Chris Owen

Mapping of brain function after MPTP-induced neurotoxicity in a primate Parkinson's disease model

Neurophysiological studies of the brain in normal and Parkinsons disease (PD) patients have indicated intricate connections for basal ganglia-induced control of signaling into the motor cortex. To investigate if similar mechanisms are controlling function in the primate brain (Macaca fascicularis) after MPTP-induced neurotoxicity, we conducted PET studies of cerebral blood flow, oxygen and glucose metabolism, dopamine transporter, and D2 receptor function. Our observations after MPTP-induced dopamine terminal degeneration of the caudate and putamen revealed increased blood flow (15%) in the globus pallidus (GP), while blood flow was moderately decreased (15-25%) in the caudate, putamen, and thalamus and 40 % in the primary motor cortex (PMC). Oxygen extraction fraction was moderately increased (10-20%) in other brain areas but the thalamus, where no change was observable. Oxygen metabolism was increased in the GP and SMA (supplementary motor area including premotor cortex, Fig. 3) by a range of 20-40% and decreased in the putamen and caudate and in the PMC. Glucose metabolism was decreased in the caudate, putamen, thalamus, and PMC (range 35-50%) and enhanced in the GP by 15%. No change was observed in the SMA. In the parkinsonian primate, [(11)C]CFT (2beta-carbomethoxy-3beta-(4-fluorophenyltropane) dopamine transporter binding was significantly decreased in the putamen and caudate (range 60-65%). [(11)C]Raclopride binding of dopamine D(2) receptors did not show any significant changes. These experimental results obtained in primate studies of striato-thalamo-cortico circuitry show a similar trend as hypothetized in Parkinsons disease-type degeneration.

Treatment of vasospasm with a 480-nm pulsed-dye laser

Laser energy at a wavelength of 480 nm was applied in 1-microseconds pulses of 3 to 10 mJ to two models of vasospasm. Rabbit common carotid arteries (CCAs) were constricted chronically by the application of human blood within a silicone sheath. Peak vasospasm developed 24 to 48 hours later, and persisted for up to 6 days. Endovascular laser treatment was delivered to 40 CCAs via a 200-microns diameter silica quartz fiber introduced through the femoral artery. The CCA caliber increased from 60% of the pre-vasospasm control diameter to a minimum post-laser diameter of 83% of control. No instances of laser-induced perforation or of arterial thrombosis were observed for up to 60 days after treatment. Prophylactic laser application to nine normal vessels was able to attenuate the development of vasospasm if blood was applied immediately thereafter (88% vs. 59% of control diameter, p less than 0.02), but not if blood was applied 7 days later. Studies in 16 normal CCAs established that there was a considerable margin between the laser energy required to induce dilatation and that which caused perforation, providing that the fiber remained relatively central within the artery. Morphological examination demonstrated focal loss of endothelial cells immediately after laser application, followed approximately 7 days later by the development of areas of intimal hyperplasia. Only minimal changes were observed in the medial or adventitial layers. In a second study, the basilar artery of seven dogs was constricted chronically by two intracisternal injections of autologous blood 3 days apart. Five dogs received endovascular laser treatment 7 or 10 days after the first injection, when basilar artery diameter was reduced to a mean of 61% and 77% of control, respectively. Immediately following treatment, basilar artery diameter increased to 104% and 102% of resting diameter, respectively. Both untreated and laser-treated arteries were smaller than the control diameter at 30 days (80% and 82%, respectively), but in each group the vasodilatory response to hypercapnia was preserved. These findings indicate that 1-microsecond laser pulses are well tolerated by systemic and cerebral arteries in two different animal models, and suggest that the 480-nm pulsed-dye laser may have an application for the treatment or prophylaxis of cerebral vasospasm.

A Novel Method for Determining the Phase of T-Wave Alternans: Diagnostic and Therapeutic Implications

Background—T-wave alternans (TWA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. However, to estimate and suppress TWA effectively, the phase of TWA must be accurately determined. Methods and Results—We developed a method that computes the beat-by-beat integral of the T-wave morphology, over time points within the T-wave with positive alternans. Then, we estimated the signed derivative of the T-wave integral sequence, which allows the classification of each beat to a binary phase index. In animal studies, we found that this method was able to accurately identify the T-wave phase in artificially induced alternans (P<0.0001). The coherence of the phase increased consistently after acute ischemia induction in all body-surface and intracardiac leads (P<0.0001). Also, we developed a phase-resetting detection algorithm that enhances the diagnostic utility of TWA. We further established an algorithm that uses the phase of TWA to deliver appropriate polarity-pacing pulses (all interventions compared with baseline, P<0.0001 for alternans voltage; P<0.0001 for Kscore), to suppress TWA. Finally, we demonstrated that using the phase of TWA we can suppress spontaneous TWA during acute ischemia; 77.6% for alternans voltage (P<0.0001) and 92.5% for Kscore (P<0.0001). Conclusions—We developed a method to quantify the temporal variability of the TWA phase. This method is expected to enhance the utility of TWA in predicting ventricular arrhythmias and sudden cardiac death and raises the possibility of using upstream therapies to abort a ventricular tachyarrhythmia before its onset.

