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Results for “Dorsolateral Prefrontal Cortex”

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PubMed2002

Decrease of middle cerebral artery blood flow velocity after low-frequency repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in a variety of neuropsychiatric disorders. Both, inhibition and activation of cortical areas may be achieved using different stimulation parameters. Using low-frequency rTMS (0.9 Hz), inhibition of cortical areas can be observed. METHODS: In the present study, 38 right-handed, healthy, normotensive subjects (aged 21-50 years, mean 30.2 years, SD=4.9; 17 women) were enrolled. Twenty-five participants received active rTMS (5 min of 0.9 Hz rTMS, stimulus intensity 90% of motor threshold) of the right dorsolateral prefrontal cortex. Sham stimulation (n=13 subjects) occurred in the same manner as active rTMS, except that the angle of the coil was at 45 degrees off the skull. Simultaneously, ipsilateral and contralateral maximal middle cerebral artery (MCA) flow velocity (and pulsatility index, PI) was monitored using transcranial Doppler sonography. RESULTS: In the group with active rTMS, maximal MCA flow velocity decreased from a baseline (before rTMS) of 101.6 cm/s (SD=26.0) to a mean of 92.6 cm/s (SD=23.7) immediately after rTMS, T=5.06, P<0.001. This equals a mean decrease of 9.0 cm/s (SD=8.3) or approximately 8.9% of baseline flow. Five and 10 min after rTMS, there was a return to baseline. PI significantly decreased 10 min after rTMS (mean difference -0.05, SD=0.05, T=2.29, P<0.05). In the contralateral MCA, maximal flow velocity tended to increase 10 min after rTMS (mean difference +7.4 cm/s, SD=17.5; T=-2.03, P=0.054). With sham rTMS, no significant changes occurred. CONCLUSIONS: The results from our study support the hypothesis that low-frequency rTMS may influence cerebral blood flow (CBF) over short periods of time, inducing a temporary decrease of maximal CBF in the ipsilateral MCA followed by an increase in the contralateral MCA.

Adult↗

PubMed2000

Segregation of working memory functions within the dorsolateral prefrontal cortex.

It is now widely accepted that the prefrontal cortex (PFC) plays a critical role in the neural network subserving working memory (WM). At least three related questions are still under debate: (1) is the PFC critical for all constituent processes of WM (i.e., short-term storage, manipulation, and utilization of mental representations) or only in one or a few of them? (2) Is there segregation of function among different cytoarchitectonic subdivisions of the PFC? (3) If this be the case, is this segregation based on the nature of the information being processed or on the type of cognitive operation performed? The present review article describes findings in the monkey supporting a modular "domain-specific" model of PFC functional organization with respect to WM operations. In this model, the dorsolateral prefrontal cortex (DLPFC) is composed of several subregions, based primarily on the nature of the information being processed in WM. Storage and processing functions are integrally related in each area. Future studies designed to map as yet uncharted areas of prefrontal cortex with refined anatomical and physiological approaches may provide a critical test of the model and evaluate the extent to which it applies generally or, instead, mainly to visual domains or only to dorsolateral convexity areas.

Animals↗

PubMed2006

Transcriptome alterations in schizophrenia: disturbing the functional architecture of the dorsolateral prefrontal cortex.

The availability of methods for quantifying tissue concentrations of messenger RNAs in the postmortem of the human brain has provided a number of new findings in schizophrenia. However, understanding how these findings actually relate to the disease process of schizophrenia requires knowledge both of the factors that might give rise to such changes in gene expression and of the impact of these changes on the function of the affected neural circuits. Consequently, this chapter provides a review of the potential causes and consequences of some of the schizophrenia-related transcriptome changes in the dorsolateral prefrontal cortex, a brain region implicated in the pathophysiology of certain core cognitive deficits in this illness.

Animals↗

PubMed2004

1H MRS study of dorsolateral prefrontal cortex in healthy individuals before and after lithium administration.

