Normal intracortical excitability in developmental stuttering.

Persistent developmental stuttering (PDS) shares clinical features with task-specific dystonias. In these dystonias, intracortical inhibition is abnormally weak. We therefore sought to determine intracortical inhibition and intracortical facilitation in PDS. In 18 subjects with PDS since childhood (mean age, 39.4 [SD 13.0] years) and 18 speech-fluent controls (43.6 [14.3] years), we investigated resting and active motor thresholds as well as intracortical inhibition and facilitation of the optimal representation of the abductor digiti minimi of the dominant hand using transcranial magnetic stimulation. In PDS, the resting and active motor thresholds were increased, whereas intracortical inhibition and facilitation were normal. Normal intracortical excitability makes a pathophysiological analogy between focal dystonia and PDS less likely. The enhanced motor threshold suggests reduced motor cortical neuronal membrane excitability in PDS.     

Transcranial magnetic stimulation shows impaired transcallosal inhibition in Marchiafava–Bignami syndrome

A case of Marchiafava–Bignami (MB) syndrome with selective callosal involvement was evaluated by clinical examination and magnetic resonance imaging (MRI) in the acute phase and 6 months after the onset of symptoms; at the same time, the corticospinally and transcallosally mediated effects elicited by transcranial magnetic stimulation (TMS) were investigated. The first MRI study showed the presence of extensive abnormal signal intensity throughout the entire corpus callosum. After high-dose corticosteroid administration her symptoms rapidly resolved, in parallel with the reversion of MRI changes, except for severe cognitive impairment. Follow-up TMS examination revealed persistent transcallosal inhibition (TI) abnormalities. This report indicates that the measurement of TI during the course of MB syndrome is useful for evaluating functional changes to the corpus callosum, including their evaluation with time and after treatment and for elucidating the pathophysiology of MB syndrome.     

Practice‐related reduction of electromyographic mirroring activity depends on basal levels of interhemispheric inhibition

Paired‐pulse transcranial magnetic stimulation (TMS) is used to measure the excitability of interhemispheric inhibition (IHI) between the hand areas of the two motor cortices. It varies from person to person, and is highly predictive of individual differences in callosal anatomy (fractional anisotropy) and even motor behaviour, e.g. the amount of involuntary electromyographic (EMG) ‘mirroring’ in one hand during rapid contraction of the other. The present experiments tested whether it also predicts how well individuals can improve motor performance in a task involving the two hands. Healthy participants were given 100 trials to maximize the initial acceleration of a ballistic finger movement made with one hand while trying to maintain a tonic low level of EMG activity in the other hand. Initially, each movement was accompanied by additional unwanted EMG mirroring in the other hand. However, after practice, participants had on average increased acceleration by approximately one‐third without changing the amount of EMG mirroring in the contralateral hand; indeed, in some individuals EMG mirroring activity declined. TMS measures showed that there was an increase in corticospinal excitability in the trained hemisphere, but there was no change in the excitability of short‐ or long‐latency IHI from the trained to non‐trained hemisphere. Nevertheless, in each individual, the baseline (pre‐practice) excitability of short‐latency IHI was highly predictive (r = 0.65; P = 0.0019) of the change in EMG mirroring. The implication is that a physiological measure of brain excitability at rest can predict behaviour in response to training.     

Measurements of transcallosally mediated cortical inhibition for differentiating parkinsonian syndromes.

Clinicopathologic evidence suggests differential involvement of cortex and corpus callosum (CC) in various disorders presenting with a parkinsonian syndrome. We tested the hypothesis of whether neurophysiologic and morphometric assessments of CC as surrogate parameters of cortical involvement could be helpful in differential diagnosis of parkinsonian disorders. The integrity of CC was assessed neurophysiologically by measuring the ipsilateral silent period (iSP) evoked by transcranial magnetic stimulation (TMS) in a total of 25 patients with idiopathic parkinsonian syndromes (IPS), corticobasal ganglionic degeneration (CBD), progressive supranuclear palsy (PSP), or multiple system atrophy (MSA). Additionally, morphometric analyses of magnetic resonance imaging (MRI) measurements of CC was carried out in all patients. iSP was abnormal in all 5 CBD and all 5 PSP patients, whereas it was intact in all 10 IPS patients and all 5 MSA patients. Among various MRI parameters of CC, testing between different groups revealed a significant difference only for measurements of the middle part of the truncus. CBD and PSP patients exhibited a significant atrophy as compared with control subjects. These data suggest impairment of callosal integrity in patients with CBD and PSP. iSP measurements may be a useful clinical neurophysiologic test in differential diagnosis of patients with parkinsonian syndromes.     

