex-related intraspinal plasticity and synaptic reorganization in the lumbosacral spinal cord after SCI. One is that spinal interneuron plasticity in an injured spinal cord may underlie the rise of bladder contractions. Another is that the re-emergence of bladder function following SCI is a matter of developing access to existing spinal circuits sub-serving micturition (390). The presence of such spinal bladder reflex circuits is analogous to the spinal cord center pattern generator for locomotion. In addition, the sprouting of bladder primary afferents to target spinal bladder reflex circuits is probably an automatic restoration phenomenon. Taken together, it is likely that the disruption of supraspinal descending micturition pathways in adults stimulates interneuronal plasticity anatomically and physiologically, causing the re-emergence of spinal bladder reflexes after SCI.

Neurotrophic factors and other molecules Neuronal plasticity after SCI is believed to be a result of increased expression of neurotrophic factors. Normal levels

1437


of NGF provide trophic support to bladder primary afferents and chemically maintain their sensitivity. Following SCI, NGF expression increases in the lumbosacral spinal cord, DRG, and bladder (305, 350). Not only do small diameter afferent neurons upregulate NGF but other types of cells do so, including Schwann cells, astrocytes, microglia, and bladder urothelial cells (26, 182). Increased NGF in SCI rats acts on primary C-fiber afferents and is considered a predominant stimulation for their sprouting, because delivery of NGF antibodies decreases the fiber density and distribution in the dorsal horn (61, 180). The NGF receptor, trkA, is upregulated in primary afferent neurons and the bladder (277). In DRG neurons increased NGF levels upregulates PACAP and TRPV1 expressions and downregulates A-type K+ channel currents (319, 375). Injury-related NGF elevation is associated with other SCI secondary disorders such as autonomic dysreflexia and neuropathic pain. NGF-induced C-fiber afferent sprouting leads to establishment of neuronal plasticity responsible for the development of autonomic dysreflexia in high level spinal cord-injured individuals. Intrathecal NGF antibody delivery blocks colon distension-induced autonomic dysreflexia in SCI rats (180). Increased NGF also sensitizes primary afferent nociceptors relevant to hyperalgesia and allodynia (127,328). Thus, manipulating expressions of local NGF and its receptor has potential to restore micturition reflexes and other autonomic disorders following SCI. Increased expression of GDNF, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) occur in the injured spinal cord (298,364). The level of trkB rises in bladder afferent neurons after SCI (277). BDNF is related to small to medium diameter peptidergic primary afferents and its upregulation contributes to neuropathic pain by heightening pain sensitivity (266). To date, the role of injury-related GDNF, BDNF, and NT-3 upregulation in LUT dysfunction remains unknown. Cellular adhesion molecules mediate the connection of axon terminals and neighboring cells and facilitate appropriate synapse formation. Neural cell adhesion molecule (NCAM) is a critical factor in the development of the CNS. Polysiaalic acid-bound NCAM reduces hemophilic binding but increases axonal defasciculation (248, 327). The level of polysialic acid-NCAM is upregulated in the L6/S1 spinal cord of postnatal day 6 (P6) rats (390), implying that it may have an effect in the plasticity of transition from spinal to supraspinal micturition. Following SCI there is an elevation of both polysialic and NCAM in the lumbosacral spinal cord (34, 391). Polysialic acid-NCAM regulates the interaction of BDNF and its receptor trkB by influencing phosphorylation (351). Therefore, polysialic acid-NCAM may play a role in the emergence of spinal micturition reflexes following SCI.

Cellular or peripheral nerve grafting for therapeutic strategies Cellular transplantation into the lesion site of injured spinal cords can prevent tissue loss and provide a permissive

1438


substrate to enable axon regeneration. Implanting genetically modified cells secreting neurotrophic factors or other cytokines may stimulate axon growth or have a role of neuroprotection. In rat spinal cord contusion models, grafting neural stem cells into an injured spinal cord improves voiding efficiency by increasing catecholaminergic and serotonergic axon growth (242). Implantation of neuronal and glial precursors into the spinal cord contusion site reduces intravesical pressure and detrusor overactivity (243). Similar results are obtained by transplantation of transgenic fibroblasts or Schwann cells secreting BDNF and NT-3 (241,293). A peripheral nerve grafting combined with chondroitinase administration at the lesion site of a complete transected spinal cord at the thoracic level facilitates brainstem and propriospinal axon regeneration and substantially improves urinary function (197). It indicates that enhanced nerve grafting strategies represent a potential regenerative treatment for LUT dysfunction after complete SCI. However, the efficiency of voiding with such reconstructive strategies will be critical to establish to avoid possible urinary tract infections triggered by residual urine.

Techniques for functional assessments Metabolic cages: A metabolic cage is an easy and low-cost method to obtain micturition patterns, particularly in functional bladder volume and frequency of urination. Bladder volume, proportionally related to the severity of SCI in rat (274, 368), can be acquired by the measurement of urine collected in such cages (52). Bladders are manually expressed before placing the animals in the metabolic cages for 24 h to evaluate voiding behavior. The voided urine is collected on an electronic scale connected to a microcomputer for recording micturition volume and frequency (242, 243). Data are recorded and stored using data acquisition software. Water consumption for each animal is determined by the amount of water remaining in the water bottle after 24 h periods in the metabolic cage. Cystometry urodynamic assessment: Cystometry is the most common experimental technique to analyze urodynamics. To perform this intervention, a urinary or transvesical catheter has to be implanted into the bladder dome. The bladder is then filled with saline and intravesical pressure is concomitantly recorded to observe the relationship between bladder volume and pressure during filling and emptying. Cystometry can be achieved on either conscious or anesthetized rats. The disadvantage of conscious rats is that they are difficult to handle whereas anesthesia normally influences bladder reflexes (383). To address this issue, urethane-light anesthetized rats are used in some laboratories (60, 221). The urodynamic pattern in anesthetized rats is similar to conscious rats in bladder hyperreflexia and DSD after upper motor neuron lesion SCI (274). The urodynamic parameters under cystometry assessments include the amplitude of bladder contraction, duration of contraction, bladder capacity (volume threshold to initiate micturition), functional voiding volume



(volume expelled in micturition), residual volume after micturition, interval between two adjacent micturitions, and voiding efficiency (voiding volume divided by bladder capacity) (382). Notably, nonvoiding bladder contractions emerge during the bladder filling phase as a typical result of DSD in spinal cord injured rats. EUS electromyography: To assess DSD, EUS electromyography (EMG) is usually employed in combination with cystometry. Wire electrodes are inserted into the EUS to record muscle activity during filling and emptying. Data is normally expressed as mean EMG activity, mean EMG power frequency, mean EMG-spiking activity, and duration of contraction. Importantly, the coordination between detrusor and sphincter activities can be analyzed to verify if dyssynergia is present. In addition, the change of EUS EMG during the whole micturition cycle is measured by power spectrum analysis using Fourier transform algorithm (274). Normally, cystometry combined with EUS EMG recording provides the most effective information about coordination of bladder and EUS. A caveat is that it is a terminal assay at the end of experiment (151). Other techniques used for LUT functional assessment include videofluoroscopy and corpus spongiosum pressure recording. Videofluoroscopy is a clinical relevant technique in which the bladder is filled with radio-opaque medium and the volume is detected by X-ray (354, 355). Penis corpus spongiosum pressure is traditionally monitored by an implanted telemeter to evaluate sexual function that has been validated for evaluating LUT function in spinal cord injured rats (264, 265). Additionally, transabdominal ultrasound can be used to detect the volume of urine in spinal cord injured rats (164). This noninvasive technique has potential clinical application to estimate bladder volume.

Sexual dysfunction Sexual behaviors are different in men and women. The dissimilarity in central neural circuits controlling sexual activities between the sexes is critical to understand gender-related divergence. Accordingly, SCI with similar severities or spinal levels causes differential sexual consequences in men and women. Sexual dimorphism in neural control is present in CNS including the spinal cord and brain, peripheral DRG primary afferent neurons and their target muscles. In spinal levels, sexual dimorphic nuclei are comprised of Onuf’s nucleus, the spinal nucleus of the bulbocavernosus (SNB), the spinal ejaculation center, the spinal gastrin-releasing peptide (GRP) system, and primary sensory afferents (97). (i) Onuf’s nucleus is involved in the maintenance of micturition and defecatory continence as well as in muscular contraction during orgasm (267). The number of neurons in Onuf’s nucleus and descending serotonergic fiber terminals are greater in males than in females (96, 167, 168, 255). (ii) The SNB contains a pool of motoneurons in the lower lumbar spinal cord of mammalian, which project to the striated muscles of perineum



such as the bulbocavernosus and levator ani. Male rats have many more and larger SNB cells than females (36, 63), a dimorphism resulting from differences in perinatal androgen signaling through an androgen receptor-mediated mechanism (36). The bulbocavernosus and levator ani muscles are absent or vestigial in females. (iii) The spinal ejaculation center is a sexually dimorphic population of neurons dorsolateral to the central canal in the L3-L4 spinal cord segments, which express galanin, cholecystokinin, and enkephalin (259, 260, 273). These neurons send ascending projections to the thalamus as well as descending projections to the SNB nucleus and autonomic nuclei involved in ejaculation. Males have more neurons in this region than females. The nucleus is recognized as the ejaculation center since specific deletion of the neurons completely eliminates ejaculation, but no other aspects of male sexual behavior (339). Following ejaculation, these neurons express the immediate early gene c-fos (340). (iv) GRPexpressing neurons located at the L3-L4 spinal levels exhibit a clear male-dominant sexual dimorphism (291). The neurons project to the SNB and parasympathetic nuclei in the more caudal segments of lumbosacral spinal cord. GRP is a crucial excitatory molecule in ejaculation and penile reflexes (291). (v) Primary sensory afferents show sex differences that are dependent on effects of testosterone (231). Specifically, DRG cell numbers are similar in males and females on embryonic day 18, whereas a sex differentiation emerges by postnatal day 10 stemming from a large number of dying cells in the DRG of females during this interval (237). Females treated with testosterone propionate during the perinatal period exhibit masculine development of DRG neuron number, indicating sexually dimorphic development of DRG neurons. (vi) In the brain, sexual dimorphic nuclei are located in the hypothalamus, septum, bed nucleus of the stria terminalis, hippocampus, amygdala, and olfactory systems (292, 326, 389). These nuclei join in neural networks related to sexually distinct reproductive and nonreproductive behaviors. Autonomic innervation is essential for sexual function. In both males and females, reflex sexual arousal results from increased parasympathetic activity accompanied by inhibition of sympathetic activity, causing NO-mediated vasodilation of corpus cavernosum (42, 49, 147). In contrast, psychogenic sexual arousal appears to be facilitated by the sympathetic nervous system (301, 312). Sexual climax is mediated by a spinal reflex since anesthetized, acutely spinalized rats can respond to genital stimulation. In anesthetized spinal male rats, urethral stimulation elicits penile erection, ejaculation, and rhythmic contractions of the striated perineal muscles. In females, vaginal and uterine contractions and rhythmic contractions of the perineal muscles are elicited. These responses show many similarities to those observed during sexual climax in unanesthetized humans and animals (31, 230). Both parasympathetic and sympathetic nervous systems regulate sexual climax reflex (219). Ejaculation requires the coordination of both the somatic and sympathetic nervous systems. Generally, normal sexual function requires local spinal reflexes and descending cortical modulation.

1439



Sexual dysfunction occurs following SCI. The disruption of descending supraspinal projections causes a range of sexual problems. The symptom is highly dependent on injury level and completeness. The most common abnormalities are arousal and orgasm. In upper motor neuron injury, patients preserve reflexic genital arousal because PPNs in sacral segments mediate erection. However, infraconal or cauda equina injuries (lower motor neuron lesion) often interrupt spinal reflexic vasocongestion, whereas the capacity of sympathetically mediated psycogenic arousal remains intact (70, 313). With regard to reproductive infertility, it is commonly seen in males if they have difficulty maintaining erections, eliciting ejaculation, and sensing orgasm. By contrast, most females with upper motor neuron injury are able to undergo successful pregnancy and some also maintain the ability to experience orgasm, mediated partially by intact vagal systems (311,362). In those with SCI above the T6 level, sexual activity and sperm retrieval using electro- or vibro-stimulation may trigger autonomic dysreflexia, which could be considered as a type of arousal (69, 87, 89). To assess sexual response and reproductive function following experimental SCI, ex copula visual scoring is used to evaluate sexual arousal and copulatory events. Pressure recording of the corpus cavernosum or corpus spongiosum is the most common assessment of erectile function in preclinical trials. Perineal muscle EMG can be used to study the urethrogenital reflex in sexual climax. Vaginal blood flow measurements are established to investigate sexual arousal in female rats (151).

Gastrointestinal Dysfunction SCI affects the physiology of the GI tract. Due to the impairment of the central neuronal reflexic arc dominating digestion system, GI problems following SCI include delayed gastric empty, altered gastric acid secretion, abnormal colonic myoenteric activity, and bowel dysfunction. The incidence of chronic GI problems in patients with SCI is very high Table 3

(62.5%), most of which are associated with defecation difficulties (40.3%) (320). The symptoms are serious enough to adversely influence various aspects of daily living, although they are vague and subjective. Rehabilitation goals aim to achieve continence of stool, voluntary defecation, and prevention of GI complications. The only intervention is the implementation of an individualized bowel care program which is based on documented dieting, oral/rectal medications, suppositories, lubricant gels for digital stimulation, and scheduling of bowel care by attendees for persons with high level SCI (e.g. quadriplegia).

Neuroanatomical basis Neuronal control of the GI system involves a complex interaction between the somatic and autonomic nervous systems, including sympathetic, parasympathetic, and unique enteric nervous system (ENS). The principle GI functions, such as digestion, absorption, propulsion of nutrients, and the maintenance of proper fluid balance, are critically dependent upon a hierarchy of these three systemic neural controls. The ENS controls the smooth musculature, secretory glands, and microvasculature of the GI tract, which is modulated by sympathetic and parasympathetic activities. The external anal sphincter (EAS) receives somatic nerve input such that it is under voluntary control (Table 3). Based upon embryological development, the GI tract can be classified into three different parts, including (i) the foregut, which gives rise to the esophagus, stomach, duodenum, and major duodenal papilla, (ii) the midgut, from the major duodenal papilla where the bile duct enters to the mid-transverse colon, and (iii) the hindgut, from the mid-transverse colon to the anus (138). However, clinically the GI tract is conventionally divided into upper and lower compartments as a boundary at duodenal papilla. The ENS, so called “brain of the gut,” is an intrinsic nervous system of the intestine, which includes Auerbach’s plexus between the longitudinal and the circular

Neuronal Control of the Gastrointestinal Tract

Neural control

Organs

Neuron location

Peripheral nerves (N.)

Sympathetic

Upper GI tract

T5-T12

Splanchnic N.

Distal colon, Rectum, IAS

L1-L2

Hypogastric N.

Upper GI tract

Vagus

Vagus N.

Distal colon, Rectum, IAS

S2-S4 (human) L6-S1 (rat)

Pelvic N.

ACh/mAChR

EAS

S2-S4 (human) L6-S1 (rat) (Onuf’s N.)

Pudendal N.

