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Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (V̇O2peak) and physical activity level are associated with cerebral MOR availability and whether these phenotypes predict endogenous opioid release after a session of exercise.We studied 64 healthy lean men who performed a maximal incremental cycling test for V̇O2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA; in minutes per week), and underwent positron emission tomography with [11C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional positron emission tomography scan also after a 1-h session of moderate-intensity exercise and 12 of them also after a bout of high-intensity interval training.Higher self-reported MVPA level predicted greater opioid release after high-intensity interval training, and both V̇O2peak and MVPA level were associated with a larger decrease in cerebral MOR binding after aerobic exercise in the ventral striatum, orbitofrontal cortex, and insula. That is, more trained individuals showed greater opioid release acutely after exercise in brain regions especially relevant for reward and cognitive processing. Fitness was not associated with MOR availability.We conclude that regular exercise training and higher aerobic fitness may induce neuroadaptation within the MOR system, which might contribute to improved emotional and behavioral responses associated with long-term exercise.

The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer’s disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-β and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-β positron emission tomography (with [(18)F]MK6240 and [(18)F]AZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of [(18)F]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t(186) = −4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = −0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (ρ = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.

Background Associative learning and memory processes, including the generalization of previously learned associations, may be altered in schizophrenia. Deficits in schizophrenia in stimulus generalization, one of the simplest forms of memory, could interfere with the ability to efficiently categorize related, similar information, potentially leading to impairments in daily functioning. Methods To measure generalization in schizophrenia, 37 individuals with a nonaffective psychotic disorder and 32 demographically matched healthy control subjects underwent a Pavlovian fear conditioning and generalization procedure, which accounted for variation in perceptual ability across participants, while undergoing functional magnetic resonance imaging. Skin conductance and neural responses to conditioned (CS+), neutral (CS−), and generalization stimuli were measured. Explicit memory ratings reflecting successful generalization were also collected after the scanning, as well as measures of symptom severity. Results Compared with healthy control subjects, individuals with nonaffective psychotic disorders showed significant deficits in fear generalization across multiple measurements, with impairments in memory ratings and reductions in activation and deactivation of the salience and default networks, respectively, during fear generalization. Moreover, in the psychotic disorder group, greater behavioral and neural abnormalities in generalization were associated with higher levels of negative symptoms. Conclusions Fear generalization is impaired in psychotic illness. Given that successful generalization relies on a dynamic balance between excitatory and inhibitory neurotransmission, these results reveal a potentially quantifiable mechanism linked to negative symptoms that can be investigated further in future human and experimental animal studies.

Dopamine, a catecholamine neurotransmitter, has historically been associated with the encoding of reward, whereas its role in aversion has received less attention. Here, we systematically gather the vast evidence for a role of dopamine in the simplest form of aversive learning: passive aversive conditioning and extinction. In the past, crude methods were used to augment or inhibit dopamine in order to study its relationship with fear conditioning and extinction. More advanced techniques such as conditional genetic, chemogenic, and optogenetic approaches now provide causal evidence for dopamine’s role in these learning processes. Dopamine neurons encode fear and extinction-related information and convey the signal via activation of D1, D2, D3, and D4 receptor sites particularly in the amygdala, prefrontal cortex, and striatum in order to continuously form, consolidate, retrieve, and update fear and extinction memory in a dynamic and reciprocal manner. Based on the reviewed literature, we conclude that dopamine is crucial for the encoding of passive aversive conditioning and contributes in a way that is comparable to its role in encoding reward.

Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. To address this issue, we pooled data from four independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) to stimuli that were paired (the CS + ) or not paired (CS−) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS + vs. CS− SCRs) and responses to CS + and CS− separately were assessed. We found that acquisition of differential conditioned fear responses was significantly lower in individuals with schizophrenia than in healthy controls (Cohen’s d = 0.53). This effect was primarily related to a significantly higher response to the CS− stimulus in the schizophrenia compared to the control group. Moreover, the magnitude of this response to the CS− in the schizophrenia group was correlated with the severity of delusional ideation (p = 0.006). Other symptoms or antipsychotic dose were not associated with fear conditioning measures. In conclusion, individuals with schizophrenia who endorse delusional beliefs may be over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of abnormal associative learning in psychosis.

