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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., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2019. Published by Elsevier Inc.)

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 < .001). No overall treatment-associated differences were noted in the Fugl-Meyer Assessment (mean [SE], baseline: 163.8 [6.8]; 3 weeks after treatment: 171.1 [7.2]; 3 weeks after the end of treatment: 173.5 [6.9]; 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 < .05) and an increase of neural activity over the posterior parietal cortex., Conclusions and Relevance: Cerebellar intermittent θ-burst stimulation promotes gait and balance recovery in patients with stroke by acting on cerebello-cortical plasticity. These results are important to increase the level of independent walking and reduce the risk of falling., Trial Registration: ClinicalTrials.gov Identifier: NCT03456362.

Objective: To determine the ability of transcranial magnetic stimulation (TMS) in detecting synaptic impairment in patients with Alzheimer's disease (AD) and predicting cognitive decline since the early phases of the disease., Methods: We used TMS-based parameters to evaluate long-term potentiation (LTP)-like cortical plasticity and cholinergic activity as measured by short afferent inhibition (SAI) in 60 newly diagnosed patients with AD and 30 healthy age-matched subjects (HS). Receiver operating characteristic (ROC) curves were used to assess TMS ability in discriminating patients with AD from HS. Regression analyses examined the association between TMS-based parameters and cognitive decline. Multivariable regression model revealed the best parameters able to predict disease progression., Results: Area under the ROC curve was 0.90 for LTP-like cortical plasticity, indicating an excellent accuracy of this parameter in detecting AD pathology. In contrast, area under the curve was only 0.64 for SAI, indicating a poor diagnostic accuracy. Notably, LTP-like cortical plasticity was a significant predictor of disease progression (p=0.02), while no other neurophysiological, neuropsychological and demographic parameters were associated with cognitive decline. Multivariable analysis then promoted LTP-like cortical plasticity as the best significant predictor of cognitive decline (p=0.01). Finally, LTP-like cortical plasticity was found to be strongly associated with the probability of rapid cognitive decline (delta Mini-Mental State Examination score ≤-4 points at 18 months) (p=0.04); patients with AD with lower LTP-like cortical plasticity values showed faster disease progression., Conclusions: TMS-based assessment of LTP-like cortical plasticity could be a viable biomarker to assess synaptic impairment and predict subsequent cognitive decline progression in patients with ADs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2018. Published by Elsevier Inc.)

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., (Copyright © 2017. Published by Elsevier Inc.)

Objective: To determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish Alzheimer disease (AD) from frontotemporal dementia (FTD)., Methods: Paired-pulse TMS was used to investigate short-interval intracortical inhibition (SICI) and facilitation (ICF), long-interval intracortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis., Results: A total of 175 participants met the inclusion criteria. We diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. We found that while patients with AD are characterized by a specific impairment of SAI, FTD shows a remarkable dysfunction of SICI-ICF intracortical circuits. With the use of the best indexes, TMS differentiated FTD from AD with a sensitivity of 91.8% and specificity of 88.6%, AD from HC with a sensitivity of 84.8% and specificity of 90.6%, and FTD from HC with a sensitivity of 90.2% and specificity of 78.1%. These results were confirmed in patients with mild disease., Conclusions: TMS is a noninvasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice., Classification of Evidence: This study provides Class III evidence that TMS measures can distinguish patients with AD from those with FTD., (© 2017 American Academy of Neurology.)

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.

