Losses and gains: chronic pain and altered brain morphology.

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THEMED ARTICLE y Pain

Review

Losses and gains: chronic pain and altered brain morphology Expert Rev. Neurother. 13(11), 1221–1234 (2013)

David Borsook*, Nathalie Erpelding and Lino Becerra Center for Pain and the Brain, P.A.I.N. Group, Boston Children’s Hospital, Harvard Medical School, c/o 9 Hope Avenue, Waltham, MA, USA *Author for correspondence: [email protected]

As in many fields of neuroscience, alterations in brain morphology, and specifically gray matter volume and cortical thickness, have been repeatedly linked to chronic pain disorders. Numerous studies have shown changes in cortical and subcortical brain regions suggesting a dynamic process that may be a result of chronic pain or contributing to a more generalized phenomenon in chronic pain including comorbid anxiety and depression. In this review, we provide a perspective of pain as an innate state of pain based on alterations in structure and by inference, brain function. A better neurobiological understanding of gray matter changes will contribute to our understanding of how structural changes contribute to chronic pain (disease driver) and how these changes may be reversed (disease modification or treatment). KEYWORDS: antidepressants • boutons • brain • connectivity • cortex • dendrites • dendritic tree • fMRI • opioids • thalamus • voxel-based morphology

Recent evidence from MRI studies suggests changes in brain morphology across chronic pain conditions [1–3]. Both increases and decreases in gray matter in various cortical and subcortical brain regions have been reported across studies as summarized in a recent metaanalysis in chronic pain disorders [4]. In the latter study, 12 brain regions had decreased gray matter volume, whereas two clusters had increased gray matter volume in patients compared to controls. However, the questions remain: how these changes take place in the context of chronic pain and how they can eventually be used for clinical or pharmacological therapeutic approaches. Additionally, it is unknown whether these alterations are related to other factors such as disease duration and/or age. Changes in brain morphology may also have an effect on brain function. Thus, the implications of understanding these changes in different chronic pain conditions are significant as they may provide a biomarker for disease state or treatment effects and may provide insights into the neurobiological underpinnings of changes in the nervous system that are related to chronic pain. In this review, three areas are discussed: evidence of brain morphological alterations in chronic pain where alterations in brain structure will be defined in chronic pain; measures of brain morphological

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10.1586/14737175.2013.846218

changes and our understanding of chronic pain where plasticity and structural brain changes will be discussed and neurobiological underpinnings, where potential neurobiological processes will be outlined that may contribute to morphometric changes. To do this, English language literature search of chronic pain and altered brain morphology using PubMed, was conducted. Keywords used included chronic pain plus gray matter, sMRI, white matter, voxel-based morphometry, CTA, FA, opioid, structural, morphological, neurochemical, peripheral pain and central pain. Additional strategies included manual searches for relevant articles from the selected papers’ reference lists as well as utilization of PubMed’s related articles function. Evidence of brain morphological alterations in pain

A number of clinical conditions produce brain alterations which may impact the chronic pain disorder. A few clinical examples are discussed which provide evidence for significant structural changes which may contribute to chronic pain disorders. Central pain syndromes

Classical examples where damage to the CNS results in pain include spinal cord injury

2013 Informa UK Ltd

ISSN 1473-7175

1221


Review

Borsook, Erpelding & Becerra

(SCI) [5] and stroke [6], involving regions such as thalamus and opercular insular region [7]. In most clinical cases, such damage is obvious and measurable, and affects afferent pain pathways such as the spinothalamic tract. Post-stroke pain occurs in a significant number of patients (19–74%) and remains persistent in some (1–8%) of the individuals [8]. Post-SCI pain (i.e., traumatic, inflammatory, neoplastic and degenerative) is present in significant numbers of patients [9]. While these two disorders are representative examples, many neurological and neurodegenerative disorders may also result in chronic pain [10]. Some, like Parkinson’s disease, alter brain chemistry as a result of structural brain changes that may ultimately result in chronic pain syndromes [11]. While these are ‘ forme fruste’ examples, it is also intriguing that some ablative processes such as cingulotomy [12] and thalamic ultrasound [13] may produce pain relief in uncontrolled trials and thus evidence that changes in brain structure or chemistry modify the behavioral manifestation of the underlying chronic pain condition. Peripheral pain syndromes

