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See detailDosimetry for 6-[18F]Fluoro-L-DOPA in humans based on in vivo microPET scans and ex vivo tissue distribution in mice
Bretin, Florian ULg; Warnock, Geoffrey ULg; Bahri, Mohamed Ali ULg et al

Poster (2012, September)

Radiation dosimetry of new radiopharmaceuticals generally starts with studies in small animals such as mice and rats. The traditional technique has long been ex vivo measurement of the biodistribution ... [more ▼]

Radiation dosimetry of new radiopharmaceuticals generally starts with studies in small animals such as mice and rats. The traditional technique has long been ex vivo measurement of the biodistribution over time using harvested organs at different times post administration of the radiopharmaceutical. Since this approach requires a significant amount of animals, dynamic microPET studies, where the biodistribution of the tracer over time can be determined in vivo in a single scan, are an invaluable alternative. Due to known imaging artifacts and limitations, such as partial volume effect, a hybrid technique combining harvesting organs (post-scan) and dynamic imaging was introduced to achieve a cross-calibration to account for these limitations. Since 6-[18F]Fluoro-L-DOPA is a widely used PET tracer to study the dopaminergic system in neurology and oncology and there is no sound published dosimetry data, absorbed doses for major organs in humans were estimated using the traditional ex vivo technique and by dynamic microPET imaging in mice, allowing direct comparison of the results from the two techniques. The tissue distribution over time of 6-[18F]Fluoro-L-DOPA was determined by radioassay of harvested organs at 2, 5, 10, 30, 60, 120 minutes post administration (n=5 at each time point) in isoflurane-anaesthetized mice. Dynamic PET images were acquired with a FOCUS 120 microPET for 120 minutes after injection of 6-[18F]Fluoro-L-DOPA followed by radioassay of harvested organs (n=4). A bladder voiding scenario was used to simulate excretion every 2 h. The organ time-activity-curves (TACs) from both methods were extrapolated from a simulated 35 g standard mouse to a 70 kg standard male human using a technique based on organ to bodyweight ratios. The absorbed doses in major human organs were calculated with the commercially available human dosimetry software OLINDA/EXM (Version 1.1) using the extrapolated TACs. The extrapolated organ TACs obtained using the two methods showed a high correlation (average r = 0.94 ± 0.05, p < 0.001). However, TACs from PET alone under- or overestimated the activity in individual organs in contrast to TACs obtained using the cross-calibration of the PET data with the activity in post-scan dissected organs. Those organs in the excretion pathways, comprising bladder wall, kidneys and liver, received the highest organ doses. The total body absorbed dose was 0.0118 mGy/MBq for both the imaging based and harvesting based methods. The effective dose was 0.0193 mSv/MBq for the hybrid imaging-harvesting technique and 0.0189 mSv/MBq for the pure harvesting technique. Scaling errors in the PET TACs are likely caused by quantification errors such as partial volume effects and image artifacts. The use of a hybrid imaging technique to cross-calibrate the TACs improved the accuracy of the imaging-based dosimetry estimates. Therefore the hybrid technique combining dynamic imaging and harvesting organs (post-scan) is a suitable alternative to the gold standard ex vivo radioassay method. It yields comparable results yet reduces significantly the amount of animals needed in the study and can accelerate data acquisition. [less ▲]

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See detailPET In Conscious Rodents - Quantification of Stress During The Training Process
Warnock, Geoffrey ULg; Bahri, Mohamed Ali ULg; Bretin, Florian ULg et al

Poster (2012, September)

Recently several methods for performing PET studies in conscious rodents have been developed [1-3]. These methods have the potential to greatly improve the translational nature of PET studies in rodents ... [more ▼]

