Neural correlates of verbal and nonverbal working memory deficits in individuals with schizophrenia and their high-risk siblings

Impaired working memory and functional brain activation deficits within prefrontal cortex (PFC) may be associated with vulnerability to schizophrenia. This study compared working memory and PFC activation in individuals with schizophrenia, their unaffected siblings and healthy comparison participants. We administered a "2back" version of the "nback" task. Functional MRI (fMRI) was used to measure brain activity. Nineteen individuals with DSM-IV schizophrenia, 18 of their siblings, and 72 healthy comparison participants underwent fMRI scans while performing word and face "nback" working memory tasks. Repeated trials (items whose prior presentation was not in the correct nback position) allowed us to assess group differences in the ability to code the temporal order of items. Individuals with schizophrenia and their siblings performed worse than controls on repeated lure trials, suggesting an association between schizophrenia and impairments in the coding of temporal order within working memory. Both individuals with schizophrenia and their siblings also demonstrated abnormal brain activation in PFC, such that both groups had hyperactivation in response to word stimuli and hypoactivation in response to face stimuli. These results provide further evidence that individuals with schizophrenia and their siblings are impaired in their ability to encode the temporal order of items within working memory and that disturbances in working memory and PFC activation may be genetic markers of the vulnerability to 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.     

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.     

Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia

OBJECTIVE: Abnormal activation of the dorsolateral prefrontal cortex and a related cortical network during working memory tasks has been demonstrated in patients with schizophrenia, but the responsible mechanism has not been identified. The present study was performed to determine whether neuronal pathology of the dorsolateral prefrontal cortex is linked to the activation of the working memory cortical network in patients with schizophrenia. METHOD: The brains of 13 patients with schizophrenia and 13 comparison subjects were studied with proton magnetic resonance spectroscopic ((1)H-MRS) imaging (to measure N-acetylaspartate as a marker of neuronal pathology) and with [(15)O]water positron emission tomography (PET) during performance of the Wisconsin Card Sorting Test (to measure activation of the working memory cortical network). An independent cohort of patients (N=7) was also studied in a post hoc experiment with (1)H-MRS imaging and with the same PET technique during performance of another working memory task (the "N-back" task). RESULTS: Measures of N-acetylaspartate in the dorsolateral prefrontal cortex strongly correlated with activation of the distributed working memory network, including the dorsolateral prefrontal, temporal, and inferior parietal cortices, during both working memory tasks in the two independent groups of patients with schizophrenia. In contrast, N-acetylaspartate in other cortical regions and in comparison subjects did not show these relationships. CONCLUSIONS: These findings directly implicate a population of dorsolateral prefrontal cortex neurons as selectively accounting for the activity of the distributed working memory cortical network in schizophrenia and complement other evidence that dorsolateral prefrontal cortex connectivity is fundamental to the pathophysiology of the disorder.     

Prefrontal broadband noise, working memory, and genetic risk for schizophrenia

OBJECTIVE: It has been suggested that increased variability of prefrontal physiological responses may represent a fundamental mechanism underlying frontal lobe deficits in schizophrenia. Increased response variability ("noise") is thought to result from impaired phase resetting of stimulus-induced dynamic changes of ongoing rhythmic oscillations (field potentials) generated in the apical dendrites of pyramidal neurons. In the present study, the authors explored whether this particular physiological abnormality predicts working memory performance and is related to the genetic risk for schizophrenia. METHOD: Prefrontal response variability of discrete frequency components was investigated across a broad frequency range (0.5-45.0 Hz) during processing of an oddball paradigm in patients with schizophrenia (N=66), their clinically unaffected siblings (N=115), and healthy comparison subjects (N=89). RESULTS: As hypothesized, prefrontal noise was negatively correlated with working memory performance across all subjects. In addition, it was observed that prefrontal noise possesses trait characteristics and is strongly associated with genetic risk for schizophrenia. CONCLUSIONS: Frontal lobe-related cognitive function depends on the ability to synchronize cortical pyramidal neurons, which is in part genetically controlled. Increased prefrontal "noise" is an intermediate phenotype related to genetic susceptibility for schizophrenia.     

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.     

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.     

Schizophrenic Patients and Their Unaffected Siblings Share Increased Resting-State Connectivity in the Task-Negative Network but Not Its Anticorrelated Task-Positive Network

Background:

Abnormal connectivity of the anticorrelated intrinsic networks, the task-negative network (TNN), and the task-positive network (TPN) is implicated in schizophrenia. Comparisons between schizophrenic patients and their unaffected siblings enable further understanding of illness susceptibility and pathophysiology. We examined the resting-state connectivity differences in the intrinsic networks between schizophrenic patients, their unaffected siblings, and healthy controls.

