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Repetitive transcranial magnetic stimulation (rTMS) is emerging as a non-invasive therapeutic strategy in the battle against Alzheimer’s disease. Alzheimer’s disease patients primarily show alterations of the default mode network for which the precuneus is a key node. Here, we hypothesized that targeting the precuneus with TMS represents a promising strategy to slow down cognitive and functional decline in Alzheimer’s disease patients. We performed a randomized, double-blind, sham-controlled, phase 2, 24-week trial to determine the safety and efficacy of precuneus stimulation in patients with mild-to-moderate Alzheimer’s disease. Fifty Alzheimer’s disease patients were randomly assigned in a 1:1 ratio to either receive precuneus or sham rTMS (mean age 73.7 years; 52% female). The trial included a 24-week treatment, with a 2-week intensive course in which rTMS (or sham) was applied daily five times per week, followed by a 22-week maintenance phase in which stimulation was applied once weekly. The Clinical Dementia Rating Scale–Sum of Boxes was selected as the primary outcome measure, in which post-treatment scores were compared to baseline. Secondary outcomes included score changes in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, Mini-Mental State Examination and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale. Moreover, single-pulse TMS in combination with EEG was used to assess neurophysiological changes in precuneus cortical excitability and oscillatory activity. Our findings show that patients that received precuneus repetitive magnetic stimulation presented a stable performance of the Clinical Dementia Rating Scale–Sum of Boxes score, whereas patients treated with sham showed a worsening of their score. Compared with the sham stimulation, patients in the precuneus stimulation group also showed also significantly better performances for the secondary outcome measures, including the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, Mini-Mental State Examination and Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale. Neurophysiological results showed that precuneus cortical excitability remained unchanged after 24 weeks in the precuneus stimulation group, whereas it was significantly reduced in the sham group. Finally, we found an enhancement of local gamma oscillations in the group treated with precuneus stimulation but not in patients treated with sham. We conclude that 24 weeks of precuneus rTMS may slow down cognitive and functional decline in Alzheimer’s disease. Repetitive TMS targeting the default mode network could represent a novel therapeutic approach in Alzheimer’s disease patients.

Background the use of combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) for the functional evaluation of the cerebral cortex in health and disease is becoming increasingly common. However, there is still some ambiguity regarding the extent to which brain responses to auditory and somatosensory stimulation contribute to the TMS-evoked potential (TEP). Objective/Hypothesis to measure separately the contribution of auditory and somatosensory stimulation caused by TMS, and to assess their contribution to the TEP waveform, when stimulating the motor cortex (M1). Methods 19 healthy volunteers underwent 7 blocks of EEG recording. To assess the impact of auditory stimulation on the TEP waveform, we used a standard figure of eight coil, with or without masking with a continuous noise reproducing the specific time-varying frequencies of the TMS click, stimulating at 90% of resting motor threshold. To further characterise auditory responses due to the TMS click, we used either a standard or a sham figure of eight coil placed on a pasteboard cylinder that rested on the scalp, with or without masking. Lastly, we used electrical stimulation of the scalp to investigate the possible contribution of somatosensory activation. Results auditory stimulation induced a known pattern of responses in electrodes located around the vertex, which could be suppressed by appropriate noise masking. Electrical stimulation of the scalp alone only induced similar, non-specific scalp responses in the in the central electrodes. TMS, coupled with appropriate masking of sensory input, resulted in specific, lateralized responses at the stimulation site, lasting around 300 ms. Conclusions if careful control of confounding sources is applied, TMS over M1 can generate genuine, lateralized EEG activity. By contrast, sensory evoked responses, if present, are represented by non-specific, late (100–200 ms) components, located at the vertex, possibly due to saliency of the stimuli. Notably, the latter can confound the TEP if masking procedures are not properly used.

Difficulties in gait and balance disorders are among the most common mobility limitations in multiple sclerosis (MS), mainly due to a damage of cerebellar circuits. Moreover, the cerebellum plays a critical role in promoting new motor tasks, which is an essential function for neurorehabilitation. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol able to increase cerebellar activity, on gait and balance in a sample of 20 hospitalized participants with MS, undergoing vestibular rehabilitation (VR), an exercise-based program primarily designed to reduce vertigo and dizziness, gaze instability, and/or imbalance and falls in MS. Patients were assigned to receive either c-iTBS or sham iTBS before being treated with VR during 2 weeks. VR consisted of two types of training: gaze stability and postural stability exercises. The primary outcome measure was the change from baseline in the Tinetti Balance and Gait scale (TBG). The secondary outcome measures were changes from baseline in Berg Balance Scale (BBS), Fatigue Severity Scale (FSS), Two Minute Walking Test (2MWT), and Timed 25-ft walk test (T25FW) scales. MS patients treated with c-iTBS-VR showed a significant improvement in the TBG as compared to patients treated with sham iTBS-VR. Moreover, MS patients in the c-iTBS groups showed better performances in the vestibular-ocular reflex exercises. Combined c-iTBS and VR improves gait and balance abilities more than standard VR treatment in MS patients with a high level of disability.

