Objective: Short intracortical inhibition (SICI) is a GABAA-mediated phenomenon, argued to mediate selective muscle activation during coordinated motor activity. Markedly reduced SICI has been observed in the acute period following stroke and, based on findings in animal models, it has been posited this disinhibitory phenomenon may facilitate neural plasticity and contribute to early motor recovery. However, it remains unresolved whether SICI normalizes over time, as part of the natural course of stroke recovery. Whether intracortical inhibition contributes to motor recovery in chronic stroke also remains unclear. Notably, SICI is typically measured at rest, which may not fully reveal its role in motor control. Here we investigated SICI at rest and during voluntary motor activity to determine: (1) whether GABAA-mediated inhibition recovers, and (2) how GABAA-mediated inhibition is related to motor function, in the chronic phase post-stroke. Methods: We studied 16 chronic stroke survivors (age: 64.6 ± 9.3 years; chronicity: 74.3 ± 52.9 months) and 12 age-matched healthy controls. We used paired-pulse transcranial magnetic stimulation (TMS) to induce SICI during three conditions: rest, submaximal grip, and performance of box-and-blocks. Upper-extremity Fugl-Meyer Assessment and Box-and-Blocks tests were used to evaluate motor impairment in stroke survivors and manual dexterity in all participants, respectively. Results: At rest, SICI revealed no differences between ipsilesional and contralesional hemispheres of either cortical or subcortical stroke survivors, or healthy controls (P's > 0.05). During box-and-blocks, however, ipsilesional hemisphere SICI was significantly reduced (P = 0.025), especially following cortical stroke (P < 0.001). SICI in the ipsilesional hemisphere during box-and-blocks task was significantly related to paretic hand dexterity (r = 0.56, P = 0.039) and motor impairment (r = 0.56, P = 0.037). Conclusions: SICI during motor activity, but not rest, reveals persistent impairment in chronic stroke survivors indicating that inhibitory brain circuits responsible for motor coordination do not fully normalize as part of the natural history of stroke recovery. Observation that reduced SICI (i.e., disinhibition) is associated with greater motor impairment and worse dexterity in chronic hemiparetic individuals suggests the response considered to promote neuroplasticity and recovery in the acute phase could be maladaptive in the chronic phase post-stroke.

April 27, 2018April 10, 2018Free AccessNeuropathic Tremor Secondary to Chronic Immune Demyelinating Polyneuropathy with Robust Response to Intravenous Immune Globulin (P6.340)C Chauncey Spears, Christopher W. Hess, Michael S. Okun, William J. Triggs, and Leonardo AlmeidaAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.P6.340 Letters to the Editor

Introduction: Short intracortical inhibition (SICI) is a GABAa-mediated phenomenon argued to mediate motor selectivity. SICI is markedly reduced, producing motor disinhibition, in the sub-acute period following cortical (CORT), but not subcortical (SC), stroke. Previous work suggests SICI may normalize as part of the natural course of recovery. Importantly, SICI is typically measured at rest complicating our understanding of its role in motor control and recovery following stroke. Here we investigated task-dependent differences in SICI in chronic stroke survivors. Hypothesis: We hypothesized: i) differences between SICI measured at rest and during voluntary movement and ii) SICI during voluntary movement would reveal persistent impairments following CORT stroke. Methods: We tested 13 adults (65±8.5 yr, 11 male) with chronic (72.8±52.6 mo) stroke (5 CORT, 8 SC) and 7 controls (CON)(58±6.9 yr, 4 male) using paired-pulse transcranial magnetic stimulation during 3 tasks: rest, grip, box & blocks (B&B). Motor evoked responses (MEPs) were measured from the first dorsal interosseous of the paretic and non-dominant hands of stroke and CON, respectively. SICI was induced by conditioning the test MEP at 0.8 resting or 0.7 active, motor threshold at the interstimulus interval producing maximal SICI at R (3 ms CON, 3.7 ms Stroke) and quantified as the ratio of conditioned/unconditioned MEParea. Stimulation intensity was adjusted to maintain test MEP amplitude at 1mV pk-pk across tasks. Results: At rest, SICI was similar between groups (p > 0.5). However during grip, CORT revealed significantly less SICI than CON or SC (p’s .05). During B&B, CORT again revealed less SICI than CON (p =.04); however SICI was similar between CORT and SC (p >.05). Across tasks, SICI produced by CON and SC was similar (p >.05) while CORT revealed less SICI during both grip and B&B (p’s <.005) compared to rest. Conclusions: Measured at rest, SICI is similar across groups suggesting GABAa circuits are normalized as part of the natural course of stroke recovery. However, SICI measured during voluntary motor tasks reveals persistent impairments, which are more widespread following CORT stroke and may interfere with rehabilitation involving voluntary movement.

