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BackgroundDisturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve patients with first-episode psychosis from healthy control subjects.MethodsWe included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from 18F-fluorodopa (18F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion.ResultsIndividual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p = .003) and included dopamine synthesis capacity (Ki4p) in the nucleus accumbens (p = .664), GABA levels in the ACC (p = .019), glutamate plus glutamine levels in the thalamus (p = .678), and the interaction term Ki4p × GABA (p = .016).ConclusionsOur multimodal approach proved superior classification accuracy, implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between Ki4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information.

Background Multiple sclerosis (MS) is a debilitating disease of the central nervous system for which no definitive therapy has yet been developed. The etiology remains uncertain, but there is evidence of genetic susceptibility to the disease, including contributions from mitochondrial DNA (mtDNA) variations to the pathogenesis of MS. G15257A and G15812A are variations of the mtDNA tRNA(Thr) gene in MS sufferers of different populations. The present study tested the hypothesis of an association of the G15257A and G15812A variations of the mtDNA tRNA(Thr) gene to the susceptibility to MS in an Iranian population. Material and methods Two hundred subjects included 100 MS patients and 100 unrelated healthy controls. DNA was extracted from blood samples by means of a salting-out method. The mtDNA fragment was amplified by polymerase chain reaction (PCR). Restriction fragment length polymorphism (RFLP) analysis was done by digestion of the PCR products with Acc I and Rsa I restriction endonuclease enzymes for mtDNA G15257A and G15812A variations, respectively. Afterwards, the restriction products were visualized by electrophoresis using 3% Agarose gel and safe DNA gel staining. To confirm the accuracy of genotyping procedure, sequencing of the mtDNA fragments was carried out in randomly selected samples. Results The mtDNA G15257A variation was found in one of the 100 patients and one of the 100 controls (P = 0.637) (odds ratio [OR] = 1, 95% confidence interval [95% CI] = 0.0–79.2). The mtDNA G15812A variation was not found in any of the 100 patients or 100 controls (0%) (P = 1) (OR = 1, 95% CI = 0.0–79.2). Conclusion The evidence from the present study is inconsistent with the hypothesis that the G15257A and G15812A variations in the mtDNA tRNA(Thr) gene are associated with susceptibility to MS in the selected population.

Background Multiple sclerosis (MS) affects the brain and spinal cord and long has been the topic of global research; yet there is no commonly accepted cause and no cure for the disease. Mounting evidence supports the role of genetics in susceptibility to MS. From this perspective, a current effort focuses on the neurogenetics of the complex pathogenesis of MS in relation to factors such as mitochondrial DNA (mtDNA) variations. T4216C and A4917G are common mitochondrial gene variations associated with MS. The present study tested whether mtDNA T4216C variation in the NADH Dehydrogenase 1 (ND1) mtDNA gene and A4917G variation in the mtDNA NADH Dehydrogenase 2 (ND2) gene are associated with MS in an Iranian population. Material and methods Blood samples were collected from 100 patients with MS and 100 unrelated healthy controls, and DNA extraction was performed by salting-out. By means of appropriate primers, polymerase chain reaction (PCR) amplification was carried out for the mtDNA fragment. Afterwards, the PCR products were digested using Nla III and Acc I restriction endonuclease enzymes for analysis of Restriction Fragment Length polymorphism (RFLP) in mtDNA T4216C and A4917G variations, respectively. With electrophoresis by means of 3% agarose gel and safe DNA gel stain, we imaged restriction products in a UV transilluminator. The accuracy of genotyping procedure was confirmed by sequencing the mtDNA fragment. Results No significant statistical difference in the frequency of the T4216C mtDNA variation was found between the patients (24%) and the control subjects (21%) (P = 0.61). Logistic regression analysis showed an OR of 1.1 (95% CI = 0.5–2.4). Moreover, there was no significant statistical difference in the frequency of mtDNA A4917G variation between the cases (11%) and the controls (9%) (P = 0.637). Logistic regression analysis revealed an odds ratio (OR) of 1.2 with 95% CI of 0.4–3.5. Conclusion The present study revealed no association between MS and T4216C variation in the ND1 mtDNA gene and A4917G variation in the mtDNA ND2 gene in the Iranian population.

