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Biomedical subjects

R A Weeks

Publications and source records attributed to R A Weeks.

At least 19 recordsLinked to original sources
PubMed2001

Comparison of auditory, somatosensory, and visually instructed and internally generated finger movements: a PET study.

We sought to determine how the pattern of cerebral activation, and in particular in frontal motor areas, during the performance of conditional motor tasks is dependent upon the modality of instruction (visual, auditory, or somatosensory). Regional cerebral blood flow (rCBF) changes with externally instructed movements were also compared with internally generated, self-paced, movements. We used positron emission tomography (PET) with the tracer H2(15O) to measure rCBF in 22 healthy volunteers. External stimuli consisted of the randomized presentation of single or double impulses using a single modality for each condition. In the movement scans, the subjects used the index and middle fingers of their right hands to press a left button for a single and a right button for a double impulse, respectively. In the control scans, subjects were required to covertly distinguish a single from a double stimulus without a motor response. Data were analyzed using conventional subtraction techniques with a statistical threshold of Z > 2.33 with corrections for multiple comparisons. When the activation differences between the three externally instructed movement conditions were statistically compared, nonsignificant trends toward increased rCBF in the sensory cortex of the modality of the cue were observed but no differential activity in cortical motor areas. Internally generated movements, when compared to externally triggered movements, were associated with enhanced activation in bilateral medial and lateral premotor, dorsolateral prefrontal and superior parietal regions, largely confirming previous reports. The data indicate that, on a regional level, modality-specific processing in a conditional motor task does not occur in frontal motor areas and is probably confined to sensory areas.

Adolescent↗
PubMed1999

A PET study of human auditory spatial processing.

To learn more about human auditory spatial processing, we used positron emission tomography (PET) to measure regional cerebral blood flow in human volunteers engaged in sound localization tasks. Spectral and binaural cues of localized sound were reproduced by a sound system and delivered via headphones. During localization tasks, subjects activated inferior parietal lobules (IPL) bilaterally. In a second experiment, matched in design to the first, subjects made non-spatial auditory discriminations based on frequency, activating the IPL bilaterally with left hemispheric predominance. A between-study comparison revealed that the right IPL was significantly more activated during the sound localization task compared with the feature discrimination task, suggesting a preferential role for the right IPL in auditory spatial processing.

Adult↗
PubMed1999

Period of susceptibility for cross-modal plasticity in the blind.

Cross-modal plasticity in blind subjects contributes to sensory compensation when vision is lost early in life, but it is not known if it does so when visual loss occurs at an older age. We used H2(15)O positron emission tomography to identify cerebral regions activated in association with Braille reading, and repetitive transcranial magnetic stimulation to induce focal transient disruption of function during Braille reading, in 8 subjects who became blind after age 14 years (late-onset blind), after a lengthy period of normal vision. Results were compared with those previously reported obtained from congenitally and early-onset blind subjects. As shown by H2(15)O positron emission tomographic scanning, the occipital cortex was strongly activated in the congenitally blind and early-onset blind groups but not in the late-onset blind group. Occipital repetitive transcranial magnetic stimulation disrupted the Braille reading task in congenitally blind and early-onset blind subjects but not in late-onset blind subjects. These results indicate that the susceptible period for this form of functionally relevant cross-modal plasticity does not extend beyond 14 years.

Adult↗
PubMed1999

PET study of visually and non-visually guided finger movements in patients with severe pan-sensory neuropathies and healthy controls.

Although patients with sensory neuropathies and normal muscle power are rare, they have been extensively studied because they are a model for dissociating the sensory and motor components of movement. We have examined these patients to determine the cerebral functional anatomy of movement in the absence of proprioceptive input. In addition, the disabling symptoms of these patients can be substantially improved by visually monitoring their movements. We hypothesized that, during visually guided movements, these patients would show overactivity of regions specialized for visuomotor control with the possible additional involvement of areas that normally process somatosensory information. We used positron emission tomography (PET) and the tracer H(2)(15)O to determine the functional anatomy of visually and non-visually guided finger movements in three patients with long-standing pan-sensory neuropathies and normal muscle power and six healthy controls. Five conditions were performed with the right hand: a sequential finger movement task under visual guidance, the same motor task without observation of the hand, monitoring a video of the same sequential finger movement, a passive visual task observing a reversing checkerboard, and an unconstrained rest condition. Data were analyzed using conventional subtraction techniques with a statistical threshold of z>2.33 with corrections for multiple comparisons. When compared with the control group, activation was not deficient in any brain areas of the patient cohort in any of the contrasts tested. In particular, in the non-visually guided movement task, in which meaningful visual and proprioceptive input was absent, the patient group activated primary motor, premotor, and cerebellar regions. This suggests that these areas are involved in motor processing independent of sensory input. In all conditions involving visual observation of hand movements, there was highly significant overactivity of the left parietal operculum (SII) and right parieto-occipital cortex (PO) in the patient group. Recent non-human primate studies have suggested that the PO region contains a visual representation of hand movements. Overactivity of this area and the activation of SII by visual input appear to indicate that compensatory overactivity of visual areas and cross-modal plasticity of somatosensory areas occur in deafferented patients. These processes may underlie their ability to compensate for their proprioceptive deficits.

