Cerebral blood flow velocity decreases during cognitive stimulation in Huntington's disease.

OBJECTIVE: To examine whether activation of cerebral blood flow velocity during cognitive stimulation, as measured by transcranial Doppler ultrasonography (TCD), is altered in patients with Huntington's Disease (HD). BACKGROUND: Previous research suggests that resting cerebral blood flow in symptomatic and asymptomatic HD patients is reduced from expected premorbid levels. The effects of cognitive activation on this relative hypoperfusion in HD has not been studied extensively. METHODS: We measured TCD flow velocity during rest and cognitive testing with the Porteus Maze Test and the Trails Test in 12 normal control subjects and 10 gene-positive HD patients. Percent change (i.e., flow during testing/resting) of flow velocity in the anterior and middle cerebral arteries were compared between groups. Correlations among percent flow velocity change, a disability rating scale, and cognitive test scores were calculated. RESULTS: In control subjects, anterior cerebral artery flow velocity and middle cerebral artery velocity increased during cognitive testing (p=0.001). HD patients showed a smaller blood flow velocity increase in the anterior cerebral arteries during the Porteus Maze Test (p < 0.001) and the Trails Test, Part B (p < 0.001). In the left anterior cerebral artery, flow velocity fell an average of 4.2% below resting baseline levels during the Porteus Maze Test, and 1.2% below resting levels during the Trails Test. The magnitude of the cerebral blood flow velocity changes in the anterior cerebral artery correlated with a number of cognitive test scores and with a rating scale of functional disability. In addition, logistic regression was able to discriminate the HD patients from the control group based on blood flow velocity changes (p=0.0025). When HD patients were divided into more (i.e., HD with chorea; n=4) and less impaired (i.e., without chorea; n=6) groups, both showed significant decreases in left anterior cerebral artery flow velocity during visual spatial executive cognition testing compared with control subjects. CONCLUSIONS: These results suggest that activation of visual spatial executive functions cause decreased flow velocity in the anterior cerebral artery, but not the middle cerebral artery, in HD patients. These changes are related to test performance and functional capabilities.

Altered patterns of regional cerebral blood flow in patients with Huntington's disease: a SPECT study during rest and cognitive or motor activation.

UNLABELLED: Previous research using functional transcranial Doppler sonography showed that blood flow velocity in the anterior cerebral artery is significantly less in patients with Huntington's disease (HD) than in healthy volunteers while they are completing mazes. The current research used SPECT to study regional cerebral blood flow (rCBF) in patients with HD during rest and maze testing. METHODS: Seven patients with HD and 9 healthy volunteers were injected twice with 0.96-1.15 GBq 99mTc-labeled hexamethylpropylene amine oxime. During the 10 min after injection, subjects either solved mazes or rested with their eyes open while looking at a modified maze. After SPECT, count density was obtained from 11 brain regions and corrected for decay and injected dose. Two types of data generated from this experiment, including absolute regional counts per pixel in the regions of interest and count density computed as a percentage of activity in the lateral cerebellum, were compared between groups. RESULTS: During rest, the absolute regional count density was greater in the HD brains than in the healthy brains (P < 0.001). Count density was typically between 8% and 13% higher in the HD group than in the healthy group. The single exception was the caudate density, for which the 2 groups had similar values. No significant differences in absolute regional count density were observed between groups during maze testing. When rCBF was calculated as a percentage of cerebellar rCBF, analysis of covariance found decreases in HD caudate density (P < 0.001) and orbital frontal cortex density (P < 0.005) during maze testing. Changes in rCBF in the caudate nucleus predicted gene status (P = 0.0007) and correlated with time to complete the mazes (P < 0.05). CONCLUSION: Patients with HD showed an increase in resting rCBF for all brain regions measured except the caudate nucleus. When rCBF was calculated as a percentage of cerebellar blood flow, rCBF in the striatum and orbital cortex in patients with HD was less during maze testing than during rest. Although the cause of these rCBF changes in HD patients is unclear, nitric oxide synthase, a regulator of vasomotor activity, may be involved.

Behavioral changes in Anolis carolinensis following injection with fluoxetine.

