Non-invasive, targeted bioelectronic brain modulation for enhancing cognition

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.