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D J Brooks

Publications and source records attributed to D J Brooks.

At least 109 records · Page 6Linked to original sources
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

In vivo [11C]flumazenil-PET correlates with ex vivo [3H]flumazenil autoradiography in hippocampal sclerosis.

By using [11C]flumazenil-positron emission tomography ([11C]FMZ-PET), we have previously shown that reductions of central benzodiazepine receptors (cBZRs) are restricted to the hippocampus in mesial temporal lobe epilepsy (mTLE) caused by unilateral hippocampal sclerosis (HS). Receptor autoradiographic studies on resected hippocampal specimens from the same patients demonstrated loss of cBZRs that was over and above loss of neurons in the CA1 subregion. Here, we report the first direct comparison of in vivo cBZR binding with [11C]FMZ-PET and ex vivo binding using [3H]FMZ autoradiography. We applied a magnetic resonance imaging-based method for partial volume effect correction to the PET images of [11C]FMZ volume of distribution ([11C]FMZ Vd) obtained in 10 patients with refractory mTLE due to unilateral, histologically verified HS. Saturation autoradiography was performed on the hippocampal specimens obtained from the same patients, allowing calculation of receptor availability ([3H]FMZ Bmax). After correction for partial volume effect, [11C]FMZ Vd in the body of the epileptogenic hippocampus was reduced by a mean of 42.1% compared with normal controls. [3H]FMZ Bmax, determined autoradiographically from the same hippocampal tissue, was reduced by a mean of 42.7% compared with control hippocampi. Absolute in vivo and ex vivo measurements of cBZR binding for the body of the hippocampus were significantly correlated in each individual. Our study demonstrates that reduction of available cBZR on remaining neurons in HS can be reliably detected in vivo by using [11C]FMZ-PET after correction for partial volume effect.

Adult↗
PubMed1998

The early diagnosis of Parkinson's disease.

Current accepted clinical criteria for the diagnosis of Parkinson's disease (PD) provide high sensitivity for detecting parkinsonism but generally show poor specificity for identifying brainstem Lewy body disease. Biochemical markers that can be used to reliably diagnose clinical and preclinical PD have thus far been sought unsuccessfully. It is now known that some PD kindreds have a mutation of the alpha-synuclein gene, but this cannot be used as a genetic marker for most familial and sporadic cases. Functional imaging provides a means of discriminating typical from atypical PD, revealing characteristic patterns of loss of dopaminergic function. In addition, PET and SPECT show preserved levels of striatal metabolism and dopamine receptor binding in PD, whereas levels are reduced in the atypical variants. [18F]Dopa PET can also detect preclinical PD. In one series there was a reported 40% prevalence of preclinical dopaminergic dysfunction in asymptomatic adult relatives of familial PD patients. Finally, PET and SPECT can both be used to follow PD progression objectively. Such studies suggest an annual 4 to 12% loss of dopamine terminal function in early PD and a preclinical disease window of only a few years. In the future, functional imaging is likely to play an increasingly important role in assessing the efficacy of putative neuroprotective agents.

Biomarkers↗
PubMed1998

Ropinirole in the treatment of early Parkinson's disease: a 6-month interim report of a 5-year levodopa-controlled study. 056 Study Group.

The efficacies of ropinirole and levodopa were compared after 6 months of treatment in a planned interim analysis of a 5-year, double-blind, randomized, multicenter study of patients with early Parkinson's disease requiring dopaminergic therapy. The percentage of improvement in the Unified Parkinson's Disease Rating Scale total motor examination score was significantly higher for levodopa (44%) than for ropinirole (32%). The proportion of "responders" (Unified Parkinson's Disease Rating Scale improvement of at least 30%) did not differ between groups (levodopa, 58%; ropinirole, 48%). There was no difference between the groups for improvement on the Clinical Global Impression scale in patients with Hoehn and Yahr stages I, I.5, or II, but a significantly higher proportion of patients with Hoehn and Yahr stages II.5 or III showed Clinical Global Impression score improvement with levodopa. Emergent adverse events occurred in 84% of patients in both treatment groups, the principal symptom in each group being nausea. The incidence of serious adverse events was low (8% for ropinirole, 9% for levodopa). The results suggest that ropinirole and levodopa are equally effective in less severe Parkinson's disease; in more advanced Parkinson's disease, levodopa is superior.

Adult↗
PubMed1998

Ropinirole versus bromocriptine in the treatment of early Parkinson's disease: a 6-month interim report of a 3-year study. 053 Study Group.

