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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 2 = 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.

Objective To assess the usefulness of upper limb (UE) motor evoked potential (MEPs) as a marker of motor impairment in a cohort of people with progressive multiple sclerosis (PwPMS). Methods we evaluated UE and lower extremities (LE) MEPs, 6-minutes walk-test (6MWT), 10-meter walk-test (10MWT), EDSS, 9-hole peg-test (9HPT), and measures of strength (MRC) and tone (MAS) to the UE and LE in 50 PwPMS (EDSS 4.0–6.5; P ≥ 3, C ≤ 2). Results Bilateral absence of LE-MEPs, found in 74% of cases, was associated with worse 10MWT and 6MWT. UE-MEPs were rarely absent (8%) but often delayed (74%). Abnormal UE-MEPs were associated with worse performance at 9HPT (25.8 vs 33.2 s). UE-MEPs latency correlated with 10MWT (rho = 0.597), 6MWT (rho = −0.425) and EDSS (rho = 0.296). Conclusion UE-MEPs may represent a clinically relevant outcome measure to quantify corticospinal tract integrity in PwPMS, at least when LE-MEPs cannot provide a measurable response. Significance The strive for novel remyelination strategies in MS points to the need for quantitative conduction measurements in addition to clinical outcomes. The frequent absence of MEPs to the lower limbs in PwPMS may greatly limits their usefulness in monitoring progression or response to therapies. With this respect, the upper extremities may represent a better target.

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.

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, Highlights • Controllable pulse parameter TMS device was used to systematically modulate pulse shape. • Pulse shape influenced primary motor cortex thresholds and input-output curves. • Increasing pulse symmetry increased threshold with PA but lowered it with AP direction. • Biphasic stimuli yield the summed output of directionally selective neural populations.

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.

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.

Objectives To assess the efficacy of high-frequency (20Hz) brain stimulation on lower limb motor function in subjects with chronic (>6mo) 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.

Background Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a potential treatment for Parkinson's disease (PD). H-coils, inducing deeper and wider magnetic fields compared to traditional coils, may be potentially useful in PD, characterized by widespread, bilateral involvement of cortico-subcortical circuits. Objective To evaluate the safety of repetitive deep TMS (rDTMS) with H-coil as add-on treatment of motor symptoms in PD. Methods Twenty-seven PD patients (aged 60.1 ± 6.8 y; PD-duration: 6.3 ± 2.8 y; motor-UPDRS: 39.6 ± 10.1) underwent 12 rDTMS sessions over 4 weeks at excitatory (10 Hz) frequency over primary motor (M1) and bilateral prefrontal (PF) regions. Motor UPDRS off therapy was assessed before and after the last rDTMS session, together with safety records at each treatment session. Results No drop-outs or adverse events were recorded. Motor UPDRS significantly improved after rDTMS (10.8 points average reduction; P Conclusions High-frequency rDTMS might be a safe treatment for PD motor symptoms. Further placebo-controlled, randomized studies are warranted.

Neglect treatment with prismatic lenses (PL) has been demonstrated to be effective in improving hemispatial neglect. This study aimed to compare the effect of cathodal transcranial direct current stimulation (c-tDCS), anodal tDCS (a-tDCS) or sham stimulation in modulating the PL effect in stroke patients. Fifteen subacute stroke patients with pathological performance on the Behavioral Inattention Test (BIT) battery, indicative of neglect, were included in this study. Patients underwent to a-tDCS over the right posterior parietal cortex (PPC), c-tDCS over the left PPC and sham stimulation during three PL training sessions (with PL of 10? rightward shift), in random sequence and separated by at least 1 day. Thirty “invisible” pointing (visual target not visible) were performed before and after each session to evaluate the after-effect of the PL training. Leftward shift after PL training was significantly reduced by a-tDCS over the ipsilasional PPC in comparison with c-tDCS over the contralesional PPC (p = 0.019) and sham stimulation (p = 0.047). No difference in the after-effect was obtained comparing the c-tDCS and sham stimulation. Error correction during the PL training do not significantly differed among the three sessions. A-tDCS over the ipsilesional PPC reduced the leftward deviation possibly interfering with the network involved in visuo-motor adaptation to PL training.

