Prefrontal Cognitive Function Research Articles

COMT genotype, gender and cognition in community-dwelling, older adults

A common polymorphism (Val158Met) in the gene encoding for the catechol- O-methyltransferase (COMT) enzyme has been associated with differences in prefrontal cognitive function in schizophrenic patients and healthy adults. While several studies indicate that the Met allele is associated with better performance on measures of executive function, working memory and verbal fluency, results have been inconsistent. Furthermore, fewer studies have investigated this relationship in older adults, a group known to experience impairments in prefrontal cognitive functions. Additionally, findings vary according to the gender distribution of study participants. We examined whether COMT genotype interacted with gender to impact cognition in a cohort of 163 healthy, older adults. Memory, verbal ability and areas of prefrontal cognitive function, including attention, speed-of-processing, and executive function, were assessed. We found no significant association between COMT genotype and any cognitive measure. However, gender interacted with COMT genotype to impact cognitive performance. Males homozygous for the Val allele performed better than both the Val/Met and Met/Met groups on measures of delayed recall. Heterozygous women performed better than their homozygous counterparts on the measure of verbal ability. These findings suggest that gender may be an important variable in consideration of the impact of COMT on cognition. Further, when gender is taken into consideration, any negative impact of COMT genotype may extend to cognitive domains other than those associated with prefrontal regions.

Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain‐derived neurotrophic factor gene

The measures of prefrontal cognition have been used as endophenotype in molecular-genetic studies. Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive functions and in the pathogenesis of major psychoses. This study investigates the relationship between Val66Met polymorphisms of the BDNF gene and prefrontal cognitive function in 129 patients with schizophrenia and 111 patients with bipolar mood disorder. Cognitive tests included the Wisconsin Card Sorting Test (WCST), with such domains as number of perseverative errors, non-perseverative errors, completed corrected categories, conceptual level responses, and set to the first category, and the N-back test, where mean reaction time and percent of correct reactions were measured. Genotyping for Val66Met BDNF polymorphism was done by polymerase chain reaction method. In schizophrenia, no relationship between Val66Met polymorphism of the BDNF gene and the results of the WCST was observed. Patients with Val/Val genotype had a higher percentage of correct reactions in the N-back test than those with the remaining genotypes. Bipolar patients with Val/Val genotype obtained significantly better results on three of five domains of the WCST. No relationship between BDNF polymorphism and the results of the N-back test was found in this group. A limitation to the results could be variable psychopathological state and medication during cognitive testing and lack of Hardy-Weinberg equilibrium in schizophrenia group. Val66Met polymorphism of the BDNF gene may be associated with cognitive performance on the WCST in bipolar mood disorder but not in schizophrenia. An association of this polymorphism with performance on the N-back test in schizophrenia and not in bipolar illness may suggest that in schizophrenia, the BDNF system may be connected with early phases of information processing.

Longitudinal studies of antisaccades in antipsychotic-naive first-episode schizophrenia

Prefrontal cortical dysfunctions, including disturbances in adaptive context-specific behavior, have been reported in neuropsychological and brain imaging studies of schizophrenia. Some data suggest that treatment with antipsychotic medications may ameliorate these deficits. We investigated antisaccade performance in 39 antipsychotic-naive, first-episode schizophrenia patients who were re-evaluated 6 weeks after treatment initiation. A group of matched healthy subjects were examined at similar time-points. Patients and healthy individuals available for longer-term testing were re-assessed 26 and 52 weeks after initial testing. Before treatment, patients showed elevated rates of response suppression errors and prolonged latencies of correct antisaccades. Increased rates of antisaccade errors were associated with faster response latencies during a separate, visually guided saccade task, but only prior to treatment. Throughout the 1-year follow-up, patients progressively improved in their ability to voluntarily suppress context-inappropriate behavior. Although treatment assignment was by clinician choice, results of exploratory analyses revealed that patients treated with risperidone progressively planned and initiated correct antisaccades more quickly than patients receiving haloperidol. Deficits in the voluntary control of spatial attention are exaggerated during acute episodes of illness, but remain an enduring aspect of prefrontal dysfunction in schizophrenia even after treatment. During acute illness, speeded sensorimotor transformations may compound these deficits and contribute to the heightened distractibility associated with acute psychosis. Continued improvement in task performance throughout the 1-year follow-up suggests that partial normalization of prefrontal cognitive functions resulting from antipsychotic treatment may have a longer and more gradual time course than the reduction of acute psychotic symptoms.

