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We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct ‘neuroinflammatory signatures’. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. ‘radicular’ versus ‘axial’ back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of ‘fibromyalgianess’ (i.e. the degree of pain centralization, or ‘nociplastic pain’). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex–thalamus connectivity across groups. Our findings support the existence of ‘neuroinflammatory signatures’ that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.

Background Few studies have investigated how inflammation early in the disease course may affect AD progression over time despite converging evidence that elevated levels of inflammation are associated with AD in cross-sectional studies. Methods Two-hundred ninety-two research participants with CSF biomarkers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included in this study. Cox proportional hazards models were used to investigate whether baseline levels of inflammatory CSF markers were associated with incident mild cognitive impairment or AD and time to conversion. Potential moderating effects of sex and APOE4 were also examined. Results Elevated levels of pro-inflammatory markers TNF-α, IL-9, and IL-12p40 at baseline were associated with higher rates of conversion to MCI/AD. Interactions with sex and APOE4 were observed, such that women with elevated TNF- α and all APOE4 carriers with elevated IL-9 levels had shorter times to conversion. Additionally, TNF-α mediated the relationship between elevated IL-12p40 and IL-9. Conclusion Elevated inflammation markers are associated with incident MCI or AD, and the factors of sex and APOE4 status modify the time to conversion.

ObjectiveTo determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions.MethodsThirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [11C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses.ResultsCompared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks.ConclusionsThese findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.

Using positron emission tomography, we recently demonstrated elevated brain levels of the 18kDa translocator protein (TSPO), a glial activation marker, in chronic low back pain (cLBP) patients, compared to healthy controls (HC). Here, we first sought to replicate the original findings in an independent cohort (15 cLBP, 37.8±12.5 y/o; 18 HC, 48.2±12.8 y/o). We then trained random forest (RF) machine learning algorithms based on TSPO imaging features combining discovery and replication cohorts (totaling 25 cLBP, 42.4±13.2 y/o; 27 HC, 48.9±12.6 y/o), in order to explore whether image features other than the mean contain meaningful information that might contribute to the discrimination of cLBP patients and HC. Feature importance was ranked usind SHapley Additive exPlanations (SHAP) values, and the classification performance (in terms of AUC values) of classifiers containing only the mean, other features, or all features was compared using the DeLong test. Both region-of-interest (ROI) and voxelwise analyses replicated the original observation of thalamic TSPO signal elevations in cLBP patients compared to HC (p’s

The weak association between disability levels and "peripheral" (ie, knee) findings suggests that central nervous system alterations may contribute to the pathophysiology of knee osteoarthritis (KOA). Here, we evaluated brain metabolite alterations in patients with KOA, before and after total knee arthroplasty (TKA), using 1H-magnetic resonance spectroscopy (MRS). Thirty-four presurgical patients with KOA and 13 healthy controls were scanned using a PRESS sequence (TE = 30 ms, TR = 1.7 seconds, voxel size = 15 × 15 × 15 mm). In addition, 13 patients were rescanned 4.1 ± 1.6 (mean ± SD) weeks post-TKA. When using creatine (Cr)-normalized levels, presurgical KOA patients demonstrated lower N-acetylaspartate (NAA) (P0.001), higher myoinositol (mIns) (P0.001), and lower Choline (Cho) (P0.05) than healthy controls. The mIns levels were positively correlated with pain severity scores (r = 0.37, P0.05). These effects reached statistical significance also using water-referenced concentrations, except for the Cho group differences (P ≥ 0.067). Post-TKA patients demonstrated an increase in NAA (P0.01), which returned to the levels of healthy controls (P0.05), irrespective of metric. In addition, patients demonstrated postsurgical increases in Cr-normalized (P0.001), but not water-referenced mIns, which were proportional to the NAA/Cr increases (r = 0.61, P0.05). Because mIns is commonly regarded as a glial marker, our results are suggestive of a possible dual role for neuroinflammation in KOA pain and post-TKA recovery. Moreover, the apparent postsurgical normalization of NAA, a putative marker of neuronal integrity, might implicate mitochondrial dysfunction, rather than neurodegenerative processes, as a plausible pathophysiological mechanism in KOA. More broadly, our results add to a growing body of literature suggesting that some pain-related brain alterations can be reversed after peripheral surgical treatment.

Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [(11)C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [(11)C]-(L)-deprenyl-D(2) PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [(11)C]PBR28 PET. 11 FM patients and 11 HC were scanned using [(11)C]-(L)-deprenyl-D(2) PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V(T)) were computed from the [(11)C]PBR28 data. [(11)C]-(L)-deprenyl-D(2) was quantified using λk(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [(11)C]PBR28 V(T) and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [(11)C]-(L)-deprenyl-D(2) signal, including those demonstrating elevated [(11)C]PBR28 signal in patients (p’s≥0.53, uncorrected). The elevations in [(11)C]PBR28 V(T) and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [(11)C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p’s

BACKGROUND: Chronic pain and mood disorders share common neuroanatomical substrates involving disruption of the reward system. Although increase in negative affect (NA) and decrease in positive affect (PA) are well-known factors complicating the clinical presentation of chronic pain patients, our understanding of the mechanisms underlying the interaction between pain and PA/NA remains limited. Here, we used a validated task probing behavioral and neural responses to monetary rewards and losses in conjunction with functional magnetic resonance imaging (fMRI) to test the hypothesis that dysfunction of the striatum, a key mesolimbic structure involved in the encoding of motivational salience, relates to mood alterations comorbid with chronic pain. METHODS: Twenty-eight chronic musculoskeletal pain patients (chronic low back pain, n=15; fibromyalgia, n=13) and 18 healthy controls underwent fMRI while performing the Monetary Incentive Delay (MID) task. Behavioral and neural responses were compared across groups and correlated against measures of depression (Beck Depression Inventory) and hedonic capacity (Snaith-Hamilton Pleasure Scale). RESULTS: Compared to controls, patients demonstrated higher anhedonia and depression scores, and a dampening of striatal activation and incentive-related behavioral facilitation (reduction in reaction times) during reward and loss trials of the MID task (ps

BACKGROUND. Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [(11)C]Martinostat positron emission tomography (PET). METHODS. In a case-control study, relative [((11))C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS. Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls. CONCLUSIONS. These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans. FUNDING. National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.

Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (eg, microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far, the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared with healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18 kDa translocator protein, in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared with both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared with more superior segments). Furthermore, the neuroforaminal translocator protein signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.

Objective Cortical spreading depression (CSD) underlies the neurobiology of migraine with aura (MWA). Animal studies reveal networks of microvessels linking brain-meninges-bone marrow. CSD activates the trigeminovascular system, evoking a meningeal inflammatory response. Accordingly, this study examines the upregulation of an inflammatory marker in extra-axial tissues in migraine with visual aura. Methods We used simultaneously acquired 11 C-PBR28 positron emission tomography/magnetic resonance imaging data of 18kDa translocator protein (an inflammatory marker) in MWA patients (n = 11) who experienced headaches and visual aura in the preceding month. We measured mean tracer uptake (standardized uptake value ratio [SUVR]) in 4 regions of interest comprising the meninges plus the adjacent overlying skull bone (parameningeal tissues [PMT]). These data were compared to healthy controls and patients with pain (chronic low back pain). Results MWA had significantly higher mean SUVR in PMT overlying occipital cortex than both other groups, although not in the PMT overlying 3 other cortical areas. A positive correlation was also found between the number of visual auras and tracer uptake in occipital PMT. Interpretation A strong persistent extra-axial inflammatory signal was found in meninges and calvarial bone overlying the occipital lobe in migraine with visual auras. Our findings are reminiscent of CSD-induced meningeal inflammation and provide the first imaging evidence implicating inflammation in the pathophysiology of migraine meningeal symptoms. We suspect that this inflammatory focus results from a signal that migrates from underlying brain and if so, may implicate newly discovered bridging vessels that crosstalk between brain and skull marrow, a finding of potential relevance to migraine and other neuroinflammatory brain disorders. ANN NEUROL 2020;87:939-949.

