Models of Auditory Hallucination

Yale University

Status: Terminated

Conditions: Schizophrenia; Schizo Affective Disorder; Auditory Hallucination

Treatments: Device: Transcranial Magnetic Stimulation (TMS)

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT04210557

2000023640

1R21MH116258-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

The purpose of this study is to address the shortcoming in clinical hallucination research by causally manipulating the neural loci of conditioned hallucination task behavior in-person in patients with psychosis using transcranial magnetic stimulation (TMS), tracking the impact of this manipulation on the number of times participants with hallucinations report hearing tones that were not presented. With such a causal intervention, the veracity of this explanation of hallucinations will be either validated or disconfirmed. If validated, the task can be further developed as a biomarker for predicting the hallucination onset, guiding, developing or tracking the effects of treatments for hallucinations.

Full description

Hallucinations are percepts without stimulus. 70% of patients with schizophrenia suffer distressing auditory hallucinations. Their mere presence increases the risk of suicide. Most reach remission with D2 dopamine receptor blocking drugs after 1 year of adherence. However, 30% of patients have intractable hallucinations, and 50% are non-adherent to their medications, commonly because of unfavorable side-effects - those intractable and non-adherent patients continue to suffer. There is a clear need for a mechanistic understanding of hallucinations as a prelude to rational treatment design.

This study provides the initial steps towards the development of an interventional biomarker for clinical hallucinations, grounded in computational neuroscience.

Computational psychiatry involves harnessing the power of computational neuroscience to address the clinical needs of those suffering from serious mental illnesses. There has been much discussion of the promise of the approach. There have been few studies thus far and they have largely involved correlative methods like functional neuroimaging. This study will address this shortcoming by causally manipulating the neural loci of computational model parameters in-person in patients with psychosis using transcranial magnetic stimulation (TMS), tracking the impact of this manipulation on behavioral task performance . With such a causal intervention, the veracity of the model's explanation of hallucinations will be either validated or disconfirmed. If validated, the model can be further developed as a biomarker for predicting the hallucination onset, guiding, developing or tracking the effects of treatments for hallucinations. If disconfirmed, the model ought to be discarded and other alternatives should be pursued.

Enrollment: 1 patient

Sex: All

Ages: 18 to 45 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Aged 18 - 45 years
• Voice hearing patients
• Meet diagnostic criteria for DSM-V schizophrenia or schizophreniform disorder
• Report hearing voices at least once a day
• Score > 3 on PANSS P3 (hallucinations item)

Exclusion criteria

• DSM-V substance use disorder within the past 6 months

• Previous head injury with neurological symptoms and/or unconsciousness

• Intellectual disability (IQ < 70)

• Non-English speaker

• Contraindications for TMS, including:

  • History of seizures
  • Metallic implants
  • Pacemaker
  • Pregnancy

• Less than 6 weeks of a stable dose of psychotropic medication(s)

• Comorbid mood or anxiety diagnosis

• Clinically/behaviorally instability and unable to cooperate with TMS procedures

• Clinically significant medical condition(s)

• Unstable medical condition(s) based on EKG, medical history, physical examination, and routine lab work

• Personal history of stroke

• Family history of seizures

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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1 participants in 2 patient groups

TMS to insula

Active Comparator group

Description:

This study will recruit 30 clinical voice hearers (P+H+). They will complete two parallel forms of the conditioned hallucinations task (with different visual and auditory stimuli) on two occasions, separated by a week. TMS and sham will be delivered in a randomized counterbalanced order. Hypothesis: Inhibiting the insula will decrease prior over-weighting. If this computational perturbation is responsible for conditioned hallucinations, then ameliorating it with TMS that increases insula engagement will decrease conditioned hallucination responses. Furthermore, the prior weighting parameter will be reduced following active TMS compared with sham.

Treatment:

Device: Transcranial Magnetic Stimulation (TMS)

TMS to cerebellum

Active Comparator group

Description:

This study will recruit a further 70 clinical voice hearers. Again, they will complete parallel forms of the conditioned hallucinations task on two occasions, separated by a week. They will receive excitatory TMS over the cerebellum (and sham on the other occasion, in a randomized counterbalanced order). Hypotheses: Exciting the cerebellum will increase belief-updating. If poor belief-updating contributes to conditioned hallucinations, increasing cerebellum engagement should decrease conditioned hallucinations and alter the belief-updating model parameter compared with sham TMS.

Treatment:

Device: Transcranial Magnetic Stimulation (TMS)