Motor cortical circuits in Parkinson disease and dystonia

Handbook of Clinical Neurology, Vol. 161 (3rd series) Clinical Neurophysiology: Diseases and Disorders K.H. Levin and P. Chauvel, Editors https://doi.org/10.1016/B978-0-444-64142-7.00047-3 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 10

Motor cortical circuits in Parkinson disease and dystonia 1

KAVIRAJA UDUPA1* AND ROBERT CHEN2 Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore, India 2

Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada

Abstract We review the motor cortical and basal ganglia involvement in two important movement disorders: Parkinson’s disease (PD) and dystonia. Single and paired pulse transcranial magnetic stimulation studies showed altered excitability and cortical circuits in PD with decreased silent period, short interval intracortical inhibition, intracortical facilitation, long afferent inhibition, interhemispheric inhibition, and cerebellar inhibition, and increased long interval intracortical inhibition and short interval intracortical facilitation. In dystonia, there is decreased silent period, short interval intracortical inhibition, long afferent inhibition, interhemispheric inhibition, and increased intracortical facilitation. Plasticity induction protocols revealed deficient plasticity in PD and normal and exaggerated plasticity in dystonia. In the basal ganglia, there is increased b (14–30 Hz) rhythm in PD and characteristic 5–18 Hz band synchronization in dystonia. These motor cortical circuits, cortical plasticity, and oscillation profiles of the basal ganglia are altered with medications and deep brain stimulation treatment. There is considerable variability in these measures related to interindividual variations, different disease characteristics, and methodological considerations. Nevertheless, these pathophysiologic studies have expanded our knowledge of cortical excitability, plasticity, and oscillations in PD and dystonia, improved our understanding of disease pathophysiology, and helped to develop new treatments for these conditions.

INTRODUCTION Parkinson’s disease (PD) and dystonia are common movement disorders. PD is characterized by the cardinal symptoms of tremor, rigidity, bradykinesia, and postural abnormalities (Lang and Lozano, 1998), and nonmotor symptoms are increasingly being recognized. Dystonia is a syndrome characterized by sustained or intermittent muscle contractions resulting in abnormal postures, repetitive movements, or both (Fahn et al., 1998; Albanese et al., 2013). Involvement of basal ganglia (BG) structures and pathways are the hallmarks of these disorders, with alterations of firing patterns in BG structures in the direct and indirect pathways. Changes in thalamocortical projections lead to abnormal cortical physiology in these disorders. Thus, cortical changes

may be secondary to BG involvement or due to direct cortical involvement. Investigations using transcranial magnetic stimulation (TMS), imaging and electrophysiologic (electroencephalography [EEG], electrocorticography [EcoG], and local field potential [LFP]) approaches have demonstrated the involvement of the motor cortical system in PD and dystonia. In this chapter, we summarize studies of motor cortical excitability, plasticity, and oscillations in PD and dystonia.

TRANSCRANIAL MAGNETIC STIMULATION TMS provides a noninvasive measure of cortical activity and cortical neuronal networks in the primary motor cortex and other cortical structures (Hallett, 2000;

*Correspondence to: Dr. Robert Chen, 7MC-409, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada. Tel: +1-416-603-5207, Fax: +1-416-603-5004, E-mail: [email protected]

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Chen et al., 2008). Single, paired, and triple pulse techniques have been used to study the cortical networks and the complex interactions among these cortical networks (Chen et al., 2008; Ni et al., 2011). TMS can be used to measure cortical excitability (using single pulse TMS), properties of intracortical circuits (using paired pulse TMS), and cortical plasticity using established protocols (Chen and Udupa, 2009). Findings are summarized in Table 10.1. Hence, TMS plays a significant role in understanding the pathophysiology of movement disorders and the effects of deep brain stimulation (DBS) on cortical networks.

SINGLE PULSE TMS MEASURES Measures such as motor threshold (MT, minimal stimulation intensity to generate a small motor evoked potential [MEP]), MEP amplitude at a given stimulation intensity, recruitment curve (RC) (input–output curve measuring MEP amplitudes with increasing stimulation intensities) and silent period (SP, a pause in the electromyographic activity during voluntary contraction following TMS) quantify the excitability of the corticospinal system. These measures are briefly described in the following sections, followed by a discussion of how these measures are altered in PD and dystonia.

ALTERATIONS OF SINGLE PULSE TMS MEASURES IN PD (TABLE 10.1) Motor threshold MT is considered a measure of corticospinal excitability. It refers to the lowest TMS intensity capable of eliciting small MEPs and is usually defined as more than 50 mV in amplitude in muscles at rest or 200 mV in active muscles in at least 5 out of 10 trials (Chen et al., 2008). MT likely reflects the membrane excitability of cortical neurons, because it is increased by drugs that block voltage-gated sodium channels. Some studies found increased excitability in PD (reduced MT compared to healthy controls (Valls-Sole et al., 1994; Tremblay and Tremblay, 2002)) but the majority of studies showed no change in this measure of excitability, which depends on various factors such as the disease stage, dopamine medication status (ON or OFF dopaminergic state), and deep brain stimulation state (ON and OFF stimulation). One of the explanations for increased motor excitability in PD is the inability to completely relax the muscles due to tremor and rigidity, which can be partially corrected with medications (Cantello et al., 2002). A study found that resting MT of the upper extremity negatively correlates with the Unified Parkinson’s Disease Rating Scale (UPDRS) part-III score, suggesting that this measure could reflect the severity of PD (Park et al., 2016).

Table 10.1 Excitability and plasticity measures in Parkinson’s disease and dystonia Excitability and plasticity measures Single pulse TMS measures Motor threshold Recruitment curve Silent period Central motor conduction time Motor mapping Paired pulse TMS measures Short interval intracortical inhibition Long interval intracortical inhibition Intracortical facilitation Short interval intracortical facilitation Short afferent inhibition Long afferent inhibition Interhemispheric inhibition Cerebellar inhibition Plasticity studies Motor cortical plasticity Basal ganglia plasticity

Parkinson’s disease

Dystonia

"/$ $ # #/" Increased cortical representation of body muscles over the motor strip

$ $ # $ Distorted motor cortical representation with reduced interdigit separation at S1

# " #/$ " $ (OFF)/# (ON) # # #

# $/# " ? $ # # $

Maladaptive plasticity Decreased LTP and depotentiation

Exaggerated plasticity Enhanced LTP and no LTD

#, decreased; ", increased; $, no change; ?, unknown.

