Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression.

The mechanisms of action of the rapid antidepressant effects of ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, have not been fully elucidated. This study examined the effects of ketamine on ligand binding to a metabotropic glutamatergic receptor (mGluR5) in individuals with major depressive disorder (MDD) and healthy controls. Thirteen healthy and 13 MDD nonsmokers participated in two [11C]ABP688 positron emission tomography (PET) scans on the same day-before and during intravenous ketamine administration-and a third scan 1 day later. At baseline, significantly lower [11C]ABP688 binding was detected in the MDD as compared with the control group. We observed a significant ketamine-induced reduction in mGluR5 availability (that is, [11C]ABP688 binding) in both MDD and control subjects (average of 14±9% and 19±22%, respectively; P<0.01 for both), which persisted 24 h later. There were no differences in ketamine-induced changes between MDD and control groups at either time point (P=0.8). A significant reduction in depressive symptoms was observed following ketamine administration in the MDD group (P<0.001), which was associated with the change in binding (P<0.04) immediately after ketamine. We hypothesize that glutamate released after ketamine administration moderates mGluR5 availability; this change appears to be related to antidepressant efficacy. The sustained decrease in binding may reflect prolonged mGluR5 internalization in response to the glutamate surge.

In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence.

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.

Imaging of cerebral α4ß2* nicotinic acetylcholine receptors with (-)-[(18)F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain.

The positron emission tomography (PET) radioligand (-)-[(18)F]flubatine is specific to α4ß2(⁎) nicotinic acetylcholine receptors (nAChRs) and has promise for future investigation of the acetylcholine system in neuropathologies such as Alzheimer's disease, schizophrenia, and substance use disorders. The two goals of this work were to develop a simplified method for α4ß2(⁎) nAChR quantification with bolus plus constant infusion (B/I) (-)-[(18)F]flubatine administration, and to assess the radioligand's sensitivity to acetylcholine fluctuations in humans. Healthy human subjects were imaged following either bolus injection (n=8) or B/I (n=4) administration of (-)-[(18)F]flubatine. The metabolite-corrected input function in arterial blood was measured. Free-fraction corrected distribution volumes (VT/fP) were estimated with modeling and graphical analysis techniques. Next, sensitivity to acetylcholine was assessed in two ways: 1. A bolus injection paradigm with two scans (n=6), baseline (scan 1) and physostigmine challenge (scan 2; 1.5mg over 60min beginning 5min prior to radiotracer injection); 2. A single scan B/I paradigm (n=7) lasting up to 240min with 1.5mg physostigmine administered over 60min beginning at 125min of radiotracer infusion. Changes in VT/fP were measured. Baseline VT/fP values were 33.8±3.3mL/cm(3) in thalamus, 12.9±1.6mL/cm(3) in cerebellum, and ranged from 9.8 to 12.5mL/cm(3) in other gray matter regions. The B/I paradigm with equilibrium analysis at 120min yielded comparable VT/fP values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means <4% different). Changes in VT/fP following physostigmine administration were small and most pronounced in cortical regions, ranging from 0.8 to 4.6% in the two-scan paradigm and 2.8 to 6.5% with the B/I paradigm. These results demonstrate the use of B/I administration for accurate quantification of (-)-[(18)F]flubatine VT/fP in 120min, and suggest possible sensitivity of (-)-[(18)F]flubatine binding to physostigmine-induced changes in acetylcholine levels.

Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD.

BACKGROUND: Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [(11)C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [(11)C]MRB (a NET ligand) and [(11)C]AFM (a SERT ligand) to evaluate in vivo IC50 values of ATX in monkeys. METHODS: Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01-0.12mg/kg/h and 0.045-1.054mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (VT) and IC50 values were estimated. RESULTS: ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC50 of 31±10 and 99±21ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0-1.8mg/kg, approx. 300-600ng/mL plasma), ATX would occupy >90% of NET and >85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates. CONCLUSION: Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET.

Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

BACKGROUND: Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters. METHODS: We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor. RESULTS: TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7 ng/mL and 50.8 ng/mL, respectively, consistent with modest selectivity for NET in vivo. Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5 ng/mL and 23.9 ng/mL, respectively. A single-dose, open-label PET study (4-20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [(11)C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30-40 h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21 ng/mL, and at doses of greater than 4 mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35 ng/mL. CONCLUSIONS: These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.

Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study.

Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [(11)C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [(11)C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [(11)C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively--OMAR VT, anandamide and cortisol--correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder.

Dissociated pattern of activity in visual cortices and their projections during human rapid eye movement sleep.

Positron emission tomography was used to measure cerebral activity and to evaluate regional interrelationships within visual cortices and their projections during rapid eye movement (REM) sleep in human subjects. REM sleep was associated with selective activation of extrastriate visual cortices, particularly within the ventral processing stream, and an unexpected attenuation of activity in the primary visual cortex; increases in regional cerebral blood flow in extrastriate areas were significantly correlated with decreases in the striate cortex. Extrastriate activity was also associated with concomitant activation of limbic and paralimbic regions, but with a marked reduction of activity in frontal association areas including lateral orbital and dorsolateral prefrontal cortices. This pattern suggests a model for brain mechanisms subserving REM sleep where visual association cortices and their paralimbic projections may operate as a closed system dissociated from the regions at either end of the visual hierarchy that mediate interactions with the external world.

Glucose utilization in a patient with hepatoma and hypoglycemia. Assessment by a positron emission tomography.

Tumor glucose use in patients with non-islet-cell tumors has been difficult to measure, particularly in hepatoma, because of hepatic involvement by neoplasm. We studied a patient with nonhepatic recurrence of hepatoma after successful liver transplantation. Tumor tissue contained messenger RNA for insulin-like growth factor-II (IGF-II), and circulating high molecular weight components and E-peptide of IGF-II were increased. Glucose use measured by isotope dilution with [3-3H]glucose was 7.94 mg/kg fat-free mass per min, and splanchnic glucose production was 0.93 mg/kg fat-free mass per min. Glucose uptake and glucose model parameters were independently measured in tissues by positron emission tomography with 18F-fluoro-2-deoxy-D-glucose. Glucose uptake by heart muscle, liver, skeletal muscle, and neoplasm accounted for 0.8, 14, 44, and 15% of total glucose use, respectively. Model parameters in liver and neoplasm were not significantly different, and glucose transport and phosphorylation were twofold and fourfold greater than in muscle. This suggests that circulating IGF-II-like proteins are partial insulin agonists, and that hypoglycemia in hepatoma with IGF-II production is predominantly due to glucose uptake by skeletal muscle and suppression of glucose production.

Parabiotic transfer of cancer anorexia/cachexia in male rats.

To demonstrate that the anorexia and depletion of cachexia reverses on tumor removal, F344 rats underwent sarcoma resection when their food intake fell to 0 g/day. In survivors of surgery, reversal in food intake was apparent within 3 days postoperatively, followed after 2 days by gain in host weight. To detect whether the transmission of anorexia/cachexia in these tumor-bearing (TB) rats was via the circulation, four groups were studied: single non-tumor bearing (NTB); single TB; parabiotic NTB; and parabiotic TB. The measured blood exchange rate between parabiotic halves was 1.2-1.5%/min. No cachectic effect was detected in either half of the NTB parabionts. There was no evidence of sarcoma metastases in the tumor-free half of the parabiotic TB pair. All the rats associated with the presence of tumor showed cachectic effects but the degree and timing of effect varied among the three conditions, single TB, parabiotic TB half, and parabiotic tumor-free half. In all variables examined (fall in food intake, time of first fall in food intake, host weight loss, elevation of blood urea nitrogen) the severities were always in the same sequence: single TB greater than parabiotic TB half greater than parabiotic tumor-free half greater than NTB. In addition, the TB parabiotic pair had a significantly longer survival time and grew a significantly larger tumor than did the single TB animal. The parabiotic tumor had a slower initial growth rate and a slower deceleration rate than the singlet tumor. These results provide evidence for the humoral mediation of cancer-associated cachexia.