The Val66Met polymorphism of the brain‐derived neurotrophic factor gene is associated with risk for psychosis: Evidence from a family‐based association study

Schizophrenia (SZ) is a prevalent and severe mental disorder. One of the most favored hypotheses for the etiology of SZ is the neurodevelopmental hypothesis. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, promotes the development, regeneration, and survival of neurons and has been linked to the neuropathology of SZ. The present study tested, in a sample of 94 nuclear families, the hypothesis that the BDNF gene Val66Met polymorphism is associated to SZ and its psychopathologic phenotype using a multidimensional symptom approach. Furthermore, considering a reported reduction of BDNF in the frontal cortex of patients with SZ, we studied the relationship between this polymorphism and prefrontal function. The transmission disequilibrium test (TDT) showed a preferential transmission of allele Val from heterozygous parents to the affected offspring (P = 0.002), suggesting a possible role of this gene in the vulnerability to SZ spectrum disorders. The findings remained essentially unchanged when the analysis was restricted to the subgroup of patients with SZ (P = 0.009) and when a multidimensional approach to the diagnosis was used. Quantitative transmission disequilibrium test (QTDT) analyses did not demonstrate a significant association between the prefrontal tests assessed (Wisconsin Card Sorting Test and Trail Making Test) and the transmission of the BDNF alleles. Our finding suggests that the investigated BDNF polymorphism plays an important role in the phenotype of psychosis, but not in the performance of tests of prefrontal cognitive functions analyzed in these patients.

Relationship between prefrontal cognitive functions and dopaminergic transmission: A [18F]-fluoro- l-DOPA PET study

Relationship between prefrontal cognitive functions and dopaminergic transmission: A [18F]-fluoro- l-DOPA PET study

Extract of Ginkgo biloba leaves reverses yohimbine-induced spatial working memory deficit in rats

Extract of Ginkgo biloba is used to alleviate age-related decline in cognitive function, which may be associated with the loss of catecholamines in the prefrontal cortex. The purpose of this study was to verify whether alpha-2 adrenergic activity is involved in the facilitative effects of extract of Ginkgo biloba on prefrontal cognitive function. Male Wistar rats were trained to reach criterion in the delayed alternation task (0, 25, and 50-s delay intervals). A pilot study found that 3 or 4 mg/kg of yohimbine (intraperitoneal) reduced the choice accuracy of the delayed alternation task in a dose and delay-dependent manner, without influencing motor ability or perseverative behaviour. Acute oral pre-treatment with doses of 50, 100, or 200 mg/kg (but not 25 mg/kg) of extract of Ginkgo biloba prevented the reduction in choice accuracy induced by 4 mg/kg yohimbine. These data suggest that the prefrontal cognition-enhancing effects of extract of Ginkgo biloba are related to its actions on alpha-2-adrenoceptors.

Prefrontal cognitive functions in stabilized first-episode patients with schizophrenia spectrum disorders: A dissociation between dorsolateral and orbitofrontal functioning

Specific prefrontal cognitive impairments have been reported in first-episode and chronic schizophrenia. We sought to investigate potential impairments in specific prefrontal cortical cognitive functions among stabilized patients with a first-episode of schizophrenia. A sample of 80 individuals with a first-episode of schizophrenia spectrum disorders and 22 healthy volunteers underwent a neurocognitive battery assessing orbitofrontal (OFC) [The Iowa Gambling Task (GT)], and dorsolateral prefrontal (DLPFC) functions (WAIS III Backward digits, verbal fluency test (FAS), and Trail Making Test). Cognitive data were obtained following stabilization of acute psychotic symptoms. Clinical symptoms after six weeks of treatment were assessed by using the SAPS and SANS scales. While there were no significant group differences in overall scores and in the profile of progress of performance along periods on the GT, patient group showed a significant impairment when performing DLPFC tasks. Only FAS score was correlated to the severity of negative symptomatology. The OFC functions are unimpaired at the early phases of psychosis and in contrast there is a significant deficit in DLPFC functions in first-episode of schizophrenia.

