Biomedical subjects

J K Zubieta

Publications and source records attributed to J K Zubieta.

At least 19 recordsLinked to original sources

PubMed2001

Regional mu opioid receptor regulation of sensory and affective dimensions of pain.

The endogenous opioid system is involved in stress responses, in the regulation of the experience of pain, and in the action of analgesic opiate drugs. We examined the function of the opioid system and mu-opioid receptors in the brains of healthy human subjects undergoing sustained pain. Sustained pain induced the regional release of endogenous opioids interacting with mu-opioid receptors in a number of cortical and subcortical brain regions. The activation of the mu-opioid receptor system was associated with reductions in the sensory and affective ratings of the pain experience, with distinct neuroanatomical involvements. These data demonstrate the central role of the mu-opioid receptors and their endogenous ligands in the regulation of sensory and affective components of the pain experience.

Adult↗

PubMed2001

Cognitive function in euthymic bipolar I disorder.

Recent reports have suggested the presence of persistent cognitive impairments in patients diagnosed with Bipolar Disorder even after prolonged euthymic phases. In this work, various domains of cognitive function were examined in asymptomatic patients diagnosed with Bipolar I Disorder (BDI) in comparison with healthy subjects. Fifteen otherwise healthy BDI patients with a prior history of psychosis during mania completed a neuropsychological testing battery after a prolonged asymptomatic remission. Their scores were compared to those of individually matched healthy subjects with unpaired two-tailed t-tests at P<0.01. Relationships between cognitive performance measures and clinical variables related to illness severity were also examined with Pearson correlations, P<0.05. We detected poorer performance on measures of verbal learning, executive functioning and motor coordination in BDI patients compared to control volunteers. Scores on tests of executive functioning were negatively correlated with the number of episodes of mania and depression. Social and occupational scores were also associated with a poorer performance on measures of verbal learning and executive function. Euthymic BDI patients, therefore, demonstrate reductions in specific cognitive domains even after prolonged asymptomatic phases. Some of these deficits appear to be associated with a more severe course of illness and poorer social and occupational functioning.

Adult↗

PubMed2001

Assessment of muscarinic receptor concentrations in aging and Alzheimer disease with [11C]NMPB and PET.

Cerebral cholinergic deficits have been described in Alzheimer disease (AD) and as a result of normal aging. At the present time, there are very limited options for the quantification of cholinergic receptors with in vivo imaging techniques such as PET. In the present study, we examined the feasibility of utilizing [11C]N-methyl-4-piperidyl benzilate (NMPB), a nonselective muscarinic receptor ligand, in the study of aging and neurodegenerative processes associated with cholinergic dysfunction. Based on prior data describing the accuracy of various kinetic methods, we examined the concentration of muscarinic receptors with [11C]NMPB and PET using two- and three-compartment kinetic models. Eighteen healthy subjects and six patients diagnosed with probable AD were studied. Pixel-by-pixel two-compartment model fits showed acceptable precision in the study of normal aging, with comparable results to those obtained with a more complex and less precise three-compartment model. Normal aging was associated with a reduction in muscarinic receptor binding in neocortical regions and thalamus. In AD patients, the three-compartment model appeared capable of dissociating changes in tracer transport from changes in receptor binding, but suffered from statistical uncertainty, requiring normalization to a reference region, and therefore limiting its potential use in the study of neurodegenerative processes. After normalization, no regional changes in muscarinic receptor concentrations were observed in AD.

Adult↗

PubMed2001

Vesicular monoamine transporter concentrations in bipolar disorder type I, schizophrenia, and healthy subjects.

