Biomedical subjects

Elliot A Stein

Publications and source records attributed to Elliot A Stein.

At least 19 recordsLinked to original sources

PubMed2006

Quantification of alpha4beta2* nicotinic receptors in the rat brain with microPET and 2-[18F]F-A-85380.

The radioligand 2-[(18)F]F-A-85380 has been used for PET studies of the alpha4beta2* subtype of nicotinic acetylcholine receptors (nAChRs) in the living brain of humans and nonhuman primates. In order to extend the capacity of microPET to quantify neuroreceptors in rat brain, we carried out studies of 2-[(18)F]F-A-85380 to measure the apparent binding potential BP* in individual rats, which were studied repeatedly over several months. Using a bolus-plus-infusion paradigm, 2-[(18)F]F-A-85380 (specific activity 20-1300 GBq/micromol) was administered intravenously over 8 to 9 h with K(bol) values of 350 to 440 min and a mean infusion rate of 0.03+/-0.01 nmol/kg/h. Studies included a 2-h nicotine infusion initiated 2 h before the end of scanning to displace specifically bound radioactivity. Steady state binding in brain was obtained within 5 h as defined by the occurrence of constant radioactivity concentrations in brain regions and constant, free arterial plasma levels of nonmetabolized radioligand. BP* averages (+/-SEM) for thalamus, forebrain, and cerebellum were 5.9+/-0.7, 2.6+/-0.4, and 1.0+/-0.1, respectively, which are consistent with the alpha4beta2* nAChR distribution in rat brain measured in vitro. Studies of receptor occupancy determined the ED(50) to be 0.29 nmol/kg/h. The demonstration that alpha4beta2* nAChRs are quantifiable in the rat brain using PET measurements, coupled with the ability to conduct longitudinal studies over several months in the same rats, suggests potential applications to studies of chronic nicotine use, its treatment, and abnormal functioning of alpha4beta2* receptors in a rat model.

Animals↗

PubMed2006

Cingulate activation increases dynamically with response speed under stimulus unpredictability.

Functional magnetic resonance imaging studies of cognition require repeated and consistent engagement of the cognitive process under investigation. Activation is generally averaged across trials that are assumed to tax a specific mental operation or state, whereas intraindividual variability in performance between trials is usually considered error variance. A more recent analysis approach postulates that these fluctuations can reflect variation in the very process taxed by the particular trial type. In the present study, participants responded to targets presented randomly in 1 of 4 peripheral locations. By employing a function of reaction time (RT) of individual trials as a linear regressor, brain regions were identified whose activation varied with RT on a trial-by-trial basis. Whole-brain analysis revealed that the anterior cingulate, posterior cingulate, and left angular/superior temporal gyri were more active in trials with faster RT but only when the target location was unpredictable. No such association was seen in trials where the target location was predicted by a central cue. These results suggest a role for the cingulate and angular gyri in the dynamic regulation of attention to unpredictable events. This is in accordance with the function of a default network that is active in the absence of top-down-focused attention and is thought to continuously provide resources for broad and spontaneous information gathering. Exploiting intertrial performance variability may be particularly suitable for capturing such spontaneous and elusive phenomena as stimulus-driven processes of attention.

Adaptation, Physiological↗

PubMed2006

Neuroanatomical dissociation between bottom-up and top-down processes of visuospatial selective attention.

Allocation of attentional resources to portions of the available sensory input can be regulated by bottom-up processes, i.e., spontaneous orientation towards an oncoming stimulus (stimulus-driven attention), and by top-down processes, i.e., intentionally and driven by knowledge, expectation and goals. The present study aimed at advancing the understanding of brain networks mediating bottom-up and top-down control of visuospatial attention by employing a paradigm that parametrically varied demands on these two processes. Spatial predictability of peripheral targets was parametrically varied by centrally cueing one, two, three or four of four possible locations. Reaction time decreased linearly with more precise valid cueing of the target location and increased with more precise invalid cueing. Event-related functional magnetic resonance imaging (fMRI) enabled measurement of blood oxygenation level-dependent (BOLD) responses to cues and to targets. A mostly left-hemispheric network consisting of left intraparietal sulcus, inferior and superior parietal lobule, bilateral precuneus, middle frontal gyri including superior frontal sulci, and middle occipital gyri displayed BOLD responses to cues that increased linearly with more precise spatial cueing, indicating engagement by top-down spatial selective attention. In contrast, bilateral temporoparietal junction, cingulate gyrus, right precentral gyrus and anterior and posterior insula, bilateral fusiform gyri, lingual gyri and cuneus displayed BOLD responses to targets that increased with their spatial unpredictability, indicating engagement by stimulus-driven orienting. The results suggest two largely dissociated neural networks mediating top-down and bottom-up control of visuospatial selective attention.

