Hypothalamic GABAA receptor blockade modulates cerebral cortical systems sensitive to acute stressors

Pharmacologic blockade of GABA binding sites in the hypothalamus elicits a pattern of physiological and behavioral arousal. The latter outcome implicates a perturbation in the neural functioning of higher brain centers. The effect that hypothalamic GABA_A receptor modulation has on the function of cerebral cortical neural substrates linked with responses to stressors was assessed using microinfusion of bicuculline methiodide (BMI) into the medial hypothalamus of freely moving, handling habituated rats. BMI led to rapid increases in frontal cortical dopamine (DA) utilization (calculated from the sum of the levels of the DA metabolites, homovanilic and dihydroxyphenylacetic acids, divided by DA levels) resembling that identified following restraint-induced stress. Also, cortical GABA_A receptor function [using chloride (Cl^–) enhancement of³H-flunitrazepam (Flu) binding as an index] was disrupted; i.e. there was a loss of typical Cl^– enhancement of³H-Flu binding in animals after BMI infusions. However, placing animals in restraint after BMI infusion reversed the effects of BMI, with both DA utilization and Cl^– facilitated³H-Flu binding similar to control basal values. Muscimol infusions in separately prepared animals did not alter either frontal cortical DA utilization or GABA_A receptor function. The present results implicate GABA in the hypothalamus as gating activity of cortical systems involved in sensation of and/or responses to stressors. These findings may have important implications for effects of autonomic arousal on neural substrates involved in mediating stress responses.     

Dementia lacking distinctive histopathology: clinicopathological evaluation of 32 cases

We report the neuropathological findings in 32 patients, aged 46–86 years, with demential lacking distinctive histopathology. All of the patients were classified clinically as having Pick's or atypical Pick's disease, but the routine neuropathological evaluation showed no specific histopathological changes such as Pick bodies, senile plaques, neurofibrillary tangles or Lewy bodies. In 50% of the cases the first symptoms appeared before 65 years of age. However, there were 9 patients with onset in the eighth decade. Positive family history was found only in 6 presenile cases. The retrospective evaluation of the clinical records revealed the consistent presence of frontal symptomatology, including loss of personal awareness, inappropriate euphoria and stereotyped behavior. Speech disorders were observed in 80% of the cases, whereas temporospatial disorientation and memory impairment were less frequent. Praxis and gnosis were strikingly preserved in most of the cases. The macroscopic neuropathological examination revealed frontal or temporopolar atrophy in 97% of the cases, while the hippocampus and subcortical structures were relatively spared in the majority of the cases. Histologically, four groups were recognized. Group A showed moderate to severe neuron loss and gliosis in the frontal and/or temporopolar cortex without subcortical involvement. In group B, the neocortical cell loss was widespread, and the striatum and substantia nigra displayed differential degrees of gliosis but no neuron loss. Group C patients showed a lesion distribution comparable to that observed in group B but with severe neuron loss in at least one subcortical region. Four cases formed group D, which was characterized by the preservation of the pyramidal neurons in the neocortex and variable subcortical changes. Despite these differences in the topography of pathological changes, all of the cases shared a similar clinical profile. These findings further demonstrate the epidemiological and neuropathological heterogeneity of dementia lacking distinctive histopathology. Furthermore, they suggest that the same clinical manifestations may correspond to several distinct pathological processes in this condition.     

Ear and eye representation in the frontal cortex,area 8b,of the macaque monkey: an electrophysiological study

We evoked both ear and eye movements in area 8b, the rostral area of frontal cortex, in two monkeys. In some sites it was possible to evoke only ear movements or only eye movements; in other locations we evoked both ear and eye movements by varying the intensity of electrical stimulation. The electrically evoked ear movements were forward, or backward, or oblique (upward-forward; upward-backward). In two penetrations the ear movements were bilateral, in the other penetrations they were contralateral. Ipsilateral ear movements were not observed. The evoked eye movements were mainly fixed-vector saccades, contralateral and with an upward orientation of about 45°. If we considered only the sites where the threshold was equal to or lower than 50 A, the stimulation of this area evoked mainly ear movements. In addition we recorded the electrical activity of 195 neurons. Of these neurons: 74% (145/195) discharged before ear movements (ear cells); 20% (40/195) discharged before ear and eye movements (ear-eye cells); 5% (10/195) discharged only before eye movements (eye cells). Ninety-one percent (132/145) of ear cells presented a preferred direction; 90% (36/40) of ear-eye cells presented a preferred direction for ear movements, and 15% (6/40) presented a preferred direction for eye movements. Eighty-five percent (34/40) of cells did not present a preferred direction for visually guided saccades and were active when the monkey made saccades toward the unlit targets (checking saccades). Our results show that a field of area 8b is related to ear movements and to eye-ear movements. The findings that it is possible to obtain both ear and eye movements with low-intensity currents and that there are cells firing for the two types of movements suggest that area 8b may be involved in the orientation and coordination of both ear and eye. This area might be considered a rostral extension of supplementary eye field (SEF) or a different region. However, based on its distinct functional characteristics and connectivity, it is probably better regarded as a separate field. Regardless, the combination of 8b and SEF may constitute a cortical center for orienting processes.     

