Absence of an apolipoprotein E epsilon4 allele is associated with increased parietal regional cerebral blood flow asymmetry in Alzheimer disease.

BACKGROUND: The apolipoprotein E (Apo E) epsilon4 allele has been associated with parietal metabolic abnormalities and asymmetries in asymptomatic subjects at risk for Alzheimer disease (AD). However, previous research has shown minimal effect of the epsilon4 allele on regional cerebral blood flow (rCBF) and metabolism in patients with probable AD. OBJECTIVE: To determine whether the Apo E epsilon4 allele is associated with parietal rCBF abnormalities and asymmetries in patients with probable AD. PATIENTS AND METHODS: Thirty patients with AD with the epsilon4 allele (epsilon4+ AD), 22 patients with AD without the epsilon4 allele (epsilon4- AD), and 14 healthy control subjects underwent single-photon emission computed tomography (SPECT) scanning with 740 MBq technetium Tc 99m hexamethylpropyleneamine oxime. Ratios of parietal-unaffected regions and a left-right parietal asymmetry index were compared between both patient groups. RESULTS: The group with epsilon4- AD was younger (P = .005, Student t test) and had an earlier age of onset (P = .005) than the group with epsilon4+ AD. Analysis of covariance revealed no significant difference in the parietal rCBF ratio, controlling for age of onset and Mini-Mental State Examination score (F(1,48) = 0.06; P = .81). However, contrary to hypothesis, significantly greater parietal rCBF asymmetry was seen in patients with epsilon4- AD (mean +/- SD, 9.7% +/- 5.5%) than those with epsilon4+ AD (6.3% +/- 4.7%; F(1,50) = 5.89; P = .02; analysis of variance). When number of epsilon4 allele copies was considered, this effect appeared to accrue primarily from a difference between patients with 0 and with 2 epsilon4 allele copies. An exploratory analysis of multiple cortical structures suggested that this asymmetry extended to additional regions (superior temporal) and to combined association cortex. CONCLUSIONS: Greater parietal rCBF asymmetry is involved in epsilon4- AD than in epsilon4+ AD. Lack of the epsilon4 allele may be associated with other (as yet undiscovered) genetic or environmental risk factors, which confer greater neuropathological asymmetry.

Comparison of the smooth eye tracking disorder of schizophrenics with that of nonhuman primates with specific brain lesions.

The smooth pursuit eye tracking deficit (ETD) often associated with schizophrenia has generated enormous interest over the last 20 years. The deficit is observed in about 80% of schizophrenics and in half of their first degree relatives. It is not affected by neuroleptic medication and is not due to inattention. A review of 52 studies (and actual records when available) on ETD in schizophrenia reveals that the deficit can consistently be described as low gain pursuit augmented with catch-up saccades and often peppered with intrusive saccades. A review of the brain areas that have been shown to be involved in pursuit provides the necessary background for the subsequent section which details the nature of the smooth tracking deficits following experimental lesions. This section reveals that the ETD following lesions of the frontal lobe is unique in that it closely resembles the ETD of schizophrenics. This finding lends further support for frontal lobe theories of schizophrenia.

Neural responses related to smooth-pursuit eye movements and their correspondence with electrically elicited smooth eye movements in the primate frontal eye field.

