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PubMed2006

Dopamine increases inhibition in the monkey dorsolateral prefrontal cortex through cell type-specific modulation of interneurons.

Dopaminergic modulation of the dorsolateral prefrontal cortex (DLPFC) plays an important role in cognitive functions, including working memory. At optimal concentrations, dopamine (DA) enhances pyramidal cell (PC) firing to increase task-related activity. However, spatial and temporal "tuning" of the persistent firing that underlies this mnemonic activity requires inhibitory control from gamma-aminobutyric acidergic (GABAergic) interneurons. How DA modulates the inhibitory control provided by different types of interneurons in the primate cortex is not known. We studied the effects of DA and DA receptor-specific agonists and antagonists on GABAergic inhibition and interneuron excitability in slices from primate DLPFC. Using whole-cell voltage-clamp recordings from layer 2/3 pyramidal neurons, we examined the effects of DA on spontaneous (action potential dependent) and miniature (action potential independent) inhibitory postsynaptic currents. We found that DA can increase inhibition via a presynaptic, action potential-dependent mechanism. In current-clamp recordings from physiologically and morphologically identified interneurons, we investigated the pharmacology and cell type specificity of this effect. DA increased the excitability of fast-spiking (FS), nonadapting interneurons via activation of D1- but not D2-type receptors. In contrast, DA had no effect on interneurons with adapting firing patterns. Thus, DA and D1 receptor activation affect local recurrent circuits by selectively modulating FS interneurons that control the firing of PCs through perisomatic innervation.

Animals↗

PubMed2004

Functional properties of fast spiking interneurons and their synaptic connections with pyramidal cells in primate dorsolateral prefrontal cortex.

Recent studies suggest that fast-spiking (FS) interneurons of the monkey dorsolateral prefrontal cortex (DLPFC) exhibit task-related firing during working-memory tasks. To gain further understanding of the functional role of FS neurons in monkey DLPFC, we described the in vitro electrophysiological properties of FS interneurons and their synaptic connections with pyramidal cells in layers 2/3 of areas 9 and 46. Extracellular spike duration was found to distinguish FS cells from non-FS interneuron subtypes. However, a substantial overlap in extracellular spike duration between these populations would make classification of individual interneurons difficult. FS neurons could be divided into two main morphological groups, chandelier and basket neurons, with very similar electrophysiological properties but significantly different horizontal spread of the axonal arborization. In paired cell recordings, unitary inhibitory postsynaptic potentials (IPSPs) elicited by FS neurons in pyramidal cells had rapid time course, small amplitude at resting membrane potential, and were mediated by GABA(A) receptors. Repetitive FS neuron stimulation, partially mimicking the sustained firing of interneurons in vivo, produced short-term depression of the unitary IPSPs, present at connections made by both basket and chandelier neurons and due at least in part to presynaptic mechanisms. These results suggest that FS neurons and their synaptic connections with pyramidal cells have homogeneous physiological properties. Thus different functional roles of basket and chandelier neurons in the DLPFC in vivo must arise from the distinct properties of the interneuronal axonal arborization or from a different functional pattern of excitatory and inhibitory connections with other components of the DLPFC neuronal network.

Action Potentials↗

PubMed2004

GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex in schizophrenia.

This study aimed to investigate the binding affinity of [3H]GABA and [3H]beta-alanine to GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex (Brodmanns' area 9) in schizophrenia. Using post mortem tissue from individuals diagnosed with schizophrenia (n=6) and control subjects (n=6), the density of GAT-1 was established by displacing [3H]GABA with muscimol, and for GAT-3 [3H]beta-alanine was used. Data analysis showed a significant decrease of GAT-1 levels (45%), and a significant increase of GAT-3 density (23%) within the dorsolateral prefrontal cortex of individuals diagnosed with schizophrenia when compared to age- and sex-matched controls. The observed decrease of GAT-1 could be explained as a consequence of the GABA hypo-function or the result of volumetric shrinkage of the cerebral cortex previously reported in this disease. The observed elevation of GAT-3 levels could be due to a compensatory effect for any functional loss of GABA re-uptake by the decreased GAT-1 levels.

Adult↗

PubMed2005

Functional specialization within the dorsolateral prefrontal cortex: a review of anatomical and physiological studies of non-human primates.