BACKGROUND: Vagal nerve stimulation (VNS) emerged as an anti-epileptic therapy, and more recently as a potential antidepressant intervention.OBJECTIVE/HYPOTHESIS: We hypothesized that salutary effects of VNS are mediated, at least in part, by augmentation of the inhibitory effects of cortical monoaminergic neurotransmission at appropriate receptors, specifically adrenoceptors. Our objective was to measure the effect of acute VNS on α2 adrenoceptor binding.METHODS: Using positron emission tomography (PET), we measured changes in noradrenaline receptor binding associated with acute VNS stimulation in six anesthetized Göttingen minipigs. We used the selective α2 adrenoceptor antagonist [11C]yohimbine, previously shown to be sensitive to competition from the receptor's endogenous ligands, as a surrogate marker of monoamine release. PET records were acquired 4-6 weeks after the implant of a VNS electrode in minipigs before and within 30 min of the initiation of 1 mA stimulation. Kinetic analysis with the Logan graphical linearization generated tracer volumes of distribution for each condition. We used an averaged value of the distribution volume of non-displaceable ligand (VND), to calculate binding potentials for selected brain regions of each animal.RESULTS: VNS treatment markedly reduced the binding potential of yohimbine in limbic, thalamic and cortical brain regions, in inverse correlation with the baseline binding potential.CONCLUSION: The result is consistent with release of noradrenaline by antidepressant therapy, implying a possible explanation for the antidepressant effect of VNS.

Biogas production from animal slurry can provide substantial contributions to reach renewable energy targets, yet due to the low methane potential of slurry, biogas plants depend on the addition of co-substrates to make operations profitable. The environmental performance of three underexploited co-substrates, straw, organic household waste and the solid fraction of separated slurry, were assessed against slurry management without biogas production, using LCA methodology. The analysis showed straw, which would have been left on arable fields, to be an environmentally superior co-substrate. Due to its low nutrient content and high methane potential, straw yields the lowest impacts for eutrophication and the highest climate change and fossil depletion savings. Co-substrates diverted from incineration to biogas production had fewer environmental benefits, due to the loss of energy production, which is then produced from conventional fossil fuels. The scenarios can often provide benefits for one impact category while causing impacts in another.

Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [(11)C]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis of dopaminergic sensitivity toward uncertainty, and suggest that dopaminergic sensitivity to uncertainty is pronounced in pathological gambling, but not among non-gambling healthy controls. The findings have implications for understanding dopamine dysfunctions in pathological gambling and addictive behaviors.

Udgivelsesdato: 2010-Feb-15 PET studies with the DOPA decarboxylase substrate 6-[(18)F]fluoro-l-DOPA (FDOPA) reveal the storage of [(18)F]-fluorodopamine within synaptic vesicles, mainly of dopamine fibres. As such, FDOPA PET is a sensitive indicator of the integrity of the nigrostriatal dopamine innervation. Nonetheless, there have been several reports of focal elevations of FDOPA utilization in brain of patients with Parkinson's disease (PD), all based on reference tissue methods. To investigate this phenomenon further, we used voxel-wise steady-state kinetic analysis to search for regions of elevated FDOPA utilization (K; ml g(-1) min(-1)) and steady-state trapping (V(d); ml g(-1)) in a group of well-characterized patients with early, asymmetric PD, who were contrasted with an age-matched control group. Subtraction of the population mean parametric maps revealed foci of increased FDOPA utilization K (+25%) in the bilateral medial nucleus accumbens, whereas the expected declines in the trapping of FDOPA were seen in the caudate and putamen. This observation suggests hyperfunction of catecholamine fibres innervating specifically the limbic striatum, which could guide the design of future prospective FDOPA-PET studies of the impulse control disorders occurring in some PD patients under treatment with dopamine agonists. A focus of increased FDOPA influx and also V(d) was detected in the periaqueductal grey, consistent with some earlier reports based on reference tissue analysis. Increased FDOPA trapping in the periaqueductal grey of PD patients seems consistent with recent reports of increased activity of serotonin neurons in a rat model of parkinsonism.