The mechanism of action of lithium is still largely unknown. However, recent animal and human studies suggested the possible neuroprotective effects of this medication. In particular, a recent magnetic resonance spectroscopy (MRS) study showed the increase of cortical brain levels of N-acetyl-aspartate (NAA), a putative marker of neuronal integrity/functioning, in both bipolar patients and normal controls after 4 weeks of lithium administration. We investigated the effects of lithium on NAA levels in a sample of healthy individuals using in vivo 1H MRS in dorsolateral prefrontal cortex (DLPFC), a region likely implicated in the pathophysiology of bipolar disorder. In vivo short echo-time 1H-MRS measurements of 8 cm3 single voxels placed bilaterally in the DLPFC were conducted at baseline and after 4 weeks of lithium administration on 12 healthy individuals (mean age+/-SD = 25.0+/-9.8 years; six males). After lithium administration, no significant differences in NAA, phosphocreatine plus creatine, glycerophosphocholine plus phosphocholine (or choline-containing molecules), and myo-inositol absolute levels or ratios were found in DLPFC (paired t-tests, p > 0.05). Contrary to prior MRS reports in bipolar patients, we found that lithium administration did not significantly increase NAA levels in the DLPFC of healthy individuals. Future longitudinal studies will be needed to further investigate whether chronic lithium treatment increases NAA levels in other brain regions in healthy individuals, and whether it promotes changes in these levels in specific brain regions in bipolar patients.

Adolescent↗

PubMed2000

Dorsolateral prefrontal cortex and the implicit association of concepts and attributes.

The Implicit Association Test (IAT) examines the differential association of two object categories (e.g. flower and insect) with attribute categories (e.g. pleasant and unpleasant). When items from congruent categories (e.g. flower + pleasant) share a response key, performance is faster and more accurate than when items from incongruent categories (e.g. insect + pleasant) share a key. Performing incongruent word classification engages inhibitory processes to overcome the prepotent tendency to map emotionally congruent items to the same response key. Using fMRI on subjects undergoing the IAT, we show that the left dorsolateral prefrontal cortex, and to a lesser extent the anterior cingulate cortex, mediate inhibitory processes where manipulation of word association is required.

Adult↗

PubMed2001

Hypoperfusion in the supplementary motor area, dorsolateral prefrontal cortex and insular cortex in Parkinson's disease.

The changes of regional cerebral blood flow (rCBF) in Parkinson's disease (PD) were investigated. Because of individual differences in brain volume and the extent of brain atrophy, previous functional imaging studies involved potential methodological difficulties. In this study, using the statistical parametric mapping technique, 99mTechnetium-labeled hexamethylpropyleneamineoxime brain single-photon emission computed tomography images from 18 patients with PD were transformed into standard brain-based stereotaxic coordinate spaces and then compared with such images for 11 control subjects matched for age and extent of brain atrophy. A rCBF decrement in the supplementary motor area (SMA) and such decrement in the dorsolateral prefrontal cortex (DLPFC) were observed in the summarized PD images as compared with controls (p<0.005). In a subgroup in the Hoehn-Yahr III/IV stage (11 cases), the rCBF decrement was demonstrated not only in the SMA, but also in the DLPFC and insular cortex (p<0.001). There was a correlation between the degree of the rCBF decrement in the DLPFC or the insular cortex and the score of the unified Parkinson's disease rating scale (p<0.05), while the rCBF decrement in the SMA showed no relationship with the severity of disease. The function of the SMA is closely associated with the nigro-striatal pathway and its impairment can explain the basic akinetic symptoms in PD, which are responsive to L-DOPA treatment. On the other hand, the DLPFC and insular cortex may play key roles in specific symptoms of impairment at advanced stages, such as impaired working memory, postural instability and autonomic dysfunction. We hypothesize that the impairment of the DLPFC and insular function is correlated with the progression of the disease and is related to DOPA-refractory symptoms, which are major problems in the care of patients with advanced PD.

Adult↗

PubMed2005

Increased expression in dorsolateral prefrontal cortex of CAPON in schizophrenia and bipolar disorder.

