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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.)

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.)

Background: Current psychological and pharmacological treatments for Anorexia Nervosa (AN) provide only moderate effective support, and there is an urgent need for research to improve therapies, especially in developing age. Non-invasive brain stimulation has suggested to have the potential to reducing AN symptomatology, via targeting brain alterations, such as hyperactivity of right prefrontal cortex (PFC). We suppose that transcranial direct current stimulation (tDCS) to the PFC may be effective in children and adolescents with AN. Methods: We will conduct a randomized, double blind, add-on, placebo-controlled trial to investigate the efficacy of tDCS treatment on clinical improvement. We will also investigate brain mechanisms and biomarkers changes acting in AN after tDCS treatment. Eighty children or adolescent with AN (age range 10–18 years) will undergo treatment-as-usual including psychiatric, nutritional and psychological support, plus tDCS treatment (active or sham) to PFC (F3 anode/F4 cathode), for six weeks, delivered three times a week. Psychological, neurophysiological and physiological measures will be collected at baseline and at the end of treatment. Participants will be followed-up one, three, six months and one year after the end of treatment. Psychological measures will include parent- and self-report questionnaires on AN symptomatology and other psychopathological symptoms. Neurophysiological measures will include transcranial magnetic stimulation (TMS) with electroencephalography and paired pulse TMS and repetitive TMS to investigate changes in PFC connectivity, reactivity and plasticity after treatment. Physiological measures will include changes in the functioning of the endogenous stress response system, body mass index (BMI) and nutritional state. Discussion: We expect that tDCS treatment to improve clinical outcome by reducing the symptoms of AN assessed as changes in Eating Disorder Risk composite score of the Eating Disorder Inventory-3. We also expect that at baseline there will be differences between the right and left hemisphere in some electrophysiological measures and that such differences will be reduced after tDCS treatment. Finally, we expect a reduction of endogenous stress response and an improvement in BMI and nutritional status after tDCS treatment. This project would provide scientific foundation for new treatment perspectives in AN in developmental age, as well as insight into brain mechanisms acting in AN and its recovery. Trial registration The study was registered at ClinicalTrials.gov (ID: NCT05674266) and ethical approval for the study was granted by the local research ethics committee (process number 763_OPBG_2014). [ABSTRACT FROM AUTHOR]

Short latency afferent inhibition ( SAI) is a paired-pulse transcranial magnetic stimulation ( TMS) protocol that consists in the inhibition of the motor evoked potentials ( MEPs) by afferent sensory impulses. SAI is thought to be mediated by cholinergic projections over M1 and can be considered a putative marker of central cholinergic activity. It is known that memory processes are regulated by acetylcholine. Nonetheless, the influence of memory tasks on SAI has not been investigated. Here we tested changes in SAI circuits in healthy subjects performing a computerized non-verbal recognition memory task ( RMT) requiring to recognize previously encoded faces. SAI protocol was recorded during five phases of the RMT: baseline, encoding, consolidation, retrieval, and post-task. In the control task, subjects were asked to judge a visual feature of not previously presented faces. SAI protocol was applied over the same conditions as in the RMT. We found that SAI remarkably increases during the retrieval phase of the RMT as compared to baseline. On the other hand no change was observed during the control task. These findings show that SAI can be modulated by ongoing memory processes and support the hypothesis that SAI can be considered as a neurophysiological marker of central cholinergic activity. [ABSTRACT FROM AUTHOR]

Converging evidence suggests a crucial role of right inferior frontal gyrus (r-IFG) and right pre-supplementary motor area (r-preSMA) in movement inhibition control. The present work was aimed to investigate how the effective connectivity between these prefrontal areas and the primary motor cortex could change depending on the activity of the cerebellar cortex. Paired transcranial magnetic stimulation (TMS) was delivered in healthy subjects over the r-IFG/left primary motor area (l-M1) and over r-preSMA/l-M1 before (100 ms after the fixation cross onset) and 50, 75, 100, 125, and 150 ms after the presentation of a Go/NoGo visual cue establishing the specific time course and the causal interactions of these regions in relation to l-M1 as measured by motor evoked potentials (MEPs). The same paired-pulse protocol was applied following sham or real cerebellar continuous theta burst stimulation (cTBS). Following sham cTBS, for NoGo trials only, MEPs collected showed the expected pattern of activation for both r-IFG-l-M1 and r-preSMA-l-M1 connectivity, characterized by peaks of increased and decreased MEP amplitude regularly repeated every 50 ms. Following cerebellar cTBS, this pattern of activation related to NoGo trials was modified selectively for the r-IFG-M1 but not for r-preSMA-M1 connection. A common monitoring action of r-IFG and r-preSMA in inhibitory control was confirmed. The effects of cerebellar cTBS showed a specific interaction between cerebellum and r-IFG activity during the inhibitory process. [ABSTRACT FROM AUTHOR]

