The Effect of Repetitive Transcranial Magnetic Stimulation (rTMS) on Working Memory
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional

Summary: 
      Deficits in working memory (WM) performance are the most significant cognitive impairments in
      schizophrenia (SCZ). It has also been shown that WM performance is contingent on the cortex
      synchronization, a process that relies on brain inhibition. Repetitive Transcranial Magnetic
      Stimulation (rTMS) has been demonstrated as an effective treatment for patients with SCZ and
      has been shown to increase brain inhibition and improve cognitive performance. In this study
      the investigators intend to:

        -  evaluate rTMS as a treatment for WM deficits in SCZ

        -  evaluate rTMS as a method to increase WM performance in healthy individuals

        -  determine if improvements in WM performance are related to enhanced synchronization of
           brain networks

        -  determine whether genetic polymorphisms predict cortical function and treatment response

        -  evaluate the influence of rTMS treatment on brain structure.
    

Detailed description: 
      To directly investigate whether enhanced gamma synchrony mediates rTMS enhancement of WM in
      patients with SCZ, and in healthy individuals the investigators propose the following study.
      The relationship between the improvements in WM performance and increased gamma synchrony
      following rTMS over the DLPFC will be investigated. Moreover, using statistical models, the
      investigators will further examine whether increased gamma synchrony mediates WM improvement
      in these patients. Therefore, in this study the investigators hope to clarify the
      neurophysiological mechanisms through which rTMS exerts its therapeutic effects on WM
      performance and develop rTMS as a novel therapeutic tool to enhance the treatment options
      available for one of the core cognitive deficits in this disorder.

      There is considerable evidence to support the fact that WM deficits in schizophrenia are
      heritable and have a strong genetic component. This evidence emerges from genetic association
      studies, and studies demonstrating that unaffected relatives of schizophrenia patients also
      suffer WM deficits. Therefore, treatment response to rTMS may be at least partly contingent
      on genetic variation within each individual. In particular, GABAergic genes that code for
      GABAergic proteins which largely determine cortical inhibition may play a key role in
      treatment response to rTMS over the DLPFC. However, several other gene systems that interact
      with the GABAergic system may also play a role, and would also merit investigation. Similarly
      brain structure may also determine treatment response. For instance, volume or thickness of
      the DLPFC and DLPFC related circuitry has been shown to play a role in WM performance, and
      therefore, may be a biomarker of treatment response.

      Objective 1: To improve WM in patients with SCZ, and in healthy individuals using rTMS.

      Hypothesis 1:20 Hz rTMS over the DLPFC will be superior to sham stimulation in improving WM
      performance in patients with SCZ, and healthy individuals.

      Objective 2: To evaluate if high frequency rTMS results in enhanced gamma synchrony SCZ and
      healthy individuals.

      Hypothesis 2: 20 Hz rTMS over the DLPRC will be superior to sham stimulation at increasing
      gamma synchrony in patients with SCZ, and healthy individuals.

      Objective 3: To determine if the rTMS induced increase in gamma band synchrony mediates the
      therapeutic effects of rTMS on WM performance in patients with SCZ and healthy individuals.

      Hypothesis 3: Increased gamma band synchrony will be shown to mediate the therapeutic effects
      of rTMS on WM performance in SCZ and healthy individuals.

      Objective 4: To test whether key polymorphisms in the GABAergic system, and related gene
      systems determine γ oscillatory activity and WM improvement following rTMS.

      Hypothesis 4: GABAergic gene and related gene polymorphisms will determine variation in γ
      oscillatory activity and WM performance following rTMS treatment.

      Objective 5: To examine whether brain structure is a biomarker of treatment response to rTMS
      Hypothesis 5: Increase in cortical thickness at DLPFC and in microstructural integrity in
      cortico-cortical white matter tracts connecting to DLPFC will correlate with n-back task
      performance after rTMS treatment.
    

Intervention name(s): repetitive Transcranial Magnetic Stimulation
Intervention type(s): Device
Intervention description(s): Magnetic pulses to specified brain regions.
Other intervention name(s): MagPro X100 Series (Medtronic A/S, Copenhagen, Denmark)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: working memory; schizophrenia; cognition; rTMS