Jonathan M. Links

Neural Systems and Cue-Induced Cocaine Craving

We have extended our previous work investigating the neural correlates of cue-induced cocaine craving through the use of positron emission tomography with greater spatial resolution (<4.6 mm), an evocative script, and a pixel-by-pixel analysis. Craving and cerebral glucose metabolism were measured after presentation of cocaine-related or neutral cues to 11 cocaine abusers. Cocaine cues elicited a higher degree of craving than has been previously reported and resulted in left hemispheric activation of lateral amygdala, lateral orbitofrontal cortex, and rhinal cortex and right hemispheric activation of dorsolateral prefrontal cortex and cerebellum. The intensity of activation in these areas (except cerebellum), as well as left insula, was also correlated with craving. Deactivation occurred in left ventral pole and left medial prefrontal cortex. The results suggest that induction of drug craving involves a neural network that assigns incentive motivational value to environmental stimuli through the coactivation of brain regions that process information about memories and emotions.

Measurement of absolute left ventricular volume from gated blood pool studies

A new method for obtaining absolute left ventricular volume from gated blood pool studies was evaluated in a torso phantom and in 35 patients who also underwent single-plane contrast ventriculography. Gated 400 left anterior oblique and static anterior views were acquired. Left ventricular volume at end-diastole was given by the ratio of the attenuation-corrected end-diastolic count rate from the gated study to the count rate per milliliter from a blood sample. Attenuation correction was made by dividing the end-diastolic count rate by e ud, where u = the linear attenuation coefficient of water and d = the distance from the skin marker to the center of the left ventricle in the anterior view divided by sin 400 to yield the depth of left ventricle in the left anterior oblique view. In the phantom studies, the correlation between radionuclide and true volume was 0.99 (radionuclide = 1.03 true − 3 ml); the standard error of the estimate was 8 ml. In the patient studies, the radionuclide end-diastolic volume was used to calibrate the left ventricular time-activity curve, yielding left ventricular volume throughout the cardiac cycle. The correlation between radionuclide and angiographic enddiastolic volume was 0.95 (radionuclide = 0.97 angiographic + 3 ml); the standard error of the estimate was 36 ml. The correlation between radionuclide and angiographic end-systolic volume was 0.95 (radionuclide − 1.01 angiographic + I ml); the standard error of the estimate was 33 ml. This method permits direct determination of absolute left ventricular volume without assumptions about the shape of the ventricle or the necessity of using regression equations to convert volume “units” to true volume.

Increased Occupancy of Dopamine Receptors in Human Striatum during Cue-Elicited Cocaine Craving

In all, 19 research subjects, with current histories of frequent cocaine use, were exposed to cocaine-related cues to elicit drug craving. We measured the change of occupancy of dopamine at D2-like receptors with positron emission tomography (PET) and inferred a change of intrasynaptic dopamine (endogenous dopamine release), based on the displacement of radiotracer [11C]raclopride. Receptor occupancy by dopamine increased significantly in putamen of participants who reported cue-elicited craving compared to those who did not. Further, the intensity of craving was positively correlated with the increase in dopamine receptor occupancy in the putamen. These results provide direct evidence that occupancy of dopamine receptors in human dorsal striatum increased in proportion to subjective craving, presumably because of increased release of intrasynaptic dopamine.

