Working memory functioning in schizophrenia patients and their first-degree relatives: cognitive functioning shedding light on etiology

There is accumulating evidence for involvement of the prefrontal cortex (PFC) in the pathophysiology of schizophrenia. A primary function supported by the PFC is working memory (WM). Findings from WM studies in schizophrenia can provide insight into the nature of clinical symptoms and cognitive deficits associated with this disorder, as well as begin to suggest areas of underlying neuropathology. To date, studies have not adequately investigated different WM domains (e.g., verbal, spatial, or object) or processing requirements (e.g., maintenance, monitoring, or manipulation), shown to be associated with distinct patterns of neural activation, in schizophrenia patients and their well relatives. Accordingly, this study evaluated the performance of schizophrenia patients, their first-degree biological relatives, and nonpsychiatric controls on a comprehensive battery of WM tasks and investigated the association among WM deficits and schizophrenia-spectrum psychopathology. The findings indicate that schizophrenia patients are consistently impaired on WM tasks, irrespective of WM domain or processing requirements. In contrast, their unaffected relatives are only impaired on WM tasks with higher central executive processing requirements. This pattern of WM performance may further implicate DLPFC dysfunction in the liability for schizophrenia and has implications for future cognitive, genetic, and neurodevelopmental research.     

Prefrontal cortex dysfunction mediates deficits in working memory and prepotent responding in schizophrenia.

BACKGROUND: Schizophrenic patients show deficits in working memory (WM) and inhibition of prepotent responses. We examined brain activity while subjects performed tasks that placed demands on WM and overriding prepotent response tendencies, testing predictions that both processes engage overlapping prefrontal cortical (PFC) regions and that schizophrenic patients show reduced PFC activity and performance deficits reflecting both processes. METHODS: Functional magnetic resonance imaging data were acquired while 16 schizophrenic and 15 healthy subjects performed the N-Back task that varied WM load and a version of the AX-CPT that required overriding a prepotent response tendency. RESULTS: Both tasks engaged overlapping cortical networks (e.g., bilateral dorsolateral PFC, Broca's area, parietal cortex). Increased WM load monotonically increased activity; preparation to override a prepotent response produced greater and more enduring activity. Group differences on each task emerged in a right dorsolateral PFC region: schizophrenic subjects showed lesser magnitude increases under conditions of high WM and prepotent response override demands, with concomitant performance impairments. CONCLUSIONS: Schizophrenic patients exhibit PFC-mediated deficits in WM and preparation to override prepotent responses. Findings are consistent with the operation of a single underlying PFC-mediated cognitive control mechanism and with physiologic dysfunction of the dorsolateral PFC in schizophrenic patients reflecting impairments in this mechanism.     

Lateral and medial hypofrontality in first-episode schizophrenia: functional activity in a medication-naive state and effects of short-term atypical antipsychotic treatment

OBJECTIVE: The dorsolateral prefrontal cortex and the anterior cingulate cortex are critical components of the brain circuitry underlying executive control. The objective of this study was to investigate control-related dorsolateral prefrontal cortex functioning and conflict-related anterior cingulate cortex functioning in a group of never medicated first-episode schizophrenia patients to determine whether both regions show dysfunction at illness onset. A second objective was to assess short-term effects of atypical antipsychotic medication on dorsolateral prefrontal cortex and anterior cingulate cortex functioning. METHOD: First-episode schizophrenia patients (N=23) and healthy comparison subjects (N=24) underwent event-related fMRI and performed a cognitive task designed to functionally dissociate the two regions. Four weeks after initiation of pharmacotherapy for patients, a subset of 11 patients and 16 comparison subjects underwent a repeat assessment. RESULTS: At baseline, patients exhibited hypoactivation in the dorsolateral prefrontal cortex and anterior cingulate cortex. After 4 weeks of antipsychotic treatment, the patients demonstrated improved functioning in the anterior cingulate cortex but not in the dorsolateral prefrontal cortex. CONCLUSIONS: These findings confirm the presence of dorsolateral prefrontal cortex dysfunction early in the course of schizophrenia and suggest that anterior cingulate cortex functioning may be altered at illness onset as well. Results also suggest that anterior cingulate cortex functioning may be especially sensitive to remedial antipsychotic treatment effects. These findings are consistent with an emerging literature documenting short-term benefits of atypical antipsychotic medication for the neural circuitry underlying cognitive deficits in schizophrenia.     

Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia.

