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Biomedical subjects

R G Brown

Publications and source records attributed to R G Brown.

At least 19 recordsLinked to original sources
PubMed2002

Striatal contribution to cognition: working memory and executive function in Parkinson's disease before and after unilateral posteroventral pallidotomy.

The basal ganglia are intimately connected to the frontal cortex via five fronto-striatal circuits. While the role of the frontal cortex in cognition has been extensively studied, the contribution of the basal ganglia to cognition has remained less clear. In Parkinson's disease, posteroventral pallidotomy (PVP) involves surgical lesioning of the internal section of the globus pallidus (GPi, the final output pathway from the basal ganglia) to relieve the motor symptoms of the disorder. PVP in Parkinson's disease provides a unique opportunity to investigate the impact of disruption of striatal outflow to the frontal cortex on cognition. We assessed executive function and working memory after withdrawal of medication in 13 patients with Parkinson's disease before and 3 months after unilateral PVP compared to 12 age- and IQ-matched normals assessed twice with an interval of 3 months. The tests used were: Wisconsin Card Sorting (WCST), Self-Ordered Random Number Sequences, Missing Digit Test, Paced Visual Serial Addition Test (PVSAT), and Visual Conditional Associative Learning Test (VCALT). After PVP, the patients performed significantly better on the Self-Ordered Random Number Sequences and the WCST, an improvement that was also observed in the normals across the two assessment and is therefore likely to reflect practice effects. Relative to the normals, the patients showed significant differential change following PVP on the Missing Digit Test and PVSAT, on which they performed worse after compared to before surgery, while the controls performed better on the second assessment. For the patients, performance on the VCALT also indicated deterioration after PVP, but the changes approached significance. The side of PVP had no effect on the results. The pattern of change observed 3 months after PVP was maintained at 15-month follow-up. The results suggest that striatal outflow to the frontal cortex may be essential for those aspects of executive function that showed deterioration after PVP.

Adult↗
PubMed2002

Rumination and executive function in depression: an experimental study.

BACKGROUND: Major depression is associated with cognitive deficits, particularly those requiring central executive functioning. Depressed patients also tend to focus on and think about their symptoms and problems ("ruminate") more than non-depressed controls. Although an association has been found between rumination and impaired performance on a central executive processing task, the causal relation between impaired executive functioning and rumination has not been determined. This study sought to directly manipulate rumination and assess the impact on executive functioning in depression as measured by random number generation. METHODS: Depressed patients (n=14) and non-depressed controls (n=14) were compared on a random number generation task, performed after both a rumination induction and after a distraction induction, with order of inductions counter balanced within each group. RESULTS: Compared with the distraction induction, the rumination induction produced a significant increase in both ruminations and the tendency towards stereotyped counting responses (thought to reflect a failure of inhibitory executive control) in depressed patients but not in controls. However, after distraction, no difference in random number generation or rumination was found between the two groups. CONCLUSIONS: The aspects of executive function involved in random number generation are not fundamentally impaired in depressed patients. In depressed patients, the rumination induction seems to trigger the continued generation of ruminative stimulus independent thoughts, which interferes with concurrent executive processing.

Adult↗
PubMed2002

[Correlation between reaction time and bradykinesia in Huntington's disease].

BACKGROUND: Bradykinesia is the clinical feature of Huntington's disease most closely related to functional discapacity and stage, probably as a consequence of spreading of neuronal injury. The aim of the present article is to verify whether a choice reaction time could be considered an estimate measurement of clinical bradykinesia, and its possible relationships with other evolutive parameters such as functional discapacity, clinical stage and prefrontal executive dysfunction. METHODS: Fifteen patients were studied (9 in advanced stage and 6 initials), equal number of controls and 3 asymptomatic gene carriers. We used clinical bradykinesia and functional capacity scales, an extensive prefrontal battery and a computerized paradigm of reaction time. RESULTS: Clinical bradykinesia and reaction time are closely related. The associations between reaction time with those parameters indicatives of prefrontal dysfunction, functional discapacity and clinical stage are closer and more significatives than those that could be established with clinical bradykinesia. CONCLUSIONS: Reaction time is an objective measurement of global motor slowness that allow us assigning each subject to a specific stage, and avoid possible errors derived from interobserver bias in clinical scales.

English Abstract↗
PubMed2001

Dissociation between intentional and incidental sequence learning in Huntington's disease.

