[Show abstract][Hide abstract] ABSTRACT: Highlights Transplants of hESC-DA survive long term and restore DA neurotransmission in vivo The functional potency of hESC-DA is similar to human fetal midbrain DA neurons hESC-DA are capable of long-distance, target-specific innerva-tion of the host brain The axonal outgrowth capacity of hESC-DA meets the require-ments for use in humans Authors In Brief Grealish et al. provide preclinical evi-dence that hESC-derived dopamine neu-rons are functionally equivalent to those derived from fetal tissue, supporting continued development of hESC-derived cells as a clinical approach for the treat-ment of Parkinson's disease.
[Show abstract][Hide abstract] ABSTRACT: Overexpression of the translocator protein, TSPO (18 kDa), for- merly known as the peripheral benzodiazepine receptor, is a hall- mark of activation of cells of monocytic lineage (microglia and macrophages) during neuroinflammation. Radiolabeling of TSPO ligands enables the detection of neuroinflammatory lesions by PET. Two new radioligands, 11C-labeled N,N-diethyl-2-(2-(4- methoxyphenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl) acetamide (DPA-713) and 18F-labeled N,N-diethyl-2-(2-(4-(2- fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl) acetamide (DPA-714), both belonging to the pyrazolopyrimidine class,werecompared invivo and invitro using arodent model of neuroinflammation. Methods: 11C-DPA-713 and 18F-DPA-714, as well as the classic radioligand 11C-labeled (R)-N-methyl- N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), were used in the same rat model, in which intrastria- tal injection of (R,S)-a-amino-3-hydroxy-5-methyl-4-isoxazolo- propionique gave rise to a strong neuroinflammatory response. Comparativeendpointsincludedinvitroautoradiographyandin vivo imaging on a dedicated small-animal PET scanner under identical conditions. Results: 11C-DPA-713 and 18F-DPA-714 could specifically localize the neuroinflammatory site with a sim- ilar signal-to-noise ratio in vitro. In vivo, 18F-DPA-714 performed better than 11C-DPA-713 and 11C-PK11195, with the highest ra- tio of ipsilateral to contralateral uptake and the highest binding potential. Conclusion: 18F-DPA-714 appears to be an attractive alternative to 11C-PK11195becauseof itsincreasedbioavailabil- ity in brain tissue and its reduced nonspecific binding. Moreover, its labeling with 18F, the preferred PET isotope for radiopharma-
[Show abstract][Hide abstract] ABSTRACT: The development of dyskinesias following chronic L-DOPA replacement therapy remains a major problem in the long-term treatment of Parkinson's disease. This study aimed at evaluating the effect of IRC-082451 (base of BN82451), a novel multitargeting hybrid molecule, on L-DOPA-induced dyskinesias (LIDs) and hypolocomotor activity in a non-human primate model of PD. IRC-082451 displays multiple properties: it inhibits neuronal excitotoxicity (sodium channel blocker), oxidative stress (antioxidant) and neuroinflammation (cyclooxygenase inhibitor) and is endowed with mitochondrial protective properties. Animals received daily MPTP injections until stably parkinsonian. A daily treatment with increasing doses of L-DOPA was administered to parkinsonian primates until the appearance of dyskinesias. Then, different treatment regimens and doses of IRC-082451 were tested and compared to the benchmark molecule amantadine. Primates were regularly filmed and videos were analyzed with specialized software. A novel approach combining the analysis of dyskinesias and locomotor activity was used to determine efficacy. This analysis yielded the quantification of the total distance travelled and the incidence of dyskinesias in 7 different body parts. A dose-dependent efficacy of IRC-082451 against dyskinesias was observed. The 5 mg/kg dose was best at attenuating the severity of fully established LIDs. Its effect was significantly different from that of amantadine since it increased spontaneous locomotor activity while reducing LIDs. This dose was effective both acutely and in a 5-day sub-chronic treatment. Moreover, positron emission tomography scans using radiolabelled dopamine demonstrated that there was no direct interference between treatment with IRC-082451 and dopamine metabolism in the brain. Finally, post-mortem analysis indicated that this reduction in dyskinesias was associated with changes in cFOS, FosB and ARC mRNA expression levels in the putamen. The data demonstrates the antidyskinetic efficacy of IRC-082451 in a primate model of PD with motor complications and opens the way to the clinical application of this treatment for the management of LIDs.