Eight adult male lizards of the genus and species Anolis carolinensis were used in this experiment. In order to induce aggressive responding, animals were caged separately and daily underwent pairing with another male, during which aggressive responses and changes in skin color were measured. After obtaining a baseline measure of aggressive responding, animals were injected either with fluoxetine or vehicle-controls in a cross-over design. Subjects were then exposed to five more days of (non drug) pairing with the intruder male, after which they underwent a second trial with fluoxetine/vehicle. Finally, two post-drug paired-trials were obtained. Fluoxetine injection significantly reduced the aggressive responding in the males while causing the postorbital eyespot to significantly darken. Subjects also showed increased aggressivity and skin-color reactivity subsequent to the two drug trials, although it is unclear if the fluoxetine, or non-specific factors of the injection paradigm, accounted for these changes. These results suggest that serotonergic CNS systems tonically regulate aggression in Anolis carolinesis, similar to that seen in many other species. They further suggest that eyespot-darkening and aggressive responding can be pharmacologically dissociated, implicating serotonin in the regulation of this phenomenon.

Effects of serotonergic drugs on lateralized aggression and aggressive displays in Anolis carolinensis.

Previous work demonstrated that the brains of many reptiles, including the American chameleon Anolis carolinensis (A. carolinensis), are functionally 'split'. Because the left eye in this species projects predominantly to the right hemisphere, and vice versa, inferences about lateralized brain functioning can be made in A. carolinensis by observation of eye use during behavioral encounters. Using this model, past work suggested that territorial aggression in Anolis is under the preferential control of the right hemisphere, and that acute stress or chronic alcohol exposure selectively reduces right hemisphere mediated territorial aggression. In addition, drugs which increase serotonin (5-HT) in the synaptic cleft inhibit aggressive responding in anoles in both hemispheres. The current experiment examined whether or not the administration of the serotonin agonists 8-hydroxy-2-(di-n-propylamine) tetralin (8-OHDPAT), quipazine, or meta-chlorophenylbiguanide (mCPBG) alter territorial aggression in Anolis. Nine adult socially isolated male A. carolinensis underwent a series of behavioral trials during which an antagonistic male was introduced into the cage. Once stable responding was initiated, all subjects were injected in a semi-randomized crossover manner with the following agents, (1) lactated Ringer's, (2) the 5-HT2 agonist quipazine (1.5 mg/kg and 3.0 mg/kg), (3) the 5-HT1 agonist 8-OHDPAT (83 mg/kg), and (4) the 5-HT3 agonist mCPBG (3.0 mg/kg and 9 mg/kg). Twenty minutes post injections, the male intruder was reintroduced into the subject's cage. Several behaviors were recorded, including: (1) the time to the first aggressive response, (2) the number of aggressive episodes mediated by the left eye or right eye, and (3) changes in skin color and posture. Aggressive responding was virtually eliminated in all subjects injected with 8-OHDPAT. On the other hand, one-way ANOVA found that both the 9 mg/kg dose of mCPBG (P=0.007), and the 3.0 mg/kg dose of quipazine (P=0.035), selectively decreased territorial aggression mediated by the left eye/right hemisphere compared to lactated Ringer's controls, but had no effect on aggression mediated by the right eye/left hemisphere. Although 8-OHDPAT inhibited aggression, injected subjects developed phenotypic displays of aggressive coloring/posturing, such as blackening of the eye spot and a raising of the neck crest. These results suggest that aggressive action can be differentiated from phenotypic displays that accompany aggression by a 5-HT1 agonist. They also indicate that there is an asymmetrical effect of 5-HT2/5-HT3 serotonin agonists on hemispheric mediation of aggression in this species.

The use of fetal neocortical transplants to treat the hyperactivity resulting from cortical suction lesions in adult rats.

