Search for Novel Transcranial Magnetic Stimulation (TMS) Targets for Mental Illness

Participants will receive Transcranial Magnetic Stimulation (TMS) at a random location in the left prefrontal cortex, excluding sites that are potentially unsafe. Extensive behavioral testing will be conducted to determine which behaviors are modulated by stimulating which circuits.

Patients who meet inclusion criteria for a primary diagnosis of MDD, OCD, GAD, or Schizophrenia (n=90) and consent to treatment will be assigned two random stimulation sites in the left prefrontal cortex and receive 2 days of accelerated iTBS treatment at the first stimulation site. Patients will have a 2 month break before coming back for 2 days of accelerated iTBS treatment at the second stimulation site. Patients with schizophrenia will be offered to participate in a third arm of the trial using a schizophrenia-specific target. This arm will also include fMRI scans and behavioral testing pre- and post- aiTBS. There will be two days (6 hours total) of behavioral testing and MRI scanning before each stimulation session and two days (6 hours total) after each stimulation session. Participants will be given the option of completing the behavioral testing in one day, before and after stimulation sessions. All the patients will receive active stimulation, which will facilitate enrollment and eliminate ethical concerns about placebo treatment in vulnerable patient populations. All participants will be blinded to their target coordinates and scales will be administered by a blinded study staff.

Eligibility Criteria:
Inclusion Criteria:

* Age 18-65
* English proficiency sufficient for informed consent, questionnaires/tasks, and treatment
* Primary diagnosis of one of the following: major depressive disorder (MDD), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), or schizophrenia (determined by focal assessment using the Structured Clinical Interview for DSM-5)

  * ≥20 on the Beck Depression Inventory for patients with MDD
  * ≥16 on the Beck Anxiety Inventory for patients with GAD
  * ≥16 on the Yale-Brown Obsessive-Compulsive Scale for patients with OCD
  * ≥58 on the Positive and Negative Symptom Scale for patients with schizophrenia
* Stable psychotropic medication regimen, or remain medication free, for 4 weeks prior to treatment (Medication changes during study enrollment period will be tracked for post hoc analysis).
* Primary clinician (e.g. psychiatrist, therapist, psychologist, APRN, PA, etc.) responsible for psychiatric care before, during, and after the trial

Exclusion Criteria:

* Active pregnancy as determined by a urine pregnancy test
* Cluster B personality disorders (antisocial personality disorder, borderline personality disorder, histrionic personality disorder, narcissistic personality disorder)
* PTSD with active, clinically significant symptoms, as determined by clinician
* Diagnosis of Schizoaffective Disorder, Bipolar Type
* Recent (within 4 weeks) or concurrent use of rapid-acting antidepressant agent (ketamine/esketamine/ECT)
* Ferromagnetic metallic implant that would contraindicate receiving TMS or obtaining MRI
* Any other TMS or MRI safety concerns identified by the clinician
* Receiving or planning to receive other TMS treatments during course of participation
* History of:

  * Neurosurgical intervention for mental illness
  * Moderate to severe autism spectrum disorder
  * Intellectual disability
  * Severe cognitive impairment
  * Significant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis)
  * Untreated or insufficiently treated endocrine disorder
  * Eating disorders
  * Treatment with investigational drug or intervention during the study period
* Current evidence of:

  * Mania or hypomania
  * Active suicidal ideation or a suicide attempt within the past year
  * Contraindications to either TMS or MRI (e.g., metallic implants, etc.).
  * Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
  * Significantly increased seizure risk as determined by a clinician
* For participants with schizophrenia:

  * Evidence of impaired capacity to consent, e.g. impaired insight into illness, as deemed by a licensed psychiatrist or psychologist on the study team
  * Hospitalization with psychosis in the past 6 months
* Positive urine drug screen for illicit substances
* Existing tinnitus (ringing in the ears)
* Any other condition deemed by the PI to interfere with the study or increase risk to the participant