Microsurgical Clip Obliteration of Middle Cerebral Aneurysm Using Intraoperative Flow Assessment

Cerebral aneurysms are abnormal widening or ballooning of a localized segment of an intracranial blood vessel. Surgical clipping is an important treatment for aneurysms which attempts to exclude blood from flowing into the aneurysmal segment of the vessel while preserving blood flow in a normal fashion. Improper clip placement may result in residual aneurysm with the potential for subsequent aneurysm rupture or partial or full occlusion of distal arteries resulting in cerebral infarction. Here we describe the use of an ultrasonic flow probe to provide quantitative evaluation of arterial flow before and after microsurgical clip placement at the base of a middle cerebral artery aneurysm. This information helps ensure adequate aneurysm reconstruction with preservation of normal distal blood flow.

CAN WE HARMONIZE PIB AND FLORBETAPIR DATASETS

plasma free fraction of 1060.5% and 3862% of parent fraction remaining at 10 min. Blood flow was decreased compared to controls (on average over the target regions -1264% and -1166% for aMCI andADD respectively) andwas significant in posterior cingulate cortex (p<0.0001) (Figures 1-2). R1 correlated significantly (p<0.0001) with [15O]-H2O SUVr in all cortical regions (Pearson’s r ranged from 0.63 to 0.88 for the parietal and temporal cortex respectively). Mean VT was significantly increased compared to controls in relevant cortical regions for aMCI (on average +34613%) and for ADD (+38614%) (Figure 4). Compared to VT, SUVr overestimated differences between aMCI and HC in all regions (on average +863%) while underestimating differences between ADD and aMCI (-1061%). Conclusions: Quantitative PET imaging using absolute VT increases discriminating power between the different groups compared to static SUVr (Figure 5), the latter being sensitive to heterogeneous perfusion changes. 1 van Berckel, BN et al. J. Nucl. Med. 54, 1570-1576 (2013).

A Novel Method for Determining the Phase of T-Wave AlternansClinical Perspective: Diagnostic and Therapeutic Implications

Background—T-wave alternans (TWA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. However, to estimate and suppress TWA effectively, the phase of TWA must be accurately determined. Methods and Results—We developed a method that computes the beat-by-beat integral of the T-wave morphology, over time points within the T-wave with positive alternans. Then, we estimated the signed derivative of the T-wave integral sequence, which allows the classification of each beat to a binary phase index. In animal studies, we found that this method was able to accurately identify the T-wave phase in artificially induced alternans (P<0.0001). The coherence of the phase increased consistently after acute ischemia induction in all body-surface and intracardiac leads (P<0.0001). Also, we developed a phase-resetting detection algorithm that enhances the diagnostic utility of TWA. We further established an algorithm that uses the phase of TWA to deliver appropriate polarity-pacing pulses (all interventions compared with baseline, P<0.0001 for alternans voltage; P<0.0001 for Kscore), to suppress TWA. Finally, we demonstrated that using the phase of TWA we can suppress spontaneous TWA during acute ischemia; 77.6% for alternans voltage (P<0.0001) and 92.5% for Kscore (P<0.0001). Conclusions—We developed a method to quantify the temporal variability of the TWA phase. This method is expected to enhance the utility of TWA in predicting ventricular arrhythmias and sudden cardiac death and raises the possibility of using upstream therapies to abort a ventricular tachyarrhythmia before its onset.

A Novel Method for Determining the Phase of T-Wave AlternansClinical Perspective

Background—T-wave alternans (TWA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. However, to estimate and suppress TWA effectively, the phase of TWA must be accurately determined. Methods and Results—We developed a method that computes the beat-by-beat integral of the T-wave morphology, over time points within the T-wave with positive alternans. Then, we estimated the signed derivative of the T-wave integral sequence, which allows the classification of each beat to a binary phase index. In animal studies, we found that this method was able to accurately identify the T-wave phase in artificially induced alternans (P<0.0001). The coherence of the phase increased consistently after acute ischemia induction in all body-surface and intracardiac leads (P<0.0001). Also, we developed a phase-resetting detection algorithm that enhances the diagnostic utility of TWA. We further established an algorithm that uses the phase of TWA to deliver appropriate polarity-pacing pulses (all interventions compared with baseline, P<0.0001 for alternans voltage; P<0.0001 for Kscore), to suppress TWA. Finally, we demonstrated that using the phase of TWA we can suppress spontaneous TWA during acute ischemia; 77.6% for alternans voltage (P<0.0001) and 92.5% for Kscore (P<0.0001). Conclusions—We developed a method to quantify the temporal variability of the TWA phase. This method is expected to enhance the utility of TWA in predicting ventricular arrhythmias and sudden cardiac death and raises the possibility of using upstream therapies to abort a ventricular tachyarrhythmia before its onset.