PubMed Health⌕ Search

Biomedical subjects

Maren Carbon

Publications and source records attributed to Maren Carbon.

At least 19 recordsLinked to original sources
PubMed2006

Metabolic brain networks associated with cognitive function in Parkinson's disease.

The motor manifestations of Parkinson's disease (PD) have been linked to an abnormal spatial covariance pattern involving basal ganglia thalamocortical pathways. By contrast, little is known about the functional networks that underlie cognitive dysfunction in this disorder. To identify such patterns, we studied 15 non-demented PD patients using FDG PET and a voxel-based network modeling approach. We detected a significant covariance pattern that correlated (p<0.01) with performance on tests of memory and executive functioning. This PD-related cognitive pattern (PDCP) was characterized by metabolic reductions in frontal and parietal association areas and relative increases in the cerebellar vermis and dentate nuclei. To validate this pattern, we analyzed data from 32 subsequent PD patients of similar age, disease duration and severity. Prospective measurements of PDCP activity predicted memory performance (p<0.005), visuospatial function (p<0.01), and perceptual motor speed (p<0.005) in this validation sample. PDCP scores additionally exhibited an excellent degree of test-retest reliability (intraclass correlation coefficient, ICC=0.89) in patients undergoing repeat FDG PET at an 8-week interval. Unlike the PD-related motor pattern, PDCP expression was not significantly altered by antiparkinsonian treatment with either intravenous levodopa or deep brain stimulation (DBS). These findings substantiate the PDCP as a reproducible imaging marker of cognitive function in PD. Because PDCP expression is not altered by routine antiparkinsonian treatment, this measure of network activity may prove useful in clinical trials targeting the progression of non-motor manifestations of this disorder.

Brain↗
PubMed2006

Correlates of movement initiation and velocity in Parkinson's disease: A longitudinal PET study.

Limited data exist concerning the mechanisms that underlie the different motor features of Parkinson's disease (PD) and their course over time. Our aims were (1) to identify longitudinal changes in PD patients and (2) to determine the neural correlates of the changes in movement initiation and velocity that occur in the course the disease. Thirteen early stage PD patients were scanned twice off antiparkinsonian medication with H(2)15O PET. Imaging was performed at baseline and again after 2 years while the subjects performed a motor task that was kinematically controlled across time. Paced reaching movements were made towards targets that were presented in a predictable order. Measures of movement onset time (OT) and mean velocity (MV) were recorded during PET. OT and MV decreased significantly from baseline to follow-up. With advancing disease, increasing subcortical activation was detected in the pallidum bilaterally and in the left putamen. In the cortex, motor-related activation increased in the right pre-SMA, anterior cingulate cortex and the left postcentral gyrus. Progressive delays in movement initiation (OT) correlated with increases in the right dorsal premotor cortex (dPMC). Slowing of movement (MV) was associated with declining activation in the left dorsolateral prefrontal cortex and dPMC. Our data suggest that with advancing PD, motor performance is associated with the recruitment of brain regions normally involved in the execution of more complex tasks.

Adult↗
PubMed2006

Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism.

Parkinson's disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group x time interaction, P<0.001). On FDG PET, the GAD animals exhibited an increase in glucose utilization in the right motor cortex relative to GFP controls (P<0.001). Metabolism in this region correlated with clinical ratings at end point (P<0.01). Histology confirmed GAD expression in treated animals. These findings suggest that STN AAV-GAD is well tolerated and potentially effective in a primate model of PD. The changes in motor cortical glucose utilization observed after gene therapy are consistent with the modulation of metabolic brain networks associated with this disorder.

Animals↗
PubMed2006

Functional imaging of sequence learning in Parkinson's disease.

Sequence learning, a cognitive task linked to cortico-striatal function, is impaired in Parkinson's disease (PD). We chose this task as a behavioral paradigm to study the functional architecture of PD in treated and untreated conditions. In our studies, participants were scanned with H(2)(15)O while performing a kinematically controlled motor sequence learning task and a matching motor baseline task. Experiments revealed that a specific sequence learning network predicts learning in normal subjects, and in independent cohorts of early and advanced PD patients. The analysis of the relationship of network activity to learning performance revealed diverging influences of dopaminergic therapy and deep brain stimulation (DBS). DBS of the internal GP and of STN increased network activity and task performance, while levodopa decreased both measures. In separate studies, we investigated the role of dopaminergic modulation on brain activation during sequence learning. In healthy subjects dopamine transporter (DAT) binding correlated with learning-related brain activation in prefrontal, premotor and cingulate cortices, and in the thalamus. By contrast, in PD most of these regional relationships were lost. Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic input. In a final set of studies, we found a significant decline in learning performance in early stage PD patients followed over the course of 2 years. Longitudinal declines in learning-related activation were found in parietal areas, while concomitant increases were localized to the left hippocampus. These observations support hypotheses on disease-stage and task-specific effects within the different cortico-striato-pallido-thalamocortical loops and the mesocortical system in PD.

