Novel, Individualized Brain Stimulation, Network-based Approaches to Improve Cognition

Study Overview
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Brief Summary
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Impaired working memory (WM) plays a crucial role in normal aging, in mild cognitive impairment (MCI) and cognitive decline associated with dementia, such as Alzheimer's disease (AD). The aging-related differences in WM are hypothesized to be based on various neurobiological origins, for example alterations in the dynamic interplay between the large-scale brain networks have proven an important role. Recent studies have shown that non-invasive brain stimulation (NIBS) methods can modulate neuronal activity, plasticity and large-scale brain network interactions. The investigators hypothesize that multifocal NIBS can improve WM. By successive and concurrent stimulation of multiple brain regions of the WM network by transcranial alternating current stimulation (tACS) and/or repetitive transcranial magnetic stimulation (rTMS) the investigators will study dynamic interactions between distinct cortico-cortical and subcortico-cortical brain areas. By leveraging multimodal systems neuroscience information during multifocal stimulation, the investigators expect to acquire better mechanistic understand through which NIBS acts on the brain and improves cognitive functions, such as WM.

Detailed Description
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Mild cognitive impairment (MCI) describes an intermediate stage from normal cognitive functioning to dementia, and identifies a spectrum of diseases that includes impairment in both memory and non-memory cognitive domains. A deficient working memory (WM) plays a crucial role in normal aging, MCI, and cognitive decline associated with dementia, such as Alzheimer's disease (AD). WM refers to the on-line temporary storage and manipulation of information to be employed in ongoing processing, and is central to the execution of a variety of daily functions. The loss of WM efficiency related to either aging or neurodegenerative process is hypothesized to have various neurobiological roots, among which altered functioning of the fronto-parietal networks play an important role. The processing, exchange, and storing of information rely on intra- and interregional connectivity that allow neuronal populations to synchronize their firing. Based on this, intra- and cross frequency oscillatory interactions have been demonstrated as core basis for working memory processes, besides other cognitive functions. Any impairment preventing the adaptation and synchronization of the oscillatory activities within this network will inevitably lead to temporary or permanent loss of function. In this project, based on the mentioned pathophysiological concepts, the investigators will develop and test novel, individualized, multifocal, physiology-inspired non-invasive brain stimulation (NIBS) approaches aimed at enhancing interregional processing in memory-related fronto-parieto-cerebello networks with consecutive behavioral modulation of WM processes impacting on daily life activities in aged healthy volunteers (HV) and MCI patients. The investigators approach these aims in a step-wise manner: (1) The investigators will explore entrainment of oscillatory activity in the fronto-parietal network with transcranial alternative current stimulation (tACS) at frequencies relevant to memory encoding (theta) to boost WM in healthy seniors. (2) Then, the investigators will explore cross-frequency entrainment of interregional oscillatory interactions in the frontal and parietal target network with bifocal tACS to boost WM in healthy seniors. (3) Based on the current knowledge about the extensive involvement of the cerebellum in cognitive processes by its modulatory effects onto the fronto-parietal networks crucial for cognition, the investigators will leverage our experience in non-invasive modulation of the cerebellar outputs by means of repetitive transcranial magnetic stimulation (rTMS). rTMS over the cerebellum will be applied just before cortical entrainment to further enhance its physiological and behavioral effects. (4) Finally, the investigators will select the most effective approach from the previous work-packages to be applied in MCI patients and quantify the behavioral benefits. Besides the behavioral effects, the investigators will apply multimodal systems neuroscience approaches by means of neuroimaging (structural and functional magnetic resonance imaging; s/fMRI) and electrophysiological (Electroencephalography - EEG, transcranial magnetic stimulation - TMS) methods to determine the underlying network mechanisms and patterns of intrinsic connectivity changes. As there is significant spatial heterogeneity in fronto-parietal peak activity in healthy seniors and patients, stimulation targets will be individually defined based on fMRI. By leveraging the mechanistic aspects derived from individualized multifocal stimulation, the investigators expect to better understand the mechanisms through which NIBS techniques act on the brain and improve cognitive functions. The investigators will also test and quantify within a virtual reality (VR) task how well the intervention-driven cognitive improvement translates into daily life.

