Short-interval Intracortical Inhibition Research Articles

Transcranial direct current stimulation in stroke – Motor excitability and motor function

ObjectiveTo characterize motor excitability changes and changes of motor performance induced by a single anodal and cathodal transcranial direct current stimulation (tDCS) session in stroke patients. MethodsTwenty subacute stroke patients participated. Motor performance was tested with the Box and Block Test [BBT]. Motor cortex excitability (short interval intracortical inhibition [SICI], intracortical facilitation [ICF], long interval intracortical inhibition [LICI]) was examined by paired pulse transcranial magnetic stimulation before and after a single tDCS session (20 minutes, 1,0 mA). On two different occasions, patients received anodal and cathodal tDCS over the affected hemisphere. TMS recordings were taken from both hands consecutively. ResultsAnodal tDCS significantly reduced SICI without changing ICF or LICI. Cathodal tDCS did not change motor excitability. Both types of tDCS did not alter motor performance. Even prior to anodal tDCS, SICI in the affected hemisphere was lower than in the unaffected hemisphere and was correlated with BBT changes after anodal tDCS. ConclusionsAnodal, but not cathodal tDCS specifically modulated intracortical inhibitory circuits, leading to a disinhibition. SignificanceThe results amplify our knowledge on excitability modulations of tDCS in stroke patients.

Cerebellar transcranial current stimulation - An intraindividual comparison of different techniques.

Transcranial current stimulation (tCS) techniques have been shown to induce cortical plasticity. As an important relay in the motor system, the cerebellum is an interesting target for plasticity induction using tCS, aiming to modulate its excitability and connectivity. However, until now it remains unclear, which is the most effective tCS method for inducing plasticity in the cerebellum. Thus, in this study, the effects of anodal transcranial direct current stimulation (tDCS), 50 Hz transcranial alternating current stimulation (50 Hz tACS), and high frequency transcranial random noise stimulation (tRNS) were compared with sham stimulation in 20 healthy subjects in a within-subject design. tCS was applied targeting the cerebellar lobe VIIIA using neuronavigation. We measured corticospinal excitability, short-interval intracortical inhibition (SICI), short-latency afferent inhibition (SAI), and cerebellar brain inhibition (CBI) and performed a sensor-based movement analysis at baseline and three times after the intervention (post1 = 15 min; post2 = 55 min; post3 = 95 min). Corticospinal excitability increased following cerebellar tACS and tRNS compared to sham stimulation. This effect was most pronounced directly after stimulation but lasted for at least 55 min after tACS. Cortico-cortical and cerebello-cortical conditioning protocols, as well as sensor-based movement analyses, did not change. Our findings suggest that cerebellar 50 Hz tACS is the most effective protocol to change corticospinal excitability.

Balance Training Modulates Cortical Inhibition in Individuals with Parkinson’s Disease: A Randomized Controlled Trial

Background Most individuals with Parkinson’s disease (PD) develop balance dysfunction. Previous studies showed that individuals with PD have abnormal corticomotor changes related to severity of motor symptoms and disease progression. Cortical disinhibition was observed in PD and this alteration can be an early sign of PD. Balance training seems to be an effective intervention to improve balance in individuals with PD. However, it is not much known about the effect of balance training on cortical neuroplasticity in PD population. Objective To investigate the effects of balance training on corticomotor excitability in individuals with PD. Methods Twenty-eight PD participants were recruited and randomly assigned to either the balance training (BT) or the control (CON) group. Both groups underwent 16 training sessions over 8 weeks. Outcome measures for corticomotor inhibition included the cortical silent period (CSP) and short-interval intracortical inhibition (SICI) on transcranial magnetic stimulation. Balance performance was measured using the Mini-Balance Evaluation Systems Test (Mini-BEST) and the Timed Up and Go (TUG) test. Results Participants in the BT group showed a significant increase in corticomotor inhibition (CSP: P = .028, SICI: P = .04) and a significant improvement in balance performance (Mini-BEST: P = .001, TUG: P = .04) after training. Compared to the CON group, the BT group showed a greater increase in corticomotor inhibition (CSP: P = .017, SICI: P = .046) and better improvement in balance (Mini-BEST: P = .046). Conclusion Balance training could modulate corticomotor inhibition in the primary motor cortex and improve balance performance in individuals with PD.