Background: Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer’s disease (AD) patients. Objective: In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) classification and APOE genotype. Methods: 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of amyloid-β (Aβ) deposition (A) and fibrillar tau (T), in four groups: A+/T–E4 (n = 9), A+/T–E3 (n = 18), A+/T+ E4 (n = 21), and A+/T+ E3 (n = 17). We applied intermittent theta burst stimulation protocol over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination (MMSE) scores respect to the baseline. Results: A+/T–E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T–E3 and to A+/T+ patients independently from genotype (p 0.05). Conclusion: Our results suggest that APOE4 in patients with isolated Aβ pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline.

Available online 20 May 2022 Understanding age-related changes in cortical excitability and their relation to cognitive functions will help to improve interventions based on non-invasive brain stimulation that aim to support cognitive function in older adults. Here, we investigate the relationship between cortical excitability, executive function, and underlying neural activity in samples of healthy young and older adults. These participants performed a Simon task during electroencephalogram (EEG) recording. During the task, participants had to respond to the colour of a lateralized stimulus while ignoring its spatial location. We studied event-related brain potential correlates of attentional and inhibitory control [i.e., the posterior contralateral negativity (N2pc) and central contralateral negativity (N2cc), respectively] related to the Simon task performance. We also used transcranial magnetic stimulation (TMS) EEG coregistration. In detail, we applied single-pulse TMS during EEG recording in order to analyse global mean field power (GMFP) and TMS-evoked potentials (TEPs) as correlates of cortical excitability. We found lower GMFP amplitude within 101–200 ms in older compared to young adults. Moreover, older adults showed smaller N45 amplitude and slower P180 latency. These findings suggest cortical excitability alterations related to ageing. Older adults also exhibited longer reaction times and N2pc and N2cc latencies, indicating that it took them longer to allocate attention to the target stimulus and inhibit the tendency to respond to the attended location. Finally, in older adults, cortical excitability alterations correlated with longer reaction times and N2pc latencies. These results suggest that age-related alterations in cortical excitability represent a dysfunctional change associated with physiological ageing. 2022 IBRO. Published by Elsevier Ltd. All rights reserved. This study was funded by European Commission Marie- Skłodowska Curie Actions, Individual Fellowships; 655423-NIBSAD, from the Basque Government through the BERC 2018-2021 program, from the Agencia Estatal de Investigacio´ n through BCBL’s Severo Ochoa excellence award SEV-2015-0490 and by the CARITRO Foundation.

When we look at our body parts, we are immediately aware that they belong to us and we rarely doubt about the integrity, continuity, and sense of ownership of our body. Despite this certainty, immersive virtual reality (IVR) may lead to a strong feeling of embodiment over an artificial body part seen from a first-person perspective (1PP). Although such feeling of ownership (FO) has been described in different situations, it is not yet understood how this phenomenon is generated at neural level. To track the real-time brain dynamics associated with FO, we delivered transcranial magnetic stimuli over the hand region in the primary motor cortex (M1) and simultaneously recorded electroencephalography (EEG) in 19 healthy volunteers (11 male/8 female) watching IVR renderings of anatomically plausible (full-limb) versus implausible (hand disconnected from the forearm) virtual limbs. Our data show that embodying a virtual hand is temporally associated with a rapid drop of cortical activity of the onlookers' hand region in the M1 contralateral to the observed hand. Spatiotemporal analysis shows that embodying the avatar's hand is also associated with fast changes of activity within an interconnected fronto-parietal circuit ipsilateral to the brain stimulation. Specifically, an immediate reduction of connectivity with the premotor area is paralleled by an enhancement in the connectivity with the posterior parietal cortex (PPC) which is related to the strength of ownership illusion ratings and thus likely reflects conscious feelings of embodiment. Our results suggest that changes of bodily representations are underpinned by a dynamic cross talk within a highly-plastic, fronto-parietal network.SIGNIFICANCE STATEMENTObserving an avatar's body part from a first-person perspective (1PP) induces an illusory embodiment over it. What remains unknown are the cortical dynamics underpinning the embodiment of artificial agents. To shed light on the physiological mechanisms of embodiment we used a novel approach that combines noninvasive stimulation of the cortical motor-hand area and whole-scalp electroencephalographic (EEG) recordings in people observing an embodied artificial limb. We found that just before the illusion started, there is a decrease of activity of the motor-hand area accompanied by an increase of connectivity with the parietal region ipsilateral to the stimulation that reflects the ratings of the embodiment illusion. Our results suggest that changes of bodily representations are underpinned by a dynamic cross talk within a fronto-parietal circuit.

Electroencephalographic (EEG) signals evoked by transcranial magnetic stimulation (TMS) are usually recorded with passive electrodes (PE). Active electrode (AE) systems have recently become widely available, compared to PE, they allow for easier electrode preparation and a higher-quality signal, due to the preamplification at the electrode stage, which reduces electrical line noise. The performance between the AE and PE can differ, especially with fast EEG voltage changes, which can easily occur with TMS-EEG, however, a systematic comparison in the TMS-EEG setting has not been made. Therefore, we recorded TMS-evoked EEG potentials (TEPs) in a group of healthy subjects in two sessions, one using PE and the other using AE. We stimulated the left primary motor cortex and right medial prefrontal cortex and used two different approaches to remove early TMS artefacts, Independent Component Analysis and Signal Space Projection&mdash, Source Informed Recovery. We assessed statistical differences in amplitude and topography of TEPs, and their similarity, by means of the concordance correlation coefficient (CCC). We also tested the capability of each system to approximate the final TEP waveform with a reduced number of trials. The results showed that TEPs recorded with AE and PE do not differ in amplitude and topography, and only few electrodes showed a lower-than-expected CCC between the two methods of amplification. We conclude that AE are a viable solution for TMS-EEG recording.

