The Huntington's Disease health-related Quality of Life questionnaire (HDQoL): a disease-specific measure of health-related quality of life.

Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by motor, cognitive and psychiatric disturbances, and yet there is no disease-specific patient-reported health-related quality of life outcome measure for patients. Our aim was to develop and validate such an instrument, i.e. the Huntington's Disease health-related Quality of Life questionnaire (HDQoL), to capture the true impact of living with this disease. Semi-structured interviews were conducted with the full spectrum of people living with HD, to form a pool of items, which were then examined in a larger sample prior to data-driven item reduction. We provide the statistical basis for the extraction of three different sets of scales from the HDQoL, and present validation and psychometric data on these scales using a sample of 152 participants living with HD. These new patient-derived scales provide promising patient-reported outcome measures for HD.

Spatial memory impairment in rats with fornix transection is not accompanied by a simple encoding deficit for directions of objects in visual space.

In Experiment 1, rats learned 6 discriminations among pairs of complex wide-angle visual displays, presented concurrently, using a computer-controlled Y maze. Fornix-transected rats were unimpaired relative to controls regardless of whether the displays comprised a single large "objectlike" figure or "scenelike" arrays of spatially distributed figures. Experiment 2 compared 2 versions of a visual discrimination in which either object identity (independent of location within the visual field) or location within the visual field (independent of object identity) had to be used. The fornix-transected rats performed normally with either cue. In Experiment 3, however, the same group was clearly impaired on a standard spatial memory test, spatial delayed nonmatching to sample. Although the fornix-transected rats were more likely to choose rapidly and inaccurately, their deficit was not a by-product of impulsive responding. The spatial impairment was not merely a difficulty in encoding direction of a single item within visual space, but more complex configural deficits could not be ruled out.

The role of perirhinal cortex in visual discrimination learning for visual secondary reinforcement in rats.

Perirhinal cortex in monkeys has been thought to be involved in visual associative learning. The authors examined rats' ability to make associations between visual stimuli in a visual secondary reinforcement task. Rats learned 2-choice visual discriminations for secondary visual reinforcement. They showed significant learning of discriminations before any primary reinforcement. Following bilateral perirhinal cortex lesions, rats continued to learn visual discriminations for visual secondary reinforcement at the same rate as before surgery. Thus, this study does not support a critical role of perirhinal cortex in learning for visual secondary reinforcement. Contrasting this result with other positive results, the authors suggest that the role of perirhinal cortex is in "within-object" associations and that it plays a much lesser role in stimulus-stimulus associations between objects.

Perirhinal cortex ablation in rats selectively impairs object identification in a simultaneous visual comparison task.

In Experiment 1, rats discriminated among computer-generated visual displays (scenes) comprising 3 different shapes (objects). One constant scene (unrewarded) appeared on every trial together with a trial-unique variable scene (rewarded). Four types of variable scene were intermingled: (a) unfamiliar objects in different positions from the constant; (b) unfamiliar objects in same positions as the constant; (c) same objects as the constant in different positions; (d) same objects and positions, recombined. Aspiration lesions of perirhinal cortex impaired performance with type (b) only. Experiment 2 tested spatial delayed nonmatching-to-sample. The perirhinal group were impaired nonsignificantly, and less than fornix-transected rats in an earlier study. Rats' perirhinal cortex, like monkeys', subserves object identification in the absence of memory requirement but does not contribute substantially to hippocampal system spatial memory function.

Anterior rhinal cortex and amygdala: dissociation of their contributions to memory and food preference in rhesus monkeys.