The dorsolateral prefrontal cortex (DLPFC) possesses cortico-cortical connections with the parietal and premotor cortices that are involved in visuomotor control of actions. Studies have shown that the DLPFC, especially the caudal part, has a crucial role in cognitive control of motor behavior, and that it uses spatial information in conjunction with information such as object identity, behavioral rules, and rewards. Current anatomical and physiological studies indicate that the DLPFC may not be a single entity. Anatomical studies show that preferential anatomical connections exist between subregions of the DLPFC and the parietal/premotor cortices. Physiological studies based on data obtained from monkeys performing a variety of cognitive tasks report region-specific neuronal activity within the DLPFC. In this article, I review evidence for functional segregation within the DLPFC and postulate that at least two distinct subregions, i.e., the dorsal and ventral parts, can be identified.

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PubMed2003

Decisional role of the dorsolateral prefrontal cortex in ocular motor behaviour.

Three patients with a unilateral cortical lesion affecting the dorsolateral prefrontal cortex (DLPFC), i.e. Brodmann area 46, were tested using different paradigms of reflexive saccades (gap and overlap tasks), intentional saccades (antisaccades, memory-guided and predictive saccades) and smooth pursuit movements. Visually guided saccades with gap and overlap, latency of correct antisaccades and memory-guided saccades and the gain of smooth pursuit were normal, compared with controls. These results confirm our anatomical data showing that the adjacent frontal eye field (FEF) was unimpaired in these patients. The specific pattern of abnormalities after a unilateral DLPFC lesion, compared with that of the FEF lesions previously reported, consists mainly of: (i) a bilateral increase in the percentage of errors in the antisaccade task (misdirected reflexive saccades); (ii) a bilateral increase in the variable error in amplitude, without significant decrease in the gain, in the memory-guided saccade task; and (iii) a bilateral decrease in the percentage of anticipatory saccades in the predictive task. Taken together, these results suggest that the DLPFC plays a crucial role in the decisional processes, preparing saccades by inhibiting unwanted reflexive saccades (inhibition), maintaining memorized information for ongoing intentional saccades (short-term spatial memory) or facilitating anticipatory saccades (prediction), depending upon current external environmental and internal circumstances.

Adult↗

PubMed1980

Neuronal activity in the monkey dorsolateral prefrontal cortex during a discrimination task with delay.

Ninety-nine single neuron activities of the dorsolateral prefrontal cortex of 3 monkeys were recorded during performance of a Konorski task. Green or red lights were presented successively with a separation of fixed delay interval. The monkey responded as soon as the second stimulus was presented. If the two stimuli were color-matched, the 'YES' lever press was rewarded; if the two stimuli were not, the 'NO' lever press was rewarded. In the second task, after paired color stimuli, a tone pip was presented as the 'GO' signal for lever presses. During sample and matching periods 50 neurons increased their discharge rates and 10 decreased. In 86% of increasing type neurons rate increase occurred during both periods. During auditory GO periods, 27 neurons increased their rates and 11 decreased. Discharge peak was before or at the moment of hold key release. In 60% of these neurons were also observed the rate changes to sample and matching stimuli. Differential activations between left and right levers were found in 20%. It was suggested that the prefrontal cortex is related to a sensorial attention mechanism to the visual stimulus which enables correct choice of the behavior to be rewarded.

Animals↗

PubMed1993

Dorsolateral prefrontal cortex dysfunction in the major psychoses; symptom or disease specificity?

Neurophysiological deficits in the left dorsolateral prefrontal cortex (DLPFC) have been described in positron emission tomography studies of schizophrenia and depression. In schizophrenia and depression this deficit has been associated with the syndromes of psychomotor poverty and psychomotor retardation, respectively. Such findings lead to a prediction that DLPFC dysfunction is symptom rather than disease related. This prediction was empirically tested in a retrospective study that pooled data from 40 patients meeting research diagnostic criteria for depression and 30 patients meeting DSM-III R criteria for schizophrenia. The patients were categorised into those with and without poverty of speech, a symptom that is an observable manifestation of psychomotor impairment. The profile of regional cerebral blood flow (rCBF), measured in all subjects under resting conditions, was subsequently compared in these two groups. Patients with poverty of speech had significantly lower rCBF in the left DLFPC. This reduction of rCBF was independent of diagnosis. The findings support the view that the study of symptoms, or symptom clusters, can provide information additional to that of traditional diagnostic systems in the study of the major psychoses.

