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Sossi V.,University of British Columbia | De La Fuente-Fernandez R.,Pacific Parkinsons Research Center | Nandhagopal R.,Pacific Parkinsons Research Center | Schulzer M.,Pacific Parkinsons Research Center | And 4 more authors.
Movement Disorders | Year: 2010

Increase in dopamine (DA) turnover was found to occur early in symptomatic Parkinson's disease (PD) and to be functionally related to the dopamine transporter (DAT). The objectives of this study were to examine changes in DA turnover in the asymptomatic PD phase; to compare them with changes in other dopaminergic markers, and to investigate a possible relationship between DAT and DA turnover. Eight subjects from families at increased risk of PD due to LRRK2 mutation were investigated. Positron emission tomography imaging was performed with: 18F-fluorodopa to determine the effective DA distribution volume (EDV), the inverse of DA turnover, and the DA uptake rate Kocc, a marker of DA synthesis and storage; 11C-methylphenidate (MP, a DAT marker) and 11C-dihydrotetrabenazine (DTBZ, a VMAT2 marker) to estimate the binding potentials BPND_MP and BPND_DTBZ. On average, EDV showed the largest reduction from age-matched control values (42%) followed by BPND_MP (23%) and BPND_DTBZ (17%), whereas Kocc remained in the normal range for all subjects. No correlation was found between EDV and any other marker. DA turnover was found to be elevated in asymptomatic mutation carriers at increased risk of PD. Such change was determined to be larger than and statistically independent from changes observed with the other markers. These results support a compensatory role of increased DA turnover in presymptomatic disease and indicate that at this stage, in contrast to the symptomatic PD phase, increased turnover is not related to DAT. © 2010 Movement Disorder Society.


Kim D.J.,University of British Columbia | Yogendrakumar V.,Pacific Parkinsons Research Center | Chiang J.,University of British Columbia | Ty E.,Pacific Parkinsons Research Center | And 3 more authors.
PLoS ONE | Year: 2013

Noisy galvanic vestibular stimulation has been associated with numerous cognitive and behavioural effects, such as enhancement of visual memory in healthy individuals, improvement of visual deficits in stroke patients, as well as possibly improvement of motor function in Parkinson's disease; yet, the mechanism of action is unclear. Since Parkinson's and other neuropsychiatric diseases are characterized by maladaptive dynamics of brain rhythms, we investigated whether noisy galvanic vestibular stimulation was associated with measurable changes in EEG oscillatory rhythms within theta (4-7.5 Hz), low alpha (8-10 Hz), high alpha (10.5-12 Hz), beta (13-30 Hz) and gamma (31-50 Hz) bands. We recorded the EEG while simultaneously delivering noisy bilateral, bipolar stimulation at varying intensities of imperceptible currents - at 10, 26, 42, 58, 74 and 90% of sensory threshold - to ten neurologically healthy subjects. Using standard spectral analysis, we investigated the transient aftereffects of noisy stimulation on rhythms. Subsequently, using robust artifact rejection techniques and the Least Absolute Shrinkage Selection Operator regression and cross-validation, we assessed the combinations of channels and power spectral features within each EEG frequency band that were linearly related with stimulus intensity. We show that noisy galvanic vestibular stimulation predominantly leads to a mild suppression of gamma power in lateral regions immediately after stimulation, followed by delayed increase in beta and gamma power in frontal regions approximately 20-25 s after stimulation ceased. Ongoing changes in the power of each oscillatory band throughout frontal, central/parietal, occipital and bilateral electrodes predicted the intensity of galvanic vestibular stimulation in a stimulus-dependent manner, demonstrating linear effects of stimulation on brain rhythms. We propose that modulation of neural oscillations is a potential mechanism for the previously-described cognitive and motor effects of vestibular stimulation, and noisy galvanic vestibular stimulation may provide an additional non-invasive means for neuromodulation of functional brain networks. © 2013 Kim et al.