MOTOR CORTICAL CIRCUITS IN PARKINSON DISEASE AND DYSTONIA

Central motor conduction time Central motor conduction time (CMCT) is the conduction time of corticospinal fibers from the motor cortex to motor neurons in the spinal cord or brainstem. It is calculated by subtracting the peripheral conduction time from the latency of the MEP elicited by motor cortical TMS (Udupa and Chen, 2013a). Upon stimulating a motor nerve, the M wave is the direct muscle response and the F wave is the muscle response produced by activation of the a motoneuron by the antidromic volley. Thus peripheral conduction time may be calculated using the formula (F wave latency + M wave latency – 1)/2. Other methods of obtaining the peripheral conduction time include electrical or magnetic stimulation over the spine. CMCTs in active muscles were found to be normal (Dick et al., 1984; Cantello et al., 1991; Abbruzzese et al., 1997; Mochizuki et al., 1999; Bhatia et al., 2003; Udupa and Chen, 2013a) in PD. However, some studies found decreased CMCT with the target muscle at rest in PD (Kandler et al., 1990), which is normalized by dopaminergic medication (Soysal et al., 2008). This may be related to difficulties with muscle relaxation in PD. On the other hand, increased CMCT has been reported in PD patients (Schneider et al., 2008; Perretti et al., 2011) with Parkin gene mutations, suggesting that this measure may be used to distinguish patients with Parkin mutation from those with early onset PD. Prolonged CMCT has also been found in patients with a parkinsonian syndrome secondary to multiple system atrophy or progressive supranuclear palsy (Udupa and Chen, 2013a) due to corticospinal tract involvement in these disorders. Thus CMCT can be used to differentiate the subgroups of certain types of parkinsonian disorders.

Silent period Silent period (SP) is a pause in ongoing voluntary EMG activity produced by TMS. It is elicited by single pulse TMS delivered during voluntary muscle contraction. While the first part of the SP is due in part to decreased spinal cord excitability, the latter part is almost exclusively due to cortical inhibition. Prolonged SP suggests hyperactivity whereas shortened SP suggests decreased activity of inhibitory circuits in the motor cortex. This type of inhibition is likely mediated by GABAB receptors, as it is increased by the GABAB agonist baclofen (Siebner et al., 1998) and the GABA reuptake inhibitor tiagabine (Werhahn et al., 1999). SP duration is shortened in PD and this reduction is greater on the more affected side (Cantello et al., 1992, 2002; Nakashima et al., 1995). Further studies have shown that dopaminergic treatment normalizes the reduction of SP (Priori et al., 1994). A study reported paradoxical lengthening of SP

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with dopaminergic medications in patients with dyskinesia; both dyskinesia and SP were normalized by pallidal stimulation (Chen et al., 2001). Thus, SP may be an indirect measure of clinical severity in PD.

Recruitment curve This parameter, also known as input–output or stimulus– response curve, refers to the increase in MEP amplitude with increasing TMS intensity. Compared to MT, this measure assesses neurons that are intrinsically less excitable or spatially further from the center of activation by TMS. RCs are likely related to the strength of corticospinal projections and are generally steeper in muscles with low MT, such as intrinsic hand muscles. In a study measuring RC in Parkin mutation-positive PD patients and gene carriers, no difference was found in RC among PD patients, gene carriers, and controls (Schneider et al., 2008).

Mapping of muscle representation Mapping is performed by stimulation at a number of different scalp positions with a focal figure-of-eight coil. The number of excitable scalp positions, location of the optimal position for stimulation, and the center of gravity (an amplitude-weighted representative position on the motor map) can be determined. Motor maps are affected by both the location and excitability of the motor representation. A study has shown increased cortical representation of body muscles over the motor strip in PD, probably due to tonic hyperactivation of motor cortical circuitry (Filippi et al., 2001). Thus, various single pulse TMS measures are useful in the investigation of motor cortical excitability in PD (Table 10.1). Although many studies have investigated excitability changes in PD compared to healthy controls, there are few longitudinal studies investigating single pulse TMS measures following the course of the disease and taking into account differences due to clinical phenotypes, disease stage, and medication profile.

INTRACORTICAL CIRCUITS MEASURED BY PAIRED PULSE TMS Paired TMS techniques involve delivering two TMS pulses at different interstimulus intervals (ISI) to study intracortical circuits (Fig. 10.1). The circuits activated depend on the stimulus intensities, ISI, the site of stimulation, and TMS coil orientations, which activate different neuronal populations. Some of the common intracortical circuits studied with paired pulse, probable mechanisms, and findings in PD and dystonia are summarized in Table 10.2.

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A B

C

D 50 ms 1 mV

Fig. 10.1. An illustration of paired pulse TMS protocols. (A) A test stimulus alone (blue arrow) to the motor cortex generated a MEP with peak-to-peak amplitude of 1 mV. (B) Short-interval intracortical inhibition (SICI): a subthreshold conditioning stimulus (red arrow) delivered 2 ms prior to the test (blue arrow) stimulus reduced the MEP amplitude to 0.5 mV. (C) Intracortical facilitation (ICF): a subthreshold conditioning stimulus (red arrow) delivered 10 ms prior to the test (blue arrow) stimulus increased the MEP amplitude to 1.5 mV. (D) Long-interval intracortical inhibition (LICI): a suprathreshold conditioning stimulus (green arrow, which generates an MEP of its own 1 mV) delivered 100 ms prior to the test (blue arrow) stimulus reduced MEP amplitude to 0.5 mV.

Short interval intracortical inhibition Short interval intracortical inhibition (SICI) is evoked by a subthreshold conditioning stimulus followed by a test stimulus at short ISI of 1–5 ms (Kujirai et al., 1993). This is a measure of cortical inhibition mediated by GABAA receptors (Ziemann, 2004; Chen et al., 2008). Several studies found reduced SICI in resting PD patients on medication in the OFF state that normalized in the ON state (Ridding et al., 1995a; Hanajima et al., 1996; Strafella et al., 2000). However, several studies have reported normal SICI (Chen et al., 2001; Cunic et al., 2002), concluding that a reduced SICI is partly due to increased facilitation rather than reduced inhibition (MacKinnon et al., 2005; Ni et al., 2013). SICI in active muscles appeared to be unaffected in PD. Since SICI is reduced prior to and during voluntary movement, reduction of SICI in PD may compensate for bradykinesia, improving movement and explaining a normal active SICI.

found increased LICI in PD (Berardelli et al., 1996; Valzania et al., 1997). However, in other studies LICI was decreased at longer ISIs (150–300 ms). These abnormalities in LICI were normalized with dopaminergic medications (Berardelli et al., 1996) and apomorphine (Pierantozzi et al., 2001). Further, inability of PD patients to completely relax during these studies might have been an issue, as LICI during muscle activation was found to be increased in PD (Berardelli et al., 1996). Although SP and LICI are thought to be mediated by GABAB, PD tends to affect these two measures in opposite directions. A decrease in SP could be due to reduced inhibition of the corticospinal drive during tonic muscle contraction, whereas an increase in LICI may correspond to reduced motor cortical activity associated with the impaired execution of rapid movements. The opposite findings for SICI and LICI may be because LICI inhibits SICI, likely through presynaptic GABAB receptors (Sanger et al., 2001).

Intracortical facilitation Intracortical facilitation (ICF) is evoked by a subthreshold conditioning stimulus followed by a test stimulus at ISI of 10 to 20 ms. One study reported that this measure was reduced in patients with early PD in both hemispheres (Bares et al., 2003). However, other studies found no difference in ICF in PD patients (Kojovic et al., 2012, 2015). Thus in addition to the inhibitory circuits, excitatory circuits may also be affected in PD.

Short interval intracortical facilitation These facilitatory circuits are elicited by a suprathreshold pulse (S1) followed by a threshold pulse (S2) at short ISIs of 1–5 ms, resulting in three peaks (around 1.5, 2.8, and 4.5 ms) and two troughs (around 2 and 3 ms) in the excitability pattern of M1 (Fig. 10.2). A study found increased short interval intracortical facilitation (SICF) and decreased SICI in the OFF-medication state, which was normalized by dopaminergic medications (Ni et al., 2013). Changes in these intracortical circuits correlated with improvement in UPDRS scores with medication. Furthermore, increased facilitation was partly responsible for decreased SICI and could represent compensatory mechanisms for impaired synaptic inhibition in PD.

