Comparison of cerebrovascular effects of intravenous cocaine injection in fetal, newborn, and adult sheep

Cocaine may cause stroke, intracranial hemorrhage, seizures, and neurobehavioral abnormalities in fetuses, newborns, and adults, and there could be developmental and/or species differences in mechanisms for these cocaine-induced cerebrovascular effects. To evaluate developmental differences in responses to cocaine, we compared the cerebrovascular and metabolic responses to a 2 mg/kg iv cocaine dose in unanesthetized fetal (n = 8, previously reported, direct fetal injection), newborn (n = 6), and adult (n = 12) sheep. We measured cerebral blood flow, mean arterial blood pressure, and arterial and venous O(2) content, and we calculated cerebral O(2) consumption and cerebral vascular resistance at baseline and at 30 s and at 5, 15, and 60 min after cocaine injection. Cerebral blood flow increased 5 min after injection in the fetus and newborn, but not until 15 min in the adult. In the fetus, cocaine caused a transient cerebral vasoconstriction at 30 s; in all three groups, cocaine caused cerebral vasodilation, which was delayed in the adult. Cerebral metabolic O(2) consumption increased 5 min after injection in the fetus and newborn, but not until 15 min after injection in the adult. Arterial O(2) content decreased 5 min after injection in the fetus and 15 min after injection in the adult. We speculate that clinical differences in response to cocaine injection may be explained, in part, by these developmental differences in the cerebrovascular and metabolic responses to cocaine.     

Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT( 1 ) Receptor Antagonists in the Brain

1. Circulating and locally formed Angiotensin II regulates the cerebral circulation through stimulation of AT(1) receptors located in cerebrovascular endothelial cells and in brain centers controlling cerebrovascular flow. 2. The cerebrovascular autoregulation is designed to maintain a constant blood flow to the brain, by vasodilatation when blood pressure decreases and vasoconstriction when blood pressure increases. 3. During hypertension, there is a shift in the cerebrovascular autoregulation to the right, in the direction of higher blood pressures, as a consequence of decreased cerebrovascular compliance resulting from vasoconstriction and pathological growth. In hypertension, when perfusion pressure decreases as a consequence of blockade of a cerebral artery, reduced cerebrovascular compliance results in more frequent and more severe strokes with a larger area of injured tissue. 4. There is a cerebrovascular angiotensinergic overdrive in genetically hypertensive rats, manifested as an increased expression of cerebrovascular AT(1) receptors and increased activity of the brain Angiotensin II system. Excess AT(1) receptor stimulation is a main factor in the cerebrovascular pathological growth and decreased compliance, the alteration of the cerebrovascular eNOS/iNOS ratio, and in the inflammatory reaction characteristic of cerebral blood vessels in genetic hypertension. All these factors increase vulnerability to brain ischemia and stroke. 5. Sustained blockade of AT(1) receptors with peripheral and centrally active AT(1) receptor antagonists (ARBs) reverses the cerebrovascular pathological growth and inflammation, increases cerebrovascular compliance, restores the eNOS/iNOS ratio and decreases cerebrovascular inflammation. These effects result in a reduction of the vulnerability to brain ischemia, revealed, when an experimental stroke is produced, in protection of the blood flow in the zone of penumbra and substantial reduction in neuronal injury. 6. The protection against ischemia resulting is related to inhibition of the Renin-Angiotensin System and not directly related to the decrease in blood pressure produced by these compounds. A similar decrease in blood pressure as a result of the administration of beta-adrenergic receptor and calcium channel blockers does not protect from brain ischemia. 7. In addition, sustained AT(1) receptor inhibition enhances AT(2) receptor expression, associated with increased eNOS activity and NO formation followed by enhanced vasodilatation. Direct AT(1) inhibition and indirect AT(2) receptor stimulation are associated factors normalizing cerebrovascular compliance, reducing cerebrovascular inflammation and decreasing the vulnerability to brain ischemia.8. These results strongly suggest that inhibition of AT(1) receptors should be considered as a preventive therapeutic measure to protect the brain from ischemia, and as a possible novel therapy of inflammatory conditions of the brain.     

Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT 1 Receptor Antagonists in the Brain

SUMMARY 1. Circulating and locally formed Angiotensin II regulates the cerebral circulation through stimulation of AT₁ receptors located in cerebrovascular endothelial cells and in brain centers controlling cerebrovascular flow.2. The cerebrovascular autoregulation is designed to maintain a constant blood flow to the brain, by vasodilatation when blood pressure decreases and vasoconstriction when blood pressure increases.3. During hypertension, there is a shift in the cerebrovascular autoregulation to the right, in the direction of higher blood pressures, as a consequence of decreased cerebrovascular compliance resulting from vasoconstriction and pathological growth. In hypertension, when perfusion pressure decreases as a consequence of blockade of a cerebral artery, reduced cerebrovascular compliance results in more frequent and more severe strokes with a larger area of injured tissue.4. There is a cerebrovascular angiotensinergic overdrive in genetically hypertensive rats, manifested as an increased expression of cerebrovascular AT₁ receptors and increased activity of the brain Angiotensin II system. Excess AT₁ receptor stimulation is a main factor in the cerebrovascular pathological growth and decreased compliance, the alteration of the cerebrovascular eNOS/iNOS ratio, and in the inflammatory reaction characteristic of cerebral blood vessels in genetic hypertension. All these factors increase vulnerability to brain ischemia and stroke.5. Sustained blockade of AT₁ receptors with peripheral and centrally active AT₁ receptor antagonists (ARBs) reverses the cerebrovascular pathological growth and inflammation, increases cerebrovascular compliance, restores the eNOS/iNOS ratio and decreases cerebrovascular inflammation. These effects result in a reduction of the vulnerability to brain ischemia, revealed, when an experimental stroke is produced, in protection of the blood flow in the zone of penumbra and substantial reduction in neuronal injury.6. The protection against ischemia resulting is related to inhibition of the Renin–Angiotensin System and not directly related to the decrease in blood pressure produced by these compounds. A similar decrease in blood pressure as a result of the administration of β-adrenergic receptor and calcium channel blockers does not protect from brain ischemia.7. In addition, sustained AT₁ receptor inhibition enhances AT₂ receptor expression, associated with increased eNOS activity and NO formation followed by enhanced vasodilatation. Direct AT₁ inhibition and indirect AT₂ receptor stimulation are associated factors normalizing cerebrovascular compliance, reducing cerebrovascular inflammation and decreasing the vulnerability to brain ischemia.8. These results strongly suggest that inhibition of AT₁ receptors should be considered as a preventive therapeutic measure to protect the brain from ischemia, and as a possible novel therapy of inflammatory conditions of the brain.     

A model of neurovascular coupling and the BOLD response PART II

A mathematical model is developed which describes a signalling mechanism of neurovascular coupling with a model of a pyramidal neuron and its corresponding fMRI BOLD response. In the first part of two papers (Part I) we described the integration of the neurovascular coupling unit extended to include a complex neuron model, which includes the important Na/K ATPase pump, with a model that provides a BOLD signal taking its input from the cerebral blood flow and the metabolic rate of oxygen consumption. We showed that this produced a viable signal in terms of initial dip, positive and negative BOLD signals. In this paper (PART II) our model predicts the variations of the BOLD response due to variations in neuronal activity and indicates that the BOLD signal could be used as an initial biomarker for neuronal dysfunction or variations in the perfusion of blood to the cerebral tissue. We have compared the simulated hypoxic BOLD response to experimental BOLD signals observed in the hippocampus during hypoxia showing good agreement. This approach of combined quantitative modelling of neurovascular coupling response and its BOLD response will enable more specific assessment of a brain region.     