Adaptive threshold hunting reveals differences in interhemispheric inhibition between young and older adults

Interhemispheric inhibition between bilateral motor cortices is important for the performance of unimanual activities and may be compromised with advancing age. Conventionally, interhemispheric inhibition is assessed using paired‐pulse transcranial magnetic stimulation (TMS) with constant conditioning and test stimulation parameters. Adaptive threshold hunting TMS, whereby a target motor‐evoked potential amplitude is maintained in the presence of the conditioning, may provide an alternative means of assessment. Furthermore, interhemispheric inhibition may suppress late indirect‐waves more so than early indirect‐waves which can be preferentially elicited using anterior–posterior (AP) and posterior–anterior (PA) induced currents, respectively. The aim of this study was to assess age‐related effects on interhemispheric inhibition using both conventional and threshold hunting techniques with PA‐ and AP‐induced current. In 15 young and 15 older adults, short (10 ms) and long (40 ms) interval interhemispheric inhibition was examined in the nondominant extensor carpi radialis muscle at rest and during voluntary extension of the contralateral wrist. With the conventional technique, there were no age‐related differences in short‐interval interhemispheric inhibition. With threshold hunting and AP‐induced current, young adults exhibited greater short‐interval interhemispheric inhibition during contralateral activation compared with rest and compared with older adults. Furthermore, long‐interval interhemispheric inhibition was greater in older adults compared with young for both conventional and threshold hunting techniques. Age‐related differences in interhemispheric inhibition are evident with threshold hunting using PA‐ and AP‐induced current.     

Abnormal neural response to phonological working memory demands in persistent developmental stuttering

Persistent developmental stuttering is a neurological disorder that commonly manifests as a motor problem. Cognitive theories, however, hold that poorly developed cognitive skills are the origins of stuttering. Working memory (WM), a multicomponent cognitive system that mediates information maintenance and manipulation, is known to play an important role in speech production, leading us to postulate that the neurophysiological mechanisms underlying stuttering may be associated with a WM deficit. Using functional magnetic resonance imaging, we aimed to elucidate brain mechanisms in a phonological WM task in adults who stutter and controls. A right‐lateralized compensatory mechanism for a deficit in the rehearsal process and neural disconnections associated with the central executive dysfunction were found. Furthermore, the neural abnormalities underlying the phonological WM were independent of memory load. This study demonstrates for the first time the atypical neural responses to phonological WM in PWS, shedding new light on the underlying cause of stuttering.     

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor‐evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not‐evocable motor‐evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first‐ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age‐matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS‐evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics.     

Transcranial magnetic stimulation in developmental stuttering: Relations with previous neurophysiological research and future perspectives

Developmental stuttering (DS) is a disruption of the rhythm of speech, and affected people may be unable to execute fluent voluntary speech. There are still questions about the exact causes of DS. Evidence suggests there are differences in the structure and functioning of motor systems used for preparing, executing, and controlling motor acts, especially when they are speech related. Much research has been obtained using neuroimaging methods, ranging from functional magnetic resonance to diffusion tensor imaging and electroencephalography/magnetoencephalography. Studies using transcranial magnetic stimulation (TMS) in DS have been uncommon until recently. This is surprising considering the relationship between the functionality of the motor system and DS, and the wide use of TMS in motor-related disturbances such as Parkinson’s Disease, Tourette’s Syndrome, and dystonia. Consequently, TMS could shed further light on motor aspects of DS. The present work aims to investigate the use of TMS for understanding DS neural mechanisms by reviewing TMS papers in the DS field. Until now, TMS has contributed to the understanding of the excitatory/inhibitory ratio of DS motor functioning, also helping to better understand and critically review evidence about stuttering mechanisms obtained from different techniques, which allowed the investigation of cortico-basal-thalamo-cortical and white matter/connection dysfunctions.     

Changes in cortical inhibition during task-specific contractions in primary writing tremor patients.