Introduction: Patients with Scans-Without-Evidence-of-Dopaminergic-Deficit (SWEDD) often present asymmetric rest tremor not responsive to levodopa. Although a dystonic origin of this tremor has been proposed, the underlying pathophysiology of such condition is still unclear. An abnormal activity in the Cerebello-Thalamo-Cortical circuit is involved in the pathogenesis of tremor and other movement disorders. Here we used different paradigms of cerebellar transcranial magnetic stimulation to evaluate the Cerebello-Thalamo-Cortical functioning in patients with normal scans., Methods: Cerebello-Thalamo-Cortical circuit was investigated in 12 patients with normal scans, 8 patients with Parkinson's Disease (PD), 8 patients with adult-onset isolated dystonia and 9 healthy controls. We studied the effects of a single cerebellar magnetic pulse over the excitability of the contralateral primary motor cortex tested with Motor-Evoked-Potentials (Cerebellar-Inhibition) both at rest and during arm extension. Furthermore, we also tested the effects of cerebellar continuous-Theta-Burst-Stimulation on Motor-Evoked-Potentials amplitude., Results: patients with normal scans compared to controls show a deficient Cerebellar-Inhibition at rest but not in arm extension; in both conditions they differ from PD but not from dystonic patients. Cerebellar Continuous-Theta-Burst-Stimulation induced the expected long-lasting cortical inhibition of Motor-Evoked-Potentials amplitude in patients with normal scans differently from PD and dystonic patients., Conclusions: patients with normal scans show a mild impairment in Cerebello-Thalamo-Cortical circuit that emerges only at rest. Such neurophysiological phenotype differs from the one observed in PD and dystonic patients, suggesting a distinct involvement of this pathway in the pathophysiology of these disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Multimodal treatments are emerging as effective approaches for motor recovery in traumatic brain injury (TBI). Various evidence has demonstrated that repetitive transcranial magnetic stimulation (rTMS) may improve outcomes in people with motor disorders. Behavioral gains from rTMS protocols may be maximized when brain stimulation is coupled with carefully designed occupational/physical therapy. We present the case of a 25-year-old man with chronic TBI (a bilateral corticosubcortical parieto-occipital lesion) who underwent three weeks of cerebellar intermittent theta burst stimulation (iTBS), a form of rTMS, combined with neurorehabilitation treatment. The Fugl-Meyer Assessment (FMA), Berg Balance Scale (BBS), Jebsen-Taylor Hand Function Test, and accelerometer gait analysis were administered before and after treatment. The results showed improvements in balance performance (BBS: T0=47; T1=53; +10.72%), motor recovery (FMA: T0=93/100; T1=96/100; +3.00%), step length (T0=50.4±7.2; T1=53.8±2.2 cm, p<0.001), and walking speed (T0=0.87±0.06; T1=0.91±0.04 m/sec,p<0.001). Combined cerebellar rTMS and neurore-Clinical effects of non-invasive cerebellar magnetic stimulation treatment combined with neuromotor rehabilitation in traumatic brain injury. A single case study. habilitation seems to be a promising treatment for motor and balance dysfunctions in TBI patients.

Dystonia is generally regarded as a disorder of the basal ganglia and their efferent connections to the thalamus and brainstem, but an important role of cerebellar-thalamo-cortical (CTC) circuits in the pathophysiology of dystonia has been invoked. Here in a sham controlled trial, we tested the effects of two-weeks of cerebellar continuous theta burst stimulation (cTBS) in a sample of cervical dystonia (CD) patients. Clinical evaluations were performed by administering the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). We used TMS to measure the inhibitory connectivity between the cerebellum and the contralateral motor cortex (cerebellar brain inhibition [CBI]), and the excitability of the contralateral primary motor cortex assessing intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP). Paired associative stimulation (PAS) was tested to evaluate the level and the topographical specificity of cortical plasticity, which is abnormally enhanced and non-focal in CD patients. Two weeks of cerebellar stimulation resulted in a small but significant clinical improvement as measured by the TWSTRS of approximately 15%. Cerebellar stimulation modified the CBI circuits and reduced the heterotopic PAS potentiation, leading to a normal pattern of topographic specific induced plasticity. These data provide novel evidence CTC circuits could be a potential target to partially control some dystonic symptoms in patients with cervical dystonia., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Evidence for effective improvement of the symptoms of cerebellar stroke is still limited. Here, we investigated the effects of repetitive transcranial magnetic stimulation (rTMS) applied over the injured cerebellar hemisphere in six patients with posterior circulation stroke. We applied a two-week course of cerebellar intermittent theta burst stimulation (iTBS). Before and after the iTBS treatment, paired-pulse TMS methods were used to explore: i) the functional connectivity between the cerebellar hemisphere and the contralateral primary motor cortex (M1), by means of the cerebellar brain inhibition (CBI) protocol; and ii) the intracortical circuits in the contralateral M1, by means of the short intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF) protocols. Patients were also evaluated using the Modified International Cooperative Ataxia Rating Scale (MICARS). Cerebellar iTBS induced a decrease in CBI and an increase in ICF at an interstimulus interval of 15 msec. These neurophysiological changes were paralleled by a clinical improvement, shown by the MICARS posture and gait subscale scores. Cerebellar iTBS could be a promising tool to promote recovery of cerebellar stroke patients.