There are clinical studies demonstrating that peripherally induced pain syndromes (e.g., diabetic neuropathy, osteoarthritis, complex regional pain syndrome, etc.) change the brain both functionally and structurally. A recent meta-analysis on structural changes in chronic pain conditions has shown multiple regions being affected [4]. Including 23 studies on a total of 490 patients and 509 healthy control subjects, 12 clusters with decreased gray matter volume have been identified in patients, including regions that are thought to be implicated in pain processing such as thalamus, insula, anterior cingulate cortex, inferior frontal gyrus and putamen, but also had brain areas that are not implicated in pain-processing (e.g., superior frontal gyrus, middle frontal gyrus). Contrary, the parahippocampal gyrus and hippocampus had increased gray matter volumes in patients, likely involved in pain modulation, pain sensitivity and anxiety. Consequently, because several brain regions were significantly increased or decreased in these chronic pain patients that are classically not involved in pain processing, the authors suggest that these brain regions may be involved in comorbid symptoms such as cognitive and emotional dysfunctions and/or chronic fatigue. Additionally, the study results impressively indicate that multiple brain regions seem to be structurally altered in chronic pain disorders that may be dependent on the chronic pain condition, its duration, genetic markup, etc., emphasizing the need for a better characterization of different chronic pain types. Immune-related pain syndromes

Immune-related diseases may produce alterations in brain structure. For example, immune-related changes in brain structure are represented by multiple sclerosis where pain is a common manifestation experienced in 75% of patients [14]. Additionally, immune- or cytokine-induced changes in chronic pain have been suggested by a number of investigators [15–17]. Underlying changes produced by neuroimmune insults are represented in 1222

the acute manifestation of influenza producing generalized pain [18]. Furthermore, Crohn’s disease – a form of inflammatory bowel disorder characterized by an overproduction of inflammatory enzymes – was shown to have morphological changes in cortical and subcortical structures [19]. However, it remains unclear whether chronic pain drives structural brain changes or whether a cascade of immunological processes has detrimental effects on neurons and glia, thereby modifying gray and white matter in the brain. Acute pain versus chronic pain

Brain alterations seem to differ based on the nature of pain (i.e., chronic vs acute). Several studies have investigated gray matter changes under repeated acute pain. For example, Teutsch et al., [20] have shown that repeated painful stimulation over 8 consecutive days induced gray matter increases in painrelated brain regions such as midcingulate cortex, medial temporal cortex, premotor cortex and parietal lobule, which disappeared after the repeated stimulation had stopped. Another study investigating cortical correlates of thermal pain sensitivity revealed that greater sensitivity to heat and cold pain correlated with cortical thickening in the primary somatosensory, midcingulate and orbitofrontal cortices, thereby providing evidence for a neural basis of interindividual differences in pain sensitivity [21]. These findings also relate to recent experimental results demonstrating that healthy subjects who had to perform a difficult cognitive task under concurrent pain, some individuals focused more on pain (i.e., measured with slower reaction times in cognitive task) which correlated with greater gray matter in brain regions related to pain (e.g., anterior insula, anterior midcingulate cortex, thalamus and caudate) compared to subjects whose task performance increased during painful stimulation [22]. Accordingly, studies investigating acute pain and its impact on gray matter of healthy volunteers may give important insight into the relationship between chronic pain disorders and structural brain changes, and importantly, may eventually be used as predictors for identifying individuals with higher risk of developing chronic pain. These study findings suggest that there are probable premorbid factors, for example, predisposing factors that determine individuals as more sensitive or more pain-oriented than others. In addition to possible preexisting abnormalities, there is evidence that gray matter changes may also result as a function of persistent pain, for example, gray matter volume in the thalamus correlated positively with the pain duration in patients with temporomandibular disorder [23]. Other studies suggest that gray matter changes are reversible after successful recovery from chronic pain [1,24–26]. Depression & pain

Interestingly, a number of patients with major depressive disorder (MDD) develop chronic pain over the course of their condition. MDD patients were shown to have significantly lower gray matter volumes in the amygdala, the dorsal frontomedial cortex and the paracingulate cortex compared to healthy Expert Rev. Neurother. 13(11), (2013)


Chronic pain & altered brain morphology

controls [27]. Additionally, a recent meta-analysis indicated that patients with MDD show gray matter volume reductions in the anterior cingulate cortex, middle and inferior frontal gyrus, hippocampus and thalamus [28], brain regions involved in emotional and cognitive processing, stress responsiveness, as well as pain processing. Accordingly, this finding raises the question whether comparable brain changes are involved in seemingly disported disorders, for example, whether changes in the hippocampus can be interpreted as stress-related processes in both depression and pain. Hence, it is conceivable that brain regions involved in chronic pain may contribute to the evolution of comorbid disorders as a result of structural and functional brain changes. Medication

There is both experimental and clinical evidence that drugs induce long-lasting structural changes in chronic pain syndromes. For example, opioid-induced hyperalgesia [29], altered pain thresholds in methadone addicts [30,31] and drug refractory headache [32] which strongly suggest that repeated and high doses of medication induce morphological changes. Additionally, clinical studies provide evidence that prolonged opioid use induces significant changes in brain structure and function [33,34] and that many of these morphine-induced changes were persistent even months after cessation of the drug [35]. In addition to gray matter changes, high doses of opioids produce significant changes in white matter tracts [36–39], and even though these leukoencephalopathies are usually reversible, they may have long-term consequences on brain structure and function [38,40,41]. Finally, certain drug effects may now be considered as altering neural circuits as, for example, the use of antidepressants or anticonvulsants (e.g., lamotrigine) may alter neural connectivity through dendritic sprouting [42–44]. The issue of drug-induced neurogenesis is discussed in more detail in the section on neurobiological underpinnings below.

