Abnormal Network Activity Research Articles

High resolution positron emission tomography demonstrates basal ganglia dysfunction in early Parkinson's disease

High resolution positron emission tomography (PET) with the newly developed HRRT scanner (Siemens/CTI) permits the reliable quantification of 18-Fluorodeoxyglucose (FDG) uptake as a marker of neuronal activity in small subcortical nuclei which are involved in the pathophysiology of Parkinson's disease (PD). We investigated the normalized cerebral metabolic rates of glucose (nCMRGlc) with HRRT PET in basal ganglia (BG) nuclei of 10 early-stage PD patients and in 9 healthy volunteers. PET data were co-registered to magnetic resonance images and analyzed in a three-dimensional volume-of-interest (VOI) approach. After normalization for global brain activity, PD patients showed a significantly higher nCMRGlc than controls bilaterally in the BG output nuclei (pallidum, substantia nigra) and unilateral in the caudate and putamen. The metabolic activity of the nucleus accumbens, the subthalamic nucleus, the corpus amygdaloideum and the red nucleus was normal. These first HRRT PET data in living parkinsonian humans extend previous brain imaging findings of abnormal network activity in the BG and confirm output nuclei and striatal overactivation also in early stage PD patients.

Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease

Parkinson's disease (PD) is characterized by elevated expression of an abnormal metabolic brain network that is reduced by clinically effective treatment. We used fluorodeoxyglucose (FDG) positron emission tomography (PET) to determine the basis for motor improvement in 12 PD patients receiving unilateral subthalamic nucleus (STN) infusion of an adenoassociated virus vector expressing glutamic acid decarboxylase (AAV-GAD). After gene therapy, we observed significant reductions in thalamic metabolism on the operated side as well as concurrent metabolic increases in ipsilateral motor and premotor cortical regions. Abnormal elevations in the activity of metabolic networks associated with motor and cognitive functioning in PD patients were evident at baseline. The activity of the motor-related network declined after surgery and persisted at 1 year. These network changes correlated with improved clinical disability ratings. By contrast, the activity of the cognition-related network did not change after gene transfer. This suggests that modulation of abnormal network activity underlies the clinical outcome observed after unilateral STN AAV-GAD gene therapy. Network biomarkers may be used as physiological assays in early-phase trials of experimental therapies for PD and other neurodegenerative disease.

Assessment of the progression of Parkinson's disease: a metabolic network approach

Clinical research into Parkinson's disease has focused increasingly on the development of interventions that slow the neurodegeneration underlying this disorder. These investigations have stimulated interest in finding objective biomarkers that show changes in the rate of disease progression with treatment. Through radiotracer-based imaging of nigrostriatal dopaminergic function, a specific class of biomarkers to monitor the progression of Parkinson's disease has been identified, and these biomarkers were used in the clinical trials of drugs with the potential to modify the course of the disease. However, in some of these studies there was discordance between the imaging outcome measures and blinded clinical ratings of disease severity. Research is underway to identify and validate alternative ways to image brain metabolism, through which the efficacy of new therapies for Parkinson's disease and related disorders can be assessed. During recent years, spatial covariance analysis has been used with (18)F-fluorodeoxyglucose PET to detect abnormal patterns of brain metabolism in patients with neurodegenerative disorders. Rapid, automated, voxel-based algorithms have been used with metabolic imaging to quantify the activity of disease-specific networks. This approach has helped to characterise the unique metabolic patterns associated with the motor and cognitive features of Parkinson's disease. The results of several studies have shown correction of abnormal motor, but not cognitive, network activity by treatment with dopaminergic therapy and deep brain stimulation. The authors of a longitudinal imaging study of early-stage Parkinson's disease reported substantial differences in the development of these metabolic networks over a follow-up of 4 years. WHERE NEXT?: Developments in network imaging have provided the basis for several new applications of metabolic imaging in the study of Parkinson's disease. A washout study is currently underway to determine the long-duration effects of dopaminergic therapy on the network activity related to Parkinson's disease, which will be useful to plan future trials of disease-modifying drugs. Network approaches are also being applied to the study of atypical parkinsonian syndromes. The characterisation of specific patterns associated with atypical parkinsonian syndromes and classic Parkinson's disease will be the basis for a fully automated imaging-based procedure for early differential diagnosis. Efforts are underway to quantify the networks related to Parkinson's disease with less invasive imaging methods. Assessments of network activity with perfusion-weighted MRI show excellent concordance with measurements done with established radiotracer techniques. This approach will ultimately enable the assessment of abnormal network activity in people who are genetically at risk of Parkinson's disease.

