Journal articles on the topic 'FMRI opioid'

AbstractBackground and purposeOpioids are potent analgesics. Opioids exert effects after interaction with opioid receptors. Opioid receptors are present in the peripheral- and central nervous system (CNS), but the analgesic effects are primarily mediated via receptors in the CNS. Objective methods for assessment of opioid effects may increase knowledge on the CNS processes responsible for analgesia. The aim of this review was to provide an overview of the most common objective methods for assessment of the spinal and supraspinal effects of opioids and discuss their advantages and limitations.MethodThe literature search was conducted in Pub Med (http://www.ncbi.nlm.nih.gov/pubmed) from November 2014 to June 2016, using free-text terms: “opioid”, “morphine” and “oxycodone” combined with the terms “pupillometry,” “magnetic resonance spectroscopy,” “fMRI,” “BOLD,” “PET,” “pharmaco-EEG”, “electroencephalogram”, “EEG,” “evoked potentials,” and “nociceptive reflex”. Only original articles published in English were included.ResultsFor assessment of opioid effects at the supraspinal level, the following methods are evaluated: pupillometry, proton magnetic resonance spectroscopy, functional resonance magnetic imaging (fMRI), positron emission tomography (PET), spontaneous electroencephalogram (EEG) and evoked potentials (EPs). Pupillometry is a non-invasive tool used in research as well as in the clinical setting. Proton magnetic resonance spectroscopy has been used for the last decades and it is a non-invasive technique for measurement of in vivo brain metabolite concentrations. fMRI has been a widely used non-invasive method to estimate brain activity, where typically from the blood oxygen level-dependent (BOLD) signal. PET is a nuclear imaging technique based on tracing radio labeled molecules injected into the blood, where receptor distribution, density and activity in the brain can be visualized. Spontaneous EEG is typically quantified in frequency bands, power spectrum and spectral edge frequency. EPs are brain responses (assessed by EEG) to a predefined number of short phasic stimuli. EPs are quantified by their peak latencies and amplitudes, power spectrum, scalp topographies and brain source localization.For assessment of opioid effects at the spinal level, the following methods are evaluated: the nociceptive withdrawal reflex (NWR) and spinal EPs. The nociceptive withdrawal reflex can be recorded from all limbs, but it is standard to record the electromyography signal at the biceps femoris muscle after stimulation of the ipsilateral sural nerve; EPs can be recorded from the spinal cord and are typically recorded after stimulation of the median nerve at the wrist.Conclusion and ImplicationsThe presented methods can all be used as objective methods for assessing the centrally mediated effects of opioids. Advantages and limitations should be considered before implementation in drug development, future experimental studies as well as in clinical settings. In conclusion, pupillometry is a sensitive measurement of opioid receptor activation in the CNS and from a practical and economical perspective it may be used as a biomarker for opioid effects in the CNS. However, if more detailed information is needed on opioid effects at different levels of the CNS, then EEG, fMRI, PET and NWR have the potential to be used. Finally, it is conceivable that information from different methods should be considered together for complementary information.

The aims of this study were to assess the effects of a μ-opioid antagonist, naloxone, on endogenous opioid systems and to evaluate the effect of naloxone on the CNS response to mild noxious heat. Doubled-blinded experiments were performed in a cross-over design in 10 healthy male volunteers. Functional magnetic resonance imaging (fMRI) data were collected before and during the infusion and also during thermal stimuli. Increased signal was observed in a number of cortical and subcortical brain regions for naloxone versus saline infusion. Cortical activation was induced in regions including cingulate, prefrontal cortex, and insula. Subcortical regions showing increased signal change included hippocampus and entorhinal cortex. A 46°C stimulus delivered to the back of the hand induced an overall increase in activation in a number of regions in the naloxone group that were not seen in the saline group (e.g., insula, orbitofrontal cortex, thalamus, and hippocampus). These results show that naloxone, even in the absence of psychophysical effects, produces activation in several brain regions that are known to have high levels of μ-opioid receptors and may be involved in endogenous analgesia. Our study is an example of how fMRI can measure subtle changes in brain activation induced by pharmacological agents without cognitive effects.

