Cerebellar TMS Research Articles

463. Personalization and Network Specificity of Cerebellar TMS in Schizophrenia

463. Personalization and Network Specificity of Cerebellar TMS in Schizophrenia

The Past, Current and Future Research in Cerebellar TMS Evoked Responses-A Narrative Review.

Transcranial magnetic stimulation coupled with electroencephalography (TMS-EEG) is a novel technique to investigate cortical physiology in health and disease. The cerebellum has recently gained attention as a possible new hotspot in the field of TMS-EEG, with several reports published recently. However, EEG responses obtained by cerebellar stimulation vary considerably across the literature, possibly due to different experimental methods. Compared to conventional TMS-EEG, which involves stimulation of the cortex, cerebellar TMS-EEG presents some technical difficulties, including strong muscle twitches in the neck area and a loud TMS click when double-cone coils are used, resulting in contamination of responses by electromyographic activity and sensory potentials. Understanding technical difficulties and limitations is essential for the development of cerebellar TMS-EEG research. In this review, we summarize findings of cerebellar TMS-EEG studies, highlighting limitations in experimental design and potential issues that can result in discrepancies between experimental outcomes. Lastly, we propose a possible direction for academic and clinical research with cerebellar TMS-EEG.

The effect of cerebellar TMS on error processing: A combined single-pulse TMS and ERP study

Abstract The present study investigated temporal aspects of cerebellar contributions to the processing of performance errors as indexed by the error-related negativity (ERN) in the response-locked event-related potential (ERP). We co-registered EEG and applied single-pulse transcranial magnetic stimulation (spTMS) to the left posterolateral cerebellum and an extra-cerebellar control region (vertex) while healthy adult volunteers performed a Go/Nogo Flanker Task. In Go trials, TMS pulses were applied at four different time points, with temporal shifts of -100 ms, -50 ms, 0 ms, or +50 ms relative to the individual error latency (IEL, i.e., individual ERN peak latency + median error response time). These stimulation timings were aggregated into early (-100 ms, -50 ms) and late (0 ms, +50 ms) stimulation for the analysis. In Nogo trials, TMS pulses occurred 0 ms, 100 ms, or 300 ms after stimulus onset. Mixed linear model analyses revealed that cerebellar stimulation did not affect error rates overall. No effects were found for response times. As hypothesized, ERN amplitudes were decreased for cerebellar stimulation. No significant differences were found for the error positivity (Pe). Similar to TMS application to probe cerebellar-brain inhibition in the motor domain, the inhibitory tone of the cerebellar cortex may have been disrupted by the pulses. Reduced inhibitory output of the cerebellar cortex may have facilitated the processing of error information for response selection, which is reflected in a decreased ERN.

Reply to: “Reflecting the causes of variability of EEG responses elicited by cerebellar TMS”

In their commentary on our recently published paper about electroencephalographic responses induced by cerebellar transcranial magnetic stimulation (Fong et al., 2023), Gassmann and colleagues (Gassmann et al., 2023b) try to explain the differences between our results and their own previous work on the same topic. We agree with them that many of the differences arise from our use of a different magnetic stimulation coil. However, two unresolved questions remain. (1) Which method is most likely to achieve optimal activation of cerebellar output? (2) To what extent are the evoked cerebellar responses contaminated by concomitant sensory input? We highlight the role of careful experimental design and of combining electrophysiological and behavioural data to obtain reliable TMS-EEG data.

Reflecting the causes of variability of EEG responses elicited by cerebellar TMS

Recently, Fong et al. published EEG responses in cerebral cortex elicited by cerebellar TMS (cbTMS) (Fong et al., 2023), which differ from our recently identified cbTMS-EEG responses (Gassmann et al., 2022). Fong et al. argued that this discrepancy is due to coil placement unsuitable for eliciting cerebellar brain inhibition (CBI) in our study. However, we reliably elicited CBI in our subjects. Consequently, this leads to a compelling discussion on possible reasons for the observed discrepancies in cbTMS-evoked EEG responses. Reliably measuring cbTMS-evoked EEG responses could become an important neurophysiological tool to test effective cerebellum-to-cortex connectivity.

