Biomedical subjects

A D Lawrence

Publications and source records attributed to A D Lawrence.

At least 19 recordsLinked to original sources

PubMed2006

Relationship between impulsive sensation seeking traits, smoking, alcohol and caffeine intake, and Parkinson's disease.

BACKGROUND: An inverse relation exists between smoking and coffee intake and Parkinson's disease (PD). The present study explored whether this is explained by low sensation seeking, a personality trait believed to characterise PD. METHODS: A total of 106 non-demented patients with PD and 106 age and sex matched healthy controls completed a short version of Zuckerman's Sensation Seeking Scale (SSS), the Geriatric Depression Scale, and the Trait Anxiety Inventory. Data were collected on past and current cigarette smoking, and participants also completed food frequency questionnaires to estimate current caffeine and alcohol intake. RESULTS: Patients with PD had lower sensation seeking and higher depression and anxiety scores. They were also less likely to have ever smoked, and had lower caffeine and alcohol intakes. Analysis of the data using conditional logistic regression suggested that the inverse association of PD risk with sensation seeking was independent of smoking, and caffeine and alcohol intake. Moreover, low sensation seeking explained some of the apparent effect of caffeine and alcohol intake on PD. However, the effect of smoking was weakened only slightly when SSS was included in the regression model. CONCLUSION: This study raises the possibility that there is a neurobiological link between low sensation seeking traits--which might underlie the parkinsonian personality--and the hypothetical protective effect of cigarette smoking and caffeine consumption on PD.

Aged↗

PubMed2005

Factors influencing susceptibility to compulsive dopaminergic drug use in Parkinson disease.

BACKGROUND: In the course of treatment, a small group of patients with Parkinson disease (PD) develop a harmful pattern of compulsive dopaminergic drug use, called the dopamine dysregulation syndrome (DDS). Individual factors may influence susceptibility. OBJECTIVES: To identify predisposing factors to DDS in a population of outpatients with PD. METHODS: The authors compared clinical features, impulsive sensation seeking (ISS) personality traits, past experimental drug use, alcohol consumption, smoking behaviors, and depressive symptoms in 25 patients with DDS to an outpatient sample of 100 patients with PD who were not compulsively overusing dopaminergic medication. RESULTS: Patients with DDS had a significantly younger age at disease onset, higher dopaminergic drug intake, greater past experimental drug use, more depressive symptoms, scored higher on ISS ratings, and tended to have higher alcohol intake. Using logistic regression analysis, we found that novelty seeking personality traits, depressive symptoms, alcohol intake, and age at PD onset were significant predictors of DDS. CONCLUSIONS: These factors may help to identify early patients who are more vulnerable to developing a pattern of compulsive dopaminergic drug use and help minimize its consequences.

Adult↗

PubMed2005

Distributed neural actions of anti-parkinsonian therapies as revealed by PET.

There is a limited understanding of how different anti-parkinsonian treatments act at the neuronal systems level. Using positron emission tomography we examined the effects of levodopa and deep brain stimulation of the subthalamic nucleus on patterns of regional cerebral blood flow in patients with Parkinson's disease during a homogenous cognitive-behavioural state rather than during an unspecified resting state. We found that when medicated precuneus, frontal, parietal, cerebellar and midbrain areas were relatively more activated than when stimulated, whereas when stimulated the precentral gyrus, caudate and thalamus were relatively more activated than when medicated. Areas that were activated by both treatments included the temporal gyri, anterior thalamus, and midbrain. Regions of prefrontal cortex showed relatively greater activation in the "off treatment" conditions of both the medicated and stimulated groups. Our findings suggest that the two treatment methods may lead to symptomatic relief via both common and different sites of action.

Aged↗

PubMed2005

Anaerobic synthesis of vitamin B12: characterization of the early steps in the pathway.

