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.

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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.

SummaryA 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.