Depression is a leading cause of morbidity and mortality, conferring substantial healthcare and societal costs. By studying methods to non-invasively target neural circuitry involved in reward responsivity, information generated by this project will improve understanding of the circuit alterations that underlie motivation and pleasure deficits in depression, and could also lead to the development of biologically-based markers of neurostimulation-based treatment response.

Rewards play a central role in driving behavior. Reward system dysfunctions are increasingly conceptualized as transdiagnostic phenomena, relevant to many psychopathologies. The opportunity to directly modulate reward processing through targeted intervention could have broad mechanistic and clinical value in psychiatry, both for disorders in which reward-responsive circuits are overactive or underactive. The overarching goal of this proposal focuses on one such opportunity in individuals with depression: the investigators will evaluate whether an electrophysiological measure of reward consummation, the Reward Positivity (RewP), which is consistently blunted in depression, can be moved by targeted neurostimulation of a prefrontal-striatal reward circuit.

The premise of the proposed work is a well-developed empirical literature that substantiates the RewP as a measure of subjective reward valuation, with depression-associated blunting of the RewP likely reflecting attenuated reward consummation. Non-invasive brain stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), modulate cortical activity and offer novel avenues to probe reward circuitry. Previous research establishes that excitation of a fronto-cingulate reward circuit with rTMS increases RewP magnitude in nicotine addiction, but the extent to which blunted RewP in depression can be rescued via rTMS is unknown.

The investigators therefore propose pilot research to begin to address this literature gap via a repeated-measures study that uses a multi-measure approach to probe reward system functioning under passive and performance-dependent reward conditions. The investigators will examine sham-controlled effects of single session intermittent theta burst stimulation (iTBS) to a dorsomedial prefrontal/anterior cingulate cortex (dmPFC/dACC) target in individuals with major depressive disorder (MDD). The investigators will examine iTBS effects on anticipatory and later consummatory reward measures in addition to our primary focus on the RewP, thus capitalizing on the temporal precision EEG affords by decomposing reward processing into subcomponent processes and examining their differential sensitivity to neurostimulation.

Specific Aim 1 examines case-control RewP differences before stimulation, and changes in RewP magnitude as a function of iTBS in MDD.

Specific Aim 2 examines case-control and within-group MDD iTBS effects on a later-stage consummatory reward measure, the late positive potential (LPP).

Specific Aim 3 examines case-control and within-group MDD iTBS effects on reward anticipation.

Our approach is innovative because i) there is little precedent for using the well-validated RewP or similar measures as indices of rTMS modulation, despite putative hypofunction of reward circuitry in MDD and ii) the investigators target a region strongly implicated in depressive pathophysiology but distinct from the Food and Drug Administration-approved dorsolateral prefrontal rTMS target for depression and ii). Here, the investigators evaluate measures tapping reward anticipation and consummation to assay positive valence system functioning in response to iTBS, setting the stage for future biomarker validation and full-course rTMS clinical trials.

• Our studies require some in-person visits to our research lab, located at 42nd Ave and Clement St in San Francisco.

Inclusion Criteria:

• All participants

  • 18-65 years old
  • Normal (or corrected to normal) vision

• Participants with MDD

  • Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for MDD
  • Screened for TMS and MRI safety
  • On a stable psychiatric medication regime for > 1 month

Exclusion Criteria (all participants):

• Premorbid IQ estimate < 70
• Past or present neurological problems (including seizures and head trauma resulting in neurological or cognitive sequelae)
• Loss of consciousness > 30 minutes or any loss of consciousness with neurological sequelae
• Major medical conditions (e.g., seizure disorders, treatment with anticonvulsant medication, endocrine disorders, significant cardiac pathology), or other physical conditions if they preclude participation in EEG, TMS, or MRI protocols (e.g. peripheral nerve damage, limb paralysis etc.)
• Substance dependence, within the past year, current (past 3 months) substance misuse, or failed urine toxicology on the day of neuroimaging sessions
• Known claustrophobia
• Pregnancy (a pregnancy urine test will be conducted to rule-out pregnancy)

Exclusion criteria (Participants with MDD only)

• Past or present DSM-5 (SCID-5) 'Schizophrenia Spectrum or Other Psychotic Disorder' diagnosis
• Past or present DSM-5 (SCID-5) Bipolar and Related Disorders Diagnosis
• Past or present DSM-5 (SCID-5) MDD with psychotic features (mood congruent or mood incongruent)
• Past or present DSM-5 (SCID-5) Gambling Disorder

Exclusion Criteria (HCs only)

• DSM-5 (SCID-5) criteria for any psychiatric disorder