BACKGROUND: Previous analyses of vesicular monoamine transporter (VMAT2) binding in euthymic bipolar disorder type I (BDI) patients have shown increases of this presynaptic marker in the thalamus and ventral midbrain. To assess the diagnostic specificity of those findings, we compared VMAT2 concentrations between euthymic BDI patients, patients diagnosed with schizophrenia (SCH), and age-matched healthy volunteers. METHODS: Binding sites for VMAT2 were quantified with (+)-alpha-[11C]DTBZ (dihydrotetrabenazine) and positron emission tomography. Fifteen euthymic BDI and 12 SCH patients and 15 group-matched healthy controls were studied. [11C]DTBZ tracer transport and binding potentials were examined in the thalamus and ventral midbrain with factorial analyses of variance and post hoc Tukey's honestly significantly different tests. RESULTS: Analysis of variance detected diagnosis effects in binding potentials in both brain regions. Binding of VMAT2 in the thalamus was higher in BDI patients than in control subjects and SCH patients. Conversely, ventral brainstem binding was nearly identical between BDI and SCH patients and were higher than in the control group. CONCLUSIONS: The patterns of regional VMAT2 expression, and by extension, the concentration of monoaminergic synaptic terminals, differ between BDI, SCH, and a control group. These findings may relate to both similarities and differences in the presentation or clinical course of these syndromes and require further examination.

Adult↗

PubMed2001

Neuroimaging of aging and estrogen effects on central nervous system physiology.

OBJECTIVE: To review the literature on neuroimaging studies focusing on gender differences in the aging process and on the effects of postmenopausal estrogen use on the brain. DESIGN: Pertinent studies were identified through a computer MEDLINE search. References of selected articles were hand-searched for additional citations. CONCLUSION(S): The current literature suggests that estrogen replacement may decrease brain white matter lesions, increase cerebral blood flow, alter regional brain activation patterns during cognitive processing, and have modulatory effects on various neurotransmitter systems. Overall, this points to a functional plasticity in higher order brain processing that can be altered by gonadal steroids.

Aging↗

PubMed2001

Long-term estrogen replacement is associated with improved nonverbal memory and attentional measures in postmenopausal women.

OBJECTIVE: To determine the cognitive domains improved or preserved by long-term hormone replacement therapy (HRT). DESIGN: A comprehensive neuropsychological test battery was administered to healthy postmenopausal women who had been treated or not treated with long-term HRT without interruption since menopause. SETTING: Women were recruited by advertisement from a university town and surrounding areas. PATIENT(S): Women 60 years or older were studied who were treated (n = 16) or not treated (n = 13) with HRT. INTERVENTION(S): Neuropsychological testing included tests of memory, verbal fluency, executive functions, attention and concentration, and psychomotor function. Tests of intellectual function, depressive symptoms, and emotional functioning assessed general functions and comparability of the groups. MAIN OUTCOME MEASURE(S): Neuropsychological testing scores were compared between groups. RESULT(S): No statistically significant differences between the groups were found for general demographic, intellectual, and psychological measures. Scores from both the Weschler Memory Scale Visual Reproduction (delayed recall) and the Digit Vigilance Test (attention) showed statistically significant better performance and fewer errors in the group of women on HRT. CONCLUSION(S): Long-term postmenopausal HRT is associated with higher scores in tests of nonverbal memory and attention.

Aged↗

PubMed2001

Effects of long-term hormone therapy on cholinergic synaptic concentrations in healthy postmenopausal women.

Experimental evidence suggests that gonadal steroids regulate brain neurochemical systems associated with cognitive function, such as the cholinergic system. This study examines the effect of long-term postmenopausal hormone therapy on the brain concentrations of cholinergic synaptic terminals in women using single photon emission computed tomography and the radiotracer [(123)I]iodobenzovesamicol ([(123)I]IBVM). [(123)I]IBVM labels the vesicular acetylcholine transporter (VAChT) located in the presynaptic terminals of these neurons. Sixteen healthy women treated with hormone therapy since the menopause and 12 women not treated with hormones were studied. There were no significant differences in regional IBVM binding indexes between the 2 groups. The length of hormone replacement therapy correlated positively with VAChT binding indexes in multiple cortical areas (P < 0.05): frontal cortex (Spearman rank correlation: rho = 0.79), parietal cortex (rho = 0.62), temporal cortex (rho = 0.80), anterior cingulate (rho = 0.71), and posterior cingulate (rho = 0.63), but not in the basal ganglia (rho = 0.35; P = 0.2). An earlier onset of menopause in hormone-treated women was associated with higher VAChT indexes in the anterior cingulate (rho = -0.56; P = 0.02) and posterior cingulate (rho = -0.63; P = 0.01). The opposite was found in the posterior cingulate of women not treated with hormones (rho = 0.58; P = 0.04). Women treated with estrogen alone also showed higher VAChT indexes than women treated with estrogen and progestin in the posterior cingulate cortex (by Mann-Whitney U test: z = 2.42; P = 0.015). Although an overall effect of postmenopausal hormone therapy was not found, associations between an index of cortical cholinergic terminal concentrations and the length of hormonal replacement suggest that hormone therapy may influence the survival or plasticity of these cells in postmenopausal women. The data also suggest possible differential effects of estrogen and estrogen with progestin treatments in brain areas critical for cognitive processing.

