Mapping Abnormal Excitatory and Inhibitory Neurochemical Circuitry in Schizophrenia with rTMS and MRS

Lawrence Kegeles, M.D., Ph.D.

Columbia University

Funded in December, 2005: $100000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Mapping Abnormal Dopamine Regulation in Schizophrenia

Investigators will image patients with schizophrenia to determine whether they have an imbalance in the chemicals that normally regulate levels of the neurotransmitter dopamine and whether this imbalance correlates with cognitive problems, such as memory, and with negative symptoms, such as social withdrawal.

Scientists have speculated that, in patients with schizophrenia, cognitive problems and negative symptoms are caused by too much or too little dopamine in certain brain regions.  Since postmortem studies reveal that dopamine cells are not damaged (unlike, for example, in Parkinson’s disease), the Columbia researchers hypothesize that schizophrenia may be caused by poor dopamine regulation in certain parts of the brain.

Investigators will use magnetic resonance spectroscopy (MRS) imaging in patients with schizophrenia and in healthy volunteers to measure levels of two neurotransmitters that regulate dopamine levels, which are out of balance in patients with schizophrenia.  One of these neurotransmitters, GABA, inhibits dopamine release.  The other, glutamate, stimulates it.  The researchers will see whether they can make the levels of both neurotransmitters more pronounced, by repetitively using “transcranial magnetic stimulation” (rTMS).  In rTMS, a magnet is repetitively held above the patient’s head to stimulate greater production of GABA and glutamate.  The researchers anticipate that changes produced by rTMS will be smaller in schizophrenia patients compared to the volunteers, suggesting abnormalities in release of these two excitatory and inhibitory regulators of dopamine.  The investigators also will test patients’ cognitive functioning and severity of negative symptoms before and after rTMS, to determine whether any changes in these are correlated with changes in levels of GABA and glutamate.  If so, the findings could lead to development of drugs that work on restoring GABA and glutamate balance in regulating dopamine or on improving the ability of rTMS to restore this balance.  

Significance: If this project demonstrates that the regulatory neurotransmitters GABA and glutamate affect dopamine regulation and that improved regulation is correlated with improved symptoms in people with schizophrenia, this research could lead to new approaches to treatment of this debilitating disorder.

ABSTRACT

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Mapping Abnormal Excitatory and Inhibitory Neurochemical Circuitry in Schizophrenia with rTMS and MRS

The goal of this project is to improve understanding of excitatory and inhibitory neurotransmitter dysregulation in schizophrenia. The classical dopamine hypothesis of schizophrenia holds that a critical neurotransmitter abnormality in this illness is subcortical dopamine hyperactivity. Recent postmortem and pharmacological evidence suggest that this hyperdopaminergic state might be secondary to regulatory failure by the major excitatory and inhibitory transmitters glutamate and gamma aminobutyric acid (GABA) in the prefrontal cortex.

This study will aim to map the circuitry of this dysregulation using an anatomically localized intervention, repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC), combined with localized measures of neurochemical response to the intervention using magnetic resonance spectroscopy (MRS). This response will be evaluated locally in the left DLPFC and subcortically in the left striatum by comparing MRS measurements before and after rTMS. We will administer both high- and low-frequency rTMS in a single-dose, balanced-order, sham-controlled design and measure both GABA and the mixture of excitatory amino-acid transmitters glutamate and glutamine in both regions.

These interventions and measurements will be made in patients with schizophrenia as well as in healthy control subjects. The patients participating in these studies will also subsequently undergo a clinical treatment series of rTMS administrations under a separate study protocol. On completion of that treatment series, we will make one additional MRS measurement to assess the neurochemical correlates of rTMS treatment of schizophrenia. Outcome measures of clinical response to rTMS will focus on negative symptoms and working memory deficits. By correlating clinical effects of rTMS administration with the MRS outcome measures, the project can show the neurochemical circuitry basis of response to rTMS. These data in turn have the potential to lead to novel interventions, possibly pharmacological or rTMS itself, targeting specific symptoms, the working memory deficits and negative symptoms of schizophrenia.

INVESTIGATOR BIOGRAPHIES

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Lawrence Kegeles, M.D., Ph.D.

Assistant Professor of Clinical Psychiatry and Radiology, Columbia University

HYPOTHESIS

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Hypothesis:
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.

Goals:
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.

Methods:
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.

SELECTED PUBLICATIONS

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Kegeles L.S., Martinez D., Kochan L.D., Hwang D.R., Huang Y., Mawlawi O., Suckow R.F., Van Heertum R.L., and Laruelle M. NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans. Synapse. 2002 Jan;43(1):19-29.

Kegeles L.S., Abi-Dargham A., Zea-Ponce Y., Rodenhiser-Hill J., Mann J.J., Van Heertum R.L., Cooper T.B., Carlsson A., and Laruelle M. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000 Oct 1;48(7):627-40.

Kegeles L.S., Shungu D.C., Anjilvel S., Chan S., Ellis S.P., Xanthopoulos E., Malaspina D., Gorman J.M., Mann J.J., Laruelle M., and Kaufmann C.A. Hippocampal pathology in schizophrenia: magnetic resonance imaging and spectroscopy studies. Psychiatry Res. 2000 May 15;98(3):163-75.