Review

were related to pain decrease and increased overall function. Accordingly, these findings: suggest a direct relationship between the brain structure and chronic pain states, emphasize the dynamic nature of gray matter changes and may eventually be used as a marker for a ‘restored’ brain in pain-free states. Measures of structural brain changes & our understanding of chronic pain Lessons learned from chronic pain syndromes

A number of lessons can be learned from clinical insights in which gray matter alterations have been linked to chronic pain. First, structural and functional neural circuits and brain function are altered as a result of a chronic pain morphometricphenotype [3]. Second, morphological alterations may underlie transition from chronic pain to pain relief [1,24–26]. Third, paininduced changes may depend on the chronic pain duration [23] and intensity of the pain [45] potentially contributing to changes in central sensitization [46] and centralization of pain [47]. Plasticity in the healthy brain

Neurosystems research has suggested that the brain is highly plastic [48]. For example, alterations in gray matter volume have been observed as a result of juggling [49], golf training [50], music [51], education [52] and extensive learning [53,54] in healthy individuals. As noted above, similar ‘training’ with acute pain stimuli also produces measureable changes in gray matter volume [20]. Additionally, training can also induce changes in white matter architecture [55]. Together, these data indicate that the healthy brain constantly undergoes dynamic morphological alterations. Although the exact underlying processes of structural brain changes remain unknown, there is evidence that gray matter changes could be due to alterations in cell volume, synaptic densities, cerebral blood flow and/or interstitial fluid [56–58]. Plasticity in chronic pain

Reversal of chronic pain syndromes: correlation with morphological changes

A number of studies have provided data showing reversal of gray matter changes in patients with chronic pain disorders following pain relief [1,24–26]. For example, Seminowicz et al., [24] were able to show significant gray matter increase after successful treatment in patients with chronic back pain after successful surgery, and interestingly, dorsolateral prefrontal cortex thickening correlated with reduction of pain and physical disability, increased primary motor cortex thickness was associated with lower physical disability and anterior insula gray matter thickness was correlated to pain reduction. Similarly, patients with chronic pain due to hip osteoarthritis exhibited gray matter reductions in the dorsolateral prefrontal cortex, anterior cingulate cortex and insula before surgery, which reversed to comparable gray matter thickness in healthy controls after successful surgery and alleviation of the pain [1,26]. Another study in patients with osteoarthritis [25] reported gray matter decreases in the thalamus which were reversed after hip arthroplasty and www.expert-reviews.com

Gray matter volume may be increased or decreased in chronic pain disorders [4] or may change as a result of pain relief [1,24– 26]. Most studies suggest a decrease in gray matter volume in chronic pain [4], however, to date, there are contradictory gray matter volume changes in different pain syndromes (FIGURE 1A). TABLE 1 summarizes the regions shown to have significant changes in brain morphology [4]. In humans, subcortical (e.g., nucleus accumbens, caudate nucleus and thalamus) and cortical regions (e.g., dorsolateral prefrontal cortex and medial prefrontal cortex) have shown alterations in gray matter volume implicating a brain-wide response to chronic pain [4]. The questions remain whether these structural changes can be considered adaptive or maladaptive in chronic pain disorders and how specific they are for the different groups of pain syndromes. Interestingly, in some brain regions, the structural changes in chronic pain may seem rational. For example, cortical thickening in the somatosensory cortex [59] or decreased gray matter volume in the hippocampus [60] have been reported in persistent migraine. These structural changes in the somatosensory 1223

Review


Macroscopic (VBM) regional changes in health and disease


Somatosensory cortex

Insula Anterior

Posterior

Macroscopic (VBM) reversal of changes in chronic pain with treatment

Healthy

Chronic pain (untreated)

Chronic pain (treated)

No pain

Figure 1. Dynamic changes in structural brain measures of chronic pain. (A) Macroscopic (VBM) regional changes in health and disease: Dynamic changes in the same region (e.g., primary somatosensory cortex) may be increased (e.g., migraine) or decreased (e.g., in chronic pain) (TABLE 1). (B) Macroscopic (VBM) reversal of chages in chronic pain with treatment: Chronic pain disorders predominantly show gray matter decreases, which are reversible upon successful recovery and pain relief. VBM: Voxel-based morphmetry.

