Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal dopamine (DA) levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. Dopamine D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm HDC deficiency as a rare cause of TS and identify histamine-dopamine interactions in the basal ganglia as an important locus of pathology.

Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the brain. We measured the neuroinflammatory response produced by a systemic administration of the Escherichia coli lipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer [ 11 C]PBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min [ 11 C]PBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second [ 11 C]PBR28 scan. LPS administration significantly increased [ 11 C]PBR28 binding 30-60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with [ 11 C]PBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.neuroinflammation | PBR28 | endotoxin | microglia | cytokines

Synaptic vesicle glycoprotein 2A (SV2A) is ubiquitously present in presynaptic terminals. Here we report kinetic modeling and test-retest reproducibility assessment of the SV2A positron emission tomography (PET) radioligand [C]UCB-J in humans. Five volunteers were examined twice on the HRRT after bolus injection of [C]UCB-J. Arterial blood samples were collected for measurements of radiometabolites and free fraction. Regional time-activity curves were analyzed with 1-tissue (1T) and 2-tissue (2T) compartment models to estimate volumes of distribution ( V). Parametric maps were generated using the 1T model. [C]UCB-J metabolized fairly quickly, with parent fraction of 36 ± 13% at 15 min after injection. Plasma free fraction was 32 ± 1%. Regional time-activity curves displayed rapid kinetics and were well described by the 1T model, except for the cerebellum and hippocampus. V values estimated with the 2T model were similar to 1T values. Parametric maps were of high quality and V values correlated well with time activity curve (TAC)-based estimates. Shortening of acquisition time from 120 min to 60 min had a negligible effect on V values. The mean absolute test-retest reproducibility for V was 3-9% across regions. In conclusion, [C]UCB-J exhibited excellent PET tracer characteristics and has potential as a general purpose tool for measuring synaptic density in neurodegenerative disorders.

Microglia play an essential role in many brain diseases. Microglia are activated by local tissue damage or inflammation, but systemic inflammation can also activate microglia. An important clinical question is whether the effects of systemic inflammation on microglia mediates the deleterious effects of systemic inflammation in diseases such as Alzheimer's dementia, multiple sclerosis, and stroke. Positron Emission Tomography (PET) imaging with ligands that bind to Translocator Protein (TSPO) can be used to detect activated microglia. The aim of this study was to evaluate whether the effect of systemic inflammation on microglia could be measured with PET imaging in nonhuman primates, using the TSPO ligand [11C]PBR28. Methods Six female baboons (Papio anubis) were scanned before and at 1 h and/or 4h and/or 22h after intravenous administration of E. coli lipopolysaccharide (LPS; 0.1 mg/kg), which induces systemic inflammation. Regional time-activity data from regions of interest (ROIs) were fitted to the two-tissue compartmental model, using the metabolite-corrected arterial plasma curve as input function. Total volume of distribution (VT) of [11C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in VT from baseline. Serum levels of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) were used to assess correlations between systemic inflammation and microglial activation. In one baboon, immunohistochemistry was used to identify cells expressing TSPO. Results LPS administration increased [11C]PBR28 binding (F(3,6)=5.1, p=.043) with a 29±16 % increase at 1h (n = 4) and a 62±34% increase at 4h (n = 3) post-LPS. There was a positive correlation between serum IL-1β and IL-6 levels and the increase in [11C]PBR28 binding. TSPO immunoreactivity occurred almost exclusively in microglia and rarely in astrocytes. Conclusion In the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO that is readily detected with [11C]PBR28 PET. The effect of LPS on [11C]PBR28 binding is likely mediated by inflammatory cytokines. Activation of microglia may be a mechanism through which systemic inflammatory processes influence the course of diseases such as Alzheimer's, multiple sclerosis, and possibly depression.

