Evidence of Dopaminergic Processing of Executive Inhibition

Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand (11C-raclopride) after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites) and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Rapid quantitative pharmacodynamic imaging by a novel method: theory, simulation testing and proof of principle

Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge drug over a short time scale, and functional imaging to rapidly provide quantitative estimates of drug sensitivity including EC50 (the concentration of drug that produces half the maximum possible effect). We first test the method with simulated data, assuming a typical sigmoidal dose-response curve and assuming imperfect imaging that includes artifactual baseline signal drift and random error. With these few assumptions, rapid quantitative pharmacodynamic imaging reliably estimates EC50 from the simulated data, except when noise overwhelms the drug effect or when the effect occurs only at high doses. In preliminary fMRI studies of primate brain using a dopamine agonist, the observed noise level is modest compared with observed drug effects, and a quantitative EC50 can be obtained from some regional time-signal curves. Taken together, these results suggest that research and clinical applications for rapid quantitative pharmacodynamic imaging are realistic.Comment: 26 pages total, 4 tables, 10 figures. The original PDF file at https://peerj.com/articles/117/ includes active hyperlinks. This version is the final published version. (Differs from v2 only in that I corrected the abstract on the arXiv.org page.

Kinetic Modelling in Human Brain Imaging

Geneeskunde en GesondheidswetenskappeKerngeneeskundePlease help us populate SUNScholar with the post print version of this article. It can be e-mailed to: [email protected]

The Role of Aerobic Glycolysis in the Resting Human Brain

The human brain accounts for 2% of total body weight, though it consumes 20% of the body\u27s energy supply. Most of this energy is provided by the complete oxidation of glucose to carbon dioxide and water, though some fraction of glucose undergoes aerobic glycolysis without concomitant oxidative phosphorylation. Elevation in neuronal activity increases aerobic glycolysis due to the disproportionate increase in blood flow and glucose utilization greater than oxygen consumption. Since aerobic glycolysis produces significantly less energy than complete oxidation of glucose, its role in cellular activities has been overlooked, though its presence in the resting brain has been known for several decades. In this thesis, we investigate three aspects of resting aerobic glycolysis using positron emission tomography. First, we characterize the regional distribution of aerobic glycolysis in the awake, eyes closed human brain. We show that brain regions with high levels of functional activity in the resting state, including the default network and prefrontal cortex, have elevated aerobic glycolysis. In addition, we show that aerobic glycolysis is modulated by prior task performance. Performance of a complex visuomotor rotation learning task increases aerobic glycolysis in premotor cortex for several hours following task completion. Further, we show that regional brain metabolism is correlated to neurotransmitter receptor density. Aerobic glycolysis is highest in regions with a balanced density of excitatory and inhibitory receptors. Taken together, these results demonstrate the functional significance of resting aerobic glycolysis and its modulation by transient functional activity. These data provide supporting evidence for the synaptic homeostasis hypothesis, indicating elevation in brain metabolism, specifically aerobic glycolysis, during wakefulness associated with alterations in synaptic strength and receptor density