-

Para-sympathetic

Somatic

ENS plexus (P.) Auerbach’s P. Meissner’s P.

Neurotransmitter and receptor in organs

Function

NE/α-AR

Inhibit muscle activity Inhibit secretion

ACh/mAChR NO, VIP

Contract smooth muscle Relax smooth muscle Contract smooth muscle

ACh/nAChR

Contract striated muscle

IAS, internal anal sphincter; EAS, external anal sphincter; ACh, acetylcholine; mAChR, muscarinic acetylcholine receptor; nAChR, nicotinic acetylcholine receptor; NE, norepinephrine; AR, adrenergic receptor; NO, nitric oxide; VIP, vasoactive intestinal peptide.

1440




Figure 14 Schematic drawing neuronal control of the gastrointestinal (GI) tract. Vagal sensory afferent neurons are located in the nodose ganglion and collect information of the gut. Ascending afferent fibers terminate in the nucleus tractus solitarii (NTS) where the information of converging projections from high CNS centers is integrated. Subsequently, the signal is relayed to parasympathetic neurons in the dorsal motor nucleus of vagus (DMV). These vago-vagal reflex circuits modulate smooth muscle movement and digestion process throughout the GI tract. The stomach is dominated by vagal parasympathetic control. In humans sacral parasympathetic efferent fibers originating from S2-S4 spinal cord levels (L6-S1 in rats) join the descending colon and rectum through the pelvic nerve. The mesenteric nerve from T5-T12 levels and the hypogastric nerve from T12-L2 levels contain sympathetic input to the stomach, intestine, and colon. The external anal sphincter (EAS) is innervated by somatic pudendal nerves, originating from motoneurons at S2-S4 spinal levels in humans (L6-S1 in rats). CNX, cranial nerve X; SMG, superior mesenteric ganglion; IMG, inferior mesenteric ganglion; g, ganglion; n, nerve.

muscle layers, and Meissner’s plexus in the submucosa (119). Auerbach’s plexus contains unmyelinated fibers and postganglionic parasympathetic neurons, whereas Meissner’s plexus relays local sensory and motor responses to Auerbach’s plexus, prevertebral ganglia, and the spinal cord. The ENS control of the intestine is modulated by central connections from parasympathetic and sympathetic nerves (Fig. 14). The vagus nerve descends from the brainstem providing


parasympathetic regulation from the esophagus all the way to the splenic flexure of colon. In humans, parasympathetic fibers originate from the S2-S4 spinal levels (L6-S1 in rats) and join the descending colon and rectum via the pelvic nerve. The splanchnic nerves (including great and lesser splanchnic nerves) from the T5-T12 spinal levels and the hypogastric nerve from the T12-L2 levels convey sympathetic preganglionic innervation to postganglionic neurons

1441


controlling the colon. The EAS muscle is innervated by somatic pudendal nerve, whose cell bodies are located in Onuf’s nuclei at the ventral gray matter of the S2-S4 spinal cord (L6-S1 in rats) (296). Thus, in lower GI tract, a neural network consisting of parasympathetic, sympathetic, and somatic input orchestrates the activities to effect stool storage and propulsion. Unlike the intestines, stomach ENS lacks the capacity to independently control the activity. The stomach is dominated by parasympathetic vagus nerve, and gastric sensory information is transmitted via the vagal afferents to neurons of the NTS in the brainstem. These vago-vagal reflex circuits modulate smooth muscle movement and digestion processes from the oral cavity to the transverse colon (72). The vagal control diminishes caudally. Vagal sensory afferent neurons are located within the nodose ganglion and collect information from the gut. Ascending vagal fibers terminate onto second order neurons in the NTS by way of glutamatergic synapses (141). The vagal afferent terminals are mechanosensitive and/or chemosensitive. Information of converging projections from high CNS centers is integrated by neurons in the NTS and is relayed to parasympathetic neurons within DMV (336). Specifically, the dorsal vagal complex (DVC), which consists of the area postrema (AP), the NTS, and the DMV, is an integration center of gastric reflex function at the brainstem level (336). The basal motor outflow to the stomach can be blocked by application of GABA-ergic antagonists to the DVC, suggesting that NTS GABA-ergic projections onto DMV neurons predominantly regulate the tonic activity of the upper GI tract (15,40,131,132,314). Parasympathetic neurons in the DMV are cholinergic and synapse onto postganglionic neurons positioned nearby the stomach via nicotinic receptors. Cholinergic preganglionic DMV neurons form parallel inhibitory and excitatory pathways to gastric smooth muscle viscera by stimulating postganglionic neurons via nicotinic and muscarinic receptors, respectively. In turn, postganglionic excitatory neurons release ACh and substance P necessary for gastric tone and motility, whereas the inhibitory neurons release ATP, VIP, and NO exerting profound gastric relaxation (55, 184). Therefore, gastric tone and motility are reduced when the activity of excitatory cholinergic pathways decreases or NO/VIP-mediated inhibitory activity increases. The ENS is the basis of the primary reflex circuit mediating both filling and emptying of the distal colon. Enteric reflexes can generate proximal to distal propulsion of colonic contents and relaxation of the internal anal sphincter. Smalldiameter pelvic visceral afferents enter the superficial dorsal horn of spinal cord where secondary sensory neurons relay the primary information to SPNs in the IML of thoracolumbar spinal cord, the brainstem integration sites, the parabrachial nucleus, and the PAG. The PAG also receives parasympathetic afferents and interconnects with the hypothalamus and the amygdala. This spinobulbar and suprabulbar projections provide the substrate for the hierarchical somato-autonomic reflexes (84, 299). The PMC is believed to coregulate the

1442


rectosigmoid alongside the bladder based on its efferent distribution (344). Neurons in the PMC project not only to the DMV but also to sacral parasympathetic nuclei, inferring that they control both upper and lower GI functions. Behavioral motivation for stool and urine evacuation is generated by a signal in the forebrain.

Complications and pathophysiology after SCI GI complications are particularly responsible for 11% of hospitalization in patients with SCI (6,236). Functional GI motility disorders manifest a broad range of symptoms including gastric dilation, delayed gastric emptying, gastric ulceration, prolonged bloating, abdominal pain, and diminished propulsive transit along the entire length of GI tract. The extent of symptoms varies based on the level of SCI. Severe GI consequences may persist for years after the initial injury and affect the patients’ nutritional status. However, there are very few studies that have investigated changes in GI control in SCI animals (137, 138, 335).

Upper GI dysfunction Individuals with SCI may develop upper GI dysfunction including esophageal, gastric, and proximal duodenal disorders. The motor control of the esophagus is a complex interaction of proximal voluntary striated musculature and distal involuntary smooth muscles. SCI-related esophageal dysfunction manifests problems in the propulsion of ingesta to the stomach and the prevention of gastroesophageal reflux of stomach contents. The high incidence of gastroesophageal reflux, hiatal hernia, heartburn, and esophageal chest pain accompanied by esophagitis and diminished esophageal contractility is reported following SCI (118, 321). The rate of dysphagia increases in patients with cervical spinal injury. Due to the difficulties of endoscopic, manometric, and histological examinations in high-level spinal cord injured persons, the mechanism of esophageal dysfunction after SCI remains unknown. The functions of the stomach are to store and digest food particles as well as propulsion of ingesta into the duodenum. In addition to the occurrence of peptic ulceration, derangements in upper GI reflex emptying and motility are often reported after mid-thoracic SCI (159,304,366). The principle functions of the proximal duodenum include neutralization of acid in the chyme delivered from the stomach, and reduction of particles to simple molecules for absorption. The duodenum releases GI peptides and hormones that participate in the feedback mechanisms between the antrum, pylorus, and duodenum (82). Motilin, a 22-amino acid peptide released from the upper intestine, can stimulate gastric and intestinal myoelectric activity. Peptide YY (PYY), a 36-amino acid peptide hormone released from enterochromaffin cells (specialized epithelial cells) within the ileum and colon, diminishes gastric acid secretion, gastric emptying, intestinal propulsion, and pancreatic exocrine secretion. In normal individuals, there are



(A)

(B)


T3 SCI

Lower GI dysfunction

10 mmHg

Small and large intestinal movement is largely autonomous, being influenced to some extent by the spinal cord and minimally by the brain. The colon generates intrinsic rhythmic slow waves that originate from the submucosal plexus and occur sequentially at adjacent points moving along the colonic axis. It has important functions in serving as a stool reservoir, providing for growth of symbiotic bacteria, secreting mucus for feces lubrication, and propelling stool toward the anus. The colon resorbs electrolytes, short-chain fatty acids, bacterial metabolites, and fluids from feces. “Neurogenic bowel” is a critical consequence of GI dysfunction following SCI. The term refers to colonic disorders stemming from the lack of nervous system control related to neural lesions located in the brain or spinal cord levels. It clinically manifests symptoms such as constipation, incontinence, and discoordination of defecation. The ENS remains functionally intact during the occurrence of neurogenic bowel. However, it is unclear whether the enteric gut nerve circuitry changes as a local synaptic remodeling in response to spinal lesion (78,79). Based on the level of injury, neurogenic bowel is classified into two different types: upper motor neuron bowel and lower motor neuron bowel. These two types of colonic dysfunctions display characteristic symptoms with distinct underlying neural mechanisms. Upper motor neuron bowel: The upper motor neuron bowel occurs after the damage of descending supraspinal pathways above the conus medullaris. The syndrome manifests as constipation with fecal retention along with a spastic anal sphincter. Usually patients need a chemical or mechanical treatment to induce defecation. High level SCI is associated with prolonged mouth-to-cecum transit (283). Below the ileocecal valve, the disordered colon is described as “spastic” because of the excessive colonic wall and anal tone observed. The striated EAS muscle, normally under voluntary control, remains tight as a result of losing descending inhibitory regulation (306). Individuals with upper motor neuron bowel after SCI show a higher basal colonic muscle activity than normal, as recorded by surface electromyography (2, 78). This could lead to abnormal segmental peristalsis or propulsive peristalsis, and a hyperactive holding reflex with spastic EAS constriction, resulting in fecal distention of the colon. Similar to hyperreflexic bladder with upper motor neuron injury, colonic dysfunction following high level SCI exhibits increased colorectal pressure. Measurement of intracolonic pressure by infusion of water into the rectum shows a rapid rise in subjects with high level SCI, exceeding 40 mmHg in comparison to 5 to 15 mmHg in normal subjects (112). This suggests a hyperreflexic response of the descending colon in upper motor neuron bowel. Subsequent investigations have demonstrated, with colonic compliances, the reduction of colorectal pressure to normal range by gradually or intermittently infusing water (210, 261). Transit time through the colon has been used as a parameter of colonic transportation ability to evaluate anorectal motility. By tracing swallowed radiopaque

T3 control 10 mmHg

Figure 15 Traumatic SCI diminishes mechanical sensitivity of the stomach to fluid distension. Representative gastric pressure traces in rats with high thoracic contused SCI (T3 SCI, upper trace) and surgical (laminectomy only) controls (T3 Control, lower trace) demonstrate that during 6 min of continuous filling (at a rate of 1 mL/min, starting at closed arrowhead and terminating at open arrowhead) T3 SCI rats exhibit a smaller increase in gastric pressure and pressure-evoked motility waves are less pronounced, measured at 3 days postinjury. Initial pressure peak (asterisks) is an artifact of initiating the filling cycle. Gastric distension is performed by passing a saline-filled catheter via an incision into the proximal duodenum and through the occluded pylorus. Gastric distension is maintained at the termination of the filling cycle (with permission from Ref. 138).

postprandial (following a meal) increases in plasma PYY and motilin levels, correlating to neural mechanisms. To understand whether abnormal gut hormone release is important in the development of such GI abnormalities, the levels of serum motilin and PYY were measured and compared to uninjured, paraplegic and quadriplegic patients (294). The results indicate that motilin levels are largely similar across the three groups, though there is a trend toward elevated motilin levels in the paraplegic group. Likewise, levels of PYY in chronic SCI individuals are similar in the fasted state but are significantly elevated in the early postprandial state of quadriplegic subjects. Both spontaneous gastric contractions and the esophagealgastric relaxation reflexes are significantly diminished in rats 3 days after contusion injury at the upper thoracic spinal cord and are not ameliorated by celiac sympathectomy, indicating that changes in the sensitivity of vago-vagal reflexes may be responsible for post-SCI gastroparesis (Fig. 15) (138, 335). Mid-thoracic SCI models demonstrate inhibition of gastric emptying and duodenal transit (114, 116, 158, 287). Noninvasive breath tests for gastric emptying that utilize [13 C]isotope-enriched substrates have been validated in humans and rodents (110, 341). Using this technique, investigators compared the time-course of recovery of gastric emptying and motility after T3-spinal contusion injury, T3-spinal transection, and laminectomy. SCI at the T3 level produces a significant reduction in gastric emptying, irrespective of contusion or transection, which persists for at least 3 weeks after injury. Functional recovery of gastric emptying is established at 6 weeks post T3 contusion. However, it does not occur in animals with spinal cord transection (278). The recovery of gastric emptying after contusion SCI may correlate with plasticity of vagal and enteric neurocircuitry.


1443


markers, colon and rectal transit times have been investigated in humans with thoracic SCI (12). Serial colonic radiographs after radiopaque ingestion demonstrates markedly delayed transit time of colon and rectum (22). This is confirmed by another study using indium-111 amberlite scintigraph showing a significantly slower emptying half-time (166). The results indicate that upper motor neuron bowel in patients with chronic SCI involves the entire colorectum, and may require the intervention of oral laxative agents in addition to rectal suppository medications and digital reflex stimulation to effectively elicit stool evacuation. Lower motor neuron bowel: The lower motor neuron bowel results from infraconal lesions such as cauda equina or pelvic nerve impairments, which damage motor and parasympathetic projections to the colon and rectum. In this type of spinal cord lesion, the lower GI tract is described areflexic, being analogous to that of lower motor neuron bladder. It is manifested in a “relaxed” colon, perturbed peristalsis, slow stool propulsion, and constipation. There is often no spinal cord-mediated reflex peristalsis. The EAS is denervated because of neuronal death, increasing the risk of incontinence. The rectal-anal inhibitory reflex is retained even in the lesions of conus medullaris or cauda equine (22, 79). The levator ani muscles lose tone and the sigmoid and rectum descend into the pelvic floor, opening the rectal lumen which contributes to incontinence (20). It is believed that parasympathetic stimuli are more important to colorectal transport than sympathetic stimuli (22). Clinical observations confirm that bilateral sympathectomy does not cause any obvious alterations of bowel routines (85). However, one study does not fully support this conclusion (183). Using radiopaque markers and abdominal X-ray detection, investigators studied GI and segmental colonic transit time in patients with acute and chronic SCI. In acute supraconal or conal/cauda equina injured subjects, gastrointestinal transit times (GITT) and segmental colonic transit times (CTT) of the ascending, transverse, and descending colon are significantly prolonged. However, rectosigmoid transit times are prolonged in patients with conal/cauda equina lesion. In patients with chronic supraconal lesions GITT and CTT of the transverse and descending colons are prolonged. In patients with chronic conal/cauda equina lesions GITT and CTT of the transverse, descending, and rectosigmoid colons are prolonged (183). Therefore, upper motor neuron lesion in SCI renders generalized colonic dysfunction, whereas chronic lower motor neuron injury causes severe rectosigmoid dysfunction. In patients with conal or cauda equina lesions, rectal evacuation becomes severely compromised because the reflex arc from rectum to the spinal cord is damaged, manifesting prolonged rectosigmoid transit times.