Functional disorders-FD account for major disability and impairment. As multidisciplinary approach appears to be the most effective treatment, placebo can effectively relieve symptoms in some cases. Our aim was to assess FD outcome after sham rTMS and to identify response predictors. Sixteen consecutive patients (13 females, age 29.9 ± 11.2 years, disease duration-DD 3.8 years, range 0–26) underwent multiple sessions (5.4 + 4.5) of sham rTMS with H-coil as symptomatic treatment for FD. Global Clinical Impression of Improvement (CGI-I) was collected from the treating physician and correlated with clinical-demographical data using Spearman test. A coexisting neurological disease was diagnosed in 4 patients, while 8 had a psychiatric disorder; 8 patients presented with either sensitive or motor deficits, 7 had hyperkinetic movement disorders and 3 a mixture of both. Twelve patients improved following treatment (CGI-I 2.9 + 1.0) with only 1 patient with psychogenic tremor showing a mild and transitory feeling of postural instability. A greater CGI-I was found for shorter disease duration (r − 0.871, p

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.

Objective repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for the treatment of post-stroke motor deficits. Since the crucial role of non-primary motor cortices and contralesional brain areas is emerging for motor recovery in chronic stroke; we assessed safety and efficacy of bilateral rTMS over the motor areas associated to physical training (PT) on upper extremity (UE) motor function. Methods double-blind, placebo-controlled trial on 20 patients with chronic stroke conditioning moderate to mild upper limb motor impairment. Eleven sessions of high frequency rTMS were delivered with the H-coil over the motor areas bilaterally. Subjects were randomly allocated to the real rTMS plus PT or the placebo (sham) rTMS plus PT. UE impairment was evaluated by the Fugl-Meyer assessment for UE (FM-UE), Modified Ashworth Scale (MAS) and hand grip strength at baseline (T0), after treatment (T1) and one-month follow-up (T2). Results no serious adverse events were reported. At T1 FM-UE significantly improved in both groups, while at T2 the improvement was significant only for the real group. The improvement was significantly higher in the real compared with the sham group. In the real group, greater improvement in FM-UE was found in patients moderately impaired compared with less impaired at baseline. Spasticity and hand grip strength also significantly improved in the real group at T1 and amelioration of spasticity persisted also at T2. Conclusion bilateral high-frequency rTMS with H-coil associated with PT is safe and enhances the effect of PT alone. Although plegic patients were not included, subjects with moderate rather than mild motor impairment may mainly benefit from this stimulation protocol.

Our aim is to investigate intra-session reliability of lower limbs (LL) motor evoked potentials (MEPs) amplitudes elicited by Transcranial Magnetic Stimulation (TMS) and measured from Tibialis-Anterior (TA) and Abductor-Hallucis (AH), comparing double cone and circular coil. TMS was used in healthy subjects (HS) (n = 7) to elicit MEPs in TA and AH of both LL, at rest and during low level muscle contraction. Double cone and circular coil were used. Two sets of eight responses were recorded for each coil in a random order, using a stimulation intensity of 100% of the maximum stimulator output. Intra-session reliability was calculated using Intraclass correlation coefficients (ICC). Double cone and circular coil showed excellent intra-session reliability in TA and AH of both LL, at rest and during low level muscle contraction (ICC ⩾ 0.75 in all experimental conditions). Interestingly, circular coil failed to elicit measurable MEPs at rest in non-dominant limb in 3 out of 7 HS. Double cone coil is an efficient alternative to circular coil in order to measure LL MEPs amplitudes in HS. Since circular coil did not elicit MEPs in all HS, double cone coil could be more useful in neurological patients to better detect MEPs in cortico-spinal tract pathological conditions.

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.

