Sergiu Groppa

A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee

Transcranial magnetic stimulation (TMS) is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction. This includes but is not limited to patients with multiple sclerosis, amyotrophic lateral sclerosis, stroke, movement disorders, disorders affecting the spinal cord, facial and other cranial nerves. These guidelines cover practical aspects of TMS in a clinical setting. We first discuss the technical and physiological aspects of TMS that are relevant for the diagnostic use of TMS. We then lay out the general principles that apply to a standardized clinical examination of the fast-conducting corticomotor pathways with single-pulse TMS. This is followed by a detailed description of how to examine corticomotor conduction to the hand, leg, trunk and facial muscles in patients. Additional sections cover safety issues, the triple stimulation technique, and neuropediatric aspects of TMS.

Consensus paper: Combining transcranial stimulation with neuroimaging

In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses.

Manual activity shapes structure and function in contralateral human motor hand area

From longitudinal voxel-based morphometry (VBM) studies we know that relatively short periods of training can increase regional grey matter volume in trained cortical areas. In 14 right-handed patients with writers cramp, we employed VBM to test whether suppression (i.e., immobilization) or enhancement (i.e., training) of manual activity lead to opposing changes in grey matter in the contralateral primary motor hand area (M1(HAND)). We additionally used transcranial magnetic stimulation (TMS) to evaluate concurrent changes in regional excitability. Patients were recruited from a clinical trial which was designed to improve handwriting-associated dystonia. Initially the dystonic hand was immobilized for 4 weeks with the intention to reverse faulty plasticity. After immobilization, patients accomplished a motor re-training for 8 weeks. T1-weighted MRIs of the whole brain and single-pulse TMS measurements of the resting motor threshold (RMT) were performed every 4 weeks. Immobilization of the right hand resulted in a relative grey matter decrease in the contralateral left M1(HAND) along with a decrease in corticomotor excitability as indexed by an increase in RMT. Subsequent training reversed the effects of immobilization, causing an increase in regional grey matter density and excitability of left M1(HAND). The relative changes in grey matter correlated with the relative shifts in RMT. This prospective within-subject VBM study in task-specific hand dystonia shows that the grey matter density of M1(HAND) is dynamically shaped by the level of manual activity. This bi-directional structural plasticity is functionally relevant as local grey matter changes are mirrored by changes in regional excitability.

Physiological and anatomical decomposition of subthalamic neurostimulation effects in essential tremor

Postural tremor is the leading symptom in essential tremor, but in some cases intention tremor and limb ataxia emerge and can become highly disabling features. Deep brain stimulation of the thalamus or subthalamic white matter improve tremor and ataxia; however, the underlying network mechanisms are enigmatic. To elucidate the mechanisms of deep brain stimulation in essential tremor, we pursued a multimodal approach combining kinematic measures of reach-to-grasp movements, clinical assessments, physiological measures of neuronal excitability and probabilistic tractography from diffusion tensor imaging. Seven patients with essential tremor (age 62.9 ± 10.3 years, two females) received thalamic deep brain stimulation and a clinical examination of severity of limb tremor and ataxia at off stimulation, using therapeutic and supratherapeutic stimulation parameters. A reach-to-grasp task based on acoustic cues was also performed. To examine the electrical properties of target structures, we determined the chronaxie of neural elements modulated. A control group of 13 healthy subjects (age 56 ± 7.6 years, five females) underwent whole-brain diffusion tensor imaging at 3 T. Probabilistic tractography was applied in healthy subjects from seeds in cerebellum and midbrain to reconstruct the connectivity pattern of the subthalamic area. The positions of stimulation electrodes in patients were transferred into probability maps and connectivity values were correlated to clinical outcome measures. Therapeutic stimulation improved ataxia and tremor mainly during the target period of the reaching paradigm (63% reduction compared with off stimulation). Notably the acceleration (29%) and deceleration periods (41%) were improved. By contrast, supratherapeutic stimulation worsened ataxia during the deceleration period with a 55% increase of spatial variability, while maintaining near complete suppression of tremor. Chronaxie measures were in the range of rapidly-conducting myelinated fibres with significantly different values for the anti-tremor effect of therapeutic stimulation (27 s) and the pro-ataxic effect of supratherapeutic stimulation (52 s). The degree of connectivity to the dentato-thalamic tract at the stimulating electrode correlated significantly with the reduction of tremor in the therapeutic condition. Our data suggest that stimulation induced tremor reduction and induction of ataxia by supratherapeutic stimulation are mediated by different fibre systems. Probalistic tractography identified the dentato-thalamic tract as a likely target of tremor suppression. Stimulation-induced ataxia may be caused by additional recruitment of adjacent fibre systems at higher amplitudes. Stimulation with short pulse duration may help to increase the therapeutic window and focus on the anti-tremor effect.

