Paired Associative Stimulation in the Dorsolateral Prefrontal Cortex in Patients With Schizophrenia

NCT ID: NCT01545999

Last Updated: 2025-02-24

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 72 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-03-31
• Study Completion Date: 2025-12-31

Brief Summary

The purpose of this study is to

1. assess the effect of PAS in schizophrenia in the dorsolateral prefrontal cortex (DLPFC)

2. assess the effect of PAS induced long-term potentiation (LTP) on the performance of patients with schizophrenia on a cognitive task related to DLFPC.

Detailed Description

Neuroplasticity refers to changes in the strength of communication between different neurons. Long-term potentiation (LTP) is one form of neuroplasticity and refers to the strengthening of such communication. LTP is believed to be a cellular substrate of learning and memory. Paired associative stimulation (PAS) is a transcranial magnetic stimulation (TMS) paradigm that is believed to induce LTP in human subjects. However, its effects have been shown to be minimal in patients with schizophrenia suggesting impaired LTP in schizophrenia. The lack of PAS effect in schizophrenia has been observed in the motor cortex (M1). Thus, the investigators propose to assess the effect of PAS in schizophrenia in the dorsolateral prefrontal cortex (DLPFC), an area of the brain that is especially relevant to learning and memory, and to the pathology in schizophrenia. The investigators also propose to assess the effect of PAS induced LTP on the performance of patients with schizophrenia on a cognitive task that is related to DLFPC.

Hypothesis 1: Patients with schizophrenia will have reduced PAS-LTP in DLPFC in comparison with healthy controls.

Hypothesis 2a: PAS-LTP in patients with schizophrenia and healthy controls randomized to PAS-25 and PAS-100 will correlate with performance on the N-back task at baseline (pre-PAS).

Hypothesis 2b: Healthy controls randomized to PAS-25 will perform better after one session of PAS-25 on the 1- and 7-day N-back task compared to healthy controls randomized to PAS-100.

Hypothesis 2c: Among healthy controls randomized to PAS-25, the magnitude of improvement on the 1- and 7-day N-back task (compared to pre-PAS) that is in excess of the magnitude of improvement on the 1- and 7-day N-back task among subjects randomized to PAS-100 will correlate with the degree of PAS-LTP.

Hypothesis 3a: Patients with schizophrenia who are randomized to receive a 2-week course of PAS-25 will have improved PAS-LTP in DLPFC compared to patients with schizophrenia randomized to 2-week course of PAS-100.

Hypothesis 3b: Patients with schizophrenia who are randomized to receive a 2-week course of PAS-25 will have improved performance on the N-back working memory task compared to patients with schizophrenia randomized to 2-week PAS-100 at 1- and 7-day post-PAS course N-back.

Hypothesis 3c: Patients with schizophrenia who are randomized to receive a 2-week course of PAS-25 will have increased DLPFC cortical thickness compared to patients with schizophrenia randomized to 2-week PAS-100.

Hypothesis 4: Among patients with schizophrenia and healthy controls, PAS-LTP will decrease with age, and the decrease will be more pronounced in healthy controls than in patients.

Conditions

Schizophrenia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

PAS 25

In humans, paired associative stimulation (PAS-25) is a transcranial magnetic stimulation (TMS) protocol that has been shown to result in LTP-like plasticity (PAS-LTP) in the motor cortex (M1). PAS-LTP has been shown to be dependent on the NMDAR and to correlate significantly with performance on a motor learning task.

Group Type: ACTIVE_COMPARATOR

Brain Stimulation via Transcranial Magnetic Stimulation

Intervention Type: OTHER

PAS-25 will consist of 180 PNS delivered to right median nerve, each paired with a single TMS pulse delivered over left DLPFC with an interstimulus interval of 25 ms. This ISI was designed to generate approximately synchronous arrival of both inputs in M1 and was reported to markedly enhance TMS-induced MEP following PAS-25.

Patients with schizophrenia will be asked to continue with a 2-week course (5 days/week) of daily PAS-25 or PAS-100 to assess potential of a repetitive course of PAS-25 on enhancing working memory in patients with Schizophrenia. One and seven days after the 2-week course PAS-25 or PAS-100, patients with schizophrenia will be assessed with the N-back task.

