NEURO-COGS: Neurometabolic Mechanisms of Cognitive Training in Schizophrenia

Schizophrenia is associated with cognitive and visual impairments that can persist across the lifespan and are not fully addressed by current antipsychotic treatments. These impairments may be related to disruptions in brain metabolism and excitatory/inhibitory balance. This study is designed to better understand neurochemical and neurophysiological mechanisms of cognitive and visual functioning in schizophrenia and to evaluate whether these mechanisms change following cognitive training.

The study will enroll adults with schizophrenia or schizoaffective disorder and demographically similar healthy control participants. Participants will complete baseline clinical assessments, cognitive and visual tasks, electroencephalography, structural magnetic resonance imaging, and magnetic resonance spectroscopy. Magnetic resonance spectroscopy will be used to measure brain metabolite concentrations, including metabolites related to brain metabolism and excitatory/inhibitory function.

After baseline assessments, participants will be randomly assigned to one of two computerized cognitive training programs: perceptual discrimination training or cognitive control training. Both training programs are delivered through the BrainHQ platform and include approximately 10 hours of training over a 2- to 6-week period. Perceptual discrimination training focuses on visual stimulus discrimination, signal-to-noise resolution, and attentional control. Cognitive control training focuses on maintaining cognitive context in working memory during response selection.

After completing cognitive training, participants will return for follow-up assessments, including repeat clinical assessments, cognitive and visual tasks, EEG, MRI, and magnetic resonance spectroscopy. Participants may also choose to complete an optional extended baseline component with additional baseline scanning visits before cognitive training.

The primary outcomes include behavioral performance on the DPX task variant, EEG variables related to excitatory/inhibitory balance, and magnetic resonance spectroscopy measures of neurometabolite concentrations. Secondary outcomes include symptom and functioning measures such as the Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Scale for the Assessment of Positive Symptoms, World Health Organization Disability Assessment Schedule, and Global Functioning Social/Role scales.

Inclusion criteria

All participants (healthy control and SZ):

• Age: 18-79
• Have given written informed consent
• Be able to read and write in English
• General health status: Participants should be in good general physical health (no major neurological disorder or head injury with prolonged unconsciousness, and no current moderate or severe substance use disorder)
• Geographic location: Minnesota counties that are approximately within 1 hour driving distance to Twin Cities, including, but not limited to, Hennepin, Ramsey, Washington, Anoka, Wright, Carver, Scott, Dakota, Sherburn
• Agree to refrain from using recreational drugs for 1 week prior to each scanning session, including, but not limited to, marijuana

For people with schizophrenia (SZ):

• Current DSM-5 diagnosis of schizophrenia or schizoaffective disorder. Participants should be in stable psychiatric health, evidenced by no suicide attempt or psychiatric hospitalization within the past 1 month. (Initial diagnosis will be assessed using SCID 5 or MINI-7, and confirmation of ongoing SZ status and symptom changes will be monitored at each major timepoint using BPRS.)
• All SZ must have achieved clinical stability, defined as outpatient status for at least one month prior to study participation, plus stable doses of psychiatric medications for at least 1 month prior to study participation (as reported by participants and confirmed via medication list (procured by participants via their own medical or pharmacy records) and/or current pill bottle labels).
• All participants should have symptom ratings below a rating of 7 "extremely severe" on a severity scale of 1-7 on the BPRS and/or below grade 3 on longitudinal assessment defined by (as determined by the PI):

• Grade 1: Worsening of 1 point on any item within each BPRS factor
• Grade 2: Worsening of 2 points on any item within each BPRS factor
• Grade 3: Worsening of 3+ points on any item within each BPRS factor, or a change to a rating of extremely severe
• Grade 4: Suicide attempt with intent to die

Exclusion criteria

Exclusion criteria

for both groups are:

• Presence of major neurological disorder
• Conditions preventing MR scanning or other MRI contraindications:

Implanted devices or ferromagnetic objects, current pregnancy (positive pregnancy test on day of MRI scanning or currently breast-feeding), etc. Significant movement disorders including tardive dyskinesia that could disrupt MRI and MRS recordings. Medically significant condition considered unsuitable for the current study (e.g., epilepsy, etc.)

• Estimated IQ < 70
• Other relevant comorbidity (e.g., epilepsy, developmental disability) or visual impairment
• Presence of current substance use disorder (moderate or severe; excluding caffeine and nicotine), as measured by the MINI-7 or SCID 5 based on DSM-5 criteria.

For healthy controls, additionally:

• Personal or immediate first-degree family history of a psychotic or mood disorder. Specifically, current or past history of meeting DSM-5 criteria for schizophrenia spectrum or other psychotic disorders, or Bipolar I or II Disorder, major depressive disorder, posttraumatic stress disorder, panic disorder, obsessive compulsive disorder, dysthymic disorder. Those with a first or second-degree relative with a current or past history of meeting DSM-5 criteria for schizophrenia or other psychotic disorders or bipolar I or II disorder, because they might have an underlying genetic susceptibility for psychosis symptoms.
• Presence of symptoms of the following DSM-5 disorders (as assessed by the MINI-7 or SCID 5):
• Major Depressive Episode
• Suicidality
• Manic and Hypomanic Episodes
• Panic disorder
• Obsessive-Compulsive Disorder
• Posttraumatic Stress Disorder
• Alcohol Use Disorder
• Substance Use Disorder (Non-Alcoholic)
• Psychotic Disorders and Mood Disorders with Psychotic Features
• Medication or substance induced psychosis
• Major Depressive Disorder (MDD)
• MDD with Psychotic Features
• Bipolar I
• Bipolar II
• Other Specified Bipolar and Related Disorder