The human dorsal premotor cortex facilitates the excitability of ipsilateral primary motor cortex via a short latency cortico-cortical route.

In non‐human primates, invasive tracing and electrostimulation studies have identified strong ipsilateral cortico‐cortical connections between dorsal premotor‐ (PMd) and the primary motor cortex (M1HAND). Here, we applied dual‐site transcranial magnetic stimulation (dsTMS) to left PMd and M1HAND through specifically designed minicoils to selectively probe ipsilateral PMd‐to‐M1HAND connectivity in humans. A suprathreshold test stimulus (TS) was applied to M1HAND producing a motor evoked potential (MEP) of about 0.5 mV in the relaxed right first dorsal interosseus muscle (FDI). A subthreshold conditioning stimulus (CS) was given to PMd 2.0–5.2 ms after the TS at intensities of 50‐, 70‐, or 90% of TS. The CS to PMd facilitated the MEP evoked by TS over M1HAND at interstimulus intervals (ISI) of 2.4 or 2.8 ms. There was a second facilitatory peak at ISI of 4.4 ms. PMd‐to‐M1HAND facilitation did not change as a function of CS intensity. Even at higher intensities, the CS alone failed to elicit a MEP or a cortical silent period in the pre‐activated FDI, excluding a direct spread of excitation from PMd to M1HAND. No MEP facilitation was present while CS was applied rostrally over lateral prefrontal cortex. Together our results indicate that our dsTMS paradigm probes a short‐latency facilitatory PMd‐to‐M1HAND pathway. The temporal pattern of MEP facilitation suggests a PMd‐to‐M1HAND route that targets intracortical M1HAND circuits involved in the generation of indirect corticospinal volleys. This paradigm opens up new possibilities to study context‐dependent intrahemispheric PMd‐to‐M1HAND interactions in the intact human brain. Hum Brain Mapp, 2012.

Acute Changes in Motor Cortical Excitability During Slow Oscillatory and Constant Anodal Transcranial Direct Current Stimulation

Transcranial oscillatory current stimulation has recently emerged as a noninvasive technique that can interact with ongoing endogenous rhythms of the human brain. Yet, there is still little knowledge on how time-varied exogenous currents acutely modulate cortical excitability. In ten healthy individuals we used on-line single-pulse transcranial magnetic stimulation (TMS) to search for systematic shifts in corticospinal excitability during anodal sleeplike 0.8-Hz slow oscillatory transcranial direct current stimulation (so-tDCS). In separate sessions, we repeatedly applied 30-s trials (two blocks at 20 min) of either anodal so-tDCS or constant tDCS (c-tDCS) to the primary motor hand area during quiet wakefulness. Simultaneously and time-locked to different phase angles of the slow oscillation, motor-evoked potentials (MEPs) as an index of corticospinal excitability were obtained in the contralateral hand muscles 10, 20, and 30 s after the onset of tDCS. MEPs were also measured off-line before, between, and after both stimulation blocks to detect any lasting excitability shifts. Both tDCS modes increased MEP amplitudes during stimulation with an attenuation of the facilitatory effect toward the end of a 30-s tDCS trial. No phase-locking of corticospinal excitability to the exogenous oscillation was observed during so-tDCS. Off-line TMS revealed that both c-tDCS and so-tDCS resulted in a lasting excitability increase. The individual magnitude of MEP facilitation during the first tDCS trials predicted the lasting MEP facilitation found after tDCS. We conclude that sleep slow oscillation-like excitability changes cannot be actively imposed on the awake cortex with so-tDCS, but phase-independent on-line as well as off-line facilitation can reliably be induced.