Focal rTMS in Alzheimer’s disease (AD) revealed cognitive benefits. H-coil can depolarize deeper and wider structures compared with focal coils, thus targeting widespread networks involved in neurodegenerative disorders. We aimed to evaluate H-coil rTMS safety and efficacy in AD. Thirty AD subjects (70.21 ± 8.66 y.o.), randomized in real or sham groups, underwent 16 rTMS sessions (3 weekly for 4 weeks, 1 weekly for other 4 weeks), over fronto-parieto-temporal lobes at 10 Hz. Neuropsychological assessment was performed at baseline, after 4 weeks (4w), at the end of treatment (8w). Primary outcome was an improvement in Alzheimer’s disease scale-cognitive (ADAS-cog). No serious side effects were reported. Four subjects were excluded (1 acute myocardial infarction in the sham group, 1 misdiagnosis, 2 missing data), thus statistical analysis included 26 subjects. At 4w, percent ADAS-cog improvement from baseline (4 w%) was greater in the real compared with the sham group (p = 0.042). The relationship between baseline ADAS-cog and 4 w% differed between the two groups (p = 0.009), with higher improvement for less cognitively impaired subjects at baseline only in the real. These findings suggest that H-coil may be safe and effective in AD and that deep rTMS may better impact the course of the disease when administered at earlier stages.

While robot-assisted rehabilitation is often found to help recovery, their use often remain limited to clinical trials. Amongst the reasons that may explain their under-use is the difficulty to bridge the gap between the score on a robot-assisted exercise and the control processes that mediate the measured performance. This paper illustrates the potential benefits of a multi-task approach for evaluating sensorimotor control processes. Results from a stroke patient are compared to those of a control group.

Highlights • S–D time constants are longer for anterior–posterior than posterior–anterior induced currents. • Brief (30 μs) anterior-posterior currents evoke the longest latency MEP. • Selective stimulation of neural elements may be achieved by manipulating pulse width and orientation., 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

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, pConclusions: 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.

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

Walking impairment has a strong impact on quality of life of multiple sclerosis (MS) patients. Excitatory Transcranial-Repetitive-Magnetic-Stimulation (rTMS) enhances corticospinal excitability and plasticity, potentially favouring the effects of neurorehabilitation. The aim of this study is to explore the impact of neurophysiological and clinical features on rTMS efficacy on walking in progressive MS patients undergoing neurorehabilitation. 42 progressive MS patients, randomized into real and sham-placebo rTMS, underwent 11 rTMS sessions during neurorehabilitation. Motor-threshold (RMT), duration of disease progression, walking speed (10mt-walking-test) and endurance (2 and 6 mwt) were assessed at baseline and at the end of treatment, as well as Modified-Ashworth-Scale (MAS), pain and spasticity VAS, Fatigue-Severity-Scale, EDSS, MS-walking-scale-12, PASAT and nine-hole-peg-test. Real rTMS patients showed greater improvement both in 10mt (p = 0.007) and 6mwt (p = 0.04). Greater disability was associated with greater 6mwt improvement in all patients (p = 0.01) and in the real-rTMS subgroup (p = 0.04), not in sham. In real-rTMS group, RMT negatively correlated with 6mwt improvement (p = 0.003). The potential for improvement, greater in more disabled patients after rTMS, can be exploited using this treatment associated with neurorehabilitation. RMT, resulting from combination of corticospinal excitability and of corticomotor fibres available for conduction, could be considered a predictive marker of therapeutic response to rTMS neuromodulation.