We recently showed elevated levels of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in chronic low back pain patients (cLBP) compared to healthy controls(Loggia et al., 2015). Here, we test whether TSPO signal 1) can further subtype cLBP patients based on their clinical presentation, and 2) is associated with functional connectivity measures (because neuroinflammation may affect neuronal communication(Clark et al., 2015)). Patients with axial (cLBPAX; n=26; 43.7±16.6 y.o.) or radicular cLBP (cLBPRAD; n=28; 48.3±13.2 y.o.) received an integrated PET/MRI scan with the TSPO ligand [11C]PBR28. TSPO signal was quantified using standardized uptake values normalized by whole-brain signal (SUVR). Functional connectivity from primary somatosensory cortex (S1) (i.e., a region significant in the PET group comparison) was calculated from BOLD resting-state fMRI data. Connectivity and PET measures were compared across groups, correlated with and against each other and against the Fibromyalgia Screening Questionnaire (FSQ) scores, measure of pain “centralization”. Because two different scanners were used (BrainPET: 10 cLBPAX, 15 cLBPRAD; Biograph mMR: 16 cLBPAX, 13 cLBPRAD), scanner was included as a covariate in all analyses. Moreover, PET analyses also included Ala147Thr TSPO genotype, which predicts binding affinity to [11C]PBR28. In S1, TSPO signal and functional connectivity to the thalamus were: 1) higher in cLBPRAD compared to cLBPAX; 2) positively correlated with each other and 3) positively correlated with FSQ scores. Our data support the existence of different “neuroinflammatory signatures” in patients with different clinical presentation and that S1 neuroinflammatory signal is more pronounced in patients with higher pain “centralization”. Further, because S1 TSPO signal was correlated to S1-thalamus connectivity, our data support an association between neuroinflammatory changes and changes in neuronal communication, possibly indicating that the observed alterations reflect “neurogenic neuroinflammation”. Future studies are needed to determine whether neuroinflammation and related connectivity changes are possible therapeutic targets for chronic pain. 1R21NS087472-01A1; 1R01NS095937-01A; 1R01NS094306-01A1; W81XWH-14-1-0543.

The weak association between disability levels and “peripheral” (i.e., knee) findings suggests that central nervous system alterations may contribute to the pathophysiology of knee osteoarthritis (KOA). Here, we evaluated brain metabolite alterations in KOA patients, before and after total knee arthroplasty (TKA), using 1H-magnetic resonance spectroscopy (MRS). Thirty-four pre-surgical KOA patients and 13 healthy controls were scanned using a PRESS sequence (TE=30ms, TR=1.7s, voxel size=15 × 15 × 15mm). Additionally, a subset of patients (n=13) were re-scanned 4.1±1.6 (mean±SD) weeks post-TKA. When using Creatine (Cr)-normalized levels, pre-surgical KOA patients demonstrated lower N-acetylaspartate (NAA) (p≤0.01) and higher myoinositol (mIns) (p≤0.001), compared to healthy controls. The mIns levels were positively correlated with pain severity scores (r=0.37, p 0.05), irrespective of metric. Additionally, patients demonstrated post-surgical increases in Cr-normalized (p

Negative affect (NA) is a significant cause of disability for chronic pain patients. While little is known about the mechanism underlying pain-comorbid NA, previous studies have implicated neuroinflammation in the pathophysiology of both depression and chronic pain. Here, we tested the hypothesis that NA in pain patients is linked to elevations in the brain levels of the glial marker 18kDa translocator protein (TSPO), and changes in functional connectivity. 25 cLBP patients (42.4±13 years old; 13F, 12M) with chronic low back pain (cLBP) and 27 healthy control subjects (48.9±13 years old; 14F, 13M) received an integrated (i.e., simultaneous) positron emission tomography (PET) / magnetic resonance imaging (MRI) brain scan with the second-generation TSPO ligand [11C]PBR28. The relationship between [11C]PBR28 signal and NA was assessed first with regression analyses against Beck Depression Inventory (BDI) scores in patients, and then by comparing cLBP patients with little-to-no, or mild-to-moderate depression against healthy controls. Further, the relationship between PET signal, BDI and frontolimbic functional connectivity was evaluated in patients with mediation models. PET signal was positively associated with BDI scores in patients, and significantly elevated in patients with mild-to-moderate (but not low) depression compared to controls, in anterior middle and pregenual anterior cingulate cortices (aMCC, pgACC). In the pgACC, PET signal was also associated with this region’s functional connectivity to the dorsolateral PFC (pgACC-dlPFC), and mediated of the association between pgACC-dlPFC connectivity and BDI. These observations support a role for glial activation in pain-comorbid NA, identifying in neuroinflammation a potential therapeutic target for this condition.