The anaerobic biosynthesis of vitamin B12 is slowly being unravelled. Recent work has shown that the first committed step along the anaerobic route involves the sirohydrochlorin (chelation of cobalt into factor II). The following enzyme in the pathway, CbiL, methylates cobalt-factor II to give cobalt-factor III. Recent progress on the molecular characterization of this enzyme has given a greater insight into its mode of action and specificity. Structural studies are being used to provide insights into how aspects of this highly complex biosynthetic pathway may have evolved. Between cobalt-factor III and cobyrinic acid, only one further intermediate has been identified. A combination of molecular genetics, recombinant DNA technology and bioorganic chemistry has led to some recent advances in assigning functions to the enzymes of the anaerobic pathway.

Anaerobiosis↗

PubMed2005

Aerobic synthesis of vitamin B12: ring contraction and cobalt chelation.

The aerobic biosynthetic pathway for vitamin B12 (cobalamin) biosynthesis is reviewed. Particular attention is focused on the ring contraction process, whereby an integral carbon atom of the tetrapyrrole-derived macrocycle is removed. Previous work had established that this chemically demanding step is facilitated by the action of a mono-oxygenase called CobG, which generates a hydroxy lactone intermediate. This mono-oxygenase contains both a non-haem iron and an Fe-S centre, but little information is known about its mechanism. Recent work has established that in bacteria such as Rhodobacter capsulatus, CobG is substituted by an isofunctional protein called CobZ. This protein has been shown to contain flavin, haem and Fe-S centres. A mechanism is proposed to explain the function of CobZ. Another interesting aspect of the aerobic cobalamin biosynthetic pathway is cobalt insertion, which displays some similarity to the process of magnesium chelation in chlorophyll synthesis. The genetic requirements of cobalt chelation and the subsequent reduction of the metal ion are discussed.

Aerobiosis↗

PubMed2001

Neuropsychology of fear and loathing.

For over 60 years, ideas about emotion in neuroscience and psychology have been dominated by a debate on whether emotion can be encompassed within a single, unifying model. In neuroscience, this approach is epitomized by the limbic system theory and, in psychology, by dimensional models of emotion. Comparative research has gradually eroded the limbic model, and some scientists have proposed that certain individual emotions are represented separately in the brain. Evidence from humans consistent with this approach has recently been obtained by studies indicating that signals of fear and disgust are processed by distinct neural substrates. We review this research and its implications for theories of emotion.

Amygdala↗

PubMed2001

In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion.

A major challenge in the assessment of brain injury and its relationship to the ensuing functional deficits is the accurate delineation of the areas of damage. Here, we test the hypothesis that the anatomical distribution pattern of activated microglia, a normally dormant population of resident brain macrophages, can be used as a surrogate marker of neuronal injury not only at the primary lesion site but also in the antero- and retrograde projection areas of the lesioned neurones. Two patients with asymmetrical herpes simplex encephalitis were serially scanned 6 and 12 months after the acute illness using PET with [11C] (R)-PK11195, a marker of activated microglia/brain macrophages. The evolving structural changes in the brain were measured by volumetric MRI and compared with the pattern of [11C](R)-PK11195 binding. Corresponding to the clinically observed cognitive deficits, quantitative [11C](R)-PK11195-PET revealed highly significant signal increases within the affected limbic system and additionally in areas connected to the limbic system by neural pathways, including the lingual gyrus in the occipital lobe and the inferior parietal lobe, which had normal morphology on structural MRI. The increased [11C](R)-PK11195 binding, signifying the presence of activated microglia, persisted many months (>12) after antiviral treatment. Cortical areas that showed early high [11C](R)-PK11195 binding subsequently underwent atrophy. These observations demonstrate that in vivo imaging of activated microglia/brain macrophages provides a dynamic measure of active tissue changes following an acute focal lesion. Importantly, the glial tissue response in the wake of neuronal damage is protracted and widespread within the confines of the affected distributed neural system and can be related to the long-term functional deficits.

Adult↗

PubMed2000

Impaired planning but intact decision making in early Huntington's disease: implications for specific fronto-striatal pathology.