OBJECTIVE: The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms. METHOD: Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the "n-back" sequential-letter working memory task. RESULTS: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms. CONCLUSIONS: These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory.     

Working memory abnormalities in chronic interictal epileptic psychosis and schizophrenia revealed by magnetoencephalography

Working memory (WM) deficits are considered a core cognitive dysfunction in schizophrenia. To determine cognitive abnormalities in chronic interictal psychosis (CIP), and to assess whether these abnormalities are distinguishable from those seen in schizophrenia in terms of WM deficits, we used magnetoencephalography during a WM task performed by patients with CIP, nonpsychotic epilepsy, and schizophrenia and by healthy subjects. Multiple Source Beamformer and Brain-Voyager were used for analysis. In both patients with CIP and those with schizophrenia, we found dorsolateral prefrontal hyperactivation and left inferior temporal hypoactivation, as indicated by alpha event-related desynchronization and synchronization, respectively. Patients with schizophrenia also showed alpha2 event-related desynchronization in the mid-prefrontal cortex relative to healthy controls. Direct comparison of patients with CIP and schizophrenia rendered no difference in source-power changes. Our findings indicate similar functional cognitive abnormalities in CIP and schizophrenia in the prefrontal and left temporal cortex, which supports the possibility that these disorders share common underlying pathophysiological mechanisms.     

Alterations in functional activation in euthymic bipolar disorder and schizophrenia during a working memory task

Dysfunctions in prefrontal cortical networks are thought to underlie working memory (WM) impairments consistently observed in both subjects with bipolar disorder and schizophrenia. It remains unclear, however, whether patterns of WM‐related hemodynamic responses are similar in bipolar and schizophrenia subjects compared to controls. We used fMRI to investigate differences in blood oxygen level dependent activation during a WM task in 21 patients with euthymic bipolar I, 20 patients with schizophrenia, and 38 healthy controls. Subjects were presented with four stimuli (abstract designs) followed by a fifth stimulus and required to recall whether the last stimulus was among the four presented previously. Task‐related brain activity was compared within and across groups. All groups activated prefrontal cortex (PFC), primary and supplementary motor cortex, and visual cortex during the WM task. There were no significant differences in PFC activation between controls and euthymic bipolar subjects, but controls exhibited significantly increased activation (cluster‐corrected P < 0.05) compared to patients with schizophrenia in prefrontal regions including dorsolateral prefrontal cortex (DLPFC). Although the bipolar group exhibited intermediate percent signal change in a functionally defined DLPFC region of interest with respect to the schizophrenia and control groups, effects remained significant only between patients with schizophrenia and controls. Schizophrenia and bipolar disorder may share some behavioral, diagnostic, and genetic features. Differences in the patterns of WM‐related brain activity across groups, however, suggest some diagnostic specificity. Both patient groups showed some regional task‐related hypoactivation compared to controls across the brain. Within DLPFC specifically, patients with schizophrenia exhibited more severe WM‐related dysfunction than bipolar subjects. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

An FMRI study of episodic encoding and recognition of words in patients with schizophrenia in remission

OBJECTIVE: Verbal memory deficits are among the most severe cognitive deficits observed in patients with schizophrenia. This study examined patterns of brain activity during episodic encoding and recognition of words in patients with schizophrenia. METHOD: Functional magnetic resonance imaging (fMRI) was used to study regional brain activation in 10 healthy male comparison subjects and 10 male outpatients with schizophrenia during performance of a modified version of the words subtest of Warrington's Recognition Memory Test. RESULTS: Despite having intact performance in word recognition, the patients with schizophrenia had less activation of the right dorsolateral and anterior prefrontal cortex, right anterior cingulate, and left lateral temporal cortex during word encoding, compared with the healthy comparison subjects. During word recognition, the patients had impairments in activation of the bilateral dorsolateral prefrontal and lateral temporal cortices. CONCLUSIONS: Schizophrenia was associated with attenuated frontotemporal activation during episodic encoding and recognition of words. These results from an fMRI study replicate earlier findings derived from a positron emission tomography study.     

Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis

OBJECTIVE: Context processing is a cognitive construct associated with activity in the middle frontal gyrus. Schizophrenia-related deficits in context processing tasks have been associated with prefrontal cortical dysfunction. This study evaluated whether prefrontal cortical dysfunction related to context processing occurred in first-episode, never-medicated schizophrenia patients, whether this dysfunction also occurred in patients with nonschizophrenia psychosis, and whether this dysfunction was related to psychotic symptom expression. METHOD: A modified version of the AX continuous performance task was conducted during event-related functional magnetic resonance imaging in 18 never-medicated, first-episode schizophrenia patients, 12 never-medicated patients with first-episode nonschizophrenia psychosis, and 28 comparison participants without psychiatric disorder. RESULTS: In-scanner measures of errors and interference reaction time showed that the schizophrenia patients had a specific deficit in context processing. Trials with greater context processing demands corresponded to activity in the middle frontal gyrus (Brodmann's area 9) in the comparison subjects and in the patients with nonschizophrenia psychosis, but not in the schizophrenia patients. Individual differences in prefrontal cortical dysfunction were associated with context processing measures and disorganization symptoms. The schizophrenia patients also showed increased activity in the anterior (Brodmann's area 10) and inferior prefrontal cortices (Brodmann's area 45/46) when they were maintaining context over a delay. CONCLUSIONS: Prefrontal dysfunctions related to context processing were found only in schizophrenia patients early in the course of the illness, and these dysfunctions were related to disorganization symptoms. Instead of using context processing during a continuous performance task, schizophrenia patients may use an inefficient encoding and retrieval strategy.     

fMRI study of maintenance and manipulation processes within working memory in first-episode schizophrenia

OBJECTIVE: Working memory, a critical cognitive capacity that is affected in schizophrenia, can be divided into maintenance and manipulation processes. Previous behavioral research suggested that manipulation is more affected than maintenance in patients with chronic schizophrenia. In this study of first-episode schizophrenia patients, the authors evaluated the extent to which the two working memory processes are affected early in the course of schizophrenia. METHOD: Study subjects were 11 first-episode schizophrenia patients and 11 matched healthy comparison subjects. Each group performed two verbal working memory tasks while undergoing functional magnetic resonance imaging. One task required maintenance of information; the other required manipulation of information in addition to maintenance. RESULTS: Under behaviorally matched conditions, both groups activated a predominantly left-sided frontal-parietal network. The manipulation plus maintenance task elicited activation of greater magnitude and spatial extent. With both tasks, patients showed less bilateral dorsolateral prefrontal cortex activation and greater ventrolateral prefrontal cortex activation, relative to the comparison subjects. A group-by-task interaction was observed for activation at the left dorsolateral and ventrolateral prefrontal cortex. The increase in activation when patients engaged in the manipulation plus maintenance task was disproportionately less in the dorsolateral prefrontal cortex and greater in the ventrolateral prefrontal cortex. CONCLUSIONS: These functional neuroanatomical findings add support to earlier suggestions that manipulation of information is selectively more affected than maintenance of information in persons with schizophrenia. They also suggest the presence of interacting regions of dysfunctional and compensatory prefrontal responses in the dorsolateral and ventrolateral prefrontal cortex, respectively, that are more prominent when information is manipulated. This disrupted prefrontal network is present relatively early in the course of schizophrenia.     

Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia

Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient‐control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination. Hum Brain Mapp 36:3793–3804, 2015. © 2015 Wiley Periodicals, Inc.     

The entorhinal cortex in first-episode psychotic disorders: a structural magnetic resonance imaging study

OBJECTIVE: Neuropathological findings regarding the entorhinal cortex in schizophrenia are conflicting. The authors used structural magnetic resonance imaging to examine the entorhinal cortex volumes of healthy subjects and medication-naive patients experiencing their first episode of psychotic illness. METHOD: The study included 33 patients with schizophrenia and related disorders, 11 patients with nonschizophrenic disorders, and 43 matched healthy subjects. All subjects were rated on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms, and volumetric measurements of the entorhinal cortex were obtained for all subjects. The authors examined differences across the groups as well as clinical correlations of entorhinal cortex volumes adjusted for intracranial volume. RESULTS: A significant diagnosis effect was seen in the left entorhinal cortex: patients with schizophrenia and related disorders and patients with nonschizophrenic psychotic disorders had smaller left entorhinal cortex volumes than healthy subjects. The mean entorhinal cortex volume of patients with schizophrenic disorders did not differ from that of patients with nonschizophrenic psychotic disorders. In patients with schizophrenic disorders, the entorhinal cortex volume positively correlated with severity of delusions. The mean entorhinal cortex volume of patients with nondelusional psychotic disorders was significantly smaller than that of patients with delusional psychotic disorders and healthy subjects. CONCLUSIONS: Smaller entorhinal cortex volume in first-episode, neuroleptic-naive psychotic disorders may not be a confound of the effects of illness chronicity or antipsychotic treatment. Entorhinal cortex pathology appears to have a significant association with positive symptoms, specifically delusions. The impairment of functions in which the entorhinal cortex participates-such as novelty detection, associative learning, and processing episodic, recognition, and autobiographical memory-could be responsible for its association with psychotic disorders and delusions.     