Methods:

Resting-state functional magnetic resonance images were obtained from 25 individuals in each subject group. The posterior cingulate cortex/precuneus and right dorsolateral prefrontal cortex were used as seed regions to identify the TNN and TPN through functional connectivity analysis. Interregional connectivity strengths were analyzed using overlapped intrinsic networks composed of regions common to all subject groups.

Results:

Schizophrenic patients and their unaffected siblings showed increased connectivity in the TNN between the bilateral inferior temporal gyri. By contrast, schizophrenic patients alone demonstrated increased connectivity between the posterior cingulate cortex/precuneus and left inferior temporal gyrus and between the ventral medial prefrontal cortex and right lateral parietal cortex in the TNN. Schizophrenic patients exhibited increased connectivity between the left dorsolateral prefrontal cortex and right inferior frontal gyrus in the TPN relative to their unaffected siblings, though this trend only approached statistical significance in comparison to healthy controls.

Conclusion:

Resting-state hyperconnectivity of the intrinsic networks may disrupt network coordination and thereby contribute to the pathophysiology of schizophrenia. Similar, though milder, hyperconnectivity of the TNN in unaffected siblings of schizophrenic patients may contribute to the identification of schizophrenia endophenotypes and ultimately to the determination of schizophrenia risk genes.     

Prefrontal Inefficiency Is Associated With Polygenic Risk for Schizophrenia

Considering the diverse clinical presentation and likely polygenic etiology of schizophrenia, this investigation examined the effect of polygenic risk on a well-established intermediate phenotype for schizophrenia. We hypothesized that a measure of cumulative genetic risk based on additive effects of many genetic susceptibility loci for schizophrenia would predict prefrontal cortical inefficiency during working memory, a brain-based biomarker for the disorder. The present study combined imaging, genetic and behavioral data obtained by the Mind Clinical Imaging Consortium study of schizophrenia (n = 255). For each participant, we derived a polygenic risk score (PGRS), which was based on over 600 nominally significant single nucleotide polymorphisms, associated with schizophrenia in a separate discovery sample comprising 3322 schizophrenia patients and 3587 control participants. Increased polygenic risk for schizophrenia was associated with neural inefficiency in the left dorsolateral prefrontal cortex after covarying for the effects of acquisition site, diagnosis, and population stratification. We also provide additional supporting evidence for our original findings using scores based on results from the Psychiatric Genomics Consortium study. Gene ontology analysis of the PGRS highlighted genetic loci involved in brain development and several other processes possibly contributing to disease etiology. Our study permits new insights into the additive effect of hundreds of genetic susceptibility loci on a brain-based intermediate phenotype for schizophrenia. The combined impact of many common genetic variants of small effect are likely to better reveal etiologic mechanisms of the disorder than the study of single common genetic variants.Key words: schizophrenia, DLPFC, working memory, intermediate phenotype, fMRI, genetic risk score     

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.     

An fMRI investigation of procedural learning in unaffected siblings of individuals with schizophrenia

Vulnerability for schizophrenia is related, in part, to genetic predisposition. The identification of pathophysiological abnormalities associated with the disorder that are also present in unaffected family members of individuals with schizophrenia may assist in delineating the genetic contributions to vulnerability for schizophrenia. Previous functional Magnetic Resonance Imaging (fMRI) investigations of procedural learning in patients with schizophrenia identified reduced activity in the frontal cortex, basal ganglia, and parietal cortex during performance of the serial reaction time (SRT) task suggesting that abnormal function of these regions may relate to genetic vulnerability for schizophrenia. In order to examine this hypothesis, 12 unaffected siblings of patients and 15 controls underwent fMRI during performance of the SRT task. Unaffected siblings demonstrated normal performance on the SRT task. However, compared to controls unaffected siblings demonstrated less activity in regions of the frontal and parietal lobes and, to a lesser extent, basal ganglia, during procedural learning. Interestingly, unaffected siblings demonstrated greater activity in regions of the frontal cortex during the control condition compared to the procedural learning condition of the SRT task, an idiosyncratic pattern that was also observed in patient groups but not control subjects of two prior imaging studies. The findings support previous investigations suggesting that altered cerebral neurophysiology during performance of cognitive tasks may be related to genetic vulnerability for schizophrenia. Identification of genes related to the function of cerebral regions such as the prefrontal cortex, parietal lobe, and basal ganglia may assist in delineating the genetic contributions to schizophrenia.     

Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression.