Aged↗
PubMed2006

Preclinical Huntington's disease: compensatory brain responses during learning.

Motor sequence learning is abnormal in presymptomatic Huntington's disease (p-HD). The neural substrates underlying this early manifestation of HD are poorly understood. To study the mechanism of this cognitive abnormality in p-HD, we used positron emission tomography to record brain activity during motor sequence learning in these subjects. Eleven p-HD subjects (age, 45.8 +/- 11.0 years; CAG repeat length, 41.6 +/- 1.8) and 11 age-matched control subjects (age, 45.3 +/- 13.4 years) underwent H(2) (15)O positron emission tomography while performing a set of kinematically controlled motor sequence learning and execution tasks. Differences in regional brain activation responses between groups and conditions were assessed. In addition, we identified discrete regions in which learning-related activity correlated with performance. We found that sequence learning was impaired in p-HD subjects despite normal motor performance. In p-HD, activation responses during learning were abnormally increased in the left mediodorsal thalamus and orbitofrontal cortex (OFC; BA 11/47). Impaired learning performance in these subjects was associated with increased activation responses in the precuneus (BA 18/31). These data suggest that enhanced activation of thalamocortical pathways during motor learning can compensate for caudate degeneration in p-HD. Nonetheless, this mechanism may not be sufficient to sustain a normal level of task performance, even during the presymptomatic stage of the disease.

Adult↗
PubMed2006

Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents.

Although second-generation antipsychotics (SGAs) are used increasingly in children and adolescents, data on the effectiveness and safety in pediatric populations are still sparse. Much of the safety information is derived from studies conducted in adults. This derivation is problematic because children and adolescents are exposed to SGAs during a phase of unparalleled physical and psychologic development that can affect pharmacokinetic and pharmacodynamic drug actions, efficacy, and side-effect patterns. This article presents an overview of SGA-related side effects in children and adolescents and strategies to monitor health outcomes effectively in youngsters receiving SGAs.

Adolescent↗
PubMed2004

Microstructural white matter changes in carriers of the DYT1 gene mutation.

We tested the hypothesis that the DYT1 genotype is associated with a disorder of anatomical connectivity involving primarily the sensorimotor cortex. We used diffusion tensor magnetic resonance imaging (DTI) to assess the microstructure of white matter pathways in mutation carriers and control subjects. Fractional anisotropy (FA), a measure of axonal integrity and coherence, was reduced (p < 0.005) in the subgyral white matter of the sensorimotor cortex of DYT1 carriers. Abnormal anatomical connectivity of the supplementary motor area may contribute to the susceptibility of DYT1 carriers to develop clinical manifestations of dystonia.

Adult↗
PubMed2004

Executive processes in Parkinson's disease: FDG-PET and network analysis.

It is assumed widely that the clinical expression of Parkinson's Disease (PD), both motor and cognitive, is subtended by topographically distributed brain networks. However, little is known about the functional neuroanatomy of executive dysfunction in PD. Our objective was to validate further in a PD group the use of network analysis to assess the relationship between executive processes and pathological disorganization of frontostriatal networks. We studied 15 patients with idiopathic PD, and 7 age-matched normal controls, using resting [(18)F]fluorodeoxyglucose (FDG) and high-resolution positron emission tomography (PET). We carried out network analysis on regional metabolic data to identify specific covariation patterns associated with motor and executive dysfunction. We detected two independent patterns relating respectively to the two clinical abnormalities. The first pattern (principal component 1) was topographically similar to that described previously in other PD populations. Subject scores for this pattern discriminated patients from controls and correlated significantly with bradykinesia ratings (P = 0.013, r = 0.655) in PD patients. The second pattern (principal component 2) was characterized by relative ventromedial frontal, hippocampal, and striatal hypometabolism, associated with mediodorsal thalamic hypermetabolism. In the PD group, scores from this pattern correlated with scores on the conditional associative learning (CAL; P = 0.01, r = 0.690) and the Brown Peterson paradigm (BPP; P = 0.017, r = -0.651) tests, respectively assessing strategy and planning, and working memory. According to these findings, the networks subserving bradykinesia and executive dysfunction in PD seems to be topographically distinct and to involve different aspects of subcortico-cortical processing.

Adult↗
PubMed2004

Assessment of disease progression in parkinsonism.