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

Background: the influence of pulse width, pulse waveform and current direction on transcranial magnetic stimulation (TMS) outcomes is of critical importance. However, their effects have only been investigated indirectly with motor-evoked potentials (MEP). By combining TMS and EEG it is possible to examine how these factors affect evoked activity from the cortex and compare that with the effects on MEP. Objective: we used a new controllable TMS device (cTMS) to vary systematically pulse width, pulse waveform and current direction and explore their effects on global and local TMS-evoked EEG response. Methods: In 19 healthy volunteers we measured (1) resting motor threshold (RMT) as an estimate of corticospinal excitability; (2) global mean field power (GMFP) as an estimate of global cortical excitability; and (3) local mean field power (LMFP) as an estimate of local cortical excitability. Results: RMT was lower with monophasic posterior-to-anterior (PA) pulses that have a longer pulse width (p

BACKGROUND: In Huntington's disease there is evidence of structural damage in the motor system, but it is still unclear how to link this to the behavioral disorder of movement. One feature of choreic movement is variable timing and coordination between sequences of actions. We postulate this results from desynchronization of neural activity in cortical motor areas. OBJECTIVES: The objective of this study was to explore the ability to synchronize activity in a motor network using transcranial magnetic stimulation and to relate this to timing of motor performance. METHODS: We examined synchronization in oscillatory activity of cortical motor areas in response to an external input produced by a pulse of transcranial magnetic stimulation. We combined this with EEG to compare the response of 16 presymptomatic Huntington's disease participants with 16 age-matched healthy volunteers to test whether the strength of synchronization relates to the variability of motor performance at the following 2 tasks: a grip force task and a speeded-tapping task. RESULTS: Phase synchronization in response to M1 stimulation was lower in Huntington's disease than healthy volunteers (P

Background Electrophysiological measures can help understand brain function both in healthy individuals and in the context of a disease. Given the amount of information that can be extracted from these measures and their frequent use, it is essential to know more about their inherent reliability. Objective/Hypothesis To understand the reliability of electrophysiology measures in healthy individuals. We hypothesized that measures of threshold and latency would be the most reliable and least susceptible to methodological differences between study sites. Methods Somatosensory evoked potentials from 112 control participants; long-latency reflexes, transcranial magnetic stimulation with resting and active motor thresholds, motor evoked potential latencies, input/output curves, and short-latency sensory afferent inhibition and facilitation from 84 controls were collected at 3 visits over 24 months at 4 Track-On HD study sites. Reliability was assessed using intra-class correlation coefficients for absolute agreement, and the effects of reliability on statistical power are demonstrated for different sample sizes and study designs. Results Measures quantifying latencies, thresholds, and evoked responses at high stimulator intensities had the highest reliability, and required the smallest sample sizes to adequately power a study. Very few between-site differences were detected. Conclusions Reliability and susceptibility to between-site differences should be evaluated for electrophysiological measures before including them in study designs. Levels of reliability vary substantially across electrophysiological measures, though there are few between-site differences. To address this, reliability should be used in conjunction with theoretical calculations to inform sample size and ensure studies are adequately powered to detect true change in measures of interest.

Objective During EEG the discharge of TMS generates a long-lasting decay artefact (DA) that makes the analysis of TMS-evoked potentials (TEPs) difficult. Our aim was twofold: (1) to describe how the DA affects the recorded EEG and (2) to develop a new adaptive detrend algorithm (ADA) able to correct the DA. Methods We performed two experiments testing 50 healthy volunteers. In experiment 1, we tested the efficacy of ADA by comparing it with two commonly-used independent component analysis (ICA) algorithms. In experiment 2, we further investigated the efficiency of ADA and the impact of the DA evoked from TMS over frontal, motor and parietal areas. Results Our results demonstrated that (1) the DA affected the EEG signal in the spatiotemporal domain; (2) ADA was able to completely remove the DA without affecting the TEP waveforms; (3). ICA corrections produced significant changes in peak-to-peak TEP amplitude. Conclusions ADA is a reliable solution for the DA correction, especially considering that (1) it does not affect physiological responses; (2) it is completely data-driven and (3) its effectiveness does not depend on the characteristics of the artefact and on the number of recording electrodes. Significance We proposed a new reliable algorithm of correction for long-lasting TMS-EEG artifacts.