Increased prefrontal cerebral blood flow in first-episode schizophrenia following treatment: longitudinal positron emission tomography study

OBJECTIVE: Cognitive deficits, particularly those related to executive function and behavioural control, are a core feature of patients with schizophrenia and implicate disturbances of the prefrontal cortex (PFC). Consistent with this, functional imaging studies have identified abnormalities of PFC activity in chronically affected patients. The objective of the current study was to investigate executive-control related neural activity from first onset of the illness through to symptom stabilization. METHOD: The authors examined eight neuroleptic-na?ve first-episode psychosis (FEP) patients within 3 days of first presentation and eight healthy age- premorbid-IQ, and gender-matched controls (CTL). All FEP patients were later confirmed with a diagnosis of schizophrenia. Subjects underwent H2-15O positron emission tomography (PET) while performing the Stroop interference task that has previously been shown to engage the PFC in healthy samples. In a double-blind paradigm, FEP patients were randomly treated with either haloperidol or risperidone for 8 weeks, after which CTLs and all but one of the FEP patients were re-scanned. RESULTS: Behaviorally, there was no change in task performance from baseline to follow up for either the FEPs or CTLs. However, there were significant changes in functional activation in both groups across the same period. For CTLs, task-performance was associated with greater recruitment of posterior brain regions at follow up compared to baseline, while for FEP this involved greater recruitment frontal regions. Concurrently, FEP also showed significant improvement in positive symptomatology. CONCLUSIONS: These findings suggest that disturbances of the PFC often seen in FEP may be, at least partially, associated with acute symptom expression. However, it is still unclear whether this increase in frontal activity is due to symptom stabilization per se, the effects of medication, a lack of neurophysiological 'learning' with experience/practice, or a combination of these factors. In the context of the CTLs performance, we interpret the patient findings as reflective of greater neurophysiological effort required for task accomplishment relative to the learned, more automated, processing apparent in the CTLs.     

Prefrontal dysconnectivity links to working memory deficit in first-episode schizophrenia

Working memory (WM) deficit is a core feature of schizophrenia and is characterized by abnormal functional integration in the prefrontal cortex, including the dorsolateral prefrontal cortex (dLPFC), dorsal anterior cingulate cortex (dACC), and ventrolateral prefrontal cortex (vLPFC). However, the specific mechanism by which the abnormal neuronal circuits that involve these brain regions contribute to this deficit is still unclear. Therefore, this study focused on these regions and sought to answer which abnormal causal relationships in these regions can be linked to impaired WM in schizophrenia. We used spectral dynamic causal modeling to estimate directed (effective) connectivity between these regions based on resting-state functional magnetic resonance imaging data from healthy control (HC) subjects and patients with first-episode schizophrenia (FES). By comparing these effective connections in the controls and patients, we found that the effective connectivity from the dACC to the dLPFC and from the right dLPFC to the left vLPFC was weaker in the FES group than in the HC group. Furthermore, these effective connections displayed a positive correlation with WM performance in the HCs. However, in the FES patients, the effective connectivity from the dACC to the dLPFC was not correlated with WM performance, and the effective connectivity from the right dLPFC to the left vLPFC was negatively correlated with WM performance. These results could be explained by an aberrant top-down mechanism of WM processing and provide new evidence for the dysconnectivity hypothesis of schizophrenia.     

Psychopathology and working memory-induced activation of the prefrontal cortex in schizophrenia-like psychosis of epilepsy: Evidence from magnetoencephalography

Aim: The aim of this study was to investigate whether magnetoencephalographic oscillations underlying working memory dysfunction in the dorsolateral prefrontal cortex (DLPFC) are related to psychopathological disturbance in patients with schizophrenia‐like psychosis of epilepsy (SLPE). Methods: Twelve patients with SLPE and 14 non‐psychotic epilepsy controls participated in this study. Magnetoencephalography was recorded while patients performed a visual working memory (WM) task. Psychopathology was assessed using a four‐factor structure of the Brief Psychiatric Rating Scale, and regression analyses were carried out to examine the relative impact of severity of psychopathology on WM‐induced activation of the DLPFC. Results: We found that activation of the WM‐compromising DLPFC, as indicated by increased alpha desynchronization in patients with SLPE compared with their non‐psychotic counterparts, showed a positive linear correlation with disorganization symptom scores. This association remained significant after controlling for confounding factors, including age, task performance, IQ, and duration of psychosis. Conclusion: Our results indicate that abnormal activation in prefrontal areas engaged during working memory may be critical to domains of psychopathology, in particular disorganized thought‐processing in patients with SLPE.     

