Age-dependent differences in flurothyl seizure sensitivity in mice treated with a ketogenic diet

Despite strong clinical data confirming the anticonvulsant efficacy of a ketogenic diet (KGD) in pediatric patients, corroborative experimental data in young animals are limited. In the present study, the effects of a KGD on flurothyl seizure susceptibility were examined in normal juvenile mice after a dietary duration of 3, 7, or 12 days, and in adult mice for 15 days. In all groups of KGD-treated mice, blood beta-hydroxybutyrate levels were significantly elevated over those measured in controls. The present KGD was anticonvulsant (i.e. delayed onset) against the first (clonic) flurothyl-induced seizure for juvenile mice treated for either 7 or 12 days, but not for juvenile mice and adult mice fed the diet for 3 and 15 days, respectively. While this KGD was not anticonvulsant against the second (tonic extension) seizure induced by flurothyl in any of the juvenile groups, it significantly delayed tonic extension in the adult group. In addition, juvenile mice fed a KGD exhibited a lower mortality rate following flurothyl-induced seizures compared to mice fed a standard diet. In our discussion of animal models of the KGD, we highlight the need to understand better the impact of important variables such as dietary composition, genetic background, and mode of seizure induction in the study of the KGD.     

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     

The Cerebral Cortex of the Rat and Visual Attentional Function: Dissociable Effects of Mediofrontal, Cingulate, Anterior Dorsolateral, and Parietal Cortex Lesions on a Five-Choice Serial Reaction Time Task

Dissociable effects of bilateral excitotoxic lesions of differentregions of the rat neocortex, including medial prefrontal andanterior cingulate cortices, were investigated in a five-choiceserial reaction time task that provides several indices of theaccuracy and speed of attentional function. Whereas medial prefrontalcortical lesions impaired performance of the task as revealedby a reduction in choice accuracy, an increase in the latencyto respond correctly to the visual target and enhanced perseverativeresponding, lesions of the anterior cingulate cortex specificallyincreased premature responding. By contrast, lateral frontalcortical lesions did not significantly disrupt baseline performanceof the task, but rather increased the latency to respond correctlyto the visual target during various behavioral manipulations,for example, when the length of the intertrial interval wasvaried unpredictably and during interpolation of distractingbursts of white noise. Lesions of the parietal cortex failedto disrupt any aspect of task performance investigated. These behavioral effects in the five-choice task were comparedwith the effect of these same lesions on acquisition and retentionof a one-trial passive avoidance task. The main finding fromthis paradigm was that lesions of the lateral frontal cortexproduced a significant disruption to the retention of passiveavoidance, which stands in marked contrast to the successfulretention observed by animals of the other lesion groups. Inaddition, this pattern of results reveals that the "disinhibitory"effect of cingulate cortex lesions are relatively specific tothe five-choice attentional task. Finally, the results of the present study are compared withthe findings of previous experiments using the five-choice task,which have examined the effect of selective manipulations ofthe ascending noradrenergic, cholinergic, dopaminergic. andserotonergic projections. In particular, the deficits in attentionalfunction observed following cholinergic lesions of the nucleusbasalis magnocellularis appear to be attributable to cholinergicdenervation of the medial frontal cortex. These results arediscussed in terms of the role of parallel distributed neuralsystems within the neocortex that mediate continuous attentionalperformance in the rat.     

Reticulospinal and reticuloreticular pathways for activating the lumbar back muscles in the rat

Erratum

Reticulospinal and reticuloreticular pathways for activating the lumbar back muscles in the rat     

Forebrain norepinephrine: role in controlled information processing in the rat.

A series of experiments examined the effects of 6-hydroxydopamine (6-OHDA)-induced depletion of forebrain norepinephrine (NE) on the performance of a visual detection (spatial localization) task. The behavioral paradigm used was an analogue of Leonard's 5-choice serial reaction time task for humans. The 6-OHDA lesion of the dorsal noradrenergic bundle (DNAB) produced a 98% depletion of the NE content in the neocortex, and a much smaller depletion (32%) of the NE content in the hypothalamus. As reported previously, performance of visual discrimination was unaffected by DNAB lesions, even when the discrimination was made more difficult by decreasing the intensity of the visual stimuli. However, the lesion produced a significant decrease in accuracy and a significant increase in omissions when a burst of loud white noise was presented just prior to the onset of the visual discriminanda. Similarly, a significant decrease in discriminative accuracy was produced in the rats with forebrain NE depletion by systemic administration of the psychomotor stimulant, d-amphetamine (0.2 to 0.8 mg/kg). In both of these experiments, the lesion-induced discrimination impairment was not magnified by reducing the brightness of the visual discriminanda, suggesting that the behavioral impairment was not caused by a decreased ability to detect the visual stimuli. In addition, the lesion impaired discriminative accuracy when the visual discriminanda were presented at an unpredictable rate. The implications of these behavioral impairments produced by forebrain NE depletion for theories of catecholamine involvement in attentional processes and arousal are discussed in terms of a possible role for the DNAB in controlled or "effortful" processing.     