PAS 100

To control for non-specific effects of PAS protocol, the investigators will use a modified PAS protocol (PAS-100) that does not result in any neurophysiologic effects. Patients with schizophrenia and healthy controls will be assessed first with the N-back task and then randomized

Group Type: SHAM_COMPARATOR

Brain Stimulation via Transcranial Magnetic Stimulation

Intervention Type: OTHER

PAS-25 will consist of 180 PNS delivered to right median nerve, each paired with a single TMS pulse delivered over left DLPFC with an interstimulus interval of 25 ms. This ISI was designed to generate approximately synchronous arrival of both inputs in M1 and was reported to markedly enhance TMS-induced MEP following PAS-25.

Patients with schizophrenia will be asked to continue with a 2-week course (5 days/week) of daily PAS-25 or PAS-100 to assess potential of a repetitive course of PAS-25 on enhancing working memory in patients with Schizophrenia. One and seven days after the 2-week course PAS-25 or PAS-100, patients with schizophrenia will be assessed with the N-back task.

Interventions

Brain Stimulation via Transcranial Magnetic Stimulation

PAS-25 will consist of 180 PNS delivered to right median nerve, each paired with a single TMS pulse delivered over left DLPFC with an interstimulus interval of 25 ms. This ISI was designed to generate approximately synchronous arrival of both inputs in M1 and was reported to markedly enhance TMS-induced MEP following PAS-25.

Patients with schizophrenia will be asked to continue with a 2-week course (5 days/week) of daily PAS-25 or PAS-100 to assess potential of a repetitive course of PAS-25 on enhancing working memory in patients with Schizophrenia. One and seven days after the 2-week course PAS-25 or PAS-100, patients with schizophrenia will be assessed with the N-back task.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Age 18 or above
• All races and ethnicities.
• Females and males.
• Meet DSM-IV TR criteria for a current diagnosis of schizophrenia or schizoaffective disorder.
• Clinically stable as operationalized by (1) either having not been hospitalized within 3 months or having been hospitalized for 3 months or more prior to assessment, and (2) having had no change in antipsychotic medication dosage within the 4 weeks prior to assessment.
• Willingness and ability to speak English
• Willingness to provide informed consent
• Corrected visual ability that enables reading of newspaper headlines and corrected hearing capacity that is adequate to respond to a raised conversational voice.

• Age 18 or above
• Willingness and ability to speak English
• Willingness to provide informed consent
• Corrected visual ability that enables reading of newspaper headlines and corrected hearing capacity that is adequate to respond to a raised conversational voice.

Exclusion Criteria

• Meets criteria for a cognitive disorder secondary to a neurological or other medical disorder affecting the central nervous system (for example, multiple sclerosis, history of traumatic brain injury, stroke, untreated hypothyroidism).
• Mini Mental Status Examination score of 17 and less because a subject with a very low MMSE score is unlikely to be able to compete the NP battery.
• Diagnosis of bipolar disorder or current major depressive episode.
• Meets diagnostic criteria for current alcohol or other drug dependence within 6 months of testing
• Electroconvulsive Therapy (ECT) within 6 months of testing.
• Left handedness.
• Incompetency to consent

• DSM IV TR psychiatric diagnosis except for simple phobias or an adjustment disorder.
• Other neurological disorder affecting central nervous system.
• Psychotropic medication except for sedative /hypnotics at a stable dose for at least 4 weeks.
• Family history of a primary psychotic disorder in a first-degree relative.
• Left handedness.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

National Alliance for Research on Schizophrenia and Depression

OTHER

Sponsor Role: collaborator

Centre for Addiction and Mental Health

OTHER

Sponsor Role: lead

Responsible Party

Tarek Rajji

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tarek K Rajji, MD

Role: PRINCIPAL_INVESTIGATOR

Centre for Addiction and Mental Health

Locations

Centre for Addiction and Mental Health

Toronto, Ontario, Canada

Countries

Canada

Related Links

http://www.camh.net/research

Information about research at the Centre for Addiction and Mental Health, Canada's largest mental health and addiction teaching

Other Identifiers

#165/2009-04

Identifier Type: -

Identifier Source: org_study_id