Dear Editor, We present the case of a patient found with focal neurological deficit of unknown time of onset associated to ECG abnormalities suggestive of acute coronary syndrome. Besides highlighting the link between neurological and cardiac disorders, the main challenge of such unusual combination featuring two emergencies is to establish the trigger and the triggered so as to promptly adopt the most appropriate diagnostic and therapeutic measures. A 68-year-old Hispanic woman, with unremarkable past medical history, was found at home (7.00 a.m.) with right hemiplegia and impaired speech. Her relatives promptly called the emergency and witnessed generalized tonic– clonic seizure while the mobile emergency team was on the way. The emergency staff found her unconscious with tonic–clonic seizure and subsequent right hemiplegia. The electrocardiogram (ECG) showed ST-segment elevation in the anterior and lateral leads suggestive of acute coronary syndrome. The patient received urapidil 5 mg, midazolam 2 mg and ASA 500 mg intravenously and was brought to our Emergency Department (8.20 a.m.). The neurological examination demonstrated persistent right hemiplegia and global aphasia. The ECG confirmed ST alterations, while the transthoracic echocardiogram (TTE) showed anterior and apical hypokinesia with moderate left ventricular dysfunction (45 %). Initial troponin T level was 0.08 lg/L and rose up to 0.627 lg/L 4 h later (\0.038 normal value). The patient was sedated with midazolam and propofol e.v. and intubated for airway protection allowing further diagnostic tests in otherwise uncooperative subject. Head CT scan showed no evidence of hemorrhage, early ischemic changes or hypodensity. The ECG, repeated 45 min later showed a partial regression of the ST alterations. A repeated TTE showed diffuse mid-apical hypokinesia and basal hyperkinesia with left ventricular apical ballooning. Transesophageal echocardiogram excluded aortic dissection and potential cardiac sources of cerebral embolism. Urgent coronary angiography excluded coronary artery disease and left ventriculography revealed the characteristic findings of ‘‘Takotsubo Shape’’. Brain MRI showed hyperintense lesions on T2-weighted MRI images in the anterior medial left temporal lobe and left amygdale without signal restriction on diffusion weighted imaging (DWI) suggestive of acute ischemic lesion. Around 2 pm sedation was gradually tapered and the neurologic examination documented persisting right hemiparesis. The EEG showed synchronous and asynchronous slow waves over the temporal lobes with left side predominance. Levetiracetam 1000 mg bid was started. Lumbar puncture was performed to exclude encephalitis. Over the course of the next day, the patient fully recovered to normal neurological examination. Serum troponin T normalized and repeated TTE on day 10 was normal. Familiar history (mother and aunt) of epilepsy was reported later on. The patient was discharged at home with the diagnosis of partial status epilepticus with associated Takotsubo cardiomyopathy (TTC). Follow-up MRI at 2 months was within normal. The patient presented with acute neurological impairment along with signs of acute coronary syndrome posing the issue of dealing with two emergencies associated with & Raffaella Chieffo raffaella.chieffo@hsr.it

Purpose We used a controllable pulse parameter transcranial magnetic stimulation (cTMS) device to assess whether adjusting pulse width and coil orientation would allow more selective stimulation of different neuronal populations. Methods Young healthy subjects participated in experiments involving single pulse stimulation over the hand motor area elicited by a cTMS device connected to a figure-of-eight coil. Experiment 1 (n=10) evaluated the effect of coil orientation (posterior-anterior, PA; anterior-posterior, AP) and pulse width (30, 60 and 120 μs) on the strength-duration curve, the input-output (IO) curve and the latency of the motor evoked potentials (MEPs) in the first dorsal interosseous muscle. Experiment 2 (n=12) evaluated the effect of coil orientations (PA, AP) and pulse width (30 and 120 μs) on short-latency afferent inhibition (SAI), tested with electrical median nerve stimulation at the wrist prior to TMS (inter-stimulus intervals: N20 latency +2 and +4 ms). All tests were completed during background contraction (∼10% maximum). Results The mean strength-duration time constants were shorter for PA than AP directed currents when estimated using motor threshold data (231 vs. 294 μs; t-test, p = 0.008) and IO data (252 vs. 296 μs; t-test, p < 0.001). ANOVA revealed an interaction of pulse width and orientation on MEP latencies (p = 0.001), due mainly to the increase in latencies with short duration AP stimuli. A similar pulse width and orientation interaction was observed for SAI (p = 0.011), resulting from the stronger inhibition with AP stimuli of short duration. Conclusion PA and AP oriented pulses appear to activate neural populations with different time constants. The AP-sensitive neural populations that elicit the longest latency MEPs are more readily stimulated by short than by long duration pulses, and appear more sensitive to SAI. Manipulating pulse width may improve the selectivity of AP stimulation.