Adult↗

PubMed2006

Less activation of the left dorsolateral prefrontal cortex in response to a meal: a feature of obesity.

BACKGROUND: In an exploratory positron emission tomography study of postprandial regional cerebral blood flow, which is a marker of neuronal activity, obese men differed from lean men in several brain regions, including the prefrontal cortex. The subjects received a meal proportional to their body size; therefore, the meal volume was different for each person. OBJECTIVE: We investigated whether differences in the brain responses of obese and lean men to a meal represent satiety or feelings of gastric distension. DESIGN: We studied 9 lean (x +/- SD body fat: 15 +/- 5%; age: 33 +/- 10 y) and 9 obese (body fat: 31 +/- 4%; age: 32 +/- 10 y) men given a fixed amount (400 mL) of a liquid meal. We compared their results with those in 11 lean (body fat: 16 +/- 5%; age: 35 +/- 8 y) and 11 obese (body fat: 33 +/- 5%; age: 28 +/- 5 y) previously studied men given a meal proportional to their body size. We performed analyses by using a two-level, random-effects approach in the STATISTICAL PARAMETRIC MAPPING software package and a significance level of P < or = 0.001, uncorrected for multiple comparisons. RESULTS: Compared with lean men, obese men had consistently less postprandial activation in the left dorsolateral prefrontal cortex, irrespective of meal size. CONCLUSION: Because the dorsolateral prefrontal cortex has been implicated in the inhibition of inappropriate behavior, satiety, and meal termination, differential responses of neuronal activity to food intake in this area may contribute to a propensity for obesity or to the difficulty in losing weight experienced by obese men.

Adult↗

PubMed2002

Cell adhesion molecule expression in the dorsolateral prefrontal cortex and anterior cingulate cortex in major depression in the elderly.

BACKGROUND: Neuroimaging studies have demonstrated changes in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in major depression. AIMS: We investigated the expression of cell adhesion molecules (CAMs) in the prefrontal cortex in depression. METHOD: Immunohistochemistry to localise CAMs in post-mortem tissue from 20 subjects with major depression and 20 controls, and image analysis to quantify their expression. RESULTS: We found significant increases in CAMs in the grey matter of the DLPFC in the depression group but no comparable differences in the ACC or occipital cortex. In the white matter there was a non-significant increase in intercellular adhesion molecule-I in the DLPFC in the depression group but no increase in the other areas or for vascular cell adhesion molecule-I in any area. Paired tests showed specificity for the DLPFC in the depression group only. CONCLUSIONS: The increase in CAM expression in the DLPFC suggests an inflammatory reaction and is consistent with ischaemia.

Aged↗

PubMed2006

Go-no-go task performance improvement after anodal transcranial DC stimulation of the left dorsolateral prefrontal cortex in major depression.

BACKGROUND: We recently showed that repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) can affect the performance in an affective go-no-go (AGN) task. We aimed to extend this previous investigation testing whether one session of anodal transcranial direct current stimulation (tDCS) of the left DLPFC, as compared with anodal occipital and sham tDCS, affects this AGN task performance. METHODS: Twenty-six patients with major depression were randomized to receive anodal tDCS of the left DLPFC, occipital cortex or sham tDCS (the cathode electrode was placed over the frontopolar area for the three conditions). An AGN task was performed immediately before and after treatment. Performance changes (pre and post-treatment) were compared across groups of treatment and correlated with Hamilton Depression Rating Scale (HDRS) score changes. RESULTS: The results show that anodal stimulation of the left DLPFC was the only condition that induced a significant improvement in task performance as shown by the increase in the number of correct responses. In addition, this effect was specific for figures with positive emotional content. This performance enhancement was not correlated with mood changes after 10 days of tDCS treatment. LIMITATIONS: Although the effects of tDCS are less focal than rTMS, it can induce a longer and stronger modulation of cortical excitability. CONCLUSIONS: Our findings suggest that left DLPFC activity is associated with positive emotional processing, confirming and extending results of previous studies that associated right DLPFC and orbito-frontal cortex activity with emotional processing. Furthermore the effects of tDCS on mood and cognition seem to be independent in major depression. These lines of evidence together shed light on the neural circuitry involved with emotional processing in major depression.

Adult↗

PubMed2005

1H Magnetic resonance spectroscopy study of dorsolateral prefrontal cortex in unipolar mood disorder patients.

