Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins.

OBJECTIVE: The authors previously reported that in monozygotic twins discordant for schizophrenia the affected twin almost invariably had a smaller anterior pes hippocampus, measured with magnetic resonance imaging (MRI), and invariably had less regional cerebral blood flow (rCBF) in the dorsolateral prefrontal cortex during performance of the Wisconsin Card Sorting Test. The present study was an investigation of the relationship between hippocampal pathology and prefrontal hypofunction in the same twin pairs. METHOD: Nine pairs of monozygotic twins discordant for schizophrenia underwent MRI scanning for determination of anterior hippocampal volume and xenon-inhalation rCBF testing for determination of prefrontal physiological activation associated with the Wisconsin Card Sorting Test. RESULTS: The differences within twin pairs on the MRI and rCBF measures were strongly and selectively correlated. Specifically, the more an affected twin differed from the unaffected twin in left hippocampal volume, the more they differed in prefrontal physiological activation during the Wisconsin Card Sorting Test. In the affected twins as a group, prefrontal activation was strongly related to both left and right hippocampal volume. These relationships were not found in the group of unaffected twins. CONCLUSIONS: This finding is consistent with the notion that schizophrenia involves pathology of and dysfunction within a widely distributed neocortical-limbic neural network that has been implicated in, among other activities, the performance of cognitive tasks requiring working memory.     

Regional cerebral blood flow and cognitive function in Huntington's disease and schizophrenia. A comparison of patients matched for performance on a prefrontal-type task

Matching patients with etiologically distinct but clinically overlapping cognitive disorders on performance of a regionally specific neuropsychological task is a novel and potentially powerful approach to highlighting differences in the pathophysiological mechanisms of impaired cognition. We used this strategy to compare patients with Huntington's disease (HD) and schizophrenia (SC), disorders that share similarities in cognitive impairment. Patients were matched on the basis of performance on the Wisconsin Card Sorting test of "prefrontal" function, after which neuropsychological test data and regional cerebral blood flow data were determined while patients who performed the Wisconsin Card Sorting test were examined. Patients with HD performed worse on visuospatial tasks and recall memory than did patients with SC, although Wechsler Adult Intelligence Scales-Revised IQ and Wechsler Memory Scale memory quotients were equivalent. These differences could not be attributed to differences on the index task, the Wisconsin Card Sorting Test. Patients with HD and SC exhibited a double dissociation in regional cerebral blood flow. The patients with SC had relatively low frontal and high parietal flows, while patients with HD exhibited the reverse of this pattern. Thus, the regional cerebral blood flow and neuropsychological findings in this study appeared to demonstrate that the single final common cognitive impairment of executive function in HD and SC is associated with two markedly dissimilar pathophysiological states.     

A functional magnetic resonance imaging study of social cognition in schizophrenia during an acute episode and after recovery

OBJECTIVE: Difficulty with social interactions is a characteristic of schizophrenia. The authors used functional magnetic resonance imaging (fMRI) to investigate brain activation changes during a social cognition paradigm in patients with schizophrenia during and after an acute episode and their association with social and executive function. METHOD: In a longitudinal study design, 14 patients with schizophrenia experiencing an acute episode had an fMRI scan. They returned for a follow-up scan after clinical improvement. Fourteen healthy comparison subjects were also scanned twice with approximately the same time interval between scans as in the patient group. The authors employed a social cognition fMRI paradigm involving empathic and forgivability judgments. Schizophrenia symptoms, social functioning and illness insight scales, and the Wisconsin Card Sorting Test were used to examine whether improvement on these measures was associated with recovery of brain activation in response to the social cognition paradigm. RESULTS: After recovery from the acute episode, patients exhibited increased activation in the left medial prefrontal cortex, which was, in turn, significantly correlated with improved insight and social functioning. Decreased symptom severity and improved performance on the Wisconsin Card Sorting Test were not significantly associated with increased left medial prefrontal cortex activation. CONCLUSIONS: This is the first study to the authors' knowledge to use a social cognition paradigm to reveal improved left medial prefrontal cortex activation in schizophrenia after recovery from an acute episode. These results suggest that restored left medial prefrontal cortex activation may mediate improvement of insight and social functioning in patients with schizophrenia.     