In vivo imaging of insulin receptors in monkeys using 18F-labeled insulin and positron emission tomography.

We previously described a prosthetic group methodology for incorporating 18F into peptides and showed that 18F-labeled insulin (18F-insulin) binds to insulin receptors on human cells (IM-9 lymphoblastoid cells) with affinity equal to that of native insulin (1). We now report studies using 18F-insulin with positron emission tomography to study binding to insulin receptors in vivo. Positron emission tomography scans were performed in six rhesus monkeys injected with 0.3-1.4 mCi of 18F-insulin (approximately 0.1 nmol, SA 4-11 Ci/mumol). Integrity of the tracer in blood, determined by immunoprecipitation, was 94% of control for the first 5 min and decreased to 31% by 30 min. Specific, saturable uptake of 18F was observed in the liver and kidney. Coinjection of unlabeled insulin (200 U, approximately 1 nmol) with the 18F-insulin reduced liver and increased kidney uptake of the labeled insulin. Liver radioactivity was decreased by administration of unlabeled insulin at 3 min, but not 5 min, after administration of the tracer, while some kidney radioactivity could be displaced 5 min after injection. Clearance of 18F was predominantly in bile and urine. 18F-insulin is a suitable analogue for studying insulin receptor-ligand interactions in vivo, especially in the liver and kidney.

Evaluation of bias and variance in low-count OSEM list mode reconstruction.

Statistical algorithms have been widely used in PET image reconstruction. The maximum likelihood expectation maximization reconstruction has been shown to produce bias in applications where images are reconstructed from a relatively small number of counts. In this study, image bias and variability in low-count OSEM reconstruction are investigated on images reconstructed with MOLAR (motion-compensation OSEM list-mode algorithm for resolution-recovery reconstruction) platform. A human brain ([(11)C]AFM) and a NEMA phantom are used in the simulation and real experiments respectively, for the HRRT and Biograph mCT. Image reconstructions were repeated with different combinations of subsets and iterations. Regions of interest were defined on low-activity and high-activity regions to evaluate the bias and noise at matched effective iteration numbers (iterations × subsets). Minimal negative biases and no positive biases were found at moderate count levels and less than 5% negative bias was found using extremely low levels of counts (0.2 M NEC). At any given count level, other factors, such as subset numbers and frame-based scatter correction may introduce small biases (1-5%) in the reconstructed images. The observed bias was substantially lower than that reported in the literature, perhaps due to the use of point spread function and/or other implementation methods in MOLAR.

Applications of the line-of-response probability density function resolution model in PET list mode reconstruction.

Resolution degradation in PET image reconstruction can be caused by inaccurate modeling of the physical factors in the acquisition process. Resolution modeling (RM) is a common technique that takes into account the resolution degrading factors in the system matrix. Our previous work has introduced a probability density function (PDF) method of deriving the resolution kernels from Monte Carlo simulation and parameterizing the LORs to reduce the number of kernels needed for image reconstruction. In addition, LOR-PDF allows different PDFs to be applied to LORs from different crystal layer pairs of the HRRT. In this study, a thorough test was performed with this new model (LOR-PDF) applied to two PET scanners-the HRRT and Focus-220. A more uniform resolution distribution was observed in point source reconstructions by replacing the spatially-invariant kernels with the spatially-variant LOR-PDF. Specifically, from the center to the edge of radial field of view (FOV) of the HRRT, the measured in-plane FWHMs of point sources in a warm background varied slightly from 1.7 mm to 1.9 mm in LOR-PDF reconstructions. In Minihot and contrast phantom reconstructions, LOR-PDF resulted in up to 9% higher contrast at any given noise level than image-space resolution model. LOR-PDF also has the advantage in performing crystal-layer-dependent resolution modeling. The contrast improvement by using LOR-PDF was verified statistically by replicate reconstructions. In addition, [(11)C]AFM rats imaged on the HRRT and [(11)C]PHNO rats imaged on the Focus-220 were utilized to demonstrated the advantage of the new model. Higher contrast between high-uptake regions of only a few millimeter diameter and the background was observed in LOR-PDF reconstruction than in other methods.

