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Two cases are presented involving neuropsychiatric symptoms occurring in the context of coronavirus disease 2019 (COVID-19) infections. The first case involved a middle-age man with no known psychiatric history who presented with acute psychotic symptoms (delusions, hallucinations, disorganization) after recovery from a recent respiratory illness. This patient tested positive for COVID-19 on admission. The patient's symptoms were not consistent with delirium and testing did not suggest a neurological etiology. The patient's psychosis eventually resolved 6 weeks after its abrupt onset with treatment with antipsychotic medication. The second case involved a 44-year-old man with a history of depression and psychotic symptoms who presented after a serious suicide attempt and tested positive for COVID-19 on admission. The patient had subsequent negative tests while on the inpatient psychiatric unit before again testing positive later in his admission. The patient's positive COVID-19 tests appeared to coincide with exacerbations in his mood symptoms, which led to the suicide attempt and psychotic episode that initially caused his admission. This patient was successfully treated with clozapine. In both of these cases, the question arose as to whether there was a link between the COVID-19 infections and the neuropsychiatric symptoms. Growing evidence suggests that severe neuropsychiatric sequelae can develop after COVID-19 infection.

Background Positron emission tomography studies have demonstrated less dopamine D2/3 receptor availability and blunted psychostimulant-induced dopamine release in cocaine-dependent subjects (CDSs). No studies in CDSs have reported the in vivo status of D2/3 and dopamine release in the cortex. Basic and functional imaging studies suggest a role for prefrontal cortical dopaminergic abnormalities in impaired executive function and relapse in cocaine dependence. We used [11C]FLB 457 positron emission tomography and amphetamine to measure cortical D2/3 receptors and dopamine release in CDSs. Methods [11C]FLB 457 and positron emission tomography were used to measure D2/3 receptor binding potential in cortical regions of interest in recently abstinent CDSs (n = 24) and healthy control subjects (n = 36) both before and after 0.5 mg kg−1 of oral d-amphetamine. Binding potential relative to nondisplaceable uptake (BPND) and binding potential relative to total plasma concentration (BPP) were derived using an arterial input function-based kinetic analysis. Cortical dopamine release in regions of interest was measured as the change in BPND and BPP after amphetamine. Results Baseline D2/3 receptor availability (BPP and BPND) and amphetamine-induced dopamine release (ΔBPND and ΔBPP) were significantly lower in the cortical regions in CDSs compared with healthy control subjects. Fewer D2/3 receptors and less dopamine release in CDSs were not associated with performance on working memory and attention tasks. Conclusions The results of this study suggest that deficits in dopamine D2/3 transmission involve the cortex in cocaine dependence. Further studies to understand the clinical relevance of these findings are warranted.

Background New York City's first case of SARS-associated coronavirus (SARS-CoV-2) disease 2019 (COVID-19) was identified on 1 March 2020, prompting rapid restructuring of hospital-based services to accommodate the increasing numbers of medical admissions. Non-essential services were eliminated but in-patient treatment of psychiatric illnesses was necessarily maintained. Aims To detail the response of the NYU Langone Health in-patient psychiatric services to the COVID-19 outbreak from 1 March to 1 May 2020. Method Process improvement/quality improvement study. Results Over this time period, our two in-patient psychiatric units (57 total beds) treated 238 patients, including COVID-19-positive and -negative individuals. Testing for COVID-19 was initially limited to symptomatic patients but expanded over the 62-day time frame. In total, 122 SARS-CoV-2 polymerase chain reaction (PCR) tests were performed in 98 patients. We observed an overall rate of COVID-19 infection of 15.6% in the patients who were tested, with an asymptomatic positive rate of 13.7%. Although phased roll-out of testing impaired the ability to fully track on-unit transmission of COVID-19, 3% of cases were clearly identified as results of on-unit transmission. Conclusions Our experience indicates that, with appropriate precautions, patients in need of in-patient psychiatric admission who have COVID-19 can be safely managed. We provide suggested guidelines for COVID-19 management on in-patient psychiatric units which incorporate our own experiences as well as published recommendations.

Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm.The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT).[(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power.This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

Background Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia (SCH) relative to healthy control subjects (HCs). A limitation of these studies, performed with D2/3 antagonist radiotracers, is the failure to provide information about D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G proteins [D2/3 HIGH]). The endogenous agonist dopamine binds with preference to D2/3 HIGH receptors relative to D2/3 LOW receptors, making it critical to understand the status of D2/3 HIGH receptors in SCH. Methods D2/3 agonist positron emission tomography radiotracer [11C]N-propyl-norapomorphine ([11C]NPA) binding potential (BPND) was measured in 14 off-medication subjects with SCH and 14 matched HCs at baseline and after the administration of 0.5 mg kg–1 oral D-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and was expressed as a percentage of BPND at baseline. Results A trend-level increase was observed in comparing baseline [11C]NPA BPND (repeated-measures analysis of variance, F1,26 = 3.34, p = .08) between the SCH and HC groups. Amphetamine administration significantly decreased BPND in all striatal regions across all subjects in both groups. No differences were observed in [11C]NPA ΔBPND (repeated-measures analysis of variance, F1,26 = 1.9, p = .18) between HCs and subjects with SCH. Amphetamine significantly increased positive symptoms in subjects with SCH (19.5 ± 5.3 vs. 23.7 ± 4.1, paired t test, p Conclusions This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in SCH.

Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND.

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [(11)C]MDL 100907 and [(11)C]DASB to characterize the 5-HT(2A) receptor and serotonin transporter in Asperger's Disorder. Seventeen individuals with Asperger's Disorder (age=34.3 ± 11.1 years) and 17 healthy controls (age=33.0 ± 9.6 years) were scanned with [(11)C]MDL 100907. Of the 17 patients, eight (age=29.7 ± 7.0 years) were also scanned with [¹¹C]DASB, as were eight healthy controls (age=28.7 ± 7.0 years). Patients with Asperger's Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by two-tissue compartment modeling. The primary outcome measure was regional binding potential BP(ND). Neither regional [¹¹C]MDL 100907 BP(ND) nor [¹¹C]DASB BP(ND) was statistically different between the Asperger's and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT(2A) receptors and serotonin transporters in adult subjects with Asperger's disorder.

Positron emission tomography (PET) studies performed with [(11) C]raclopride have consistently reported lower binding to D(2/3) receptors and lower amphetamine-induced dopamine (DA) release in cocaine abusers relative to healthy controls. A limitation of these studies that were performed with D(2/3) antagonist radiotracers such as [(11) C]raclopride is the failure to provide information that is specific to D(2/3) receptors configured in a state of high affinity for the agonists (i.e., D(2/3) receptors coupled to G-proteins, D(2/3 HIGH) ). As the endogenous agonist DA binds with preference to D(2/3 HIGH) relative to D(2/3 LOW) receptors (i.e., D(2/3) receptors uncoupled to G-proteins) it is critical to understand the in vivo status of D(2/3 HIGH) receptors in cocaine dependence. Thus, we measured the available fraction of D(2/3) (HIGH) receptors in 10 recently abstinent cocaine abusers (CD) and matched healthy controls (HC) with the D(2/3) antagonist and agonist PET radiotracers [(11) C]raclopride and [(11) C]NPA.[(11) C]raclopride and [(11) C]NPA binding potential (BP) (BP(ND) ) in the striatum were measured with kinetic analysis using the arterial input function. The available fraction of D(2/3 HIGH) receptors, i.e., % R(HIGH) available = D(2/3 HIGH) /(D(2/3 HIGH) + D(2/3 LOW) ) was then computed as the ratio of [(11) C]NPA BP(ND) /[(11) C]raclopride BP(ND) .No differences in striatal [(11) C]NPA BP(ND) (HC = 1.00 ± 0.17; CD = 0.97 ± 0.17, P = 0.67) or available % R(HIGH) (HC = 39% ± 5%; CD = 41% ± 5%, P = 0.50) was observed between cocaine abusers and matched controls.The results of this [(11) C]NPA PET study do not support alterations in D(2/3 HIGH) binding in the striatum in cocaine dependence.

