The present pilot study will apply accelerated intermittent theta burst stimulation (aiTBS) to a novel transcranial magnetic stimulation (TMS) target for anxiety derived via causal network mapping.

Anxiety-related disorders represent the most common class of mental-health disorders and are associated with high rates of non-response and relapse to current treatments. Transcranial magnetic stimulation (TMS) applied to the dorsolateral prefrontal cortex (dlPFC) has been shown to reduce anxiety comorbid with major depressive disorder (MDD). However, anxiety-specific targets have received insufficient attention.

An anxiety specific transcranial magnetic stimulation (TMS) target was recently derived via causal network mapping and was shown to reduce anxiety versus depression symptoms to a greater extent than the conventional dlPFC target in an MDD sample with comorbid anxiety. While potentially promising, this target has yet to be trialed in an anxiety-related disorder sample.

The current open-label study will be the first to evaluate the preliminary effectiveness and safety of this novel right dorsomedial prefrontal cortex (dmPFC) TMS target. MRI-guided neuronavigation will be used to locate this target in each participant. An accelerated intermittent theta-burst (aiTBS) dosing regimen will be used. Based on a 90% resting motor threshold (adjusted for cortical depth), 50 sessions of iTBS will be administered (1800 pulses per session, with a 50-minute inter-session interval) and delivered in a schedule of 10 sessions per day for 5 consecutive days. Clinical assessments and resting-state functional MRI scans will be conducted before and after aiTBS. Heart rate variability (HRV) and eye-movement measures will be collected before and after aiTBS.

Inclusion Criteria:

1. Diagnosis of generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), and/or post-traumatic stress disorder (PTSD) as defined by DSM-5 criteria.
2. Male or female between 18 and 60 years old.
3. Right-handed.
4. Can understand and sign an informed consent document.
5. Beck Anxiety Inventory (BAI) score of 16 or higher.
6. On a stable medication/psychotherapy regimen for at least 6 weeks prior to baseline visit and throughout the duration of the study.
7. In good general health, as ascertained by medical history.
8. Pharmacological treatment resistance or psychotherapeutic treatment resistance.

Exclusion Criteria:

1. Substance use disorders, eating disorders, significant suicidal ideation, mental disorder due to a medical or neurocognitive condition, lifetime psychosis, bipolar disorder, developmental disorders.
2. History of brain surgery and epilepsy.
3. Presence of metallic foreign bodies, such as cardiac pacemakers and stents.
4. Any medical condition or medication that increases the risk of seizures.
5. Pregnancy.
6. Intellectual disability.
7. Current severe somatic disease, such as cancer, heart failure, pneumonia, etc.
8. Severe claustrophobia that prevents the use of MRI.

15 participants were initially recruited. 3 participants were excluded from the final analysis: 2 withdrew following the first day of aiTBS due to perceived worsening of nightmares and headaches, and 1 was excluded after abruptly discontinuing a prescribed anxiety medication and initiating a new medication. 12 participants were included in the final analysis.

From initiation of aiTBS through the 1-month follow-up visit.

Adverse events and treatment-emergent side effects were monitored throughout treatment and follow-up.