P 58 EEG responses from direct cerebellar activation with Transcranial Magnetic Stimulation

Introduction: Measuring cortical responses from cerebellar stimulation might provide diagnostic biomarkers for the dentato-thalamo-cortical pathway's integrity. Recent studies have investigated the feasibility of delivering cerebellar stimulation through transcranial magnetic stimulation-electroencephalography (TMS-EEG). TMS-EEG presents several potential advantages and could provide more information than previous methods, which rely on motor output measures. However, past TMS-EEG studies were subject to considerable limitations, including contamination of the TMS-evoked potentials by peripherally-evoked potentials (PEPs). Therefore, we aimed to investigate cortical signatures of cerebellar stimulation, while controlling for confounding factors. Methods: We recruited 23 healthy, right-handed volunteers (13 females, mean ± SD age, 22.4±2.2 years). For each, resting motor threshold was used to titrate the intensity necessary to elicit a detectable cerebellar brain inhibition, which was set as the cerebellar TMS-intensity. A total of 280 single TMS pulses were then delivered to the cerebellum, 140 corresponding to REAL and 140 to SHAM condition. SHAM consisted of TMS to the right shoulder, whereas REAL consisted of both TMS to the right cerebellar hemisphere and to the right shoulder. Two further conditions were tested: TMS to the right occipital cortex and TMS to the right trapezius muscle, with otherwise the same parameters of the REAL condition. These conditions aimed to control for confounding factors, respectively collateral occipital cortex activation and PEPs from cerebellar TMS stimulation. EEG-signals of the different conditions were compared with respect to the evoked responses and changes in the time-frequency response via cluster-based t-tests. Results: Comparison of REAL and SHAM revealed significant differences. While some of these differences were explained by the occipital control stimulation, a left-hemispheric prefrontal early positive deflection at 20-26 ms and a left-hemispheric temporal negative deflection peaking at 45 ms (i.e. both contralateral to the cerebellar stimulation) were specific to the cerebellar stimulation. Furthermore, increased frontal theta power immediately after the TMS pulse was specific to the cerebellar stimulation. Conclusions: The investigation of multiple control conditions allowed for unmasking the cortical response resulting specifically from cerebellar TMS. The observed left-hemispheric prefrontal and subsequent temporal cortex responses were only present in conditions involving cerebellar stimulation and could neither be explained by collateral occipital stimulation, nor by a non-specific somatosensory input. These results are anatomically plausible, as targets of the dentato-thalamo-cortical pathway predominantly involve the contralateral prefrontal cortex and structural connectivity between the cerebellum and the contralateral superior temporal sulcus could be demonstrated in past studies.