Short and long latency afferent inhibition Long interval cortical inhibition Long interval cortical inhibition (LICI) is evoked by a suprathreshold-conditioning stimulus followed by a test stimulus at a longer ISI of 100–200 ms. Several studies

Short (SAI) and long (LAI) latency afferent inhibition involves median nerve stimulation followed by M1-TMS at short (23 ms) or long (200 ms) latencies to inhibit M1 excitability. These afferent inhibitions are mediated by cholinergic and GABAergic cortical circuits.

Table 10.2 Different intracortical circuits measured using paired pulse TMS protocols and their findings in Parkinson’s disease and dystonia SICI Method Conditioning stimulus/ Sub-threshold S1 for SICF TMS Test stimulus/S2 for Supra-threshold SICF TMS Inter-stimulus interval 1–6 (ms) Proposed GABAA neurotransmitter/ ?dopamine receptor Findings in movement disorders Parkinson’s disease # Dystonia #

LICI

SICF

ICF

SIHI

LIHI

CBI

SAI

LAI

Supra-threshold TMS Supra-threshold TMS 50–200

Supra-threshold TMS Sub-threshold TMS 1.0–1.5, 2.3–3.0, 4.1–5.0 ?Glutamate (# by GABAA)

Sub-threshold TMS Supra-threshold TMS 8–30

Supra-threshold TMS Supra-threshold TMS 8–12

Supra-threshold TMS Supra-threshold TMS 40

Cerebellar stim. Supra-threshold TMS 5–7

Median nerve stim. Supra-threshold TMS 20

Median nerve stim. Supra-threshold TMS 200

Glutamate

?

GABAB

?

ACh " by GABAA

?

" ?

#/$ $

? ?

# #

# $

$ (# on meds) $

# #

GABAB

" $/"

ACh, acetylcholine; CBI, cerebellar inhibition; ICF, intracortical facilitation; GABA, g-aminobutyric acid; LAI, long latency afferent inhibition; LICI, long interval intracortical inhibition; LIHI, long interval interhemispheric inhibition; SAI, short latency afferent inhibition; SICF, short interval intracortical facilitation; SICI, short interval intracortical inhibition; SIHI, short interval interhemispheric inhibition; #, decreased; ", increased; $, no change; ?, unknown.

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K. UDUPA AND R. CHEN SAI was found to be normal in PD patients OFF medications, but levodopa administration reduced SAI. On the other hand, LAI is reduced in PD and is unaffected by medications (Sailer et al., 2003).

Interhemispheric inhibition The cerebral hemispheres inhibit each other through the callosal connection, which can be elicited as interhemispheric inhibition (IHI) at short (around 10 ms) and long (around 40 ms) ISIs. IHI was reduced in PD patients, especially those with mirror movements, at long ISIs of 20–50 ms (Li et al., 2007a). Moreover, IHI reduced SICI in normal subjects and PD patients without mirror movements, whereas IHI increased ICF in both PD patients with and without mirror movements but not in normal subjects. Thus, reduced transcallosal inhibitory action coupled with its effects on intracortical inhibitory circuits may contribute to mirror movements in PD.

Cerebellar inhibition

Fig. 10.2. Short-interval intracortical facilitation (SICF) in normal subjects (controls) and patients with Parkinson’s disease (PD). SICF is evoked by a suprathreshold first pulse (S1) followed by a threshold second pulse (S2). At interstimulus interval (ISI) of about 1.5ms (peak 1), 3.0 ms (peak 2), and 4.5 ms (peak 3), the MEP produced by SICF is greater than S1 alone, but at ISI of about 2.0 ms (trough 1) and 4.0 ms (trough 2), there is no facilitation. (A) Example of recordings from single subjects. Surface EMG was recorded from the first dorsal interosseous muscle and averaged 10 trials. (B) Group results in normal subjects (controls, open circles), PD patients on medications (PD ON, triangles) and PD patients off medications (PD OFF, filled circles). The X-axis indicates the ISI and Y-axis the degree of SICI; the graph represents the amplitude of paired-pulse induced MEP expressed as a percentage of the MEP amplitude induced by test stimulus alone. Values more than 100% indicate facilitation and those less than 100% indicate inhibition. *P < 0.05, **P < 0.01, comparing PDOFF to control. #P < 0.05, comparing PD OFF to PD ON. “S” P < 0.05, comparing PD ON to control. SICF is exaggerated in PD OFF but was restored to normal in PD ON. MEP, motor evoked potential; PD, Parkinson’s disease; SICI, short interval intracortical inhibition. Values are expressed as percentage of MEP amplitude from S1 alone. Values above 100% indicate facilitation and values below 100% indicate inhibition. Adapted from Ni Z, Bahl N, Gunraj CA, et al. (2013). Increased motor cortical facilitation and decreased inhibition in Parkinson disease. Neurology 80: 1746–1753.

The cerebellum inhibits the contralateral primary motor cortex through cerebellothalamocortical pathways, which can be tested by paired TMS pulses to cerebellum followed by M1 at ISI of 5–8 ms (Ugawa et al., 1995; Pinto and Chen, 2001). This phenomenon is known as cerebellar inhibition, which is reduced in PD (Ni et al., 2010). Thus different intracortical circuits can be elicited by paired pulse paradigms. The excitability of most of these circuits is reduced in PD except for LICI and SICF, in which it is increased (Table 10.1).

Effects of deep brain stimulation on intracortical circuits in PD It has been shown that thalamic DBS restored cerebellar inhibition (Molnar et al., 2004; Fig. 10.3A) in patients with essential tremor, suggesting that DBS facilitates rather than inhibits transmission in the target area. Subthalamic nucleus (STN)-DBS normalizes the SICI (Cunic et al., 2002; Pierantozzi et al., 2002), similar to the effects of levodopa (Fig. 10.3B), but globus pallidus internus (GPi)-DBS had no effect on SICI (Chen et al., 2001) in PD. These differential effects may be related to the clinical finding that dopaminergic medications can be reduced with STN-DBS but not with GPi-DBS, and GPi-DBS is more efficacious in treating levodopainduced dyskinesia (LID). STN-DBS increased SICI in PD patients off medications, similar to the effects of dopaminergic drugs. Thus GPi and STN stimulation have different effects on cortical circuits and may be related to their different clinical effects.

