Curr Neurol Neurosci Rep (2015) 15:52 DOI 10.1007/s11910-015-0575-8

DEMENTIA (KS MARDER, SECTION EDITOR)

TMS as a Tool for Examining Cognitive Processing Naomi Nevler 1,2 & Elissa L. Ash 1,2

# Springer Science+Business Media New York 2015

Abstract Transcranial magnetic stimulation (TMS) is a noninvasive method where an externally placed, rapidly changing magnetic field causes induction of weak electric currents that lead to changes in neuronal polarization and activity. TMS is a modality that has emerged as a unique tool in the study of functional neuroscience for several reasons. TMS can be used to selectively activate or inhibit specific cortical structures, leading to transient perturbations in their function. Systematic study of these perturbations has been employed to determine the function of specific cortical structures and to investigate structure-function relationships. These studies extend to the functional mapping of brain structures as well as brain networks. While TMS was first validated in studies of motor cortex function, it has been applied to the study of cognition and cognitive processing. BVirtual lesions^ can be transiently induced in areas of eloquent cortex that allow for the evaluation of their function in cognition and behavior and can be used to evaluate the modes and hierarchy of control of these functions. When TMS is delivered in a repetitive fashion, long-term alterations of cortical function are induced which can be used to study functional brain plasticity, and the changes in brain plasticity in different cognitive states, This article is part of the Topical Collection on Dementia * Elissa L. Ash [email protected] Naomi Nevler [email protected] 1

Center for Memory and Attention Disorders, Department of Neurology, Tel Aviv Medical Center, 6 Weizmann st., 64239 Tel Aviv, Israel

2

Sackler Faculty of Medicine, Tel Aviv University, 69978 Ramat Aviv, Israel

including aging and diseases involving cognition. Furthermore, repetitive TMS strategies have been developed as possible modulators of cognitive function, with potential to serve as cognitive enhancers in both healthy and disease states. In this review, specific attention is given to the use of TMS in the evaluation of neurophysiologic changes in Alzheimer’s disease (AD), as well as the potential role of TMS as a cognitive enhancing therapy in AD. Keywords TMS . Cognitive function . Memory . Learning . Plasticity . Attention . Alzheimer’s disease . LTP . LTD . Functional connectivity . Brain networks

Introduction Transcranial magnetic stimulation (TMS) is performed by the passage of an electrical current through a coil of wire, which generates a magnetic field perpendicular to the flow of electricity through the coil. This field enters painlessly through the skull and leads to the generation of an electrical field within the brain tissue. TMS thus causes passive electrical stimulation of neural tissue. In the early 1980s, Merton and Morton first stimulated the human motor cortex non-invasively, using scalp electrodes [1]. Barker introduced the possibility of performing the same stimulation using magnetic rather than electrical methods [2], thus reducing the scalp discomfort associated with electrical currents. The magnetic coil induces electrical currents within the cerebral cortex that run in parallel to the coil. Neurons are activated by these currents according to their relative tangentiality to the current. Early coils were round shaped and induced the greatest currents at their periphery, while at the center, the electrical activity was zero. Changing the coil parameters, such as shape and metal type, enables flexibility, thus enabling modulation of the electrical field and

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its effects within the cortex [3, 4]. Superficial coils with a round or figure of eight configuration are able to provide magnetic fields that enter to a depth of 1–3 cm. Further innovations have lead to the development of the H-coil that enables the TMS pulse to reach to a range of 4–6 cm within the brain. [3]. The new H-coil has been tested and showed good safety and tolerability [5–7]. TMS has an overall excellent safety profile; theoretical considerations include possible seizure induction, hearing loss (TMS pulses produce a clicking sound (90–130 dB), frequency range (2–7 kHz), local head or neck discomfort, tissue heating, and effects of induced voltage on metallic implants. These risks are dependent on the number of pulses and on the intensity of stimulation. TMS is avoided in subjects with brain or cochlear implants, but clinical experience shows that it is safe if an appropriate distance between the coil and the stimulus generator and electronic components is respected, including in patients with metallic implants in the mouth cavity. Full safety information and guidelines have been published [8, 9].