MEG coherence imaging compared to electrocortical recordings from NeuroPace implants to determine the location of ictal onset in epilepsy patients

Abstract NeuroPace has developed an experimental therapy for epilepsy that utilizes intracranial electrodes (subdural and depth) bipolar electrode pairs to monitor key epileptic network sites for the onset of seizure. When the beginning of a seizure is detected, a sequence of high frequency electric stimuli is delivered to one or more of the electrode pairs to disrupt the abnormal network activity. Thus, for both detection and treatment, it is important the electrodes are at sites of high epileptic network connectivity. Epileptic network connectivity of a cortical site can be quantified by the average coherence with other sites in the epileptic network. In this paper, MEG coherence imaging is used to generate whole brain images of epileptic network connectivity and study the relationship between seizure reduction and electrode placement.

Abnormal metabolic network activity in Parkinson's disease: test-retest reproducibility.

Parkinson's disease (PD) is associated with an abnormal pattern of regional brain function. The expression of this PD-related covariance pattern (PDRP) has been used to assess disease progression and the response to treatment. In this study, we validated the PDRP network as a measure of parkinsonism by prospectively computing its expression (PDRP scores) in (15)O-water (H(2)(15)O) and (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans from PD patients and healthy volunteers. The reliability of this measure was also assessed within subjects using a test-retest design in mildly affected and advanced PD patients scanned at baseline and during treatment with levodopa or deep brain stimulation (DBS). We found that PDRP expression was significantly elevated in PD patients (P<0.001) relative to controls in a prospective analysis of brain scans obtained with either H(2)(15)O or FDG PET. A significant correlation (R(2)=0.61; P<0.001) was evident between PDRP scores computed from H(2)(15)O and FDG images in PD subjects scanned with both tracers. Test-retest reproducibility was very high (intraclass correlation coefficient (ICC)>0.92) for PDRP scores measured both within PET session and between sessions separated by up to 2 months. This high reproducibility was observed in both early stage and advanced PD patients scanned at baseline and during treatment. The within-subject variability of this measure was less than 10% for both unmedicated and treated conditions. These findings suggest that the PDRP network is a reproducible and stable descriptor of regional functional abnormalities in parkinsonism. The quantification of PDRP expression in PD patients can serve as a potential biomarker in PET intervention studies for this disorder.

Network modulation by the subthalamic nucleus in the treatment of Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted tool for the treatment of Parkinson's disease (PD). Although the precise mechanism of action of this intervention is unknown, its effectiveness has been attributed to the modulation of pathological network activity. We examined this notion using positron emission tomography (PET) to quantify stimulation-induced changes in the expression of a PD-related covariance pattern (PDRP) of regional metabolism. These metabolic changes were also compared with those observed in a similar cohort of patients undergoing STN lesioning. We found that PDRP activity declined significantly ( P < 0.02) with STN stimulation. The degree of network modulation with DBS did not differ from that measured following lesioning ( P = 0.58). Statistical parametric mapping (SPM) revealed that metabolic reductions in the internal globus pallidus (GPi) and caudal midbrain were common to both STN interventions ( P < 0.01), although declines in GPi were more pronounced with lesion. By contrast, elevations in posterior parietal metabolism were common to the two procedures, albeit more pronounced with stimulation. These findings indicate that suppression of abnormal network activity is a feature of both STN stimulation and lesioning. Nonetheless, these two interventions may differ metabolically at a regional level.