Effects of Theta Burst Stimulation on the Brain, Behavior, and Clinical Symptoms in Adults with Bipolar Disorder

Bipolar Disorder (BD) is a common and highly debilitating psychiatric disorder, however, the predisposing brain mechanisms are poorly understood. Here, the investigators aim to examine the immediate effect of transcranial brain stimulation (TBS) on brain activity and emotions in adults with and without BD as a first stage toward understanding the predisposing brain mechanisms of BD. The investigators hypothesize that TBS will reduce brain activity while playing a game with rewards in all adults, but the TBS will reduce brain activity more in the adults with BD compared to adults without BD. Furthermore, the investigators hypothesize that this reduced brain activity will be associated with reduced BD symptoms, such as negative emotions.

This study aims to examine the effects of noninvasive stimulation on brain activity as measured by functional magnetic resonance imaging (fMRI) in participants with and without Bipolar I Disorder. Eligible participants will undergo 5 study visits: a screening visit, a baseline MRI visit, and 3 cTBS visits. Participants will receive brain stimulation and undergo fMRI scanning at each of the 3 cTBS study visits, however, at one of the visits, the brain stimulation will be a sham. The research associates and participants will be blinded to when the sham occurs, which will be randomized beforehand. Certain information is withheld to protect the scientific integrity of the study design

Eligibility Criteria:
Inclusion Criteria:

1. All participants

   * 18-35 years of age
   * Scoring less than or equal to 8 on the Hamilton Rating Scale for Depression (HRSD) at screen visit
2. Participants with Bipolar Disorder (BD)

   * Diagnosis of Bipolar Disorder I/II (BDI/II) (DSM-5 criteria) in remission (euthymic for \>2 months) or with mild-moderate hypomania
   * \<15 on the Young Mania Rating Scale
   * Not psychotic
   * \<3 on delusions, hallucinations, unusual thought content, and conceptual disorganization items of the Positive and Negative Syndrome Scale (PANSS)
   * Unmedicated or on any combination (except antidepressant monotherapy) of anxiolytics (benzodiazepines, buspirone, pregabalin, hydroxyzine) as needed, and/or atypical antipsychotics, and/or lithium, and/or other mood stabilizers, and/or non-SNRI antidepressants and/or non benzodiazepine hypnotics taken for \>2 months, as these are commonly-prescribed medications for BD
3. Participants without Bipolar Disorder

   * No present or lifetime history of BD or psychiatric disorder other than anxiety or non BD mood disorders
   * Not in a current depressive episode
   * No family history of BD

Exclusion Criteria:

1. All participants

   * History of head injury, neurological, pervasive developmental disorder (e.g. autism), systemic medical disease and treatment (medical records, participant report)
   * Family history of epilepsy (TBS exclusion criterion)
   * Use of substances with seizure risk (e.g., stimulants) in the past month, assessed as at screening, baseline, and before each fMRI-cTBS-fMRI session
   * Mini-Mental State Examination score (cognitive state) \<24
   * Premorbid National Adult Reading Test Intelligent Quotient estimate\<85
   * Visual disturbance: \<20/40 Snellen visual acuity
   * Left/mixed handedness
   * History of alcohol/substance use disorder (SUD; all substances, including nicotine), and/or illicit substance use (except cannabis) over the last 6 months (SCID-5). Note: lifetime/present cannabis use (at non-abuse (\<3 times in the past month) and non SUD levels) will be allowed, given its common usage in BD and young adults. Cannabis SUD over the last 6 months will not be allowed. Urine tests on scan days will exclude current illicit substance use (except cannabis). Salivary alcohol tests on scan days will exclude intoxicated individuals
   * Binge drinking in the week before, and/or \>3 units/day for the 3 days before, and/or alcohol in the last 12 hrs before, any cTBS scan day, confirmed at screening and scan days (to avoid TBS during alcohol withdrawal). Alcohol/nicotine/ caffeine/cannabis use (below SCID-5 SUD, binge levels) will be allowed, and used as covariates
   * MRI exclusion criteria: metallic objects, e.g., surgical implants; claustrophobia; proneness; positive pregnancy test for females (performed at the MRRC) or self-report pregnancy
   * Inability to understand English
   * \<18 years of age or \>35 year of age

     * SNRI antidepressants and bupropion will not be allowed, as they can elevate seizure risk, a contraindication for TBS
     * Scoring greater than or equal to 8 on HRSD and in depressive episode is confirmed on SCID-5 at screen visit
     * Scoring greater than or equal to 18 on HRSD at any visit
     * In current depressive episode
2. Participants with Bipolar Disorder

   * BD diagnosis other than BDI/II
   * More severe hypo/mania (YMRS\>15)
   * Psychosis
   * Using psychotropic medications other than those allowed in inclusion criteria
3. Participants without Bipolar Disorder

   * Present/ lifetime history of any psychiatric disorder other than anxiety and non BD mood disorders
   * Family history of of BD