Raclopride Positron Emission Tomography Research Articles

Effects of deep brain stimulation on dopamine D2 receptor binding in patients with treatment-refractory depression

BackgroundDepression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. MethodsSix patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. ResultsDepression and anxiety symptoms improved after 3–6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LimitationsThis study was limited to the small sample size and lack of a healthy control group. ConclusionsChronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.

The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise.

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n=16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n=18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.

Alterations in type 2 dopamine receptors across neuropsychiatric conditions: A large-scale PET cohort

PurposeAberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls. MethodsHere, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D2R) availability using [11C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls, and subjects with Parkinson’s disease (PD), antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D2R availability. We also analyzed the interregional correlation in D2R availability within each group. ResultsSubjects with PD showed the clearest decline in D2R availability. Overall, the groups showed high interregional correlation in D2R availability, while this pattern was weaker in violent offenders. Subjects with schizophrenia, pathological gambling, depression, or overweight did not show clear changes in either the regional receptor availability or the interregional correlation. ConclusionWe conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also how coupled regions are across people. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region coupling might be disrupted in violence.

Systemic inflammation enhances stimulant-induced striatal dopamine elevation in tobacco smokers

Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [11C]raclopride positron emission tomography three times—at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [11C]raclopride binding potential (ΔBPND) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment.

Binding of the Dual-Action Anti-Parkinsonian Drug AG-0029 to Dopamine D2 and Histamine H3 Receptors: A PET Study in Healthy Rats.

Introduction: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D2/D3 agonist/H3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods: Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D2/D3 receptor ligand [11C]raclopride or the histamine H3 receptor ligand [11C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [11C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [11C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution (VT) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results: Dopamine D2/3 receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the VT values of [11C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H3 receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions: Target engagement of AG-0029 as an agonist at dopamine D2/D3 receptors and an antagonist at histamine H3 receptors could be demonstrated in the rat brain with [11C]raclopride and [11C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D2/D3 and moderate (submicromolar) affinity to H3 receptors.

Potential Treat-to-Target Approach for Methamphetamine Use Disorder: A Pilot Study of Adenosine 2A Receptor Antagonist With Positron Emission Tomography.

Introduction: The misuse of stimulant drugs such as methamphetamine is a global public health issue. One important neurochemical mechanism of methamphetamine use disorder may be altered dopaminergic neurotransmission. For instance, previous studies using positron emission tomography (PET) have consistently shown that striatal dopamine D2-type receptor availability (quantified as binding potential; BPND) is lower in methamphetamine use disorder. Further, methamphetamine use is known to induce chronic neuroinflammation through multiple physiological pathways. Upregulation of D2-type receptor and/or attenuation of neuroinflammation may therefore provide a therapeutic effect for this disorder. In vitro studies have shown that blockage of adenosine 2A (A2A) receptors may prevent D2-receptor downregulation and neuroinflammation-related brain damage. However, no study has examined this hypothesis yet. Methods and Analysis: Using a within-subject design, this trial will assess the effect of the selective A2A receptor antagonist, istradefylline, primarily on D2-type BPND in the striatum, and secondarily on neuroinflammation in the whole brain in individuals with methamphetamine use disorder. The research hypotheses are that istradefylline will increase striatal D2-type BPND and attenuate neuroinflammation. Twenty participants with methamphetamine use disorder, aged 20–65, will be recruited to undergo [11C]raclopride PET (for every participant) and [11C]DAA1106 PET (if applicable) once before and once after administration of 40 mg/day istradefylline for 2 weeks. Neuropsychological measurements will be performed on the same days of the PET scans.

DyNAMiC: A prospective longitudinal study of dopamine and brain connectomes: A new window into cognitive aging.