We compared the efficacy and safety of ropinirole with that of bromocriptine after 6 months of treatment in a planned interim analysis of a 3-year, double-blind, randomized, multicenter study of 335 patients with early Parkinson's disease requiring dopaminergic therapy. Patients, treated with or without selegiline, received either ropinirole or bromocriptine. The mean Unified Parkinson's Disease Rating Scale (UPDRS) total motor examination scores (Part III) at baseline were similar in the four strata. Overall, and in the non-selegiline subgroup, the percentage improvement in the UPDRS total motor examination score was significantly higher for ropinirole than for bromocriptine, as was the proportion of "responders." In the selegiline subgroup, however, there was no significant difference between treatments. Similarly, in the non-selegiline subgroup, there was a significantly higher proportion of "improvers" on the Clinical Global Impression scale with ropinirole than with bromocriptine, whereas in the selegiline subgroup, there was no significant difference. Emergent adverse events occurred in 80% of patients in both treatment groups, the principal symptom in each group being nausea. The incidence of serious adverse events was low (3% for ropinirole, 6.6% for bromocriptine). The data indicate that (a) in the absence of selegiline, ropinirole is effective and superior to bromocriptine; and (b) selegiline does not affect the response in patients treated with ropinirole, but enhances the effects of bromocriptine.

Adult↗
PubMed1998

Increased activation of frontal areas during arm movement in idiopathic torsion dystonia.

Most positron emission tomography (PET) studies of regional cerebral function in idiopathic torsion dystonia (ITD) have failed to show abnormalities, but there have been few studies of the changes in regional cerebral blood flow (rCBF) that occur during movement in dystonia. Using PET, we have studied six patients with familial generalized ITD both at rest and while moving a joystick with the right hand. The patterns of CBF change obtained were compared with those in six age-matched control subjects. In the dystonia group, free selection of movement was associated with relative increases in rCBF above that observed in control subjects in the left premotor area, the supplementary motor area (SMA), the anterior cingulate cortex, and the left dorsolateral prefrontal area. Subcortical increases were observed within the cerebellum and the putamen. There was a relative decrease in flow through the contralateral primary sensorimotor cortex. These findings contrast with those reported in patients with Parkinson's disease undertaking the same task in which the activity in the SMA and putamen was decreased. We suggest that arm dystonia in ITD is associated with overactivity of the premotor areas, including the SMA, and that this results from release of the thalamus from the normal inhibitory influence of the globus pallidus internal segment. Other abnormalities of basal ganglia control of brain stem centers may be involved in axial dystonia.

Adult↗
PubMed1998

Functional imaging of tremor.

We review the insight that has been obtained from positron emission tomography (PET) and magnetic resonance imaging (MRI) activation studies on the functional anatomy underlying different forms of tremor. The effects of treatment, both pharmacologic and interventional approaches, on the dysfunctional cerebral systems involved in tremor, also are considered. Finally, we speculate on the neuropharmacologic basis of different types of tremor based on available in vivo PET evidence.

Brain↗
PubMed1998

Comparison of EEG, MRI and PET in reading epilepsy: a case report.

The pathophysiological and neuroanatomical bases of reading epilepsy (RE) are unclear. We performed video-EEG, high quality MRI and [11C]diprenorphine PET in a patient with RE to detect structural and functional abnormalities. EEG showed multifocal seizure onset bilaterally in temporal and fronto-central regions. MRI was normal, whereas [11C]diprenorphine PET revealed peri-ictal opioid binding decreases in both temporal lobes and the left frontal lobe. These findings confirm that RE is due to abnormal activity in the network subserving reading.

Adult↗
PubMed1998

Advances in the understanding of early Huntington's disease using the functional imaging techniques of PET and SPET.

The functional imaging techniques of positron emission tomography (PET) and single photon emission tomography (SPET) have been used to study regional brain function in Huntington's disease (HD) in vivo. Reduced striatal glucose metabolism and dopamine receptor binding are evident in all symptomatic HD patients and in approximately 50% of asymptomatic adult mutation carriers. These characteristics correlate with clinical measures of disease severity. Reduced cortical glucose metabolism and dopamine receptor binding, together with reduced striatal and cortical opioid receptor binding, have also been demonstrated in symptomatic patients with HD. Repeat PET measures of striatal function have been used to monitor the progression of this disease objectively. In the future, functional imaging will provide a valuable way of assessing the efficacy of both fetal striatal cell implants and putative neuroprotective agents, such as nerve growth factors.