The Maltreatment and Abuse Chronology of Exposure (MACE) scale is a retrospective self-report scale that measures 10 distinct types of childhood maltreatment. Despite its increasing use, the factor structure of the MACE has not been thoroughly investigated. As such, the viability of the MACE total and subscale scores are uncertain. The current study investigated the factor structure of the MACE in order to quantify the reliability of its total and subscale scores. Two independent samples of participants (N=1051 & N=582) who completed the MACE were included in this study. Using confirmatory item response models, we tested one-factor and several bifactor models of participants’ responses. We used model-based indices to estimate the reliability of the MACE total and subscale scores, and to quantify the essential unidimensionality of the scale. We found the MACE total score was a reliable and valid measure of overall childhood maltreatment. In contrast, although we found MACE subscale scores exhibited adequate reliability, the vast majority of their reliable variance reflected general maltreatment and not any particular type of maltreatment as intended. We also found that the MACE is essentially unidimensional and some of its items exhibit differential item functioning by gender. Our results provide support for a one-factor structure of the MACE, as well as continued use of the MACE total score. Our results caution against the use of MACE subscale scores, which have little practical use insofar that they provide little unique, reliable information above and beyond the total score.

Background Secure attachment is important in maintaining an individual’s health and well-being. Attachment disturbances increase the risk for developing psychiatric disorders such as affective disorders. Yet, the neurobiological correlates of human attachment are poorly understood at the neurotransmitter level. We investigated whether adult attachment style is linked to functioning of the opioid and serotonergic systems in the human brain. Methods We used positron emission tomography with radioligands [11C]carfentanil and [11C]MADAM to quantify mu opioid receptor (n = 39) and serotonin transporter (n = 37) availability in volunteers with no current psychiatric disorders. Attachment style was determined according to the Dynamic-Maturational Model of Attachment and Adaptation with the structured Adult Attachment Interview. Results Secure attachment was associated with higher mu opioid receptor availability in the hippocampus, amygdala, thalamus, and prefrontal cortex when compared with insecure (i.e., avoidant or ambivalent groups combined) attachment. In contrast, attachment style was not associated with serotonin transporter availability. Conclusions Our results provide preliminary in vivo evidence that the opioid system may be involved in the neurocircuits associated with individual differences in adult attachment behavior. The results suggest that variation in mu opioid receptor availability may be linked with the individuals’ social relationships and psychosocial well-being and thus contributes to risk for psychiatric morbidity.

In contrast to cardiac sympathetic activity which can be assessed with established PET tracers, there are currently no suitable radioligands to measure cardiac parasympathetic (cholinergic) activity. A radioligand able to measure cardiac cholinergic activity would be an invaluable clinical and research tool since cholinergic dysfunction has been associated with a wide array of pathologies (e.g., chronic heart failure, myocardial infarction, arrythmias). [18F]Fluoroethoxybenzovesamicol (FEOBV) is a cholinergic radiotracer that has been extensively validated in the brain. Whether FEOBV PET can be used to assess cholinergic activity in the heart is not known. Hence, this study aimed to evaluate the properties of FEOBV for cardiac PET imaging and cholinergic activity mapping. PET data were collected for 40 minutes after injection of 230 ± 50 MBq of FEOBV in four healthy participants (1 female; Age: 37 ± 10; BMI: 25 ± 2). Dynamic LV time activity curves were fitted with Logan graphical, 1-tissue compartment, and 2-tissue compartment models, yielding similar distribution volume estimates for each participant. Our initial data show that FEOBV PET has favorable tracer kinetics for quantification of cholinergic activity and is a promising new method for assessing parasympathetic function in the heart.

Funder: Helmholts International BigBrain Analytics & Learning Laboratory, 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., For the Cambridge authors (Coles, Fryer & Aigbirhio): This work was funded by an MRC PET Neuroscience programme grant (Training and Novel Probes Programme in PET Neurochemistry - MR/K02308X/1) and by an MRC Developmental Pathway Funding Scheme grant (MR/L013215/1). This research in Cambridge was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. JPC was supported by a British Journal of Anaesthesia/Royal College of Anaesthetists grant from the National Institute of Academic Anaesthesia.

BackgroundIndividuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power.MethodsTo address this issue, data were pooled from 4 independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) during fear conditioning to stimuli that were paired (the CS+) and not paired (CS-) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS+ vs. CS-SCRs) and responses to CS+ and CS-separately were assessed.ResultsAcquisition of differential conditioned fear responses was significantly lower in individuals with schizophrenia than in healthy controls (Cohen’s d = 0.53). This effect was primarily related to a significantly higher response to the CS-stimulus in the schizophrenia compared to the control group. The magnitude of this response to the CS- in the schizophrenia group was correlated with the severity of delusional ideation. Other symptoms or antipsychotic dose were not associated with fear conditioning measures.ConclusionsIndividuals with schizophrenia who endorse delusional beliefs are over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of aberrant learning in psychosis.

Background Functional recovery of patients with clinical and subclinical psychosis is associated with clinical, neuropsychological and developmental factors. Less is known about how these factors predict functional outcomes in the same models. We investigated functional outcomes and their predictors in patients with first-episode psychosis (FEP) or a confirmed or nonconfirmed clinical high risk of psychosis (CHR-P vs. CHR-N). Methods Altogether, 130 patients with FEP, 60 patients with CHR-P and 47 patients with CHR-N were recruited and extensively examined at baseline (T0) and 9 (T1) and 18 (T2) months later. Global Assessment of Functioning (GAF) at T0, T1 and T2 and psychotic, depression, and anxiety symptoms at T1 and T2 were assessed. Functional outcomes were predicted using multivariate repeated ANOVA. Results During follow-up, the GAF score improved significantly in patients with FEP and CHR-P but not in patients with CHR-N. A single marital status, low basic education level, poor work situation, disorganization symptoms, perceptual deficits, and poor premorbid adjustment in patients with FEP, disorganization symptoms and poor premorbid adjustment in patients with CHR-P, and a low basic education level, poor work situation and general symptoms in patients with CHR-N predicted poor functional outcomes. Psychotic symptoms at T1 in patients with FEP and psychotic and depression symptoms at T1 and anxiety symptoms at T2 in patients with CHR-P were associated with poor functioning. Conclusions In patients with FEP and CHR-P, poor premorbid adjustment and disorganization symptomatology are common predictors of the functional outcome, while a low education level and poor work situation predict worse functional outcomes in patients with FEP and CHR-N. Interventions aimed at improving the ability to work and study are most important in improving the functioning of patients with clinical or subclinical psychosis.

BackgroundFunctional recovery of patients with clinical and sub-clinical psychosis is associated with clinical, neuropsychological and developmental factors. Less is known how these factors predict functional outcome in same models.AimWe investigated functional outcome and its predictors in patients with first-episode psychosis (FEP) or confirmed vs. non-confirmed clinical high risk to psychosis (CHR-P vs. CHR-N).MethodsAltogether, 130 FEP, 60 CHR-P and 47 CHR-N patients were recruited and extensively examined at baseline (T0) and at 9 (T1) and 18 (T2) months after baseline. Global Assessment of Functioning (GAF) at T0, T1 and T2, and psychotic, depression and anxiety symptoms at T1 and T2 were assessed. Functional outcome was predicted in multivariate repeated ANOVA.ResultsDuring follow-up, GAF improved significantly in FEP and CHR-P but not in CHR-N patients. In FEP, single marital status, low basic education, poor work situation, disorganised symptoms, perceptual deficits and poor premorbid adjustment, in CHR-P, disorganised symptoms and poor premorbid adjustment and in CHR-N, low basic education, poor work situation and general symptoms predicted poor functional outcome. In FEP, psychotic symptoms at T1 and in CHR-P, psychotic and depression symptoms at T1 and anxiety symptoms at T2 associated with poor functioning.DiscussionIn FEP and CHR-P patients, poor premorbid adjustment and disorganised symptomatology are common predictors for functional outcome, while poor education and work situation predict poor functional outcome in FEP and CHR-N patients. Interventions aimed to improve studying and ability to work are most important in improving functioning of patients with clinical or subclinical psychosis.

