Elsevier

NeuroImage

Volume 42, Issue 3, September 2008, Pages 1164-1177
NeuroImage

Frontal–striatal–thalamic mediodorsal nucleus dysfunction in schizophrenia-spectrum patients during sensorimotor gating

https://doi.org/10.1016/j.neuroimage.2008.05.039Get rights and content

Abstract

Prepulse inhibition (PPI) refers to a reduction in the amplitude of the startle eyeblink reflex to a strong sensory stimulus, the pulse, when it is preceded shortly by a weak stimulus, the prepulse. PPI is a measure of sensorimotor gating which serves to prevent the interruption of early attentional processing and it is impaired in schizophrenia-spectrum patients. In healthy individuals, PPI is more robust when attending to than ignoring a prepulse. Animal and human work demonstrates that frontal–striatal–thalamic (FST) circuitry modulates PPI. This study used functional magnetic resonance imaging (fMRI) to investigate FST circuitry during an attention-to-prepulse paradigm in 26 unmedicated schizophrenia-spectrum patients (13 schizotypal personality disorder (SPD), 13 schizophrenia) and 13 healthy controls. During 3T-fMRI acquisition and separately measured psychophysiological assessment of PPI, participants heard an intermixed series of high- and low-pitched tones serving as prepulses to an acoustic-startle stimulus. Event-related BOLD response amplitude curves in FST regions traced on co-registered anatomical MRI were examined. Controls showed greater activation during attended than ignored PPI conditions in all FST regions—dorsolateral prefrontal cortex (Brodmann areas 46, 9), striatum (caudate, putamen), and the thalamic mediodorsal nucleus. In contrast, schizophrenia patients failed to show differential BOLD responses in FST circuitry during attended and ignored prepulses, whereas SPD patients showed greater-than-normal activation during ignored prepulses. Among the three diagnostic groups, lower left caudate BOLD activation during the attended PPI condition was associated with more deficient sensorimotor gating as measured by PPI. Schizophrenia-spectrum patients exhibit inefficient utilization of FST circuitry during attentional modulation of PPI. Schizophrenia patients have reduced recruitment of FST circuitry during task-relevant stimuli, whereas SPD patients allocate excessive resources during task-irrelevant stimuli. Dysfunctional FST activation, particularly in the caudate may underlie PPI abnormalities in schizophrenia-spectrum patients.

Introduction

Abnormalities in sensory gating or the ability to gate out irrelevant sensory information from the environment are frequently reported in patients with schizophrenia (American-Psychiatric-Association 1994, p. 280). Prepulse inhibition (PPI) is a reliable psychophysiological index of sensorimotor gating which provides a well-validated animal model for testing the potency of antipsychotics, as well as, a useful framework for examining deficits in the early stages of information processing among schizophrenia-spectrum patients (Kumari and Sharma, 2002). In humans, PPI is defined as the reduction of the amplitude of the startle eyeblink reflex when a non-startling prestimulus (the prepulse) precedes a startling stimulus (the pulse) by a brief interval (30–300 ms), compared with the amplitude elicited by the startle stimulus alone, see reviews by Blumenthal (1999) and Filion et al. (1998). This inhibition in the amplitude of the startle response is thought to be due to a momentary inhibitory sensorimotor gating process elicited by the prepulse that serves to protect the earliest stages of processing of the prepulse (Graham, 1975). PPI is maximal when the interval between the prepulse and the pulse stimulus is approximately 120 ms (Blumenthal, 1999).