Recently several methods for performing PET studies in conscious rodents have been developed [1-3]. These methods have the potential to greatly improve the translational nature of PET studies in rodents. One of the most easily implemented methods is the training of a rat to tolerate head fixation in a restraining device. Training consists of intervals of restraint over several days. However, the stress induced by this training procedure has not been quantified in detail. Limited changes in plasma corticosterone have been reported, but this data may be confounded by sample timing and baseline levels. An implantable telemetry system (Telemetry Research) was used to remotely measure blood pressure, heart rate and core temperature during training. Transmitters were implanted in the abdominal cavity under isoflurane anesthesia, with the blood pressure sensor fixed in the abdominal aorta. Training was started after a recovery period of at least 1 week. Training consisted of a 5 min period of acclimatization in the cage containing the restraining device, followed by increasing durations of restraint in the device on subsequent training days (15, 30, 45, 60, 90 min). Telemetry data was acquired from 5 min prior to acclimatization to 60 minutes post-training. In this initial pilot study, a single rat was trained, without head fixation, for 4 consecutive days and again on day 7. All reported values are mean ± SEM across the five training days. In the home cage, prior to acclimatization, baseline heart rate (HR) was 294 ± 15 bpm. During the acclimatization period, HR was elevated to 411 ± 7 bpm. Immediately after starting training, HR was 419 ± 16 bpm. During the training period HR showed a tendency to decrease, with raised periods at undefined intervals. After return to the home cage, HR remained elevated for 15-20 min before returning to a value (313 ± 9 bpm) close to baseline. A similar pattern was seen in blood pressure (mean; BP). Baseline BP was 76 ± 7 mmHg, increasing to 94 ± 9 mmHg during acclimatization. After commencing training, a peak in BP was reached at 102 ± 8 mmHg. After the 15-20 min recovery interval, BP returned to a baseline of 77 ± 9 mmHg. The HR and BP responses to acclimatization and to the training protocol persisted throughout all training days, with the main noticeable difference being the number of bouts of increased HR, which increased with training duration. Core body temperature (baseline: 37.45 ± 0.21 °C) increased during restraint training, with a subsequent post-training peak (38.21 ± 0.03 °C). Measurement of core temp is complicated during longer training sessions by the need to charge the transmitter. This early data indicates that stress induced by the training procedure for conscious PET persists after several days of training. In subsequent studies the head will be fixed and the effect of the training on plasma corticosterone and central glucose metabolism (using [18F]FDG) will be examined. [1] Momosaki et al. (2004) Synapse 54:207–213 [2] Wyss et al. (2009) NeuroImage 48:339–347 [3] Itoh et al. (2009) J Nucl Med 50:749–756 [less ▲]

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See detailSelf-appraisal and medial prefrontal activation in early stage Alzheimer’s disease
Genon, Sarah ULg; Collette, Fabienne ULg; Angel, Lucie et al

Poster (2012, June 12)

Introduction Self-referential processing in healthy subjects is related to activation within cortical midline structures, such as the medial prefrontal cortex (MPFC) and the posterior cingulate cortex ... [more ▼]

