Intracortical motor conduction is associated with hand dexterity in progressive multiple sclerosis.

BACKGROUND: Hand dexterity dysfunction is a key feature of disability in people with progressive multiple sclerosis (PMS). It underlies corticospinal tract (CST) and cerebellar integrity, as well as disruption of cortical networks, which are hardly assessed by standard techniques. Transcranial magnetic stimulation is a promising tool for evaluating the integrity of intracortical motor pathways. OBJECTIVE: To investigate neurophysiological correlates of motor hand impairment in PMS. METHODS: Antero-posterior (AP) stimulation of the primary motor cortex activates the CST indirectly through polysynaptic pathways, while a direct CST activation occurs with latero-medial (LM) directed current. Thirty PMS and 15 healthy controls underwent dominant hand motor evoked potentials (MEP) using AP and LM-directed stimulation, and a clinical assessment of dexterity (nine-hole peg test) and strength (MRC scale, grip and pinch). RESULTS: PMS with AP-LM latency difference 2.5 standard deviation above the mean of controls (33%) showed worse dexterity but no difference in upper limb strength. Accordingly, AP-LM latency shortening predicted dexterity (R2 = 0.538, p < 0.001), but not strength impairment. On the contrary, absolute MEP latencies only correlated with strength (grip: R2 = 0.381, p = 0.014; MRC: R2 = 0.184, p = 0.041). CONCLUSION: AP-LM latency shortening may be used to assess the integrity polysynaptic intracortical networks implicated in dexterity impairment.

Repetitive Transcranial Magnetic Stimulation With H-Coil Coupled With Cycling for Improving Lower Limb Motor Function After Stroke: An Exploratory Study.

BACKGROUND/OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been recognized as a promising intervention for the treatment of post-stroke motor deficits. Here, we explore safety, feasibility, and potential effectiveness of high-frequency rTMS (HF-rTMS) delivered with the Hesed coil (H-coil) during active cycling on paretic lower extremity (LE) motor function in chronic stroke. MATERIALS AND METHODS: Twelve subjects with a first-ever stroke were recruited in this double-blind, placebo controlled, crossover study. Eleven sessions of HF-rTMS (40 2s-trains of 20 Hz at 90% resting leg motor threshold) were delivered over the LE motor areas using the H-coil during active cycling for three weeks. Each subject underwent both real and sham rTMS treatments separated by a four-week washout period, in a random sequence. Vital signs were recorded before and after each rTMS session. Any discomfort related to stimulation and side effects were recorded. LE function was also evaluated with Fugl-Meyer assessment (FMA-LE), spasticity was assessed with modified-Ashworth scale and measures of gait speed and endurance (10-meter and 6-min walk tests, respectively) were recorded. RESULTS: No participant reported serious adverse effects. During real rTMS, 4 of 12 subjects reported mild side effects including transitory dizziness and muscle twitches on shoulder, so that intensity of stimulation initially set at 90% of RMT was reduced to 80% of RMT on average in these four subjects. Only real treatment was associated with a significant and sustained improvement in FMA-LL (67% responders vs. 9% of the sham). Spasticity significantly ameliorated only after the real rTMS. Real treatment did not offer advantages on walking timed measures when compared with sham. CONCLUSIONS: This exploratory study suggests that bilateral HF-rTMS combined with cycling is safe and potentially effective in ameliorating paretic LE motor function and spasticity, rather than gait speed or endurance, in chronic stroke.

Beyond rehabilitation in MS: Insights from non-invasive brain stimulation.

Although the number of disease-modifying treatments for people with multiple sclerosis (pwMS) has meaningfully increased in the past years, targeting repair or compensation for central nervous system damage associated with the disease process remains an important clinical goal. With this aim, neurorehabilitation is a powerful approach targeting central nervous system plasticity. Another driver of brain plasticity is non-invasive brain stimulation (NIBS), receiving recent attention in neurology, particularly for its potential synergy with neurorehabilitation and as add-on treatment for several neurological conditions, from pain to fatigue to sensorimotor and cognitive deficits. In this review, we will resume the evidence exploring the neurobiological basis of NIBS and its applications to MS-related conditions.

Optical coherence tomography and visual evoked potentials: which is more sensitive in multiple sclerosis?

