▪ Abstract The prefrontal cortex has long been suspected to play an important role in cognitive control, in the ability to orchestrate thought and action in accordance with internal goals. Its neural basis, however, has remained a mystery. Here, we propose that cognitive control stems from the active maintenance of patterns of activity in the prefrontal cortex that represent goals and the means to achieve them. They provide bias signals to other brain structures whose net effect is to guide the flow of activity along neural pathways that establish the proper mappings between inputs, internal states, and outputs needed to perform a given task. We review neurophysiological, neurobiological, neuroimaging, and computational studies that support this theory and discuss its implications as well as further issues to be addressed

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An integrative theory of prefrontal cortex function

Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

The L-Arginine-Nitric Oxide Pathway

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

https://science.sciencemag.org/content/sci/217/4558/408.full.pdf

The Cholinergic Hypothesis of Geriatric Memory Dysfunction

Objectives: Contingency management is a promising intervention for Methamphetamine Use Disorder (MUD).Impaired executive function may decrease adherence to such treatment, but there are few data on whether impairment in executive function predicts treatment outcomes. We therefore evaluated whether baseline performance on tests of executive function predicted treatment response in a trial of contingency management for MUD.
Methods: Thirty participants with MUD and 23 healthy controls performed the Connors Continuous Performance Task (CPT) and the Trail Making Task. MUD participants then entered an 8-week contingency management trial. Participants were categorized as responders (n=17; no methamphetamine-positive urine tests) or non-responders (n=13; >1 positive test). The Kruskal-Wallis test was used to compare scores in participants with MUD and healthy controls, and in responders versus non-responders.
Results: Participants withMUD performed worse than controls on the CPT (d-prime) (p=0.012); non-responders performed worse than responders (p = 0.034). Performance of MUD participants did not differ significantly from controls on the Trail Making Task B (time to completion), but variation was high with non-responders performing worse than responders (p=0.013).
Conclusion: These findings suggest that tests of executive function at baseline may be useful in predicting treatment response in MUD. Future work in larger samples may ultimately allow a more personalized treatment approach to methamphetamine use disorder.

https://www.longdom.org/open-access/executive-function-and-contingency-management-in-methamphetamine-use-disorder.pdf

Executive Function and Contingency Management in Methamphetamine Use Disorder.

CI-943 is a novel drug candidate that has antipsychotic-like activity in a variety of behavioral tests in rodents and primates, but has no affinity for brain dopamine (DA) receptors. In order to obtain information on the neuroanatomical substrates for its behavioral actions, we used the autoradiographic 2-deoxy-D-[1-14C]-glucose method to map and quantify the distribution of CI-943 effects on the regional cerebral metabolic rate(s) for glucose (rCMRglc) in the rat. The effects of CI-943 (40 mg/kg) were assessed at 10 and at 60 min after the drug was administered intraperitoneally. In the globus pallidus and the substantia nigra pars reticulata, rCMRglc were increased at 60 min following treatment, and in the lateral habenula, rCMRglc was increased at 10 and 60 min after treatment. In contrast, the predominant effect of CI-943 in other areas (e.g., most cortical, several thalamic, basal ganglia, limbic, and midbrain areas) was to reduce rCMRglc. The metabolic pattern produced by CI-943 was unique and consistent with previous findings that CI-943 resembles other antipsychotic drugs in behavioral tests but differs from those agents in tests prodictive of extrapyramidal dysfunction.

Cerebral metabolic effects of CI-943 (8-Ethyl-7,8-dihydro-1,3,5-trimethyl-1Himidazo[1,2,-c]pyrazolo[3,4-e]-pyrimidine), a potential antipsychotic drug

The effects of drug abuse on glucose metabolism.

UNLABELLED Quantitative modeling of cerebral metabolic rate for glucose (CMRglc) using PET with the FDG method requires calculation of the integral of the time course of radioactivity in arterial plasma. Numeric integration has typically been used but requires 30 or more blood samples taken between 15 s and 100 min after injection of the radiotracer. Our laboratory has developed an alternative integration method that fits the values of the plasma samples to an analytically integrable function using only 4-6 samples taken between 40 and 110 min after radiotracer injection. METHODS The plasma integrals were calculated by both the analytic and the numeric methods with data from FDG PET studies that were not used in the development of the analytic method. In 39 PET studies from 22 healthy volunteers, 30 plasma samples were taken over 110 min. RESULTS The plasma integrals determined by the analytic and numeric methods yielded a within-subject correlation coefficient of >0.95 and differences of <10%. CONCLUSION Because the analytic method requires less blood sampling and does not require sampling immediately after radiotracer injection, the experimental procedure is simplified without loss of accuracy in CMRglc computation, and the effect of missing or incorrect samples is reduced.

Edythe D. London

Papers

Executive Function and Contingency Management in Methamphetamine Use Disorder.

Cerebral metabolic effects of CI-943 (8-Ethyl-7,8-dihydro-1,3,5-trimethyl-1Himidazo[1,2,-c]pyrazolo[3,4-e]-pyrimidine), a potential antipsychotic drug

The effects of drug abuse on glucose metabolism.

Validation of an analytic method of calculating cerebral glucose metabolism using PET

Consequences of Adolescent Smoking: Cognitive Performance, Brain Function, and Policy Implications