Concomitant exploration of structural, functional, and neurochemical brain mechanisms underlying age‐related cognitive decline is crucial in promoting healthy aging. Here, we present the DopamiNe, Age, connectoMe, and Cognition (DyNAMiC) project, a multimodal, prospective 5‐year longitudinal study spanning the adult human lifespan. DyNAMiC examines age‐related changes in the brain’s structural and functional connectome in relation to changes in dopamine D1 receptor availability (D1DR), and their associations to cognitive decline. Critically, due to the complete lack of longitudinal D1DR data, the true trajectory of one of the most age‐sensitive dopamine systems remains unknown. The first DyNAMiC wave included 180 healthy participants (20–80 years). Brain imaging included magnetic resonance imaging assessing brain structure (white matter, gray matter, iron), perfusion, and function (during rest and task), and positron emission tomography (PET) with the [11C]SCH23390 radioligand. A subsample (n = 20, >65 years) was additionally scanned with [11C]raclopride PET measuring D2DR. Age‐related variation was evident for multiple modalities, such as D1DR; D2DR, and performance across the domains of episodic memory, working memory, and perceptual speed. Initial analyses demonstrated an inverted u‐shaped association between D1DR and resting‐state functional connectivity across cortical network nodes, such that regions with intermediate D1DR levels showed the highest levels of nodal strength. Evident within each age group, this is the first observation of such an association across the adult lifespan, suggesting that emergent functional architecture depends on underlying D1DR systems. Taken together, DyNAMiC is the largest D1DR study worldwide, and will enable a comprehensive examination of brain mechanisms underlying age‐related cognitive decline.

Nicotine Patch Alters Patterns of Cigarette Smoking-Induced Dopamine Release: Patterns Relate to Biomarkers Associated With Treatment Response.

IntroductionTobacco smoking is a major public health burden. The first-line pharmacological treatment for tobacco smoking is nicotine replacement therapy (eg, the nicotine patch (NIC)). Nicotine acts on nicotinic-acetylcholine receptors on dopamine terminals to release dopamine in the ventral and dorsal striatum encoding reward and habit formation, respectively.Aims and MethodsTo better understand treatment efficacy, a naturalistic experimental design combined with a kinetic model designed to characterize smoking-induced dopamine release in vivo was used. Thirty-five tobacco smokers (16 female) wore a NIC (21 mg, daily) for 1-week and a placebo patch (PBO) for 1-week in a randomized, counter-balanced order. Following 1-week under NIC and then overnight abstinence, smokers participated in a 90-minute [11C]raclopride positron emission tomography scan and smoked a cigarette while in the scanner. Identical procedures were followed for the PBO scan. A time-varying kinetic model was used at the voxel level to model transient dopamine release peaking instantaneously at the start of the stimulus and decaying exponentially. Magnitude and spatial extent of dopamine release were estimated. Smokers were subcategorized by nicotine dependence level and nicotine metabolism rate.ResultsDopamine release magnitude was enhanced by NIC in ventral striatum and diminished by NIC in dorsal striatum. More-dependent smokers activated more voxels than the less-dependent smokers under both conditions. Under PBO, fast metabolizers activated more voxels in ventral striatum and fewer voxels in dorsal striatum compared to slow metabolizers.ConclusionsThese findings demonstrate that the model captured a pattern of transient dopamine responses to cigarette smoking which may be different across smoker subgroup categorizations.ImplicationsThis is the first study to show that NIC alters highly localized patterns of cigarette smoking-induced dopamine release and that levels of nicotine dependence and nicotine clearance rate contribute to these alterations. This current work included a homogeneous subject sample with regards to demographic and smoking variables, as well as a highly sensitive model capable of detecting significant acute dopamine transients. The findings of this study add support to the recent identification of biomarkers for predicting the effect of nicotine replacement therapies on dopamine function which could help refine clinical practice for smoking cessation.

Dissecting Motor and Cognitive Component Processes of a Finger-Tapping Task With Hybrid Dopamine Positron Emission Tomography and Functional Magnetic Resonance Imaging.