Focal suction lesions of the right frontoparietal cortex in rats produce locomotor hyperactivity. We attempted to reverse these changes by grafting homologous cortex from 16-day-old embryos into the lesion site. Various aspects of activity were measured in computerized photocell chambers until 14 weeks past transplantation. Three groups of animals were tested: sham-operated controls, lesions only (LO), and lesion plus transplant (LT). Hyperactivity was demonstrated for all measures in LO and/or LT groups. There was a partial reversal by the transplants of the increases in vertical activity produced by lesions at 14 weeks after transplant. However, on other measures, such as distance per movement, only LT animals were ever hyperactive, and on others, such as total distance, hyperactivity appeared earlier in the LT group than in LO. Brain chemistry analyses revealed right-sided norepinephrine depletions in posterior cortex in all groups and a bilateral cortical serotonin depletion in LT animals only. Results suggest that transplanted tissue can either ameliorate or exacerbate locomotor changes produced by cortical ablation depending on the particular behavior and on when it is measured.

Effects of alcohol consumption on lateralized aggression in Anolis carolinensis.

Previous work has suggested that the lizard Anolis carolinensis, like many other reptiles, has a functionally split brain. Specifically, the left eye of this species projects primarily to the right hemisphere (and vice versa), there is no corpus callosum, and the physical placement of the eyes restricts their field(s) of vision to one region of hemispace. The current experiment used this preparation to examine the effect of alcohol administration and withdrawal on lateralized brain functioning during territorial aggression. Thirteen adult males were divided into control (CON) or alcohol (ETOH) groups. Baseline territorial aggression was assessed, following which ETOH subjects were then given twice daily solutions of 19% alcohol. After 19 days of ETOH consumption, territorial aggression was again assessed. Eye use during aggressive encounters was measured either following short periods (24 h) of alcohol withdrawal, or 90 m following alcohol consumption. Control subjects were found to have a predominance of left eye/right hemisphere-mediated aggressive responses, as has previously been reported. Alcohol withdrawn subjects were found to have a suppression of left eye/right hemisphere-mediated aggression. This reached statistical significance on several measures of aggression, including the number of dewlaps and headbob (P < 0.001) and the total number of aggressive responses (P = 0.001). Consumption of ETOH reversed this pattern and reinstated the normal pattern of left eye/right hemisphere dominance during aggression. Conversely, right eye/left hemisphere mediation of aggression was found to be increased, or not affected, during alcohol withdrawal, and to show no differences from CON following ETOH administration. Extrapolating from other recent findings in this species, these results suggest that the stress caused by ETOH withdrawal on the CNS may differentially effect the right hemisphere of the brain while having little effect on the left.

Vasomotor hyporeactivity in the anterior cerebral artery during motor activation in Huntington's disease patients.

This experiment used functional transcranial Doppler ultrasonography to demonstrate that blood flow velocity in the anterior cerebral artery is hyporeactive in Huntington's disease (HD) patients during maze testing (P<0.05). These vascular changes are due to tracing, as opposed to problem solving, components of the maze task. Using logistic regression, the reactivity of the ACA during activation is able to categorize patients as being either gene negative, or positive, for HD (P=0.0007). The possible role that nitric oxide/peroxynitrite may play in this phenomena is discussed.

Dorsal lesions of the prefrontal cortex: effects on alcohol consumption and subcortical monoaminergic systems.

Male Wistar rats were subjected to either bilateral aspiration lesions of the dorsal regions of the prefrontal cortex (PFC) or sham lesions and placed on a 6-week, modified sucrose-fading procedure. At the time of sacrifice, the size of the lesion, both in anterior-posterior and medial-lateral dimensions, was measured. Following sacrifice, levels of dopamine (DA), serotonin (5-HT), norepinephrine (NE), and their metabolites were measured in the midbrain (raphe) and nucleus accumbens (NA). Lesioned animals had reductions in 5-HT in the NA, and DA and NE in the raphe. The lesioned group drank more of a solution of 5% alcohol than controls early in the sucrose fading, and less during the later stages. In the lesioned group, the size of the left- and right-hemisphere lesions predicted 5-HIAA levels in the NA, and 5-HT and 5-HIAA levels in the raphe. A laterality effect was noted, such that the size of left-hemisphere lesions were positively associated with raphe 5-HT and 5-HIAA levels, and negatively associated with 5-HT levels in the NA, while right-hemisphere lesions showed the opposite relationships. In addition, the width of the left-hemisphere lesion predicted some measures of alcohol intake. These results suggest that, in the rat, the dorsal PFC is involved in the regulation of monoamines in subcortical regions known to be important in the regulation of reinforced behaviors, and that this regulation differs between hemispheres and shows a laterality effect. In addition, the dorsal PFC appears to have a subtle involvement in the regulation of alcohol intake.