Adult↗

PubMed2006

Hemodynamic and metabolic changes induced by cocaine in anesthetized rat observed with multimodal functional MRI.

RATIONALE: Physiological changes (such as heart rate and respiration rate) associated with strong pharmacological stimuli could change the blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) mapping signals, independent of neural activity. OBJECTIVES: This study investigates whether the physiological changes per se associated with systemic cocaine administration (1 mg/kg) contaminate the BOLD fMRI signals by measuring BOLD and cerebral blood flow (CBF) fMRI and estimating the cerebral metabolic rate of oxygen (CMRO(2)) changes. MATERIALS AND METHODS: BOLD and CBF fMRI was performed, and changes in CMRO(2) were estimated using the BOLD biophysical model. RESULTS: After systemic cocaine administration, blood pressure, heart rate, and respiration rate increased, fMRI signals remained elevated after physiological parameters had returned to baseline. Cocaine induced changes in the BOLD signal within regions of the reward pathway that were heterogeneous and ranged from -1.2 to 5.4%, and negative changes in BOLD were observed along the cortical surface. Changes in CBF and estimated CMRO(2) were heterogeneous and positive throughout the brain, ranging from 14 to 150% and 10 to 55%, respectively. CONCLUSIONS: This study demonstrates a valuable tool to investigate the physiological and biophysical basis of drug action on the central nervous system, offering the means to distinguish the physiological from neural sources of the BOLD fMRI signal.

Algorithms↗

PubMed2005

Noninvasive quantification of cerebral blood volume in humans during functional activation.

Like cerebral blood flow (CBF), cerebral blood volume (CBV) is an important physiological parameter closely associated with brain activity and thus, noninvasive quantification of CBV during brain activation provides another opportunity to investigate the relationship between neuronal activity and hemodynamic changes. In this paper, a new method is presented that is able to quantify CBV at rest and during activation. Specifically, using an inversion recovery pulse sequence, a set of brain images was collected at various inversion times (TIs). At each TI, functional images were acquired with a block-design visual stimulation paradigm. A biophysical model comprised of multiple tissue components was developed and was utilized for the determination of CBV using the visual stimulation data. MRI experiments on five healthy volunteers showed that CBV was 5.0 +/- 1.5 ml blood/100 ml brain during rest and increased to 6.6 +/- 1.8 ml blood/100 ml brain following visual stimulation. Furthermore, experiments with visual stimulation at two frequencies (2 and 8 Hz) showed that the increases in CBV correlated with the strength of stimulation. This technique, with its ability to measure quantitative CBV values noninvasively, provides a valuable tool for quantifying hemodynamic signals associated with brain activation.

Algorithms↗

PubMed2005

Nonlinear responses of cerebral blood volume, blood flow and blood oxygenation signals during visual stimulation.

Hemodynamic-based functional magnetic resonance imaging (fMRI) techniques provide a great utility for noninvasive functional brain mapping. However, because the hemodynamic signals reflect underlying neural activity indirectly, characterization of these signals following brain activation is essential for experimental design and data interpretation. In this report, the linear (or nonlinear) responses to neuronal activation of three hemodynamic parameters based primarily on changes of cerebral blood volume, blood flow and blood oxygenation were investigated by testing these hemodynamic responses' additivity property. Using a recently developed fMRI technique that acquires vascular space occupancy (VASO), arterial spin labeling (ASL) perfusion and blood oxygenation level-dependent (BOLD) signals simultaneously, the additivity property of the three hemodynamic responses in human visual cortex was assessed using various visual stimulus durations. Experiments on healthy volunteers showed that all three hemodynamic-weighted signals responded nonlinearly to stimulus durations less than 4 s, with the degree of nonlinearity becoming more severe as the stimulus duration decreased. Vascular space occupancy and ASL perfusion signals showed similar nonlinearity properties, whereas the BOLD signal was the most nonlinear. These data suggest that caution should be taken in the interpretation of hemodynamic-based signals in fMRI.

Adult↗

PubMed2005

A rotation-invariant spherical harmonic decomposition method for mapping intravoxel multiple fiber structures.

