Maralee Y. Litschge

Positron emission tomography imaging of amphetamine‐induced dopamine release in the human cortex: A comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [11C]raclopride and [123I]IBZM, do not provide sufficient signal to noise ratio to quantify D2 receptors in extrastriatal areas, such as cortex, where the concentration of D2 receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D2 radioligands [11C]FLB 457 and [11C]fallypride to measure amphetamine‐induced changes in DA transmission in the human cortex. D2 receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg−1, oral), using both [11C]FLB 457 and [11C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BPND) in eight cortical regions. Under controlled conditions, [11C]FLB 457 BPND was 30–70% higher compared with [11C]fallypride BPND in cortical regions. Amphetamine induced DA release led to a significant decrease in [11C]FLB 457 BPND in five out the eight cortical regions evaluated. In contrast, no significant decrease in [11C]fallypride BPND was detected in cortex following amphetamine. The difference between [11C]FLB 457 and [11C]fallypride ability to detect changes in the cortical D2 receptor availability following amphetamine is related to the higher signal to noise ratio provided by [11C]FLB 457. These findings suggest that [11C]FLB 457 is superior to [11C]fallypride for measurement of changes in cortical synaptic dopamine. Synapse 63:447–461, 2009.

Tiagabine increases [11C]flumazenil binding in cortical brain regions in healthy control subjects

Accumulating evidence indicates that synchronization of cortical neuronal activity at γ-band frequencies is important for various types of perceptual and cognitive processes and that GABA-A receptor-mediated transmission is required for the induction of these network oscillations. In turn, the abnormalities in GABA transmission postulated to play a role in psychiatric conditions such as schizophrenia might contribute to the cognitive deficits seen in this illness. We measured the ability to increase GABA in eight healthy subjects by comparing the binding of [11C]flumazenil, a positron emission tomography (PET) radiotracer specific for the benzodiazepine (BDZ) site, at baseline and in the presence of an acute elevation in GABA levels through the blockade of the GABA membrane transporter (GAT1). Preclinical work suggests that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands (termed ‘GABA shift’). Theoretically, such an increase in the affinity of GABA-A receptors should be detected as an increase in the binding of a GABA-A BDZ-receptor site-specific PET radioligand. GAT1 blockade resulted in significant increases in mean (± SD) [11C]flumazenil-binding potential (BPND) over baseline in brain regions representing the major functional domains of the cerebral cortex: association cortex +15.2±20.2% (p=0.05), sensory cortex +13.5±15.5% (p=0.03) and limbic (medial temporal lobe, MTL) +16.4±20.2% (p=0.03). The increase in [11C]flumazenil-BPND was not accounted for by differences in the plasma-free fraction (fP; paired t-test p=0.24) or changes in the nonspecific binding (pons VT, p=0.73). Moreover, the ability to increase GABA strongly predicted (r=0.85, p=0.015) the ability to entrain cortical networks, measured through EEG γ synchrony during a cognitive control task in these same subjects. Although additional studies are necessary to further validate this technique, these data provide preliminary evidence of the ability to measure in vivo, with PET, acute fluctuations in extracellular GABA levels and provide the first in vivo documentation of a relationship between GABA neurotransmission and EEG γ-band power in humans.

Positron emission tomography imaging of D(2/3) agonist binding in healthy human subjects with the radiotracer [(11)C]-N-propyl-norapomorphine: preliminary evaluation and reproducibility studies.

(−)‐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.

Human Biodistribution and Dosimetry of the D2/3 Agonist 11C-N-Propylnorapomorphine (11C-NPA) Determined from PET

We measured the whole-body distribution of intravenously injected 11C-N-propylnorapomorphine (11C-NPA), a dopamine agonist PET tracer, in human subjects and determined the resulting absorbed radiation doses. Methods: Six subjects (3 women, 3 men) were injected with 11C-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. Results: The average NPA whole-body radiation dose was 3.17 × 10−3 mSv per MBq of injected 11C-NPA. The organ receiving the highest dose was the gallbladder wall, with an average of 2.81 × 10−2 mSv·MBq−1. Conclusion: On the basis of averaged dosimetry results, an administration of less than 1,780 MBq (<48 mCi) of 11C-NPA yields an organ dose of under 50 mSv (5 rem) to all organs.

