Approximately one third of individuals with Major Depressive Disorder (MDD) are considered treatment-resistant, subject to severe disability and risk of suicide, and exhibit symptoms anchored in abnormalities of Research Domain Criteria (RDoC) Negative Valence Systems behavioral processes. In the present study we plan to use low-intensity focused ultrasound in 120 persons with treatment-resistant MDD to modulate deep white matter tracts connecting the thalamus and different regions of the prefrontal cortex reversibly and non-invasively, with the aim of assigning a causal, mechanistic role to large scale brain circuits in the production of those critical behavioral abnormalities. A successful study will help to attain the precise definition of neuromodulation targets for this clinical population in utter need of help.
Persons 18-65 years old, with sex and ethnicity recruitment targets including a M:F proportion of 1:2 and White:Black:Hispanic:Native American proportion as close as possible to 8:2:2:1 to reflect the regional epidemiology of TRD (63% White American; 16% African American; 14% Hispanic of any race; 5% Native American),
DSM-5-TR diagnosis of MDD as confirmed by MINI structured interview followed by consultation with a board-certified psychiatrist,
two or more adequate (6 week) trials of antidepressants with different mechanisms,
evidence-based psychotherapy,
Clinical history of at least minor neurocognitive disorder of neurodegenerative origin,
PROMIS (Cognitive Function scale) score ≤40 (i.e., mean - 1SD), collected at baseline
clinical history of relevant structural pathology of the central nervous system, including Parkinson's disease, multiple sclerosis, and brain malignant neoplasia,
uncontrolled diabetes mellitus (as evidenced by a fasting glycemia ≥ 120 mg/dL or hemoglobin A1c ≥ 6.5%) or hypertension (as evidenced by two consecutive readings ≥ 140/90 mmHg) to ensure medical stability, collected at baseline
Crossover
Low-intensity focused ultrasound
Other intervention80-second stimulus with an estimated tissue ISSPA=2.26 W/cm2, with (sham) or without (verum) interposition of Sorbothane film
Post-Sonication Changes in Functional Connectivity
Changes in resting-state functional (fMRI) connectivity (FC) between thalamus and either Anterior Cingulate (ACC) or Orbitofrontal (OFC) cortices after LIFU or Sham stimulation.
Post-Sonication Changes in Reward and Repetitive Mentation
Changes in BOLD activation of either Anterior Cingulate (ACC) or Orbitofrontal Cortex (OFC) during Monetary Incentive Delay and Induced Rumination Tasks corresponding to changes in reward and repetitive thinking, respectively.
Post-Sonication Changes in Functional Connectivity and Anhedonic and Ruminative Symptoms
Changes in functional connectivity of thalamo-frontal and thalamo-anteiror cingulate regions and the correlation to changes in Snaith-Hamilton Pleasure Scale scores (minimum score: 0; maximum score: 14; lower scores mean better outcomes) and Brief State Rumination Inventory Scores (minimum value: 0; maximum value: 25; lower scores mean better outcomes) to evaluate anhedonic and ruminative symptoms respectively.
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