TMS Techniques and Their Effects on Neuronal Physiology TMS was first used to map the motor cortex, but the same technique may be applied to any part of the cortex. TMS is a powerful technique that can be used to map cognitive function and to intervene in cognitive processes [10]. It is possible to stimulate individual muscles or muscle groups to contract via TMS over the primary motor cortex. We have included a table of the important parameters that are used in TMS experiments to measure cortical responses (Table 1). The muscle contraction created by the cortical stimulation is called the motor evoked potential (MEP). Stimulating different parts of the cortex while observing for muscle contraction and measuring MEPs has allowed for mapping of the motor cortex. The central conduction time (CCT) is a primary TMS measurement, representing the time required for the cortical stimulus of a primary motor neuron to reach the second-order neuron in the spinal cord or brainstem. The active motor threshold (AMT) for MEP represents the excitability of the cortex stimulated and is influenced by structural tissue parameters as well as the functional status of the neurons, such as ion channel function [10]. It has been shown that different drugs that act on ion channels may change the threshold for cortical stimulation [11]. MEP modulation is a phenomenon observed in TMS studies and is used as a physiological marker of the effects of stimulation. Applying TMS to the motor cortex during continuous voluntary muscle activation causes an inhibitory silent period (SP) in the EMG recordings [10, 12, 13]. In the same setting, when applying the TMS pulse to the motor cortex ipsilateral to the contracting muscle, a similar

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period of cessation of electromyographic activity is observed, albeit with a slightly delayed onset and of shorter duration. This is referred to as transcallosal inhibition (TCI) [10, 12]. Short interval intra-cortical inhibition (SICI) is measured by giving a paired stimulus, the first being subthreshold and the later supra-threshold. When the interval between the two stimuli is short (1–5 ms), the net result is diminution of the MEP amplitude produced [10, 11, 14]. This phenomenon was linked to GABA-A receptor activity being modulated by the conditioning sub-threshold stimulus [15]. When the same paired stimulus is applied at a longer interval, there is facilitation of MEP [14]. Another cortical inhibition of MEP is the short afferent inhibition (SAI), produced by applying the TMS pulse 20 ms after a peripheral somato-sensory stimulus. This measure has been shown to represent cholinergic cortical inhibition [10, 16]. It is important to acknowledge that the magnetic pulse induces neuronal currents in a non-specific way; thus, inhibitory and excitatory pathways may be activated simultaneously. This results in neuronal modulation with various consequences [17]. Another significant discovery is that the effect of the TMS pulse depends not only on the parameters of the coil and pulse but also on the activity state of the tissue itself: The less active neurons show the greatest response [18, 19]. For example, when a single magnetic pulse is given to a cortical area related to a certain cognitive ability while the individual is engaged in a cognitive task, it causes interference with the cognitive process. However, applying the same stimulus shortly before the task facilitates the performance of the subject, indicating that the effect of the magnetic stimulation depends not only on the intensity and location of the pulse itself but also on the functional state of the cells being stimulated.

TMS as a Tool for Mapping Brain-Cognition Relationships A single TMS pulse or a short sequence of pulses has the potential to transiently disrupt ongoing cortical activity in the region being stimulated. This phenomenon has been termed Bvirtual lesion^ [13, 18, 19, 20]. The practical effect is seen and measured as a disturbance or modulation of performance in a specific task. This method provides a unique and powerful tool to identify brain-behavior relationships. TMS methods allow for the identification of a direct association between the studied site and the behavioral outcome in a temporary and non-invasive fashion, allowing for mapping of areas of cortex less accessible by previous techniques. It is important to remember the various effects of TMS and their complexity when interpreting results of these studies. Even so, this new method, in combination with other familiar approaches such as functional imaging

Curr Neurol Neurosci Rep (2015) 15:52 Table 1

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Key TMS parameters mentioned in the review

Parameter

Definition

Significance

Motor evoked potential (MEP)