The ability to acquire and act upon serial order information is fundamental to almost all forms of adaptive behaviour. There is growing evidence that such knowledge may be acquired through a number of different means, each perhaps with its own neuronal substrate. One major distinction is between serial order information acquired intentionally and leading to explicit conscious knowledge of the sequence structure, and information acquired incidentally through experience. While this latter form of knowledge influences behaviour, it may do so without the participant being aware of the sequential information, i.e. it is acquired implicitly. Evidence from physiological and lesion studies in animals and imaging studies in humans suggests that these two forms of learning may have dissociable neuronal substrates. Specifically, the striato-thalamo-cortical circuit centred on the caudate nucleus is proposed to be involved in intentional sequence learning and that based on the putamen on incidental learning. The present study tested one part of this proposed dissociation by assessing patients with Huntington's disease on tasks of the two forms of learning. On the test of trial-and-error intentional learning there were marked deficits, which were closely related to disease progression and to measures of executive cognitive dysfunction. This finding was in contrast to the finding from the incidental learning task. Performance of the Huntington's disease group was essentially normal and unrelated to measures of disease progression and cognitive status. The results, although supportive of the proposed dual-system hypothesis, offer only partial confirmation. Further direct study is required using similar tasks in patients with putamenal disorder or lesions within the skeletomotor striato-thalamo-cortical circuit.

Adult↗
PubMed2000

Negative symptoms: the 'pathology' of motivation and goal-directed behaviour.

In many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia, symptoms are present that appear to reflect an essential absence of normal movement, cognition and emotional states. These negative symptoms might reflect fundamental impairments in basic brain mechanisms that underlie goal-directed behaviour. Knowledge of the pathology and pathophysiology of these diseases, combined with evidence from basic science, offers opportunities for understanding the neurobiological basis of goal-directed behaviour, particularly the interaction between limbic structures and striato-thalamo-cortical circuits. The study of patients with negative symptoms also provides opportunities for testing cognitive models of goal-directed behaviour, and eventually to map such models onto the neurobiology of both normal and abnormal behaviour.

Behavior↗
PubMed2000

The impact of deep brain stimulation on executive function in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) improves Parkinson's disease and increases frontal blood flow. We assessed the effects of bilateral DBS on executive function in Parkinson's disease patients, seven with electrodes implanted in the STN and six in the GPi. Patients were assessed off medication with stimulators off, on and off again. The groups showed differential change with stimulation on the Reitan Trail-Making test (TMT B) (STN more improved) and on some measures of random number generation and Wisconsin Card Sorting (STN improved, GPi worse with stimulation). Across the groups, stimulation speeded up responding (Stroop control trial, TMT A) and improved performance on paced serial addition and missing digit tests. Conversely, conditional associative learning became more errorful with stimulation across the two groups. In general, change in performance with stimulation was significant for the STN but not the GPi group. These results support two opposite predictions. In support of current models of Parkinson's disease, 'releasing the brake' on frontal function with DBS improved aspects of executive function. Conversely, disruption of basal ganglia outflow during DBS impaired performance on tests requiring changing behaviour in novel contexts as predicted by Marsden and Obeso in 1994.

Association Learning↗
PubMed1999

Impact of deep brain stimulation on upper limb akinesia in Parkinson's disease.

Recent pathophysiological models of Parkinson's disease have led to new surgical approaches to treatment including deep brain stimulation (DBS) and lesioning of basal ganglia structures. Various measures of upper limb akinesia were assessed in 6 patients with bilateral DBS of the internal pallidum and 6 with DBS of the subthalamic nucleus. Stimulation improved a number of aspects of motor function, and particularly movement time, and force production. Time to initiate movements, and to perform repetitive movements also improved but less dramatically. Processes indicating preparatory motor processes showed no significant change. Few significant differences were found between the internal pallidum and subthalamic nucleus groups. In general, the effects of DBS closely parallel previous reports of the effects of dopaminergic medication. It is suggested that disrupted pallidal output in Parkinson's disease interferes with the rate, level, and coordination of force production but has little effect on preparatory processes. The similarity of the effects of subthalamic nucleus and internal pallidum stimulation suggests this disrupted outflow is the most important determinant of upper limb akinesia in Parkinson's disease. The effects of DBS were similar to the effects of unilateral pallidal lesions reported elsewhere.

