Orbitofrontal cortex and representation of incentive value in associative learning.
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Clinical evidence indicates that damage to ventromedial prefrontal cortex disrupts goal-directed actions that are guided by motivational and emotional factors. As a consequence, patients with such damage characteristically engage in maladaptive behaviors. Other research has shown that neurons in the corresponding orbital region of prefrontal cortex in laboratory animals encode information regarding the incentive properties of goals or expected events. The present study investigates the effect of neurotoxic orbitofrontal cortex (OFC) lesions in the rat on responses that are normally influenced by associations between a conditioned stimulus (CS) and the incentive value of reinforcement. Rats were first trained to associate a visual CS with delivery of food pellets to a food cup. As a consequence of learning, rats approached the food cup during the CS in anticipation of reinforcement. In a second training phase, injection of LiCl followed consumption of the food unconditioned stimulus (US) in the home cage, a procedure used to alter the incentive value of the US. Subsequently, rats were returned to the conditioning chamber, and their responding to the CS in the absence of the food US was tested. Lesions of OFC did not affect either the initial acquisition of a conditioned response to the light CS in the first training phase or taste aversion learning in the second training phase. In the test for devaluation, however, OFC rats exhibited no change in conditioned responding to the visual CS. This outcome contrasts with the behavior of control rats; after devaluation of the US a significant decrease occurred in approach to the food cup during presentation of the CS. The results reveal an inability of a cue to access representational information about the incentive value of associated reinforcement after OFC damage. (+info)
Specific cognitive deficits in mild frontal variant frontotemporal dementia.
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Eight patients with relatively mild frontal variant frontotemporal dementia (fvFTD) were compared with age- and IQ-matched control volunteers on tests of executive and mnemonic function. Tests of pattern and spatial recognition memory, spatial span, spatial working memory, planning, visual discrimination learning/attentional set-shifting and decision-making were employed. Patients with fvFTD were found to have deficits in the visual discrimination learning paradigm specific to the reversal stages. Furthermore, in the decision-making paradigm, patients were found to show genuine risk-taking behaviour with increased deliberation times rather than merely impulsive behaviour. It was especially notable that these patients demonstrated virtually no deficits in other tests that have also been shown to be sensitive to frontal lobe dysfunction, such as the spatial working memory and planning tasks. These results are discussed in relation to the possible underlying neuropathology, the anatomical connectivity and the hypothesized heterogeneous functions of areas of the prefrontal cortex. In particular, given the nature of the cognitive deficits demonstrated by these patients, we postulate that, relatively early in the course of the disease, the ventromedial (or orbitofrontal) cortex is a major locus of dysfunction and that this may relate to the behavioural presentation of these patients clinically described in the individual case histories. (+info)
Modulation of dialysate levels of dopamine, noradrenaline, and serotonin (5-HT) in the frontal cortex of freely-moving rats by (-)-pindolol alone and in association with 5-HT reuptake inhibitors: comparative roles of beta-adrenergic, 5-HT1A, and 5-HT1B receptors.
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(-)-Pindolol, which possesses significant affinity for 5-HT1A, 5-HT1B, and beta 1/2-adrenergic receptors (AR)s, dose-dependently increased extracellular levels of dopamine (DA) and noradrenaline (NAD) versus 5-HT, in dialysates of the frontal cortex (FCX), but not accumbens and striatum, of freely-moving rats. In distinction, the preferential beta 1-AR antagonist, betaxolol, and the preferential beta 2-AR antagonist, ICI118,551, did not increase basal levels of DA, NAD, or 5-HT. Further, they both dose-dependently and markedly blunted the influence of (-)-pindolol upon DA and NAD levels. The selective 5-HT1A receptor antagonist, WAY100,635, slightly attenuated the (-)-pindolol-induced increase in DA and NAD levels, while the selective 5-HT1B antagonist, SB224,289, was ineffective. These data suggest that (-)-pindolol facilitates frontocortical dopaminergic (and adrenergic) transmission primarily by activation of beta 1/2-ARs and, to a lesser degree, by stimulation of 5-HT1A receptors, whereas 5-HT1B receptors are not involved. (-)-Pindolol potentiated the increase in FCX levels of 5-HT elicited by the 5-HT reuptake inhibitors, fluoxetine and duloxetine, and also enhanced their ability to elevate FCX levels of DA--though not of NAD. In contrast to (-)-pindolol, betaxolol and ICI118,551 did not affect the actions of fluoxetine, whereas both WAY100,635 and SB224,289 potentiated the increase in levels of 5-HT--but not DA or NAD levels--elicited by fluoxetine. In conclusion, (-)-pindolol modulates, both alone and together with 5-HT reuptake inhibitors, dopaminergic, adrenergic, and serotonergic transmission in the FCX via a complex pattern of actions at beta 1/2-ARs, 5-HT1A, and 5-HT1B receptors. These findings have important implications for clinical studies of the influence of (-)-pindolol upon the actions of antidepressant agents. (+info)
Effects of local inactivation of monkey medial frontal cortex in learning of sequential procedures.
