Prefrontal control over motor cortex cycles at beta-frequency during movement inhibition

A fully adapted behavior requires maximum efficiency to inhibit processes in the motor domain [ 1 ]. Although a number of cortical and subcortical brain regions have been implicated, converging evidence suggests that activation of right inferior frontal gyrus (r-IFG) and right presupplementary motor area (r-preSMA) is crucial for successful response inhibition [ 2, 3 ]. However, it is still unknown how these prefrontal areas convey the necessary signal to the primary motor cortex (M1), the cortical site where the final motor plan eventually has to be inhibited or executed. On the basis of the widely accepted view that brain oscillations are fundamental for communication between neuronal network elements [ 4–6 ], one would predict that the transmission of these inhibitory signals within the prefrontal-central networks (i.e., r-IFG/M1 and/or r-preSMA/M1) is realized in rapid, periodic bursts coinciding with oscillatory brain activity at a distinct frequency. However, the dynamics of corticocortical effective connectivity has never been directly tested on such timescales. By using double-coil transcranial magnetic stimulation (TMS) and electroencephalography (EEG) [ 7, 8 ], we assessed instantaneous prefrontal-to-motor cortex connectivity in a Go/NoGo paradigm as a function of delay from (Go/NoGo) cue onset. In NoGo trials only, the effects of a conditioning prefrontal TMS pulse on motor cortex excitability cycled at beta frequency, coinciding with a frontocentral beta signature in EEG. This establishes, for the first time, a tight link between effective cortical connectivity and related cortical oscillatory activity, leading to the conclusion that endogenous (top-down) inhibitory motor signals are transmitted in beta bursts in large-scale cortical networks for inhibitory motor control

Paradoxical facilitation after depotentiation protocol can precede dyskinesia onset in early Parkinson’s disease

Loss of dopamine, a key modulator of synaptic signalling, and subsequent pulsatile non-physiological levodopa replacement is believed to underlie altered neuroplasticity in Parkinson's disease (PD). Animal models suggest that maladaptive plasticity (e.g. deficient depotentiation at corticostriatal synapses) is key in the development of levodopa-induced dyskinesia (LID), a common complication following levodopa replacement in PD. Human studies using transcranial magnetic stimulation protocols have shown similar depotentiation deficit in patients with LID. We hypothesized that subtle depotentiation deficits should precede LID if these deficits are mechanistically linked to LID onset. Moreover, patients on pulsatile levodopa-based therapy may show these changes earlier than those treated with levodopa-sparing strategies. We recruited 22 early non-dyskinetic PD patients (<5 years since diagnosis) and 12 age-matched healthy controls. We grouped patients into those on Levodopa-Based (n = 11) and Levodopa-Sparing therapies (n = 11). Patients were selected to obtain groups matched for age and disease severity. We used a theta-burst stimulation protocol to investigate potentiation and depotentiation in a single session. We report significant depotentiation deficits in the Levodopa-Based group, compared to both Levodopa-Sparing and Healthy Control groups. Potentiation and Depotentiation responses were similar between Levodopa-Sparing and Healthy Control groups. Although differences persist after accounting for potential confounds (e.g. levodopa-equivalent dose), these results may yet be caused by differences in disease severity and cumulative levodopa-equivalent dose as discussed in the text. In conclusion, we show for the first time that paradoxical facilitation in response to depotentiation protocols can occur in PD even prior to LID onset

Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer's disease

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

Paired associative stimulation enforces the communication between interconnected areas

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

Practical and Efficient Procedure for the In Situ Preparation of B-Alkoxyoxazaborolidines. Enantioselective Reduction of Prochiral Ketones

A new method for the in situ elaboration of B-alkoxyoxazaborolidines is presented. Their use in the enantioselective reduction of prochiral aromatic ketones provides excellent chemical and optical yields of chiral alcohols

Cerebellar Control on Prefrontal-Motor Connectivity During Movement Inhibition

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&nbsp;ms after the fixation cross onset) and 50, 75, 100, 125, and 150&nbsp;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&nbsp;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

Cerebellar theta burst stimulation in stroke patients with ataxia

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

Cerebellar theta burst stimulation in stroke patients with ataxia

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

Cerebellar theta burst stimulation in stroke patients with ataxia

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

Restored Asymmetry of Prefrontal Cortical Oscillatory Activity after Bilateral Theta Burst Stimulation Treatment in a Patient with Major Depressive Disorder: A TMS-EEG Study

none4Recently, transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) has been adopted to assess cortical oscillatory activity in humans, highlighting altered neuronal oscillations in neuropsychiatric disorders[2]. Several evidence supportthe hypothesis that the major depressive disorder (MDD) is characterized by a cortical asymmetry in frontal regions and that repetitive transcranial magnetic stimulation (rTMS) could be an effective neurostimulation treatment in refractory depression,modulating cortical excitability.nonePellicciari, Maria Concetta; Ponzo, Viviana; Caltagirone, Carlo; Koch, GiacomoPellicciari, Maria Concetta; Ponzo, Viviana; Caltagirone, Carlo; Koch, Giacom