BACKGROUND: A large number of studies suggest the presence of deficits in dorsolateral prefrontal cortex function during performance of working memory tasks in individuals with schizophrenia. However, working memory deficits may also present in other psychiatric disorders, such as major depression. It is not clear whether people with major depression also demonstrate impaired prefrontal activation during performance of working memory tasks. METHODS: We used functional magnetic resonance imaging to assess the patterns of cortical activation associated with the performance of a 2-back version of the N-Back task (working memory) in 38 individuals with schizophrenia and 14 with major depression. RESULTS: We found significant group differences in the activation of dorsolateral prefrontal cortex associated with working memory performance. Consistent with prior research, participants with schizophrenia failed to show activation of right dorsolateral prefrontal cortex in response to working memory tasks demands, whereas those with major depression showed clear activation of right and left dorsolateral prefrontal cortex as well as bilateral activation of inferior and superior frontal cortex. CONCLUSIONS: During performance of working memory tasks, deficits in prefrontal activation, including dorsolateral regions, are more severe in participants with schizophrenia (most of whom were recently released outpatients) than in unmedicated outpatients with acute nonpsychotic major depression.     

Working memory deficits and levels of N-acetylaspartate in patients with schizophreniform disorder

OBJECTIVE: The authors used proton magnetic resonance spectroscopic imaging ((1)H-MRSI) to assess potential reductions of N-acetylaspartate (a marker of neuronal integrity) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophreniform disorder. In addition, they assessed the relationship between N-acetylaspartate levels and working memory deficits. METHOD: Twenty-four patients with DSM-IV schizophreniform disorder and 24 healthy subjects were studied. Subjects underwent (1)H-MRSI and were given the N-back working memory test. RESULTS: The schizophreniform disorder patients had selective reductions of N-acetylaspartate ratios in the hippocampal area and the dorsolateral prefrontal cortex, and a positive correlation was seen between N-acetylaspartate ratios in the dorsolateral prefrontal cortex and performance during the 2-back working memory condition. CONCLUSIONS: Similar to findings reported in schizophrenia studies, N-acetylaspartate reductions in the hippocampal area and the dorsolateral prefrontal cortex were seen in patients with schizophreniform disorder. Moreover, the results support other evidence that neuronal pathology in the dorsolateral prefrontal cortex accounts for a proportion of working memory deficits already present at illness outset.     

Inefficient executive cognitive control in schizophrenia is preceded by altered functional activation during information encoding: an fMRI study

Working memory deficits are a core feature of schizophrenia. Previous working memory studies suggest a load dependent storage deficit. However, explicit studies of higher executive working memory processes are limited. Moreover, few studies have examined whether subcomponents of working memory such as encoding and maintenance of information are differentially affected by these deficits. Therefore, the aim of the present study was to examine the neural substrates of working memory subprocesses requiring stimulus encoding, maintenance and higher executive processing. Using functional magnetic resonance imaging a modified Sternberg working memory task involving verbal stimulus material was applied. The event-related design enabled the segregation of encoding, active maintenance and executive manipulation of information. Forty-one patients with schizophrenia and 41 healthy subjects were included. Relative to normal controls, schizophrenic patients demonstrated a significantly stronger activation pattern in a fronto-parietal network during executive information manipulation. Additionally, significant relative hypoactivity was detectable in the thalamus. Conversely, during stimulus encoding the patients demonstrated lower activation relative to controls in the prefrontal cortex and the anterior cingulate gyrus. The present findings indicate a pronounced prefrontal functional hyperactivation within the neural network subserving higher executive working memory control processes in schizophrenia. Moreover, they suggest that these altered activations during executive control are related to a preceding abnormality of information encoding. During encoding, a reduced activation in mainly dorsolateral prefrontal and anterior cingulate regions was observed. These results could be explained by increased top-down control processing from prefrontal cortex as a compensation for functional deficits occurring during encoding.     

Prefrontal Brain Network Connectivity Indicates Degree of Both Schizophrenia Risk and Cognitive Dysfunction

Objective:

Cognitive dysfunction is a core feature of schizophrenia, and persons at risk for schizophrenia may show subtle deficits in attention and working memory. In this study, we investigated the relationship between integrity of functional brain networks and performance in attention and working memory tasks as well as schizophrenia risk.

Methods:

A total of 235 adults representing 3 levels of risk (102 outpatients with schizophrenia, 70 unaffected first-degree relatives of persons with schizophrenia, and 63 unrelated healthy controls [HCs]) completed resting-state functional magnetic resonance imaging and a battery of attention and working memory tasks (Brief Test of Attention, Hopkins Verbal Learning Test, and Brief Visuospatial Memory Test) on the same day. Functional networks were defined based on coupling with seeds in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and primary visual cortex. Networks were then dissected into regional clusters of connectivity that were used to generate individual interaction matrices representing functional connectivity within each network.

Results:

Both patients with schizophrenia and their first-degree relatives showed cognitive dysfunction compared with HCs. First canonicals indicated an inverse relationship between cognitive performance and connectivity within the DLPFC and MPFC networks. Multivariate analysis of variance revealed multivariate main effects of higher schizophrenia risk status on increased connectivity within the DLPFC and MPFC networks.