The effects of concurrent bilateral anodal tDCS of primary motor cortex and cerebellum on corticospinal excitability: a randomized, double-blind sham-controlled study

Transcranial direct current stimulation (tDCS) applied to the primary motor cortex (M1), and cerebellum (CB) can change the level of M1 corticospinal excitability (CSE). A randomized double-blinded crossover, the sham-controlled study design was used to investigate the effects of concurrent bilateral anodal tDCS of M1 and CB (concurrent bilateral a-tDCSM1+CB) on the CSE. Twenty-one healthy participants were recruited in this study. Each participant received anodal-tDCS (a-tDCS) of 2 mA, 20 min in four pseudo-randomized, counterbalanced sessions, separated by at least 7 days (7.11 days ± 0.65). These sessions were bilateral M1 stimulation (bilateral a-tDCSM1), bilateral cerebellar stimulation (bilateral a-tDCSCB), concurrent bilateral a-tDCSM1+CB, and sham stimulation (bilateral a-tDCSSham). Transcranial magnetic stimulation (TMS) was delivered over the left M1, and motor evoked potentials (MEPs) of a contralateral hand muscle were recorded before and immediately after the intervention to measure CSE changes. Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval intracortical inhibition (LICI) were assessed with paired-pulse TMS protocols. Anodal-tDCS significantly increased CSE after concurrent bilateral a-tDCSM1+CB and bilateral a-tDCSCB. Interestingly, CSE was decreased after bilateral a-tDCSM1. Respective alterations in SICI, LICI, and ICF were seen, including increased SICI and decreased ICF, which indicate the involvement of glutamatergic and GABAergic systems in these effects. These results confirm that the concurrent bilateral a-tDCSM1+CB have a facilitatory effect on CSE, whereas bilateral a-tDCSM1 exert some inhibitory effects. Moreover, the effects of the 2 mA, 20 min a-tDCS on the CB were consistent with its effects on the M1.

Motor-evoked potentials after focal electrical stimulation predict drug-induced convulsion potentials in rats

Drug-induced convulsions—often caused by the inhibition of GABA receptors and stimulation of glutamate receptors—are difficult to predict in animals. In this study, we attempted to detect the proconvulsant potential using motor-evoked potentials (MEPs) after focal electrical stimulation or upon using a functional observational battery (FOB). Pentylenetetrazole, kainic acid, and pilocarpine were used as convulsion-inducing drugs, and baclofen was used as a negative control. First, each compound was administered to male rats, and the FOB tests were performed. All drugs induced behavioral changes, but no commonality was found. Single electrical stimulation train MEPs were recorded under anesthesia for 60 min (at 5 min intervals) after administration of each drug. A dose-dependent increase in MEPs was observed for each convulsion-inducing drug. Moreover, paired electrical stimulation (conditioned and test) of the cerebral motor cortex was conducted with a 1–15 ms interstimulus interval (ISI), 10 min after administration of the drug. All convulsion-inducing drugs inhibited the short-interval intracortical inhibition (ISI: 3 ms), which may be associated with GABA. Intracortical facilitation (ISI: 11 ms), related to glutamate, was not enhanced by any drug but was inhibited by pilocarpine. Dose correlation was not found in short-interval intracortical inhibition or intracortical facilitation in any drugs. No changes in MEPs were observed after baclofen administration. These results suggest that it is possible to evaluate the convulsion potential and associated mechanisms using MEP, independent of the behavioral changes. The early identification of convulsion potential using this model will lead to more efficient drug development.