Aged↗

PubMed2000

Nicotine effects on regional cerebral blood flow in awake, resting tobacco smokers.

The hypothesis for this research was that regional cerebral blood flow (rCBF) would increase following nasal nicotine administration to overnight abstinent tobacco smokers in relationship to the known brain distribution of nicotinic cholinergic receptors (nAChRs). Nine male and nine female healthy adult smokers were studied. They abstained overnight from tobacco products for 10 or more hours prior to study the next morning. Nicotine nasal spray was given in doses of 1-2.5 mg total with half in each nostril while the subject was awake and resting in a supine position. Oleoresin of pepper solution in a similar volume was used as an active placebo to control for the irritating effects of nicotine. Both substances were given single blind to the subjects. Positron emission tomography (PET) with H(2)(15)O was used to measure rCBF. The data from each subject volunteer were normalized to global activity to better assess regional brain changes. Both nasal nicotine and pepper spray produced similar increases in CBF in somesthetic area II, consistent with the irritant effects of both substances. The mean rCBF effects of nasal pepper were subtracted from those of nasal nicotine to determine the actions of nicotine alone. The latter produced increases in rCBF in the thalamus, pons, Brodman area 17 of the visual cortex, and cerebellum. Some brain areas that contain a large number of nAChRs, such as the thalamus, showed an increase in CBF. Other areas that have few nAChRs, such as the cerebellum, also showed an increase in relative CBF. The hippocampal/parahippocampal areas showed greater regional decreases (left) and lesser increases (right) in CBF that correlated with the increase in plasma arterial nicotine concentrations. The results obtained indicate complex primary and secondary effects of nicotine in which only some regional brain CBF changes correlate with the known distribution of nAChR. No gender differences were noted.

Administration, Intranasal↗

PubMed2000

In vivo measurement of the vesicular monoamine transporter in schizophrenia.

Given evidence for excessive striatal dopamine activity in schizophrenia, we sought to test the hypothesis that dopaminergic innervation in the striatum is abnormally elevated, and a secondary hypothesis that age-related loss is accelerated. Twelve schizophrenic subjects on stable doses of medications, along with 12 age and sex-matched healthy control subjects, underwent positron emission tomography (PET) studies with [11C]dihydrotetrabenazine (DTBZ), which binds to the vesicular monoamine transporter, type 2 (VMAT2). DTBZ binding reflects principally dopaminergic projections in the striatum and appears in animal models, over treatment periods as long as two weeks, not to be regulated by antipsychotic drugs. Using an equilibrium analysis, we obtained measurements of the binding potential (BP) of [11C]DTBZ, as well as a transport (K(1)) measure, corresponding to regional cerebral blood flow. BP in the striatum showed no difference between the patient and control groups, and no differential effect of age. We did not find evidence supporting the hypothesis that excessive dopamine activity in schizophrenia could be explained by increased density of striatal dopamine terminals.

Adolescent↗

PubMed2000

High vesicular monoamine transporter binding in asymptomatic bipolar I disorder: sex differences and cognitive correlates.