The action potential of a muscle cell Enables mapping of motor cortex created by cortical stimulation of the motor cortex Central conduction time (CCT) Time lapse between cortical stimulation Functional indication of a demyelinating and action potential at second order injury along the corticospinal tract neuron Active motor threshold (AMT) The minimal stimulus intensity that Represents the excitability of a specific provokes a miniscule motor response area of cortex. Used to evaluate (usually visible) influences of various factors on neuronal excitability Silent period (SP) A short pause in EMG activity seen Reflects cortical inhibition on muscle when applying a cortical stimulus activity. Modifications of this while the subject performs continuous parameter have been observed in voluntary contraction of the same TMS studies of AD patients muscle group Transcortical inhibition (TCI) A similar setting as with SP but the Reflects cortico-cortical inhibition. stimulus is applied to the cortex Modifications of this parameter ipsilateral to the activated muscle have been observed in patients with neurodegenerative disorders Short interval intra-cortical A reduction in MEP amplitude created A reflection of cortico-cortical inhibition (SICI) by application of a conditioning inhibition stimulus at a short interval (5 Hz) leads to increased cortical excitability [12]. These effects may be correlated to the duration of stimulation, or to the total number of pulses delivered. One example of an rTMS protocol aimed to induce changes in synaptic plasticity is the theta-burst stimulation (TBS): It consists of 10 bursts of four pulses at 100 Hz; each burst is separated from the next one by 200 ms [37]. This short, highfrequency pattern reflects LTP and has been modified to induce a variety of cortical modulations [38•]. The mimicking of these processes by TMS could be used to theoretically change the properties of neurons and neuronal networks for longer

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periods of time than the periods of actual stimulation, and thus has lasting effects on behavior. These changes in cortical reactivity can be measured by various methods, including paired TMS pulse-EEG recordings [39–41]. The cortical reactivity of a given brain region is measured before and after application of an intervention, be it rTMS or another form of intervention such as a cognitive task, and can provide a measure of brain plasticity evoked by the intervention. That the electrophysiologic characteristics of the brain region stimulated are altered by the intervention is strong evidence supporting the link between stimulation and induction of synaptic plasticity [42]. Parameters of plasticity are likely different at different ages and may correlate with stages of development and aging, reflecting changes in neuronal physiology over the lifespan [38•]. Studies suggest that higher stimulus intensities are required to achieve similar measures of cortical reactivity in older as opposed to younger subjects [43]. TMS measures of brain plasticity may be developed as surrogate markers of brain health or cognitive reserve [38•]. It is important to mention that the relationship between facilitatory and suppressive effects of rTMS is highly dependent on a multitude of neuronal factors, including the state of brain activity at the time of rTMS, and thus may result in paradoxical effects [18]. This issue may hamper our ability to reliably predict rTMS outcomes. The reliability and validity of TMS measures (test-retest, or repeatability) have been investigated with confounding results, but several studies have demonstrated good test-retest reliability for different TMS measures in studies of motor, visual, and prefrontal cortex (reviewed in [13]). State-dependent effects need to be more thoroughly investigated and accounted for [18] (reviewed in [13]). A partial list of possible state-dependent factors includes diurnal changes, hormonal effects, medication effects, and levels of anxiety or mood changes, disease states including the varying degrees thereof, age, premorbid function, brain reserve, and others.

Using rTMS to Modulate Cognitive Processes in Alzheimer’s Disease Alzheimer’s disease (AD) is the most common cause of dementia [44] and is characterized by a progressive deterioration of memory, cognitive, and global function. In the early stages, memory processes and complex behaviors are compromised, whereas in later stages, patients develop severe functional deterioration. The large majority of AD is considered late-onset, with symptoms beginning after age 60. Extensive resources are expended on diagnosis and care of patients with AD, and these numbers will increase in the future as the general population ages. Vast resources have also been similarly spent on research into the pathophysiology of AD as well as in the advancement of various treatment strategies. These efforts

