Periodic Reporting for period 1 - TUNING-BRAKES (Fine-tuning the brain’s brakes – modulating inhibitory control with transcranial alternating current stimulation)
Reporting period: 2019-03-01 to 2021-02-28
Inhibitory control, or the ability to suppress unwanted thoughts or behaviour, is essential in everyday life, yet often underappreciated. The critical importance of inhibition becomes clear when the process fails, as in attention deficit hyperactivity disorder (ADHD) and Tourette’s syndrome where there is too little inhibition, or as in Parkinson’s disease where there is too much, resulting in slowness of movement (bradykinesia) and rigidity. Over the past decade, lesion studies, single cell recordings and neuroimaging research have identified a fronto-subthalamic network mediating behavioural inhibition. The power (i.e. amplitude) of oscillations in the beta band (15-30Hz) within these regions has been linked to successful inhibition. However, very little is known about how beta oscillations facilitate communication between the different cortical and subcortical areas. This not only limits our mechanistic understanding of the brain’s inhibitory control system, it also hampers the development of more effective treatment strategies for neurological and psychiatric patients suffering from inhibitory control deficits.
The overarching aim of this proposal was to identify oscillatory signatures that are causally relevant for inhibitory control, and to develop an innovative neuromodulatory approach to restore normal inhibitory control. Specifically, we made use of novel transcranial alternating current stimulation (tACS) approaches, capable of dynamically synchronising or desynchronising oscillatory activity, to (1) Investigate the causal role of beta oscillatory phase (WP1), and cross-frequency coupling between the beta and gamma frequencies (WP2). (2) Develop a proof of concept for a non-invasive adaptive stimulation approach to ameliorate abnormal neural communication (WP3).
The overarching aim of this proposal was to identify oscillatory signatures that are causally relevant for inhibitory control, and to develop an innovative neuromodulatory approach to restore normal inhibitory control. Specifically, we made use of novel transcranial alternating current stimulation (tACS) approaches, capable of dynamically synchronising or desynchronising oscillatory activity, to (1) Investigate the causal role of beta oscillatory phase (WP1), and cross-frequency coupling between the beta and gamma frequencies (WP2). (2) Develop a proof of concept for a non-invasive adaptive stimulation approach to ameliorate abnormal neural communication (WP3).
Large-scale neural communication is thought to come about through groups of neurons engaging in rhythmic synchronization. This creates short temporal windows of low and high excitability of the region. Communication has been proposed to be most effective if the neuronal output of a sending population arrives at the receiving population at its most excitable phase (position on the cycle). A stable phase-relation between both populations for an extended period of time is called coherence. In the absence of coherence, inputs from one population to the other will arrive at random phases of the excitability cycle, and result in less effective communication. If inhibitory control depends on communication in the fronto-subthalamic network in beta range, then stop-signals arriving at certain phases should be processed faster than on other phases, resulting in an oscillatory pattern of behavior over a beta cycle.
The modulatory role of phase can be investigating by combining a stop-signal task with EEG recordings, extracting the phase at which a stop-signal was presented and correlate it to behavioral performance. The problem with this approach is that one cannot control the number of stop-signal trials per phase and that in a stop-signal task there is a high dependency of trial history on performance. In WP1 we solved this problem by entraining the brain with beta tACS and presenting an equal number of stop-signals on 8 equidistance phases of the beta wave. In addition, performance on each of these 8 phases followed an individual tracking algorithm circumventing the trial history dependency. The results showed that behavioural performance followed a sinusoidal pattern, with better inhibitory control when the stop-signals were presented at the trough phase of the entraining beta wave and decreased inhibitory control when presented at the peak. This indicates that beta oscillation phase plays a causal role in inhibitory control.
A mechanism to facilitate and maintain phase coherence between brain areas includes cross-frequency coupling: the amplitude of a relatively high frequency can be coupled to a specific phase of another (lower) frequency. Beta-gamma coupling has been suggested to play a role in inhibitory control. Although this view has been challenged by researchers pointing out that the observed coupling might be driven by the analysis methods used. In WP2 we provided participants with cross-frequency tACS, comprising of beta stimulation with bursts of gamma coupled to the peak or trough of the beta wave, and compared stop-signal task performance during these stimulation conditions with performance during beta stimulation by itself and placebo stimulation. The results revealed that all active stimulation conditions equally improved inhibitory control compared to placebo, suggesting no causal role for beta-gamma coupling in inhibitory control.