Brain↗
PubMed1999

The effects of posteroventral pallidotomy on the preparation and execution of voluntary hand and arm movements in Parkinson's disease.

We studied the effect of posteroventral pallidotomy on movement preparation and execution in 27 parkinsonian patients using various motor tasks. Patients were evaluated after overnight withdrawal of medication before and 3 months after unilateral pallidotomy. Surgery had no effect on initiation time in unwarned simple and choice reaction time tasks, whereas movement time measured during the same tasks was improved for the contralesional hand. Movement times also improved for isometric and isotonic ballistic movements. In contrast, repetitive, distal and fine movements measured in finger-tapping and pegboard tasks were not improved after pallidotomy. Preparatory processes were investigated using both behavioural and electrophysiological measures. A precued choice reaction time task suggested an enhancement of motor preparation for the contralesional hand. Similarly, movement-related cortical potentials showed an increase in the slope of the late component (NS2) when the patients performed joystick movements with the contralesional hand. However, no significant change was found for the early component (NS1) or when the patient moved the ipsilesional hand. The amplitude of the long-latency stretch reflex of the contralesional hand decreased after surgery. In summary, the data suggest that pallidotomy improved mainly the later stages of movement preparation and the execution of proximal movements with the contralesional limb. These results provide detailed quantitative data on the impact of posteroventral pallidotomy on previously described measures of upper limb akinesia in Parkinson's disease.

Electroencephalography↗
PubMed1998

Relation of coagulation parameters to patency and recurrent ischemia in the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial.

Current protocols for use of tissue-type plasminogen activator in acute myocardial infarction include heparin estimated by the activated partial thromboplastin time (aPTT). Recent reports indicate a risk of recurrent ischemic events with long aPTT values. Longer aPTT values in the Thrombolysis in Myocardial Infarction-II (TIMI II) Trial, obtained within the first 48 hours, were associated with patency at 18 to 48 hours and better left ventricular function at discharge (average 9.6 days), but also with emergency catheterizations within the first 48 hours and, weakly, with recurrent ischemia during the first 18 hours. A moderate decrease in fibrinogen, compared with a "small" decrease, was also associated with patency, but a "large" decrease was associated with hemorrhagic events. Patency was associated with higher fibrinogen values and higher plasminogen values at baseline. The aPTT results support frequent monitoring during the first 24 to 48 hours to ensure optimal clinical outcome. The coagulation factor results suggest that there may be an optimum window for fibrinogenolysis in this setting.

Fibrinogen↗
PubMed1998

Executive processes in Parkinson's disease--random number generation and response suppression.

In producing random numbers, subjects typically deviate systematically from statistical randomness. It is considered that these biases reflect constraints imposed by underlying structures and processes, rather than a deficient concept of randomness. Random number generation (RNG) places considerable demands on executive processes, and provides a possibly useful tool for their investigation. A group of patients with Parkinson's disease (PD) and a group of controls were tested on a RNG task, both alone and with a concurrent attention-demanding task (manual tracking). Both groups showed the biases in RNG described previously, including a strong counting tendency and repetition avoidance. Overall RNG performance did not differ between the groups, although differences were found in the counting biases in the patient and control groups, with the controls showing a bias towards counting in twos, and the patients a bias towards counting in ones. The secondary task reversed the bias shown by controls and exacerbated the bias in the patients. A network modulation model may help explain many of the features of RNG. We suggest that naturally biased output from an associative network must be actively suppressed by an attention-demanding, limited-capacity process. This suppression may be disrupted by the pathophysiology of PD and by concurrent tasks. Convergent evidence from various sources is discussed which supports a role of the dorsolateral prefrontal cortex (DLPFC) in this process.

Aged↗
PubMed1998

Training improves the speed of aimed movements in Parkinson's disease.