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have provided a much better understanding of the risk factors associated with the disorder, although disappointingly, to date, disease-modifying therapies are still lacking. AD is associated with the presence of neurofibrillary tangles and amyloid neuritic plaques in various brain structures. The relationship between the accumulation of these histopathological changes and development of AD is unclear. The earliest brain changes are classically seen in the entorhinal cortex and hippocampus, with extension of pathology to other limbic system structures and then other cortical areas [45]. Brain regions showing functional deficits in the earliest stages of AD are the anterior medial temporal lobes, the sub-callosal region, precuneus, and the posterior cingulate cortex (PCC) [46]. Functional connectivity studies have also implicated the PCC and related structures of the default mode network in the pathogenesis of AD. These areas show disrupted connectivity in early AD [47]. Frontal perfusion and metabolic defects and frontal lobe pathological changes are more often observed with advanced AD [48]. TMS Studies Investigating Pathophysiologic Brain Changes in AD Magnetic stimulation is being increasingly used to identify changes in different measures in the brains of patients with AD and other types of dementia and cognitive impairments. An index of important studies identifying electrophysiological changes in AD by TMS is found in Table 2a. Initial studies identified changes in motor threshold (MT) according to the stage of illness: In the early stages of AD, patients showed a reduction of MT, representing motor cortex hyperexcitability [49, 50]. These cortical changes are measurable before any clinical manifestation of motor impairment and may signify cortical adaptation to neurodegenerative processes. When general brain atrophy prevails during later stages of the disease, MT increases, which correlates with cortical hypoexcitability [49, 51]. The central conduction time (CCT; the time required for the cortical stimulus of a primary motor neuron to reach the second-order neuron in the spinal cord or brainstem) is mostly preserved, indicating normal function of remaining cortico-spinal neurons [51]. Recent studies have demonstrated a reduction in short afferent inhibition (SAI; produced by applying the TMS pulse 20 ms after a peripheral somato-sensory stimulus, which has been shown to represent cholinergic cortical inhibition) in AD patients as well as in amnestic mild cognitive impairment (MCI) [49, 52] (Table 2a). This finding correlates with the hypothesis of cholinergic neuronal loss in AD. Administration of an acetylcholinesterase inhibitor (AChE-I) rectifies SAI in AD patients [53, 54], likely due to restoration of cholinergic tone. The SAI is unique in its relation to AD, since other inhibitory and excitatory measurements such as LICI and SICI were not found to differ in AD patients versus controls [52].

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In a recent study comparing DTI and TMS in AD patients, both TMS and DTI metrics were prominently altered in AD patients, but impaired white matter integrity was not associated with increased ipsilateral silent period latency or reduced RMT, suggesting that other pathophysiological mechanisms may account for the observation of decreased transcallosal inhibition and increased motor excitability in AD [55]. Different rTMS protocols, including those described above, have been used to investigate neural plasticity in AD patients. Inghilleri et al. performed repetitive stimulation at 5Hz frequency in AD patients and healthy controls and found that MEP facilitation was impaired in the patient group [56]. This protocol simulates short-term synaptic facilitation, which is mostly a function of glutamatergic NMDA receptors. Thetaburst stimulation protocols are used to imitate mechanisms of LTP and LTD. A continuous theta-burst protocol used by Huang et al. caused a prolonged suppression of MEPs while a similar but intermittent protocol produced MEP facilitation for periods of up to 60 min, depending on the total amount of pulses given to the subjects [57]. When applying theta-burst protocols with LTP-like and LTD-like effects on AD patients and healthy controls, Koch et al. showed that patients with moderate AD reached less MEP facilitation with the LTPlike protocol as compared to controls [58]. However, the LTD-like protocol resulted in the same degree of depression in both groups, demonstrating the impairment of LTP-like together with normal LTD-like cortical plasticity in AD patients. This finding may represent a change in the inherent balance of LTP and LTD in the AD brain and may be viewed as an electrophysiologic correlate of clinical pathology. The heterogeneity of these results may reflect the heterogeneity of the patient population studied, given that AD patients may often have a significant amount of co-morbid brain pathologies. rTMS as a Cogntive Enhancer in AD rTMS has been investigated for its potential as a therapeutic intervention in abnormal cognitive processes and has been investigated as a cognitive enhancing treatment in mild to moderate AD. As mentioned above, patients with mild AD show measures of increased cortical excitability as compared to controls, which may make these patients more specifically responsive to TMS treatment [50, 59, 60]. This hyperexcitability may reflect impaired cholinergic activity and a deficit of N-methyl-D-aspartic glutamate receptors [50, 61, 62]. Neuronal loss might be one of the reasons responsible for motor cortex hyperexcitability in AD patients [61, 63]. In accordance with this assumption, clinical studies have demonstrated that rTMS over DLPFC improves naming in mild (mean Mini-Mental State Exam (MMSE) score of 18–20) and moderate to severe (mean MMSE ~15) stage AD patients (mean age ~75 in both groups) [64, 65].