Adult↗
PubMed1998

A study of medial pallidotomy for Parkinson's disease: clinical outcome, MRI location and complications.

We have studied the effects of unilateral ventral medial pallidotomy in 26 patients with medically intractable Parkinson's disease with marked drug-induced dyskinesias. Preoperatively, all patients were assessed during one 5-day admission according to the Core Assessment Programme for Intracerebral Transplantation (CAPIT) protocol, including rating in the 'practically defined off' and 'best on' states before and during a single-dose levodopa challenge. Motor performance was assessed with subset categories of the Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests and a standard dyskinesia rating scale. Pallidotomy was performed under stereotaxic CT guidance with intra-operative extracellular microelectrode recording made from the basal ganglia. All patients were re-assessed 3 months postoperatively and a subgroup (n = 9) have so far also been re-assessed after 1 year. Pre- and postoperative performance scores were compared in order to determine which categories of performance improved postoperatively. Significance was accepted at P < 0.005 in order to take into account the multiple number of comparisons performed. Patient medication was compared pre- and postoperatively and the morbidity associated with surgery was also recorded. The most significant improvement postoperatively was the diminution of 'on' dyskinesias contralaterally (67%, P = 0.0001); however, ipsilateral (45%, P = 0.0006) and axial (50%, P = 0.0008) dyskinesias also improved. Contralateral to pallidotomy, the median 'off' motor UPDRS score improved by 27% (P = 0.001) and a significant improvement was also observed in contralateral rigidity by 25% (P = 0.001). There were trends towards improvement in contralateral tremor (33%, P = 0.016) and bradykinesia (24%, P = 0.013) scores. Ipsilateral rigidity improved by 22% (P = 0.005), but other ipsilateral motor scores did not alter significantly. The 'off' gait/postural instability score and 'off' walking time showed marginally significant improvements by 7% (P = 0.007) and 29% (P = 0.014), respectively. On medication, no significant postoperative improvements in parkinsonism were detected. Anti-parkinsonian medication increased by 11% postoperatively. In the subgroup who were available for assessment 1 year postoperatively, responses were generally maintained. Two (7.7%) of the 26 patients had fatal complications (one cerebral haemorrhage and one haemorrhagic infarct) directly related to surgery. Among the remaining 24 patients, four (15.4% of the total 26) had major complications (two persisting and two transient). Ten patients (38.5%) had minor complications. The majority of the complications (major and minor) occurred in the earlier operated patients and the complication rate subsequently declined with increasing operative experience. The remaining 10 patients (38.5%) had no significant side-effects. One of these 10 patients died from an incidental malignant glioma 6 months postoperatively. These findings confirm that levodopa-induced dyskinesias are dramatically reduced following ventral medial pallidotomy and constitute the principal indication for pallidotomy. Improvements in underlying parkinsonism were of smaller magnitude. Pallidotomy may also offer some patients an opportunity to increase antiparkinsonian medication. Patient selection for medial pallidotomy should, therefore, be based largely on anticipated improvements in levodopa-induced dyskinesias, but this must be balanced against the associated morbidity and mortality.

Aged↗
PubMed1998

Cerebral activation in malformations of cortical development.

Malformations of cortical development (MCD) are an important aetiology of localization-related epilepsy. Previous MRI and [11C]flumazenil PET studies have demonstrated widespread structural and neuroreceptor abnormalities beyond the region of MCD that is visually apparent on MRI. We investigated the ability of brain regions affected by MCD to participate in normal cognitive and motor tasks and compared the responses seen in such patients with those in normal subjects. We studied five patients known to have MCD affecting the occipital region and seven normal subjects using H2 (15)O PET whilst they were performing a visual attention task. We also studied five right-handed patients known to have MCD affecting the left frontal lobe and seven right-handed normal subjects, using H2 (15)O PET whilst they were performing a motor learning task with the right hand. The patient and normal control data were examined using statistical parametric mapping to determine the ability of the brain region affected by MCD to participate in the task and also to detect evidence for atypical organization of cortical function in association with the MCD. Eight of the ten patients with MCD showed significant alteration of relative regional cerebral blood flow during the task compared with 'rest' in the affected brain region. These regions included focally dysgenetic cortex, the cortex lining schizencephalic clefts, heterotopic bands, subependymal grey matter heterotopia, and the cortex overlying band and subependymal heterotopia. In addition there was a significant alteration in the overall activation pattern in five patients compared with the normal control groups; in all five patients this atypical organization involved regions of cortex that appeared entirely normal on MRI. We conclude that regions of MCD may participate in normal cognitive functions but widespread cortical atypical organization may be seen. These findings have implications for surgical planning in any such patients.