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To examine the role of the medial frontal cortex, supplementary motor area (SMA), and pre-SMA in the acquisition and control of sequential movements, we locally injected muscimol into 43 sites in the medial frontal cortex while monkeys (n = 2) performed a sequential button-press task. In this task, the monkey had to press two of 16 (4 x 4 matrix) buttons illuminated simultaneously in a predetermined order. A total of five pairs were presented in a fixed order for completion of a trial. To clarify the differential contribution of the medial frontal cortex for new acquisition and control of sequential movements, we used novel and learned sequences (that had been learned after extensive practice). We found that the number of errors increased for novel sequences, but not for learned sequences, after pre-SMA inactivations. A similar, but insignificant, trend was observed after SMA injections. The reaction time of button presses for both novel and learned sequences was prolonged by inactivations of both SMA and pre-SMA, with a trend for the effect to be larger for SMA inactivations. These findings suggest that the medial frontal cortex, especially pre-SMA, is related to the acquisition, rather than the storage or execution, of the correct order of button presses. (+info)
Progressive frontal gait disturbance with atypical Alzheimer's disease and corticobasal degeneration.
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OBJECTIVES: The clinical neuropsychological, neuroradiological, and neuropathological description of two patients presenting with a frontal gait disturbance. METHODS: Clinical case note review, neuropsychological assessment, functional imaging with (15)O(2) and (18)F-fluorodopa PET, and neuropathology. RESULTS: Both patients presented with frontal gait impairment and only later developed more widespread cognitive impairment. In both cases (15)O(2) PET disclosed focal hypometabolism in the medial frontal lobes and in one patient (18)F-fluorodopa uptake into the caudate and putamen was normal. The neuropathological examination in one patient showed Alzheimer's histopathology together with large swollen eosinophilic neurons characteristic of corticobasal degeneration, which were particularly prominent in the medial frontal lobes. CONCLUSION: Focal degeneration of the medial frontal lobes may present as an isolated gait disturbance and should be considered in the differential diagnosis of patients who present without an obvious structural abnormality on neuroimaging. (+info)
Pharmacological studies of the acute and chronic effects of (+)-3, 4-methylenedioxymethamphetamine on locomotor activity: role of 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B/1D) receptors.
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The 5-hydroxytryptamine(1B/1D) (5-HT(1B/1D)) antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127935) and 5-HT(1A) antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY 100635) were used to assess whether hyperactivity induced by 3 mg/kg (+)-3, 4-methylenedioxymethamphetamine [(+)-MDMA] is mediated by 5-HT(1B/1D) and/or 5-HT(1A) receptors. Activity in the periphery and center of an open field as well as rearing activity were measured in photobeam monitors. (+)-MDMA-induced peripheral and central activities were blocked by GR 127935 (0.3, 0.625, 1.25, and 2.5 mg/kg); central hyperactivity was blocked by 0.1, 0.3, and 0.625 mg/kg GR 127935. WAY 100635 (0.5-2 mg/kg) had little effect on (+)-MDMA-induced activity except for an enhancement of central activity at one dose (0.5 mg/kg). Central activity induced by (+)-MDMA increased from day 1 to day 5 of treatment with (+)-MDMA (3 mg/kg), whereas peripheral, central, and rearing activity significantly increased in (+)-MDMA-treated rats pretreated daily with GR 127935 (2.5 mg/kg). Withdrawal from (+)-MDMA, but not GR 127935 + (+)-MDMA, pretreatment was associated with heightened hyperactivity induced by the 5-HT(1B/1A) agonist RU 24969 (2 mg/kg i. p.); treatments were not associated with alterations in 5-HT and 5-hydroxyindoleacetic acid content or turnover in frontal cortex. These data support a role for 5-HT(1B/1D) in mediating the acute hyperactivity evoked by (+)-MDMA. The development of sensitization to (+)-MDMA was associated with supersensitivity to a 5-HT(1B/1A) agonist, suggesting that these receptors may contribute to sensitization. However, sensitization to (+)-MDMA developed even under conditions of 5-HT(1B/1D) receptor blockade, which is somewhat counter to this speculation. Perhaps, under circumstances of continued 5-HT(1B/1D) blockade, other mechanisms (e.g., dopamine) predominate in the progressive enhancement of behavior with repeated (+)-MDMA treatment. (+info)
Spatial attention and neglect: parietal, frontal and cingulate contributions to the mental representation and attentional targeting of salient extrapersonal events.