BACKGROUND: We have previously reported linkage of markers on chromosome 1q22 to schizophrenia, a finding supported by several independent studies. Within this linkage region, we have identified significant linkage disequilibrium between schizophrenia and markers within the gene for carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON). Prior sequencing of the ten exons of CAPON failed to reveal a coding mutation associated with illness. METHODS AND FINDINGS: We screened a human fetal brain cDNA library and identified a new isoform of CAPON that consists of the terminal two exons of the gene, and verified the expression of the predicted corresponding protein in human dorsolateral prefrontal cortex (DLPFC). We examined the expression levels of both the ten-exon CAPON transcript and this new isoform in postmortem brain samples from the Stanley Array Collection. Quantitative real-time PCR analysis of RNA from the DLPFC in 105 individuals (35 with schizophrenia, 35 with bipolar disorder, and 35 psychiatrically normal controls) revealed significantly (p < 0.005) increased expression of the new isoform in both schizophrenia and bipolar disorder. Furthermore, this increased expression was significantly associated (p < 0.05) with genotype at three single-nucleotide polymorphisms previously identified as being in linkage disequilibrium with schizophrenia. CONCLUSION: Based on the known interactions between CAPON, neuronal nitric oxide synthase (nNOS), and proteins associated with the N-methyl-D-aspartate receptor (NMDAR) complex, overexpression of either CAPON isoform would be expected to disrupt the association between nNOS and the NMDAR, leading to changes consistent with the NMDAR hypofunctioning hypothesis of schizophrenia. This study adds support to a role of CAPON in schizophrenia, produces new evidence implicating this gene in the etiology of bipolar disorder, and suggests a possible mechanism of action of CAPON in psychiatric illness.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder.

OBJECTIVES: Bipolar disorder (BPD) affects more than 2 million adults in the USA and ranks among the top 10 causes of worldwide disabilities. Despite its prevalence, very little is known about the etiology of BPD. Recent evidence suggests that cellular energy metabolism is disturbed in BPD. Mitochondrial function is altered, and levels of high-energy phosphates, such as phosphocreatine (PCr), are reduced in the brain. This evidence has led to the hypothesis that deficiencies in energy metabolism could account for some of the pathophysiology observed in BPD. To further explore this hypothesis, we examined levels of creatine kinase (CK) mRNA, the enzyme involved in synthesis and metabolism of PCr, in the hippocampus (HIP) and dorsolateral prefrontal cortex (DLPFC) of control, BPD and schizophrenia subjects. METHODS: Tissue was obtained from the Harvard Brain Tissue Resource Center. Real-time quantitative polymerase chain reaction (HIP, DLPFC) and gene expression microarrays (HIP) were employed to compare the brain and mitochondrial 1 isoforms of CK. RESULTS: Both CK isoforms were downregulated in BPD. Furthermore, mRNA transcripts for oligodendrocyte-specific proteins were downregulated in the DLPFC, whereas the mRNA for the neuron-specific protein microtubule-associated protein 2 was downregulated in the HIP. CONCLUSION: Although some of the downregulation of CK might be explained by cell loss, a more general mechanism seems to be responsible. The downregulation of CK transcripts, if translated into protein levels, could explain the reduction of high-energy phosphates previously observed in BPD.

Adult↗

PubMed2006

Towards human BCI applications based on cognitive brain systems: an investigation of neural signals recorded from the dorsolateral prefrontal cortex.