Introduction Self-referential processing in healthy subjects is related to activation within cortical midline structures, such as the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC; Northoff et al., 2006). Little is know about the engagement of these structures during self-referential processing at different stages of Alzheimer’s disease (AD). The PCC and the MPFC have been found to be activated during a self-appraisal task of adjectives in patients at very early stage of the disease (patients with Mild Cognitive Impairment, MCI; Ries et al., 2006). In contrast, in a similar task, Ruby et al. (2009) have found that mild demented patients activated the dorsal part of the MPFC (DMPFC) to a lesser extent than healthy controls (HC). Ruby et al. did not assess depression symptoms in their patients. Yet, MPFC activations have been found to be modified during self-referential processing in depressed participants (Lemogne et al., 2012). Therefore, in this study, we examined brain correlates of self-appraisal processing in AD patients when controlling for depressive symptoms. Methods Twenty-two mild AD patients and 22 HC matched on age, level of education and gender (respectively: 76±5y; 11±3y; 12M10F) to the AD patients (respectively: 76±7y; 11±3y; 11M11F) were recruited. To control for dementia severity and depression, the participants were administrated the Mattis Dementia Rating (MDR) and the Geriatric Depression Scale (GDS). A self-appraisal task intermixed with a recognition task was administered in an fMRI experimentation. In the self-appraisal task, the participants saw adjectives and had to indicate if the trait describes them (Self-condition; SC) or the King Albert II (for men)/the Queen Fabiola (for women; Other-condition; OC). The adjectives were presented in blocks of 6 items. Participants performed 9 runs consisting in one block of SC and one block of OC followed by a recognition phase where participants were presented with the 12 adjectives that they had just previously seen randomly mixed with 12 new adjectives. They were asked to indicate for each adjective whether they had seen it in the previous task. Statistical analyses focused on the self-appraisal task. Brain activations related to the self appraisal process were isolated in each participant by subtracting brain activation related to OC items from brain activation related to SC items. Then at the group level, we examined differences between groups (HC>AD and AD>HC) and a conjunction analysis examined brain activations that were common to both groups. Preprocessing and statistical analyses were performed with SPM8 (p<.001 uncorrected with a-priori hypotheses). Results GDS scores were similar in AD (3±3) and HC (3±3; T(42) = .1; P=.9) groups. No region was found to be significantly more activated during self-appraisal process in HC than in AD and vice versa when performing direct statistical comparison. Moreover, a conjunction analysis revealed that the VMPFC was the only region commonly activated in AD and HC during self-appraisal process (Punc<.001). Conclusions Our results revealed that AD patients engaged the ventral part of the MPFC to a similar extent than HC during self-appraisal judgements. These results and the results found in patients with MCI by Ries et al. (2006) suggest that at initial stages of AD, patients engaged self-related regions when they performed judgements about themselves as HC do. The divergence with the findings by Ruby et al. (2009) may be related either to the fact that they did not controlled for depressive symptoms or to the fact that their patients showed on average lower scores at the MDR (124) than our patients (127). One can assume that engagement of the self-related regions during self-appraisal judgements in the AD patients depends on the severity of the dementia and/or depressive symptoms. In conclusion, MPFC may be engaged during self-referential processing in very mild AD patients without depressive symptoms. References: Lemogne, C., Delaveau, P., Freton, M., Guionnet, S. & Fossati, P. (2012). Medial prefrontal cortex and the self in major depression. Journal of Affective Disorders, 136, 1-11. Ries, M. L., Schmitz, T.W., Kawahara, T.N., Torgerson, B.M., Trivedi, M.A. & Johnson, S.C. (2006). Task-dependent posterior cingulated activation in mild cognitive impairment. NeuroImage, 29, 485-492. Ruby, P., Collette, F., D’Argembeau, A., Péters, F., Degueldre, C., Balteau, E., Luxen, A., Maquet, P. & Salmon, E. (2009). Perspective taking to assess self-personality: What’s modified in Alzheimer’s disease ? Neurobiology of Aging, 30(10), 1637-1651. [less ▲]

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See detailNEMA NU4-2008 Performance Evaluation for the MicroPET FOCUS 120 and Iodine-124
Taleb, Dounia ULg; Bahri, Mohamed Ali ULg; Warnock, Geoffrey ULg et al

in IEEE proceedings of ANIMMA 2011 (2012, March 12)

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See detailThe influence of cognitive reserve on inter-individual variability in resting-state cerebral metabolism in normal aging
Bastin, Christine ULg; Salmon, Eric ULg; Bahri, Mohamed Ali ULg et al

in Alzheimer's & Dementia : The Journal of the Alzheimer's Association (2012), 8(4), 80-81

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See detailMetabolic activity in external and internal awareness networks in severely brain-damaged patients.
Thibaut, Aurore ULg; Bruno, Marie-Aurélie ULg; Chatelle, Camille ULg et al

in Journal of Rehabilitation Medicine (2012), 44(6), 487-94

OBJECTIVE: An extrinsic cerebral network (encompassing lateral frontoparietal cortices) related to external/sensory awareness and an intrinsic midline network related to internal/self-awareness have been ... [more ▼]

