Richard E. Carson

Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia

Both dopaminergic neurotransmission and prefrontal cortex (PFC) function are known to be abnormal in schizophrenia. To test the hypothesis that these phenomena are related, we measured presynaptic dopaminergic function simultaneously with regional cerebral blood flow during the Wisconsin Card Sorting Test (WCST) and a control task in unmedicated schizophrenic subjects and matched controls. We show that the dopaminergic uptake constant Ki in the striatum was significantly higher for patients than for controls. Patients had significantly less WCST-related activation in PFC. The two parameters were strongly linked in patients, but not controls. The tight within-patient coupling of these values, with decreased PFC activation predicting exaggerated striatal 6-fluorodopa uptake, supports the hypothesis that prefrontal cortex dysfunction may lead to dopaminergic transmission abnormalities.

Physiological activation of a cortical network during performance of the Wisconsin Card Sorting Test: A positron emission tomography study

To determine the neural circuitry engaged by performance of the Wisconsin Card Sorting Test (WCST), a neuropsychological test traditionally considered to be sensitive to prefrontal lesions, regional cerebral blood flow was measured with oxygen-15 water and positron emission tomography (PET) while young normal subjects performed the test as well as while they performed a specially designed sensorimotor control task. To consider which of the various cognitive operations and other experiential phenomena involved in the WCST PET scan are critical for the pattern of physiological activation and to focus on the working memory component of the test, repeat WCST scans were also performed on nine of the subjects after instruction on the test and practice to criteria. We confirmed that performance of the WCST engages the frontal cortex and also produces activation of a complex network of regions consistently including the inferior parietal lobule but also involving the visual association and inferior temporal cortices as well as portions of the cerebellum. The WCST activation in the dorsolateral prefrontal cortex (DLPFC) remained significant even after training and practice on the test, suggesting that working memory may be largely responsible for the physiological response in DLPFC during the WCST and, conversely, that the DLPFC plays a major role in modulating working memory.

Linearized Reference Tissue Parametric Imaging Methods: Application to [11C]DASB Positron Emission Tomography Studies of the Serotonin Transporter in Human Brain:

The authors developed and applied two new linearized reference tissue models for parametric images of binding potential (BP) and relative delivery (R1) for [11C]DASB positron emission tomography imaging of serotonin transporters in human brain. The original multilinear reference tissue model (MRTMO) was modified (MRTM) and used to estimate a clearance rate (k′2) from the cerebellum (reference). Then, the number of parameters was reduced from three (MRTM) to two (MRTM2) by fixing k′2. The resulting BP and R1 estimates were compared with the corresponding nonlinear reference tissue models, SRTM and SRTM2, and one-tissue kinetic analysis (1TKA), for simulated and actual [11C]DASB data. MRTM gave k′2 estimates with little bias (<1%) and small variability (<6%). MRTM2 was effectively identical to SRTM2 and 1TKA, reducing BP bias markedly over MRTMO from 12–70% to 1–4% at the expense of somewhat increased variability. MRTM2 substantially reduced BP variability by a factor of two or three over MRTM or SRTM. MRTM2, SRTM2, and 1TKA had R1 bias <0.3% and variability at least a factor of two lower than MRTM or SRTM. MRTM2 allowed rapid generation of parametric images with the noise reductions consistent with the simulations. Rapid parametric imaging by MRTM2 should be a useful method for human [11C]DASB positron emission tomography studies.

Identification and differentiation of resting myocardial ischemia and infarction in man with positron computed tomography, 18F-labeled fluorodeoxyglucose and N-13 ammonia.