Three different short-interval intracortical inhibition methods in early diagnosis of amyotrophic lateral sclerosis

Objectives: To compare the utility of conventional amplitude measurements of short-interval intracortical inhibition (A-SICI) with two threshold-tracking (T-SICI) methods, as aids to early diagnosis of amyotrophic lateral sclerosis (ALS). The new parallel threshold-tracking method (T-SICIp) was compared with the previously used serial tracking method (T-SICIs). Methods: 112 consecutive patients referred with the suspicion of ALS and 40 healthy controls were prospectively included. Based on clinical follow-up, patients were divided into 67 patients with motor neuron disease (MND) comprising progressive muscular atrophy (PMA) as well as ALS, and 45 patient controls. SICI was recorded from first dorsal interosseus muscle using the three different protocols. Results: MND patients had significantly reduced T-SICIp, T-SICIs and A-SICI, compared with healthy controls and patient controls, while healthy and patient controls were similar. Paradoxically, T-SICIp was least affected in MND patients with the most upper motor neuron (UMN) signs (Spearman ρ = 0.537, P < 0.0001) whereas there was no correlation for T-SICIs or A-SICI. T-SICIp also provided the best discrimination between patient controls and MND as determined by the receiver operating characteristic (ROC) curves. For patients with no UMN signs, area under ROC curve for 2-3ms inter-stimulus intervals was 0.931 for T-SICIp, 0.771 for T-SICIs and 0.786 for A-SICI. Conclusions: SICI is a sensitive measure for detection of cortical involvement in ALS patients. T-SICIp has higher sensitivity and specificity than T-SICIs and A-SICI, particularly in patients without any upper motor neuron signs.

Is it possible to compare inhibitory and excitatory intracortical circuits in face and hand primary motor cortex?

Face muscles are important in a variety of different functions, such as feeding, speech and communication of non‐verbal affective states, which require quite different patterns of activity from those of a typical hand muscle. We ask whether there are differences in their neurophysiological control that might reflect this. Fifteen healthy individuals were studied. Standard single‐ and paired‐pulse transcranial magnetic stimulation (TMS) methods were used to compare intracortical inhibitory (short interval intracortical inhibition (SICI); cortical silent period (CSP)) and excitatory circuitries (short interval intracortical facilitation (SICF)) in two typical muscles, the depressor anguli oris (DAO), a face muscle, and the first dorsal interosseous (FDI), a hand muscle. TMS threshold was higher in DAO than in FDI. Over a range of intensities, resting SICF was not different between DAO and FDI, while during muscle activation SICF was stronger in FDI than in DAO (P = 0.012). At rest, SICI was stronger in FDI than in DAO (P = 0.038) but during muscle contraction, SICI was weaker in FDI than in DAO (P = 0.034). We argue that although many of the difference in response to the TMS protocols could result from the difference in thresholds, some, such as the reduction of resting SICI in DAO, may reflect fundamental differences in the physiology of the two muscle groups. Key points Transcranial magnetic stimulation (TMS) single‐ and paired‐pulse protocols were used to investigate and compare the activity of facilitatory and inhibitory intracortical circuits in a face (depressor anguli oris; DAO) and hand (first dorsal interosseous; FDI) muscles. Several TMS intensities and interstimulus intervals were tested with the target muscles at rest and when voluntarily activated.At rest, intracortical inhibitory activity was stronger in FDI than in DAO. In contrast, during muscle contraction inhibitory activity was stronger in DAO than in FDI. As many previous reports have found, the motor evoked potential threshold was higher in DAO than in FDI.Although many of the differences in response to the TMS protocols could result from the difference in thresholds, some, such as the reduction of resting short interval intracortical inhibition in DAO, may reflect fundamental differences in the physiology of the two muscle groups.

Citicoline Treatment in Acute Ischemic Stroke: A Randomized, Single-Blind TMS Study.