PLoS ONE 01/2013; 8(1):e52680. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPO radioligands, [(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2-[(18)F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide] and [(11)C]SSR180575 (7-chloro-N,N-dimethyl-5-[(11)C]methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), showed a significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.
Journal of Neuroscience 08/2012; 32(32):10809-18. · 6.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to characterize the transgenic Huntington rat model with in vivo imaging and identify sensitive and reliable biomarkers associated with early and progressive disease status. In order to do so, we performed a multimodality (DTI and PET) longitudinal imaging study, during which the same TgHD and wildtype (Wt) rats were repetitively scanned. Surprisingly, the relative ventricle volume was smaller but increased faster in TgHD compared to Wt animals. DTI (mean, axial, radial diffusivity) revealed subtle genotype-specific aging effects in the striatum and its surrounding white matter, already in the presymptomatic stage. Using ¹⁸F-FDG and ¹⁸F-Fallypride PET imaging, we were not able to demonstrate genotype-specific aging effects within the striatum. The outcome of this longitudinal study was somewhat surprising as it demonstrated a significant differential aging pattern in TgHD versus Wt animals. Although it seems that the TgHD rat model does not have a sufficient expression of disease yet at the age of 12 months, further validation of this model is highly beneficial since there is still an incomplete understanding of the early disease mechanisms of Huntington's disease.
[Show abstract][Hide abstract] ABSTRACT: Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects.
Here we report the radiolabelling of SSR180575 with (11)C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats.
The image contrast and the binding of [(11)C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [(11)C]PK11195. Competition studies demonstrate that [(11)C]SSR180575 has high specific binding for the TSPO.
[(11)C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.
European Journal of Nuclear Medicine 10/2010; 38(3):509-14. · 4.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In vivo diffusion tensor imaging (DTI) was performed on the quinolinic acid (QUIN) rat model of Huntington's disease, together with behavioral assessment of motor deficits and histopathological characterization. DTI and histology revealed the presence of a cortical lesion in 53% of the QUIN animals (QUIN(+ctx)). Histologically, QUIN(+ctx) were distinguished from QUIN(-ctx) animals by increased astroglial reaction within a subregion of the caudate putamen and loss of white matter in the external capsula. Although both techniques are complementary, the quantitative character of DTI makes it possible to pick up subtle differences in tissue microstructure that are not identified with histology. DTI demonstrated differential changes of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) in the internal and external capsula, and within a subregion of the caudate putamen. It was suggested that FA increased due to a selective loss of the subcortical connections targeted by degenerative processes at the early stage of the disease, which might turn the striatum into a seemingly more organized structure. When tissue degeneration becomes more severe, FA decreased while AD, RD and MD increased.
Neurobiology of aging 08/2010; 33(5):945-59. · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The key role of neuroinflammation in acute and chronic neurological disorders has stimulated the search for specific radiotracers targeting the peripheral benzodiazepine receptor (PBR)/18 kDa translocator protein (TSPO), a hallmark of neuroinflammation. Here we evaluate the new radiotracer for positron emission tomography (PET) [(18)F]PBR111 in a rodent model of acute inflammation and compare it with [(11)C]CLINME, an (11)C-labelled tracer of the same chemical family, and with the isoquinolinic carboxamide [(11)C]PK11195.
We studied radiometabolites by HPLC, in vitro binding by autoradiography and in vivo brain kinetics as well as in vivo specificity of binding using PET imaging.
We show that this radiotracer has a high in vitro specificity for PBR/TSPO versus central benzodiazepine receptors, as reflected by the drastic reduction of its binding to target tissue by addition of PK11195 or PBR111, while addition of flumazenil does not affect binding. Only intact [(18)F]PBR111 is detected in brain up to 60 min after i.v. injection, and PET imaging shows an increased uptake in the lesion as compared to the contralateral side as early as 6 min after injection. Administration of an excess of PK11195 and PBR111, 20 min after [(18)F]PBR111 administration, induces a rapid and complete displacement of [(18)F]PBR111 binding from the lesion. Modelling of the PET data using the simplified reference tissue model showed increased binding potential (BP) in comparison to [(11)C]PK11195.