A non-human primate test of abstraction and set shifting: An automated adaptation of the Wisconsin Card Sorting Test

Functional assessment of the prefrontal cortices in the non-human primate began with the seminal work of Jacobsen in the 1930s. However, despite nearly 70 years of research, the precise nature of the cognitive function of this region remains unclear. One factor that has limited progress in this endeavor has been the lack of behavioral tasks that parallel most closely those used with humans. In the present study, we describe a test for the non-human primate that was adapted from the Wisconsin Card Sorting Task (WCST), perhaps the most widely used test of prefrontal cognitive function in humans. Our adaptation of this task, the Conceptual Set-Shifting Task (CSST), uses learning criteria and stimuli nearly identical to those of the WCST. The CSST requires the animal to initially form a concept by establishing a pattern of responding to a given stimulus class, maintain responding to that stimulus class, and then shift to a different stimulus class when the reward contingency changes. The data presented here establishes baseline performance on the CSST for young adult rhesus monkeys and demonstrates that components of prefrontal cognitive function can be effectively assessed in the non-human primate in a manner that parallels the clinical assessment of humans.

Cognitive functions in prepsychotic patients

Objective Cognitive dysfunctions are now widely understood as an essential feature of schizophrenia. A great number of cognitive disturbances have been described in drug-naive first-episode patients as well. The full-blown psychotic symptoms are usually preceded by a longer prodromal period, in which non-specific psychological disturbances are already present. The late prodromal phase is also coined as the prepsychotic state, with attenuated, isolated psychotic symptoms. The aim of the present study was to detect cognitive dysfunctions among young adults at the prepsychotic stage with the use of a standardized computer based cognitive test battery. Method Eleven (9 men, 2 women) young Hungarian adults referred to the Outpatient Clinic of the Department of Psychiatry at the University of Debrecen were studied. The patients were re-evaluated for psychotic symptoms after 12 months. The patients had no history of psychiatric disorders or psychotic episodes and were referred by general practitioners on account of non-specific emotional or behavioural abnormalities. The subjects were asked to perform a series of 13 computerized neuropsychological tests of the Cambridge Neuropsychological Test. The performance of the patients were compared to that of the standardized database of the Cambridge Neuropsychological Test. Results and discussion The performance of the prepsychotic patients was significantly lower compared to the healthy individuals in the paired associate learning (PAL, p<0.001), Spatial recognition memory (SRM, p<0.05), Rapid visual processing (RVP, p<0.05), and Spatial working memory (SWM, p<0.05) tests. Conclusion Cognitive deficits were found mainly in attentional, frontal and prefrontal cognitive functions. These impairments may be present at the early stages of the development of psychosis and the standardized cognitive test battery (CANTAB) might be a useful tool for the detection of early cognitive impairments and provide a rationale for early intervention in individuals at risk of developing psychosis.

Stress Interferes with Working Memory

The prefrontal cortex, located just above the eyes, is necessary for the higher order executive functions of the brain, including planning and working memory. Birnbaum et al. studied rats and monkeys performing tasks that require intact working memory. High activity of an intracellular signaling enzyme, protein kinase C (PKC), disrupted the animals' ability to remember. A cellular correlate of working memory, measured by recording neurons' electrical activity, showed this same sensitivity to high PKC. Because stress causes release of norepinephrine, a known activator of PKC, stress may exert its well-established inhibitory effect on prefrontal cognitive function through PKC. S. G. Birnbaum, P. X. Yuan, M. Wang, S. Vijayraghavan, A. K. Bloom, D. J. Davis, K. T. Gobeske, J. D. Sweatt, H. K. Manji, A. F. T. Arnsten, Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 306 , 882-884 (2004). [Abstract] [Full Text]

Heart rate variability and its relation to prefrontal cognitive function: the effects of training and detraining.

The aim of the present study was to investigate the relationship between physical fitness, heart rate variability (HRV) and cognitive function in 37 male sailors from the Royal Norwegian Navy. All subjects participated in an 8-week training program, after which the subjects completed the initial cognitive testing (pretest). The subjects were assigned into a detrained group (DG) and a trained group (TG) based on their application for further duty. The DG withdrew from the training program for 4 weeks after which all subjects then completed the cognitive testing again (post-test). Physical fitness, measured as maximum oxygen consumption (VO2(max)), resting HRV, and cognitive function, measured using a continuous performance task (CPT) and a working memory test (WMT), were recorded during the pre-test and the post-test, and the data presented as the means and standard deviations. The results showed no between-group differences in VO2(max) or HRV at the pre-test. The DG showed a significant decrease in VO2(max) from the pre- to the post-test and a lower resting HRV than the TG on the post-test. Whereas there were no between-group differences on the CPT or WMT at the pre-test, the TG had faster reaction times and more true positive responses on tests of executive function at the post-test compared to the pre-test. The DG showed faster reaction times on non-executive tasks at the post-test compared to the pre-test. The results are discussed within a neurovisceral integration framework linking parasympathetic outflow to the heart to prefrontal neural functions.