Striatal dopamine is involved in facilitation of motor action as well as various cognitive and emotional functions. Positron emission tomography (PET) is the primary imaging method used to investigate dopamine function in humans. Previous PET studies have shown striatal dopamine release during simple finger tapping in both the putamen and the caudate. It is likely that dopamine release in the putamen is related to motor processes while dopamine release in the caudate could signal sustained cognitive component processes of the task, but the poor temporal resolution of PET has hindered firm conclusions. In this study we simultaneously collected [11C]Raclopride PET and functional Magnetic Resonance Imaging (fMRI) data while participants performed finger tapping, with fMRI being able to isolate activations related to individual tapping events. The results revealed fMRI-PET overlap in the bilateral putamen, which is consistent with a motor component process. Selective PET responses in the caudate, ventral striatum, and right posterior putamen, were also observed but did not overlap with fMRI responses to tapping events, suggesting that these reflect non-motor component processes of finger tapping. Our findings suggest an interplay between motor and non-motor-related dopamine release during simple finger tapping and illustrate the potential of hybrid PET-fMRI in revealing distinct component processes of cognitive functions.

Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward.

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).

Effects of an Adenosine A2A Receptor Antagonist on Striatal Dopamine D2-Type Receptor Availability: A Randomized Control Study Using Positron Emission Tomography.

Introduction: Altered dopaminergic neurotransmission, especially in the functioning of dopamine D2-type receptors, is considered central to the etiology of a variety of neuropsychiatric disorders. In particular, individuals with substance use disorders have been consistently observed to exhibit lower D2-type receptor availability (quantified as binding potential; BPND) using positron emission tomography (PET). Upregulation of D2-type receptor density thus may therefore provide a therapeutic effect for substance use disorders. Importantly, in vitro studies reveal that D2 receptors coexist with adenosine 2A (A2A) receptors to form the highest density of heteromers in the whole striatum, and there is a functional interaction between these two receptors. As such, blockade of A2A receptor’s function may prevent D2 receptor downregulation, yet no study has currently examined this hypothesis in humans.Methods and Analysis: This double-blind, randomized controlled trial aims to evaluate the effect of the A2A receptor antagonist istradefylline (compared to placebo) on both dopamine D2-type receptor availability in the human brain and on neuropsychological measurements of impulsivity. It is hypothesized that istradefylline will both increase striatal D2-type BPND and improve control of impulsivity more than placebo. Forty healthy participants, aged 20–65 with no history of psychiatric or neurological disorders, will be recruited and randomized into two groups and will undergo [11C]raclopride PET, once before and once after administration of either 40 mg/day istradefylline or placebo for 2 weeks. Neuropsychological measurements will be administered on the same days of the PET scans.Ethics and Dissemination: The study protocol was approved by the Certified Review Boards (CRB) of National Center of Neurology and Psychiatry (CR18-011) and prospectively registered with the Japan Registry of Clinical Trials (jRCTs031180131; https://jrct.niph.go.jp/latest-detail/jRCTs031180131). The findings of this study will be disseminated through peer reviewed scientific journals and conferences.Clinical Trial Registration:www.ClinicalTrials.gov, identifier jRCTs031180131.

Dopamine release during psychological stress in euthymic bipolar I disorder: a Positron Emission Tomography study with [11C]raclopride

BackgroundNeurochemical mechanisms underlying stress induced relapse of mood episodes in Bipolar I Disorder (BD) remain unknown. This study investigated whether euthymic BD patients have a greater dopamine release in ventral striatum, caudate and putamen in response to psychological stress using Positron Emission Tomography (PET) scanning with the radiotracer [11C]raclopride. MethodsEuthymic patients with BD (n = 10) and 10 matched healthy controls underwent two [11C]raclopride PET scans, one during a “stress” and the other in a “no stress” condition separated by at least 24 h. Montreal Imaging Stress Test (MIST) was used to induce stress during stress condition. Participants received an injection of [11C]raclopride over one minute followed by PET scan for 60 min. Participants were assessed for mood symptom severity at baseline, and before and after each scan. The reduction in [11C]raclopride binding in stress condition compared with non-stress rest condition for each subject provided an estimate of dopamine release due to stress. ResultsThere was a significant effect of stress in reducing the [11C]raclopride binding in the ventral striatum, caudate and putamen; however, no significant effects of group or condition x group interaction were found. LimitationsSmall sample size and recruitment of euthymic patients who may be less vulnerable to stress may limit the generalizability of findings. ConclusionsOur findings showed that psychological stress led to dopamine release in the basal ganglia for all participants but the magnitude of dopamine release during a stress task was not different between euthymic BD patients and healthy controls.

