Auditory Stimulation for Schizophrenia

(RESPITE Trial)

Overseen By Chloe A Huston, MA

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Fabio Ferrarelli

Must be taking: Antipsychotics

Disqualifiers: Intellectual disability, Head injury, Neurological disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 5

Duration: 4 weeks

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores differences in sleep between individuals with certain mental health conditions, such as schizophrenia, and those without. It tests whether playing sounds during deep sleep can enhance brain activity and thinking skills. Participants will receive either real sound stimulation (closed-loop auditory stimulation) or fake sound stimulation (sham auditory stimulation) on different nights. Individuals with schizophrenia or similar conditions who have lived with these conditions for five years or less, as well as healthy individuals without a psychiatric history, may be eligible to join. As an unphased trial, this study provides a unique opportunity to contribute to groundbreaking research on sleep and mental health.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications. However, it mentions that participants with early-course schizophrenia can have a lifetime exposure to antipsychotic medications of up to 5 years, suggesting that continuing current antipsychotic medications might be allowed.

What prior data suggests that auditory stimulation is safe for individuals with schizophrenia?

Research has shown that closed-loop auditory stimulation is generally safe for people with schizophrenia. Studies have found that this method can enhance certain brain activities during sleep without causing major side effects. Participants have tolerated the treatment well, with no reports of serious negative effects. This suggests the treatment is safe for individuals, including those with mental health conditions like schizophrenia. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about auditory stimulation for schizophrenia because it offers a non-invasive approach that could enhance cognitive function and reduce symptoms without the side effects associated with medications like antipsychotics. Unlike typical treatments that primarily target neurotransmitter imbalances, closed-loop auditory stimulation works by synchronizing brain waves, potentially leading to improved brain connectivity and function. This innovative method could provide quicker relief and is particularly appealing for patients looking for alternatives to drug-based therapies.

What evidence suggests that auditory stimulation is effective for schizophrenia?

Research has shown that closed-loop auditory stimulation, which plays sounds during specific sleep stages, might improve sleep quality and brain function in people with schizophrenia. Studies have found that this technique can enhance memory by boosting sleep spindles, brain waves crucial for memory and learning. Early results indicated that patients with schizophrenia who received this treatment had better memory compared to those who did not. In this trial, participants will experience different sequences of sham and active auditory stimulation to evaluate its effects. This method is gaining popularity because it addresses sleep issues common in schizophrenia, potentially leading to better mental health. ^{2 5 6 7 8}

Who Is on the Research Team?

Fabio Ferrarelli, MD, PhD

Principal Investigator

University of Pittsbrugh

Are You a Good Fit for This Trial?

This trial is for individuals aged 18-40 with early-course schizophrenia, schizophreniform, or schizoaffective disorder without a family history of similar conditions. They must have experienced psychosis for ≤5 years and had limited exposure to antipsychotic meds (≤5 years). Healthy controls without psychiatric disorders can also join. Exclusions include pregnancy, inability to consent, intellectual disabilities, significant neurological issues, certain sleep disorders, substance abuse (except cannabis/alcohol), and medical illnesses affecting the brain.

Inclusion Criteria

I have been diagnosed with schizophrenia or a related disorder, without drug causes, and haven't had a psychotic episode before.

My immediate family has no history of schizophrenia or mood disorders with psychosis.

My condition is early-stage schizophrenia.

Exclusion Criteria

Current or past co-morbidity for alcohol or psychoactive substance dependence

Substance abuse other than cannabis and/or alcohol within the past one year

DSM-IV intellectual disability

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants complete clinical evaluation, IQ assessment, and initial sleep EEG recordings

1 week

1 visit (in-person)

Treatment

Participants undergo closed-loop auditory stimulation during sleep across multiple nights

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for changes in sleep spindle and slow wave activity and memory consolidation

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Closed-loop auditory stimulation
• Sham auditory stimulation

Trial Overview The study aims to compare brain activity during sleep between healthy individuals and those with schizophrenia-related diagnoses. It will test if playing tones during deep sleep can improve specific sleep features and cognitive performance in patients. Participants will receive either sham auditory stimulation or closed-loop auditory stimulation as part of the research.

