A theoretical model of blood-brain exchange is developed and a procedure is derived that can be used for graphing multiple-time tissue uptake data and determining whether a unidirectional transfer process was dominant during part or all of the experimental period. If the graph indicates unidirectionality of uptake, then an influx constant (Ki) can be calculated. The model is general, assumes linear transfer kinetics, and consists of a blood-plasma compartment, a reversible tissue region with an arbitrary number of compartments, and one or more irreversible tissue regions. The solution of the equations for this model shows that a graph of the ratio of the total tissue solute concentration at the times of sampling to the plasma concentration at the respective times (Cp) versus the ratio of the arterial plasma concentration-time integral to Cp should be drawn. If the data are consistent with this model, then this graph will yield a curve that eventually becomes linear, with a slope of Ki and an ordinate intercept less than or equal to the vascular plus steady-state space of the reversible tissue region.

/pdf/graphical-evaluation-of-blood-to-brain-transfer-constants-2e29v1hms2.pdf

Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data:

The authors present a unified account of 2 neural systems concerned with the development and expression of adaptive behaviors: a mesencephalic dopamine system for reinforcement learning and a “generic” error-processing system associated with the anterior cingulate cortex The existence of the error-processing system has been inferred from the error-related negativity (ERN), a component of the event-related brain potential elicited when human participants commit errors in reaction-time tasks The authors propose that the ERN is generated when a negative reinforcement learning signal is conveyed to the anterior cingulate cortex via the mesencephalic dopamine system and that this signal is used by the anterior cingulate cortex to modify performance on the task at hand They provide support for this proposal using both computational modeling and psychophysiological experimentation

/pdf/the-neural-basis-of-human-error-processing-reinforcement-246y7vy4ka.pdf

The neural basis of human error processing: Reinforcement learning, dopamine, and the error-related negativity.

Functional magnetic resonance imaging (fMRI) is currently the mainstay of neuroimaging in cognitive neuroscience. Advances in scanner technology, image acquisition protocols, experimental design, and analysis methods promise to push forward fMRI from mere cartography to the true study of brain organization. However, fundamental questions concerning the interpretation of fMRI data abound, as the conclusions drawn often ignore the actual limitations of the methodology. Here I give an overview of the current state of fMRI, and draw on neuroimaging and physiological data to present the current understanding of the haemodynamic signals and the constraints they impose on neuroimaging data interpretation.

What we can do and what we cannot do with fMRI

Anatomic and physiologic data are used to analyze the energy expenditure on different components of excitatory signaling in the grey matter of rodent brain. Action potentials and postsynaptic effects of glutamate are predicted to consume much of the energy (47% and 34%, respectively), with the resting potential consuming a smaller amount (13%), and glutamate recycling using only 3%. Energy usage depends strongly on action potential rate--an increase in activity of 1 action potential/cortical neuron/s will raise oxygen consumption by 145 mL/100 g grey matter/h. The energy expended on signaling is a large fraction of the total energy used by the brain; this favors the use of energy efficient neural codes and wiring patterns. Our estimates of energy usage predict the use of distributed codes, with <or=15% of neurons simultaneously active, to reduce energy consumption and allow greater computing power from a fixed number of neurons. Functional magnetic resonance imaging signals are likely to be dominated by changes in energy usage associated with synaptic currents and action potential propagation.

https://journals.sagepub.com/doi/pdf/10.1097/00004647-200110000-00001

An Energy Budget for Signaling in the Grey Matter of the Brain

The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders

— A method has been developed for the simultaneous measurement of the rates of glucose consumption in the various structural and functional components of the brain in vivo. The method can be applied to most laboratory animals in the conscious state. It is based on the use of 2-deoxy-D-[14C]glucose ([14C]DG) as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues. [14C]DG is used because the label in its product, [14C]deoxyglucose-6-phosphate, is essentially trapped in the tissue over the time course of the measurement. A model has been designed based on the assumptions of a steady state for glucose consumption, a first order equilibration of the free [14C]DG pool in the tissue with the plasma level, and relative rates of phosphorylation of [14C]DG and glucose determined by their relative concentrations in the precursor pools and their respective kinetic constants for the hexokinase reaction. An operational equation based on this model has been derived in terms of determinable variables. A pulse of [14C]DG is administered intravenously and the arterial plasma [14C]DG and glucose concentrations monitored for a preset time between 30 and 45min. At the prescribed time, the head is removed and frozen in liquid N2-chilled Freon XII, and the brain sectioned for autoradiography. Local tissue concentrations of [14C]DG are determined by quantitative autoradiography. Local cerebral glucose consumption is calculated by the equation on the basis of these measured values.