SY1.8. Application of TMS in movement disorders

I will summarize several TMS applications in movement disorders. Function of supplementary motor area (SMA) and preSMA revealed by QPS (Shimzu T et al). We studied functional differences between the pre-SMA and SMA in sequence learning in humans. To induce LTP/LTD, we administered quadripulse transcranial magnetic stimulation (QPS) with an inter-stimulus interval of 5 or 50 ms (QPS-5/50) over the pre-SMA or SMA in healthy volunteers. QPS-5 over the pre-SMA increased the error rate without any changes in movement speed. When administered over the SMA, QPS affected the rate of reaction time reduction across trials without any changes in the error rate. Cerebellar involvement and cerebellar stimulation treatments. Essential tremor (Hanajima et al). Several lines of evidence suggested a cerebellar pathophysiology of essential tremor (ET). It was recently confirmed by human pathology, neuroimaging studies and others. This hypothesis was also confirmed by cerebellar TMS over cerebellum (cerebellar inhibition: CBI) and prism adaptation task in ET patients (Hanajima et al). Cerebellar stimulation treatments in movement disorders (Çan, M et al). Many researchers have been interested in cerebellar involvement in movement disorders and also cerebellar stimulation as one of treatment methods. However, our magnetic coil must activate cerebellum in some extent but not purely cerebellum alone, and always activate some other structures. The simulation study showed considerable amount of currents must be induced in the cerebellum even with a small coil. Cerebellar stimulation is one of future projects of TMS. Transcranial focused ultrasound stimulation (tFUS). Very low intensity tFUS makes reversible functional changes in human brain. This reversible modulation is used for functional studies of human brains. Its focality and ability to induce functional changes in deep brain structures, such as thalamus, must enable this method to be used in movement disorders. Alternative leg movements induction by lumbar rTMS (Nishimura et al). The lumbar gait center is known to produce gait-like alternative leg movements in animals. We made a system to voluntary induce a gait-like leg movement triggered by her/his own upper limb EMGs. This system induced alternative leg movements, gait like movements, in patients with paraplegia due to spinal cord injury.

Cerebellar Transcranial Magnetic Stimulation Disrupts Vestibular Reflexes in Standing Balance

Despite its seemingly effortless execution, standing balance is a complex task maintained by the integration of sensory feedback from visual, somatosensory (muscle, skin, joint receptors), and vestibular (inner ear) systems. The vestibular system provides feedback about head acceleration and can be manipulated experimentally by passing an electrical current percutaneously through the mastoid processes. The cerebellum plays an important role in standing balance by integrating sensory feedback to refine activity in postural muscles. A recent study has shown that experimentally depressing cerebellar activity with repetitive transcranial magnetic stimulation can influence postural sway and muscle reflex responses following electrical vestibular stimulation. The aim of this study was to investigate the impact of acute cerebellar stimulation on vestibular muscle reflex responses in different head positions during standing balance. We applied a novel combination of stochastic electrical vestibular stimulation (SVS, ±2.5 mA, 0–20 Hz) and single‐pulse cerebellum transcranial magnetic stimulation (TMS, 60% maximum stimulator output) on fifteen healthy adults (6 males, 9 females; 21–32 years old) in two head positions: head forward and head right. Muscle reflexes were recorded bilaterally with surface electromyography (EMG) from lower leg (soleus and medial gastrocnemius) and neck (sternocleidomastoid) muscles. Time‐based cumulant density and frequency‐based coherence analyses were used to evaluate the relationship between the SVS and evoked EMG responses one second before (Pre) and one second after (Post) cerebellar TMS. 50 TMS pulses were delivered per head position. Preliminary analysis performed on left medial gastrocnemius (LMG) head right data indicated a significant reduction in the short latency (SL, P = 0.0377) and medium latency (ML, P < 0.0001) reflexes following cerebellar TMS (Fig. 1). In addition, a significant drop in the coherence between the SVS and LMG Pre to Post was found using a difference of coherence test. These findings support the cerebellum to be an important center for the integration of vestibular feedback for the control of standing balance.Support or Funding InformationMount Royal University Faculty of Science and TechnologyFigure 1

Cerebellar Transcranial Magnetic Stimulation Reduces the Silent Period on Hand Muscle Electromyography During Force Control.

This study aimed to investigate whether cerebellar transcranial magnetic stimulation (C-TMS) affected the cortical silent period (cSP) induced by TMS over the primary motor cortex (M1) and the effect of interstimulus interval (ISI) on cerebellar conditioning and TMS to the left M1 (M1-TMS). Fourteen healthy adult participants were instructed to control the abduction force of the right index finger to 20% of the maximum voluntary contraction. M1-TMS was delivered during this to induce cSP on electromyograph of the right first dorsal interosseous muscle. TMS over the right cerebellum (C-TMS) was conducted prior to M1-TMS. In the first experiment, M1-TMS intensity was set to 1 or 1.3 × resting motor threshold (rMT) with 20-ms ISI. In the second experiment, the intensity was set to 1 × rMT with ISI of 0, 10, 20, 30, 40, 50, 60, 70, or 80 ms, and no-C-TMS trials were inserted. In results, cSP was significantly shorter in 1 × rMT condition than in 1.3 × rMT by C-TMS, and cSP was significantly shorter for ISI of 20–40 ms than for the no-C-TMS condition. Further, motor evoked potential for ISI40-60 ms were significantly reduced than that for ISI0. Thus, C-TMS may reduce cSP induced by M1-TMS with ISI of 20–40 ms.