Primary writing tremor (PWT) is a rare disease of unknown pathophysiology. We studied changes in silent period (SP) duration, after transcranial magnetic stimulation (TMS), set at 20% above the motor threshold in 6 PWT patients and 7 healthy control subjects. SP duration was tested during a task-specific act, i.e., writing that induced tremor in all patients in the affected hand (Wr); nonspecific voluntary contraction of intensity, matching that developed during writing (VCWr); and during near maximal voluntary contraction (VCNmax). There were no differences in SP duration during Wr and VCWr contraction on the right affected side or between sides in both PWT patients and control subjects, nor between the groups. However, during VCNmax, SP significantly shortened on both sides in PWT patients, whereas there were no changes in control subjects. Although it appears that inhibitory mechanism are not directly involved in the generation of the tremulous activity, the shortening of SP indicates that central inhibitory mechanisms are affected in PWT patients. Therefore, whereas the underlying pathophysiological mechanisms in PWT and writer's cramp may share common features, the results indicate that PWT is not a variant of focal task-specific dystonia but rather a separate nosological entity.     

An acute bout of exercise modulates both intracortical and interhemispheric excitability

Primary motor cortex (M1) excitability is modulated following a single session of cycling exercise. Specifically, short‐interval intracortical inhibition and intracortical facilitation are altered following a session of cycling, suggesting that exercise affects the excitability of varied cortical circuits. Yet we do not know whether a session of exercise also impacts the excitability of interhemispheric circuits between, and other intracortical circuits within, M1. Here we present two experiments designed to address this gap in knowledge. In experiment 1, single and paired pulse transcranial magnetic stimulation (TMS) were used to measure intracortical circuits including, short‐interval intracortical facilitation (SICF) tested at 1.1, 1.5, 2.7, 3.1 and 4.5 ms interstimulus intervals (ISIs), contralateral silent period (CSP) and interhemispheric interactions by measuring transcallosal inhibition (TCI) recorded from the abductor pollicus brevis muscles. All circuits were assessed bilaterally pre and two time points post (immediately, 30 min) moderate intensity lower limb cycling. SICF was enhanced in the left hemisphere after exercise at the 1.5 ms ISI. Also, CSP was shortened and TCI decreased bilaterally after exercise. In Experiment 2, corticospinal and spinal excitability were tested before and after exercise to investigate the locus of the effects found in Experiment 1. Exercise did not impact motor‐evoked potential recruitment curves, Hoffman reflex or V‐wave amplitudes. These results suggest that a session of exercise decreases intracortical and interhemispheric inhibition and increases facilitation in multiple circuits within M1, without concurrently altering spinal excitability. These findings have implications for developing exercise strategies designed to potentiate M1 plasticity and skill learning in healthy and clinical populations.     

An EEG index of sensorimotor interhemispheric coupling after unilateral stroke: clinical and neurophysiological study

Brain connectivity has been employed to investigate on post‐stroke recovery mechanisms and assess the effect of specific rehabilitation interventions. Changes in interhemispheric coupling after stroke have been related to the extent of damage in the corticospinal tract (CST) and thus, to motor impairment. In this study, we aimed at defining an index of interhemispheric connectivity derived from electroencephalography (EEG), correlated with CST integrity and clinical impairment. Thirty sub‐acute stroke patients underwent clinical and neurophysiological evaluation: CST integrity was assessed by Transcranial Magnetic Stimulation and high‐density EEG was recorded at rest. Connectivity was assessed by means of Partial Directed Coherence and the normalized Inter‐Hemispheric Strength (nIHS) was calculated for each patient and frequency band on the whole network and in three sub‐networks relative to the frontal, central (sensorimotor) and occipital areas. Interhemipheric coupling as expressed by nIHS on the whole network was significantly higher in patients with preserved CST integrity in beta and gamma bands. The same index estimated for the three sub‐networks showed significant differences only in the sensorimotor area in lower beta, with higher values in patients with preserved CST integrity. The sensorimotor lower beta nIHS showed a significant positive correlation with clinical impairment. We propose an EEG‐based connectivity index which is a measure of the interhemispheric cross‐talking and correlates with functional motor impairment in subacute stroke patients. Such index could be employed to evaluate the effects of training aimed at re‐establishing interhemispheric balance and eventually drive the design of future connectivity‐driven rehabilitation interventions.     

Abnormal responses to repetitive transcranial magnetic stimulation in multiple system atrophy.

