Spinal interoceptive pathways (SIPs) convey bodily signals to an interoceptive system in the brain and their dysregulation is linked to major depressive disorder (MDD). Current treatments are partially effective and the role of SIPs in MDD is vastly unexplored. Preliminary data suggests that SIPs are feasible therapeutic targets in MDD. The central hypothesis is that non-invasive spinal cord stimulation will modulate SIPs to elucidate their role and therapeutic potential in MDD using an R61/33 phased innovation approach.

R61 phase specific aims (SA). The specific goal will be to evaluate spinal and brain-based SIPs target engagement markers of transcutaneous spinal direct current stimulation (tsDCS) in MDD with two SAs: SA1) To determine tsDCS SIPs modulation using laser-evoked potentials (LEPs) as electroencephalography (EEG)- based neural measures of target engagement. SA2) To evaluate optimal tsDCS dose based upon tolerability and SIPs target engagement markers. Anodal tsDCS will be evaluated as a tool to modulate SIPs in MDD. SIPs (Aδ and C fibers) can be evaluated via LEPs as neural measures (EEG) elicited in MDD-relevant brain regions within an interoceptive system. Prior data shows anodal tsDCS inhibits SIPs and LEPs N2 component will be assessed as tsDCS engagement markers. Adults with MDD (n=67) will participate in a double-blind, crossover, sham-controlled study to evaluate tsDCS at 0,2.5,3, and 3.5 mA. The working hypothesis is that tsDCS will induce a change in LEPs (SA1) in a dose-dependent and tolerable manner (SA2), supporting their use as SIPs engagement markers. Go/No-Go milestones: Compared to sham, the active tsDCS dose that induces a change in LEPs at a preestablished threshold will be evidence of SIPs engagement and "Go" criteria for the R33 phase.

Inclusion Criteria:

• 18 to 60 yrs., inclusive,

• Female or Male,

• With current MDD episode according to MINI 7.0.2. duration (≥4 weeks and

  ≤ 2 yrs.),

• Current BMI ≥18.5 and ≤ 35.99 kg/mts2

• MADRS score at screening ≥18

• Currently on an FDA- approved antidepressant medication at a stable therapeutic dose for ≥ 8 weeks,

• Psychotherapeutic interventions are allowed if dose/frequency stable for ≥4 weeks,

• Anxiety disorders allowed if no more than moderate in severity and are not the main diagnosis,

• Using an effective contraceptive method (participants with childbearing potential), and 10)Able to complete study related tasks.

Exclusion Criteria:

• Treatment resistance during current depressive episode (>2 treatment trials at adequate doses/duration), including medication and neuromodulation treatments.
• Current/lifetime diagnosis of bipolar disorder or schizophrenia spectrum disorders.
• Significant risk of suicide according to CSSRS or clinical judgment, or suicidal behavior in the past year.
• Psychotic symptoms during the current MDD episode or in the past 6 months.
• Current (past month) substance use disorder (nicotine, caffeine allowed).
• Current unstable neurological conditions including seizure disorders (infantile seizures are not exclusionary), neurodegenerative disorders, or stroke.
• Evidence of severe peripheral neuropathy.
• History of moderate to severe traumatic brain injury (e.g., skull fracture or loss of consciousness >10 minutes) or spinal cord injury.
• Unstable clinically significant medical conditions (e.g., uncontrolled hypertension as indicated by a systolic >150 mmHg or diastolic >95mmHg).
• History of cancer allowed if remitted for the past 5 years.
• Use of anticonvulsant medications and calcium channel blockers at screening.
• Current severe pain conditions or need for chronic use of pain medication including NSAIDs and opiates.
• Implanted electronic medical devices.
• Neuromodulation interventions in the past month.
• Active skin lesions on electrode placement sites.
• pregnant or breastfeeding.
• Suspected IQ <80.
• Any other relevant clinical reason as judged by the clinician.

Data will be shared according to NIMH Data sharing plan and uploaded to a data repository.

Upon completion of primary statistical plan and unblinding of data.

Deidentified data will be shared on a biorepository.