Rehabilitative management Bowel program: The bowel program is a comprehensive individualized treatment plan to avoid incontinence, achieve effective and efficient colonic evacuation, and prevent the

1444


complications of neurogenic bowel dysfunction. The contents may contain consideration of diet, physical activity, equipment, oral or rectal medications, as well as scheduling of bowel care. Diet is an essential component of the overall program (18). Adequate fiber intake in the form of whole grains, fruits, and vegetables allows the stool to form sufficient bulk and plasticity, and keeps it flowing freely along the GI tract. Taking sufficient fluid keeps the stool soft and facilitates its transit. However, high fat meals and dairy products tend to reduce successful propulsion. A regular schedule of bowel care is individually developed and the procedure is carried out by the patient or attendant to periodically evacuate stool from the distal colon (129, 270). Interruption of bowel care sessions can cause excessive buildup of stool in the colon which becomes increasingly tense, less plastic, and more difficult to eliminate. This can distend the colon and reduce the effectiveness of peristalsis. In addition, adaptive equipment which maintains the injured individual in proper position plays a critical role to facilitate the efficient passage of stool. For example, an appropriate commode chair takes advantage of gravity and places the abdominal muscles at maximum mechanical effect for defecation (258). Medications: Medications used in the management of neurogenic bowel dysfunction are focused on modulating stool consistency, motility, and defecation. Several categories of agents useful to individuals with SCI include bulk-forming agents (fiber), stool softeners, laxatives, prokinetic agents, and a variety of compounded agents. Bulk-forming agents are orally administered, indigestible, and nonabsorbable fibers that increase the intraluminal water content and overall volume of stool (45, 134). Fiber has been shown to decrease colonic transit time in neurologically intact subjects. Most patients with SCI need a high-fiber diet, which improves continence through modulation of stool consistency (58). Docusate sodium and potassium are the most commonly used stool softeners, which have a role in lowering the surface tension of stool, and thereby allowing water and lipids to enter and soften the fecal mass (56, 95). Other agents with stoolsoftening action consist of liquid paraffin, mineral oil, and seed oils (described as intestinal lubricant laxatives). Polyphenolic derivatives represent another group of commonly used stimulants. By enhancing intestinal motility through the effect on the myenteric plexus, stimulant laxatives act to decrease the time available for water and electrolyte resorption (37, 220). Notably, all stimulants have the potential for dose-dependent side effects, such as abdominal cramping, diarrhea, or electrolyte imbalance.

Techniques for functional assessments Gastrointestinal transit: The time of GI transit can be assessed by the transportation of orally administered radiopaque marker in patients or dye in experimental animals. After a nontoxic, nonabsorbable marker or dye is fed to the stomach, the movement of the substance can be detected by X-ray or spectrophotometry throughout transportation in the GI tract



during the period of any time interval (114, 117, 285). Visualization techniques including video fluoroscopy and magnetic resonance imaging (MRI) have been used in clinical or experimental settings to visualize GI motility by detection of solid food labeled with tracer (62, 202, 295). These noninvasive methods are attractive as they can be combined with sensory or motor functional measurements. Hydrogen breath test is clinically used to evaluate the pathophysiology of the GI tract (90, 310, 317). The basis is that bodily sources of hydrogen do not exist except those produced by bacterial metabolism in the cecum; therefore, detected hydrogen in expiration following carbohydrate administration indicates the arrival of the nutrient bolus into the cecum. This technique can be used to measure GI transit time. Electromyography: EMG recording of EAS activity is useful to investigate the physiology and pathophysiology of the sphincter muscles in animals with SCI (136). Two parameters, baseline electric activity and the contraction induced by sphincter distension, can be obtained after bipolar electrodes are implanted into the sphincter muscle. It has been used to assess functional recovery of autonomic reflexes after the period of spinal shock and the occurrence of sphincter muscle hyperreflexia (137). As anesthetics often attenuate muscle hyperreflexia, this technique is normally applied in conscious animals. EAS EMG recording is usually administered as a terminal experiment. Gastrointestinal pressure: Techniques that measure GI pressure in digestion disease can be used to assess colonic motility in SCI rats. Manometry can quantify motor activity described as the amplitude, duration, frequency, and number of contractions by a fluid-filled catheter inserted into the colon and attached to recording probes (234). By using this technique, a reduction of distal colonic motility has been observed in rats with spinal cord transection during the acute phase of post injury (235). In conjunction with oral marker delivery, decreased colonic motility can be more clearly recognized (240). Another technique uses surgically implanted strain gauge transducers to record the mechanical activity along GI tract induced by feeding (146,233). It is applied in clinical settings to monitor GI motility in postoperative GI tract paresis.


brain-spinal cord connections may be developed to minimize undesired abnormalities and improve the quality of daily living. Pharmacological approaches are currently applied to patients with SCI to treat autonomic problems in the clinical arena, while traditional palliative methods may soon be replaced with preventative methods (280, 281). Although numerous attempts have been implemented to induce injured CNS axon regeneration for sensory and motor functional recovery, the aim of finding a cure for paralysis has not yet been achieved. Unlike the no-response or low-response of the injured corticospinal tracts to interventional stimuli, injured brainstem-derived axon projections appear prone to regrow if provided appropriate grafts and/or stimulation at the spinal cord lesion site. Techniques of inducing axon growth may possibly be effective in restoring autonomic neural connections since most supraspinal projections involved in the autonomic regulations originate from vital brainstem nuclei. It was recently demonstrated that grafting neural stem cells into an injured rat spinal cord can rebuild neuronal pathways which dramatically improves motor or sensory functions (35, 207). Critically, similar results have been observed in cardiovascular recovery when specific differentiation-determinant neural stem cells were grafted into a T4-transected spinal cord (145). Taken together, novel approaches pertaining to pharmacological intervention, targeting axon regeneration, and cellular grafting techniques hold promise for improving autonomic dysfunction after SCI.

Acknowledgements We gratefully acknowledge the support from the Craig H. Neilsen Foundation (S. H., 280072) and an endowment from the University of Kentucky Spinal Cord and Brain Injury Research Center (A. G. R.).

References 1.

Conclusion Traumatic SCI damages multiple nervous system components including motor, sensory, and autonomic. In recent decades, more and more research has gradually been focusing on autonomic dysfunctions after SCI, which can evoke prolonged catastrophic deficiencies. Disordered hemodynamics, micturition and sexual dysfunctions, as well as GI problems are increasing as priorities in clinical and long-term management. Despite partial elucidation of the neural basis, there is an urgent need to fully understand the pathophysiology of the autonomic nervous system following SCI. Based on our knowledge and technical progress, effective therapeutic interventions including neuronal protection, rebuilding spinal reflex circuits, minimizing aberrant plasticity, and repairing


2. 3. 4. 5. 6. 7. 8. 9.

Consortium for Spinal Cord Medicine. Acute management of autonomic dysreflexia: Individuals with spinal cord injury presenting to health-care facilities. J Spinal Cord Med 25 (Suppl 1): S67-88, 2002. Aaronson MJ, Freed MM, Burakoff R. Colonic myoelectric activity in persons with spinal cord injury. Dig Dis Sci 30 (4): 295-300, 1985. Albanese A, Jenner P, Marsden CD, Stephenson JD. Bladder hyperreflexia induced in marmosets by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine. Neurosci Lett 87 (1-2): 46-50, 1988. Alilain WJ, Horn KP, Hu H, Dick TE, Silver J. Functional regeneration of respiratory pathways after spinal cord injury. Nature 475 (7355): 196-200, 2011. Anderson JT, Bradley WE. Bladder and urethral innervation in multiple sclerosis. Br J Urol 48 (4): 239-43, 1976. Anderson KD. Targeting recovery: Priorities of the spinal cord-injured population. J Neurotrauma 21 (10): 1371-83, 2004. Anderson KE. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 45 (3): 253-308, 1993. Andersson K. alpha1-adrenoceptors and bladder function. Eur Urol 36 (Suppl. 1): 96-102, 1999. Araki I, De Groat WC. Unitary excitatory synaptic currents in preganglionic neurons mediated by two distinct groups of interneurons in neonatal rat sacral parasympathetic nucleus. J Neurophysiol 76 (1): 215-26, 1996.

1445


10. 11. 12. 13.

14. 15. 16.

17. 18. 19. 20.

21.

22.

23. 24. 25. 26. 27.

28. 29. 30. 31. 32.

33. 34.

35.

Araki I, de Groat WC. Developmental synaptic depression underlying reorganization of visceral reflex pathways in the spinal cord. J Neurosci 17 (21): 8402-8407, 1997. Araki I, Matsui M, Ozawa K, Takeda M, Kuno S. Relationship of bladder dysfunction to lesion site in multiple sclerosis. J Urol 169 (4): 1384-1387, 2003. Arhan P, Devroede G, Jehannin B, Lanza M, Faverdin C, Dornic C, Persoz B, Tetreault L, Perey B, Pellerin D. Segmental colonic transit time. Dis Colon Rectum 24 (8): 625-629, 1981. Athwal BS, Berkley KJ, Hussain I, Brennan A, Craggs M, Sakakibara R, Frackowiak RS, Fowler CJ. Brain responses to changes in bladder volume and urge to void in healthy men. Brain 124 (Pt 2), 369-77, 2001. Atkinson PP, Atkinson JL. Spinal shock. Mayo Clin Proc 71 (4): 384-9, 1996. Babic T, Browning KN, Travagli RA. Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex. Am J Physiol Gastrointest Liver Physiol 300 (1): G21-32, 2011. Bacon SJ, Smith AD. Preganglionic sympathetic neurones innervating the rat adrenal medulla: Immunocytochemical evidence of synaptic input from nerve terminals containing substance P, GABA or 5hydroxytryptamine. J Auton Nerv Syst 24 (1-2): 97-122, 1988. Bandler R, Keay KA. Columnar organization in the midbrain periaqueductal gray and the integration of emotional expression. Prog Brain Res 107: 285-300, 1996. Banwell JG, Creasey GH, Aggarwal AM, Mortimer JT. Management of the neurogenic bowel in patients with spinal cord injury. Urol Clin North Am 20 (3): 517-26, 1993. Barrington FJF. The effect of lesions of the hind- and mid-brain on micturition in the cat. Q J Exp Physiol 15: 81-102, 1925. Bartolo DC, Read NW, Jarratt JA, Read MG, Donnelly TC, Johnson AG. Differences in anal sphincter function and clinical presentation in patients with pelvic floor descent. Gastroenterology 85 (1): 68-75, 1983. Bennett DL, Dmietrieva N, Priestley JV, Clary D, McMahon SB. trkA, CGRP and IB4 expression in retrogradely labelled cutaneous and visceral primary sensory neurones in the rat. Neurosci Lett 206 (1): 33-6, 1996. Beuret-Blanquart F, Weber J, Gouverneur JP, Demangeon S, Denis P. Colonic transit time and anorectal manometric anomalies in 19 patients with complete transection of the spinal cord. J Auton Nerv Syst 30 (3): 199-207, 1990. Bilello JF, Davis JW, Cunningham MA, Groom TF, Lemaster D, Sue LP. Cervical spinal cord injury and the need for cardiovascular intervention. Arch Surg 138 (10): 1127-9, 2003. Birder LA, de Groat WC. Increased c-fos expression in spinal neurons after irritation of the lower urinary tract in the rat. J Neurosci 12 (12): 4878-89, 1992. Birder LA, de Groat WC. Induction of c-fos expression in spinal neurons by nociceptive and nonnociceptive stimulation of LUT. Am J Physiol 265 (2 Pt 2), R326-33, 1993. Birder LA, Wolf-Johnston A, Griffiths D, Resnick NM. Role of urothelial nerve growth factor in human bladder function. Neurourol Urodyn 26 (3): 405-9, 2007. Blok BF, De Weerd H, Holstege G. Ultrastructural evidence for a paucity of projections from the lumbosacral cord to the pontine micturition center or M-region in the cat: A new concept for the organization of the micturition reflex with the periaqueductal gray as central relay. J Comp Neurol 359 (2): 300-9, 1995. Blok BF, Sturms LM, Holstege G. Brain activation during micturition in women. Brain 121 (Pt 11) 2033-42, 1998. Blok BF, van Maarseveen JT, Holstege G. Electrical stimulation of the sacral dorsal gray commissure evokes relaxation of the external urethral sphincter in the cat. Neurosci Lett 249 (1): 68-70, 1998. Blok BF, Willemsen AT, Holstege G. A PET study on brain control of micturition in humans. Brain 120 (Pt 1) 111-21, 1997. Bohlen JG, Held JP, Sanderson MO. The male orgasm: Pelvic contractions measured by anal probe. Arch Sex Behav 9 (6): 503-21, 1980. Bojsen-Moller F, Tranum-Jensen J. Whole-mount demonstration of cholinesterase-containing nerves in the right atrial wall, nodal tissue, and atrioventricular bundle of the pig heart. J Anat 108 (Pt 3), 375-86, 1971. Boland RA, Lin CS, Engel S, Kiernan MC. Adaptation of motor function after spinal cord injury: Novel insights into spinal shock. Brain 134 (Pt 2), 495-505, 2011. Bonfanti L, Merighi A, Theodosis DT. Dorsal rhizotomy induces transient expression of the highly sialylated isoform of the neural cell adhesion molecule in neurons and astrocytes of the adult rat spinal cord. Neuroscience 74 (3): 619-23, 1996. Bonner JF, Connors TM, Silverman WF, Kowalski DP, Lemay MA, Fischer I. Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J Neurosci 31 (12): 467586, 2011.

