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Elliot A Stein

Publications and source records attributed to Elliot A Stein.

13 recordsLinked to original sources
PubMed2004

Neural substrates mediating human delay and trace fear conditioning.

Previous functional magnetic resonance imaging (fMRI) studies with human subjects have explored the neural substrates involved in forming associations in Pavlovian fear conditioning. Most of these studies used delay procedures, in which the conditioned stimulus (CS) and unconditioned stimulus (UCS) coterminate. Less is known about brain regions that support trace conditioning, a procedure in which an interval of time (trace interval) elapses between CS termination and UCS onset. Previous work suggests significant overlap in the neural circuitry supporting delay and trace fear conditioning, although trace conditioning requires recruitment of additional brain regions. In the present event-related fMRI study, skin conductance and continuous measures of UCS expectancy were recorded concurrently with whole-brain blood oxygenation level-dependent (BOLD) imaging during direct comparison of delay and trace discrimination learning. Significant activation was observed within the visual cortex for all CSs. Anterior cingulate and medial thalamic activity reflected associative learning common to both delay and trace procedures. Activations within the supplementary motor area (SMA), frontal operculum, middle frontal gyri, and inferior parietal lobule were specifically associated with trace interval processing. The hippocampus displayed BOLD signal increases early in training during all conditions; however, differences were observed in hippocampal response magnitude related to the accuracy of predicting UCS presentations. These results demonstrate overlapping patterns of activation within the anterior cingulate, medial thalamus, and visual cortex during delay and trace procedures, with additional recruitment of the hippocampus, SMA, frontal operculum, middle frontal gyrus, and inferior parietal lobule during trace conditioning. These data suggest that the hippocampus codes temporal information during trace conditioning, whereas brain regions supporting working memory processes maintain the CS-UCS representation during the trace interval.

Adolescent↗
PubMed2003

Multiple neuronal networks mediate sustained attention.

Sustained attention deficits occur in several neuropsychiatric disorders. However, the underlying neurobiological mechanisms are still incompletely understood. To that end, functional MRI was used to investigate the neural substrates of sustained attention (vigilance) using the rapid visual information processing (RVIP) task in 25 healthy volunteers. In order to better understand the neural networks underlying attentional abilities, brain regions where task-induced activation correlated with task performance were identified. Performance of the RVIP task activated a network of frontal, parietal, occipital, thalamic, and cerebellar regions. Deactivation during task performance was seen in the anterior and posterior cingulate, insula, and the left temporal and parahippocampal gyrus. Good task performance, as defined by better detection of target stimuli, was correlated with enhanced activation in predominantly right fronto-parietal regions and with decreased activation in predominantly left temporo-limbic and cingulate areas. Factor analysis revealed that these performance-correlated regions were grouped into two separate networks comprised of positively activated and negatively activated intercorrelated regions. Poor performers failed to significantly activate or deactivate these networks, whereas good performers either activated the positive or deactivated the negative network, or did both. The fact that both increased activation of task-specific areas and increased deactivation of task-irrelevant areas mediate cognitive functions underlying good RVIP task performance suggests two independent circuits, presumably reflecting different cognitive strategies, can be recruited to perform this vigilance task.

Adolescent↗
PubMed2003

Cingulate hypoactivity in cocaine users during a GO-NOGO task as revealed by event-related functional magnetic resonance imaging.

Although extensive evidence exists for the reinforcing properties of drugs of abuse such as cocaine, relatively less research has addressed the functional neuroanatomical correlates of the cognitive sequelae of these drugs. We present a functional magnetic resonance imaging study of a GO-NOGO task in which successful performance required prepotent behaviors to be inhibited. Significant cingulate, pre-supplementary motor and insula hypoactivity was observed for both successful NOGOs and errors of commission in chronic cocaine users relative to cocaine-naive controls. This attenuated response, in the presence of comparable activation levels in other task-related cortical areas, suggests cortical and psychological specificity in the locus of drug abuse-related cognitive dysfunction. The results suggest that addiction may be accompanied by a disruption of brain structures critical for the higher-order, cognitive control of behavior.