MOTOR CORTICAL CIRCUITS IN PARKINSON DISEASE AND DYSTONIA MEP amplitude (ratio of control)

Ratio of conditioned/uconditioned MEP

*** ** * 1.2

** *

1.0 0.8 0.6 0.4 OFF

HALF

173

2.5

ON

NORMAL

Test condition

2.0

1.5

OFF Half ON Control * P < 0.05

1.0

0.5

0.0 2 (SICI)

10 (ICF)

Interstimulus interval (ms)

Fig. 10.3. Changes in intracortical circuits with deep brain stimulation (DBS). (A) Effects of thalamic DBS on the excitability of the cerebellothalamocortical pathway. Conditioning stimulus was applied to the cerebellum and test stimulus applied to the contralateral motor cortex. Interstimulus intervals (ISIs) from 3 to 7 ms were tested. Cortical suppression from cerebellar stimulation was examined in healthy normal control subjects and in essential tremor patients with thalamic DBS in three DBS test conditions (ON, HALF, and OFF). When comparing conditioned MEPs to unconditioned MEPs, ratios <1 indicate suppression and >1 indicate facilitation. There was less suppression with the OFF condition, and the ON condition restored levels toward normal. The results were averaged for ISIs of 5–7 ms. Solid bars represent the results from all six patients, and open bars represent the four patients whose tremor scores improved with DBS. There was less suppression in the OFF condition, and ON restored levels of suppression toward control values, indicating that thalamic DBS facilitates transmission in the cerebellothalamocortical pathway. The findings were similar for all six patients (solid bars) and four patients whose tremor scores improved with DBS (open bars). Error bars indicate SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 based on post hoc testing. (B) STN DBS modulates intracortical circuits: SICI and ICF. STN stimulation (ON) significantly increased SICI compared to the HALF (half-filled circle, half of the optimum amplitude) and stimulation turned off (OFF, open circle) states. There was no difference between DBS-ON state (filled circle) and healthy control (filled triangle), indicating STN-DBS normalized SICI in these patients. STN stimulation had no significant effect on ICF. Panel (A): Adapted from Molnar GF, Sailer A, Gunraj CA, et al. (2004). Thalamic deep brain stimulation activates the cerebellothalamocortical pathway. Neurology 63: 907–909.

Decreased SAI and LAI normalized with STN-DBS in PD patients (Fig. 10.4; Sailer et al., 2007; Wagle Shkula et al., 2013). Thus the effects of STN-DBS may be different from dopaminergic medications that reduced SAI (Sailer et al., 2003). Longitudinal studies evaluating SAI and LAI preoperatively and at different time points after surgery demonstrated normalization of SAI and LAI with chronic (6 months) STN-DBS in PD (Wagle Shkula et al., 2013), but not at 1 month after surgery, indicating that the effects of STN-DBS on cortical circuits requires long-term stimulation, likely related to long-term plastic changes in the BG-cortical circuits. The acute effects of DBS can be studied by switching the stimulator ON or OFF to assess the effects on excitability measures. Some studies found that no changes in motor thresholds were observed in PD patients with either STN or GPi-DBS (Cunic et al., 2002; Fraix et al., 2008). A study showed prolongation of SP following STN-DBS (Dauper et al., 2002) in PD patients, suggesting hyperactivity of GABAB mediated inhibitory circuits. On the other hand, GPi-DBS shortened the SP

(Chen et al., 2001) in PD, indicating that STN and GPi-DBS cause different changes in cortical inhibitory circuits. Reduction in SP may be related to the antidyskinetic effects of GPi-DBS. A study measuring SICI and SP sequentially at different time points (10, 20, 30, 60, and 120 min) after switching OFF for 2 h in patients with chronic STN-DBS (6–12 months after surgery with optimal stimulation and medication) showed that SICI tends to decrease with time and followed the tremor and rigidity score changes; whereas SP changed only at 2 h after switching the DBS OFF (Kobayashi et al., 2016), suggesting that SICI and not SP reflects the clinical changes following switching OFF DBS in PD. It has been shown that thalamic DBS facilitates rather than blocks transmission in the thalamus (Molnar et al., 2004, 2005) as demonstrated by increased MEP amplitude with TMS of the motor cortex with thalamic DBS ON compared to OFF. Thalamic DBS increases motor cortex excitability, consistent with functional imaging studies (Perlmutter et al., 2002; Hershey et al., 2003). TMS has shown that DBS changes in motor cortical excitability and its effects depend on the clinical condition and the stimulation site.

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Fig. 10.4. Short latency afferent inhibition in Parkinson’s disease patients with subthalamic nucleus deep brain stimulation. The X-axis indicates the different experimental conditions and the Y-axis indicates the degree of short latency afferent inhibition. Graph represents the amplitude of paired-pulse induced MEP expressed as a ratio of the MEP amplitude induced by test alone. Values more than 1 indicate facilitation and those less than 1 indicate inhibition. *P < 0.05, comparing patients at ON medication OFF stimulation state to healthy controls and patients at ON medication ON stimulation state. The ring asterisks above the columns represent significant inhibition compared to test alone. Note that short latency afferent inhibition was normal in PD patients at OFF medication state, while it was reduced at ON medication state. Reduced inhibition at the ON medication state was normalized by the DBS. MEP, motor evoked potential. Adapted from Sailer A, Cunic DI, Paradiso GO, et al. (2007). Subthalamic nucleus stimulation modulates afferent inhibition in Parkinson disease. Neurology 68: 356–363.

A study that delivered TMS to the M1 at specific times after single pulse STN-DBS found that M1 excitability increases at the two specific latencies of about 3 and 23 ms after STN-DBS (Fig. 10.5A; Kuriakose et al., 2010). The short latency facilitation (3 ms) is likely due to antidromic activation of the cortical-STN pathways as demonstrated by STN-DBS in anesthetized rats (Li et al., 2007b) and in an optogenetic study (Gradinaru et al., 2009), whereas the longer latency (23 ms) may be due to orthodromic conduction through the indirect BG pathway (Fig. 10.5B). Thus, DBS may activate axons within the target region and induce excitability changes in the areas connected to the target to produce the desired clinical effects.

PLASTICITY STUDIES IN PD Abnormal plasticity in the cortex and the BG are important aspects of the pathophysiology of disorders of the BG such as PD and dystonia. Aberrant plasticity may

underlie the generation of abnormal movements and may be corrected with treatment such as DBS. TMS can be used to induce cortical plasticity using established protocols such as regular repetitive TMS, paired associative stimulation (PAS), and y burst stimulation (Chen and Udupa, 2009). PAS involves repeated pairing of peripheral nerve stimulation with M1 stimulation at specific intervals to induce long-term potentiation based on principles of spike timing dependent plasticity (Stefan et al., 2000). Studies in PD have implicated maladaptive plasticity, especially in patients with LID using PAS and TBS protocols (Bagnato et al., 2006; Morgante et al., 2006; Ueki et al., 2006; Schwingenschuh et al., 2010; Huang et al., 2011; Suppa et al., 2011; Kishore et al., 2012a,b, 2014; Kojovic et al., 2012, 2015; Udupa and Chen, 2013b). Deficient M1 plasticity could be secondary to deficient LTP and lack of depotentiation, as seen in corticostriatal synapses in animal models of PD (Picconi et al., 2003; Calabresi et al., 2016), and lack of depotentiation in GPi and substantia nigra pars reticulata synapses tested in patients with PD undergoing DBS surgery (Prescott et al., 2014). STN-DBS together with dopaminergic medications restored PAS plasticity in advanced, dyskinetic PD patients (Kim et al., 2015), likely by normalizing maladaptive plasticity. Another study (Udupa et al., 2016) showed that repeated pairing of STN-DBS and M1-TMS at two (3 and 23 ms) specific latencies increased M1 excitability. These studies showed that modulation of altered basal ganglia–motor cortical plasticity could be one of the mechanisms of action of STN-DBS in PD (Udupa and Chen, 2015). Future research harnessing the combined use of TMS and DBS in PD patients with DBS may explore the potential clinical benefits of this approach.

