TMS + Exposure Therapy for Pediatric OCD

Pediatric OCD is a public health problem and many remain symptomatic even after receiving efficacious treatments. The success of exposure and response prevention (ERP), a first-line behavioral treatment, depends on the ability to refrain from compulsions during exposure tasks. Improving this "therapy critical behavior" is a potentially important strategy for ERP augmentation. Repetitive transcranial magnetic stimulation (rTMS) can be leveraged to stimulate healthier functioning of brain circuits underlying therapy critical behaviors. The overall objective of this project is to test whether augmenting ERP with rTMS over cortical nodes of select cortico-striatal circuits implicated in compulsivity can normalize connectivity and enhance response prevention in youth and young adults with OCD. This project will use a masked RCT design to test whether ERP+TMS engages 1) hypothesized circuits involved in compulsivity and 2) observed response prevention during ERP exposure tasks. Youth ages 12-21 years with OCD will complete a full course of ERP plus randomly assigned TMS regimens of sham, inhibitory theta burst stimulation (iTBS) to the dorsolateral prefrontal cortext (dlPFC), or continuous theta burst stimulation (cTBS) to the presupplementary motor area (pSMA; n=20 per group). Milestones for the R61 phase are determination that at least one active rTMS condition a) changes resting state functional connectivity in the hypothesized circuit within- and between-subjects and b) is safe and feasible.

• Transcranial Magnetic Stimulation: intermittent theta burst to dorsolateral prefrontal cortex (Device), also known as TMS, Neuromodulation, iTBS: TMS will be delivered over the dorsolateral prefrontal cortex (dlPFC) using an intermittent bursting pattern
• Exposure with Response Prevention (Behavioral), also known as ERP, Exposure Therapy, Cognitive-Behavioral Therapy, CBT: ERP will be delivered daily, immediately following TMS
• Transcranial Magnetic Stimulation: Sham (Device), also known as TMS, Neuromodulation: Sham stimulation will use the Magstim sham air-cooled coil, which produces auditory signals and appears identical to an active coil but contains a mu-metal shield that diverts the majority of the magnetic flux such that a minimal (<3%) magnetic field is delivered to the cortex
• Transcranial Magnetic Stimulation: continuous theta burst to pre supplementary motor area (Device), also known as TMS, iTBS, Neuromodulation: TMS will be delivered over the pre supplementary motor area (preSMA) using a continuous bursting pattern

Primary outcomes

• Functional Magnetic Resonance Imaging (fMRI): connectivity of the pSMA-DLS circuit [change from baseline at two weeks (post-treatment)]: z-score representing change in resting state connectivity between presupplementary motor area (pSMA) and dorsolateral striatum (DLS)
• Functional Magnetic Resonance Imaging (fMRI): connectivity of the dlPFC-DMS circuit [change from baseline at two weeks]: z-score representing change in resting connectivity between dorsolateral prefrontal cortex and dorsomedial striatum (DMS)
• Observed Compulsive Behavior [two weeks]: Mean proportion of time during which compulsions are observed during ERP sessions

Secondary outcomes

• Child/Adult Yale-Brown Obsessive Compulsive Inventory [change from baseline at two weeks (post-treatment)]: Independent-Evaluator (IE) rated measure of OCD symptom severity. Rated on 0 (no symptoms) to 40 (most extreme symptoms) scale

Sex: All, ages: 12 Years to 21 Years

Inclusion Criteria:

* Between the ages of 12 and 21 years.
* Presence of OCD, as indicated by a score of > 16 on the Children's Yale-Brown Obsessive Compulsive Scale, indicating moderate or greater OCD symptoms.
* Presence of motor compulsions on CY-BOCS compulsion checklist
* English fluency to ensure comprehension of informed consent and study measures and instructions.

Exclusion Criteria:

* Decline to provide informed consent.
* Has a personal history, or a family history in a first-born relative, of any medical or psychiatric disorder, disease, condition, injury, symptoms or circumstance that, in the opinion of the principal investigator, may: (1) impact the risk profile of TMS; (2) reduce the subject's ability to fulfill the study requirements as per protocol; or (3) adversely impact the integrity of the data or the validity of the study results." Some examples include: epilepsy or seizure disorder(s), bipolar disorder or any psychiatric disorder associated with a risk of mania, intracranial pathology, traumatic brain injury, brain tumor, stroke, implanted medical devices or metallic objects in the head, or moderate-severe heart disease
* Pregnant according to the medical history or a urine pregnancy test; and menstruating females who are heterosexually active and not using a highly effective form of contraception (tubal ligation, FDA-approved hormonal contraceptive, or an IUD)
* Inability to undergo MRI.
* Left handedness.
* Is deemed to be at imminent risk of suicide according to the Ask Suicide-Screening Questions (ASQ) (i.e. answers YES to ≥ one (1) of the four screening questions) and/or in the medical opinion of the investigator
* History of, or risk factors for, neurocardiogenic syncope (history of syncope/ presyncope related to noxious stimuli, anxiety, micturation, or posture).
* Concurrent psychotherapy of any kind for OCD.
* Concurrent TMS or receipt of any TMS experimental or clinical treatment less than 3 months prior to enrollment.
* Taking a medication deemed to pose high seizurogenic potential per physician review
* Taking a medication that has not reached stability criterion (same medication and dose for 6 weeks with no planned changes over the study period)

• Results publication: Conelea C, Breitenfeldt C, Wilens A, Carpenter L, Greenberg B, Herren J, Jacob S, Lewis C, McLaughlin N, Mueller BA, Nelson S, O'Connor E, Righi G, Widge AS, Fiecas M, Benito K. The NExT trial: Protocol for a two-phase randomized controlled trial testing transcranial magnetic stimulation to augment exposure therapy for youth with OCD. Trials. 2024 Dec 18;25(1):835. doi: 10.1186/s13063-024-08629-1. PMID 39696590

• Kristen Benito, PhD, Principal investigator, Emma Pendleton Bradley Hospital
• Christine Conelea, PhD, Principal investigator, University of Minnesota