1446


36. Breedlove SM, Arnold AP. Hormone accumulation in a sexually dimorphic motor nucleus of the rat spinal cord. Science 210 (4469): 564-6, 1980. 37. Brenner DM. Stimulant laxatives for the treatment of chronic constipation: Is it time to change the paradigm? Gastroenterology 142 (2): 402-4, 2012. 38. Brown A, Jacob JE. Genetic approaches to autonomic dysreflexia. Prog Brain Res 152: 299-313, 2006. 39. Brown A, Ricci MJ, Weaver LC. NGF message and protein distribution in the injured rat spinal cord. Exp Neurol 188 (1): 115-27, 2004. 40. Browning KN, Travagli RA. Mechanism of action of baclofen in rat dorsal motor nucleus of the vagus. Am J Physiol Gastrointest Liver Physiol 280 (6): G1106-13, 2001. 41. Burgard EC, Fraser MO, Thor KB. Serotonergic modulation of bladder afferent pathways. Urology 62 (4 Suppl 1), 10-5, 2003. 42. Bush PA, Aronson WJ, Buga GM, Rajfer J, Ignarro LJ. Nitric oxide is a potent relaxant of human and rabbit corpus cavernosum. J Urol 147 (6): 1650-5, 1992. 43. Calaresu FR, Yardley CP. Medullary basal sympathetic tone. Annu Rev Physiol 50: 511-24, 1988. 44. Cameron AA, Smith GM, Randall DC, Brown DR, Rabchevsky AG. Genetic manipulation of intraspinal plasticity after spinal cord injury alters the severity of autonomic dysreflexia. J Neurosci 26 (11): 292332, 2006. 45. Cameron KJ, Nyulasi IB, Collier GR, Brown DJ. Assessment of the effect of increased dietary fibre intake on bowel function in patients with spinal cord injury. Spinal Cord 34 (5): 277-83, 1996. 46. Cano G, Card JP, Rinaman L, Sved AF. Connections of Barrington’s nucleus to the sympathetic nervous system in rats. J Auton Nerv Syst 79 (2-3): 117-28, 2000. 47. Castro-Diaz D, Taracena Lafuente JM. Detrusor-sphincter dyssynergia. Int J Clin Pract Suppl 151: 17-21, 2006. 48. Caverson MM, Ciriello J, Calaresu FR. Direct pathway from cardiovascular neurons in the ventrolateral medulla to the region of the intermediolateral nucleus of the upper thoracic cord: An anatomical and electrophysiological investigation in the cat. J Auton Nerv Syst 9 (2-3): 451-75, 1983. 49. Cellek S, Moncada S. Nitrergic neurotransmission mediates the nonadrenergic non-cholinergic responses in the clitoral corpus cavernosum of the rabbit. Br J Pharmacol 125 (8): 1627-9, 1998. 50. Chalmers J, Arnolda L, Llewellyn-Smith I, Minson J, Pilowsky P, Suzuki S. Central neurons and neurotransmitters in the control of blood pressure. Clin Exp Pharmacol Physiol 21 (10): 819-29, 1994. 51. Chancellor MB, Kaplan SA, Blaivas JG. Detrusor-external sphincter dyssynergia. In: Block JWG, editor. Ciba Foundation Symposium. Chichester, West Sussex: Wiley, 1990, p. 195-213. 52. Chancellor MB, Rivas DA, Acosta R, Erhard MJ, Moore J, Salzman SK. Detrusor-myoplasty, innervated rectus muscle transposition study, and functional effect on the spinal cord injury rat model. Neurourol Urodyn 13 (5): 547-57, 1994. 53. Chancellor MB, Yoshimura N. Physiology and pharmacology of the bladder and urethra. In: Walsh PC et al., editors. Campbell’s Urology. Philadelphia: W.B. Saunders Co., 2002, p. 831-886. 54. Chang HH, Havton LA. Serotonergic 5-HT(1A) receptor agonist (8OH-DPAT) ameliorates impaired micturition reflexes in a chronic ventral root avulsion model of incomplete cauda equina/conus medullaris injury. Exp Neurol 239: 210-7, 2013. 55. Chang HY, Mashimo H, Goyal RK. Musings on the wanderer: What’s new in our understanding of vago-vagal reflex? IV. Current concepts of vagal efferent projections to the gut. Am J Physiol Gastrointest Liver Physiol 284 (3): G357-66, 2003. 56. Chapman RW, Sillery J, Fontana DD, Matthys C, Saunders DR. Effect of oral dioctyl sodium sulfosuccinate on intake-output studies of human small and large intestine. Gastroenterology 89 (3): 489-93, 1985. 57. Chen D, Apple DF, Jr., Hudson LM, Bode R. Medical complications during acute rehabilitation following spinal cord injury–current experience of the Model Systems. Arch Phys Med Rehabil 80 (11): 1397-401, 1999. 58. Chen D, Nussbaum SB. The gastrointestinal system and bowel management following spinal cord injury. Phys Med Rehabil Clin N Am 11 (1): 45-56, viii, 2000. 59. Chen Q, Takahashi S, Zhong S, Hosoda C, Zheng HY, Ogushi T, Fujimura T, Ohta N, Tanoue A, Tsujimoto G, Kitamura T. Function of the lower urinary tract in mice lacking alpha1d-adrenoceptor. J Urol 174 (1): 370-4, 2005. 60. Cheng CL, de Groat WC. The role of capsaicin-sensitive afferent fibers in the lower urinary tract dysfunction induced by chronic spinal cord injury in rats. Exp Neurol 187 (2): 445-54, 2004. 61. Christensen MD, Hulsebosch CE. Spinal cord injury and anti-NGF treatment results in changes in CGRP density and distribution in the dorsal horn in the rat. Exp Neurol 147 (2): 463-75, 1997. 62. Christmann V, Rosenberg J, Seega J, Lehr CM. Simultaneous in vivo visualization and localization of solid oral dosage forms in the rat



63. 64.

65. 66. 67. 68.

69.

70.

71.

72. 73.

74.

75. 76. 77. 78. 79. 80.

81. 82. 83. 84.

85. 86. 87.

88.

gastrointestinal tract by magnetic resonance imaging (MRI). Pharm Res 14 (8): 1066-72, 1997. Cihak R, Gutmann E, Hanzlikova V. Involution and hormone-induced persistence of the M. sphincter (levator) ani in female rats. J Anat 106 (Pt 1), 93-110, 1970. Claus-Walker J, Halstead LS. Metabolic and endocrine changes in spinal cord injury: II (section 1). Consequences of partial decentralization of the autonomic nervous system. Arch Phys Med Rehabil 63 (11): 569-75, 1982. Coelho A, Cruz F, Cruz CD, Avelino A. Effect of onabotulinumtoxinA on intramural parasympathetic ganglia: An experimental study in the guinea pig bladder. J Urol 187 (3): 1121-6, 2012. Coote JH. Bulbospinal serotonergic pathways in the control of blood pressure. J Cardiovasc Pharmacol 15 (Suppl. 7): S35-41, 1990. Coris EE, Ramirez AM, Van Durme DJ. Heat illness in athletes: The dangerous combination of heat, humidity and exercise. Sports Med 34 (1): 9-16, 2004. Cormier CM, Mukhida K, Walker G, Marsh DR. Development of autonomic dysreflexia after spinal cord injury is associated with a lack of serotonergic axons in the intermediolateral cell column. J Neurotrauma 27 (10): 1805-18, 2010. Courtois FJ, Charvier KF, Leriche A, Vezina JG, Cote M, Belanger M. Blood pressure changes during sexual stimulation, ejaculation and midodrine treatment in men with spinal cord injury. BJU Int 101 (3): 331-7, 2008. Courtois FJ, Goulet MC, Charvier KF, Leriche A. Posttraumatic erectile potential of spinal cord injured men: How physiologic recordings supplement subjective reports. Arch Phys Med Rehabil 80 (10): 1268-72, 1999. Dampney RA, Tagawa T, Horiuchi J, Potts PD, Fontes M, Polson JW. What drives the tonic activity of presympathetic neurons in the rostral ventrolateral medulla? Clin Exp Pharmacol Physiol 27 (12): 1049-53, 2000. De Giorgio R, Camilleri M. Human enteric neuropathies: Morphology and molecular pathology. Neurogastroenterol Motil 16 (5): 515-31, 2004. de Groat WC, Booth AM, Yashimura N. Neurophysiology of micturition and its modification in animal models of human disease. In: Maggi CA, editor. The Autonomic Nervous System (Vol. 3). London, UK: Harwood Academic Pubishers, 1993, pp. 227-289. de Groat WC, Kawatani M, Hisamitsu T, Cheng CL, Ma CP, Thor K, Steers W, Roppolo JR. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Auton Nerv Syst 30 (Suppl): S71-7, 1990. de Groat WC. Influence of central serotonergic mechanisms on lower urinary tract function. Urology 59 (5 Suppl. 1), 30-6, 2002. de Groat WC, Yoshimura N. Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury. Prog Brain Res 152: 59-84, 2006. de Groat WC, Yoshimura N. Changes in afferent activity after spinal cord injury. Neurourol Urodyn 29 (1): 63-76, 2010. Devroede G, Arhan P, Duguay C, Tetreault L, Akoury H, Perey B. Traumatic constipation. Gastroenterology 77 (6): 1258-67, 1979. Devroede G, Lamarche J. Functional importance of extrinsic parasympathetic innervation to the distal colon and rectum in man. Gastroenterology 66 (2): 273-80, 1974. Ding YQ, Zheng HX, Gong LW, Lu Y, Zhao H, Qin BZ. Direct projections from the lumbosacral spinal cord to Barrington’s nucleus in the rat: A special reference to micturition reflex. J Comp Neurol 389 (1): 149-60, 1997. Ditunno JF, Little JW, Tessler A, Burns AS. Spinal shock revisited: A four-phase model. Spinal Cord 42 (7): 383-95, 2004. Dockray GJ, Burdyga G. Plasticity in vagal afferent neurones during feeding and fasting: Mechanisms and significance. Acta Physiol (Oxf) 201 (3): 313-21, 2011. Downey JA, Chiodi HP, Darling RC. Central temperature regulation in the spinal man. J Appl Physiol 22 (1): 91-4, 1967. Drake MJ, Fowler CJ, Griffiths D, Mayer E, Paton JF, Birder L. Neural control of the lower urinary and gastrointestinal tracts: Supraspinal CNS mechanisms. Neurourol Urodyn 29 (1): 119-27, 2010. Goligher JC, Duthie HL, Nixon HH. Surgery of the anus, rectum and colon. London: Balliere Tindall and Cassell, 1967, p. 40. Eglen RM, Hegde SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 48 (4): 531-65, 1996. Ekland MB, Krassioukov AV, McBride KE, Elliott SL. Incidence of autonomic dysreflexia and silent autonomic dysreflexia in men with spinal cord injury undergoing sperm retrieval: Implications for clinical practice. J Spinal Cord Med 31 (1): 33-9, 2008. Elkelini MS, Bagli DJ, Fehlings M, Hassouna M. Effects of intravesical onabotulinumtoxinA on bladder dysfunction and autonomic dysreflexia after spinal cord injury: Role of nerve growth factor. BJU Int 109 (3): 402-7, 2012.



89. Elliott S, Krassioukov A. Malignant autonomic dysreflexia in spinal cord injured men. Spinal Cord 44 (6): 386-92, 2006. 90. Enck P, Wienbeck M. Repeated noninvasive measurement of gastrointestinal transit in rats. Physiol Behav 46 (4): 633-7, 1989. 91. Fam B, Yalla SV. Vesicourethral dysfunction in spinal cord injury and its management. Semin Neurol 8 (2): 150-5, 1988. 92. Fealey RD, Szurszewski JH, Merritt JL, DiMagno EP. Effect of traumatic spinal cord transection on human upper gastrointestinal motility and gastric emptying. Gastroenterology 87 (1): 69-75, 1984. 93. Fehlings MG, Tator CH. The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury. Exp Neurol 132 (2): 220-8, 1995. 94. Fisher JP, Seifert T, Hartwich D, Young CN, Secher NH, Fadel PJ. Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans. J Physiol 588 (Pt 7), 1117-27, 2010. 95. Fleming V, Wade WE. A review of laxative therapies for treatment of chronic constipation in older adults. Am J Geriatr Pharmacother 8 (6): 514-50, 2010. 96. Forger NG, Breedlove SM. Sexual dimorphism in human and canine spinal cord: Role of early androgen. Proc Natl Acad Sci U S A 83 (19): 7527-31, 1986. 97. Forger NG. The organizational hypothesis and final common pathways: Sexual differentiation of the spinal cord and peripheral nervous system. Horm Behav 55 (5): 605-10, 2009. 98. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci 9 (6): 453-66, 2008. 99. Frankel HL, Mathias CJ, Spalding JM. Mechanisms of reflex cardiac arrest in tetraplegic patients. Lancet 2 (7946): 1183-5, 1975. 100. Frankel HL, Michaelis LS, Golding DR, Beral V. The blood pressure in paraplegia. I. Paraplegia 10 (3): 193-200, 1972. 101. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth R, Hilz MJ, Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, Mathias C, Raj SR, Robertson D, Sandroni P, Schatz IJ, Schondorf R, Stewart JM, van Dijk JG. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosci 161 (1-2): 46-8, 2011. 102. Freire-Maia L, Azevedo AD. The autonomic nervous system is not a purely efferent system. Med Hypotheses 32 (2): 91-9, 1990. 103. Frisbie JH, Steele DJ. Postural hypotension and abnormalities of salt and water metabolism in myelopathy patients. Spinal Cord 35 (5): 3037, 1997. 104. Furlan JC, Fehlings MG, Shannon P, Norenberg MD, Krassioukov AV. Descending vasomotor pathways in humans: Correlation between axonal preservation and cardiovascular dysfunction after spinal cord injury. J Neurotrauma 20 (12): 1351-63, 2003. 105. Furlan JC, Fehlings MG. Cardiovascular complications after acute spinal cord injury: Pathophysiology, diagnosis, and management. Neurosurg Focus 25 (5): E13, 2008. 106. Gallien P, Robineau S, Verin M, Le Bot MP, Nicolas B, Brissot R. Treatment of detrusor sphincter dyssynergia by transperineal injection of botulinum toxin. Arch Phys Med Rehabil 79 (6): 715-7, 1998. 107. Ganesan V, Borzyskowski M. Characteristics and course of urinary tract dysfunction after acute transverse myelitis in. Dev Med Child Neurol 43 (7): 473-5, 2001. 108. Garshick E, Kelley A, Cohen SA, Garrison A, Tun CG, Gagnon D, Brown R. A prospective assessment of mortality in chronic spinal cord injury. Spinal Cord 43 (7): 408-16, 2005. 109. Garstang SV, Miller-Smith SA. Autonomic nervous system dysfunction after spinal cord injury. Phys Med Rehabil Clin N Am 18 (2): 275-96, vi-vii, 2007. 110. Ghoos YF, Maes BD, Geypens BJ, Mys G, Hiele MI, Rutgeerts PJ, Vantrappen G. Measurement of gastric emptying rate of solids by means of a carbon-labeled octanoic acid breath test. Gastroenterology 104 (6): 1640-7, 1993. 111. Giannantoni A, Mearini E, Del Zingaro M, Porena M. Six-year followup of botulinum toxin A intradetrusorial injections in patients with refractory neurogenic detrusor overactivity: Clinical and urodynamic results. Eur Urol 55 (3): 705-11, 2009. 112. Glick ME, Meshkinpour H, Haldeman S, Hoehler F, Downey N, Bradley WE. Colonic dysfunction in patients with thoracic spinal cord injury. Gastroenterology 86 (2): 287-94, 1984. 113. Goa KL, Sorkin EM. Gabapentin. A review of its pharmacological properties and clinical potential in epilepsy. Drugs 46 (3): 409-27, 1993. 114. Gondim FA, Alencar HM, Rodrigues CL, da Graca JR, dos Santos AA, Rola FH. Complete cervical or thoracic spinal cord transections delay gastric emptying and gastrointestinal transit of liquid in awake rats. Spinal Cord 37 (11): 793-9, 1999.