OSCILLATIONS RECORDED THROUGH EEG, EcoG, AND LOCAL FIELD POTENTIALS Cortical and subcortical structures in the brain interact through neuronal oscillations and pathological disruptions of such oscillatory networks may lead to different neurological disorders (Llinas et al., 1999), including PD and dystonia. These neuronal oscillatory activities can be recorded using techniques such as EEG (Brown and Marsden, 2001), magnetoencephalography (MEG) (Llinas et al., 1999), and LFP (Brown and Williams, 2005) recordings. LFP can be recorded with microelectrodes intraoperatively or from the DBS electrodes postoperatively through externalized leads prior to their connection to the implanted pulse generator. Neuronal synchronization between different brain regions may be used to better understand these neuronal networks and connections.

MOTOR CORTICAL CIRCUITS IN PARKINSON DISEASE AND DYSTONIA

12

*

11

*

MEP amplitude ratios

10

175

Cortex

*

*

*

9

Striatum

*

8

Thalamus

*

7 6

SNc

5 4 3

GPe

~3 ms

2

GPi/SNr

~23 ms

1 0 Test 2

3

4

5

6

7

8

STN

10 15 EP-2 EP EP+2

Time from STN DBS to TMS (ms)

A

B

Fig. 10.5. Connections between the subthalamic nucleus (STN) and the primary motor cortex (M1) studied using STN-DBS and M1-TMS. (A) The time course of cortical facilitation following STN stimulation. The figures show the MEP amplitude elicited by anterioposterior direction TMS at different times after STN stimulation expressed as ratios to MEP amplitude produced by TMS without STN stimulation. Error bars represent standard error. Significant MEP facilitation occurred at 2, 3, 4, and 5 ms and the medium latency (23 ms) evoked potential latency. (B) Schematic representation of possible pathways explaining the STN-M1 interaction at short and medium latencies. TMS coil on cortex and STN DBS are schematically represented. The direct and indirect pathways are shown: black solid lines represent the excitatory glutamatergic, solid gray lines represent inhibitory GABAergic and dotted gray lines represent the nigrostriatal dopaminergic pathways. Red dotted lines indicate the antidromic conduction through cortico-subthalamic (hyperdirect pathway) may mediate the short latency (2–5 ms) facilitation. The green dotted lines through the subthalamo-pallidothalamocortical projections may mediate the medium latency (23 ms) cortical facilitation after STN DBS. Panel (A): Adapted from Kuriakose R, Saha U, Castillo G, et al. (2010). The nature and time course of cortical activation following subthalamic stimulation in Parkinson’s disease. Cereb. Cortex 20: 1926–1936. Panel (B): Adapted from Udupa K, Chen R (2015). The mechanisms of action of deep brain stimulation and ideas for the future development. Prog Neurobiol 133: 27–49.

Brain oscillations are generally subdivided into different bands based on their frequencies, such as delta (d, 1–4 Hz), theta (y, 4–7 Hz), alpha (a, 7–13 Hz), b (14–30 Hz), and g (30–100 Hz). Brown and colleagues proposed an “oscillation model” of the BG to explain the interaction of different oscillatory rhythms in the BG-cortical networks with movements (Brown and Williams, 2005). In this model, synchronized 5–30 Hz (y [5–7 Hz] and b [13–30 Hz]) activities antagonize motor processing (antikinetic), thereby disturbing coding necessary for voluntary movement. On the other hand, g oscillations increased in both BG and motor cortical regions with voluntary movements (Hutchison et al., 2004; Kuhn et al., 2009) and have been termed prokinetic rhythms. b Oscillations are also considered an “idling rhythm” to maintain the status quo of the “default resting network state,” with decrease of b oscillatory activity upon movement, paving the way to increased g oscillations (Engel and Fries, 2010; Little and Brown, 2014).

Abnormal oscillations may play an important role in PD (Bevan et al., 2002) and increased b oscillations are seen in PD patients (Stein and Bar-Gad, 2013) in both nonhuman primates (Moran et al., 2012) and rat models of PD (Avila et al., 2010). In PD, excessive b rhythms and decreased g rhythms have been observed in different regions of the BG such as the striatum, STN, and pallidum, and in cortical motor areas (Brown, 2003; Hammond et al., 2007; Little et al., 2012; Pollok et al., 2012). These findings correlated with the degree of bradykinesia and rigidity (Kuhn et al., 2009). The cortex has been proposed as the driver for the upper b frequency range in the BG based on the findings of causality-based estimates of directionality between cortico-BG circuits (Litvak et al., 2011; Oswal et al., 2013). LFPs recorded from DBS electrodes showed prominent 14- to 30-Hz oscillations in the GPi and STN following dopaminergic medication withdrawal (Brown et al., 2001; Levy et al., 2002) that decreased with levodopa medications. This change correlated with bradykinesia and rigidity

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(Kuhn et al. 2009; Little et al., 2012). Further, the g oscillations are related to state of arousal (Kempf et al., 2009), motor vigor, and motivation (Mazzoni et al. 2007), which are characteristically reduced in PD, thus providing an alternate explanation for reduced prokinetic rhythm. Thus cortical (recorded using EEG, MEG, and electrocorticography) (Silberstein et al., 2005; Litvak et al., 2011; Crowell et al. 2012) and subcortical oscillations (recorded with single unit activity) (Levy et al., 2002) and multiunit activities (Weinberger et al., 2006) or LFPs (Kuhn et al., 2004) depend on various factors such as dopaminergic replacement status (Priori et al., 2004; Brown and Williams, 2005; Marceglia et al., 2006), planning, and execution of voluntary movements, as well as clinical state of the disease in patients with PD. Understanding these factors will help provide information on the pathophysiology of PD and help plan better management strategies based on electrophysiologic (cortical EEG or MEG and subcortical LFP) findings in PD.

Modulation of oscillations by DBS in PD It has been proposed that DBS works by disrupting pathological oscillations, normalizing b and g oscillations (Lozano et al., 2002). The reduction in b oscillations following DBS correlated with improvement in clinical scores of rigidity and bradykinesia (Kuhn et al., 2006; Little et al., 2012). However, this reduction of b oscillations following DBS is not a consistent finding, as several studies failed to demonstrate this modulation (Foffani et al., 2006; Priori et al., 2006; Rossi et al., 2008). Since most studies are performed within a few days of DBS, postoperative lesion effect and edema might have an influence on LFP oscillations. To address this issue, a study measured LFP oscillations a few days after surgery and again about a month later and found consistent desynchronization in b power of LFP oscillations during STN-DBS (Rosa et al., 2011). However, in a study that examined the modulation of b oscillation by STN-DBS in nine PD patients under four experimental conditions of levodopa ON or OFF and DBS ON or OFF, DBS-ON found that the decrease in b oscillations was more pronounced with levodopa than with STNDBS and DBS did not further decrease the level of b oscillations produced by levodopa (Giannicola et al., 2010). The authors concluded that the improvement produced by DBS might be due to mechanisms other than b desynchronization. In addition, STN-LFP recordings have identified y oscillations (4–10 Hz) in PD patients off medications. Peak-dose and diphasic (onset and end of levodopa action) LID is associated with increased y oscillations with mean peak frequency around 7.4 Hz, indicating similar neurophysiologic phenomena for these

two types of dyskinesias (Alegre et al., 2012). Thus, studying the effects of DBS on BG and cortical oscillations will provide further information on mechanisms of DBS and help in better management of PD.