Abstract Emotions can be characterized by dimensions of arousal and valence (pleasantness). While the functional brain bases of emotional arousal and valence have been actively investigated, the neuromolecular underpinnings remain poorly understood. We tested whether the opioid and dopamine systems involved in reward and motivational processes would be associated with emotional arousal and valence. We used in vivo positron emission tomography to quantify μ-opioid receptor and type 2 dopamine receptor (MOR and D2R, respectively) availability in brains of 35 healthy adult females. During subsequent functional magnetic resonance imaging carried out to monitor hemodynamic activity, the subjects viewed movie scenes of varying emotional content. Arousal and valence were associated with hemodynamic activity in brain regions involved in emotional processing, including amygdala, thalamus, and superior temporal sulcus. Cerebral MOR availability correlated negatively with the hemodynamic responses to arousing scenes in amygdala, hippocampus, thalamus, and hypothalamus, whereas no positive correlations were observed in any brain region. D2R availability—here reliably quantified only in striatum—was not associated with either arousal or valence. These results suggest that emotional arousal is regulated by the MOR system, and that cerebral MOR availability influences brain activity elicited by arousing stimuli.

Connectome genetics seeks to uncover how genetic factors shape brain functional connectivity; however, the causal impact of a single gene’s activity on whole-brain networks remains unknown. We tested whether the sole targeted deletion of the mu opioid receptor gene (Oprm1) alters the brain connectome in living mice. Hypothesis-free analysis of combined resting-state fMRI diffusion tractography showed pronounced modifications of functional connectivity with only minor changes in structural pathways. Fine-grained resting-state fMRI mapping, graph theory, and intergroup comparison revealed Oprm1-specific hubs and captured a unique Oprm1 gene-to-network signature. Strongest perturbations occurred in connectional patterns of pain/aversion-related nodes, including the mu receptor-enriched habenula node. Our data demonstrate that the main receptor for morphine predominantly shapes the so-called reward/aversion circuitry, with major influence on negative affect centers.

Abstract Background The neurobiological mechanisms underlying anhedonia and other negative symptoms in schizophrenia are unknown. Understanding this would help identify treatments for these symptoms. Pre-clinical and human evidence shows the mu-opioid receptor plays a key role in reward processing and anhedonia. However, the contribution of Mu Opioid Receptor (MOR) signalling to negative symptoms and the reward processing abnormalities in schizophrenia is unknown. Here, we investigated for the first time in vivo in patients whether MOR availability is altered in schizophrenia and if this is associated with the neural processes underlying reward anticipation in patients with schizophrenia using multimodal neuroimaging. Methods Forty volunteers (n=20 patients with schizophrenia and 20 age and sex-matched healthy controls) received an [11C]-carfentanil PET scan to measure MOR availability, a structural MRI scan and a functional MRI scan while performing the Monetary Incentive Delay (MID) task to measure the neural response to reward anticipation. All the patients met criteria for persistent negative symptoms. Our primary ROI for the PET analysis was the striatum. In addition, we analysed MOR availability in brain regions in the hedonic network (the striatum, insula and anterior cingulate cortex). The fMRI analysis focused on brain regions in this hedonic network as these have previously associated with MOR mediated reward processing in humans and preclinical studies. Brain volumes of regions of interest (ROIs) were also extracted. Results The analysis showed significantly lower MOR availability in the striatum of patients with schizophrenia relative to controls (patients vs. controls (mean binding potential (BPND) ± SEM): 1.54 ± 0.06 vs. 1.7 ± 0.05, Cohen’s d= 0.7, t=-2.2, df (37), p<0.05). There was also a significant effect of both group (F (5, 222) = 334.5, p<0.05) and ROI (F (1, 222) = 5.65, p<0.05) on BPND measures in the hedonic brain network. The group* ROI interaction was not significant (F (5, 222) = 0.2167, p>0.05). There were no significant differences in the volume of the striatum or other brain regions between groups (patients vs controls: mean ± SEM (mm3) 13019 ± 302 vs 12937 ± 327 respectively, p = 0.86). Reward anticipation in controls was associated with increased neural activation in a widespread network of brain regions including the ventral striatum and insula. The activation in the ventral striatum was significantly lower in patients compared to healthy controls. MOR availability was positively correlated with neural activation in the insula during reward anticipation in controls (spearman’s rho=0.6, p=0.006) but not in patients (spearman’s rho=0.13, p=0.57). In contrast, MOR availability in the striatum was not associated with neural activation in the striatum. Discussion These data show for the first time in vivo that mu-opioid receptor availability is lower in schizophrenia across the hedonic brain network. Moreover, patients with schizophrenia show altered coupling between mu-opioid signalling in the insula and brain activation during reward anticipation. These findings identify the mu-opioid receptor as a potential therapeutic target for reward dysfunction in schizophrenia.