New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis.

Using a sample of sibling pairs discordant for psychosis, the authors attempted to replicate the findings of previous studies suggesting that the functional genetic polymorphism Val158Met in the catechol O-methyltransferase (COMT) gene influences prefrontal cognitive function and increases the risk for schizophrenia. Eighty-nine sibling pairs discordant for psychosis were genotyped for this polymorphism and were assessed with the Wisconsin Card Sorting Test, a measure of prefrontal function. Additionally, the preferential transmission of alleles for this polymorphism was analyzed in a sample of 89 nuclear families in order to examine the genetic association. In the healthy siblings, a linear relationship was seen in which performance on the Wisconsin Card Sorting Test was associated in an allele dosage fashion with COMT genotype (i.e., fewer perseverative errors with higher number of methionine alleles). However, this association was not observed in patients. Furthermore, no evidence of genetic association with psychosis was detected. These results seem to confirm the role of COMT genotype in the modulation of executive functions related to frontal lobe function in healthy individuals but not in schizophrenia patients.

Genetic and neurochemical modulation of prefrontal cognitive functions in children.

The catechol O-methyltransferase (COMT) gene affects how long dopamine acts in the prefrontal cortex. The Methionine polymorphism, which results in a slower breakdown of prefrontal dopamine, is associated with better adult prefrontal cortex function. The authors investigated the relation between the COMT gene polymorphism and cognitive performance in children. Children were tested on cognitive tasks that depend on the dorsolateral prefrontal cortex and seem to be sensitive to the level of dopamine there (dots-mixed task), depend on that neural region but appear insensitive to its dopamine content (self-ordered pointing), and depend on other neural systems (recall memory and mental rotation). After data collection, cheek swabs were obtained from all children. DNA was extracted and genotyped for the COMT gene with polymerase chain reaction. Children who were homozygous for the Methionine polymorphism performed significantly better on the dots-mixed task but not on others. The findings provide an existence proof that genotypic differences can relate to differences in cognitive performance in typically developing children. The authors achieved a level of specificity never previously attempted; the COMT polymorphism was found to be differentially related to performance on tasks linked to the same prefrontal region by whether cognitive requirements of the tasks were sensitive to the level of dopamine found. These results challenge accepted notions that since dopamine is important for some cognitive functions dependent on the prefrontal cortex, it is important for all. The differential sensitivity of distinct cognitive abilities to specific neurotransmitters may make possible targeted pharmacological interventions.

Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients.

The aim of the study was to test a possible association between the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene and performance on a neurocognitive test, the Wisconsin Card Sorting Test (WCST), in bipolar patients. Fifty-four bipolar patients were studied, 18 male and 36 female, aged 18-72 (mean 46 years). The number of perseverative errors (WCST-P), non-perseverative errors (WCST-NP), completed corrected categories (WCST-CC), conceptual level responses (WCST-%CONC) and set to the first category (WCST-1st CAT) were measured in relation to the Val66Met genotypes of BDNF. The percentages of subjects with Val/Val, Val/Met and Met/Met genotypes were respectively 81.5, 16.7 and 1.8%. Subjects with Val/Val and Val/Met genotypes did not differ on clinical factors except for the age of onset of the illness, which was earlier in Val/Val than Val/Met genotype (27 years versus 38 years). The performance in all domains of WCST was significantly better in subjects with Val/Val BDNF genotype compared with Val/Met genotype. The results suggest a role of BDNF in prefrontal cognitive function in bipolar illness. The tests of prefrontal cognition may be considered as endophenotypic markers in bipolar illness.

Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females

Using the Wisconsin Card Sorting Test, it has been determined, that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect dopamine metabolism, is associated with prefrontal cognitive function. This study of a cohort of 120 healthy young Chinese females attempted to utilize P300 event-related potentials to replicate this finding and to test the relationship between this COMT polymorphism and cortical physiology. The results demonstrate that subjects bearing the Met/Met homozygote have significantly lower mean P300 latencies than do analogs bearing the Val allele. A significant association between this COMT polymorphism and perseverative errors was not demonstrated in the Wisconsin Card Sorting Test, however. We suggest that, although the COMT Val158Met genetic polymorphism may play a role in cognitive function, ethnicity and testing method may affect the association. Since statistical relationships between P300 components and both the COMT genetic polymorphism and schizophrenic disorders have been demonstrated, it seems reasonable to suggest that this COMT genetic variant may affect the P300 abnormality in schizophrenia.