Receptor characteristics and recovery of function following kainic acid lesions and fetal transplants of the striatum. I. Cholinergic systems.

The relationship between striatal muscarinic cholinergic receptor development and locomotor activity/T-maze alternation behavior in adult female rats with kainic acid lesions (kal) and fetal transplants of the striatum (str) was examined. Kal led to a number of deficits under conditions of spontaneous locomotion, including: (1) decreased stereotypical and increased horizontal movements during spontaneous overnight locomotion, (2) decreased spontaneous alternation on a T-maze, and (3) deficits on a sensorimotor neurological exam. Lesion-induced deficits following injection with cholinergic agonists (pilocarpine)/antagonists (scopolamine) included: (1) hypoactivity on vertical activity and stereotypical activity following scopolamine injection, and (2) increased stereotypical activity and decreased horizontal activity following pilocarpine injection. Transplants differentially affected the different types of behavioral deficits. Transplants reversed some of the deficits under conditions of spontaneous locomotion, including the hyperactivity noted during the night period, but only partially reversed the sensorimotor neurological exam and had no effect on spontaneous alternations in the T-maze. The transplants did not reverse the lesion-induced deficits following scopolamine injection, but partially reversed the lesion-induced changes in locomotion following pilocarpine injection. The striatal transplants had reduced numbers of M1 but increased numbers of M2 muscarinic cholinergic receptors. Cholinergic receptor density correlated with scores on the sensorimotor functioning and alternation tasks, but not with the locomotor measures. Conversely, the cross-sectional area of the str correlated strongly with the transplant-induced recovery in the lesion group. These results suggest that the development of cholinergic receptor systems within the transplants proceeds abnormally, and that the abnormal development of the transplant may impact on the transplant's ability to remediate lesion-induced deficits.

Behavioral recovery following kainic acid lesions and fetal implants of the striatum occurs independent of dopaminergic mechanisms.

Transplantation of fetal striatal tissue into rats with kainic acid lesions of the striatum reversed the spontaneous locomotor abnormalities caused by the lesions, but had no effect on the lesion-induced hyperactivity that followed amphetamine or apomorphine injection. Conversely, transplants into intact (non-lesioned) striatum led to abnormalities in spontaneous locomotion, but did not effect locomotion under amphetamine or apomorphine conditions. Dopamine autoradiography found a relative absence of dopamine receptors within the transplants. These results suggest that the mechanism which accounts for transplant-induced recovery of spontaneous locomotion is independent of striatal dopamine mechanisms.

Receptor characteristics and recovery of function following kainic acid lesions and fetal transplants of the striatum. II. Dopaminergic systems.

This experiment reports the development of striosomal-like patches in fetal striatal transplants grafted either into the intact, or kainic acid-lesioned, striatum of adult female rat brain. Although D2 receptor density approached control levels in the area of the patches, otherwise the transplanted striatum was relatively empty of dopamine receptors, and overall D2 development of the graft was strikingly reduced from controls. Transplants reversed lesion-induced hyperactivity under saline, but not amphetamine/apomorphine conditions, and led to an increased sensitivity of lesion and grafted animals following haloperidol injection. Transplants into the intact brain led to a lesion-like effect. M1 muscarinic cholinergic/D2 receptor density inversely correlated with behavior following amphetamine/apomorphine injections, while striatal cross-sectional area inversely correlated with activity after saline injection. These results suggest that abnormal maturation of the grafted striatum correlates with deficits in activity in grafted animals, and suggests that abnormal transplant development significantly impacts on transplant-induced behavioral changes.

Lateralized effects of ethanol on aggression and serotonergic systems in Anolis carolinensis.

