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Results for “Dorsolateral Prefrontal Cortex”

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PubMed2005

Neural mechanisms of affective interference in schizotypy.

Negatively valenced stimuli foster cognitive impairment in schizotypy and schizophrenia. To identify relevant brain mechanisms, the authors had 16 positive-schizotypy and 16 control participants perform an emotional Stroop task, judging the ink color of negative and neutral words during functional magnetic resonance imaging (fMRI) of regional brain activity. Schizotypy individuals showed increased right and decreased left activity in dorsolateral prefrontal cortex, indicating a deficit in maintenance of attentional set in the presence of negative emotional distractors. They also showed abnormal activity in ventral limbic areas, including decreased activity in nucleus accumbens and increased activity in hippocampus and amygdala, a circuit involved in the integration of cognitive and affective processes. These results indicate that aspects of emotion-cognition processes and the brain mechanisms that implement them are similar in schizotypy and schizophrenia.

Adult↗

PubMed2004

An fMRI study of episodic memory: retrieval of object, spatial, and temporal information.

Sixteen participants viewed a videotaped tour of 4 houses that highlighted a series of objects and their spatial locations. Participants were tested for memory of object, spatial, and temporal-order information while undergoing functional magnetic resonance imaging. Preferential activation was observed in the right parahippocampal gyrus during the retrieval of spatial-location information. Retrieval of contextual information (spatial location and temporal order) was associated with activation in the right dorsolateral prefrontal cortex. In bilateral posterior parietal regions, greater activation was associated with processing of visual scenes regardless of the memory judgment. These findings support current theories positing roles for frontal and medial temporal regions during episodic retrieval and suggest a specific role for the hippocampal complex in the retrieval of spatial-location information.

Adult↗

PubMed2006

Contemplation of moral dilemmas eliminates sex differences on the Iowa gambling task.

Men outperform women on the Iowa Gambling Task (IGT; A. Bechara, H. Damasio, D. Tranel, & A. R. Damasio, 1997). In this study, the authors show that sex differences are not due to differences in general emotional arousal or the abilities to calculate or reverse responses. Imaging studies have shown that, during the IGT, men increase activity in the right dorsolateral prefrontal cortex (PFC) and lateral orbital PFC, whereas women increase activity in the left medial orbital PFC. Deliberation of personal moral (PM) dilemmas also increases activity in medial and lateral dorsal PFC, whereas deliberation of moral impersonal (MI) dilemmas increases activity in lateral dorsal PFC. In the present study, men and women performed the IGT during PM, MI, or control deliberations. Deliberation of only PM dilemmas increased women's IGT performance to the level of men.

Adolescent↗

PubMed2005

Prefrontal brain magnetic activity: effects of memory task demands.

Changes in spatiotemporal profiles of brain magnetic activity were investigated in healthy volunteers as a function of varying demands for phonological storage of spoken pseudowords. Greater activity for the phonological memory task was restricted to the dorsolateral prefrontal cortex (DLPFC) in the left hemisphere. During performance of the memory task, activity was initially found in the left superior temporal gyrus (between 100 and 200 ms), followed by activity in the ventrolateral prefrontal, motor, and premotor cortices (between 200 and 300 ms). Activity in DLPFCs was first observed consistently across participants later, between 300 and 400 ms. The data are consistent with the purported role of posterior temporal cortices in phonological analysis and in the online storage of phonological information, the contribution of ventrolateral and motor processing areas in establishment and short-term maintenance of articulatory representations through rehearsal, and the role of DLPFCs in the executive control of the maintenance operation.

Acoustic Stimulation↗

PubMed2005

Executive functioning and speed of processing in phenylketonuria.

