Accelerated and Extended-iTBS Targeting Inhibitory Control in Veterans With ADHD

Neuropsychiatric disorders such as Attention Deficit/Hyperactivity Disorder (ADHD), Traumatic Brain Injury (TBI), Posttraumatic Stress Disorder (PTSD), Substance Use Disorder (SUD), and suicidality impose major public health burdens. In 2021, the Centers for Disease Control and Prevention reported a 4% increase in the suicide rate, marking the largest annual rise since 2001, with 14.1 deaths per 100,000 of the United States standard population.

Among Veterans, the unadjusted suicide rate escalated from 23.3 per 100,000 in 2001 to 31.7 per 100,000 in 2020, with the highest rates (46.1 per 100,000) observed in young Veterans aged 18 to 34 years. Studies have indicated an association between ADHD and increased suicide risk. The estimated global lifetime prevalence of symptomatic ADHD in adults is 6.8%, with a higher prevalence observed in combat Veterans (10.6%). In addition, ADHD constitutes an important risk factor for both traumatic brain injury and substance use disorders. Annually, approximately 1.7 million new TBI cases are reported, exhibiting a rising trend in combat-related instances, often associated with cognitive and psychological sequelae. In the U.S., the estimated PTSD lifetime prevalence is 6.8%, with higher rates in Veterans (12.9%). SUD also stands out as another substantial contributor to the global burden of diseases, exerting a costly impact on health, productivity, crime rates, economy, and social dynamics, with a lifetime prevalence of 9.9%. A commonality across these prevalent neuropsychiatric disorders in Veterans is a deficit in inhibitory control and increased impulsivity.

Inhibitory control broadly describes the capacity to restrain impulsive behaviors, emotions, and thoughts, and suppress distracting stimuli. Clinically, impaired inhibitory response presents as heightened impulsivity, detrimentally impacting affective, cognitive, social, and occupational functioning. In ADHD, deficits in inhibitory control and heightened impulsivity are central, particularly in the combined and predominantly hyperactive/impulsive presentations. Neuroimaging studies have consistently identified hypoactivation in the right inferior frontal gyrus (rIFG), a region integral to response inhibition. This impairment and reduced connectivity between the rIFG and other brain regions involved in inhibitory control contribute to the impulsivity in ADHD, manifesting as poor decision-making, emotional dysregulation, and risk-taking behaviors. These deficits can exacerbate challenges in daily functioning, including difficulties in occupational settings, interpersonal relationships, and adherence to treatment regimens. In PTSD, disruptions in inhibitory brain networks compromise the ability to detach from trauma-related stimuli and associated emotional responses. This dysfunction is linked to increased arousal and impulsivity, which heighten the risk of comorbid conditions such as TBI and SUD. In SUD, the inability to disengage from pervasive drug-seeking behavior constitutes one of its main underlying mechanisms. In Veterans with SUD, impulsivity emerges as an important predictor of noncompliance with care, a crucial facet of relapse prevention. Similarly, individuals with TBI often exhibit impulsive behaviors and poor inhibition, with impaired prepotent response inhibition, adversely affecting rehabilitation and social functioning. Inhibitory response also plays a critical role in suicidality, with impulsivity working as a significant risk factor, especially in those with a history of suicide attempts. The association between impulsivity and suicide risk is notably pronounced among Veterans, wherein impaired inhibitory control has been identified as a potential predictor of suicidal behavior. Moreover, research indicates that Veterans with multiple suicide attempts exhibit higher levels of impulsivity compared to those with a single attempt. ADHD is linked to a higher susceptibility to suicide, likely due to its impulsive phenotype and an increased burden of comorbidities. Notably, ADHD remains an independent risk factor for suicidal behavior after adjusting for comorbidities such as depression, SUD, and PTSD. Together, these findings highlight impaired inhibitory control and impulsivity as transdiagnostic targets of clinical relevance, particularly in ADHD, where these features are defining and predictive of broader psychiatric risk.

