Transcranial magnetic stimulation for the deficit syndrome of schizophrenia

From the time of Kraepelin s (1) description of the syndrome we now call schizophrenia, negative symptoms such as alogia, affective flattening, anhedonia, asociality, avolition and attentional impairment have been recognized as its important features. The development and course of this deficit syndrome of schizophrenia has been documented to be independent from positive psychotic symptoms both crosssectionally and longitudinally (2). Unfortunately, treatment strategies for the deficit syndrome of schizophrenia are inadequate. The conventional neuroleptics were generally recognized as being largely ineffective against negative symptoms (3). Although the atypical antipsychotics produce fewer parkinsonian side-effects, whether they reduce the primary negative symptoms of schizophrenia has not been shown, with the possible exception of clozapine (4). Given the clinical salience of the deficit syndrome, concerted efforts to treat it are important. In relation to this, it is relevant to comment upon the neurobiological underpinnings of the negative syndrome. A large body of work has related the negative syndrome to a disturbance in executive function and working memory, and reducedand/oranomalousactivationof the cortex, primarily the frontal cortex (5). Functional imaging studies have supported the idea that there is reduced functional activation of the prefrontal cortex during tasks that involve frontal-executive functioning (6). Some histopathological and pharmacological studies have suggested that there may be dysfunction of excitatory (7) and/or inhibitory (8) cortical function in schizophrenia, especially in the prefrontal cortex. Neurochemically, it has been related to hypofunction at the N-methyl-D-adenosine receptor, and agonists at this receptor such as glycine and Dcycloserine have been investigated (9). It has also been suggested that the reduced inhibition may be because of excessive activation of subcortical dopamine (10). Another line of investigation has focused on signaling by brain-derived neurotrophic factor through its receptor, the tyrosine kinase Trk (tropomyosin-related kinase) B receptor. Reduced signaling in this pathway leads to a reduction in GAD67 mRNA expression and gamma-aminobutyric acid (GABA) synthesis in the parvalbumin-expressing subpopulation of GABA neurons in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia (11). The pyramidal neurons regulate gamma-band oscillations in the frontal cortex that are proportional to the working memory load and that are know to be abnormal in schizophrenia (12). Disturbance in the chandelier neuron – pyramidal neuron complex because of reduced inhibitory activity – may be the basis for some of the disturbance in schizophrenia (13). In simple terms, schizophrenia may therefore be seen as a disorder of reduced cortical inhibition. Neurophysiological studies using event-related potential support this hypothesis (14). Investigational studies using transcranial magnetic stimulation (TMS) have shown that lack of cortical inhibitory control may be involved in the pathophysiology of schizophrenia (15). The obvious question, which has been asked previously, and which Prikryl et al. (16) pose in this issue, is whether the abnormal excitability of the cortex can be corrected by brain stimulation. It is possible to alter cortical excitability using repetitive TMS (rTMS). Several studies have shown that high-frequency rTMS (.1 Hz) increases cortical excitability, whereas low-frequency rTMS (,1 Hz) decreases it (17,18). This differential effect is best manifest in the motor cortex but possibly applies to other cortical regions as well. Moreover, higher intensity stimulation is likely to induce longer lasting modification of cortical excitability (19). After rTMS over the motor cortex, changes in motor threshold can be shown for many minutes after cessation of stimulation, possibly up to an hour (19). Whether effects persist beyond that period or stimulation leads to a persistent change in excitability at a subthreshold level is not known. The challenge in schizophrenia is to establish that any effect of stimulation will persist beyond the