In this brief article, we report preliminary results from an NIH-funded project to use functional brain imaging to study the natural history of neurodegeneration during the earliest clinical stages of PD. We used positron emission tomography (PET) to measure DAT binding (18F-FPCIT), resting glucose metabolism (18FFDG), and brain activation (H215O) responses in 20 newly diagnosed PD patients. The longitudinal study is being conducted at three time points for each measurement during a 5-year period. The interim results indicate the evolution of abnormal metabolic brain networks and activation responses occurring in parallel with presynaptic nigrostriatal dopamine dysfunction in early PD.

Aged↗
PubMed2004

Non-invasive magnetic detection of human injury currents.

OBJECTIVE: Injury currents are a hallmark of acute lesions in polarized cells. Our objective was to develop a non-invasive technique for monitoring human near-DC injury currents in vivo. METHODS: Using diagnostic muscle biopsy as controlled paradigm, injury-related magnetic DC-fields were mapped for 60 min postsurgery over leg muscle lesions of 9 subjects. A 49-channel magnetometer was used in combination with a mechanical horizontal modulation of the subject beneath the sensor array. RESULTS: Magnetic DC-field maps showed salient differences between biopsy and contralateral legs in 8/9 patients with a characteristic slowly decaying field in all biopsy legs. A variety of anomalous DC-field patterns was recorded over the biopsy sites, corresponding to theoretically predicted geometric variations of equivalent DC-current dipoles, i.e. wound surfaces, pointing into opposing muscle fibre ends. By contrast, all control measurements showed an elongated dipolar DC-field pattern. Additionally, mean global DC-field strengths were significantly higher over biopsy legs compared to the contralateral site. CONCLUSIONS: Our pilot data illustrate that human injury currents can be detected using non-invasive magnetometry. Thus, DC-magnetometry may provide an essential new tool for clinical monitoring of injury currents, possibly also in brain tissue, e.g. in case of anoxic or peri-infarct depolarizations.

Adult↗
PubMed2004

Caudate nucleus: influence of dopaminergic input on sequence learning and brain activation in Parkinsonism.

In this study, we tested the hypotheses that (1) the acquisition of sequential information is related to the integrity of dopaminergic input to the caudate nucleus; and (2) the integrity of dopaminergic input to the caudate nucleus correlates significantly with brain activation during sequence acquisition. Twelve early stage Parkinson's disease (PD) patients and six age-matched healthy volunteers were scanned using a dual tracer PET imaging design. All subjects were scanned with [(18)F]fluoropropyl-betaCIT (FPCIT) to measure striatal dopamine transporter (DAT) binding and with [(15)O]water to assess activation during a sequence learning task where movements were made to a repeating sequence of eight targets. Caudate and putamen DAT binding in the PD cohort was reduced by 15% and 43%, respectively. In PD, caudate DAT binding correlated with target acquisition (R = 0.57, P < 0.05), while putamen DAT binding did not correlate with performance. In volunteers, caudate DAT binding correlated with learning-related activation (P < 0.05, corrected for multiple comparisons) in the left dorsolateral and ventral prefrontal cortices, the anterior cingulate and premotor regions, and the right cerebellum. A significant correlation with caudate DAT binding was additionally detected in the right anteromedial thalamus, extending into the rostral midbrain. By contrast, in the PD cohort, most of these regional relationships were lost: Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic tone. Our findings suggest that sequence learning is normally associated with tight coupling between dopaminergic input to the caudate and thalamo-cortical functional activity. Despite minimal reductions in nigro-caudate input, PD patients demonstrate a loss of this coupling early in the disease.

Aged↗
PubMed2003

Impaired sequence learning in carriers of the DYT1 dystonia mutation.

Previous positron emission tomography (PET) studies have shown that nonmanifesting carriers of the DYT1 dystonia mutation express an abnormal pattern of resting glucose metabolism. To determine whether motor behavior is impaired in these subjects, we compared movement and sequence learning in 12 clinically unaffected DYT1 carriers with 12 age-matched controls. Regional differences in brain function during task performance were assessed with simultaneous H(2) (15)O/PET. We found that motor performance was similar in the DYT1 and control groups, with no significant differences in movement time and spatial accuracy measured during each of the tasks. In contrast, sequence learning was reduced in gene carriers relative to controls (p < 0.01). PET imaging during motor execution showed increased activation in gene carriers (p < 0.001, uncorrected) in the left premotor cortex and right supplementary motor area, with concomitant reduction in the posterior medial cerebellum. During sequence learning, activation responses in DYT1 carriers were increased in the left ventral prefrontal cortex, and lateral cerebellum. These findings suggest that abnormalities in motor behavior and brain function exist in clinically nonmanifesting DYT1 carriers. Although localized increases in neural activity may enable normal movement execution in these subjects, this mechanism may not compensate for their defect in sequence learning.