1447


115. Gondim FA, Lopes AC, Jr., Oliveira GR, Rodrigues CL, Leal PR, Santos AA, Rola FH. Cardiovascular control after spinal cord injury. Curr Vasc Pharmacol 2 (1): 71-9, 2004. 116. Gondim FA, Rodrigues CL, da Graca JR, Camurca FD, de Alencar HM, dos Santos AA, Rola FH. Neural mechanisms involved in the delay of gastric emptying and gastrointestinal transit of liquid after thoracic spinal cord transection in awake rats. Auton Neurosci 87 (1): 52-8, 2001. 117. Goodman RD, Lewis AE, Schuck EA, Greenfield MA. Gastrointestinal transit. Am J Physiol 169 (1): 236-41, 1952. 118. Gore RM, Mintzer RA, Calenoff L. Gastrointestinal complications of spinal cord injury. Spine (Phila Pa 1976) 6 (6): 538-44, 1981. 119. Goyal RK, Hirano I. The enteric nervous system. N Engl J Med 334 (17): 1106-15, 1996. 120. Granata AR, Ruggiero DA. Evidence of disynaptic projections from the rostral ventrolateral medulla to the thoracic spinal cord. Brain Res 781 (1-2): 329-34, 1998. 121. Griffiths D, Derbyshire S, Stenger A, Resnick N. Brain control of normal and overactive bladder. J Urol 174 (5): 1862-7, 2005. 122. Grigorean VT, Sandu AM, Popescu M, Iacobini MA, Stoian R, Neascu C, Strambu V, Popa F. Cardiac dysfunctions following spinal cord injury. J Med Life 2 (2): 133-45, 2009. 123. Grimm DR, DeMeersman RE, Garofano RP, Spungen AM, Bauman WA. Effect of provocative maneuvers on heart rate variability in subjects with quadriplegia. Am J Physiol 268 (6 Pt 2), H2239-45, 1995. 124. Guha A, Tator CH. Acute cardiovascular effects of experimental spinal cord injury. J Trauma 28 (4): 481-90, 1988. 125. Guha A, Tator CH, Rochon J. Spinal cord blood flow and systemic blood pressure after experimental spinal cord injury in rats. Stroke 20 (3): 372-7, 1989. 126. Guyenet PG, Haselton JR, Sun MK. Sympathoexcitatory neurons of the rostroventrolateral medulla and the origin of the sympathetic vasomotor tone. Prog Brain Res 81: 105-16, 1989. 127. Gwak YS, Nam TS, Paik KS, Hulsebosch CE, Leem JW. Attenuation of mechanical hyperalgesia following spinal cord injury by administration of antibodies to nerve growth factor in the rat. Neurosci Lett 336 (2): 117-20, 2003. 128. Habler HJ, Janig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol 425: 545-62, 1990. 129. Halm MA. Elimination concerns with acute spinal cord trauma. Assessment and nursing interventions. Crit Care Nurs Clin North Am 2 (3): 385-98, 1990. 130. Hassessian H, Poulat P, Hamel E, Reader TA, Couture R. Spinal cord serotonin receptors in cardiovascular regulation and potentiation of the pressor response to intrathecal substance P after serotonin depletion. Can J Physiol Pharmacol 71 (7): 453-64, 1993. 131. Herman MA, Alayan A, Sahibzada N, Bayer B, Verbalis J, Dretchen KL, Gillis RA. micro-Opioid receptor stimulation in the medial subnucleus of the tractus solitarius inhibits gastric tone and motility by reducing local GABA activity. Am J Physiol Gastrointest Liver Physiol 299 (2): G494-506, 2010. 132. Herman MA, Cruz MT, Sahibzada N, Verbalis J, Gillis RA. GABA signaling in the nucleus tractus solitarius sets the level of activity in dorsal motor nucleus of the vagus cholinergic neurons in the vagovagal circuit. Am J Physiol Gastrointest Liver Physiol 296 (1): G101-11, 2009. 133. Hiersemenzel LP, Curt A, Dietz V. From spinal shock to spasticity: Neuronal adaptations to a spinal cord injury. Neurology 54 (8): 157482, 2000. 134. Hillemeier C. An overview of the effects of dietary fiber on gastrointestinal transit. Pediatrics 96 (5 Pt 2), 997-9, 1995. 135. Hoang TX, Pikov V, Havton LA. Functional reinnervation of the rat lower urinary tract after cauda equina injury and repair. J Neurosci 26 (34): 8672-9, 2006. 136. Holmes GM, Rogers RC, Bresnahan JC, Beattie MS. External anal sphincter hyperreflexia following spinal transection in the rat. J Neurotrauma 15 (6): 451-7, 1998. 137. Holmes GM, Van Meter MJ, Beattie MS, Bresnahan JC. Serotonergic fiber sprouting to external anal sphincter motoneurons after spinal cord contusion. Exp Neurol 193 (1): 29-42, 2005. 138. Holmes GM. Upper gastrointestinal dysmotility after spinal cord injury: Is diminished vagal sensory processing one culprit? Front Physiol 3: 277, 2012. 139. Holstege G. Some anatomical observations on the projections from the hypothalamus to brainstem and spinal cord: An HRP and autoradiographic tracing study in the cat. J Comp Neurol 260 (1): 98-126, 1987. 140. Horn JP, Stofer WD. Preganglionic and sensory origins of calcitonin gene-related peptide-like and substance P-like immunoreactivities in bullfrog sympathetic ganglia. J Neurosci 9 (7): 2543-61, 1989.

1448


141. Hornby PJ. Receptors and transmission in the brain-gut axis. II. Excitatory amino acid receptors in the brain-gut axis. Am J Physiol Gastrointest Liver Physiol 280 (6): G1055-60, 2001. 142. Hou S, Duale H, Cameron AA, Abshire SM, Lyttle TS, Rabchevsky AG. Plasticity of lumbosacral propriospinal neurons is associated with the development of autonomic dysreflexia after thoracic spinal cord transection. J Comp Neurol 509 (4): 382-99, 2008. 143. Hou S, Duale H, Rabchevsky AG. Intraspinal sprouting of unmyelinated pelvic afferents after complete spinal cord injury is correlated with autonomic dysreflexia induced by visceral pain. Neuroscience 159 (1): 369-79, 2009. 144. Hou S, Lu P, Blesch A. Characterization of supraspinal vasomotor pathways and autonomic dysreflexia after spinal cord injury in F344 rats. Auton Neurosci 176 (1-2): 54-63, 2013. 145. Hou S, Tom VJ, Graham L, Lu P, Blesch A. Partial restoration of cardiovascular function by grafting embryonic neural stem cell grafts after complete spinal cord transection. J Neurosci 33: 17138-17149, 2013. 146. Huge A, Kreis ME, Jehle EC, Ehrlein HJ, Starlinger M, Becker HD, Zittel TT. A model to investigate postoperative ileus with strain gauge transducers in awake rats. J Surg Res 74 (2): 112-8, 1998. 147. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 170 (2): 843-50, 1990. 148. Innes IR, Kosterlitz HW. The effects of preganglionic and postganglionic denervation on the responses of the nictitating membrane to sympathomimetic substances. J Physiol 124 (1): 25-43, 1954. 149. Inokuchi H, Yoshimura M, Polosa C, Nishi S. Adrenergic receptors (alpha 1 and alpha 2) modulate different potassium conductances in sympathetic preganglionic neurons. Can J Physiol Pharmacol 70 (Suppl): S92-7, 1992. 150. Inoue K, Ogata H, Hayano J, Miyake S, Kamada T, Kuno M, Kumashiro M. Assessment of autonomic function in traumatic quadriplegic and paraplegic patients by spectral analysis of heart rate variability. J Auton Nerv Syst 54 (3): 225-34, 1995. 151. Inskip JA, Ramer LM, Ramer MS, Krassioukov AV. Autonomic assessment of animals with spinal cord injury: Tools, techniques and translation. Spinal Cord 47 (1): 2-35, 2009. 152. Ishizuka O, Alm P, Larsson B, Mattiasson A, Andersson KE. Facilitatory effect of pituitary adenylate cyclase activating polypeptide on micturition in normal, conscious rats. Neuroscience 66 (4): 1009-14, 1995. 153. Jacob JE, Pniak A, Weaver LC, Brown A. Autonomic dysreflexia in a mouse model of spinal cord injury. Neuroscience 108 (4): 687-93, 2001. 154. Janig W, McLachlan EM. Organization of lumbar spinal outflow to distal colon and pelvic organs. Physiol Rev 67 (4): 1332-404, 1987. 155. Janig W, Morrison JF. Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Prog Brain Res 67: 87-114, 1986. 156. Jansen AS, Nguyen XV, Karpitskiy V, Mettenleiter TC, Loewy AD. Central command neurons of the sympathetic nervous system: Basis of the fight-or-flight response. Science 270 (5236): 644-6, 1995. 157. Jeske I, McKenna KE. Quantitative analysis of bulbospinal projections from the rostral ventrolateral medulla: Contribution of C1-adrenergic and nonadrenergic neurons. J Comp Neurol 324 (1): 1-13, 1992. 158. Kabatas S, Yu D, He XD, Thatte HS, Benedict D, Hepgul KT, Black PM, Sabharwal S, Teng YD. Neural and anatomical abnormalities of the gastrointestinal system resulting from contusion spinal cord injury. Neuroscience 154 (4): 1627-38, 2008. 159. Kao CH, Ho YJ, Changlai SP, Ding HJ. Gastric emptying in spinal cord injury patients. Dig Dis Sci 44 (8): 1512-5, 1999. 160. Karlsson AK. Autonomic dysreflexia. Spinal Cord 37 (6): 383-91, 1999. 161. Karlsson AK. Autonomic dysfunction in spinal cord injury: Clinical presentation of symptoms and signs. Prog Brain Res 152: 1-8, 2006. 162. Karsenty G, Reitz A, Wefer B, Boy S, Schurch B. Understanding detrusor sphincter dyssynergia–significance of chronology. Urology 66 (4): 763-8, 2005. 163. Keast JR, De Groat WC. Segmental distribution and peptide content of primary afferent neurons innervating the urogenital organs and colon of male rats. J Comp Neurol 319 (4): 615-23, 1992. 164. Keirstead HS, Fedulov V, Cloutier F, Steward O, Duel BP. A noninvasive ultrasonographic method to evaluate bladder function recovery in spinal cord injured rats. Exp Neurol 194 (1): 120-7, 2005. 165. Kerr FW, Alexander S. Descending autonomic pathways in the spinal cord. Arch Neurol 10: 249-61, 1964. 166. Keshavarzian A, Barnes WE, Bruninga K, Nemchausky B, Mermall H, Bushnell D. Delayed colonic transit in spinal cord-injured patients measured by indium-111 Amberlite scintigraphy. Am J Gastroenterol 90 (8): 1295-300, 1995.



167. Kojima M, Sano Y. Sexual differences in the topographical distribution of serotonergic fibers in the anterior column of rat lumbar spinal cord. Anat Embryol (Berl) 170 (2): 117-21, 1984. 168. Kojima M, Takeuchi Y, Goto M, Sano Y. Immunohistochemical study on the localization of serotonin fibers and terminals in the spinal cord of the monkey (Macaca fuscata). Cell Tissue Res 229 (1): 23-36, 1983. 169. Krassioukov A. Which pathways must be spared in the injured human spinal cord to retain cardiovascular control? Prog Brain Res 152: 39-47, 2006. 170. Krassioukov AV, Bunge RP, Pucket WR, Bygrave MA. The changes in human spinal sympathetic preganglionic neurons after spinal cord injury. Spinal Cord 37 (1): 6-13, 1999. 171. Krassioukov A, Claydon VE. The clinical problems in cardiovascular control following spinal cord injury: An overview. Prog Brain Res 152: 223-9, 2006. 172. Krassioukov A, Eng JJ, Warburton DE, Teasell R. A systematic review of the management of orthostatic hypotension after spinal cord injury. Arch Phys Med Rehabil 90 (5): 876-85, 2009. 173. Krassioukov AV, Fehlings MG. Effect of graded spinal cord compression on cardiovascular neurons in the rostro-ventro-lateral medulla. Neuroscience 88 (3): 959-73, 1999. 174. Krassioukov AV, Furlan JC, Fehlings MG. Autonomic dysreflexia in acute spinal cord injury: An under-recognized clinical entity. J Neurotrauma 20 (8): 707-16, 2003. 175. Krassioukov AV, Johns DG, Schramm LP. Sensitivity of sympathetically correlated spinal interneurons, renal sympathetic nerve activity, and arterial pressure to somatic and visceral stimuli after chronic spinal injury. J Neurotrauma 19 (12): 1521-9, 2002. 176. Krassioukov AV, Karlsson AK, Wecht JM, Wuermser LA, Mathias CJ, Marino RJ. Assessment of autonomic dysfunction following spinal cord injury: Rationale for additions to International Standards for Neurological Assessment. J Rehabil Res Dev 44 (1): 103-12, 2007. 177. Krassioukov AV, Weaver LC. Episodic hypertension due to autonomic dysreflexia in acute and chronic spinal cord-injured rats. Am J Physiol 268 (5 Pt 2), H2077-83, 1995. 178. Krassioukov AV, Weaver LC. Morphological changes in sympathetic preganglionic neurons after spinal cord injury in rats. Neuroscience 70 (1): 211-25, 1996. 179. Krebs M, Ragnarrson KT, Tuckman J. Orthostatic vasomotor response in spinal man. Paraplegia 21 (2): 72-80, 1983. 180. Krenz NR, Meakin SO, Krassioukov AV, Weaver LC. Neutralizing intraspinal nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury. J Neurosci 19 (17): 7405-14, 1999. 181. Krenz NR, Weaver LC. Sprouting of primary afferent fibers after spinal cord transection in the rat. Neuroscience 85 (2): 443-58, 1998. 182. Krenz NR, Weaver LC. Nerve growth factor in glia and inflammatory cells of the injured rat spinal cord. J Neurochem 74 (2): 730-9, 2000. 183. Krogh K, Mosdal C, Laurberg S. Gastrointestinal and segmental colonic transit times in patients with acute and chronic spinal cord lesions. Spinal Cord 38 (10): 615-21, 2000. 184. Krowicki KZ, Sivarao VD, Abrahams PT, Hornby JP. Excitation of dorsal motor vagal neurons evokes non-nicotinic receptor-mediated gastric relaxation. J Auton Nerv Syst 77 (2-3): 83-9, 1999. 185. Kruse MN, Bray LA, de Groat WC. Influence of spinal cord injury on the morphology of bladder afferent and efferent neurons. J Auton Nerv Syst 54 (3): 215-24, 1995. 186. Kuipers R, Mouton LJ, Holstege G. Afferent projections to the pontine micturition center in the cat. J Comp Neurol 494 (1): 36-53, 2006. 187. Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE. Recommendations for blood pressure measurement in humans and experimental animals. Part 2: Blood pressure measurement in experimental animals: A statement for professionals from the subcommittee of professional and public education of the American Heart Association council on high blood pressure research. Hypertension 45 (2): 299-310, 2005. 188. Kuru M. Nervous control of micturition. Physiol Rev 45: 425-94, 1965. 189. Laird AS, Carrive P, Waite PM. Cardiovascular and temperature changes in spinal cord injured rats at rest and during autonomic dysreflexia. J Physiol 577 (Pt 2), 539-48, 2006. 190. Landrum LM, Thompson GM, Blair RW. Does postsynaptic alpha 1-adrenergic receptor supersensitivity contribute to autonomic dysreflexia? Am J Physiol 274 (4 Pt 2), H1090-8, 1998. 191. Lane MA, Fuller DD, White TE, Reier PJ. Respiratory neuroplasticity and cervical spinal cord injury: Translational perspectives. Trends Neurosci 31 (10): 538-47, 2008. 192. Lane MA, Lee KZ, Fuller DD, Reier PJ. Spinal circuitry and respiratory recovery following spinal cord injury. Respir Physiol Neurobiol 169 (2): 123-32, 2009. 193. Lane MA, Lee KZ, Salazar K, O’Steen BE, Bloom DC, Fuller DD, Reier PJ. Respiratory function following bilateral mid-cervical contusion injury in the adult rat. Exp Neurol 235 (1): 197-210, 2012. 194. Lane MA, White TE, Coutts MA, Jones AL, Sandhu MS, Bloom DC, Bolser DC, Yates BJ, Fuller DD, Reier PJ. Cervical prephrenic



195.