OBJECTIVE: An extrinsic cerebral network (encompassing lateral frontoparietal cortices) related to external/sensory awareness and an intrinsic midline network related to internal/self-awareness have been identified recently. This study measured brain metabolism in both networks in patients with severe brain damage. DESIGN: Prospective [18F]-fluorodeoxyglucose-positron emission tomography and Coma Recovery Scale-Revised assessments in a university hospital setting. SUBJECTS: Healthy volunteers and patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), emergence from MCS (EMCS), and locked-in syndrome (LIS). RESULTS: A total of 70 patients were included in the study: 24 VS/UWS, 28 MCS, 10 EMCS, 8 LIS and 39 age-matched controls. VS/UWS showed metabolic dysfunction in extrinsic and intrinsic networks and thalami. MCS showed dysfunction mostly in intrinsic network and thalami. EMCS showed impairment in posterior cingulate/retrosplenial cortices. LIS showed dysfunction only in infratentorial regions. Coma Recovery Scale-Revised total scores correlated with metabolic activity in both extrinsic and part of the intrinsic network and thalami. CONCLUSION: Progressive recovery of extrinsic and intrinsic awareness network activity was observed in severely brain-damaged patients, ranging from VS/UWS, MCS, EMCS to LIS. The predominance of intrinsic network impairment in MCS could reflect altered internal/self-awareness in these patients, which is difficult to quantify at the bedside. [less ▲]

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See detailThe influence of cognitive reserve on inter-individual variability in resting-state cerebral metabolism in normal aging
Bastin, Christine ULg; Yakushev, Igor; Bahri, Mohamed Ali ULg et al

in Frontiers in Human Neuroscience (2012)

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See detailCognitive reserve impacts on inter-individual variability in resting-state cerebral metabolism in normal aging
Bastin, Christine ULg; Yakushev, Igor; Bahri, Mohamed Ali ULg et al

in NeuroImage (2012), 63

There is a great deal of heterogeneity in the impact of aging on cognition and cerebral functioning. One potential factor contributing to individual differences among the elders is the cognitive reserve ... [more ▼]

There is a great deal of heterogeneity in the impact of aging on cognition and cerebral functioning. One potential factor contributing to individual differences among the elders is the cognitive reserve, which designates the partial protection from the deleterious effects of aging that lifetime experience provides. Neuroimaging studies examining task-related activation in elderly people suggested that cognitive reserve takes the form of more efficient use of brain networks and/or greater ability to recruit alternative networks to compensate for age-related cerebral changes. In this multi-centre study, we examined the relationships between cognitive reserve, as measured by education and verbal intelligence, and cerebral metabolism at rest (FDG-PET) in a sample of 74 healthy older participants. Higher degree of education and verbal intelligence was associated with less metabolic activity in the right posterior temporoparietal cortex and the left anterior intraparietal sulcus. Functional connectivity analyses of resting-state fMRI images in a subset of 41 participants indicated that these regions belong to the default mode network and the dorsal attention network respectively. Lower metabolism in the temporoparietal cortex was also associated with better memory abilities. The findings provide evidence for an inverse relationship between cognitive reserve and resting-state activity in key regions of two functional networks respectively involved in internal mentation and goal-directed attention. [less ▲]

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See detailRelation entre la réserve cognitive et le métabolisme cérébral au repos dans le vieillissement normal.
Bastin, Christine ULg; Yakushev, Igor; Bahri, Mohamed Ali ULg et al

in Proceedings of the XIIème Colloque International sur le Vieillissement Cognitif (2012)

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See detailValuing One's Self: Medial Prefrontal Involvement in Epistemic and Emotive Investments in Self-views.
D'Argembeau, Arnaud ULg; Jedidi, Haroun ULg; Balteau, Evelyne ULg et al

in Cerebral Cortex (2012), 22

Recent neuroimaging research has revealed that the medial prefrontal cortex (MPFC) is consistently engaged when people form mental representations of themselves. However, the precise function of this ... [more ▼]

Recent neuroimaging research has revealed that the medial prefrontal cortex (MPFC) is consistently engaged when people form mental representations of themselves. However, the precise function of this region in self-representation is not yet fully understood. Here, we investigate whether the MPFC contributes to epistemic and emotive investments in self-views, which are essential components of the self-concept that stabilize self-views and shape how one feels about oneself. Using functional magnetic resonance imaging, we show that the level of activity in the MPFC when people think about their personal traits (by judging trait adjectives for self-descriptiveness) depends on their investments in the particular self-view under consideration, as assessed by postscan rating scales. Furthermore, different forms of investments are associated with partly distinct medial prefrontal areas: a region of the dorsal MPFC is uniquely related to the degree of certainty with which a particular self-view is held (one's epistemic investment), whereas a region of the ventral MPFC responds specifically to the importance attached to this self-view (one's emotive investment). These findings provide new insight into the role of the MPFC in self-representation and suggest that the ventral MPFC confers degrees of value upon the particular conception of the self that people construct at a given moment. [less ▲]