Background: Levodopa-induced dyskinesias are associated with thalamo-cortical disinhibition and frontal area overactivation. Neuroimaging and transcranial magnetic stimulation studies have highlighted the involvement of the right inferior frontal cortex in levodopa-induced dyskinesias.Methods: Using transcranial magnetic stimulation, we tested connectivity between the inferior frontal and contralateral motor cortex in Parkinson's disease patients with and without levodopa-induced dyskinesias compared with age-matched controls. Furthermore, in dyskinetic patients, connectivity between the inferior frontal and contralateral motor cortex was assessed before and after a single session of continuous theta-burst stimulation applied over the inferior frontal cortex.Results: Dyskinetic patients showed abnormal facilitatory connectivity between the inferior frontal and motor cortex when compared with the nondyskinetic group. Continuous theta-burst stimulation over the inferior frontal cortex eliminated such facilitatory connectivity and decreased the levodopa-induced dyskinesias that was induced by a supramaximal dose of levodopa.Conclusion: In dyskinetic patients, a weaker inhibitory cortico-cortical interaction between the inferior frontal and contralateral motor cortex could be involved in levodopa-induced dyskinesias and restored by continuous theta-burst stimulation over the inferior frontal cortex. © 2016 Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ), total tau (t-tau), and phosphorylated tau proteins are associated with different clinical progression in Alzheimer's disease (AD). We enrolled forty newly diagnosed AD patients, who underwent lumbar puncture, and carried out a K-means cluster analysis based on CSF biomarkers levels, resulting in two AD patient groups: Cluster 1 showed relatively high levels of Aβ and low levels of tau; Cluster 2 showed relatively low levels of Aβ and high levels of tau. Cortical plasticity was tested using the intermittent and continuous theta burst stimulation (iTBS and cTBS) protocols evoking respectively long-term potentiation (LTP) and depression (LTD). Cholinergic transmission was tested by the short-latency afferent inhibition protocol. Neurophysiological evaluation showed that the two AD groups differed in terms of cortical plasticity: after iTBS, Cluster 2 patients showed a remarkable reversal of LTP toward LTD that was not observed in Cluster 1. LTD and central cholinergic transmission did not differ between groups. Patients were assessed longitudinally with Mini-Mental State Examination at 6, 12, and 18 month follow-ups. Cluster 2 AD had a faster cognitive decline already evident at the 12 month follow-up. High tau CSF levels were associated with LTD-like cortical plasticity and faster clinical progression. These results suggest that more aggressive tau pathology is associated with prominent LTD-like mechanisms of cortical plasticity and faster cognitive decline. [ABSTRACT FROM AUTHOR]

Paired associative stimulation (PAS) protocols induce forms of spike-timing-dependent-plasticity (STDP) when paired pulses are repeatedly applied with different timing over interconnected cortical areas such as the posterior parietal cortex (PPC) and the primary motor cortex (M1). However, the assessment of PAS effects is usually limited to M1 through recording of motor-evoked potential (MEP) amplitude. Here, by combining transcranial magnetic stimulation (TMS) with EEG we aimed at investigating PAS effects over both areas (PPC, M1) and the modulation induced on their connectivity in humans. In different PAS conditions, PPC preceded or followed M1 TMS by 5 ms. We found that TMS-evoked potentials (TEPs) changed differently according to the long-term depression (LTD) or potentiation (LTP) after-effect assessed by MEPs, but did not vary at PPC level. Moreover, there was no change in local oscillatory power. However, there was a remarkable increase of coherence between the PPC and the M1 areas. When the PAS protocol induced LTD as revealed by MEPs, there was a specific increase of the coherence between PPC and M1 within the beta band. On the contrary, when PAS induced LTP, the coherence crucially increased in the alpha band. The same LTP results were confirmed when rotating the stimulating coil in M1 during the PAS protocol. In conclusion, we report new evidence that opposite STDP-like effects induced by corticocortical PAS are associated with increased communication between involved brain areas and that antithetic forms of STDP-like after-effects result in distinct cortical rhythms connectivity changes. [ABSTRACT FROM AUTHOR]