Background: Frontotemporal dementia (FTD) is a presenile neurodegenerative disease for which there is no effective pharmacological treatment. Recently, a link has been proposed between neuroinflammation and FTD. Objective: Here, we aim to investigate the effects of palmitoylethanolamide (PEA) combined with luteoline (PEA-LUT), an endocannabinoid with anti-inflammatory and neuroprotective effects, on behavior, cognition, and cortical activity in a sample of FTD patients. Methods: Seventeen patients with a diagnosis of probable FTD were enrolled. Cognitive and neurophysiological evaluations were performed at baseline and after 4 weeks of PEA-LUT 700 mg×2/day. Cognitive effects were assessed by Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, Frontal Assessment Battery (FAB), Screening for Aphasia in Neurodegeneration, Activities of Daily Living-Instrumental Activities of Daily Living, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating scale. To investigate in vivo neurophysiological effects of PEA-LUT, we used repetitive and paired-pulse transcranial magnetic stimulation (TMS) protocols assessing LTP-like cortical plasticity, short-interval intracortical inhibition, long-interval intracortical inhibition (LICI), and short-latency afferent inhibition. Moreover, we used TMS combined with EEG to evaluate the effects on frontal lobe cortical oscillatory activity. Results: Treatment with PEA-LUT was associated with an improvement in NPI and FAB scores. Neurophysiological evaluation showed a restoration of LICI, in particular at ISI 100 ms, suggesting a modulation of GABA(B) activity. TMS-EEG showed a remarkable increase of TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range. Conclusion: PEA-LUT could reduce behavioral disturbances and improve frontal lobe functions in FTD patients through the modulation of cortical oscillatory activity and GABA(B)ergic transmission. Keywords: Brain inflammation; EEG; GABA activity; behavioral symptoms; executive functions; frontotemporal dementia; transcranial magnetic stimulation.

The cerebellum plays a critical role in promoting learning of new motor tasks, which is an essential function for motor recovery. Repetitive transcranial magnetic stimulation (rTMS) of the cerebellum can be used to enhance learning. In this study, we investigated the effects of cerebellar intermittent theta burst stimulation (c-iTBS), a high-frequency rTMS protocol, on visuo-motor learning in a sample of hemiparetic patients due to recent stroke in the territory of the contralateral middle cerebral artery. Eight stroke patients were enrolled for the purposes of the study in the chronic stage of recovery (i.e., at least 6 months after stroke). In two sessions, Patients were randomly assigned to treatment with real or sham c-iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side. c-iTBS was applied immediately before the learning phase of a visuo-motor adaptation task. Real, but not sham, c-iTBS improved visuo-motor learning as revealed by an increased performance in of the learning phase of the visuo-moto adaptation task. Moreover, we also found that real but not sham c-iTBS induced a sustained improvement in the re-adaptation of the recently learned skill (i.e., when patients were re-tested after 30 min). Taken together, these data point to c-iTBS as a potential novel strategy to promote motor learning in patients with stroke.

The cerebellum is strongly implicated in learning new motor skills. Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation, can be used to influence cerebellar activity. Our aim was to explore the potential of cerebellar TBS in modulating visuo-motor adaptation, a form of motor learning, in young healthy subjects. Cerebellar TBS was applied immediately before the learning phase of a visuo-motor adaptation task (VAT), in two different experiments. Firstly, we evaluated the behavioral effects of continuous (cTBS), intermittent (iTBS) or sham TBS on the learning, re-adaptation and de-adaptation phases of VAT. Subsequently, we investigated the changes induced by iTBS or sham TBS on motor cortical activity related to each phase of VAT, as measured by concomitant TMS/EEG recordings. We found that cerebellar TBS induced a robust bidirectional modulation of the VAT performance. More specifically, cerebellar iTBS accelerated visuo-motor adaptation, by speeding up error reduction in response to a novel perturbation. This gain of function was still maintained when the novel acquired motor plan was tested during a subsequent phase of re-adaptation. On the other hand, cerebellar cTBS induced the opposite effect, slowing the rate of error reduction in both learning and re-adaptation phases. Additionally, TMS/EEG recordings showed that cerebellar iTBS induced specific changes of cortical activity in the interconnected motor networks. The improved performance was accompanied by an increase of TMS-evoked cortical activity and a generalized desynchronization of TMS-evoked cortical oscillations. Taken together, our behavioral and neurophysiological findings provide the first-time multimodal evidence of the potential efficacy of cerebellar TBS in improving motor learning, by promoting successful cerebellar-cortical reorganization.

Objective To validate two indexes of interhemispheric signal propagation (ISP) and balance (IHB) by combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG). Methods We used TMS-EEG to non-invasively stimulate the two hemispheres of 50 healthy volunteers and measured interhemispheric dynamics in terms of ISP and IHB. We repeated our evaluation after three weeks to assess the reliability of our indexes. We also tested whether our TMS-EEG measures were correlated with traditional interhemispheric inhibition (IHI), as measured with motor-evoked potentials (MEPs). Results Our main results showed that ISP and IHB (1) have a high reproducibility among all the participants tested; (2) have a high test-retest reliability (3) are linearly correlated with IHI, as measured with MEPs. Conclusions The main contribution of this study lies in the proposal of new TMS-EEG cortical measures of interhemispheric dynamics and in their validation in terms of intra- and inter-subject reliability. We also provide the first demonstration of the correlation between ISP and IHI. Significance Our results are relevant for the investigation of interhemispheric dynamics in clinical populations where MEPs are not reliable.