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See detailViability for the Siemens Ecat HR+ of the new stability test of PET scanners elaborated by the Belgian Hospital Physicist Association
Nguyen, Daniel ULg; Dalemans, Christophe; Bahri, Mohamed Ali ULg et al

in European Journal of Nuclear Medicine and Molecular Imaging (2011, October), 38(S2), 174

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See detailHypnotic modulation of resting state fMRI default mode and extrinsic network connectivity
Demertzi, Athina ULg; Soddu, Andrea ULg; FAYMONVILLE, Marie-Elisabeth ULg et al

in Progress in Brain Research (2011), 193

Resting state fMRI (functional magnetic resonance imaging) acquisitions are characterized by low-frequency spontaneous activity in a default mode network (encompassing medial brain areas and linked to ... [more ▼]

Resting state fMRI (functional magnetic resonance imaging) acquisitions are characterized by low-frequency spontaneous activity in a default mode network (encompassing medial brain areas and linked to self-related processes) and an anticorrelated “extrinsic” system (encompassing lateral frontoparietal areas and modulated via external sensory stimulation). In order to better determine the functional contribution of these networks to conscious awareness, we here sought to transiently modulate their relationship by means of hypnosis. We used independent component analysis (ICA) on resting state fMRI acquisitions during normal wakefulness, under hypnotic state, and during a control condition of autobiographical mental imagery. As compared to mental imagery, hypnosis-induced modulation of resting state fMRI networks resulted in a reduced “extrinsic” lateral frontoparietal cortical connectivity, possibly reflecting a decreased sensory awareness. The default mode network showed an increased connectivity in bilateral angular and middle frontal gyri, whereas its posterior midline and parahippocampal structures decreased their connectivity during hypnosis, supposedly related to an altered “self” awareness and posthypnotic amnesia. In our view, fMRI resting state studies of physiological (e.g., sleep or hypnosis), pharmacological (e.g., sedation or anesthesia), and pathological modulation (e.g., coma or related states) of “intrinsic” default mode and anticorrelated “extrinsic” sensory networks, and their interaction with other cerebral networks, will further improve our understanding of the neural correlates of subjective awareness. [less ▲]

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See detailPerformance evaluation of the General Electric eXplore CT 120 micro-CT using the vmCT phantom.
Bahri, Mohamed Ali ULg; Warnock, Geoffrey ULg; Plenevaux, Alain ULg et al

in Nuclear Instruments & Methods in Physics Research Section A (2011), 648

The eXplore CT 120 is the latest generation micro-CT from General Electric. It is equipped with a high power tube and a flat panel detector. It allows high resolution and high contrast fast CT scanning of ... [more ▼]

The eXplore CT 120 is the latest generation micro-CT from General Electric. It is equipped with a high power tube and a flat panel detector. It allows high resolution and high contrast fast CT scanning of small animals. The aim of this study was to compare the performance of the eXplore CT 120 with the one of the eXplore Ultra, its predecessor for which the methodology using the vmCT phantom was already described [1]. The phantom was imaged using typical rat (fast scan or F) or mouse (in vivo bone scan or H) scanning protocols. With the slanted edge method, a 10% modulation transfer function (MTF) was observed at 4.4 (F) and 3.9-4.4 (H) mm-1 corresponding to 114 μm resolution. A fairly larger MTF was obtained with the coil method with the MTF for the thinnest coil (3.3 mm-1 ) equal to 0.32 (F) and 0.34 (H). The geometric accuracy was better than 0.3%. There was a highly linear (R2 > 0.999) relationship between measured and expected CT numbers for both the CT number accuracy and linearity sections of the phantom. A cupping effect was clearly seen on the uniform slices and the uniformity-to-noise ratio ranged from 0.52 (F) to 0.89 (H). The air CT number depended on the amount of polycarbonate surrounding the area where it was measured: a difference as high as approximately 200 HU was observed. This hindered the calibration of this scanner in HU. This is likely due to the absence of corrections for beam hardening and scatter in the reconstruction software. However in view of the high linearity of the system, the implementation of these corrections would allow a good quality calibration of the scanner in HU. In conclusion, the eXplore CT 120 achieved a better spatial resolution than the eXplore Ultra (based on previously reported specifications) and future software developments to include beam hardening and scatter corrections will make the new generation CT scanner even more promising. [less ▲]