We studied the response of the motor cortex to brief trains of suprathreshold repetitive transcranial magnetic stimulations (rTMS) in patients with the Parkinson-variant of multiple system atrophy (MSA-P) and compared it to patients with idiopathic Parkinson's disease (PD) and healthy controls. Eight subjects were studied in each group, and patients were matched for disease severity as assessed by Hoehn & Yahr stages. rTMS was delivered at rest and during low-level contractions in trains of 10 stimulations at 5 Hz, and stimulation intensity was set to result in an motor evoked potential (MEP) in the first dorsal interosseus muscle of 0.5 to 1.0 mV. In MSA-P, MEP amplitude at rest was already reduced after the second stimulus and remained so, while it did not change in PD and controls. During contraction, MEP size did not change during the train in any group. The silent period that followed the last stimulus was of similar duration as the first stimulus in MSA-P, but was increased in PD and controls. These findings indicate that abnormal inhibition occurs within the motor cortex in MSA-P, despite dopaminergic treatment and indicate differences in cortical dysfunction between MSA-P and PD. We suggest that these abnormalities reflect the motor cortex pathology found in MSA-P.     

Altered dorsal premotor–motor interhemispheric pathway activity in focal arm dystonia

Given the possible role of dorsal premotor cortex (PMd) in the pathophysiology of dystonia, we used transcranial magnetic stimulation (TMS) methods to study PMd and PMd–primary motor cortex (M1) interactions in patients with focal arm dystonia. Here, we tested the connectivity between left PMd and right M1 as well as the intracortical excitability of PMd in 11 right‐handed patients with focal arm/hand dystonia and nine age‐matched healthy controls. The results showed that excitability of the inhibitory connection between PMd and M1 was reduced in patients, but there was no significant difference to healthy subjects in the excitability of the facilitatory connection. A triple stimulation technique in which pairs of TMS pulses are given over PMd and their interaction measured in terms of the effect on the baseline PMd‐M1 connection failed to reveal the usual pattern of interaction between the pairs of PMd stimuli. Indeed, the results in patients were similar to those seen in a group of young healthy subjects after the excitability of PMd had been changed by pretreatment with high‐frequency rTMS. We suggest that reduced transcallosal inhibition from the PMd may be involved in the altered pattern of abnormal muscle contractions of agonists and antagonists (overflow). © 2007 Movement Disorder Society     

Changes of inhibitory interneurons during transcallosal stimulations

Summary The present study was performed in order to determine the influence of ipsilateral transcranial magnetic stimulations (TMS) on the silent period evoked by contralateral cortical stimulations. Ipsilateral TMS preceded the contralateral magnetic or electrical cortex stimulation by 0–50ms. In all subjects, the duration of the silent period was decreased in interstimulus intervals of 20–30ms when using magnetic ipsi- and contralateral stimuli. No change in the silent period was seen with ipsilateral magnetic and contralateral electrical stimulations. Decreases of motor evoked potential amplitudes were an inconsistant phenomenon.The results indicate that ipsilateral TMS in activate inhibitory cortical interneurons, probably via transcallosal pathways. Different time courses and different degrees of inhibition indicate that motor excitation and inhibition may be mediated by different neuronal circuits.     

Evidence for impaired cortical inhibition in patients with unipolar major depression.

BACKGROUND: Several lines of evidence suggest that central cortical inhibitory mechanisms, especially associated with gamma-aminobutyric acid (GABA) neurotransmission, may play a role in the pathophysiology of major depression. Transcranial magnetic stimulation is a useful tool for investigating central cortical inhibitory mechanisms associated with GABAergic neurotransmission in psychiatric and neurological disorders. METHODS: By means of transcranial magnetic stimulation, different parameters of cortical excitability, including motor threshold, the cortical silent period, and intracortical inhibition/facilitation, were investigated in 20 medication-free depressed patients and 20 age- and gender-matched healthy volunteers. RESULTS: Silent period and intracortical inhibition were reduced in depressed patients, consistent with a reduced GABAergic tone. Moreover, patients showed a significant hemispheric asymmetry in motor threshold. CONCLUSIONS: This study provides evidence of reduced GABAergic tone and motor threshold asymmetry in patients with major depression.     

Right-shift for non-speech motor processing in adults who stutter

Introduction

In adults who do not stutter (AWNS), the control of hand movement timing is assumed to be lateralized to the left dorsolateral premotor cortex (PMd). In adults who stutter (AWS), the network of speech motor control is abnormally shifted to the right hemisphere. Motor impairments in AWS are not restricted to speech, but extend to non-speech orofacial and finger movements. We here investigated the lateralization of finger movement timing control in AWS.