Adult↗
PubMed2003

Functional MRI of human amygdala activity during Pavlovian fear conditioning: stimulus processing versus response expression.

Although laboratory animal studies have shown that the amygdala plays multiple roles in conditional fear, less is known about the human amygdala. Human subjects were trained in a Pavlovian fear conditioning paradigm during functional magnetic resonance imaging (fMRI). Brain activity maps correlated with reference waveforms representing the temporal pattern of visual conditional stimuli (CSs) and subject-derived autonomic responses were compared. Subjects receiving paired CS-shock presentations showed greater amygdala activity than subjects receiving unpaired CS-shock presentations when their brain activity was correlated with a waveform generated from their behavioral responses. Stimulus-based waveforms revealed learning differences in the visual cortex, but not in the amygdala. These data support the view that the amygdala is important for the expression of learned behavioral responses during Pavlovian fear conditioning.

Adult↗
PubMed2002

Cognitive mechanisms of nicotine on visual attention.

Understanding nicotine's neurobiological and cognitive mechanisms may help explain both its addictive properties and potential therapeutic applications. As such, functional MRI was used to determine the neural substrates of nicotine's effects on a sustained attention (rapid visual information-processing) task. Performance was associated with activation in a fronto-parietal-thalamic network in both smokers and nonsmokers. Along with subtle behavioral deficits, mildly abstinent smokers showed less task-induced brain activation in the parietal cortex and caudate than did nonsmokers. Transdermal nicotine replacement improved task performance in smokers and increased task-induced brain activation in the parietal cortex, thalamus, and caudate, while nicotine induced a generalized increase in occipital cortex activity. These data suggest that nicotine improves attention in smokers by enhancing activation in areas traditionally associated with visual attention, arousal, and motor activation.

Administration, Cutaneous↗
PubMed2002

Ca(2+)-activated potassium (K(Ca)) channel inhibition decreases neuronal activity-blood flow coupling.

A number of possible mediators have been proposed to couple neuronal activity with local cerebral metabolic activity and blood flow, but the mechanisms by which these mediators act is still unclear. In order to explore these coupling mechanisms, we used the rodent whisker-barrel cortex (WBC) model to test the hypothesis that modulation of K(Ca) channels is an important step in this coupling process. Anesthetized rats were prepared for laser-Doppler flowmetry (LDF) or evoked potential recordings utilizing a thinned cranial window over WBC. Superfusion of the K(Ca) channel blockers tetraethylammonium (TEA) or iberiotoxin directly onto WBC attenuated the magnitude of the whisker evoked LDF changes. Similar effects were seen after intravenous administration of TEA. Although attenuated, neither the temporal profile of the elicited blood flow responses nor the evoked electrical activity in WBC were affected by K(Ca) blockade. These data suggest that the process of cerebral metabolism/blood flow coupling in the rodent WBC involves K(Ca) channels.

Animals↗
PubMed2002

Blockade of ionotropic glutamatergic transmission in the ventral tegmental area reduces heroin reinforcement in rat.

RATIONALE: While the role of the mesocorticolimbic (MCL) dopamine (DA) system in mediating the reinforcing properties of drugs of abuse has been well established, how and where other neurotransmitter systems interact to modify this system is less well understood. OBJECTIVES: The present study sought to assess whether blockade of ionotropic glutamate receptors in the ventral tegmental area (VTA) would modulate heroin self-administration (SA) behavior in rats. METHODS: The effects of systemic or regional administration of ionotropic glutamate receptor antagonists into the VTA on the maintenance of heroin SA were assessed. Rats were reinforced each time they responded on a lever with a single injection of intravenous heroin. To determine the specificity of their effects on heroin SA, the ability of these antagonists to modify locomotion and food-reinforced behavior was also examined. RESULTS: Systemic or regional administration of the non-competitive NMDA antagonist dizocilpine into the VTA significantly increased the rate of heroin SA and shifted the heroin dose-response curve to the right. Similarly, when systemically administered, ketamine, another non-competitive NMDA antagonist, also increased the rate of heroin SA. However, when administered directly into the VTA, ketamine or AP5 [ D-(-)-2-amino-5-phosphonopentanoic acid, a competitive NMDA antagonist], dose-dependently blocked heroin SA. In contrast, 6,7-dinitroquinoxaline-2,3-dione (DNQX), an AMPA/kainate receptor antagonist, significantly increased heroin SA. CONCLUSION: These data suggest that ionotropic glutamate receptors in the VTA, presumably by modulating MCL DA efferents and/or tegmental interneurons, modulate opiate reinforcement.

