1. Low-frequency repetitive transcranial magnetic stimulation (rTMS) applied to the dorsolateral prefrontal cortex (DLPFC) increases gamma-aminobutyric acid (GABA) levels. Baseline GABA levels and the GABA response to low-frequency rTMS are abnormally low in schizophrenia.
2. High-frequency rTMS applied to the DLPFC increases glutamate/glutamine (Glx) levels. Baseline Glx levels and the Glx response to high-frequency rTMS are abnormally low in schizophrenia.
3. In schizophrenia, rTMS-induced increases in GABA levels correlate with improvements in working memory, and increases in Glx levels correlate with improvements in negative symptoms.
The goal of this project is to improve understanding of excitatory and inhibitory neurotransmitter dysregulation in schizophrenia. The circuitry of this dysregulation will be mapped using an anatomically localized intervention (rTMS applied to the DLPFC) combined with localized measures of baseline and stimulated neurochemical response (magnetic resonance spectroscopy or MRS in the DLPFC and striatum before and after rTMS). By correlating clinical effects of rTMS with the MRS outcome measures, the project has the potential to lead to new interventions, possibly pharmacological or rTMS itself, targeting specific symptoms (working memory deficits and negative symptoms) of schizophrenia.
1. In a balanced-order design, two rTMS administrations to the left DLPFC (one high-frequency and the other low-frequency) will be given to each of 16 patients with schizophrenia and 16 healthy control subjects, separated by one week. Half the subjects in each group will be randomized to active rTMS, and half to a sham rTMS condition. Each rTMS session will be preceded and also followed by an MRS examination to measure both GABA and Glx within each examination. Each MRS examination will acquire data from both the left DLPFC and the left striatum.
2. The 16 patients will also independently undergo a course of daily (active or sham) high-frequency rTMS treatments to the left DLPFC. After this course of rTMS treatment, an additional MRS examination will be acquired to evaluate the neurochemical alterations associated with the treatment.
3. Working memory and negative symptoms will be assessed. The correlations of improvements in these ratings with the changes in MRS measures (increases in GABA and Glx, respectively) will be evaluated as indicators of therapeutic effects of single high- and low-frequency administrations of rTMS, and also of the treatment course of high-frequency rTMS.