OBJECTIVE: It has been hypothesized that anomalies in monoaminergic function underlie some of the manifestations of bipolar disorder. In this study the authors examined the possibility that trait-related abnormalities in the concentration of monoaminergic synaptic terminals may be present in patients with asymptomatic bipolar disorder type I. METHOD: The concentration of a stable presynaptic marker, the vesicular monoamine transporter protein (VMAT2), was quantified with (+)[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography. Sixteen asymptomatic patients with bipolar I disorder who had a prior history of mania with psychosis (nine men and seven women) and individually matched healthy subjects were studied. Correlational analyses were conducted to examine the relationship between regional VMAT2 binding, cognitive function, and clinical variables. RESULTS: VMAT2 binding in the thalamus and ventral brainstem of the bipolar patients was higher than that in the comparison subjects. VMAT2 concentrations in these regions correlated with performance on measures of frontal, executive function. In addition, sex differences in VMAT2 binding were detected in the thalamus of the bipolar patients; the male patients had higher binding than the women. No sex differences in binding were observed in the healthy comparison group. CONCLUSIONS: These initial results suggest that higher than normal VMAT2 expression and, by extension, concentration of monoaminergic synaptic terminals, may represent a trait-related abnormality in patients with bipolar I disorder and that male and female patients show different patterns. Also, VMAT2 concentrations may be associated with some of the cognitive deficits encountered in euthymic bipolar disorder.

Adult↗

PubMed1999

Arterial/venous plasma nicotine concentrations following nicotine nasal spray.

BACKGROUND AND OBJECTIVES: Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine. SUBJECTS AND METHODS: Nine male and nine female healthy adult smokers were studied. They all abstained from use of tobacco overnight for 10 h or more prior to the study. Nicotine nasal spray was given in doses of 1-2.5 mg total, with half in each nostril while the subject was supine. Both A and V blood samples were obtained prior to and 3, 6, 10, 15, 20, and 30 min post-nasal nicotine spray. RESULTS AND CONCLUSIONS: Nasal nicotine administration produced greater A than V plasma levels. There were no gender differences in A/V nicotine concentrations, disproving the above hypothesis, suggesting that other physiochemical factors besides skeletal muscle mass must be involved. Heart rate increases correlated well with arterial plasma nicotine levels (r = 0.77). Males had less variance than females in the expected increase in arterial plasma nicotine concentrations with increased number of nasal sprays. Although there was considerable overlap, mean A cotinine concentrations were consistently slightly larger than V concentrations.

Administration, Intranasal↗

PubMed1999

Quantification of delta-opioid receptors in human brain with N1'-([11C]methyl) naltrindole and positron emission tomography.

The regional binding of N1'-([11C]methyl)naltrindole (MeNTI), a selective delta-opioid antagonist, was studied in healthy human subjects with positron emission tomography (PET). After the bolus intravenous administration of high specific activity [11C]MeNTI, PET was performed over 90 minutes. Arterial plasma samples were obtained during the scanning period and assayed for the presence of radiolabeled metabolites. The data were analyzed with various kinetic (two- and three-compartment models, Patlak graphical analysis) and nonkinetic (apparent volume of distribution and activity at a late scanning time) approaches. This tracer showed irreversible binding characteristics during the scanning period used. The results of the analyses also were compared with the density and distribution of delta-opioid receptors in the human brain in vitro. Additionally, computer simulations were performed to assess the effects of changes in receptor binding and tracer transport changes on the perceived binding parameters obtained with the models. A constrained three-compartment kinetic model was demonstrated to be superior to other quantification models for the description of MeNTI kinetics and quantification of delta receptor binding in the human brain with 11C-labeled MeNTI.

Adult↗

PubMed1999

Gender and age influences on human brain mu-opioid receptor binding measured by PET.