BackgroundBariatric surgery is the most effective method for weight loss in morbid obesity. There is significant individual variability in the weight loss outcomes, yet factors leading to postoperative weight loss or weight regain remain elusive. Alterations in the µ-opioid receptor (MOR) and dopamine D2 receptor (D2R) systems are associated with obesity, appetite control, and reward processing. The magnitude of initial brain receptor system perturbation is a plausible predictor of long-term surgical weight loss outcomes. The aim was to test this hypothesis by measuring obese subjects’ MOR and D2R availability with positron emission tomography (PET) preoperatively before bariatric surgery and then assessing their weight development association with regional MOR and D2R availabilities at 2-year follow-up.MethodsWe studied 19 morbidly obese women (mean BMI 40, mean age 43) scheduled to undergo bariatric surgery, i.e. Roux-en-Y gastric bypass or sleeve gastrectomy, according to their standard clinical treatment. Preoperative MOR and D2R availabilities were measured using PET with [11C]carfentanil and [11C]raclopride, respectively. Subject weight was recorded at 3, 6, 12, and 24 months after surgery. Radiotracer binding potentials (BPND) were extracted and correlated with patient weight at different time points. ROIs were delineated in the striatum and in limbic and paralimbic components of the emotion and reward networks.ResultsMOR availabilities were not correlated with preoperative weight. MOR availabilities in the amygdala (r = −0.54), insula (r = −0.46), ventral striatum (r = −0.48) and putamen (r = −0.49) were associated with subject weight at 3 months. Significant association was found in the amygdala at 6 months (r = −0.53), 12 (r = −0.49), and 24 months (r = −0.50). D2R availabilities were associated with neither preoperative weight nor weight loss at any follow-up time point.ConclusionsTo our knowledge, this is the first study to demonstrate that neuroreceptor markers prior to bariatric surgery in patients with morbid obesity are associated with the postoperative weight loss. Preoperative MOR availability in the amygdala was associated with long-term postoperative weight development after surgery suggesting that postoperative weight regain may derive from dysfunction in the opioid system. Postoperative weight loss outcomes after bariatric surgery may be partially predicted based on preoperative receptor availability opening up new potential for treatment possibilities.Clinical Trials RegistrationSleevePET2, NCT01373892, http://www.clinicaltrials.gov

Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (VO2peak) and physical activity level are associated with cerebral MOR availability, and whether these phenotypes predict endogenous opioid release following aerobic exercise. We studied 64 healthy lean men who performed a maximal incremental cycling test for VO2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA, min/week), and underwent positron emission tomography with [11C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional PET scan also after a one-hour session of moderate-intensity exercise. Higher VO2peak and self-reported MVPA level was associated with larger decrease in cerebral MOR binding after aerobic exercise in ventral striatum, orbitofrontal cortex and insula. That is, higher fit and more trained individuals showed greater opioid release acutely following exercise in brain regions especially relevant for reward and cognitive processing. Higher VO2peak also associated with lower baseline BPND in the reward and pain circuits, i.e., in frontal and cingulate cortices as well as in temporal lobes and subcortically in thalamus and putamen. We conclude that higher aerobic fitness and regular exercise training may induce neuroadaptation within the MOR system which might contribute to improved emotional and behavioural responses associated with long-term exercise.

BackgroundObesity is a growing burden to health and economy worldwide. Obesity is associated with central μ-opioid receptor (MOR) downregulation, and the interaction between MOR and dopamine D2 receptor (D2R) system in the ventral striatum is disrupted among obese subjects. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying subjects undergoing surgical weight loss (bariatric surgery) procedure.MethodsWe recruited 20 healthy non-obese (mean BMI 22) and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and D2R availability was measured using positron emission tomography (PET) with [11C]carfentanil and [11C]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed to obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery.ResultsIn the control subjects, MOR and D2R availabilities were associated in the ventral striatum (r = .62) and dorsal caudate (r = .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r = .12) but unaltered association in dorsal caudate (r = .43). The association between MOR and D2R availabilities in the ventral striatum was recovered (r = .62) among obese subjects following the surgery-induced weight loss (mean total weight loss 22 %).ConclusionsBariatric surgery and concomitant weight loss recovers the interaction between MOR and D2R in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioural interventions for treating obesity.Clinical Trials RegistrationSleevePET2, NCT01373892, http://www.clinicaltrials.gov