One of the critical issues in brain-computer interface (BCI) research is how to translate a person's intention into brain signals for controlling computer programs. The motor system is currently the primary focus, where signals are obtained during imagined motor responses. However, cognitive brain systems are also attractive candidates, in that they may be more amenable to conscious control, yielding better regulation of magnitude and duration of localized brain activity. We report on a proof of principle study for the potential use of a higher cognitive system for BCI, namely the working memory (WM) system. We show that mental calculation reliably activates the WM network as measured with functional magnetic resonance imaging (fMRI). Moreover, activity in the dorsolateral prefrontal cortex (DLPFC) indicates that this region is active for the duration of mental processing. This supports the notion that DLPFC can be activated, and remains active, at will. Further confirmation is obtained from a patient with an implanted electrode grid for diagnostic purposes, in that gamma power within DLPFC increases during mental calculation and remains elevated for the duration thereof. These results indicate that cortical regions involved in higher cognitive functions may serve as a readily self-controllable input for BCI applications. It also shows that fMRI is an effective tool for identifying function-specific foci in individual subjects for subsequent placement of cortical electrodes. The fact that electrocorticographic (ECoG) signal confirmed the functional localization of fMRI provides a strong argument for incorporating fMRI in BCI research.

Attention↗

PubMed1992

The dorsolateral prefrontal cortex, schizophrenia and PET.

Central neurophysiology can be measured with PET. These measurements are providing insights into the regional abnormalities associated with schizophrenia. Cohorts of schizophrenic subjects have been studied cross-sectionally in attempts to identify common regional deficits. More recently the advent of fast dynamic measurements of regional cerebral blood flow have allowed rapid serial measurements in the same subject in different brain states (activation studies). These complementary approaches are based upon, and are interpreted with reference to, a number of methodological considerations and underlying hypotheses. The key hypotheses underpinning cross-sectional and activation studies are discussed within the framework of the lesion model and functional anatomy models of brain function. This brief review of some assumptions, ideas and methodological constraints is illustrated with empirical data implicating the dorsolateral prefrontal cortex in schizophrenic symptoms.

Behavior↗

PubMed2005

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex affects divided attention immediately after cessation of stimulation.

Transcranial magnetic stimulation has evolved into a powerful neuroscientific tool allowing to interfere transiently with specific brain functions. In addition, repetitive TMS (rTMS) has long-term effects (e.g. on mood), probably mediated by neurochemical alterations. While long-term safety of rTMS with regard to cognitive functioning is well established from trials exploring its therapeutic efficacy, little is known on whether rTMS can induce changes in cognitive functioning in a time window ranging from minutes to hours, a time in which neurochemical effects correlated with stimulation have been demonstrated. This study examined effects of rTMS on three measures of executive function in healthy subjects who received one single rTMS session (40 trains of 2 s duration 20 Hz stimuli) at the left dorsolateral prefrontal cortex (DLPFC). Compared to a sham condition one week apart, divided attention performance was significantly impaired about 30-60 min after rTMS, while Stroop-interference and performance in the Wisconsin Card Sorting Test was unaffected after rTMS. Repetitive TMS of the left DLPFC, at stimulation parameters used in therapeutic studies, does not lead to a clinically relevant impairment of executive function after stimulation. However, the significant effect on divided attention suggests that cognitive effects of rTMS are not limited to the of acute stimulation, and may possibly reflect known neurochemical alterations induced by rTMS. Sensitive cognitive measures may be useful to trace those short-term effects of rTMS non-invasively in humans.

Adult↗

PubMed1995

Wisconsin Card Sorting Test performance in obsessive-compulsive disorder: no evidence for involvement of dorsolateral prefrontal cortex.

Wisconsin Card Sorting Test (WCST) performances were studied in 33 patients with obsessive-compulsive disorder (OCD) and 33 age-, sex-, and education-matched normal comparison subjects; the OCD patients were divided into four subgroups on the basis of their symptomatology. Neither the two groups of subjects nor the four OCD subgroups differed on any of the WCST neuropsychological indices. No relationship was demonstrated between test performance and clinical-epidemiological characteristics of the OCD patients. All of the OCD patients were being treated with fluvoxamine maleate, which improves OCD symptoms and could also improve WCST performances. Nevertheless, no remarkable differences in the WCST indices were observed in patients treated with fluvoxamine when compared with patients who had not received a specific therapy for at least 3 weeks. Since the WCST is widely considered sensitive to dysfunction of the dorsolateral prefrontal cortex, our results do not support the involvement of that brain region in OCD.

Anti-Anxiety Agents↗

PubMed2002

Recruitment of anterior dorsolateral prefrontal cortex in human reasoning: a parametric study of relational complexity.