Carrier Proteins↗
PubMed2003

Learning networks in health and Parkinson's disease: reproducibility and treatment effects.

In a previous H(2) (15)O/PET study of motor sequence learning, we used principal components analysis (PCA) of region of interest (ROI) data to identify performance-related activation patterns in normal subjects and patients with Parkinson's disease (PD). In the present study, we determined whether these patterns predicted learning performance in subsequent normal and untreated PD cohorts. Using a voxel-based PCA approach, we correlated the changes in network activity that occurred during antiparkinsonian treatment and their relationship to learning performance. We found that the previously identified ROI-based patterns correlated with learning performance in the prospective normal (P < 0.01) and untreated PD (P < 0.05) cohorts. Voxel analysis revealed that target retrieval was related to a network characterized by bilateral activation of the dorsolateral prefrontal, premotor and anterior cingulate cortex, the precuneus, and the occipital association areas as well as the right ventral prefrontal and inferior parietal regions. Target acquisition was associated with a different network involving activation of the caudate, putamen, and right dentate nucleus, as well as the left ventral prefrontal and inferior parietal areas. Antiparkinsonian therapy gave rise to changes in retrieval performance that correlated with network modulation (P < 0.01). Increases in network activation and learning performance occurred with internal pallidal deep brain stimulation (GPi DBS); decrements in these measures were present with levodopa. Our findings suggest that network analysis of activation data can provide stable descriptors of learning performance. Network quantification can provide an objective means of assessing the effects of therapy on cognitive functioning in neurodegenerative disorders.

Adult↗
PubMed2003

Functional imaging of cognition in Parkinson's disease.

PURPOSE OF REVIEW: Cognitive deficits that occur even early in the course of Parkinson's disease have received increasing attention in current imaging research. The exact physio-pathological processes mediating the deficits and the complex relationship of cognitive signs and antiparkinsonian treatment are not well understood. A clearer understanding of these mechanisms could potentially influence treatment choices, drug development and, ultimately, patient care. RECENT FINDINGS: Abnormal networks identified in studies of resting state metabolism in Parkinson's disease represent metabolic markers for remote effects of striato-nigral degeneration. These metabolic changes include subcortico-cortical networks, in particular cognitive cortico-striato-pallidal-thalamocortical loops. Recent brain studies focus on intervention-related brain changes. They illustrate different task-specific changes in brain activation with deep brain stimulation and with levodopa. Variable results of stimulation can be attributed to different effects on segregated cortico-striato-pallidal-thalamocortical loops during stimulation. By contrast, the heterogeneity observed in studies with levodopa possibly reflects the disease-stage and task-specific effects of levodopa. A decline in caudate dopamine modulated basal ganglia outflow appears to contribute to executive dysfunction and to brain activation changes in these loops at early Parkisnon's disease stages, while mesocortical degeneration mediated increases of inefficient dorsolateral prefrontal cortex activation may display a feature of more advanced disease stages only. SUMMARY: Despite evidence for the role of dopamine and cortico-striato-pallidal-thalamocortical loops in cognition, the specific contributions of mesocortical dopamine depletion and striatal dysfunction with downstream consequences on the loops remain to be separated. Additionally, more research is needed into the role of non-dopaminergic pathology in cognitive decline in Parkinson's disease.

Cerebral Cortex↗
PubMed2002

Pallidal stimulation for parkinsonism: improved brain activation during sequence learning.

We used (15)O-labeled water and positron emission tomography to assess the effect of deep brain stimulation of the internal globus pallidus on motor sequence learning in Parkinson's disease. Seven right-handed patients were scanned on and off stimulation while they were performing a motor sequence learning task and a kinematically matched motor execution reference task. The scans were performed after a 12-hour medication washout. Stimulation parameters were adjusted for maximal motor improvement; experimental task parameters were held constant across stimulation conditions. Internal globus pallidus stimulation improved motor ratings by 37% (p < 0.01). During the sequence learning task, stimulation improved performance as measured by several correct anticipatory movements (p < 0.01) and by verbal report (p < 0.001). Concurrent positron emission tomography imaging during learning demonstrated significant (p < 0.01) increases in brain activation with stimulation in the left dorsolateral prefrontal cortex, bilaterally in premotor cortex, and in posterior parietal and occipital association areas. Stimulation did not affect the activity of these regions during the performance of the motor execution reference task. These findings suggest that internal globus pallidus deep brain stimulation can enhance the activity of prefrontal cortico-striato-pallidothalamic loops and related transcortical pathways. Improved sequence learning with stimulation may be directly related to these functional changes.

Adult↗
PubMed2002

Primary dystonia: is abnormal functional brain architecture linked to genotype?

The DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations.

Adult↗