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Results for “Dorsolateral Prefrontal Cortex”

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PubMed2006

Region specific regulation of NR1 in rhesus monkeys following chronic antipsychotic drug administration.

BACKGROUND: Altered NMDA receptor subunit protein levels have been reported in various regions of the schizophrenic brain; however, chronic antipsychotic administration in schizophrenic subjects may confound interpretation. METHODS: The effects of chronic antipsychotic drug administration (haloperidol and clozapine) on protein levels of NR1, NR2A and NR2B proteins were evaluated in the nucleus accumbens (NAc), putamen (PUT), dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), and entorhinal cortex (EC) of rhesus monkeys using Western blot analysis. RESULTS: Haloperidol administration significantly decreased NR1 expression in the DLPFC. In contrast, NR2B expression was not affected by antipsychotic administration in any brain region examined. NR2A was not reliably detected in any of the brain regions. CONCLUSIONS: Results indicate that the NR1 subunit in the DLPFC may be a substrate for antipsychotic action and that glutamatergic hypofunction in the DLPFC commonly associated with cognitive dysfunction in schizophrenia may be associated with haloperidol administration.

Animals↗

PubMed2006

Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features.

BACKGROUND: Major depressive disorder is characterized by increased and sustained emotional reactivity, which has been linked to sustained amygdala activity. It is also characterized by disruptions in executive control, linked to abnormal dorsolateral prefrontal cortex (DLPFC) function. These mechanisms have been hypothesized to interact in depression. This study explored relationships between amygdala and DLPFC activity during emotional and cognitive information processing in unipolar depression. METHOD: Twenty-seven unmedicated patients with DSM-IV unipolar major depressive disorder and 25 never-depressed healthy control subjects completed tasks requiring executive control (digit sorting) and emotional information processing (personal relevance rating of words) during event-related functional magnetic resonance imaging (fMRI) assessment. RESULTS: Relative to control subjects, depressed subjects displayed sustained amygdala reactivity on the emotional tasks and decreased DLPFC activity on the digit-sorting task. Decreased relationships between the time-series of amygdala and DLPFC activity were observed within tasks in depression, but different depressed individuals showed each type of bias. CONCLUSIONS: Depression is associated with increased limbic activity in response to emotional information processing and decreased DLPFC activity in response to cognitive tasks though these may reflect separate mechanisms. Depressed individuals also display decreased relationships between amygdala and DLPFC activity, potentially signifying decreased functional relationships among these structures.

Adolescent↗

PubMed2006

Critical factors in gene expression in postmortem human brain: Focus on studies in schizophrenia.

BACKGROUND: Studies of postmortem human brain are important for investigating underlying pathogenic molecular mechanisms of neuropsychiatric disorders. They are, however, confounded by pre- and postmortem factors. The purpose of this study was to identify sources of variation that will enable a better design of gene expression studies and higher reliability of gene expression data. METHODS: We assessed the contribution of multiple variables to messenger RNA (mRNA) expression of reference (housekeeping) genes measured by reverse transcriptase-polymerase chain reaction (RT-PCR) by multiple regression analysis in a large number (N = 143) of autopsy samples from the hippocampus and white and grey matter of the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia and normal control subjects. RESULTS: The strongest predictor of gene expression was total RNA quality. Other significant factors included pH, postmortem interval, age and the duration of the agonal state, but the importance of these factors depended on transcript measured, brain region analyzed, and diagnosis. The quality of RNA obtained from the DLPFC white matter was also adversely affected by smoking. CONCLUSIONS: Our results show that normalization of expression data of target genes with a geometric mean of multiple housekeeping genes should be used to control for differences in RNA quality between samples. The results also suggest that accurate assessment of other confounding factors and their inclusion as regressors in the analysis is critical for obtaining reliable and accurate quantification of mRNA expression.

Adult↗

PubMed2004

Dynamic and strategic aspects of executive processing.

Executive cognitive functions have been postulated to include both dynamic behavioral selection and strategic goal-setting or response preparation. To investigate the relation between these aspects of executive processing, we embedded an event-related oddball paradigm within a blocked design. Subjects responded to infrequent targets presented within a series of standard stimuli that required no response; this task alternated with a visually similar nontask condition. Using functional magnetic resonance imaging (fMRI), we found that a set of brain regions including dorsolateral prefrontal cortex (dlPFC), insular cortex, cingular cortex, and the basal ganglia demonstrated transient activation both to target stimuli and to the onset of task blocks. Within the parietal cortex, there was a dissociation such that the supramarginal gyrus exhibited greater activity to the target stimuli than to block onsets, while the converse pattern was observed in the intraparietal sulcus. Sustained positive activity during task blocks was present in the caudate and supplementary motor area, while sustained negative activity was present in the precuneus and medial parietal cortex. We conclude that dlPFC and related brain regions mediate both dynamic and strategic processing, through the preparation and selection of rules for behavior.