1. Intracortical microstimulation of a portion of the monkey frontal eye field (FEF) lying in the floor and posterior bank of the arcuate sulcus evokes smooth, rather than saccadic eye movements. To further explore this region's involvement in pursuit, we recorded from FEF neurons in the vicinity of sites from which smooth eye movements (SEMs) were elicited electrically and studied their responses during smooth-pursuit and saccadic tasks. In this report, we describe the neurons' responses during visually guided smooth pursuit and compare their locations and response properties with those of elicited SEMs. 2. One hundred and ninety-three neurons, recorded from the FEF region in six hemispheres of three rhesus monkeys, were classified as "pursuit neurons". These neurons responded during smooth-pursuit tracking of moving visual stimuli but had no, or only minimal, responses in conjunction with visually guided saccades. Pursuit neurons were located in a small region of the arcuate fundus and posterior bank that overlapped, and extended slightly beyond, the region from which SEMs were elicited with microstimulation. 3. All pursuit neurons had a preferred pursuit direction, and all directions were represented with no strong bias toward ipsilateral, contralateral, up, or down. The directional tuning of 80 pursuit cells was measured quantitatively by testing pursuit in several directions and fitting the responses to a Gaussian function. Tuning indices (the sigma parameter of the Gaussian fit) varied between 13 degrees and 136 degrees. The median tuning index, 44.5 degrees, corresponds to a full width at half maximum of 105 degrees. The ubiquity of selectivity for pursuit direction and the wide distribution of preferred directions indicates that pursuit direction uses a place-code type of representation in FEF; however, the broad directional tuning of most neurons suggests that pursuit direction is given by a weighted average of optimal directions across the population of pursuit neurons active at any given time. 4. In general, the responses of pursuit neurons increased with pursuit velocity. Of 13 neurons formally tested with 2 s of constant-velocity tracking in their preferred direction across a range of target speeds, pursuit velocity sensitivity ranged from 0.24 to 1.42 spikes.s-1.deg-1.s-1, with an average sensitivity of 0.70. This relationship suggests that pursuit neurons represent pursuit magnitude using a rate code; this parallels our previous observation that at most SEM sites, the velocity and acceleration of the electrically elicited eye movements increased as a function of the stimulation current.(ABSTRACT TRUNCATED AT 400 WORDS)

Smooth eye movements elicited by microstimulation in the primate frontal eye field.

1. We electrically stimulated the macaque monkey's frontal eye field (FEF) region to localize and to analyze the smooth pursuit eye movement representation. Rhesus monkeys were trained to fixate stationary spots of light, and trains of stimulation (usually 250-500 ms at 10-100 microA) were applied while the fixation targets remained lit and stationary. This paradigm was used in a total of 485 electrode penetrations through the arcuate sulcus region of six hemispheres in three adult monkeys. Smooth eye movements (SEMs), clearly distinct from saccades, were elicited at 86 sites in 53 of these penetrations. These SEMs had an average peak velocity of 11 degrees/s and an average latency of 39 ms. 2. The initial acceleration and peak velocity of elicited SEMs increased with stimulation intensity at any given site. On the other hand, SEM direction was characteristic of a given stimulation site and did not vary with stimulation intensity. These findings indicate that SEM amplitude is coded by the intensity of neural activity, and SEM direction is coded by the location of this activity within the cortex ("rate" vs. "place" codes). 3. SEMs elicited in the presence of a stationary fixation target (closed-loop conditions) typically reached a plateau velocity early in the stimulation and maintained that velocity throughout most of the stimulation train. However, when retinal slip was eliminated by artificially stabilizing the fixation target on the fovea (open-loop conditions), the electrical stimulation caused the eye to accelerate for longer periods and to attain higher velocities than in the closed-loop condition. Eye velocities obtained at the same site in open- and closed-loop conditions diverged from one another approximately 100 ms after SEM onset, consistent with the visual latency of the pursuit system. These findings suggest that the FEF primarily conveys an eye acceleration signal, rather than an eye velocity goal, to the pursuit system, and that this signal can be affected by visual retinal errors before effecting the smooth eye movements. 4. SEMs were elicited from a small portion of the arcuate fundus and neighboring posterior bank lying directly posterior to the principal sulcus. Functionally, this SEM region was surrounded by the saccadic FEF and by somatic premotor cortex. 5. Even though ipsilateral, contralateral, and vertical SEMs were elicited, the distribution of SEM directions was skewed toward ipsilateral movements. This tendency was more pronounced for sites in the arcuate fundus, whereas SEMs elicited from the posterior arcuate bank were often directed contralaterally and vertically.(ABSTRACT TRUNCATED AT 400 WORDS)

Smooth-pursuit eye movement representation in the primate frontal eye field.

Physiological and behavioral data reported here show an involvement of the primate frontal eye field (FEF) cortex in smooth-pursuit eye movements, in addition to its well-established role in saccadic eye movements. Microstimulation just ventral to the small saccade representation of the FEF elicits eye movements that, in contrast to elicited saccades, have low velocities, continue smoothly without interruption during prolonged stimulation, and are usually directed ipsilaterally to the stimulated hemisphere. Neurons in this region respond in association with smooth-pursuit eye movements and visual motion. Tracking deficits following experimental lesions of the FEF depend critically upon the status of this ventral region: superficial lesions sparing it leave smooth-pursuit eye movements intact, whereas lesions removing it produce substantial deficits in the anticipatory initiation, motion-induced acceleration, asymptotic velocity, and predictive continuation of ipsilateral smooth pursuit.