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The syndrome of contralesional neglect reflects a lateralized disruption of spatial attention. In the human, the left hemisphere shifts attention predominantly in the contralateral hemispace and in a contraversive direction whereas the right hemisphere distributes attention more evenly, in both hemispaces and both directions. As a consequence of this asymmetry, severe contralesional neglect occurs almost exclusively after right hemisphere lesions. Patients with left neglect experience a loss of salience in the mental representation and conscious perception of the left side and display a reluctance to direct orientating and exploratory behaviours to the left. Neglect is distributed according to egocentric, allocentric, world-centred, and object-centred frames of reference. Neglected events can continue to exert an implicit influence on behaviour, indicating that the attentional filtering occurs at the level of an internalized representation rather than at the level of peripheral sensory input. The unilateral neglect syndrome is caused by a dysfunction of a large-scale neurocognitive network, the cortical epicentres of which are located in posterior parietal cortex, the frontal eye fields, and the cingulate gyrus. This network coordinates all aspects of spatial attention, regardless of the modality of input or output. It helps to compile a mental representation of extrapersonal events in terms of their motivational salience, and to generate 'kinetic strategies' so that the attentional focus can shift from one target to another. (+info)
Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease A 3D [(18)F]dopa-PET study.
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We have studied focal changes in dopaminergic function throughout the brain volume in early and advanced Parkinson's disease by applying statistical parametric mapping (SPM) to 3D [(18)F]dopa-PET. Data from seven early hemi-Parkinson's disease and seven advanced bilateral Parkinson's disease patients were compared with that from 12 normal controls. Parametric images of [(18)F]dopa influx rate constant (K(i)(o)) were generated for each subject from dynamic 3D [(18)F]dopa datasets and transformed into standard stereotactic space. Significant changes in mean voxel [(18)F]dopa K(i)(o) values between the normal control group and each Parkinson's disease group were localized with SPM. Conventional region of interest analysis was also applied to comparable regions on the untransformed image datasets. In early left hemi-Parkinson's disease, significant extrastriatal increases in [(18)F]dopa K(i)(o) were observed in the left anterior cingulate gyrus and the dorsal midbrain region (P < 0.05, corrected) along with decreases in striatal [(18)F]dopa K(i)(o). In advanced Parkinson's disease, significant extrastriatal decreases in [(18)F]dopa K(i)(o) were observed in the ventral and dorsal midbrain regions (P < 0.05, corrected). No significant changes in [(18)F]dopa K(i)(o) were observed in the anterior cingulate region. In a direct comparison between the early and late Parkinson's disease groups, we observed relative [(18)F]dopa K(i)(o) reductions in ventral and dorsal midbrain, and dorsal pontine regions along with striatal [(18)F]dopa K(i)(o) reductions. Similiar results were found with a region of interest approach, on non-transformed data, except for the focal midbrain [(18)F]dopa K(i)(o) increase seen in early Parkinson's disease. In conclusion, using SPM with [(18)F]dopa-PET, we have objectively localized changes in extrastriatal, pre-synaptic dopaminergic function in Parkinson's disease. The significance of the increased dopaminergic activity of anterior cingulate in early Parkinson's disease remains unclear, but may be compensatory. The [(18)F]dopa signal in dorsal midbrain and pontine regions suggests that [(18)F]dopa is taken up by serotonergic and noradrenergic neurons which also degenerate in advanced Parkinson's disease. This suggests, therefore, that Parkinson's disease is a monoaminergic neurodegenerative disorder. (+info)