Conclusions:

These data suggest that excessive connectivity within brain networks coupled to the DLPFC and MPFC, respectively, accompany cognitive deficits in persons at risk for schizophrenia. This might reflect compensatory reactions in neural systems required for cognitive processing of attention and working memory tasks to brain changes associated with schizophrenia.Key words: resting state, fMRI, default-mode network, attention, working memory     

A preliminary functional magnetic resonance imaging study in offspring of schizophrenic parents

Studies of high-risk offspring (HR) of schizophrenic patients have found abnormalities in attention, working memory and executive functions, suggesting impaired integrity of the prefrontal cortex and related brain regions. The authors conducted a preliminary high-field (3 T) functional magnetic resonance imaging (fMRI) study to assess performance and activation during a memory-guided saccade (MGS) task, which measures spatial working memory. HR subjects showed significant decreases in fMRI-measured activation in the dorsolateral prefrontal cortex (Brodmann's areas 8 and 9/46) and the inferior parietal cortex (Brodmann's area 40) compared to age- and sex-matched healthy controls (HC). Abnormal functional integrity of prefrontal and parietal regions of the heteromodal association cortical (HAC) regions in subjects at genetic risk for schizophrenia is consistent with findings observed in adults with the illness [Callicott et al., Cereb. Cortex 10 (2000) 1078; Manoach et al., Biol. Psychiatry 48 (2000) 99.]. These abnormalities need to be prospectively investigated in nonpsychotic individuals at risk for schizophrenia in order to determine their predictive value for eventual emergence of schizophrenia or related disorders.     

Dysfunctional prefrontal regional specialization and compensation in schizophrenia

OBJECTIVE: It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits. METHOD: Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects. RESULTS: High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high- and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex. CONCLUSIONS: The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition.     

Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down

OBJECTIVE: Numerous neuroimaging studies have examined the function of the dorsolateral prefrontal cortex in schizophrenia; although abnormalities usually are identified, it is unclear why some studies find too little activation and others too much. The authors' goal was to explore this phenomenon. METHOD: They used the N-back working memory task and functional magnetic resonance imaging at 3 T to examine a group of 14 patients with schizophrenia and a matched comparison group of 14 healthy subjects. RESULTS: Patients' performance was significantly worse on the two-back working memory task than that of healthy subjects. However, there were areas within the dorsolateral prefrontal cortex of the patients that were more active and areas that were less active than those of the healthy subjects. When the groups were subdivided on the basis of performance on the working memory task into healthy subjects and patients with high or low performance, locales of greater prefrontal activation and locales of less activation were found in the high-performing patients but only locales of underactivation were found in the low-performing patients. CONCLUSIONS: These findings suggest that patients with schizophrenia whose performance on the N-back working memory task is similar to that of healthy comparison subjects use greater prefrontal resources but achieve lower accuracy (i.e., inefficiency) and that other patients with schizophrenia fail to sustain the prefrontal network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in schizophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex.     

Dorsolateral prefrontal cortex activity during maintenance and manipulation of information in working memory in patients with schizophrenia

CONTEXT: It remains unclear whether altered regional brain physiological activity in patients with schizophrenia during working memory tasks relates to maintenance-related processes, manipulation-related (ie, executive) processes, or both. OBJECTIVE: To examine regional functional activations of the brain during maintenance- and manipulation-related working memory processing in patients with schizophrenia and in healthy comparison subjects. DESIGN: Functional images of the brain were acquired in 11 schizophrenic patients and 12 healthy control subjects (matched for age, sex, handedness, and parental education) during 2 spatial working memory paradigms, one contrasting maintenance-only processing with maintenance and manipulation processing and the other contrasting parametrically varying maintenance demands. RESULTS: Patients and controls showed activation of a large, spatially distributed network of cortical and subcortical regions during spatial working memory processing. When task demands required explicit manipulation of information held in memory, controls recruited right dorsolateral prefrontal cortex (Brodmann areas 45 and 46) to a significantly greater extent than patients. A similar effect was observed for the larger memory set sizes of the memory set size task. No other brain regions showed activation differences between groups for either task. These differences persisted when comparing activation maps for memory set sizes in which the 2 groups were equivalent in behavioral accuracy and when comparing subgroups of patients and controls matched for behavioral accuracy on either task. CONCLUSIONS: Physiological disturbances in the dorsolateral prefrontal cortex contribute differentially to patients' difficulties with maintaining spatial information across a brief delay, as well as with manipulating the maintained representation. These differences persisted when comparing conditions in which the 2 groups were equivalent in behavioral accuracy.     

Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients

Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia.Key words: ventral striatum, orbitofrontal cortex, ventromedial prefrontal cortex, monetary incentive delay task, genetic vulnerability, cue processing