Adolescent↗

PubMed2005

Evidence for the importance of basal ganglia output nuclei in semantic event sequencing: an fMRI study.

Semantic event sequencing is the ability to plan ahead and order meaningful events chronologically. To investigate the neural systems supporting this ability, an fMRI picture sequencing task was developed. Participants sequenced a series of four pictures presented in random order based on the temporal relationship among them. A control object discrimination task was designed to be comparable to the sequencing task regarding semantic, visuospatial, and motor processing requirements but without sequencing demands. fMRI revealed significant activation in the dorsolateral prefrontal cortex and globus pallidus internal part in the picture sequencing task compared with the control task. The findings suggest that circuits involving the frontal lobe and basal ganglia output nuclei are important for picture sequencing and more generally for the sequential ordering of events. This is consistent with the idea that the basal ganglia output nuclei are critical not only for motor but also for high-level cognitive function, including behaviors involving meaningful information. We suggest that the interaction between the frontal lobes and basal ganglia output nuclei in semantic event sequencing can be generalized to include the sequential ordering of behaviors in which the selective updating of neural representations is the key computation.

Basal Ganglia↗

PubMed2006

Characterization of KIAA0513, a novel signaling molecule that interacts with modulators of neuroplasticity, apoptosis, and the cytoskeleton.

KIAA0513 was previously identified as upregulated in the dorsolateral prefrontal cortex of subjects with schizophrenia by microarray analysis. In the present study, the differential expression in the schizophrenic subjects was confirmed by quantitative RT-PCR. The limited homology to proteins of known function and lack of functional domains in the encoded protein have made it difficult to predict a function for KIAA0513. We used in situ hybridization, RNA blots, western blots, and immunocytochemistry to examine KIAA0513 expression in normal brain and peripheral tissues. The gene is ubiquitously expressed but is enriched in the brain, particularly in the cerebellum. Finally, interacting proteins were identified using a yeast two-hybrid screen to functionally characterize the protein. KIAA0513 interacts with KIBRA, HAX-1, and INTS4, which also interact with proteins involved in neuroplasticity, apoptosis, and cytoskeletal regulation. Therefore, KIAA0513 is likely to be involved in signaling pathways related to these processes.

Animals↗

PubMed2006

Spontaneous magnetoencephalographic activity in patients with obsessive-compulsive disorder.

Non-invasive functional imaging techniques have begun to delineate the underlying neurophysiological basis of obsessive-compulsive disorder (OCD). In the present study, we investigated slow (2-6 Hz) and fast (12.5-30 Hz) spontaneous magnetoencephalographic (MEG) activity in ten patients with obsessive-compulsive disorders compared to ten healthy control subjects. Fast MEG activity was significantly elevated in OCD patients. The corresponding dipole density maxima were concentrated on the left superior temporal gyrus. Although no differences were detected in the absolute dipole numbers between controls and OCD patients regarding slow MEG activity, only the latter showed a clustering of slow MEG activity over their left dorsolateral prefrontal cortex. We conclude that alterations of spontaneous MEG activity in prefrontal and temporal cortices may be linked to the pathogenesis of OCD. Therefore, we provide further functional neuroimaging evidence that the complex features of OCD have neural correlates, which may help in a future understanding of this disease.

Adult↗

PubMed2005

Repetitive transcranial magnetic stimulation (rTMS) at high and low frequency: an efficacious therapy for major drug-resistant depression?