Phase amplitude coupling Phase amplitude coupling (PAC) refers to the correlation between the phases of low-frequency oscillations and the amplitudes of high-frequency rhythms that manifests due to high-frequency neuronal oscillations occurring at particular phases of low-frequency rhythms (Fig. 10.6). Increased PAC between low-frequency STN b (13–30 Hz, measured with LFP) and highfrequency M1 g (50–200 Hz, measured with ECoG) oscillations was observed in PD compared with dystonia and epilepsy patients (de Hemptinne et al., 2013). Intraoperative STN-DBS reduced the phase-amplitude correlation between b and g rhythms in the M1 measured with ECoG, and this reduction in phase-amplitude interaction correlated with the degree of reduction in parkinsonian motor signs (de Hemptinne et al., 2015). Furthermore, EEG-PAC may become a biomarker for the parkinsonian state, as a higher PAC modulation index was observed in the OFF-medication state that normalized in the ON-medication state (Swann et al., 2015). These findings suggest that interactions between M1-BG oscillations could be further explored as a possible feedback signal for the development of a closed-loop DBS system (Udupa et al., 2015).

Individualized frequency of stimulation by DBS in PD Traditionally, PD is treated with high-frequency (120–185 Hz) DBS. However, not all nuclei and clinical situations require stimulation at frequencies above 100 Hz. DBS in the PPN, for example, is most effective at stimulation frequencies between 20 and 60 Hz (Stefani et al., 2007; Ferraye et al., 2010; Moro et al., 2010; Hamani et al., 2011; Benabid and Torres, 2012). In a study that aimed to test the oscillation model of the BG, Tsang et al. (2012b) measured STN LFP from externalized leads in PD patients treated with STN-DBS. The authors determined the peak y and b frequencies that increased with wrist movements and with levodopa for each contact in each patient (Fig. 10.7A and B). They found that y and b frequencies decreased and the peak g frequency increased with wrist movements and with levodopa. The peak frequency for each band varied considerably from patient to patient. The clinical effects of STN DBS at the nearest individual STN-LFP frequencies were tested. DBS at y and b frequencies produced little clinical effect and did not block the effects of levodopa. However, DBS at the individualized g frequency peaks

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A

B

C

´ 10–3

Frequency for amplitude (Hz)

150

Amplitude of gamma

12 8 4

2.5 2

110

1.5 1

0.5

70

0

D

3

0 180 360 Phase of beta

10

20 Frequency for phase (Hz)

30

Fig. 10.6. Schematic representation of phase-amplitude coupling calculation. (A) Raw signal with different frequency contents. (B) Filtering applied to extract different frequencies: low (b, left) and high (g, right) frequency bands are shown as examples. (C) Phase of b (left) and amplitude of g (right) frequency bands are extracted. (D) Amplitude of high g frequency is plotted against frequency of b phase to obtain modulation index (left), indicating that the amplitude of g oscillations varied according to the phase of b rhythm. The heat-map of comodulogram (right) shows phase-amplitude coupling for a range of b and g frequencies. In this example, there was prominent coupling between the phase of 12–19 Hz oscillations and the amplitude of 120–150 Hz oscillations.

produced clinical improvement similar to conventional high-frequency stimulation (Fig. 10.7C). While these findings need further confirmation, they raise the possibility that treatment at individualized g frequency may be more effective than a fixed high frequency in personalized setup (Wagle Shkula and Okun, 2012). Moreover, lower frequency g stimulation will significantly prolong battery life compared to conventional high-frequency stimulation. Thus, individualized parameter settings based on neurophysiologic oscillation studies may be further developed as a way to better control symptoms in PD patients.

1998; Albanese et al., 2013). Based on the anatomical distribution of symptoms, dystonia is classified into focal (e.g., writer’s cramp, blepharospasm), segmental (e.g., cervical dystonia or torticollis), and generalized forms. Although treatment with botulinum toxin often leads to symptomatic benefit in focal and segmental dystonia, it only plays a limited role in the treatment of patients with generalized dystonia, and medications are often of limited efficacy.

DYSTONIA

MT and CMCT are found to be within normal limits in cervical dystonia patients compared with healthy controls (Schwenkreis et al., 1999). Other cortical excitability measures such as MEP amplitude and recruitment curve in patients with myoclonus dystonia (DYT-11)

Dystonia is a syndrome characterized by sustained or intermittent muscle contractions resulting in abnormal postures, repetitive movements, or both (Fahn et al.,

SINGLE PULSE TMS STUDIES IN DYSTONIA (TABLE 10.1)

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K. UDUPA AND R. CHEN 0.8

OFF MED ON MED

10 Hz 0.4

30

*

26.5 Hz 0.2

25

48 Hz

0 1

10

20

30

40

50

60

70

80

90 100

A 0.6

Hemibody and axial scores

Power (µV2)

0.6

* *

20 15 10 5

Power (µV2)

0 Premovement Movement

0.4 9 Hz

C

q MED q MOVE b MED b MOVE g MED g MOVE STIM OFF OFF MED

HF

ON MED

0.2 30 Hz

80 Hz

0

B

1

10

20

30

40

50

60

70

80

90 100

Frequency (Hz)

Fig. 10.7. Examples of STN frequency spectrum and effects of STN DBS at individualized frequencies. (A) Power spectral data from a Parkinson’s disease patient recorded from the right STN contact pair 2–3. The horizontal axis shows the resting frequency spectra between 1 and 100 Hz in the OFF and ON dopaminergic medication states. Individualized dopamine-dependent frequencies for this patient were 10 Hz for the y band, which showed the greatest reduction in spectral power between 4 and 10 Hz in the ON compared to OFF states; 26.5 Hz for the b band, which was the frequency with greatest reduction between 11 and 30 Hz in the ON compared to OFF states; and 48 Hz for the g band, which showed the greatest increase between 31 and 100 Hz in the ON compared to OFF states. (B) Movement-related spectra between 1 and 100 Hz in the premovement (4–3.5 s) and the movement execution (0–0.5 s) periods from an average of 79 trials of self-initiated wrist movements in the ON dopaminergic medication state. Individualized movement-related frequencies for this patient were 9 Hz for the y band, which showed the greatest reduction between 4 and 10 Hz in the movement compared to premovement periods; 30 Hz for the b band, which showed the greatest reduction between 11 and 30 Hz in the movement compared to premovement periods; and 80 Hz for the g band, which showed the greatest increase between 31 and 100 Hz in the movement compared to premovement periods. (C) Hemibody and axial motor Unified Parkinson’s Disease Rating Scale (mUPDRS) scores for eight different DBS frequencies in the OFF and ON dopaminergic medication states rated by a live rater and data recorded from 13 patients. The gray bars represent mUPDRS scores obtained in the OFF dopaminergic medication state, while the green bars represent the ON dopaminergic medication states. HF: high frequencies used for chronic STN DBS; MED: individualized dopamine-dependent frequencies; MOVE: individualized movement-related frequencies; STIM-OFF: subthalamic nucleus DBS turned off. *P < 0.05. g Med, g Move and high-frequency (HF) stimulation all produced significant improvement in motor signs compared to no stimulation. Stimulation at b or y frequencies were not significantly different from no stimulation. Panels (A–C): Adapted from Tsang EW (2012). Subthalamic deep brain stimulation at individualized frequencies for Parkinson disease, Neurology 78: 1930–1938.