BackgroundRecent research on animal models of ischemic stroke supports the idea that pharmacological treatment potentially enhancing intrinsic brain plasticity could modulate acute brain damage, with improved functional recovery. One of these new drugs is citicoline, which could provide neurovascular protection and repair effects.ObjectivesThe objective of this randomized, single-blind experimental study was to evaluate whether the treatment with Rischiaril® Forte was able to restore intracortical excitability measures, evaluated through transcranial magnetic stimulation (TMS) protocols, in patients with acute ischemic stroke.MethodsPatients with acute ischemic stroke were recruited and assigned to an eight-week therapy of standard treatment (control group - CG) or CDP-choline (Rischiaril® Forte, containing 1,000 mg of citicoline sodium salt) added to conventional treatment (treatment group - TG). Each subject underwent a clinical evaluation and neurophysiological assessment using TMS, pretretament and posttreatment.ResultsA total of thirty participants (mean [SD] age, 68.1 [9.6] years; 11 women [37%]) completed the study. We did not observe significant changes in clinical scores after CDP-choline treatment (all p > 0.05), but we observed a significant improvement in short-interval intracortical inhibition (SAI) (p = 0.003) in the TG group compared to the CG group.ConclusionsThe eight-week treatment with citicoline after acute ischemic stroke may restore intracortical excitability measures, which partially depends on cholinergic transmission. This study extends current knowledge of the application of citicoline in acute ischemic stroke.

Neurophysiological assessment of juvenile parkinsonism due to primary monoamine neurotransmitter disorders

No studies have investigated voluntary movement abnormalities and their neurophysiological correlates in patients with parkinsonism due to inherited primary monoamine neurotransmitter (NT) disorders. Nine NT disorders patients and 16 healthy controls (HCs) were enrolled. Objective measurements of repetitive finger tapping were obtained using a motion analysis system. Primary motor cortex (M1) excitability was assessed by recording the input/output (I/O) curve of motor-evoked potentials (MEP) and using a conditioning test paradigm for short-interval intracortical inhibition (SICI) assessment. M1 plasticity-like mechanisms were indexed according to MEPs amplitude changes after the paired associative stimulation protocol. Patient values were considered abnormal if they were greater or lower than two standard deviations from the average HCs value. Patients with aromatic amino acid decarboxylase, tyrosine hydroxylase, and 6-pyruvoyl-tetrahydropterin synthase defects showed markedly reduced velocity (5/5 patients), reduced movement amplitude, and irregular rhythm (4/5 patients). Conversely, only 1 out of 3 patients with autosomal-dominant GTPCH deficiency showed abnormal movement parameters. Interestingly, none of the patients had a progressive reduction in movement amplitude or velocity during the tapping sequence (no sequence effect). Reduced SICI was the most prominent neurophysiological abnormality in patients (5/9 patients). Finally, the I/O curve slope correlated with movement velocity and rhythm in patients. We provided an objective assessment of finger tapping abnormalities in monoamine NT disorders. We also demonstrated M1 excitability changes possibly related to alterations in motor execution. Our results may contribute to a better understanding of the pathophysiology of juvenile parkinsonism due to dopamine deficiency.

Assessment of cortical inhibition depends on inter individual differences in the excitatory neural populations activated by transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is used to probe inhibitory intracortical neurotransmission and has been used to infer the neurobiological dysfunction that may underly several neurological disorders. One technique, short-interval intracortical inhibition (SICI), indexes gamma-aminobutyric acid (GABA) mediated inhibitory activity and is a promising biomarker. However emerging evidence suggests SICI does not exclusively represent GABAergic activity because it may be influenced by inter-individual differences in the specific excitatory neural populations activated by TMS. Here we used the latency of TMS motor evoked potentials (MEPs) to index these inter-individual differences, and found that a significant proportion of the observed variability in SICI magnitude was accounted for by MEP latency, r = − 0.57, r2 = 0.33, p = .014. We conclude that SICI is influenced by inter-individual differences in the excitatory neural populations activated by TMS, reducing the precision of this GABAergic probe. Interpreting SICI measures in the context of MEP latency may facilitate a more precise assessment of GABAergic intracortical inhibition. The reduced cortical inhibition observed in some neuropathologies could be influenced by reduced activity in specific excitatory neural populations. Including MEP latency assessment in research investigating SICI in clinical groups could assist in differentiating the cortical circuits impacted by neurological disorders.

