Pupillometric evidence for the decoupling of attention from perceptual input during offline thought

Accumulating evidence suggests that the brain can efficiently process both external and internal information. The processing of internal information is a distinct "offline" cognitive mode that requires not only spontaneously generated mental activity; it has also been hypothesized to require a decoupling of attention from perception in order to separate competing streams of internal and external information. This process of decoupling is potentially adaptive because it could prevent unimportant external events from disrupting an internal train of thought. Here, we use measurements of pupil diameter (PD) to provide concrete evidence for the role of decoupling during spontaneous cognitive activity. First, during periods conducive to offline thought but not during periods of task focus, PD exhibited spontaneous activity decoupled from task events. Second, periods requiring external task focus were characterized by large task evoked changes in PD; in contrast, encoding failures were preceded by episodes of high spontaneous baseline PD activity. Finally, high spontaneous PD activity also occurred prior to only the slowest 20% of correct responses, suggesting high baseline PD indexes a distinct mode of cognitive functioning. Together, these data are consistent with the decoupling hypothesis, which suggests that the capacity for spontaneous cognitive activity depends upon minimizing disruptions from the external world.     

Transfer entropy—a model-free measure of effective connectivity for the neurosciences

Understanding causal relationships, or effective connectivity, between parts of the brain is of utmost importance because a large part of the brain’s activity is thought to be internally generated and, hence, quantifying stimulus response relationships alone does not fully describe brain dynamics. Past efforts to determine effective connectivity mostly relied on model based approaches such as Granger causality or dynamic causal modeling. Transfer entropy (TE) is an alternative measure of effective connectivity based on information theory. TE does not require a model of the interaction and is inherently non-linear. We investigated the applicability of TE as a metric in a test for effective connectivity to electrophysiological data based on simulations and magnetoencephalography (MEG) recordings in a simple motor task. In particular, we demonstrate that TE improved the detectability of effective connectivity for non-linear interactions, and for sensor level MEG signals where linear methods are hampered by signal-cross-talk due to volume conduction.     

Hypoglycemia-induced noradrenergic activation in the VMH is a result of decreased ambient glucose

During insulin-induced hypoglycemia, there is an increase in extracellular norepinephrine (NE) in the ventromedial hypothalamus (VMH). This brain area is known to play an important role in integrated hormonal and behavioral responses to systemic hypoglycemia. Selective glucoprivation restricted to the VMH is both necessary and sufficient to initiate secretion of counterregulatory hormones. The present study was designed to investigate whether increased release of NE in the VMH depends on detection of glucoprivation localized in this area. In awake, chronically catheterized male Sprague-Dawley rats, extracellular NE in the VMH was monitored using 1-mm microdialysis probes perfused with Krebs Ringer buffer (KRB) or KRB + 100 mM d-glucose (d-Glc). During insulin-induced hypoglycemia (glycemic nadir approximately 2.4 mM) extracellular NE was increased to >160% of baseline (P < 0.01) only in the KRB + insulin group. There was no increase in NE from baseline when glucose was added to the perfusate to maintain euglycemia at the periprobe environment. The sympathoadrenal response to hypoglycemia, present in the KRB + insulin group, was attenuated in the d-Glc + insulin group. The present results confirm that noradrenergic activation in the VMH during systemic hypoglycemia depends on detection of glucoprivation locally in this area. These data provide additional support for the importance of increased noradrenergic activity in the VMH in the counterregulatory hormonal responses to hypoglycemia.     