IMPORTANCE: Gait and balance impairment is associated with poorer functional recovery after stroke. The cerebellum is known to be strongly implicated in the functional reorganization of motor networks in patients with stroke, especially for gait and balance functions. OBJECTIVE: To determine whether cerebellar intermittent θ-burst stimulation (CRB-iTBS) can improve balance and gait functions in patients with hemiparesis due to stroke. DESIGN, SETTING, PARTICIPANTS: This randomized, double-blind, sham-controlled phase IIa trial investigated efficacy and safety of a 3-week treatment of CRB-iTBS coupled with physiotherapy in promoting gait and balance recovery in patients with stroke. Thirty-six patients with consecutive ischemic chronic stroke in the territory of the contralateral middle cerebral artery with hemiparesis were recruited from a neuro-rehabilitation hospital. Participants were screened and enrolled from March 2013 to June 2017. Intention-to-treat analysis was performed. INTERVENTIONS: Patients were randomly assigned to treatment with CRB-iTBS or sham iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side immediately before physiotherapy daily during 3 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the between-group difference in change from baseline in the Berg Balance Scale. Secondary exploratory measures included the between-group difference in change from baseline in Fugl-Meyer Assessment scale, Barthel Index, and locomotion assessment with gait analysis and cortical activity measured by transcranial magnetic stimulation in combination with electroencephalogram. RESULTS: A total of 34 patients (mean [SD] age, 64 [11.3] years; 13 women [38.2%]) completed the study. Patients treated with CRB-iTBS, but not with sham iTBS, showed an improvement of gait and balance functions, as revealed by a pronounced increase in the mean (SE) Berg Balance Scale score (baseline: 34.5 [3.4]; 3 weeks after treatment: 43.4 [2.6]; 3 weeks after the end of treatment: 47.5 [1.8]; P .05) and Barthel Index scores (mean [SE], baseline: 71.1 [4.92]; 3 weeks after treatment: 88.8 [2.1]; 3 weeks after the end of treatment: 92.2 [2.4]; P > .05). Patients treated with CRB-iTBS, but not sham iTBS, showed a reduction of step width at the gait analysis (mean [SE], baseline: 16.8 [4.8] cm; 3 weeks after treatment: 14.3 [6.2] cm; P

Somatosensory temporal discrimination threshold (STDT) is defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. Although STDT is altered in several neurological disorders, its neural bases are not entirely clear. We used continuous theta burst stimulation (cTBS) to condition the excitability of the primary somatosensory cortex in healthy humans to examine its possible contribution to STDT. Excitability was assessed using the recovery cycle of the N20 component of somatosensory evoked potentials (SEP) and the area of high-frequency oscillations (HFO). cTBS increased STDT and reduced inhibition in the N20 recovery cycle at an interstimulus interval of 5 ms. It also reduced the amplitude of late HFO. All three effects were correlated. There was no effect of cTBS over the secondary somatosensory cortex on STDT, although it reduced the N120 component of the SEP. STDT is assessed conventionally with a simple ascending method. To increase insight into the effect of cTBS, we measured temporal discrimination with a psychophysical method. cTBS reduced the slope of the discrimination curve, consistent with a reduction of the quality of sensory information caused by an increase in noise. We hypothesize that cTBS reduces the effectiveness of inhibitory interactions normally used to sharpen temporal processing of sensory inputs. This reduction in discriminability of sensory input is equivalent to adding neural noise to the signal.SIGNIFICANCE STATEMENTPrecise timing of sensory information is crucial for nearly every aspect of human perception and behavior. One way to assess the ability to analyze temporal information in the somatosensory domain is to measure the somatosensory temporal discrimination threshold (STDT), defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. In this study, we found that STDT depends on inhibitory mechanisms within the primary somatosensory area (S1). This finding helps interpret the sensory processing deficits in neurological diseases, such as focal dystonia and Parkinson's disease, and possibly prompts future studies using neurostimulation techniques over S1 for therapeutic purposes in dystonic patients.

Memory loss is one of the first symptoms of typical Alzheimer's disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two-week, randomized, sham-controlled, double-blinded trial the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients' PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN. Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD.

Since early days after stroke, the brain undergoes a complex reorganization to allow compensatory mechanisms that promote functional recovery. However, these mechanisms are still poorly understood and there is urgent need to identify neurophysiological markers of functional recovery after stroke. Here we aimed to track longitudinally the time-course of cortical reorganization by measuring for the first time EEG cortical activity evoked by TMS pulses in patients with subcortical stroke. Thirteen patients in the sub-acute phase of ischemic subcortical stroke with motor symptoms completed the longitudinal study, being evaluated within 20 days and after 40, 60 and 180 days after stroke onset. For each time-point, EEG cortical activity evoked by single TMS pulses was assessed over the motor and parietal cortex of the affected and unaffected hemisphere. We evaluated global TMS-evoked activity and TMS-evoked oscillations in different frequency bands. These measurements were paralleled with clinical and behavioral assessment. We found that motor cortical activity measured by TMS-EEG varied across time in the affected hemisphere. An increase of TMS-evoked activity was evident at 40 days after stroke onset. Moreover, stroke patients showed a significant increase in TMS-evoked alpha oscillations, as highlighted performing analysis in the time-frequency domain. Notably, these changes indicated that crucial mechanisms of cortical reorganization occur in this short-time window. These changes coincided with the clinical improvement. TMS-evoked alpha oscillatory activity recorded at baseline was associated to better functional recovery at 40 and 60 days' follow-up evaluations, suggesting that the power of the alpha rhythm can be considered a good predictor of motor recovery. This study demonstrates that cortical activity increases dynamically in the early phases of recovery after stroke in the affected hemisphere. These findings point to TMS-evoked alpha oscillatory activity as a potential neurophysiological markers of stroke recovery and could be helpful to determine the temporal window in which neuromodulation should be potentially able to drive neuroplasticity in an effective functional direction.

The neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) have been mostly investigated by peripheral motor-evoked potentials (MEPs). New TMS-compatible EEG systems allow a direct investigation of the stimulation effects through the analysis of TMS-evoked potentials (TEPs).We investigated the effects of 1-Hz rTMS over the primary motor cortex (M1) of 15 healthy volunteers on TEP evoked by single pulse TMS over the same area. A second experiment in which rTMS was delivered over the primary visual cortex (V1) of 15 healthy volunteers was conducted to examine the spatial specificity of the effects. Single-pulse TMS evoked four main components: P30, N45, P60 and N100. M1-rTMS resulted in a significant decrease of MEP amplitude and in a significant increase of P60 and N100 amplitude. There was no effect after V1-rTMS.1-Hz rTMS appears to increase the amount of inhibition following a TMS pulse, as demonstrated by the higher N100 and P60, which are thought to originate from GABAb-mediated inhibitory post-synaptic potentials. Our results confirm the reliability of the TMS-evoked N100 as a marker of cortical inhibition and provide insight into the neuromodulatory effects of 1-Hz rTMS. The present finding could be of relevance for therapeutic and diagnostic purposes. © 2014 Elsevier Inc.

Background Studies using Transcranial Magnetic Stimulation (TMS) have demonstrated the possibility to target different neuronal populations within the primary motor cortex (M1) by changing coil orientation and stimulation intensity. The absence of a direct electrophysiological response such as motor evoked potentials has limited this investigation in areas outside M1. This problem can be solved with the use of combined TMS and electroencephalography, which allows direct recording of cortical responses to TMS pulses. Materials and methods In this work on healthy human subjects we compared early (10–70 ms) and late (70–250 ms) transcranial evoked potentials (TEP) and TMS-related spectral perturbation (TRSP) obtained by delivering magnetic pulses over the pre-SMA with variable coil orientation (0°; 90°; 180° and 270°) and stimulation intensity (100%, 120% and 140% of resting motor threshold). Results both early and late TEP were generally larger when the coil handle was pointing backwards (0[o). This result was true also for early TRSP but, surprisingly, late TRSP was greater when the coil was pointing at 180°. Additionally, stimulating the pre-SMA with a 90° orientation activated the right M1, thus limiting the spatial specificity of the stimulation. Conclusions these results suggest that parameters such as coil orientation and stimulation intensity are critical when stimulating the pre-SMA and they should be taken into account in physiological and clinical studies.

Appropriate orientation towards potentially salient novel environmental stimuli requires a system capable of detecting change in the sensorium. Mismatch negativity (MMN), an evoked potential calculated by subtracting the response to a standard repeated stimulus and a rare 'oddball' stimulus, is proposed as such a change detection mechanism. It is most widely studied in the auditory domain, but here we chose to explore the mechanism of somatosensory MMN, and specifically its dependence on the cerebellum. We recorded event-related potentials (ERPs) evoked in response to auditory and sensory stimuli from 10 healthy subjects before and after anodal, cathodal and sham transcranial direct current stimulation (tDCS) of the right cerebellar hemisphere. There was a significant increase in peak amplitude of somatosensory MMN after anodal tDCS (F(1,9) = 8.98, P < 0.02, mean difference anodal pre-post: -1.02 μV) and a significant reduction in peak amplitude of somatosensory MMN after cathodal tDCS (F(1,9) = 7.15, P < 0.03, mean difference cathodal pre-post: 0.65 μV). The amplitude of auditory MMN was unchanged by tDCS. These results reveal the capability of tDCS to cause bidirectional modulation of somatosensory MMN and the dependence of somatosensory MMN on the cerebellum.

The pFC has a crucial role in cognitive control, executive function, and sensory processing. Functional imaging, neurophysiological, and animal studies provide evidence for a functional connectivity between the dorsolateral pFC (DLPFC) and the primary motor cortex (M1) during free choice but not instructed choice selection tasks. In this study, twin coil, neuronavigated TMS was used to examine the precise timing of the functional interaction between human left DLPFC and ipsilateral M1 during the execution of a free/specified choice selection task involving the digits of the right hand. In a thumb muscle that was not involved in the task, a conditioning pulse to the left DLPFC enhanced the excitability of the ipsilateral M1 during free selection more than specified selection 100 msec after presentation of the cue; the opposite effect was seen at 75 msec. However, the difference between free and externally specified conditions disappeared when a task-specific muscle was investigated. In this case, the influence from DLPFC was dominated by task involvement rather than mode of selection, suggesting that other processes related to movement execution were also operating. Finally, we show that the effects were spatially specific because they were absent when an adjacent area of DLPFC was stimulated. These results reveal temporally and spatially selective interactions between BA 46 and M1 that are both task and muscle specific.

Background The effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood. Objectives By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients. Methods PD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group. Results STN-DBS enhanced early global TMS-evoked activity (∼45–80ms) and high-alpha TMS-evoked oscillations (11–13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (∼80–130ms) and beta TMS-evoked oscillations (13–30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values. Conclusions Our data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity.