Short-term arm immobilization modulates excitability of inhibitory circuits within, and between, primary motor cortices.

Previous research has suggested that short‐term immobilization of the arm may be a low‐cost, non‐invasive strategy to enhance the capacity for long‐term potentiation (LTP)‐like plasticity in primary motor cortex (M1). Short‐term immobilization reduces corticospinal excitability (CSE) in the contralateral M1, and interhemispheric inhibition (IHI) from ipsi‐ onto contralateral M1 is increased. However, it is unclear whether reduced CSE and increased IHI are associated with changes in intracortical inhibition, which has been shown to be important for regulating neuroplasticity in M1. The current study used transcranial magnetic stimulation to evaluate the effects of short‐term (6 h) arm immobilization on CSE, IHI, and intracortical inhibition measured bilaterally in 43 neurotypical young adults (23 immobilized). We replicated previous findings demonstrating that immobilization decreased CSE in, and increased IHI onto, the immobilized hemisphere, but a significant change in intracortical inhibition was not observed at the group level. Across individuals, decreased CSE was associated with a decreased short‐interval intracortical inhibition, an index of GABAA‐ergic inhibition, within the immobilized hemisphere only in the immobilization group. Previous research has demonstrated that decreases in GABAA‐ergic inhibition are necessary for the induction of LTP‐like plasticity in M1; therefore, decreased intracortical inhibition after short‐term arm immobilization may provide a novel mechanism to enhance the capacity for LTP‐like plasticity within M1 and may be a potential target for strategies to augment plasticity capacity to enhance motor learning in health and disease.

Electrodiagnostic findings in facial onset sensory motor neuronopathy (FOSMN)

ObjectiveTo determine the electrodiagnostic characteristics of facial onset sensory and motor neuronopathy (FOSMN). MethodsElectrophysiological data from 10 FOSMN patients in Newcastle-upon-Tyne and Sydney were reviewed. Relevant literature was reviewed. ResultsFindings on standard electrophysiological assessment were in broad agreement with those published: blink reflexes were abnormal in all but one patient; sensory nerve action potentials were reduced but compound muscle action potentials preserved; mixed acute and chronic neurogenic change was identified on needle electromyography in bulbar and cervico-thoracic muscles in approximately 50% of patients.Upper limb somatosensory evoked potential (SEP) central conduction times were increased (n = 4) and progressed on repeat testing (n = 3). Upper motor neuron dysfunction was revealed by several measures [ipsilateral motor evoked potentials (MEPs) (n = 1); reduced short interval intra-cortical inhibition on threshold-tracking transcranial magnetic stimulation (n = 2); absent beta-band intermuscular coherence (n = 3)]. ConclusionsElectrodiagnostic investigation of FOSMN should include blink reflex testing, SEPs and tests of upper motor neuron function. The combination of progressive lower motor neuron disease and upper motor neuron disease on neurophysiological investigation provides further support for the contention that FOSMN is a rare variant of motor neurone disease. SignificanceThese findings will aid the neurologist and neurophysiologist in making a confident diagnosis of FOSMN, thus expediting appropriate care.

Reduced Intracortical Facilitation to TMS in Both Isolated REM Sleep Behavior Disorder (RBD) and Early Parkinson's Disease with RBD.

Background: a reduced intracortical facilitation (ICF), a transcranial magnetic stimulation (TMS) measure largely mediated by glutamatergic neurotransmission, was observed in subjects affected by isolated REM sleep behavior disorder (iRBD). However, direct comparison between iRBD and Parkinson’s disease (PD) with RBD is currently lacking. Methods: resting motor threshold, contralateral cortical silent period, amplitude and latency of motor evoked potentials, short-interval intracortical inhibition, and intracortical facilitation (ICF) were recorded from 15 drug-naïve iRBD patients, 15 drug-naïve PD with RBD patients, and 15 healthy participants from the right First Dorsal Interosseous muscle. REM sleep atonia index (RAI), Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Epworth Sleepiness Scale (ESS) were assessed. Results: Groups were similar for sex, age, education, and patients for RBD duration and RAI. Neurological examination, MMSE, ESS, and GDS were normal in iRBD patients and controls; ESS scored worse in PD patients, but with no difference between groups at post hoc analysis. Compared to controls, both patient groups exhibited a significantly decreased ICF, without difference between them. Conclusions: iRBD and PD with RBD shared a reduced ICF, thus suggesting the involvement of glutamatergic transmission both in subjects at risk for degeneration and in those with an overt α-synucleinopathy.