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See detailUse of a beta microprobe system to measure arterial input function in PET via an arteriovenous shunt in rats
Warnock, Geoffrey ULg; Bahri, Mohamed Ali ULg; Goblet, David ULg et al

in European Journal of Nuclear Medicine and Molecular Imaging Research (2011), 1

Kinetic modeling of physiological function using imaging techniques requires the accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The ... [more ▼]

Kinetic modeling of physiological function using imaging techniques requires the accurate measurement of the time-activity curve of the tracer in plasma, known as the arterial input function (IF). The measurement of IF can be achieved through manual blood sampling, the use of small counting systems such as beta microprobes, or by derivation from PET images. Previous studies using beta microprobe systems to continuously measure IF have suffered from high background counts. In the present study, a light-insensitive beta microprobe with a temporal resolution of up to 1 s was used in combination with a pump-driven femoral arteriovenous shunt to measure IF in rats. The shunt apparatus was designed such that the placement of the beta microprobe was highly reproducible. The probe-derived IF was compared to that obtained from manual sampling at 5-s intervals and IF derived from a left ventricle VOI in a dynamic PET image of the heart. Probe-derived IFs were very well matched to that obtained by "gold standard" manual blood sampling, but with an increased temporal resolution of up to 1 s. The area under the curve (AUC) ratio between probe- and manually derived IFs was 1.07 ± 0.05 with a coefficient of variation of 0.04. However, image-derived IFs were significantly underestimated compared to the manually sampled IFs, with an AUC ratio of 0.76 ± 0.24 with a coefficient of variation of 0.32. IF derived from the beta microprobe accurately represented the IF as measured by blood sampling, was reproducible, and was more accurate than an image-derived technique. The use of the shunt removed problems of tissue-background activity, and the use of a light-tight probe with minimal gamma sensitivity refined the system. The probe/shunt apparatus can be used in both microprobe and PET studies. [less ▲]

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See detailBrain energization in response to deep brain stimulation of subthalamic nuclei in Parkinson's disease.
Garraux, Gaëtan ULg; Bahri, Mohamed Ali ULg; Lemaire, Christian ULg et al

in Journal of Cerebral Blood Flow & Metabolism (2011)

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment in a subgroup of medically refractory patients with Parkinson's disease (PD). Here, we compared resting-state (18)F ... [more ▼]

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment in a subgroup of medically refractory patients with Parkinson's disease (PD). Here, we compared resting-state (18)F-fluorodeoxyglucose (FDG) positron emission tomography images in the stimulator off (DBS_OFF) and on (DBS_ON) conditions in eight PD patients in an unmedicated state, on average 2 years after bilateral electrode implantation. Global standardized uptake value (SUV) significantly increased by approximately 11% in response to STN-DBS. To avoid any bias in the voxel-based analysis comparing DBS_ON and DBS_OFF conditions, individual scan intensity was scaled to a region where FDG-SUV did not differ significantly between conditions. The resulting FDG-SUV ratio (FDG-SUVR) was found to increase in many regions in response to STN-DBS including the target area of surgery, caudate nuclei, primary sensorimotor, and associative cortices. Contrary to previous studies, we could not find any regional decrease in FDG-SUVR. These findings were indirectly supported by comparing the extent of areas with depressed FDG-SUVR in DBS_OFF and DBS_ON relatively to 10 normal controls. Altogether, these novel results support the prediction that the effect of STN-DBS on brain activity in PD is unidirectional and consists in an increase in many subcortical and cortical regions.Journal of Cerebral Blood Flow & Metabolism advance online publication, 6 April 2011; doi:10.1038/jcbfm.2011.41. [less ▲]

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