Abstract Objective Working memory (WM) deficits are associated with opioid use disorder (OUD). However, little research addresses WM during withdrawal. We used the N-back WM paradigm to assess whether differences exist between persons in withdrawal versus stable opioid doses. We also examined whether N-back performance or associated brain activity during either withdrawal or satiation predict subsequent abstinence versus relapse. Method We evaluated N-Back performance and associated brain function of 20 OUD patients during 3 T fMRI. Participants were actively using opioids during the first scan (SOWS M = 8.10, SD = 9.22) and abstained 24 hours before the second scan (SOWS M = 28.26, SD = 11.64), buprenorphine treatment began afterwards. Twelve participants (age: M = 33.92, SD = 5.99) completed both scans and were included in within-subject contrasts. Sixteen participants (age: M = 34.38, SD = 5.38) completed at least one scan and were evaluated on whether brain activation or performance was associated with relapse. Results Paired-sample t-tests revealed no significant difference on N-back accuracy (0-back: t = 0.78, p = .45, d = 0.23; 2-back: t = −0.28, p = .78, d = 0.08) or brain activation (2-back versus 0-back) across regions of interest (ROIs) associated with WM in prior studies between satiated and abstinent assessments (ts < 0.5, ps > .05). Contrasting relapsing and abstinent groups at follow-up revealed no significant difference in N-back accuracy (0-back: t = −0.30, p = .77, d = 0.14; 2-back: t = 0.43, p = .67, d = 0.22) or associated ROI brain activation (ts < 1.29, ps > .05). Conclusion This is the first investigation of brain and behavioral measures of WM in opiate withdrawal and relapse. No significant differences were found, and effect sizes were small. Further research that investigates direct (compensatory activation) and task-indirect systems (default network, motivation) during cognitive challenges is needed.

Drug dependence is defined as a chronic relapsing brain disorder that is defined by a compulsion to seek and use drugs despite negative consequences. Drug-related cues and stress are known to be key factors for drug use. It has been argued that drug use could be seen as self-medication in patients with drug dependence and co-occurring personality disorders. However, the relevance of co-occurring personality disorders for stress reactivity after drug use is not clear.Thirty drug-dependent patients on stable opioid maintenance treatment with and without personality disorders were examined in a randomized placebo-controlled crossover study to investigate the effects of diacetylmorphine (DAM = heroin) on stress reactivity. They were compared with 20 healthy volunteers receiving saline. The drug-dependent patients administered either their individual prescribed DAM dose or saline. Afterwards they completed four emotional tasks while brain responses were measured with functional magnetic resonance imaging (fMRI). Before and after the fMRI investigation, adrenocorticotropic hormone (ACTH), cortisol, DAM blood levels, and psychological stress parameters, such as anxiety, anger, and craving were measured.The findings of DAM effects on stress reactivity in patients with drug dependence and co-occurring personality disorders will be reported and clinical implications regarding specific psychosocial interventions will be discussed.

