Non-invasive Brain Stimulation for Neurodegenerative Disorders: From Investigation to Therapeutic Application

Editorial

03 March 2022

Editorial: Non-invasive Brain Stimulation for Neurodegenerative Disorders: From Investigation to Therapeutic Application

Francesco Di Lorenzo

Antonio Oliviero

Andrea Guerra

and

Peter J. Fried

2,147 views

2 citations

Editors

Francesco Di Lorenzo

Santa Lucia Foundation (IRCCS)

Antonio Oliviero

Fundación del Hospital Nacional de Parapléjicos

Andrea Guerra

Department of Neuroscience, School of Medicine and Surgery, University of Padua

Peter J Fried

Beth Israel Deaconess Medical Center, Harvard Medical School

Impact

Original Research

20 May 2021

Patient-Tailored, Home-Based Non-invasive Brain Stimulation for Memory Deficits in Dementia Due to Alzheimer's Disease

Lucie Bréchet

, 5 more and

Alvaro Pascual-Leone

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that can cause dementia (Alzheimer's disease-related dementia, ADRD) with growing cognitive disability and vast physical, emotional, and financial pressures not only on the patients but also on caregivers and families. Loss of memory is an early and very debilitating symptom in AD patients and a relevant predictor of disease progression. Data from rodents, as well as human studies, suggest that dysregulation of specific brain oscillations, particularly in the hippocampus, is linked to memory deficits. Animal and human studies demonstrate that non-invasive brain stimulation (NIBS) in the form of transcranial alternating current stimulation (tACS) allows to reliably and safely interact with ongoing oscillatory patterns in the brain in specific frequencies. We developed a protocol for patient-tailored home-based tACS with an instruction program to train a caregiver to deliver daily sessions of tACS that can be remotely monitored by the study team. We provide a discussion of the neurobiological rationale to modulate oscillations and a description of the study protocol. Data of two patients with ADRD who have completed this protocol illustrate the feasibility of the approach and provide pilot evidence on the safety of the remotely-monitored, caregiver-administered, home-based tACS intervention. These findings encourage the pursuit of a large, adequately powered, randomized controlled trial of home-based tACS for memory dysfunction in ADRD.

9,057 views

35 citations

Original Research

09 March 2021

The Effect of Transcranial Random Noise Stimulation on Cognitive Training Outcome in Healthy Aging

Michela Brambilla

, 5 more and

Anna-Katharine Brem

4,478 views

13 citations

Percent variation of Unified Parkinson's Disease rating scale (UPDRS) part III tremor subscore at T2 compared to basal. Real group is obtained by merging M1-PFC and M1 together. T-test, *p < 0.05. Positive values indicate improvement.

Original Research

18 February 2021

Bilateral Repetitive Transcranial Magnetic Stimulation With the H-Coil in Parkinson's Disease: A Randomized, Sham-Controlled Study

Francesca Spagnolo

, 8 more and

Letizia Leocani

5,166 views

23 citations

Random effect of time on ADAS-cog scores at an individual level. BLUP, best linear unbiased predictor.

Clinical Trial

18 February 2021

Repetitive Transcranial Magnetic Stimulation With H-Coil in Alzheimer's Disease: A Double-Blind, Placebo-Controlled Pilot Study

Letizia Leocani

, 9 more and

Giancarlo Comi

5,860 views

18 citations

Review

05 February 2021

Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability

Federico Ranieri

, 2 more and

Vincenzo Di Lazzaro

In the last 20 years, several modalities of neuromodulation, mainly based on non-invasive brain stimulation (NIBS) techniques, have been tested as a non-pharmacological therapeutic approach to slow disease progression in amyotrophic lateral sclerosis (ALS). In both sporadic and familial ALS cases, neurophysiological studies point to motor cortical hyperexcitability as a possible priming factor in neurodegeneration, likely related to dysfunction of both excitatory and inhibitory mechanisms. A trans-synaptic anterograde mechanism of excitotoxicity is thus postulated, causing upper and lower motor neuron degeneration. Specifically, motor neuron hyperexcitability and hyperactivity are attributed to intrinsic cell abnormalities related to altered ion homeostasis and to impaired glutamate and gamma aminobutyric acid gamma-aminobutyric acid (GABA) signaling. Several neuropathological mechanisms support excitatory and synaptic dysfunction in ALS; additionally, hyperexcitability seems to drive DNA-binding protein 43-kDA (TDP-43) pathology, through the upregulation of unusual isoforms directly contributing to ASL pathophysiology. Corticospinal excitability can be suppressed or enhanced using NIBS techniques, namely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as well as invasive brain and spinal stimulation. Experimental evidence supports the hypothesis that the after-effects of NIBS are mediated by long-term potentiation (LTP)-/long-term depression (LTD)-like mechanisms of modulation of synaptic activity, with different biological and physiological mechanisms underlying the effects of tDCS and rTMS and, possibly, of different rTMS protocols. This potential has led to several small trials testing different stimulation interventions to antagonize excitotoxicity in ALS. Overall, these studies suggest a possible efficacy of neuromodulation in determining a slight reduction of disease progression, related to the type, duration, and frequency of treatment, but current evidence remains preliminary. Main limitations are the small number and heterogeneity of recruited patients, the limited “dosage” of brain stimulation that can be delivered in the hospital setting, the lack of a sufficient knowledge on the excitatory and inhibitory mechanisms targeted by specific stimulation interventions, and the persistent uncertainty on the key pathophysiological processes leading to motor neuron loss. The present review article provides an update on the state of the art of neuromodulation in ALS and a critical appraisal of the rationale for the application/optimization of brain stimulation interventions, in the light of their interaction with ALS pathophysiological mechanisms.