Rearing cats with eyelid suture has both early and late effects on cells in the lateral geniculate nucleus.

We have assessed the effects of duration of infant-onset deprivation, and therefore the age of the subject at the time of data collection, on the physiology and morphology of cells in the lateral geniculate nucleus (LGN) of cats. Twenty-two kittens underwent lid suture. Electrophysiological experiments were performed in 12 of these subjects when they were between 5 and 16 months of age. The remaining 10 cats were studied between 17 and 29 months. In 16 of these same subjects we also measured LGN soma sizes to permit a direct within-subject comparison of the morphological and physiological effects of lid suture. Physiological data from cats recorded before 17 months of age showed a reduction in the encounter rate of Y-cells in deprived LGN laminae. In contrast, none of the cats which were 17 months or older at the time of recording showed a reduction in the encounter rate of deprived Y cells, giving the appearance of a more normal X/Y-cell ratio. Preliminary observations suggest that these late changes in the physiological effects of deprivation are not due to a recovery of Y-cells, but are more likely due to the superimposition of a reduction in the encounter rate for X-cells known to be typical of a variety of adult-onset deprivations. Finally, the physiological and morphological differences between non-deprived and deprived LGN laminae are correlated for the individual subjects.

Compulsory treatment of alcoholism: the case against.

The need for compulsory detention in the management of alcohol-dependent persons is reviewed with a particular focus on legislation in New South Wales (NSW). It is argued that there is no justification for the severe loss of civil liberties in order to provide a general power of involuntary alcoholism treatment since such treatment is basically ineffective and in any case little treatment is actually given to those detained. The selective operation of the NSW Inebriates Act (in terms of class and race biases) is noted. The special circumstances of those who suffer severe alcohol-related brain damage and those who are in acute life-threatening circumstances are discussed. It is suggested that these cases are adequately covered by existing Mental Health and Guardianship legislation, obviating the need for special legislation such as an Inebriates Act.

Divided attention performance in cannabis users and non-users following alcohol and cannabis separately and in combination.

The effect of delta 9-tetrahydrocannabinol (delta 9-THC) and alcohol, singly and in combination, on divided attention performance was investigated in cannabis users and non-users who were matched for alcohol use. Both cannabis and alcohol produced decrements in central and peripheral signal detections. Drug and alcohol effects were greater for signal presentations in the periphery. Cannabis users were less impaired in peripheral signal detection than non-users while intoxicated by cannabis and/or alcohol. These findings suggest the development of tolerance and cross-tolerance in regular cannabis users and/or the ability to compensate for intoxication effects.

The development of cell size in the dorsal lateral geniculate nucleus of monocularly paralyzed cats.

Nissl profiles of cell somata in the lateral geniculate nuclei (LGN) of adult cats which had been reared from 3 to 4 weeks of age with monocular paralysis (MP) were compared to those from normally reared adult cats. In all subjects, measurements were made in 3 different regions of the binocular segments of the A and A1 laminae and in the monocular segment in both LGNs. In the cats reared with MP, reductions in average cell size of about 20%, relative to normal, were detected throughout the binocular segments of the A and A1 laminae in both LGNs whether their innervation was provided by the paralyzed or mobile eye. There were no detectable effects in the monocular segments. These results are discussed in comparison to the morphological effects of other rearing procedures, particularly strabismus and monocular deprivation.

Interhemispheric connections of cortical sensory areas in tree shrews.