Aged↗
PubMed1999

Modality-specific frontal and parietal areas for auditory and visual spatial localization in humans.

Although the importance of the posterior parietal and prefrontal regions in spatial localization of visual stimuli is well established, their role in auditory space perception is less clear. Using positron emission tomography (PET) during auditory and visual spatial localization in the same subjects, modality-specific areas were identified in the superior parietal lobule, middle temporal and lateral prefrontal cortices. These findings suggest that, similar to the visual system, the hierarchical organization of the auditory system extends beyond the temporal lobe to include areas in the posterior parietal and prefrontal regions specialized in auditory spatial processing. Our results may explain the dissociation of visual and auditory spatial localization deficits following lesions involving these regions.

Adult↗
PubMed1999

Huntington's disease progression. PET and clinical observations.

Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months in nine asymptomatic adult Huntington's disease mutation carriers, four patients with symptomatic disease, seven mutation-negative controls and three subjects at risk for the disease. Eight of the nine asymptomatic Huntington's disease mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of striatal D2 binding of 4.0%. Only five of these eight, however, showed active progression, and they had a mean annual loss of D2 binding of 6.5%. All nine asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated active progression and they had a mean annual loss of 4.5%. Our four symptomatic Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly greater in the known mutation carriers than in the combined at-risk and gene-negative groups (P < 0.05). At follow-up PET all subjects were clinically assessed using the Unified Huntington's Disease Rating Scale. Scores for motor function and total functional capacity correlated with PET measures of striatal dopamine receptor binding both in the asymptomatic mutation carriers (D1, P < 0.01) and across the combined asymptomatic and clinically affected Huntington's disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET measures of striatal D1 and D2 dopamine binding can be used to identify asymptomatic Huntington's disease mutation carriers who are actively progressing and who would thus be suitable for putative neuroprotective therapies. Measures of disease progression rates in Huntington's disease patients and asymptomatic mutation carriers will be of critical importance in future trials of experimental restorative treatments.

Adult↗
PubMed1999

Movement-related cerebellar activation in the absence of sensory input.

Movement-related cerebellar activation may be due to sensory or motor processing. Ordinarily, sensory and motor processing are obligatorily linked, but in patients who have severe pansensory neuropathies with normal muscle strength, motor activity occurs in isolation. In the present study, positron emission tomography and functional magnetic resonance imaging in such patients showed no cerebellar activation with passive movement, whereas there was prominent movement-related cerebellar activation despite absence of proprioceptive or visual input. The results indicate that motor processing occurs within the cerebellum and do not support the recently advanced view that the cerebellum is primarily a sensory organ.

Aged↗
PubMed1998

Cortical areas with enhanced activation during object-centred spatial information processing. A PET study.

The phenomenon of object-centred unilateral neglect suggests that some neural networks process spatial information relative to reference objects. To examine object-centred information processing, we measured regional cerebral blood flow in 11 normal subjects with PET. During each PET scan, a subject viewed a sample stimulus followed by a cue on a video screen. The sample consisted of two polygons, termed 'objects', each located in a corner of the screen. A small target spot appeared in a corner of each polygon. There were two tasks: the visuomotor task and the matching-to-sample task. In the visuomotor task, the subject moved a joystick in a direction indicated by either the location of the target spot inside the object (if object-centred coordinates were operative) or the location of the object relative to the video screen (if screen-centred coordinates were operative). In the matching-to-sample task, the subject moved the joystick to report whether the relevant spatial information (object- or screen-centred) in the cue matched the sample. In both the visuomotor and the matching-to-sample task, use of object-centred (versus screen- or viewer-centred) information caused augmented activation in the inferior occipitotemporal cortex, bilaterally, in the left superior occipital gyrus, and in both the thalamus and the brainstem. In addition, in the visuomotor task such activation occurred in the right posterior parietal cortex and in the left ventral premotor, dorsolateral prefrontal and anterior supplementary motor areas. These findings suggest the involvement of the occipitotemporal cortex and a broad frontoparietal network when, as in the visuomotor task, object-centred information guides movement. When the same data underlie declarative reports, as in the matching-to-sample task, the occipitotemporal cortex remains engaged but the frontoparietal network diminishes in importance.