Repetitive transcranial magnetic stimulation (rTMS) has been recognized as a promising intervention for treatment of post-stroke deficits. We evaluated the feasibility, safety and efficacy of excitatory Hz rTMS with H-coil over the leg motor areas combined with active cycling on paretic lower limb motor function in chronic post-stroke. rTMS was delivered with the H-coil targeting the lower limbs (real or sham for 11 sessions over 3weeks, with cross-over after 4weeks wash-out, in 12 subjects with first stroke more than 6months before. Lower limb function was assessed with the Fugl-Meyer lower limb scale (FM-LL), with additional timed measures (10-m and 6min walking tests) and modified ashworth scale to the lower limb. No participant reported adverse effects. Real rTMS treatment was associated with a significant improvement in FM-LL scores ( p p =0.007 chi square). The 10min test did not significantly improve and the 6min test improved after both treatments ( p

Stroke is the leading cause of adult disability. Unfortunately, less than 40% of stroke survivors completely recover, despite intensive acute care and rehabilitation training. Non invasive brain stimulation (NIBS) techniques have been recognized as a promising intervention to improve motor recovery after stroke. Repeated sessions of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) can, indeed, induce changes in cortical excitability and long term plasticity. Several protocols of stimulation have been already tested and proven efficient in modulating the lesioned as well as the unlesioned hemisphere after stroke. However, not all patients can be considered as responder to NIBS. We provide an overview of the rationale, open questions and future perspectives for NIBS after stroke.

Progressive supranuclear palsy-PSP is the second most common parkinsonian syndrome after Parkinson’s disease-PD, with some overlapping clinical features in the early phases. Non-invasive neurophysiological techniques, such as transcranial magnetic stimulation-TMS, could be useful for the differential diagnosis. Seventeen PD, 13 PSP and 11 healthy controls-HC subjects were included in this study. TMS evaluation included resting motor threshold-RMT, motor evoked potentials-MEP amplitude and latency, response to inhibitory-SICI and facilitating-ICF conditioned stimuli, cortical silent period-CSP, and ipsilateral silent period-iSP. Statistical analysis was performed using either parametric or non-parametric ANOVA according to data distribution. PSP and PD groups did not significantly differ in UPDRS. TMS assessment showed different distribution of RMT across the groups (p.008), with PSP patients showing the highest values and PD the lowest (PSP vs PD p.002). Group also affected iSP duration (p.016), being longest in PSP and lowest in HC (PSP vs HC p.005). On paired-pulse inhibition and facilitation, a significant effect for ISI ( p

Walking impairment affects multiple sclerosis (MS) patients and impacts their quality of life. Despite a known relationship between objective and subjective walking measures, gait and neurophysiological motor parameters relationships remains to be explored. 50 progressive MS people underwent functional and neurophysiological assessments: 10-meters-walking-test (10 mWT), 2 and 6 min-walking-test (2 mWT, 6 mWT), modified-Ashworth-scale (MAS), spasticity and pain numerical-rating-scale (NRS), fatigue-severity-scale (FSS), expanded-disability-status-scale (EDSS), and 12-items-MS-walking-scale (MSWS-12). A walking-fatigability-index (WFi, performance decay from 2 to 6 min during 6 mWT) was calculated according to the formula: [(2 mWT ∗ 3 − 6 mWT)/2 mWT ∗ 3]. Resting-motor-threshold (RMT, the lowest intensity for evoking an electromyographic or visually-evident muscle activation) was obtained using a H-coil. Correlations were explored using the Spearman-rho coefficient (significance set at p = 0.05). RMT correlated positively with the 10 mWT ( p = 0.012) and with MSWS-12 ( p = 0.005), and negatively with the 2 mWT (p = 0.016), but not with 6 mWT, nor with fatigue (FSS) or fatigability (WFi). WFi significantly correlated with disability (EDSS; p p = 0.007). RMT, as measure of pyramidal reserve, is correlated with subjective impact of MS on walking, predicting walking speed rather than endurance or fatigability, the latter being associated with disability and spasticity. The lack of association between subjective fatigue and objective fatigability suggests different mechanisms underling the two phenomena.