Voluntary movement control and execution are regulated by the influence of the cerebellar output over different interconnected cortical areas, through dentato-thalamo connections. In the present study we applied transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to directly assess the effects of cerebellar theta-burst stimulation (TBS) over the controlateral primary motor cortex (M1) and posterior parietal cortex (PPC) in a group of healthy volunteers. We found a TBS-dependent bidirectional modulation over TMS-evoked activity; specifically, cTBS increased whereas iTBS decreased activity between 100 and 200 ms after TMS, in a similar manner over both M1 and PPC areas. On the oscillatory domain, TBS induced specific changes over M1 natural frequencies of oscillation: TMS-evoked alpha activity was decreased by cTBS whereas beta activity was enhanced by iTBS. No effects were observed after sham stimulation. Our data provide novel evidence showing that the cerebellum exerts its control on the cortex likely by impinging on specific set of interneurons dependent on GABA-ergic activity. We show that cerebellar TBS modulates cortical excitability of distant interconnected cortical areas by acting through common temporal, spatial and frequency domains.

Question Voluntary movement control and execution are regulated by the influence of the cerebellar output over different interconnected cortical areas, through dentato-thalamo connections. However, in humans, connectivity and plasticity dynamics of the cerebellar-thalamo-cortical connections have been only indirectly explored. Methods In the present study we applied in a group of healthy volunteers transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to directly assess the effects of three theta-burst stimulation (TBS) protocols (intermittent, continuous and sham) over the primary motor cortex (M1) and the posterior parietal cortex (PPC) of the contralateral hemisphere. Results We found a TBS-dependent bidirectional modulation over TMS-evoked activity; specifically, cTBS increased whereas iTBS decreased activity between 100 and 200 ms after TMS, in a similar manner over both M1 and PPC areas. On the oscillatory domain, TBS induced specific changes over M1 natural frequencies of oscillation: TMS-evoked alpha activity was decreased by cTBS whereas beta activity was enhanced by iTBS. No effects were observed after sham stimulation. Conclusions Our data provide novel evidence showing that the cerebellum exerts its control on the cortex likely by impinging on specific set of interneurons dependent on GABA-ergic activity. We show that cerebellar TBS modulates cortical excitability of distant interconnected cortical areas by acting through common temporal, spatial and frequency domains. Download : Download high-res image (481KB) Download : Download full-size image Download : Download high-res image (558KB) Download : Download full-size image

Question Learning may occur through associative changes in the synaptic strength of neural connections that can be induced by coupling of activity of interconnected neurons with precise timing (spike-timing dependent plasticity, STDP). It is debated if this model can be applied in the context of large-scale cortical networks in humans. Methods We combined transcranial magnetic stimulation with concurrent electroencephalography to directly investigate if precise repeated activation of pre and post-synaptic large-scale cortical inputs produces STDP effects within the parietal-prefrontal network of 15 healthy volunteers. Results We found direct evidence for bidirectional STDP after effects over the DLPFC ruled by the PPC pre-synaptic inputs. Specifically, when the pre-synaptic input (PPC) precedes repeatedly the post-synaptic activation (DLPFC) by 10 ms a LTD-like effect of TMS-evoked activity is induced within the DLPFC. When the temporal order of the two stimulated areas is reverted, i.e. the pre-synaptic input (PPC) follows the post-synpatic input (DLPFC), we observed an LTP-like effect. Interestingly, such changes were accompained by PAS-depedendent modulations of the natural frequency of oscillation of the DLPFC, i.e. gamma activity. Conclusions We provide novel evidence that paired associative stimulation of posterior parietal cortex (PPC) and dorsolateral prefrontal cortex (DLPFC) induces bidirectional STDP effects in the post synaptic area (DLPFC) both in the time and in the time/frequency domain. Download : Download high-res image (811KB) Download : Download full-size image Download : Download high-res image (407KB) Download : Download full-size image

Background: In Huntington’s disease there is evidence of structural damage in the motor system, but it is still unclear how to link this to the behavioral disorder of movement. One feature of choreic movement is variable timing and coordination between sequences of actions. We postulate this results from desynchronization of neural activity in cortical motor areas. Objectives: The objective of this study was to explore the ability to synchronize activity in a motor network using transcranial magnetic stimulation and to relate this to timing of motor performance. Methods: We examined synchronization in oscillatory activity of cortical motor areas in response to an external input produced by a pulse of transcranial magnetic stimulation. We combined this with EEG to compare the response of 16 presymptomatic Huntington’s disease participants with 16 age-matched healthy volunteers to test whether the strength of synchronization relates to the variability of motor performance at the following 2 tasks: a grip force task and a speeded-tapping task. Results: Phase synchronization in response to M1 stimulation was lower in Huntington’s disease than healthy volunteers (P

Changes in the synaptic strength of neural connections are induced by repeated coupling of activity of interconnected neurons with precise timing, a phenomenon known as spike-timing-dependent plasticity (STDP). It is debated if this mechanism exists in large-scale cortical networks in humans. We combined transcranial magnetic stimulation (TMS) with concurrent electroencephalography (EEG) to directly investigate the effects of two paired associative stimulation (PAS) protocols (fronto-parietal and parieto-frontal) of pre and post-synaptic inputs within the human fronto-parietal network. We found evidence that the dorsolateral prefrontal cortex (DLPFC) has the potential to form robust STDP. Long-term potentiation/depression of TMS-evoked cortical activity is prompted after that DLPFC stimulation is followed/preceded by posterior parietal stimulation. Such bidirectional changes are paralleled by sustained increase/decrease of high-frequency oscillatory activity, likely reflecting STDP responsivity. The current findings could be important to drive plasticity of damaged cortical circuits in patients with cognitive or psychiatric disorders.