Udgivelsesdato: 2010-Jan The autosomal dominant spinocerebellar ataxias, commonly referred to as SCAs, are clinically and genetically heterogeneous neurodegenerative disorders. Twenty-eight genetic subtypes have been identified, of which 7 are caused by expansion of a CAG trinucleotide repeat that encodes a polyglutamine tract in the respective proteins. SCA17 is caused by a CAG/CAA repeat expansion in the TATA box-binding protein-gene (TBP). In some cases the clinical phenotype of SCA17 overlaps that of Huntington's disease (HD), hence the use of the term Huntington's disease-like. We screened 89 patients with a Huntington's disease-like phenotype without the HD-gene mutation and 178 patients with genetically unclassified cerebellar ataxia for the mutation in TBP. A 33-year old woman presenting with an HD like phenotype with a de novo 54 CAG/CAA repeat expansion was identified. Her normal allele included 38 repeats. The patient's mother and father both carried normal range repeats, 38/38 and 33/39 respectively. Analysis of the repeat structures revealed that the expansion had occurred upon expansion of the longer paternal allele. We conclude that, however rare, SCA17 must be considered as a cause of Huntington's disease-like phenotypes and ataxia syndromes, also in isolated cases.

Hyperoxic therapy for cerebral ischemia reduces cerebral blood flow (CBF) principally from the vasoconstrictive effect of oxygen on cerebral arterioles. Based on a recent study in normal volunteers, we now claim that the vasodilatory effect of carbon dioxide predominates when 5% CO(2) is added to inhaled oxygen (the mixture known as carbogen). In the present study, we measured CBF by positron emission tomography (PET) during inhalation of test gases (O(2), carbogen, and atmospheric air) in healthy volunteers (n = 10) and in patients with occlusive carotid artery disease (n = 6). Statistical comparisons by an additive ANOVA model showed that carbogen significantly increased CBF by 7.51 + or - 1.62 ml/100 g/min while oxygen tended to reduce it by -3.22 + or - 1.62 ml/100 g/min. A separate analysis of the hemisphere contralateral to the hypoperfused hemisphere showed that carbogen significantly increased CBF by 8.90 + or - 2.81 ml/100 g/min whereas oxygen inhalation produced no reliable change in CBF (-1.15 + or - 2.81 ml/100 g/min). In both patients and controls, carbogen was as efficient as oxygen in increasing Sa(O2) or PaO(2) values. The study demonstrates that concomitant increases of CBF and Sa(O2) are readily obtained with carbogen, while oxygen increases only Sa(O2). Thus, carbogen improves oxygen transport to brain tissue more efficiently than oxygen alone. Further studies with more subjects are, however, needed to investigate the applicability of carbogen for long-term inhalation and to assess its therapeutic benefits in acute stroke patients.

Udgivelsesdato: 2009-Mar Attention deactivates the inferior medial prefrontal cortex (IMPC), but it is uncertain if emotions can attenuate this deactivation. To test the extent to which common emotions interfere with attention, we measured changes of a blood flow index of brain activity in key areas of the IMPC with positron emission tomography (PET) of labeled water (H(15)2O) uptake in brain of 14 healthy subjects. The subjects performed either a less demanding or a more demanding task of attention while they watched neutral and emotive images of people in realistic indoor or outdoor situations. In the less demanding task, subjects used the index finger to press any key when a new image appeared. In the more demanding task, subjects chose the index or middle finger to press separate keys for outdoor and indoor scenes. Compared to the less demanding task, in a global search of all gray matter, the more demanding significantly lowered blood flow (rCBF) in left IMPC, left and right insula, and right amygdala, and significantly raised blood flow in motor cortex and right precuneus. Restricted searches of rCBF changes by emotion, at coordinates of significant effect in previous studies of the medial prefrontal and temporal cortices, revealed significant activation in the fusiform gyrus, independently of the task. In contrast, we found no effect of emotional content in the IMPC, where emotions failed to override the effect of the task. The results are consistent with a role of the IMPC in the selection among competitive inputs from multiple brain regions, as predicted by the theory of a default mode of brain function. The absent emotional interference with the deactivation of the default state suggests that the inferior prefrontal cortex continued to serve the attention rather than submit to the distraction.

