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Clinical Trial
. 2015 Apr;36(4):1442-57.
doi: 10.1002/hbm.22714. Epub 2014 Dec 11.

Effective Connectivity During Episodic Memory Retrieval in Schizophrenia Participants Before and After Antipsychotic Medication

Affiliations
Free PMC article
Clinical Trial

Effective Connectivity During Episodic Memory Retrieval in Schizophrenia Participants Before and After Antipsychotic Medication

Nathan L Hutcheson et al. Hum Brain Mapp. .
Free PMC article

Abstract

Background: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto-temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto-temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication.

Methods: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1-week of antipsychotic treatment.

Results: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto-temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1-week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions.

Conclusions: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto-temporal dysconnectivity. Patterns of fronto-temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits.

Keywords: antipsychotic medication; effective connectivity; episodic memory; functional connectivity; hippocampus; memory encoding; memory retrieval; prefrontal cortex; schizophrenia; unmedicated.

Conflict of interest statement

Conflict of interest: All authors declare that they have no conflicts of interest.

Figures

Figure 1.
Figure 1.
Locations of the 11 spherical ROIs used for effective connectivity analyses, overlaid on a single subject T1 anatomic image in the axial plane. All spheres have a radius of 5 mm and coordinates are x, y, and z in MNI space and are mirrored on the left and right hemisphere except for the precuneus.
Figure 2.
Figure 2.
Schematic of steps used to analyze effective connectivity data. Shown are both the preprocessing steps and the statistical methods used to generate within- and between-group circle plots. Abbreviations: DARTEL, diffeomorphic anatomical registration through exponentiated lie algebra; HC, Healthy Control; HRF, hemodynamic response function; MVAR, multivariate autoregressive; RNC, retrieve new correct; ROC, retrieve old correct; ROI, region of interest; SPM, statistical parametric mapping; SZ, Schizophrenia; TR, repetition time.
Figure 3.
Figure 3.
Effective connectivity paths among the 11 ROI within the memory network in Healthy Controls (HC) and unmedicated patients with schizophrenia (SZ). The top row has within-group results for the unmedicated SZ group (n = 21) and matched HC group (n = 20). The bottom row has the between-group results showing paths that were significantly greater in HC than unmedicated SZ (HC > SZ) or paths that were significantly greater in SZ compared to HC (SZ > HC). Frontal brain regions are depicted in red and the posterior brain regions in blue. The sizes of the ROI circle and its label correspond to that region’s degree (number of in and out paths). Paths with greater strength (t values) are depicted as having thicker lines- t values range:3.35–7.31. ROIs are arranged as if looking on top of head from above with left on left and right on right. Abbreviations: HIP, posterior hippocampus; IFG, inferior frontal gyrus; Medial, medial frontal gyrus; MFG, middle frontal gyrus; STG, superior temporal gyrus. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 4.
Figure 4.
Effective connectivity paths among the 11 regions measured using a leave-one-out resampling technique within the sample of unmedicated participants with schizophrenia (n = 21). The plots show paths that were present in a portion of the 21 leave-one-out samples. Frontal brain regions are depicted in red and posterior brain regions in blue. The size of the Region of Interest (ROI) circle and its label correspond to that region’s degree (sum of the number of in and out paths). Paths with greater strength (t values) are depicted as having thicker lines- t values range 7.92–26.67. ROIs are arranged as if looking on top of head from above with left on left and right on right. Abbreviations are as follows: HIP, posterior hippocampus; IFG, inferior frontal gyrus; Medial, medial frontal gyrus; MFG, middle frontal gyrus; STG, superior temporal gyrus. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 5.
Figure 5.
Effective connectivity paths among the 11 regions measured within a sample of patients with schizophrenia (SZ; n = 16) before and after medication and Healthy Controls (HC; n = 16). The top row shows the withingroup results for SZ before and after medication and a matched HC subsample. The bottom row shows paths that were significantly greater in SZ after 1 week of medication compared to unmedicated SZ (Medicated SZ > Unmedicated SZ) and paths that were significantly greater before medication (Unmedicated SZ > Medicated SZ). Frontal brain regions are depicted in red and the posterior brain regions in blue. The size of the Region of Interest (ROI) circle and its label correspond to that region’s degree (number of in and out paths). Paths with greater strength (t values) are depicted as having thicker lines- t value range 3.10–19.09. ROIs are arranged as if looking on top of head from above with left on left and right on right. Abbreviations: HIP, posterior hippocampus; IFG, inferior frontal gyrus; Medial, medial frontal gyrus; MFG, middle frontal gyrus; STG, superior temporal gyrus. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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