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is proposed for the treatment of drug-resistant depression. Studies performed in accordance with evidence-based medicine (EBM) are scarce, particularly in seeking optimal treatment and evaluation parameters. We aimed to test various types of rTMS in a large sample of depressed patients following EBM rules and to investigate treatment-related changes in plasma levels of neurotransmitters involved in depression. METHODS: Seventy-one drug-resistant depressed patients were randomly assigned to low (1 Hz) or high (17 Hz) rate TMS, applied for 5 days over the left dorsolateral prefrontal cortex (L-DLPFC). Patients were separated into two study designs. One group (20 patients) received only active treatment, while the other entered a double-blind, placebo-controlled, crossover design. Pre- and post-treatment blood samples were taken for evaluation of plasma levels of dopamine and serotonin. RESULTS: After a week of treatment patients had a measurable benefit. However, overall the placebo stimulation did not differ significantly from real stimulation, nor were differences observed between the two rates of rTMS. The only difference emerged when the real stimulation was applied at 17 Hz following placebo treatment. Plasma levels of neurotransmitters between active and placebo rTMS were similar. CONCLUSIONS: Using the treatment schedule of 1 week, although a clinical improvement after active treatment was indeed observed, this was both clinically and biochemically indistinguishable from that seen in the placebo arm. SIGNIFICANCE: This suggests that most of the previous emphasis, for short period of treatment, should be tempered down and that further work is required in order to verify whether optimal stimulation and evaluation parameters for TMS-treatment of depression beyond the placebo effect may be found following EBM rules.

Adult↗

PubMed2003

Dissociable brain mechanisms for inhibitory control: effects of interference content and working memory capacity.

In this study, event-related fMRI was used to examine whether the resolution of interference arising from two different information contents activates the same or different neuronal circuitries. In addition, we examined the extent to which these inhibitory control mechanisms are modulated by individual differences in working memory capacity. Two groups of participants with high and low working memory capacity [high span (HS) and low span (LS) participants, respectively] performed two versions of an item recognition task with familiar letters and abstract objects as stimulus materials. Interference costs were examined by means of the recent negative probe technique with otherwise identical testing conditions across both tasks. While the behavioral interference costs were of similar magnitude in both tasks, the underlying brain activation pattern differed between tasks: The object task interference-effects (higher activation in interference trials than in control trials) were restricted to the anterior intraparietal sulcus (IPS). Interference effects for familiar letters were obtained in the anterior IPS, the left postero-ventral and the right dorsolateral prefrontal cortex (PFC) as well as the precuneus. As the letters were more discernible than the objects, the results suggest that the critical feature for PFC and precuneus involvement in interference resolution is the saliency of stimulus-response mappings. The interference effects in the letter task were modulated by working memory capacity: LS participants showed enhanced activation for interference trials only, whereas for HS participants, who showed better performance and also lower interference costs in the letter task, the above-mentioned neuronal circuitry was activated for interference and control trials, thereby attenuating the interference effects. The latter results support the view that HS individuals allocate more attentional resources for the maintenance of task goals in the face of interfering information from preceding trials with familiar stimulus materials.

Adult↗

PubMed2004

The cortical organization of audio-visual sentence comprehension: an fMRI study at 4 Tesla.

Neuroimaging studies of written and spoken sentence processing report greater left hemisphere than right hemisphere activation. However, a large majority of our experience with language is face-to-face interaction, which is much richer in information. The current study examines the neural organization of audio-visual (AV) sentence processing using functional magnetic resonance imaging (fMRI) at 4 Tesla. Participants viewed the face and upper body of a speaker via a video screen while listening to her produce, in alternating blocks, English sentences and sentences composed of pronounceable non-words. Audio-visual sentence processing was associated with activation in the left hemisphere in Broca's area, dorsolateral prefrontal cortex, the superior precentral sulcus, anterior and middle portions of the lateral sulcus, middle superior portions of the temporal sulcus, supramarginal gyrus and angular gyrus. Further, AV sentence processing elicited activation in the right anterior and middle lateral sulcus. Between-hemisphere analyses revealed a left hemisphere dominant pattern of activation. The findings support the hypothesis that the left hemisphere may be biased to process language independently of the modality through which it is perceived. These results are discussed in the context of previous neuroimaging results using American Sign Language (ASL).

Adult↗

PubMed2004

The interfering effect of related events on recognition memory discriminability: a functional magnetic resonance imaging study.

Retrieval of information from memory often involves the selection of an event among competing related events, a process that frequently gives rise to interference effects. The present study used a forced-choice recognition test to identify neural correlates of the interfering effect of related events on recognition memory discriminability. Participants encoded landscape pictures divided into three segments. One segment was presented during encoding, and a forced-choice recognition task contrasted a studied and a nonstudied segment for each landscape. For half of the landscapes, the third segment was presented between encoding and recognition tasks to induce associative interference by reducing recognition discriminability. A behavioral study with 40 subjects yielded a significant difference in the correct recognition rate between control and interference trials (76% and 64%, respectively, p<0.001). A subsequent event-related fMRI study with 16 subjects yielded significant activations for correct interference recognition trials relative to control trials in left superior parietal regions, which suggests that these regions play a role in the representation of stimuli and associated information. The opposite contrast yielded significant activations in inferior prefrontal regions bilaterally, right dorsolateral prefrontal cortex and right parahippocampal cortex. Since this contrast was conducted using only correctly recognized trials, these findings could reflect an index of memory discriminability or saliency which could influence conscious recollection.