Previous neuropsychological data have suggested that deficits in early Huntington's disease (HD) include executive impairments, which often are linked with frontal-lobe dysfunction. This study sought to investigate the profile of cognitive deficits using two computerised tasks whose performance is known to rely on intact functions of separate areas of the prefrontal cortex. Twenty patients with early HD and 20 matched controls were given the one-touch Tower of London, a stringent measure of visuo-spatial planning, and a decision making task, which involved selecting and gambling on outcomes on the basis of their differing probabilities. Patients were significantly less accurate than controls on the planning test, which is sensitive to frontal lobe lesions and is strongly associated with the dorsolateral prefrontal cortex in functional imaging studies. On the decision making task, patients were unimpaired on the quality of their decision making, in contrast to previous reports of impairment on this task in patients with ventromedial prefrontal cortex lesions. This dissociation of performance is discussed in terms of the usual path of progression of HD through the striatum and the resultant pattern of disruption of the functioning of the different cortico-striatal functional loops.

Adult↗

PubMed2000

Visual object and visuospatial cognition in Huntington's disease: implications for information processing in corticostriatal circuits.

The primate visual system contains two major streams of visual information processing. The ventral stream is directed into the inferior temporal cortex and is concerned with visual object cognition, whereas the dorsal stream is directed into the posterior parietal cortex and is concerned with visuospatial cognition. Both of these processing streams send projections to the basal ganglia, and the ventral stream may also receive reciprocal connections from the basal ganglia. Although a role for the basal ganglia in visual object and visuospatial cognition has been suggested, little work has been carried out in this area in humans. The primary site of neuropathology in Huntington's disease is the basal ganglia, and hence Huntington's disease provides an important model for the role of the human basal ganglia in visual object and visuospatial cognition, and its breakdown in disease. We examined performance on a wide battery of tests of both visual object and visuospatial recognition memory, working memory, attention, associative learning and perception, enabling us to specify more fully the role of the basal ganglia in visual object and visuospatial cognition, and the disruption of these processes in Huntington's disease. Huntington's disease patients exhibited deficits on tests of pattern and spatial recognition memory; showed impaired simultaneous matching and delay-independent delayed matching-to-sample deficits; showed spared accuracy but impaired reaction times in visual search; were impaired in spatial but not visual object working memory; and showed impaired pattern-location associative learning. The results of our investigations suggest a particular role for the striatum in context-dependent action selection, in line with current computational theories of basal ganglia function.

Adult↗

PubMed1999

Discrimination, reversal, and shift learning in Huntington's disease: mechanisms of impaired response selection.

In a series of three experiments, we investigated different aspects of response selection in early-stage clinically symptomatic Huntington's disease (HD) patients in the context of discrimination learning. A series of structurally related response selection tasks involving discrimination, reversal, and shift learning were employed. In Experiment 1, the mechanisms of our previously reported [37] finding of impaired extra-dimensional shift learning were explored. The results suggested that impaired shift learning in HD is a result of perseverative responding. In Experiment 2, performance on a concurrent-pair (CP) discrimination and reversal task was examined. HD patients showed no deficits in CP discrimination learning or reversal. In Experiment 3, the performance of HD patients on a probabilistic discrimination and reversal task was examined. HD patients were impaired in the learning of a probabilistic discrimination, and also its reversal. This reversal deficit was again the result of perseverative responding. In addition, there was a strong correlation between HD patients' activities of daily living scores and reversal errors. The result are consistent with current theories of the role of the basal ganglia in cognition, and suggest specific impairments in response selection mechanisms in HD, in particular, in overcoming selection biases based on prior reinforcement.

Adult↗

PubMed1998

Evidence for striatal dopamine release during a video game.

Dopaminergic neurotransmission may be involved in learning, reinforcement of behaviour, attention, and sensorimotor integration. Binding of the radioligand 11C-labelled raclopride to dopamine D2 receptors is sensitive to levels of endogenous dopamine, which can be released by pharmacological challenge. Here we use 11C-labelled raclopride and positron emission tomography scans to provide evidence that endogenous dopamine is released in the human striatum during a goal-directed motor task, namely a video game. Binding of raclopride to dopamine receptors in the striatum was significantly reduced during the video game compared with baseline levels of binding, consistent with increased release and binding of dopamine to its receptors. The reduction in binding of raclopride in the striatum positively correlated with the performance level during the task and was greatest in the ventral striatum. These results show, to our knowledge for the first time, behavioural conditions under which dopamine is released in humans, and illustrate the ability of positron emission tomography to detect neurotransmitter fluxes in vivo during manipulations of behaviour.