Effect of instructional cues on schizophrenic patients' performance on the Wisconsin Card Sorting Test.

OBJECTIVE: Schizophrenic patients are particularly deficient on measures of executive functioning, notably the Wisconsin Card Sorting Test. This study was conducted to determine the efficacy of a cuing strategy in facilitating performance on this cognitive measure of the integrity of prefrontal brain structures and functioning. METHOD: Twenty-four schizophrenic inpatients and 24 demographically matched inpatients with mood disorders were administered the Wisconsin Card Sorting Test either with instructional cues at the beginning of the task or with the standard administration procedure. RESULTS: There was a significant benefit of cues for the patients with affective disorders as well as for the schizophrenic patients. The schizophrenic subjects in the uncued condition maintained poor but stable performance throughout the course of the task. CONCLUSIONS: The study suggests that the deficit in executive functioning of schizophrenic patients may lie in the formation of concepts, not in their application.     

A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition

OBJECTIVE: In the prefrontal cortex, the enzyme catechol O-methyltransferase (COMT) is critical in the metabolic degradation of dopamine, a neurotransmitter hypothesized to influence human cognitive function. The COMT gene contains a functional polymorphism, Val158Met, that exerts a fourfold effect on enzyme activity. The current study investigated whether prefrontal cognition varies with COMT genotype. METHOD: Val158Met was genotyped in 73 healthy volunteers. A task of prefrontal cognition, the Wisconsin Card Sorting Test, was also administered. RESULTS: Subjects with only the low-activity met allele made significantly fewer perseverative errors on the Wisconsin Card Sorting Test than did subjects with the val allele. CONCLUSIONS: These data are consistent with those of previous studies, suggesting that a functional genetic polymorphism may influence prefrontal cognition.     

The effect of amphetamine on regional cerebral blood flow during cognitive activation in schizophrenia

To explore the role of monoamines on cerebral function during specific prefrontal cognitive activation, we conducted a double-blind placebo-controlled crossover study of the effects of 0.25 mg/kg oral dextroamphetamine on regional cerebral blood flow (rCBF) as determined by 133Xe dynamic single-photon emission-computed tomography (SPECT) during performance of the Wisconsin Card Sorting Test (WCST) and a sensorimotor control task. Ten patients with chronic schizophrenia who had been stabilized for at least 6 weeks on 0.4 mg/kg haloperidol participated. Amphetamine produced a modest, nonsignificant, task-independent, global reduction in rCBF. However, the effect of amphetamine on task-dependent activation of rCBF (i.e., WCST minus control task) was striking. Whereas on placebo no significant activation of rCBF was seen during the WCST compared with the control task, on amphetamine significant activation of the left dorsolateral prefrontal cortex (DLPFC) occurred (p = 0.0006). Both the mean number of correct responses and the mean conceptual level increased (p less than 0.05) with amphetamine relative to placebo. In addition, with amphetamine, but not with placebo, a significant correlation (p = -0.71; p less than 0.05) emerged between activation of DLPFC rCBF and performance of the WCST task. These findings are consistent with animal models in which mesocortical catecholaminergic activity modulates and enhances the signal-to-noise ratio of evoked cortical activity.     

Prefrontal cortical dysfunction in depression determined by Wisconsin Card Sorting Test performance.