Brain glucose metabolism in noninsulin-dependent diabetes mellitus: a study in Pima Indians using positron emission tomography during hyperinsulinemia with euglycemic glucose clamp.

To determine whether insulin or noninsulin-dependent diabetes mellitus affects brain glucose metabolism, brain glucose utilization was studied in the basal state and during hyperinsulinemic euglycemic glucose clamps in nondiabetic and diabetic Pima Indians by positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (18FDG). Glucose utilization in 75 brain areas was determined by analysis of single scans and by least squares estimation of the rate parameters for the FDG model; these data were compared to results in normal caucasian volunteers. No effect of ethnicity or diabetic status on brain glucose utilization was observed. During the hyperinsulinemic clamps (mean insulin, 11,708 +/- 3,026 pmol/L), clearance of 18FDG from blood was accelerated, and accumulation of brain radioactivity was reduced. However, glucose utilization by the brain was identical to results during sham glucose clamps (mean insulin, 204 +/- 56 pmol/L) performed in the same patients. During the studies with hyperinsulinemia, k4 (representing loss of tissue radioactivity) was increased in most brain areas (mean increase, 0.0031 +/- 0.0018 min-1; P less than 0.02). The possible mechanisms for this effect are multiple, and the physiological significance, if any, is unknown. Further studies of the effects of insulin on brain glucose metabolism are needed.

Precision and accuracy considerations of physiological quantitation in PET.

The ability to differentiate regional patterns of flow and metabolism between various patient populations depends upon the signal-to-noise characteristics of the data. The approach chosen for producing quantitative data will affect the detection sensitivity of a method. Methods based on mathematical models can reduce intersubject variability by accounting for factors unrelated to the physiological measure of interest, in particular, differences in the input function. However, errors in the model and in the implementation of a model-based method can increase variability compared to simpler, empirical methods. Normalization of physiological measures can significantly reduce intersubject variation; however, interpretation of normalized results can be more complex. The advantages and disadvantages of various approaches for physiological quantitation are considered.

Assessment of dynamic neurotransmitter changes with bolus or infusion delivery of neuroreceptor ligands.

To describe the effect of endogenous dopamine on [11C]raclopride binding, we previously extended the conventional receptor ligand model to include dynamic changes in neurotransmitter concentration. Here, we apply the extended model in simulations of neurotransmitter competition studies using either bolus or bolus-plus-infusion (B/I) tracer delivery. The purpose of this study was (1) to develop an interpretation of the measured change in tracer binding in terms of underlying neurotransmitter changes, and (2) to determine tracer characteristics that maximize sensitivity to neurotransmitter release. A wide range of kinetic parameters was tested based on existing reversible positron emission tomography tracers. In simulations of bolus studies, the percent reduction in distribution volume (deltaV) caused by a neurotransmitter pulse was calculated. For B/I simulations, equilibrium was assumed, and the maximum percent reduction in tissue concentration (deltaC) after neurotransmitter release was calculated. Both deltaV and deltaC were strongly correlated with the integral of the neurotransmitter pulse. The values of deltaV and deltaC were highly dependent on the kinetic properties of the tracer in tissue, and deltaV could be characterized in terms of the tissue free tracer concentration. The value of deltaV was typically maximized for binding potentials of approximately 3 to 10, with deltaC being maximized at binding potentials of approximately 1 to 2. Both measures increased with faster tissue-to-blood clearance of tracer and lower nonspecific binding. These simulations provide a guideline for interpreting the results of neurotransmitter release studies and for selecting radiotracers and experimental design.

Weighted integration method for local cerebral blood flow measurements with positron emission tomography.