In contrast to cardiac sympathetic activity which can be assessed with established PET tracers, there are currently no suitable radioligands to measure cardiac parasympathetic (cholinergic) activity. A radioligand able to measure cardiac cholinergic activity would be an invaluable clinical and research tool since cholinergic dysfunction has been associated with a wide array of pathologies (e.g., chronic heart failure, myocardial infarction, arrythmias). [18F]Fluoroethoxybenzovesamicol (FEOBV) is a cholinergic radiotracer that has been extensively validated in the brain. Whether FEOBV PET can be used to assess cholinergic activity in the heart is not known. Hence, this study aimed to evaluate the properties of FEOBV for cardiac PET imaging and cholinergic activity mapping. PET data were collected for 40 minutes after injection of 230 ± 50 MBq of FEOBV in four healthy participants (1 female; Age: 37 ± 10; BMI: 25 ± 2). Dynamic LV time activity curves were fitted with Logan graphical, 1-tissue compartment, and 2-tissue compartment models, yielding similar distribution volume estimates for each participant. Our initial data show that FEOBV PET has favorable tracer kinetics for quantification of cholinergic activity and is a promising new method for assessing parasympathetic function in the heart.

Individual differences in educational attainment are linked to differences in intelligence, and predict important social, economic, and health outcomes. Previous studies have found common genetic factors that influence educational achievement, cognitive performance and total brain volume (i.e., brain size). Here, in a large sample of participants from the UK Biobank, we investigate the shared genetic basis between educational attainment and fine-grained cerebral cortical morphological features, and associate this genetic variation with a related aspect of cognitive ability. Importantly, we execute novel statistical methods that enable high-dimensional genetic correlation analysis, and compute high-resolution surface maps for the genetic correlations between educational attainment and vertex-wise morphological measurements. We conduct secondary analyses, using the UK Biobank verbal–numerical reasoning score, to confirm that variation in educational attainment that is genetically correlated with cortical morphology is related to differences in cognitive performance. Our analyses relate the genetic overlap between cognitive ability and cortical thickness measurements to bilateral primary motor cortex as well as predominantly left superior temporal cortex and proximal regions. These findings extend our understanding of the neurobiology that connects genetic variation to individual differences in educational attainment and cognitive performance.

Central opioidergic mechanisms may modulate the positive effects of physical exercise such as mood elevation and stress reduction. How exercise intensity and concomitant effective changes affect central opioidergic responses is unknown. We studied the effects of acute physical exercise on the cerebral μ-opioid receptors (MOR) of 22 healthy recreationally active males using positron emission tomography (PET) and the MOR-selective radioligand [11C]carfentanil. MOR binding was measured in three conditions on separate days: after a 60-min aerobic moderate-intensity exercise session, after a high-intensity interval training (HIIT) session, and after rest. Mood was measured repeatedly throughout the experiment. HIIT significantly decreased MOR binding selectively in the frontolimbic regions involved in pain, reward, and emotional processing (thalamus, insula, orbitofrontal cortex, hippocampus, and anterior cingulate cortex). Decreased binding correlated with increased negative emotionality. Moderate-intensity exercise did not change MOR binding, although increased euphoria correlated with decreased receptor binding. These observations, consistent with endogenous opioid release, highlight the role of the μ-opioid system in mediating affective responses to high-intensity training as opposed to recreational moderate physical exercise.