Diencephalic Noradrenaline Depletion Impairs the Corticosterone Response to Footshock but does not Affect Conditioned Fear

This study tested the hypothesis that hypothalamic noradrenaline (NA) depletion induced by 6-hydroxydopamine alters neuroendocrine, but not behavioural, responses to aversive stimuli. Sham-operated and NA depleted rats were exposed to pairings of an auditory (clicker) CS and (footshock) US in a distinctive environment. Subjects were tested for preference of a 'safe' environment over the one in which they were shocked, as a measure of effective conditioning to the contextual stimuli present in the distinctive environment. Subjects were also tested, in a separate operant chamber, for the suppression of drinking in the presence of the auditory stimulus, as a measure of effective conditioning to the explicit auditory CS. Blood samples were collected immediately following each phase of the behavioural experiment and were later analysed for plasma Corticosterone concentration. Behavioural and Corticosterone responses of individual control animals to the CS were positively correlated, consistent with previous results. This correlation was not present in the NA depleted group. The lesioned rats also showed a severely attenuated Corticosterone response to the footshock US. By contrast, NA depletion had no effect on any behavioural measure of CS or contextual conditioning. Together with previous experiments, these results suggest that diencephalic NA projections are more likely to mediate neuroendocrine, and coeruleo-cortical NA projections are more likely to mediate behavioural responses to conditioned and unconditioned aversive stimuli.     

Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man.

Attentional "set" shifting was assessed in a group of 20 neurosurgical patients with localized excisions of the frontal lobes, a group of 20 patients with unilateral temporal lobe lesions and a group of 11 patients who had undergone amygdalo-hippocampus removal. These three patient groups were compared with groups of both young (age-matched) and elderly normal control volunteers on a computerized test of visual discrimination learning involving both an intra- and an extra-dimensional shift. The frontal lobe group were selectively impaired in their ability to shift response set to a previously irrelevant dimension but not to shift attention to new exemplars of a previously relevant dimension. A similar pattern was observed in the elderly group of normal control volunteers. By comparison, both the temporal lobe patients and the amygdalo-hippocampectomy patients were unimpaired in their ability to perform either shift, although both groups had significantly prolonged selection latencies at the extra-dimensional shift stage of the task. These data are compared to previous findings from patients with idiopathic Parkinson's disease and are discussed in terms of a specific attentional set shifting deficit following frontal lobe damage.     

Athletic footwear: unsafe due to perceptual illusions

Modern athletic footwear provides remarkable plantar comfort when walking, running, or jumping. However, when injurious plantar loads elicit negligible perceived plantar discomfort, a perceptual illusion is created whereby perceived impact is lower than actual impact, which results in inadequate impact-moderating behavior and consequent injury. The objective of this study was to examine how plantar tactile (mechanical) events affect perceived plantar discomfort. Also, we evaluated the feasibility of a footwear safety standard we propose, which requires elimination of the above illusion. Twenty subjects gave numerical estimates of plantar discomfort produced by simulated locomotion (concurrent vertical (0.1-0.7 kg.cm-2) and horizontal (0.1-0.9 kg.cm-2) plantar loads), with the foot supported by either a smooth rigid surface or a rigid surface with 2 mm high rigid irregularities. Vertical or horizontal load alone evoked no discomfort (P greater than 0.05), whereas together, discomfort emanated from loads as low as 0.4 kg.cm-2. Irregularities heightened discomfort by a factor of 1.89. This suggests that the proposed safety standard is feasible, since compliance could be achieved simply by adding surface irregularities to insoles and by other changes that heighten localized plantar loads. However, until this standard is adhered to, it might be more appropriate to classify athletic footwear as "safety hazards" rather than "protective devices".