The goal of this clinical trial is to learn if training with the Prism system can reduce PTSD symptoms in US military Veterans and civilians with PTSD. Prism is a form of neurofeedback training that uses EEG signals to promote self-regulation of brain function. The main question this study aims to answer is:

Does Prism training lead to decreased PTSD symptoms in US Veterans and civilians when used in addition to usual PTSD treatment?

Researchers will compare Prism training to a sham training (a look-alike training that does not provide real feedback on brain activity) to see if Prism training decreases PTSD symptoms.

Participants will:

• Complete two one-hour in-person training sessions a week for about 8 weeks (15 sessions)
• Complete two booster training sessions one month and two months after finishing the main training course
• Participate in three detailed interviews: one before training, a second after nine weeks of training, and a third one month after the last booster training session (about 20 weeks after the initial visit)

Inclusion Criteria

Subjects must meet the following inclusion criteria:

1. Ages 18 to 65 (older limit to avoid those with potentially reduced brain plasticity due to age);

2. Male, female, and gender-nonconforming subjects will be allowed. Sites will make efforts to enroll both male and female subjects in roughly equal proportions;

3. Diagnosis of PTSD comorbidities will be confirmed by clinical chart review and structured interview with the Diagnostic Interview for Anxiety, Mood, and Obsessive-compulsive and Related Neuropsychiatric Disorders (DIAMOND), a semi-structured diagnostic interview instrument for DSM-5 psychiatric disorders with good test-retest reliability (Tolin et al. 2018);

4. Diagnosis of PTSD based on CAPS-5-R (scored as CAPS-5) total score with a minimum severity score of 26 at Baseline in the CAPS-5 score;

5. 1-26 years from index trauma;

6. Ability to give signed informed consent according to the judgment of the site investigator;

7. Normal or corrected-to-normal vision of at least 20/30 as per eye chart screening;

8. Normal or corrected-to-normal hearing as per subject report and interview with study staff;

9. Willingness and ability to adhere to the study schedule;

10. Comorbid major depression will be allowed as long as the primary care is PTSD, because it is frequently comorbid with PTSD, and its inclusion will render our study results salient to the real-world clinical population;*

11. Any psychotropic medication must have been at a stable dose for at least 4 weeks prior to screening;

12. At the time of recruitment, patients must have no plan of changing their medication or psychotherapy during the study duration if applicable (subjects will only be dropped if significant psychotropic medication changes happen as a result of clinical instability that, in the opinion of the principal investigator (PI), would jeopardize their ability to learn or participate).

    • Note: This is a clarification that comorbid depression is allowed and not an inclusion requirement.

Exclusion Criteria

Potential subjects will be excluded for the following:

1. Completed at least one adequate course of trauma-focused behavioral therapy in the past one (1) year without improvement in PTSD symptoms, as documented in medical records. (Subjects are ineligible if medical records do not show evidence of symptom improvement from the previous trauma focused therapy that had been conducted in the year prior to Screening); Non-response will be determined by clinical judgment and qualitative note content. If PCL-5 or CAPS-5 scores are available within 2 weeks prior to beginning treatment and within 2 weeks post-treatment, an improvement of <10 points in PCL-5 and <10 points in CAPS-5 will be used as a threshold indicating non-response in addition to clinical judgement.

   • Note: This criterion is to avoid treatment resistant patients; such patients will be enrolled in future studies);

2. Lifetime diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar I or II disorder, psychosis not otherwise specified, or delusional disorder;

3. Any Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) Mood or anxiety disorder (in addition to those described in the previous exclusion) that is the primary focus of mental health treatment in the 6 months prior to screening, per the site investigator's clinical judgment;

4. Intellectual disability (known full scale IQ<70) per the site investigator's clinical judgment;

5. DSM-5 diagnosis of moderate or severe substance use disorder within 3 months of screening;

6. Prescribed benzodiazepine which cannot be stopped for the duration of the study (with a washout period of at least 2 weeks prior to the first Prism training session) or replaced with short-acting benzodiazepines taken only at night for sleeping;

7. Any suicidal behavior in the last 6 months (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior) prior to screening and during the screening period and or current (in the last 6 months) significant suicidality (defined as Level 4+ on the C-SSRS) or current significant homicidality;

8. Within 3 months of beginning cognitive behavioral therapy (CBT) or any evidence-based PTSD psychotherapy, although continuing established maintenance supportive therapy will be permitted;

9. Any significant neurological/neurosurgical history, including brain surgery, of penetrating, neurovascular, infectious, or other major brain injury, of epilepsy, or of other major neurological abnormality or known cognitive impairment;

10. A history of moderate or severe traumatic brain injury (TBI) or history of gross structural damage on brain imaging;

11. Any unstable medical condition per the investigator's clinical judgment;

12. Any psychiatric hospitalization within the last 6 months;

13. Enrollment in another interventional clinical study at screening or within 2 months prior to screening, or within the duration of this study;

14. Pregnancy is allowed, but excluded if at week 20 or later in the pregnancy at Baseline because early labor in the late term of the pregnancy would require the subject to withdraw from the study.

15. Acute symptoms of infection with SARS-CoV-2 (COVID-19) at time of screening or 2 months prior to screening as per interview and chart review;

16. Under criminal investigation or pending legal charges with potential incarceration;

17. Individuals who lack stable contact information (including lack of a telephone number);

18. Subjects who anticipate working during the hours of midnight to 6 AM during the study;

19. Subjects with narcolepsy;

20. Subjects who have a Legally Authorized Representative;

21. A positive result on the urine toxicology screen for any illegal substance besides marijuana. * * Note: If urine tests positive for any illegal substance, the results will not be included in the subject's medical record. However, these test results will remain part of the subject's confidential study record.