Interhemispheric connections were studied in tree shrews (Tupaia belangeri) after multiple injections of horseradish peroxidase or horseradish peroxidase conjugated to wheat germ agglutinin into the cortex of one cerebral hemisphere. After an appropriate survival period, the areal pattern of connections was revealed by flattening the other hemisphere, cutting sections parallel to the cortical surface, and staining with tetramethylbenzidine. Architectonic boundaries were identified by using sections stained for myelinated fibers. Labeled cells and axon terminations formed largely overlapping distributions that covaried in density, although labeled cells appeared to be more evenly distributed than labeled terminations. Connections were concentrated along the border of area 17 (V-I) with area 18 (V-II). However, connections also extended as far as 2 mm into area 17 to include cortex representing parts of the visual field 10 degrees or more from the zero vertical meridian. Clusters of dense connections spanned the width of area 18, where they alternated with regions of fewer connections. These clusters roughly corresponded in location to regions with heavier myelination. In the visually responsive temporal cortex, connections were also unevenly distributed. The organization of most of this cortex is not understood, but one subdivision, the temporal dorsal area (TD), has been identified on the basis of reciprocal connections with area 17. The central part of the TD had few interhemispheric connections, while most of the outer border had dense connections. The auditory cortex had dense and patchy connections throughout. The pattern in the primary somatosensory cortex (S-I) varied according to the representation of body parts, so that the cortex related to the forepaw had sparse connections, while connections were dense but uneven over much of the representation of the face, nose, and mouth. A focus of connections was found at the border of the forepaw and face representations, where the myelination of S-I cortex is interrupted. Dense, uneven connections also characterized the second somatosensory area, S-II. The motor cortex was densely connected, with only slightly fewer terminations rostral to the forepaw region of S-I. Other parts of frontal cortex had dense connections. The distribution of cortical connections varied with depth for at least some areas, so that clusters of cells and terminations were found in supragranular layers in S-I, S-II, and TD, while infragranular labeled cells were more evenly distributed.(ABSTRACT TRUNCATED AT 400 WORDS)

The shift in X/Y ratio after chronic monocular paralysis: a binocularly mediated, barbiturate-sensitive effect in the adult lateral geniculate nucleus.

Adult-onset stimulus modifications, such as monocular paralysis, alter the physiology of the lateral geniculate nucleus (LGN), reducing the encounter rate for X-latency cells in all of the principal layers of both LGNs whether the innervating eye is paralyzed or mobile. These reductions in encounter rate for X-latency cells are confined to those portions of the LGN representing central binocular visual space and are sensitive to the level of anesthesia in that, while these effects are evident in subjects sedated during recording, no such reductions are found when subjects are anesthetized with sodium pentobarbital during recording. Finally, conduction velocity and receptive field classification data from these experiments confirm, as the shifts in OX latency distributions would indicate, that chronic monocular paralysis does have a selective impact upon the recordability of LGN X-cells. These observations together with earlier ones involving monocular paralysis suggest that this adult-onset modification reduces the encounter rate for X-cells by disrupting a binocular mechanism which controls the relative excitability of X- and Y-cells which represent central visual space.

Sensitivity of the mature lateral geniculate nucleus to components of monocular paralysis.

Immobilization of the globe by tenotomization of the extrinsic muscles of one eye reduces the encounter rate for X-latency cells in the contralateral dorsal lateral geniculate nucleus (LGN) of adult cats. The reduction in the relative encounter rate for X-latency cells after tenotomy was comparable to that previously observed in the adult cat following concurrent paralysis of the extrinsic and intrinsic muscles of one eye by transection of cranial nerves III, IV, and VI. Paralysis of the intrinsic muscles alone by atropinization, on the other hand, had no detectable effect upon this aspect of LGN physiology. It appears, therefore, that monocular paralysis by cranial nerve section has its effects on LGN X-latency cells through its paralysis of the extrinsic eye muscles. Furthermore, the reduction in the relative encounter rate for X-latency cells produced by tenotomy occurred in spite of early, incomplete return of mobility of the globe. Thus, unilaterally diminished mobility of the globe, in contrast to the complete, sustained immobility characteristic of monocular praralysis, appears sufficient to alter this aspect of LGN physiology in adult cats. The general observation that sensory modifications, in the adult cat, are capable of inducing shifts in the relative recording probabilities for X- and Y-latency cells in the LGN has been repeatedly made. Further, recent, independent observations have provided confirmation for the phenomenon of X/Y ratio shifts in the LGN following adult-onset stimulus modification.

Divided attention performance of cannabis users and non-users following cannabis and alcohol.

The effects of delta9-tetrahydrocannabinol (delta9-THC) and alcohol, and their combination, on divided attention performance were compared for cannabis users and non-users of both sexes. Performance by all subjects was significantly impaired following 2.6 and 5.2 mg delta9-THC but not at blood alcohol concentrations of 48 and 96 mg/100 ml. The combined effect of the 2 drugs depended upon prior experience with cannabis. A synergistic action occurred in non-users while an antagonistic effect occurred in the group of users. Differences in the alcohol effects between users and non-users provided evidence of cross-tolerance between cannabis and alcohol.