OBJECTIVE: Neuroimaging studies have demonstrated reduced prefrontal cortical blood flow and metabolism in depression, but the neurobehavioral significance of these observations is not yet established. METHOD: The Wisconsin Card Sorting Test, a widely used neuropsychological index of prefrontal cortical function, was administered to 79 patients with major depression who had been unmedicated for at least 28 days, to 47 patients with schizophrenia who had never received antipsychotic medication, and to 61 healthy comparison subjects. RESULTS: Depressed patients demonstrated significant deficits on multiple Wisconsin Card Sorting Test measures compared with healthy individuals. These deficits were correlated with the severity of depression and were less severe than those demonstrated by patients with schizophrenia. CONCLUSIONS: These results provide neuropsychological evidence for significant prefrontal cortical dysfunction in depression.     

Wisconsin Card Sorting Test performance in schizophrenia: remediation of a stubborn deficit.

OBJECTIVE: Schizophrenic patients typically perform poorly on the Wisconsin Card Sorting Test, which is a putative index of prefrontal functioning. The authors attempted to remediate the deficits of schizophrenic patients on this measure by giving detailed instructions and monetary reinforcement. METHOD: Forty-six inpatients with chronic schizophrenia and 20 control subjects with other psychiatric illnesses were given the Wisconsin Card Sorting Test under four conditions that varied in monetary reinforcement and level of instructions. The schizophrenic patients were given the Brief Psychiatric Rating Scale (BPRS) and three information processing measures (the Continuous Performance Test, Span of Apprehension, and Pin Test). RESULTS: Schizophrenic patients performed worse than psychiatric control subjects across most conditions. Monetary reinforcement had little effect on performance, but detailed instructions significantly improved the scores for both groups. When instructions were withdrawn and monetary reinforcement was maintained, both groups continued to show improved performance over baseline. Symptoms were not significantly associated with Wisconsin Card Sorting Test performance. One measure (the Pin Test) correlated significantly with performance on the Wisconsin Card Sorting Test. CONCLUSIONS: The results suggest the importance of combining motivational with instructional factors for training psychiatric patients in problem solving.     

The relationship between regional cerebral blood flow and the Wisconsin Card Sorting Test in negative schizophrenia

The purpose of this study was to explore the relationship between regional cerebral blood flow (rCBF) and problem-solving thinking in negative schizophrenia. Twenty-one negative schizophrenic patients and 12 normal controls were studied with single photon emission computed tomography (SPECT). Measures of regional cerebral blood flow (rCBF) were taken both at rest and during a prefrontal activation task using Wisconsin Card Sorting Test (WCST). Compared with controls, poor performances on the WCST of total trials category (TT), perseverative errors (PE) and non-perseverative errors (NE) were found in negative schizophrenic (P < 0.05). During WCST activation, patients showed interhemispheric differences in the prefrontal region, but under rest conditions, no such differences manifested. The negative schizophrenia group had a significantly lower rCBF change rate in profrontal lobe during stimulant WCST than those in normal controls (P < 0.05). The negative schizophrenic patient has executive function deficits and lower rCBF perfusion in left profrontal lobes, which suggest that the negative schizophrenic patient has dysfunction of the left profrontal region.     

Neuropsychological and oculomotor correlates of spatial working memory performance in schizophrenia patients and controls.

Recent reports of spatial working memory deficits in schizophrenia provide evidence for dorsolateral prefrontal cortical (DLPFC) dysfunction. However, the question of how spatial working memory performance relates to other task impairments in schizophrenia considered reflective of frontal dysfunction, such as the Wisconsin Card Sorting Test (WCST) and smooth pursuit eye tracking, has been largely unexplored. Spatial working memory, as measured by a computerized visual-manual delayed response task (DRT), was evaluated in 42 schizophrenia patients and 54 normal controls. Subjects also completed a battery of neuropsychological and oculomotor tasks. Schizophrenia patients performed as accurately as controls on a no-delay, sensory-motor control condition, but showed a significant impairment in spatial accuracy with the addition of an 8-s delay and verbal distraction task. For the patients, working memory impairment was associated with fewer categories on the WCST, impaired eye tracking, fewer words learned on the Rey Auditory Verbal Learning Test, but not with measures of general cognitive and clinical functioning. Results suggest the presence of a sub-group of schizophrenia patients with common pathophysiology that accounts for the co-variance of several tasks implicating prefrontal dysfunction.     