Adult↗

PubMed1998

A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. Cambridge Neuropsychological Test Automated Battery.

Several tests from the CANTAB neuropsychological test battery previously shown to be sensitive to frontal lobe dysfunction were administered to a large group of normal volunteers (N = 341) ranging in age from 21 to 79 years. The main tests included a computerized form of the Tower of London test of planning, a self-ordered spatial working memory task, and a test of attentional set formation and shifting. A computerized form of the Corsi spatial span task was also given. Age-related graded declines in performance were seen, sometimes in a discontinuous manner, especially for the attentional set shifting task (at the extradimensional shift stage). Patterns of deficits reminiscent of frontal lobe or basal ganglia damage were observed in the oldest age group (74-79). However, overall the data were only partially consistent with the hypothesis that frontal lobe functions are the most sensitive to effects of aging. Factor analyses showed that performance in the executive tests was not simply related to a measure of fluid intelligence, and their performance had a factor loading structure distinct from that for the CANTAB tests of visual memory and learning previously administered to the same sample. Finally, only limited support was found for the hypothesis that cognitive aging depends on slowed information processing.

Adult↗

PubMed1998

The cognitive psychopharmacology of Alzheimer's disease: focus on cholinergic systems.

The primary pathology in Alzheimer's disease (DAT) occurs in the basal forebrain cholinergic system (BFCS), which provides the major cholinergic innervation to the neocortex, hippocampus and amygdala. Consistent with the 'cholinergic hypothesis' of dementia in DAT, the most effective treatments so far developed for DAT are drugs which act to boost the functions of the BFCS. These include the centrally acting cholinesterase inhibitor tacrine, and the cholinergic agonist nicotine, acute administration of which leads to an improvement in attentional functions, in line with recent animal studies of the role of the BFCS in cognition. We conclude that future research should include the development of more potent, longer-lasting, less toxic cholinergic agents, which appear to be the best candidates for alleviating the cognitive symptomatology of DAT. Such drugs may also be useful in the treatment of a number of other cognitive disorders, including Lewy body dementia, attention deficit/hyperactivity disorder, and schizophrenia.

Acetylcholine↗

PubMed1998

Evidence for specific cognitive deficits in preclinical Huntington's disease.

The performance of 54 subjects genetically at risk for Huntington's disease was examined in double-blind fashion on a series of computerized tests from the Cambridge Neuropsychological Test Automated Battery. None of the subjects exhibited clinical movement disorder characteristic of Huntington's disease. Of the 54 subjects, 22 were Huntington's disease mutation carriers and 32 were non-carriers. On a comprehensive battery of neuropsychological tests previously shown to be sensitive to the early stages of clinical Huntington's disease, Huntington's disease mutation carriers exhibited highly specific cognitive deficits. In particular, Huntington's disease mutation carriers performed significantly less well than non-carriers, matched for age and IQ, on tests of attentional set shifting and semantic verbal fluency. Furthermore, performance on these two tests was significantly correlated, even after partialling out the effects of age and IQ. It is suggested that these cognitive impairments relate to a common deficit in inhibitory control mechanisms, under the control of striatofrontal mechanisms, and that such a deficit is present in Huntington's disease mutation carriers prior to the onset of definite motor symptomatology. The implications for the nature of the cognitive decline seen in Huntington's disease, and possible future treatment strategies, are discussed.

Adult↗

PubMed1998

The relationship between striatal dopamine receptor binding and cognitive performance in Huntington's disease.

