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PubMed1998

Contribution of human prefrontal cortex to delay performance.

Neurological patients with focal lesions in the dorsolateral prefrontal cortex and age-matched control subjects were tested on an auditory version of the delayed-match-to-sample task employing environmental sounds. Subjects had to indicate whether a cue (s/S1) and a subsequent target sound (S2) were identical. On some trials, S1 and S2 were separated by a silent period of 5 sec. On other trials, the 5-sec delay between S1 and S2 was filled with irrelevant tone pips that served as distractors. Behaviorally, frontal patients were impaired by the presence of distractors. Electrophysiologically, patients generated enhanced primary auditory cortex-evoked responses to the tone pips, supporting a failure in inhibitory control of sensory processing after prefrontal damage. Intrahemispheric reductions of neural activity generated in the auditory association cortex and additional intrahemispheric reductions of attention-related frontal activity were also observed in the prefrontal patients. Together, these findings suggest that the dorsolateral prefrontal cortex is crucial for gating distracting information as well as maintaining distributed intrahemispheric neural activity during auditory working memory.

Acoustic Stimulation↗

PubMed1989

Role of the dorsolateral prefrontal cortex in organizing visually guided behavior.

Unit activity was recorded in the prefrontal cortex of rhesus monkeys during performance of a delayed task with two motor responses, a saccade and an arm movement, to a complex pattern of auditory and visual stimuli. The peculiarity of the paradigm was that onset of the different sensory stimuli, orienting saccade and arm movement, were dissociated in time and occurred at prefixed time intervals. Two hundred and sixteen task-related units were recorded. The data show that the dorsolateral part of the prefrontal cortex plays a crucial role in temporal organization of visually guided behaviour. This cortical area contains the neural substrate of an encoding strategy for remembered or current events and objects in the behavioural surround that are not, as yet, foveated. This encoding mechanism subserves a particular cognitive process. Whether events or objects are, or are not, encoded depends on their significance for future behaviour. While foveation deletes their neural trace, it activates a class of cells that appear involved in the preparation of arm movements towards the foveated region. The destruction of these two complementary mechanisms would disrupt the organism's capacity to integrate temporally and spatially discontinuous information for performance of goal-directed acts.

Animals↗

PubMed2002

Basal-ganglia 'projections' to the prefrontal cortex of the primate.

We used retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 to examine the extent and organization of basal-ganglia-thalamocortical projections to five regions of prefrontal cortex in the cebus monkey (Cebus apella): medial and lateral area 9 (9m and 9l), dorsal and ventral area 46 (46d and 46v) and lateral area 12 (12l). All of these prefrontal areas were found to be targets of basal-ganglia output that originated in the internal segment of the globus pallidus (GPi) and/or the pars reticulata of the substantia nigra (SNpr). Approximately one-third of the total volume of these nuclei was directed toward prefrontal cortex, a volume comparable to that directed at the cortical motor areas. The origins of the outputs to different prefrontal areas were topographically organized. Different portions of SNpr (the rostral and caudal thirds) projected to areas 9m and 12l. Similarly, different output nuclei (GPi and SNpr) projected to adjacent portions of the same cytoarchitectonic field (46d and 46v). Furthermore, the outputs to prefrontal areas were segregated from those to motor areas of cortex. Thus, basal-ganglia outputs to prefrontal cortex are both extensive and topographically organized, forming a rich anatomical substrate for basal-ganglia influences on the cognitive operations of the frontal lobe.

Animals↗

PubMed1997

Magnetic fields from human prefrontal cortex differ during two recognition tasks.