Negative BOLD fMRI response in the visual cortex carries precise stimulus-specific information

Sustained positive BOLD (blood oxygen level-dependent) activity is employed extensively in functional magnetic resonance imaging (fMRI) studies as evidence for task or stimulus-specific neural responses. However, the presence of sustained negative BOLD activity (i.e., sustained responses that are lower than the fixation baseline) has remained more difficult to interpret. Some studies suggest that it results from local "blood stealing" wherein blood is diverted to neurally active regions without a concomitant change of neural activity in the negative BOLD regions. However, other evidence suggests that negative BOLD is a result of local neural suppression. In both cases, regions of negative BOLD response are usually interpreted as carrying relatively little, if any, stimulus-specific information (hence the predominant reliance on positive BOLD activity in fMRI). Here we show that the negative BOLD response resulting from visual stimulation can carry high information content that is stimulus-specific. Using a general linear model (GLM), we contrasted standard flickering stimuli to a fixation baseline and found regions of the visual cortex that displayed a sustained negative BOLD response, consistent with several previous studies. Within these negative BOLD regions, we compared patterns of fMRI activity generated by flickering Gabors that were systematically shifted in position. As the Gabors were shifted further from each other, the correlation in the spatial pattern of activity across a population of voxels (such as the population of V1 voxels that displayed a negative BOLD response) decreased significantly. Despite the fact that the BOLD signal was significantly negative (lower than fixation baseline), these regions were able to discriminate objects separated by less than 0.5 deg (at approximately 10 deg eccentricity). The results suggest that meaningful, stimulus-specific processing occurs even in regions that display a strong negative BOLD response.     

Contribution to sympathetic vasomotor tone of tonic glutamatergic inputs to neurons in the RVLM

The role of excitatory amino acid (EAA) receptors in the rostral ventrolateral medulla (RVLM) in maintaining resting sympathetic vasomotor tone remains unclear. It has been proposed that EAA receptors in the RVLM mediate excitatory inputs both to presympathetic neurons and to interneurons in the caudal ventrolateral medulla (CVLM), which then provide a counterbalancing inhibition of RVLM presympathetic neurons. In this study, we tested this hypothesis by determining the effect of blockade of EAA receptors in the RVLM on mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), after inhibition of CVLM neurons. In anesthetized rats, bilateral injections of muscimol in the CVLM increased MAP, HR, and RSNA. Subsequent bilateral injections of kynurenic acid (Kyn, 2.7 nmol) in the RVLM caused a modest reduction of approximately 20 mmHg in the MAP but had no effect, when compared with the effect of vehicle injection alone, on HR or RSNA. By approximately 50 min after the injections of Kyn or vehicle in the RVLM, the MAP had stabilized at a level close to its original baseline level, but the HR and RSNA stabilized at levels above baseline. The results indicate that removal of tonic EAA drive to RVLM neurons has little effect on the tonic activity of RVLM presympathetic neurons, even when inputs from the CVLM are blocked. Thus the tonic activity of RVLM presympathetic neurons under these conditions is dependent on excitatory synaptic inputs mediated by non-EAA receptors and/or the autoactivity of these neurons.     

5-Fluoronicotine,noranhydroecgonine, and pyridyl-methylpyrrolidine release acetylcholine and biogenic amines in rat cortex in vivo

The effects of nicotinic receptor agonists 5-fluoronicotine, noranhydroecgonine and pyridyl-methylpyrrolidine on the cortical release of acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were investigated with microdialysis in rat. 5-Fluoronicotine significantly elevated ACh to 76% above basal values and DA to 69% above baseline. Pyridyl-methylpyrrolidine significantly increased the release of ACh to 39% above basal values and NE to 63% above baseline. Noranhydroecgonine significantly elevated NE to 64% above basal values and DA to 147% above baseline. 5-Fluoronicotine did not affect NE release; pyridylmethylpyrrolidine did not alter DA release; and noranhydroecgonine did not significantly elevate ACh release. None of these agonists increased the release of 5-HT. All responses were blocked by prior administration of mecamylamine, a nicotinic receptor antagonist. The distinctive neurotransmitter-related profiles for the three agonists are suggestive of activity at subtypes of nicotinic receptors, an effect that may be related to the structural diversity of these compounds.     

Modulation of laryngeal and respiratory pump muscle activities with upper airway pressure and flow.