The lateralized effects of ethanol (ETOH) upon behavior and monoamine biochemistry in the lizard, Anolis carolinensis, were examined. Eight adult male anoles consumed solutions of 19% ethanol (ETOH) twice daily over the course of 18 days, while controls consumed water. ETOH decreased the use of the left eye/right hemisphere, but not the right eye/left hemisphere, during territorial aggression (p<0.05). During crossover (i.e., ETOH to water and vice versa) this effect was reversible and replicable. Biochemically, an asymmetry was observed in 5-HT levels in the raphe both in ETOH and controls. ETOH increased levels of serotonin (5-HT; p<0.05), and 5-HIAA/5-HT ratios (p<0.05) in the raphe; serotonin levels in several brain regions correlated with aggressive responses. These results suggest that ETOH boosts 5-HT levels in animals subchronically exposed to ETOH. They further suggest that asymmetry in endogenous 5-HT systems may account for the asymmetrical regulation of aggression generally, and may explain the behavioral effects of ETOH upon lateralized aggression.

Anatomical predictors of behavioral recovery following fetal striatal transplants.

The ability of fetal striatal transplants to reverse behavioral deficits produced by kainic acid striatal lesions was assessed in adult female rats. Three groups of animals, including a lesion-only, a lesion and transplant, and a control group were assessed on several measures, including rewarded alternation, a sensorimotor neurological examination and on spontaneous locomotor activity. Anterior-medial striatal lesions led to a decreased performance on the rewarded alternation and sensorimotor neurological examination and caused the animals to be hyperactive in horizontal and stereotypical movements. The transplants partially reversed the rewarded alternation and locomotor deficits, but had little effect on the sensorimotor neurological deficit. Histologically, the transplanted fetal tissue survived well within the kainate-treated striatal region, and partially reversed the lesion-induced cell loss. Neuronal cell counts successfully predicted outcome on several of the behavioral measures, suggesting that the extent of behavioral recovery depends partially on quantitative aspects of the transplantation methodology.

Reduced activity and protein expression of NOS in R6/2 HD transgenic mice: effects of L-NAME on symptom progression.

Previous work found that dietary l-arginine alters symptom progression in mice transgenic for Huntington's disease (HD), and that cerebral blood flow (CBF) is abnormal in early stage HD patients. Both of these findings potentially implicate nitric oxide (NO) and its converting enzyme, nitric oxide synthase (NOS), in HD. The current experiment found that both NOS enzymatic activity and neuronal NOS (nNOS) protein expression were reduced (P<0.05) in R6/2 HD transgenic mice compared to non-HD controls (CON). Conversely, inducible NOS (iNOS) protein expression was not significantly different between groups. The changes in nNOS were accompanied by changes in protein expression of calmodulin kinase II (CaMKII) (P<0.05) and calmodulin kinase IV (CaMKIV) (P<0.05). Protein expression of 3-nitrotyrosine (3-NT), a marker for the neurotoxin peroxynitrite, was slightly increased in non-drug treated HD and was accompanied by increased immunostaining of 3-NT in cells adhering to the vasculature and choroid plexus. Mice that received the broad-spectrum NOS inhibitor N(g)-nitro-L-arginine methyl ester hydrochloride (L-NAME) via their drinking water had reduced NOS enzyme activity. NOS activity varied as a function of L-NAME dose, was virtually eliminated in the 500-mg/l groups, and correlated (P<0.05) with the behavioral scores as revealed by regression and correlation analyses. High dose L-NAME (500 mg/l) accelerated symptom onset in HD transgenics. These results support the hypothesis that nNOS activity and NO production are abnormal in HD, this in the setting of a more global dysregulation of calcium protein expression. Taken collectively with earlier data from our laboratory demonstrating abnormal CBF findings in early-stage HD patients, these results suggest that abnormalities in NOS function may significantly contribute to the neurodegeneration found in HD.

Dietary arginine alters time of symptom onset in Huntington's disease transgenic mice.