Cocaine abusers show a blunted response to alcohol intoxication in limbic brain regions

Cocaine and alcohol are frequently used simultaneously and this combination is associated with enhanced toxicity. We recently showed that active cocaine abusers have a markedly enhanced sensitivity to benzodiazepines. Because both benzodiazepines and alcohol facilitate GABAergic neurotransmission we questioned whether cocaine abusers would also have an enhanced sensitivity to alcohol that could contribute to the toxicity. In this study we compared the effects of alcohol (0.75 g/kg) on regional brain glucose metabolism between cocaine abusers (n = 9) and controls (n = 10) using PET and FDG. Alcohol significantly decreased whole brain metabolism and this effect was greater in controls (26+/-6%) than in abusers (17+/-10%) even though they had equivalent levels of alcohol in plasma. Analysis of the regional measures showed that cocaine abusers had a blunted response to alcohol in limbic regions, cingulate gyrus, medial frontal and orbitofrontal cortices. CONCLUSIONS: The blunted response to alcohol in cocaine abusers contrasts with their enhanced sensitivity to benzodiazepines suggesting that targets other than GABA-benzodiazepine receptors are involved in the blunted sensitivity to alcohol and that the toxicity from combined cocaine-alcohol use is not due to an enhanced sensitivity to alcohol in cocaine abusers. The blunted response to alcohol in limbic regions and in cortical regions connected to limbic areas could result from a decreased sensitivity of reward circuits in cocaine abusers.     

Hypoxic regulation of the fetal cerebral circulation.

Fetal cerebrovascular responses to acute hypoxia are fundamentally different from those observed in the adult cerebral circulation. The magnitude of hypoxic vasodilatation in the fetal brain increases with postnatal age although fetal cerebrovascular responses to acute hypoxia can be complicated by age-dependent depressions of blood pressure and ventilation. Acute hypoxia promotes adenosine release, which depresses fetal cerebral oxygen consumption through action of adenosine on neuronal A1 receptors and vasodilatation through activation of A2 receptors on cerebral arteries. The vascular effect of adenosine can account for approximately half the vasodilatation observed in response to hypoxia. Hypoxia-induced release of nitric oxide and opioids can account for much of the adenosine-independent cerebral vasodilatation observed in response to hypoxia in the fetus. Direct effects of hypoxia on cerebral arteries account for the remaining fraction, although the vascular endothelium contributes relatively little to hypoxic vasodilatation in the immature cerebral circulation. In contrast to acute hypoxia, fetal cerebral blood flow tends to normalize during acclimatization to chronic hypoxia even though cardiac output is depressed. However, uncompensated chronic hypoxia in the fetus can produce significant changes in brain structure and function, alteration of respiratory drive and fluid balance, and increased incidence of intracranial hemorrhage and periventricular leukomalacia. At the level of the fetal cerebral arteries, chronic hypoxia increases protein content and depresses norepinephrine release, contractility, and receptor densities associated with contraction but also attenuates endothelial vasodilator capacity and decreases the ability of ATP-sensitive and calcium-sensitive potassium channels to promote vasorelaxation. Overall, fetal cerebrovascular adaptations to chronic hypoxia appear prioritized to conserve energy while preserving basic contractility. Many gaps remain in our understanding of how the effects of acute and chronic hypoxia are mediated in fetal cerebral arteries, but studies of adult cerebral arteries have produced many powerful pharmacological and molecular tools that are simply awaiting application in studies of fetal cerebral artery responses to hypoxia.     

Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex

Functional magnetic resonance imaging (fMRI) based on blood oxygen level-dependent (BOLD) contrast is widely used for probing brain activity, but its relationship to underlying neural activity remains elusive. Here, we combined fMRI with fiber-optic recordings of fluorescent calcium indicator signals to investigate this relationship in rat somatosensory cortex. Electrical forepaw stimulation (1-10 Hz) evoked fast calcium signals of neuronal origin that showed frequency-dependent adaptation. Additionally, slower calcium signals occurred in astrocyte networks, as verified by astrocyte-specific staining and two-photon microscopy. Without apparent glia activation, we could predict BOLD responses well from simultaneously recorded fiber-optic signals, assuming an impulse response function and taking into account neuronal adaptation. In cases with glia activation, we uncovered additional prolonged BOLD signal components. Our findings highlight the complexity of fMRI BOLD signals, involving both neuronal and glial activity. Combined fMRI and fiber-optic recordings should help to clarify cellular mechanisms underlying BOLD signals.     

Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI

Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data. These results open the door to a new type of fMRI analysis that more accurately reflects the true neuronal activity.     

Investigating the Potential Influence of Cause of Death and Cocaine Levels on the Differential Expression of Genes Associated with Cocaine Abuse

The development of new therapeutic strategies for the treatment of complex brain disorders such as drug addiction is likely to be advanced by a more complete understanding of the underlying molecular pathophysiology. Although the study of postmortem human brain represents a unique resource in this regard, it can be challenging to disentangle the relative contribution of chronic pathological processes versus perimortem events to the observed changes in gene expression. To begin to unravel this issue, we analyzed by quantitative PCR the midbrain expression of numerous candidate genes previously associated with cocaine abuse. Data obtained from chronic cocaine abusers (and matched control subjects) dying of gunshot wounds were compared with a prior study of subjects with deaths directly attributable to cocaine abuse. Most of the genes studied (i.e., tyrosine hydroxylase, dopamine transporter, forkhead box A2, histone variant H3 family 3B, nuclear factor kappa B inhibitor alpha, growth arrest and DNA damage-inducible beta) were found to be differentially expressed in chronic cocaine abusers irrespective of immediate cause of death or perimortem levels of cocaine, suggesting that these may represent core pathophysiological changes arising with chronic drug abuse. On the other hand, chemokine C-C motif ligand 2 and jun proto-oncogene expression were unaffected in cocaine-abusing subjects dying of gunshot wounds, in contrast to the differential expression previously reported in cocaine-related fatalities. The possible influence of cause of death and other factors on the cocaine-responsiveness of these genes is discussed.     

Regulation of oxygen transport during brain activation: stimulus-induced hemodynamic responses in human and animal cortices

BACKGROUND: The correlation between regional changes in neuronal activity and changes in hemodynamics is a major issue for noninvasive neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and near-infrared optical imaging (NIOI). A tight coupling of these changes has been assumed to elucidate brain function from data obtained with those techniques. In the present study, we investigated the relationship between neuronal activity and hemodynamic responses in the occipital cortex of humans during visual stimulation and in the somatosensory cortex of rats during peripheral nerve stimulation. METHODS: The temporal frequency dependence of macroscopic hemodynamic responses on visual stimuli was investigated in the occipital cortex of humans by simultaneous measurements made using fMRI and NIOI. The stimulus-intensity dependence of both microscopic hemodynamic changes and changes in neuronal activity in response to peripheral nerve stimulation was investigated in animal models by analyzing membrane potential (fluorescence), hemodynamic parameters (visible spectra and laser-Doppler flowmetry), and vessel diameter (image analyzer). RESULTS: Above a certain level of stimulus-intensity, increases in regional cerebral blood flow (rCBF) were accompanied by a decrease in regional cerebral blood volume (rCBV), i.e., dissociation of rCBF and rCBV responses occurred in both the human and animal experiments. Furthermore, the animal experiments revealed that the distribution of increased rCBF and O2 spread well beyond the area of neuronal activation, and that the increases showed saturation in the activated area. CONCLUSIONS: These results suggest that above a certain level of neuronal activity, a regulatory mechanism between regional cerebral blood flow (rCBF) and rCBV acts to prevent excess O2 inflow into the focally activated area.     