Continuous Dopaminergic Stimulation Improves Cortical Maladaptive Changes in Advanced Parkinson's Disease.

With the progression of Parkinson's disease (PD), pulsatile treatment with oral levodopa causes maladaptive changes within basal ganglia-thalamo-cortical circuits, which are clinically expressed as motor fluctuations and dyskinesias. At the level of the motor cortex, these changes may be detected using transcranial magnetic stimulation (TMS), as abnormal corticospinal and intracortical excitability and absent response to plasticity protocols. We investigated the effect of continuous dopaminergic stimulation on cortical maladaptive changes related to oral levodopa treatment. Twenty patients with advanced PD were tested using TMS within 1 week before and again 6 months after the introduction of levodopa-carbidopa intestinal gel. We measured resting and active motor thresholds, input/output curve, short interval intracortical inhibition curve, cortical silent period, and response to intermittent theta burst stimulation. Patients were clinically assessed with Part III and Part IV of the Movement Disorders Society Unified Parkinson's Disease Rating Scale. Six months after the introduction of levodopa-carbidopa intestinal gel, motor fluctuations scores (P = 0.001) and dyskinesias scores (P < 0.001) were reduced. Resting and active motor threshold (P=0.012 and P = 0.015) and x-intercept of input/output curve (P=0.005) were also decreased, while short-interval intracortical inhibition and response to intermittent theta bust stimulation were improved (P=0.026 and P=0.031, respectively). Changes in these parameters correlated with clinical improvement. In patients with advanced PD, switching from intermittent to continuous levodopa delivery increased corticospinal excitability and improved deficient intracortical inhibition and abnormal motor cortex plasticity, along with amelioration of motor fluctuations and dyskinesias. Continuous dopaminergic stimulation ameliorates maladaptive changes inflicted by chronic pulsatile dopaminergic stimulation. © 2022 International Parkinson and Movement Disorder Society.

Neurophysiological and behavioural correlates of ocrelizumab therapy on manual dexterity in patients with primary progressive multiple sclerosis

BackgroundHand dexterity impairment is a key feature of disability in people with primary progressive multiple sclerosis (PPMS). So far, ocrelizumab, a recombinant humanized monoclonal antibody that selectively depletes CD20-expressing B cells, is the only therapy approved for PPMS and recent analysis reported its ability to reduce the risk of upper limb disability progression. However, the neural mechanisms underlying hand impairment in PPMS and the brain networks behind the effect of ocrelizumab on manual dexterity are not fully understood.ObjectiveMain aims of our study were: (i) to investigate neurophysiological and behavioural correlates of hand function impairment in subjects with PPMS, and (ii) to use neurophysiologic and behavioural measures to track the effects of ocrelizumab therapy on manual dexterity.MethodsSeventeen PPMS patients and 17 healthy-controls underwent routine neurophysiological protocols assessing the integrity of cortico-spinal and somatosensory pathways and advanced transcranial magnetic stimulation (TMS) protocols evaluating inhibitory (short and long interval intracortical inhibition, short-latency afferent inhibition) and facilitatory (motor thresholds, intracortical facilitation, short-interval intracortical facilitation) circuits in the primary motor cortex. All subjects also underwent behavioural analysis of hand dexterity by means of nine-hole peg test and finger movement analysis, and hand strength with handgrip and three-point pinch test. Neurophysiological and clinical assessments of hand functionality were also performed after 1 year of ocrelizumab therapy.ResultsAt baseline PPMS patients displayed a significant impairment of hand dexterity and strength compared to healthy controls (all p < 0.03). Neurophysiological study disclosed prolonged latencies of standard somatosensory and motor evoked potentials (all p < 0.025) and an overall reduction of intracortical excitability at TMS protocols, involving both excitatory and inhibitory circuits. Importantly, hand dexterity impairment, indexed by delayed 9HPT, correlated with TMS protocols investigating cortical sensorimotor integration (short-latency afferent inhibition, SAI), p = 0.009. Both parameters, 9HPT (p = 0.01) and SAI (p = 0.01), displayed a significant improvement after 1 year of therapy with ocrelizumab.ConclusionIntracortical sensorimotor networks are involved in hand dexterity dysfunction of PPMS. Ocrelizumab therapy displays a beneficial effect on hand dexterity impairment most likely through intracortical networks implicated in fast sensorimotor integration.

