Although a range of cognitive and information-processing deficits have been consistently observed in schizophrenia, a meta-analysis of neuropsychological studies found that the largest effect sizes for cognitive dysfunction in schizophrenia are for verbal learning and memory (3
). This suggests that there may be a more severe deficit in learning and memory against a background of less severe generalized cognitive dysfunction (68
). This memory impairment is not accounted for by demographic variables such as education or sex (74
), or by clinical variables such as medication exposure, or duration and severity of illness (2
). The cognitive profile of long-term memory deficits is similar for both unmedicated first-episode and previously-treated patients (75
), and remains stable over time (76
). Memory impairment is also a stronger predictor of patients’ functional outcome than either clinical symptoms or a range of other cognitive or demographic variables (8
). These functional measures include activities of daily living and occupational performance (9
The pattern of memory deficits in patients with schizophrenia is similar to what is seen in patients with PFC lesions (described above) or in patients with dementing disorders that affect fronto-striatal function, such as Huntington’s or Parkinson’s dementia. As in these other disorders, encoding and retrieval processes appear to be more impaired than long-term storage (68
). Patients with schizophrenia do not show the pattern of rapid forgetting that is observed in cortical dementias such as Alzheimer’s disease.
In general, the relative severity of memory deficits in schizophrenia depends on the specific conditions under which information is learned and the way in which retrieval is tested. For instance, during encoding, it appears that patients typically do not utilize semantic encoding strategies in order to facilitate encoding and retrieval (68
). This may reflect an underlying failure in the self-generation of organizational strategies (81
). This “strategic memory” account is supported by findings that patients can benefit from training in semantic organizational strategies (86
), from being administered blocked versus un-blocked lists of words (68
), and from engaging in “deep” semantic rather than “shallow” perceptual level of item-specific processing during encoding (87
During retrieval, schizophrenia patients exhibit deficits more consistently on recall tests than on recognition tasks (86
). This is not to say, however, that recognition is unimpaired—indeed, a recent meta-analysis of memory studies in schizophrenia found moderate effects on recognition performance and large effects on recall performance (2
). Further exploration of recognition memory has suggested that patients with schizophrenia may rely more on familiarity, rather than recollection of the event. Consistent with this idea, one study showed that patients exhibited intact familiarity based recognition , but recollection was severely impaired (89
), although this pattern was not observed in a different study (90
). This general pattern of memory deficits bears similarity to what has been observed both in patients with focal hippocampal dysfunction (37
) and in patients with focal prefrontal lesions (58
). One caveat to interpreting the results described above, however, is that selective recollection/recall deficits might simply reflect greater sensitivity of these measures, as compared to familiarity/recognition measures (92
). Accordingly, one goal of the CNTRICS initiative will be to more precisely ascertain whether selective patterns of memory deficits might be obtained even when using measures that are equated for sensitivity.
Given the results described above, it is not surprising that functional imaging studies of episodic memory in schizophrenia have consistently reported abnormal patterns of activity in the MTL and PFC (93
). Heckers and colleagues (94
) were the first to find evidence of abnormal hippocampal recruitment during word retrieval. Unlike healthy participants who activated a right frontal-temporal network during word retrieval, schizophrenia patients had reduced hippocampal and abnormally increased frontal activation. Reductions in hippocampal volume and memory-related activation were subsequently replicated in the schizophrenia literature (see 95
, for review). However, these hippocampal abnormalities were invariably accompanied by evidence of abnormal PFC recruitment (e.g., 96). This has led some to propose that memory impairment in schizophrenia might reflect abnormal functional connectivity between the PFC, the hippocampus, thalamus, and cerebellum (97
). This fronto-temporal disconnection hypothesis of schizophrenia (98
) has received some support through functional connectivity analysis of activity in PFC and MTL seed regions (99
), although it should be noted that these studies are correlational and do not establish causality or directionality. Current limitations in the temporal resolution of the fMRI signal have made it difficult to determine whether episodic memory deficits in schizophrenia result from a focal deficit in a key MTL, PFC or other brain region that has upstream and downstream effects, or from a more distributed dysfunction in the integration of activity between these key brain regions.
