Reduced plastic brain responses in schizophrenia: a transcranial magnetic stimulation study

Abstract

Background: Abnormalities in brain plasticity, possibly related to abnormal cortical inhibition (CI), have been proposed to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation (TMS) provides a dynamic method for non-invasive study of plastic processes in the human brain. We aimed to determine whether patients with schizophrenia would exhibit an abnormal response to repetitive TMS (rTMS) applied to the motor cortex and whether this would relate to deficient cortical inhibition. Methods: Measures of motor cortical excitability and cortical inhibition were made before and after a single 15-min train of 1-Hz rTMS applied to the motor cortex in medicated and unmedicated patients with schizophrenia as well as healthy controls. Results: All three groups had equal motor cortical excitability prior to rTMS, although both patient groups had a shorter cortical silent period (CSP) and less cortical inhibition than the control group. Cortical excitability, as assessed by motor threshold levels, did not reduce in both medicated and unmedicated patients in response to rTMS as was seen in the control group. Significant differences were also seen between the groups in response to the rTMS for motor-evoked potential (MEP) size and cortical silent period duration. Conclusions: Both medicated and medication free patients with schizophrenia demonstrated reduced brain responses to rTMS and deficits in cortical inhibition.

Introduction

It has been suggested that abnormalities of neural plasticity may underlie important neuropsychiatric disorders such as schizophrenia (Haracz, 1985). Neural and brain plasticity refer to the brain's ability to change structure and function in response to experience (Kolb and Whishaw, 1998). The mechanisms involved in these plastic responses include changes in synaptic activity, increases in dendritic length, changes in spine density, synapse formation, increased glial activity and neurogenesis (Kempermann et al., 2000). Two well-explored plastic mechanisms are long-term potentiation (LTP) and long-term depression (LTD). These are activity-dependent alterations in synaptic activity levels produced by repeated neuronal stimulation and are believed to be involved in learning and memory Braunewell and Manahan-Vaughan, 2001, Miller and Mayford, 1999.

Several lines of research suggest that there are likely to be abnormalities of neural plasticity in patients with schizophrenia. First, several post mortem studies have found abnormalities in brain components required for adaptive cellular processes including GAP-43 (Benowitz and Routtenberg, 1997) and MAP-2 (Cotter et al., 1997) as well as abnormal axonal sprouting and abnormal axodendritic synapses Uranova, 1996, Uranova et al., 1996. Second, evidence implicates dysfunction at N-methyl d-aspartate (NMDA) glutamate receptors in the pathogenesis of schizophrenia (Olney and Farber, 1995) and normal NMDA receptor function is crucial for a number of forms of synaptic plasticity including hippocampal LTP and LTD (Malenka and Nicoll, 1993). There is also evidence that adult patients with schizophrenia have an overrepresentation of the immature' NR2D subunit of the NMDA receptor in the prefrontal cortex (PFC) (Akbarian et al., 1996). This pattern of the NMDA receptor is associated with abnormal LTD and LTP (Okabe et al., 1998). Finally, several recent genetic studies suggest the involvement in schizophrenia of abnormalities in proteins, such as dysbindin and neuregulin 1 (NRG1), which are involved in NMDA receptor regulation and synaptic plasticity Stefansson et al., 2002, Straub et al., 2002.

Transcranial magnetic stimulation (TMS) techniques can be used to study the excitability of motor systems and brain plastic processes in vivo. Single and paired pulse TMS techniques can be used to assess inhibitory activity in the motor cortex Ferbert et al., 1992, Kujirai et al., 1993. Several studies have found that patients with schizophrenia exhibit deficits on TMS measures of cortical inhibitory activity Daskalakis et al., 2002, Fitzgerald et al., 2002a, Fitzgerald et al., 2002b, Fitzgerald et al., 2003. Repetitive TMS (rTMS) applied to the motor cortex can be used to alter cortical excitability in a way that persists beyond the time of the stimulation train (Chen and Seitz, 2001). For example, stimulation for 15 min at 1 Hz in normal subjects reduces cortical excitability as demonstrated by an increase in resting motor threshold (RMT) levels and decreased motor-evoked potential (MEP) size Chen et al., 1997, Fitzgerald et al., 2002a, Fitzgerald et al., 2002b. Although the mechanism underlying this reduction in excitability remains uncertain, the stimulation parameters utilized in these experiments are remarkably similar to those applied in basic cellular physiology experiments to induce LTD (Hoffman and Cavus, 2002).

The aim of this study was to investigate brain plasticity and cortical inhibition in schizophrenia utilizing the response to a prolonged period of low frequency rTMS. Although previous research has documented reduced inhibition in schizophrenia, no studies have directly explored rTMS-induced plasticity. We studied these in three groups, a group of unmedicated patients, a group of patients on stable antipsychotic medication and a group of normal volunteers. It was hypothesized that the patient groups would demonstrate less change in motor cortical excitability when stimulated with a low frequency rTMS train and reduced baseline cortical inhibition.