Rhesus monkeys were trained on 2 versions of delayed nonmatching-to-sample, one with multiple pairs of objects and the other with a single pair, to evaluate their ability to remember objects. They then received either bilateral aspiration lesions of the anterior rhinal cortex or bilateral excitotoxic lesions of the amygdala, or were retained as unoperated controls. On re-presentation of the multiple-pair task, monkeys with anterior rhinal cortex lesions failed to show the improvement observed in both other groups in remembering the objects over delay intervals ranging from 10 to 60 s. Also, monkeys with anterior rhinal cortex lesions were impaired relative to the controls in relearning the single-pair version of the task. Conversely, on a formal test of food preference, monkeys with amygdala lesions showed abnormal patterns of food choice, whereas monkeys with anterior rhinal cortex lesions did not. Visual memory impairments formerly attributed to amygdala damage are probably due to the rhinal cortex damage associated with aspiration lesions of the amygdala.

Objects and positions in visual scenes: effects of perirhinal and postrhinal cortex lesions in the rat.

The authors assessed rats' encoding of the appearance or egocentric position of objects within visual scenes containing 3 objects (Experiment 1) or 1 object (Experiment 2A). Experiment 2B assessed encoding of the shape and fill pattern of single objects, and encoding of configurations (object + position, shape + fill). All were assessed by testing rats' ability to discriminate changes from familiar scenes (constant-negative paradigm). Perirhinal cortex lesions impaired encoding of objects and their shape; postrhinal cortex lesions impaired encoding of egocentric position, but the effect may have been partly due to entorhinal involvement. Neither lesioned group was impaired in detecting configural change. In Experiment 1, both lesion groups were impaired in detecting small changes in relative position of the 3 objects, suggesting that more sensitive tests might reveal configural encoding deficits.

Rats with hippocampal lesions learn about allocentric place cues in a non-navigational task.

Hippocampal-lesioned rats (HPC) and sham controls (SH) learned constant-negative visual discriminations among scenes in a Y-maze. Any arm could be start arm for a trial. Two choice scenes ("constant" and "variable") were shown in the other arms. In Experiment 1, each problem had 2 constants. One or the other constant appeared on every trial, and the variable changed every trial; choosing the variable was rewarded. There were 4 problem types. Each constant might be always in a given direction from the start arm (added egocentric [Ego] cue), always in a given maze arm (added allocentric [Allo] cue), both, or neither. SH rats' visual learning was enhanced by Ego and by Allo cues. HPC rats' visual learning was enhanced by Ego cues, and by Allo cues, but only if there was no Ego cue. Experiment 2 confirmed that Allo cues helped HPC rats as much as SH, in the absence of Ego cues. Rats with HPC lesions can learn about allocentric place cues when navigation and idiothetic cue control are not required.

A computer-controlled maze environment for testing visual memory in the rat.

A computer-controlled version of a Y-maze was developed to allow automated testing of rats' learning and memory with visual stimuli. Each of the 3 arms terminated with 2 adjacent monochromatic screens, 43 cm from the maze centre, providing a total stimulus area 47 cm wide by 18.5 cm high. The displays were abstract patterns extending across 2 screens, generated by algorithms which provided a large pool of discriminable patterns. The patterns used were of 2 general classes: Scenes (internally complex patterns with varying numbers of foreground shapes distributed across contrasted backgrounds) and Objects (internally homogeneous single figures, confined to the central part of the display). They could be stationary or have oscillatory movement. Subjects' location in the maze was monitored by infrared beam photodetectors; approach to correct patterns was rewarded with food. Pigmented rats of the Hooded Lister and Dark Agouti strains were tested. All could acquire 2-pair concurrent visual discriminations comprising 2 positive and 2 negative patterns, either Scenes or Objects; most could acquire 4-pair discriminations. Dark Agouti rats generally performed better than Hooded Listers. A novel training procedure using one positive and many negative patterns resulted in rapid learning of novel discriminations with either moving or non-moving patterns. The apparatus is an effective environment for visual learning by rats, suitable for a wide range of tasks in neuropsychology and psychopharmacology.

Elemental and configural visual discrimination learning following lesions to perirhinal cortex in the rat.

