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Original Investigation |

Altered Hippocampal-Parahippocampal Function During Stimulus Encoding:  A Potential Indicator of Genetic Liability for Schizophrenia

Roberta Rasetti, MD, PhD1; Venkata S. Mattay, MD1,2; Michael G. White, BS1,2; Fabio Sambataro, MD, PhD1,3; Jamie E. Podell, BS1; Brad Zoltick, MA1; Qiang Chen, PhD1,2; Karen F. Berman, MD1; Joseph H. Callicott, MD1; Daniel R. Weinberger, MD1,2,4,5,6,7
[+] Author Affiliations
1Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, Maryland
2Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
3Brain Center for Motor and Social Cognition, Istituto Italiano di Tecnologia @ UNIPr, Parma, Italy
4Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland
5Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
6Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
7The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA Psychiatry. 2014;71(3):236-247. doi:10.1001/jamapsychiatry.2013.3911.
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Importance  Declarative memory—the ability to learn, store, and retrieve information—has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder.

Objective  To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia.

Design, Setting, and Participants  Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and included a total of 308 participants (181 normal control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants were white of European ancestry.

Main Outcomes and Measures  All participants completed a declarative memory task involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while undergoing functional magnetic resonance imaging. Differences in hippocampus and parahippocampus activation and coupling across groups and correlations with accuracy were analyzed. Analyses were repeated in pairwise-matched samples.

Results  Both patients with schizophrenia and their healthy siblings showed reduced parahippocampal activation (bilaterally) and hippocampal-parietal (BA 40) coupling during the encoding of novel stimuli when compared with normal control participants. There was a significant positive correlation between parahippocampal activation during encoding and the visual-memory score.

Conclusions and Relevance  These results suggest that altered hippocampal-parahippocampal function during encoding is an intermediate biologic phenotype related to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-parahippocampal function with neuroimaging represents a potentially useful approach to understanding genetic mechanisms that confer risk for schizophrenia.

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Figure 1.
Main Effect of Diagnosis on Hippocampal Formation (HF) Activation

The figure illustrates blood oxygenation level–dependent (BOLD) signal differences across groups. A, The image shows the effect of diagnosis in HF activation during encoding of neutral scenes in the whole sample (normal control [NC] participants = 181, siblings [SIBs] = 65, and patients with schizophrenia [PTs] = 62) (left HF: x = −24, y = −36, z = −12 [Z = 3.94 and F = 10.46]; right HF: x = 24, y = −27, z = −9 [Z = 3.80 and F = 9.83]; all PFDR–whole-brain-corrected < .05; FDR indicates false-discovery rate). The graphs of contrast estimates from the significant voxels are shown in the middle (for the left HF) and on the right (for the right HF). B, The image shows the effect of diagnosis in HF activation during encoding of neutral scenes in the pairwise-matched sample of NCs (n = 54) and PTs (n = 54) (left HF: x = −24, y = −36, z = −9 [Z = 3.44 and PFDR_HF_ROI = .01, ROI indicates region of interest]; right HF: x = 24, y = −27, z = −9 [Z = 3.59 and PFDR_HF_ROI = .01]). The graphs of contrast estimates from the significant voxels are shown in the middle (for the left HF) and on the right (for the right HF). C, Pairwise-matched sample of NCs and SIBs (n = 110). The effect of diagnosis in HF activation during encoding of neutral scenes in the pairwise-matched sample of NCs (n = 55) and SIBs (n = 55) (left HF: x = −18, y = −36, z = −3 [Z = 3.06 and PFDR_HF_ROI = .06]). The graph of contrast estimates from the significant voxel is shown on the right (left HF). For illustrative purposes, the maps are thresholded at P = .01, uncorrected k>5. au indicates arbitrary unit.

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Figure 2.
Main Effect of Diagnosis on Posterior Hippocampus–Inferior Parietal Lobule (IPL) Coupling in Pairwise-Matched Samples

Between-group differences in psychophysiological interaction (PPI). A, Pairwise-matched sample of normal control (NC) participants and patients with schizophrenia (PTs) (N = 108). Decreased right posterior hippocampus/right IPL functional coupling was observed in PTs when compared with NCs (right IPL: x = 54, y = −42, z = 51 [Z = 2.96 and PFDR_IPL_ROI = .06; FDR indicates false-discovery rate; ROI, region of interest]; graph in the middle: contrast estimates from the significant voxel). A similar decrease was observed in the right posterior hippocampus/left IPL functional coupling (left IPL: x = −60, y = −36, z = 45 [Z = 3.63 and PFDR_IPL_ROI = .05]; graph on the right: contrast estimates from the significant voxel). Similar results were observed when seed was located in the left posterior hippocampus (see text for details). B, Pairwise-matched sample of NCs and siblings (SIBs) (N = 110). Decreased left posterior hippocampus/right IPL functional coupling was observed in SIBs when compared with NCs (right IPL: x = 39, y = −48, z = 42 [Z = 3.66 and PFDR_IPL_ROI = .02]; graph in the middle: contrast estimates from the significant voxel). A similar decrease was observed in the left posterior hippocampus/left IPL functional coupling (left IPL: x = −39, y = −48, z = 51 [Z = 2.81 and PFDR = .04; graph on the right: contrast estimates from the significant voxel). For illustrative purposes, the maps are thresholded at P = .05, uncorrected k>5. au indicates arbitrary unit; HF, hippocampal formation.

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Figure 3.
Scatterplot

Scatterplot illustrates the positive correlation between hippocampal formation engagement and visual-memory scores in the sample of normal control participants. au indicates arbitrary unit. N = 78, r = 0.33, and P = .003.

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