Studies in nonhuman primates and humans have demonstrated that amphetamine-induced dopamine release in the cortex can be measured with [(11)C]FLB 457 and PET imaging. This technique has been successfully used in recent clinical studies to show decreased dopamine transmission in the prefrontal cortex in schizophrenia and alcohol dependence. Here, we present data from a cohort of twelve healthy controls in whom an oral amphetamine challenge (0.5 mg kg(−1)) did not lead to a significant reduction in [(11)C]FLB 457 BP(ND) (i.e., binding potential relative to non-displaceable uptake). Two factors that likely contributed to the inability to displace [(11)C]FLB 457 BP(ND) in this cohort relative to successful cohorts are: (1) the acquisition of the baseline and post-amphetamine scans on different days as opposed to the same day and (2) the initiation of the post-amphetamine [(11)C]FLB 457 scan at ~ 5 hours as opposed to ~ 3 hours following oral amphetamine. Furthermore, we show [(11)C]FLB 457 reproducibility data from a legacy dataset to support greater variability in cortical BP(ND) when the test and re-test scans are acquired on different days as compared to the same day. These results highlight the methodological challenges that continue to plague the field with respect to imaging dopamine release in the cortex.

Background Impulsive physical aggression is a common and problematic feature of many personality disorders. The serotonergic system is known to be involved in the pathophysiology of aggression, and multiple lines of evidence have implicated the serotonin 2A receptor (5-HT 2A R). We sought to examine the role of the 5-HT 2A R in impulsive aggression specifically in the orbitofrontal cortex (OFC), given that our own studies and an extensive literature indicate that serotonergic disturbances in the OFC are linked to aggression. We have previously hypothesized that increased 5-HT 2A R function in the OFC is a state phenomenon that promotes impulsive aggression. Methods Serotonin 2A receptor availability was measured with positron emission tomography and the selective 5-HT 2A R antagonist radioligand [ 11 C]MDL100907 in two groups of impulsively aggressive personality disordered patients—14 with current physical aggression, and 15 without current physical aggression—and 25 healthy control subjects. Clinical ratings of various symptom dimensions were also obtained. Results Orbitofrontal 5-HT 2A R availability was greater in patients with current physical aggression compared with patients without current physical aggression and healthy control subjects; no differences in OFC 5-HT 2A R availability were observed between patients without current physical aggression and healthy control subjects. No significant differences in 5-HT 2A R availability were observed in other brain regions examined. Among both groups of impulsively aggressive personality disordered patients combined, OFC 5-HT 2A R availability was correlated, specifically, with a state measure of impulsive aggression. Conclusions These findings are consistent with our previously described model in which impulsive aggression is related to dynamic changes in 5-HT 2A R function in the OFC.

In a recent PET study, we demonstrated the ability to measure amphetamine-induced DA release in the human cortex with the relatively high affinity dopamine D2/3 radioligand [11C]FLB 457 (Narendran et al., [2009] Synapse 63:447–461). The aim of this study was to evaluate the reproducibility and reliability of [11C]FLB 457 in the same imaging paradigm we used to measure amphetamine-induced DA transmission. Six healthy human subjects (three males/three females) were studied twice with [11C]FLB 457, once at baseline and again 3 h following the end of the baseline scan. D2/3 receptor binding parameters were estimated using a two-tissue compartment kinetic analysis in the cortical regions of interest and cerebellum (reference region). The test–retest variability and intraclass correlation coefficient were assessed for distribution volume (VT), binding potential relative to plasma concentration (BPP), and binding potential relative to nondisplaceable uptake (BPND) of [11C]FLB 457. The test–retest variability of [11C]FLB 457 VT, BPP, and BPND were ≤15%, consistent with the published test–retest variability for this ligand in other brain regions (Sudo et al., [2001] Nucl Med Commun 22:1215–1221; Vilkman et al., [2000] Eur J Nucl Med 27:1666–1673). In addition, no significant decrease in [11C]FLB 457 BPND was observed in the second scan compared to the first one. This suggests that the contribution of carryover mass of [11C]FLB 457 to the measured reduction in [11C]FLB 457 BPND following amphetamine was relatively low. These data support the further validation of [11C]FLB 457 as a tool to measure amphetamine-induced dopamine release in the human cortex. Synapse 65:35–40, 2011. © 2010 Wiley-Liss, Inc.