Imaging opiate receptors in the human brain by positron tomography

Carfentanil is a potent, synthetic opiate that binds to mu opiate receptors with very high affinity (K1 = 0.051 n M, 37°). In rat brain, carfentanil is 90 and 250 times more selective for mu opiate receptors compared with delta and kappa opiate receptors, respectively. Carbon-11-carfentanil was synthesized by reacting [11C]methyliodide with the carboxylic acid precursor of carfentanil. Carbon-11-carfentanil was injected intravenously in man and a baboon and the distribution of the radioactivity in the brain was monitored using positron emission tomography. High concentrations of radioactivity were observed in the basal ganglia and thalamus, intermediate concentrations in the frontal and parietal cerebral cortex, and low concentrations in the cerebellum and occipital cortex; this distribution corresponds to the known regional density of opiate receptors measured using in vitro techniques. This heterogeneous distribution could be abolished by pretreatment with naloxone (1 mg/kg), an opiate antagonist. The percent inhibition of binding by naloxone is approximately 90% in the caudate nucleus and medial thalamus for the period 30–60 min after injection; therefore, this method is associated with a high level of specific binding to opiate receptors compared with nonspecific binding sites. The ability to measure opiate receptors in vivo in man makes it possible to study a variety of neurologic and psychiatric disorders in which opiate receptors are thought to be abnormal and to study physiologic role of opiate receptors in the central nervous system.

Past adult lead exposure is associated with longitudinal decline in cognitive function

Objective: To determine whether adults with past exposure to neurotoxicants have progressive declines in cognitive function years after exposure has ceased, and whether tibia lead is a predictor of the magnitude of change. Methods: A total of 535 former organolead manufacturing workers with a mean age of 55.6 years, a mean duration of 16 years since last occupational lead exposure, and low blood lead levels at the first study visit and 118 controls were evaluated with neurobehavioral tests two to four times over 4 years. “Peak” tibia lead levels, estimated from current levels measured by X-ray fluorescence, were used to predict changes in cognitive function over time. Results: In former lead workers, peak tibia lead ranged from −2.2 to 98.7 μg Pb/g bone mineral. Compared to controls, former lead workers performed worse over time for three tests of visuo-constructive ability and verbal memory and learning (p < 0.05). In former lead workers, peak tibia lead predicted declines for six tests of verbal memory and learning, visual memory, executive ability, and manual dexterity (p < 0.05 for four tests and < 0.10 for two additional tests). On average, for these six tests, an increase of 15.7 μg/g of peak tibia lead was equivalent in its effects on annual test decline to 5 more years of age at baseline. Conclusions: These are the first data to suggest that cognitive function can progressively decline due to past occupational exposures to a neurotoxicant.

Multicompartmental Analysis of [11C]-Carfentanil Binding to Opiate Receptors in Humans Measured by Positron Emission Tomography:

[11C]-Carfentanil is a high affinity opiate agonist that can be used to localize mu opiate receptors in humans by positron emission tomography (PET). A four-compartment model was used to obtain quantitative estimates of rate constants for receptor association and dissociation. PET studies were performed in five normal subjects in the absence and presence of 1 mg/kg naloxone. Arterial plasma concentration of [11C]-carfentanil and its labeled metabolites were determined during each PET study. The value of k3/k4 = Bmax/kd was determined for each subject in the presence and absence of naloxone. There was a significant reduction in the value of k3/k4 from 3.4 ± 0.92 to 0.26 ± 0.13 in the thalamus (p < 0.01) and from 1.8 ± 0.33 to 0.16 ± 0.065 in the frontal cortex (p < 0.001). Mean values of frontal cortex/occipital cortex and thalamus/occipital cortex ratios were determined for the interval 35–70 min after injection when receptor binding is high relative to nonspecific binding. The relationship between the measured region/occipital cortex values and the corresponding values of k3/k4 in the presence and absence of naloxone was: regions/occipital cortex = 0.95 + 0.74 (k3/k4) with r = 0.98 (n = 20). Simulation studies also demonstrated a linear relationship between the thalamus/occipital cortex or frontal cortex/occipital cortex ratio and k3/k4 for less than twofold increases or decreases in k3/k4. Simulation studies in which thalamic blood flow was varied demonstrated no significant effect on the region/occipital cortex ratio at 35–70 min for a twofold increase or fourfold decrease in blood flow. Therefore, the region/occipital cortex ratio can be used to quantitate changes in k3/k4 when tracer kinetic modeling is not feasible.