The endogenous opioid system supports a multitude of functions related to appetitive behavior in humans and animals, and it has been proposed to govern hedonic aspects of feeding thus contributing to the development of obesity. Here we used positron emission tomography to investigate whether feeding results in hedonia-dependent endogenous opioid release in humans. Ten healthy males were recruited for the study. They were scanned with the μ-opioid-specific ligand [(11)C]carfentanil three times, as follows: after a palatable meal, a nonpalatable meal, and after an overnight fast. Subjective mood, satiety, and circulating hormone levels were measured. Feeding induced significant endogenous opioid release throughout the brain. This response was more pronounced following a nonpalatable meal versus a palatable meal, and independent of the subjective hedonic responses to feeding. We conclude that feeding consistently triggers cerebral opioid release even in the absence of subjective pleasure associated with feeding, suggesting that metabolic and homeostatic rather than exclusively hedonic responses play a role in the feeding-triggered cerebral opioid release. SIGNIFICANCE STATEMENT The endogenous opioid system supports both hedonic and homeostatic functions. It has been proposed that overeating and concomitant opioid release could downregulate opioid receptors and promote the development of obesity. However, it remains unresolved whether feeding leads to endogenous opioid release in humans. We used in vivo positron emission tomography to test whether feeding triggers cerebral opioid release and whether this response is associated with pleasurable sensations. We scanned volunteers using the μ-opioid receptor-specific radioligand [(11)C]carfentanil three times, as follows: after an overnight fast, after consuming a palatable meal, and after consuming a nonpalatable meal. Feeding led to significant endogenous opioid release, and this occurred also in the absence of feeding-triggered hedonia. Feeding-triggered opioid release thus also reflects metabolic and homeostatic responses rather than hedonic responses exclusively.

Emotions are states of vigilant readiness that guide human and animal behaviour during survival‐salient situations. Categorical models of emotions posit neurally and physiologically distinct basic human emotions (anger, fear, disgust, happiness, sadness and surprise) that govern different survival functions. Opioid receptors are expressed abundantly in the mammalian emotion circuit, and the opioid system modulates a variety of functions related to arousal and motivation. Yet, its specific contribution to different basic emotions has remained poorly understood. Here, we review how the endogenous opioid system and particularly the μ receptor contribute to emotional processing in humans. Activation of the endogenous opioid system is consistently associated with both pleasant and unpleasant emotions. In general, exogenous opioid agonists facilitate approach‐oriented emotions (anger, pleasure) and inhibit avoidance‐oriented emotions (fear, sadness). Opioids also modulate social bonding and affiliative behaviour, and prolonged opioid abuse may render both social bonding and emotion recognition circuits dysfunctional. However, there is no clear evidence that the opioid system is able to affect the emotions associated with surprise and disgust. Taken together, the opioid systems contribute to a wide array of positive and negative emotions through their general ability to modulate the approach versus avoidance motivation associated with specific emotions. Because of the protective effects of opioid system‐mediated prosociality and positive mood, the opioid system may constitute an important factor contributing to psychological and psychosomatic resilience. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc

Electromagnetic noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation and transcranial electrical stimulation, are widely used in research and represent emerging clinical treatment options for many brain disorders. The brain-wide neurobiological effects of electromagnetic NIBS, however, are not yet fully characterized. The combination of NIBS with molecular brain imaging is a powerful tool for the investigation of these effects. Here, we conducted a systematic review of all published studies investigating the effects of all forms of electromagnetic NIBS using molecular imaging (positron emission tomography, single photon emission computed tomography). A meta-analysis was also conducted when sufficient studies employed similar methodologies. A total of 239 articles were identified, of which 71 were included in the review. Information was extracted about the study design, NIBS parameters, imaging parameters, and observed local and remote effects caused by the stimulation. Regional cerebral blood flow and glucose metabolism were the most common outcome measures, followed by dopamine neurotransmission. While the vast majority of studies obtained remote effects of stimulation in interconnected regions, approximately half of the studies showed local effects at the stimulation site. Our meta-analysis on motor cortex stimulation also showed consistent remote effects. The literature review demonstrates that although the local effects of NIBS as captured by molecular imaging are sometimes modest, there are robust remote changes in brain activity and neurotransmitter function. Finally, we discuss the potential pitfalls and methodological issues and identify gaps in the current knowledge that could be addressed using these techniques.