OBJECTIVE: To assess the sensitivity of optic coherence tomography (OCT) and visual evoked potentials (VEPs) to visual pathway abnormalities in multiple sclerosis (MS). METHODS: A total of 40 MS subjects, 28 with optic neuritis (ON) at least 3 months before (bilateral in 5), underwent assessment of visual acuity, Expanded Disability Status Scale (EDSS), OCT and VEPs, the latter quantified with a 0-4 conventional score. RESULTS: OCT and VEPs were abnormal in 36% and 56% respectively in all eyes (p=0.11), 68% and 86% in eyes with previous ON (p=0.12), and in 19% versus 40% in eyes without ON history (p=0.007). Combining VEP and OCT increased sensitivity to 89% in ON and 44% in non-ON eyes. Considering all eyes, global retinal nerve fibre layer (RNFL) thickness and VEP score were significantly correlated between them (ρ=-0.63, p<0.001) and with EDSS (RNFL: ρ=0.40, p<0.001; VEP score: ρ=0.47, p<0.001). Disease duration correlated with VEP score (ρ=0.25, p=0.025) and RNFL thickness (ρ=-0.71, p<0.001). CONCLUSIONS: In eyes without ON, VEPs were more frequently abnormal than OCT, while the two techniques showed similar sensitivity in eyes previously affected by ON. The correlation of VEPs and OCT measures with disability prompts further exploration of the two techniques as potential markers of disease burden.

Deep repetitive transcranial magnetic stimulation with H-coil on lower limb motor function in chronic stroke: a pilot study.

OBJECTIVES: To assess the efficacy of high-frequency (20 Hz) brain stimulation on lower limb motor function in subjects with chronic (> 6 mo) subcortical stroke. DESIGN: Double-blind, placebo-controlled crossover study. SETTING: University hospital. PARTICIPANTS: Right-handed subjects (N=10) affected by a first-ever subcortical stroke in the territory of the middle cerebral artery were included in this study. INTERVENTIONS: Repetitive transcranial magnetic stimulation (rTMS) was delivered with the H-coil, specifically designed to target deeper and larger brains regions. Each subject received both real and sham rTMS in a random sequence. The 2 rTMS cycles (real or sham) were composed of 11 sessions each, administered over 3 weeks and separated by a 4-week washout period. MAIN OUTCOME MEASURES: Lower limb functions were assessed by the lower limb Fugl-Meyer scale, the 10-m walk test, and the 6-minute walk test before and 1 day after the end of each treatment period, as well as at a 4-week follow-up. RESULTS: Real rTMS treatment was associated with a significant improvement in lower limb motor function. This effect persisted over time (follow-up) and was significantly greater than that observed with sham stimulation. A significant increase in walking speed was also found after real rTMS, but this effect did not reach statistical significance in comparison with the sham stimulation. CONCLUSIONS: These data demonstrated that 3 weeks of high-frequency deep rTMS could induce long-term improvements in lower limb functions in the chronic poststroke period, lasting at least 1 month after the end of the treatment.

The Contribution of Vessel Wall Magnetic Resonance Imaging to the Diagnosis of Primary and Secondary Central Nervous System Vasculitis.

BACKGROUND: To describe high-resolution brain vessel wall MRI (VW-MRI) patterns and morphological brain findings in central nervous system (CNS) vasculitis patients. METHODS: Fourteen patients with confirmed CNS Vasculitis from two tertiary centers underwent VW-MRI using a 3T scanner. The images were reviewed by two neuroradiologists to assess vessel wall enhancement characteristics and locations. RESULTS: Fourteen patients were included (six females; average age 48 ± 19 years). Diagnoses included primary CNS vasculitis (PCNSV) in six patients and secondary CNS vasculitis (SCNSV) in eight, half of which were infection-related. Thirteen patients showed vessel wall enhancement, which was intense in eleven patients (84.6%) and concentric in twelve (92.3%), affecting the anterior circulation in nine patients (69.2%), posterior in two patients (15.4%), and both circulations in two patients (15.4%). The enhancement patterns were similar across different CNS vasculitis types. DWI changes corresponded with areas of vessel wall enhancement in 77% of patients. Conclusions: CNS vasculitis is often associated with intense, concentric vessel wall enhancement in VW-MRI, especially in the anterior circulation. The consistent presence of DWI alterations in affected territories suggests a possible link to microembolization or hypoperfusion. These imaging findings complement parenchymal brain MRI and MRA/DSA data, potentially increasing the possibility of a clinical diagnosis of CNS vasculitis.