Udgivelsesdato: 2008-Apr-1 INTRODUCTION: In positron emission tomography (PET) studies of cerebral blood flow (CBF) and metabolism, the large interindividual variation commonly is minimized by normalization to the global mean prior to statistical analysis. This approach requires that no between-group or between-state differences exist in the normalization region. Given the variability typical of global CBF and the practical limit on sample size, small group differences in global mean easily elude detection, but still bias the comparison, with profound consequences for the physiological interpretation of the results. MATERIALS AND METHODS: Quantitative [15O]H2O PET recordings of CBF were obtained in 45 healthy subjects (21-81 years) and 14 patients with hepatic encephalopathy (HE). With volume-of-interest (VOI) and voxel-based statistics, we conducted regression analyses of CBF as function of age in the healthy group, and compared the HE group to a subset of the controls. We compared absolute CBF values, and CBF normalized to the gray matter (GM) and white matter (WM) means. In additional simulation experiments, we manipulated the cortical values of 12 healthy subjects and compared these to unaltered control data. RESULTS: In healthy aging, CBF was shown to be unchanged in WM and central regions. In contrast, with normalization to the GM mean, CBF displayed positive correlation with age in the central regions. Very similar artifactual increases were seen in the HE comparison and also in the simulation experiment. CONCLUSION: Ratio normalization to the global mean readily elevates CBF in unchanged regions when a systematic between-group difference exists in gCBF, also when this difference is below the detection threshold. We suggest that the routine normalization to the global mean in earlier studies resulted in spurious interpretations of perturbed CBF. Normalization to central WM yields less biased results in aging and HE and could potentially serve as a normalization reference region in other disorders as well.

Udgivelsesdato: 2006-Jun The left inferior prefrontal cortex (LIPC) is involved in speech comprehension by people who hear normally. In contrast, functional brain mapping has not revealed incremental activity in this region when users of cochlear implants comprehend speech without silent repetition. Functional brain maps identify significant changes of activity by comparing an active brain state with a presumed baseline condition. It is possible that cochlear implant users recruited alternative neuronal resources to the task in previous studies, but, in principle, it is also possible that an aberrant baseline condition masked the functional increase. To distinguish between the two possibilities, we tested the hypothesis that activity in the LIPC characterizes high speech comprehension in postlingually deaf CI users. We measured cerebral blood flow changes with positron emission tomography (PET) in CI users who listened passively to a range of speech and non-speech stimuli. The pattern of activation varied with the stimulus in users with high speech comprehension, unlike users with low speech comprehension. The high-comprehension group increased the activity in prefrontal and temporal regions of the cerebral cortex and in the right cerebellum. In these subjects, single words and speech raised activity in the LIPC, as well as in left and right temporal regions, both anterior and posterior, known to be activated in speech recognition and complex phoneme analysis in normal hearing. In subjects with low speech comprehension, sites of increased activity were observed only in the temporal lobes. We conclude that increased activity in areas of the LIPC and right temporal lobe is involved in speech comprehension after cochlear implantation.