Positron emission tomography (PET) can be used for in vivo measurement of specific neuroreceptors and transporters using radioligands, while voxel-based morphometric analysis of magnetic resonance images allows automated estimation of local grey matter densities. However, it is not known how regional neuroreceptor or transporter densities are reflected in grey matter densities. Here, we analyzed brain scans retrospectively from 325 subjects and compared grey matter density estimates with three different neuroreceptors and transporter availabilities. µ-opioid receptors (MORs) were measured with [11C]carfentanil (162 scans), dopamine D2 receptors with [11C]raclopride (91 scans) and serotonin transporters (SERT) with [11C]MADAM (72 scans). The PET data were modelled with simplified reference tissue model. Voxel-wise correlations between binding potential and grey matter density images were computed. Regional binding of all the used radiotracers was associated with grey matter density in region and ligand-specific manner independently of subjects’ age or sex. These data show that grey matter density and MOR and D2R neuroreceptor / SERT availability are correlated, with effect sizes (r2) ranging from 0.04 to 0.69. This suggests that future studies comparing PET outcome measure different groups (such as patients and controls) should take grey matter density differences between the groups into account.

Processing of positron emission tomography (PET) data typically involves manual work, causing inter-operator variance. Here we introduce the Magia toolbox that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia with four tracers: [11C]carfentanil, [11C]raclopride, [11C]MADAM, and [11C]PiB. We used data from 30 control subjects for each tracer. Five operators manually delineated reference regions for each subject. The data were processed using Magia using the manually and automatically generated reference regions. We first assessed inter-operator variance resulting from the manual delineation of reference regions. We then compared the differences between the manually and automatically produced reference regions and the subsequently obtained binding potentials and standardized-uptake-value-ratios. The results show that manually produced reference regions can be remarkably different from each other, leading to substantial differences also in outcome measures. While the Magia-derived reference regions were anatomically different from the manual ones, Magia produced outcome measures highly consistent with the average of the manually obtained estimates. For [11C]carfentanil and [11C]PiB there was no bias, while for [11C]raclopride and [11C]MADAM Magia produced 3–5% higher binding potentials. Based on these results and considering the high inter-operator variance of the manual method, we conclude that Magia can be reliably used to process brain PET data.

Structural and functional abnormalities of the amygdala in schizophrenia have been well documented. Post-mortem studies suggest that the lateral nucleus is particularly affected in schizophrenia. It is not known whether the amygdala subnuclei are differently affected at the time of the first-episode psychosis or already at high-risk state. 75 first-episode psychosis patients (FEP), 45 clinical high-risk patients (CHR) and 76 population controls participated in this cross-sectional case-control study. Participants underwent T1-weighted 3T MRI scans, from which the amygdala was segmented using a newly developed automated algorithm. Because early adverse events increase risk for psychosis and affect the amygdala, we also tested whether experiences of childhood maltreatment associate with the putative amygdala subnuclei abnormalities. Compared to the population controls, FEP had smaller volumes of the lateral, and basal nuclei. In CHR, only the lateral nucleus was significantly smaller compared to the control subjects. Experience of childhood maltreatment was inversely associated with lateral nucleus volumes in FEP but not in CHR. These results show that the lateral and basal nuclei of the amygdala are already affected in FEP. These volumetric changes may reflect specific cellular abnormalities that have been observed in post-mortem studies in schizophrenia in the same subnuclei. Decreased volume of the lateral nucleus in CHR suggest that a smaller lateral nucleus could serve as a potential biomarker for psychosis risk. Finally, we found that the lateral nucleus volumes in FEP may be sensitive to the effects of childhood maltreatment.

IntroductionModelling of the radioactivity images produced by PET scanners into biologically meaningful quantities, such as binding potential, is a complex multi-stage process involving data retrieval, preprocessing, drawing reference regions, kinetic modelling, and post-processing of parametric images. The process is challenging to automatize mainly because of manual work related to input generation, thus prohibiting large-scale standardized analysis of brain PET data. To resolve this problem, we introduce the Magia pipeline that enables processing of brain PET data with minimal user intervention. We investigated the accuracy of Magia in the automatic brain-PET data processing with four tracers binding to different binding sites: [11C]raclopride, [11C]carfentanil, [11C]MADAM, and [11C]PiB.Materials and methodsFor each tracer, we processed 30 historical control subjects’ data with manual and automated methods. Five persons manually delineated the reference regions (cerebellar or occipital cortex depending on tracer) for each subject according to written and visual instructions. The automatic reference-region extraction was based on FreeSurfer parcellations. We first assessed inter-operator variance resulting from manual delineation of reference regions. Then we compared the differences between the manually and automatically produced reference regions and the subsequently obtained metrics.ResultsThe manually delineated reference regions were remarkably different from each other. The differences translated into differences in outcome measures (binding potential or SUV-ratio), and the intra-class correlation coefficients were between 47 % and 96 % for the tracers. While the Magia-derived reference regions were topographically very different from the manually defined reference regions, Magia produced outcome measures highly consistent with average of the manually obtained estimates. For [11C]carfentanil and [11C]PiB there was no bias, while for [11C]raclopride and [11C]MADAM Magia produced 3-5 % higher binding potentials as a result of slightly lower time-integrals of reference region time-activity curves.ConclusionEven if Magia produces reference regions that are anatomically different from manually drawn reference regions, the resulting outcome measures are highly similar. Based on these results and considering the high inter-operator variance of the manual method, the high level of standardization and strong scalability of Magia, we conclude that Magia can be reliably used to process brain PET data.