In WP3 we developed a platform for recording on-going brain activity and initiating stimulation based on features of this activity. This was a technically challenging project calling for accurate prediction of the brain activity into the future as well as a very short delay between the determination of the desired starting point and the stimulation onset. After many iterations we have achieved a set-up with a high accuracy (~70% with a narrow error range) and short delay (13ms). Currently, we are comparing the performance the stop-signal task when we provide stimulation that is in-phase with the on-going brain activity (enhancing the on-going activity) with anti-phase stimulation (disrupting on-going activity). We expect that stop-signal task performance will decrease with the anti-phase stimulation.
The results of this action and closed-loop platform have been presented at various scientific conferences and meetings. They will be published in the form peer-reviewed international journal articles and all data and associated software will be made available. We have teamed up contact with several industry partners to develop the closed-loop platform further into a ready-to-use device that can be used in a home-setting under remote expert supervision.
The modulatory role of phase can be investigating by combining a stop-signal task with EEG recordings, extracting the phase at which a stop-signal was presented and correlate it to behavioral performance. The problem with this approach is that one cannot control the number of stop-signal trials per phase and that in a stop-signal task there is a high dependency of trial history on performance. In WP1 we solved this problem by entraining the brain with beta tACS and presenting an equal number of stop-signals on 8 equidistance phases of the beta wave. In addition, performance on each of these 8 phases followed an individual tracking algorithm circumventing the trial history dependency. The results showed that behavioural performance followed a sinusoidal pattern, with better inhibitory control when the stop-signals were presented at the trough phase of the entraining beta wave and decreased inhibitory control when presented at the peak. This indicates that beta oscillation phase plays a causal role in inhibitory control.
A mechanism to facilitate and maintain phase coherence between brain areas includes cross-frequency coupling: the amplitude of a relatively high frequency can be coupled to a specific phase of another (lower) frequency. Beta-gamma coupling has been suggested to play a role in inhibitory control. Although this view has been challenged by researchers pointing out that the observed coupling might be driven by the analysis methods used. In WP2 we provided participants with cross-frequency tACS, comprising of beta stimulation with bursts of gamma coupled to the peak or trough of the beta wave, and compared stop-signal task performance during these stimulation conditions with performance during beta stimulation by itself and placebo stimulation. The results revealed that all active stimulation conditions equally improved inhibitory control compared to placebo, suggesting no causal role for beta-gamma coupling in inhibitory control.
In WP3 we developed a platform for recording on-going brain activity and initiating stimulation based on features of this activity. This was a technically challenging project calling for accurate prediction of the brain activity into the future as well as a very short delay between the determination of the desired starting point and the stimulation onset. After many iterations we have achieved a set-up with a high accuracy (~70% with a narrow error range) and short delay (13ms). Currently, we are comparing the performance the stop-signal task when we provide stimulation that is in-phase with the on-going brain activity (enhancing the on-going activity) with anti-phase stimulation (disrupting on-going activity). We expect that stop-signal task performance will decrease with the anti-phase stimulation.
The results of this action and closed-loop platform have been presented at various scientific conferences and meetings. They will be published in the form peer-reviewed international journal articles and all data and associated software will be made available. We have teamed up contact with several industry partners to develop the closed-loop platform further into a ready-to-use device that can be used in a home-setting under remote expert supervision.
The results from this action provide important new fundamental insights into how inhibitory control is implemented in the brain. In addition, they are also relevant for future therapeutic strategies. For example, if one would like to increase inhibitory control in ADHD or Tourette Syndrome by means of high frequency repetitive Transcranial Magnetic Stimulation (TMS) it would be apt to provide the TMS pulses at the trough of the ongoing beta oscillations for optimal spread through the network. Due to the work carried out in this project we are now in the position to start studies in this direction.