Assessment of transient dopamine responses to smoked cannabis

BackgroundDopaminergic mechanisms that may underlie cannabis’ reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D2/3 receptor antagonist [11C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample. MethodsPET emission data were acquired from regular cannabis users (n = 14; 7 M/7 F; 19–32 years old) over 90 min immediately after [11C]raclopride administration (584 ± 95 MBq) as bolus followed by constant infusion (Kbol = 105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 min after scan start. Plasma concentrations of Δ9-THC and metabolites and ratings of subjective “high” were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [11C]raclopride binding, linear-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region). ResultsCannabis smoking increased plasma Δ9-THC levels (peak: 0−10 min) and subjective high (peak: 0−30 min). Significant clusters (>16 voxels) modeled by transient reductions in [11C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans. ConclusionsThese preliminary data support the sensitivity of [11C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.

Automatic classification of idiopathic Parkinson’s disease and atypical Parkinsonian syndromes combining [11C]raclopride PET uptake and MRI grey matter morphometry

Objective. To explore the viability of developing a computer-aided diagnostic system for Parkinsonian syndromes using dynamic [11C]raclopride positron emission tomography (PET) and T1-weighted magnetic resonance imaging (MRI) data. Approach. The biological heterogeneity of Parkinsonian syndromes renders their statistical classification a challenge. The unique combination of structural and molecular imaging data allowed different classifier designs to be tested. Datasets from dynamic [11C]raclopride PET and T1-weighted MRI scans were acquired from six groups of participants. There were healthy controls (CTRL n = 15), patients with Parkinson’s disease (PD n = 27), multiple system atrophy (MSA n = 8), corticobasal degeneration (CBD n = 6), and dementia with Lewy bodies (DLB n = 5). MSA, CBD, and DLB patients were classified into one category designated as atypical Parkinsonism (AP). The distribution volume ratio (DVR) kinetic parameters obtained from the PET data were used to quantify the reversible tracer binding to D2/D3 receptors in the subcortical regions of interest (ROI). The grey matter (GM) volumes obtained from the MRI data were used to quantify GM atrophy across cortical, subcortical, and cerebellar ROI. Results. The classifiers CTRL vs PD and CTRL vs AP achieved the highest balanced accuracy combining DVR and GM (DVR-GM) features (96.7%, 92.1%, respectively), followed by the classifiers designed with DVR features (93.3%, 88.8%, respectively), and GM features (69.6%, 86.1%, respectively). In contrast, the classifier PD vs AP showed the highest balanced accuracy (78.9%) using DVR features only. The integration of DVR-GM (77.9%) and GM features (72.7%) produced inferior performances. The classifier CTRL vs PD vs AP showed high weighted balanced accuracy when DVR (80.5%) or DVR-GM features (79.9%) were integrated. GM features revealed poorer performance (59.5%). Significance. This work was unique in its combination of structural and molecular imaging features in binary and triple category classifications. We were able to demonstrate improved binary classification of healthy/diseased status (concerning both PD and AP) and equate performance to DVR features in multiclass classifications.

The Interplay Between Postsynaptic Striatal D2/3 Receptor Availability, Adversity Exposure and Odd Beliefs: A [11C]-Raclopride PET Study