Seventeen individuals at risk for Huntington's disease and five symptomatic patients, who had previously undergone [11C]SCH23390 and [11C]raclopride PET to assess in vivo levels of striatal dopamine D1 and D2 receptor binding, had neuropsychological assessment on a series of tests known to be sensitive to symptomatic Huntington's disease, including tests of verbal fluency, memory, attention and planning. Compared with age- and IQ-matched healthy volunteers, clinically symptomatic carriers of the Huntington's disease mutation were found to be impaired on tests of verbal fluency, spatial span, planning and sequence generation, as were clinically asymptomatic Huntington's disease mutation carriers. In asymptomatic individuals, both striatal dopamine receptor levels and cognitive performance were lower in subjects approaching their estimated age of onset. In addition, performance on these tasks was found to correlate with PET measures of striatal D1 and D2 receptor binding levels, especially D2 binding. These results are consistent with a role for the striatum, as part of the complex corticobasal ganglia-thalamocortical circuitry, in the optimal scheduling and sequencing of responses, and suggest that cognitive manifestations of striatal dysfunction can be evidenced in carriers of the Huntington's disease mutation prior to the onset of overt clinical movement disorder.

Adult↗

PubMed1996

Executive and mnemonic functions in early Huntington's disease.

Eighteen patients with early Huntington's disease were compared with age- and IQ-matched control volunteers on tests of executive and mnemonic function taken from the Cambridge Neuropsychological Test Automated Battery. Tests of pattern and spatial recognition memory, spatial span, spatial working memory, spatial planning and visual discrimination learning/attentional set shifting were employed. These tests have previously been found to be sensitive to the later stages of Huntington's disease. Patients with early Huntington's disease were found to have a wide range of cognitive impairments encompassing both visuospatial memory and executive functions, a pattern distinct from those seen in other basal ganglia disorders. In contrast to patients with more advanced Huntington's disease, early Huntington's disease patients were not impaired at simple reversal learning, but were impaired at performing an extradimensional shift (EDS). The results will be discussed in relation to the hypothesized neuropathological staging of Huntington's disease and to the anatomical connectivity of the striatum.

Adult↗

PubMed1995

Alzheimer disease, attention, and the cholinergic system.

Recent neuropsychological studies suggest that, in addition to prominent mnemonic dysfunction, attentional impairments are a core feature of Alzheimer disease (AD). As is the case for memory, attention is not a unitary process, and only certain components of attention are disrupted in mild AD, particularly sustained and spatial attention. In this article we review evidence from both human and nonhuman neuropsychopharmacology that leads us to suggest that (at least some of) the attentional impairments seen in AD can be related to damage to the basal forebrain cholinergic system (BFCS), in particular the nucleus basalis of Meynert (nbM), which undergoes significant neuronal loss in AD. The BFCS provides the major cholinergic innervation to the cortex and innervates brain regions such as the thalamus, prefrontal cortex, and parietal lobes known to be involved in attentional operations. In addition, studies conducted by our group suggest that drugs acting to stimulate the cholinergic system, in particular tacrine and nicotine, can significantly improve attentional function in patients with AD as measured by improved performance on objective computerised cognitive tasks. Furthermore, cholinergic drugs may also have some utility in other disorders with attentional pathology, such as Parkinson's disease.

Alzheimer Disease↗

PubMed1987

Feedback effects on sequential ordering in humans.

Under various feedback conditions, 38 college undergraduates were asked to rearrange abstract graphic characters on a computer screen, placing them in arbitrarily designated "correct" sequences. Two sets of seven horizontally arrayed stimuli were used. In Experiment 1, subjects in Group 1 learned to arrange the first set under Selection Feedback in which a "+" appeared above each character after it was selected in the correct order and to arrange the second set under Order Feedback in which a correct response produced a copy of the character in its correct ordinal position at the top of the screen. For Group 2 the order of these conditions was reversed. In Experiment 2, for subjects in Group 3, correct responses produced neither of these types of feedback. Subjects in Group 4 received Order Feedback only until the first set was correctly ordered once. Order Feedback was more effective than Selection Feedback during initial acquisition of the first set but not during maintenance; no differences were found for the second set. Only 2 of 9 subjects successfully put the characters in correct sequential order under the No Feedback condition. When, in Experiment 2, Order Feedback was eliminated after the first correctly arranged sequence, the steady-state criteria were met more slowly than in Experiment 1.

Journal Article↗