196.

197. 198.

199. 200. 201. 202. 203. 204. 205. 206. 207.

208.

209.

210. 211. 212. 213. 214. 215.

216.

217. 218. 219. 220.

interneurons in the normal and lesioned spinal cord of the adult rat. J Comp Neurol 511 (5): 692-709, 2008. Leal PR, Cruz PR, Lopes AC, Jr., Lima RC, Jr., Carvalho FM, da Graca JR, dos Santos AA, Rola FH, Gondim FA. A new model of autonomic dysreflexia induced by gastric distension in the spinal cord-transected rat. Auton Neurosci 141 (1-2): 66-72, 2008. Lebedev VP, Krasyukov AV, Nikitin SA. Electrophysiological study of sympathoexcitatory structures of the bulbar ventrolateral surface as related to vasomotor regulation. Neuroscience 17 (1): 189-203, 1986. Lee YS, Lin CY, Jiang HH, Depaul M, Lin VW, Silver J. Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. J Neurosci 33 (26): 10591-606, 2013. Lehmann KG, Lane JG, Piepmeier JM, Batsford WP. Cardiovascular abnormalities accompanying acute spinal cord injury in humans: Incidence, time course and severity. J Am Coll Cardiol 10 (1): 46-52, 1987. Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapy option for voiding disorders: Current state of the art. Eur Urol 44 (2): 165-74, 2003. Lindan R, Joiner E, Freehafer AA, Hazel C. Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury. Paraplegia 18 (5): 285-92, 1980. Linsenmeyer TA, Oakley A. Accuracy of individuals with spinal cord injury at predicting urinary tract infections based on their symptoms. J Spinal Cord Med 26 (4): 352-7, 2003. Liu S, Chen JD. Colonic electrical stimulation regulates colonic transit via the nitrergic pathway in rats. Dig Dis Sci 51 (3): 502-5, 2006. Llewellyn-Smith IJ, Weaver LC. Changes in synaptic inputs to sympathetic preganglionic neurons after spinal cord injury. J Comp Neurol 435 (2): 226-40, 2001. Llewellyn-Smith IJ. Anatomy of synaptic circuits controlling the activity of sympathetic preganglionic neurons. J Chem Neuroanat 38 (3): 231-9, 2009. Loewy AD, Spyer, KM. Central Regulation of Autonomic Functions, New York: Oxford University Press, 1990. Longhurst JC, Mitchell JH. Reflex control of the circulation by afferents from skeletal muscle. Int Rev Physiol 18: 125-48, 1979. Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, Conner JM, Marsala M, Tuszynski MH. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150 (6): 1264-73, 2012. Lujan HL, Palani G, Peduzzi JD, DiCarlo SE. Targeted ablation of mesenteric projecting sympathetic neurons reduces the hemodynamic response to pain in conscious, spinal cord-transected rats. Am J Physiol Regul Integr Comp Physiol 298 (5): R1358-65, 2010. Lundberg JM. Pharmacology of cotransmission in the autonomic nervous system: Integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev 48 (1): 11378, 1996. MacDonagh R, Sun WM, Thomas DG, Smallwood R, Read NW. Anorectal function in patients with complete supraconal spinal cord lesions. Gut 33 (11): 1532-8, 1992. Madden CJ, Morrison SF. Serotonin potentiates sympathetic responses evoked by spinal NMDA. J Physiol 577 (Pt 2), 525-37, 2006. Maggi CA. The role of peptides in the regulation of the micturition reflex: An update. Gen Pharmacol 22 (1): 1-24, 1991. Maiorov DN, Fehlings MG, Krassioukov AV. Relationship between severity of spinal cord injury and abnormalities in neurogenic cardiovascular control in conscious rats. J Neurotrauma 15 (5): 365-74, 1998. Maiorov DN, Weaver LC, Krassioukov AV. Relationship between sympathetic activity and arterial pressure in conscious spinal rats. Am J Physiol 272 (2 Pt 2), H625-31, 1997. Mallek JT, Inaba K, Branco BC, Ives C, Lam L, Talving P, David JS, Demetriades D. The incidence of neurogenic shock after spinal cord injury in patients admitted to a high-volume level I trauma center. Am Surg 78 (5): 623-6, 2012. Mallory BS. Autonomic function in the isolated spinal cord. In: Downey JA, Myers SJ, Gonzales EG, Lieberman JS, editors. The Physiological Basis of Rehabilitation Medicine. Boston: Butterworth-Heinemann, 1994, pp. 519-541. Marina N, Taheri M, Gilbey MP. Generation of a physiological sympathetic motor rhythm in the rat following spinal application of 5-HT. J Physiol 571 (Pt 2), 441-50, 2006. Marsh DR, Weaver LC. Autonomic dysreflexia, induced by noxious or innocuous stimulation, does not depend on changes in dorsal horn substance p. J Neurotrauma 21 (6): 817-28, 2004. Marson L, Cai R, Makhanova N. Identification of spinal neurons involved in the urethrogenital reflex in the female rat. J Comp Neurol 462 (4): 355-70, 2003. Mascolo N, Meli R, Autore G, Capasso F. Senna still causes laxation in rats maintained on a diet deficient in essential fatty acids. J Pharm Pharmacol 40 (12): 882-4, 1988.

1449


221. Masuda N, Masuda H, Matsuyoshi H, Chancellor MB, de Groat WC, Yoshimura N. Effects of intrathecal injection of a hyperpolarizationactivated channel (Ih) inhibitor ZD7288 on bladder function in urethane-anesthetized rats. Neurourol Urodyn 27 (8): 838-44, 2008. 222. Mathias CF, Low DA, Frankel HL. Autonomic disturbances in spinal cord injury. In: Bannister RMC, editor. Autononic Failure. Oxford: Oxford University Press, 1992, pp. 839-881. 223. Mathias CJ, Christensen NJ, Corbett JL, Frankel HL, Goodwin TJ, Peart WS. Plasma catecholamines, plasma renin activity and plasma aldosterone in tetraplegic man, horizontal and tilted. Clin Sci Mol Med 49 (4): 291-9, 1975. 224. Mathias CJ, Frankel HL, Christensen NJ, Spalding JM. Enhanced pressor response to noradrenaline in patients with cervical spinal cord transection. Brain 99 (4): 757-70, 1976. 225. Mathias CJ. Autonomic diseases: Management. J Neurol Neurosurg Psychiatry 74 (Suppl 3): iii42-7, 2003. 226. Mathias CJ. Orthostatic hypotension and paroxysmal hypertension in humans with high spinal cord injury. Prog Brain Res 152: 231-43, 2006. 227. Matsumoto G, Hisamitsu T, de Groat WC. Non-NMDA glutamatergic excitatory transmission in the descending limb of the spinobulbospinal micturition reflex pathway of the rat. Brain Res 693 (1-2): 246-50, 1995. 228. Matsumoto G, Hisamitsu T, de Groat WC. Role of glutamate and NMDA receptors in the descending limb of the spinobulbospinal micturition reflex pathway of the rat. Neurosci Lett 183 (1-2): 58-61, 1995. 229. Mayorov DN, Adams MA, Krassioukov AV. Telemetric blood pressure monitoring in conscious rats before and after compression injury of spinal cord. J Neurotrauma 18 (7): 727-36, 2001. 230. McKenna KE, Chung SK, McVary KT. A model for the study of sexual function in anesthetized male and female rats. Am J Physiol 261 (5 Pt 2), R1276-85, 1991. 231. McKenna KE, Nadelhaft I. The organization of the pudendal nerve in the male and female rat. J Comp Neurol 248 (4): 532-49, 1986. 232. McLean DE, Kearney J, Cawley MF. Environmentally responsive temperature instability in pediatric spinal cord injury. Spinal Cord 37 (10): 705-9, 1999. 233. Meile T, Glatzle J, Habermann FM, Kreis ME, Zittel TT. Nitric oxide synthase inhibition results in immediate postoperative recovery of gastric, small intestinal and colonic motility in awake rats. Int J Colorectal Dis 21 (2): 121-9, 2006. 234. Meshkinpour H, Harmon D, Thompson R, Yu J. Effects of thoracic spinal cord transection on colonic motor activity in rats. Paraplegia 23 (5): 272-6, 1985. 235. Meshkinpour H, Nowroozi F, Glick ME. Colonic compliance in patients with spinal cord injury. Arch Phys Med Rehabil 64 (3): 111-2, 1983. 236. Middleton JW, Lim K, Taylor L, Soden R, Rutkowski S. Patterns of morbidity and rehospitalisation following spinal cord injury. Spinal Cord 42 (6): 359-67, 2004. 237. Mills AC, Sengelaub DR. Sexually dimorphic neuron number in lumbosacral dorsal root ganglia of the rat: Development and steroid regulation. J Neurobiol 24 (11): 1543-53, 1993. 238. Minson JB, Arnolda LF, Llewellyn-Smith IJ. Neurochemistry of nerve fibers apposing sympathetic preganglionic neurons activated by sustained hypotension. J Comp Neurol 449 (4): 307-18, 2002. 239. Minson JB, Llewellyn-Smith IJ, Pilowsky PM, Chalmers JP. Bulbospinal neuropeptide Y-immunoreactive neurons in the rat: Comparison with adrenaline-synthesising neurons. J Auton Nerv Syst 47 (3): 233-43, 1994. 240. Mintchev MP, Sanmiguel CP, Bowes KL. Electrogastrographic impact of multi-site functional gastric electrical stimulation. J Med Eng Technol 23 (1): 5-9, 1999. 241. Mitsui T, Fischer I, Shumsky JS, Murray M. Transplants of fibroblasts expressing BDNF and NT-3 promote recovery of bladder and hindlimb function following spinal contusion injury in rats. Exp Neurol 194 (2): 410-31, 2005. 242. Mitsui T, Kakizaki H, Tanaka H, Shibata T, Matsuoka I, Koyanagi T. Immortalized neural stem cells transplanted into the injured spinal cord promote recovery of voiding function in the rat. J Urol 170 (4 Pt 1), 1421-5, 2003. 243. Mitsui T, Shumsky JS, Lepore AC, Murray M, Fischer I. Transplantation of neuronal and glial restricted precursors into contused spinal cord improves bladder and motor functions, decreases thermal hypersensitivity, and modifies intraspinal circuitry. J Neurosci 25 (42): 9624-36, 2005. 244. Miura A, Kawatani M, de Groat WC. Excitatory synaptic currents in lumbosacral parasympathetic preganglionic neurons elicited from the lateral funiculus. J Neurophysiol 86 (4): 1587-93, 2001. 245. Miura A, Kawatani M, De Groat WC. Excitatory synaptic currents in lumbosacral parasympathetic preganglionic neurons evoked by stimulation of the dorsal commissure. J Neurophysiol 89 (1): 382-9, 2003. 246. Miyazato M, Oshiro T, Chancellor MB, de Groat WC, Yoshimura N, Saito S. An alpha1-adrenoceptor blocker terazosin improves urine storage function in the spinal cord in spinal cord injured rats. Life Sci 92 (2): 125-30, 2013.

1450


247. Miyazato M, Sasatomi K, Hiragata S, Sugaya K, Chancellor MB, de Groat WC, Yoshimura N. GABA receptor activation in the lumbosacral spinal cord decreases detrusor overactivity in spinal cord injured rats. J Urol 179 (3): 1178-83, 2008. 248. Monnier PP, Beck SG, Bolz J, Henke-Fahle S. The polysialic acid moiety of the neural cell adhesion molecule is involved in intraretinal guidance of retinal ganglion cell axons. Dev Biol 229 (1): 1-14, 2001. 249. Montgomerie JZ. Infections in patients with spinal cord injuries. Clin Infect Dis 25 (6): 1285-90; quiz 1291-2, 1997. 250. Morrison JF, Steers WD, Brading A, Blok B, Fry C, de Groat WC, Kakizaki H, Levin R, Thor KB. Neurophisiology and neuropharmacology. In: Abram P, et al., editors. Incontinence. Jersey: Health Publications Ltd., 2002, pp. 83-164. 251. Morrison JF. The discovery of the pontine micturition centre by F. J. F. Barrington. Exp Physiol 93 (6): 742-5, 2008. 252. Myers J, Lee M, Kiratli J. Cardiovascular disease in spinal cord injury: An overview of prevalence, risk, evaluation, and management. Am J Phys Med Rehabil 86 (2): 142-52, 2007. 253. Nadelhaft I, Vera PL, Card JP, Miselis RR. Central nervous system neurons labelled following the injection of pseudorabies virus into the rat urinary bladder. Neurosci Lett 143 (1-2): 271-4, 1992. 254. Nadelhaft I, Vera PL. Neurons in the rat brain and spinal cord labeled after pseudorabies virus injected into the external urethral sphincter. J Comp Neurol 375 (3): 502-17, 1996. 255. Nakagawa S. Onuf’s nucleus of the sacral cord in a South American monkey (Saimiri): its location and bilateral cortical input from area 4. Brain Res 191 (2): 337-44, 1980. 256. Nankovic V, Snur I, Nankovic S, Sokolovic-Matejcic B, Kvesic D. Spinal shock. Diagnosis and therapy. Problems and dilemmas. Lijec Vjesn 117 (Suppl 2): 30-2, 1995. 257. Nathan PW, Smith MC. The location of descending fibres to sympathetic preganglionic vasomotor and sudomotor neurons in man. J Neurol Neurosurg Psychiatry 50 (10): 1253-62, 1987. 258. Nelson A, Malassigne P, Amerson T, Saltzstein R, Binard J. Descriptive study of bowel care practices and equipment in spinal cord injury. SCI Nurs 10 (2): 65-7, 1993. 259. Newton BW. A sexually dimorphic population of galanin-like neurons in the rat lumbar spinal cord: Functional implications. Neurosci Lett 137 (1): 119-22, 1992. 260. Nicholas AP, Zhang X, Hokfelt T. An immunohistochemical investigation of the opioid cell column in lamina X of the male rat lumbosacral spinal cord. Neurosci Lett 270 (1): 9-12, 1999. 261. Nino-Murcia M, Stone JM, Chang PJ, Perkash I. Colonic transit in spinal cord-injured patients. Invest Radiol 25 (2): 109-12, 1990. 262. Nosjean A, Guyenet PG. Role of ventrolateral medulla in sympatholytic effect of 8-OHDPAT in rats. Am J Physiol 260 (3 Pt 2), R600-9, 1991. 263. Noto H, Roppolo JR, Steers WD, de Groat WC. Excitatory and inhibitory influences on bladder activity elicited by electrical stimulation in the pontine micturition center in the rat. Brain Res 492 (1-2): 99-115, 1989. 264. Nout YS, Bresnahan JC, Culp E, Tovar CA, Beattie MS, Schmidt MH. Novel technique for monitoring micturition and sexual function in male rats using telemetry. Am J Physiol Regul Integr Comp Physiol 292 (3): R1359-67, 2007. 265. Nout YS, Schmidt MH, Tovar CA, Culp E, Beattie MS, Bresnahan JC. Telemetric monitoring of corpus spongiosum penis pressure in conscious rats for assessment of micturition and sexual function following spinal cord contusion injury. J Neurotrauma 22 (4): 429-41, 2005. 266. Obata K, Yamanaka H, Dai Y, Tachibana T, Fukuoka T, Tokunaga A, Yoshikawa H, Noguchi K. Differential activation of extracellular signalregulated protein kinase in primary afferent neurons regulates brainderived neurotrophic factor expression after peripheral inflammation and nerve injury. J Neurosci 23 (10): 4117-26, 2003. 267. Onufronwicz B. Notes on the arrangement and function of the cell groups of the sacral region of the spinal cord. J Nerv Men Dis 26 (8): 498-504, 1899. 268. Osborn JW, Taylor RF, Schramm LP. Determinants of arterial pressure after chronic spinal transection in rats. Am J Physiol 256 (3 Pt 2), R666-73, 1989. 269. Panicker JN, De Seze M, Fowler CJ. Neurogenic lower urinary tract dysfunction. Handb Clin Neurol 110: 209-20, 2013. 270. Pardee C, Bricker D, Rundquist J, MacRae C, Tebben C. Characteristics of neurogenic bowel in spinal cord injury and perceived quality of life. Rehabil Nurs 37 (3): 128-35, 2012. 271. Pavcovich LA, Valentino RJ. Central regulation of micturition in the rat the corticotropin-releasing hormone from Barrington’s nucleus. Neurosci Lett 196 (3): 185-8, 1995. 272. Petit H, Wiart L, Gaujard E, Le Breton F, Ferriere JM, Lagueny A, Joseph PA, Barat M. Botulinum A toxin treatment for detrusor-sphincter dyssynergia in spinal cord disease. Spinal Cord 36 (2): 91-4, 1998. 273. Phan DC, Newton BW. Cholecystokinin-8-like immunoreactivity is sexually dimorphic in a midline population of rat lumbar neurons. Neurosci Lett 276 (3): 165-8, 1999.