Neuroimaging and postmortem studies have suggested the involvement of the dorsolateral prefrontal cortex (DLPFC) in the pathophysioloy of unipolar disorder. We examined with in vivo 1H magnetic resonance spectroscopy (MRS) the levels of specific metabolites in the DLPFC of adult unipolar patients and the role of illness chronicity on DLPFC abnormalities. Nineteen unmedicated unipolar mood disorder patients and 19 age- and gender-matched healthy controls underwent a short echo-time 1H MRS examination localized to an 8-cm3 single voxel placed in the left DLPFC. There were no significant differences in metabolite levels, including N-acetylaspartate (NAA), phosphocreatine plus creatine (PCr+Cr) and choline-containing-compounds (GPC+PC), between the two groups. However, NAA/PCr+Cr ratios were significantly lower in the chronic than in the less chronically ill patients and healthy controls. The low levels of NAA/PCr+Cr ratios in the left DLPFC of unipolar patients who had been more chronically ill suggest a potential role for illness chronicity in neuronal abnormalities in the DLPFC in unipolar disorder. This could possibly be accounted for by neurodegenerative processes arising with the progression of the illness. Future 1H MRS investigations should longitudinally examine the role of illness chronicity on DLPFC abnormalities and their relationship with the symptoms of unipolar disorder.

Adult↗

PubMed2001

Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia.

Schizophrenia has been associated with anatomical and functional abnormalities of the dorsolateral prefrontal cortex (DLPFC), which may reflect abnormal connections of DLPFC neurons. We measured mRNA levels of growth-associated protein (GAP-43), a peptide linked to the modifiability of neuronal connections, in post-mortem brain tissue from two cohorts of patients with schizophrenia and controls. Using the RNase protection assay (RPA), we found a significant reduction in GAP-43 mRNA in the DLPFC, but not in the hippocampus, of patients with schizophrenia. With in situ hybridization histo- chemistry (ISHH), performed on a separate cohort, we confirmed the reduction of GAP-43 mRNA in the DLPFC of patients with schizophrenia. We detected reduced GAP-43 mRNA per neuron in layers III, V and VI of patients with schizophrenia compared with normal controls and patients with bipolar disorder. Thus, glutamate neurons in DLPFC of schizophrenic patients may synthesize less GAP-43, which could reflect fewer and/or less modifiable connections than those in normal human brain, and which may be consistent with the deficits of prefrontal cortical function that characterize schizophrenia.

Adult↗

PubMed2003

MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients.

BACKGROUND: Schizophrenia, bipolar illness, and major depressive disorder have distinct presentations, but share some common symptoms. Hence, some common cellular and molecular abnormalities may be identifiable in these disorders. METHODS: We examined cell-specific markers in the dorsolateral prefrontal cortex of brains from 18 patients with bipolar or major depressive disorder, and 18 matched controls, using in situ hybridization histochemistry and staining for nicotinamide-dinucleotide phosphate-diaphorase (NADPH). The distribution of NADPH-positive interstitial cells of the white matter and the expression of the mRNA for the 67 KD form of glutamic acid decarboxylase (GAD(67)) had previously been shown to be altered in prefrontal cortex of schizophrenics. Other markers identifying glutamatergic neuronal populations were alpha-type II calcium/calmodulin dependent protein kinase (CAMKII-alpha), brain derived neurotrophic factor, (BDNF) and the putative transcription factor, T-brain-1 (TBR1). RESULTS: Expression of GAD67 and the distribution of NADPH-positive cells in the white matter were not significantly altered in the dorsolateral prefrontal cortex of depressed subjects. Expression of CAMKII-alpha and TBR1 mRNAs was significantly increased in bipolar patients but not in major depressed patients, and there was a trend toward reduced BDNF expression in both groups. Abnormal patterns of gene expression and neuronal distribution in schizophrenics are markedly different from those in depressed patients. CONCLUSIONS: The findings that TBR1 and CAMKII-alpha expression is increased only in bipolar patients suggests abnormalities of specific genes related to a major cortical cell type and its connectivity.

Adult↗

PubMed1999

Errors of memory-guided saccades in humans with lesions of the frontal eye field and the dorsolateral prefrontal cortex.