In this study, the extent to which bradykinesia in patients with idiopathic Parkinson's disease can be influenced by practice and by specific training strategies was investigated. Fifteen patients with Parkinson's disease tested after withdrawal of anti-Parkinson medication, and 15 matched control subjects, practised a ballistic aiming task. Performance was tested before, during and after training and again 1 h later. The Parkinson's disease patients and control subjects were randomly assigned to one of two training schedules, practising with or without rhythmic auditory cues. At baseline, the Parkinson's disease patients showed longer movement times, with a marked decrease in maximum acceleration and deceleration in the initial open-loop phase compared with those of the control subjects. With training, they were able to make significant improvement in the speed of aimed movements, particularly in the early movement phase, without any deterioration in accuracy. These effects transferred to an untrained limb and were at least partially maintained after a 1-h delay. While patients remained impaired relative to control subjects at all phases of training and follow-up, the patients' performance at the end of training did not differ significantly from the control subjects' baseline function. Contrary to expectation, rhythmic auditory cues did not enhance improvement in the speed of aimed movements in either patients or control subjects. If anything, less improvement was shown in the cued groups, although there were suggestions that the aiming skill was retained better over the delay period. The results demonstrate preserved abilities to improve speed of single ballistic aiming movements in Parkinson's disease patients and the possibility of reducing bradykinesia by training.

Aged↗
PubMed1998

The effects of transcranial magnetic stimulation over the dorsolateral prefrontal cortex on suppression of habitual counting during random number generation.

Random number generation is an attention-demanding task that engages working memory and executive processes. Random number generation requires holding information 'on line', suppression of habitual counting, internally driven response generation and monitoring of responses. Evidence from PET studies suggests that the dorsolateral prefrontal cortex (DLPFC) is involved in the generation of random responses. We examined the effects of short trains of transcranial magnetic stimulation (TMS) over the left or right DLPFC or medial frontal cortex on random number generation in healthy normal participants. As in previous evidence, in control trials without stimulation participants performed poorly on the random number generation task, showing repetition avoidance and a tendency to count. Brief disruption of processing with TMS over the left DLPFC changed the balance of the individuals' counting bias, increasing the most habitual counting in ones and reducing the lower probability response of counting in twos. This differential effect of TMS over the left DLPFC on the balance of the subject's counting bias was not obtained with TMS over the right DLPFC or the medial frontal cortex. The results suggest that, with disruption of the left DLPFC with TMS, habitual counting in ones that has previously been suppressed is released from inhibition. From these findings a network modulation model of random number generation is proposed, whereby suppression of habitual responses is achieved through the modulatory influence of the left DLPFC over a number-associative network in the superior temporal cortex. To allow emergence of appropriate random responses, the left DLPFC inhibits the superior temporal cortex to prevent spreading activation and habitual counting in ones.

Adult↗
PubMed1998

Phytochrome regulation and differential expression of gibberellin 3beta-hydroxylase genes in germinating Arabidopsis seeds.

Despite extensive studies on the roles of phytochrome in photostimulated seed germination, the mechanisms downstream of the photoreceptor that promote germination are largely unknown. Previous studies have indicated that light-induced germination of Arabidopsis seeds is mediated by the hormone gibberellin (GA). Using RNA gel blot analyses, we studied the regulation of two Arabidopsis genes, GA4 and GA4H (for GA4 homolog), both of which encode GA 3beta-hydroxylases that catalyze the final biosynthetic step to produce bioactive GAs. The newly isolated GA4H gene was expressed predominantly during seed germination. We show that expression of both GA4 and GA4H genes in imbibed seeds was induced within 1 hr after a brief red (R) light treatment. In the phytochrome B-deficient phyB-1 mutant, GA4H expression was not induced by R light, but GA4 expression still was, indicating that R light-induced GA4 and GA4H expression is mediated by different phytochromes. In contrast to the GA4 gene, the GA4H gene was not regulated by the feedback inhibition mechanism in germinating seeds. Our data demonstrate that expression of GA 3beta-hydroxylase genes is elevated by R light, which may result in an increase in biosynthesis of active GAs to promote seed germination. Furthermore, our results suggest that each GA 3beta-hydroxylase gene plays a unique physiological role during light-induced seed germination.

Amino Acid Sequence↗
PubMed1998

An unusual enhancement of motor performance during bimanual movement in Parkinson's disease.

In both clinical and laboratory tests, patients with Parkinson's disease have considerable difficulty in performing different manual tasks simultaneously with the two hands. The present study reports on an unusual enhancement in performance under such conditions in a substantial proportion of patients tested. When performed at the same time as repetitive tapping tasks, the ability to rapidly place pegs in holes improved in almost half of the patients compared with unimanual performance of the peg task. Various possible explanations are considered for this unusual finding. The two most plausible, and testable, relate to either the withdrawal of attention from the task permitting a more automatic mode of execution, or a facilitation provided by sensory feedback from the simultaneous tapping task.

Adult↗