Adolescent↗
PubMed1998

The functional neuroanatomy of simple and complex sequential finger movements: a PET study.

The brain regions activated by simple repetitive and sequential finger movements of different length were localized by measuring regional cerebral blood flow (rCBF) with PET. The experimental design consisted of finger movements cued by auditory pacing at 0.5 Hz. In all conditions of different sequence length the contralateral primary sensorimotor and premotor cortex, supplementary motor area and ipsilateral cerebellar cortex were activated. These areas showed a large increase in activation from rest to simple repetitive movement, and a further increase with the shortest sequence, suggesting an executive role in running sequences. The ipsilateral premotor area (Brodmann area 6), bilateral posterior parietal areas (Brodmann area 7) and precuneus showed an increase in rCBF related only to the length of the sequences, without any change from rest to simple repetitive movement. These areas are more selectively related to sequence performance. This finding is consistent with the hypothesis that these areas function in the storage of motor sequences in spatial working memory. Our results suggest that sequential finger movements recruit discrete sets of brain areas with different functions.

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↗
PubMed1997

Dopaminergic function in familial Parkinson's disease: a clinical and 18F-dopa positron emission tomography study.

There is increasing evidence for familial aggregation in Parkinson's disease (PD). It is possible that some asymptomatic relatives of PD patients have subclinical nigral Lewy body pathology and their identification could help determine the true prevalence of the disease. We used 18F-dopa positron emission tomography to investigate nigrostriatal dopaminergic terminal function in asymptomatic members of 7 unrelated kindreds in which at least 2 members had parkinsonism. Eight (25%) of the 32 asymptomatic relatives showed abnormal putamen 18F-dopa uptake (2.5 standard deviations below the normal mean). When discriminant function analysis was applied, all of these 8 subjects plus another 3 were classified with high probability as having PD. On neurological examination, 5 of the 32 relatives scanned had an isolated mild postural tremor and 2 of these 5 had reduced putamen uptake. Our findings provide further support for a role of inheritance in the etiology of PD and suggest that the penetrance for nigrostriatal dopaminergic dysfunction in familial clusters of PD is higher than the prevalence of clinical parkinsonism reported in epidemiological surveys.

Adult↗
PubMed1997

Alterations in opioid receptor binding in Parkinson's disease patients with levodopa-induced dyskinesias.

Levodopa-induced dyskinesias remain a major challenge in the therapeutic management of Parkinson's disease (PD). Their etiology is unknown although dysfunction of striatal opioid transmission has been implicated in experimental models of PD. To determine whether the opioid system is involved in human dyskinetic PD, we measured in vivo opioid receptor binding in PD patients with and without levodopa-induced dyskinesias, using positron emission tomography (PET) and the opioid receptor ligand [11C]diprenorphine. Striatal and thalamic/occipital uptake ratios were calculated using a region of interest (ROI) approach. In addition, we used statistical parametric mapping (SPM) and images reflecting the volume of distribution of [11C]diprenorphine to assess changes in cerebral receptor binding on a voxel-by-voxel basis. By using the ROI approach, we found significantly reduced striatal and thalamic opioid binding in dyskinetic, but not in nondyskinetic, PD patients. The SPM approach confirmed reduced availability in these areas and, in addition, showed decreased cingulate and increased prefrontal opioid receptor binding in the dyskinetic patients. Our findings confirm that altered opioid transmission is part of the pathophysiology of levodopa-induced dyskinesias in PD and support further investigation into the role of opioid agents in the management of these involuntary movements.

Adult↗
PubMed1997

Cortical control of movement in Huntington's disease. A PET activation study.