Adolescent↗
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↗
PubMed1998

Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [18F]dopa PET.

OBJECTIVES: To measure the rate of progression in striatal [18F]dopa metabolism in a large group (n=32) of patients with Parkinson's disease, to estimate the average duration of preclinical period, and to examine the influence of the PET method on the assessment of rate of progression and preclinical period. METHODS: Thirty two patients with Parkinson's disease (mean age 58 (SD 13) years, mean duration 39 (SD 33) months) were assessed with [18F]dopa PET and UPDRS scoring on two occasions a mean of 18 (SD 6) months apart. PET data were sampled with separate caudate and putamen and total striatal regions of interest, and both graphical (Ki) and ratio methods of analysis. RESULTS: The mean annual rate of deterioration in [18F]dopa uptake varied according to structure and method of analysis, with putamen Ki showing the most rapid mean rate of progression (4.7% of normal mean per year). The group showed a significant deterioration (p<0.0004, paired two tailed t test) in UPDRS and in the putamen (p=0.008) and total striatal (p=0.012) [18F]dopa uptake measured using a graphical analysis, but no significant change in caudate or putamen uptake measured by a ratio approach. A study of sensitivity confirmed that putamen Ki was the most sensitive measure of disease progression, caudate ratio the least. Symptom onset in Parkinson's disease was estimated at a mean putamen [18F]dopa uptake (Ki) of 75% of normal and a mean caudate [18F]dopa uptake (Ki) of 91% of normal. CONCLUSIONS: Estimation of mean rate of progression varies according to the sensitivity of a functional imaging method to clinical severity. Sensitivity and reproducibility of method must be considered when designing studies of disease progression and neuroprotection. The mean preclinical period in Parkinson's disease is unlikely to be longer than seven years.

Aged↗
PubMed1998

Role of the human rostral supplementary motor area and the basal ganglia in motor sequence control: investigations with H2 15O PET.

The aim of this study was to investigate the functional anatomy of distributed cortical and subcortical motor areas in the human brain that participate in the central control of overlearned complex sequential unimanual finger movements. On the basis of previous research in nonhuman primates, a principal involvement of basal ganglia medial premotor loops [corrected] was predicted for central control of finger sequences performed automatically. In pertinent areas, a correlation of activation levels with the complexity of a motor sequence was hypothesized. H2 15O positron emission tomography (PET) was used in a group of seven healthy male volunteers [mean age 32.0 +/- 10.4 yr] to determine brain regions where levels of regional cerebral blood flow (rCBF) correlated with graded complexity levels of five different key-press sequences. All sequences were overlearned before PET and involved key-presses of fingers II-V of the right hand. Movements of individual fingers were kept constant throughout all five conditions by external pacing at 1-Hz intervals. Positive correlations of rCBF with increasing sequence complexity were identified in the contralateral rostral supplementary motor area (pre-SMA) and the associated pallido-thalamic loop, as well as in right parietal area 7 and ipsilateral primary motor cortex (M1). In contrast, while rCBF in contralateral M1 and [corrected] extensive parts of caudal SMA was increased compared with rest during task performance, significant correlated increases of rCBF with sequence complexity were not observed. Inverse correlations of rCBF with increasing sequence complexity were identified in mesial prefrontal-, medial temporal-, and anterior cingulate areas. The findings provide further evidence in humans supporting the notion of a segregation of SMA into functionally distinct subcomponents: although pre-SMA was differentially activated depending on the complexity of a sequence of learned finger movements, such modulation was not detectable in caudal SMA (except the most antero-superior part), implicating a motor executive role. Our observations of complexity-correlated rCBF increases in anterior globus pallidus suggest a specific role for the basal ganglia in the process of sequence facilitation and control. They may act to filter and focus input from motor cortical areas as patterns of action become increasingly complex.

Adult↗
PubMed1998

Prefrontal cortex activity in people with schizophrenia and control subjects. Evidence from positron emission tomography for remission of 'hypofrontality' with recovery from acute schizophrenia.