From Blood Oxygenation Level Dependent (BOLD) Signals to Brain Temperature Maps

A theoretical framework is presented for converting Blood Oxygenation Level Dependent (BOLD) images to brain temperature maps, based on the idea that disproportional local changes in cerebral blood flow (CBF) as compared with cerebral metabolic rate of oxygen consumption (CMRO ₂) during functional brain activity, lead to both brain temperature changes and the BOLD effect. Using an oxygen limitation model and a BOLD signal model, we obtain a transcendental equation relating CBF and CMRO ₂ changes with the corresponding BOLD signal, which is solved in terms of the Lambert W function. Inserting this result in the dynamic bioheat equation describing the rate of temperature changes in the brain, we obtain a nonautonomous ordinary differential equation that depends on the BOLD response, which is solved numerically for each brain voxel. Temperature maps obtained from a real BOLD dataset registered in an attention to visual motion experiment were calculated, obtaining temperature variations in the range: (−0.15, 0.1) which is consistent with experimental results. The statistical analysis revealed that significant temperature activations have a similar distribution pattern than BOLD activations. An interesting difference was the activation of the precuneus in temperature maps, a region involved in visuospatial processing, an effect that was not observed on BOLD maps. Furthermore, temperature maps were more localized to gray matter regions than the original BOLD maps, showing less activated voxels in white matter and cerebrospinal fluid.     

Cerebral pressure-flow relations in hypertensive elderly humans: transfer gain in different frequency domains.

The dynamics of the cerebral vascular response to blood pressure changes in hypertensive humans is poorly understood. Because cerebral blood flow is dependent on adequate perfusion pressure, it is important to understand the effect of hypertension on the transfer of pressure to flow in the cerebrovascular system of elderly people. Therefore, we examined the effect of spontaneous and induced blood pressure changes on beat-to-beat and within-beat cerebral blood flow in three groups of elderly people: normotensive, controlled hypertensive, and uncontrolled hypertensive subjects. Cerebral blood flow velocity (transcranial Doppler), blood pressure (Finapres), heart rate, and end-tidal CO(2) were measured during the transition from a sit to stand position. Transfer function gains relating blood pressure to cerebral blood flow velocity were assessed during steady-state sitting and standing. Cerebral blood flow regulation was preserved in all three groups by using changes in cerebrovascular resistance, transfer function gains, and the autoregulatory index as indexes of cerebral autoregulation. Hypertensive subjects demonstrated better attenuation of cerebral blood flow fluctuations in response to blood pressure changes both within the beat (i.e., lower gain at the cardiac frequency) and in the low-frequency range (autoregulatory, 0.03-0.07 Hz). Despite a better pressure autoregulatory response, hypertensive subjects demonstrated reduced reactivity to CO(2). Thus otherwise healthy hypertensive elderly subjects, whether controlled or uncontrolled with antihypertensive medication, retain the ability to maintain cerebral blood flow in the face of acute changes in perfusion pressure. Pressure regulation of cerebral blood flow is unrelated to cerebrovascular reactivity to CO(2).     

Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging

Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow, and cerebral blood flow responses to brain activation that ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in a progressive age-dependent vascular-mediated neurodegeneration.     

Astrocyte activation in vivo during graded photic stimulation

Astrocytes have important roles in control of extracellular environment, de novo synthesis of neurotransmitters, and regulation of neurotransmission and blood flow. All of these functions require energy, suggesting that astrocytic metabolism should rise and fall with changes in neuronal activity and that brain imaging can be used to visualize and quantify astrocytic activation in vivo . A unilateral photic stimulation paradigm was used to test the hypothesis that graded sensory stimuli cause progressive increases in the uptake coefficient of [2-¹⁴C]acetate, a substrate preferentially oxidized by astrocytes. The acetate uptake coefficient fell in deafferented visual structures and it rose in intact tissue during photic stimulation of conscious rats; the increase was highest in structures with monosynaptic input from the eye and was much smaller in magnitude than the change in glucose utilization (CMR_glc) by all cells. The acetate uptake coefficient was not proportional to stimulus rate and did not correlate with CMR_glc in resting or activated structures. Simulation studies support the conclusions that acetate uptake coefficients represent mainly metabolism and respond to changes in metabolism rate, with a lower response at high rates. A model portraying regulation of acetate oxidation illustrates complex relationships among functional activation, cation levels, and astrocytic metabolism.     

Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain.