Cerebellar transcranial magnetic stimulation: The role of coil type from distinct manufacturers

BackgroundStimulating the cerebellum with transcranial magnetic stimulation is often perceived as uncomfortable. No study has systematically tested which coil design can effectively trigger a cerebellar response with the least discomfort. ObjectiveTo determine the relationship between perceived discomfort and effectiveness of cerebellar stimulation using different coils: MagStim (70 mm, 110 mm-coated, 110-uncoated), MagVenture and Deymed. MethodsUsing the cerebellar-brain inhibition (CBI) protocol, we conducted a CBI recruitment curve with respect to each participant’s maximum tolerated-stimulus intensity (MTI) to assess how effective each coil was at activating the cerebellum. ResultsOnly the Deymed double-cone coil elicited CBI at low intensities (−20% MTI). At the MTI, the MagStim (110 mm coated/uncoated) and Deymed coils produced reliable CBI, whereas no CBI was found with the MagVenture coil. Conclusions: The Deymed double-cone coil was most effective at cerebellar stimulation at tolerable intensities. These results can guide coil selection and stimulation parameters when designing cerebellar TMS studies.

Modulation of oculomotor control & adaptation with cerebellar TMS: effects on slow-tonic vergence adaptation.

Modulation of oculomotor control & adaptation with cerebellar TMS: effects on slow-tonic vergence adaptation.

Modulation of oculomotor control & adaptation with cerebellar TMS: effects on saccades.

Modulation of oculomotor control & adaptation with cerebellar TMS: effects on saccades.

Slow-frequency TMS over the vermis impairs motion detection. A preliminary study on the lasting effects of cerebellar TMS over behavior

Slow-frequency TMS over the vermis impairs motion detection. A preliminary study on the lasting effects of cerebellar TMS over behavior

Indian psychiatric society initiated travel fellowship training in psychiatry: A unique opportunity for young psychiatrists.