Sensory information processing in neuroleptic-naive first-episode schizophrenic patients: a functional magnetic resonance imaging study

BACKGROUND: Schizophrenic disorders are thought to involve widespread abnormalities in information processing. The present study used functional magnetic resonance imaging and a simple and robust paradigm that involved auditory and visual activation to examine basic sensory input circuits. Our aim was to determine which stages of the input processing network are disturbed in first-episode schizophrenic patients. METHODS: Twelve neuroleptic-naive inpatients (paranoid subtype) were compared with 11 healthy subjects by means of echo-planar functional magnetic resonance imaging. In a block design, the paradigm included the simultaneous presentation of a moving 6-Hz checkerboard and auditory stimuli in the form of drumbeats. The subjects were asked to simply look and listen. RESULTS: In comparison with control subjects, patients showed reduced activation in the right thalamus, the right prefrontal cortex, and the parietal lobe (restricted to the dorsal visual pathway) bilaterally. There were no notable differences in the primary visual cortex or the object-specific occipitotemporal pathway. In addition, patients presented with a reduced signal change to auditory stimulation in the left acoustic cortex. CONCLUSIONS: The present study supports the concept of widespread cortical and subcortical deficits in schizophrenia. Our findings suggest abnormal functioning early in the information processing and in high-order association cortices already at illness onset, before the administration of medication or the most confounding effects of illness duration. The main regions have been implicated in visual motion perception and discrimination as well as in attention to sensorial events and perceptual synthesis.     

A specific deficit in context processing in the unaffected siblings of patients with schizophrenia

BACKGROUND: Understanding the biological basis of complex, heritable illnesses such as schizophrenia is facilitated by sensitive and functionally specific measures of intermediate processes. Context processing is a theoretically motivated construct associated with executive function. Impairments in this process have been associated with dysfunction of the prefrontal cortex. In the present study, we evaluated whether a specific deficit in context processing could be associated with the unexpressed genetic liability to schizophrenia. METHODS: Twenty-four patients with schizophrenia, 24 unaffected siblings and 36 control subjects completed a version of the AX task with (1) a condition that required context processing and (2) an expectancy condition in which intact context processing could lead to errors. RESULTS: Patients and unaffected siblings performed relatively worse in the context processing condition, whereas controls performed relatively worse in the expectancy condition. A double dissociation between siblings and controls (F = 9.5, P<.005) constituted strong evidence of a specific deficit in context processing associated with a familial or genetic liability to schizophrenia. Preliminary evidence of high diagnostic efficiency was also noted (specificity, 38%; and sensitivity, 100%). CONCLUSIONS: Context processing deficits have been associated with dorsolateral prefrontal cortex dysfunctions in schizophrenia. Such a dysfunction may occur even when genetic liability to schizophrenia is unexpressed clinically. The present method of demonstrating a double dissociation may be a useful approach to exploring endophenotypes related to specific cognitive and neural processes that can be measured in ways sensitive to subtle group differences.     

Altered transfer of visual motion information to parietal association cortex in untreated first-episode psychosis: implications for pursuit eye tracking

Visual motion processing and its use for pursuit eye movement control represent a valuable model for studying the use of sensory input for action planning. In psychotic disorders, alterations of visual motion perception have been suggested to cause pursuit eye tracking deficits. We evaluated this system in functional neuroimaging studies of untreated first-episode schizophrenia (N=24), psychotic bipolar disorder patients (N=13) and healthy controls (N=20). During a passive visual motion processing task, both patient groups showed reduced activation in the posterior parietal projection fields of motion-sensitive extrastriate area V5, but not in V5 itself. This suggests reduced bottom-up transfer of visual motion information from extrastriate cortex to perceptual systems in parietal association cortex. During active pursuit, activation was enhanced in anterior intraparietal sulcus and insula in both patient groups, and in dorsolateral prefrontal cortex and dorsomedial thalamus in schizophrenia patients. This may result from increased demands on sensorimotor systems for pursuit control due to the limited availability of perceptual motion information about target speed and tracking error. Visual motion information transfer deficits to higher-level association cortex may contribute to well-established pursuit tracking abnormalities, and perhaps to a wider array of alterations in perception and action planning in psychotic disorders.     