Background Attention Deficit Hyperactivity Disorder (ADHD) is a psychiatric disorder that starts in childhood. The mechanism of action of methylphenidate (MPH), the most common treatment for ADHD, is unclear. In vitro, the affinity of MPH for the norepinephrine transporter (NET) is higher than that for the dopamine transporter (DAT). The goal of this study was to use Positron Emission Tomography to measure the occupancy of NET by MPH in vivo in humans. Methods We used (S,S)-[11C]methylreboxetine ([11C]MRB) to determine the Effective Dose 50 (ED50) of MPH for NET. In a within-subject design, healthy subjects (n=11) received oral, single-blind placebo and 2.5 mg, 10 mg, and 40 mg of MPH 75 minutes prior to [11C]MRB injection. Dynamic PET imaging was performed for 2 hrs with the High Resolution Research Tomograph. The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential (BPND) in the thalamus and other NET-rich regions. Results BPND was reduced by MPH in a dose-dependent manner in thalamus and other NET-rich regions. The global ED50 was estimated to be 0.14 mg/kg, therefore the average clinical maintenance dose of MPH (0.35–0.55 mg/kg) produces 70–80% occupancy of NET. Conclusions For the first time in humans, we demonstrate that oral MPH significantly occupies NET at clinically relevant doses. The ED50 is lower than that for DAT (0.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of MPH in ADHD.

Depression is associated with systemic inflammation. In animals, systemic inflammation can induce neuroinflammation and activation of microglia; however, postmortem studies have not convincingly shown that there is neuroinflammation in depression. The purpose of this study was to use positron emission tomography (PET) with [11C]PBR28, which binds to the neuroinflammation marker translocator protein 18 kDa (TSPO), to compare the level of TSPO between individuals with depression and control subjects. Ten individuals who were in an acute episode of major depression and 10 control subjects matched for TSPO genotype and other characteristics had a PET scan with arterial input function to quantify levels of TSPO in brain regions of interest (ROIs). Total volume of distribution (VT) of [11C]PBR28 was used as a measure of total ligand binding. The primary outcome was the difference in VT between the two groups; this was assessed using a linear mixed model with group as a between-subject factor and region as a within-subject factor. There was no statistically significant difference in [11C]PBR28 binding (VT) between the two groups. In fact, 7 of 10 individuals with depression had lower [11C]PBR28 binding in all ROIs compared to their respective genotype-matched control subjects. Future studies are needed to determine whether individuals with mild-to-moderate depression have lower TSPO levels and to assess whether individuals with severe depression and/or with elevated levels of systemic inflammation might have higher TSPO levels than control subjects.

Objectives The role of the norepinephrine transporter (NET) in cocaine dependence has never been demonstrated via in vivo imaging due to the lack of suitable NET radioligands. Here we report our preliminary studies evaluting the NET in individuals with cocaine dependence (COC) in comparison to healthy controls (HC) using (S,S)-[11C]methylreboxetine ([11C]MRB), the most promising C-11 labeled positron-emission tomography (PET) radioligand for NET developed to date. Methods Twenty two human volunteers (10 COC and 12 HC) underwent dynamic 11C-MRB-PET acquisition using a High Resolution Research Tomograph (HRRT). Binding potential (BPND) parametric images were computed using the simplified reference tissue model (SRTM2) with occipital cortex as reference region. BPND values were compared between the two groups. Results Locus coeruleus (LC), hypothalamus, and pulvinar showed a significant inverse correlation with age among HC (age range = 25–54 years; p = 0.04, 0.009, 0.03 respectively). The BPND was significantly increased in thalamus (27%; p < 0.02) and dorsomedial thalamic nuclei (30%; p < 0.03) in COC as compared to HC. Upon age normalization, the upregulation of NET in COC also reached significance in LC (63%, p < 0.01) and pulvinar (55%, p < 0.02) regions. Conclusion Our results suggest that (a) brain NET concentration declines with age in HC, and (b) there is a significant upregulation of NET in thalamus and dorsomedial thalamic nucleus in COC as compared to HC. Our results also suggest that the use of [11C]MRB and HRRT provides an effective strategy for studying alterations of the NET system in humans.