Recent neuroimaging studies reported complex changes in cerebral blood flow (CBF) in early-staged Huntington's disease (HD) patients. Deckel and co-workers [Deckel and Duffy, Brain Res. (in press); Deckel and Cohen, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 24 (2000) 193; Deckel et al., Neurology 51 (1998) 1576; Deckel et al., J. Nucl. Med. 41 (2000) 773] suggested that these findings might be accounted for, in part, by alterations in cerebral nitric oxide (NO) and its byproduct, peroxynitrite. The current experiment tested this hypothesis by altering NO levels via manipulations of dietary L-arginine (ARG), the dietary precursor of NO, in mice transgenic for HD. Seventy-one mice were assigned at 12 weeks of age to one of three isocaloric diets that varied in their content of ARG. These diets included: (a) 0% ARG, (b) 1.2% ARG (i.e. typical mouse chow), or (c) 5% ARG. The 5% ARG diets in HD mice accelerated the time of onset of body weight loss (P<0.05) and motor impairments (P<0.05), and increased resting CBF in HD relative to control (P<0.05). Conversely, the 0% ARG diet demonstrated no loss of body weight and had no changes in CBF relative to controls. However, the 0% ARG HD group continued to show significant deficits on motor testing (P<0. 05). The 1.2% ARG HD group showed reduced body weight loss, better motor functioning, and fewer changes in CBF compared to the 5% ARG HD group. Immunocytochemistry analysis found greater deposition of nitrotyrosine in the cortex, and vasculature, of HD+ mice, 5% and 1. 2%>0% arginine diets. When collapsed across all conditions, CBF inversely correlated (P<0.05) both with the body weight and motor changes suggesting that changes in CBF are associated with behavioral decline in HD mice. Collectively, these findings indicate that dietary consumption of the NO precursor ARG has a measurable, but complex, effect on symptom progression in HD transgenic mice, and implicates NO in the pathophysiology of HD.

Tests of executive functioning predict scores on the MacAndrew Alcoholism Scale.

1. Previous work reported that tests of executive functioning (EF) predict the risk of alcoholism in subject populations selected for a "high density" of a family history of alcoholism and/or the presence of sociopathic traits. The current experiment examined the ability of EF tests to predict the risk of alcoholism, as measured by the MacAndrew Alcoholism Scale (MAC), in outpatient subjects referred to a general neuropsychological testing service. 2. Sixty-eight male and female subjects referred for neuropsychological testing were assessed for their past drinking histories and administered the Wisconsin Card Sorting Test, the Wechsler Adult Intelligence Scale-Revised, the Trails (Part B) Test, and the MAC. Principal Components analysis (PCA) reduced the number of EF tests to two measures, including one that loaded on the WCST, and one that loaded on the Similarities, Picture Arrangement, and Trails tests. Multiple hierarchical regression first removed the variance from demographic variables, alcohol consumption, and verbal (i.e., Vocabulary) and non-verbal (i.e., Block Design) IQ, and then entered the executive functioning factors into the prediction of the MAC. 3. Seventy-six percent of the subjects were classified as either light, infrequent, or non-drinkers on the Quantity-Frequency-Variability scale. The factor derived from the WCST on PCA significantly added to the prediction of risk on the MAC (p = .0063), as did scores on Block Design (p = .033). Relatively more impaired scores on the WCST factor and Block Design were predictive of higher scores on the MAC. The other factors were not associated with MAC scores. 4. These results support the hypothesis that decrements in EF are associated with risk factors for alcoholism, even in populations where the density of alcoholic behaviors are not unusually high. When taken in conjunction with other findings, these results implicate EF test scores, and prefrontal brain functioning, in the neurobiology of the risk for alcoholism.

Increased CBF velocity during word fluency in Huntington's disease patients.

1. This study examined the effects of word fluency and reading on cerebral blood flow in Huntington's disease (HD) patients. 2. Changes in cerebral flow velocity in the anterior (ACA) and middle (MCA) cerebral arteries were measured with functional transcranial Doppler ultrasonography (fTCD) in 13 normal controls and 9 gene positive HD patients. To control for motor effects of word fluency, two "control" conditions, including silent word fluency and a reading test, were also administered to all subjects. 3. Cerebral blood flow velocity was increased during the out loud word fluency test in the ACA, but not MCA, in the HD group compared to controls. This increase was due to motor components of the test, as during silent word fluency the HD group had a decrease in cerebral blood flow relative to controls. Significant correlations between blood flow in the ACA and word fluency test scores were found. Cerebral blood flow velocity during testing also was able to predict group assignment (i.e., control vs. mild HD vs. moderate HD). 4. These findings add to a growing body of literature suggesting that CBF velocity in HD is abnormal during cognitive and motor tasks. Although previous work reported that CBF velocity in HD is decreased during hand use on a maze test, the current experiment finds that speech production increases cerebral blood flow velocity in HD patients. Collectively, these results point to a fundamental disturbance in the regulation of CBF in HD. Mechanisms that could account for these findings, including the potential involvement of nitric oxide, are discussed.