Background: Progressive Supranuclear Palsy (PSP) is an atypical degenerative Parkinsonism characterized by postural instability, supranuclear gaze palsy and frontal deficits. Recent imaging studies revealed that the volume of cerebellar peduncles and midbrain were reduced in PSP. Transcranial magnetic stimulation (TMS) studies demonstrated a cerebellar involvement in PSP showing an impairment of functional connectivity between the cerebellar hemisphere (Cb) and the contralateral primary motor cortex (M1) (cerebellar brain inhibition-CBI)., Objective: To investigate the plasticity of the cerebello-thalamo-cortical circuits in ten PSP patients after two-week course of cerebellar intermittent theta burst stimulation (iTBS), a form of repetitive TMS., Methods: Before and after the iTBS sessions we measured functional connectivity between Cb and contralateral M1 (CBI), short intracortical inhibition (SICI) and intracortical facilitation (ICF) and short latency afferent inhibition (SLAI) in contralateral M1. We also performed resting state functional magnetic resonance (rs-fMRI) and we administered clinical rating scale (PSP-RS)., Results: At baseline PSP patients had decreased efficiency of CBI, SICI and SLAI in comparison to PD patients and healthy subjects. Cerebellar iTBS increased the deficient functional cerebellar-motor connectivity as assessed by CBI. No effect was seen for SICI/ICF and SLAI circuits. Following iTBS there was an increased signal in the head of the caudate nucleus bilaterally as shown by rs-fMRI. Moreover, PSP-RS showed an improvement of dysarthria in all patients., Conclusions: iTBS enhanced functional connectivity between the cerebellar hemisphere, the caudate nucleus and the cortex, that was paralleled by some clinical improvement. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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. [ABSTRACT FROM AUTHOR]

Introduction Mechanisms of cortical plasticity have been widely investigated in Alzheimer’s disease (AD) patients with TMS protocols, showing a clear impairment of Long-Term Potentiation (LTP) cortical-like plasticity and a relative sparing of Long Term Depression (LTD) mechanisms. Recently a new TMS protocol, investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1), elicited in a bidirectional way LTP and LTD effects. Objective We investigated mechanisms of spike-timing dependent plasticity in AD patients and the effects of the modulation of PPC-M1 pathway on cholinergic transmission, greatly impaired in AD patients. Material and methods Twelve AD patients and eight age-matched healthy subjects (HS) were evaluated. We used bifocal TMS to repeatedly activate the connections between the PPC and M1 of the left-dominant hemisphere. PPC TMS preceded or followed the M1 stimulation by 5 ms, respectively PAS +5 and PAS −5. To best activate the ipsilateral PPC-M1 connection, the conditioning stimulus was applied over the left PPC at an intensity of 90% of the ipsilateral resting motor threshold. For the PAS protocol, 100 pairs of stimuli were continuously delivered at a rate of 0.2 Hz for ∼8.3 min. Motor evoked potentials and central cholinergic way, evaluated with Short-latency afferent inhibition (SAI) protocol, were evaluated before and after PAS (+5 or −5) protocol. Results as expected HS showed an LTP-like cortical plasticity following PAS −5 protocol and an LTD-like cortical plasticity after PAS +5 protocol, while AD patients did not show any modification of the amplitude of MEP after repeated activation of PPC-M1 connections. As compared to HS, AD patients showed worst SAI values. Interestingly, after PAS +5 protocol, in AD patients SAI levels were restored. Conclusions The data here presented confirm that in AD patients there is an altered cortical plasticity. The central cholinergic way is altered in AD patients, but after the application of PAS +5 protocol his levels are restored, suggesting a possible role of PPC-M1 pathway on modulation of this inhibitory intracortical circuit. PAS protocol is able to investigate the mechanisms of altered cortical plasticity in AD patients. Central cholinergic transmission can be modulated by stimulation of PPC-M1 connections. [ABSTRACT FROM AUTHOR]