We measured the whole-body distribution of intravenously injected (11)C-N-propylnorapomorphine ((11)C-NPA), a dopamine agonist PET tracer, in human subjects and determined the resulting absorbed radiation doses.Six subjects (3 women, 3 men) were injected with (11)C-NPA (nominal dose, 370 MBq). A total of 9 consecutive whole-body PET scans were obtained for each subject. In addition, time-activity curves for 12 organs were determined, and residence times were computed for each subject. Dosimetry was determined for the various body organs and the whole body.The average NPA whole-body radiation dose was 3.17 x 10(-3) mSv per MBq of injected (11)C-NPA. The organ receiving the highest dose was the gallbladder wall, with an average of 2.81 x 10(-2) mSv.MBq(-1).On the basis of averaged dosimetry results, an administration of less than 1,780 MBq (48 mCi) of (11)C-NPA yields an organ dose of under 50 mSv (5 rem) to all organs.

Background Rodent models as well as studies in humans have suggested alterations in serotonin (5-HT) innervation and transmission in early-onset genetically determined or type II alcoholism. This study examines two indices of serotonergic transmission, 5-HT transporter levels and 5-HT 1A availability, in vivo, in type II alcoholism. This is the first report of combined tracers for pre- and postsynaptic serotonergic transmission in the same alcoholic subjects and the first study of 5-HT 1A receptors in alcoholism. Methods Fourteen alcohol-dependent subjects were scanned (11 with both tracers, 1 with [ 11 C]DASB only, and two with [ 11 C]WAY100635 only). Twelve healthy control subjects (HC) subjects were scanned with [ 11 C]DASB, and another 13 were scanned with [ 11 C]WAY100635. Binding potential (BP p , mL/cm 3 ) and the specific to nonspecific partition coefficient (BP ND , unitless) were derived for both tracers using a two-tissue compartment model and compared with control subjects across different brain regions. Relationships to severity of alcoholism were assessed. Results No significant differences were observed in regional BP p or BP ND between patients and control subjects in any of the regions examined. No significant relationships were observed between regional 5-HT transporter availability, 5-HT 1A availability, and disease severity, with the exception of a significant negative correlation between 5-HT transporters and years of dependence in amygdala and insula. Conclusion This study did not find alterations in measures of 5-HT 1A or 5-HT transporter levels in patients with type II alcoholism.

Changes in endogenous dopamine levels can be detected in humans using positron emission tomography scans by measuring the amount by which a specific D2/3 radioligand is displaced. In some cases, a challenge drug such as amphetamine is introduced to increase the amount of dopamine released into the synaptic cleft. Although intravenous amphetamine is often utilized, oral amphetamine has been shown to be just as effective in increasing endogenous dopamine levels. Based on our own use of oral amphetamine as a challenge drug, we have retroactively reviewed our study charts to determine the cardiovascular safety of 0.5 mg kg(-1) oral d-amphetamine. Of 172 amphetamine administrations in 144 individuals, only 2.8% of subjects experienced any transient adverse effects. In addition, we found no clinically relevant differences in increases of vital signs between healthy controls and patients. We therefore reaffirm the safety of 0.5 mg kg(-1) oral amphetamine in subjects previously screened for cardiovascular risk factors.

Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence.To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects. [11C]FLB 457 binding potential, specific compared to nondisplaceable uptake (BPND), was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg-1 of d-amphetamine.Amphetamine-induced displacement of [11C]FLB 457 binding potential (ΔBPND) was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe.The results of this study, for the first time, unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism.