Cognitive Enhancement Therapy in substance misusing schizophrenia: Results of an 18-month feasibility trial

Substance use is a frequent problem in schizophrenia, and although many substance misusing patients with the disorder also experience considerable cognitive impairments, such individuals have been routinely excluded from clinical trials of cognitive remediation that could support their functional and addiction recoveries. This study conducted a small-scale feasibility trial of Cognitive Enhancement Therapy (CET) in substance misusing schizophrenia patients to assess the feasibility and efficacy of implementing comprehensive neurocognitive and social-cognitive remediation in this population. A total of 31 schizophrenia outpatients meeting addiction severity criteria for alcohol and/or cannabis use were randomized to 18months of CET or usual care. Feasibility findings indicated high degrees of satisfaction with CET, but also presented significant challenges in the recruitment and retention of substance misusing patients, with high levels of attrition (50%) over the study period, primarily due to positive symptom exacerbation. Intent-to-treat efficacy analyses showed large and significant improvements in neurocognition (d=.86), social cognition (d=1.13), and social adjustment (d=.92) favoring CET. Further, individuals treated with CET were more likely to reduce alcohol use (67% in CET vs. 25% in usual care) during treatment (p=.021). These results suggest that once engaged and stabilized, CET is a feasible and potentially effective treatment for cognitive impairments in patients with schizophrenia who misuse alcohol and/or cannabis. Substance misusing patients who are able to engage in treatment may be able to benefit from cognitive remediation, and the treatment of cognitive impairments may help improve substance use outcomes among this underserved population.

Brief Report: Is Cognitive Rehabilitation Needed in Verbal Adults with Autism? Insights from Initial Enrollment in a Trial of Cognitive Enhancement Therapy

Cognitive rehabilitation is an emerging set of potentially effective interventions for the treatment of autism spectrum disorder, yet the applicability of these approaches for “high functioning” adults who have normative levels of intelligence remains unexplored. This study examined the initial cognitive performance characteristics of 40 verbal adults with autism enrolled in a pilot trial of Cognitive Enhancement Therapy to investigate the need for cognitive rehabilitation in this population. Results revealed marked and broad deficits across neurocognitive and social-cognitive domains, despite above-average IQ. Areas of greatest impairment included processing speed, cognitive flexibility, and emotion perception and management. These findings indicate the need for comprehensive interventions designed to enhance cognition among verbal adults with autism who have intact intellectual functioning.

Cognitive enhancement therapy for adult autism spectrum disorder: Results of an 18‐month randomized clinical trial

Cognitive remediation is a promising approach to treating core cognitive deficits in adults with autism, but rigorously controlled trials of comprehensive interventions that target both social and non‐social cognition over a sufficient period of time to impact functioning are lacking. This study examined the efficacy of cognitive enhancement therapy (CET) for improving core cognitive and employment outcomes in adult autism. Verbal adult outpatients with autism spectrum disorder (N = 54) were randomized to an 18‐month, single‐blind trial of CET, a cognitive remediation approach that integrates computer‐based neurocognitive training with group‐based training in social cognition, or an active enriched supportive therapy (EST) comparison focused on psychoeducation and condition management. Primary outcomes were composite indexes of neurocognitive and social‐cognitive change. Competitive employment was a secondary outcome. Intent‐to‐treat analyses indicated that CET produced significant differential increases in neurocognitive function relative to EST (d = .46, P = .013). Both CET and EST were associated with large social‐cognitive improvements, with CET demonstrating an advantage at 9 (d = .58, P = 0.020), but not 18 months (d = .27, P = 0.298). Effects on employment indicated that participants treated with CET were significantly more likely to gain competitive employment than those in EST, OR = 6.21, P = 0.023, which was mediated by cognitive improvement. CET is a feasible and potentially effective treatment for core cognitive deficits in adult autism spectrum disorder. The treatment of cognitive impairments in this population can contribute to meaningful improvements in adult outcomes. Autism Res 2018, 11: 519–530.

The ability to increase extracellular GABA predicts frontal cortical gamma synchrony

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.