Lee G.,University of British Columbia | Byram A.C.,University of British Columbia | Owen A.M.,University of Western Ontario | Ribary U.,Simon Fraser University | And 5 more authors.
Canadian Journal of Neurological Sciences | Year: 2015

Background: Acquired brain injury is a critical public health and socioeconomic problem in Canada, leaving many patients in vegetative, minimally conscious, or locked-in states, unresponsive and unable to communicate. Recent advances in neuroimaging research have demonstrated residual consciousness in a few exemplary patients with acquired brain injury, suggesting potential misdiagnosis and changes in prognosis. Such progress, in parallel with research using multimodal brain imaging technologies in recent years, has promising implications for clinical translation, notwithstanding the many challenges that impact health care and policy development. This study explored the perspectives of Canadian professionals with expertise either in neuroimaging research, disorders of consciousness, or both, on the potential clinical applications and implications of imaging technology. Methods: Twenty-two professionals from designated communities of neuroimaging researchers, ethicists, lawyers, and practitioners participated in semistructured interviews. Data were analyzed for emergent themes. Results: The five most dominant themes were: (1) validation and calibration of the methods; (2) informed consent; (3) burdens on the health care system; (4) implications for the Canadian health care system; and (5) possibilities for improved prognosis. Conclusions: Movement of neuroimaging from research into clinical care for acquired brain injury will require careful consideration of legal and ethical issues alongside research reliability, responsible distribution of health care resources, and the interaction of technological capabilities with patient outcome. Copyright © The Canadian Journal of Neurological Sciences Inc. 2015.


Cheng J.-C.K.,University of British Columbia | Cheng J.-C.K.,Washington University in St. Louis | Blinder S.,Pacific Parkinsons Research Center | Rahmim A.,Johns Hopkins University | Sossi V.,University of British Columbia
IEEE Transactions on Nuclear Science | Year: 2010

We describe a scatter calibration technique which improves the quantitative accuracy of the positron emission tomography data in specific scanning conditions: i.e., scans with high random fraction (RF) and/or low number of counts. Such a situation is often encountered in dynamic imaging on scanners with a large number of lines-of-response (LOR) such as the high resolution research tomograph (HRRT). In this paper, we first describe how high RFs and low number of counts affect the scatter scaling process. We then demonstrate experimentally, with phantom studies, the bias in the scatter estimate introduced by the commonly used tail-fitting technique employed in the single scatter simulation (SSS) method. A significant bias in scatter fraction (SF) was found for frames which contain a RF higher than 50% and/or with a number of counts less than 20 M. Finally, we present a new scatter scaling technique which compensates this bias. The scatter calibration technique is based on using the scatter estimate obtained from a reference frame, in which the bias due to high RFs and low number of counts is minimized, to calibrate the scatter in each dynamic frame. The calibration also separately accounts for the change in SF due to the pulse pile-up effect. A much more consistent and accurate SF value was assigned to each segment of the scatter sinogram thus leading to a more quantitative reconstructed image with a better axial uniformity after the scatter calibration. The new calibration technique was tested with phantom, monkey, and human data and was found to significantly improve the quantitative aspect of the early frames: such improvement is expected to positively affect the feasibility of rather novel image analysis methods, such as determination of image derived input function. © 2010 IEEE.


Sossi V.,University of British Columbia | Sossi V.,Pacific Parkinsons Research Center | Dinelle K.,University of British Columbia | Schulzer M.,Pacific Parkinsons Research Center | And 4 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2010

Purpose: Levodopa and dopamine (DA) agonist therapy are two common treatments for Parkinson's disease (PD). There is controversy about the effects of these treatments on disease progression and imaging markers. Here we used multi-tracer positron emission tomography imaging and a unilateral 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate in vivo the effects of chronic levodopa and pramipexole treatments on measurements of vesicular monoamine transporter type 2 (VMAT2), dopamine transporter (DAT) levels, and on levodopa-induced changes in synaptic DA levels [Δ(DA)]. Methods: Twenty-three unilaterally 6-OHDA lesioned rats underwent an 11C- dihydrotetrabenazine (DTBZ, VMAT2 marker), an 11C-methylphenidate (MP, DAT marker), and a double 11C-raclopride (RAC, D 2-type receptor marker) scan. They were assigned to three treatment groups: saline (N=7), pramipexole (N=8), and levodopa (N=8). After 4 weeks of treatment, imaging was repeated. Results: Results showed (1) a significant treatment effect on DTBZ, with pramipexole decreasing DTBZ binding compared to levodopa, (2) significant side and treatment-striatal side interaction effects for MP, indicating that levodopa tends to decrease MP binding compared to pramipexole, and (3) no treatment effect on Δ(DA). Conclusion: These data indicate that while chronic dopaminergic pharmacological treatment affects DTBZ and MP binding, it does not affect levodopa-induced changes in synaptic DA level. © 2010 Springer-Verlag.