A new rotation-invariant spherical harmonic decomposition (SHD) method is proposed in this paper for analyzing high angular resolution diffusion (HARD) imaging. Regular SHD methods have been used to characterize the features of the apparent diffusion coefficient (ADC) profile measured by the HARD technique. However, these regular SHD methods are rotation-variant, i.e., the magnitude and/or the phase of the harmonic components changes with the rotation of the ADC profile. We propose a new rotation-invariant SHD (RI-SHD) method based on the rotation-invariant property of a diffusion tensor model. The basic idea of the proposed method is to reorient the measured ADC profile into a local coordinate system determined by the three eigenvectors of the diffusion tensor in each imaging voxel, and then apply a SHD to the ADC profile. Both simulations and in vivo experiments were carried out to validate the method. Comparisons were made between the component maps from a regular SHD method, diffusion circular spectrum mapping (DCSM) method and the proposed RI-SHD method. The results indicate that the regular SHD maps vary significantly with the rotation of the diffusion-encoding scheme, whereas the maps of the DCSM and the proposed method remain unchanged. In particular, the (0,0)-th, (2,2)-th and (4,4)-th component maps from the RI-SHD method exhibited good consistency with the 0th, 2nd and 4th order maps of the DCSM method, respectively. Compared with the regular SHD methods used in HARD imaging, the proposed RI-SHD method is superior in characterizing the diffusion patterns of multiple fiber structures between different brain regions or across subjects.

Adult↗

PubMed2005

Neural correlates of high and craving during cocaine self-administration using BOLD fMRI.

Modern theories of drug dependence hold the hedonic effects of drug-taking central to understanding the motivation for compulsive drug use. Previous neuroimaging studies have begun to identify brain regions associated with acute drug effects after passive delivery. In this study, a more naturalistic model of cocaine self-administration (SA) was employed in order to identify those sites associated with drug-induced high and craving as measures of reward and motivation. Non-treatment seeking cocaine-dependent subjects chose both when and how often i.v. cocaine administration occurred within a medically supervised SA procedure. Both functional magnetic resonance imaging (fMRI) data and real-time behavioral ratings were acquired during the 1-h SA period. Drug-induced HIGH was found to correlate negatively with activity in limbic, paralimbic, and mesocortical regions including the nucleus accumbens (NAc), inferior frontal/orbitofrontal gyrus (OFC), and anterior cingulate (AC), while CRAVING correlated positively with activity in these regions. This study provides the first evidence in humans that changes in subjective state surrounding cocaine self-administration reflect neural activity of the endogenous reward system.

Adult↗

PubMed2005

Head motion suppression using real-time feedback of motion information and its effects on task performance in fMRI.

A voluntary head motion suppression method using feedback to subjects of their own head motion information is demonstrated. A real-time fMRI system was developed on standard MR imaging hardware for this purpose. The head motion information was simplified as a four-way arrow display that changed color from green to red when a composite head motion index went beyond a specified threshold. The arrow indicators were integrated into a version of the commonly used visual N-BACK task. Results suggest a significant suppression of head motion consistently in all subjects while the influence on task performance and brain activation was minimal. It is proposed that under certain experimental conditions, voluntary head motion suppression may feasibly be employed without significant compromise of fMRI data.

Adult↗

PubMed2004

Comparability of functional MRI response in young and old during inhibition.

When using fMRI to study age-related cognitive changes, it is important to establish the integrity of the hemodynamic response because, potentially, it can be affected by age and disease. However, there have been few attempts to document such integrity and no attempts using higher cognitive rather than perceptual or motor tasks. We used fMRI with 28 healthy young and older adults on an inhibitory control task. Although older and young adults differed in task performance and activation patterns, they had comparable hemodynamic responses. We conclude that activation during cognitive inhibition, which was predominantly increased in elders, was not due to vascular confounds or specific changes in hemodynamic coupling.

Adult↗

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↗

PubMed2004

Opiate tolerance by heroin self-administration: an fMRI study in rat.

Functional MRI (fMRI) was employed to determine whether repeated heroin self-administration (SA) produces tolerance or sensitization in the brain of heroin-SA rats. Twelve rats were evenly divided into saline and heroin (0.06 mg/kg, 4 hr/day) SA groups. There was a progressive increase in drug-SA behavior and daily heroin intake during the 8-9 days of heroin-SA training. Within 24 hr after the last session of daily SA, acute heroin (0.1 mg/kg) administration induced regional blood oxygen level-dependent (BOLD) signals in both groups of rats. The positive BOLD signals appeared mainly in the cortical regions, including the prefrontal cortex, cingulate, and olfactory cortex, while the negative BOLD signals were predominantly located in subcortical regions such as caudate and putamen, nucleus accumbens, thalamus, and hypothalamus. However, the number of activated voxels or BOLD-signal intensity was significantly less in heroin-SA rat in regions of prefrontal cortex, nucleus accumbens, and thalamus, etc., compared to the changes in the saline control rats. Application of gamma-vinyl GABA (100 mg/kg), an irreversible GABA-transaminase inhibitor, failed to block opiate actions in the heroin-SA rats. Together, these data suggest that repeated heroin-SA produces tolerance or desensitization of opiate actions in the rat brain, which may in turn potentiate drug SA behavior and drug intake.