Question Deep brain stimulation (DBS) of the subthalamic nucleus (STN) represents an effective therapy in Parkinson’s disease (PD). The effects of STN-DBS on cortical reactivity are still poorly understood. By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG), we explored the effects of STN-DBS either alone or in combination with levodopa (LD), on cortical activity evoked by TMS of the primary motor cortex (M1) in a sample of PD patients chronically treated with STN implantation. Methods Six advanced PD patients treated with STN-DBS were tested in three clinical conditions on distinct days: (i) on therapy/on DBS; (ii) off therapy/on DBS; (iii) off therapy/off DBS. In each condition, 80 single TMS pulses were delivered over left M1 while simultaneously acquiring EEG. We evaluated TMS-induced changes in the time domain and in the time/frequency domain. Results In the OFF/ON condition there was a significant increase of GMFP peaking at 60–70 ms (P2) compared to OFF/OFF condition. In ON/ON condition a significant increase of GMFP peaking at 60–70 ms (P2) and at 100 ms (P3) was observed compared to OFF/OFF condition. Time/frequency analysis showed a synchronization of activity in the 10–17 Hz range over central-posterior region within the P2 time window in the OFF/ON condition compared to OFF/OFF. The same analysis conducted on the P3 time window revealed a synchronization of activity in the 11–16 Hz range of frequency over central regions when comparing OFF/ON condition to ON/ON. Conclusions Our data reveal that bilateral STN-DBS induces a significant modulation of cortical global reactivity at early components. The association of LD therapy produces additional distinct modulation of later components. These findings could be related to cortical induced modulation of GABAergic intracortical activity.

Hyperammonaemia is observed after prolonged, intense exercise, or in patients with hepatic failure. In the latter, it isassociatedwith a set of neurological and psychiatric abnormalities termedhepatic encephalopathy. The aimsof our study were: 1. to measure vigilance in a condition of induced hyperammonaemia; 2. to assess whether caffeine modulates the effects of hyperammonaemia on vigilance, if any. Ten healthy volunteers (28.5±5 years; 5 males) underwent three experimental sessions consisting of two-hourly measurements of capillary ammonia, subjective sleepiness (Karolinska Sleepiness Scale) and vigilance (Psychomotor Vigilance Task, PVT), in relation to the intake of breakfast (+/�coffee), an amino acid mixture which induces hyperammonaemia (amino acid challenge; AAC), and AAC+coffee (only for participants who had coffee with their standard breakfast). The AAC resulted in: 1. the expected increase in capillary ammonialevels,withhighest valuesatapproximately4hafter the administration; 2. a significant increase in subjective sleepiness ratings; 3. a sustained increase in PVT-based reaction times. When caffeine was administered after the AAC, both subjective sleepiness and the slowing in RTs were significantly milder than in the AAC-only condi- tion. In conclusion, acute hyperammonaemia induces an increase in subjective sleepiness and a sustained decrease in vigilance, which are attenuated by the administration of as ingle espresso coffee.

The development of neuroimaging techniques is one of the most impressive advancements in neuroscience. The main reason for the widespread use of these instruments lies in their capacity to provide an accurate description of neural activity during a cognitive process or during rest. This important advancement is related to the possibility to selectively detect changes of neuronal activity in space and time by means of different biological markers. Specifically, functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and nearinfrared spectroscopy (NIRS) use metabolic markers of ongoing neuronal activity to provide an accurate description of the activation of specific brain areas with high spatial resolution. Similarly, electroencephalography (EEG) is able to detect electric markers of neuronal activity, providing an accurate description of brain activation with high temporal resolution. The application of these techniques during a cognitive task allows important inferences regarding the relation between the detected neural activity, the cognitive process involved in an ongoing task, and behaviour: this is known as a “correlational approach”.

Background Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by cortical and striatal pathology. One of the first HD-related alterations is the progressive degeneration of cannabinoid type 1 receptors in basal ganglia, which are highly expressed in GABAergic neurons of the striatum. Aims Given the GABAergic nature of TMS-evoked EEG activity, we investigated whether GABAergic deficits in preHD patients produce any significant change in TMS-EEG measures, compared to healthy volunteers (HV). Methods We stimulated the primary motor cortex (M1) and premotor area (PM) with single-pulse TMS (90% of RMT) while recording EEG in 16 preHD patients and 16 HV. TMS-evoked activity was analysed in time, space and oscillatory domains. Results Time-domain analysis revealed a strong reduction of later M1-TMS-evoked activity (150–250 ms after TMS) in preHD patients, compared to HV. The effect was prominent over the site of stimulation. Oscillatory-domain analysis revealed that this effect was due to a strong desynchronization of TMS-evoked responses of HD patients in the theta and alpha range. Conclusions The observed decrease of GABAb-mediated TEPs may be a consequence of the lower GABAergic inhibition that causes excitotoxicity in HD patients. This interpretation is corroborated by the weak synchronisation in slow (theta and alpha) and late (150–250 ms) post-synaptic potentials evoked by TMS, that are thought to be of GABAb origin.