Introduction. Restoration of upper extremity (UE) functional use remains a challenge for individuals following stroke. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive modality that modulates cortical excitability and is being explored as a means to potentially ameliorate these deficits. The purpose of this study was to evaluate, in the presence of chronic stroke, the effects of low-frequency rTMS to the contralesional hemisphere as an adjuvant to functional task practice (FTP), to improve UE functional ability. Methods. Twenty-two individuals with chronic stroke and subsequent moderate UE deficits were randomized to receive 16 sessions (4 times/week for 4 weeks) of either real-rTMS or sham-rTMS followed by 1-hour of paretic UE FTP. Results. No differences in UE outcomes were revealed between the real-rTMS and sham-rTMS intervention groups. After adjusting for baseline differences, no differences were revealed in contralesional cortical excitability postintervention. In a secondary analysis, data pooled across both groups revealed small, but statistically significant, improvements in UE behavioral measures. Conclusions. rTMS did not augment changes in UE motor ability in this population of individuals with chronic stroke. The chronicity of our participant cohort and their degree of UE motor impairment may have contributed to inability to produce marked effects using rTMS.

Background and Objective:We previously reported a randomized, sham-controlled trial of 5 Hz dorsolateral prefrontal left- and right-side repetitive transcranial magnetic stimulation (rTMS) in 48 participants with a medically refractory major depressive disorder. Depression improved most with right-side cranial stimulation, both rTMS and sham, and to a lesser degree with left rTMS. Because depression is often associated with cognitive impairment, in this study we sought to determine whether our earlier participants had treatment-induced changes in cognition, which cognitive domains (language, executive, visuospatial, verbal episodic memory, attention) were affected, and whether treatment-induced cognitive changes were related either to improvement in depression or to other treatment variables, such as right versus left treatment and rTMS versus sham. Methods:We used hierarchical regression analyses to determine how variables measured at baseline or associated with treatment affected changes in neuropsychological functions. The variables were neuropsychological function in the 5 domains, severity of depression, change in depression with treatment, rTMS versus sham, laterality of stimulation, and rTMS-laterality interaction. Results:Compared to sham, right rTMS was associated with 1.24 standard deviations greater gain in language function, 1.09 standard deviations greater gain in visuospatial function, and 2.38 standard deviations greater gain in verbal episodic memory than left rTMS. These improvements did not appear to be directly related to the relief from depression. Conclusions:Our results suggest that disorders of cognition and mood in depression may have different mechanisms, but right rTMS may treat both. We propose potential mechanisms underlying the right-side rTMS effect. Clinical Trial Registration:Clinicaltrials.gov NCT00711568.

Millions of individuals experience tinnitus, the perception of sound in the absence of auditory stimulation.1 Chronic tinnitus may disrupt sleep and be associated with substantial irritability, depression, and anxiety. Treatment of disabling tinnitus may include the use of sound generators, drugs, and behavioral therapies, but is often unsatisfactory.1,2Tinnitus is usually, but not always, associated with injury or disease of the peripheral auditory system (e.g., hearing loss due to noise exposure). Our understanding of the pathophysiologic basis of tinnitus is incomplete, but increasingly recognizes the importance of long-term central maladaptations to peripheral triggering …

Corti M, Patten C, Triggs W: Repetitive transcranial magnetic stimulation of motor cortex after stroke: A focused review. Am J Phys Med Rehabil 2012;91:254Y270.Repetitive Transcranial Magnetic Stimulation (rTMS) is known to modulate cortical excitability and has thus been suggested to be a therapeutic approach for improving the efficacy of rehabilitation for motor recovery after stroke. In addition to producing effects on cortical excitability, stroke may affect the balance of transcallosal inhibitory pathways between motor primary areas in both hemispheres: the affected hemisphere (AH) may be disrupted not only by the infarct itself but also by the resulting asymmetric inhibition from the unaffected hemisphere, further reducing the excitability of the AH. Conceptually, therefore, rTMS could be used therapeutically to restore the balance of interhemispheric inhibition after stroke. rTMS has been used in two ways: low-frequency stimulation (<= 1 Hz) to the motor cortex of the unaffected hemisphere to reduce the excitability of the contralesional hemisphere or high-frequency stimulation (91 Hz) to the motor cortex of the AH to increase excitability of the ipsilesional hemisphere. The purpose of this systematic review is to collate evidence regarding the safety and efficacy of high-frequency rTMS to the motor cortex of the AH. The studies included investigated the concurrent effects of rTMS on the excitability of corticospinal pathways and upper-limb motor function in adults after stroke. This review suggests that rTMS applied to the AH is a safe technique and could be considered an effective approach for modulating brain function and contributing to motor recovery after stroke. Although the studies included in this review provide important information, double-blinded, sham-controlled Phase II and Phase III clinical trials with larger sample sizes are needed to validate this novel therapeutic approach.