[(18)F]PBR111 is a metabolically stable tracer with a high specific in vitro and in vivo binding to TSPO. In addition, considering the longer half-life of (18)F over (11)C, these results support [(18)F]PBR111 as a promising PET tracer of the PBR/TSPO for neuroinflammation imaging.
European Journal of Nuclear Medicine 05/2010; 37(5):962-72. · 4.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present study, we aimed to evaluate the impact of neurodegeneration of the nigrostriatal tract in a rodent model of Parkinson's disease on the different MR contrasts (T(2), T(1), CBF and CBV) measured in the striatum.
Animals were injected with 6-hydroxydopamine (6OHDA) in the substantia nigra resulting in massive loss of nigrostriatal neurons and hence dopamine depletion in the ipsilateral striatum. Using 7T MRI imaging, we have quantified T(2), T(1), CBF and CBV in the striata of 6OHDA and control rats. To validate the lesion size, behavioral testing, dopamine transporter muSPECT and tyrosine hydroxylase staining were performed.
No significant differences were demonstrated in the absolute MRI values between 6OHDA animals and controls; however, 6OHDA animals showed significant striatal asymmetry for all MRI parameters in contrast to controls.
These PD-related asymmetry ratios might be the result of counteracting changes in both intact and affected striatum and allowed us to diagnose PD lesions. As lateralization is known to occur also in PD patients and might be expected in transgenic PD models as well, we propose that MR-derived asymmetry ratios in the striatum might be a useful tool for in vivo phenotyping of animal models of PD.
MAGMA Magnetic Resonance Materials in Physics Biology and Medicine 02/2010; 23(2):65-75. · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with [(18)F]DPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. In vivo PET imaging showed significant increase in DPA (N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) uptake on the injured side compared with that in the contralateral area on days 7, 11, 15, and 21 after ischemia; the maximal binding value was reached 11 days after ischemia. In vitro autoradiography confirmed these in vivo results. In vivo and in vitro [(18)F]DPA-714 binding was displaced from the lesion by PK11195 and DPA-714. Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that [(18)F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 09/2009; 30(1):230-41. · 5.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is characterised by degeneration of the nigrostrial connection causing dramatic changes in the dopaminergic pathway underlying clinical pathology. Till now, no MRI tools were available to follow up any specific PD-related neurodegeneration. However, recently, diffusion tensor imaging (DTI) has received considerable attention as a new and potential in vivo diagnostic tool for various neurodegenerative diseases. To assess this in PD, we performed DTI in the acute 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate diffusion properties in the degenerating nigrostriatal pathway and its connecting structures. Injection of a neurotoxin in the striatum causes retrograde neurodegeneration of the nigrostriatal tract, and selective degeneration of nigral neurons. The advantage of this model is that the lesion size is well controllable by the injected dose of the toxin. The degree of functional impairment was evaluated in vivo using the amphetamine rotation test and microPET imaging of the dopamine transporter (DAT). Despite a nearly complete lesion of the nigrostriatal tract, DTI changes were limited to the ipsilateral substantia nigra (SN). In this study we demonstrate, using voxel-based statistics (VBS), an increase in fractional anisotropy (FA), whereas all eigenvalues were significantly decreased. VBS enabled us to visualise neurodegeneration of a cluster of neurons but failed to detect degeneration of more diffuse microstructures such as the nigrostriatal fibres or the dopaminergic endings in the striatum. VBS without a priori information proved to be better than manual segmentation of brain structures as it does not suffer from volume averaging and is not susceptible to erroneous segmentations of brain regions that show very little contrast on MRI images such as SN.
NMR in Biomedicine 04/2009; 22(7):697-706. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Overexpression of the translocator protein, TSPO (18 kDa), formerly known as the peripheral benzodiazepine receptor, is a hallmark of activation of cells of monocytic lineage (microglia and macrophages) during neuroinflammation. Radiolabeling of TSPO ligands enables the detection of neuroinflammatory lesions by PET. Two new radioligands, (11)C-labeled N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-alpha]pyrimidin-3-yl]acetamide (DPA-713) and (18)F-labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-alpha]pyrimidin-3-yl)acetamide (DPA-714), both belonging to the pyrazolopyrimidine class, were compared in vivo and in vitro using a rodent model of neuroinflammation.
