Brain hemodynamic responses to the complex noises used in this study were robust, including activation of the primary and secondary auditory cortices, medial geniculate nuclei and the inferior colliculus. Responses in the brainstem auditory nuclei and the medial geniculate nuclei were not expected, as more sophisticated experimental designs using cardiac gating typically are required to detect responses in these small structures (16
). Detecting responses in these low-level auditory structures seems reasonable, however, given the stimulus energy and broadband nature of the stimulus used.
Group differences in hemodynamic response during the sensory gating task included greater activation of the left hippocampus, bilateral thalamus and left prefrontal cortex in subjects with schizophrenia, relative to comparison subjects. This finding is similar to results from our previous fMRI study using repeated clicks to study sensory gating (5
). The largest observed group difference in response was greater activation of the hippocampus in subjects with schizophrenia. The hippocampus is morphologically and neurochemically altered in schizophrenia (17
). Involvement of the structure in sensory gating deficits in schizophrenia had been proposed previously (18
). While our previous study is to date the only fMRI report of direct involvement of the hippocampus in gating deficits in schizophrenia, recent evidence from neurosurgical studies of patients undergoing invasive presurgical evaluation for epilepsy suggests its involvement in normal sensory gating (19
). Animal studies have strongly implicated the involvement of the hippocampus in both normal sensory gating, and in animal models of deficient sensory gating (22
Greater responses during the sensory gating task also were observed in the thalamus in subjects with schizophrenia, relative to healthy comparison subjects. The thalamus plays a key role in gating information to the cortex, mediated by the nucleus reticularis, a thin layer of GABAergic inhibitory neurons (25
). Although early studies suggested involvement of the thalamus in auditory sensory gating, only recently has auditory gating been demonstrated in neurons in the nucleus reticularis of the thalamus (23
Greater hemodynamic response in subjects with schizophrenia also was observed in the prefrontal cortex, consistent with our prior study using repeated clicks to assess gating (5
). The prefrontal cortex has long been hypothesized to play a role in inhibitory processes such as sensory gating (26
). Invasive recordings suggest the prefrontal cortex plays a role in the early stages of the gating response (19
). Recent MEG studies further support prefrontal cortex involvement in gating responses, both in the auditory and somatosensory domains (27
). The responses observed in the present study also may reflect differences in higher cognitive processes such as attention, which typically are not thought to play a dominant role in early sensory gating. Self reports in the present study indicating that many subjects with schizophrenia found the noises to be overtly distracting, suggest additional cognitive resources, which may include response of the prefrontal cortex, were engaged by these subjects. Future studies that modulate the level of distraction and control for attention are needed to further parse the role of the prefrontal cortex in sensory gating tasks.
Greater hemodynamic responses observed in the present study are consistent with physiological models of an altered balance between excitatory and inhibitory neurotransmission in schizophrenia. It is possible, for example, that the greater responses in subjects with schizophrenia reflect an inhibitory deficit stemming from abnormal GABA neurotransmission that has been proposed as a “final common pathway” for cortical dysfunction in schizophrenia (28
). Such an inhibitory deficit may be lead to the inappropriate excitation of a network of brain regions, as has been proposed previously (5
). Alternately, the increased responses observed in the present study may stem from compensatory processes. Since no overt demands were made on subjects in the magnet, however, it is difficult to speculate about what deficit would be compensated for, if any, in the schizophrenia subjects.
The positive correlation between hemodynamic responses in the fMRI task and evoked responses during the paired-click sensory gating paradigm suggests that the “urban white noise” sensory gating paradigm may at least partially tap into neurobiological processes involved in gating mechanisms studied previously. It also is possible, however, that the correlation between the phenomena may be mediated by a common underlying biological factor not directly measured. The modest correlation coefficients observed are not unexpected given the substantial difference in both the paradigms used and the responses measured. Typical P50 auditory gating tasks, which are thought to be largely pre-attentive, record responses to discrete stimuli at a 50 ms latency. The “urban white noise” fMRI task 1) is not a discrete stimulus, lasting several seconds, and 2) incorporates both early responses, such as the P50, and later responses, which are known to be more dependent on additional cognitive processes.
There are several limitations to this study. All subjects with schizophrenia were treated with neuroleptics, which may alter their responses, or the measured BOLD signal. Braus et al (1999) has shown that neuroleptic treatment, particularly treatment with typical neuroleptics, may alter in the BOLD response in some brain regions (29
). Recent studies have not, however, shown medication effects on the BOLD response in the context of bipolar disorder (30
) or schizophrenia (31
). Another limitation of this study is the use of silence as a baseline comparison. Because resting state activity may be altered in schizophrenia (32
), future studies using graded auditory stimuli or other control conditions are necessary. An additional caveat is that the open-ended question used to elicit the self reports described here lacked structure, and as such likely had low sensitivity to capture the salient aspects of subject’s experiences.
Using a clinically meaningful sensory gating task, this study found hyper-activation of the hippocampus, thalamus and prefrontal cortex that was very similar to responses observed in our prior study using repeated clicks. Also, correlations were observed between responses to the “urban white noise” and P50 suppression as measured by EEG. Thus, our results suggest that patients’ neuronal responses to simulated sensory overstimulation may share a common mechanism with responses to simple clicks as measured in a typical repeated-click paradigm. Results presented here also further support the notion of hyper-activity of the hippocampus, thalamus and prefrontal cortex as a pathological feature of schizophrenia.