Schizophrenia and schizotypal personality disorder (SPD) patients show abnormal inhibition of the startle eyeblink response during a passive, uninstructed PPI paradigm which has been interpreted as a deficit in early automatic attentional processing (Braff et al., 1978, Braff et al., 1992, Cadenhead et al., 1993, Cadenhead et al., 2000, Grillon et al., 1992, Kumari et al., 1999, Swerdlow et al., 2006). In addition to studies examining passive PPI, several studies have shown that active attentional modulation of PPI is also impaired in schizophrenia and SPD patients (Dawson et al., 1993, Dawson et al., 2000, Hazlett et al., 1998, Hazlett et al., 2003, Hazlett et al., 2007, Hazlett et al., in press). In these attention-to-prepulse studies, the participants are typically instructed to attend to one type of prepulse (e.g., high-pitch tone) and simply ignore another prepulse (e.g., low-pitch tone). Active attention PPI studies have reported that healthy individuals show greater PPI at the 120 ms probe position following an attended prepulse than an ignored prepulse. In contrast, schizophrenia and SPD patients failed to show differential PPI during attended and ignored prepulses. These results are consistent with the concept that schizophrenia-spectrum patients are impaired in the allocation of controlled attentional processes to an important, task-relevant stimulus (Callaway and Naghdi 1982).

There is evidence from animal studies that PPI is modulated by cortico-striato-thalamic-pallido-pontine circuitry, for reviews see (Koch and Schnitzler, 1997, Swerdlow et al., 2001) and theories of the pathology of schizophrenia have implicated dysfunction in this circuitry (Bunney, 1990, Carlsson and Carlsson, 1990, Swerdlow and Koob, 1987). Our previous [18F]-deoxyglucose positron emission tomography (PET) finding that among healthy individuals, greater PPI is significantly correlated with higher relative glucose metabolism in dorsolateral prefrontal cortex (DLPFC) regions (Hazlett and Buchsbaum, 2001, Hazlett et al., 1998) is consistent with animal models of the circuitry modulating PPI. In contrast, unmedicated schizophrenia patients showed this relationship in a much smaller portion of prefrontal cortex (Hazlett and Buchsbaum, 2001, Hazlett et al., 1998). Recent work using functional magnetic resonance imaging (fMRI) in healthy individuals found increased blood oxygen-level dependent (BOLD) response in prefrontal cortex, thalamus, mediodorsal nucleus (MDN), and striatum during PPI modulation (Hazlett et al., 2001, Kumari et al., 2003, Kumari et al., 2007a) and decreased activation in schizophrenia patients (Kumari et al., 2003, Kumari et al., 2007a).

Previous fMRI work in schizophrenia examining frontal–striatal–thalamic (FST) circuitry during startle modulation, e.g., Kumari et al., (2003) is somewhat difficult to interpret given the confound of antipsychotic medication. A recent fMRI study examining schizophrenia patients on typical vs. atypical neuroleptics (doctor's choice) showed that patients taking atypical neuroleptics had better PPI and more FST activation than those taking typical neuroleptics (Kumari et al., 2007a). The present study examines whether the BOLD response in FST circuitry during PPI modulation differs from normal in a sample of unmedicated schizophrenia and SPD patients. Understanding brain dysfunction underlying deficient PPI modulation in schizophrenia-spectrum patients may yield insights into disease pathophysiology and help target regions for psychopharmacological treatment. Although prior neuroimaging studies have investigated the neurobiology underlying PPI deficits in schizophrenia, this is the first to include SPD patients and examine the event-related time course of FST activation. An important aim of the present study was to examine the degree to which SPD resembles schizophrenia in terms of abnormal BOLD activation and its time course in FST regions during an active attention PPI paradigm.

Similar to schizophrenia, SPD is characterized by difficulties with social interactions and language, as well as, paranoid, odd behavior, ideas of reference and magical thinking. However, since individuals with SPD are not frankly psychotic, they have not generally required neuroleptic medication or recurrent hospitalization which avoids the confounds of medication and chronicity. Nevertheless, SPD is related to schizophrenia in terms of genetics (Kendler et al., 1993, Kety et al., 1967) and shared biological markers (Cadenhead et al., 2000, Dickey et al., 2002, Siever and Davis, 2004).