Event-related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia

OBJECTIVE: Neuropsychological studies have demonstrated verbal episodic memory deficits in schizophrenia during word encoding and retrieval. This study examined neural substrates of memory in an analysis that controlled for successful retrieval. METHOD: Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation during word encoding and recognition in 14 patients with schizophrenia and 15 healthy comparison subjects. An unbiased multiple linear regression procedure was used to model the BOLD response, and task effects were detected by contrasting the signal before and after stimulus onset. RESULTS: Patients attended during encoding and had unimpaired reaction times and normal response biases during recognition, but they had lower recognition discriminability scores, compared with the healthy subjects. Analysis of contrasts was restricted to correct items. Previous findings of a deficit in bilateral prefrontal cortex activation during encoding in patients were reproduced, but patients showed greater parahippocampal activation rather than deficits in temporal lobe activation. During recognition, left dorsolateral prefrontal cortex activation was lower in the patients and right anterior prefrontal cortex activation was preserved, as in the authors' previous study using positron emission tomography. Successful retrieval was associated with greater right dorsolateral prefrontal cortex activation in the comparison subjects, whereas orbitofrontal, superior frontal, mesial temporal, middle temporal, and inferior parietal regions were more active in the patients during successful retrieval. CONCLUSIONS: The pattern of prefrontal cortex underactivation and parahippocampal overactivation in the patients suggests that functional connectivity of dorsolateral prefrontal and temporal-limbic structures is disrupted by schizophrenia. This disruption may be reflected in the memory strategies of patients with schizophrenia, which include reliance on rote rehearsal rather than associative semantic processing.     

Prefrontal-posterior parietal networks in schizophrenia: primary dysfunctions and secondary compensations

Background

Working memory (WM) deficits are well known in schizophrenia and have been associated with abnormal activation patterns of the prefrontal cortex (PFC) during cognitive performance. The magnitude and particularly the direction of the PFC activation— i.e., increased (hyperfrontality) or decreased (hypofrontality)— in schizophrenia, as well as its pathophysiological implications, remain controversial. Working memory is supported by a distributed neural network, whose main components are the PFC and the posterior parietal (PPC) cortices. Monkey studies indicate that, during WM performance, PFC functional lesions may be compensated by the PPC if task demands center mainly on anticipating responses, but not if they center on remembering cues. We hypothesized that a primarily dysfunctional PFC in schizophrenia might show hypofrontality or hyperfrontality as a result, respectively, of efficient or inefficient PPC compensation, as dictated by task demands. To test our proposition, we biased the demands of WM tasks toward anticipating responses or remembering cues and measured its impact on the PFC-PPC functional balance in a group of schizophrenic patients and one of normal control subjects.

Methods

We used functional magnetic resonance imaging to measure correlates of neuronal activity in the PFC and PPC of schizophrenic patients and control subjects performing WM tasks that either demanded information retention or allowed for response anticipation.

Results

When compared to control subjects, schizophrenic patients exhibited decreased PFC activation and increased PPC activation during anticipatory WM performance, and increased PFC activation during mnemonic WM performance.

Conclusions

In schizophrenia, a PFC dysfunction results in hypo- or hyperfrontality as a function of whether other alternate areas of a PFC-PPC network for WM are available and efficacious in supporting specific task demands.     

A subsequent-memory effect in dorsolateral prefrontal cortex

The importance of brain regions for long-term memory encoding has been examined by comparison of encoding-related neural activity on trials in which successful recollection subsequently occurred to the encoding-related activity on trials in which successful recollection did not occur. We applied similar analyses to event-related functional magnetic resonance imaging (fMRI) data to explore the relative roles of dorsolateral and ventrolateral prefrontal cortex (PFC) regions during specific components of a working-memory (WM) maintenance task. The results of this study indicated that increases in dorsolateral PFC activity during encoding was related to subsequent retrieval-success. These results lend support to the hypothesis that ventrolateral PFC mediates a limited-capacity WM buffer that supports rehearsal maintenance functions while dorsolateral PFC mediates WM organization functions that accommodate the capacity limits of WM maintenance.