Rats were tested in a series of two-choice visual discrimination tasks in a computer-controlled testing apparatus. The discriminations used a range of discriminanda, which varied in complexity. The discriminations included relatively simple form discriminations, more complex form discriminations and discriminations between compound stimuli that shared many features. It was found that rats with perirhinal cortex lesions were unimpaired in all discriminations except those that involved the compound stimuli with overlapping features. Using these stimuli, rats with perirhinal cortex lesions were unimpaired when the stage of learning did not necessitate discriminating stimuli on the basis of more than one feature. However, when efficient performance of the task needed the configuration of more than one feature to be taken into account, perirhinal lesioned rats were impaired. These results are interpreted as revealing the role of the perirhinal cortex in providing multifeature information about the properties of visual objects.

Rats' processing of visual scenes: effects of lesions to fornix, anterior thalamus, mamillary nuclei or the retrohippocampal region.

We analysed the effects of lesions of hippocampal-diencephalic projections -- fornix (FX) mamillary bodies (MB) and anterior thalamic nuclei (AT) -- and retrohippocampal (RH) lesions including entorhinal cortex and ventral subiculum, upon scene processing. All lesions except FX were neurotoxic. Rats learned to discriminate among computer-generated visual displays ("scenes") each comprising three different shapes ("objects"). The paradigm was constant-negative; one constant scene (unrewarded) appeared on every trial together with a trial-unique variable scene (rewarded). Four types of variable scene were intermingled: (1) unfamiliar objects in different positions from those of the constant (type O+P), (2) unfamiliar objects in same positions as in the constant (type O), (3) same objects as the constant in different positions (type P), (4) same objects and positions as the constant but recombined (type X). Group RH performed like controls while groups FX, AT and MB showed (surprisingly) enhanced performance on types X and O. One explanation is that normal rats attempt to process all objects in a scene concurrently, while hippocampal-projection lesions disrupt this tendency, producing a narrower attention, which paradoxically aids performance with some variable types. The results confirm that the entorhinal cortex has a different function from other components of the hippocampal system.

Configural learning without configural training.

Rats learned discriminations in which 2 familiar compound visual stimuli AB and CD were nonreinforced, whereas less-familiar compounds (EF, GH, IJ...) were reinforced (constant-negative paradigm). Such discriminations can in principle be acquired through elemental (nonconfigural) learning. Three different types of compound--object/object, object/position, and shape/fill-pattern--were used, and the number of familiar compounds extended to 3 or 4. In all cases, when rats were tested for the first time with previously unseen recombinations of the familiar elements--for example, AC, BD--they preferred these to the familiar compounds, implying that they had encoded configural information during the original training. Moreover, preference remained constant despite extended exposure to configural training in the test phase. The findings extend the evidence that configural representations are formed independently of explicit configural training.

Researcher allegiance and meta-analysis: the case of cognitive therapy for depression.

K. S. Dobson (1989) conducted a meta-analysis of 28 studies of cognitive-behavioral therapy for depression that used the Beck Depression Inventory as outcome measure. He concluded that the outcome of this type of therapy was superior to that of other forms of psychotherapy and to that of pharmacotherapy. The present study reanalyzed the same studies, and a further set of 37 similar ones published from 1987 to 1994, taking into account variations in sample size and researcher allegiance. This study confirmed Dobson's conclusions for his original sample but showed that about half the difference between CT and other treatments was predictable from researcher allegiance. However, comparable analyses of the later set of studies showed no effect of researcher allegiance. Two causes for these phenomena are (a) a historical effect, whereby both effect sizes and allegiance were large in earlier years and declined over time and (b) a treatment effect whereby effect size and allegiance were correlated, but more for some treatments than others. This correlation has also weakened over time.

The performance of postencephalitic amnesic subjects on two behavioural tests of memory: concurrent discrimination learning and delayed matching-to-sample.