Reasoning and problem solving depend on the ability to represent and integrate complex relationships among stimuli. For example, deciding whether an animal is dangerous requires integrating information about the type of animal, its size, its distance from oneself, and one's proximity to shelter. Relational complexity increases with the number of such interdependent elements that must be simultaneously considered to solve a problem. We used functional magnetic resonance imaging to identify brain regions that respond selectively in processing high levels of relational complexity. Performance on nonverbal reasoning problems in which relational complexity was varied parametrically was compared with performance on control problems in which relational complexity was held constant while difficulty was manipulated by adding distractor forms to the problems. Increasing complexity and adding distractors both led to increased activation in parietal and in dorsolateral prefrontal cortex, with high levels of relational complexity selectively activating anterior left prefrontal cortex. Our data provide evidence that brain regions specific to integrating complex relations among stimuli are distinct from those involved in coping with general task difficulty and with working-memory demands.

Adult↗

PubMed2006

Detection of adeno-associated virus 2 and parvovirus B19 in the human dorsolateral prefrontal cortex.

Although animal parvoviruses have long been recognized as causes of brain pathology in multiple animal models, especially during early development, human parvoviruses are rarely thought of as neurotropic or causes of neuropathology in humans. However, several recent case reports have suggested possible associations of parvovirus B19 (B19) infection with various neurological and neuropsychiatric symptoms. Adeno-associated virus 2 (AAV2) is related to B19 but has thus far not been shown to be associated with any human disease but is of clinical interest because of the recent use of recombinant AAV vectors in human gene therapy, including gene delivery to the brain. To date, there have been no large-scale studies of the propensity of wild-type human parvoviruses to infect the brain. The Stanley Medical Research Institute Brain Collection offered a unique opportunity to study a large sample (n = 104) of dorsolateral prefrontal cortex (DLPC) DNAs isolated from unaffected control, schizophrenic, and bipolar disorder brains for the presence of parvoviral sequences. This is the first investigator-blinded study to document the presence of parvoviral sequences in the DLPC by utilizing highly sensitive nested polymerase chain reaction (nPCR) and DNA sequencing. Of the overall sample, 6.7% to 12.5% were positive for AAV2, and 14.4% to 42.3% were positive for B19 sequences, with no statistical differences among subgroups. This is the first report to demonstrate the presence of human parvoviruses in a large cohort of adult DLPC, which underscores the need to gain a better insight into the basic biology of parvovirus-brain interactions, including mechanisms of infection and persistence.

Adult↗

PubMed2003

Catechol O-methyltransferase (COMT) mRNA expression in the dorsolateral prefrontal cortex of patients with schizophrenia.

Human prefrontal cortical neurons express catechol O-methyltransferase (COMT), an enzyme that inactivates the neurotransmitter dopamine. A functional polymorphism of COMT, Val(108/158) Met, affects prefrontal function, and the high-activity Val allele has been reported to be a genetic risk factor for schizophrenia. We used in situ hybridization histochemistry to measure mRNA levels of COMT in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia (N=14) and of normal controls (N=15). While the groups did not differ in terms of mean level of COMT mRNA, there was a significantly different laminar pattern of COMT mRNA expression in pyramidal neurons (F=2.68, df=4,108, P <0.04); patients with schizophrenia had relatively lower levels in the superficial (II/III) layers and higher levels in the intermediate/deep (IV/V) layers (P&<0.01), while in controls, the expression was homogeneous across layers. Neither the mean level nor the laminar distribution of COMT mRNA was related to the Val(108/158) Met genotype, suggesting that the feedback regulation of mRNA level is not a compensation for the functional effect of the COMT polymorphism. The disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the DLPFC of patients with schizophrenia.

Adult↗

PubMed2006

Involvement of human left dorsolateral prefrontal cortex in perceptual decision making is independent of response modality.