274. Pikov V, Gillis RA, Jasmin L, Wrathall JR. Assessment of lower urinary tract functional deficit in rats with contusive spinal cord injury. J Neurotrauma 15 (5): 375-86, 1998. 275. Potter PJ. Disordered control of the urinary bladder after human spinal cord injury: What are the problems? Prog Brain Res 152: 51-7, 2006. 276. Price MJ, Campbell IG. Thermoregulatory responses of spinal cord injured and able-bodied athletes to prolonged upper body exercise and recovery. Spinal Cord 37 (11): 772-9, 1999. 277. Qiao L, Vizzard MA. Up-regulation of tyrosine kinase (Trka, Trkb) receptor expression and phosphorylation in lumbosacral dorsal root ganglia after chronic spinal cord (T8-T10) injury. J Comp Neurol 449 (3): 217-30, 2002. 278. Qualls-Creekmore E, Tong M, Holmes GM. Time-course of recovery of gastric emptying and motility in rats with experimental spinal cord injury. Neurogastroenterol Motil 22 (1): 62-9, e27-8, 2010. 279. Rabchevsky AG. Segmental organization of spinal reflexes mediating autonomic dysreflexia after spinal cord injury. Prog Brain Res 152: 265-74, 2006. 280. Rabchevsky AG, Kitzman PH. Latest approaches for the treatment of spasticity and autonomic dysreflexia in chronic spinal cord injury. Neurotherapeutics 8 (2): 274-82, 2011. 281. Rabchevsky AG, Patel SP, Duale H, Lyttle TS, O’Dell CR, Kitzman PH. Gabapentin for spasticity and autonomic dysreflexia after severe spinal cord injury. Spinal Cord 49 (1): 99-105, 2011. 282. Rabchevsky AG, Patel SP, Lyttle TS, Eldahan KC, O’Dell CR, Zhang Y, Popovich PG, Kitzman PH, Donohue KD. Effects of gabapentin on muscle spasticity and both induced as well as spontaneous autonomic dysreflexia after complete spinal cord injury. Front Physiol 3: 329, 2012. 283. Rajendran SK, Reiser JR, Bauman W, Zhang RL, Gordon SK, Korsten MA. Gastrointestinal transit after spinal cord injury: Effect of cisapride. Am J Gastroenterol 87 (11): 1614-7, 1992. 284. Ranson RN, Motawei K, Pyner S, Coote JH. The paraventricular nucleus of the hypothalamus sends efferents to the spinal cord of the rat that closely appose sympathetic preganglionic neurones projecting to the stellate ganglion. Exp Brain Res 120 (2): 164-72, 1998. 285. Reynell PC, Spray GH. The simultaneous measurement of absorption and transit in the gastro-intestinal tract of the rat. J Physiol 131 (2): 452-62, 1956. 286. Rizvi TA, Ennis M, Aston-Jones G, Jiang M, Liu WL, Behbehani MM, Shipley MT. Preoptic projections to Barrington’s nucleus and the pericoerulear region: Architecture and terminal organization. J Comp Neurol 347 (1): 1-24, 1994. 287. Rodrigues CL, Gondim FA, Leal PR, Camurca FD, Freire CC, dos Santos AA, Rola FH. Gastric emptying and gastrointestinal transit of liquid throughout the first month after thoracic spinal cord transection in awake rats. Dig Dis Sci 46 (8): 1604-9, 2001. 288. Rossier AB, Ott R, Roussan MS. Urinary manometry in patients with spinal cord injury: Neurourological considerations in the rehabilitation of acute and chronic neurogenic bladder. Arch Phys Med Rehabil 56 (5): 187-94, 1975. 289. Ruggiero DA, Cravo SL, Arango V, Reis DJ. Central control of the circulation by the rostral ventrolateral reticular nucleus: Anatomical substrates. Prog Brain Res 81: 49-79, 1989. 290. Rummery NM, Tripovic D, McLachlan EM, Brock JA. Sympathetic vasoconstriction is potentiated in arteries caudal but not rostral to a spinal cord transection in rats. J Neurotrauma 27 (11): 2077-89, 2010. 291. Sakamoto H, Matsuda K, Zuloaga DG, Hongu H, Wada E, Wada K, Jordan CL, Breedlove SM, Kawata M. Sexually dimorphic gastrin releasing peptide system in the spinal cord controls male reproductive functions. Nat Neurosci 11 (6): 634-6, 2008. 292. Sakamoto H. Brain-spinal cord neural circuits controlling male sexual function and behavior. Neurosci Res 72 (2): 103-16, 2012. 293. Sakamoto K, Uvelius B, Khan T, Damaser MS. Preliminary study of a genetically engineered spinal cord implant on urinary bladder after experimental spinal cord injury in rats. J Rehabil Res Dev 39 (3): 34757, 2002. 294. Saltzstein RJ, Mustin E, Koch TR. Gut hormone release in patients after spinal cord injury. Am J Phys Med Rehabil 74 (5): 339-44, 1995. 295. Sanmiguel CP, Casillas S, Senagore A, Mintchev MP, Soffer EE. Neural gastrointestinal electrical stimulation enhances colonic motility in a chronic canine model of delayed colonic transit. Neurogastroenterol Motil 18 (8): 647-53, 2006. 296. Sarna SK. Physiology and pathophysiology of colonic motor activity (1). Dig Dis Sci 36 (6): 827-62, 1991. 297. Sasek CA, Wessendorf MW, Helke CJ. Evidence for co-existence of thyrotropin-releasing hormone, substance P and serotonin in ventral medullary neurons that project to the intermediolateral cell column in the rat. Neuroscience 35 (1): 105-19, 1990. 298. Satake K, Matsuyama Y, Kamiya M, Kawakami H, Iwata H, Adachi K, Kiuchi K. Up-regulation of glial cell line-derived neurotrophic factor (GDNF) following traumatic spinal cord injury. Neuroreport 11 (17): 3877-81, 2000.



299. Sato A, Schmidt RF. Somatosympathetic reflexes: Afferent fibers, central pathways, discharge characteristics. Physiol Rev 53 (4): 916-47, 1973. 300. Schmid A, Huonker M, Stahl F, Barturen JM, Konig D, Heim M, Lehmann M, Keul J. Free plasma catecholamines in spinal cord injured persons with different injury levels at rest and during exercise. J Auton Nerv Syst 68 (1-2): 96-100, 1998. 301. Schmid DM, Curt A, Hauri D, Schurch B. Clinical value of combined electrophysiological and urodynamic recordings to assess sexual disorders in spinal cord injured men. Neurourol Urodyn 22 (4): 314-21, 2003. 302. Schreihofer AM, Sved AF. The ventrolateral medulla and sympathtic regulation of arterial pressure. In: Llewellyn-Smith IJ, et al., editors. Central Regulation of Autonomic Functions. Oxford Scholarship Online, 2011, pp. 78-97. 303. Schurch B, Schmid DM, Stohrer M. Treatment of neurogenic incontinence with botulinum toxin A. N Engl J Med 342 (9): 665, 2000. 304. Segal JL, Milne N, Brunnemann SR. Gastric emptying is impaired in patients with spinal cord injury. Am J Gastroenterol 90 (3): 466-70, 1995. 305. Seki S, Sasaki K, Fraser MO, Igawa Y, Nishizawa O, Chancellor MB, de Groat WC, Yoshimura N. Immunoneutralization of nerve growth factor in lumbosacral spinal cord reduces bladder hyperreflexia in spinal cord injured rats. J Urol 168 (5): 2269-74, 2002. 306. Shafik A. Electrorectogram study of the neuropathic rectum. Paraplegia 33 (6): 346-9, 1995. 307. Sie JA, Blok BF, de Weerd H, Holstege G. Ultrastructural evidence for direct projections from the pontine micturition center to glycineimmunoreactive neurons in the sacral dorsal gray commissure in the cat. J Comp Neurol 429 (4): 631-7, 2001. 308. Silverman JD, Kruger L. Selective neuronal glycoconjugate expression in sensory and autonomic ganglia: Relation of lectin reactivity to peptide and enzyme markers. J Neurocytol 19 (5): 789-801, 1990. 309. Simpson LL. Molecular pharmacology of botulinum toxin and tetanus toxin. Annu Rev Pharmacol Toxicol 26: 427-53, 1986. 310. Simren M, Stotzer PO. Use and abuse of hydrogen breath tests. Gut 55 (3): 297-303, 2006. 311. Sipski ML. The impact of spinal cord injury on female sexuality, menstruation and pregnancy: A review of the literature. J Am Paraplegia Soc 14 (3): 122-6, 1991. 312. Sipski ML, Alexander CJ, Rosen RC. Physiologic parameters associated with sexual arousal in women with incomplete spinal cord injuries. Arch Phys Med Rehabil 78 (3): 305-13, 1997. 313. Sipski ML, Alexander CJ, Rosen R. Sexual arousal and orgasm in women: Effects of spinal cord injury. Ann Neurol 49 (1): 35-44, 2001. 314. Sivarao DV, Krowicki ZK, Hornby PJ. Role of GABAA receptors in rat hindbrain nuclei controlling gastric motor function. Neurogastroenterol Motil 10 (4): 305-13, 1998. 315. Smith CP, Chancellor MB. Emerging role of botulinum toxin in the management of voiding dysfunction. J Urol 171 (6 Pt 1), 2128-37, 2004. 316. Snow JC, Sideropoulos HP, Kripke BJ, Freed MM, Shah NK, Schlesinger RM. Autonomic hyperreflexia during cystoscopy in patients with high spinal cord injuries. Paraplegia 15 (4): 327-32, 1978. 317. Staniforth DH. Comparison of orocaecal transit times assessed by the lactulose/breath hydrogen and the sulphasalazine/sulphapyridine methods. Gut 30 (7): 978-82, 1989. 318. Steele PA, Choate JK. Innervation of the pacemaker in guinea-pig sinoatrial node. J Auton Nerv Syst 47 (3): 177-87, 1994. 319. Steers WD, Tuttle JB. Mechanisms of disease: The role of nerve growth factor in the pathophysiology of bladder disorders. Nat Clin Pract Urol 3 (2): 101-10, 2006. 320. Stiens SA, Bergman SB, Goetz LL. Neurogenic bowel dysfunction after spinal cord injury: Clinical evaluation and rehabilitative management. Arch Phys Med Rehabil 78 (3 Suppl), S86-102, 1997. 321. Stinneford JG, Keshavarzian A, Nemchausky BA, Doria MI, Durkin M. Esophagitis and esophageal motor abnormalities in patients with chronic spinal cord injuries. Paraplegia 31 (6): 384-92, 1993. 322. Stornetta RL, Akey PJ, Guyenet PG. Location and electrophysiological characterization of rostral medullary adrenergic neurons that contain neuropeptide Y mRNA in rat medulla. J Comp Neurol 415 (4): 482500, 1999. 323. Stornetta RL, Rosin DL, Simmons JR, McQuiston TJ, Vujovic N, Weston MC, Guyenet PG. Coexpression of vesicular glutamate transporter-3 and gamma-aminobutyric acidergic markers in rat rostral medullary raphe and intermediolateral cell column. J Comp Neurol 492 (4): 477-94, 2005. 324. Strack AM, Sawyer WB, Hughes JH, Platt KB, Loewy AD. A general pattern of CNS innervation of the sympathetic outflow demonstrated by transneuronal pseudorabies viral infections. Brain Res 491 (1): 156-62, 1989. 325. Sugarman B, Brown D, Musher D. Fever and infection in spinal cord injury patients. JAMA 248 (1): 66-70, 1982.

