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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.

Humans have an individual profile of the electroencephalographic power spectra at the 8 to 16 Hz frequency during non-rapid eye movement sleep that is stable over time and resistant to experimental perturbations. We tested the hypothesis that this electroencephalographic "fingerprint" is genetically determined, by recording 40 monozygotic and dizygotic twins during baseline and recovery sleep after prolonged wakefulness. We show a largely greater similarity within monozygotic than dizygotic pairs, resulting in a heritability estimate of 96%, not influenced by sleep need and intensity. If replicated, these results will establish the electroencephalographic profile during sleep as one of the most heritable traits of humans.

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 MEASURESThe 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. RESULTSA 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.

Anodal and cathodal transcranial direct current stimulations (tDCS) are both established techniques to induce cortical excitability changes. Typically, in the human motor system, such cortical modulations are inferred through changes in the amplitude of the motor evoked potentials (MEPs). However, it is now possible to directly evaluate tDCS-induced changes at the cortical level by recording the transcranial magnetic stimulation evoked potentials (TEPs) using electroencephalography (EEG). The present study investigated the modulation induced by the tDCS on the motor system. The study evaluates changes in the MEPs, in the amplitude and distribution of the TEPs, in resting state oscillatory brain activity and in behavioral performance in a simple manual response task. Both the short-and long-term tDCS effects were investigated by evaluating their time course at~0 and 30 min after tDCS. Anodal tDCS over the left primary motor cortex (M1) induced an enhancement of corticospinal excitability, whereas cathodal stimulation produced a reduction. These changes in excitability were indexed by changes in MEP amplitude. More interestingly, tDCS modulated the cortical reactivity, which is the neuronal activity evoked by TMS, in a polarity-dependent and site-specific manner. Cortical reactivity increased after anodal stimulation over the left M1, whereas it decreased with cathodal stimulation. These effects were partially present also at long term evaluation. No polarity-specific effect was found either on behavioral measures or on oscillatory brain activity. The latter showed a general increase in the power density of low frequency oscillations (theta and alpha) at both stimulation polarities. Our results suggest that tDCS is able to modulate motor cortical reactivity in a polarity-specific manner, inducing a complex pattern of direct and indirect cortical activations or inhibitions of the motor system-related network, which might be related to changes in synaptic efficacy of the motor cortex.

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.

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