Bilateral Repetitive Transcranial Magnetic Stimulation With the H-Coil in Parkinson's Disease: A Randomized, Sham-Controlled Study.

Background: Pilot open-label application of high-frequency repetitive transcranial magnetic stimulation (rTMS) with H-coil in Parkinson's Disease (PD) have shown promising results. Objective: To evaluate safety and efficacy of high-frequency rTMS with H-coil in PD in a double-blind, placebo-controlled, randomized study. Methods: Sixty patients with PD were randomized into 3 groups: M1-PFC (real stimulation on primary motor-M1 and pre-frontal cortices-PFC), M1 (real rTMS on M1, sham on PFC), Sham (apparent stimulation). Primary outcome was baseline-normalized percent improvement in UPDRS part III OFF-therapy at the end of treatment (12 rTMS sessions, 4 weeks). Secondary outcomes were improvement in UPDRS part III sub-scores, timed tests, and neuropsychological tests. Statistical analysis compared improvement following real and sham stimulation at the end of the protocol using either a t-test or a Mann-Whitney test. Results: All patients tolerated the treatment and concluded the study. One patient from M1-PFC group was excluded from the analysis due to newly discovered uncontrolled diabetes mellitus. No serious adverse effect was recorded. At the end of treatment, patients receiving real rTMS (M1-PFC and M1 combined) showed significantly greater improvement compared to sham in UPDRS part III total score (p = 0.007), tremor subscore (p = 0.011), and lateralized sub-scores (p = 0.042 for the more affected side; p = 0.012 for the less affected side). No significant differences have been oserved in safety and efficacy outcomes between the two real rTMS groups. Notably, mild, not-distressing and transient dyskinesias occurred in 3 patients after real rTMS in OFF state. Conclusions: The present findings suggest that high-frequency rTMS with H-coil is a safe and potentially effective procedure and prompt larger studies for validation as add-on treatment in PD.

Changes in cortical motor outputs after a motor relapse of multiple sclerosis.

BACKGROUND: Motor recovery following a multiple sclerosis (MS) relapse depends on mechanisms of tissue repair but also on the capacity of the central nervous system for compensating of permanent damage. OBJECTIVES: We aimed to investigate changes in corticospinal plasticity and interhemispheric connections after a relapse of MS using transcranial magnetic stimulation (TMS). METHODS: Twenty healthy and 13 relapsing-remitting MS subjects with a first motor relapse were included. TMS mapping and ipsilateral silent period (iSP) were performed after relapse and at 6-month follow-up. RESULTS: Strength and dexterity of the paretic hand were impaired at baseline and improved over time. After relapse, mapamplitude and mapdensity were decreased for the ipsilesional-corticospinal tract (IL-CST) while expanded for the contralesional-CST (CL-CST). At follow-up, map parameters normalized for the CL-CST independently from recovery while the increase of outputs from the IL-CST was associated with straight and dexterity improvement. iSP measurements were impaired in MS irrespective of the phase of the disease. Prolonged iSPduration at baseline was associated with less dexterity recovery. CONCLUSIONS: After a motor relapse, TMS mapping shows acute changes in corticospinal excitability and rearrangements of motor outputs. iSP is less influenced by the phase of disease but may better predict recovery, possibly reflecting the integrity of interhemispheric motor networks.

TMS of primary motor cortex with a biphasic pulse activates two independent sets of excitable neurones.