Udgivelsesdato: 2005-Nov-7 Behavioral response to novelty in rats has been linked both to dopamine transmission in the ventral striatum, and to propensity to self-administer psychostimulant drugs. In order to probe the relationship between behavioral response to novelty and dopamine systems we have developed a behavioral model for correlation with positron emission tomography (PET) of dopamine transmission in brain of Göttingen minipigs. In the present study, we measured exploration of a novel object by recording the number of contacts, and duration of contact with a novel object, in groups of six male and six female adult minipigs. We hypothesized that these novelty scores would correlate with the amphetamine-evoked dopamine release in ventral striatum, measured 2 weeks later in a PET study of the availability of binding sites for the dopamine D2/3 antagonist [11C]raclopride. There were significant correlations between duration of contact with a novel object and the amphetamine-evoked reductions in binding potential (DeltapB) in the left ventral striatum of the 12 animals; Comparison of results by gender revealed that the correlation was driven mainly by the male group, and was not present in the female group. We interpret these results to show that propensity to explore an unfamiliar object is relatively elevated in pigs with low basal occupancy of dopamine D2/3 receptors by endogenous dopamine, and with high amphetamine-induced occupancy of released dopamine in the male pigs.

Udgivelsesdato: 2005-Apr-15 Abnormal central dopamine (DA) neurotransmission has been implicated in the impulsivity, inattention, and hyperactivity of attention deficit hyperactivity disorder (ADHD). We hypothesized that a pharmacological challenge with methylphenidate (MP) at a therapeutic dose increases extracellular DA concentrations in proportion to the severity of these specific ADHD symptoms. To test this hypothesis, we measured by PET the effect of acute challenge with MP on the availability of striatal binding sites for [11C]raclopride (pB), an index of altered interstitial DA concentration, in nine unmedicated adolescents (1 female, 8 males; age 13.7 +/- 1.8 years) with a current diagnosis of ADHD. We estimated the pB of [11C]raclopride for brain dopamine D2/3 receptors first in a baseline resting condition, and again after an acute challenge with MP (0.3 mg/kg, p.o.), and calculated the percentage change in (%DeltapB) in left and right striatum. On another day, measurements of impulsivity and inattention were performed using a computerized continuous performance test. There was a significant correlation between the magnitude of %DeltapB in the right striatum and the severity of inattention and impulsivity. MP-evoked %DeltapB correlated with standard scores for impulse control (r = 0.68; P = 0.02), attention (r = 0.81; P = 0.005), information processing (r = 0.66; P = 0.02), and consistency of attention, or variability (r = 0.60; P = 0.04). In conclusion, the results link inattention and impulsivity with sensitivity of brain DA receptor availability to an MP challenge, corroborating the hypothesis that MP serves to potentiate decreased DA neurotransmission in ADHD.

Musicians exchange non-verbal cues as messages when they play together. This is particularly true in music with a sketchy outline. Jazz musicians receive and interpret the cues when performance parts from a regular pattern of rhythm, suggesting that they enjoy a highly developed sensitivity to subtle deviations of rhythm. We demonstrate that pre-attentive brain responses recorded with magnetoencephalography to rhythmic incongruence are left-lateralized in expert jazz musicians and right-lateralized in musically inept non-musicians. The left-lateralization of the pre-attentive responses suggests functional adaptation of the brain to a task of communication, which is much like that of language.

Udgivelsesdato: 2004-Feb-15 The Stroop test (ST) assesses the integrity of prefrontal and cingulate functioning. Patients with major depression perform poorly on the ST, pointing to disturbed function in these areas. We therefore used positron emission tomography to study 41 in-patients with major depression and 46 age- and gender-matched controls during neuropsychological activation with the ST. Magnetic resonance imaging was used for coregistration and for description of the localization of white matter lesions (WML). The cerebral blood flow (CBF) changes during ST were mapped for each of the two study groups, and inter-group differences were calculated on a voxel-by-voxel basis. The patients were followed for 3 to 5 years to ensure diagnostic stability. The control group activated anterior cingulate regions, prefrontal cortices, insula, thalamus and cerebellum. Despite the patients' slower performance with more errors, no significant differences were found comparing the activations in the two groups. The performance was, however, correlated to the number of WML in frontal lobes, insula and adjacent to the basal ganglia, whereas WML in other locations was not related to performance. We thus partly explain the poorer performance by increased frequency of WML in frontostriatal pathways in the depressed patients, impairing neurotransmission.