Positron emission tomography (PET) imaging studies in cocaine abusers have shown that low dopamine release in the striatum following an amphetamine challenge is associated with higher relapse rates. One possible mechanism that might lead to lower amphetamine-induced dopamine release is low availability of dopamine storage vesicles in the presynaptic terminals for release. Consistent with this hypothesis, postmortem studies have shown low levels of vesicular monoamine transporter, type 2 (VMAT2), the membrane protein that regulates the size of the vesicular dopamine pool, in cocaine abusers relative to healthy subjects. To confirm the postmortem findings, the authors used PET and the VMAT2 radioligand [¹¹C]-(+)-dihydrotetrabenazine (DTBZ) to assess the in vivo VMAT2 availability in a group of 12 recently abstinent cocaine-dependent subjects and matched healthy comparison subjects.[¹¹C]DTBZ nondisplaceable binding potential (BP(ND)) was measured by kinetic analysis using the arterial input function or, if arterial input was unavailable, by the simplified reference tissue method.[¹¹C]DTBZ BP(ND) was significantly lower in the cocaine abusers than in the comparison subjects in the limbic striatum (10.0% lower), associative striatum (-13.4%), and sensorimotor striatum (-11.5%).The results of this in vivo PET study confirm previous in vitro reports of low VMAT2 availability in the striatum of cocaine abusers. It also suggests a compensatory down-regulation of the dopamine storage vesicles in response to chronic cocaine abuse and/or a loss of dopaminergic terminals. Further research is necessary to understand the clinical relevance of this observation to relapse and outcome in abstinent cocaine abusers.

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [(11)C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [(11)C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [(11)C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [(11)C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [(11)C]flumazenil VT in Group II in association cortices (6.8 ± 0.8 mL g-1 vs. 7.3 ± 0.4 mL g-1;p = 0.03), sensory cortices (6.7 ± 0.8 mL g-1 vs. 7.3 ± 0.5 mL g-1;p = 0.02) and limbic regions (5.2 ± 0.6 mL g-1 vs. 5.7 ± 0.3 mL g-1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [(11)C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.

Genetic, pharmacologic, and physiological data suggest that individuals with anorexia nervosa (AN) have altered striatal dopamine (DA) function.We used an amphetamine challenge and positron emission tomography [(11) C]raclopride paradigm to explore DA striatal transmission in 10 recovered (REC) AN compared with 9 control women (CW).REC AN and CW were similar for baseline, postamphetamine [(11) C]raclopride binding potential (BP(ND) ) and change (Δ) in BP(ND) for all regions. In CW, ventral striatum Δ BP(ND) was associated with euphoria (r = -0.76; p = 0.03), which was not found for REC AN. Instead, REC AN showed a significant relationship between anxiety and Δ BP(ND) in the precommissural dorsal caudate (r = -0.62, p = 0.05).REC AN have a positive association between endogenous DA release and anxiety in the dorsal caudate. This finding could explain why food-related DA release produces anxiety in AN, whereas feeding is pleasurable in healthy participants.

Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [(11)C]MDL 100907 and [(11)C]DASB to characterize the 5-HT(2A) receptor and serotonin transporter in Asperger's Disorder. Seventeen individuals with Asperger's Disorder (age=34.3 ± 11.1 years) and 17 healthy controls (age=33.0 ± 9.6 years) were scanned with [(11)C]MDL 100907. Of the 17 patients, eight (age=29.7 ± 7.0 years) were also scanned with [¹¹C]DASB, as were eight healthy controls (age=28.7 ± 7.0 years). Patients with Asperger's Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by two-tissue compartment modeling. The primary outcome measure was regional binding potential BP(ND). Neither regional [¹¹C]MDL 100907 BP(ND) nor [¹¹C]DASB BP(ND) was statistically different between the Asperger's and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT(2A) receptors and serotonin transporters in adult subjects with Asperger's disorder.