Curr Neurol Neurosci Rep (2015) 15:52 Table 2

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TMS studies in AD

Authors

Number of patients

AD severity

Mean MMSE

Mean age (years±SD)

Brief summary of major findings

A. Electrophysiologic studies Perretti et al. (1996) 15

Moderate to severe

17.2

67.2±7.8

Ferreri et al. (2003)

16

Mild to moderate

Not provided

75±6.9

Di Lazzaro et al. (2004)

28

Early stage AD

19.35±3.8

71.3±6.8

Di Lazzaro et al. (2005)

20

Mild to moderate

19.1±5.5

70.5±6.9

Elevated motor threshold in 40 % of patients with correlation to dementia severity. Relatively preserved CCT. Indicating cortical neuronal hypoexcitability with preserved corticospinal tracts Lower motor threshold in early AD patients without clinical motor impairment, as compared to healthy controls. This study supports the hypothesis of motor cortex hyperexcitability and reorganization in the early stages of AD Reduced motor threshold in AD patients confirms cortical hyperexcitability. Diminished SAI and SICI also noted. After a single oral dose of Rivastigmine, inhibitory parameters increased with no change in motor threshold. Suggests intracortical excitatory mechanisms responsible for hyperexcitability A decreased SAI in AD patients and the restoration of it following a single dose of Ach-E-I may predict response to long term treatment with Rivastigmine

Inghilleri et al. (2006)

20

Mild to moderate

16±1

71±2.1

Battaglia et al. (2007)

10

Mild to moderate

20±3.9

70.1±7.4

Niskanen et al. (2011)

15

Mild to moderate

18.9±4.1

73.7±7.5

Koch et al. (2012)

14

Moderate

19.36

Not provided

Wegrzyn et al. (2013)

19

Mild to moderate

21.7±4.9

71.8±4.7

B. Treatment studies Cotelli et al. (2006)

15

Mild to moderate

17.8±3.7

76.6±6.0

Cotelli et al. (2008)

24

Mild Moderate to severe

19.7±1.6 14.3±2.6

75.0±6.2 77.6±5.8

Cotelli et al. (2011)

10

Moderate

16.1

72.8

Ahmed et al. (2012)

45

Mild to moderate & Severe

14.84±5.5

68.4

rTMS in normal controls elicits increase in MEP amplitude, while in AD patients a reduction in MEP size was noted. Suggests altered cortical plasticity in AD patients Utilized a PAS protocol to elicit an LTP-like response in the motor cortex of AD patients vs. controls. The study showed lack of MEP facilitation in AD patients as seen in the control group, supporting the hypothesis of impaired neural plasticity in AD Hyperexcitability as a protective mechanism in AD correlates with volume loss exclusively in the sensorimotor cortex Utilized various TBS protocols and demonstrated an impaired LTP like after effect in AD patients compared to healthy controls Combined DTI and TMS to show lack of correlation between white matter disintegrity and reduced motor thresholds and other TMS parameters characteristic of AD rTMS to the right or left DLPFC improves action naming in AD patients. Sham stimulation was used as control condition rTMS of DLPFC improves action and object naming in moderate to severe AD patients. Sham stimulation was used as control condition High frequency rTMS treatment protocol to the Lt. DLPFC improves auditory sentence comprehension in AD patients. A 4-week real treatment group was compared to a 2-week placebo (sham) followed by 2-week real treatment group Daily treatment high frequency rTMS applied to the DLPFC bilaterally for 5 days improved cognitive and functional measures in AD patients. The effect was maintained for 3 months. High frequency protocol was compared to low-frequency and sham treatment groups