We report the first neural recording during ecstatic meditations called jhanas and test whether a brain reward system plays a role in the joy reported. Jhanas are Altered States of Consciousness (ASC) that imply major brain changes based on subjective reports: (1) external awareness dims, (2) internal verbalizations fade, (3) the sense of personal boundaries is altered, (4) attention is highly focused on the object of meditation, and (5) joy increases to high levels. The fMRI and EEG results from an experienced meditator show changes in brain activity in 11 regions shown to be associated with the subjective reports, and these changes occur promptly after jhana is entered. In particular, the extreme joy is associated not only with activation of cortical processes but also with activation of the nucleus accumbens (NAc) in the dopamine/opioid reward system. We test three mechanisms by which the subject might stimulate his own reward system by external means and reject all three. Taken together, these results demonstrate an apparently novel method of self-stimulating a brain reward system using only internal mental processes in a highly trained subject.

Fibromyalgia (FM) represents a condition that is still controversial in its entity, pathophysiology, diagnosis and management. The aim of this review is to focus on imaging aspects of FM, especially on novel approaches in molecular imaging, with a special focus on neuroimaging. Novel functional and molecular imaging findings may represent, eventually, future biomarkers both in research settings and in terms of clinical practice. Several imaging techniques have already been tested in clinical trials in the FM field, including functional MRI, positron emission tomography (PET) imaging with 18F-FDG in FM, PET imaging of the dopaminergic system, PET imaging of the GABAergic system, PET imaging with neuroinflammation and neuroimmune parameters, PET imaging of the opioid system and H215O-PET activation studies. Therefore, the potential role in the FM field of fMRI and different PET tracers has been discussed in different settings, serving as a comprehensive guide of novel imaging options both in research and in the clinical field.

Abstract Rationale Alcohol use disorder is a common and devastating mental illness for which satisfactory treatments are still lacking. Nalmefene, as an opioid receptor modulator, could pharmacologically support the reduction of drinking by reducing the (anticipated) rewarding effects of alcohol and expanding the range of treatment options. It has been hypothesized that nalmefene acts via an indirect modulation of the mesolimbic reward system. So far, only a few imaging findings on the neuronal response to nalmefene are available. Objectives We tested the effect of a single dose of 18 mg nalmefene on neuronal cue-reactivity in the ventral and dorsal striatum and subjective craving. Methods Eighteen non-treatment-seeking participants with alcohol use disorder (67% male, M = 50.3 ± 13.9 years) with a current high-risk drinking level (M = 76.9 ± 52 g of pure alcohol per day) were investigated using a cue-reactivity task during functional magnetic resonance imaging (fMRI) in a double-blind, placebo-controlled, cross-over study/design. In addition, self-reported craving was assessed before and after exposure to alcohol cues. Results An a priori defined region of interest (ROI) analysis of fMRI data from 15 participants revealed that nalmefene reduced alcohol cue-reactivity in the ventral, but not the dorsal striatum. Additionally, the subjective craving was significantly reduced after the cue-reactivity task under nalmefene compared to placebo. Conclusion In the present study, reduced craving and cue-reactivity to alcohol stimuli in the ventral striatum by nalmefene indicates a potential anti-craving effect of this drug via attenuation of neural alcohol cue-reactivity.