The performance of a group of three postencephalitic subjects with anterograde amnesia was examined on a series of concurrent visual discrimination problems and on a test of visual recognition, delayed matching-to-sample. These tests were chosen as they have been used to assess experimental models of anterograde amnesia in nonhuman primates. In comparison with a group of normal subjects the postencephalitic group were impaired on the more difficult concurrent discrimination problems. They also performed poorly on the matching-to-sample task when given lists of items to remember or given increased retention intervals. The pattern of performance of the postencephalitic group matched closely that of a group of Korsakoff subjects, indicating that these behavioural tests are equally sensitive to different types of anterograde amnesia.

Concurrent and sequential pattern discrimination learning by patients with Korsakoff amnesia.

Patients with Korsakoff's syndrome and alcoholic controls learned to discriminate sets of pairs of patterns presented concurrently, in order to test predictions based on monkeys' performance in similar tasks following medial temporal or diencephalic lesions. In Experiment 1 the subjects learned a 2-pair, a 6-pair and a 10-pair set; the Korsakoff group were impaired on the first and last, but not on the second set. In Experiment 2, the same subjects learned single pairs sequentially, and 2-pair and 8-pair sets concurrently. The effect of 2 types of feedback for correct responses (visual or non-visual) was also compared. The Korsakoff patients were markedly poorer than controls under all conditions; the type of feedback made little difference. In several respects the patients' impairment differed from what had been predicted from the animal experiments.

A novel test of visual learning in the rat: effects of 8 -OH-DPAT and WAY-100579.

The 5-HT(1A) agonist 8-OH-DPATand the 5-HT(3) antagonist WAY-100579 were tested in a novel computerized visual learning task. Since rats show substantial learning of new problems within each single session, drug effects on new learning could be compared within subjects. Both the reaction time (RT) and choice accuracy were measured. A dose of 0.3 mg/kg of 8-OH-DPAT lengthened the RTs while 0.1 mg/kg of 8-OH-DPAT and 0.1 mg/kg of WAY-100579 shortened the RTs. In the absence of drugs, accuracy was independent of the RT for RTs > 1.5 s. Therefore, in order to unconfound the drug effects on accuracy from motor effects, only responses with longer RTs were analysed. Both 0.3 and 0.1 mg/kg of 8-OH-DPAT and 0.1 mg/kg of WAY-100579 significantly impaired accuracy, though some learning was seen in all cases. These findings may have implications for animal models of Alzheimer's disease.

Fear of water in children and adults: etiology and familial effects.

Water-fearful children (non-swimmers. 5-8 yrs and adults (non-swimmers or late learners, 23-73 yr) were compared with non-fearful controls of similar swimming ability. Parallel assessments were carried out with children and adults to investigate water-related experiences, water fear and competence in parents and siblings, and the relationship of water fear to other fear dimensions. Children were assessed behaviorally and by self and mother's report, adults by self-report. In neither children nor adults was there clear evidence that fearful and non-fearful groups differed in incidence of aversive water-related experience before fear onset. Parents usually believed that children's fear was present at first contact. In both samples, we found parent-offspring and sibling resemblances in fear. Analysis of details of children's contact with parents suggested that social learning within the family decreased water fear rather than increasing it; when both child and parent showed fear, that was as likely to reflect genetic influences as modeling. Young children's water fear forms part of a generic cluster, fear of the Unknown or Danger, while in adults it becomes independent of generic fears.

Behavioural effects of long-term multi-sensory stimulation.