Schematic representation of mechanisms implicated in the origin of hyperexcitability in ALS and of proposed sites of interaction of different techniques of stimulation of the corticospinal system. Excitatory glutamatergic input to upper motor neurons (UMN, red) is mainly provided by upstream layer 2 and 3 pyramidal neurons (L2/3, light blue) and modulated by astrocytes (AS, green). Different populations of interneurons (IN, black) provide GABAergic input within M1 (a single simplified connection to UMN apical dendrite is represented). All the above cell groups and synaptic connections can be affected by ALS pathophysiological alterations, and current evidence suggests an interplay between functional and molecular alterations, such as TDP-43 cytoplasmic accumulation. It is proposed that most NIBS protocols selectively modulate bursting cells of layers 2 and 3 that project upon layer 5 pyramidal cells or a reverberating local circuit within M1 including GABAergic interneurons; cTBS selectively suppresses the excitability of monosynaptic connections to CSNs; 5-Hz rTMS may produce its effects by enhancing the excitability of CSNs; anodal tDCS and other invasive and non-invasive spinal stimulation techniques interact with corticospinal axons. Stimulation protocols with a documented inhibitory effect on corticospinal excitability are indicated in blue. Histological insert shows TDP-43 skein-like inclusions in the cytoplasm of motor neurons of the hypoglossal nuclei in the medulla oblongata (×100 original magnification). Neuromodulation techniques—rTMS, repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation; iTBS/cTBS, intermittent/continuous theta burst stimulation; PAS, paired associative stimulation.

14,129 views

19 citations

Review

03 November 2020

On the Use of TMS to Investigate the Pathophysiology of Neurodegenerative Diseases

Vishal Rawji

, 3 more and

Lorenzo Rocchi

Neurodegenerative diseases are a collection of disorders that result in the progressive degeneration and death of neurons. They are clinically heterogenous and can present as deficits in movement, cognition, executive function, memory, visuospatial awareness and language. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation tool that allows for the assessment of cortical function in vivo. We review how TMS has been used for the investigation of three neurodegenerative diseases that differ in their neuroanatomical axes: (1) Motor cortex—corticospinal tract (motor neuron diseases), (2) Non-motor cortical areas (dementias), and (3) Subcortical structures (parkinsonisms). We also make four recommendations that we hope will benefit the use of TMS in neurodegenerative diseases. Firstly, TMS has traditionally been limited by the lack of an objective output and so has been confined to stimulation of the motor cortex; this limitation can be overcome by the use of concurrent neuroimaging methods such as EEG. Given that neurodegenerative diseases progress over time, TMS measures should aim to track longitudinal changes, especially when the aim of the study is to look at disease progression and symptomatology. The lack of gold-standard diagnostic confirmation undermines the validity of findings in clinical populations. Consequently, diagnostic certainty should be maximized through a variety of methods including multiple, independent clinical assessments, imaging and fluids biomarkers, and post-mortem pathological confirmation where possible. There is great interest in understanding the mechanisms by which symptoms arise in neurodegenerative disorders. However, TMS assessments in patients are usually carried out during resting conditions, when the brain network engaged during these symptoms is not expressed. Rather, a context-appropriate form of TMS would be more suitable in probing the physiology driving clinical symptoms. In all, we hope that the recommendations made here will help to further understand the pathophysiology of neurodegenerative diseases.

14,531 views

34 citations

Motor scores changes in the subitems “dystonia” (left) and “chorea” (right). The histogram shows UHDRS-I subscores at different time intervals (T0, T1, and T2), following either sham (gray columns) or anodal ctDCS (red columns). Note that real (anodal) stimulation significantly reduced dystonia, with a smaller effect on choreic movements. Data are shown as mean values ± 1 S.E. (*p < 0.05).

Brief Research Report

03 December 2020

Cerebellar Direct Current Stimulation (ctDCS) in the Treatment of Huntington's Disease: A Pilot Study and a Short Review of the Literature

Tommaso Bocci

, 3 more and

Alberto Priori

3,523 views

11 citations

Systematic Review

19 October 2020

A Systematic Review of Non-invasive Brain Stimulation Applications to Memory in Healthy Aging

Robin A. Goldthorpe

, 1 more and

Ines R. Violante

It has long been acknowledged that memory changes over the course of one's life, irrespective of diseases like dementia. Approaches to mitigate these changes have however yielded mixed results. Brain stimulation has been identified as one novel approach of augmenting older adult's memory. Thus far, such approaches have however been nuanced, targeting different memory domains with different methodologies. This has produced an amalgam of research with an unclear image overall. This systematic review therefore aims to clarify this landscape, evaluating, and interpreting available research findings in a coherent manner. A systematic search of relevant literature was conducted across Medline, PsycInfo, Psycarticles and the Psychology and Behavioral Sciences Collection, which uncovered 44 studies employing non-invasive electrical brain stimulation in healthy older adults. All studies were of generally good quality spanning numerous memory domains. Within these, evidence was found for non-invasive brain stimulation augmenting working, episodic, associative, semantic, and procedural memory, with the first three domains having the greatest evidence base. Key sites for stimulation included the left dorsolateral prefrontal cortex (DLPFC), temporoparietal region, and primary motor cortex, with transcranial direct current stimulation (tDCS) holding the greatest literature base. Inconsistencies within the literature are highlighted and interpreted, however this discussion was constrained by potential confounding variables within the literature, a risk of bias, and challenges defining research aims and results. Non-invasive brain stimulation often did however have a positive and predictable impact on older adult's memory, and thus warrants further research to better understand these effects.

8,806 views

24 citations