Studies have shown that the extraction of glucose per unit flow is increased in moderately ischemic myocardium primarily due to anaerobic glucose metabolism manifested as lactate production, whereas myocardial infarction is characterized by the loss of metabolically active myocardium. To determine the feasibility of demonstrating these metabolic abnormalities reflecting both ischemia and infarction, we used positron computed tomography (PCT) to evaluate relative regional myocardial exogenous glucose utilization and perfusion in 15 patients with recent myocardial infarction. The positron-emitting tracers of glucose metabolism and perfusion, 18F-2-fluoro-2-deoxyglucose (FDG) and N-13 ammonia, respectively, were used. Fourteen of 19 documented infarctions were demonstrated by PCT to have concordantly decreased glucose utilization and perfusion. However, in an additional 11 regions, glucose utilization was disproportionately increased relative to perfusion, consistent with ischemic glucose consumption. These findings correlated with the presence of postinfarction angina, the site of ischemic electrocardiographic changes during chest pain, and the presence of regional left ventricular dysfunction and severe coronary artery disease. Because three ECG infarct zones not detected by PCT demonstrated ischemic glucose utilization, only two of 19 electrocardiographically defined infarctions had no detectable metabolic abnormality.We conclude that the changes in regional FDG and N-13 ammonia concentrations detected with PCT in patients who had had a recent myocardial infarction are consistent with regional exogenous glucose utilization and perfusion in moderately ischemic and irreversibly infarcted myocardium. This approach has the potential to identify and differentiate resting myocardial ischemia from infarction and to assess tissue viability after an ischemic event.

Tomographic mapping of human cerebral metabolism: Auditory stimulation

Cerebral metabolic responses to verbal and nonverbal auditory stimuli were examined, using 18F-fluorodeoxyglucose and positron CT. Twenty right-handed subjects were studied in both control and stimulated states. Monaural verbal stimuli produced diffuse metabolic changes in the left hemisphere and bilateral activation of the transverse and posterior temporal lobes. Monaural nonverbal stimulation with chords demonstrated bilateral parietotemporal activations and diffuse right greater than left frontotemporal asymmetries. Tone sequence pairs presented monaurally produced asymmetries that differed by the subjects analysis strategy. Nonanalytical, musically naive subjects had right greater than left frontotemporal asymmetries, whereas analytic or musically sophisticated subjects had an absence of right greater than left relative hypermetabolism and demonstrated left greater than right temporal asymmetries. Binaural presentation of a factual story and music produced diffuse bilateral activations of the temporal and frontal cortex. Known anatomic asymmetries of the perisylvian cortex were revealed by high-resolution tomography. These results demonstrate that metabolic responses to auditory stimuli are determined by the content of the stimulus and the analysis strategy of the subject rather than the side of stimulation. The results also demonstrate the capacity of functional imaging techniques to study the physiologic cerebral mechanisms underlying auditory processing.

Comparison of bolus and infusion methods for receptor quantitation : application to [18F]cyclofoxy and positron emission tomography

Positron emission tomography studies with the opiate antagonist [18F]cyclofoxy ([18F]CF) were performed in baboons. Bolus injection studies demonstrated initial uptake dependent on blood flow. The late uptake showed highest binding in caudate nuclei, amygdala, thalamus, and brainstem and the least accumulation in cerebellum. By 60 min postinjection, regional brain radioactivity cleared at the same rate as metabolite-corrected plasma, i.e., transient equilibrium was achieved. Compartmental modeling methods were applied to time-activity curves from brain and metabolite-corrected plasma. Individual rate constants were estimated with poor precision. The model estimate of the total volume of distribution (VT), representing the ratio of tissue radioactivity to metabolite-corrected plasma at equilibrium, was reliably determined. The apparent volume of distribution (Va), the concentration ratio of tissue to metabolite-corrected plasma during transient equilibrium, was compared with the fitted VT values to determine if single-scan methods could provide accurate receptor measurements. Va significantly overestimated VT and produced artificially high image contrast. These differences were predicted by compartment model theory and were caused by a plasma clearance rate that was close to the slowest tissue clearance rate. To develop a simple method to measure VT, an infusion protocol consisting of bolus plus continuous infusion (B/I) of CF was designed and applied in a separate set of studies. The Va values from the B/I studies agreed with the VT values from both B/I and bolus studies. This infusion approach can produce accurate receptor measurements and has the potential to shorten scan time and simplify the acquisition and processing of scan and blood data.

