A transcranial magnetic stimulation study of abnormal cortical inhibition in schizophrenia

Abstract

Previous research suggests that patients with schizophrenia demonstrate deficits in a range of parameters of motor cortical and cognitive inhibition. I-wave facilitation and long-interval cortical inhibition (LICI) are two paired pulse transcranial magnetic stimulation paradigms that appear to assess aspects of cortical inhibitory function that have not previously been assessed in this patient group. Eighteen patients with schizophrenia (nine medication-free) were compared with eight control subjects. We assessed resting motor threshold (RMT) levels, LICI and I-wave facilitation. RMT levels did not differ between the three groups. There was a significant overall difference in I-wave facilitation levels. Both patient groups as compared with the control group showed increased facilitation. There were no differences between the groups in the measure of LICI. Patients with schizophrenia appear to have increased I-wave facilitation. Increased I-wave facilitation suggests deficient function of cortical inhibitory GABAergic activity. This is consistent with previous research that has found deficient cortical inhibition in patients with schizophrenia.

Introduction

A number of studies have suggested that schizophrenia may involve an abnormality of the functioning of cortical inhibitory circuits. Studies of this sort initially utilized a variety of cognitive and evoked potential paradigms to demonstrate deficits in aspects of inhibitory processing. In an example of this type of research, Freedman et al., in a series of studies, demonstrated that patients with schizophrenia demonstrated reduced inhibition of the P50 auditory evoked potential in a paired pulse conditioning–test stimulus paradigm (Freedman et al., 1996, Freedman et al., 1983, Freedman et al., 1997). Differences between patients and controls have also been found in a series of cognitive priming paradigms designed to assess the capacity of subjects to inhibit aspects of automatic or planned responses, although this literature is complex and its findings not completely clear (e.g. Park et al., 2002, Peters et al., 2000, Williams, 1996).

More recently, a number of transcranial magnetic stimulation (TMS) techniques have been used to explore inhibitory processes in the motor cortex in schizophrenia. The motor cortex is of interest in the disorder as there is clear evidence of abnormalities in motor function that are independent of the effects of antipsychotic medication and may precede the onset of the disorder. For example, Walker et al. described choreoathetoid movements and posturing of the upper limbs in children who would later develop schizophrenia (Walker et al., 1994), and abnormalities in motor control have been described in neuroleptic-naive first onset patients (Caligiuri and Lohr, 1994). TMS paradigms used to date to assess inhibitory processes include the cortical silent period (CSP), cortical inhibition (CI) produced with paired pulse TMS (ppTMS) and inter-hemispheric inhibition (IHI) (also known as transcallosal inhibition) (Appendix A). The CSP is a period of suppression of tonic motor activity that follows descending excitatory activity produced by a TMS stimulus to the motor cortex (Cantello et al., 1992). It appears to be predominately the result of cortical activity, especially at GABA_B receptors (Sanger et al., 2001, Werhahn et al., 1999). Studies of the CSP have found a reduction in its duration in both unmedicated (Daskalakis et al., 2002) and medicated patients compared to controls (Fitzgerald et al., 2002b). The degree of CI produced with ppTMS models using a short inter-stimulus interval (SICI) also appears to be a cortical effect, but it is determined by activity at GABA_A receptors (Kujirai et al., 1993, Sanger et al., 2001). The degree of SICI has been the focus of several studies. The first of these reported a reduction compared to controls in patients receiving treatment with atypical antipsychotic medication (Fitzgerald et al., 2002b). Subsequently a reduction in SICI has also been reported in unmedicated patients (predominately medication naive) (Daskalakis et al., 2002), although reduced SICI was only reported in medicated, but not unmedicated patients, in a second study (Pascual-Leone et al., 2002). IHI has also been explored in several studies. Three groups have reported abnormal IHI with a method utilizing unilateral stimulation of the motor cortex (Boroojerdi et al., 1999, Fitzgerald et al., 2002a, Hoppner et al., 2001), and two studies using bilateral cortical stimulation techniques have also demonstrated changes (Daskalakis et al., 2002, Fitzgerald et al., 2002a).

Several other paradigms have been developed that are useful in the assessment of inhibitory function in the brain. The first involves a ppTMS paradigm but with differing stimulus properties than those previously described. In this paradigm, long-interval cortical inhibition (LICI) (Kujirai et al., 1993) is assessed with an initial supra-threshold stimulus combined with a supra-threshold second stimulus. The initial stimulus will produce an inhibition of the evoked motor response to the second (test) stimulus when presented at an appropriate inter-stimulus interval (50–200 ms) (Nakamura et al., 1997, Valls-Sole et al., 1992). LICI also appears to be a cortical event related to GABA_B activity (Nakamura et al., 1997, Sanger et al., 2001).

The second paradigm involves assessment of descending I-wave facilitation. TMS of the human motor cortex results in multiple discharges in the cortico-spinal tract (Ziemann et al., 1998a). The first descending volley is produced by direct neuronal stimulation (D-wave), and this is followed by waves of activation produced through the stimulation of cortical interneurones (I-waves) (Ziemann and Rothwell, 2000). With a paired pulse protocol that differs from that described above, the facilitation of I-wave activity is assessed. This protocol involves paring a supra-threshold first and sub-threshold second stimulus (Ziemann et al., 1998a). It has been shown that the production of I-waves is dependent on GABA function; in particular, enhanced GABAergic activity at GABA_A receptors suppresses the facilitatory I-wave activity (Ziemann et al., 1998b).

The aim of this study was to extend previous research into inhibitory deficits in schizophrenia by assessing LICI and I-wave facilitation in patients with the disorder. We tested both paradigms in a group of medication-free patients, a group of patients currently receiving antipsychotic medication and a group of normal control subjects. We hypothesized that the patient groups would demonstrate reduced LICI and increased I-wave facilitation.