Prefrontal Activation Deficits During Episodic Memory in Schizophrenia

University of California-Davis Imaging Research Center, 4701 X St., Sacramento, CA 95817, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 06/2009; 166(8):863-74. DOI: 10.1176/appi.ajp.2009.08091307
Source: PubMed


Episodic memory impairments represent a core deficit in schizophrenia that severely limits patients' functional outcome. This quantitative meta-analysis of functional imaging studies of episodic encoding and retrieval tests the prediction that these deficits are most consistently associated with dysfunction in the prefrontal cortex.
Activation likelihood estimation (ALE) was used to perform a quantitative meta-analysis of functional imaging studies that contrasted patients with schizophrenia and healthy volunteers during episodic encoding and retrieval. From a pool of 36 potential studies, 18 whole-brain studies in standard space that included a healthy comparison sample and low-level baseline contrast were selected.
As predicted, patients showed less prefrontal activation than comparison subjects in the frontal pole, dorsolateral and ventrolateral prefrontal cortex during encoding, and the dorsolateral prefrontal cortex and ventrolateral prefrontal cortex during retrieval. The ventrolateral prefrontal cortex encoding deficits were not present in studies that provided patients with encoding strategies, but dorsolateral prefrontal cortex deficits remained and were not secondary to group performance differences. The only medial temporal lobe finding was relatively greater patient versus comparison subject activation in the parahippocampal gyrus during encoding and retrieval.
The finding of prominent prefrontal dysfunction suggests that cognitive control deficits strongly contribute to episodic memory impairment in schizophrenia. Memory rehabilitation approaches developed for patients with frontal lobe lesions and pharmacotherapy approaches designed to improve prefrontal cortex function may therefore hold special promise for remediating memory deficits in patients with schizophrenia.

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    • "For example, an fMRI meta-analysis (Ragland et al., 2009), found that the most consistent reductions in task-related activation in schizophrenia during encoding and retrieval were in the lateral PFC. Moreover, PFC dysfunction and associated memory deficits were reduced when cognitive control demands were minimized by providing incidental encoding strategies (Bonner-Jackson et al., 2005; Ragland et al., 2005, 2009). However, the lateral prefrontal cortex is composed of functionally and anatomically distinct subregions (D'Esposito et al., 1999; Petrides, 2000; Petrides et al., 2002), and the regional specificity of these episodic memory related PFC deficits in SZ is not well established. "
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    ABSTRACT: Background: Dorsal (DLPFC) and ventral (VLPFC) subregions in lateral prefrontal cortex play distinct roles in episodic memory, and both are implicated in schizophrenia. We test the hypothesis that schizophrenia differentially impairs DLPFC versus VLPFC control of episodic encoding. Methods: Cognitive control was manipulated by requiring participants to encode targets and avoid encoding non-targets based upon stimulus properties of test stimuli. The more automatic encoding response (target versus non-target) was predicted to engage VLPFC in both groups. Conversely, having to overcome the prepotent encoding response (non-targets versus targets) was predicted to produce greater DLPFC activation in controls than in patients. Encoding occurred during event-related fMRI in a sample of 21 individuals with schizophrenia and 30 healthy participants. Scanning was followed by recognition testing outside the scanner. Results: Patients were less successful differentially remembering target versus non-target stimuli, and retrieval difficulties correlated with more severe disorganized symptoms. As predicted, the target versus non-target contrast activated the VLPFC and correlated with retrieval success in both groups. Conversely, the non-target versus target contrast produced greater DLPFC activation in controls than in patients, and DLPFC activation correlated with performance only in controls. Conclusion: Individuals with schizophrenia can successfully engage the VLPFC to provide control over semantic encoding of individual items, but are specifically impaired at engaging the DLPFC to main context for task-appropriate encoding and thereby generate improved memory for target versus non-target items. This extends previous cognitive control models based on response selection tasks to the memory domain.
    Full-text · Article · Nov 2015 · Frontiers in Human Neuroscience
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    • "nditions versus control condition and viceversa ; ( d ) involvement of adult healthy participants ; ( e ) activation foci reported in 3D coordinates ( x , y , z ) in stereotactic space . Despite the presence of studies that have focused their analyses on specific Regions of Interest ( ROIs ) and may therefore bias the detection of cerebral areas ( Ragland et al . , 2009 ) , we included both whole brain and ROIs analyses because of the exiguous number of studies that have investigated the whole brain activity in reappraisal ( see Table 1 ) . Exclusion criteria were : ( a ) studies investigating emotion regulation strategies different than reappraisal ; ( b ) studies investigating reappraisal of positive"
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    ABSTRACT: Neuroimaginginvestigationshaveidentifiedtheneuralcorrelatesofreappraisalinexecutiveareas.Thesefindingshavebeeninterpretedasevidenceforrecruitmentofcontrolledprocesses,attheexpenseofautomaticprocesseswhenrespondingtoemotionalstimuli.However,activationofsemanticareashasalsobeenreported.Theaimofthepresentworkwastoaddresstheissueoftheimportanceofsemanticareasinemotionregulationbycomparingrecruitmentofexecutiveandemanticneuralsubstratesinstudiesinvestigatingdifferentreappraisalstrategies.Withthisaim,wereviewedneuroimagingstudiesonreappraisalandweclassifiedthemintwomaincategories:reappraisalofstimuli(RS)andreappraisalviaperspectivetaking(RPT).Weappliedacoordinate-basedmeta-analysistosummarizetheresultsoffMRIstudiesondifferentreappraisalstrategies.Ourresultsshowedthatreappraisal,whenconsideredregardlessofthespecificinstructionusedinthestudies,involvedbothexecutiveandsemanticareasofthebrain.Whenconsideringdifferentreappraisalstrategiesseparately,incontrast,wefoundareasassociatedwithexecutivefunctiontobeprominentlyrecruitedbyRS,evenifalsosemanticareaswereactivated.Instead,inRPTthemostimportantclustersofbrainactivitywerefoundinparietalandtemporalsemanticareas,withoutsignificantclustersinexecutiveareas.Theseresultsindicatethatmodulationofactivityinsemanticareasmayconstituteanimportantaspectofemotionregulationinreappraisal,suggestingthatsemanticprocessesmaybemoreimportanttounderstandthemechanismofemotionregulationthanpreviouslythought.
    Full-text · Article · Jul 2015 · Frontiers in Psychology
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    • "They are often seen at the initial diagnosis and may already be present in the prodromal phase of the illness (Tandon, et al., 2009). Functional MRI (fMRI) can reliably map episodic memory processes using appropriate tasks (Hutcheson, et al., 2012; Ragland, et al., 2009). Early work investigating episodic memory in schizophrenia focused on abnormal activation of specific brain regions such as the hippocampus (Heckers , et al., 1999) and prefrontal cortex (Ragland, et al., 2001). "
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    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.
    Full-text · Article · Dec 2014 · Human Brain Mapping
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