The cerebellum is involved in motor execution. It controls the primary motor cortex (M1) activity and ensures the correct amount of inhibition to produce the right motor output. Besides, it plays an important role in the error monitoring mechanisms during bimanual coordination. We investigated the role of the cerebellum in the modulation of M1excitability and M1-M1 interhemispheric inhibition (IHI) using transcranial direct current stimulation (tDCS). Thirteen healthy volunteers received cerebellar tDCS at 2 mA for 20 min among three randomized sessions (anodal right, anodal left, sham). M1 excitability (PA direction, single-pulse, 1 mV MEP) and short-latency IHI (PA direction, paired-pulse, conditioning stimulus 110% RMT, ISI 8 and 10 ms) were determined before, 5 min after the onset, and 30 min after the end of stimulation. All measures were taken bilaterally. The M1 excitability compared before, during and after cerebellar tDCS did not change among sessions (ANOVA, p > 0.05). The short-latency M1-M1 IHI was always determined, but it did not change among sessions (ANOVA, p > 0.05). The cerebellar anodal tDCS does not interfere with the motor cortex excitability and with the transcallosal inhibition at rest.

Objective Progressive Supranuclear Palsy-PSP is the second most common parkinsonian syndrome after Parkinson’s disease-PD. Non-invasive neurophysiological techniques, such as transcranial magnetic stimulation-TMS, could prove useful to gain insight into these pathologies and for differential diagnosis. Methods Seventeen PD, 13 PSP and 11 healthy controls-CT were included in this study. TMS evaluation included resting motor threshold-RMT, motor evoked potentials-MEP amplitude, response to inhibitory-SICI and facilitating-ICF conditioning stimuli, cortical-CSP and ipsilateral silent period-iSP. Statistical analysis was performed using either parametric or non-parametric ANOVA and post-hoc tests according to data distribution. Results PSP and PD groups did not significantly differ in UPDRS. RMT distributed differently across groups (p.008), with PSP patients showing highest values and PD lowest (PSPvs.PD p.002). Group also affected iSP duration (p.016), being longest in PSP and lowest in HC (PSPvs.CT p.005). On paired-pulse inhibition and facilitation, a significant effect for inter-stimulus interval-ISI ( p Conclusions This study suggests that TMS can help differentiate PD and PSP. PSP patients displayed different response to the perturbation induced by conditioning stimuli and iSP elongation, probably due to impairment of GABA-mediated neurotransmission.

Objective Walking impairment affect multiple sclerosis (MS) patients, impacting their quality of life. Despite a known relationship between objective and subjective walking measures, gait and neurophysiological motor parameters relationships remains to be explored. Methods 50 progressive MS people underwent following assessments: 10-meters-walking-test (10 mWT), 2 and 6 min-walking-test (2 mWT, 6 mWT), Modified-Ashworth-Scale (MAS), Spasticity and pain Numerical-Rating-Scale (NRS), Fatigue-Severity-Scale (FSS), expanded-disability-status-scale (EDSS), 12-items-MS-walking-scale (MSWS-12). A Walking-Fatigability-Index (WFi, performance decay from 2 to 6 min during 6 mWT) was calculated according to the formula:[(2 mWT ∗ 3–6 mWT)/2 mWT ∗ 3]. Resting-motor-threshold (RMT, the lowest intensity for evoking an electromyographic or visually-evident muscle activation) was obtained using a H-Coil. Correlations were explored using the Spearman-rho coefficient (significance set at p = 0.05). Results RMT correlated positively with the 10 mtWT ( p = 0.012) and with MSWS-12 ( p = 0.005), and negatively with the 2 mWT ( p = 0.016), but not with 6 mWT, nor with fatigue (FSS) or fatigability (WFi). WFi was significantly correlated with disability (EDSS; p p = 0.007). Conclusions Resting motor threshold, as measure of pyramidal reserve, is correlated with subjective impact of MS on walking, predicting walking speed rather than endurance or fatigability, the latter being associated with disability and spasticity. The lack of association between subjective fatigue and objective fatigability suggests different mechanisms underling the two phenomena.