cortex may be analogous to gray matter increases due to repeated exposure to pain [20], as recurrent migraine attacks may drive increased cortical thickness in brain regions involved in sensory aspects of pain processing. This corroborates rapid alterations in brain structure in acute pain syndromes such as menstrual pain (dysmenorrhea) [61]. Contrary, somatosensory cortices showed no thinning in chronic trigeminal neuropathy [62] and no thickness changes in other disorders such as chronic pancreatitis [63]. Decreased gray matter volume and increased functional activity in the hippocampus in migraine [60] may result from chronic stress due to chronic pain and is potentially mediated by cortisol [64] and cytokines [65]. Cortisol-induced changes may not occur without the presence of stress [66]. In fact, there is evidence that cortisol may be permanently elevated in chronic pain [67] and the response may thus be blunted in conditions where hippocampal alterations or damage are present [68]. Additionally, glucocorticoids can also act as pro-inflammatory agents in the CNS [69]. Although some cytokines may exert protective functions [70], immune systems modulate dendritic morphology and physiology [71] and pro- and anti-inflammatory cytokines may have detrimental effects on the brain [72]. These examples provide evidence that ongoing stressors may induce an imbalance and/or maladaptation in the allostatic load [73,74] and may therefore be implicated in chronic pain conditions [67,75]. Recent evidence that epigenetic factors may contribute to long-lasting pain by facilitating IL-6 dependent changes in astrocytes [76] indicates that the 1224

complex nature of processes may take place even after micro-injury to neural systems. Furthermore, chronic pain-like behavior may induce IL-1 in the hippocampus [77] and other brain regions (prefrontal cortex) following nerve injury [78]. In summary, chronic pain is likely driven by a complex interaction of adaptation (i.e., gray matter changes due to increased nociceptive drive) and maladaptation processes (i.e., stress and immune system), however, to date, the importance of other factors such as age, disease duration, chronicity, reversal and/or drug effects on brain plasticity have not been sufficiently addressed and are needed to enhance our understanding of the ‘vulnerability’ of pain-related brain regions. Treatment-induced plasticity

Plastic changes in the brain can be induced with medication (see Medication and FIGURE 1B). Although not fully understood, it is believed that targeting receptor or neurotransmitter processing may indirectly affect dendritic activity. Two examples of neurotrophic effects of drugs used as analgesics are discussed below.

Antidepressants

Many antidepressants have a lag time between drug administration and therapeutic effect. This discrepancy has led to the hypothesis that antidepressants induce alterations in dendritic morphology [42] which then causes neurotrophin changes in brain regions implicated in depression such as hippocampus, nucleus accumbens and prefrontal cortex [79]. Some antidepressants are able to restore plasticity in some brain regions [80]. In animal models of depression, antidepressants (viz., amitriptyline) have an effect on dendritic spines by reversing (increasing) spine density [81]. Opioids

Unlike antidepressants, opioids may have deleterious effects on dendritic spine integrity. For example, opioids including morphine produce a collapse of dendritic spines whereas [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and the semisynthetic opioid and highly potent m-receptor agonist etorphine, may lead to the development of new dendritic spines [82]. In addition to the loss of dendritic spines induced by morphine, there may also be an associated loss of excitatory (a-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid; AMPA) synapses [83]. Most excitatory synapses occur on dendritic spines [84]. Accordingly, alterations of dendritic spines may contribute to observed decreases in gray matter volume in patients taking opioids [34]. Expert Rev. Neurother. 13(11), (2013)


#

#

Migraine

#

#

#

#

#

TMD

TMD

TN

TN

"

"

"

""CBP

CBP

"

"

#

#

#

dlPFC

#

FP

#

#

IFG

#

M1

#

#

mPFC

#

#

OFC

Cortical changes

#

PH

"

"

"

#

#

#

pIns

"

#

PM

#

A

#

Cau

#

Cer

"

GP

H

"

NAc

"

Put

"

T

#

#

#

#

"

"

#

"

#

#

#

"

#

#

#

#

#

#

#

[164]

[163]

[162]

[161]

[160]

[159]

[158]

[157]

[156]

[155]

[154]

[153]

[152]

[151]

[150]

[149]

[148]

[147]

[146]

[145]

[144]

[143]

#

vmPFC

"

#

STG

[142]

#

S2

Ref.

#

S1

Subcortical changes

The studies are sorted by disorder followed by the citation. # denotes gray matter decreases and " denotes gray matter increases in cortical and subcortical regions. A: Amygdala; ACC: Anterior cingulate cortex; aIns: Anterior insula; Cau: Caudate; CBP: Chronic back pain; Cer: Cerebellum; CRPS: Complrex regional pain syndrome; CTS: Carpal tunnel syndrome; dlPFC: Dorsolateral prefrontal cortex; FM: Fubromyalgia; FP: Frontal pole; GP: Globus pallidus; H: Hypothalamus; HF: High-frequency; HSV: Herpes simplex virus; IBS: Irritable bowel syndrome; IFG: Inferior frontal gyrus; LF: Low frequency; M1: Primary motor cortex; mPFC: Medial prefrontal cortex; NAc: Nucleus accumbens; OA: Osteoarthritis; OFC: Orbitofrontal cortex; PH: Parahippocampus; pIns: Posterior insula; PM: Premotor cortex; PP: Pelvic pain; Put: putamen; S1: Primary somatosensory cortex; S2: Secondary somatosensory cortex; STG: Superior temporal gyrus; T: Thalamus; TMD: Temporomandibular disorder; TN: Trigeminal neuralgia; vmPFC: Ventromedial prefrontal cortex.