Neurophysiological Correlates of Motor and Cognitive Dysfunction in Prodromal and Overt Dementia with Lewy Bodies.

The neurophysiological correlates of cognitive and motor symptoms in prodromal and overt dementia with Lewy bodies (DLB) are still to be elucidated. To evaluate if cognitive and motor features of patients with prodromal and overt DLB are associated with the impairment of specific neurotransmitter circuits, evaluated in vivo with transcranial magnetic stimulation (TMS). Fifty-one patients with DLB (twenty-five prodromal; twenty-six with dementia) underwent neuropsychological and clinical evaluation, with twenty-five patients having at least one follow-up evaluation. All patients were assessed with TMS at baseline, with protocols assessing cholinergic circuits (short latency afferent inhibition, SAI), GABAergic circuits (short interval intracortical inhibition, SICI), and glutamatergic circuits (intracortical facilitation, ICF). Compared to HC, SICI, ICF, and SAI resulted significantly impaired in both prodromal and overt DLB, with the latter showing a reduced SICI and SAI also compared to prodromal DLB. There was a significant correlation between motor deficits, evaluated with the UPDRS-III, and the impairment of GABAergic (SICI) (r = 0.729, p < 0.001) and glutamatergic (ICF) (r -0.608, p < 0.001) circuits; global cognition, evaluated with the Mini-Mental State Examination, correlated with the impairment of cholinergic (SAI) circuits (r=-0.738, p < 0.001). Worsening of cognitive functions at follow-up was associated with reduced cholinergic functions at baseline (R2 = 0.53, p < 0.001). These results suggest that motor and cognitive dysfunctions in prodromal and overt DLB depend on specific and independent neurotransmitter circuits.

Blood flow restriction exercise of the tibialis anterior in people with stroke: a preliminary study

Blood flow restriction exercise (BFR-E) could be a useful training adjunct for patients with weakness after stroke to augment the effects of exercise on muscle activity. We aimed to examine neurophysiological changes (primary aim) and assess patient perceptions (secondary aim) following BFR-E. Fourteen participants with stroke performed BFR-E (1 session) and exercise without blood flow restrictsion (Exercise only) (1 session), on two days, ≈7 days apart. In each session, two sets of tibialis anterior (TA) contractions were performed and electromyography (EMG) was recorded. Eight participants underwent transcranial magnetic stimulation (single-pulse stimulation, short interval intracortical inhibition (SICI), intracortical facilitation (ICF)) and peripheral electrical stimulation (maximal peak-to-peak M-wave (M-max)) of the TA before, immediately-after, 10-min-after and 20-min-after BFR-E and Exercise only. Numerical rating scores (NRS) for pain, discomfort, fatigue, safety, focus and difficulty were collected for all subjects (n = 14). Paired comparisons and linear mixed models assessed the effects of BFR-E and Exercise only. No adverse events due to exercise were reported. There was no contraction-number × condition interaction for EMG amplitude during exercise (p = 0.15), or time × condition interaction for single-pulse stmulation, SICI, ICF or M-max amplitude (p = 0.34 to p = 0.97). There was no difference between BFR-E and Exercise only in NRS scores (p = 0.10 to p = 0.50). Using our training paradigm, neurophysiological parameters, feasibility, tolerability and perceptions of safety were not different between BFR-E and Exercise only. As participants were generally well-functioning, our results are not generalizable to lower functioning people with stroke, different (more intense) exercise protocols or longer term training over weeks or months.