BACKGROUND: Biphasic pulses produced by most commercially available TMS machines have a cosine waveform, which makes it difficult to study the interaction between the two phases of stimulation. OBJECTIVE: We used a controllable pulse TMS (cTMS) device delivering quasi-rectangular pulse outputs to investigate whether monophasic are more effective than biphasic pulses. METHODS: Temporally symmetric ("biphasic") or highly asymmetric ("monophasic") charge-balanced biphasic stimuli were used to target the hand area of motor cortex in the anterior-posterior (AP) or posterior-anterior (PA) initial current direction. RESULTS: We observed the lowest motor thresholds and shortest motor evoked potential (MEP) latencies with initial PA pulses, and highest thresholds and longest latencies with AP pulses. Increasing pulse symmetry tended to increase threshold with a PA direction whereas it lowered thresholds and shortened latencies with an AP direction. Furthermore, it steepened the MEP input-output curve with both directions. CONCLUSIONS: "Biphasic" TMS pulses can be viewed as two monophasic pulses of opposite directions, each stimulating a different set of interneurons with different thresholds (PA < AP). At threshold, the reverse phase of an initially PA pulse increases threshold compared with "monophasic" stimulation. At higher intensities, the reverse phase begins to activate AP-sensitive neurones and increase the effectiveness of stimulation above that of a "monophasic" PA pulse. "Biphasic" stimulation with initially AP pulses is dominated at threshold by activation produced by the lower threshold reverse (PA) phase. SIGNIFICANCE: The effects of biphasic stimulation are best understood as the summed output of two independent sets of directionally selective neural populations.

Noninvasive Neuromodulation in Poststroke Gait Disorders: Rationale, Feasibility, and State of the Art.

Walking rehabilitation is one of the primary goals in stroke survivors because of its great potential for recovery and its functional relevance in daily living activities. Although 70% to 80% of people in the chronic poststroke phases are able to walk, impairment of gait often persists, involving speed, endurance, and stability. Walking involves several brain regions, such as the sensorimotor cortex, supplementary motor area, cerebellum, and brainstem, which are approachable by the application of noninvasive brain stimulation (NIBS). NIBS techniques, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been reported to modulate neural activity beyond the period of stimulation, facilitating neuroplasticity. NIBS methods have been largely applied for improving paretic hand motor function and stroke-associated cognitive deficits. Recent studies suggest a possible effectiveness of these techniques also in the recovery of poststroke gait disturbance. This article is a selective review about functional investigations addressing the mechanisms of lower-limb motor system reorganization after stroke and the application of NIBS for neurorehabilitation.

Effect of coil orientation on strength-duration time constant and I-wave activation with controllable pulse parameter transcranial magnetic stimulation.

OBJECTIVE: To compare the strength-duration (S-D) time constants of motor cortex structures activated by current pulses oriented posterior-anterior (PA) or anterior-posterior (AP) across the central sulcus. METHODS: Motor threshold and input-output curve, along with motor evoked potential (MEP) latencies, of first dorsal interosseus were determined at pulse widths of 30, 60, and 120 µs using a controllable pulse parameter (cTMS) device, with the coil oriented PA or AP. These were used to estimate the S-D time constant and we compared with data for responses evoked by cTMS of the ulnar nerve at the elbow. RESULTS: The S-D time constant with PA was shorter than for AP stimulation (230.9 ± 97.2 vs. 294.2 ± 90.9 µs; p<0.001). These values were similar to those calculated after stimulation of ulnar nerve (197 ± 47 µs). MEP latencies to AP, but not PA stimulation were affected by pulse width, showing longer latencies following short duration stimuli. CONCLUSION: PA and AP stimuli appear to activate the axons of neurons with different time constants. Short duration AP pulses are more selective than longer pulses in recruiting longer latency corticospinal output. SIGNIFICANCE: More selective stimulation of neural elements may be achieved by manipulating pulse width and orientation.

Motor Cortical Plasticity to Training Started in Childhood: The Example of Piano Players.

Converging evidence suggest that motor training is associated with early and late changes of the cortical motor system. Transcranial magnetic stimulation (TMS) offers the possibility to study plastic rearrangements of the motor system in physiological and pathological conditions. We used TMS to characterize long-term changes in upper limb motor cortical representation and interhemispheric inhibition associated with bimanual skill training in pianists who started playing in an early age. Ipsilateral silent period (iSP) and cortical TMS mapping of hand muscles were obtained from 30 strictly right-handed subjects (16 pianists, 14 naïve controls), together with electromyographic recording of mirror movements (MMs) to voluntary hand movements. In controls, motor cortical representation of hand muscles was larger on the dominant (DH) than on the non-dominant hemisphere (NDH). On the contrary, pianists showed symmetric cortical output maps, being their DH less represented than in controls. In naïve subjects, the iSP was smaller on the right vs left abductor pollicis brevis (APB) indicating a weaker inhibition from the NDH to the DH. In pianists, interhemispheric inhibition was more symmetric as their DH was better inhibited than in controls. Electromyographic MMs were observed only in naïve subjects (7/14) and only to voluntary movement of the non-dominant hand. Subjects with MM had a lower iSP area on the right APB compared with all the others. Our findings suggest a more symmetrical motor cortex organization in pianists, both in terms of muscle cortical representation and interhemispheric inhibition. Although we cannot disentangle training-related from preexisting conditions, it is possible that long-term bimanual practice may reshape motor cortical representation and rebalance interhemispheric interactions, which in naïve right-handed subjects would both tend to favour the dominant hemisphere.