"

#

CBP

CBP

CBP

Affecting the back

Limb Amputation

Limb Amputation

CTS

CRPS

Affecting the limbs

#

#

"

TMD

#

#

#

Migraine (no Aura)

TN

"

#

Migraine (HF vs LF)

"

#

#

Migraine

Migraine (HF vs LF)

#

aIns

#

#

ACC

Migraine

Migraine

Facial pain (Idiop.)

Affecting the head

Disorder

Table 1. Cortical and subcortical gray matter changes in chronic pain disorders.



Review

1225

1226

ACC

"

"

"

"

FM

FM

#

#

dlPFC

FP

"

IFG

M1

"

"

mPFC

OFC

Cortical changes

"

"

PH

"

pIns

PM

S1

S2

STG

"

vmPFC

"

"

"

"

#

A

"

Cau

Cer

"

GP

"

"

H

Subcortical changes

"

NAc

"

Put

"

"

"

T

[178]

[177]

[176]

[175]

[174]

[173]

[172]

[171]

[170]

[169]

[168]

[167]

[166]

[165]

Ref.

The studies are sorted by disorder followed by the citation. # denotes gray matter decreases and " denotes gray matter increases in cortical and subcortical regions. A: Amygdala; ACC: Anterior cingulate cortex; aIns: Anterior insula; Cau: Caudate; CBP: Chronic back pain; Cer: Cerebellum; CRPS: Complrex regional pain syndrome; CTS: Carpal tunnel syndrome; dlPFC: Dorsolateral prefrontal cortex; FM: Fubromyalgia; FP: Frontal pole; GP: Globus pallidus; H: Hypothalamus; HF: High-frequency; HSV: Herpes simplex virus; IBS: Irritable bowel syndrome; IFG: Inferior frontal gyrus; LF: Low frequency; M1: Primary motor cortex; mPFC: Medial prefrontal cortex; NAc: Nucleus accumbens; OA: Osteoarthritis; OFC: Orbitofrontal cortex; PH: Parahippocampus; pIns: Posterior insula; PM: Premotor cortex; PP: Pelvic pain; Put: putamen; S1: Primary somatosensory cortex; S2: Secondary somatosensory cortex; STG: Superior temporal gyrus; T: Thalamus; TMD: Temporomandibular disorder; TN: Trigeminal neuralgia; vmPFC: Ventromedial prefrontal cortex.

Opioids

Opioids

Drugs

HSV

#

"

IBS

Infection and pain

"

IBS

Gastrointestinal

"

"

#

#

aIns

"FM

Generalized syndrome

OA (Hip)

OA (Hip)

#

#

PP (Men)

Affecting the joints

#

PP (Women)

PP (Men)

PP (Vulvar)

Affecting the pelvic region

Disorder

Table 1. Cortical and subcortical gray matter changes in chronic pain disorders (cont.).


Review Borsook, Erpelding & Becerra

Expert Rev. Neurother. 13(11), (2013)


Review

Chronic pain

Microscopic (dendritic) changes

Neurobiological underpinnings: dendrites & gray matter volume

The dynamic changes observed in gray matter seem to relate to alterations in dendritic spine volume observed in animal models. The analogy is that of a deciduous tree in summer (thicker, increased volume) vs winter (thinner, decreased volume). Multiple regions have altered gray matter volume in animal models of chronic pain [87] and one report supports alterations in dendritic complexity in a model of neuropathic pain [88]. Similar changes have been reported in stress in mice correlating gray matter loss with dendrites and their synapses (FIGURE 2) [89]. However, changes in dendritic spine anatomy are not unique to chronic pain and are postulated in other neurological/ psychiatric conditions such as depression [90] and mild traumatic brain injury [91]. Processes involved in driving dendritic complexity including pruning, altered bouton numbers and micro-connectivity provide insights into processes that contribute to alterations in gray matter in chronic pain [88]. Synaptic plasticity drives dendritic morphological plasticity [92]. Such changes may result in long-term alterations in circuit function. Depending on the nature of the changes, increased dendritic activity results in synaptic amplification in response to synaptic inputs [93]. Larger spines seem to be more permanent and smaller spines are thought to be transient [93], suggesting that the memory or persistent function (ongoing activity) is related to their state and anatomy and that without activity, these less wellformed dendritic spines may collapse. Changes in dendritic spines underlie changes in synaptic strength that may be altered, sometimes rapidly, by aging [94], gender [95], stress [96], pharmacological agents [97], the environment [98] and disease [99]. Some of these examples are discussed in the context of chronic pain below. Aging