Although stimulant medications (e.g., methylphenidate and related compounds) are FDA-approved first-line treatments for ADHD, their limitations are increasingly well documented in clinical and population-based studies. While effective for inattentive symptoms, their efficacy in addressing impulsivity, the primary target of this study, is comparatively limited. Moreover, stimulants have a notable range of adverse effects, including insomnia, hyporexia, irritability, and greater cardiovascular risk. In addition, the development of tachyphylaxis in some patients may attenuate therapeutic effectiveness over time, complicating long-term management. The potential for misuse, diversion, and dependency, along with concerns about long-term cost-effectiveness and stigma, further highlights the clinical and public health limitations of relying on pharmacologic strategies. Prolonged stimulant use has also been associated with increased risk of hypertension and arterial disease. These limitations underscore the critical need to evaluate safe and effective non-pharmacological interventions that can serve either as standalone treatments or as adjuncts to standard approaches, particularly for Veterans for whom medication is contraindicated, poorly tolerated, or ineffective. iTBS has a favorable safety profile, with side effects being mostly mild and transient (e.g., scalp discomfort, headache, or facial twitching). The risk of seizure with iTBS is comparable to that of conventional TMS protocols, with both estimated to carry an incidence \<0.01% when administered according to established safety guidelines, as planned in this study. Given the theoretical risk associated with concurrent use of TMS and stimulants, this trial will implement careful monitoring to ensure participant's safety. While this application focuses on developing non-invasive brain stimulation, the proposal as outlined here would also serve as an adjunct to other non-medication options for ADHD, such as cognitive rehabilitation.

Transcranial magnetic stimulation (TMS) is an effective treatment for depression, smoking cessation, and OCD, and has promise in treating PTSD. Concerning ADHD, an increase in striatal dopamine, equivalent to the effects of dextroamphetamine, was observed following TMS treatment. Standard TMS has been investigated as a treatment for ADHD with mixed results. Left prefrontal TMS yields improvements in inattentive symptoms of ADHD, while other trials indicate that the right prefrontal cortex is underactive and might be a more effective target. TMS over the right prefrontal cortex demonstrated benefits in modulating inhibitory control and attention. fMRI studies demonstrate hypoactivation of the right prefrontal cortex during inhibitory control in individuals with ADHD. This lateralization likely explains why TMS to the left dorsolateral prefrontal cortex might have yielded limited responses. Regardless, questions of laterality on target underscore the necessity for precision approaches. In addition, conventional TMS protocols, which involve daily sessions for up to six weeks, pose a substantial time and financial burden. In this context, there has been increased adoption of intermittent Theta Burst Stimulation (iTBS), a second-generation TMS modality. iTBS generated enhanced cortical excitability, facilitating synaptic connections through putative long-term potentiation-like effects. iTBS also stands out given its favorable safety profile and brief duration. To date, few trials have examined TBS for inhibitory control, particularly within the context of nicotine addiction, with positive outcomes targeting the rIFG. The right IFG exerts a pivotal role in modulating inhibitory response, notably its prepotent component. This cortical region is a key node within the inhibitory control circuitry, in conjunction with the pre-supplementary motor area and striatum. Improved inhibitory responses have been associated with enhanced top-down mediation facilitated via the rIFG. With these factors in mind, this proposal will assess feasibility and acceptability of iTBS on inhibitory control through a pilot randomized controlled trial, with precision functional connectivity targeting of the IFG. The investigators' design, featuring a high pulse dose concentrated within a single day, reflects the experience delivering non-invasive brain stimulation to Veterans, and leverages recent advances in accelerated TMS that permit, for the first time, large "doses" of TMS in a short period, which the investigators hope will increase access. Given the prevalence of inhibitory control deficits across neuropsychiatric disorders in Veterans, coupled with the challenges related to psychostimulants, there is compelling empirical justification to pursue accelerated and extended iTBS as a novel therapeutic modality.