Official Title
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Novel, Individualized Brain Stimulation, Network-based Approaches to Improve Cognition in Healthy Seniors and Patients With MCI

Conditions
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Mild Cognitive Impairment, Healthy Aging

Intervention / Treatment
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* Device: tACS
* Device: TMS
* Device: TIS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: normal cognitive performance as assessed by a cognitive screening for healthy subjects mild cognitive impairment as assessed by detailed cognitive testing ± positive AD diagnostic biomarkers for MCI subjects Exclusion Criteria: Psychiatric disorders including major depression, major vascular lesions, or other brain pathologies that might present with cognitive decline.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Entrainment with personalized bi-focal fronto-parietal synchronized tACS in HV - within-frequency<br>double-blind, randomized, sham-controlled, cross-over trials assessing the effects of individualized fronto-parietal tACS on a visual working memory task in aged HV | Device: tACS<br>* a non-invasive brain stimulation technique that allows interaction with endogenous cortical oscillatory rhythms<br>|
| Experimental: Entrainment with personalized bi-focal fronto-parietal synchronized tACS in HV - cross-frequency<br>double-blind, randomized, sham-controlled, cross-over trials assessing the effects of individualized cross-frequency fronto-parietal tACS stimulation on a visual WM task in aged HV | Device: tACS<br>* a non-invasive brain stimulation technique that allows interaction with endogenous cortical oscillatory rhythms<br>|
| Experimental: Cerebellar rTMS to modify the effects of cortico-cortical, fronto-parietal tACS in HV<br>double-blind, randomized, sham-controlled, cross-over trial assessing the effects of cerebellar stimulation on individualized fronto-parietal tACS stimulation during a visual WM task in aged HV | Device: tACS<br>* a non-invasive brain stimulation technique that allows interaction with endogenous cortical oscillatory rhythms<br>Device: TMS<br>* a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain, it will be specifically cerebellar stimulation<br>|
| Experimental: Neuromodulation protocol in MCI patients (precise protocol to be chosen on results of previous arms)<br>double-blind, randomized, sham-controlled, cross-over trials assessing the effects of individualized striatal TIS combined with cereberal TMS on a visual working memory task in MCI patients | Device: TMS<br>* a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain, it will be specifically cerebellar stimulation<br>Device: TIS<br>* temporal interference stimulation targeted to striatum, a non-invasive brain stimulation technique that allows interaction with endogenous cortical oscillatory rhythms deep in the brain<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Working memory performance | We will compare the baseline-normalized reaction time and error rate of a N-back task between the real and sham stimulation condition in a cross-over design. | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The reproducibility of the outcomes of this proof-of-concept brain stimulation in MCI between centers | Twenty MCI patients will be recruited in each participating center. The reproducibility of the effects induced by the intervention will be assessed by comparing the baseline-normalized error rate of a N-back task between the two centers. | through study completion, an average of 1 year | 
| The neural underpinning of NIBS-induced changes quantified by s/fMRI and network-based analytical approaches. | The changes in intra- and inter-regional fMRI connectivity within and between cognitive brain networks will be compared between the real and sham stimulations. | The changes will be computed from the difference between connectivity at baseline and 1 hour post-stimulation. | 
| The neural underpinning of NIBS-induced changes quantified by EEG. | We will measure cortical excitability by TMS-EEG pairing via TMS-evoked potentials. | Baseline and 1 hour after the delivery of real or sham intervention - cross-over design. | 
| Transfer of the acquired WM abilities during the intervention into a daily-life relevant scenario as assessed by The Virtual Supermarket Shopping Task. | The accuracy of the post-stimulation WM task in a VR-based daily life scenario as assessed by The Virtual Supermarket Shopping Task will be compared between the real or sham intervention (cross-over design). | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TMS, non-invasive brain stimulation, tACS, cognition, working memory, MCI, healthy ageing, EEG, neuroimaging (MRI), oscillatory activity