The present study represents our second successful use of magnetoencephalography to identify different sources of human prefrontal activity corresponding to subjects' engagement in different tasks. We used two visual recognition tasks: a familiar person recognition and an abstract pattern recognition task in the context of a design suitable for eliciting Contingent Negative Variations (CNVs) and their concurrent slow magnetic fields in this preliminary study of 5 subjects. Each trial of either task was started by one of two specific warning symbols (S1), indicating whether a person's picture or an abstract pattern should be attended during the presentation of a second stimulus (S2), and compared to the corresponding person's picture or pattern contained in the third stimulus, (S3) that followed. The S2 and S3 stimuli were common to both tasks, and were composed of patterns made with four line traces superimposed on photographs of persons familiar to each subject. Subjects responded with a right hand button press, following S3, indicating their judgments regarding the identity of the patterns or persons' pictures contained in the S2 and the S3 stimuli, for the two tasks, respectively. Results showed that the sources of the CNV equivalent magnetic fields were localized in different cortical regions depending on the task and that this difference was consistent across all subjects. The sources were localized in the right hemisphere, in medial areas of the prefrontal cortex for the person recognition task and in the dorsolateral prefrontal cortex for the pattern recognition task. The same degree of consistency was not found for the left hemisphere sources. Moreover, as in our previous study, we found no difference between the sources active during the first and the second CNV periods (occurring during the S1-S2 and the S2-S3 intervals, respectively), within each task condition.

Adult↗

PubMed1992

Determinants of the slow acquisition of medical and sulcal prefrontal cortex self-stimulation: an individual differences approach.

Stimulation-naive rats were tested for motor activity during noncontingent electrical stimulation of the medial prefrontal cortex (MPC) or sulcal prefrontal cortex (SPC). Defecation during stimulation was also measured. The rats were then tested using a conditioned taste aversion paradigm for aversion to a novel flavor (0.1% saccharin) paired with stimulation. Finally, the rats were trained to acquire self-stimulation over 26 days of training. Large individual differences were seen in motor activity, defecation, and conditioned taste aversion to initial stimulation and in the subsequent speed of self-stimulation acquisition. In the MPC-stimulated group, acquisition speed was positively correlated with motor activity to initial stimulation and negatively correlated with defecation to this stimulation. In the SPC-stimulated group, the same correlations were evident, but only when rats suffering seizures prior to self-stimulation acquisition were excluded from the analysis. Such preacquisition seizures, which were only found in the SPC-stimulated group, retarded self-stimulation acquisition. In most rats, MPC or SPC stimulation failed to condition a taste aversion to saccharin. These results suggest that the slow acquisition of MPC and SPC self-stimulation may be partly related to the motor suppressive, aversive, and convulsive properties of initial stimulation.

Animals↗

PubMed1994

Effect of phencyclidine on dopamine release in the rat prefrontal cortex; an in vivo microdialysis study.

The effect of phencyclidine (PCP) on the extracellular dopamine levels in the rat prefrontal cortex was investigated using an in vivo brain dialysis technique. PCP increased extracellular dopamine levels in the prefrontal cortex of freely-moving rats after the systemic (7.5 mg/kg i.p.) or the local injection (100 microM and 500 microM). The local injection of MK-801, which is a more selective and potent NMDA receptor antagonist than PCP also increased the extracellular dopamine levels (from 10 microM to 100 microM). These results suggest that part of the effect of PCP is attributable to its antagonist effect on the NMDA receptor.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Desmethylimipramine promotes recovery of self-stimulation from the prefrontal cortex following footshock.

Intracranial self-stimulation (ICSS) was assessed from the prefrontal cortex in CD-1 mice immediately (0 h), 24 h and 168 h following exposure to uncontrollable footshock. Marked reductions in ICSS rates were observed in all mice immediately following the stressor. Although the ICSS alterations were transient in some animals, ICSS rates were reduced in the majority of animals 24-h and 168-h poststressor. Mice of either the shock or no shock treatment groups were administered either saline or desmethylimipramine (DMI, 5 mg/kg x 2) for 20 consecutive days. Chronic DMI ameliorated the stressor-induced ICSS deficits from the prefrontal cortex. Potential explanations for the stressor-provoked variations in ICSS and the effects of DMI are discussed.