Dinelle K.,Pacific Parkinsons Research Center | Ngo H.,University of British Columbia | Blinder S.,Pacific Parkinsons Research Center | Vafai N.,Pacific Parkinsons Research Center | And 3 more authors.
Medical Physics | Year: 2011

Purpose: Subject motion during positron emission tomography (PET) brain scans can reduce image quality and may lead to incorrect biological outcome measures, especially for data acquired with high resolution tomographs. A semiautomatic method for assessing the quality of frame-to-frame image realignments to compensate for subject motion in dynamic brain PET is proposed and evaluated. Methods: A test set of 256 C 11 -raclopride (a dopamine D2-type receptor antagonist) brain PET image frames was used to develop and evaluate the proposed method. The transformation matrix to be applied to each image to achieve a frame-to-frame realignment was calculated with two independent methods: Using motion data measured with the Polaris Vicra optical tracking device and using the image-based realignment algorithm AIR (automated image registration). The quality assessment method is based on the observation that there is a very low probability that two independent approaches to motion detection will produce equal, but incorrect results. Agreement between transformation matrices was taken to be a signature of an accurate motion determination and thus realignment. Each pair of realignment matrices was compared and used to calculate a metric describing the frame-to-frame image realignment accuracy. In order to determine the range of values of the metric that correspond to a successful realignment, a comparison was made to a detailed visual inspection of the frame-to-frame realigned images for each image in the test set. The threshold on the metric for realignment acceptance was then selected to optimize the numbers of true-positives (realignments accepted by both the protocol and the operator) and minimize the number of false-positives (accepted by the protocol but not the operator). Results: The proposed method categorized 53% of the image realignments in the test dataset as successful, of which 11% were incorrectly categorized (6% of the total dataset). Implementation of the proposed assessment tool resulted in a 45% time savings compared to the same visual inspection applied to all image realignments. Conclusions: The frame-to-frame image realignment assessment tool presented here required less operator time to evaluate realignment success compared to a method requiring visual inspection of all realigned images, while maintaining the same level of accuracy in the realigned dataset. This practical method can be easily implemented at any center with motion monitoring capabilities or, for centers lacking this technology, methods of estimating image realignment parameters that use independent information. In addition, the procedure is flexible, allowing modifications to be made for different tracer types and/or downstream analysis goals. © 2011 American Association of Physicists in Medicine.


Nandhagopal R.,Pacific Parkinsons Research Center | Troiano A.R.,Pacific Parkinsons Research Center | Mak E.,Pacific Parkinsons Research Center | Schulzer M.,Pacific Parkinsons Research Center | And 2 more authors.
Pain Medicine | Year: 2010

Background: Pain is a prominent nonmotor symptom in Parkinson's disease (PD) but has not been well studied. Objective: The aim of this study is to assess thermal experience and emotional content, as well as side-to-side sensory differences in PD " off" and " on" dopaminergic therapy following thermal cutaneous stimulation. Design: Cross-sectional design. Setting: University teaching hospital. Methods: Twelve PD subjects experiencing motor fluctuations but no pain symptoms and 13 healthy controls participated in the study. Heat pain and emotional content were assessed using a thermode and visual analog scales in medication on and off states in PD and without medication in healthy controls. Results: There were no side to side differences in heat pain intensity or between PD medication on state and PD medication off state. Unexpectedly, PD subjects reported a higher degree of unpleasantness in response to heat pain while on medication compared with the off state. Conclusions: These results suggest that the perception of heat pain is mediated, at least in part, by nondopaminergic systems in PD, while dopamine might modulate the affective component of pain. Wiley Periodicals, Inc.