Approximately 30% of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [18F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and eleven female controls completed study procedures. Subjects received one FAL PET scan while performing a “2-back” task, and one while performing a “0-back” (attentional control, “baseline”) task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain.

Although substantial evidence has established that microglia and astrocytes play a key role in the establishment and maintenance of persistent pain in animal models, the role of glial cells in human pain disorders remains unknown. Here, using the novel technology of integrated positron emission tomography-magnetic resonance imaging and the recently developed radioligand 11C-PBR28, we show increased brain levels of the translocator protein (TSPO), a marker of glial activation, in patients with chronic low back pain. As the Ala147Thr polymorphism in the TSPO gene affects binding affinity for 11C-PBR28, nine patient–control pairs were identified from a larger sample of subjects screened and genotyped, and compared in a matched-pairs design, in which each patient was matched to a TSPO polymorphism-, age- and sex-matched control subject (seven Ala/Ala and two Ala/Thr, five males and four females in each group; median age difference: 1 year; age range: 29–63 for patients and 28–65 for controls). Standardized uptake values normalized to whole brain were significantly higher in patients than controls in multiple brain regions, including thalamus and the putative somatosensory representations of the lumbar spine and leg. The thalamic levels of TSPO were negatively correlated with clinical pain and circulating levels of the proinflammatory citokine interleukin-6, suggesting that TSPO expression exerts pain-protective/anti-inflammatory effects in humans, as predicted by animal studies. Given the putative role of activated glia in the establishment and or maintenance of persistent pain, the present findings offer clinical implications that may serve to guide future studies of the pathophysiology and management of a variety of persistent pain conditions. * Abbreviations : LBP : low back pain SUV : standardized uptake value

Dopamine (DA) in the ventral striatum (VST) has long been implicated in addiction pathologies, yet its role in temporal decision-making is not well-understood.To determine if VST DA D2 receptor availability corresponds with greater impulsive choice in both nontreatment-seeking alcoholics (NTS) and social drinkers (SD).NTS subjects (n = 10) and SD (n = 13) received PET scans at baseline with the D2/D3 radioligand [(11)C]raclopride (RAC). Outside the scanner, subjects performed a delay discounting procedure with monetary rewards. RAC binding potential (BPND) was estimated voxelwise, and correlations were performed to test for relationships between VST BPND and delay discounting performance. Self-reported impulsivity was also tested for correlations with BPND.Across all subjects, greater impulsive choice for $20 correlated with lower BPND in the right VST. NTS showed greater impulsive choice than SD and were more impulsive by self-report. Across all subjects, the capacity of larger rewards to reduce impulsive choice (the magnitude effect) correlated negatively (p = 0.028) with problematic alcohol use (AUDIT) scores. Self-reported impulsivity did not correlate with BPND in VST.Preference for immediate reinforcement may reflect greater endogenous striatal DA or lower D2 number, or both. Alcoholic status did not mediate significant effects on VST BPND, suggesting minimal effects from alcohol exposure. The apparent lack of BPND correlation with self-reported impulsivity highlights the need for objective behavioral assays in the study of the neurochemical substrates of behavior. Finally, our results suggest that the magnitude effect may be more sensitive to alcohol-induced problems than single discounting measures.

Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol's classically conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal DA release in humans. Employing positron emission tomography (PET), we hypothesized that beer's flavor alone can reduce the binding potential (BP) of [(11)C]raclopride (RAC; a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [(11)C]RAC PET scans: one while tasting beer, and one while tasting Gatorade. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [(11)C]RAC BP, indicating that the alcohol-associated flavor cues induced DA release. BP reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal DA release, absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism.