Quantification of neuroreceptors in the living human brain. II. Inhibition studies of receptor density and affinity

A method for estimating receptor density (Bmax) in the living human brain by positron emission tomography was exemplified by a ligand, 3-N-[11C]methylspiperone ([11C]NMSP), that binds to D2 dopamine receptors with high affinity. The ligand binds essentially irreversibly (i.e., with very little dissociation) to the receptors during the 2-h scanning period. Transfer constants were estimated at steady state. In a previous article, we presented a method for the determination of k3, the rate of binding of the labeled ligand. In the present work, we varied k3 by reducing the number of available receptors with a previously administered receptor blocking agent, haloperidol. We calculated a receptor density of 9.2 pmol g−1 in the caudate nucleus of four normal volunteers, and an inhibitory constant of haloperidol of 1.4 nM by comparing tracer accumulation in the absence and the presence of the blocking agent. The values agreed with measurements of NMSP receptor density and haloperidol inhibitory potency in vitro in brain homogenates from human autopsy material.

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.

The longitudinal association of lead with blood pressure.

Background. Several investigators have reported an association of blood lead or bone lead with increased blood pressure and hypertension, but questions remain concerning whether these effects are acute or chronic in nature. Methods. In this longitudinal study, we evaluated the relation of lead, measured in blood and tibia, to changes in blood pressure between 1994 and 1998. We studied 496 current and former employees of a chemical-manufacturing facility in the eastern United States who had previous occupational exposure to inorganic and organic lead. Cohort members who provided three or four blood pressure measurements during the study were included. Results. Mean age at baseline was 55.8 years with a mean of 18 years since last occupational exposure to lead. Blood lead at baseline averaged 4.6 &mgr;g/dL (standard deviation [SD] = 2.6) or 0.22 &mgr;mole/Liter (SD = 0.13). Tibia lead at year three averaged 14.7-&mgr;g/gm (SD = 9.4) bone mineral. Change in systolic blood pressure during the study was associated with lead dose, with an average annual increase of 0.64 mmHg (standard error [SE] = 0.25), 0.73 mmHg (SE = 0.26), and 0.61 mmHg (SE = 0.27) for every standard deviation increase in blood lead at baseline, tibia lead at year three, or peak past tibia lead, respectively. Conclusions. The results support an etiologic role for lead in the elevation of systolic blood pressure among adult males and are consistent with both acute and chronic modes of action.

Neurobehavioral function and tibial and chelatable lead levels in 543 former organolead workers

Objective: To evaluate the associations between tibial lead, dimercaptosuccinic acid (DMSA)-chelatable lead, and neurobehavioral function in former organolead manufacturing workers with past exposure to organic and inorganic lead. Methods: Data were collected from 543 subjects with a mean age of 58 years and an average of 17.8 years since last lead exposure. Years since last exposure to lead was used to estimate tibial lead levels in the year of last occupational lead exposure, termed “peak tibial lead.” Current tibial lead levels, measured by x-ray fluorescence, were extrapolated back using a clearance half-time of lead in tibia of 27 years, assuming first-order clearance from tibia. Results: Peak tibial lead levels ranged from −2.2 to 105.9 μg Pb/g bone mineral, and DMSA-chelatable lead levels were between 1.2 and 136 μg. After adjustment for confounding variables, peak tibial lead was a significant negative predictor of performance on the Wechsler Adult Intelligence Scale–Revised vocabulary subtest (p = 0.02), serial digit learning test (p = 0.04), Rey Auditory-Verbal Learning Test (immediate recall and recognition, p = 0.03 for each), Trail Making Test B (p = 0.03), finger tapping (dominant hand [p = 0.02] and nondominant hand [p < 0.01]), Purdue pegboard (dominant hand, nondominant hand, both hands, and assembly, p < 0.01 for each), and Stroop Test (p < 0.01). Moreover, with one exception, average neurobehavioral test scores were poorer at higher peak tibial lead levels. DMSA-chelatable lead was only significantly associated with choice reaction time (p = 0.01). Conclusion: Peak tibial lead was consistently associated with poorer neurobehavioral test scores, particularly in the domains of manual dexterity, executive ability, verbal intelligence, and verbal memory.