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Biomedical subjects

N M Alpert

Publications and source records attributed to N M Alpert.

At least 73 records · Page 4Linked to original sources
PubMed1996

A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery.

BACKGROUND: Previous studies have used symptom provocation and positron emission tomography to delineate the brain systems that mediate various anxiety states. Using an analogous approach, the goal of this study was to measure regional cerebral blood flow changes associated with posttraumatic stress disorder (PTSD) symptoms. METHODS: Eight patients with PTSD, screened as physiologically responsive to a script-driven imagery symptom provocation paradigm, were exposed sequentially to audiotaped traumatic and neutral scripts in conjunction with positron emission tomography. Heart rate and subjective measures of emotional state were obtained for each condition. Statistical mapping techniques were used to determine locations of significant brain activation. RESULTS: Increases in normalized blood flow were found for the traumatic as compared with control conditions in right-sided limbic, paralimbic, and visual areas; decreases were found in left inferior frontal and middle temporal cortex. CONCLUSIONS: The results suggest that emotions associated with the PTSD symptomatic state are mediated by the limbic and paralimbic systems within the right hemisphere. Activation of visual cortex may correspond to the visual component of PTSD reexperiencing phenomena.

Adult↗
PubMed1996

Quantification of dopamine transporter density in monkeys by dynamic PET imaging of multiple injections of 11C-CFT.

Idiopathic Parkinson's disease (PD) is characterized by loss of dopaminergic terminals in the basal ganglia. The cocaine analog, CFT (WIN 35,428), has been shown to bind selectively to the pre-synaptic dopamine transporters and thus represents an important probe for monitoring disease progression. In this study, we evaluated [11C] labeled CFT as a PET ligand for the quantitative in vivo assay of dopamine transporter density in three normal rhesus monkeys (Macaca mulatta). One of the animals was studied after treatment with the neurotoxin, MPTP. Simulation studies demonstrated that a three injection protocol is necessary for quantitation of dopamine transporter density. The protocol consists of an initial high specific activity injection, a low specific activity "displacement dose" at 30 min, and a final high specific activity injection at approximately 90 min. Dynamic PET imaging and arterial blood sampling were started immediately before the first injection and continued for 2 h. Blood data were corrected for [11C] labeled CFT metabolites. Compartmental models describing the dynamics of labeled and the unlabeled ligand explicitly were fitted to the PET and metabolite corrected blood data. Prior to MPTP treatment, modeling of the striatal data required a saturable receptor term and yielded mean estimates of: B'max = 113 pmol/g and KD = 33 nm (n = 3). These values for B'max are in reasonable agreement with published values for [3H] CFT binding in vitro. After multiple treatments with MPTP (0.6 mg/kg x 3), B'max in one of the animals was reduced from 122 to 10.2 pmol/g. KD was relatively unaffected by MPTP treatment. These data provide additional basis for the use of [11C] CFT in monitoring the progression of Parkinson's disease and other conditions that are associated with the loss of dopaminergic nerve terminals.

Animals↗
PubMed1996

Functional imaging of human right hemispheric activation for exploratory movements.

We employed positron emission tomography to examine the functional anatomy of the exploratory-motor aspect of spatial attention. Subjects moved their right hand under nonexploratory (control) versus exploratory (active) conditions. Movement architecture and eye movements were matched across conditions. Statistical parametric maps of the exploratory (active) minus nonexploratory (control) tasks in subjects using their right hand in the right hemispace demonstrated activation in right cingulate, premotor and posterior parietal areas. The net activation of multiple right hemisphere cortical areas ipsilateral to the active limb and hemispace strongly supports the predicted, distributed network anatomy and is consistent with possible right hemispheric dominance for exploratory attentional movements.

Adult↗
PubMed1996

Improved methods for image registration.