Functional imaging studies of schizophrenia-spectrum patients suggest that there may be abnormalities in frontal activation in both schizophrenia and SPD but that SPD patients can recruit alternative, compensatory regions to accomplish cognitive tasks requiring frontal lobe activation (Buchsbaum et al., 2002). In the thalamus, we have reported decreased relative glucose metabolism in the mediodorsal nucleus bilaterally in schizophrenia patients, but not in SPD compared with healthy controls during a serial-verbal learning task (Hazlett et al., 1999). However, shape analysis showed that the SPD group had significantly fewer pixels in the region of the right MDN than did controls suggesting size reduction. During the same task, SPD patients showed increased relative glucose metabolism in the ventral putamen. This finding is consistent with decreased dopaminergic activity in the ventral putamen since dopamine is inhibitory in this region. In contrast, schizophrenia patients showed decreased relative glucose metabolism compared with healthy controls in this region (Shihabuddin et al., 2001). More recently, significant size reduction and shape differences of the caudate nucleus in SPD have been reported (Levitt et al., 2002, Levitt et al., 2004). Taken together, these findings support the idea that impairment in the schizophrenia spectrum may be associated with abnormalities in FST circuitry.

The main aim of the present fMRI study was to examine the event-related time course of the BOLD response during attended and ignored prepulses in unmedicated schizophrenia-spectrum patients (SPD and schizophrenia) and healthy individuals. Based on animal models of the modulation of PPI (reviewed by Swerdlow et al., 2001) and related neuroimaging work in humans (Hazlett et al., 1998, Hazlett et al., 2001, Kumari et al., 2003, Kumari et al., 2007a), we hypothesized that compared with healthy controls schizophrenia patients would show less differential BOLD activation in FST regions during the attend minus ignore PPI condition. We also hypothesized that SPD patients would show less marked abnormalities than the schizophrenia patients. We expected BOLD response abnormalities in SPD might involve fewer brain areas modulating PPI and affected in schizophrenia, or that the BOLD response might be enhanced in some brain areas compared with healthy controls, possibly serving to protect the SPD patients from the most severe deficits of schizophrenia. In addition to our hypothesis-driven region-of-interest approach, we conducted a more conventional and exploratory whole-brain analysis. Lastly, for a subgroup of participants, we calculated correlation coefficients between FST BOLD activation during the attended PPI condition and psychophysiological measurement of PPI which was obtained in a separate session within a week of the fMRI scan. Across the three groups, we predicted that lower FST activation would be associated with poorer PPI.

Section snippets

Participants

Thirteen unmedicated schizophrenia patients (5 never medicated, 8 previously medicated but off all psychoactive medication for a minimum of two weeks and long-acting antipsychotics for six weeks prior to their scan), 13 SPD patients (12 never medicated, one received antipsychotic medication on one occasion ten years prior to this study), and 13 healthy controls comprised the final sample for this study. The groups did not significantly differ in age or sex distribution (Table 1). Data from an

FST circuitry

The multiple-brain-region analysis resulted in a complex pattern of group differences in BOLD activation which showed that the healthy controls had greater BOLD response activation curves during the attend than the ignore PPI condition in frontal–striatal–thalamic (FST) regions across hemispheres, whereas both patient groups failed to show this pattern of attentional modulation. Schizophrenia patients tended to show less differential attend-ignore BOLD activation mainly due to a lack of BOLD

Discussion

To our knowledge, this is the first study to examine the time course of frontal–striatal–MDN activation during a PPI paradigm in an unmedicated schizophrenia-spectrum sample. Our main finding is that compared with healthy controls, schizophrenia patients showed diminished BOLD activation curves in the DLPFC, caudate, putamen, and MDN during the attended PPI condition while the SPD patients tended to show greater-than-normal activation during the ignored PPI condition. Our findings indicate that

Acknowledgments

This research was supported by an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD) and MH073911 to E.A.H.

The authors wish to thank Frank Macaluso for his technical assistance with MRI acquisition.

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