Treated phenylketonuria (PKU) has been linked to dopaminergic depletion in the dorsolateral prefrontal cortex, potentially leading to selective executive impairment. White matter abnormalities may lead to generalized slowing of information processing. These 2 hypotheses were evaluated in adults with PKU on a lifelong diet. Those with PKU were significantly slower than the control group regardless of working memory load on an n-back task and marginally slower regardless of trial type (inhibitory or noninhibitory) on a flanker task. There were no significant differences in speed on object alternation learning or perceptual judgment tasks. There were no group differences in accuracy on any task. These findings do not appear consistent with the selective executive hypothesis. A cognitive slowing account may prove more informative in adults with PKU, but more evidence is needed. The findings suggest that continuous dietary management is a fairly successful strategy in terms of cognitive outcome for adults.

Adolescent↗

PubMed2006

Functional neuroimaging of working memory in schizophrenia: task performance as a moderating variable.

Functional neuroimaging studies in schizophrenia have demonstrated abnormal activation of dorsolateral prefrontal cortex (DLPFC) during working memory (WM) performance. However, findings of increased and decreased activity have been reported. The authors used meta-analysis to investigate whether diverging results arise as a function of differential WM task performance between patients and control participants. Results indicate that the magnitude of the group difference in WM performance is a moderator of DLPFC activation differences, and concepts such as hypo- or hyperfrontality do not universally characterize WM findings in schizophrenia. Thus, the variability in the WM activation findings between participants with schizophrenia and control participants reflects the specific conditions under which WM functions are evaluated, not just the WM construct per se.

Data Interpretation, Statistical↗

PubMed2001

Brain activations associated with shifts in response criterion on a recognition test.

Sensitivity and bias can be manipulated independently on a recognition test. The goal of this fMRI study was to determine whether neural activations associated with manipulations of a decision criterion would be anatomically distinct from neural activations associated with manipulations of memory strength and episodic retrieval. The results indicated that activations associated with shifting criteria (a manipulation of bias) were located in bilateral regions of the lateral cerebellum, lateral parietal lobe, and the dorsolateral prefrontal cortex extending from the supplementary motor area. These regions were anatomically distinct from activations in the prefrontal cortex produced during memory-based retrieval processes (manipulations of sensitivity), which tended to be more medial and anterior. These later activations are consistent with previous studies of episodic retrieval. Determining patterns of neural activations associated with decision-making processes relative to memory processes has important implications for Cognitive Neuroscience, including the use of these patterns to compare memory models in different paradigms.

Adolescent↗

PubMed1998

Impaired recruitment of the hippocampus during conscious recollection in schizophrenia.

Poor attention and impaired memory are enduring and core features of schizophrenia. These impairments have been attributed either to global cortical dysfunction or to perturbations of specific components associated with the dorsolateral prefrontal cortex (DLPFC), hippocampus and cerebellum. Here, we used positron emission tomography (PET) to dissociate activations in DLPFC and hippocampus during verbal episodic memory retrieval. We found reduced hippocampal activation during conscious recollection of studied words, but robust activation of the DLPFC during the effort to retrieve poorly encoded material in schizophrenic patients. This finding provides the first evidence of hippocampal dysfunction during episodic memory retrieval in schizophrenia.

Adult↗

PubMed1993

Prefrontal neuronal activity in rhesus monkeys performing a delayed anti-saccade task.

Patients with damage to the dorsolateral prefrontal cortex are impaired on cognitive tasks such as the Wisconsin Card Sort Test, the Stroop Test and an anti-saccade paradigm, in which sensory-guided habitual responses must be suppressed in favour of conceptually or memory-guided responses. We report here recordings from prefrontal neurons in rhesus monkeys trained to perform a delayed anti-saccade task based on tests that have been used with humans. Activity in the same prefrontal neurons was recorded across conditions when saccades were made toward a remembered target, and also when this prepotent response was suppressed and a saccade in the opposite direction required. Our findings show that most prefrontal neurons code the location of the visual stimulus in working memory, and that this memory can be engaged to suppress as well as prescribe a response. These results establish, in a subset of prefrontal neurons, the iconic nature of the memory code, and suggest a role for visual memory in response suppression.

Animals↗

PubMed2004

A general mechanism for perceptual decision-making in the human brain.

