Rapid Entrainment and Signal-guided Neuromodulation for Behavioral Health

Rapid Entrainment and Signal-guided Neuromodulation for Behavioral Health: A Transdiagnostic, Personalized Neuromodulation and Neuroimmune Study to Develop Objective Endpoints and Risk/Durability Profiles for Rapid-Acting Interventions (RESYNC-BH)

RESYNC-BH is a research study testing a personalized, non-drug brain-and-body treatment program for adults with ongoing behavioral health symptoms such as depression, anxiety, trauma-related symptoms, sleep problems, attention difficulties, or substance-use concerns. Rather than treating participants only according to a psychiatric diagnosis, the study assigns them to one of several treatment approaches based on their symptoms, physiologic measures, and clinical presentation. Treatment may include noninvasive brain or nerve stimulation, light, sound, vibration, regulated breathing, and AIP-informed integrative psychotherapy.

The study has two main purposes. First, investigators want to determine whether these personalized treatment combinations can produce rapid and lasting improvements in symptoms, daily functioning, and maladaptive patterns such as avoidance, hypervigilance, rumination, craving, or emotional shutdown. Second, investigators want to identify objective changes in the brain and body that occur before, during, and after treatment. These measures include brain activity, heart rate and heart rate variability, other physiologic signals, cognitive measures, blood biomarkers, and standardized behavioral health questionnaires.

The study hypothesis is that meaningful behavioral health improvement is accompanied by measurable changes in brain, body, and behavioral signals, and that early changes in these signals can help predict which treatment approach is most appropriate for an individual, whether treatment is working, whether a person is becoming less stable, and whether improvement is likely to last. The long-term goal is to develop more objective and personalized ways to monitor behavioral health treatment response rather than relying only on symptoms reported at occasional clinic visits.

RESYNC-BH is a prospective, adaptive, transdiagnostic behavioral health study evaluating a personalized intervention platform called PRESET-Rx. The study is designed to characterize rapid changes in brain, body, and behavioral state and to determine whether early multimodal changes can be used to improve treatment matching, identify risk of destabilization, and predict durability of benefit.

PRESET-Rx combines a standardized psychotherapeutic framework with noninvasive state-modulation approaches selected according to the participant's baseline symptom pattern, physiologic profile, and clinical presentation. Participants are assigned to one of four predefined intervention stacks. The stacks emphasize different mechanisms, including autonomic regulation, multisensory entrainment, cortical neuromodulation, or AIP-informed integrative psychotherapy with minimal or no active neuromodulation. Initial assignment is constrained to the two stacks judged most appropriate for the participant's baseline profile, with randomization between those options. Participants who do not show adequate response may be reassigned at prespecified decision points according to safety and response criteria.

All intervention stacks use a structured session arc that includes preparation and stabilization, state-modulation when indicated, AIP-informed integrative psychotherapy, and integration. Study interventions may include transcutaneous auricular vagus nerve stimulation, low-intensity transcranial electrical stimulation, regulated breathing, patterned light and sound stimulation, vibroacoustic stimulation, and related noninvasive techniques. AIP-informed integrative psychotherapy serves as the common therapeutic framework across the intervention stacks.

The study uses dense multimodal measurement to characterize changes that occur both within individual sessions and across the treatment course. Neurophysiologic and physiologic measures may include EEG, quantitative EEG, fNIRS, heart rate and heart rate variability, respiration, electrodermal activity, and other noninvasive measures. Selected sessions also include simultaneous measurement of the participant and clinician to examine therapeutic dyad dynamics such as physiologic and neural synchrony. Additional exploratory measures may include eye tracking, audiovisual interaction analysis, and environmental measures.

Participants may also contribute digital data from compatible personal wearable devices, such as watches or rings, to provide information about sleep, activity, and related physiologic patterns outside the clinic. Participation in wearable data collection is optional. Blood samples are collected at selected time points to evaluate inflammatory or related biomarkers associated with stress, autonomic regulation, and neurobiological state.

The intervention is delivered during an acute treatment phase of approximately six structured sessions over about 4-6 weeks, with flexibility based on scheduling and clinical stability. Participants are then followed longitudinally to evaluate the persistence of observed changes.

Some participants may independently receive ketamine as part of routine clinical care from a treating clinician. Ketamine is not a study intervention and is not assigned, initiated, scheduled, administered or modified by the study. When ketamine exposure occurs, it is recorded as a concomitant clinical treatment and may be included as a covariate in study analyses.

Inclusion Criteria:

• Age 18 to 70 years at the time of consent
• Able to understand the study and provide signed informed consent
• Willing and able to comply with study procedures and follow-up assessments for approximately 12 months
• Presence of clinically significant behavioral-health symptoms and/or functional impairment in at least one of the following domains, as determined by clinical interview and standardized measures:
• Depressive symptoms
• Anxiety symptoms
• Trauma- and stressor-related symptoms
• Substance-related symptoms not requiring immediate detoxification
• Attentional/impulsivity or executive-function symptoms
• A formal DSM-5 diagnosis is not required if symptoms and impairment are clinically meaningful and appropriate for outpatient behavioral-health intervention
• Medically stable, in the judgment of the investigator, for outpatient behavioral-health treatment and applicable noninvasive neuromodulation or multisensory entrainment
• If taking psychotropic or other relevant medications, on a stable dose for at least 4 weeks before baseline, with no planned changes during the acute intervention phase except as clinically necessary
• Sufficient proficiency in English or another IRB-approved language to understand study procedures and provide informed consent, with approved translated materials or interpreter support when available
• If of reproductive potential, agrees to applicable pregnancy-prevention requirements during the acute intervention phase
• Willing to follow study lifestyle and safety requirements, including restrictions on alcohol and substance use before study sessions and applicable post-session safety recommendations

Exclusion Criteria:

• History of seizure disorder or other condition that, in the investigator's judgment, would make exposure to stroboscopic or patterned light stimulation unsafe

• Severe photosensitivity or light sensitivity that could be worsened by exposure to flashing or patterned light

• Implanted electronic or other medical device that is incompatible with study neuromodulation procedures

• Unstable or clinically significant cardiovascular, neurologic, or other medical condition that could make study participation unsafe

• Unstable or high-risk psychiatric condition, including:

  • Recent suicide attempt or current imminent suicide risk
  • Active psychosis
  • Uncontrolled mania or other acute psychiatric instability requiring a higher level of care

• Pregnant or breastfeeding at screening or during participation

• Acute intoxication or inability/unwillingness to comply with study safety restrictions regarding alcohol or non-prescribed/recreational substance use before study sessions

• Unstable or rapidly changing psychotropic medication regimen at baseline

• Concurrent participation in another interventional trial targeting behavioral health or neuromodulation that, in the investigator's judgment, would confound study outcomes or create a safety concern

• Any other medical, psychiatric, cognitive, or behavioral condition that, in the investigator's judgment, would prevent safe participation or meaningful completion of study procedures