Abstract Background:One-third of adults with sickle cell disease (SCD) have daily, chronic pain. Despite the high prevalence of chronic pain in adults with SCD, the mechanism of is not well defined. In other chronic pain disorders, functional MRI (fMRI) demonstrates a re-organization of the brain's connectivity, which may be maladaptive and contribute to the development of a chronic pain syndrome. We performed fMRI in adults with SCD as well as age-matched controls in order to test two hypotheses: 1) functional connectivity is different between adults with SCD and controls, and 2) differences in functional connectivity among adults with SCD are associated with a more severe pain phenotype. Methods:We performed resting-state fMRI in adults with SCD and age-matched controls. Functional connectivity was calculated using two approaches: 1) a seed-voxel approach with the seed being periaqueductal gray (PAG), an area of the brain known to inhibit pain sensation, and 2) an inter-network functional connectivity strength (FCS) analysis, in which seven brain functional networks were selected based on previous brain modularity analysis findings. To calculate the inter-network FCS between networks A and B, the summation of all functional connectivities between two networks are used. Thereafter, the networks that were significantly different in FCS between SCD and controls were used to determine the association between altered functional connectivity and pain phenotype within SCD subjects. Pain phenotype measurements in SCD subjects included a day-of-study pain score, a 15-day diary to document daily pain and opioid use, McGill pain and Pain DETECT questionnaires, and quantitative sensory testing in response to mechanical, cold, and heat stimuli. Statistical analyses were performed using FSL and Matlab software. Results: A total of 27 adults were examined, including 13 with SCD (9 HbSS, 4 HbSC) and 14 age-matched controls. Seed-based functional connectivity analyses revealed significantly decreased connectivity in SCD as compared to controls between PAG and the regions involved in pain, sensation, salience, emotion, learning, and memory (temporal gyrus, anterior/posterior insula, parahippocampal gyrus, fusiform gyrus, precunes, posterior cingulate gyrus, anterior cingulate, subcallosal gyrus, paracentral gyrus, inferior/superior parietal lobe, inferior frontal gyrus and superior temporal gyrus) (P<0.001, t-test with AlphaSim correction). Furthermore, inter-network analyses show significantly decreased FCS in SCD as compared to controls among networks involved in salience, emotion, learning, and memory (between the salience network and the striatum network, between the salience network and the temporal network, and within both the salience network and the hippocampus network) (P<0.001, t-test). When these inter-network differences in FCS between SCD subjects and controls were examined within SCD subjects to determine the association with clinical phenotype, significant associations were found with age (rs=0.63, P<0.024, Spearman correlation analysis), SCD genotype (SS vs SC) (r2=0.43, P<0.016, linear regression analysis), and number of diary days with pain score >5 (r2=0.5, P<0.011, linear regression analysis). Conclusions: In adults with SCD compared to controls, there were differences in inter-network FCS, including the salience, striatum, temporal, and hippocampus networks, which are crucial networks for salience, emotion, learning, and memory. When these inter-network FCS differences were examined within adults with SCD, significant associations were found with age, SCD genotype and number of pain days. Taken together, these data suggest that altered connectivity in the brain of adults with SCD contributes to the development of a chronic pain syndrome. These changes in functional connectivity on fMRI could be used as a biomarker to determine the efficacy of interventions targeted to decrease chronic pain. Disclosures Field: NKT Therapeutics: Research Funding; Astellas Pharmaceuticals: Research Funding.

