PRISM Neurofeedback Training for MDD Anhedonic Patients

During the study, participants will perform the following:

• Complete clinical assessments using questionnaires, an MRI scan, and tasks that probe reward responsivity, learning, and motivation.
• Perform at least 10 sessions but optimally 15 (+/-3) neurofeedback training sessions (performed twice a week on nonconsecutive days for 5-8 weeks).
• Complete the same clinical assessments, post-NF training MRI scan, and tasks same as in the screening/baseline stage.

Researchers will compare the sham and treatment arm to evaluate if the neurofeedback effect reduced MDD symptoms in MDD patients with Anhedonia.

MDD subjects

Inclusion criteria

• Ages 22 to 65
• Any gender and all ethnic/racial origins
• Diagnosis of MDD with Anhedonia, established according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5). MDD diagnosis will be determined via the Structured Clinical Interview for DSM-5 (SCID-V) with ≥17 on the Hamilton Depression Rating Scale (HDRS)-211 and ≥25 on the Snaith-Hamilton Pleasure Scale (SHAPS-C)
• Fluency in written and spoken English
• Ability to give signed, informed consent either written or electronic (via REDCap eConsent)
• Normal or corrected-to-normal vision and hearing
• Ability to adhere to the study schedule

Exclusion criteria

(All Subjects):

Imaging Exclusions 1. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.

• Contraindications to MRI (e.g., metal in the body, claustrophobia). 3. Hairstyles that prevent application of the EEG net (e.g., braids, dreadlocks, cornrows, recently dyed hair) Comorbidity Exclusions

• A history of schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar disorder, delusional disorder, organic mental disorder, severe borderline or antisocial personality disorder, current bulimia nervosa2, current binge eating disorder2, or current anorexia nervosa3.
• Lifetime Diagnosis of autism or intellectual disability at the discretion of the investigator.
• Current primary diagnosis of posttraumatic stress disorder (PTSD), specific phobia, panic disorder, social anxiety disorder, obsessive compulsive disorder, or generalized anxiety disorder; subjects with MDD as a primary diagnosis may be included.
• First-degree relatives with a history of psychotic disorder or psychotic symptoms outside of the context of a mood disorder (i.e., MDD or bipolar disorder)
• Any suicidal behavior in the past 1 year (i.e., actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior) assessed using Columbia -Suicide Severity Rating Scale (C-SSRS) prior to screening and during the screening period.
• Diagnosis for current moderate or severe substance or alcohol use disorder (SUD/AUD) within the past month (as defined in DSM-5-substance use disorder) with the exception of cocaine or stimulant abuse which will lead to an automatic exclusion.

Additional Substance and Drug Use Exclusions

• Any current drug use as assessed by a positive result on urine drug test (covering cocaine, opiates, amphetamines, methamphetamines, phencyclidine, MDMA, benzodiazepines, methadone, oxycodone, tricyclic antidepressants, and barbiturates)

• Allow positive result for cannabinoids if participant verbally confirms they have not used MJ in past 12 hours prior to study visit
• Use of any antibiotics in the 24 hours prior to an MRI scan procedure
• Recent use (within 4 weeks) or any current medication that affects blood flow or blood pressure, or which is vasodilating/vasoconstricting (for participants undergoing neuroimaging) Medical Exclusions

• Any unstable medical condition, as per the clinical judgement of the investigator.

• A history of seizures, at risk for seizure (e.g., history of significant head trauma with loss of consciousness for greater than or equal to 5 minutes or familial or personal history of epilepsy) or have been diagnosed with a seizure disorder.

Treatment Exclusions

• Any prescribed Benzodiazepine which cannot be ceased for the duration of the study (with a washout period of at least 2 weeks prior to the first Prism training session) or which cannot be replaced with short-acting benzodiazepines that are taken only for sleeping during the night at equivalent daily dose of up to 3 mg.
• History of ECT, TMS, or Ketamine in the current Major Depressive Episode (allowable in previous MDEs)
• Completion of two full courses of other therapies within the current episode
• Any psychotropic medication other than a stable dose of antidepressants, e.g., bupropion, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitor (SNRIs), St. John's Wort, or SAMe.
• Any change in - or initiation of - fluoxetine within the past 8 weeks or other SSRIs or SNRIs antidepressants, bupropion, simulants, or other psychiatric medications within the past 4 weeks. At the time of recruitment, patients must have no intention of changing their medication or psychotherapy during the study duration.
• Recent initiation (within the past 2 months) of psychotherapy; continuation of established maintenance supportive therapy will be permitted.
• Enrollment in another therapeutic clinical study at screening or within 2 months prior to screening or intended enrollment within the duration of this study