Reduced Serotonin Type 1A Receptor Binding in Panic Disorder

Recent animal models suggest that disturbances in serotonin type-1A receptor (5-HT1AR) function may contribute to chronic anxiety, although it is not clear at all whether such models constitute relevant models for panic disorder (PD) in humans. The selective 5-HT1AR radioligand [18F]trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (FCWAY) permits in vivo assessment of central 5-HT1AR binding using positron emission tomography (PET). We studied 16 unmedicated symptomatic outpatients with PD and 15 matched healthy controls. Seven patients had an additional diagnosis of a current major depressive episode, however PD was the primary diagnosis. A 120 min PET study of 5-HT1AR binding was acquired using a GE Advance scanner in three-dimensional mode. Using quantitative PET image analysis, regional values were obtained for [18F]-FCWAY volume of distribution (DV), corrected for plasma protein binding, and K1, the delivery rate of [18F]-FCWAY from plasma to tissue. MRI scanning was performed using a GE Signa Scanner (3.0 Tesla) to provide an anatomical framework for image analysis and partial volume correction of PET data. PD patients showed lower DV in the anterior cingulate (t = 4.3; p < 0.001), posterior cingulate (t = 4.1; p < 0.001), and raphe (t = 3.1; p = 0.004). Comparing patients with PD, patients with PD and comorbid depression, and healthy controls revealed that DVs did not differ between PD patients and PD patients with comorbid depression, whereas both patient groups differed significantly from controls. These results provide for the first time in vivo evidence for the involvement of 5-HT1ARs in the pathophysiology of PD.

Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease

We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinsons disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinsons disease effect of the low-calorie diet.

Species-specific calls evoke asymmetric activity in the monkey's temporal poles.

It has often been proposed that the vocal calls of monkeys are precursors of human speech, in part because they provide critical information to other members of the species who rely on them for survival and social interactions. Both behavioural and lesion studies suggest that monkeys, like humans, use the auditory system of the left hemisphere preferentially to process vocalizations. To investigate the pattern of neural activity that might underlie this particular form of functional asymmetry in monkeys, we measured local cerebral metabolic activity while the animals listened passively to species-specific calls compared with a variety of other classes of sound. Within the superior temporal gyrus, significantly greater metabolic activity occurred on the left side than on the right, only in the region of the temporal pole and only in response to monkey calls. This functional asymmetry was absent when these regions were separated by forebrain commissurotomy, suggesting that the perception of vocalizations elicits concurrent interhemispheric interactions that focus the auditory processing within a specialized area of one hemisphere.

Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging.

The Simplified Reference Tissue Model (SRTM) produces functional images of receptor binding parameters using an input function derived from a reference region and assuming a model with one tissue compartment. Three parameters are estimated: binding potential (BP), relative delivery (R1), and the reference region clearance constant k′2 Since k′2 should not vary across brain pixels, the authors developed a two-step method (SRTM2) using a global value of k′2. Whole-brain simulations were performed using human input functions and rate constants for [18F]FCWAY, [11C]flumazenil, and [11C]raclopride, and parameter SD and bias were determined for SRTM and SRTM2. The global mean of k′2 was slightly biased (2% to 6%), but the median was unbiased (<1%) and was used as the global value. Binding potential noise reductions with SRTM2 were 4% to 14%, 20% to 53%, and 10% to 30% for [18F]FCWAY, [11C]flumazenil, and [11C]raclopride, respectively, with larger reductions for shorter scans. R1 noise reduction was larger than that of BP. Simulations were also performed to assess bias when the reference and/or tissue regions followed a two-tissue compartment model. Owing to the constrained k′2, SRTM2 showed somewhat larger biases due to violations of the one-compartment model assumption. These studies demonstrate that SRTM2 should be a useful method to improve the quality of neuroreceptor functional images.