San Francisco,
California
94121
Purpose:
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.
Study summary:
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.
Criteria:
Inclusion Criteria:
- all participants 18-65 years Normal (or corrected to normal) vision
- participants with MDD
- Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria
for MDD
- Safety screened for TMS and MRI safety
- 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