Adult↗

PubMed2005

Maturation of medial temporal lobe response and connectivity during memory encoding.

The medial temporal lobe (MTL) plays an important role in memory encoding. The development and maturation of MTL and other brain regions involved in memory encoding are, however, poorly understood. We used functional magnetic resonance imaging to examine activation and effective connectivity of the MTL in children and adolescents during encoding of outdoor visual scenes. Here, we show that MTL response decreases with age whereas its connectivity with the left dorsolateral prefrontal cortex (PFC) increases with age. Our findings provide evidence for dissociable maturation of local and distributed memory encoding processes involving the MTL and furthermore suggest that increased functional interactions between the MTL and the PFC may underlie the development of more effective memory encoding strategies.

Adolescent↗

PubMed2005

Task difficulty in a simultaneous face matching task modulates activity in face fusiform area.

The level of difficulty of a task can alter the neural network that activates for performance of the task. Previous studies have shown increased activation with task difficulty in the frontal lobes while the effects in the extrastriate visual areas have been unclear. We hypothesized that the face fusiform area (FFA), an area specialized for face processing, would increase activation as task difficulty increased in a face matching task. The difficulty level was increased by degrading the quality of the images. The degradation levels were 10%, 20%, 40% and 60%. Based on the correct response rate, the data were divided into a baseline level (composed of non-degraded and 10% degraded images) and a difficult level (composed of the 20%, 40% and 60% degraded images). Brain activation was measured using functional magnetic resonance imaging. The baseline face matching task activated a wide network of regions that included bilaterally the occipital, temporal and parietal lobes and the right frontal lobe. A novel behavioral finding was that task difficulty did not linearly increase with image degradation. The novel brain imaging finding was that the FFA is modulated by task difficulty and performance in the task was linearly correlated to activation in FFA. In addition, we found that activation in the dorsolateral prefrontal cortex (DLPFC) had increased activation as task difficulty increased. When adding the response time as a covariate, the differences in the DLPFC did not remain statistically significant. Increased task difficulty also led to a decrease in activation of visual areas in the extrastriate cortex. Task difficulty increased activation in the FFA to enhance the face processing and suppressed activation in visual extrastriate areas that processed low level properties of the stimuli. Task difficulty led to enhanced response in the FFA and suppressed response in other visual areas.

Adult↗

PubMed2005

Neuroimaging studies of obsessive-compulsive disorder in adults and children.

Obsessive-compulsive disorder (OCD) is a severe, highly prevalent and chronically disabling disorder that usually emerges during childhood or adolescence. Neuroimaging studies play an important role in advancing our understanding of the pathophysiology of OCD and in developing neurocircuitry models of this psychiatric illness. This paper provided an updated, comprehensive review and analysis of the relevant literature on baseline functional and structural neuroimaging studies of OCD in both paediatric and adult patients. The neuroanatomical findings were presented in the context of two models: executive dysfunction, which implicates the dorsolateral prefrontal cortex, caudate nucleus, thalamus, and striatum; and modulatory control, which implicates the orbitofrontal and medial prefrontal cortex and the cingulate gyrus. Neuroanatomical findings were not consistent across all studies, and limitations were examined. Recommendations for future research directions and the implications of the results for improved treatment were explored.

Adolescent↗

PubMed2006

Effects of frequent cannabis use on hippocampal activity during an associative memory task.

Interest is growing in the neurotoxic potential of cannabis on human brain function. We studied non-acute effects of frequent cannabis use on hippocampus-dependent associative memory, investigated with functional Magnetic Resonance Imaging (fMRI) in 20 frequent cannabis users and 20 non-users matched for age, gender and IQ. Structural changes in the (para)hippocampal region were measured using voxel-based morphometry (VBM). Cannabis users displayed lower activation than non-users in brain regions involved in associative learning, particularly in the (para)hippocampal regions and the right dorsolateral prefrontal cortex, despite normal performance. VBM-analysis of the (para)hippocampal regions revealed no differences in brain tissue composition between cannabis users and non-users. No relation was found between (para)hippocampal tissue composition and the magnitude of brain activity in the (para)hippocampal area. Therefore, lower brain activation may not signify neurocognitive impairment, but could be the expression of a non-cognitive variable related to frequent cannabis use, for example changes in cerebral perfusion or differences in vigilance.