Basal-corticofrontal circuits in schizophrenia and obsessive-compulsive disorder: a controlled, double dissociation study.

BACKGROUND: Several lines of research suggest that prefrontal cortex dysfunctions observed in obsessive compulsive disorder (OCD) and schizophrenia (SKZ) are linked to two partially independent neuroanatomic systems: the ventromedial prefrontal cortex and the dorsolateral prefrontal cortex, with different neuroanatomic connections, including the striatum. The primary aim of this study was to test this hypothesis using a double dissociation study of neuropsychological tasks performance of the dorsolateral prefrontal cortex and ventromedial prefrontal cortex. METHODS: We administered the Wisconsin Card Sorting Test, the Gambling Task, and the four-disk version of the Tower of Hanoi to 110 SKZ and 67 OCD patients and 56 control subjects. RESULTS: A clear double dissociation of Wisconsin Card Sorting Test and Gambling Task performances was found, with SKZ patients performing the Wisconsin Card Sorting test significantly worse than OCD patients and control subjects and OCD patients performing the Gambling Task significantly worse than SKZ and control subjects. Both SKZ and OCD patients performed the Tower of Hanoi significantly worse than control subjects. CONCLUSIONS: Results from our double dissociation study confirm the hypothesis of involvement of different frontal lobe subsystems within basal-corticofrontal circuits function in SKZ and OCD.     

A composite neural network model for perseveration and distractibility in the Wisconsin card sorting test.

A composite artificial neural network model is proposed to simulate the performance of the Wisconsin Card Sorting Test. The Wisconsin Card Sorting Test is a test of executive functions where prefrontal deficits are matched to some quantitative measures such as percentage of perseverative errors and number of failures to maintain set. In this work, the proposed model is used to simulate the performances of healthy subjects and patients with prefrontal involvement particularly on these measures. The model is designed in such a way that one of the subsystems, namely, the Hopfield network, serves as the working memory and the other, the Hamming block, as the hypothesis generator. The results show that the proposed relatively simple model is capable of simulating the wide range of the performances of both normal subjects and prefrontal patients on the Wisconsin Card Sorting Test. While lowering the Hamming distance in the Hamming block gave rise to progressively more perseverative responses, changing the threshold vector of the Hopfield network resulted in more set maintenance failures. The former manipulation disrupts the abstraction or mental flexibility and the latter sustained attention or perseverance both of which are the major functions of the prefrontal system.     

The effects of frontal lobe lesions on goal achievement in the water jug task.

Patients with prefrontal cortex lesions are impaired on a variety of planning and problem-solving tasks. We examined the problem-solving performance of 27 patients with focal frontal lobe damage on the Water Jug task. The Water Jug task has never been used to assess problem-solving ability in neurologically impaired patients nor in functional neuroimaging studies, despite sharing structural similarities with other tasks sensitive to prefrontal cortex function, including the Tower of Hanoi, Tower of London, and Wisconsin Card Sorting Task (WCST). Our results demonstrate that the Water Jug task invokes a unique combination of problem-solving and planning strategies, allowing a more precise identification of frontal lobe lesion patients' cognitive deficits. All participants (patients and matched controls) appear to be utilizing a hill-climbing strategy that does not require sophisticated planning; however, frontal lobe lesion patients (FLLs) struggled to make required "counterintuitive moves" not predicted by this strategy and found within both solution paths. Left and bilateral FLLs were more impaired than right FLLs. Analysis of the left hemisphere brain regions encompassed by the lesions of these patients found that poor performance was linked to left dorsolateral prefrontal cortex damage. We propose that patients with left dorsolateral prefrontal cortex lesions have difficulty making a decision requiring the conceptual comparison of nonverbal stimuli, manipulation of select representations of potential solutions, and are unable to appropriately inhibit a response in keeping with the final goal.     