The hypothesis that upper airway (UA) pressure and flow modulate respiratory muscle activity in a respiratory phase-specific fashion was assessed in anesthetized, tracheotomized, spontaneously breathing piglets. We generated negative pressure and inspiratory flow in phase with tracheal inspiration or positive pressure and expiratory flow in phase with tracheal expiration in the isolated UA. Stimulation of UA negative pressure receptors with body temperature air resulted in a 10--15% enhancement of phasic moving-time-averaged posterior cricoarytenoid electromyographic (EMG) activity above tonic levels obtained without pressure and flow in the UA (baseline). Stimulation of UA positive pressure receptors increased phasic moving-time-averaged thyroarytenoid EMG activity above tonic levels by 45% from baseline. The same enhancement of posterior cricoarytenoid or thyroarytenoid EMG activity was observed with the addition of flow receptor stimulation with room temperature air. Tidal volume and diaphragmatic and abdominal muscle activity were unaffected by UA flow and/or pressure, whereas respiratory timing was minimally affected. We conclude that laryngeal afferents, mainly from pressure receptors, are important in modulating the respiratory activity of laryngeal muscles.     

Norepinephrine induces BDNF and activates the PI-3K and MAPK cascades in embryonic hippocampal neurons

Both antidepressant treatment and physical exercise have been shown to increase circulating levels of norepinephine (NE) and hippocampal brain-derived neurotrophic factor (BDNF). Increases in BDNF have been shown to be associated with enhanced dendritic arborization and neuronal survival, which forms the theoretical basis of the Neurotrophin Hypothesis of antidepressant action. Using isolated embryonic hippocampal neurons and immunoblotting, we show that application of NE increases BDNF and phosphorylated Trk, and that these increases can be prevented by ERK and PI-3K inhibitors. In addition, NE-induced increases in phospho-ERK2 and PI-3K were each suppressed by a PI-3K and MAPK inhibitor, respectively. Furthermore, phosphorylation of cAMP-response element binding (CREB) protein was also increased by NE and brought down to baseline levels by MAPK and PI-3K inhibitors. And finally, because both the MAPK and PI-3K inhibitors suppress phosphorylation of both TrkB (upstream) and CREB (downstream), these results indicate that NE-induced BDNF expression follows a cyclic pathway, reminiscent of a positive feedback loop. The results of this study provide an in vitro model of the intracellular signaling mechanisms activated by NE, via ligand-G-protein-coupled receptor (GPCR)-to-BDNF-RTK transactivation, that is putatively thought to occur in vivo as a result of excitatory neural activity.     

Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity

Recent studies have implicated reactive oxygen species (ROS) in the pathogenesis of hypertension and activation of the sympathetic nervous system (SNS). Because nitric oxide (NO) exerts a tonic inhibition of central SNS activity, increased production of ROS could enhance inactivation of NO and result in activation of the SNS. To test the hypothesis that ROS may modulate SNS activity, we infused Tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl), a superoxide dismutase mimetic, or vehicle either intravenously (250 microg x kg(-1) x min(-1)) or in the lateral ventricle (50 microg x kg body wt(-1) x min(-1)), and we determined the effects on blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamus (PH) measured by the microdialysis technique, renal sympathetic nerve activity (RSNA) measured by direct microneurography, the abundance of neuronal NO synthase (nNOS)-mRNA in the PH, paraventricular nuclei (PVN), and locus coeruleus (LC) measured by RT-PCR, and the secretion of nitrate/nitrite (NO(x)) in the dialysate collected from the PH of Sprague-Dawley rats. Tempol reduced BP whether infused intravenously or intracerebroventricularly. Tempol reduced NE secretion from the PH and RSNA when infused intracerebroventricularly but raised NE secretion from the PH and RSNA when infused intravenously. The effects of intravenous Tempol on SNS activity were blunted or abolished by sinoaortic denervation. Tempol increased the abundance of nNOS in the PH, PVN, and LC when infused intracerebroventricularly, but it decreased the abundance of nNOS when infused intravenously. When given intracerebroventricularly, Tempol also reduced the concentration of NO(x) in the dialysate collected from the PH. Pretreatment with N(omega)-nitro-l-arginine methyl ester did not abolish the effects of intracerebral Tempol on BP, heart rate, NE secretion from the PH, and RSNA suggesting that the effects of Tempol on SNS activity may be in part dependent and in part independent of NO. In all, these studies support the notion that ROS may raise BP via activation of the SNS. This activation may be mediated in part by downregulation of nNOS and NO production, in part by mechanisms independent of NO. The discrepancy in results between intracerebroventricular and intravenous infusion of Tempol can be best explained by direct inhibitory actions on SNS activity when given intracerebral. By contrast, Tempol may exert direct vasodilation of the peripheral circulation and reflex activation of the SNS when given intravenously.     

Protected P-Element Termini Suggest a Role for Inverted-Repeat-Binding Protein in Transposase-Induced Gap Repair in Drosophila Melanogaster

P-element transposition is thought to occur by a cut-and-paste mechanism that generates a double-strand break at the donor site, the repair of which can lead to internally deleted elements. We have generated a series of both phenotypically stronger and weaker allelic derivatives of vg(21), a vestigial mutant caused by a P-element insertion in the 5' region of the gene. Virtually all of the new alleles arose by internal deletion of the parental element in vg(21), and we have characterized a number of these internally deleted P elements. Depending upon the selection scheme used, we see a very different spectrum of amount and source of P-element sequences in the resultant derivatives. Strikingly, most of the breakpoints occur within the inverted-repeats such that the last 15-17 bp of the termini are retained. This sequence is known to bind the inverted-repeat-binding protein (IRBP). We propose that the IRBP may act to preserve the P-element ends when transposition produces a double-strand gap. This allows the terminus to serve as a template upon which DNA synthesis can act to repair the gap. Filler sequences found at the breakpoints of the internally deleted P elements resemble short stretches, often in tandem arrays, of these terminal sequences. The structure of the filler sequences suggests replication slippage may occur during the process of gap repair.     

Stress of stoicism: Low emotionality and high control lead to increases in allostatic load

The present longitudinal study examined the combined effects of task persistence and negative emotionality (NE) on allostatic load (AL), a physiological indicator of chronic stress. In line with John Henryism theory, we hypothesized that high persistence combined with low NE may be indicative of a high-effort coping style, leading to high arousal of the nervous system and, as a consequence, increased AL. Mothers reported on children’s NE (N = 158, 72 females) at age 9. Persistence was measured at age 9 using a behavioral measure assessing persistence on an impossible task. AL was measured at ages 9 and 17. The AL measure captured hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, cardiovascular, and metabolic activity. Consistent with previous research, persistence protected against high AL in the context of high NE. However, combined with low NE, high behavioral persistence was associated with higher physiological stress. Our results have implications for both clinical and intervention contexts.     

Dopamine Transporter Loss in 6-OHDA Parkinson’s Model Is Unmet by Parallel Reduction in Dopamine Uptake

The dopamine transporter (DAT) regulates synaptic dopamine (DA) in striatum and modulation of DAT can affect locomotor activity. Thus, in Parkinson’s disease (PD), DAT loss could affect DA clearance and locomotor activity. The locomotor benefits of L-DOPA may be mediated by transport through monoamine transporters and conversion to DA. However, its impact upon DA reuptake is unknown and may modulate synaptic DA. Using the unilateral 6-OHDA rat PD model, we examined [³H]DA uptake dynamics in relation to striatal DAT and tyrosine hydroxylase (TH) protein loss compared with contralateral intact striatum. Despite >70% striatal DAT loss, DA uptake decreased only ∼25% and increased as DAT loss approached 99%. As other monoamine transporters can transport DA, we determined if norepinephrine (NE) and serotonin (5-HT) differentially modulated DA uptake in lesioned striatum. Unlabeled DA, NE, and 5-HT were used, at a concentration that differentially inhibited DA uptake in intact striatum, to compete against [³H]DA uptake. In 6-OHDA lesioned striatum, DA was less effective, whereas NE was more effective, at inhibiting [³H]DA uptake. Furthermore, norepinephrine transporter (NET) protein levels increased and desipramine was ∼two-fold more effective at inhibiting NE uptake. Serotonin inhibited [³H]DA uptake, but without significant difference between lesioned and contralateral striatum. L-DOPA inhibited [³H]DA uptake two-fold more in lesioned striatum and inhibited NE uptake ∼five-fold more than DA uptake in naïve striatum. Consequently, DA uptake may be mediated by NET when DAT loss is at PD levels. Increased inhibition of DA uptake by L-DOPA and its preferential inhibition of NE over DA uptake, indicates that NET-mediated DA uptake may be modulated by L-DOPA when DAT loss exceeds 70%. These results indicate a novel mechanism for DA uptake during PD progression and provide new insight into how L-DOPA affects DA uptake, revealing possible mechanisms of its therapeutic and side effect potential.     