A new technique called the weighted integration method for the measurement of local CBF (LCBF) in humans with positron emission tomography (PET) is presented. LCBF is calculated from weighted time integrals of the blood and tissue radioactivity curves. This method is computationally efficient and achieves nearly optimal statistical estimation of LCBF. The predicted root mean squared error of the weighted integration method is verified by simulation studies and is only 1-2% larger than the minimum possible error that can be achieved by an ideal estimation algorithm. For LCBF of greater than 30 ml/min/100 g, the weighted integration method provides reduced noise compared with the integrated projection technique, the PET autoradiographic method, and the steady-state technique. In addition, an error analysis is performed to study the sensitivity of the weighted integration method to tissue mixtures, blood sample timing errors, and changes in LCBF during the data collection period.

Examination of blood-brain barrier permeability in dementia of the Alzheimer type with [68Ga]EDTA and positron emission tomography.

Positron emission tomography with [68Ga]ethylenediaminetetraacetic acid ([68Ga]EDTA) was used to examine the integrity of the blood-brain barrier (BBB) in five patients with dementia of the Alzheimer type and in five healthy age-matched controls. Within a scanning time of 90 min, there was no evidence that measurable intravascular tracer entered the brain in either the dementia or the control group. An upper limit for the cerebrovascular permeability-surface area product of [68Ga]EDTA was estimated as 2 X 10(-6) s-1 in both groups. The results provide no evidence for breakdown of the BBB in patients with dementia of the Alzheimer type.

Measurement of local blood flow and distribution volume with short-lived isotopes: a general input technique.

A new technique for measuring local blood flow and distribution volume is proposed. The technique uses short-lived isotopes but is different from the equilibrium method in that no constant input is necessary, and no assumption about distribution volume is needed. The theoretical basis of the technique is developed, and the results of a computer-simulation study are presented to show the potential of the technique. The technique is expected to be easier to perform and to give more accurate flow values than the equilibrium method.

Optimization of noninvasive activation studies with 15O-water and three-dimensional positron emission tomography.

We investigated the effects of varying the injected dose, speed of injection, and scan duration to maximize the sensitivity of noninvasive activation studies with 15O-water and three-dimensional positron emission tomography. A covert word generation task was used in four subjects with bolus injections of 2.5 to 3D mCi of 15O-water. The noise equivalent counts (NEC) for the whole brain peaked at an injected dose of 12 to 15 mCi. This was lower than expected from phantom studies, presumably because of the effect of radioactivity outside of the brain. A 10 mCi injection gave an NEC of 92.4 +/- 2.2% of the peak value. As the scan duration increased from 60 to 90 to 120 seconds, the areas of activation decreased in size or were no longer detected. Therefore, we selected a 1 minute scan using 10 mCi for bolus injections. We then performed simulation studies to evaluate, for a given CBF change, the effect on signal-to-noise ratio (S/N) of longer scan duration with slow tracer infusions. Using a measured arterial input function from a bolus injection, new input functions for longer duration injections and the corresponding tissue data were simulated. Combining information about image noise derived from Hoffman brain phantom studies with the simulated tissue data allowed calculation of the S/N for a given CBF change. The simulation shows that a slow infusion permits longer scan acquisitions with only a small loss in S/N. This allows the investigator to choose the injection duration, and thus the time period during which scan values are sensitive to regional CBF.

Bolus injection versus slow infusion of [15O]water for positron emission tomography activation studies.

In positron emission tomography studies using bolus injection of [15O]water, activation responses reflect underlying CBF changes during a short time (15 to 20 seconds) after arrival of the bolus in the brain. This CBF sensitivity window may be too short for complex activation paradigms, however, particularly those of longer duration. To perform such paradigms, we used a slow infusion method of tracer administration to lengthen the CBF sensitivity window. The present study was designed to determine if this slow infusion technique yields similar results to a bolus injection with a short activation task involving memory for faces. When analyzed using statistical parametric mapping, scanning durations of either 90 or 120 seconds and a 90-second slow infusion schedule produced very similar results to a standard 60-second scan collected after bolus injection, indicating that statistically similar brain activation maps can be produced with the two infusion techniques. This slow infusion approach allows for increased flexibility in designing future studies in which a short CBF sensitivity window is a limiting factor.