Byline: Sujita. Kar, Darpan. Kaur Indian Psychiatric Society (IPS) is a powerful force in world psychiatry. Over the past several decades, it has reached several milestones; the latest of which is the initiation of Travel Fellowship Training for young faculties in psychiatry, within the country. The Committee for Research and Education Foundation and Training of IPS has started this Travel Fellowship Training for young life fellow/life ordinary member psychiatrists of IPS. This educational program focuses in strengthening the clinical skills of young psychiatrists in their areas of interest by undergoing training in any institute, within the country under the guidance of experts of the country. In the year, 2015 – IPS has awarded the travel fellowship to Dr. Darpan Kaur, Assistant Professor, Department of Psychiatry, MGM Medical College, Navi Mumbai, Maharashtra and Dr. Sujita Kumar Kar, Assistant Professor, Department of Psychiatry, King George's Medical University, Lucknow, U.P. IPS has arranged all the logistics for travel (to and fro airfare in economic class), accommodation and facilitation of official processes at the training institute. In this report, Dr. Sujita Kumar Kar and Dr. Darpan Kaur share their experience of their fellowships. Dr. Sujita Kumar Kar had opted for the fellowship training on the “Brain Stimulation Techniques” from 23[sup]rd November 2015 to 5[sup]th December 2015 and Dr. Darpan Kaur had opted for the fellowship training in child and adolescent psychiatry from 1[sup]st to 15[sup]th November 2015. Dr. Sujita Kumar Kar undertook training at the Department of Psychiatry at National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru under the mentorship of Prof. B. N. Gangadhar, Prof. Jagadisha Thirthalli, and Dr. Urvakhsh M. Mehta. In the 2 weeks training on “Brain Stimulation Techniques” at the NIMHANS, Bengaluru, the focus was to improve the clinical skills in the newer brain stimulation techniques like – repetitive Transcranial Magnetic Stimulation (rTMS), transcranial Direct Current Stimulation (tDCS), and some unique methods in electroconvulsive therapy (ECT) (especially bi-frontal and electroencephalogram [EEG] monitored ECT). With discussion with the mentors, the following schedule was drawn: *Observing different brain stimulation techniques such as rTMS, tDCS, ECT (especially bi-frontal and EEG monitored ECT) *Hands on training on these techniques *Discussion regarding difficult issues related to these techniques *Reading the resource materials provided *Writing two scientific papers *Making a presentation on a selected topic before completing the training. The trainee directly observed and conducted the hands-on administration of TMS sessions including neuro-navigation assisted rTMS, continuous and intermittent theta burst stimulation, and cerebellar TMS. He had observed tDCS procedure in patients with OCD, alcohol dependence (for anticraving purpose), and persistent auditory hallucination as well as EEG monitored ECT and bi-frontal ECT. Two academic articles are under preparation for publication. He presented a seminar on the topic, “efficacy and predictors of treatment response in rTMS in depression”. At the end of the fellowship, the trainee acquired skills to administer different types of TMS, tDCS, and ECT. He has also acquired knowledge about these brain-stimulation techniques including the potential of setting up similar laboratories elsewhere. He developed the competence of planning research using these techniques. The hospitality and support of the mentors, staff, and residents were unimaginable. Overall, it was a nice and memorable experience of academic, clinical learning which will be helpful in clinical practice, teaching as well as research collaboration. A travel fellowship program of short duration is an excellent opportunity of strong relevance to current generation psychiatrists to build up skills in their area of interest. …

P172. Clinical and neurophysiological effects of cerebellar TMS in cervical dystonia

Introduction Cervical Dystonia (CD) is a movement disorder causing involuntary neck muscle contractions which can lead to abnormal head movements and positions. Although the underlying pathophysiology of CD is poorly understood, there is a growing body of evidence suggesting that the cerebellum and its connections might play a key role in the development of focal dystonia. We therefore hypothesize that changes in cerebello-thalamocortical connections are a crucial part of CD pathophysiology. To test this hypothesis, we set out to study the impact of bilateral virtual lesions of the cerebellar hemispheres on selected clinical and neurophysiological parameters in patients with CD and matched controls. Methods An inhibitory protocol of repetitive transcranial magnetic stimulation (continuous thetaburst-stimulation, cTBS) was used to induce bilateral transient virtual lesions at the cerebellar hemispheres (CRB) in 10 patients with CD and in matched healthy controls. cTBS at the dorsal premotor cortex (PMd) and sham cTBS at the cerebellar hemispheres were used as control conditions. Clinical assessment included the subjective Clinical Global Impression (CGI) scale and the motor subcale of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-M) as rated by an experienced investigator in a blinded manner based on video sequences. Neurophysiological assessment comprised the resting motor threshold, mean motor evoked potential amplitude (at 130% RMT), and the duration of the cortical silent period (CSP), as obtained by transcranial magnetic stimulation at the motor hotspot of the contralateral first dorsal interosseus muscle. Results The protocol proved feasible and safe without any adverse effects. In CD patients (median TWSTRS-M 15.5 [range 14–22]) preliminary analysis points to an overall improvement of CD symptoms following cTBS at bilateral CRB (median CGI efficacy 3 [range 2–4]), but not in the control conditions, while the TWSTRS-M remained stable. cTBS at CRB or PMd may normalize the CSP duration, though a higher number of CD patients will be included prior to definite conclusions on the neurophysiological parameters of interest. Discussion Our preliminary results suggest that bilateral virtual lesions at the cerebellar hemispheres by cTBS may normalize neurophysiological parameters of cortical excitability in patients with CD, along with a subjective overall improvement of CD symptoms. Upon confirmation, our data may be in line with a pathogenetic – rather than compensatory – role of altered cerebello-thalamocortical connections in CD.