Introduction: In a recent work by our group we used transcranial magnetic stimulation (TMS) to repeatedly activate the connection between the posterior parietal cortex (PPC) and the primary motor cortex (M1) of the left dominant hemisphere with a paired associative stimulation (PAS) protocol. By varying inter-pulse interval and the activation of different M1 neuronal populations we were able to induce LTP or LTD-like effects as indexed by Motor Evoked Potentials (MEPs) amplitude modulation that followed either Hebbian or anti-Hebbian temporal rules. Objectives: Our aim was to further investigate the effects induced by this cortico-cortical PAS protocol over EEG activity, by means of a TMS–EEG coregistration approach. Materials and methods: 13 volunteers underwent our novel PAS protocol. Paired stimuli were applied with PPC-TMS preceding (+5ms) or following (−5ms) M1 stimulation. In a third condition, the induced current direction over M1 was changed from postero–anterior (PA) to antero–posterior (AP) and the ISI was set at +5ms. Eighty single pulse TMS were applied to M1 before and after PAS while continuously acquiring EEG from 21 electrodes and recording MEPs from the first dorsal interosseous muscle. We then analysed (i) functional coupling though event-related coherence (ERcoh) for alpha (8–12Hz) and beta (13–30Hz) band, (ii) changes in M1 reactivity through TMS-Evoked Potentials (TEPs) and (iii) MEPs amplitude. Results: When PPC preceded M1PA stimulation (+5ms) MEPs amplitude significantly decreased (p =0.001), while there was a concurrent increase in ERcoh for the beta band, topographically restricted to P3–C3 pair (p =0.02), representing the closest electrodes to the stimulated regions. TEPs analysis indicated a decrease of those components forming a dipole over left centro-parietal sites peaking at about 13 and 20ms. When PPC followed M1PA stimulation (−5ms) an increase in MEPs amplitude was induced (p=0.01) with a concurrent ERcoh increase in the alpha band for P3–C3 pair (p =0.01). TEPs component were again modulated at 13 and 20ms, with an increased amplitude after PAS administration. The AP condition led to opposite results: an increased MEP amplitude when PPC preceded M1AP stimulation (p). Conclusions: These findings shed new light on the cortical mechanisms underlying antithetic learning rules in humans. We found that both post-synaptic long term potentiation or depression are always associated to an increased functional connectivity that exclusively upsurge between the stimulated areas. However, the sign of cortical plasticity in M1 is indexed by different brain oscillation activities in the alpha and beta bands. Finally distinct plastic changes differently modulate M1 reactivity as indexed by opposite changes of TEPs amplitude. [Copyright &y& Elsevier]

Introduction: Ischemic cerebellar infarctions produce distinct clinical patterns including motor disturbances such as limb dysmetria, intention tremor, axial lateropulsion, and dysarthria. Repetitive transcranial magnetic stimulation (rTMS) might serve as an innovative tool to support functional recovery in stroke patients but has never been tested in patients with cerebellar stroke. Objectives: The aim of the present study was to determine if excitatory repetitive transcranial magnetic stimulation protocol the “intermittent theta burst stimulation” (iTBS) applied over the lateral cerebellum on patients affected by cerebellar stroke could influence the plasticity of the cerebello-thalamo-cortical-circuits. Materials and methods: Six chronic cerebellar stroke patients were submitted to two weeks of iTBS applied bilaterally over the cerebellum. All patients underwent magnetic resonance imaging (MRI) at 3T including T1-weighted volumes to reconstruct for each patient the damaged area. Before and after the iTBS treatment all patient were evaluated by the Modified International Cooperative Ataxia Rating Scale (MICARS), an useful tool for assessing and monitoring cerebellar motor function. Moreover, we explored the functional connectivity between the cerebellar hemisphere and the contralateral motor cortex (CBI), the intra-cortical inhibition (SICI) and intra-cortical facilitation (ICF) by means of paired-pulse TMS. Results: We found that after two weeks of cerebellar iTBS was a decreased CBI at ISI=5ms and induced an increase of ICF at ISI=15ms. These neurophysiological changes were paralleled by clinical improvement as assessed by the MICARS scale. Among the sub-scales of the MICARS patients reported a clinical improvement (p =0.02 at t-test) of the posture and gait items, but not in the kinetic functions, speech disorders or oculomotor items. Conclusion: These preliminary results provide novel evidence that cerebellar TBS can be used to promote functional recovery of patients with cerebellar stroke. These clinical improvement could be related to long-lasting changes in the excitability of cerebello-thalamo-cortical pathways. [Copyright &y& Elsevier]