are similar to healthy controls (van der Salm et al., 2009). The SP is decreased in patients with focal hand dystonia and spasmodic dysphonia when compared with agematched controls, suggesting impaired intracortical inhibition in dystonia (Samargia et al., 2014). The duration of SP on the affected side was shorter if it was preceded by stronger dystonic contraction (Filipovic et al., 1997). In terms of cortical muscle representation, a study using

TMS showed distorted muscle maps (Chen, 2005; Byrnes et al., 1998). Further, studies of dipole sources in the somatosensory cortex using somatosensory evoked potentials showed reduced distance between first and fifth digit (Bara-Jimenez et al., 1998; Weise et al., 2012) and MEG studies showed abnormalities in dystonic limb representation (Meunier et al., 2003). Reduced interdigit separation for the first three digits in the area 3b

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20

*

16

*

*

12

MEP amplitude (ratio to TS alone)

Euclidean (mm)

WC - IHI at rest 1.4

*

8

1.2 1 0.8 0.6 0.4

0 6

4 0

Right hand Left hand

0.2

B D1

D2

D3

D4

8 10 12 30 40 Interstimulus interval (ms)

50

D5

MEP amplitude (ratio to TS alone)

A

C

1.2 1 0.8 0.6

*

Right hand Left hand

*

0.4 0.2 0 SIHI

LIHI

Fig. 10.8. Somatosensory organization and interhemispheric inhibition (IHI) changes in dystonia. (A) High-resolution functional MRI study of area 3b of the somatosensory cortex with vibrotactile stimulation of individual digits in focal hand dystonia patients. Euclidean distance (interdigit distances in area 3b) calculated between digit 1 (D1, thumb) and other digits for writer’s cramp (WC; black bars) patients (n ¼ 12) and control subjects (CT; gray bars; n ¼ 12). There is increasing distance between D1 and all sequential digits for both groups, but the distance between D1 and each digit is reduced in WC patients. Asterisks denote P < 0.01 for a onetailed test. Error bars represent standard errors. (B) Group-averaged motor evoked potential (MEP) amplitudes (with standard errors) recorded in the right, dystonia-affected hand (conditioning stimulus [CS] to right M1, test stimulus [TS] to left M1) and left, unaffected hand (CS to left M1, TS to right M1) during rest in focal hand dystonia patients. Ratios <1 indicate suppression and >1 indicate facilitation. There was less suppression in the affected right hand, which showed reduced IHI from right to left M1. (C) Group-averaged histograms comparing short interhemispheric inhibition (SIHI) (10–12 ms) and long interhemispheric inhibition (LIHI) (30–40 ms) in the affected right hand compared to the unaffected left hand. Both SIHI and LIHI are reduced in the dystonia affected right hand. *P < 0.05. Panel (A): Adapted from Nelson AJ, Blake DT, Chen R (2009). Digit-specific aberrations in the primary somatosensory cortex in writer’s cramp. Ann Neurol 66: 146–154. Panel (B): Adapted from Nelson AJ, Hoque T, Gunraj C, et al. (2010). Impaired interhemispheric inhibition in writer’s cramp. Neurology 75: 441–410.

of the somatosensory cortex (Fig. 10.8A) was found using functional magnetic resonance imaging in focal hand dystonia patients (Nelson et al., 2009). Thus single pulse TMS studies could be used to explore the pathophysiology of dystonia (Table 10.1).

PAIRED PULSE TMS STUDIES IN DYSTONIA (TABLES 10.1 AND 10.2) Short interval intracortical inhibition SICI is decreased in resting hand muscles in upper limb dystonia, blepharospasm, cervical dystonia, doparesponsive dystonia, asymptomatic carriers of the DYT-1 gene, and functional (psychogenic) dystonia (Ridding et al., 1995b; Gilio et al., 2003; Espay et al., 2006; Chen et al., 2008). SICI is reduced when patients

with dystonia are at rest and not expressing symptoms, in unaffected body parts, and in asymptomatic gene carriers. However, some studies failed to replicate this reduced inhibition (Stinear and Byblow, 2004; Brighina et al., 2009). These differences could be due to various factors such as (a) an elevated threshold for inhibition in dystonia(that could be missed when studied with conventional methods) (Stinear and Byblow, 2004); (b) different subtypes of dystonia (DYT-5 Segawa disease had normal SICI) (Hanajima et al., 2007); and (c) the use of different coil orientations that activate different sets of indirect waves in the motor cortex (SICI was shown to be abnormal in focal hand dystonia with posterior–anterior directed current, but not anterior– posterior directed current) (Hanajima et al., 2008). SICI can potentially be used as a prognostic marker of

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therapeutic intervention as DBS increases SICI toward normal levels. These changes correlated with the degree of clinical improvement (Ruge et al., 2011b) in dystonia patients treated with GPi-DBS.

Long interval intracortical inhibition Resting LICI is reported to be normal in writer’s cramp and decreased in a group of mixed dystonia subjects and in psychogenic dystonia. In writer’s cramp during voluntary activity LICI decreases, but it increases during slight contraction in a mixed group of dystonic subjects.

Intracortical facilitation ICF was found to be increased in patients with focal hand dystonia (FHD) and blepharospasm (Sommer et al., 2002). ICF increased in cervical dystonia, which normalized during application of sensory tricks (Amadio et al., 2014). Thus sensory tricks could reduce cortical excitability and improve dystonic symptoms.

SAI and LAI In FHD, TMS studies have found diminished LAI (Abbruzzese et al., 2001) whereas SAI was normal (Kessler et al., 2005). Other studies showed altered surround inhibition and responses to sensory stimuli in patients with dystonia (Sohn and Hallett, 2004). In a study of sensorimotor integration, focal muscle vibration reduced SICI in healthy subjects but not in writer’s cramp patients. Patients with musician’s cramp exhibited reduced SICI in both vibrated and nonvibrated muscles. These findings suggest different underlying pathophysiologic mechanisms for different types of FHD.

Interhemispheric inhibition IHI was reduced in dystonia, especially in patients with mirror dystonia (dystonia induced by performing specific tasks with the unaffected arm) (Sattler et al., 2014). There was reduced IHI from the unaffected to the affected M1 at rest (right hand dystonic patients [left affected hemisphere] showed reduced IHI from right to left M1) (Fig. 10.8B and C) but not during the task of holding a pen in writer’s cramp patients (Nelson et al., 2010). A study exploring different factors that influence reduced IHI in dystonia found that musical activity and family history of dystonia are more significant factors compared to dystonia per se, age, or gender, and suggested the reduced IHI could be an endophenotypic marker of musician’s dystonia (Baumer et al., 2016).