The young brain generally responds better to chronic pain in terms of incidence and outcome and propensity for chronification [99,100]. The developing brain is assumed to be more plastic. In monkeys, there is an age-related decrease in spinal numbers and density [101]. Thus, it is possible that neurons are more adaptive in the young brain, and additionally, there may be more ‘protective’ mediators, for example T-lymphocytes [102], in young children, thus reducing the risk for chronification of www.expert-reviews.com

Decreased VBM

Increased VBM Basal Apical

Macroscopic (VBM) changes

Dendritic tree

For in vivo measurement of changes in brain morphology, the only currently available technique is MRI-based. The advent of higher strength magnetic field scanner together with more powerful analysis techniques will allow to further push the limit of resolution to determine morphometric changes [85,86] as most of the current limitations are related to the relatively low spatial resolution (typical around 1 mm in 3 Tesla MRI scanners). Additionally, when combining brains from different subjects it is challenging to precisely match brain structures, especially gyri and sulci. Although higher field MRI systems allow spatial resolutions in the micron range, the resolution is likely not high enough to distinguish cytological architecture.

Axon


Technical aspects & limitations of structural measures

Figure 2. Neural underpinnings of gray matter changes in chronic pain. (A) Macroscopic (VBM) changes: chronic pain results in alterations in gray matter volume; most studies report a decrease in gray matter volume (TABLE 1). (B) Microscopic (dendritic) changes: putative alterations in dendritic tree morphology (spine complexity and density) in neurons corresponding to regions with gray matter volume loss and those with increased gray matter volume. The changes also involve the size of dendritic boutons, relative number of branches at the basal and apical portions of the dendrite. VBM: Voxel-based morphmetry.

pain. However, no studies on morphometric changes in chronic pain in children have been reported. In adolescent hamsters, regions such as the hippocampus undergo rapid morphological changes that include pruning of dendrites proximal to the cell body, and increases in spine densities more distal to the cell body in some regions of the structure [103]. Similar alterations during adolescence have been reported in the amygdala [104]. Accordingly, a better understanding of gray matter plasticity in development and in chronic pain may provide novel insights into potential mechanisms for disease protection and reversal. Gender

Differences in gender-related incidences of chronic pain has been documented in a number of studies [105–107]. Estradiol promotes dendritic spine growth [108]. The effects of gonadal steroids on regions such as the amygdala includes an increased number of spines in adult males and rapid changes of dendritic density in adult females across the estrous cycle [109]. These data are supported by rapid gray matter changes occurring across the menstrual cycle [61]. The female brain may therefore be ‘at risk’ because of the dynamic pattern of dendritic plasticity. Sensory systems may be hypersensitive [110] and chronic pain syndromes may be exacerbated by menstrual period [111,112]. Most dendritic spines are excitatory in nature and the basis for the hyperexcitable state may be based on the modification of these dendritic systems. Consistent with these findings is the observation that ovariectomy trims dendritic spines in the rat’s somatosensory regions [113]. 1227

Review

PNS damage


Chronic pain + Comorbidity

Healt Healthy

Cytokines are also involved in disorders of the CNS in chronic pain conditions [123]. CNS damage

Central sensitization and centralization of pain


Age

Duration of illness

Physical activity

Gender

Figure 3. Dynamic model of gray matter alterations in chronic pain. (A) Following peripheral nervous system (PNS or central nervous system (CNS(usually along the spino-thalamic pathways) damage, chronic pain may manifest as a progressive condition with neurobiological processes enhancing pain experience (central sensitization) as well as the evolution of comorbidities (e.g., depression) as a result of centralization of pain which may also alter circuits and contribute to the chronic pain syndrome. (B) Changes in gray matter structure are modulated by genetic, epigenetic and environmental (e.g., age and physical activity) and physiological (e.g., immune and stress systems) factors.