Introduction: Living in a complex and dynamic environment continuously requires the rapid generation of motor responses when necessary but also the promptly inhibition of actions when they would be unsuitable. In the last years many studies have investigated the role of various cortical and subcortical brain regions in inhibitory control and converging evidences suggest a crucial role of the right Inferior Frontal Gyrus (rIFG) and of the Supplementary Motor Area (SMA). However the precise role and the exact timing of the contribution of these areas in this process remain unclear. Objectives: The aim of the present study was to investigate the role of rIFG and SMA in motor planning and motor inhibition by establishing the specific time course and the causal interactions of these regions in relation to the left primary motor area (LM1). Materials and methods: In a sample of 10 healthy subjects paired transcranial magnetic stimulation (TMS) was applied with an interstimulus interval of 6ms over the rIFG-LM1 and over SMA-LM1 before and 50, 75, 100, 125, 150ms after the presentation of visual stimuli in a simple GO/NOGO task. For each interval Motor Evoked Potentials (MEPs) and Reaction Times (RTs) were collected. Results: When paired TMS was applied over the rIFG, MEPs were markedly and selectively increased for the NOGO trials at 50 (p =0.004), 100 (p =0.002) and 150ms (p =0.002) after the stimulus onset. On the other hand, no differences were found at 75 and 125ms after cue presentation for the NOGO trials and at any delay for the GO trials. A trend for a similar temporal profile of cortico-cortical activation was found for the SMA-LM1 connectivity for the NOGO trials peaking at 50, 100 and 150ms after the cue onset. On the contrary, MEPs increased in the GO trials at 75 (p =0.015) and 125ms (p =0.004) after the cue presentation. Task accuracy was high in all experimental conditions, but we observed that Go Reaction Times (RTs) were slowed down at 100 and 150ms after the stimulus presentation in all experimental conditions. Conclusion: These findings provide evidence of a very early rIFG-M1 and SMA-M1 functional interaction to inhibit a motor response. Notably, we found that connectivity peaked repeatedly every 50ms. It is possible that these fluctuating temporal profiles of cortical interactions could resemble the underlying reverberant oscillation of beta rhythms. Indeed, the present study suggests a rIFG specialization in response inhibition and a specialization of the SMA in response planning. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Mechanisms of cortical plasticity have been widely investigated in Alzheimer’s Disease (AD) patients with transcranial magnetic stimulation (TMS) protocols as Theta Burst Stimulation, showing a clear impairment of Long-Term Potentiation (LTP) cortical-like plasticity and a relative sparing of Long Term Depression (LTD) mechanisms. Recently a new TMS protocol, investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1), elicited in a bidirectional way LTP and LTD effects. The aim of our study is to investigate mechanisms of spike-timing dependent plasticity in Alzheimer’s disease patients and furthermore to investigate the effects of the modulation of PPC-M1 pathway on cholinergic transmission, greatly impaired in AD patients. Twelve AD patients and eight age-matched healthy subjects were evaluated. We used bifocal TMS to repeatedly activate the connection between the PPC and M1 of the left-dominant hemisphere. Left PPC TMS preceded or followed the M1 stimulation by 5 ms, respectively PAS +5 and PAS −5. To best activate the ipsilateral PPC–M1 connection, the conditioning stimulus was applied over the left PPC at an intensity of 90% of the ipsilateral resting motor threshold. For the PAS protocol, 100 pairs of stimuli were continuously delivered at a rate of 0.2 Hz for â̂1/48.3 min. Motor evoked potentials and central cholinergic pathway, evaluated with Short-latency afferent inhibition (SAI) protocol, were evaluated before and after PAS (+5 or −5) protocol. As expected HS showed an LTP-like cortical plasticity following PAS −5 protocol and an LTD-like cortical plasticity after PAS +5 protocol, while AD patients didn’t show any significant modification of the amplitude of MEP after repeated activation of PPC-M1 connections. As compared to HS, AD patients showed worst SAI values. Interestingly, after PAS +5 protocol, in AD patients SAI levels were restored. The data here presented confirm that in AD patients there is an altered cortical plasticity, elicited with a new TMS protocol able to investigate the connections between PPC-M1. The central cholinergic pathway as indexed by the amount of SAI, is altered in AD patients, but it is normalized after the application of PAS +5 protocol, suggesting a possible role of PPC-M1 pathway on the modulation of this inhibitory intracortical circuit. PAS protocol is able to investigate the mechanisms of altered cortical plasticity in AD patients. Central cholinergic transmission can be modulated by stimulation of PPC-M1 connections. [ABSTRACT FROM AUTHOR]