Age-related changes in motor cortical representation and interhemispheric interactions: a transcranial magnetic stimulation study.

To better understand the physiological mechanisms responsible for the differential motor cortex functioning in aging, we used transcranial magnetic stimulation to investigate interhemispheric interactions and cortical representation of hand muscles in the early phase of physiological aging, correlating these data with participants' motor abilities. Right-handed healthy subjects were divided into a younger group (n = 15, mean age 25.4 ± 1.9 years old) and an older group (n = 16, mean age 61.1 ± 5.1 years old). Activity of the bilateral abductor pollicis brevis (APB) and abductor digiti minimi (ADM) was recorded. Ipsilateral silent period (ISP) was measured in both APBs. Cortical maps of APB and ADM were measured bilaterally. Mirror movements (MM) were recorded during thumb abductions. Motor abilities were tested using Nine Hole Peg Test, finger tapping, and grip strength. ISP was reduced in the older group on both sides, in terms of duration (p = 0.025), onset (p = 0.029), and area (p = 0.008). Resting motor threshold did not differ between groups. APB and ADM maps were symmetrical in the younger group, but were reduced on the right compared to the left hemisphere in the older group (p = 0.008). The APB map of the right hemisphere was reduced in the older group compared to the younger (p = 0.021). Older subjects showed higher frequency of MM and worse motor abilities (p < 0.001). The reduction of right ISP area correlated significantly with the worsening of motor performances. Our results showed decreased interhemispheric interactions in the early processes of physiological aging and decreased cortical muscles representation over the non-dominant hemisphere. The decreased ISP and increased frequency of MM suggest a reduction of transcallosal inhibition. These data demonstrate that early processes of normal aging are marked by a dissociation of motor cortices, characterized, at least, by a decline of the non-dominant hemisphere, reinforcing the hypothesis of the right hemi-aging model.

Excitatory deep transcranial magnetic stimulation with H-coil over the right homologous Broca's region improves naming in chronic post-stroke aphasia.

BACKGROUND: The role of the right hemisphere in poststroke aphasia recovery is still controversial and the effects of repetitive transcranial magnetic stimulation (rTMS) over the right homologous Broca's region have been seldom investigated. OBJECTIVE: This study aimed to compare the effect of excitatory, inhibitory, and sham rTMS delivered with H-coil over the right inferior frontal gyrus in chronic aphasic patients. METHODS: Five right-handed poststroke aphasic patients underwent a picture naming task before and immediately after each of 3 sessions of rTMS: excitatory (10 Hz), inhibitory (1 Hz), and sham rTMS, in random sequence and separated by at least 1 week. RESULTS: Only the excitatory 10-Hz stimulation was associated with a significant improvement in naming performance (P = .043) and was significantly more effective than 1-Hz rTMS (P = .043). CONCLUSIONS: A single session of excitatory deep brain rTMS over the right inferior frontal gyrus with H-coil significantly improves naming in right-handed chronic poststroke aphasic patients. This result is in line with the hypothesis of a positive, rather than detrimental, role of the right hemisphere in chronic aphasia due to a left-hemispheric stroke.

Mapping early changes of cortical motor output after subcortical stroke: a transcranial magnetic stimulation study.

