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Principal Investigator: Cory R Weissman
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $197,576
Funding agency: National Institute of Mental Health
PROJECT SUMMARY / ABSTRACT
Over 700,000 individuals across the world die by suicide annually. Most individuals who complete suicide suffer
from psychiatric illness, of which major depressive disorder (MDD) is most common. Suicidal ideation (SI) is
more prevalent in individuals with treatment-resistant depression (TRD) compared to those who respond to
treatment. Given treatment limitations of SI in TRD, novel interventions paired with an improved understanding
of the neurobiology of SI are needed. Repetitive transcranial magnetic stimulation (rTMS) is efficacious for TRD.
Evidence suggests that bilateral rTMS (i.e., targeting both the right and left prefrontal cortex) may be more
efficacious for SI in TRD compared to unilateral rTMS, and bilateral brain disturbances are evident from
neuroimaging studies in individuals with SI. Recent advances in rTMS delivery have greatly decreased treatment
duration: accelerated intermittent theta burst stimulation (aiTBS) condenses 6-weeks of standard rTMS into 1-
week. In fact, a unilateral form of aiTBS, the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)
System, was recently approved by the FDA for the treatment of TRD. Given the efficacy of bilateral rTMS for SI,
and recent advances in accelerated treatment paradigms, investigation of bilateral accelerated TBS (aTBS) for
the treatment of SI in TRD is warranted. Compelling evidence suggests that SI in TRD is related to aberrant
cortical inhibition bilaterally in the dorsolateral prefrontal cortex (DLPFC) and that rTMS may modulate inhibitory
neurotransmission. Mechanistically, cortical inhibition is closely associated with γ-aminobutyric acid (GABA)
signaling. Therefore, investigating cortical inhibition in the bilateral DLPFC in conjunction with bilateral aTBS
treatment may be key to understanding treatment response. We propose to use transcranial magnetic stimulation
combined with simultaneous electroencephalography (TMS-EEG) to investigate cortical inhibition as a biological
target of treatment in this study (Aim 1). A randomized double-blind clinical trial will be conducted to test the
hypothesis of superiority of bilateral aTBS to unilateral aiTBS on SI in TRD (Aim 2). Seventy-six participants will
be recruited over 5 years. The applicant serves as Medical Director of the Interventional Psychiatry Program at
UC San Diego Health, and he will facilitate appropriate recruitment of participants into this study. The career
development objectives for the applicant are: 1) develop independence as a clinical trialist with relevant statistical
approaches; 2) gain expertise in the conduct and analysis of TMS-EEG; and 3) establish working knowledge in
MRI functional connectivity analysis to guide future rTMS protocols. The applicant’s primary mentor is the Chair
of the Department of Psychiatry at UCSD, neurophysiology and clinical trial expert, Dr. Jeff Daskalakis. Dr. Greg
Appelbaum, Research Director of the Interventional Psychiatry Program will serve as co-mentor. Notable
consultants include Dr. Yvette Sheline, clinical trials and neuroimaging expert, and Dr. Risto Illmoniemi, pioneer
of TMS-EEG. The applicant will develop the skills and gain necessary experience to become an independent
interventional psychiatry physician scientist, and his work will lead to an enhanced understanding of suicide.
Terms: <21+ years old><4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><Acceleration><Adult><Adult Human><After Care><After-Treatment><Aftercare><Aminalon><Aminalone><Bilateral><Biological><Brain region><Cell Communication and Signaling><Cell Signaling><Cerebral Dominance><Clinical><Clinical Trials><Complex><Department chair><Diagnosis><Disease><Disorder><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Dysfunction><EEG><Electroencephalogram><Electroencephalography><FDA approved><Feeling suicidal><Frameless Stereotaxy><Functional MRI><Functional Magnetic Resonance Imaging><Functional disorder><Future><GABA><Goals><Grant><Health><Healthcare><Individual><Inpatients><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><Knowledge><Left><Link><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Major Depressive Disorder><Measures><Mediating><Medical Directors><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mental disorders><Mental health disorders><Mentors><Modeling><Morbidity><Morbidity - disease rate><NMR Imaging><NMR Tomography><Nerve Impulse Transmission><Nerve Transmission><Neurobiology><Neuronal Transmission><Neuronavigation><Nuclear Magnetic Resonance Imaging><Outcome><Paper><Participant><Patient Care><Patient Care Delivery><Patient Recruitments><Patients><Physician Executives><Physicians><Physiopathology><Placebos><Prefrontal Cortex><Preventative intervention><Protocol><Protocols documentation><Psychiatric Disease><Psychiatric Disorder><Psychiatry><Public Health><Publishing><Randomized><Research><Resistance><Risk Factors><Role><Sampling><Scientist><Sham Treatment><Signal Transduction><Signal Transduction Systems><Signaling><Suicidal thoughts><Suicide><Suicide precaution><Suicide prevention><System><Techniques><Technology><Testing><Therapeutic><Transcranial magnetic stimulation><Treatment Period><Treatment Protocols><Treatment Regimen><Treatment Schedule><Work><Zeugmatography><adulthood><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><axon signaling><axon-glial signaling><axonal signaling><biologic><biological signal transduction><brain laterality><care for patients><care of patients><career development><caring for patients><cerebral lateralization><clinical depression><clinical effect><clinical efficacy><combat><commit suicide><completed suicide><efficacious therapy><efficacious treatment><electric field><experience><fMRI><fatal attempt><fatal suicide><gamma-Aminobutyric Acid><glia signaling><glial signaling><health care><hemispheric specialization><improved><indexing><innovate><innovation><innovative><intent to die><intervention arm><intervention for prevention><interventional strategy><major depression><major depression disorder><mental illness><nerve signaling><neural circuit><neural circuitry><neural control><neural imaging><neural regulation><neural signaling><neuro-imaging><neurobiological><neurocircuitry><neuroimaging><neurological imaging><neuromodulation><neuromodulatory><neuronal signaling><neurophysiological><neurophysiology><neuroregulation><neurotransmission><new approaches><non-invasive brain stimulation><noninvasive brain stimulation><novel><novel approaches><novel strategies><novel strategy><participant recruitment><pathophysiology><post treatment><potential biological marker><potential biomarker><prevent suicidality><prevent suicide><prevention intervention><preventional intervention strategy><preventive intervention><programs><psychiatric illness><psychological disorder><randomisation><randomization><randomly assigned><recruit><reduce suicidality><reduce suicide><reducing suicidality><reducing suicide><repetitive transcranial magnetic stimulation><resistant><response biomarker><response markers><response to therapy><response to treatment><sham therapy><skills><social role><standard care><standard treatment><suicidal><suicidal ideation><suicidal mortality><suicidal thinking><suicidality><suicidality prevention><suicide ideation><suicide intervention><suicide mortality><suicide mortality rate><suicide rate><suicides><synaptic circuit><synaptic circuitry><temporal measurement><temporal resolution><therapeutic response><therapy response><thoughts about suicide><time measurement><tool><treatment arm><treatment days><treatment duration><treatment group><treatment response><treatment responsiveness><treatment-refractory depression><treatment-resistant depression><trend><γ-Aminobutyric Acid>