Animals↗

PubMed2001

Increased tachykinin NK(1) receptor immunoreactivity in the prefrontal cortex in schizophrenia.

BACKGROUND: Changes in levels of substance P and substance P-binding sites have been implicated in schizophrenia. However, no studies have used receptor-specific antibodies to directly investigate the substance P (neurokinin 1) receptor in schizophrenia. METHODS: We used an antibody directed against the human neurokinin-1 receptor to compare the distribution of neurokinin-1 receptors in the prefrontal cortices from six subjects with schizophrenia and six control subjects, matched for age, gender, and postmortem interval. RESULTS: In control tissue, dots of neurokinin-1 receptor immunoreactivity were observed in layer I to upper/mid layer III only. In contrast, dots of neurokinin-1 receptor immunoreactivity were observed in all layers of the prefrontal cortex in subjects with schizophrenia, and the density of dots was significantly greater than in control subjects. CONCLUSIONS: This is the first report of increased neurokinin-1 receptor immunoreactivity in the prefrontal cortex in subjects with schizophrenia. These changes may have implications for understanding the pathophysiology of the prefrontal cortex in schizophrenia and for the treatment of this disorder.

Adult↗

PubMed1998

Effects of idazoxan on dopamine release in the prefrontal cortex of freely moving rats.

To clarify the involvement of dopaminergic neuronal systems in anxiety or fear, the present study was undertaken to elucidate the effect of an anxiogenic agent, idazoxan, a selective alpha2-adrenoceptor antagonist, on dopamine release from the rat prefrontal cortex by use of in vivo microdialysis. Systemic administration of idazoxan (0.25 mg/kg, i.p.) produced significant increases in extracellular levels of dopamine. The maximum response of the facilitatory effect of dopamine release was 241.5%, which was detected 80 min after the injection of idazoxan. Idazoxan-induced (0.25 mg/kg, i.p.) increases in dopamine release were prevented by an established anxiolytic agent, diazepam (0.5 mg/kg, i.p.) and a putative anxiolytic agent tropisetron (100 microg/kg, i.p.). These results suggest that the excessive dopaminergic neuronal activity in the rat prefrontal cortex is related to idazoxan-induced anxiogenic effects. The idazoxan-induced (0.25 mg/kg, i.p.) enhancement of dopamine release was further prevented by pretreatment with serotonin (5-hydroxytryptamine; 5-HT) neurotoxin, 5,7-dihydroxytryptamine (200 microg/kg, i.c.v.). The basal output of dopamine release was not altered in 5-HT lesioned rats. These findings indicate that intact serotonergic neurons are required for the facilitatory effects of idazoxan on dopamine release. In other words, the functional interaction between dopaminergic and serotonergic neuronal systems in the rat prefrontal cortex might be involved in anxiety or fear.

5,7-Dihydroxytryptamine↗

PubMed2004

Subcellular distribution of neurabin immunolabeling in primate prefrontal cortex: comparison with spinophilin.

Prefrontal cortical functioning depends on dopaminergic neurotransmission, which in turn depends on a complex signal transduction pathway including protein phosphatase-1 (PP1). Targeted localization of PP1 by the scaffolding proteins, spinophilin and neurabin, is critical for dopaminergic modulation of glutamate neurotransmission. In this study, we report the preparation of an antiserum to neurabin, use it to study the subcellular localization of neurabin and compare that to our previous study of spinophilin, a closely related PP1 scaffold. Neurabin is found predominately in dendritic spines, but is also found in other compartments, including dendrites, axons, terminals and glia. This distribution contrasts with that of spinophilin in that neurabin is found in axon terminals where spinophilin is absent, and in parvalbumin-containing interneuron dendrites there is no significant neurabin though these dendrites contain substantial spinophilin. Within the dendritic spine compartment, however, the two proteins are similarly distributed. Both neurabin and spinophilin are concentrated in spines, and double-labeling reveals that they co-localize in most spines. Furthermore, post-embedding immunogold labeling demonstrates that within a spine, neurabin is distributed in the same pattern as spinophilin, concentrated in the postsynaptic density and the 100 nm just below. These results indicate that neurabin and spinophilin share important similarities and differences in their patterns of distribution. Varying patterns of scaffold localization may play an important role in determining the content and action of signal transduction pathways in different neuronal populations or compartments.