Udgivelsesdato: 2004-Feb The relationships among cerebral blood flow (CBF), oxygen consumption (CMRO(2)) and glucose use (CMR(glc)) constitute the basis of functional brain-imaging. Here we report spatially dissociated changes of CMRO(2) and CBF during motor activity that lead us to propose a revision of conventional CBF-CMRO(2) coupling models. In the left primary and supplementary motor cortices, CBF and CMRO(2) rose significantly during finger-thumb tapping. However, in the right putamen CBF did not rise, despite a significant increase in CMRO(2). We explain these observations by invoking a central command mechanism that regulates CBF in the putamen in anticipation of movement. By this mechanism, CBF rose in the putamen before the measurements of CBF and CMRO(2) while CMRO(2) rose when actual motion commenced.

We tested the prediction that single photon emission computed tomography (SPECT) of the blood flow distribution in speech-activated brain identifies the language-dominant hemisphere. We based the prediction on the hypothesis that language activation leads to focally increased regional cerebral blood flow (rCBF), which is reflected in the uptake of a flow tracer recorded by SPECT. We compared the results of speech activation to the results of functional transcranial Doppler (fTCD) monitoring in the same subjects. Preoperatively, 17 patients (10 women and 7 men with a mean age of 36 +/- 15 years) with diagnoses of epilepsy (n = 14) or arteriovenous malformation (AVM) (n = 3) had two SPECT and two stereo-TCD monitoring studies in each case, one at rest, and one during 3 min of speech activation. Except for two left-handed patients with right-hemisphere dominance, the subjects had the highest changes of rCBF from baseline to activation in the left posterior inferior frontal cortex and in contralateral cerebellum. The results show that changes of the level of neuronal activity reflected by the measurement of rCBF variations might be detected by SPECT. Additionally, the evaluation of hemispheric language dominance based on SPECT showed a complete agreement with the evaluation based on fTCD results (yielding a kappa coefficient equal to 1), and therefore, speech-activation SPECT mapping might be helpful in the evaluation of hemispheric language dominance, especially when fMRI and PET are not available or they are contraindicated for some reason.

The objective of this study was to test that hypothermia improves the outcome of an acute ischemic stroke. In order to test the hypothesis that hypothermia (32 °C) improves the outcome by effecting the global cerebral reduction of oxygen consumption when the blood flow is already low, we investigated the sequential changes of physiological variables during hypothermia using positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) in pigs. The cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) decreased significantly to within 50% of the baseline in 3 and 5 h as functions of time, thereby lowering the viability threshold of the brain tissue. The oxygen extraction fraction (OEF) was significantly elevated to 140% of the baseline in 4 h, indicating a reduction in the driving pressure of oxygen delivery in response to the reduced metabolic need, and then it gradually returned so that it was once again level with the baseline. The cerebral metabolic rate of glucose (CMRglc), the cerebral blood volume (CBV), and apparent diffusion coefficient (ADC) decreased to 75%, 72% and 80% of the baseline after 6 h of hypothermia in response to the lowered metabolism for maintenance of cellular integrity, and the diminution of intracranial pressure. The results of ischemia show that rapid cooling of the brain to 32 °C significantly increases the survival of tissue at risk.

Udgivelsesdato: 2001-Dec We have used positron emission tomography to investigate the cortical areas of the normal human brain involved in processing inward (Expansion) and outward (Contraction) radial motion simulated with an optic flow stimulus. The optical flow display was made out of dots moving radially away from or toward the center of the display monitor. In the Control condition, the dots' motion was randomized in order to remove any sensation of radial motion. In the Expansion condition, several loci of activation were observed: visual areas V2-V3 and the superior parietal lobule (BA 7), predominantly in the right hemisphere. In the Contraction condition activation sites were found in the same visual areas (V2 and V3) in the right hemisphere but the increase in rCBF in these regions was much lower than in the Expansion condition. BA 7 was activated in both hemispheres. When the motion component of the stimulus was isolated by subtracting the static condition from the incoherent motion condition, we obtained activations of areas V2, V3, and MT (putative V5). These results indicate that the detection of radial motion derived from an optic flow stimulus is mediated by structures forming the dorsal part of the visual cortical system and confirm that area MT is not specifically involved in flow analysis.

Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1 RS ,5 SR )-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N -demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes; their IC 50 values were 3000-fold lower for [ 3 H]serotonin than for either [ 3 H]dopamine or [ 3 H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N -methylation with C-11, yielding [ 11 C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood–brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [ 11 C]NS2456 nor its [ 11 C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.

Udgivelsesdato: 1999-Sep Neuropsychological data suggests that divided attention is more impaired than sustained attention during the early phases of Alzheimer's disease. The purpose of the present study was to compare cerebral activation patterns during sustained and divided attention between Alzheimer patients and healthy elderly. The O-15-water PET activation method was used to map sustained and divided attention in 16 patients with Alzheimer's disease (mean age +/- SD: 68 +/- 5 years; MMSE: 11-25, mean +/- SD = 19.5 +/- 4.9) and in 16 healthy age-matched control subjects. After stereotactical normalization, voxel-by-voxel t statistics was used to assess the significance of activated brain areas and to compare activations between patients and control subjects. In the healthy elderly, sustained and divided attention both elicited activation of the right inferior parietal lobule, and the right middle frontal gyrus, whereas the anterior cingulate gyrus was activated during sustained attention only. Only medial frontal structures (Brodmann Area (BA) 32/34) were activated in Alzheimer patients, and both frontal (BA-10), posterior cingulate (BA-23/31), and subcortical sites were deactivated. Compared to the healthy elderly, the activations in the patients of the right medial (BA-11) superior (BA-10) and inferior (BA-47) frontal gyri, the right middle temporal (BA-20), and the left lingual (BA-17) gyri were significantly reduced. More cortical sites differed statistically between Alzheimer patients and control subjects during divided than during sustained attention. The activation pattern elicited by attention supports the neuropsychological data that divided attention is more impaired than sustained attention in early Alzheimer's disease.

Udgivelsesdato: 1997-Oct-3 The biological accuracy of a nonlinear compartmental model describing the in vivo kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine ([18F]FDOPA) metabolism was investigated. Tissue activities for [18F]FDOPA and its labeled metabolites 3-O-methyl-[18F]FDOPA ([18F]OMFD), 6-[18F]fluorodopamine ([18F]FDA), L-3,4-dihydroxy-6-[18F]fluorophenylacetic acid ([18F]FDOPAC), and 6-[18F]fluorohomovanillic acid ([18F]FHVA) were calculated using a plasma [18F]FDOPA input function, and kinetic constants estimated previously by chromatographic fractionation of 18F-labeled compounds in plasma and brain extracts from rat. Present data accurately reflected the measured radiochemical composition in rat brain for tracer circulation times past 10 min. We formulated the hypothesis that the discrepancy between calculated and measured fractions of [18F]FDOPA and the deaminated metabolite [18F]FDOPAC at times earlier than 10 min reflected storage of [18F]FDA in vesicles without monoamine oxidase. This hypothesis explained the initially rapid appearance of [18F]FDOPAC in striatum by delayed transfer of [18F]FDA from cytosol into vesicles. We conclude that the simpler model of [18F]FDOPA compartmentation is accurate when the cytosolic and vesicular fractions of [18F]FDA are at steady-state; the approach to equilibrium has a time constant of 15-30 min. The present model is valid for positron emission tomography studies of [18F]FDOPA metabolism in living brain.