We report a system for PET-MRI registration that is improved or optimized in several areas: (1) Automatic scalp/brain segmentation replaces manual drawing operations, (2) a new fast and accurate method of image registration, (3) visual assessment of registration quality is enhanced by composite imaging methods (i.e., fusion) and (4) the entire procedure is embedded in a commercially available scientific visualization package, thereby providing a consistent graphical user interface. The segmentation algorithm was tested on 17 MRI data sets and was successful in all cases. Accuracy of image registration was equal to that of the Woods algorithm, but 10 times faster for PET-PET and 4 times faster for PET-MRI. The image fusion method allows detection of misalignments on the order of 2-3 mm. These results demonstrate an integrated system for intermodality image registration, which is important because the procedure can be performed by technicians with no anatomic knowledge and reduces the required time from hours to about 15 min on a modern computer workstation.

Algorithms↗
PubMed1996

Encoding words and pictures: a positron emission tomography study.

Subjects viewed words, pictures, crosshairs, or a large X flanked by two smaller xs on either side while their brain activity was monitored using positron emission tomography (PET). When activation from the pictures, crosshairs, or Xs condition was subtracted from activation in the words condition, the left angular gyrus and Broca's area were found to be activated. In the comparison of words and pictures, additional language areas were activated. These results provide support for the classical neurological model of reading. The results also suggest that a "word form area" is near the margin of the left angular gyrus.

Adolescent↗
PubMed1996

Comparison of two compartmental models for describing receptor ligand kinetics and receptor availability in multiple injection PET studies.

The goal of research with receptor ligands and PET is the characterization of an in vivo system that measures rates of association and dissociation of a ligand-receptor complex and the density of available binding sites. It has been suggested that multiple injection studies of radioactive ligand are more likely to identify model parameters than are single injection studies. Typically, at least one of the late injections is at a low specific activity (SA), so that part of the positron emission tomography (PET) curve reflects ligand dissociation. Low SA injections and the attendant reductions in receptor availability, however, may violate tracer kinetic assumptions, namely, tracer may no longer be in steady state with the total (labeled and unlabeled) ligand. Tissue response becomes critically dependent on the dose of total ligand, and an accurate description of the cold ligand in the tissue is needed to properly model the system. Two alternative models have been applied to the receptor modeling problem, which reduces to describing the time-varying number of available receptor sites. The first (Huang et al., 1989) contains only compartments for the hot ligand, 'hot only' (HO), but indirectly accounts for the action of cold ligand at receptor sites via SA. The second stipulates separate compartments for the hot and cold ligands, 'hot and cold' (HC), thus explicitly calculating available number of receptors. We examined these models and contrasted their abilities to predict PET activity, receptor availability, and SA in each tissue compartment. For multiple injection studies, the models consistently predicted different PET activities--especially following the third injection. Only for very high rate constants were the models identical for multiple injections. In one case, simulated PET curves were quite similar, but discrepancies appeared in predictions of receptor availability. The HO model predicted nonphysiological changes in the availability of receptor sites and introduced errors of 30-60% into estimates of B'max for test data. We, therefore, strongly recommend the use of the HC model for all analyses of multiple injection PET studies.

Animals↗
PubMed1996

Pharmacokinetics of [18F]fleroxacin in patients with acute exacerbations of chronic bronchitis and complicated urinary tract infection studied by positron emission tomography.

The pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, were measured by positron emission tomography (PET) with [18F]fleroxacin in five patients with acute bacterial exacerbations of chronic bronchitis and in five patients with symptomatic, complicated urinary tract infection. Two studies were performed with each patient, one within 24 h of the initiation and one within 24 h of the completion of a 7-day course of fleroxacin, 400 mg/day. For each study, the patient received an infusion of that day's therapeutic dose of fleroxacin (400 mg) supplemented with approximately 740 MBq of [18F]fleroxacin, and serial PET images and blood samples were collected for 6 to 8 h starting at the initiation of the infusion. Between studies, the drug was administered orally. In all infected tissues, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. In kidneys, accumulation was greater in the presence of active infection (P < 0.01), while in lungs, accumulation was lower (P < 0.02). Infection of the lung or urinary tract had no effect on drug delivery to uninvolved tissues. Also, there was no difference between the results obtained at the beginning and the end of therapy. Overall, peak concentrations of drug many times the MIC at which 90% of the infecting organisms are inhibited (MIC90) were achieved in the kidneys (> 30 micrograms/g), prostate glands (> 11 micrograms/g), and lungs (> 14 micrograms/g). Plateau concentrations (2 to 8 h; given as mean micrograms per gram +/- standard error of the mean) of drug in kidneys (15.11 +/- 0.55), prostate glands (5.08 +/- 0.19), and lungs (5.75 +/- 0.22) were also well above the MIC90 for most relevant pathogens. All patients had a good therapeutic response to fleroxacin.