Anterior brain dysfunctioning as a risk factor in alcoholic behaviors.

This study assessed the relationship between neuropsychological and electrophysiological functioning and four alcohol-related measures: the Michigan Alcoholism Screening Test (MAST), the age at which the first drink was taken, frequency of drinking to "get high", and frequency of drinking to "get drunk". Ninety-one young adult men with no history of alcohol dependence were recruited. Subjects completed a variety of alcohol-related scales and a battery of neuropsychological tests. Resting EEG activity was also recorded. Stepwise regression analysis found that neuropsychological tests commonly regarded as measuring frontal and/or temporal neocortex functioning predicted the age at which subjects took their first drink and their scores on the MAST. Tests of frontal functioning, along with tests of memory, also predicted the frequency with which subjects reported drinking to "get drunk". Tests of memory also predicted the frequency at which subjects drank to "get high". On two of the alcohol measures, including age at which the first drink was taken and frequency of drinking to "get high", left-frontal slow alpha EEG activity was a significant predictor. These results suggest that markers of anterior brain functioning/dysfunctioning are associated with self-reports of alcohol-related behaviors, and that disturbances in the integrity of the anterior neocortex may be a risk factor in the development of alcohol-related behaviors.

Locomotor hyperactivity: effects of multiple striatal transplants in an animal model of Huntington's disease.

Huntington's disease is characterized by gross degeneration of the intrinsic neurons of the striatum, restless hyperkinetic choreiform movements and dementia. Rats which received injections of kainic acid have provided an extremely viable model for this extrapyramidal movement disorder. The present preliminary report investigated the effects of multiple homotopic transplantations of normal fetal Day 17 striatal ridge tissue into the lesioned striatum of male kainic acid-treated rats. Nine weeks after transplantation, the spontaneous nocturnal hyperkinetic locomotor abnormalities as measured by horizontal activity and total distance travelled were attenuated in the striatal transplanted animals compared to sciatic nerve transplanted controls. Similarly, the exacerbated response to d-amphetamine exhibited by the animal model was attenuated in the striatal transplanted animals. The striatal transplants reconstructed much of the gross morphology of the lesioned striatum, although acetylcholinesterase was found to be reduced.

Evidence of a neurologically based "denial of illness" in patients with Huntington's disease.

Patients diagnosed with Huntington's Disease (HD) commonly show a denial of symptoms and an unawareness of the motoric, cognitive, and emotional changes that accompany this disease. To examine if this denial has a neurological component to it, 19 patients who received a positive diagnosis of HD from the presymptomatic HD clinic at the University of Connecticut Medical School, and 14 consecutive patients referred for neuropsychological testing with nonHD diagnoses, were administered a simple, eight-item self-report test that asked them to rate their cognitive and motoric abilities. Two staff members, both of whom met with the patients and were familiar with the neuropsychological test results, similarly rated the patients' deficits. HD patients were then divided into "high" (HA) vs. "low" (LA) anosognosia groups based on differences between their self-ratings and staff ratings, and given a neuropsychological battery. Correlation's between the two investigators found that the eight-item scale was highly reliable across investigators (R =.89). HD patients were significantly different from controls in their self-rating of their own capabilities in comparison to staff ratings (p <.05). ANOVA found the HA HD patients to be impaired relative to the LA HD group on a number of neuropsychological measures, including the Wisconsin Card Sorting Test and various measures pertaining to visual-spatial ability on the Wechsler Adult Intelligence Scale-Revised. These findings suggest that a component of the "illness denial" that HD patients exhibit, and that traditionally have been attributed to "psychodynamic" factors, likely have a neurological component to them. Implications of these findings for teams who are preparing to provide anosognostic HD patients with positive results regarding their HD workup is discussed.