(11)C-DPA-713 and (18)F-DPA-714, as well as the classic radioligand (11)C-labeled (R)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), were used in the same rat model, in which intrastriatal injection of (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionique gave rise to a strong neuroinflammatory response. Comparative endpoints included in vitro autoradiography and in vivo imaging on a dedicated small-animal PET scanner under identical conditions.
(11)C-DPA-713 and (18)F-DPA-714 could specifically localize the neuroinflammatory site with a similar signal-to-noise ratio in vitro. In vivo, (18)F-DPA-714 performed better than (11)C-DPA-713 and (11)C-PK11195, with the highest ratio of ipsilateral to contralateral uptake and the highest binding potential.
(18)F-DPA-714 appears to be an attractive alternative to (11)C-PK11195 because of its increased bioavailability in brain tissue and its reduced nonspecific binding. Moreover, its labeling with (18)F, the preferred PET isotope for radiopharmaceutical chemistry, favors its dissemination and wide clinical use. (18)F-DPA-714 will be further evaluated in longitudinal studies of neuroinflammatory conditions such as are encountered in stroke or neurodegenerative diseases.
Journal of Nuclear Medicine 03/2009; 50(3):468-76. · 5.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR, [(11)C]PK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of [(11)C]PK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents.
European Journal of Nuclear Medicine 11/2008; 35(12):2304-19. · 4.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review aims to make the reader aware of the potential of functional MRI (fMRI) in brain activation studies in small animal models. As small animals generally require anaesthesia for immobilization during MRI protocols, this is believed to be a serious limitation to the type of question that can be addressed with fMRI. We intend to introduce a fresh view with an in-depth overview of the surprising number of fMRI applications in a wide range of important research domains in neuroscience. These include the pathophysiology of brain functioning, the basic science of activity, and functional connectivity of different sensory circuits, including sensory brain mapping, the challenges when studying the hypothalamus as the major control centre in the central nervous system, and the limbic system as neural substrate for emotions and reward. Finally the contribution of small animal fMRI research to cognitive neuroscience is outlined. This review avoids focusing exclusively on traditional small laboratory animals such as rodents, but rather aims to broaden the scope by introducing alternative lissencephalic animal models such as songbirds and fish, as these are not yet well recognized as neuroimaging study subjects. These models are well established in many other neuroscience disciplines, and this review will show that their investigation with in vivo imaging tools will open new doors to cognitive neuroscience and the study of the autonomous nervous system in experimental animals.
NMR in Biomedicine 09/2007; 20(5):522-45. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25-30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 (CYLN2) and general transcription factors (GTF2I and GTF2IRD1) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients. Recent studies of patients with partial deletions indicate that hemizygosity of GTF2I probably contributes to mental retardation in WS. Here we investigate whether CYLN2 and GTF2IRD1 contribute to the motoric and cognitive deficits in WS. Behavioral assessment of a new patient in which STX1A and LIMK1, but not CYLN2 and GTF2IRD1, are deleted showed that his cognitive and motor coordination functions were significantly better than in typical WS patients. Comparative analyses of gene specific CYLN2 and GTF2IRD1 knockout mice showed that a reduced size of the corpus callosum as well as deficits in motor coordination and hippocampal memory formation may be attributed to a deletion of CYLN2, while increased ventricle volume can be attributed to both CYLN2 and GTF2IRD1. We conclude that the motor and cognitive deficits in Williams Syndrome are caused by a variety of genes and that heterozygous deletion of CYLN2 is one of the major causes responsible for such dysfunctions.