Acute Disease↗
PubMed1996

Simplified measurement of deoxyglucose utilization rate.

UNLABELLED: The reliability of the dose uptake ratio (DUR), a widely used index of 18F-fluoro-2-deoxy-D-glucose (18FDG) metabolism in a variety of tumors, depends on the overall rate of removal of 18FDG from the circulation. Correcting for this factor is important if DUR is to be used quantitatively for pre- and post-treatment assessments of tumors. METHODS: We developed a simplified kinetic method (SKM), based on measured blood curves from a control group, which requires one venous blood sample. We compared the simplified method to the conventional kinetic method and the widely used DUR index in 13 patients with grade 3 or 4 non-small-cell lung carcinoma. Studies were obtained before and after treatment. In all patients, dynamic PET imaging and blood activity measurement was performed for 80 min. The utilization rate of 18FDG (MRDGlc) was calculated by using a three-compartment model and correlated with a 55-min measurement of DUR and with the simplified kinetic method. RESULTS: Coefficients of determination (R2) between MRDGlc and DUR before and after treatment were 0.53 and 0.71, respectively. Using the SKM, these values improved significantly (p < 0.0001) to 0.96 and 0.94, respectively. The pooled pre- and post-treatment coefficient of determination for DUR versus MRDGlc was 0.81; for SKM, it improved significantly (p < 0.001) to 0.98. CONCLUSION: These results indicate that the observed tumor tissue uptake of 18FDG, corrected for blood 18FDG activity and glucose concentration, can reliably predict glucose metabolic rate from a single static image acquired at between 45 min and 1 hr after injection. This has substantial implications for the quantitative use of 18FDG PET to diagnose and manage malignancy.

Blood Glucose↗
PubMed1996

Evaluation of cerebral pharmacokinetics of the novel antidepressant drug, BMS-181101, by positron emission tomography.

BMS-181101 is a novel antidepressant drug that is currently under clinical investigation. The goal of this study was to evaluate the pharmacokinetics and receptor binding of this agent in the brains of healthy human volunteers. BMS-181101 was radiolabeled with 11C by methylation with [11C]CH3I of the 5-hydroxypiperazine precursor and the product was purified by high-performance liquid chromatography. Cerebral pharmacokinetics of [11C]BMS-181101 were studied by dynamic positron emission tomography imaging in six healthy volunteers. Two studies were performed in each subject. For the first study the subject was injected with 10 mCl of high specific activity [11C]BMS-181101 (approximately 1700 mCi/mumol) and serial positron emission tomography images and arterial blood samples were collected over 90 min. Thirty minutes after acquiring the final image, each subject was coinjected with a second dose, 10 mCi of [11C]BMS-181101 plus 3 mg of unlabeled drug (final specific activity approximately 1.5 mCi/mumol), and imaging/blood collection was repeated. The data were analyzed by calculating regional tracer accumulation (percent injected dose/g) at 60 min after injection and compartmental modeling. Measurements of percent injected dose/g yielded similar values for all brain regions, independent of specific activity. Kinetic modeling of time activity curves for cerebellum, caudate, putamen, thalamus, pons and temporal, occipital and frontal cortex demonstrated that tissue distribution can be described by a simple two-compartment flow model. Statistical comparisons of the apparent distribution volumes for each region failed to reveal significant differences between the high and low specific activity studies. These results indicate that the central nervous system distribution of [11C]BMS-181101 is dominated by blood flow and significant receptor-specific localization does not occur in any brain region.