OBJECTIVE: Both age and gender are being increasingly recognized as important factors influencing CNS structure and function. However, there are relatively few data on actual neurochemical differences between the sexes in human subjects or on their interaction with age. One of the central neurotransmitter systems for which sex differences have been suggested by animal models and clinical human data is the opioid. In this study the authors examined age- and gender-associated variations in mu-opioid receptor binding with positron emission tomography (PET). METHOD: Healthy human subjects were studied with PET and the radiotracer [11C]carfentanil, a selective mu-opioid agonist. Two separate subject groups were examined: one group of 24 men and 12 women was studied in a retrospective analysis of data, and a second group of 12 men and 18 women was recruited prospectively and studied with a higher-resolution scanner. RESULTS: Mu-opioid receptor binding potential (Bmax/Kd) was found to increase with age in neocortical areas and the putamen. Sex differences, with higher mu-opioid binding in women, were observed in a number of cortical and subcortical areas. Gender-by-age interactions were observed in the thalamus and the amygdala; in vivo mu-opioid binding declined in postmenopausal women to levels below those of men. CONCLUSIONS: These data imply that both age and gender are important variables to consider in the interpretation of investigations of human function in which the opioid system plays a role. Also, women's reproductive status (reproductive age versus postmenopausal) may influence the function of CNS opioid systems.

Adult↗

PubMed1998

Quantification of muscarinic cholinergic receptors with [11C]NMPB and positron emission tomography: method development and differentiation of tracer delivery from receptor binding.

Quantification of human brain muscarinic cholinergic receptors was investigated with the use of [11C]N-methyl-4-piperidyl benzylate (NMPB) and positron emission tomography (PET). Whole-brain uptake of NMPB at 90 to 110 minutes after intravenous injection was approximately 10% of the administered dose. The initial cerebral distribution of NMPB corresponded to the pattern of cerebral perfusion; however, at progressively longer postinjection intervals, regional distinctions consistent with muscarinic receptor binding were evident: activity at 90 to 110 minutes postinjection was highest in the striatum and cerebral cortex, intermediate in the thalamus and pons, and lowest in the cerebellum. After the development of a chromatographic system for isolation of authentic [11C]NMPB in plasma, tracer kinetic modeling was used to estimate receptor binding from the cerebral and arterial plasma tracer time-courses. Ligand transport rate and receptor-binding estimates were obtained with the use of compartmental models and analytical methods of varying complexity, including a two-parameter pixel-by-pixel-weighted integral approach and regional least-squares curve-fitting analyses employing both two- and three-compartment model configurations. In test-retest experiments, precision of the methods and their abilities to distinguish altered ligand delivery from binding in occipital cortex during an audiovisual presentation were evaluated. Visual stimulation increased the occipital blood-to-brain NMPB transport rate by 25% to 46% in estimates arising from the various approaches. Weighted integral analyses resulted in lowest apparent transport changes and in a concomitant trend toward apparent binding increases during visual activation. The regional least-squares procedures were superior to the pixel-by-pixel method in isolating the effects of altered tracer delivery from receptor-binding estimates, indicating larger transport effects and unaltered binding. Precision was best (less than 10% test-retest differences) for the weighted integral analyses and was somewhat lower in the least-squares analyses (10-25% differences). The authors conclude that pixel-by-pixel-weighted integral analyses of NMPB distribution introduce transport biases into receptor-binding estimates. Similar confounding effects also are predicted in noncompartmental analyses of delayed radiotracer distribution. The use of regional nonlinear least-squares fitting to two- and three-compartment models, although more labor intensive, provides accurate distinction of receptor-binding estimates from tracer delivery with acceptable precision in both intra- and intersubject comparisons.

Adult↗

PubMed1998

Brain opioid receptor measurements by positron emission tomography in normal cycling women: relationship to luteinizing hormone pulsatility and gonadal steroid hormones.

