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.

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).

Inclusion Criteria:

• Patients aged 18-65 years of age with schizophrenia or schizoaffective disorder
• No other mental health diagnoses
• Right handed males and females
• May have mild positive symptoms (score of </= 21)
• May have negative symptoms
• Ability to provide informed consent
• No restriction on concomitant medications given

Exclusion Criteria:

• Intellectual disability
• Any organic brain illness Presence of dementia symptoms or traumatic brain injury Primary diagnosis of substance use Seizure disorder Actively symptomatic with PANSS positive symptom sub-scale >21. Concurrently receiving electroconvulsive therapy (ECT)

6 months