2-Amino-5-phosphonovalerate↗
PubMed2002

GABAergic mechanisms of heroin-induced brain activation assessed with functional MRI.

Heroin has been hypothesized to activate opiate receptors and inhibit gamma-aminobutyric acid (GABA) release from inhibitory GABAergic interneurons which, in turn, activates dopamine projection cells. Since the distal sites and consequences of this disinhibition are not well understood on a systems level, heroin-induced brain activity was measured using functional MRI (fMRI) in rats. A significant blood oxygen level-dependent (BOLD) signal increase was seen in cortical regions, including prefrontal cortex, cingulate, and olfactory cortex following acute heroin administration. In contrast, a significant signal decrease was seen in several subcortical areas, including the caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. Pretreatment of gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, significantly attenuated the heroin-induced BOLD signal changes. Pretreatment of naloxone, an opiate mu receptor antagonist, eliminated the heroin-induced BOLD signal changes and posttreatment of naloxone reversed the heroin-induced BOLD signal changes. It is suggested that the heroin-induced negative and positive BOLD changes are due to direct inhibitory and indirect disinhibitory mechanisms of GABAergic activities. Administration of GVG altered these mechanisms and further suggested that involvement of the opiate's pharmacological actions can, at least in part, be mediated by inhibiting brain GABA release.

Analgesics, Opioid↗
PubMed2002

Functional cerebral hyperemia is unaffected by isovolemic hemodilution.

BACKGROUND: The cerebral hyperemic effect of hemodilution is well known; however, its mechanism and potential modifying effect on the functional hyperemic response to neuronal activation are unclear. The authors investigated the effects of isovolemic hemodilution on vibrissal stimulation-induced changes in cerebrocortical laser Doppler flow and tissue oxygen tension in the rat. METHODS: The hyperemic response to whisker stimulation was assessed in the whisker barrel cortex of 12 rats anesthetized with chloralose-urethane before and after hemodilution. Graded, isovolemic hemodilution was performed by three repeated withdrawals of 3 ml blood with replacement of equal volume of 5% serum albumin. Measured systemic hematocrit values were 39.3 +/- 1.3% (control), 29.5 +/- 1.0%, 22.3 +/- 1.5%, and 17.0 +/- 1.6% (after the three hemodilution steps). Arterial blood pressure was maintained at control levels with an infusion of methoxamine. Unilateral whisker stimulation was performed with a mechanical actuator at 8 Hz, and 10 cycles of 10 s on-30 s off periods. In six control animals, shed blood was immediately reinfused, resulting in no change in hematocrit, and whisker stimulation was performed using the same timeline as in the other animals. In six additional experiments, resting cerebral cortical oxygen tension was measured using the phosphorescence quenching technique following the same hemodilution protocol. RESULTS: Graded hemodilution increased baseline laser Doppler flow by 5.5 +/- 0.9%, 13 +/- 1.6%, and 23.7 +/- 2.2%. Vibrissal stimulation transiently increased laser Doppler flow by 17.0 +/- 2.0%. The hyperemic response was unchanged after hemodilution and was identical to that seen in the control group in all conditions. Tissue oxygen tension increased slightly but significantly with hemodilution at a rate of 1.4 mmHg per 10% hematocrit change (r = 0.83). Mean arterial pressure, arterial oxygen tension, carbon dioxide tension, and pH were within normal limits in each experimental group and were not different from control during hemodilution. CONCLUSIONS: The results suggest that an increase in baseline flow during hemodilution maintains cortical oxygen supply and consequently preserves the normal functional hyperemic response.