In a recent PET study, we demonstrated the ability to measure amphetamine-induced DA release in the human cortex with the relatively high affinity dopamine D₂/₃ radioligand [¹¹C]FLB 457 (Narendran et al., [2009] Synapse 63:447-461). The aim of this study was to evaluate the reproducibility and reliability of [¹¹C]FLB 457 in the same imaging paradigm we used to measure amphetamine-induced DA transmission. Six healthy human subjects (three males/three females)were studied twice with [¹¹C]FLB 457, once at baseline and again 3 h following the end of the baseline scan. D₂/₃ receptor binding parameters were estimated using a two-tissue compartment kinetic analysis in the cortical regions of interest and cerebellum (reference region). The test-retest variability and intraclass correlation coefficient were assessed for distribution volume (VT), binding potential relative to plasma concentration (BP(P)), and binding potential relative to non-displaceable uptake (BP(ND)) of [¹¹C]FLB 457. The test-retest variability of [¹¹C]FLB 457 VT, BPP, and BP(ND) were ≤15%, consistent with the published test-retest variability for this ligand in other brain regions (Sudo et al., [2001] Nucl Med Commun 22:1215-1221; Vilkman et al., [2000] Eur J Nucl Med 27:1666-1673). In addition, no significant decrease in [¹¹C]FLB457 BP(ND) was observed in the second scan compared to the first one. This suggests that the contribution of carryover mass of [¹¹C]FLB 457 to the measured reduction in[¹¹C]FLB 457 BP(ND) following amphetamine was relatively low. These data support the further validation of [¹¹C]FLB 457 as a tool to measure amphetamine-induced dopamine release in the human cortex.

Context A long-standing version of the dopamine hypothesis of schizophrenia postulates that hyperactivity of dopaminergic transmission at D 2 receptors in the limbic striatum is associated with the illness and that blockade of mesolimbic D 2 receptors is responsible for the antipsychotic action of D 2 receptor antagonists. Objective To localize dopaminergic hyperactivity within the striatum in schizophrenia. Design Case-control study. Setting Inpatient research unit. Participants Eighteen untreated patients with schizophrenia and 18 healthy control subjects matched for age, sex, ethnicity, parental socioeconomic status, cigarette smoking, and weight. Main Outcome Measures Percentage change in dopamine D 2 receptor availability in striatal subregions within each subject measured by positron emission tomography with carbon 11–labeled raclopride before and during pharmacologically induced dopamine depletion. Results In the associative striatum, acute dopamine depletion resulted in a larger increase in D 2 receptor availability in patients with schizophrenia (mean [SD], 15% [7%]) than in control subjects (10% [7%], P = .045), suggesting higher synaptic dopamine concentration. Within the associative striatum, this effect was most pronounced in the precommissural dorsal caudate (15% [8%] in patients vs 9% [8%] in controls, P = .03). No between-group differences were observed in the limbic and sensorimotor striatum. Conclusions These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine D(2/3) receptor agonist, and [(11)C]NPA is a suitable radiotracer to image D(2/3) receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study, the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic dopamine was assessed with PET in healthy humans and compared with that of the reference D(2/3) receptor antagonist radiotracer [11C]raclopride. Ten subjects (eight females and two males) were studied on two separate days, a minimum of 1 week apart, both with [11C]raclopride and [11C]NPA at baseline and after the administration of 0.5 mg x kg(-1) oral d-amphetamine. Kinetic modeling with an arterial input function was used to derive the binding potential relative to nonspecific uptake (BPND) in the ventral striatum (VST), caudate (CAD), and putamen (PUT). [11C]Raclopride BPND was significantly reduced by 9.7 +/- 4.4, 8.4 +/- 4.2, and 14.7 +/- 4.8% after amphetamine administration in the VST, CAD, and PUT. [11C]NPA BPND was also reduced significantly, by 16.0 +/- 7.0, 16.1 +/- 6.1, and 21.9 +/- 4.9% after the same dose of amphetamine in the VST, CAD, and PUT. Although these results suggest that [11C]NPA is more vulnerable to endogenous competition by dopamine compared with [11C]raclopride by a factor of 1.49 to 1.90, the same data for a related outcome measure, binding potential relative to plasma concentration, was not significant. Nevertheless, these data add to the growing literature that suggests D(2/3) agonist radiotracers are more vulnerable to endogenous competition by dopamine than existing D(2/3) antagonist radiotracers.

