Reduced habituation in patients with schizophrenia

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Abstract

Background

Neural habituation, the decrease in brain response to repeated stimulation, is a basic form of learning. There is strong evidence for behavioral and physiological habituation deficits in schizophrenia, and one previous study found reduced neural habituation within the hippocampus. However, it is unknown whether neural habituation deficits are specific to faces and limited to the hippocampus. Here we studied habituation of several brain regions in schizophrenia, using both face and object stimuli. Post-scan memory measures were administered to test for a link between hippocampal habituation and memory performance.

Methods

During an fMRI scan, 23 patients with schizophrenia and 21 control subjects viewed blocks of a repeated neutral face or neutral object, and blocks of different neutral faces and neutral objects. Habituation in the hippocampus, primary visual cortex and fusiform face area (FFA) was compared between groups. Memory for faces, words, and word pairs was assessed after the scan.

Results

Patients showed reduced habituation to faces in the hippocampus and primary visual cortex, but not the FFA. Healthy control subjects exhibited a pattern of hippocampal discrimination that distinguished between repeated and different images for both faces and objects, and schizophrenia patients did not. Hippocampal discrimination was positively correlated with memory for word pairs.

Conclusion

Patients with schizophrenia showed reduced habituation of the hippocampus and visual cortex, and a lack of neural discrimination between old and new images in the hippocampus. Hippocampal discrimination correlated with memory performance, suggesting reduced habituation may contribute to the memory deficits commonly observed in schizophrenia.

Introduction

Habituation, the decrease in response to a stimulus following repeated exposure with no meaningful consequence, is a basic form of learning (Rankin et al., 2009). Habituation is adaptive because it allows for the allocation of limited cognitive resources towards novel events in the environment. Neural habituation can be measured with functional magnetic resonance imaging (fMRI) as a decrease in blood–oxygen level dependent (BOLD) response to repeated stimulation. Distributed brain areas exhibit habituation to visual cues, including visual processing areas (Summerfield et al., 2008, Weigelt et al., 2008), the prefrontal cortex (Wright et al., 2001, Yamaguchi et al., 2004), and the hippocampus and amygdala (Breiter et al., 1996, Wright et al., 2001, Fischer et al., 2003, Blackford et al., 2010, Blackford et al., 2013). In many previous studies, fMRI habituation (also called fMRI adaptation or repetition suppression) has been used to localize feature-specific processing in the brain (e.g. Grill-Spector et al., 2006). However, more recent investigations have linked habituation in the hippocampal formation with cognitive performance, finding that habituation in the parahippocampus is related to successful memory retrieval (Turk-Browne et al., 2006), and that patients with mild cognitive impairment, characterized by memory deficits, show reduced hippocampal habituation (Johnson et al., 2004).

Habituation deficits have been consistently observed in patients with schizophrenia, using both behavioral and electrophysiological measures. For example, patients with schizophrenia show reduced habituation of eye-blink startle to auditory or tactile cues (Geyer and Braff, 1982, Bolino et al., 1992, Braff et al., 1992, Bolino et al., 1994), as well as reduced habituation of early evoked auditory responses (Olincy et al., 2010). Despite this wealth of evidence for disrupted habituation in schizophrenia, only one study has investigated fMRI habituation, finding reduced habituation in the right anterior hippocampus in response to repeated fearful faces (Holt et al., 2005). Many important questions remain regarding the integrity of fMRI habituation in schizophrenia, specifically whether habituation deficits are 1) present outside the hippocampus, 2) specific to social stimuli such as faces, or 3) related to memory impairments in schizophrenia. Considering the large body of previous research on sensory gating deficits (e.g. reduced pre-pulse inhibition and reduced mismatch negativity) (Braff et al., 1992, Light and Braff, 2005), and specific disruptions in early visual processing in schizophrenia (Javitt, 2009), it is possible that habituation in sensory cortex is also reduced.

Here we extend studies of habituation in schizophrenia to test for reduced fMRI habituation in the hippocampus, early visual cortex (BA 17/18) and the fusiform face area, (FFA, Kanwisher et al., 1997), a major node in the face processing network found to be hypoactive in schizophrenia patients (Quintana et al., 2003, Pinkham et al., 2008, Seiferth et al., 2009, Habel et al., 2010). Hippocampal volumes were compared between groups to investigate whether reduced hippocampal habituation occurs in the context of hippocampal volume loss, a prominent finding in schizophrenia (Nelson et al., 1998, Wright et al., 2000, Velakoulis et al., 2006). We assessed habituation to both neutral faces and objects to probe whether reduced habituation is specific to social stimuli. Finally, post-scan memory measures were collected to test whether greater hippocampal habituation predicts better memory performance. We hypothesized that patients with schizophrenia would exhibit reduced habituation in the hippocampus and visual cortex for face and object stimuli, and that hippocampal habituation would be positively correlated with memory ability.

Section snippets

Subjects

Participants included 25 patients with schizophrenia (n = 18) or schizoaffective disorder (n = 7) and 23 healthy controls. Psychotic patients were recruited from the psychiatric inpatient unit and outpatient clinics of Vanderbilt University Medical Center. Healthy controls were recruited from the surrounding community via advertisements. The study protocol was approved by the Vanderbilt University Institutional Review Board, Nashville, TN, and written informed consent was obtained from all

Target detection

Performance on the target detection task was high (> 85% correct for all conditions) and did not differ between groups, indicating both groups were monitoring the stimuli (mean percent correct ± SD for Repeated faces, Different faces, Repeated objects, and Different objects in controls: 98 ± 4, 96 ± 4, 97 ± 4, 87 ± 10 and schizophrenia patients: 96 ± 6, 92 ± 9, 96 ± 7, 86 ± 10; all p > .17).

Hippocampus

In both groups the hippocampus was activated in response to the initial presentation of Repeated faces (Supplementary Fig.

Discussion

Here we used fMRI habituation to evaluate neural responses to repeated visual images in patients with schizophrenia, finding reduced habituation to repeated faces in the hippocampus and primary visual cortex. Including Different images allowed us to identify an additional deficit in schizophrenia. Healthy controls showed a pattern of hippocampal discrimination – habituation to Repeated images and enhancement to Different images – that was absent in schizophrenia patients. Hippocampal

Role of the funding source

This work was supported by the National Institute of Mental Health (grant R01 MH070560 to SH; grant K01 MH083052 to JUB), and the National Center for Research Resources (grant UL1 RR024975-01, now at the National Center for Advancing Translational Sciences, Grant 2 UL1 TR000445-06, to LEW). The NIMH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The content is

Contributors

LEW, JUB, IG, and SH designed the study. LEW assembled the stimuli, programmed the experiment, and collected the data. LEW and JUB analyzed the data. LEW, JUB, IG, and SH interpreted the data. AL did the manual hippocampal segmentation. LEW wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflicts of interest

Dr. Williams has received funding from the National Center for Research Resources. Dr. Blackford has received funding from the National Institute of Mental Health. Andrew Luksik reports no actual or potential conflicts of interest. Dr. Gauthier has received funding from the National Institute of Health, the National Science Foundation and the James S. McDonnell Foundation. Dr. Heckers has received funding from the National Institute of Mental Health and served as an unpaid consultant to DSM-5.

Acknowledgments

The authors would like to thank Kristan Armstrong, Julia Sheffield, Dr. Baxter Rogers, and Dr. Neil Woodward for their assistance and feedback.

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