Methods

We explored PMd function in 14 right-handed AWS and 15 age matched AWNS. In separate sessions, they received subthreshold repetitive transcranial magnetic stimulation (rTMS) for 20 min at 1 Hz over the left or right PMd, respectively. Pre- and post-stimulation participants were instructed to synchronize their index finger taps of either hand with an isochronous sequence of clicks presented binaurally via earphones. Synchronization accuracy was measured to quantify the effect of the PMd stimulation.

Results

In AWNS inhibition of left PMd affected synchronization accuracy of the left hand. Conversely, in AWS TMS over the right PMd increased the asynchrony of the left hand.

Conclusions

The present data indicate an altered functional connectivity in AWS in which the right PMd seems to be important for the control of timed non-speech movements. Moreover, the laterality-shift suggests a compensatory role of the right PMd to successfully perform paced finger tapping.     

Magnetic stimulation including the triple-stimulation technique in amyotrophic lateral sclerosis

To study the relative importance of upper motor neuron (UMN) dysfunction in the weakness of amyotrophic lateral sclerosis (ALS) and to compare the sensitivity of several transcranial magnetic stimulation (TMS) parameters as means of assessing UMN impairment in ALS, we used TMS to evaluate one upper limb of 63 patients. The triple-stimulation technique (TST) and silent period (SP) were found to be the most frequently abnormal parameters (55.6% and 47.6%, respectively), without significant difference in their diagnostic sensitivity. The SP was found to be a useful parameter in patients with suspected or possible ALS. A positive correlation was found between weakness and the TST amplitude ratio, indicating that weakness may partly be caused by UMN dysfunction. Thus, the TST provides a quantitative tool for assessing UMN conduction failure. When used in association with the SP, the TST provides a sensitive diagnostic tool for use on ALS patients.     

White matter tract strength correlates with therapy outcome in persistent developmental stuttering

Persistent stuttering is a prevalent neurodevelopmental speech disorder, which presents with involuntary speech blocks, sound and syllable repetitions, and sound prolongations. Affected individuals often struggle with negative feelings, elevated anxiety, and low self‐esteem. Neuroimaging studies frequently link persistent stuttering with cortical alterations and dysfunctional cortico‐basal ganglia‐thalamocortical loops; dMRI data also point toward connectivity changes of the superior longitudinal fasciculus (SLF) and the frontal aslant tract (FAT). Both tracts are involved in speech and language functions, and the FAT also supports inhibitory control and conflict monitoring. Whether the two tracts are involved in therapy‐associated improvements and how they relate to therapeutic outcomes is currently unknown. Here, we analyzed dMRI data of 22 patients who participated in a fluency‐shaping program, 18 patients not participating in therapy, and 27 fluent control participants, measured 1 year apart. We used diffusion tractography to segment the SLF and FAT bilaterally and to quantify their microstructural properties before and after a fluency‐shaping program. Participants learned to speak with soft articulation, pitch, and voicing during a 2‐week on‐site boot camp and computer‐assisted biofeedback‐based daily training for 1 year. Therapy had no impact on the microstructural properties of the two tracts. Yet, after therapy, stuttering severity correlated positively with left SLF fractional anisotropy, whereas relief from the social–emotional burden to stutter correlated negatively with right FAT fractional anisotropy. Thus, posttreatment, speech motor performance relates to the left dorsal stream, while the experience of the adverse impact of stuttering relates to the structure recently associated with conflict monitoring and action inhibition.     

Task-dependent effects of interhemispheric inhibition on motor control

Interhemispheric communication consists of a complex balance of facilitation and inhibition that is modulated in a task-dependent manner. However, it remains unclear how individual differences in interhemispheric interactions relate to motor performance. To assess interhemispheric inhibition, we utilized the ipsilateral silent period technique (iSP; evoked by suprathreshold transcranial magnetic stimulation), which elicits inhibition of volitional motor activity. Participants performed three force production tasks: (1) unimanual (right hand) constant force, (2) bimanual constant force, (bimanual simultaneous) and (3) bimanual with right hand constant force and left hand sine wave tracking (bimanual independent). We found that individuals with greater IHI capacity demonstrated reduced mirror EMG activity in the left hand during unimanual right hand contraction. However, these same individuals demonstrated the poorest performance during the bimanual independent force production task. We suggest that a high capacity for IHI from one motor cortex to another can effectively prevent “motor overflow” during unimanual tasks, but it can also limit interhemispheric cooperation during independently controlled bimanual tasks.