How Is the Trial Designed?

Group I: Experimental: Night three- sham, night four - active Experimental Treatment 2 Interventions

This arm will receive sham auditory stimulation for the first 3 nights and active auditory stimulation for the fourth night. Night one - sham auditory stimulation, night 2 - sham auditory stimulation, night 3 - sham auditory stimulation, night 4 - active auditory stimulation

Group II: Experimental: Night three - active, night four - sham Experimental Treatment 2 Interventions

This arm will receive sham auditory stimulation for the first two nights, active auditory stimulation for the third night, and sham auditory stimulation for the fourth night. Night one - sham auditory stimulation, night two - sham auditory stimulation, night three - active auditory stimulation, night four - sham auditory stimulation

Who Is Running the Clinical Trial?

Fabio Ferrarelli

Lead Sponsor

Trials

2

Recruited

280+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

A randomized-controlled trial involving 144 patients with schizophrenia will test the efficacy of high-frequency transcranial random noise stimulation (hf-tRNS) to alleviate persistent symptoms, with the primary outcome being a 25% reduction in symptoms after 10 sessions.

The study aims to explore not only the clinical effects of hf-tRNS on symptoms like auditory hallucinations but also its impact on brain activity and cognitive functions, potentially establishing it as a new treatment option for patients resistant to traditional antipsychotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examining transcranial random noise stimulation as an add-on treatment for persistent symptoms in schizophrenia (STIM'Zo): a study protocol for a multicentre, double-blind, randomized sham-controlled clinical trial. Brunelin, J., Mondino, M., Haesebaert, J., et al.[2022]

The proposed closed-loop auditory stimulation system, which uses machine learning for real-time sleep stage tracking, effectively regulates sleep by driving EEG slow oscillations in ten subjects, showing immediate modulation effects after stimulation.

This new system demonstrated greater reliability and flexibility compared to existing methods, achieving consistent results across almost all participants in the experiment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A system based on machine learning for improving sleep. Lu, J., Yan, M., Wang, Q., et al.[2023]

In patients with schizophrenia and major depression, higher stimulation frequencies enhanced the amplitude of the N1 auditory evoked potential, indicating altered auditory processing in these conditions.

Schizophrenic patients showed a prolonged latency of the N1 component and P2 latency was also extended in those treated with high-potency neuroleptic drugs, suggesting that medication may affect auditory processing timing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of stimulation parameters on auditory stimulus processing in schizophrenia and major depression: an auditory evoked potential study. Adler, G., Adler, J., Schneck, M., et al.[2019]

In a study involving 18 patients with schizophrenia, real-time auditory stimulation during sleep successfully increased slow wave and sleep spindle activity, similar to responses seen in healthy individuals.

Despite the positive electrophysiological changes, the auditory stimulation did not lead to any improvement in memory performance, indicating that while the approach shows promise, it currently does not enhance memory consolidation in patients with schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Auditory stimulation in-phase with slow oscillations to enhance overnight memory consolidation in patients with schizophrenia? Weinhold, SL., Lechinger, J., Timm, N., et al.[2022]

In a pilot study involving 18 patients with schizophrenia and refractory auditory hallucinations, low-frequency deep transcranial magnetic stimulation (TMS) was administered, but results showed no significant difference in improvement between the active treatment and sham groups.

Despite initial encouraging results, the study concluded that this specific TMS protocol did not have a statistically significant effect on reducing auditory hallucinations or improving other clinical symptoms in the patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep transcranial magnetic stimulation add-on for the treatment of auditory hallucinations: a double-blind study. Rosenberg, O., Gersner, R., Klein, LD., et al.[2022]

Closed-loop auditory stimulation can enhance sleep rhythms, specifically increasing delta, theta, and sigma power during non-rapid eye movement (NREM) sleep, which is crucial for brain recovery and memory consolidation.

