Theta Burst Stimulation for Schizophrenia
Condition: Schizophrenia; Schizoaffective Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Study type: Interventional

Summary: 
      Purpose and objective Schizophrenia is a chronic debilitating illness with cognitive deficits
      that cause serious impairment in psychosocial recovery and with few treatments to remediate
      these deficits. One area that holds great promise for the development of novel, effective
      therapies is noninvasive brain stimulation. The investigators have used one form of brain
      stimulation, transcranial magnetic stimulation (TMS), for some time to modulate and enhance
      cognitive function in the brain, especially working memory (WM) function, which has a central
      role in most executive processing that occurs in the brain. Theta burst stimulation (TBS) is
      a paradigm of TMS which has been shown to effectively modulate WM. Moreover, TBS can modulate
      gamma neural oscillations in the brain and neural activity, both of which have been
      implicated in the physiology of WM and pathophysiology of the disease process in
      schizophrenia, making these measures highly valuable for assessing physiological effects of
      TBS on cognition, quality of life and cortical inhibition. The purpose of this study is to
      evaluate the effect of TBS on WM in patients with schizophrenia, to develop evidence for
      potential brain stimulation techniques to treat cognitive deficits in schizophrenia.

      Study activities and population group: Study subjects will be inpatient schizophrenic
      individuals with minimal positive symptoms and predominant cognitive deficits at Duke
      University Hospital. In an initial session they will be screened and taught a WM task.
      Following this, one TBS session will follow in which TBS will target dorsolateral prefrontal
      cortex. They will perform the WM task before, with and after the TBS, with an expected
      pre-post enhancement of WM performance.

      Implications - There is a great need for treatments for cognitive deficits in schizophrenia.
      The results of this study will serve to generate pilot data for a much larger grant to
      develop a TBS therapy for remediating such cognitive deficits.
    

Detailed description: 
      Purpose of the study Aim1: Evaluate the effect of theta burst stimulation (TBS) on working
      memory (WM) in patients with schizophrenia. Hypothesis 1 - There will be significant
      improvement in WM compared to baseline with one session of TBS.

      Background and Significance Schizophrenia is an illness known to have cognitive deficits,
      with a chronic and variable course. There is extensive research on cognitive deficits, with
      working memory, processing speed and verbal memory being some of the domains affected. Some
      modalities of treatment that have been tried to reverse these cognitive deficits are
      medications and cognitive behavioral therapy with minimal benefits. A few studies have shown
      modulation of working memory with routine repetitive transcranial magnetic stimulation at
      frequencies not exceeding 10 to 20 Hz of stimulation. Other studies have shown the working
      memory to be related to gamma oscillations. A few studies have also shown that transcranial
      magnetic stimulation (TMS) modulates these gamma oscillations as well. There is an extensive
      body of literature that shows that working memory has contributions from theta and gamma
      oscillations in the brain. Theta burst stimulation (TBS) is a form of transcranial magnetic
      stimulation (TMS), that entrains gamma and theta frequencies in the brain. It could be the
      most appropriate form of brain stimulation for improving cognition in schizophrenia patients
      because it has been shown to modulate brain oscillations in small samples of patients. The
      area for targeting would be the dorsolateral prefrontal cortex which is the site of origin of
      the gamma oscillations and plays a significant role in working memory.

      Design and Procedures The study is designed to be a pilot one evaluating the effect of TBS on
      WM in patients with schizophrenia. The investigators plan to screen 20 subjects to have 10
      participants. Working memory will be tested using delayed match sample task (DMS) and brief
      assessment of cognition in schizophrenia battery (BACS).

      Transcranial Magnetic Stimulation (TMS) administration The patient would be transported from
      the inpatient unit to the TMS lab following screening and consent process. They would be
      accompanied by nursing staff. During their visit to the TMS lab a sample TMS session
      including motor threshold determination will be conducted. Subjects would be allowed to
      practice the DMS task to allow for the ceiling in practice effect of the task. The BACS would
      be administered before and after the TMS session.

      Treatment Sessions Subjects would be administered left sided theta burst stimulation
      (TBS).The subject will be seated in a chair. A 64-channel electrode cap may be applied to the
      head for EEG recording. Electromyogram (EMG) electrodes will be applied to the right hand for
      motor evoked potential (MEP) recording. Subjects will perform the DMS task while sitting in
      the chair during the TMS session. EEG and EMG will be recorded throughout the treatment
      sessions. For theta burst stimulation the active motor threshold would be 80 % as used in
      most theta burst studies detailed in this review. Subjects would receive theta burst
      stimulation comprising 50 Hz bursts given at 3 to 5 Hz for close to 10 minutes which
      comprises 60 trains and 1800 pulses. The subject will be monitored until MEPs return to
      baseline. A side effects checklist will be completed at the beginning and at the end of the
      experimental session. All sessions will be performed by one of the protocol investigators, or
      by a trained and accredited research assistant supervised by the protocol investigators.

      Clinical and cognitive assessments/tasks PANSS The Positive and negative symptoms scale is
      used to assess the severity of schizophrenia. It has three subscales - positive, negative and
      general psychopathology. Each of these subscales had 7 items, the maximum scores on each of
      these subscales in 49, minimum score being 7.

      DMS task The DMS task is a modified version of the Sternberg task and has been adapted for
      use in cognitive paradigms accompanying transcranial magnetic stimulation. Each trial will
      last 13 s, with the following sequence of three task stages: encoding, retention and probe
      stages.

      BACS - Tasks to be done from the actual BACS battery of tests List Learning (Verbal Memory).
      Patients are presented with 15 words and then asked to recall as many as possible. This
      procedure is repeated 5 times. There are two alternate forms.

      Digit Sequencing Task (verbal working Memory). Patients are presented with clusters of
      numbers of increasing length. They are asked to tell the experimenter the numbers in order,
      from lowest to highest.

      Token Motor Task (Motor Speed). Patients are given 100 plastic tokens and asked to place them
      into a container as quickly as possible for 60 seconds.

      Verbal Fluency. Tests of Category Instances (Semantic Fluency) and Controlled Oral Word
      Association Test (Letter Fluency) are administered. Patients are given 60 seconds to name as
      many words as possible within a given semantic category, and in two separate trials, patients
      are given 60 seconds to generate as many words as possible that begin with a given letter.
      The total number of words from the three trials is the outcome measure.

      Tower of London (Reasoning and Problem Solving). Patients look at two pictures
      simultaneously. Each picture shows 3 different-colored balls arranged on 3 pegs, with the
      balls in a unique arrangement in each picture. The patients are told about the rules in the
      task and are asked to provide the least number of times the balls in one picture would have
      to be moved to make the arrangement of balls identical to that of the other, opposing
      picture. There are two alternate forms.

      Symbol Coding (Attention and Processing Speed). As quickly as possible, patients write
      numerals 1-9 as matches to symbols on a response sheet for 90 seconds.

      Each of the six measures are compared to a healthy control sample to create z-scores, and a
      composite score is calculated by summing these z-scores and calculating a z-score of that
      sum. The composite score has high test-retest reliability in patients with schizophrenia and
      healthy controls (ICCs > .80).
    

Intervention name(s): Theta Burst Stimulation
Intervention type(s): Device
Intervention description(s): Transcranial magnetic stimulation with theta burst stimulation
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment