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PubMed2005

Prefrontal cortex activity in self-initiated movements is condition-specific, but not movement-related.

Activity of the prefrontal cortex (PFC) has been observed in previous block-design brain imaging studies of self-initiated movements. However, the meaning of these activations remained unclear. A functional MRI experiment was carried out, which utilized an epoch and an event-related analysis approach to the data. We hypothesized that event-related activity of the PFC would argue for a contribution to movement preparation. In contrast, epoch-, but not event-related activity pointed to tonic activations, probably reflecting enhanced attentional states or working memory processing. Twenty-one subjects were examined with 845 T2*-weighted images. During active phases, subjects were instructed to perform self-initiated movements of the right index finger with intertrial intervals of about 8 s. On single subject level, epoch- and event-related regressors were entered into a combined model, estimating the exclusive contribution of either regressor. For statistical inference on multisubject level, random effects analyses were performed. For the epoch regressor, activity within the right dorso- and ventrolateral prefrontal cortex, the bilateral insula, and the right inferior parietal lobe was observed. The event-related regressor detected activity within the right inferior parietal lobe, ventral from the activity found with the epoch regressor. The present results indicate a condition-, but not a movement-related function of the PFC in self-initiated movements. Furthermore, anatomically distinct regions within the inferior parietal cortex seem to be involved in condition-specific and movement-related processes. The observed condition-specific activations are suggested to reflect attentional or working memory processes, supervising task performance, rather than movement preparation or initiation.

Adult↗

PubMed1992

Heterotopic Cortical Afferents to the Medial Prefrontal Cortex in the Rat. A Combined Retrograde and Anterograde Tracer Study.

Cortical afferent projections towards the medial prefrontal cortex (mPFC) were investigated with retrograde and anterograde tracer techniques. Heterotopical afferent projections to the medial prefrontal cortex arise in secondary, or higher order, sensory areas, motor areas and paralimbic cortices. On the basis of these projections three subfields can be discriminated within the mPFC. (1) The ventromedial part of mPFC, comprising the pre- and infralimbic areas, receives mainly projections from the perirhinal cortex. (2) The caudal two-thirds of the dorsomedial PFC, comprising frontal area 2 and the dorsal anterior cingulate area, receives projections from the secondary visual areas, the posterior agranular insular area and the retrosplenial areas. (3) The rostral one-third of the dorsomedial PFC is the main recipient of projections from the somatosensory and motor areas and the posterior agranular insular area. The laminar distribution of cells projecting to the mPFC varies considerably in the different cortical areas, just as the laminar distribution of termination of their fibres within the mPFC does. It is concluded that the corticocortical connections corroborate with subcortical connectivity in attributing to the mediodorsal projection cortex of the rat functions which are comparable to those of certain prefrontal, premotor and anterior cingulate areas in the monkey.

Journal Article↗

PubMed1986

Reinforcing properties of cocaine in the medical prefrontal cortex: primary action on presynaptic dopaminergic terminals.

The presynaptic mechanisms involved in the initiation of cocaine reinforcement were investigated using neurotoxin lesions. Rats were trained to intracranially self-administer cocaine (50 to 90 pmol) into the medial prefrontal cortex and after dose-effect analyses were completed, each rat received a unilateral 6-hydroxydopamine lesion (4 micrograms in 0.2 microliter) at the self-administration site. The lesion selectively decreased dopamine content in the medial prefrontal cortex (-45%) and decreased cocaine-maintained responding to vehicle levels. Lever-pressing could be reinstated by substituting dopamine (300 pmol) but not serotonin for cocaine. Dopamine self-administration was attenuated by including equimolar concentrations of the D2 dopaminergic antagonist sulpiride in the injectate. These results suggest that the initiation of reinforcing neuronal activity in the medial prefrontal cortex appears to result in part through the direct interaction of cocaine with presynaptic reuptake sites associated with dopaminergic nerve endings. The resulting increased synaptic concentration of the neurotransmitter may then interact with postsynaptic D2 binding sites to activate neuronal systems involved in the mediation of this reinforcement.

Animals↗

PubMed1997

Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity.

BACKGROUND: Multiple lines of evidence indicate that the prefrontal cortex is a site of dysfunction in schizophrenia. However, the apparent absence of gross structural abnormalities in this area suggests that the pathophysiological characteristics of schizophrenia may involve more subtle disturbances in prefrontal cortical circuitry, such as alterations in synaptic connectivity and transmission. In this study, immunoreactivity for synaptophysin, an integral membrane protein of small synaptic vesicles, was used to assess the integrity of cortical synaptic circuitry in schizophrenia. METHODS: Using immunocytochemical techniques and adjusted optical density measurements, we examined synaptophysin immunoreactivity in prefrontal cortical areas 9 and 46 and in area 17 (the primary visual cortex) from 10 pairs of case subjects with schizophrenia and control subjects matched on a pairwise basis for age, sex, race, and postmortem interval, and in 5 matched pairs of nonschizophrenic psychiatric case subjects and normal control subjects. RESULTS: Compared with levels found in matched control subjects, synaptophysin immunoreactivity in areas 46 and 9 was significantly decreased (P < .001 and P < .008, respectively) across all cortical layers in the case subjects with schizophrenia. In contrast, no differences were observed in area 17. In addition, levels of synaptophysin immunoreactivity in areas 46, 9, and 17 did not differ between 5 nonschizophrenic psychiatric case subjects and their matched controls, suggesting that decreased synaptophysin levels in the prefrontal cortex of patients with schizophrenia may be specific to that disorder. CONCLUSIONS: Additional studies are required to determine if the decrease in levels of synaptophysin immunoreactivity is caused by a decrease in the number or size of presynaptic terminals, a decrease in the number of synaptic vesicles per terminal, or a decrease in the expression of synaptophysin. However, all of these potential explanations are consistent with a disturbance in synaptic transmission in the prefrontal cortex of patients with schizophrenia.

Adult↗

PubMed1997

Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity.

BACKGROUND: Multiple lines of evidence indicate that the prefrontal cortex is a site of dysfunction in schizophrenia. However, the apparent absence of gross structural abnormalities in this area suggests that the pathophysiological characteristics of schizophrenia may involve more subtle disturbances in prefrontal cortical circuitry, such as alterations in synaptic connectivity and transmission. In this study, immunoreactivity for synaptophysin, an integral membrane protein of small synaptic vesicles, was used to assess the integrity of cortical synaptic circuitry in schizophrenia. METHODS: Using immunocytochemical techniques and adjusted optical density measurements, we examined synaptophysin immunoreactivity in prefrontal cortical areas 9 and 46 and in area 17 (the primary visual cortex) from 10 pairs of case subjects with schizophrenia and control subjects. matched on a pairwise basis for age, sex, race, and postmortem interval, and in 5 matched pairs of nonschizophrenic psychiatric case subjects and normal control subjects. RESULTS: Compared with levels found in matched control subjects, synaptophysin immunoreactivity in areas 46 and 9 was significantly decreased (P < .001 and P < .008, respectively) across all cortical layers in the case subjects with schizophrenia. In contrast, no differences were observed in area 17. In addition, levels of synaptophysin immunoreactivity in areas 46, 9, and 17 did not differ between 5 nonschizophrenic psychiatric case subjects and their matched controls, suggesting that decreased synaptophysin levels in the prefrontal cortex of patients with schizophrenia may be specific to that disorder. CONCLUSION: Additional studies are required to determine if the decrease in levels of synaptophysin immunoreactivity is caused by a decrease in the number or size of presynaptic terminals, a decrease in the number of synaptic vesicle per terminal, or a decrease in the expression of synaptophysin. However, all of these potential explanations are consistent with a disturbance in synaptic transmission in the prefrontal cortex of patients with schizophrenia.

Adult↗

PubMed2003

Reactivation of memory: role of medial temporal lobe and prefrontal cortex.

Memory retrieval is to bring the remembered information on-line or to reactivate the information. The critical determinant of memory retrieval mechanisms is whether the information has been maintained on-line or off-line, regardless of whether it is long-term memory or short-term, working memory. Similar reactivation processes occur during retrieval from long-term memory and from working memory when online maintenance has been interrupted. The reactivation is achieved by interactions between the posterior association areas, medial temporal lobe and prefrontal cortex. Posterior association areas maintain the representations of remembered information and are reactivated at retrieval. The medial temporal lobe is primarily involved in retrieval from off-line memory and triggers the reactivation by associating a whole set of features and episodes during encoding of the information. The prefrontal cortex is involved in retrieval from both on-line and off-line memory. It controls reactivation by setting up retrieval mode, starting retrieval attempt, and monitoring the contents of reactivated information. The prefrontal cortex also controls the selection of task-relevant information from information maintained on-line.

Animals↗

PubMed2001

Increased frontal [(18)F]fluorodopa uptake in early Parkinson's disease: sex differences in the prefrontal cortex.

Previous imaging studies in Parkinson's disease have focused mainly on the striatum, a region with very high dopaminergic activity. Using modern high-sensitivity 3D [(18)F]fluorodopa (Fdopa)-PET, mesocortical monoamine projections can be studied. To study the frontal monoaminergic system in unmedicated early Parkinson's disease in vivo, we examined 20 early Parkinson's disease patients (10 women, 10 men) and 16 healthy subjects (nine women, seven men) with 3D Fdopa-PET, using standard region-of-interest-based analysis with MRI co-registration. Women with Parkinson's disease had 87% higher Fdopa uptake in the right dorsolateral prefrontal cortex (area 46) compared with men with Parkinson's disease, whereas there was no sex difference in the control group (sex x disease interaction, P = 0.03). The uptake in the right dorsolateral prefrontal cortex was 82% higher in men with Parkinson's disease and 219% higher in women with Parkinson's disease compared with control groups (effect of disease, P < 0.0001). Also in the left dorsolateral prefrontal cortex and in the medial frontal cortex, early Parkinson's disease patients had significantly (18-94%) higher Fdopa uptake compared with healthy controls. In the putamen, both men and women with Parkinson's disease had a significantly lower (27-46%) uptake compared with healthy controls. These results indicate that frontal monoaminergic activity is increased and that there is a sex difference in the prefrontal monoaminergic system in early Parkinson's disease. The reported sex difference may be linked to clinical sex differences in the symptoms and treatment response in Parkinson's disease.

Aged↗

PubMed1996

Plasticity of the hippocampal-prefrontal cortex synapses.

This paper summarizes experiments showing that the direct excitatory glutamergic pathway projecting from area CA1 and subiculum to the prefrontal cortex in the rat express a long-lasting NMDA receptor-dependent form of LTP that can be induced for several days in the freely-moving rat. Other experiments examined its functional significance in learning and the role of dopamine in the regulation of hippocampal-prefrontal cortex plasticity.

Animals↗

PubMed2003

Amphetamine sensitization of hallucinatory-like behaviors is dependent on prefrontal cortex in nonhuman primates.

BACKGROUND: Repeated amphetamine (AMPH) exposure in nonhuman primates produces a chronic state of monoamine dysregulation and long-lasting changes in behaviors elicited by acute AMPH (including tracking, grasping "at thin air," manipulating nonapparent stimuli, and hypervigilance) in a manner that bears a marked resemblance to symptoms of both amphetamine psychosis and paranoid schizophrenia. These abnormal responses have historically been referred to as psychotomimetic or hallucinatory-like. In contrast to negative symptoms and cognitive deficits, the positive symptoms of schizophrenia including hallucinations have not traditionally been linked to prefrontal dysfunction. METHODS: The dorsomedial (9/8B), dorsolateral (46/8A), and inferior (45/12) sectors of prefrontal cortex were lesioned, singly or in combination. Lesioned and nonlesioned control monkeys were sensitized over a 6-week period using an intermittent schedule of escalating low doses of AMPH. Behavioral responses to acute AMPH after chronic exposure were compared with preexposure responses. RESULTS: Bilateral lesions of prefrontal cortex performed before subchronic AMPH suppressed the sensitization of hallucinatory-like behaviors but markedly enhanced locomotor sensitization compared with control animals. CONCLUSION: These findings indicate that the primate prefrontal cortex may be a substrate for the development of the full complement of behaviors elicited by AMPH sensitization, including hallucinatory-like behaviors.

Amphetamine↗

PubMed1991

Influence of acute and chronic haloperidol treatment on dopamine metabolism in the rat caudate-putamen, prefrontal cortex and amygdala.

The present study investigated the actions of single and repeated injections of the classical antipsychotic drug, haloperidol (1 mg.kg-1 IP), on dopamine (DA) metabolism in three distinct rat brain regions, namely the prefrontal cortex, amygdala and caudate-putamen (CP), using a high-performance liquid chromatographic assay. Acute administration of the drug caused significant elevations in concentrations of two major DA metabolites in all three areas studied. Less marked acute increases were seen in the CP following 10 days of repeated haloperidol treatment. However, in both the prefrontal cortex and the amygdala, the development of such "tolerance" was somewhat delayed in comparison, occurring only after a 22-day treatment schedule. The amygdala displayed the greatest degree of neurochemical tolerance, returning to control values by day 22 of chronic treatment. When allowance was made for the withdrawal effects of antipsychotic drug administration, a genuine tolerance phenomenon was observed in all three areas examined. These data suggest that if neurochemical tolerance is a prerequisite for functional DA receptor blockade and hence therapeutic efficacy, then both the prefrontal cortex and amygdala should be considered as potential therapeutic targets of haloperidol and perhaps antipsychotic drugs in general.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Regional changes in human cerebral blood flow during dipyridamole stress: neural activation in the thalamus and prefrontal cortex.

Intravenous dipyridamole increases the concentration of circulating adenosine and produces coronary vasodilation. However, it decreases global cerebral blood flow (CBF) due to hyperventilation side effect of adenosine. In the present study, changes in regional CBF during dipyridamole stress were identified in detail. In 11 healthy men (51-71 years of age), CBF was measured by positron emission tomography with oxygen-15-labeled water at rest (baseline) and during dipyridamole stress. All images were normalized to global CBF and transformed to standard brain anatomy. A t map between baseline and dipyridamole stress conditions was then created on a pixel-by-pixel basis. CBF was globally decreased during dipyridamole stress. However, a significant relative increase in CBF was observed bilaterally in the thalamus and prefrontal cortex, indicating neural activation in these regions. Adenosine plays an important role in the production of anginal pain by stimulation of A(1) adenosine receptors. Neural activation in the thalamus and prefrontal cortex during angina pectoris has been reported. Although no subject felt chest pain during dipyridamole stress, neural activation in the thalamus and prefrontal cortex indicates that stimulation of A(1) adenosine receptors during dipyridamole stress may produce input from the heart to the thalamus through the vagal fiber.

Blood Pressure↗

PubMed2000

Electrical cortical stimulation of the human prefrontal cortex evokes complex visual hallucinations.

Complex visual hallucinations are a well-known feature of electrical stimulation or epileptic discharge in the temporal lobe. It has been proposed that these visual hallucinations result from an electrical interference with the ventral visual processing stream in the lateral temporal lobe and the memory system in medial temporal structures, which explains their frequent visual and mnestic features. Even though recent studies have demonstrated visual and memory functions in the prefrontal cortex, up to now epileptic discharge or electrical stimulation of prefrontal structures has only rarely been reported to induce visual phenomena. We report on two patients undergoing invasive presurgical epilepsy evaluation in which electrical cortical stimulation of the left prefrontal cortex repeatedly induced complex visual hallucinations. Interestingly, the induced visual responses differed with respect to their spatial organization: whereas those evoked on the inferior frontal gyrus were perceived in the whole visual field, complex visual responses on the middle frontal gyrus were restricted to the contralateral hemispace. Based on the spatial organization of the visual experiences in our patients, animal work, and neuroimaging data it might be suggested that specific subregions of the human prefrontal cortex might contain separate visual and mnemonic processing mechanisms.

Journal Article↗

PubMed1993

Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo.

The influence of the medial prefrontal cortex (PFC) on mesolimbic dopamine activity was studied with electrophysiological techniques and in vivo voltammetry in the chloral hydrate-anesthetized male rat. Glutamate injected into the PFC selectively increased burst firing of single dopamine cells in the ventral tegmental area and enhanced the release of dopamine from nerve terminals in the nucleus accumbens. PFC injection of the local anesthetic lidocaine produced the opposite effects on burst firing and terminal release. This selective modulation of the dynamic activity of mesolimbic dopamine neurons by the prefrontal cortex might be important in motivation, learning and schizophrenia.

Animals↗

PubMed1972

Neostriatum and functions of prefrontal cortex.

A review of recent anatomical evidence shows that every neocortical area and many nuclei from the dorsal thalamus project to restricted neostriatal regions. The neurobehavioral literature offers many examples of the same results obtained with lesions, stimulations or recordings in a neocortical area and the associated neostriatal region. This evidence is abundant in the case of the prefrontal cortex and rostra1 neostriatum, but it is available also for other corticoneostriatal pairs. It seems possible to conclude that the function of a neostriatal region is determined by its cortical and possibly by its thalamic input. However, the possibility that the behavioral effects of lesions and stimulation of neostriatum were in fact produced by involving the fibers passing to and from the overlying cortex has not been convincingly excluded. An attempt was made to develop a simple concept about the relation between the prefrontal cortex and the region of neostriatum associated with it. A serial paradigm, suggesting that prefrontal cortex in adult monkeys and cats acts via neostriatum when mediating performance in certain behavioral tasks, seems to account for most of the available data.

Animals↗

PubMed1990

Preferential decrease in dopamine utilization in prefrontal cortex by zopiclone, diazepam and zolpidem in unstressed rats.

This study has compared the effects of a cyclopyrrolone, zopiclone, a benzodiazepine, diazepam, and an imidazopyridine, zolpidem, on dopamine (DA) and DOPAC levels, and DA utilization (DOPAC/DA ratio) in rat striatum and prefrontal cortex. The endogenous levels of DA were significantly increased by both zopiclone (2.5, 10 and 40 mg kg-1 p.o.) and diazepam (10 and 40 mg kg-1 p.o.) in the prefrontal cortex, whereas striatal DA content was significantly increased only with the highest dose of diazepam (40 mg kg-1 p.o.). Diazepam (10 and 40 mg kg-1 p.o.) decreased cortical level of DOPAC more markedly than striatal levels, whereas zopiclone (40 mg kg-1 p.o.) only slightly decreased striatal DOPAC levels. Zopiclone and diazepam dose-dependently decreased DA utilization, an effect which was more marked in prefrontal cortex than in striatum. This result was confirmed with zolpidem, another benzodiazepine ligand. Zopiclone was most potent at decreasing DA utilization at the cortical level. The diazepam-induced decreases in DA metabolism and utilization were antagonized by Ro 15-1788, suggesting that the effects seen were mediated by specific benzodiazepine receptors. Thus, our results clearly show that ligands acting on the benzodiazepine receptor GABA receptor chloride ionophore complex can decrease the utilization of dopamine in unstressed rats. The preferential decrease in cortical DA utilization induced by benzodiazepine ligands may be compared to the well-known activation by stress of the mesocortical DAergic system.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Sensitization to cocaine's motor activating properties produced by electrical kindling of the medial prefrontal cortex but not of the hippocampus.

A substantial body of evidence has accumulated that implicates NMDA systems in the neural changes that are associated with the development of both electrical kindling of limbic sites and sensitization to the behavioral effects of repeated stimulant exposure. This study sought to establish whether electrical kindling of the brain was a sufficient condition for inducing sensitization to cocaine's motor activating effects and, if so, whether the cross sensitization was a result of kindling of a specific locus. Rats received daily electrical stimulation of either the medial prefrontal cortex or the hippocampus. Other rats received the electrode implants and were handled daily but received no electrical stimulation. Stage 5 seizures developed in response to the stimulation in 32-35 days. Once this criterion of kindling was established and following a 14 day waiting period the effectiveness of cocaine (0.0, 5.0 or 10.0 mg/kg) in elevating horizontal motor activity was determined. For all 3 groups (sham controls, prefrontal cortical and hippocampal stimulated rats) cocaine produced a dose-dependent increase in horizontal activity. The sham controls and hippocampal rats did not differ in the magnitude of the cocaine-produced effect. However, rats that had received stimulation of the prefrontal cortex showed heightened levels of cocaine-induced activity that were particularly apparent in response to 10.0 mg/kg cocaine. These data suggest that kindling of the prefrontal cortex had sensitized rats to the behavioral effects of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2005

Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice.

BACKGROUND: Recent clinical studies have suggested that chronic use of methamphetamine (METH) induces long-term cognitive deficits. To clarify the mechanism of METH-induced cognitive impairment, we investigated the effect of METH on cognitive function in mice. METHODS: Mice were repeatedly administered METH for 7 days, and their cognitive function was assessed using a novel-object recognition task. Therapeutic effects of clozapine and haloperidol on METH-induced cognitive impairment were investigated. Western blotting and specific inhibitors were employed to determine the role of extracellular signal-regulated kinase 1/2 (ERK1/2). RESULTS: Repeated METH treatment induced an impairment of recognition of novel objects and behavioral sensitization. These effects persisted for at least 28 days after the drug withdrawal. Clozapine, but not haloperidol, reduced METH-induced cognitive impairment. Hyperphosphorylation of ERK1/2 was found in the prefrontal cortex of mice exposed to the novel objects, but was abolished in mice treated with METH. Inhibition of ERK1/2 by the microinjection of PD98059 into the prefrontal cortex resulted in cognitive impairment. CONCLUSIONS: These results suggest that repeated METH treatment induces cognitive impairment, which is associated with the dysfunction of the ERK1/2 pathway in the prefrontal cortex.

Animals↗

PubMed2004

Developmental outcomes after early prefrontal cortex damage.

The neuropsychological bases of cognitive, social, and moral development are minimally understood, with a seemingly wide chasm between developmental theories and brain maturation models. As one approach to bridging ideas in these areas, we review 10 cases of early prefrontal cortex damage from the clinical literature, highlighting overall clinical profiles and real life developmental outcomes. Based on these cases, there is preliminary evidence to support distinctive developmental differences after: (1) dorsolateral, (2) mesial, and (3) orbital-polar prefrontal lesions, for more profound impairments after bilateral damage, and possibly for recovery differences after very early vs. later childhood lesion onset. Further case and group studies are needed to confirm reliable effects of specific lesion locations, the influence of age of lesion onset, and related experiential and treatment variables in determining adult outcomes. Rather than a single underlying deficit associated with early prefrontal cortex damage, we interpret the findings to suggest that it is the altered integration and interplay of cognitive, emotional, self-regulatory, and executive/metacognitive deficits that contribute to diverse developmental frontal lobe syndromes. The findings support the fundamental importance of prefrontal cortex maturation in protracted cognitive, social-emotional, and moral development.

Adolescent↗