Deep rTMS Modulating Insula Synaptic Density and Smoking Behavior in Schizophrenia

Study Overview
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Brief Summary
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Purpose of the study: Evaluate the effect of deep repetitive transcranial magnetic stimulation (deep rTMS; hereafter abbreviated as dTMS) on synaptic density measured with positron emission tomography (PET) and the radiotracer [11C]UCB-J. We also seek to link plasticity changes in the regions targeted by the electric field (especially, the insula) to changes in the functioning of insula circuits and behavioral cigarette usage in patients with schizophrenia (SCZ). Importance of the study: This is the first study designed to directly evaluate the mechanism of action (MOA) of dTMS for smoking disruption in patients with SCZ. Patients with SCZ are a vulnerable population in high, immediate need of new smoking therapeutics for reducing premature morbidity and mortality.

Official Title
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Deep rTMS Modulating Insula Synaptic Density and Smoking Behavior in Schizophrenia

Conditions
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Schizophrenia, Smoking Cessation, Tobacco Use

Intervention / Treatment
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* Device: Active deep transcranial magnetic stimulation (dTMS)
* Device: Sham dTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 18-60 DSM-5 criteria for schizophreniform, schizophrenia, schizoaffective disorder, or psychotic disorder not otherwise specified (NOS). DSM-5 diagnosis of nicotine use disorder with current daily smoking, and a desire to cut down or quit. Negative urine toxicology (other than cannabis) maintained throughout study participation Fluent English Speaker Capacity for informed consent Exclusion Criteria: Clinically significant psychopathology other than schizophrenia, schizophreniform, schizoaffective disorder, or psychotic disorder NOS Current or past substance use disorder, except TUD Current use of smoking cessation medications/products Change in schizophrenia medication within 4 weeks Hospitalization in the last 3 months History of suicidal or homicidal tendencies History of epilepsy, stroke, cerebral aneurysm, significant head injury resulting in >10 min loss of consciousness, movement disorder, clinically significant electrolyte abnormalities, or use of clozapine (seizure risks) Pregnancy or lactation (females) Lack of effective birth control (females) Contraindications to MRI or PET Clinical Global Impressions (CGI) rating of 6 (severely ill) or 7 (extremely ill) Prisoners Contraindications to dTMS* The FDA website currently states that the Brainsway device used in this study is contraindicated for patients who have metallic objects or implanted stimulator devices in or near the head, including cochlear implants, deep brain stimulators, vagus nerve stimulators, other implanted electrodes or stimulators, aneurysm clips or coils, stents, bullet fragments, jewelry and hair barrettes. We will monitor the FDA guidelines and implement any changes to the inclusion/exclusion criteria based on their most updated recommendations.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: After enrollment, participants will be randomized between-subjects to active dTMS or sham.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active deep transcranial magnetic stimulation (dTMS)<br>Each treatment consists of 60 trains, each lasting 3 sec and interleaved with a 15 sec delay. The entire treatment is delivered over 20 min. The treatment goes for 5 days/week and for a total of 3 weeks. | Device: Active deep transcranial magnetic stimulation (dTMS)<br>* First, we find the position of the right abductor pollicis brevis (APB) motor cortex, finding the minimal motor threshold (MT) required for its activation, which determines the strength of the pulses. After determining the MT, dTMS stimulation is applied 6 cm anterior to the motor hot spot, at 120% of the MT. The target threshold is built toward gradually. During the first treatment, participants receive stimulation at 100% of the MT. During the second treatment, stimulation intensity increases to 110% of the MT. Beginning at the third treatment and continuing onward, participants receive treatment at 120% of the MT for the course of the treatment.<br>* Other names: repetitive transcranial magnetic stimulation (rTMS);|
| Sham Comparator: Sham<br>Active and sham cards do not differ in appearance, and both coils are enclosed within the same helmet, enabling double-blind administration. The same procedure will be done, the only difference is that the sham card does not deliver any stimulation. | Device: Sham dTMS<br>* Sham group will go through the same procedure. The only difference is that the sham card does not deliver stimulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insula synaptic density | PET with UCB-J will be used to look at synaptic density pre/post intervention | pre/post the treatment course over 3 weeks | 
| Smoking self-administration | Laboratory tobacco self-administration will be examined pre/post the intervention as a measure of smoking vigor | pre/post the treatment course over 3 weeks | 
| Insula-centric functional connectivity | fMRI will be used to look at insula circuit functional connectivity pre/post intervention | pre/post the treatment course over 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptoms of Psychosis | The positive and negative syndrome scale (PANSS) will be used to measure symptoms of schizophrenia | up to 4 times over 3 weeks | 
| Nicotine Craving | Craving will be assessed using two self-report items | post dTMS over 3 weeks | 
| Cigarettes per Day | Timeline Follow-back Calendars will be administered pre-dTMS and post-dTMS | pre/post the treatment course over 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PET, UCB-J, fMRI, Schizophrenia, Smoking Cessation, Tobacco Use