Non-invasive, targeted bioelectronic brain modulation for enhancing cognition

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine


Deep brain stimulation (DBS) involves delivery of focal electrical stimulation to deep brain structures using implanted electrodes [1]. DBS targeting the subthalamic nucleus has being effectively utilised in the treatment of gait disorder in Parkinson's disease and has potential in a multitude of other conditions, however implantation of the electrodes involves an invasive surgical procedure that can result in complications and limits the scalability of this treatment [2].

Non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been utilised therapeutically in a number of conditions in recent years [3, 4]. The concept that relatively high frequency (~10Hz) repetitive electrical stimulation can increase neuronal excitability through endogenous mechanisms of neuroplasticity such as long-term potentiation (LTP), has led to their use in the treatment of cognitive decline in Alzheimer's disease (AD) [4, 5] and depression [6], however efficacy has been questioned. The non-invasive nature of these techniques means that they are generally only able to stimulate the cortex and sub-cortical white matter, and whilst specialist TMS coils can be used to reach deeper structures, a stronger stimulation is required- something that poses safety concerns and results in a less focal stimulation [7]. The respective limitations of both DBS and current non-invasive brain stimulation technologies highlight the need for a safe, non-invasive, deep-reaching stimulation method with adequate focality.

Temporal interference (TI) stimulation is a novel non-invasive brain stimulation strategy that is able to selectively stimulate deep brain structures without activation of the overlying cortex [8]. In TI stimulation, multiple very high-frequency oscillating electric fields, which exhibit a small difference in frequency, are delivered to the brain via pairs of electrodes. Stimulation at these frequencies is incapable of neuronal activation due to the low-pass filtering property of cell membranes. Where the fields overlap however, the resultant electric field envelope is modulated at a frequency equal to the difference between the two high-frequency electric fields (termed the difference frequency. If the change is within the range that neurons fire, neurons can be stimulated to fire at that frequency in a manner that is as effective as direct stimulation at that frequency [8]. Furthermore, it has been shown that the area of stimulation can be directed by alteration of the injected current. These results suggest that TI stimulation has enormous potential for non-invasive, steerable, deep brain stimulation however limitations do exist. At depths currently targeted by DBS, TI stimulation activates relatively large regions of the brain [8] and spatial resolution must be improved if it is to be considered an alternative to current invasive techniques.

The mechanism by which TI stimulation drives neural activity and its origin is still poorly understood. The discovery of the mechanism of action is critical for the adoption and improvement of the TI stimulation. Preliminary computational data (unpublished) suggests that TI stimulation might be exerted via a small non-linearity in the neural response, e.g., in the capacitance of the cell, which causes the cell membrane polarisation to be proportional to not just the sum of the applied currents, but also to the square of the sum of the applied currents, leading to frequency multiplexing.

The overreaching goal of this PhD project is to discover the neurophysiological mechanisms that govern and limit brain stimulation via temporally interfering electric fields to provide the scientific grounding for clinical adoption and technological improvement.


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Description Collaboration with Boyden Lab, Massachussets Institute of Technology 
Organisation Massachusetts Institute of Technology
Department McGovern Institute For Brain Research
Country United States 
Sector Academic/University 
PI Contribution I spent a year as a visiting PhD student in the Boyden Lab at MIT learning how to perform automated patch-clamp in mice. During my time at MIT, I gathered data for our collaborative projects looking into the mechanism of action of Temporal Interference (TI) stimulation, which I continue to do at Imperial College London. Following my return to Imperial College, we have continued to collaborate with the Boyden Lab on multiple projects including human TI/EEG experiments, as well as the continuation of my TI/patch-clamp experiments.
Collaborator Contribution Ho-Jun Suk, a PhD student in the Boyden Lab at MIT trained me in the automated patch-clamp technique. In the Boyden Lab, I had a dedicated lab space and equipment in the lab to gather data for my PhD project. Since my return to Imperial College London, the Grossman Lab has regular meetings with members of the Boyden Lab involved in the project, including Edward Boyden - the principal investigator, Ho-Jun Suk and Jian-Ping Zhao- a research scientist. During these meetings we discuss ideas and further experiments for the project. The members of the Boyden Lab continue to be a valuable source of technical expertise, especially with regards to electrophysiology and voltage imaging technologies, and intellectual input. Members of the Boyden lab are undertaking animal electrophysiology and human EEG experiments to compliment the research we are doing in the Grossman Lab at Imperial College London. Furthermore, Ho-Jun will be coming to Imperial in April to aid in the set up of our automated patch-clamp equipment.
Impact Main outcomes of this collaboration so far include my proficiency in electrophysiology and the accelaration of the set up of my experiments at Imperial College London. I will continue to build on novel preliminary data colleted by myself at MIT.
Start Year 2018
Description Collaboration with De Paolo Lab, Imperial College London 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been facilitating the set up of Temporal Interference stimulation in the De Paolo lab to enable experiments. I have been performing and teaching surgical procedures to the post-doc in the lab, Dr. Shabana Khan, and running stimulation. These novel experiments focus on stimulation of implanted human neurons in the mouse brain and investigate the effect of electrical brain stimulation on axon degeneration.
Collaborator Contribution Dr. Khan brings two photon microscopy and calcium imaging expertise to the collaborative project. We have thus far been using two photon microscopy to visualise axon activation in response to the electrical brain stimulation.
Impact None so far
Start Year 2019
Description Collaboration with Hardingham Lab, Edinburgh University 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution I am collaborating with the Hardingham Lab at Edinburgh University Dementia Research Institute. We are working together on a project investigating the effect of brain stiumulation on gene expression. I will be performing brain stimulation experiments on mice and the tissue will be sent to Edinburgh for gene expression analysis.
Collaborator Contribution The Hardingham Lab will be performing gene expression analysis on brain tissue that has undergone electrical stimulation.
Impact None so far
Start Year 2019