Repetitive Transcranial Magnetic Stimulation (rTMS) is known to modulate cortical excitability and has thus been suggested to be a therapeutic approach for improving the efficacy of rehabilitation for motor recovery after stroke. In addition to producing effects on cortical excitability, stroke may affect the balance of transcallosal inhibitory pathways between motor primary areas in both hemispheres: the affected hemisphere (AH) may be disrupted not only by the infarct itself but also by the resulting asymmetric inhibition from the unaffected hemisphere, further reducing the excitability of the AH. Conceptually, therefore, rTMS could be used therapeutically to restore the balance of interhemispheric inhibition after stroke. rTMS has been used in two ways: low-frequency stimulation (≤1 Hz) to the motor cortex of the unaffected hemisphere to reduce the excitability of the contralesional hemisphere or high-frequency stimulation (>1 Hz) to the motor cortex of the AH to increase excitability of the ipsilesional hemisphere. The purpose of this systematic review is to collate evidence regarding the safety and efficacy of high-frequency rTMS to the motor cortex of the AH. The studies included investigated the concurrent effects of rTMS on the excitability of corticospinal pathways and upper-limb motor function in adults after stroke. This review suggests that rTMS applied to the AH is a safe technique and could be considered an effective approach for modulating brain function and contributing to motor recovery after stroke. Although the studies included in this review provide important information, double-blinded, sham-controlled Phase II and Phase III clinical trials with larger sample sizes are needed to validate this novel therapeutic approach.

1663 COMT Val158Met genotype influences neurodegeneration within dopamine-innervated brain structures E.D. Gennatas, J.A. Cholfin, J. Zhou, R.K. Crawford, D.A. Sasaki, A. Karydas, A.L. Boxer, S.J. Bonasera, K.P. Rankin, M.L. Gorno-Tempini, H.J. Rosen, J.H. Kramer, M. Weiner, B.L. Miller, and W.W. Seeley 1670 Primary progressive aphasia: A tale of two syndromes and the rest S.A. Sajjadi, K. Patterson, R.J. Arnold, P.C. Watson, and P.J. Nestor

Prior reports have described a transient and focal decline in transcranial magnetic stimulation (TMS)-induced motor evoked potential (MEP) amplitude following fatiguing motor tasks. However, the neurophysiological causes of this change in MEP amplitude are unknown. The aim of this study was to determine whether post-task depression of MEPs is associated with repetitive central motor initiation. We hypothesized that MEP depression is related to repeated central initiation of motor commands in task-related cortex independent of motor fatigue. Twenty healthy adults had MEPs measured from the dominant first dorsal interosseous (FDI) muscle before and after six different tasks: rest (no activity), contralateral fatiguing hand-grip, ipsilateral fatiguing hand-grip, contralateral finger tapping, ipsilateral finger tapping, and imagined hand-grip (motor imagery). Changes in MEPs from baseline were assessed for each task immediately following the task and at 2-min intervals until MEPs returned to a stable baseline. Measures of subjective effort and FDI maximum voluntary contractions (MVC) were also recorded following each task. A statistically significant drop in MEP amplitude was noted only with contralateral finger tapping and imagined grip. Changes in MEP amplitude did not correlate with subjective fatigue or effort. There was no significant change in FDI MVCs following hand-grip or finger-tapping tasks. This study extends our knowledge of the observed decline in MEP amplitude following certain tasks. Our results suggest that central initiation of motor programs may induce a change in MEP amplitude, even in the absence of objective fatigue.

Objectives/Hypothesis: The objective was to determine whether low-frequency repetitive transcranial magnetic stimulation (rTMS) improves tinnitus by decreasing neural activity in auditory processing regions of the temporal cortex and the utility of positron emission tomography (PET) for targeting treatment.Study Design: Randomized, sham-controlled crossover.Methods: Patients received a five-day course of active and sham 1-Hz rTMS (1800 pulses at 110% of motor threshold) to the temporal cortex, with a week separating active and sham treatment. Visual analogue ratings of tinnitus loudness (VARL) were assessed at baseline and the end of each treatment week; regional brain blood flow (rBBF) and glucose metabolism (via PET) were measured before and after treatment in regions of interest (ROI) beneath the stimulating coil and control sites.Results: The VARL for both ears significantly decreased after active but not sham treatment. Responders comprised 43% of patients, experiencing at least a 33% drop in tinnitus loudness. The site most consistently associated with a positive response was the secondary auditory cortex (Brodmann Area 22) in either hemisphere. PET asymmetries were variable across patients and not always accessible to rTMS. Whereas PET activity decreased significantly beneath the stimulating coil following active treatment, similar changes occurred at control sites and after sham stimulation. Change in tinnitus perception did not correlate significantly with change in PET activity at the treatment site ROI.Conclusions: Active TMS led to a significant reduction in tinnitus loudness, but PET scans failed to support the hypothesis that low-frequency rTMS improves tinnitus by reducing cortical activation at the stimulation site, questioning the utility of PET for targeting rTMS.