Stress

Stress may be a major contributor to chronic pain [114]. Stressrelated modulators such as stress hormones (i.e., cortisol) and cytokines are known to alter dendritic spines [71]. A recent study investigating the relationship between chronic pain and increased cortisol levels provides some insights to the process since it was the study to address a correlation with ongoing stress-related changes in gray matter [67]. However, these modulators may be more subtle and persistent in their effects on behavior in determining allostatic load through multiple changes on brain networks [74,75,115]. Peripheral increases in the cytokine TNF-a may lead to rapid changes in dendritic spines in the somatosensory cortex [116]. Microglia are involved in synaptogenesis by releasing immune mediators (e.g., cytokines) that modulate synaptic transmission by altering morphology of dendritic spines [71]. In addition, microglia play an important role in modulating brain circuitries, for example, their involvement in synaptic pruning during development [117]. They are also implicated in protective and pathological processes in chronic pain [15,118]. Repeated stress through lipopolysaccharide (LPS) administration induces multiple cytokine and immune cascades and affects microglia and dendritic spines that may be sustained for a long period [119]. In mice, stress-induced changes in gray matter may be due to a loss of dendrites and their synapses in the anterior cingulate cortex and hippocampus [89]. Similar changes in the anterior cingulate cortex have been reported in post-traumatic stress disorder (PTSD) [120,121]. 1228

[122]

and

Dendritic morphogenic & anti-morphogenic effects of analgesics

Some drugs may affect dendritic integrity. These changes may be considered to be morphogenic (i.e., enhance dendritic spine integrity) or anti-morphogenic (i.e., induce abnormal dendritic changes). Some pharmacological agents (i.e., analgesics) have seemingly beneficial effects on dendrite morphology. Antidepressants are among the most effective agents in chronic pain [124,125], likely by inhibiting stress-induced release of glutamate [126]. Additionally, there is evidence in role of amitriptyline acting as a morphogenic agent, as for example, chronic amitriptyline reverses decreased dendritic spine density in the olfactory bulbectomized, a postulated model of depression in rats [81]. Amitriptyline also has a powerful neurotrophic activity [127]. Other analgesics such as morphine are also considered to alter dendritic morphology [128–130], and may be responsible for altered neural circuit function and gray matter volume following chronic opioid use [34]. Morphine withdrawal may also reduce spine density and be persistent in nature [129]. In summary, these observations have significant implications for drug use that may compromise neural circuit function in chronic pain and reward circuitry [128]. Other drugs such as ketamine, purported to have significant and rapid effects on chronic pain [131], may also alter dendritic synaptogenesis given that Nmethyl-D-aspartate (NMDA) receptor antagonist rapidly reverses dendritic atrophy [132,133]. However, this issue is clearly more complex since chronic ketamine use can induce significant neuronal injury and behavioral changes [134]. White matter changes

it is not possible to think that gray matter changes are not associated with concomitant changes in white matter structure and integrity. For instance, axonal sprouting could result in increased connectivity across brain substrates and could be reflected as increased fractional anisotropy [135]. Geha et al. [156] demonstrated disrupted gray matter-white matter interactions in patients with complex regional pain syndrome (CRPS), thus indicating that gray matter changes coincide with significant white matter changes in chronic pain. Correlations with peripheral nerve damage and alterations in gray matter have been reported with concomitant alterations in white matter integrity in these foci [136]. Taken together, complex processes may act on dendritic spine morphology. Circuit strength and, by inference, circuit function is highly dependent on the integrity and functional status of dendrites [137]. As an example, epigenetic modifications can regulate dendritic morphology in animal models of stress and depression [138]. As noted by Hofer and colleagues, “Experience leaves a lasting structural trace in cortical circuits” whereby prior interoceptive and exteroceptive information alters the nature of behavior [139]. Thus, the correlation between functional activity and synaptic plasticity can be understood in the Expert Rev. Neurother. 13(11), (2013)

Expert commentary & five-year view

Synaptic drive

Adaptive

Maladaptive

Region 1

Connectivity

context of chronic pain. Imaging studies have reported a correlation in the same subjects of altered function (activation) and structure (cortical thickness or subcortical volume) [59,62], emphasizing the importance of further understanding the nature of dendritic changes and how they may disrupt circuit function and thus alter behavior (i.e., chronic pain). An interesting example of specific dysfunction is that right insula gray matter loss in patients with neurocardiogenic syncope correlates with the putative loss in sympathetic and increase in parasympathetic function [140]. Although it may be intuited that gray matter volume is a direct result of dendritic pruning, decreased complexity and size of dendritic spine, the correlation of function in chronic pain still remains elusive.