Objective: (−)-N-[11C]-propyl-norapomorphine (NPA) is a full dopamine D2/3 receptor agonist radiotracer suitable for imaging D2/3 receptors configured in a state of high affinity for agonists using positron emission tomography. The aim of the present study was to define the optimal analytic method to derive accurate and reliable D2/3 receptor parameters with [11C]NPA. Methods: Six healthy subjects (four females/two males) underwent two [11C]NPA scans in the same day. D2/3 receptor-binding parameters were estimated using kinetic analysis (using one- and two-tissue compartment models) as well as simplified reference tissue method in the three functional subdivisions of the striatum (associative striatum, limbic striatum, and sensorimotor striatum). The test–retest variability and intraclass correlation coefficient were assessed for distribution volume (VT), binding potential relative to plasma concentration (BPP), and binding potential relative to nondisplaceable uptake (BPND). Results: A two-tissue compartment kinetic model adequately described the functional subdivisions of the striatum as well as cerebellum time-activity data. The reproducibility of VT was excellent (≤10%) in all regions, for this approach. The reproducibility of both BPP (≤12%) and BPND (≤10%) was also excellent. The intraclass correlation coefficients of BPP and BPND were acceptable as well (>0.75) in the three functional subdivisions of the striatum. Although SRTM led to an underestimation of BPND values relative to that estimated by kinetic analysis by 8–13%, the values derived using both the methods were reasonably well correlated (r2 = 0.89, n = 84). Both methods were similarly effective in detecting the differences in [11C]NPA BPND between subjects. Conclusion: The results of this study indicate that [11C]NPA can be used to measure D2/3 receptors configured in a state of high affinity for the agonists with high reliability and reproducibility in the functional subdivisions of the human striatum. Synapse 63:574–584, 2009. © 2009 Wiley-Liss, Inc.

Positron emission tomography (PET) and the high affinity D(2/3) radiotracer [(18)F]fallypride allow the assessment of D(2/3) receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D(2) agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6+/-5.5% at 2 mg/day to 96.8+/-5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D(2) occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.

A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.

The aim of the present study was to define the optimal analytic method to derive accurate and reliable serotonin transporter (SERT) receptor parameters with (11)C-3-amino-4-(2-[(dimethylamino)methyl]phenylthio)benzonitrile ((11)C-DASB).Nine healthy subjects (5 females, 4 males) underwent two (11)C-DASB PET scans on the same day. Five analytic methods were used to estimate binding parameters in 10 brain regions: compartmental modeling with 1- and 2-tissue compartment models (1TC and 2TC), data-driven estimation of parametric images based on compartmental theory (DEPICT) analysis, graphical analysis, and the simplified reference tissue model (SRTM). Two variations in the fitting procedure of the SRTM method were evaluated: nonlinear optimization and basis function approach. The test/retest variability (VAR) and intraclass correlation coefficient (ICC or reliability) were assessed for 3 outcome measures: distribution volume (V(T)), binding potential (BP), and specific to nonspecific equilibrium partition coefficient (V(3)'').All methods gave similar values across all regions. The variability of V(T) was excellent (or =10%) in all regions, for the 1TC, 2TC, DEPICT, and graphical approaches. The variability of BP and V(3)'' was good in regions of high SERT density and poorer in regions of moderate and lower densities. The ICC of all 3 outcome measures was excellent in all regions. The basis function implementation of SRTM demonstrated improved reliability compared with nonlinear optimization, particularly in moderate and low-binding regions.The results of this study indicate that (11)C-DASB can be used to measure SERT parameters with high reliability and low variability in receptor-rich regions of the brain, with somewhat less reliability and increased variability in regions of moderate SERT density and poor reproducibility in low-density regions.

Striatal dopamine D2 receptors have been implicated in the neurobiology of cocaine addiction. Previous imaging studies showed reduced striatal D2 receptor availability in chronic cocaine abusers, and animal studies suggested that low D2 receptor availability promotes cocaine self-administration. Here, D2 receptor availability was assessed with positron emission tomography (PET) and [11C]raclopride in the limbic, associative, and sensori-motor subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. In addition, the relationship between regional D2 receptor availability and behavioral measures obtained in cocaine self-administration sessions was investigated in CCD subjects. [11C]Raclopride binding potential was significantly reduced by 15.2% in the limbic striatum, 15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD subjects compared to HC subjects. In CCD subjects, no relationship was detected between D2 availability in striatal regions and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine (a laboratory model of relapse). Thus, this study confirms previous reports of a modest decrease in D2 receptor availability in CCD subjects, and establishes that this decrease is generalized throughout the striatum. However, this study failed to demonstrate a relationship between D2 receptor availability and cocaine-induced cocaine-taking behavior. Additional research is warranted to unravel potential neurobiological traits that might confer vulnerability to relapse in detoxified CCD subjects.