Cerebellar inhibition In FHD, cerebellar inhibition is comparable in healthy controls. However, cerebellar modulation of intracortical circuits was abnormal (without effect from cerebellar stimulation on SICI and ICF) in FHD, whereas cerebellar stimulation increased ICF and decreased SICI in healthy controls (Daskalakis et al., 2004; Brighina et al., 2009). In summary, the paired pulse TMS studies have provided information about intracortical circuits in different types of dystonia (Tables 10.1 and 10.2). Additional studies with longitudinal design and assessment of effects of treatment may lead to biomarkers to improve management of dystonia.

PLASTICITY STUDIES IN DYSTONIA There was excessive plasticity with abnormal spread of the induced plasticity to nontargeted muscles (Quartarone et al., 2003; Weise et al., 2006) in dystonia patients with response to PAS protocol. The increased LTP-like plasticity extended to body parts unaffected by dystonia. For example, patients with cervical dystonia, blepharospasm, or oromandibular dystonia had excessive plasticity measured in their unaffected hand muscles (Quartarone et al., 2008). These clinical studies are supported by in vitro recordings in slice preparations from DYT1 mice showing that cortico-striatal synaptic LTP is enhanced, whereas LTD cannot be induced when compared with the control group (Martella et al., 2009). These studies led to the hypothesis that task-specific hand dystonia is related to excessive plasticity, possibly due to abnormal association between sensory input and motor output with deficient homeostatic control (Quartarone et al., 2006). However, plasticity responses in patients with focal hand dystonia have been variable due to methodological differences in plasticity induction protocols and interindividual variability (Sadnicka et al., 2014). Variability in plasticity response needs to be kept in mind when assessing cortical plasticity in patients with dystonia. A study (Tisch et al., 2007) explored the impact of GPi-DBS on PAS-induced cortical plasticity in primary generalized dystonic patients. When GPi-DBS was turned off, PAS increased cortical excitability in dystonia patients and the results were similar to those in healthy subjects. With GPi-DBS turned on, PAS induced a decrease rather than the expected increase in cortical excitability. A longitudinal study in dystonia found that, before surgery, PAS-induced LTP-like plasticity was increased and SICI was decreased, as expected. The LTP-like plasticity decreased after surgery, with the maximum reduction occurring before maximum clinical improvement, suggesting that reduction of LTP-like

MOTOR CORTICAL CIRCUITS IN PARKINSON DISEASE AND DYSTONIA plasticity may drive the clinical improvement and explain the delayed improvement (Ruge et al., 2011b). In generalized dystonia patients treated with chronic GPi-DBS, patients with higher degrees of LTP-like plasticity induced by PAS with DBS-ON had less deterioration in dystonic symptoms after DBS was switched off for 2 days (Ruge et al., 2011a). The authors suggested that LTP-like plasticity may play a role in maintaining the “normal” nondystonic state in patients treated with longterm DBS. In addition, repeated GPi-DBS paired with M1-TMS at latencies of 10 and 25 ms was found to induce LTP-like cortical plasticity (Ni et al., 2018). Hence, GPi-DBS was able to modulate and correct the abnormalities of intracortical networks in the M1. Furthermore, TMS provides an opportunity to understand the mechanisms of these physiologic changes induced by DBS. Thus exaggerated plasticity observed in the dystonic state is normalized by DBS and further studies on altering motor cortical plasticity could explore its potential roles in the management of dystonia.

OSCILLATIONS STUDIES IN DYSTONIA It has been reported that neuronal firing rates in the GPi negatively correlated with the clinical severity of dystonia (Lenz et al., 1998). Since the GPi inhibits the thalamus, the finding suggests that decreased inhibition of the thalamus may lead to dystonia. Furthermore, GPi neuronal activities in dystonia are different from those of PD with decreased relative power in 4–30 Hz of neuronal oscillations and a decreased frequency of GPi neuronal firing rate (70 vs 90 Hz in PD) (Silberstein et al., 2003; Tang et al., 2007). Studies recording LFP from implanted GPi-DBS electrodes during self-paced wrist extension movements in dystonia patients showed contralateral g (64–68 Hz) synchronization (increase) and bilateral b (10–24 Hz) desynchronization (reduced) before and during the movements (Tsang et al., 2012a). Importantly, there were prominent 5–18 Hz oscillations in the GPi in dystonia with strong coherence between bilateral GPi at this frequency band. The power of this frequency band and the coherence decreased with voluntary movements. Moreover, in a patient with severe secondary dystonia due to BG infarction, there was strong coherence between the GPi and the thalamus in the 5–18 Hz band (Tsang et al., 2012b). These findings agree with previous studies showing that 5–18 Hz oscillations in the GPi can drive EMG activities in dystonic muscles (Chen et al., 2006; Liu et al., 2008; Sharott et al., 2008). Therefore 5–18 Hz oscillations in the GPi may be a hallmark of dystonia (Sharott et al., 2008; Tsang et al., 2012a,b). Thus the most characteristic LFP findings in dystonia are prominent 5–18 Hz

181

oscillations and coherence between bilateral GPi at rest that attenuates with movements. The clinical significance of this frequency band could be explored further with stimulation at subject specific frequencies or its resonant frequencies.

CONCLUSIONS Research studies have shown altered cortical excitability and cortical facilitatory and inhibitory circuits in PD and dystonia as measured by single and paired pulse TMS protocols (Table 10.1). Plasticity induction protocols using TMS have found decreased plasticity in PD and normal or exaggerated plasticity in dystonia, although there is considerable variability in these measures. Recordings from the BG showed increased b (14–30 Hz) rhythm in PD and characteristic 5–18 Hz band synchronization in dystonia. These cortical circuits, plasticity measures, and oscillations are altered by medications and DBS treatment. Although many studies investigated changes in excitability, plasticity, and oscillation measures in PD and dystonia compared with healthy controls, there are few longitudinal studies investigating these measures comprehensively with large numbers of patients to account for the variability of these measures due to factors such as clinical phenotypes, disease stage, and medication profile of the patients. Future studies may improve our understanding of disease pathophysiology and lead to innovative treatment strategies. Some TMS measures could potentially be used as biomarkers in the diagnosis of movement disorders or prognostic markers of the efficacy of treatments. Combining noninvasive TMS with invasive DBS may be a way to induce plasticity in the BG-M1 circuitry and to increase the clinical benefits of DBS. Future studies could lead to individualized DBS parameter settings based on neurophysiologic parameters to better control symptoms of movement disorders and provide feedback signals for the development of closed-loop DBS systems.

ABBREVIATIONS BG, basal ganglia; CBI, cerebellar inhibition; CST, corticospinal tract; DBS, deep brain stimulation; EEG, electroencephalogram; FHD, focal hand dystonia; GABA, gamma (g)-aminobutyric acid; ICF, intracortical facilitation; LAI, long latency afferent inhibition; LFP, local field potential; LICI, long interval intracortical inhibition; LID, levodopa induced dyskinesia; LIHI, long interval interhemispheric inhibition; M1, primary motor cortex; MEG, magnetoencephalography; MEP, motor evoked potential; MT, motor threshold; the lowest stimulus intensity capable of eliciting small motor-evoked potentials; PAS, paired associative

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stimulation; PD, Parkinson’s disease; SAI, short latency afferent inhibition; SICF, short interval intracortical facilitation; SICI, short interval intracortical inhibition; SIHI, short interval interhemispheric inhibition; TMS, transcranial magnetic stimulation; UPDRS, Unified Parkinson’s Disease Rating Scale.

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