Neuroinflammation is implicated in the pathophysiology of a growing number of human disorders, including multiple sclerosis, chronic pain, traumatic brain injury, and amyotrophic lateral sclerosis. As a result, interest in the development of novel methods to investigate neuroinflammatory processes, for the purpose of diagnosis, development of new therapies, and treatment monitoring, has surged over the past 15 years. Neuroimaging offers a wide array of non- or minimally invasive techniques to characterize neuroinflammatory processes. The intent of this Review is to provide brief descriptions of currently available neuroimaging methods to image neuroinflammation in the human central nervous system (CNS) in vivo. Specifically, because of the relatively widespread accessibility of equipment for nuclear imaging (positron emission tomography [PET]; single photon emission computed tomography [SPECT]) and magnetic resonance imaging (MRI), we will focus on strategies utilizing these technologies. We first provide a working definition of "neuroinflammation" and then discuss available neuroimaging methods to study human neuroinflammatory processes. Specifically, we will focus on neuroimaging methods that target (1) the activation of CNS immunocompetent cells (e.g. imaging of glial activation with TSPO tracer [(11)C]PBR28), (2) compromised BBB (e.g. identification of MS lesions with gadolinium-enhanced MRI), (3) CNS-infiltration of circulating immune cells (e.g. tracking monocyte infiltration into brain parenchyma with iron oxide nanoparticles and MRI), and (4) pathological consequences of neuroinflammation (e.g. imaging apoptosis with [(99m)Tc]Annexin V or iron accumulation with T2* relaxometry). This Review provides an overview of state-of-the-art techniques for imaging human neuroinflammation which have potential to impact patient care in the foreseeable future.

Anand A, Barkay G, Dzemidzic M, Albrecht D, Karne H, Zheng Q-H, Hutchins GD, Normandin MD, Yoder KK. Striatal dopamine transporter availability in unmedicated bipolar disorder. Bipolar Disord 2011: 13: 406–413. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Dopamine transmission abnormalities have been implicated in the etiology of bipolar disorder (BPD). However, there is a paucity of receptor imaging studies in BPD, and little information is available about the dopamine system in BPD. Reuptake of synaptic dopamine by the dopamine transporter (DAT) is the principal mechanism regulating dopamine neurotransmission, and is often used as a marker for presynaptic dopamine function. This positron emission tomography (PET) study investigated whether DAT availability differed between BPD and healthy control subjects. Methods: A total of 11 unmedicated BPD patients in either the euthymic or depressed phase and 13 closely matched healthy subjects underwent PET imaging with the DAT-selective radiotracer [11C]CFT and a structural magnetic resonance imaging (MRI) scan. Striatal binding potential (BPND) was estimated using the multilinear reference tissue model. Region of interest and analyses were conducted to test for differences in [11C]CFT BPND between groups. Results: Unmedicated BPD subjects had significantly lower DAT availability relative to healthy controls in bilateral dorsal caudate. Conclusions: The results of this study support the hypothesis that there are abnormalities in the dopaminergic system in BPD, and suggest that DAT availability may be related to the neuropathology of BPD. Future studies are needed to determine if DAT availability cycles with disease phase.

Background Striatal dopamine (DA) has been implicated in alcohol use disorders, but it is still unclear whether or not alcohol can induce dopamine release in social drinkers. Furthermore, no data exist on dopamine responses to alcohol in dependent drinkers. We sought to characterize the DA responses to alcohol intoxication in moderately large samples of social drinkers (SD) and nontreatment-seeking alcoholics (NTS). Methods Twenty-four SD and twenty-one NTS received two [ 11 C]raclopride (RAC) PET scans; one at rest, and one during an intravenous alcohol infusion, with a prescribed ascent to a target breath alcohol concentration (BrAC), at which it was then “clamped.” The alcohol clamp was started 5 min after scan start, with a linear increase in BrAC over 15 min to the target of 80 mg%, the legal threshold for intoxication. Target BrAC was maintained for 30 min. Voxel-wise binding potential (BP ND ) was estimated with MRTM2. Results IV EtOH induced significant increases in DA in the right ventral striatum in NTS, but not SD. No decreases in DA were observed in either group. Conclusions Alcohol intoxication results in distinct anatomic profiles of DA responses in SD and NTS, suggesting that in NTS, the striatal DA system may process effects of alcohol intoxication differently than in SD.