Adult↗

PubMed2003

Insights into the pathophysiology of neuropathic pain through functional brain imaging.

We present here an example case of neuropathic pain with heat allodynia as a major symptom to illustrate how the functional imaging of pain may provide new insights into the pathophysiology of painful sensory disorders. Tissue injury of almost any kind, but especially peripheral or central neural tissue injury, can lead to long-lasting spinal and supraspinal re-organization that includes the forebrain. These forebrain changes may be adaptive and facilitate functional recovery, or they may be maladaptive, preventing or prolonging the painful condition, and interfering with treatment. In an experimental model of heat allodynia, we used functional brain imaging to show that: (1) the forebrain activity during heat allodynia is different from that during normal heat pain, and (2) during heat allodynia, specific cortical areas, specifically the dorsolateral prefrontal cortex, can attenuate specific components of the pain experience, such as affect, by reducing the functional connectivity of subcortical pathways. The forebrain of patients with chronic neuropathic pain may undergo pathologically induced changes that can impair the clinical response to all forms of treatment. Functional imaging, including PET, fMRI, and neurophysiological techniques, should help identify brain mechanisms that are critical targets for more effective and more specific treatments for chronic, neuropathic pain.

Adult↗

PubMed2005

Lack of impact of repetitive High Frequency Transcranial Magnetic Stimulation on mood in healthy female subjects.

BACKGROUND: High Frequency repetitive Transcranial Magnetic Stimulation (HF-rTMS) is currently used as an experimental tool to induce mood changes in normal volunteers and as a treatment option for depression. However, HF-rTMS, mostly performed on the left dorsolateral prefrontal cortex (DLPFC), has yielded divergent results and effects on mood which seem to be oppositely lateralized between these two groups. The inconsistent results that have been reported might be explained by methodological heterogeneity and drawbacks. METHODS: In this sham-controlled, single blind, crossover study, we tried to reproduce previous HF-rTMS findings of a negative mood induction in 28 healthy female subjects. To exclude individual anatomical differences, the left DLPFC was localised under magnetic resonance guidance (MRI). Mood assessment was performed before and just after HF-rTMS with Visual Analogue Scales and the Profile of Mood States. To detect possible delayed mood changes, ratings were also performed 30 min post HF-rTMS. RESULTS: We were unable to demonstrate significant mood changes from baseline after one single active HF-rTMS session on the left DLPFC. CONCLUSIONS: Although this study controlled for several methodological problems, the hypothesis that one single session of HF-rTMS on the left DLPFC has negative mood effects in healthy female volunteers was not supported.

Adult↗

PubMed2006

Effects of repetitive transcranial magnetic stimulation on [11C]raclopride binding and cognitive function in patients with depression.

BACKGROUND: Several studies have demonstrated that repetitive transcranial magnetic stimulation (rTMS) elicits moderate antidepressant effects. Several previous studies suggested that the dopaminergic system might be related to this therapeutic action of rTMS. We attempted to determine the effects of chronic rTMS on central dopaminergic function in depression using positron emission tomography (PET) with [11C]raclopride. METHODS: Nine patients with depression were treated with 10 daily sessions of rTMS (10 Hz, 5 s train, 20 trains at 100% motor threshold per session) over the left dorsolateral prefrontal cortex (DLPFC). Each patient underwent two [11C]raclopride PET scans and neuropsychological tests - before rTMS and 1 day after rTMS. RESULTS: In five patients, the Hamilton Rating Scale for Depression (HRSD) significantly decreased. Patients showed significant improvement in verbal memory following rTMS. There were no changes in [11C]raclopride binding in the caudate nucleus and putamen after rTMS treatment. LIMITATIONS: Our sample size was limited, and our study was an open trial lacking sham-treated controls. CONCLUSION: This study suggests that rTMS may be effective for the treatment of depression and also may improve verbal memory function. We observed no changes in [11C]raclopride binding, suggesting that there was no measurable increase in the release of dopamine at the second PET scan. Several animal studies and healthy human studies have indicated that dopamine can be released soon after acute rTMS. Our results suggest that release of striatal dopamine induced by rTMS may be only transient, or that dopamine release may be attenuated following chronic rTMS.

Adult↗