Non-invasive Neuromodulation Unit (NNU)

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

Work was conducted under clinical protocols NCT03065335, NCT03289923, NCT03895658, NCT04798274, NCT03351764 and NCT02363296 Our projects fall into 3 themes: 1) measuring neuroplasticity, 2) modulating neuroplasticity, 3) modeling the effects of neuromodulation and mining multi-modal datasets to discover biomarkers of rapid antidepressant response. Theme I: Measuring Neuroplasticity Mechanisms of Rapid Antidepressant Action collaboration with Drs. Zarate and Park. This project develops biomarkers of rapid antidepressant response through the addition of TMS-EMG, TMS-EEG neuroplasticity measures to the existing intramural research program on ketamine. Theme II: Modulating Neuroplasticity We are taking complementary approaches to modulating neuroplasticity: 1) Next generation seizure therapy, 2) paired associative stimulation (PAS), 3) multimodal imaging and stimulation to probe circuit engagement in Autism Spectrum Disorders (ASD), and 4) novel tool development to extend the spatial and temporal specificity of noninvasive neuromodulation. We have 2 projects on the topic of next generation seizure therapy: Safety and Feasibility of Individualized Low Amplitude Seizure Therapy (iLAST) - NCT03895658: Therapeutically induced seizures exert rapid antidepressant action and are robust inducers of neuroplasticity. New technologies for focal seizure induction may improve the risk/benefit ratio. This project, in collaboration with Drs. Zarate, Park, Bikson, and Datta, is a first-in-human study of focal seizure induction with minimal current exposure to improve the tolerability of seizure therapy for depression. A Feasibility Study of Transcranial Electric Stimulation Therapy (TEST) for treatment resistant depression (TRD) - NCT05172271: This project examines electroconvulsive therapy dosing by lowering the dose below seizure threshold to determine whether adverse cognitive effects are minimized and whether stimulation can be reliably and safely administered below seizure threshold. TEST is compared to sham in a randomized, double-blind fashion for the first 6 treatments of a treatment course. Antidepressant response and neuroimaging and blood-based biomarkers will also be assessed as secondary outcomes. We have 2 projects on the topic of Paired Associative Stimulation (PAS): Concurrent fMRI-guided rTMS and cognitive therapy for the treatment of major depressive episodes - NCT03289923: Paired Associative Stimulation (PAS) strengthens synaptic efficacy through repeated co-activation and coincident firing. We extend that approach to activate a targeted neural circuit through cognitive task performance, and couple that with simultaneous focal neuromodulation to enhance plasticity, as a means of enhancing circuit function. This project employs fMRI-guided TMS paired with a form of cognitive behavioral therapy for the treatment of depression (in collaboration with Dr. Strauman). Closed-loop paired associative stimulation - NCT02363296: The effects of noninvasive brain stimulation can be extremely variable across subjects. One source of this variability is known to be the state of the brain at the time of stimulation. One way of addressing this source of variability is to trigger the TMS when the brain is in an up-state or a down-state. To accomplish this, in collaboration with Christoph Zrenner of the University of Toronto, real-time signal processing is utilized to analyze the EEG and predict where the brain oscillations will be milliseconds in advance. The TMS trigger is controlled by the real-time hardware. Multimodal imaging and stimulation to probe circuit engagement in Autism Spectrum Disorders (ASD) Our project Role of GABAergic transmission in auditory processing in Autism Spectrum Disorder (DECIBELS) NCT04798274, uses MEG and fMRI to measure brain network engagement and neurochemical changes following an acute session of rTMS in healthy volunteers and adolescents with autism spectrum disorder (in collaboration with Lindsay Oberman (OCD/NNU), Audrey Thurm (OCD), and Allison Nugent (MEG Core)). Novel tool development to extend the spatial and temporal specificity of noninvasive neuromodulation. Our Computational Neuromodulation program designs and builds prototypes of next generation noninvasive brain stimulation devices. Our project Development of Non-Invasive Brain Stimulation Techniques NCT03351764 addresses fundamental challenges impacting the utility of TMS. First, the space of parameters used to produce TMS is immensely large and has barely been explored. Second, the interaction of any set of TMS parameters with any individual brain is poorly understood, and this has led to unpredictable efficacy and a large amount of inter-individual variability in TMS studies. The purpose of this technical development protocol is to address these two fundamental challenges. Our ongoing projects within this healthy volunteer protocol include: 1. Controlling ongoing cortical state during NIBS with neurofeedback. This study asks: Does controlling brain states using neurofeedback result in greater intra- and inter-individual variability in responses to rTMS? The aim of this study is to explore whether the use of real-time fMRI neurofeedback to control brain state can constrain rTMS effects to only the stimulated network . 2. Parametric studies to optimize theta-burst stimulation (TBS). While patterned stimulation such as TBS may represent a more potent form of TMS, its effects are quite unreliable between subjects. Moreover, there has not been a parametric examination of the stimulation parameters used in TBS. We have completed data collection with the intertrain interval as the first parameter examined, and are currently analyzing its parametric effects on TBS response. 3. Noninvasive focal deep brain stimulation (nfDBS) We seek to establish whether TMS can reach, in a dose-dependent way, a targeted subcortical region transynaptically which is too distant for effective direct TMS stimulation, using TMS as a probe of the fronto-amygdalar network, a key circuit implicated in emotional processing. This will be tested with the perturbation-imaging procedure of TMS/fMRI interleaving, i.e. while participants receive TMS during both resting state and task-based fMRI. Theme III: Modeling Neuroplasticity / Mining Multi-Modal Datasets Our team comprises engineering expertise to perform in silico modeling of the spatial and temporal effects of neuromodulation on neuronal function, and to apply machine learning and graph theoretical approaches to data-mining and hypothesis generation to support the discovery of common mechanisms across rapidly acting antidepressant interventions. In our project Utilizing network analysis methods to identify suitable Transcranial Magnetic Stimulation (TMS) targets for the treatment of Autism Spectrum Disorder (ASD), we perform multivariate analysis to identify TMS-targetable nodes associated with ASD domains (i.e., social interaction and restricted/repetitive behaviours). These targets will be validated in another dataset. We hypothesize that these methods will produce clinically, structurally, and functionally informed targets for testing future rTMS trials in ASD, by determining locations that are integral to networks associated with core domains and symptoms.