Animal research for closed-loop stimulation setup for epilepsy treatment

s / Brain Stimulation 8 (2015) 412e427 418 retinopathy this indexwas 86.5+ 5.5 s and 131.7+ 10.2 s respectively. In the presence of cerebellar TMS the VEP amplitude depressionwas less pronounced, and the restoration period of the VEP characteristics shortened to 92,1+ 7,2 s in patients with diabetic retinopathy. Discussion: Hence, gained data revealed that diabetic retinopathy development is linkedtoprolongedVEPlatencyperiod(P100), lowering of the N75-P100 amplitude, as well as to prolongation of the recovery period of the retina’s functional capacity in patients suffering from the second type of diabetes in the presence of photostress. Cerebellar TMS facilitatesa faster recoveryof theretina’s functionalcapacity inresponse to photostress in diabetic patients with retinopathy. It is supposed that antioxidativemechanisms,whichare inducedbycerebellar stimulation in retina, are in charge for the observed therapeutic effects.

Reliability of transcranial magnetic stimulation related measurements of tibialis anterior muscle in healthy subjects and subjects with Parkinson’s disease

s / Brain Stimulation 8 (2015) 412e427 418 retinopathy this indexwas 86.5+ 5.5 s and 131.7+ 10.2 s respectively. In the presence of cerebellar TMS the VEP amplitude depressionwas less pronounced, and the restoration period of the VEP characteristics shortened to 92,1+ 7,2 s in patients with diabetic retinopathy. Discussion: Hence, gained data revealed that diabetic retinopathy development is linkedtoprolongedVEPlatencyperiod(P100), lowering of the N75-P100 amplitude, as well as to prolongation of the recovery period of the retina’s functional capacity in patients suffering from the second type of diabetes in the presence of photostress. Cerebellar TMS facilitatesa faster recoveryof theretina’s functionalcapacity inresponse to photostress in diabetic patients with retinopathy. It is supposed that antioxidativemechanisms,whichare inducedbycerebellar stimulation in retina, are in charge for the observed therapeutic effects.

Non-invasive Cerebellar Stimulation—a Consensus Paper

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.

P29-18 Cerebellar TMS induces fluctuation of the finger movement while manually tracking a moving target

P29-18 Cerebellar TMS induces fluctuation of the finger movement while manually tracking a moving target

Effects of cerebellar TMS on motor cortex of patients with focal dystonia: a preliminary report

Recent evidence suggests a role for cerebellum in pathophysiology of dystonia. Here we explored, the cerebellar modulation of motor cortex in patients with focal upper limb dystonia. Eight patients and eight controls underwent a transcranial magnetic stimulation protocol to study the cerebellar-brain-inhibition (CBI): a conditioning cerebellar stimulus (CCS) was followed 5 ms after by the contralateral motor cortex stimulation (test stimulus: TS). We explored the effects of CBI on MEP amplitude, short intracortical inhibition (SICI) and intracortical facilitation (ICF) measures. At baseline no differences in TS-MEP amplitude, SICI or ICF were found between patients and controls. Cerebellar-conditioning significantly reduced TS-MEP amplitude, increased ICF, and decreased SICI in control subjects. In contrast, no changes in these neurophysiological measures were observed in the motor cortex of patients, regardless of which side was tested. If further confirmed, these findings suggest a reduced cerebellar modulation of motor cortex excitability in patients with focal dystonia.