The brain binding kinetics and distribution of the antidepressant venlafaxine, labelled with 11C in the O-methyl position, was studied by PET after intravenous injection in anesthetized pigs. In addition, venlafaxine's action on serotonin (5-HT) uptake was studied in vitro in blood platelets obtain from humans or pigs. Venlafaxine resembled imipramine, paroxetine and citalopram in causing a dose-dependent inhibition of 5-HT uptake in blood platelets from pigs and humans. Venlafaxine-derived radioactivity entered the living brain readily and showed higher binding potentials in diencephalic and telencephalic regions than in cerebellum. Acute administration of an antidepressant drug (i.e. imipramine, citalopram or paroxetine) enhanced the distribution and altered the binding of venlafaxine in certain brain regions. The findings show that [11C]venlafaxine is not an ideal PET radiotracer mainly because of its relatively low binding potentials and its lack of specificity for the 5-HT transporter in living brain.

Udgivelsesdato: 1996-Jun OBJECTIVE: Using the 2-deoxyglucose method, measurements of local cerebral glucose utilization in large fetal animals are very difficult and expensive. To circumvent these problems we recently modified the 2-deoxyglucose method for use in the fetal guinea pig in utero (Berger et al., J Neurochem 1994; 63: 271-279). The present study was designed to measure the rates of local cerebral glucose utilization in fetal guinea pigs at 0.75 of gestation. STUDY DESIGN: After intravenous injection of 14C 2-deoxyglucose into the dams, local cerebral glucose utilization of the fetuses was measured from the time integral of the tracer in the maternal plasma and the autoradiographically determined concentration of the tracer in various parts of the fetal brain. RESULTS: Fetal cerebral glucose utilization was low as compared to adult animals and varied in different brain structures from 19 +/- 4 to 29 +/- 7 mumol/100 g/min. CONCLUSION: This study demonstrates the feasibility to measure local cerebral glucose utilization in undisturbed fetal guinea pigs in utero. We conclude that the low rate of cerebral glucose utilization and its small overall variability may reflect the neurological immaturity of the fetal brain.

Udgivelsesdato: 1995-Sep-28 6-[18F]fluoro-L-DOPA (FDOPA) has been used as a tracer for the cerebral activity of L-3,4-dihydroxyphenylalanine (DOPA)-decarboxylase in studies of positron emission tomography (PET). However, the substitution of fluorine on the aromatic ring may alter the disposition and metabolism of FDOPA from that of endogenous DOPA. In the present study, the kinetics of the peripheral metabolism and the facilitated unidirectional blood-brain clearance of [3H]DOPA and FDOPA were compared in Wistar rats pretreated with carbidopa. In arterial plasma, FDOPA was O-methylated with an apparent rate constant (0.031 min-1) 3-fold that of [3H]DOPA in the same rats. The O-methylated metabolite of FDOPA (OMe-FDOPA) was eliminated from plasma at a rate constant (0.018 min-1) 3-fold that of OMe-[3H]DOPA. The mean unidirectional blood-brain clearance of FDOPA (4.5 mL.hg-1.min-1) in six brain regions was 60% higher than that of [3H]DOPA.

Udgivelsesdato: 1994-Apr-4 The distribution of high-affinity binding sites for the histamine H3 agonist [3H]-N alpha-methylhistamine ([3H]NAMH, 4 nM) in the rat brain was examined by autoradiography. Binding in all brain regions was displaceable with the H3 antagonist thioperamide (2 microM). The pattern of H3 binding was heterogeneous: highest levels were in the striatum and substantia nigra, which receives sparse histaminergic innervations. Intermediate H3 binding was present in neocortex and diencephalon, while low binding was evident in the medial septum and dorsal hippocampus. Hitherto unreported H3 binding sites were noted in the dorsolateral tegmentum and in the nucleus of the solitary tract (NTS). Because the NTS receives a dense histaminergic innervation, [3H]NAMH binding in the NTS was further studied by Scatchard analysis. The presence of saturable binding (Bmax = 10 +/- 4 fmol/mg, Kd = 0.6 +/- 0.3 nM, n = 3) suggested that histamine may act via H3 receptors in the NTS.