Findings from single-cell recording studies suggest that a comparison of the outputs of different pools of selectively tuned lower-level sensory neurons may be a general mechanism by which higher-level brain regions compute perceptual decisions. For example, when monkeys must decide whether a noisy field of dots is moving upward or downward, a decision can be formed by computing the difference in responses between lower-level neurons sensitive to upward motion and those sensitive to downward motion. Here we use functional magnetic resonance imaging and a categorization task in which subjects decide whether an image presented is a face or a house to test whether a similar mechanism is also at work for more complex decisions in the human brain and, if so, where in the brain this computation might be performed. Activity within the left dorsolateral prefrontal cortex is greater during easy decisions than during difficult decisions, covaries with the difference signal between face- and house-selective regions in the ventral temporal cortex, and predicts behavioural performance in the categorization task. These findings show that even for complex object categories, the comparison of the outputs of different pools of selectively tuned neurons could be a general mechanism by which the human brain computes perceptual decisions.

Animals↗

PubMed2006

Pathophysiologically based treatment interventions in schizophrenia.

Identifying the molecular alterations that underlie the pathophysiology of critical clinical features of schizophrenia is an essential step in the rational development of new therapeutic interventions for this devastating illness. Cognitive deficits, such as the impairments in working memory that arise from dysfunction of the dorsolateral prefrontal cortex, are a major determinant of functional outcome in schizophrenia. Here we consider the contributions of disturbances in glutamate, dopamine and GABA neurotransmission to the pathophysiology of working memory impairments in schizophrenia, suggest a cascade of molecular events that might link these disturbances, and argue that the molecular alterations most proximal to the pathophysiology of prefrontal dysfunction offer the most promise as targets for new drug development.

Dopamine↗

PubMed2003

An fMRI investigation of the impact of interracial contact on executive function.

We investigated whether individual differences in racial bias among white participants predict the recruitment, and potential depletion, of executive attentional resources during contact with black individuals. White individuals completed an unobtrusive measure of racial bias, then interacted with a black individual, and finally completed an ostensibly unrelated Stroop color-naming test. In a separate functional magnetic resonance imaging (fMRI) session, subjects were presented with unfamiliar black male faces, and the activity of brain regions thought to be critical to executive control was assessed. We found that racial bias predicted activity in right dorsolateral prefrontal cortex (DLPFC) in response to black faces. Furthermore, activity in this region predicted Stroop interference after an actual interracial interaction, and it statistically mediated the relation between racial bias and Stroop interference. These results are consistent with a resource depletion account of the temporary executive dysfunction seen in racially biased individuals after interracial contact.

Adult↗

PubMed2005

Cortical inhibitory neurons and schizophrenia.

Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.

Animals↗

PubMed2006

STN stimulation alters pallidal-frontal coupling during response selection under competition.

To investigate the effects of bilateral subthalamic nucleus (STN) stimulation on patterns of brain activation during random number generation (RNG), a task that requires suppression of habitual counting and response selection under competition. We used H(2)(15)O positron emission tomography to investigate the changes of regional cerebral blood flow (rCBF) induced by bilateral STN stimulation during a RNG task, in six patients with Parkinson's disease. Paced RNG at 1 Hz was compared with a control counting task. Both tasks were performed off medication with deep brain stimulation on and off. Subthalamic nucleus stimulation had a negative effect on performance of fast-paced RNG, leading to reduced randomness and increased habitual counting. Subthalamic nucleus stimulation also induced a reduction of rCBF in the left dorsal frontal gyrus, inferior frontal gyrus, dorsolateral prefrontal cortex, posterior and right anterior cingulate, and an increase of rCBF in the right internal globus pallidum (GPi) during RNG. Stimulation of the STN significantly altered pallidal coupling with frontal and temporal areas compared with when the stimulators were off. In conclusion, during RNG: (i) STN stimulation activates its output neurons to the GPi; (ii) STN stimulation induces increased inhibition of a prefrontal-cingulate network. This is the first direct evidence that STN stimulation significantly alters pallidal coupling with prefrontal, cingulate, and temporal cortices during performance of a task that requires response selection under competition.

Cerebrovascular Circulation↗

PubMed2003

Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder.