Animals↗

PubMed1990

Difference in the effects of the antidepressant tianeptine on dopaminergic metabolism in the prefrontal cortex and the nucleus accumbens of the rat. A voltammetric study.

The effects of the new tricyclic antidepressant tianeptine were investigated on dopaminergic (DAergic) metabolism in the anteromedian prefrontal cortex and the nucleus accumbens of the rat. DAergic metabolism was assessed by the measurement of DOPAC, the main presynaptic metabolite of dopamine, using in vivo voltammetry in rats ventilated with halothane (0.5-0.75% in air). Acute treatment with tianeptine (10 mg/kg, 20 mg/kg) only increased significantly DOPAC levels in the anteromedian prefrontal cortex. After chronic treatment with tianeptine (15 days, 2 times/day) the increases in DOPAC levels in this structure were altered and less pronounced with the 20 mg/kg dose. Previous studies led to suggest that both acute and chronic effects on DAergic terminals in the anteromedian prefrontal cortex may be involved in the therapeutic action of this new antidepressant.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Localization of glyoxylate dehydrogenase and glyoxylate-complex molecules in the rat prefrontal cortex: enzymohistochemical and immunocytochemical study.

Glyoxylic acid is synthesized and catabolized in cells of vertebrates; several pathways have been described. In previous papers, we have demonstrated the localization in some areas of the rat cerebral cortex both of beta-NAD-dependent glyoxylate dehydrogenase (glyoDH), using an enzymohistochemical method, and of glyoxylate-complex molecules, using immunocytochemical procedures. In this study we have applied these two techniques in various areas of the prefrontal cortex with different histological cytoarchitecture. GlyoDH has been located in most neurons, in some glial cells, and in capillary wall structures in all cortical layers of all areas of the rat prefrontal cortex. Antibodies against glyoxylate-complex molecules showed positive immunoreactivity in scattered neurons, mostly of multipolar or stellate appearance, from layers III, IV, and V in the medial precentral area, but not in cortical areas 24, 25, or 32 of the prefrontal cortex. Immunoreaction was found in the periphery of neuronal perikarya and in some of their processes. These results demonstrate the existence of a particular area-dependent neuronal cortical system, of specific but uncertain function, related to glyoxylic acid and/or glyoxylate compounds. At the electron microscope level, positive reaction was associated with synaptic sites, axonal filaments, glial cells, and several components of the blood-brain barrier. These localizations suggest the involvement of glyoxylate derivatives in synaptic functioning and also in glial cell functions.

Aldehyde Oxidoreductases↗

PubMed1999

Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET.

BACKGROUND: The aim of the present study was to investigate dopamine synthesis in the brain of drug-free schizophrenic patients, not only in the striatum but also in extrastriatal areas like the prefrontal cortex, brain areas that for a long time has been in focus of interest in the pathophysiology of schizophrenia. METHODS: PET was performed in 12 drug-free (10 drug-naive) psychotic schizophrenic patients and 10 healthy volunteers matched for age and gender using 11C-labelled L-DOPA as the tracer. The time-radioactivity curve from occipital cortex (located within Brodman area 17 and 18) was used as input function to calculate L-DOPA influx rate, Ki images, that were matched to a common brain atlas. A significant overall increase of the Ki values was found in the schizophrenic group as compared with healthy controls. RESULTS: In particular, significantly higher Ki were found in the schizophrenic patients compared to the controls in the caudate nucleus, putamen and in parts of medial prefrontal cortex (Brod 24). The Ki value reflect an increased utilization of L-DOPA, presumably due to increased activity of the amino acid decarboxylate enzyme. CONCLUSIONS: The results indicate that the synthesis of dopamine is elevated within the striatum and parts of medial prefrontal cortex in schizophrenia.