Between unaffected mental health and diagnosable psychiatric disorders, there is a vast continuum of functioning. The hypothesized link between striatal dopamine signaling and psychosis has guided a prolific body of research. However, it has been understudied in the context of multiple interacting factors, subclinical phenotypes, and pre-postsynaptic dynamics. This work investigated psychotic-like experiences and D2/3 dopamine postsynaptic receptor availability in the dorsal striatum, quantified by in vivo [11C]-raclopride positron emission tomography, in a sample of 24 healthy male individuals. Additional mediation and moderation effects with childhood trauma and key dopamine-regulating genes were examined. An inverse relationship between nondisplaceable binding potential and subclinical symptoms was identified. D2/3 receptor availability in the left putamen fully mediated the association between traumatic childhood experiences and odd beliefs, that is, inclinations to see meaning in randomness and unfounded interpretations. Moreover, the effect of early adversity was moderated by a DRD2 functional variant (rs1076560). The results link environmental and neurobiological influences in the striatum to the origination of psychosis spectrum symptomology, consistent with the social defeat and diathesis-stress models. Adversity exposure may affect the dopamine system as in association with biases in probabilistic reasoning, attributional style, and salience processing. The inverse relationship between D2/3 availability and symptomology may be explained by endogenous dopamine occupying the receptor, postsynaptic compensatory mechanisms, and/or altered receptor sensitivity. This may also reflect a cognitively stabilizing mechanism in non-help-seeking individuals. Future research should comprehensively characterize molecular parameters of dopamine neurotransmission along the psychosis spectrum and according to subtype profiling.

Distinct and Common Large-Scale Networks of the Hippocampal Long Axis in Older Age: Links to Episodic Memory and Dopamine D2 Receptor Availability.

The hippocampal longitudinal axis has been linked to dissociated functional networks relevant to episodic memory. However, the organization of axis-dependent networks and their relation to episodic memory in aging remains less explored. Moreover, age-related deterioration of the dopamine (DA) system, affecting memory and functional network properties, might constitute a source of reduced specificity of hippocampal networks in aging. Here, we characterized axis-dependent large-scale hippocampal resting-state networks, their relevance to episodic memory, and links to DA in older individuals (n = 170, 64–68 years). Partial least squares identified 2 dissociated networks differentially connected to the anterior and posterior hippocampus. These overlapped with anterior–temporal/posterior–medial networks in young adults, indicating preserved organization of axis-dependent connectivity in old age. However, axis-specific networks were overall unrelated to memory and hippocampal DA D2 receptor availability (D2DR) measured with [11C]-raclopride positron emission tomography. Further analyses identified a memory-related network modulated by hippocampal D2DR, equally connected to anterior–posterior regions. This network included medial frontal, posterior parietal, and striatal areas. The results add to the current understanding of large-scale hippocampal connectivity in aging, demonstrating axis-dependent connectivity with dissociated anterior and posterior networks, as well as a primary role in episodic memory of connectivity shared by regions along the hippocampalaxis.

A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation of striatal dopamine binding in autism

The social motivation hypothesis of autism posits that autism spectrum disorder (ASD) is characterized by impaired motivation to seek out social experience early in life that interferes with the development of social functioning. This framework suggests that impaired mesolimbic dopamine function underlies compromised responses to social rewards in ASD. Although this hypothesis is supported by functional magnetic resonance imaging (fMRI) studies, no molecular imaging study has evaluated striatal dopamine functioning in response to rewards in ASD. Here, we examined striatal functioning during monetary incentive processing in ASD and controls using simultaneous positron emission tomography (PET) and fMRI. Using a bolus + infusion protocol with the D2/D3 dopamine receptor antagonist [11C]raclopride, voxel-wise binding potential (BPND) was compared between groups (controls = 12, ASD = 10) in the striatum. Striatal clusters showing significant between-group BPND differences were used as seeds in whole-brain fMRI general functional connectivity analyses. Relative to controls, the ASD group demonstrated decreased phasic dopamine release to incentives in the bilateral putamen and left caudate, as well as increased functional connectivity between a PET-derived right putamen seed and the precuneus and insula. Within the ASD group, decreased phasic dopamine release in the putamen was related to poorer theory-of-mind skills. Our findings that ASD is characterized by impaired striatal phasic dopamine release to incentives provide support for the social motivation hypothesis of autism. PET-fMRI may be a suitable tool to evaluate novel ASD therapeutics targeting the striatal dopamine system.