Review

Region %

Brain networks



Disease 1

Disease 2

Disease 3

Disease 4

Figure 4. Dynamic changes in dendritic tree complexity in chronic pain. (A) Syn-

aptic drive: synaptic strength is correlated with the complexity of dendritic tree. Neurons Changes in brain circuits can produce with a pruned dendritic tree may have a decreased synaptic strength compared with a axonal sprouting, dendritic morphology neuron with a complex dendritic tree (indicated by thickness of). For example, repetitive changes and alterations in synaptic conpainful stimulation induces adaptive dendritic changes and cessation of nociceptive drive nectivity as noted correctly in the title of will lead to reversal of dendritic changes. In chronic pain, progressive pruning or dismana paper: “Cutting your nerve changes tling of dendritic complexity may result in a maladaptive neural activity that may ‘poison’ dendritic systems through excitotoxic means (most of the dendritic synapses are excitayour brain” [141]. We propose that tory in nature). (B) Connectivity: dendritic architecture (resulting in increased or diminchronic pain may be viewed as primary, ished synaptic drive) within a brain region impacts its interaction with other brain areas. secondary and tertiary cascades that Increased connectivity results between brain regions with increased synaptic drive, modify the brain and reconstitute neural whereas decreased connectivity exists between brain regions with diminished synaptic networks that define individual behavior. drive. Red and thicker arrows: greater gray matter volume; Blue and thinner arrows: thinner gray matter volume. (C) Brain networks: altered resting state network activity is The first cascade is the initiating event a consequence of structural changes that induce behavioral consequences in the disease on the brain as a result of an injury state, for example chronic pain, providing a morphological signature from chronic (traumatic, metabolic, etc.); the second pain [179]. cascade is the brain’s response that may adapt leading to a healthy state after recovery or maladapt leading to ‘central sensitization’ of whether behaviorally, biochemically (pharmacologically) or the system and chronic pain; the third cascade is the based on interventions (e.g., brain stimulation) and ii) how ‘centralization of pain’ inducing (secondary) comorbid these interventions affect neural networks to ultimately modchanges which are not primarily sensory in nature but may ify abnormal brain circuits [3] in chronic pain. induce alterations in emotion, cognition, sense of self, suffering, hedonic state, etc, ultimately leading to pain chronfica- Acknowledgement tion that may include treatment refractoriness or The authors would like to thank R Veggeberg for the preparation of the resistance (FIGURE 3). These cascades may be modulated by den- references. dritic spine homeostasis and may define treatments (i.e., pharmacological, neurobehavioral, and so on). As such, syn- Financial & competing interests disclosure aptic drive is defined at the level of individual neurons and This article supported by a grant from NINDS (K24 NS064050) and the their dendritic integrity, therefore it is likely that synaptic Mayday Fund/Herlands Pain Neuroscience Fund. The authors have no other activity gets altered in disease states (FIGURE 4). Since adapted relevant affiliations or financial involvement with any organization or entity and maladapted dendrites may significantly impact the con- with a financial interest in or financial conflict with the subject matter or nectivity of brain networks and brain states (FIGURE 4), it may materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this be an exciting prospect for future effective therapies to understand: i) how to therapeutically manipulate brain states, manuscript. www.expert-reviews.com

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Review


Key issues • Alterations of gray matter volume in cortical and subcortical regions are present in patients with chronic pain. • The alterations are plastic and dynamic and show reversal with clinical remission of pain. • The alterations seem to depend on neural activity that may increase or decrease dendritic complexity/density. Activity depending changes correlate with such changes. • Changes in dendritic ‘connectivity’ have a significant effect on the behavioral expression (i.e., sensory, emotional and cognitive) and impact pain sensitization and centralization of pain. Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by National University of Singapore on 05/24/14 For personal use only.

• Further understanding of the neurobiological underpinnings will provide insight for treatment improvement.

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p53 mutations: gains or losses?

Kids, candy, brain and behavior: age differences in responses to candy gains and losses.

Association between Stock Market Gains and Losses and Google Searches.

The value of exercising control over monetary gains and losses.

Welfare gains and losses caused by clinical practice guidelines.

Current topic: Hox genes: losses, gains and targets.

Abdominal Pain, the Adolescent and Altered Brain Structure and Function.

Touch Perception Altered by Chronic Pain and by Opioid Blockade.

Altered pain sensitivity in elderly women with chronic neck pain.

Divergence and Convergence of Risky Decision Making Across Prospective Gains and Losses: Preferences and Strategies.

Copy-neutral loss of heterozygosity and chromosome gains and losses are frequent in gastrointestinal stromal tumors.

Loss restlessness and gain calmness: durable effects of losses and gains on choice switching.

Surficial gains and subsoil losses of soil carbon and nitrogen during secondary forest development.

Blastocystis Mitochondrial Genomes Appear to Show Multiple Independent Gains and Losses of Start and Stop Codons.

I owe you: age-related similarities and differences in associative memory for gains and losses.

Partial Adaptation of Obtained and Observed Value Signals Preserves Information about Gains and Losses.

Delay discounting of gains and losses, glycemic control and therapeutic adherence in type 2 diabetes.

Gains, losses and lateral differences in the hearing of schizophrenic patients.

Linking altered central pain processing and genetic polymorphism to drug efficacy in chronic low back pain.

Depression Risk Predicts Blunted Neural Responses to Gains and Enhanced Responses to Losses in Healthy Children.

The Role of Anticipated Gains and Losses on Preferences About Future Caregiving.

The Trans-Pacific Partnership Agreement and health: few gains, some losses, many risks.

Contrasting losses and gains increases the predictability of behavior by frontal EEG asymmetry.

Relative gains, losses, and reference points in probabilistic choice in rats.