Adult↗

PubMed2001

BDNF mRNA expression in rat hippocampus and prefrontal cortex: effects of neonatal ventral hippocampal damage and antipsychotic drugs.

Brain-derived neurotrophic factor (BDNF) plays an important role in development, synapse remodelling and responses to stress and injury. Its abnormal expression has been implicated in schizophrenia, a neuropsychiatric disorder in which abnormal neural development of the hippocampus and prefrontal cortex has been postulated. To clarify the effects of antipsychotic drugs used in the therapy of schizophrenia on BDNF mRNA, we studied its expression in rats treated with clozapine and haloperidol and in rats with neonatal lesions of the ventral hippocampus, used as an animal model of schizophrenia. Both antipsychotic drugs reduced BDNF expression in the hippocampus of control rats, but did not significantly lower its expression in the prefrontal cortex. The neonatal hippocampal lesion itself suppressed BDNF mRNA expression in the dentate gyrus and tended to reduce its expression in the prefrontal cortex. These results indicate that, unlike antidepressants, antipsychotics down-regulate BDNF mRNA, and suggest that their therapeutic properties are not mediated by stimulation of this neurotrophin. To the extent that the lesioned rat models some pathophysiological aspects of schizophrenia, our data suggest that a neurodevelopmental insult might suppress expression of the neurotrophin in certain brain regions.

Animals↗

PubMed2005

Blockade of NMDA receptors in postnatal period decreased density of tyrosine hydroxylase immunoreactive axonal arbors in the medial prefrontal cortex of adult rats.

Malfunction of glutamatergic neurotransmission in postnatal period is considered to be a risk factor for development of schizophrenia. Thus, the present study investigates the impact of NMDA receptor blockade in the postnatal period on the density of tyrosine hydroxylase immunoreactive axonal arbors in the rat medial prefrontal cortex. Behavioral experiments revealed that adult rats (60 days old) treated in the postnatal period with a competitive antagonist of NMDA receptors, CGP 40116 (1.25 mg/kg on days 1, 3, 6, 9; 2.5 mg/kg on days 12, 15, 18; and finally 5 mg/kg on day 21, all injections s.c.), showed enhancement of the locomotor activity stimulated by quinpirole (0.3 mg/kg s.c.) and amphetamine (0.5 mg/kg s.c.), which suggests development of functional supersensitivity of dopaminergic systems. It has been found that CGP 40116, given in postnatal period decreased the density of tyrosine hydroxylase immunoreactive axonal arbors in the medial prefrontal cortex of adult animals. The decrease was observed in superficial (II/III) and deep (V/VI) layers of the medial prefrontal cortex, while the average length of tyrosine hydroxylase immunoreactive axonal arbors was increased in both superficial and deep cortical layers. Changes in the density of tyrosine hydroxylase immunoreactive axonal arbors have not been followed by a significant decrease in the content of tyrosine hydroxylase protein measured by Western blot. Thus, NMDA receptor blockade in the early period of life evokes changes in architecture of tyrosine hydroxylase immunoreactive axonal arbors and that malfunction of glutamatergic neurotransmission, in early period of life may produce anatomical changes which resemble those observed in the brains of schizophrenics.

2-Amino-5-phosphonovalerate↗

PubMed2003

Metabolic changes after repetitive transcranial magnetic stimulation (rTMS) of the left prefrontal cortex: a sham-controlled proton magnetic resonance spectroscopy (1H MRS) study of healthy brain.