1451


326. Swaab DF, Hofman MA. Sexual differentiation of the human hypothalamus in relation to gender and sexual orientation. Trends Neurosci 18 (6): 264-70, 1995. 327. Tang J, Landmesser L. Reduction of intramuscular nerve branching and synaptogenesis is correlated with decreased motoneuron survival. J Neurosci 13 (7): 3095-103, 1993. 328. Tang XQ, Tanelian DL, Smith GM. Semaphorin3A inhibits nerve growth factor-induced sprouting of nociceptive afferents in adult rat spinal cord. J Neurosci 24 (4): 819-27, 2004. 329. Tator CH. Update on the pathophysiology and pathology of acute spinal cord injury. Brain Pathol 5 (4): 407-13, 1995. 330. Teasell RW, Arnold JM, Krassioukov A, Delaney GA. Cardiovascular consequences of loss of supraspinal control of the sympathetic nervous system after spinal cord injury. Arch Phys Med Rehabil 81 (4): 506-16, 2000. 331. Thor KB, Morgan C, Nadelhaft I, Houston M, De Groat WC. Organization of afferent and efferent pathways in the pudendal nerve of the female cat. J Comp Neurol 288 (2): 263-79, 1989. 332. Thor KB, Nickolaus S, Helke CJ. Autoradiographic localization of 5-hydroxytryptamine1A, 5-hydroxytryptamine1B and 5hydroxytryptamine1C/2 binding sites in the rat spinal cord. Neuroscience 55 (1): 235-52, 1993. 333. Thornbury KD, Hollywood MA, McHale NG. Mediation by nitric oxide of neurogenic relaxation of the urinary bladder neck muscle in sheep. J Physiol 451: 133-44, 1992. 334. Tomassoni PJ, Campagnolo DI. Autonomic dysreflexia: One more way EMS can positively affect patient survival. JEMS 28 (12): 46-51, 2003. 335. Tong M, Holmes GM. Gastric dysreflexia after acute experimental spinal cord injury in rats. Neurogastroenterol Motil 21 (2): 197-206, 2009. 336. Travagli RA, Hermann GE, Browning KN, Rogers RC. Brainstem circuits regulating gastric function. Annu Rev Physiol 68: 279-305, 2006. 337. Tripovic D, Al Abed A, Rummery NM, Johansen NJ, McLachlan EM, Brock JA. Nerve-evoked constriction of rat tail veins is potentiated and venous diameter is reduced after chronic spinal cord transection. J Neurotrauma 28 (5): 821-9, 2011. 338. Tripovic D, Pianova S, McLachlan EM, Brock JA. Transient supersensitivity to alpha-adrenoceptor agonists, and distinct hyper-reactivity to vasopressin and angiotensin II after denervation of rat tail artery. Br J Pharmacol 159 (1): 142-53, 2010. 339. Truitt WA, Coolen LM. Identification of a potential ejaculation generator in the spinal cord. Science 297 (5586): 1566-9, 2002. 340. Truitt WA, Shipley MT, Veening JG, Coolen LM. Activation of a subset of lumbar spinothalamic neurons after copulatory behavior in male but not female rats. J Neurosci 23 (1): 325-31, 2003. 341. Uchida M, Endo N, Shimizu K. Simple and noninvasive breath test using 13C-acetic acid to evaluate gastric emptying in conscious rats and its validation by metoclopramide. J Pharmacol Sci 98 (4): 388-95, 2005. 342. Valentino RJ, Chen S, Zhu Y, Aston-Jones G. Evidence for divergent projections to the brain noradrenergic system and the spinal parasympathetic system from Barrington’s nucleus. Brain Res 732 (1-2): 1-15, 1996. 343. Valentino RJ, Kosboth M, Colflesh M, Miselis RR. Transneuronal labeling from the rat distal colon: Anatomic evidence for regulation of distal colon function by a pontine corticotropin-releasing factor system. J Comp Neurol 417 (4): 399-414, 2000. 344. Valentino RJ, Miselis RR, Pavcovich LA. Pontine regulation of pelvic viscera: Pharmacological target for pelvic visceral dysfunctions. Trends Pharmacol Sci 20 (6): 253-60, 1999. 345. Valentino RJ, Page ME, Luppi PH, Zhu Y, Van Bockstaele E, AstonJones G. Evidence for widespread afferents to Barrington’s nucleus, a brainstem region rich in corticotropin-releasing hormone neurons. Neuroscience 62 (1): 125-43, 1994. 346. Valentino RJ, Pavcovich LA, Hirata H. Evidence for corticotropinreleasing hormone projections from Barrington’s nucleus to the periaqueductal gray and dorsal motor nucleus of the vagus in the rat. J Comp Neurol 363 (3): 402-22, 1995. 347. Valentino RJ, Wood SK, Wein AJ, Zderic SA. The bladder-brain connection: Putative role of corticotropin-releasing factor. Nat Rev Urol 8 (1): 19-28, 2011. 348. Vera PL, Nadelhaft I. Anatomical evidence for two spinal ‘afferentinterneuron-efferent’ reflex pathways involved in micturition in the rat: A ‘pelvic nerve’ reflex pathway and a ‘sacrolumbar intersegmental’ reflex pathway. Brain Res 883 (1): 107-18, 2000. 349. Vizzard MA, Erickson VL, Card JP, Roppolo JR, de Groat WC. Transneuronal labeling of neurons in the adult rat brainstem and spinal cord after injection of pseudorabies virus into the urethra. J Comp Neurol 355 (4): 629-40, 1995. 350. Vizzard MA. Changes in urinary bladder neurotrophic factor mRNA and NGF protein following urinary bladder dysfunction. Exp Neurol 161 (1): 273-84, 2000.

1452


351. Vutskits L, Djebbara-Hannas Z, Zhang H, Paccaud JP, Durbec P, Rougon G, Muller D, Kiss JZ. PSA-NCAM modulates BDNFdependent survival and differentiation of cortical neurons. Eur J Neurosci 13 (7): 1391-402, 2001. 352. Waites KB, Canupp KC, DeVivo MJ. Epidemiology and risk factors for urinary tract infection following spinal cord injury. Arch Phys Med Rehabil 74 (7): 691-5, 1993. 353. Wallace MC, Tator CH. Spinal cord blood flow measured with microspheres following spinal cord injury in the rat. Can J Neurol Sci 13 (2): 91-6, 1986. 354. Walter JS, Wheeler JS, Fitzgerald MP, McDonnell A, Wurster RD. A spinal cord injured animal model of lower urinary tract function: Observations using direct bladder and pelvic plexus stimulation with model microstimulators. J Spinal Cord Med 28 (3): 246-54, 2005. 355. Walter JS, Wheeler JS, Robinson CJ, Wurster RD. Surface stimulation techniques for bladder management in the spinal dog. J Urol 141 (1): 161-5, 1989. 356. Weaver LC, Cassam AK, Krassioukov AV, Llewellyn-Smith IJ. Changes in immunoreactivity for growth associated protein-43 suggest reorganization of synapses on spinal sympathetic neurons after cord transection. Neuroscience 81 (2): 535-51, 1997. 357. Weaver LC, Marsh DR, Gris D, Brown A, Dekaban GA. Autonomic dysreflexia after spinal cord injury: Central mechanisms and strategies for prevention. Prog Brain Res 152: 245-63, 2006. 358. Weaver LC, Verghese P, Bruce JC, Fehlings MG, Krenz NR, Marsh DR. Autonomic dysreflexia and primary afferent sprouting after clipcompression injury of the rat spinal cord. J Neurotrauma 18 (10): 1107-19, 2001. 359. Wecht JM, De Meersman RE, Weir JP, Spungen AM, Bauman WA. Cardiac autonomic responses to progressive head-up tilt in individuals with paraplegia. Clin Auton Res 13 (6): 433-8, 2003. 360. Weld KJ, Graney MJ, Dmochowski RR. Clinical significance of detrusor sphincter dyssynergia type in patients with post-traumatic spinal cord injury. Urology 56 (4): 565-8, 2000. 361. Wheeler G. Gabapentin. Pfizer. Curr Opin Investig Drugs 3 (3): 470-7, 2002. 362. Whipple B, Komisaruk BR. Sexuality and women with complete spinal cord injury. Spinal Cord 35 (3): 136-8, 1997. 363. White TE, Lane MA, Sandhu MS, O’Steen BE, Fuller DD, Reier PJ. Neuronal progenitor transplantation and respiratory outcomes following upper cervical spinal cord injury in adult rats. Exp Neurol 225 (1): 231-6, 2010. 364. Widenfalk J, Lundstromer K, Jubran M, Brene S, Olson L. Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid. J Neurosci 21 (10): 3457-75, 2001. 365. Willette RN, Morrison S, Sapru HN, Reis DJ. Stimulation of opiate receptors in the dorsal pontine tegmentum inhibits reflex contraction of the urinary bladder. J Pharmacol Exp Ther 244 (1): 403-9, 1988. 366. Williams RE, III, Bauman WA, Spungen AM, Vinnakota RR, Farid RZ, Galea M, Korsten MA. SmartPill technology provides safe and effective assessment of gastrointestinal function in persons with spinal cord injury. Spinal Cord 50 (1): 81-4, 2012. 367. Winslow EB, Lesch M, Talano JV, Meyer PR, Jr. Spinal cord injuries associated with cardiopulmonary complications. Spine (Phila Pa 1976) 11 (8): 809-12, 1986. 368. Wrathall JR, Emch GS. Effect of injury severity on lower urinary tract function after experimental spinal cord injury. Prog Brain Res 152: 117-34, 2006. 369. Yaggie JA, Niemi TJ, Buono MJ. Adaptive sweat gland response after spinal cord injury. Arch Phys Med Rehabil 83 (6): 802-5, 2002. 370. Yamaguchi O, Shishido K, Tamura K, Ogawa T, Fujimura T, Ohtsuka M. Evaluation of mRNAs encoding muscarinic receptor subtypes in human detrusor muscle. J Urol 156 (3): 1208-13, 1996. 371. Yeo L, Singh R, Gundeti M, Barua JM, Masood J. Urinary tract dysfunction in Parkinson’s disease: A review. Int Urol Nephrol 44 (2): 415-24, 2012. 372. Yeoh M, McLachlan EM, Brock JA. Chronic decentralization potentiates neurovascular transmission in the isolated rat tail artery, mimicking the effects of spinal transection. J Physiol 561 (Pt 2), 583-96, 2004. 373. Yoo KY, Lee JU, Kim HS, Im WM. Hemodynamic and catecholamine responses to laryngoscopy and tracheal intubation in patients with complete spinal cord injuries. Anesthesiology 95 (3): 647-51, 2001. 374. Yoshimura N. Bladder afferent pathway and spinal cord injury: Possible mechanisms inducing hyperreflexia of the urinary bladder. Prog Neurobiol 57 (6): 583-606, 1999. 375. Yoshimura N, Bennett NE, Hayashi Y, Ogawa T, Nishizawa O, Chancellor MB, de Groat WC, Seki S. Bladder overactivity and hyperexcitability of bladder afferent neurons after intrathecal delivery of nerve growth factor in rats. J Neurosci 26 (42): 10847-55, 2006. 376. Yoshimura N, de Groat WC. Plasticity of Na+ channels in afferent neurones innervating rat urinary bladder following spinal cord injury. J Physiol 503 (Pt 2) 269-76, 1997.



377. Yoshimura N, Mizuta E, Kuno S, Sasa M, Yoshida O. The dopamine D1 receptor agonist SKF 38393 suppresses detrusor hyperreflexia in the monkey with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP). Neuropharmacology 32 (4): 315-21, 1993. 378. Yoshimura N, Mizuta E, Yoshida O, Kuno S. Therapeutic effects of dopamine D1/D2 receptor agonists on detrusor hyperreflexia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian cynomolgus monkeys. J Pharmacol Exp Ther 286 (1): 228-33, 1998. 379. Yoshimura N, Sasa M, Ohno Y, Yoshida O, Takaori S. Contraction of urinary bladder by central norepinephrine originating in the locus coeruleus. J Urol 139 (2): 423-7, 1988. 380. Yoshimura N, Sasa M, Yoshida O, Takaori S. Mediation of micturition reflex by central norepinephrine from the locus coeruleus in the cat. J Urol 143 (4): 840-3, 1990. 381. Yoshimura N, White G, Weight FF, de Groat WC. Different types of Na+ and A-type K+ currents in dorsal root ganglion neurones innervating the rat urinary bladder. J Physiol 494 (Pt 1) 1-16, 1996. 382. Yoshiyama M, Nezu FM, Yokoyama O, de Groat WC, Chancellor MB. Changes in micturition after spinal cord injury in conscious rats. Urology 54 (5): 929-33, 1999. 383. Yoshiyama M, Roppolo JR, De Groat WC. Alteration by urethane of glutamatergic control of micturition. Eur J Pharmacol 264 (3): 417-25, 1994. 384. Yoshiyama M, Roppolo JR, de Groat WC. Effects of LY215490, a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic



385. 386. 387.

388.

389. 390. 391.

acid (AMPA) receptor antagonist, on the micturition reflex in the rat. J Pharmacol Exp Ther 280 (2): 894-904, 1997. Yoshiyama M, Roppolo JR, De Groat WC. Interactions between NMDA and AMPA/kainate receptors in the control of micturition in the rat. Eur J Pharmacol 287 (1): 73-8, 1995. Zahner MR, Kulikowicz E, Schramm LP. Recovery of baroreflex control of renal sympathetic nerve activity after spinal lesions in the rat. Am J Physiol Regul Integr Comp Physiol 301 (5): R1584-90, 2011. Zhang Y, Guan Z, Reader B, Shawler T, Mandrekar-Colucci S, Huang K, Weil Z, Bratasz A, Wells J, Powell ND, Sheridan JF, Whitacre CC, Rabchevsky AG, Nash MS, Popovich PG. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J Neurosci 33 (32): 12970-81, 2013. Zheng JQ, Seki M, Hayakawa T, Ito H, Zyo K. Descending projections from the paraventricular hypothalamic nucleus to the spinal cord: Anterograde tracing study in the rat. Okajimas Folia Anat Jpn 72 (2-3): 119-35, 1995. Zhou JN, Hofman MA, Gooren LJ, Swaab DF. A sex difference in the human brain and its relation to transsexuality. Nature 378 (6552): 68-70, 1995. Zinck ND, Downie JW. Plasticity in the injured spinal cord: Can we use it to advantage to reestablish effective bladder voiding and continence? Prog Brain Res 152: 147-62, 2006. Zvarova K, Murray E, Vizzard MA. Changes in galanin immunoreactivity in rat lumbosacral spinal cord and dorsal root ganglia after spinal cord injury. J Comp Neurol 475 (4): 590-603, 2004.

1453

Autonomic hyperreflexia with spinal cord injury.

Chronic cervical spinal cord injury and autonomic hyperreflexia in rats.

Silencing spinal interneurons inhibits immune suppressive autonomic reflexes caused by spinal cord injury.

Spinal cord injury rehabilitation.

Spinal cord injury rehabilitation.

Spinal cord injury pain.

Acute spinal-cord injury.

Discovertebral (Andersson) lesion of the Ankylosing Spondylitis, a cause of autonomic dysreflexia in spinal cord injury.

The role of autonomic function on sport performance in athletes with spinal cord injury.

Cardiac arrest attributable to dysfunction of the autonomic nervous system after traumatic cervical spinal cord injury.

Assessment of clinical adherence to the international autonomic standards following spinal cord injury.

Pathophysiology of spinal cord injury.

Treatment of spinal-cord injury.

Epidemiology of spinal cord injury.

Estimating the autonomic function from heart rate variability in mechanically ventilated patients after spinal cord injury.

Patients with Chronic Spinal Cord Injury Exhibit Reduced Autonomic Modulation during an Emotion Recognition Task.

Complete spinal cord injury: an indication for spinal cord stimulation?

Influence of alcohol intake on the course and consequences of spinal cord injury.

Cardiovascular control, autonomic function, and elite endurance performance in spinal cord injury.

Mechanisms inducing autonomic dysreflexia during urinary bladder distention in rats with spinal cord injury.

Cardiovascular Dysfunction Presenting as Autonomic Dysreflexia in a Patient with Spinal Cord Injury.

High-resolution Anorectal Manometry for Autonomic Dysreflexia in a Patient With Incomplete Cervical Spinal Cord Injury.

Adiposity and spinal cord injury.

Thrombosis in spinal cord injury.