Perceptual decision making typically entails the processing of sensory signals, the formation of a decision, and the planning and execution of a motor response. Although recent studies in monkeys and humans have revealed possible neural mechanisms for perceptual decision making, much less is known about how the decision is subsequently transformed into a motor action and whether or not the decision is represented at an abstract level, i.e., independently of the specific motor response. To address this issue, we used functional MRI to monitor changes in brain activity while human subjects discriminated the direction of motion in random-dot visual stimuli that varied in coherence and responded with either button presses or saccadic eye movements. We hypothesized that areas representing decision variables should respond more to high- than to low-coherence stimuli independent of the motor system used to express a decision. Four areas were found that fulfilled this condition: left posterior dorsolateral prefrontal cortex (DLPFC), left posterior cingulate cortex, left inferior parietal lobule, and left fusifom/parahippocampal gyrus. We previously found that, when subjects made categorical decisions about degraded face and house stimuli, left posterior DLPFC showed a greater response to high- relative to low-coherence stimuli. Furthermore, the left posterior DLPFC appears to perform a comparison of signals from sensory processing areas during perceptual decision making. These data suggest that the involvement of left posterior DLPFC in perceptual decision making transcends both task and response specificity, thereby enabling a flexible link among sensory evidence, decision, and action.

Adult↗

PubMed2005

Impaired recruitment of the dorsolateral prefrontal cortex and hippocampus during encoding in bipolar disorder.

BACKGROUND: The aim of the present study was to examine the functional neuroanatomy of episodic memory impairment in euthymic subjects with bipolar I disorder. There is evidence that individuals with bipolar disorder have cognitive impairments not only during mood episodes but also when they are euthymic. The most consistently reported cognitive difficulty in euthymic subjects with bipolar disorder is impairment in verbal episodic memory (i.e., the ability to learn new verbal information). METHODS: The current study examined verbal learning in eight euthymic, remitted subjects with bipolar I disorder (BP-I; seven nonmedicated) and eight control subjects matched for age, gender, education, and intelligence. Subjects underwent (15)O-CO(2) positron emission tomography scanning while completing a verbal learning paradigm that consisted of encoding (learning) several lists of words. RESULTS: The BP-I subjects had more difficulties learning the lists of words compared with the control subjects. Compared with control subjects, BP-I subjects exhibited blunted regional cerebral blood flow (rCBF) increases in the left dorsolateral prefrontal cortex (Brodmann's area 9/46) during encoding. CONCLUSIONS: Consistent with previous studies, subjects with BP-I were impaired in learning new verbal information. This was associated with rCBF abnormalities in brain regions involved in learning and episodic memory.

Adult↗

PubMed2002

Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia.

To test the hypothesis that muscarinic receptors are involved in the pathology of schizophrenia, we measured muscarinic(1) (M1R) and muscarinic(4)(M4R) protein and mRNA as well as [(3)H]pirenzepine binding in Brodmann's areas (BA) 9 and 40 obtained postmortem from 20 schizophrenic and 20 age/sex-matched control subjects. There was a significant decrease in [(3)H]pirenzepine binding to BA 9 (mean +/- SEM: 151 +/- 15 vs 195 +/- 10 fmol mg(-1) ETE; P< 0.02), but not BA 40 (143 +/- 13 vs 166 +/- 11 fmol mg(-1) ETE), from subjects with schizophrenia. The level of M1R protein (0.11 +/- 0.007 vs 0.15 +/- 0.008 OD; P < 0.01), but not M4R protein, was decreased in BA9 from schizophrenic subjects with neither receptor protein being altered in BA 40. The level of M1R mRNA was decreased in BA 9 (30 +/- 7.0 vs 79 +/- 14 dpm x 10(3) mg(-1) ETE, P < 0.01) and BA 40 (28 +/- 5.9 vs 99 +/- 14, P < 0.01) with schizophrenia but M4R mRNA was only decreased in BA 40 (48 +/- 6.6 vs 89 +/- 9.9, P < 0.005). These data suggest that the M1R, at least in the dorsolateral prefrontal cortex, may have a role in the pathology of schizophrenia.

Adult↗