After acute stroke several changes in cortical excitability occur involving affected (AH) and unaffected hemisphere (UH) but whether they contribute to motor recovery is still controversial. We performed transcranial magnetic stimulation mapping of several upper limb muscles over the two hemispheres in thirteen patients at 4-12 days from subcortical stroke and after 1 month. The occurrence of mirror movements (MMs) on the healthy side during contraction of paretic muscles was measured. At baseline, cortical excitability parameters over the AH decreased in comparison with controls, while excitability over the UH increased correlating with severity of motor deficits of the affected arm at baseline as well as with poor recovery. At follow-up, map parameters of the UH became closer to those of controls independently from recovery, while for the AH the number of responsive sites increased significantly. Ipsilateral motor evoked responses (iMEPs) in the affected arm were never elicited. We observed an early impairment in dexterity of the ipsilesional hand that recovered over-time but persistently differed in comparison with controls. MMs occurrence increased at baseline correlating with reduced cortical excitability of the AH as well as with increased map density over the UH. The acute increased excitability of the UH after stroke has a negative prognostic value on recovery and negatively affects motor performance of the ipsilesional hand. Moreover, the absence of iMEPs and the normalization of motor cortical excitability at follow-up indicate that the UH primary motor area does not contribute to recovery.

Interhemispheric balance in Parkinson's disease: a transcranial magnetic stimulation study.

BACKGROUND: Parkinson's disease (PD) is characterized by various changes in motor excitability. OBJECTIVE: To examine through Transcranial Magnetic Stimulation (TMS) cortical excitability, specifically addressing interhemispheric connections in PD. METHODS: Nineteen PD patients with a predominant involvement of the left hemibody (7 females, age 61.7 years,) and 13 controls (6 females, age 61.5 years) entered the study. Patients were subdivided into two groups (early and advanced) according to the time from PD diagnosis. Participants underwent evaluation of Resting Motor Threshold (RMT) and ipsilateral Silent Period (iSP), induced by suprathreshold TMS on the ipsilateral-M1, measured as suppression of voluntary EMG activity. Mirror Movements (MM) were EMG-recorded and scored, in three upper limb muscles, during unilateral voluntary hand movement. Patients were studied at baseline (OFF drug) and after acute levodopa challenge (ON). RESULTS: PD patients showed a general reduction in RMT vs controls (P < 0.01 for right and left hemisphere) in both drug conditions. Early PD had a significantly lower RMT over the right vs the left hemisphere (P = 0.027); this difference was no longer significant after levodopa. In early PD patients, MM were mainly observed in the right arm during voluntary activation of the left, more affected side both in OFF (P = 0.033) and in ON (P = 0.046). In PD, RMT of the left, less affected M1 was significantly correlated with the right lateralized motor score (P = 0.011; Spearman's coefficient = -0.585), as well as with disease duration. In PD patients, a shorter (P = 0.039) and smaller (P = 0.037) iSP was detected when the stimulus was applied to the worse M1 (right) compared with the contralateral side. This asymmetry was significant only OFF drug. In the PD group iSP-duration from the right, less affected APB was negatively correlated with the MM recorded from the same side during the voluntary movement of the worse side (Spearman's coefficient = -0.498; P = 0.035). CONCLUSIONS: Increased cortical motor excitability in PD, consistent with previous findings, is more evident in the worse hemisphere, particularly in early PD. Asymmetric motor involvement is also associated with excessive involuntary mirroring and defective interhemispheric inhibition, both unfavoring the more affected side. Altogether, these findings suggest that asymmetric motor involvement in PD, particularly in the earlier phases of the disease, affects the interhemispheric balance of cortical excitability, movement lateralization and transcallosal inhibition.

Cortical control of unilateral simple movement in healthy aging.

Normal aging is associated with several modifications in the cerebral motor system that reflect into an increased and more bilateral activation in elderly subjects. Twelve young and nine elderly healthy right-handed subjects performed a self-initiated brisk right thumb extension while recorded with 32-channel EEG. The aging effect over cortical generators of bereithshaftspotential, reconstructed using cortical current density (CCD) method and a realistic volume conductor, was evaluated in five different periods and in both mesial and lateral motor-related areas. Over-activation occurred mainly at movement initiation in those areas related to simple movements (caudal mesial areas and both sensorimotor cortices) and in contralateral sensorimotor cortex during the post-movement phase. In those areas, the elderly group recruited a larger neuronal population than the young one in the presence of a significantly longer movement. This more likely suggests their reduced selectivity in activating the motor cortex than a compensatory mechanism to produce an optimum performance. Movement duration resulted negatively correlated with pre-SMA activity, suggesting its involvement in movement termination.