PubMed | Pacific Parkinsons Research Center
Type: Journal Article | Journal: Medical physics | Year: 2011

Subject motion during positron emission tomography (PET) brain scans can reduce image quality and may lead to incorrect biological outcome measures, especially for data acquired with high resolution tomographs. A semiautomatic method for assessing the quality of frame-to-frame image realignments to compensate for subject motion in dynamic brain PET is proposed and evaluated.A test set of 256 11C-raclopride (a dopamine D2-type receptor antagonist) brain PET image frames was used to develop and evaluate the proposed method. The transformation matrix to be applied to each image to achieve a frame-to-frame realignment was calculated with two independent methods: Using motion data measured with the Polaris Vicra optical tracking device and using the image-based realignment algorithm AIR (automated image registration). The quality assessment method is based on the observation that there is a very low probability that two independent approaches to motion detection will produce equal, but incorrect results. Agreement between transformation matrices was taken to be a signature of an accurate motion determination and thus realignment. Each pair of realignment matrices was compared and used to calculate a metric describing the frame-to-frame image realignment accuracy. In order to determine the range of values of the metric that correspond to a successful realignment, a comparison was made to a detailed visual inspection of the frame-to-frame realigned images for each image in the test set. The threshold on the metric for realignment acceptance was then selected to optimize the numbers of true-positives (realignments accepted by both the protocol and the operator) and minimize the number of false-positives (accepted by the protocol but not the operator).The proposed method categorized 53% of the image realignments in the test dataset as successful, of which 11% were incorrectly categorized (6% of the total dataset). Implementation of the proposed assessment tool resulted in a 45% time savings compared to the same visual inspection applied to all image realignments.The frame-to-frame image realignment assessment tool presented here required less operator time to evaluate realignment success compared to a method requiring visual inspection of all realigned images, while maintaining the same level of accuracy in the realigned dataset. This practical method can be easily implemented at any center with motion monitoring capabilities or, for centers lacking this technology, methods of estimating image realignment parameters that use independent information. In addition, the procedure is flexible, allowing modifications to be made for different tracer types and/or downstream analysis goals.


PubMed | Pacific Parkinsons Research Center
Type: Journal Article | Journal: Pain medicine (Malden, Mass.) | Year: 2010

Pain is a prominent nonmotor symptom in Parkinsons disease (PD) but has not been well studied.The aim of this study is to assess thermal experience and emotional content, as well as side-to-side sensory differences in PD off and on dopaminergic therapy following thermal cutaneous stimulation.Cross-sectional design.University teaching hospital.Twelve PD subjects experiencing motor fluctuations but no pain symptoms and 13 healthy controls participated in the study. Heat pain and emotional content were assessed using a thermode and visual analog scales in medication on and off states in PD and without medication in healthy controls.There were no side to side differences in heat pain intensity or between PD medication on state and PD medication off state. Unexpectedly, PD subjects reported a higher degree of unpleasantness in response to heat pain while on medication compared with the off state.These results suggest that the perception of heat pain is mediated, at least in part, by nondopaminergic systems in PD, while dopamine might modulate the affective component of pain.


PubMed | Pacific Parkinsons Research Center
Type: Journal Article | Journal: Current opinion in neurology | Year: 2010

The on-going quest for potentially disease-modifying therapies in Parkinsons disease has prompted the development of methods that can differentiate direct disease effects from compensatory processes.PET studies have suggested a number of changes at the synaptic level to maintain integrity of dopaminergic systems. Functional MRI studies support the long-held belief that relatively intact cerebellar circuits may compensate for impaired basal ganglia function. Altered connectivity and increased spatial extent of activation also appear to be mechanisms through which motor and cognitive performance can be maintained.Ascertaining which changes in brain activation in Parkinsons disease are, in fact, compensatory represents a serious challenge. Compensatory mechanisms have been demonstrated from the microscopic, synaptic level to the macroscopic, system level. Augmentation of compensatory mechanisms, in addition to ameliorating the loss of dopaminergic neurons, may represent a joint strategy for overall minimization of disability.

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