去甲肾上腺素对猕猴额叶延缓辨别作业相关神经元活动...

To study the role of norepinephrine (NE) in the cognitive function of the brain, the effects of NE, tolazoline (TOL) and propranolol (PR) on the activity of frontal neurons were examined in 3 rhesus monkeys (Macaca mulatta) during the performance of a delayed visual discrimination go/no-go task. Of the 230 task-related neurons recorded from the area medial to the superior ramus of the arcuate sulcus, 159 neurons were tested with NE applied microiontophoretically. Of these tested neurons, 11 neurons were related to starting period, 28 neurons to cue period, 66 neurons to delay period and 54 neurons to response period. About 2/3 of these neurons increased in discharge rate in the task, and the rest decreased. For most of the neurons with decrease of discharge rate in the delay period, the discharge rate was further decreased during application of NE. During application of TOL or PR, the discharge rate was increased and the effect of NE was antagonized. The present results suggest that NE may play a role in the cognitive function of the frontal neurons, particularly in attention and short-term memory, and may be involved in the inhibitory process of the neuronal activities.     

Proprioceptive proximo-distal relationships between the quadriceps and soleus muscles in man

Electrical stimulation of femoral nerve modulates voluntary tonic activity o of ipsilateral soleus muscle. Stimulus time-locked inhibitory and facilitatory phases can be distinguished. EMG temporal analysis suggests that early perturbations are correlated with spinal effects of centripetal electrical activity. The inhibitory effects which momentarily abolish voluntary soleus activity are thought to result from quadriceps Ib fibres recruitment. While no heteronymous activity is induced at rest, femoral nerve Ia fibres activation can produce soleus muscle reflex when soleus motor nucleus excitability is increased by voluntary command. Recurrent discharge resulting from soleus reflex response enhances inhibition initially due to quadriceps Ib volley. Secondary effects of isometric quadriceps contraction (and soleus contraction when the femoral stimulus elicits a reflex in this muscle) have their own effects later. These findings suggest that proprioceptive relationships of the two muscular groups are efficient during tonic isometric voluntary command.     

Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia

Noradrenergic and GABAergic systems in the medial hypothalamus influence plasma glucose and may be activated during glucoprivation. Microdialysis probes were placed into the ventromedial nucleus (VMH), lateral hypothalamus (LHA), and paraventricular nucleus (PVH) of male Sprague-Dawley rats to monitor extracellular concentrations of norepinephrine (NE) and GABA. During systemic hypoglycemia, induced by insulin (1.0 U/kg), NE concentrations increased in the VMH (P < 0.05) and PVH (P = 0.06) in a bimodal fashion during the first 10 min and 20-30 min after insulin administration. In the VMH, GABA concentrations increased (P < 0.05) in a similar manner as NE. Extracellular NE concentrations in the LHA were slightly lower (P = 0.13), and GABA levels remained at baseline. The increases in NE and GABA in the VMH were absent during euglycemic clamp; however, NE in the PVH still increased, reflecting a direct response to hyperinsulinemia. On the basis of these data, we propose that the activity of noradrenergic afferents to the medial hypothalamus is increased during hypoglycemia and influences the activity of local GABAergic systems to activate appropriate physiological compensatory mechanisms.     

Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder

It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen’s flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand ¹¹C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.     

Prefrontal cortex guides context-appropriate responding during language production

Although language processing is thought to frequently require cognitive control, little is known about the cognitive and neural basis of the control of language. Here, we demonstrate that processing of context by the PFC plays an important role in the control of language comprehension and production. Using a missing letter paradigm and fMRI, we found that increased activation in the PFC (but not in posterior regions), while encoding and maintaining context information, predicted context-appropriate responses. Furthermore, greater selection demands increased activity during responding in the same regions engaged during the encoding and maintenance of context. Overall, as in other cognitive task domains, these results suggest that PFC context processing plays an important role in the control of language.     

The lesion of the rat substantia nigra pars compacta dopaminergic neurons as a model for Parkinson's disease memory disabilities

1. In this article we review the studies of memory disabilities in a rat model o Parkinson's disease (PD).2. Intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to rats causes a partial lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats.3. These animals present learning and memory deficits but no sensorimotor impairments, thus modeling the early phase of PD when cognitive impairments are observed but the motor symptoms of the disease are barely present.4. The cognitive deficits observed in these animals affect memory tasks proposed to model habit learning (the cued version of the water maze task and the two-way active avoidance task) and working memory (a working memory version of the water maze), but spare long-term spatial memory (the spatial reference version of the Morris water maze).5. The treatment of these animals with levodopa in a dose that restores the striatal level of dopamine does not reverse these memory impairments, probably because this treatment promotes a high level of dopamine in extrastriatal brain regions, such as the prefrontal cortex and the hippocampus.6. On the other hand, the adenosine receptor antagonist, caffeine, partly reverse the memory impairment effect of SNc lesion in these rats. This effect may be due to caffeine action on nigrostriatal neurons, since it induces dopamine release and modulates the interaction between adenosine and dopamine receptor activity.7. These results suggest that the MPTP SNc-lesioned rats are a good model to study memory disabilities related to PD and that caffeine and other selective A(2A) adenosine receptor antagonists are promising drugs to treat this symptoms in PD patients.     

High binaural coherence determines successful sound localization and increased activity in posterior auditory areas

Our brain continuously receives complex combinations of sounds originating from different sources and relating to different events in the external world. Timing differences between the two ears can be used to localize sounds in space, but only when the inputs to the two ears have similar spectrotemporal profiles (high binaural coherence). We used fMRI to investigate any modulation of auditory responses by binaural coherence. We assessed how processing of these cues depends on whether spatial information is task relevant and whether brain activity correlates with subjects' localization performance. We found that activity in Heschl's gyrus increased with increasing coherence, irrespective of whether localization was task relevant. Posterior auditory regions also showed increased activity for high coherence, primarily when sound localization was required and subjects successfully localized sounds. We conclude that binaural coherence cues are processed throughout the auditory cortex and that these cues are used in posterior regions for successful auditory localization.     

Correlation Between Electroencephalogram Isoelectric Time and Hippocampal Norepinephrine Levels, Measured by Microdialysis, During Ischemia in Rats

It is suggested that norepinephrine (NE) plays a role during transient forebrain ischemia. NE may have a protective action against neuronal cell death in the hippocampus, or it may be one of the causes of injurious ischemic effects. We used the microdialysis technique to study extracellular NE levels in the rat hippocampus before, during, and after 30 min of transient incomplete forebrain ischemia (induced by four-vessel occlusion) to describe the time course of NE in this condition. There was a maximal increase (fivefold) in extracellular NE after 10 min of reflow only when the electroencephalogram was isoelectric. NE levels returned to baseline 40 min after release of the carotid clamps and remained constant for the next 80 min. Thus there appears to be a transient NE overflow in the hippocampus during ischemia, closely related to the complete loss of brain electrical activity.