BACKGROUND: Generalization from previous experiences allows us to evaluate the affective value of novel events. In a previous study, we found that negative symptoms disrupt this ability in schizophrenia. A core negative symptom is an inability to anticipate pleasure (anticipatory anhedonia). Here, in a functional MRI experiment, we examined whether the generalization of conditioned fear responses is affected by the ability to anticipate pleasure in non-psychotic individuals. METHODS: 72 non-psychotic young adults with a range of subthreshold symptoms of psychopathology underwent a functional MRI scan while participating in a Pavlovian fear conditioning and generalization paradigm. Skin conductance responses were measured throughout the experiment. During the conditioning phase, one face was used as a conditioned stimulus and paired with an electrical shock (the CS+), whereas a different face was used as a neutral stimulus that was never paired with a shock (the CS-). For the generalization phase, eight stimuli that gradually morphed from the CS+ to the CS- were selected based on each individual’s ability to discriminate the two faces. Immediately after the experiment, subjects were asked to rate how likely each stimulus was followed by the shock (explicit shock likelihood ratings). The Temporal Experience of Pleasure Scale was used to measure the ability to experience and anticipate pleasure. We hypothesized that subjects with a diminished ability to anticipate pleasure would show lower levels of fear generalization. RESULTS: Across the full cohort, we observed typical (CS+ and CS+-like morphs > CS-) generalization gradients in the explicit ratings, skin conductance responses, and the BOLD responses of the anterior insula and dorsal anterior cingulate cortex. The reversed pattern of responses (CS- > CS+ and CS+ like morphs) was observed in the posterior cingulate cortex and angular gyrus. The caudate nucleus showed highest responses to the most ambiguous morphs. Individuals with a diminished ability to anticipate pleasure showed lower generalization (as reflected by their explicit ratings) and the ability to anticipate pleasure correlated negatively with responses of the caudate nucleus to ambiguous morphs. DISCUSSION: Non-psychotic individuals with a reduced ability to experience anticipatory pleasure show impairments in the generalization of conditioned fear. This finding parallels a similar, prior finding in schizophrenia patients with prominent negative symptoms. These results suggest that impairment in fear generalization may be linked to the pathophysiology of negative symptoms, even prior to the onset of psychotic illness. The study was supported by the grant 4R01MH095904.

Positron emission tomography (PET) studies suggest opioidergic system dysfunction in morbid obesity, while evidence for the role of the dopaminergic system is less consistent. Whether opioid dysfunction represents a state or trait in obesity remains unresolved, but could be assessed in obese subjects undergoing weight loss. Here we measured brain μ-opioid receptor (MOR) and dopamine D2 receptor (D2R) availability in 16 morbidly obese women twice-before and 6 months after bariatric surgery-using PET with [(11)C]carfentanil and [(11)C]raclopride. Data were compared with those from 14 lean control subjects. Receptor-binding potentials (BPND) were compared between the groups and between the pre- and postoperative scans among the obese subjects. Brain MOR availability was initially lower among obese subjects, but weight loss (mean=26.1 kg, s.d.=7.6 kg) reversed this and resulted in ~23% higher MOR availability in the postoperative versus preoperative scan. Changes were observed in areas implicated in reward processing, including ventral striatum, insula, amygdala and thalamus (P's