Rapid transcranial magnetic stimulation is being increasingly used in the treatment of psychiatric disorders, especially major depression. However, its mechanisms of action are still unclear. The aim of this study was to assess metabolic changes by proton magnetic resonance spectroscopy following high-frequency rapid transcranial magnetic stimulation (20 Hz), both immediately after a single session and 24 h after a series of five consecutive sessions. Twelve healthy volunteers were enrolled in a prospective single-blind, randomized study [sham (n = 5) vs. real (n = 7)]. Three brain regions were investigated (right, left dorsolateral prefrontal cortex, left anterior cingulate cortex). A single as well as a series of consecutive rapid transcranial magnetic stimulations affected cortical glutamate/glutamine levels. These effects were present not only close to the stimulation site (left dorsolateral prefrontal cortex), but also in remote (right dorsolateral prefrontal cortex, left cingulate cortex) brain regions. Remarkably, the observed changes in glutamate/glutamine levels were dependent on the pre-transcranial magnetic stimulation glutamate/glutamine concentration, i.e. the lower the pre-stimulation glutamate/glutamine level, the higher the glutamate/glutamine increase observed after short- or long-term stimulation (5 days). In general, the treatment was well tolerated and no serious side-effects were reported. Neither transient mood changes nor significant differences in the outcome of a series of neuropsychological test batteries after real or sham transcranial magnetic stimulation occurred in our experiment. In summary, these data indicate that rapid transcranial magnetic stimulation may act via stimulation of glutamatergic prefrontal neurons.

Adult↗

PubMed2003

Demand on verbal working memory delays haemodynamic response in the inferior prefrontal cortex.

Event-related functional magnetic resonance imaging was used to test the involvement of the inferior prefrontal cortex in verbal working memory. Pairs of French nouns were presented to ten native French speakers who had to make semantic or grammatical gender decisions. Verbal working memory involvement was manipulated by making the categorization of the second noun optional. Decisions could be made after processing the first noun only (RELEASE condition) or after processing the two nouns (HOLD condition). Reaction times suggested faster processing for gender than for semantic category in RELEASE. Despite the absence of anatomical difference across tasks and conditions in the wide activated network, the haemodynamic response peak latencies of the inferior prefrontal cortex were significantly delayed in HOLD versus RELEASE while no such peak delay was observed in the superior temporal gyrus. Interestingly, this pattern did not interact with language tasks. This study shows that cognitive manipulation can influence haemodynamic time-course and suggests that the main cognitive process determining inferior prefrontal activation is verbal working memory rather than specific linguistic processes such as grammatical or semantic analysis.

Acoustic Stimulation↗

PubMed2002

Male rats exposed to cocaine in utero demonstrate elevated expression of Fos in the prefrontal cortex in response to environment.

Prenatal cocaine exposure has been associated with disruption in attention and short-term memory in exposed children and in animal models. The biochemical change or changes responsible for these cognitive deficits are not known. An intriguing possibility, however, is that cocaine exposure during development disrupts the morphology or function of the frontal cortex, a region thought to contribute to cognitive and executive functions. In this report, we examined the effects of intravenous prenatal cocaine exposure on the expression of the immediate-early gene, c-fos, in the adolescent offspring to determine potential sites of disruption. The expression of Fos protein was similar in unhandled rats prenatally treated with saline or cocaine. Prenatal cocaine exposed rats that were handled, but not footshocked, however, demonstrated a dramatic selective increase in Fos expression in the ventral and medial prefrontal cortex. A footshock-induced increase in Fos expression in the prefrontal cortex was noted in prenatal saline, but not prenatal cocaine rats. Interestingly, no differences were noted in baseline or footshock-induced increased Fos expression in nuclei of the amygdala in prenatal cocaine and prenatal saline rats, indicating some aspect of the central response to stress appear unchanged. The unusual activation of the neurons of the medial and ventral prefrontal cortex may be a consequence of in utero cocaine exposure that contributes to the reported deficit in cognition.

Animals↗