Adult↗
PubMed1996

Positron emission tomographic analysis of central 5-hydroxytryptamine2 receptor occupancy in healthy volunteers treated with the novel antipsychotic agent, ziprasidone.

Ziprasidone is a novel antipsychotic agent, with high affinity for dopamine D2 and serotonin (5-HT2) receptors in vitro and in animal models. The goal of this study was to determine the time course of 5-HT2 receptor occupancy (%RO) in healthy humans after a single p.o. dose. Positron emission tomography with the 5-HT2 ligand, [18F]setoperone, was performed in eight male volunteers, in the drug-naive, base-line (BL) state and 4 to 18 hr after ziprasidone (40 mg). Cerebral cortical binding potential [BP, maximum number of available receptors/KD or association rate for specific binding (k3)/dissociation rate for specific binding (k4)] was estimated using the cerebellum as reference. Transport rate from plasma to brain (K1), transport rate from brain to plasma (k2), association rate of nonspecific binding (k5) and dissociation rate of nonspecific binding (k6) were derived by fitting cerebellar time-activity curves to a three-compartment model. Fitting of cortical data to a 4-compartment model with K1/k2, k5 and k6, fixed at cerebellar values, was used to determine k3 and k4. %RO was calculated using the relation: %RO = [(BPBL-BPDRUG)/BPBL] x 100%. At BL, cortical parameter (mean +/- S.E.M) were: K1 = 0.121 +/- 0.0072 ml.min-1.g-1; k2 = 0.0581 +/- 0.004 min-1; k3 = 0.321 +/- 0.0026 min-1; k4 = 0.0957 +/- 0.0059 min-1; k5 = 0.0147 +/- 0.00066 min-1; and k6 = 0.0059 +/- 0.00042 min-1. Ziprasidone did not effect K1, k2, k5 or k6; however, k3 was reduced and k4 was elevated (P < .01). RO was nearly complete at 4 hr after dosing (98%) and remained elevated at 18 hr (46%). Plasma concentrations were well described by a biexponential function and decreased much more rapidly than RO. These results establish that ziprasidone has high potency for blocking 5-HT2 receptors in healthy humans; a potentially important characteristic of atypical antipsychotic agents.

Adult↗
PubMed1995

Topographical representations of mental images in primary visual cortex.

We report here the use of positron emission tomography (PET) to reveal that the primary visual cortex is activated when subjects close their eyes and visualize objects. The size of the image is systematically related to the location of maximal activity, which is as expected because the earliest visual areas are spatially organized. These results were only evident, however, when imagery conditions were compared to a non-imagery baseline in which the same auditory cues were presented (and hence the stimuli were controlled); when a resting baseline was used (and hence brain activation was uncontrolled), imagery activation was obscured because of activation in visual cortex during the baseline condition. These findings resolve a debate in the literature about whether imagery activates early visual cortex and indicate that visual mental imagery involves 'depictive' representations, not solely language-like descriptions. Moreover, the fact that stored visual information can affect processing in even the earliest visual areas suggests that knowledge can fundamentally bias what one sees.

Brain Mapping↗
PubMed1995

Brain mechanisms in human classical conditioning: a PET blood flow study.

Five healthy male subjects participated in a classical conditioning experiment, and positron emission tomography (PET) was used to compare regional cerebral blood flow before and after conditioning. The subjects participated in three different experimental phases. In the first (habituation) phase they listened to 24 repetitions of a tone with random intervals. In the second (acquisition) phase, the tone was paired with a brief shock to the wrist. In the third (extinction) phase, the tone was presented alone again. 15OPET scans were taken during the habituation and extinction phases. Because the habituation and extinction phases were similar, any difference in blood flow to the tones presented during extinction probably reflected conditioning that occurred during the acquisition phase. Statistical parametric mapping (SPM) analysis of the PET data showed significantly increased activation in the right hemisphere in the orbito-frontal cortex, dorsolateral prefrontal cortex, inferior and superior frontal cortices, and inferior and middle temporal corticies. The only activated areas in the left hemisphere were area 19 and the superior frontal cortex. The results are interpreted as evidence for the involvement of cortical areas in human classical conditioning.

