Modulating cognitive control related neural activity in ADHD using rhythmic Transcranial Magnetic Stimulation

Attention-deficit/hyperactivity disorder (ADHD) is characterised by difficulties with attention, impulsivity and motivation, stemming in part from unstable cognitive control. Cognitive control ensures the goal-directedness of behaviour, therefore its reliable operation is fundamental to everyday functioning. In the lab, control instability can be captured by increased variability in task performance (reaction time variability, RTV). Basic scientific studies, several from our lab, have shown that variability in the timing (phase) of frontal theta (4-8 Hz) oscillations in the brain correlates with RTV. Furthermore, foundational clinical work spearheaded by our group has found strong links between ADHD, and variability in both theta phases and behaviour (RTV). Advances in neurotechnology provide a powerful way to modulate brain oscillations, via rhythmic transcranial magnetic stimulation (rhTMS). We propose to integrate these interdisciplinary lines of research to investigate whether rhTMS can be used to normalise RTV in ADHD through regularising frontal theta (FT) phases, thus highlighting a novel non-pharmacological intervention target: FT phase variability (FT-PV). Non-pharmacological interventions in ADHD are hugely important: while psychostimulants can alleviate symptoms, they are ineffective for certain patients. Patients prefer non-pharmacological interventions, including neurostimulation, which represents a cost-efficient, personalisable, safe method, as of yet underresearched in ADHD. Our research has three specific objectives: Objective 1 (O1): Establish a causal relationship between RTV and the regulation of the timing of FT oscillations, as captured by inter-trial phase coherence (ITC, inverse of FT-PV) during a cognitive control task involving response conflict. To achieve this, we will administer theta rhTMS with simultaneous EEG to 60 neurotypical young adults. Hypotheses: FT rhTMS will significantly increase regulation of FT signalling (FT ITC) during the task compared to sham and beta rhTMS FT rhTMS will decrease RTV (standard deviation of RTs/SD-RT) during the task compared to sham and beta rhTMS. FT ITC will mediate the effect induced by theta rhTMS on SD-RT Objective 2 (O2): Investigate the effects of rhTMS neuromodulation of FT ITC on behavioural and EEG measures (ERN, N2, Pe amplitude) in 40 individuals with ADHD and the same 60 neurotypical controls. Hypotheses: On the response conflict task at baseline (pre-rhTMS/EEG-only), compared to controls, individuals with ADHD will show lower theta ITC, ERN and Pe amplitudes, higher RTV, and a smaller conflict effect on N2 amplitude. RTV will improve following theta rhTMS compared to sham and beta stimulation in both groups with larger effects in the ADHD group. FT rhTMS will modulate theta ITC and ERPs in both groups, potentially bringing them to pre-TMS neurotypical levels in ADHD. Objective 3 (O3): Investigate the longer lasting (~1 week) effects of neuromodulation on behavioural and EEG measures in young adults with ADHD and controls. Hypotheses: Observed changes in EEG measures will persist/show further improvement (increased ITC, increased amplitude of ERP components) one week after rhTMS stimulation with a significant difference to baseline (pre-rhTMS). Observed changes in behavioural performance will persist/show further improvement one week after rhTMS stimulation with a significant difference to baseline (pre-rhTMS EEG-only recording). The application of rhTMS to influence FT oscillations could potentially correct the irregular cross-trial phase synchrony in ADHD and improve multiple measures associated with the condition. If this approach proves effective, rhTMS could be trialled as a way of improving cognitive control alterations in the condition, with highly reliable (.85) measures of FT-PV as candidate intervention targets.