This quantitative meta-analysis of episodic memory functional imaging studies, with a combined sample of 123 patients with schizophrenia and 137 healthy comparison subjects, found prominent deficits in the prefrontal cortex in patients. During encoding, these deficits were in the left frontopolar (BA 10, 32), ventrolateral (BA 45), and dorsolateral (BA 46) prefrontal cortex. During retrieval, the largest effects were also in the left ventrolateral and dorsolateral prefrontal cortex. When patients were provided with semantic encoding strategies, dorsolateral prefrontal cortex deficits remained, but activation of the ventrolateral prefrontal cortex was no longer reduced. This ventrolateral prefrontal cortex sparing is consistent with previous univariate (27
) and meta-analytic studies (71
), which suggests that the ventrolateral prefrontal cortex may compensate for reduced dorsolateral prefrontal cortex function during working memory and episodic encoding (21
). In contrast, there was no evidence of reduced hippocampal or surrounding medial temporal lobe activation in patients versus comparison subjects during encoding or retrieval. The only group difference in the medial temporal lobe was a relative increase
in activation in patients in the parahippocampal gyrus during encoding and retrieval. This prominent prefrontal dysfunction was not secondary to unequal performance, as prefrontal cortex deficits remained when studies that did not control for group performance differences were eliminated.
Patient dysfunction during encoding was relatively circumscribed, including portions of the prefrontal cortex and a default mode network (74
) previously associated with increased task-related deactivation in schizophrenia across a wide array of behavioral paradigms (75
). Frontal lobe dysfunction was localized to the frontopolar, ventrolateral, and dorsolateral prefrontal cortex. These three regions are associated with discrete working memory and episodic encoding functions. The frontopolar prefrontal cortex provides for selection and processing of subgoals during working memory (77
); the ventrolateral prefrontal cortex is involved with semantic processing and working memory maintenance (79
) and binding of items with their context during working memory and episodic encoding (80
); and the dorsolateral prefrontal cortex is involved with active working memory maintenance and manipulation (67
) and with processing relationships between items during encoding (82
). These functional deficits suggest that patients have difficulty selecting and maintaining rules to process items in their context and in relation to each other to facilitate encoding. If rules are provided, schizophrenia patients appear capable of ventrolateral prefrontal cortex-mediated item-specific processing but remain unable to recruit the dorsolateral prefrontal cortex to establish more interactive relational memory representations, leading to severe deficits in relational memory (21
Patient deficits were more distributed during retrieval, even after group performance differences were eliminated. Impairments were noted in a frontocortical-cerebellar-thalamic network previously described by Andreasen and colleagues (33
) as creating a condition of “cognitive dysmetria” in which patients have trouble coordinating sensorimotor and mental processes. However, cognitive dysmetria was formulated to extend beyond episodic retrieval, and our finding that these distributed regions were not impaired during encoding suggests that cognitive dysmetria cannot uniquely explain the pattern of our findings. On the other hand, evidence is accumulating that many components of this distributed network mediate specific cognitive functions that are important for successful episodic retrieval. The dorsolateral prefrontal cortex is associated with postretrieval monitoring (84
), the anterior cingulate gyrus with error or conflict detection (86
), the thalamus with attention and working memory (87
), and the cerebellum with working memory and mental flexibility (88
). These combined functional deficits suggest a scenario in which schizophrenia patients have difficulty monitoring their response output and detecting errors in order to flexibly adjust signal-detection thresholds to optimize sensitivity to targets while avoiding nontargets.
The aforementioned regions serve functions beyond episodic memory and are impaired in schizophrenia during other cognitive and emotional paradigms. The dorsolateral prefrontal cortex is broadly implicated in cognitive control mechanisms that allow information processing and behavior to vary adaptively from moment to moment, depending on current goals (89
). Our ALE findings may reflect a more general deficit in control mechanisms such as context maintenance (90
). Likewise, the thalamus is a central relay station that gates and filters sensory input to the cortex (91
), and thalamic dysfunction may reflect a fundamental deficit in sensory integration. Because ALE combines disparate studies, our analysis is not sufficiently constrained to establish functional specificity of these memory deficits. Establishing this level of specificity would require a focused effort, such as the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative (92
), to translate cognitive neuroscience tasks that are designed to parse these complex and overlapping functions to the study of schizophrenia.
The only group difference in the medial temporal lobe was increased activation in the parahippocampal gyrus in patients during encoding and retrieval. Overactivation in this and other regions (sensorimotor, middle cingulate gyrus, and middle temporal gyrus) in patients may reflect inefficient, compensatory brain activity as extraneous task-related activation can also be seen at early stages of learning before an optimal cognitive strategy has been reached (93
), and during reorganization following acute brain injury (94
). The parahippocampal gyrus is also associated with familiarity-based episodic retrieval (9
), and excess activity in this region may reflect patients’ overreliance on familiarity-based retrieval because of a specific recollection deficit (95
). Unlike the previous ALE study (22
), we did not find reduced hippocampal activation in schizophrenia, which may have resulted from our exclusion of region-of-interest studies to preserve the validity of the ALE method. The absence of hippocampal findings on the whole-brain level may have reflected increased susceptibility of small regions to smoothing artifact, although there were still no differences when the smoothing kernel was reduced to 6 mm and the ALEs repeated (data available on request). The absence of hippocampal findings may also reflect minimal relational binding demands (96
), as most included studies employed overlearned word stimuli. As more studies are performed that contrast relational versus item-specific encoding and retrieval, it will be interesting to see if medial temporal lobe differences can be detected on a meta-analytic level.
Several caveats must be considered when interpreting the results of this meta-analysis. First, in light of the limited number of articles meeting the study criteria, it was necessary to combine studies with disparate encoding and retrieval conditions and varying stimulus characteristics. This has the advantage of revealing the most robust and replicable task effects and group differences across memory paradigms, but the disadvantage of limiting our ability to ascribe specific brain regions to discrete memory processes. With a larger group of studies to choose from, it would be informative to segregate ALE analyses based on encoding condition (e.g., item-specific versus relational), stimulus modality (e.g., verbal, nonverbal), and retrieval task (e.g., recall versus recognition, cued versus uncued, item-specific versus relational). Second, the ALE method does not account for differences in sample size across included studies. This can be a strength in that it reveals the central tendency of the data, but a limitation if a study with a small sample and large effects that may not replicate is included and unduly influences overall results. Fortunately, the majority of studies had relatively equal sample sizes. Finally, all but two studies examined patients while they were receiving antipsychotic medication, which raises the question of drug effects. However, a qualitative examination of the two studies of unmedicated patients, both retrieval studies (33
), revealed the same pattern of reduced patient activation in prefrontal, cingulate, thalamic, and cerebellar regions that was seen in the studies of medicated patients. This apparent lack of medication effects is consistent with several studies of unmedicated patients (54
) that documented reduced prefrontal activation in patients that was not restored by antipsychotic treatment (98
In sum, the results of this study provide strong support for the conclusion that episodic memory impairments in schizophrenia during encoding and retrieval are related to a reduction in memory control mechanisms implemented by the anterior, ventrolateral, and dorsolateral prefrontal cortex. These results suggest that behavioral interventions developed for remediating memory deficits in patients with frontal lobe damage (99
) may also be applicable to schizophrenia. Use of pharmaco-fMRI (100
) to identify compounds that improve prefrontal function (102
) may also lead to new medications that improve memory and daily functioning in individuals with schizophrenia.