Neurobiology of Disease 05/2007; 26(1):112-24. · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The neurophysiology of the rodent visual system has mainly been investigated by invasive and ex-vivo techniques providing fragmented data. This area of research has been deprived of functional MRI studies based on blood oxygenation level dependent (BOLD) contrast, which allows a whole brain approach with a high spatial and temporal resolution. In the present study, we looked at the neurovascular response properties of the visual system of the pigmented rat, focusing on the visual cortex (VC), the superior colliculus (SC) and the flocculus-paraflocculus of the cerebellum (FL-PFL), using BOLD fMRI under domitor anesthesia. Visual stimulation was performed monocularly or binocularly while flashing light from a strobe unit was presented. For each structure, we assessed the flashing frequency that evoked the optimal BOLD response: Neither the VC nor the FL-PFL displayed frequency dependence during monocular visual stimulation, but were most sensitive to low frequencies (1-5 Hz) when flashing light was provided binocularly. The SC responded optimally to high flashing rates (8-12 Hz) during both monocular and binocular stimulation. The signal intensity changes in the VC and FL-PFL were locked to the stimulation period, whereas the BOLD response in the SC showed a similar onset but a very slow recovery at offset. The VC and FL-PFL, but not the SC, showed signs of binocular competition. The observed correlation between frequency-dependent responses of different visual areas during binocular visual presentation suggests a functional relationship between the VC and FL-PFL rather than between the SC and FL-PFL.
Journal of Neurophysiology 06/2006; 95(5):3164-70. · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Functional MRI (fMRI) during electrical somatosensory stimulation of the rat forepaw is a widely used model to investigate the functional organization of the somatosensory cortex or to study the underlying mechanisms of the blood oxygen level-dependent (BOLD) response. In reality, somatosensory stimuli have complex timing relationships and are of long duration. However, by default electrical sensory stimulation seems to be performed at an extremely short pulse width (0.3 ms). As the pulse duration may alter the neuronal response, our aim was to investigate the influence of a much longer stimulus pulse width (10 ms) using BOLD fMRI during electrical forepaw stimulation. The optimal neuronal response was investigated by varying the stimulus frequency at a fixed pulse duration (10 ms) and amplitude (1 mA). In a parallel experiment we measured the neuronal response directly by recording the somatosensory evoked potentials (SEPs). Quantification of the BOLD data revealed a shift in the optimal response frequencies to 8-10 Hz compared with 1 Hz at 0.3 ms. The amplitude of the recorded SEPs decreased with increasing stimulation frequency and did not display any correlation with the BOLD data. Nevertheless, the summated SEPs, which are a measure of the integrated neuronal activity as a function of time, displayed a similar response profile, with a similar maximum as observed by relative BOLD changes. This shift in optimal excitation frequencies might be related to the fact that an increased pulse width of an electrical stimulus alters the nature of the stimulation, generating also sensorimotor instead of merely somatosensory input. This may influence or alter the activated pathways, resulting in a shift in the optimal response profile.
NMR in Biomedicine 03/2006; 19(1):10-7. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Functional magnetic resonance imaging (fMRI) is a unique tool to study brain activity and plasticity changes. Combination of blood-oxygen level-dependent (BOLD) fMRI and electrical forepaw stimulation has been used as a standard model to study the somatosensory pathway and brain rehabilitation in rats. The majority of fMRI studies have been performed in animals anesthetized with alpha-chloralose as functional-metabolic coupling is best preserved under this anesthesia. However, alpha-chloralose is not suitable for survival procedures due to side effects, limiting its use to single time point studies of the same animal. We therefore developed a new, totally noninvasive fMRI protocol, using sedation with the alpha2-adrenoreceptor agonist medetomidine in combination with transcutaneous monitoring of blood gases. The continuous subcutaneous administration of medetomidine resulted in stable physiological conditions over a long time and all animals tolerated the repetitive fMRI experiments well. A robust and reproducible, significant BOLD signal increase was observed upon forepaw stimulation in the contralateral primary somatosensory cortex in two consecutive medetomidine sessions in all rats, which was similar to the BOLD signal increase observed in the same animals under alpha-chloralose during a third independent session. Activation in the secondary somatosensory cortex was observed less frequently under both medetomidine and alpha-chloralose. No head motion artifacts or nonspecific brain activation was present. Sedation was quickly reversed by the administration of the antagonist atipamezole after the fMRI experiment. These results demonstrate that longitudinal fMRI studies can be performed safely under sedation with medetomidine to study functional recovery processes upon therapeutical treatment.