Animals↗

PubMed2004

Simultaneous MRI acquisition of blood volume, blood flow, and blood oxygenation information during brain activation.

Simultaneous acquisition of complementary functional hemodynamic indices reflecting different aspects of brain activity would be a valuable tool for functional brain-imaging studies offering enhanced detection power and improved data interpretation. As such, a new MRI technique is presented that is able to achieve concurrent acquisition of three hemodynamic images based primarily on the changes of cerebral blood volume, blood flow, and blood oxygenation, respectively, associated with brain activation. Specifically, an inversion recovery pulse sequence has been designed to measure VASO (vascular space occupancy), ASL (arterial spin labeling) perfusion, and BOLD (blood-oxygenation-level-dependent) signals in a single scan. The MR signal characteristics in this sequence were analyzed, and image parameters were optimized for the simultaneous acquisition of these functional images. The feasibility and efficacy of the new technique were assessed by brain activation experiments with visual stimulation paradigms. Experiments on healthy volunteers showed that this technique provided efficient image acquisition, and thus higher contrast-to-noise ratio per unit time, compared with conventional techniques collecting these functional images separately. In addition, it was demonstrated that the proposed technique was able to be utilized in event-related functional MRI experiments, with potential advantages of obtaining accurate transient information of the activation-induced hemodynamic responses.

Blood Flow Velocity↗

PubMed2004

Mapping the orientation of intravoxel crossing fibers based on the phase information of diffusion circular spectrum.

A new method is presented to map the orientation of intravoxel crossing fibers by using the phase of the diffusion circular spectrum harmonics. In a previous study [Zhan, W., Gu, H., Xu, S., Silbersweig, D.A., Stern, E., Yang, Y., 2003. Circular spectrum mapping for intravoxel fiber structures based on high angular resolution apparent diffusion coefficients. Magn. Reson. Med. 49, 1077-1088], we demonstrated that the magnitude of the 4th-order harmonic of the diffusion circular spectrum can be used to identify the existence of fiber crossings. However, the orientation of the intravoxel crossing fibers remained unknown. This study extends the diffusion circular spectrum mapping method so that it is able to identify the orientation of the intravoxel crossing fibers by utilizing the phase information of the circular spectrum. In general, the phase of the circular harmonic determines the rotation of the apparent diffusion coefficient (ADC) profile on the sampling circle that is spanned by the major and medium eigenvector of the diffusion tensor and thus can be used to determine the orientation of the crossing fibers. Simulation results show that the regular tensor-based major eigenvector maps have obvious artifacts in the fiber-crossing area, whereas the estimated crossing fibers by the proposed method are much more consistent with the orientation of the actual intravoxel fibers. Diffusion MRI experiments were performed on five healthy human brains using a 3T scanner. The brain regions with fiber crossings were selected by thresholding the magnitudes of the 4th-order circular spectrum map. Intravoxel crossing fibers were estimated by the phase of the 4th-order harmonic for each voxel within these areas. The estimated intravoxel crossing fibers demonstrated a clear consistency with the orientations of fiber tracks in the surrounding tissues, reducing the fiber orientation discontinuity of the regular major eigenvector map.

Adult↗

PubMed2004

Amygdala and hippocampal activity during acquisition and extinction of human fear conditioning.

Previous functional magnetic resonance imaging (fMRI) studies have characterized brain systems involved in conditional response acquisition during Pavlovian fear conditioning. However, the functional neuroanatomy underlying the extinction of human conditional fear remains largely undetermined. The present study used fMRI to examine brain activity during acquisition and extinction of fear conditioning. During the acquisition phase, participants were either exposed to light (CS) presentations that signaled a brief electrical stimulation (paired group) or received light presentations that did not serve as a warning signal (control group). During the extinction phase, half of the paired group subjects continued to receive the same treatment, whereas the remainder received light alone. Control subjects also received light alone during the extinction phase. Changes in metabolic activity within the amygdala and hippocampus support the involvement of these regions in each of the procedural phases of fear conditioning. Hippocampal activity developed during acquisition of the fear response. Amygdala activity increased whenever experimental contingencies were altered, suggesting that this region is involved in processing changes in environmental relationships. The present data show learning-related amygdala and hippocampal activity during human Pavlovian fear conditioning and suggest that the amygdala is particularly important for forming new associations as relationships between stimuli change.

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↗