Regional cerebral blood flow was measured with H2(15)O PET in seven patients with choreic Huntington's disease and seven age-matched control subjects. Subjects were scanned at rest and when performing paced joystick movements, in freely chosen directions, with the dominant arm. During movement, the patients showed impaired activation of contralateral primary motor, medial premotor, bilateral parietal and bilateral prefrontal areas along with increased activation of bilateral insular areas. The underactivity of frontal areas in Huntington's disease is similar to the pattern of impaired activation in Parkinson's disease and is likely to result from degeneration of basal ganglia to frontal projections. Primary motor underactivity may explain the bradykinesia that these patients exhibit and, if inhibitory neurons are involved, also their chorea.

Adult↗
PubMed1997

11C-diprenorphine binding in Huntington's disease: a comparison of region of interest analysis with statistical parametric mapping.

We compare region of interest (ROI) analytical approaches with statistical parametric mapping (SPM) of 11C-diprenorphine positron emission tomography findings in five patients with Huntington's disease (HD) and nine age-matched controls. The ROI were placed on caudate, putamen, and an occipital reference area. Ratios of striatal-occipital uptake from averaged static images centered at 60 minutes showed a mean 20% reduction in caudate (P = 0.034) and 15% reduction in putamen (P = 0.095) receptor binding in the HD patients. Dynamic data from caudate and putamen ROI, together with a plasma tracer input function, were analyzed using spectral analysis to give regional impulse response functions. Regional data at 60 minutes after impulse showed a mean 29% decrease in caudate (P = 0.006) and 23% decrease in putamen (P = 0.029) opioid binding in the HD cohort. Parametric images of tracer binding also were produced with spectral analysis on a voxel basis. The images of the unit impulse response function at 60 minutes showed a mean 31% decrease in caudate (P = 0.005) and a 26% decrease in putamen binding (P = 0.011) in HD. The voxel-based parametric images were transformed into standard stereotactic space, and a between-group comparison (patient versus controls) was performed with SPM. This approach revealed symmetrical decreases in caudate (peak 40% decrease, z score = 4.38) and putamen opioid binding (peak 24% decrease, z score = 4.686) with additional nonhypothesized changes in cingulate, prefrontal, and thalamic areas. The significance and precision of changes measured with spectral analysis applied to dynamic data sets were superior to ROI-based ratio analysis on static images. The SPM replicated the striatal reductions in opioid binding in HD and detected additional nonpredicted changes. This study suggests that SPM is a valid alternative to conventional ROI analytical approaches for determining binding changes with positron emission tomography and may have advantages over region-based analyses in exploratory studies.

Adult↗
PubMed1996

Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington's disease.

We have investigated striatal dopamine D1 and D2 receptor binding in asymptomatic subjects from Huntington's disease (HD) families using positron emission tomography. Nineteen adult subjects at risk of developing HD were scanned with 11C-SCH 23390 and 11C-raclopride to calculate the D1 and D2 receptor binding potential, respectively. Eight of the 19 were shown to have the HD mutation; of these, 4 subjects had significant reductions in striatal dopamine receptor binding. Abnormalities were more common in older subjects and were not correlated with the size of the HD mutation. There was a strong coefficient of correlation between individual levels of striatal D1 and D2 binding in subjects with the mutation. Of 6 other cases with a 50% risk of carrying the HD gene, 1 showed subclinical loss of caudate and putamen D2 binding. Our study suggests that both striatal D1 and D2 dopamine receptors are lost in parallel from both caudate and putamen in presymptomatic HD and that dopamine receptor binding provides a sensitive means of detecting subclinical striatal dysfunction.

Adult↗
PubMed1996

Proton magnetic resonance spectroscopy in Huntington's disease: evidence in favour of the glutamate excitotoxic theory.

The gene responsible for Huntington's disease (HD) has been located, but its action and the pathophysiology of HD remain unclear. Glutamate excitotoxicity may contribute to the striatal neurodegeneration seen in HD. We used localised proton magnetic resonance spectroscopy (MRS) of the brain to investigate five patients with early HD, one symptom-free gene carrier, and 14 healthy volunteers. Peak area ratios of choline-containing compounds (Cho), glutamine and glutamate (Glx), and N-acetyl moieties including N-acetylaspartate (NAx), relative to creatine (Cr), were calculated. Spectra were analysed from the striatum and the occipital and the temporal cortex. The HD patients all had an elevated Glx/Cr in spectra localised to the striatum, compared with healthy controls, and one patient also had an elevated thalamic Glx/Cr. The mean Glx/Cr was unaltered in the cortical spectra of HD patients. The asymptomatic gene carrier displayed no spectral abnormalities. Our findings suggest disordered striatal glutamate metabolism and may support the theory of glutamate excitotoxicity in HD.

Aspartic Acid↗