Acoustic Stimulation↗
PubMed1995

Functional neuroanatomy of antisaccade eye movements investigated with positron emission tomography.

Increasing interest in the role of the frontal lobe in relation to psychiatric and neurologic disorders has popularized tests of frontal function. One of these is the antisaccade task, in which both frontal lobe patients and schizophrenics are impaired despite normal performance on (pro)saccadic tasks. We used position emission tomography to examine the cerebral blood flow changes associated with the performance of antisaccades in normal individuals. We found that the areas of the brain that were more active during antisaccades than saccades were highly consistent with the oculomotor circuit, including frontal eye fields (FEFs), supplementary motor area, thalamus, and putamen. Superior parietal lobe and primary visual cortex were also significantly more active. In contrast, prefrontal areas 46 and 9 were not more active during antisaccades than during saccades. Performance of some frontal patients on the antisaccade task has been likened to a bradykinesia, or the inability to initiate a willed movement. It is the necessity to will the movement and inhibit competing responses that intuitively linked this task to the dorsolateral prefrontal cortex in frontal patients. Our data suggest that it is the FEFs in prefrontal cortex that differentiate between conditions in which the required oculomotor response changes while the stimulus remains the same, rather than areas 46 and 9, which, in human studies, have been linked to the performance of complex cognitive tasks. Such a conclusion is consistent with single-unit studies of nonhuman primates that have found that the FEFs, the executive portion of the oculomotor circuit, can trigger, inhibit, and set the target of saccades.

Adult↗
PubMed1995

A positron emission tomographic study of simple phobic symptom provocation.

BACKGROUND: The goal of this study was to determine the mediating neuroanatomy of simple phobic symptoms. METHODS: Positron emission tomography and oxygen 15 were used to measure normalized regional cerebral blood flow in seven subjects with simple phobia during control and provoked states. Stereotactic transformation and statistical parametric mapping techniques were employed to determine the locations of significant activation. RESULTS: Statistical parametric maps demonstrated significant increases in normalized regional blood flow for the symptomatic state compared with the control state in the anterior cingulate cortex, the insular cortex, the anterior temporal cortex, the somatosensory cortex, the posterior medial orbitofrontal cortex, and the thalamus. CONCLUSIONS: The results suggest that anxiety associated with the simple phobic symptomatic state is mediated by paralimbic structures. Moreover, activation of somatosensory cortex may reflect tactile imagery as one component of the phobic symptomatic condition.

Adult↗
PubMed1995

Kinetic analysis of dynamic 13C NMR spectra: metabolic flux, regulation, and compartmentation in hearts.

Control of oxidative metabolism was studied using 13C NMR spectroscopy to detect rate-limiting steps in 13C labeling of glutamate. 13C NMR spectra were acquired every 1 or 2 min from isolated rabbit hearts perfused with either 2.5 mM [2-13C]acetate or 2.5 mM [2-13C]butyrate with or without KCl arrest. Tricarboxylic acid cycle flux (VTCA) and the exchange rate between alpha-ketoglutarate and glutamate (F1) were determined by least-square fitting of a kinetic model to NMR data. Rates were compared to measured kinetics of the cardiac glutamate-oxaloacetate transaminase (GOT). Despite similar oxygen use, hearts oxidizing butyrate instead of acetate showed delayed incorporation of 13C label into glutamate and lower VTCA, because of the influence of beta-oxidation: butyrate = 7.1 +/- 0.2 mumol/min/g dry wt; acetate = 10.1 +/- 0.2; butyrate + KCl = 1.8 +/- 0.1; acetate + KCl = 3.1 +/- 0.1 (mean +/- SD). F1 ranged from a low of 4.4 +/- 1.0 mumol/min/g (butyrate + KCl) to 9.3 +/- 0.6 (acetate), at least 20-fold slower than GOT flux, and proved to be rate limiting for isotope turnover in the glutamate pool. Therefore, dynamic 13C NMR observations were sensitive not only to TCA cycle flux but also to the interconversion between TCA cycle intermediates and glutamate.