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Table 2 (continued) Authors

Number of patients

AD severity

Mean MMSE

Mean age (years±SD)

Brief summary of major findings

Rabey et al. (2013)

15

Mild to moderate

22±1.63

72.6±8.9

Ash et al. (2014)

40

Mild to moderate

Not provided

Not provided

An rTMS combined with cognitive training treatment protocol was applied and achieved a lasting improvement of 3.76 points on average in the ADAS-Cog for 4.5 months. A sham group served as control High-frequency deep rTMS to prefrontal cortex improved cognitive and clinical measures in AD patients with a lasting effect of 2 months. The study included a sham group

AD Alzheimer’s disease, MMSE Mini-Mental State Exam, CCT central conduction time, SAI short afferent inhibition, SICI short interval intra-cortical inhibition, TMS transcranial magnetic stimulation, rTMS repetitive TMS, MEP motor evoked potential, LTP long-term potentiation, TBS theta-burst stimulation, DTI diffusion tensor imaging, DLPFC dorsolateral prefrontal cortex, ADAS-Cog Alzheimer Disease Assessment Scale-Cognitive

Studies of TMS as a potential cognitive enhancer are listed in Table 2b. TMS was applied to the dorsolateral prefrontal cortex in moderate AD patients (mean MMSE 16, mean age 72) to assess the duration of its effects on language performance, and it was found that a 4-week daily TMS treatment was able to induce at least an 8-week lasting improvement in auditory sentence comprehension [66]. High-frequency and low-frequency superficial rTMS of the DLPFC was compared in a small study of AD subjects with mild to moderate or severe dementia, and a significant improvement in cognition (mean 3–4 MMSE points) was observed in the high-frequency stimulation mild to moderate group that lasted for weeks after treatment [67]. In a small study which combined daily superficial rTMS of six different brain regions with cognitive training for 6 weeks and bi-weekly treatments for 3 months [68] in mild to moderate AD patients on stable doses of AD medications, significant and similar improvements in Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) and in Clinical Global Impression of Change (CGIC) were found after both 6 weeks and 4.5 months. These findings present evidence that TMS may be helpful in restoring brain functions and could reflect rTMS potential to recruit compensatory networks that underlie memory-encoding and other cognitive processes [69]. We have performed rTMS of deep prefrontal brain regions in patients with mild to moderate AD and found modest but significant improvements in multiple cognitive measures, including global cognitive score on the NeuroTrax™ moderate to severe battery (NeuroTrax Corp., Bellaire, TX), and on language and executive functioning subscores of the ADAS-cog [70]. Unresolved issues impacting the efficacy of TMS stimulation include the frequency of stimulation, the location of stimulation, dementia severity, the efficacy of TMS in the absence of cognitive training, and the degree of methodological heterogeneity in the reported studies [71]. Studies of TMS in AD to date appear safe and promising but have included very

small number of patients and have not been adequately powered to establish efficacy and should be regarded with caution. Although most studies have included sham treatments with blinded raters, potential issues related to patient blinding exist. Further emphasis should be placed on the areas and depths of stimulation, and the development of physiological biomarkers to assess the therapeutic mechanisms of TMS in this population.

Conclusions TMS is a unique tool that can be harnessed to study cognitive processing. TMS can create virtual lesions, thereby allowing us to obtain information about the contribution of a given cortical region to a specific behavior. TMS can be combined with neuroimaging to be used to study functional connectivity and the physiology of brain networks. Furthermore, TMS techniques have been developed that mimic LTP/LTD and can allow for modulation of neuronal plasticity. TMS technology can help unravel the pathophysiological processes in disease of cognition such as Alzheimer’s disease and may also show potential as a cognitive enhancer in AD. TMS is an important tool in cognitive neuroscience and has changed the way we understand cognitive function.

Compliance With Ethics Guidelines Conflict of Interest Naomi Nevler declares no conflict of interest. Elissa L. Ash has received a grant from Brightfocus Foundation, and travel and administrative support from Brainsway, Ltd. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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