Learning of new skills may occur through Hebbian associative changes in the synaptic strength of cortical connections [spike-timing-dependent plasticity (STDP)],but how the precise temporal relationship of the presynaptic and postsynaptic inputs determines the STDP effects in humans is poorly understood. We used a novel paired associative stimulation protocol to repeatedly activate the short-latency connection between the posterior parietal cortex and the primary motor cortex (Ml) of the left-dominant hemisphere. In different experiments, we systematically varied the temporal relationships between the stimuli and the preferential activation of different Ml neuronal populations by applying transcranial magnetic stimulation over Ml with different coil orientations and in different states of cortical excitability (rest vs muscular contraction). We found evidence for the existence of both Hebbian and anti-Hebbian STDP in human long-range connections. The induction of bidirectional long-term potentiation or depression in Ml depended not only on the relative timing between the stimuli but, crucially, on the stimulation of specific neuronal populations and the activity state of the cortex. Our findings demonstrate that these mechanisms are not fixed but susceptible to rapid adaptations. This sudden transition from anti-Hebbian to Hebbian plasticity likely involves local dynamics of interaction with different populations of postsynaptic neurons. [ABSTRACT FROM AUTHOR]

The dysfunction of cholinergic neurons is a typical hallmark in Alzheimer's disease (AD). Previous findings demonstrated that high density of cholinergic receptors is found in the thalamus and the cerebellum compared with the cerebral cortex and the hippocampus. We aimed at investigating whether activation of the cerebello-thalamo-cortical pathway by means of cerebellar theta burst stimulation {TBS) could modulate central cholinergic functions evaluated in v/Voby using the neurophysiological determination of Short-Latency Afferent Inhibition (SLAI). We tested the SLAI circuit before and after administration of cerebellar continuous TBS (cTBS) in 12 AD patients and in 12 healthy age-matched control subjects (HS). We also investigated potential changes of intracortical circuits of the contralateral primary motor cortex {MD by assessing short intracortical inhibition {SICI) and intracortical facilitation (ICF). SLAI was decreased in AD patients compared to HS. Cerebellar cTBS partially restored SLAI in AD patients at later inter-stimulus intervals (ISIs), but did not modify SLAI in HS. SICI and ICF did not differ in the two groups and were not modulated by cerebellar cTBS. These results demonstrate that cerebellar magnetic stimulation is likely to affect mechanisms of cortical cholinergic activity, suggesting that the cerebellum may have a direct influence on the cholinergic dysfunction in AD. [ABSTRACT FROM AUTHOR]

In animal models of Alzheimer's disease (AD), amyloid-β fragments interfere with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). In the current study, we applied repetitive transcranial magnetic stimulation over the primary motor cortex (M1) in AD patients and in age-matched healthy controls, using protocols of theta burst stimulation (TBS) that are known to induce plastic changes resembling the LTP and LTD mechanisms described in animal models. AD patients showed consistent LTD-like effects that were comparable to those obtained in healthy controls when submitted to 40 seconds of continuous TBS. Conversely, AD patients did not show any LTP-like after effect when submitted to two different TBS protocols that induced an LTP-like effect in healthy controls such as intermittent TBS and 20 seconds of continuous TBS followed by one minute of muscular contraction. These results demonstrate the impairment of LTP-like together with normal LTD-like cortical plasticity in AD patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The posteromedial cortex including the precuneus (PC) is thought to be involved in episodic memory retrieval. Here we used continuous theta burst stimulation (cTBS) to disentangle the role of the precuneus in the recognition memory process in a sample of healthy subjects. During the encoding phase, subjects were presented with a series of colored pictures. Afterwards, during the retrieval phase, all previously presented items and a sample of new pictures were presented in black, and subjects were asked to indicate whether each item was new or old, and in the latter case to indicate the associated color. cTBS was delivered over PC, posterior parietal cortex (PPC) and vertex before the retrieval phase. The data were analyzed in terms of hits, false alarms, source errors and omissions. cTBS over the precuneus, but not over the PPC or the vertex, induced a selective decrease in source memory errors, indicating an improvement in context retrieval. All the other accuracy measurements were unchanged. These findings suggest a direct implication of the precuneus in successful context-dependent retrieval. [ABSTRACT FROM AUTHOR]