Further insights into episodic memory deficits in schizophrenia have been gained by controlling and manipulating the types of encoding strategies to be used. Initial studies imaged patients during word retrieval and found greater right hippocampal activation in controls and greater anterior prefrontal activation (BA 10) in patients during cued recall of words that were encoded in the context of a deep (semantic) orienting task, as compared with retrieval of words that were encoded with a shallow (non-semantic) task (94
). Interestingly, group differences in the hippocampus were due to greater patient than control hippocampal activity during baseline and shallow retrieval conditions, resulting in less of a hippocampal increase in patients when deep minus shallow retrieval was contrasted. This retrieval study was followed by a series of encoding studies. The first encoding study (104
) imaged patients and controls while repeating a shallow and deep orienting task that had previously been administered outside of the scanner. Contrasts between deep minus shallow encoding revealed that patients showed reduced activation in VLPFC and increased superior temporal cortex activation. However, it was unclear whether repeating the task might have affected group differences in activity. Accordingly, subsequent encoding studies administered the shallow and deep encoding tasks for the first time in the scanner (105
). In these studies, patients and controls showed equivalent VLPFC activation in contrasts between deep minus shallow processing, suggesting that functioning in the VLPFC could be restored by providing patients and unaffected family members with item-specific semantic processing strategies. However, in these studies patients also showed a more diffuse pattern of activation in the contrast between deep and shallow encoding (including evidence of greater MTL activation in patients than controls), suggesting that providing patients with an item-specific encoding strategy does not fully normalize brain responses.
As in the basic cognitive neuroscience literature (19
), the majority of imaging studies of memory in schizophrenia have used item-specific, rather than relational encoding tasks, making them relatively insensitive to modulation of DLPFC activity. However, a number of schizophrenia studies have begun to examine higher-level associative memory tasks that are more likely to depend on control processes mediated by the DLPFC and on relational binding processes mediated by the hippocampus. One approach has been the use a transitive inference (TI) paradigm (108
) to contrast relational inferences (e.g., if “A>B” & “B>C”, then “A>C”) with item-specific recognition memory (e.g., is “A” old or new?). Initial behavioral studies documented a differential patient impairment in the TI condition (113
). In a subsequent fMRI study (109
), overall TI performance was intact in schizophrenia, although patients did have a selective deficit on TI trials in which the two items in each pair had an equal reinforcement history (BD pairs), in contrast to the remaining TI trials composed of items with unequal reinforcement histories. When all TI trials were contrasted with all non-TI trials, patients had unimpaired pre-supplementary motor and VLPFC activation, and reduced activation in the anterior cingulate gyrus and right parietal cortex. When TI BD pairs were contrasted with all remaining TI pairs, patients again had reduced right parietal activation and also reduced left hippocampal activation (109
). A second approach (114
) was to examine activation during tests of memory for object pairs that could either be solved on the basis of familiarity-based recognition (i.e., new vs. old pair) or required memory for previously studied associations (i.e., intact vs. rearranged pairs). Consistent with the TI results, performance impairments were specific to the associative memory task, and were accompanied by reduced left prefrontal and anterior cingulate activation during encoding and left DLPFC and right VLPFC during retrieval.
In sum, schizophrenia clearly affects MTL structure and function, with strong evidence of reduced hippocampal volume and disrupted hippocampal modulation during associative and non-associative retrieval tasks (95
). However, MTL dysfunction is frequently accompanied by PFC dysfunction, particularly when control processing demands are increased. Provision of semantic processing strategies can help to restore item-specific control processes, dramatically improve recognition performance, and re-engage VLPFC. However, patients continue to show a more diffuse pattern of activation even when encoding strategies are controlled, and may exhibit selective dysfunction in the DLPFC and hippocampus, particularly on relational memory measures.