Clinical patterns of patients with temporal lobe epilepsy and pure amygdalar atrophy

PURPOSE: MRI volumetric measurements (MRIvol) have been proven reliable in determining mesial temporal atrophy in patients with TLE. We attempted to correlate the clinical features with different patterns of hippocampal formation (HF) and amygdala (AM) atrophy in patients with TLE without foreign tissue lesion. METHODS: We studied 65 patients with refractory TLE. They were divided into five groups according to MRIvol results: pure AM atrophy (n = 11, 10 unilateral and one bilateral), unilateral HF atrophy (n = 16), bilateral HF atrophy (n = 12), unilateral AM + HF atrophy (n = 13), and patients with normal volumes of AM and HF (n = 13). MRIvol of AM and HF were performed by using a protocol previously described by Watson et al. (Neurology 1992;42:1743-50). RESULTS: Patients with AM atrophy had later onset of seizures compared with those with unilateral HF atrophy (p < 0.01). History of febrile convulsions (p < 0.0001) and frequent secondarily generalized tonic-clonic seizures (GTCSs) were more often found in patients with HF atrophy compared with those with pure AM atrophy and those with normal volumes (p = 0.04). Prolonged postictal confusion was more often found with AM atrophy (p = 0.05). Memory impairment was more severe in patients with HF atrophy than in those with AM atrophy only or in those with normal volumes (p = 0.03). There were no significant differences among the five groups in the following parameters: age, duration of epilepsy, seizure frequency, and presence and type of aura. CONCLUSIONS: Prolonged postictal confusion appeared to be related to AM atrophy, in keeping with previous clinical observations. These patients also had a lower incidence of early febrile convulsions, older age at epilepsy onset, lower frequency of secondary GTCS, and lesser memory dysfunction compared with patients with hippocampal atrophy.     

An angiographically occult arteriovenous malformation in the medial parietal lobe presenting as seizures of medial temporal lobe origin

We present an unusual case of a patient who was diagnosed with temporal lobe epilepsy and whose seizures were reduced markedly after excision of an angiographically occult arteriovenous malformation (AVM) located in the left medial parietal lobe. A 38-year-old man had complex partial seizures characterized by motionless staring with oroalimentary and behavioral automatisms since the age of 15 years. Magnetic resonance imaging (MRI) demonstrated a small lesion extending from the left posterior cingulate gyrus to the precuneus. There was no MRI evidence of mesial temporal sclerosis. Intracranial EEG recordings showed ictal onset from the left medial parietal lobe propagating to the medial temporal lobes. Clinical signs appeared when these discharges reached the temporal lobes. After excision of the lesion (which was histologically confirmed as an AVM), together with the marginal cortex, seizures were reduced significantly. Careful diagnostic evaluation of lesions such as the this one may reveal an epileptogenic lesion (zone) far from the region where scalp ictal discharges seem to arise. In our case, we hypothesize that false localization was due to propagation of ictal discharges from the parietal focus through the limbic system.     

Apolipoprotein E polymorphisms and the risk of nonlesional temporal lobe epilepsy

PURPOSE: To evaluate whether the inheritance of the apolipoprotein E (ApoE) epsilon4 allele is a risk factor for nonlesional temporal lobe epilepsy (TLE), and to determine whether the newly described -491 A/T ApoE polymorphism may independently affect the risk of nonlesional TLE. METHODS: The study group consisted of 63 patients (35 women and 28 men; age at onset of epilepsy, 30.6 +/- 19.6 years; mean (+/-SD). All of them had received a diagnosis of nonlesional TLE after a detailed clinical, electroencephalographic, and brain magnetic resonance investigation. The ApoE polymorphisms were determined from blood samples by standard methods. The molecular study also was performed in 220 age- and sex-matched normal individuals. RESULTS: There were no differences between TLE patients and controls in either allelic or genotypic frequencies of the ApoE and -491A/T polymorphisms. Moreover, no effect of ApoE or -491A/T polymorphisms was found on the age at onset and severity of epilepsy. CONCLUSIONS: The allelic and genotypic frequencies of ApoE polymorphisms in Italian patients with nonlesional TLE are comparable to control values, indicating that ApoE polymorphisms are not a significant genetic risk factor for the occurrence of nonlesional TLE.     

