Accelerated prefrontal intermittent theta-burst stimulation in Huntington’s disease: a within-subject study of domain-specific behavioral and event-related potential changes

Background Huntington’s disease is a rare neurodegenerative movement disorder characterized by early disruption of frontostriatal systems, affecting motor, cognitive, and affective domains. Non-invasive brain stimulation targeting prefrontal networks may offer a means to modulate these distributed systems, although controlled evidence in Huntington’s disease remains limited, particularly for accelerated stimulation protocols. Objective To investigate whether accelerated intermittent theta-burst stimulation (iTBS) applied to the dorsolateral prefrontal cortex is associated with behavioral, motor and electrophysiological changes reflecting modulation of prefrontal network function in early-stage Huntington’s disease. Methods Ten patients with genetically confirmed Huntington’s disease participated in a within-subject, fixed-order longitudinal study, which included a sham exposure phase followed by active stimulation. Assessments were conducted at baseline (T0), after sham stimulation (T1), after active accelerated iTBS (T2), and at 60-day follow-up (T3). Clinical scales for motor impairment, behavioral measures targeting executive, affective, and social-cognitive domains were combined with event-related potentials (ERPs) recorded during cognitive and emotional Stroop tasks. The fixed-order design was chosen to minimize potential carry-over effects associated with accelerated stimulation protocols. Results No significant behavioral or electrophysiological changes were observed during the sham exposure phase. In contrast, active iTBS was associated with domain-specific behavioral changes, particularly in affective, executive, and social-cognitive domains, accompanied by changes in event-related potential activity, particularly within delayed N200-related responses during emotional interference. Effects were domain-specific and were not associated with normalization of electrophysiological latency profiles. Motor scales were not modified by either sham or real stimulation. Conclusion Accelerated prefrontal iTBS was associated with behavioral and electrophysiological changes following active stimulation of prefrontal network in Huntington’s disease. These findings support the feasibility of targeting distributed non-motor circuits in HD and designs accounting for cumulative and time-dependent effects of stimulation in early-phase neuromodulation studies.