OBJECTIVES: Regular access to a multi-sensory environment (MSE or Snoezelen room) was compared with a non-complex sensory environment for individuals with learning disabilities. We also tested the prediction that those individuals whose challenging behaviour was maintained by sensory consequences would benefit most from exposure to the MSE. DESIGN: The conditions were compared over 16-week periods using a double crossover design, and were matched for social contact and attention from the enabler. Participants were randomly assigned to orders of treatments. METHODS: Participants were 27 adults with severe/profound learning disabilities who exhibited challenging behaviour. Behaviour was assessed before and after each treatment phase using both direct observation and standardized assessments (the Functional Performance Record and the Problem Behaviour Inventory). The behavioural observations formed the basis of a functional analysis of each individual's challenging behaviour. RESULTS: Some participants became more calm and relaxed while in the MSE, however, the objective measures of behaviour outside the treatment settings revealed no difference between the MSE and control conditions. Challenging behaviour maintained by sensory consequences showed no greater responsivity to the MSE than to the control condition. CONCLUSIONS: The multi-sensory environment had no effects beyond those that could be ascribed to the social interaction between participant and enabler. Anecdotal evidence of favourable responses within the MSE itself could not be confirmed outside the environment.

Experimental functional analyses for challenging behavior: a study of validity and reliability.

The convergent validity of an experimental (analog) functional analysis was investigated by a comparison of three separate ways of interpreting the data derived from such an assessment: two previously published methods and the criterion Z method derived by the authors. Data from the experimental functional analysis of the challenging behavior(s) of 27 individuals with intellectual disabilities were analyzed to assess agreement between the three forms of interpretation. The test-retest reliability of all three methods over periods of 2 weeks, 1 month, and 3 months was also calculated. The results suggest that the methods of interpreting function from experimental assessments can give different results and that the test-retest reliability of the experimental functional analyses is poor. The implications of these findings are discussed in relation to clinical practice.

Health-related quality of life in Huntington's disease patients: a comparison of proxy assessment and patient self-rating using the disease-specific Huntington's disease health-related quality of life questionnaire (HDQoL).

Huntington's disease (HD) is a fatal, neurodegenerative disease for which there is no known cure. Proxy evaluation is relevant for HD as its manifestation might limit the ability of persons to report their health-related quality of life (HrQoL). This study explored patient-proxy ratings of HrQoL of persons at different stages of HD, and examined factors that may affect proxy ratings. A total of 105 patient-proxy pairs completed the Huntington's disease health-related quality of life questionnaire (HDQoL) and other established HrQoL measures (EQ-5D and SF-12v2). Proxy-patient agreement was assessed in terms of absolute level (mean ratings) and intraclass correlation. Proxies' ratings were at a similar level to patients' self-ratings on an overall Summary Score and on most of the six Specific Scales of the HDQoL. On the Specific Hopes and Worries Scale, proxies on average rated HrQoL as better than patients' self-ratings, while on both the Specific Cognitive Scale and Specific Physical and Functional Scale proxies tended to rate HrQoL more poorly than patients themselves. The patient's disease stage and mental wellbeing (SF-12 Mental Component scale) were the two factors that primarily affected proxy assessment. Proxy scores were strongly correlated with patients' self-ratings of HrQoL, on the Summary Scale and all Specific Scales. The patient-proxy correlation was lower for patients at moderate stages of HD compared to patients at early and advanced stages. The proxy report version of the HDQoL is a useful complementary tool to self-assessment, and a promising alternative when individual patients with advanced HD are unable to self-report.

The roles of perirhinal cortex, postrhinal cortex, and the fornix in memory for objects, contexts, and events in the rat.

Investigation of the anatomical substructure of the medial temporal lobe has revealed a number of highly interconnected areas, which has led some to propose that the region operates as a unitary memory system. However, here we outline the results of a number of studies from our laboratories, which investigate the contributions of the rat's perirhinal cortex and postrhinal cortex to memory, concentrating particularly on their respective roles in memory for objects. By contrasting patterns of impairment and spared abilities on a number of related tasks, we suggest that perirhinal cortex and postrhinal cortex make distinctive contributions to learning and memory: for example, that postrhinal cortex is important in learning about within-scene position and context. We also provide evidence that despite the strong connectivity between these cortical regions and the hippocampus, the hippocampus, as evidenced by lesions of the fornix, has a distinct function of its own--combining information about objects, positions, and contexts.