Objective: The authors examined the relationships between clinical characteristics, cognitive functioning, and history of violent behavior and substance use among outpatients with schizophrenia. Methods: Ninety-six patients with a diagnosis of schizophrenia or schizoaffective disorder completed a clinical and neuropsychiatric battery that included tests of general intelligence, executive and frontal lobe function, visual-motor processing, and motor function. Violent behavior was defined on the basis of arrest records. Self-reported violent behavior and substance use were recorded. The study participants were separated into three groups: history of violent arrest (N=34), nonviolent arrest (N=23), and no arrest (N=39). The three groups were compared for differences in demographic characteristics, clinical symptoms, and scores on neuropsychological tests. Results: Fifty-seven (59 percent) of the 96 participants had a history of arrest. Persons who were arrested for nonviolent crimes had a significantly lower mean±SD number of arrests (3.39±3.7) than those arrested for violent crimes (9.24±8.9). No significant differences in neuropsychological test scores or clinical ratings were found between the three groups. The prevalence of substance use disorders was 65 percent, 57 percent, and 36 percent among patients with a history of violent, nonviolent, and no arrest, respectively. Only 47 percent of participants with a criminal history accurately reported this history, and 11 percent of participants with a history of drug-related arrests acknowledged previous substance use. Conclusions: Performance on neuropsychiatric tests does not distinguish stable outpatients with schizophrenia who have a history of violent behavior from those who do not have such a history. Two established predictors of violence, a history of arrests and substance abuse, are unreliable when assessed by self-report. (Psychiatric Services 54:1635–1640, 2003)

Molecular imaging, the study of receptors, transporters and enzymes, as well as other cellular processes, has grown in recent years to be one of the most active neuroimaging areas. The application of single photon emission tomography (SPECT) and positron emission tomography (PET) techniques to the study of psychiatric illness has lead to increased understanding of disease processes as well as validated, in vivo, theories of illness etiology. Within the field of psychiatry these techniques have been applied most widely to the study of schizophrenia. Studies within schizophrenia are largely limited to either the dopamine or serotonin system. This is due in large part to the availability of suitable radiotracers as well as the current theories on the etiology of the illness. Two basic study designs are used when studying schizophrenia using molecular imaging and make up the majority of studies reviewed in this manuscript. The first type, termed "clinical studies," compares the findings from PET and SPECT studies in those with schizophrenia to normal controls in an attempt to understand the pathophysiology of the illness. The second study design, termed "occupancy studies," uses these techniques to enhance the understanding of the mechanism of action of the medications used in treating this illness. This review will focus on the findings of molecular imaging studies in schizophrenia, focusing, for the most part, on the serotonin and dopamine systems. Emphasis will be placed on how these findings and techniques are currently being used to inform the development of novel treatments for schizophrenia.

Introduction: Accumulating evidence indicates that synchronization of cortical neuronal activity at gamma-band frequencies is important for various types of perceptual and cognitive processes. Experimental models as well as preclinical studies suggest that GABAA receptor-mediated transmission is required for the induction of network oscillations. However, to date, there is no evidence linking GABA transmission with gamma-band oscillations in humans. Here we show that the ability to increase extracellular GABA levels predicts frontal cortical gamma synchrony in healthy controls. Preclinical and prior imaging work suggests that increased GABA levels enhance the affinity of GABAA receptors for benzodiazepine (BDZ) ligands via a conformational change (termed the ‘GABA-shift’). Theoretically, such an increase in affinity of GABAA receptors should be detected as an increase in the binding of a GABAA BDZ-receptor site-specific PET radioligand.

12 páginas, 5 figuras.-- The following is a report of the meeting “Synaptic Dysfunction and Schizophrenia” held at the Juan March Center for International Meetings on Biology Workshop in Madrid, Spain, 10–12 February 2003.