The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability we compared the levels of DAT occupancies that we had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [11C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [11C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockade of DAT with an estimated ED50 (dose required to block 50% of the DAT) for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine. The similar in vivo potencies at the DAT for methylphenidate than for cocaine are in agreement with their reported relative in vitro affinities (Ki 390 nM and 640 nM respectively), which is likely to reflect the similar degree of uptake (8-10% of the injected dose) and regional distribution of these two drugs in the human brain. Thus, differences in the in vivo potency of these two drugs at the DAT cannot be responsible for the differences in their rate of abuse in humans. Other variables i.e. longer duration of methylphenidate's side effects may counterbalance its reinforcing effects.     

Hyperthermia-induced vasoconstriction of the carotid artery, a possible causative factor of heatstroke.

Clinical and experimental studies indicate that hyperthermia can cause heatstroke with cerebral ischemia and brain damage. However, no study has examined the direct effects of heating carotid artery smooth muscle and tested the hypothesis that hyperthermia induces arterial vasoconstriction and, thereby, decreases cerebral blood flow. We recorded isometric tension of rabbit carotid artery strips in organ baths during stepwise temperature elevation. The heating responses were tested at basal tone, in norepinephrine- and KCl-precontracted vessels, and after electrical field stimulation. Stepwise heating from 37 degrees C to 47 degrees C induced reproducible graded contraction proportional to temperature. The responses could be elicited at basal tone and in precontracted vessels. Heating decreased the contractile responses to norepinephrine and electrical field stimulation but increased contraction to KCl. These responses were not eliminated by pretreatment with the neuronal blocker tetrodotoxin. Our results demonstrate that heating carotid artery preparations above 37 degrees C (normothermia) induced a reversible graded vasoconstriction proportional to temperature. In vivo this reaction may lead to a decrease in cerebral blood flow and cerebral ischemia with brain damage as in heatstroke. The heating-induced contraction is not mediated by a neurogenic process but is due to altered transcellular Ca2+ transport. Cooling, in particular of the neck area, therefore, should be used in the treatment of heatstroke.     

Neuronal population activity and functional imaging.

Human functional brain imaging detects blood flow changes that are thought to reflect the activity of neuronal populations and, thus, the responses of neurons that carry behaviourally relevant information. Since this relationship is poorly understood, we explored the link between the activity of single neurons and their neuronal population. The functional imaging results were in good agreement with levels of population activation predicted from the known effects of sensory stimulation, learning and attention on single cortical neurons. However, the nature of the relationship between population activation and single neuron firing was very surprising. Population activation was strongly influenced by those neurons firing at low rates and so was very sensitive to the baseline or 'spontaneous' firing rate. When neural representations were sparse and neurons were tuned to several stimulus dimensions, population activation was hardly influenced by the few neurons whose firing was most strongly modulated by the task or stimulus. Measures of population activation could miss changes in information processing given simultaneous changes in neurons' baseline firing, response modulation or tuning width. Factors that can modulate baseline firing, such as attention, may have a particularly large influence on population activation. The results have implications for the interpretation of functional imaging signals and for cross-calibration between different methods for measuring neuronal activity.     

Chronic Cerebral Hypoperfusion Induces Transient Reversible Monoaminergic Changes in the Rat Brain

Chronic restriction of cerebral blood flow in hypoperfused Wistar rats has been proposed as a new model of cerebrovascular-type dementia. Using this model, we have investigated central monoaminergic neuronal systems that are closely related to higher brain function. Monoamine and monoamine-metabolite levels were determined, as relative monoaminergic markers, at 1 day and 1,3,6 and 12 weeks after the bilateral occlusion of common carotid arteries. Dopaminergic changes in the frontal cortex and striatum were observed in hypoperfused rats at 1–3 weeks following occlusion. Serotonergic changes were recognized at four brain regions examined (frontal cortex, hippocampus, striatum and thalamus+midbrain). In particular, the immediate enhancement of serotonin turnover in the striatum appeared to influence the reaction to the acute ischemic attack such as vasoconstriction produced by hypoperfusion. Our findings suggest that chronic cerebral hypoperfusion induces transient reversible changes in central monoaminergic neuronal function within three weeks of ligation of carotid arteries. This time interval seems to represent a turning point in the process of chronic cerebral hypoperfusion-induced progressive brain injury.