“During the last while back I have noticed that noises all seem to be louder to me than they were before…I notice it most with background noises—you know what I mean, noises that are always around but you don't notice them. Now they seem to be just as loud and sometimes louder than the main noises that are going on…It's a bit alarming at times because it makes it difficult to keep your mind on something when there's so much going on that you can't help listening to.”
This quotation from a schizophrenia patient presented by McGhie and Chapman in 1961
describes a problem commonly reported by patients with the disease – the inability to filter out irrelevant information from the environment (McGhie and Chapman 1961
). Frequent reports of such problems, in the context of a disease with such varied presentation, have led investigators to suspect that this “sensory gating” deficit may be related to disease pathology. Venables (1967)
suggested that the psychotic state might be characterized as a state of hypervigilance in that psychotic patients appear to be flooded by stimuli whose intensity they cannot regulate through sensory gating mechanisms (Venables 1967
). Patients with schizophrenia might suffer from deficits in filtering sensory input, which leads to this flooding. Different types of psychopathology could then be conceptualized as attempts to deal with this flooding. Because understanding brain function during sensory gating deficits in schizophrenia may yield insights into disease pathophysiology, investigators have used these early descriptions to develop EEG methods to investigate sensory gating.
One measure of sensory gating is a conditioning-testing paradigm, in which P50 auditory evoked potentials are measured from repeated pairs of clicks, separated by 500 ms. In healthy controls, responses to the second click in the pair are suppressed, compared to the first. Schizophrenia patients have diminished inhibition of responses to the second stimulus (Adler et al. 1982
). This measure has thus revealed inhibitory deficits in sensory gating in schizophrenia (Bramon et al. 2004
). Sensory gating deficits have also been found in first-degree relatives of schizophrenia patients, suggesting these deficits represent heritable factors that increase vulnerability to schizophrenia (Freedman et al. 1997
EEG studies lack the spatial resolution to determine which brain regions mediate this deficit in schizophrenia. Animal studies and a limited number of human intracranial recording and lesion studies point to the involvement of several brain regions, including the hippocampus, thalamus and prefrontal cortex (Miller and Freedman 1995
;Erwin et al. 1991
;Knight et al. 1989
;Grunwald et al. 2003
). The most often studied region is the hippocampus. In a rodent model of sensory gating, hippocampal activity is inhibited at the 500ms inter-stimulus interval, an inhibition which is dependent upon cholinergic activity from the medial septal fimbria-fornix input (Miller and Freedman 1993
). Studies recording intracranial evoked potentials from patients undergoing invasive presurgical evaluation for epilepsy have also implicated the hippocampus in sensory gating (Freedman et al. 1991
;Grunwald et al. 2003
;Boutros et al. 2005
). Involvement of the thalamus in sensory gating has also been proposed. Early studies of depth recordings of midlatency auditory potentials in cats suggested a generator system involving the thalamus (Hinman and Buchwald 1983
). Correspondence of cat to human midlatency responses led investigators to propose the thalamus as a P50 source generator (Erwin and Buchwald 1987
). Reports of thalamic dysfunction in schizophrenia led to the hypothesis that this region may be involved in sensory gating deficits in the disease (Erwin et al. 1991
). Finally, both surface and intracranial recordings support the involvement of the dorsolateral prefrontal cortex in sensory gating (Knight et al. 1989
;Grunwald et al. 2003
Only one group has used magnetoencephalography (MEG), which has improved spatial resolution, compared to EEG, to study the neural correlates of auditory gating deficits in schizophrenia (Edgar et al. 2005
;Thoma et al. 2005
;Huang et al. 2003
;Thoma et al. 2003
). In a simultaneous MEG/EEG study, Thoma and colleagues (2003)
found impaired gating in schizophrenia patients at the M50, the likely MEG analogue to the P50 (Thoma et al. 2003
). M50 dipoles localized to the superior temporal gyrus (STG), consistent with prior MEG studies that did not evaluate gating (Reite et al. 1988
). The relationship between M50 gating and established measures of sensory gating is unclear, however, as the M50 ratio did not correlate with the P50 ratio in patients and only weakly in the left hemisphere in controls. Additional limitations of MEG, including lack of uniform sensitivity throughout the brain and the difficulty of modeling multiple simultaneous sources, suggest that further studies are needed to determine the functional neuroanatomy of this deficit.
The present study is the first to use functional magnetic resonance imaging (fMRI) to investigate the neurobiology underlying auditory sensory gating deficits in schizophrenia. The superior spatial resolution of this technique complements the high temporal resolution of EEG and MEG, allowing an evaluation of the involvement of a network of multiple specific brain regions to the deficit. One reason for the lack of such studies to date likely stems from the loud scanning environment, which interferes with stimulus presentation. A related problem specific to auditory gating experiments is the requirement for a relatively long silent period prior to stimulus presentation for inhibitory circuitry to reset (Freedman et al. 1983
). The present study addresses these issues with a paradigm that uses clustered volume acquisition. This scanning technique acquires all slices for each brain volume in 2 sec, interspersed with long periods of silence (6 sec), allowing silence during and prior to stimulus presentation, yet still providing sensitivity to the hemodynamic response.
Another issue hindering fMRI studies of sensory gating is the broad temporal resolution of the technique, which is limited to seconds, compared to the millisecond resolution obtainable in EEG/MEG. Thus, it is difficult to resolve responses from two stimuli, separated by only 500ms, as in the typical sensory gating paradigm. To address this, our paradigm compares the response of one click to the response of a brief click train (9 clicks, separated by 500s, over a total of 4000ms), rather than to two clicks, as in the typical paradigm (see Methods for paradigm details).
This study examines sensory gating deficits with fMRI and compares these results to evoked potentials from a typical paired-click paradigm using EEG. We test the hypotheses that 1) a network of brain regions, including the STG, hippocampus, thalamus and DLPFC, is involved in sensory gating deficits in schizophrenia, and 2) the newly developed fMRI sensory gating measure is correlated with typical EEG measures of this deficit.