Behavioral studies in monkeys and humans suggest that systematic and variable errors of memory-guided saccades reflect distinct neuronal computations in primate spatial memory. We recorded memory-guided saccades with a 2-s delay in three patients with unilateral ischemic lesions of the frontal eye field and in three patients with unilateral ischemic lesions of the frontal eye field and the dorsolateral prefrontal cortex. Results suggest that systematic errors of memory-guided saccades originate in the frontal eye field and variable errors in the dorsolateral prefrontal cortex. These data are the first human lesion data to support the hypothesis that these regions provide functionally distinct contributions to spatial short-term memory.

Adult↗

PubMed2004

Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression.

Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) may both be susceptibility genes for schizophrenia. As part of the evaluation of their roles in psychosis, we used reverse transcription-polymerase chain reaction to measure COMT and PRODH mRNAs in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, major depression, and normal controls (n = 15 subjects in each group). We also genotyped two common COMT polymorphisms (-287A/G and 158Val/Met) which might affect its expression. Neither COMT nor PRODH mRNA abundance differed between diagnostic groups, nor when controls were compared with all psychotic patients. COMT mRNA levels were unrelated to COMT genotypes. We conclude that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral prefrontal cortex. As COMT and PRODH are both located on chromosome 22q11, the results also argue against the hypothesis that schizophrenia is associated with a decrease in expression of all 22q11 genes, as had been suggested by the high prevalence of psychosis in people with hemizygous 22q11 deletions.

Adult↗

PubMed2006

Effect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate measures in the dorsolateral prefrontal cortex.

OBJECTIVE: This study was carried out to confirm prior evidence of an effect of a single nucleotide polymorphism (SNP) in the metabotropic glutamate receptor 3 (GRM3) gene (a putative risk factor for schizophrenia) on measures of N-acetylaspartate in healthy comparison subjects. METHOD: Fifty-four carefully screened healthy volunteers genotyped at SNP rs6465084 underwent magnetic resonance spectroscopic imaging (MRSI) at 3 T and selected neuropsychological testing. RESULTS: The A/A genotype group exhibited a significant reduction of N-acetylaspartate/creatine levels in the right dorsolateral prefrontal cortex compared to the G carriers. A tendency in the same direction was seen in the left dorsolateral prefrontal cortex and in the white matter adjacent to the prefrontal cortex. CONCLUSIONS: These findings provide further evidence that GRM3 affects prefrontal function and that variation in GRM3, monitored by SNP rs6465084, affects GRM3 function.

Aspartic Acid↗

PubMed2004

Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study.

OBJECTIVE: The efficacy of repetitive transcranial magnetic stimulation (rTMS) of the right prefrontal cortex was studied in patients with posttraumatic stress disorder (PTSD) under double-blind, placebo-controlled conditions. METHOD: Twenty-four patients with PTSD were randomly assigned to receive rTMS at low frequency (1 Hz) or high frequency (10 Hz) or sham rTMS in a double-blind design. Treatment was administered in 10 daily sessions over 2 weeks. Severity of PTSD, depression, and anxiety were blindly assessed before, during, and after completion of the treatment protocol. RESULTS: The 10 daily treatments of 10-Hz rTMS at 80% motor threshold over the right dorsolateral prefrontal cortex had therapeutic effects on PTSD patients. PTSD core symptoms (reexperiencing, avoidance) markedly improved with this treatment. Moreover, high-frequency rTMS over the right dorsolateral prefrontal cortex alleviated anxiety symptoms in PTSD patients. CONCLUSIONS: This double-blind, controlled trial suggests that in PTSD patients, 10 daily sessions of right dorsolateral prefrontal rTMS at a frequency of 10 Hz have greater therapeutic effects than slow-frequency or sham stimulation.

Adult↗

PubMed2005

Microstimulation of the dorsolateral prefrontal cortex biases saccade target selection.

A long-standing issue concerning the executive function of the primate dorsolateral prefrontal cortex is how the activity of prefrontal neurons is linked to behavioral response selection. To establish a functional relationship between prefrontal memory fields and saccade target selection, we trained three macaque monkeys to make saccades to the remembered location of a visual cue in a delayed spatial match-to-sample saccade task. We electrically stimulated sites in the prefrontal cortex with subthreshold currents during the delay epoch while monkeys performed this task. Our results show that the artificially injected signal interacts with the neural activity responsible for target selection, biasing saccade choices either towards the receptive/movement field (RF/MF) or away from the RF/MF, depending on the stimulation site. These findings might reflect a functional link between prefrontal signals responsible for the selection bias by modulating the balance between excitation and inhibition in the competitive interactions underlying behavioral selection.

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