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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.

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.