Tracking cortical excitability dynamics with transcranial magnetic stimulation in focal epilepsy.

IntroductionThe lack of reliable biomarkers constrain epilepsy management. We assessed the potential of repeated transcranial magnetic stimulation with electromyography (TMS‐EMG) to track dynamical changes in cortical excitability on a within‐subject basis.MethodsWe recruited people with refractory focal epilepsy who underwent video‐EEG monitoring and drug tapering as part of the presurgical evaluation. We performed daily TMS‐EMG measurements with additional postictal assessments 1–6 h following seizures to assess resting motor threshold (rMT), and motor evoked potentials (MEPs) with single‐ and paired‐pulse protocols. Anti‐seizure medication (ASM) regimens were recorded for the day before each measurement and expressed in proportion to the dosage before tapering. Additional measurements were performed in healthy controls to evaluate day‐to‐day rMT variability.ResultsWe performed 77 (58 baseline, 19 postictal) measurements in 16 people with focal epilepsy and 35 in seven healthy controls. Controls showed minimal day‐to‐day rMT variation. Withdrawal of ASMs was associated with a lower rMT without affecting MEPs of single‐ and paired‐pulse TMS‐EMG paradigms. Postictal measurements following focal to bilateral tonic–clonic seizures demonstrated unaltered rMT and increased short interval intracortical inhibition, while measurements following focal seizures with impaired awareness showed decreased rMT's and reduced short and long interval intracortical inhibition.ConclusionSerial within‐subject rMT measurements yielded reproducible, stable results in healthy controls. ASM tapering and seizures had distinct effects on TMS‐EMG excitability indices in people with epilepsy. Drug tapering decreased rMT, indicating increased overall corticospinal excitability, whereas seizures affected intracortical inhibition with contrasting effects between seizure types.

The landscape of neurophysiological outcome measures in ALS interventional trials: A systematic review

ObjectiveWe collated all interventional clinical trials in amyotrophic lateral sclerosis (ALS), which utilised at least one neurophysiological technique as a primary or secondary outcome measure. By identifying the strengths and limitations of these studies, we aim to guide study design in future trials. MethodsWe conducted and reported this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight databases were searched from inception. In total, 703 studies were retrieved for screening and eligibility assessment. ResultsDating back to 1986, 32 eligible interventional clinical trials were identified, recruiting a median of 30 patients per completed trial. The most widely employed neurophysiological techniques were electromyography, motor unit number estimation (including motor unit number index), neurophysiological index and transcranial magnetic stimulation (including resting motor threshold and short-interval intracortical inhibition). Almost 40% of trials reported a positive outcome with respect to at least one neurophysiological measure. The interventions targeted either ion channels, immune mechanisms or neuronal metabolic pathways. ConclusionsNeurophysiology offers many promising biomarkers that can be utilised as outcome measures in interventional clinical trials in ALS. When selecting the most appropriate technique, key considerations include methodological standardisation, target engagement and logistical burden. SignificanceFuture trial design in ALS would benefit from a standardised, updated and easily accessible repository of neurophysiological outcome measures.

Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.

Background and purposeFatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS‐CoV‐2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions.MethodsSixty‐seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS‐CoV‐2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16‐item questionnaire. Fatigue, exertion, cognitive difficulties, mood and ‘well‐being’ were evaluated through self‐administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short‐interval intracortical inhibition, intracortical facilitation, long‐interval intracortical inhibition and short‐latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks.ResultsPost COVID‐19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well‐being and reduced mental well‐being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long‐interval intracortical inhibition and short‐latency afferent inhibition were also impaired, indicating altered GABAB‐ergic and cholinergic neurotransmission. Short‐interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention.ConclusionsPatients with fatigue and cognitive difficulties following mild COVID‐19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.