Acetates↗
PubMed1994

Positron emission tomographic measurements of absolute regional myocardial blood flow permits identification of nonviable myocardium in patients with chronic myocardial infarction.

OBJECTIVES: This study tested the hypothesis that nonviable myocardium can be identified by quantitative measurements of regional myocardial blood flow obtained using positron emission tomography in conjunction with a mathematical model of nitrogen-13 (N-13) ammonia tracer kinetics. BACKGROUND: Under steady state basal conditions there is a minimal level of blood flow required to sustain myocardial viability. Therefore, the hypothesis predicts that regions with flow below a certain threshold are likely to be composed primarily of scar. METHODS: Studies were conducted in 26 patients with chronic myocardial infarction. Positron emission tomographic measurements of basal regional myocardial blood flow (N-13 ammonia) and fluorine-18 (F-18) fluorodeoxyglucose uptake were made and correlated with information about coronary anatomy and regional wall motion to assess myocardial viability. RESULTS: In patients with chronic myocardial infarction, normal zone blood flow (0.81 +/- 0.32 ml/min per g [mean +/- SD]) was greater (p < 0.02) than that of border zones (0.59 +/- 0.29 ml/min per g), which in turn exceeded (p < 0.001) that of infarct zone flow (0.27 +/- 0.17 ml/min per g). Good correlation was noted between relative F-18 fluorodeoxyglucose uptake and relative regional myocardial blood flow in all zones (r = 0.63, p < 0.001). Mismatch between blood flow and F-18 fluorodeoxyglucose uptake, with a single exception, was not observed in any segment with blood flow < 0.25 ml/min per g. All dyskinetic segments (n = 5) also had blood flow < 0.25 ml/min per g. In contrast, 43 of 45 myocardial segments (23 patients) with normal contraction or only mild hypokinesia had flow > or = 0.39 ml/min per g (average flow 0.78 +/- 0.35 ml/min per g). CONCLUSIONS: In patients with chronic myocardial infarction, myocardial viability is unlikely when basal regional myocardial blood flow is < 0.25 ml/min per g. Average basal flow in segments with normal or nearly normal wall motion is 0.78 +/- 0.35 ml/min per g. Thus, positron emission tomographic measurement of regional myocardial blood flow is helpful in identifying nonviable myocardium in these patients.

Adult↗
PubMed1994

Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography.

BACKGROUND: The study was designed to determine the mediating neuroanatomy of obsessive-compulsive disorder (OCD). METHODS: The short half-life tracer oxygen 15-labeled carbon dioxide was used to allow for repeated positron emission tomographic determinations of regional cerebral blood flow on each of eight patients with OCD during a resting and a provoked (symptomatic) state. RESULTS: Individually tailored provocative stimuli were successful in provoking OCD symptoms, in comparison with paired innocuous stimuli, as measured by self-report on OCD analogue scales (P = .002). Omnibus subtraction images demonstrated a statistically significant increase in relative regional cerebral blood flow during the OCD symptomatic state vs the resting state in right caudate nucleus (P < .006), left anterior cingulate cortex (P < .045), and bilateral orbitofrontal cortex (P < .008); increases in the left thalamus approached but did not reach statistical significance (P = .07). CONCLUSIONS: These findings are consistent with results of previous functional neuroimaging studies and contemporary neurocircuitry models of OCD. The data further implicate orbitofrontal cortex, caudate nucleus, and anterior cingulate cortex in the pathophysiology of OCD and in mediating OCD symptoms.

Adult↗