Objective Focal rTMS in Alzheimer’s disease (AD) revealed cognitive benefits. H-coil depolarize deeper and wider structures compared with focal coils, maybe targeting widespread networks involved in neurodegenerative disorders. We explored H-coil safety and efficacy in AD. Methods Thirty AD subjects (70.21 ± 8.66 y.o.), randomized in real or sham groups, underwent 16 rTMS sessions (3/week for 4 weeks, 1/week for other 4 weeks), over fronto-parieto-temporal lobes (10 Hz). Neuropsychological assessment was performed at baseline, after 4 weeks (4 w), at the end (8 w). Primary outcome: improvement in Alzheimer’s disease Scale-cognitive (ADAS-cog). Four subjects were excluded (1 acute myocardial infarction in the sham group, 1 misdiagnosis, 2 missing data), thus statistical analysis included 26 subjects. Results No serious side effects were reported. At 4 w, percent ADAS-cog improvement from baseline (4 w%) was greater in the real compared with the sham group ( p = 0.042). The relationship between baseline ADAS-cog and 4 w% differed between the two groups ( p = 0.009), with higher improvement for less cognitively impaired subjects at baseline only after real stimulation. Conclusions Excitatory deep rTMS appears feasible in AD with a promising safety and efficacy profile and may better impact the course of the disease when administered at earlier stages.

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

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.

International audience; Robot-assisted rehabilitation is often found to help in recovery, but its use is often experimental or limited to clinical trials. This paradox is partly explained by the difficulty in bridging the gap between the score on a robot-assisted exercise and the control processes that mediate the measured performance. Building upon recent computational model of motor control, this paper highlights the potential benefits of a multitask approach for evaluating sensorimotor control processes. The approach is illustrated with the results from normal and pathological sensorimotor behavior in humans.

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.

To evaluate the effect of repetitive deep transcranial magnetic stimulation—rDTMS on motor symptoms in Parkinson’s Disease—PD in a randomized, placebo controlled study. Sixty patients underwent 12 sessions (3 sessions/week) of 10 Hz rDTMS, after randomization into 3 groups: Group 1 (real rDTMS on primary motor—M1 and prefrontal—PF areas); Group 2 (M1-real/PF-sham), Group 3 (M1-sham/PF-sham). Primary outcome was percent reduction of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, OFF therapy. Secondary outcomes were: changes in UPDRSIII sub-scores; improvement in timed tests (Hand Tapping—HT, Foot Tapping—FT, Walking Time—WT, Nine Hole Peg Test—NHPT). Statistical analysis was performed using Mann–Whitney or t-test. Outcomes were tested in hierarchical order, by comparing the two real groups (1–2) only if their pooled data significantly differed from sham. No drop-outs or serious adverse effects were recorded. Both real groups improved significantly more than sham in UPDRSIII (p = .010 and p = .045, respectively), while they did not significantly differ between them. Pooled real groups showed a significant improvement vs sham in UPDRSIII (p = .007), tremor (p = .011) and lateralized sub-scores (p = .042 and p = .012 for worse and better side, respectively). Timed tests significantly improved more in the real group vs sham on the worse side (HT p = .041, FT p = .012, NHPT p = .003). rDTMS with H-coil appeared safe and effective on motor symptoms as add-on treatment in PD.