The regulation of central mu-opioid receptors in women during the menstrual cycle was explored with positron emission tomography and the selective radiotracer [11C]carfentanil. Ten healthy women were studied twice, during their follicular and luteal phases. Plasma concentrations of estradiol, progesterone, testosterone, and beta-endorphin were determined immediately before scanning. LH pulsatility was measured over the 9 h preceding each of the two positron emission tomography scans. No significant differences in the binding potential of mu-opioid receptors (binding capacity/Kd) were observed between phases of the menstrual cycle. However, significant negative correlations were observed between circulating levels of estradiol during the follicular phase and mu-receptor binding measures in the amygdala and hypothalamus, two regions thought to be involved in the regulation of GnRH pulsatility. LH pulse amplitude was positively correlated with mu binding in the amygdala, whereas LH pulse number was negatively correlated with binding in this same region. No significant associations were noted between LH pulse measures and the hypothalamus for this sample. These results suggest that amygdalar mu-opioid receptors exert a modulatory effect on GnRH pulsatility, and that circulating levels of estradiol also regulate central mu-opioid function.

Adult↗

PubMed1997

Imaging of delta- and mu-opioid receptors in temporal lobe epilepsy by positron emission tomography.

The involvement of opioid neurotransmitter systems in seizure mechanisms is well documented. In previous positron emission tomography (PET) studies in patients with unilateral temporal lobe epilepsy, we have found evidence for differential regulation of the opioid-receptor subtypes. The present study extends our previous observations to delta-opioid receptors by using the delta-receptor-selective antagonist [11C]methylnaltrindole ([11C]MeNTI). Paired measurements of delta- and mu-opioid receptor binding and metabolic activity were performed with PET using [11C]MeNTI and [11C]carfentanil ([11C]CFN) and [18F]fluorodeoxyglucose ([18F]FDG), respectively. Binding of [11C]MeNTI and [11C]CFN increased and [18F]FDG uptake decreased in the temporal cortex (TC) ipsilateral to the focus. Decreases in [18F]FDG uptake were more widespread regionally than were increases in opioid receptors. Increases in the delta- and mu-receptor binding showed different regional patterns. Increases in mu-receptor binding were confined to the middle aspect of the inferior TC, whereas binding of delta receptors increased in the mid-inferior TC and anterior aspect of the middle and superior TC. The increase in delta receptors suggests their anticonvulsant action, as previously shown for the delta-receptor subtype, whereas the different regional pattern of receptor alterations suggest the distinct roles of different opioid-receptor subtypes in seizure phenomena.

Adult↗

PubMed1996

Increased mu opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine craving.

The endogenous opioid system has been recently implicated in the reinforcing actions of cocaine and other addictive drugs. In this study we examined mu opioid receptor binding in ten cocaine-dependent men and seven nonaddicted controls using positron emission tomography and [11C] carfentanil. Mu opioid binding was increased in several brain regions of the cocaine addicts studied 1-4 days after their last use of cocaine. Binding was positively correlated with the severity of cocaine craving experienced at the time. The upregulation of mu opioid receptor binding persisted after 4 weeks of monitored cocaine abstinence. These findings demonstrate for the first time the involvement of the endogenous opioid system in cocaine dependence and cocaine craving in living human subjects.

Adult↗

PubMed1996

MR-based correction of brain PET measurements for heterogeneous gray matter radioactivity distribution.

Partial volume and mixed tissue sampling errors can cause significant inaccuracy in quantitative positron emission tomographic (PET) measurements. We previously described a method of correcting PET data for the effects of partial volume averaging on gray matter (GM) quantitation; however, this method may incompletely correct GM structures when local tissue concentrations are highly heterogeneous. We have extended this three-compartment algorithm to include a fourth compartment: a GM volume of interest (VOI) that can be delineated on magnetic resonance (MR) imaging. Computer simulations of PET images created from human MR data demonstrated errors of up to 120% in assigned activity values in small brain structures in uncorrected data. Four-compartment correction achieved full recovery of a wide range of coded activity in GM VOIs such as the amygdala, caudate, and thalamus. Further validation was performed in an agarose brain phantom in actual PET acquisitions. Implementation of this partial volume correction approach in [18F]fluorodeoxyglucose and [11C]-carfentanil PET data acquired in a healthy elderly human subject was also performed. This newly developed MR-based partial volume correction algorithm permits the accurate determination of the true radioactivity concentration in specific structures that can be defined by MR by accounting for the influence of heterogeneity of GM radioactivity.

Aged↗