The study found that this stimulation specifically improved the coupling between delta and sigma activity in the right parietal area, suggesting a targeted approach to enhance sleep-dependent neuroplasticity in specific brain regions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in cross-frequency coupling following closed-loop auditory stimulation in non-rapid eye movement sleep. Krugliakova, E., Volk, C., Jaramillo, V., et al.[2021]

Transcranial direct current stimulation (tDCS) has shown potential in reducing the severity and frequency of auditory hallucinations in schizophrenia, with three out of six randomized controlled trials reporting therapeutic benefits.

Despite these promising results, the overall evidence is inconclusive and insufficient, as many studies lack large sample sizes, preventing tDCS from being established as a reliable treatment option for auditory hallucinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of transcranial direct current stimulation for the treatment of auditory hallucinations of schizophrenia - a systematic review. Pondé, PH., de Sena, EP., Camprodon, JA., et al.[2020]

A novel auditory closed-loop stimulation technique was successfully used to manipulate theta activity during REM sleep in a study involving 16 healthy young adults, demonstrating the ability to entrain EEG activity to 5 Hz.

The stimulation led to an initial increase in theta power followed by a prolonged suppression, along with an increase in beta power, suggesting potential for further research into the effects of REM sleep on behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase-locked auditory stimulation of theta oscillations during rapid eye movement sleep. Harrington, MO., Ashton, JE., Ngo, HV., et al.[2021]

Auditory closed-loop stimulation effectively enhanced slow oscillatory activity and spindle activity during sleep, as confirmed by the study involving 12 healthy males.

Despite these enhancements, the stimulation did not improve the overnight retention of semantically-incongruent associations, indicating that this method may not be beneficial for all types of memory consolidation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No benefit of auditory closed-loop stimulation on memory for semantically-incongruent associations. Harrington, MO., Ngo, HV., Cairney, SA.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06386588

The Effects of Auditory Stimulation During Sleep on Brain ... Adult participants screened to exclude a personal history of mental illness, family history of schizophrenia spectrum disorder, and psychoactive medication use.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12230793/

Neurophysiological effects of targeting sleep spindles with ... Our results validate the use of closed-loop auditory stimulation ... schizophrenia [6–8]). However, the majority of evidence concerning ...

3. researchgate.net researchgate.net/publication/341683246_0113_Evaluating_Closed-Loop_Auditory_Stimulation_During_Sleep_as_an_Intervention_to_Improve_Memory_Consolidation_Deficits_in_Schizophrenia

0113 Evaluating Closed-Loop Auditory Stimulation During ... If it does, we will test the effects of stimulation on sleep-dependent memory deficits in patients with schizophrenia. Closed-loop auditory stimulation ...

4. mdpi.com mdpi.com/2076-3425/14/11/1138

Closed-Loop Auditory Stimulation (CLAS) During Sleep ... Exclusion criteria included current intoxication or illness at intake or during the study, self-reported chronic brain or mental illness including epilepsy ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/jsr.13636

Auditory stimulation in‐phase with slow oscillations to ... The mean (SEM, range) age was 40.7 (2.2, 23–53) years. In all, 11 patients had paranoid schizophrenia and seven had a schizoaffective psychosis.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11009689/

The effects of closed-loop auditory stimulation on sleep ... In schizophrenia, CLASS increased SO activity and spindle activity that was phase-locked to the SO upstate but failed to improve declarative memory [18]. Both ...

7. academic.oup.com academic.oup.com/sleep/article-abstract/43/Supplement_1/A45/5847500

0113 Evaluating Closed-Loop Auditory Stimulation During ... ... stimulation on sleep-dependent memory deficits in patients with schizophrenia. Closed-loop auditory stimulation shows promise as a safe ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11597015/

Closed‐loop auditory stimulation of slow‐wave sleep in ... Reduced sleep spindle activity in schizophrenia patients. The American Journal of Psychiatry, 164(3), 483–492. 10.1176/ajp.2007.164.3.483 [DOI] [PubMed] ...