We previously demonstrated that apolipoprotein D (apoD) levels are elevated in the dorsolateral prefrontal cortex and caudate obtained postmortem from subjects with schizophrenia and bipolar disorder compared to controls, suggesting a focal compensatory response to neuropathology associated with psychiatric disorders. We have now extended those studies by measuring apoD protein levels in additional brain regions from post-mortem samples of schizophrenic and bipolar disorder subjects using an enzyme-linked immunosorbent assay. Increased apoD levels were observed in the lateral prefrontal cortex (Brodmann Area 46) in both schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder, respectively). However, differences between the disease groups were observed in other brain regions. In subjects with schizophrenia, but not bipolar disorder, apoD levels were significantly elevated in the amygdala (42.8%) and thalamus (31.7%), while in bipolar disorder, but not schizophrenia, additional increases were detected in the parietal cortex (Brodmann Area 40; 123%) and the cingulate cortex (Brodmann Area 24; 57.7%). These data demonstrate that there is anatomical overlap in the pathophysiologies of schizophrenia and bipolar disorder, as well as areas of pathology that distinguish the two disorders.

Adult↗

PubMed2005

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.

This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence. The morphological correlates of schizophrenia are subtle, and range from a slight reduction in brain size to localized alterations in the morphology and molecular composition of specific neuronal, synaptic, and glial populations in the hippocampus, dorsolateral prefrontal cortex, and dorsal thalamus. These findings have fostered the view of schizophrenia as a disorder of connectivity and of the synapse. Although attractive, such concepts are vague, and differentiating primary events from epiphenomena has been difficult. A way forward is provided by the recent identification of several putative susceptibility genes (including neuregulin, dysbindin, COMT, DISC1, RGS4, GRM3, and G72). We discuss the evidence for these and other genes, along with what is known of their expression profiles and biological roles in brain and how these may be altered in schizophrenia. The evidence for several of the genes is now strong. However, for none, with the likely exception of COMT, has a causative allele or the mechanism by which it predisposes to schizophrenia been identified. Nevertheless, we speculate that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry. NMDA receptor-mediated glutamate transmission may be especially implicated, though there are also direct and indirect links to dopamine and GABA signalling. Hence, there is a correspondence between the putative roles of the genes at the molecular and synaptic levels and the existing understanding of the disorder at the neural systems level. Characterization of a core molecular pathway and a 'genetic cytoarchitecture' would be a profound advance in understanding schizophrenia, and may have equally significant therapeutic implications.

Brain↗

PubMed2005

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss.

Postmortem brain studies have shown deficits in the cortical gamma-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5' upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.

5' Flanking Region↗

PubMed2006

Alcohol dependence is associated with the ZNF699 gene, a human locus related to Drosophila hangover, in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample.

Because tolerance is an important aspect of alcohol dependence (AD) in humans, recent evidence showing that the Drosophila gene hang is critically involved in the development of alcohol tolerance in the fly suggests that variation in related human loci might be important in the etiology of alcohol-related disorders. The orthology of hang in mammals is complex, but a number of human gene products (including ZNF699) with similar levels of amino-acid identity (18-26%) and similarity (30-41%), are consistently identified as the best matches with the translated hang sequence. We tested for association between the dichotomous clinical phenotype of alcohol dependence and seven single nucleotide polymorphisms (SNPs) in ZNF699 in our sample of 565 genetically independent cases and 496 siblings diagnosed with AD, and 609 controls. In analyses of genetically independent cases and controls, four of the seven single markers show strong evidence for association with AD (0.00003<Fisher's exact P<0.001), and the most significant single marker, rs7254880, tags an associated haplotype with frequency 0.071 in cases compared to 0.034 in controls (chi2 15.563, P<0.00008, 5000 permutation P<0.001, OR 2.17); inclusion of affected siblings gives similar results. Expression analyses conducted in independent postmortem brain samples show that expression of ZNF699 mRNA is significantly reduced in the dorsolateral prefrontal cortex of individuals carrying this haplotype compared with other observed haplotype combinations.

Alcohol-Related Disorders↗