We conducted a prospective, randomized, sham-controlled, double blind, parallel group study of right or left pre-frontal rTMS in 48 subjects with medication-resistant depression. Two thousand (50 × 8 - s trains of 5 Hz) stimuli at MEP threshold were delivered each weekday for 2 weeks. We employed a sham coil and simultaneous electrical stimulation of the scalp to simulate rTMS. Mean (±S.D.) reductions in the HAMD-24 from baseline to 3-months were not significantly different between rTMS and sham treatment groups. However, right cranial stimulation (sham or rTMS) was significantly more effective than left cranial stimulation (sham or rTMS) (P = 0.012). Mean (± S.D.) reductions in the HAMD from baseline to 3 months were: left: 28.1 (± 5.36) to 19.2 (± 11.2); and right 27.2 (± 4.2) to 11.5 (± 9.4). Left rTMS achieved a reduction in HAMD 9.5 points greater than that achieved by left sham, a benefit greater than that reported in a recent multi-center Phase III trial of rTMS (O'Reardon et al., 2007), albeit not statistically significant. These results suggest that somatosensory stimuli that repeatedly engage the left hemisphere may be important to the achievement of therapeutic effect.

BACKGROUND: Most methods of sham, repetitive transcranial magnetic stimulation (rTMS) fail to replicate the look, sound, and feel of active stimulation in the absence of a significant magnetic field. OBJECTIVE/HYPOTHESIS: To develop and validate a new method of sham rTMS appropriate for a double-blind, placebo-controlled study with subject crossover. METHODS: The look and sound of active rTMS was replicated using a matched, air-cooled sham TMS coil. Scalp muscle stimulation associated with rTMS was replicated using large rubber electrodes placed over selected muscles. The intensity and pulse width of electrical stimulation necessary to match 1-Hz rTMS was developed in one sample of normal subjects. The sham technique was validated in back-to-back comparisons with active rTMS in new samples of normal subjects who were either naïve or experienced with rTMS. RESULTS: Subjects naïve to TMS could not tell which type of stimulation was active or sham or which was electrical or magnetic. Naïve subjects incorrectly picked sham stimulation as active, when forced to choose, because electrical stimulation felt more focused than magnetic stimulation. Subjects experienced with TMS could correctly identify sham and active stimulation. Experimenters could detect subtle differences between conditions. CONCLUSIONS: This method of sham rTMS closely mimics the look, sound, and feel of active stimulation at 1Hz without creating a significant magnetic field. It is valid for use with naïve subjects and in crossover studies. It can accommodate differences in scalp muscle recruitment at different sites of stimulation, and it could potentially be used with higher frequency stimulation.

Brain injury in humans causes vascular disruption and deposition of heme and iron compounds into the neuropil. In our laboratory, we have used injection of aqueous iron into brain to imitate this effect of brain injury, and have found that such injections initiate both acute and chronic epileptiform discharges and behavioral seizures. We used this type of model to study injury-associated epileptogenesis, and to develop methods that could well block important brain injury reactions that may lead to seizures. Iron injections trigger robust free radical reactions and lipid peroxidation, and we have evaluated methods for altering those reactions. Amygdalar injection of blood products causes neurochemical and molecular changes that can be altered by some treatment strategies.

Tinnitus, phantom sound perception like ringing, affects 50 million people in the U.S alone. No widely efficacious treatment for tinnitus exists. Tinnitus is linked to maladaptive reorganization of auditory cortex following peripheral injury or disease; indicated both by excessive spread of cortical activity in response to external sound and by asymmetric increases in resting metabolic activity in the temporal lobe. A week long course of low frequency rTMS applied over auditory cortex can reduce tinnitus in >50% of patients but relapse typically occurs in 5 to 10 days. No previous study of tinnitus examined change in cortical metabolism following rTMS. We obtained resting FDG PET scans before and after rTMS to determine if change in cortical metabolism relates to improvement. We also provided maintenance rTMS as symptoms returned to promote long term change.