Prefrontal neuropsychological impairment and illness duration in Schizophrenia: a study of 204 patients in Hong Kong

Previous studies investigating the progression of neuropsychological impairment in schizophrenia have yielded conflicting results. We compared prefrontal neuropsychological function and other cognitive performance in a larger sample of schizophrenic patients with different duration of illness. The inclusion of a normal control group also allowed the effect of age to be taken into account. Performance in the Wisconsin Card Sorting Test (WCST) and semantic fluency were both impaired at an early stage in the illness and did not significantly deteriorate as the illness duration increased. Against this background there was preliminary evidence for deterioration in verbal memory function. The data support a lack of progression in prefrontal dysfunction and in most other cognitive domains.     

Performance of schizophrenia patients on time-, event-, and activity-based prospective memory tasks

The present study aimed to determine whether individuals with long-term schizophrenia have impaired prospective memory (PM), the ability to remember to perform intended actions in the future. Three PM tasks (time-, event-, and activity-based) were administered to 60 schizophrenia patients and 60 matched controls. Patients performed significantly more poorly than controls on all three tasks. The between-group difference was disproportionately larger on the time-based task, a task that required a prefrontal lobe process called self-initiated retrieval. To examine the relationship between PM and prefrontal lobe functions, subjects were also administered the Design Fluency Test (DFT), the Tower of London (TOL), and the Wisconsin Card Sorting Test (WCST). For patients, performance on the event-based task was found to correlate significantly with performance on the DFT, and performance on the time-based task was found to correlate significantly with performance on the TOL. Results of this study support the importance and contribution of prefrontal lobe processes in prospective remembering and have implications for the assessment and treatment of individuals with schizophrenia.     

Remediation of cognitive deficits in schizophrenia

Studies have suggested that schizophrenia is characterized by an impairment in the dorsolateral prefrontal cortex that prevents learning of some elementary information processing tasks. To test this hypothesis, the authors administered the Wisconsin Card Sorting Test to 16 schizophrenic inpatients with standard instructions and either contingent or noncontingent reinforcement. Performance was markedly impaired under each condition. A second cohort (N = 12) was tested after receiving instructions plus rehearsal and feedback. These subjects' performance was comparable to nonpatient norms and was maintained on a subsequent day. The results indicate that deficits in performance on the Wisconsin Card Sorting Test are remediable, whether or not they are due to neurological impairment.     

Regional cerebral blood flow in Down syndrome adults during the Wisconsin Card Sorting Test: exploring cognitive activation in the context of poor performance.

BACKGROUND: Prior studies have indicated abnormal frontal lobes in Down syndrome (DS). The Wisconsin Card Sorting Test (WCST) has been used during functional brain imaging studies to activate the prefrontal cortex. Whether this activation is dependent on successful performance remains unclear. To determine frontal lobe regional cerebral blood flow (rCBF) response in DS and to further understand the effect of performance on rCBF during the WCST, we studied DS adults who perform poorly on this task. METHODS: Initial slope (IS), an rCBF index, was measured with the 133Xe inhalation technique during a Numbers Matching Control Task and the WCST. Ten healthy DS subjects (mean age 28.3 years) and 20 sex-matched healthy volunteers (mean age 28.7 years) were examined. RESULTS: Performance of DS subjects was markedly impaired compared to controls. Both DS and control subjects significantly increased prefrontal IS indices compared to the control task during the WCST. CONCLUSIONS: Prefrontal activation in DS during the WCST was not related to performance of that task, but may reflect engagement of some components involved in the task, such as effort. Further, these results show that failure to activate prefrontal cortex during WCST in schizophrenia is unlikely to be due to poor performance alone.     