A novel dual-site transcranial magnetic stimulation paradigm to probe fast facilitatory inputs from ipsilateral dorsal premotor cortex to primary motor cortex

The dorsal premotor cortex (PMd) plays an import role in action control, sensorimotor integration and motor recovery. Animal studies and human data have demonstrated direct connections between ipsilateral PMd and primary motor cortex hand area (M1(HAND)). In this study we adopted a multimodal approach combining highly focal dual-site TMS (dsTMS) and diffusion tensor imaging (DTI) to probe ipsilateral effective and structural connectivity between PMd and M1(HAND) in humans. A suprathreshold test stimulus (TS) was applied to left M1(HAND) producing a motor evoked potential (MEP) and a subsequent conditioning stimulus (CS) to ipsilateral rostromedial PMd at short latencies ranging from of 0.8 to 2.0 ms. At an interstimulus interval of 1.2 ms, dsTMS of the left M1(HAND) and PMd facilitated MEP amplitudes relative to unconditioned TMS of M1(HAND). This PMd to M1(HAND) facilitation was absent during voluntary contraction of the target muscle. During a two-choice reaction time task, PMd-M1(HAND) facilitation was only observed when dsTMS was given 125 ms after presentation of the cue and subjects responded with their right hand, but not for left hand responses. Our results reveal a short-latency PMd to M1(HAND) connection which modulates excitability of ipsilateral M1(HAND) in a task and effector specific manner. DTI revealed that individual increases in PMd to M1(HAND) facilitation were correlated with fractional anisotropy and axial diffusivity in the juxtacortical white matter underlying the caudal portion of the left superior frontal gyrus. This finding shows that the functional strength of this connection from medial PMd to M1(HAND) has a microstructural correlate in the underlying subcortical white matter. This novel dsTMS paradigm can be used to non-invasively probe effective PMd to M1(HAND) connectivity in healthy individuals and patients with impaired hand function.

Abnormal response of motor cortex to photic stimulation in idiopathic generalized epilepsy.

Background:  Intermittent photic stimulation (IPS) shortens the cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) over the primary motor hand area (M1HAND). This response is absent in healthy individuals with a photoparoxysmal response (PPR). Here we combined TMS of the M1HAND with IPS to examine whether patients with idiopathic generalized epilepsy (IGE) exhibit an abnormal cortical response pattern to IPS.

The left visual-field advantage in rapid visual presentation is amplified rather than reduced by posterior-parietal rTMS

In the present task, series of visual stimuli are rapidly presented left and right, containing two target stimuli, T1 and T2. In previous studies, T2 was better identified in the left than in the right visual field. This advantage of the left visual field might reflect dominance exerted by the right over the left hemisphere. If so, then repetitive transcranial magnetic stimulation (rTMS) to the right parietal cortex might release the left hemisphere from right-hemispheric control, thereby improving T2 identification in the right visual field. Alternatively or additionally, the asymmetry in T2 identification might reflect capacity limitations of the left hemisphere, which might be aggravated by rTMS to the left parietal cortex. Therefore, rTMS pulses were applied during each trial, beginning simultaneously with T1 presentation. rTMS was directed either to P4 or to P3 (right or left parietal cortex) either as effective or as sham stimulation. In two experiments, either one of these two factors, hemisphere and effectiveness of rTMS, was varied within or between participants. Again, T2 was much better identified in the left than in the right visual field. This advantage of the left visual field was indeed modified by rTMS, being further increased by rTMS to the left hemisphere rather than being reduced by rTMS to the right. It may be concluded that superiority of the right hemisphere in this task implies that this hemisphere is less irritable by external interference than the left hemisphere.

The resilience framework as a strategy to combat stress-related disorders

Consistent failure over the past few decades to reduce the high prevalence of stress-related disorders has motivated a search for alternative research strategies. Resilience refers to the phenomenon of many people maintaining mental health despite exposure to psychological or physical adversity. Instead of aiming to understand the pathophysiology of stress-related disorders, resilience research focuses on protective mechanisms that shield people against the development of such disorders and tries to exploit its insights to improve treatment and, in particular, disease prevention. To fully harness the potential of resilience research, a critical appraisal of the current state of the art — in terms of basic concepts and key methods — is needed. We highlight challenges to resilience research and make concrete conceptual and methodological proposals to improve resilience research. Most importantly, we propose to focus research on the dynamic processes of successful adaptation to stressors in prospective longitudinal studies.