BACKGROUND: Hypo-activation of the left dorsolateral prefrontal cortex is inconsistently found in neuroimaging studies of schizophrenia. As the left dorsolateral prefrontal cortex is involved in the generation of action, disordered function in this region may be implicated in schizophrenic symptomatology. METHOD: We used H2 15O positron emission tomography to study dorsolateral prefrontal cortical function in men with schizophrenia (n = 13) and male control subjects (n = 6) performing joystick movements on two occasions, 4-6 weeks apart. The patients were initially in relapse. To clarify dorsolateral prefrontal cortical function we also scanned another group of control subjects (n = 5) performing mouth movements. RESULTS: The control subjects performing hand or mouth movements activated the left dorsolateral prefrontal cortex to a maximum when the movements were self-selected. The men with relapsed schizophrenia exhibited left dorsolateral prefrontal cortical hypoactivation, which remitted with symptomatic improvement. CONCLUSIONS: Hypofrontality in these patients is a dynamic phenomenon across time, possibly related to current symptomatology. The most appropriate question about the presence of hypofrontality in schizophrenia may be when, rather than whether, it will occur.

Adult↗
PubMed1998

11C-flumazenil PET in neocortical epilepsy.

OBJECTIVE: To investigate focal cortical abnormalities of gamma-aminobutyric acid type A-central benzodiazepine receptors (GABA(A)-cBZRs) in patients with extratemporal partial seizures with acquired lesions and in patients with normal high-resolution MRI. METHODS: Six patients with acquired lesions and 18 patients with normal high-resolution MRI and extratemporal partial seizures, as well as 24 normal controls, were studied with 11C-flumazenil (FMZ) PET to produce voxel-by-voxel images of FMZ volume of distribution (FMZVD), which reflects density of GABA(A)-cBZRs. These images were analyzed using Statistical Parametric Mapping (SPM). Each patient was compared with the control group to reveal regions with abnormal FMZVD at p < 0.001 uncorrected, corrected to p < 0.05 for the whole brain volume. Each normal control was compared with the remaining controls in the same manner. RESULTS: All six patients with acquired lesions had a single region of reduced FMZVD. Thirteen of 18 patients with normal MRI had regions of abnormal cortical FMZVD: 10 had regions of increased FMZVD, 6 had regions of decreased FMZVD, and 3 had both regions of increased and decreased FMZVD. Seven patients had an abnormality in the lobe and 12 in the hemisphere of presumed seizure origin. CONCLUSIONS: FMZ PET analyzed with SPM is an automated, objective, sensitive, and specific means for detecting regional cortical abnormalities of GABA(A)-cBZRs in patients with partial seizures. This technique may be useful in the evaluation of patients with refractory partial seizures for surgical treatment, particularly in those patients with normal MRI.

Adolescent↗
PubMed1998

Exploring the temporal nature of hemodynamic responses of cortical motor areas using functional MRI.

OBJECTIVE: To use functional MRI (fMRI) to study grouped patterns of cerebral activation and the course of hemodynamic responses during performance of two activation tasks (paradigms) using a hand-held joystick to perform movements in a repetitively fixed direction and movements in freely selected random directions. BACKGROUND: Evidence from lesion, electrophysiologic, and functional imaging studies implicates prefrontal and mesial frontal cortex in motor preparation and primary motor cortex in motor execution. fMRI can be used to study cerebral activation and has practical advantages over other methods of functional neuroimaging. METHODS: We acquired 100 multislice T2*-weighted data sets from five healthy volunteers during performance of each paradigm using conventional fMRI. For each paradigm, rest and movement epochs were alternated every 30 seconds. After coregistration and spatial normalization, we combined the data for group studies. We used statistical parametric mapping to compare the early (first 15 seconds) components of the movement epochs with rest as well as the late (last 15 seconds) components of the movement epochs with rest. RESULTS: During the early phase of both paradigms, significant activation was present in rostral and caudal mesial premotor cortex. Right prefrontal cortex was significantly activated during the early component of freely selected joystick movements. Activation of rostral supplementary motor area was maintained during the late component of freely selected movements but decreased during repetitively fixed movements. In contrast, significant activation in contralateral sensorimotor cortex was maintained during both early and late components of both paradigms. CONCLUSIONS: fMRI can detect cortical activation. The temporal resolution of fMRI also allows adaptation of blood oxygenation level-dependent (BOLD) contrast signal to be detected in association cortex. However, the level of BOLD contrast signal in primary motor cortex remained significantly elevated throughout task performance.

Adult↗