Animals↗
PubMed2002

Focal cerebral ischemia in rats produced by intracarotid embolization with viscous silicone.

Many factors contribute to the severity of neuronal cell death and the functional outcome in stroke. We describe an embolic model of focal cerebral ischemia in the rat that does not require craniotomy and is compatible with continuous measurement of regional CBF using multichannel laser Doppler flow (LDF) technique. Either a 22 microliters (large lesion) or 11 microliters (small lesion) bolus of viscous silicone was injected cephalad into the internal carotid artery. Upon injection, LDF decreased abruptly, most severely in the parietal cortex (-74% +/- 5%) in the large lesion and in the occipital cortex (-69% +/- 10%) in the small lesion model. Over the first hour, post-embolization LDF improved in most areas (e.g. -48% +/- 9% parietal, large lesion) but declined in the small lesion group in the occipital region (-81% +/- 8%). CBF measured by [C]14-IAP autoradiography 1 h post-embolization in the large lesion model demonstrated near-hemispheric ischemia (70% of hemisphere) with sparing of cingulate cortex. Autoradiography demonstrated that ischemia in the small lesion was largely cortical. Light microscopy of brains embolized with 11 microliters of dyed silicone showed filling of pial vessels with no silicone in the Circle of Willis or parenchyma. No animals in the large lesion group survived 24 h. Thirteen of 15 animals in the small lesion group survived for two weeks with resolution of initial hemiplegia, ocular asymmetry and weight loss. Hematoxylin-eosin staining two weeks post-embolization showed signs of severe hypoxia and infarction. In conclusion, the intracarotid silicone embolization technique produces a titrable, reproducible permanent ischemic injury by blocking perfusion in the pial circulation, and is amenable to multisite monitoring with laser Doppler flowmetry. The smaller embolus produces cortical infarction with high rate of survival and neurological recovery.

Animals↗
PubMed2002

Pharmacological applications of magnetic resonance imaging.

Magnetic resonance imaging (MRI) techniques are capable of spatial and temporal resolution and within subject repeatability that far exceed other currently available methods of noninvasively investigating brain functioning. While functional MRI (fMRI) techniques have traditionally been used to investigate sensory, motor, and cognitive functions, they are also very attractive for investigating the effects of pharmacological agents in the brain. However, because pharmacological agents may interfere with the very mechanisms that give rise to the fMRI signal, careful attention to experimental design and data analysis issues must be exercised. Specifically, introducing a drug into the system could potentially alter the coupling of neural activity with regional cerebral blood flow and/or the extraction of oxygen from blood, or may cause local or global cardiovascular changes unrelated to neural activity. These concerns notwithstanding, careful attention to experimental detail and verification procedures promises to make pharmacological MRI a valuable tool for understanding the actions of drugs on the brain at many levels. The physiological and biophysical bases of blood oxygen level-dependent, arterial spin labeling, cerebral blood flow, cerebral blood volume, and spectroscopy acquisition methods are presented to illustrate where confounds may arise when a drug is added to the system. Selected studies combining administration of pharmacological agents with MRI techniques are critically reviewed to illustrate both the challenges inherent in these applications and some possible solutions. Included are studies of acute direct effects of drugs, effects of drugs on task-related activation, chronic effects of drugs, effects of drugs on cerebral metabolism, and variable effects of drugs in different populations.

Animals↗
PubMedDate not supplied

GABAergic mechanisms of opiate reinforcement .

The neurobiological mechanisms of opiate-induced reinforcement are still not completely understood. Over the past two decades, the vast majority of studies have focused on the role of the mesolimbic dopamine (DA) system. However, current studies strongly suggest that opiate actions on gamma-aminobutyric acid (GABA)-ergic cells in both the ventral tegmental area (VTA) and the nucleus accumbens (NAcc) appear to play critical roles. In this review, we focus on the neurochemical substrates of opiate reinforcement and review the role of DA and non-DA substrates, including opioid, GABA, glutamate and serotonin on opiate-reinforced behaviour and the activity of dopaminergic and GABAergic neurons in the VTA and the NAcc.

Humans↗