Smoking, reward responsiveness, and response inhibition: tests of an incentive motivational model

Background: Incentive-motivation models of addiction suggest impairment of functional activity in mesocorticolimbic reward pathways during abstinence. This study tested implications for subjective and behavioral responses to nondrug incentives, cue-elicited craving, and prefrontal cognitive functions, particularly response inhibition. Methods: We tested 26 smokers after smoking and after overnight abstinence in counterbalanced order; 26 nonsmokers were also tested twice. Measures included a simple card-sorting test performed with and without financial incentive (the CARROT), the Snaith Hamilton Pleasure Scale as an index of subjective reward responsiveness, ratings of subjective craving and withdrawal before and after exposure to a cigarette, an index of oculomotor response inhibition (saccadic vs. antisaccadic eye movements), verbal fluency, and reversed digit span. Results: Compared with the smoking condition, and independently of withdrawal severity, abstinence was associated with reduced cue reactivity, pleasure expectancies, responsiveness to financial incentive, and response inhibition (antisaccadic eye movements). Verbal fluency and reversed digit span were unaffected, contrary to findings elsewhere with heavier smokers. Nonsmokers’ scores either fell between those of abstainers and recent smokers or approximated those of recent smokers. Conclusions: The data were in general consistent with behavioral predictions derived from the incentive-motivational model of addiction and suggest that abstinence may be associated with impairments of motivation and response inhibition, which are independent of other subjectively experienced withdrawal symptoms.

Comt, schizophrenia, and prefrontal cognitive function: genetic analysis of a complex psychiatric disorder using intermediate phenotypes and a candidate allele

Comt, schizophrenia, and prefrontal cognitive function: genetic analysis of a complex psychiatric disorder using intermediate phenotypes and a candidate allele

Striatal [123I]beta-CIT SPECT and prefrontal cognitive functions in Parkinson's disease.

Twenty non-demented patients with idiopathic Parkinson's disease (PD) underwent single photon emission computed tomography (SPECT) with [123I]beta-CIT to further investigate the contribution of nigrostriatal dysfunction to cognitive and motor deficits. Compared to matched controls PD patients showed normal verbal intelligence, short-term memory and phasic alertness. There were significant (p < 0.05) deficits in tests of verbal working memory (digit ordering, reading span), strategic memory (story recall) and executive functions (card sorting), indicating a "prefrontal" cognitive deficit. Significant (p < 0.05) correlations were observed between dopamine transporter (DAT) density in the putamen and motor deficits as well as between DAT density in both striatal compartments (head of the caudate nucleus and putamen) and prefrontal functioning. Age was a major contributing factor to both cognitive status and nigrostriatal integrity as measured by [123I]beta-CIT SPECT. These results support the view that the striatum is part of a neuronal network that is mediating prefrontal cognitive functions.

The effect of dopamine depletion from the caudate nucleus of the common marmoset (Callithrix jacchus) on tests of prefrontal cognitive function.

This study examined the effects of depletion of dopamine from the caudate nucleus of the common marmoset (Callithrix jacchus), on tasks sensitive to prefrontal damage (attentional set-shifting and spatial delayed response). There was a marked impairment in performance on the spatial delayed response task, but performance on the attentional set-shifting task was relatively preserved except for an impairment in re-engagement of a previously relevant perceptual dimension. This pattern of impairment is distinct from that seen after excitotoxic lesions of the prefrontal cortex and in patients with Parkinson's disease. Though it is not possible to identify specific cognitive functions that are independent of dopaminergic modulation of the caudate nucleus, due to the partial nature of the lesion, the results do provide insight into those cognitive processes that appear most dependent on caudate dopamine.

The effect of dopamine depletion from the caudate nucleus of the common marmoset (Callithrix jacchus) on tests of prefrontal cognitive function.

This study examined the effects of depletion of dopamine from the caudate nucleus of the common marmoset (Callithrix jacchus), on tasks sensitive to prefrontal damage (attentional set-shifting and spatial delayed response). There was a marked impairment in performance on the spatial delayed response task, but performance on the attentional set-shifting task was relatively preserved except for an impairment in re-engagement of a previously relevant perceptual dimension. This pattern of impairment is distinct from that seen after excitotoxic lesions of the prefrontal cortex and in patients with Parkinson's disease. Though it is not possible to identify specific cognitive functions that are independent of dopaminergic modulation of the caudate nucleus, due to the partial nature of the lesion, the results do provide insight into those cognitive processes that appear most dependent on caudate dopamine.