Neural correlates of head restraint: Unsolicited neuronal activation and dopamine release

To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and tight head restraint. While such a restraint is now a routine procedure in brain imaging, the physiological and psychological consequences resulting from the restraint have not been elucidated. To address this problem, we developed a restraint-free brain PET system and conducted PET scans under both restrained and non-restrained conditions. We examined whether head restraint during PET scans could alter brain activities such as regional cerebral blood flow (rCBF) and dopamine release along with psychological stress related to head restraint. Under both conditions, 20 healthy male participants underwent [15O]H2O and [11C]Raclopride PET scans during working memory tasks with the same PET system. Before, during, and after each PET scan, we measured physiological and psychological stress responses, including the State-Trait Anxiety Inventory (STAI) scores. Analysis of the [15O]H2O-PET data revealed higher rCBF in regions such as the parahippocampus in the restrained condition. We found the binding potential (BPND) of [11C]Raclopride in the putamen was significantly reduced in the restrained condition, which reflects an increase in dopamine release. Moreover, the restraint-induced change in BPND was correlated with a shift in the state anxiety score of the STAI, indicating that less anxiety accompanied smaller dopamine release. These results suggest that the stress from head restraint could cause unsolicited responses in brain physiology and emotional states. The restraint-free imaging system may thus be a key enabling technology for the natural depiction of the mind.

11 C]raclopride positron emission tomography study of dopamine-D2/3 receptor binding in patients with severe major depressive episodes before and after electroconvulsive therapy and compared to control subjects.

The aim of the study was to test: (i) if D2 /D3 binding in three functional subsections of striatum is different in patients with severe major depressive episodes than in controls; and (ii) if this difference is normalized after electroconvulsive therapy (ECT). Nine inpatients were examined with positron emission tomography (PET) and the radioligand [11 C]raclopride before and after an average of 8.4 ECT sessions. Treatment response was assessed using the Montgomery-Åsberg Depression Rating Scale. Nine age- and sex-matched controls were examined twice with PET and [11 C]raclopride. [11 C]raclopride binding was significantly lower in all three subsections of striatum in patients compared to controls (Cohen's dz , 1.14-1.68; P = 0.003-0.027). Montgomery-Åsberg Depression Ratings decreased significantly after ECT (P < 0.001; Cohen's dz , 2.9). ECT had no statistically significant effect on [11 C]raclopride binding, although post-ECT binding estimates were more similar to those obtained in controls in all subsections of striatum. Using PET and [11 C]raclopride, we found support for the notion that severe major depressive episodes are associated with significantly lower dopamine D2 /D3 binding in all three subsections of striatum compared to controls. We noted no significant effect on D2 /D3 binding in the patient group after response to ECT.

Neuroanatomical predictors of L-DOPA response in older adults with psychomotor slowing and depression: A pilot study

Declining function in dopamine circuits is implicated in normal aging and late-life depression (LLD). Dopamine augmentation recently has shown therapeutic promise, but predictors of response are unknown. Depressed elders with slowed gait underwent baseline magnetic resonance imaging (MRI) and [11C]raclopride positron emission tomography (PET). Subjects then received open treatment with carbidopa/levodopa (L-DOPA) for three weeks. Linear regressions examined relationships between baseline MRI measures, [11C]raclopride binding, and behavioral outcomes. Among N=16 participants aged 72.5±6.8 years, higher left superior temporal gyrus volume was associated with higher processing speed at baseline, while cortical thinning in a processing speed network was associated with greater improvement following L-DOPA. Greater volume and cortical thickness in brain regions associated with mobility were associated with higher baseline gait speed. Higher baseline white matter hyperintensity volume predicted less post-L-DOPA improvement on dual task gait speed and IDS-SR scores. Higher [11C]raclopride binding in the associative striatum was associated with cortical thickness in some, but not all, processing speed brain regions, while higher binding in sensorimotor striatum was significantly associated with left caudate volume. Limiting the conclusions drawn from this pilot study are the small sample size and open administration of L-DOPA. Greater baseline brain volumes and cortical thickness in regions supporting cognition and gait were associated with higher behavioral performance, while lower structural integrity was associated with increased responsivity to L-DOPA. If substantiated in larger studies, these findings could facilitate the targeting of dopaminergic treatments to those LLD patients most likely to respond.