Neuroimaging of cognitive disability in schizophrenia: search for a pathophysiological mechanism

This article reviews how functional neuroimaging research of cognitive dysfunction in schizophrenia has resulted in a progression of influential pathophysiological models of the disorder. The review begins with discussion of the 'hypofrontality' model, moving from resting studies examining anterior to posterior gradients of cerebral blood flow (CBF), to cognitive activation studies employing the Wisconsin Card Sorting Test, and current functional magnetic resonance imaging (fMRI) studies of working memory and cognitive control utilizing parametric task designs and event-related procedures. A similar progression is described for development of the temporal lobe model of schizophrenia, moving from research on the temporal cortex and language processing to the hippocampal formation and long-term memory (LTM). These LTM studies found that hippocampal dysfunction was often accompanied by disrupted prefrontal function, supporting a hybrid model of impaired fronto-temporal connectivity. Developments in image analysis procedures are described that allow assessment of these distributed network models. However, given limitations in temporal and spatial resolution, current methods do not provide 'real-time' imaging of network activity, making arrival at a definitive pathophysiologic mechanism difficult. Dorsolateral prefrontal cortex (DLPFC) dysfunction and disrupted fronto-temporal integration appear to be equally viable current models. The article concludes with a discussion of how fMRI can help facilitate development of novel psychosocial and pharmacological interventions designed to improve cognition and functional outcome in patients with schizophrenia.     

Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. IV. Further evidence for regional and behavioral specificity

In previous studies we found that patients with chronic schizophrenia had lower regional cerebral blood flow (rCBF) in dorsolateral prefrontal cortex (DLPFC) than did normal subjects during performance of the Wisconsin Card Sort Test, an abstract reasoning task linked to DLPFC function. This was not the case during less complex tasks. To examine further whether this finding represented regionally circumscribed pathophysiology or a more general correlate of abstract cognition, 24 medication-free patients and 25 age- and sex-matched normal control subjects underwent rCBF measurements with the xenon 133 technique while they performed two tasks: Raven's Progressive Matrices (RPM) and an active baseline control task. While performing RPM, normal subjects activated posterior cortical areas over baseline, but did not activate DLPFC, as had been seen during the Wisconsin Card Sort Test. Like normal subjects, patients showed maximal rCBF elevations posteriorly and, moreover, they had no significant DLPFC or other cortical deficit while performing RPM. These results suggest that DLPFC dysfunction in schizophrenia is linked to pathophysiology of a regionally specific neural system rather than to global cortical dysfunction, and that this pathophysiology is most apparent under prefrontally specific cognitive demand.     

Effects of Parkinson disease on two putative nondeclarative learning tasks: probabilistic classification and gambling.

OBJECTIVE: To assess performance on two nondeclarative (implicit) memory tasks of Parkinson disease (PD) patients without dementia in the earlier or later stages of the disease (Hoehn and Yahr Scale scores of 1-2.5 or 3-4, respectively). BACKGROUND: Different subtypes of nondeclarative memory appear to depend on different components of frontostriatal circuitry. Performance on a probabilistic classification learning (PCL) task was impaired by striatal damage (eg, in PD or Huntington disease) but not by circumscribed frontal lobe damage. On the other hand, performance on the Iowa Gambling Task (IGT) was impaired by damage to the prefrontal cortex. METHOD AND RESULTS: On the PCL, the learning of the control (age- and education-matched) group (n = 19) and the early PD group (n = 16) was comparable with each other, and both groups showed better performance than the later PD group (n = 16). On the IGT, the control group learned better than both of the PD groups. The control and early PD groups were similar on measures from the Wisconsin Card Sorting Test, Stroop Test, Mini-Mental State Examination, and Beck Depression Inventory II. CONCLUSIONS: The PCL and IGT tasks appear to rely on different parts of the frontostriatal circuitry in patients with early PD. The current finding that IGT performance was impaired in early PD implies ventromedial prefrontal cortical dysfunction early in the disease.