Several functional studies suggest a more bilateral movement-related recruitment of motor areas during voluntary movement associated with physiological aging. To investigate the changes of motor cortical excitatory and inhibitory balance during physiological aging, using transcranial magnetic stimulation (TMS). We recruited right-handed 31 healthy volunteers, divided into two groups: one younger group (15 subjects, 6 females, age 25.4 ± 1.9 y) and one older group (16 subjects, 7 females, age 61.1 ± 5.1 y). Motor abilities were tested using Nine Hole Peg Test (NHPT) and finger tapping (FT). Surface electromyography (EMG) of the bilateral abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles was recorded. TMS was delivered with a Magstim 200 simulator connected to a figure-of-eight coil (Magstim 2nd generation, 70 mm of external diameter). Resting motor threshold (RMT) on each side and cortical mapping of APB and ADM muscles were analyzed. We also registered ipsilateral silent period (ISP) in both APB muscles, during maximal contraction. Older subjects showed worse motor performances (in terms of NHPT and FT of both hands) than younger ones ( p p p = 0.03). In older group, APB map on the right hemisphere was significantly reduced vs the younger group ( p = 0.021) and vs its homologous ( p = 0.042). For ADM, no significant map differences were found between elderly and young subjects, even on the right hemisphere. ISP was significantly reduced in the elderly on both sides, in terms of duration ( p = 0.025), peak ( p = 0.033) and area ( p = 0.008). Physiological aging is associated with disruption of interemispheric specialization both concerning motor cortical representation and interhemispheric interactions. This may have consequences on recovery from pathological processes and suggests that age has to be taken into account when planning therapeutic intervention aimed at restoring hand motor function.

High frequency transcranial repetitive magnetic stimulation (rTMS) enhances corticospinal excitability and plasticity, potentially favouring the effects of neurorehabilitation, as in a preliminary study by our group. We aimed at replicating our previous study and at combining results exploring baseline features. Twenty subjects with progressive MS, randomized in real and sham-placebo H-coil rTMS targeting lower limbs, underwent 11 sessions following intensive rehabilitation. Walking speed (10MWT), endurance (6 min test), modified Ashworth Scale-MAS, numeric rating scale-NRS for spasticity and pain, EDSS, PASAT, NHPT, Fatigue Severity Scale, MS walking scale-12, were assessed at baseline and end of treatment. Real rTMS had significant improvement in 10MWT and MAS vs sham, confirming data from a previous pilot study on 21 participants. Pooling data with the latter study, a correlation between resting motor threshold to the lower limb and walking improvement was found exclusively in the real rTMS group. The improvement in walking speed observed after real rTMS with the H-coil is consistent with data from our previous pilot study. Resting motor threshold could be considered as a specific therapeutic reserve index for rTMS, being predictive of therapeutic response to corticospinal neuromodulation.

To evaluate the on-line and short-term effects of different intensities of anodal and cathodal transcranial direct electric stimulation (tDCS) on the human motor cortex. 14 healthy subjects received anodal and cathodal tDCS in a random order on two separate sessions using a 35 cm 2 electrodes positioned over the left M1 and the contralateral supra-orbital region. During each session tDCS was randomly delivered at 0.5, 1, 1.5 and 2 mA with a wash out period of 25 min between intensities. The duration of stimulation was varied so that the total charge transferred was 4 mA.min for all intensities. Twelve motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) were recorded from the right first dorsal interosseous muscle before (baseline), at the beginning (on line 1), at the end (on line 2) and immediately after (post) each stimulation. Data were analysed with a repeated measures ANOVA using polarity (anodal/cathodal), intensities (0.5,1,1.5 and 2) and time (baseline, on line 1, on line2 and post) as within subject factors. Paired t tests were used for post hoc comparisons. the ANOVA showed only a significant effect of time on MEPs amplitude (F:8.7, p p = 0.001, on line 2 p = 0.002) and immediately after either polarity of stimulation ( p = 0.02) compared with baseline. Short duration application of both anodal and cathodal tDCS facilitates corticospinal output during and immediately after application. The effects seem to be independent of the intensity and the duration of stimulation if the total amount of charge delivered is constant. Our findings could be, however, the result of an interaction between TMS and tDCS simultaneously delivered. Moreover we cannot exclude a sort of cumulative effect of several tDCS stimulations with a non effective wash-out period.