Distinct prefrontal activations in processing sequence at the sentence and script level: an fMRI study

Neuropsychological studies have shown that the prefrontal cortex is important in planning and monitoring everyday behaviour. In this study, using functional magnetic resonance imaging (fMRI), we investigated whether specific prefrontal regions are involved in processing a sequence of actions. Subjects were required to perform two different tasks: Script-event order and Sentence-word order. Script sequence and word sequence processing were found to activate partially overlapping areas which are known to be implicated in language processing. In addition, the Script-task activated a large area in the dorsolateral prefrontal cortex (Brodmann area 6 and 8, BA 6 and 8), in both the left and right hemispheres, as well as the left supplementary motor area and left angular gyrus (BA 39). Our results suggest that these prefrontal areas may be more specifically involved in the process of analysing sequential links in the action domain.     

The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers

Rationale: Corticosteroids are elevated in certain neuropsychiatric disorders and this may contribute to the neuropsychological impairments reported in these disorders. Objective: To examine the effects of hydrocortisone on learning, memory and executive function. Methods: Hydrocortisone 20 mg was administered twice daily for 10 days to normal male volunteers in a randomized, placebo control, crossover, within-subject design. Learning, memory and executive function were measured using selected subtests from the Cambridge Neuropsychological Test Automated Battery. Results: Hydrocortisone caused impairments of visuo-spatial memory. These included increased within search errors and impaired use of strategies on the spatial working memory subtest. In addition, administration of hydrocortisone was associated with more errors in the paired associate learning subtest, although no effect was found on the Tower of London. Hydrocortisone speeded response latencies in certain tests (pattern and spatial recognition memory). Conclusion: These results indicate that chronic administration of hydrocortisone leads to deficits in certain tests of cognitive function sensitive to frontal lobe dysfunction and may contribute to the cognitive impairment reported in certain neuropsychiatric disorders. Received: 27 July 1998 / Final version: 9 February 1999     

Effect of novel environmental stimuli on rat behaviour and central noradrenaline function measured by in vivo microdialysis

Rationale: Although physically aversive stimuli induce functional changes in central noradrenergic neurones, little is known about the noradrenergic response to environmentally aversive stimuli. Objectives: The first aim was to characterise environmental features that are perceived as stressful by rats. The second was to investigate whether changes in the concentration of extracellular noradrenaline are induced by these environmental features. Methods: A light/dark shuttle-box was used to test rats’ behavioural response to a range of stimuli (novelty, bright light, and the presence of an unfamiliar rat), either before or after microdialysis probe implantation. Changes in the concentration of extracellular noradrenaline in the frontal cortex and hypothalamus in vivo were then evaluated on exposure to these same test conditions. Results: Naive rats spent less time in a brightly-lit test arena than a dark one. However, the behavioural response to the light arena was attenuated by the presence of an unfamiliar rat. Probe implantation intensified the response to the light arena but did not affect behaviour in the dark arena. In the microdialysis studies, there was no change in the concentration of extracellular noradrenaline on transfer of rats to the dark arena but there was an increase in both the frontal cortex (+45%) and hypothalamus (+75%) on exposure to the light arena. A similar increase was induced in both brain regions when the light arena contained an unfamiliar rat. Conclusions: Implantation of a microdialysis probe modifies the behavioural responses to certain environmental stimuli. Regardless of this, the extent to which rats perceive a novel environment as aversive is not the only determinant of the noradrenergic response to such stimuli. However, differences in stimulus controllability in the microdialysis and the behavioural experiments could influence the apparent intensity of the stress. Received: 29 October 1998 / Final version: 19 March 1999     

Converging visual and somatic sensory cortical input to the intraparietal sulcus of the rhesus monkey

A cyto- and myeloarchitectonic study reveals the presence of a distinct cortical zone ("area POa") in the lower bank of the intraparietal sulcus of the rhesus monkey. Using both autoradiographic and silver impregnation techniques, an analysis of cortical connections shows two overlapping projections to this sulcal zone. These come from (1) the middle portion of the preoccipital gyrus (area OA) and (2) the rostral inferior parietal lobule (area PF).