Testing a Transdiagnostic TMS Treatment Target

Psychiatric disorders are often studied individually. However, up to half of individuals who meet criteria for one psychiatric disorder also meet criteria for another. These individuals are difficult to diagnose and treat. Relative to those with one disorder, individuals with two or more have worse treatment outcomes, more functional impairment, and a greater risk of premature death.

Neuromodulation treatments like transcranial magnetic stimulation (TMS) work when routine psychotherapy and medications have not worked, but they typically target one disorder at a time. In fact, the TMS field is largely focused on strategies to make TMS more precise by targeting individual symptoms within a diagnosis. This strategy is important, but it may be difficult to scale and optimize in the setting of real-world psychiatric comorbidity. For example, there are 227 possible ways to meet criteria for major depressive disorder, complicating precision TMS strategies for individuals with or without comorbid disorders.

In this study, the investigators are moving in a different direction by targeting the brain network shared across psychiatric disorders in treatment-seeking individuals with more than one psychiatric disorder. This approach is based upon prior work. In a 2023 Nature Human Behavior study, the investigators analyzed four independent datasets with coordinate and lesion network mapping to test for a brain network shared across psychiatric disorders. They found that atrophy coordinates across six psychiatric disorders (193 studies) mapped to a common brain network defined by positive connectivity to the anterior cingulate and insula, and by negative connectivity to posterior parietal and lateral occipital cortices. The investigators verified that this transdiagnostic network was robust to leave-one-diagnosis-out cross validation and specific to atrophy coordinates from psychiatric versus neurodegenerative disorders (72 studies). Lesion-induced damage to this network correlated with the number of post-lesion psychiatric diagnoses in an independent dataset (194 patients). The transdiagnostic network also aligned with neurosurgical ablation targets for psychiatric disorders (4 targets), suggesting possible therapeutic relevance and generating testable hypotheses for neuromodulation. Importantly, the candidate TMS target that emerges from this transdiagnostic network is also a critical node of the convergent depression network that was derived across 14 independent datasets. This target has not been robustly tested for major depressive disorder (MDD) or transdiagnostic symptoms.

In this open-label pilot trial, the investigators will test the hypothesis that modulating the transdiagnostic network with transcranial magnetic stimulation (TMS) will be safe and tolerable. Secondary outcomes will assess changes in the cumulative burden of psychopathology in individuals with MDD plus at least one additional psychiatric disorder. This approach is novel in three important ways: 1) This study will enroll, not exclude, individuals with multiple psychiatric illnesses. Most clinical trials selectively enroll individuals with a single diagnosis, a strategy that does not generalize to real-world settings where psychiatric comorbidity is common and difficult to treat. 2) The transdiagnostic target was validated with causal sources of information (i.e., brain lesions, neurosurgical ablation). In other words, this study will optimize the "where to stimulate" factor. TMS targets are usually derived from functional neuroimaging studies that identify correlates of illness. These correlates could cause, compensate for, or be epiphenomena of treatment or other variables, an interpretation that matters for TMS. 3) The investigators will use the most rapid-acting and robust TMS protocol. In other words, they will optimize the "how to stimulate" factor. Conventional TMS protocols require scalp-targeted treatments delivered weekdays for 6-8 weeks. By contrast, the accelerated intermittent theta burst (iTBS) protocol in this study is adapted from Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), which consists of MRI-guided treatment delivered 10 times a day for 5 days.

Inclusion criteria

• Age 18-65
• English proficiency sufficient for informed consent, questionnaires/tasks, and treatment
• Diagnosis of MDD per DSM-5 criteria (Quick Structured Clinical Interview for DSM-5 Disorders) and currently experiencing a moderate to severe episode:
• >20 on Beck Depression Inventory (BDI)
• >20 on the Montgomery-Åsberg Depression Rating Scale (MADRS) 14, 15
• Moderate to severe level of treatment resistance (Maudsley Staging Method)16, 17
• Diagnosis of at least one or more of the following psychiatric conditions per DSM-5 criteria (Quick Structured Clinical Interview for DSM-5 Disorders):
• Generalized anxiety disorder (GAD), panic disorder (PD), or social anxiety disorder (SAD)
• Obsessive compulsive disorder (OCD)
• Post-traumatic stress disorder (PTSD)
• Physician referral for individuals with either schizophrenia or schizoaffective disorder
• Stable psychiatric medication regimen, or remain medication free, for 4 weeks prior to treatment and to remain on this regimen throughout the study until the two-week post-treatment visit
• Primary clinician (e.g. psychiatrist, therapist, psychologist, APRN, PA, etc.) responsible for psychiatric care before, during, and after the trial
• Agreement to lifestyle considerations
• Abstain from becoming pregnant from time of screening to two weeks after treatment (post-treatment MRI visit)
• Continue usual intake patterns of caffeine- or xanthine-containing products (e.g. coffee, tea, soft drinks, chocolate) throughout treatment
• Abstain from alcohol, tobacco, and recreational drugs for at least 24 hours before the start of each MRI and each TMS session

Exclusion criteria

• Active pregnancy as determined by a urine pregnancy test
• Positive urine drug screen for illicit substances (not including THC)
• Depressive symptoms refractory to 8 sessions of electroconvulsive therapy (ECT)
• Recent (within 4 weeks) or concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT)
• Receiving or planning to receive other TMS treatments during course of participation
• History of
• Autism spectrum disorder
• Neurosurgical intervention for depression
• Intellectual disability
• Severe cognitive impairment
• Significant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, brain lesion)
• Untreated or insufficiently treated endocrine disorder
• Treatment with investigational drug or intervention during the study period
• Depth-adjusted TMS treatment dose > 65% maximum stimulator output
• Existing tinnitus (ringing in the ears)
• Current evidence of:
• Mania or hypomania
• Active suicidal ideation or a suicide attempt (defined by C-SSRS) within the past year
• Neurological lesion
• Contraindications to either TMS or MRI (e.g., metallic implants, severe insomnia > 4 hours per night with hypnotic, etc.).
• Moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal (not including cannabis or nicotine use disorders)
• Bipolar I disorder
• For participants with schizophrenia or schizoaffective disorder referred by a physician:
• Total PANSS score >90
• Score >4 (moderate-severe) on any positive PANSS item
• Active substance use disorder (other than nicotine)
• Hospitalization for psychosis in the past 6 months
• Severe borderline personality disorder
• Any other condition deemed by the PI to interfere with the study or increase risk to the participant