The method has been applied to normal albino rats in the conscious state and under thiopental anesthesia. The results demonstrate that the local rates of glucose consumption in the brain fall into two distinct distributions, one for gray matter and the other for white matter. In the conscious rat the values in the gray matter vary widely from structure to structure (54-197 μmol/100 g/min) with the highest values in structures related to auditory function, e.g. medial geniculate body, superior olive, inferior colliculus, and auditory cortex. The values in white matter are more uniform (i.e. 33–40 μmo1/100 g/min) at levels approximately one-fourth to one-half those of gray matter. Heterogeneous rates of glucose consumption are frequently seen within specific structures, often revealing a pattern of cytoarchitecture. Thiopental anesthesia markedly depresses the rates of glucose utilization throughout the brain, particularly in gray matter, and metabolic rate throughout gray matter becomes more uniform at a lower level.

The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat.

Retrograde infusion of a hypertonic arabinose solution into the right external carotid artery of rats reversibly increases cerebrovascular permeability to [14C]sucrose in the right cerebral hemisphere. PA ([14C]sucrose permeability x capillary surface area) rises from a control mean of 11 x 10(-6) S-1 to above 200 x 10(-6) S-1. The rise correlates with an increased staining of the brain by intravascular Evans blue, and is followed by a transient, 1-1.5% increase in brain water content. At least 20 s of infusion is required for 1.6 M arabinose solution to effectively open the blood-brain barrier. The increase in cerebrovascular permeability is temporary, however, because PA remains slightly elevated 1-2 h after infusion and is normal 6 h after infusion. It is suggested that osmotic barrier opening is mediated by cerebrovascular dilatation as well as by shrinkage of the vascular endothelium. By quantitatively defining thresholds of infusate concentration and infusion time for osmotic barrier opening, and by characterizing the time course of increased PA, the experiments establish criteria for applying the osmotic method to experimental pharmacology of the central nervous system.

Quantitative aspects of reversible osmotic opening of the blood-brain barrier

Drug entry into the brain.

The postulation that hypoxia increases local cerebral blood flow (lCBF) mainly by perfusing more capillaries (the capillary recruitment hypothesis) was tested in awake adult male Sprague–Dawley rat...

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1993.62

Hypoxia increases velocity of blood flow through parenchymal microvascular systems in rat brain.

Correlational analysis of regional cerebral glucose metabolism (rCMRglc) obtained by high-resolution positron emission tomography (PET) has demonstrated reduced neocortical rCMRglc interactions in mildly/moderately demented patients with probable Alzheimer's disease (AD) Thus, identification of individual differences in patterns of rCMRglc interactions may be important for the early detection of AD, particularly among individuals at greater risk for developing AD (eg, those with a family history of AD) Recently, a statistical procedure, using multiple regression and discriminant analysis, was developed to assess individual differences in patterns of rCMRglc interdependencies We applied this new statistical procedure to resting rCMRglc PET data from mildly/moderately demented patients with probable AD and age/sex-matched controls The aims of the study were to identify a discriminant function that would (a) distinguish patients from controls and (b) identify an AD pattern in an individual at risk for AD with isolated memory impairment whose initial PET scan showed minor abnormalities, but whose second scan showed parietal hypometabolism, coincident with further cognitive decline Two discriminant functions, reflecting interactions involving regions most involved in reduced correlations in probable AD, correctly classified 87 of the patients and controls, and successfully identified the first scan of the at-risk individual as AD (probability >070) The results suggest that this statistical approach may be useful for the early detection of AD

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1993.58

Karen D. Pettigrew

Papers

The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat.

Quantitative aspects of reversible osmotic opening of the blood-brain barrier

Drug entry into the brain.

Hypoxia increases velocity of blood flow through parenchymal microvascular systems in rat brain.

Early detection of Alzheimer's disease: a statistical approach using positron emission tomographic data.