Background: Although Alcohol Use Disorder (AUD) is highly prevalent worldwide, treating this condition remains challenging. Further, potential treatments for AUD do not fully address alcohol-induced neuroadaptive changes. Understanding the effects of pharmacotherapies for AUD on the human brain may lead to tailored, more effective treatments, and improved individual clinical outcomes. Objectives: We systematically reviewed the literature for studies investigating pharmacotherapies for AUD that included neuroimaging-based treatment outcomes. We searched the PubMed, Scielo, and PsycINFO databases up to January 2021. Study eligibility criteria, participants, and interventions: Eligible studies included those investigating pharmacotherapies for AUD and employing functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and/or proton magnetic resonance spectroscopy (H-MRS). Study appraisal and synthesis methods: Two independent reviewers screened studies’ titles and abstracts for inclusion. Data extraction forms were shared among all the authors to standardize data collection. We gathered information on the following variables: sample size; mean age; sociodemographic and clinical characteristics; alcohol use status; study design and methodology; main neuroimaging findings and brain-regions of interest (i.e., brain areas activated by alcohol use and possible pharmacological interactions); and limitations of each study. Results: Out of 177 studies selected, 20 studies provided relevant data for the research topic. Findings indicate that: (1) Acamprosate and gabapentin may selectively modulate limbic regions and the anterior cingulate cortex; (2) Naltrexone and disulfiram effects may involve prefrontal, premotor, and cerebellar regions; (3) Pharmacotherapies acting on glutamate and GABA neurotransmission involve primarily areas underpinning reward and negative affective states, and; (4) Pharmacotherapies acting on opioid and dopamine systems may affect areas responsible for the cognitive and motor factors of AUD. Limitations: Most of the studies were focused on naltrexone. A small number of studies investigated the action of disulfiram and gabapentin, and no neuroimaging studies investigated topiramate. In addition, the time between medication and neuroimaging scans varied widely across studies. Conclusions: We identified key-brain regions modulated by treatments available for AUD. Some of the regions modulated by naltrexone are not specific to the brain reward system, such as the parahippocampal gyrus (temporal lobe), parietal and occipital lobes. Other treatments also modulate not specific regions of the reward system, but play a role in the addictive behaviors, including the insula and dorsolateral prefrontal cortex. The role of these brain regions in mediating the AUD pharmacotherapy response warrants investigation in future research studies.

Since the introduction of the gate-control theory, a plethora of evidence to support the spinal processing of pain signals has come to light. Cognitive and affective aspects of the pain experience indicate the importance of supraspinal structures, but the biological mechanisms have remained inadequately explored. Within the past decade, imaging techniques have emerged that enable in vivo assessment of the central opioidergic system and the central processing of pain. The two most important imaging modalities to this end are functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). This article will describe the underlying principles of these techniques and explain their importance in determining the loci of opioidergic pathways and their neuromodulatory influence on acute and chronic pain conditions, role in placebo effects, implication in drug dependence, and potential role in studying the analgesic efficacy of new drugs.

Abstract Sickle cell disease (SCD) is associated with impaired cognitive function, pain, cerebral stroke and other neural dysfunctions suggestive of altered brain function. The most common reason for hospitalization of SCD patients is pain. Sickle pain is unique compared to other clinical pain conditions because it includes chronic pain as well as acute pain due to vasoocclusive crisis. The neuropathic and nociceptive aspects of pain in SCD make pain treatment challenging. Opioids, the most common analgesics, are associated with liabilities, such as addiction and tolerance. As a result, patients are often under-treated because of a lack of an objective pain measurement system. We therefore sought to develop an unbiased pain quantification method using non-invasive imaging techniques to recognize the biomarkers of pain and altered brain function. We examined the brain network connectivity in SCD patients (N=14) and healthy controls (N=13) to identify altered activity between the two groups that can be used as biomarkers for chronic pain. All experimental procedures were approved by the IRB of the University of Minnesota, and all subjects gave written informed consent before participating in the study. Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) were simultaneously recorded while the subjects were in a wakeful resting state. A 3T Siemens Trio whole-body scanner and a 16 channel head coil with an echo-planar imaging (EPI) sequence were used to acquire fMRI data. EEG data was recorded using a 64-channel EEG cap and MR-compatible amplifiers. Seed-based region of interest (ROI) analysis was performed on the fMRI data using Brain Voyager QX software. EEG informed fMRI (EEG-fMRI) was performed for power and microstate analysis using Matlab and SPM8 software. Statistical activation maps (p<0.001, uncorrected) were generated from general linear models (GLM) based on the time courses found from power and microstate analysis. Seeds were placed in the insula regions, and the functional connectivity between the left and right insula appeared to be stronger in SCD patients than in healthy controls. This result was verified in EEG-fMRI analysis. Activation of the insula and striatum regions positively correlated with the beta band in SCD patients, where healthy controls showed less activation in the insula in the same frequency band. Microstates corresponding to insula activation were observed in both healthy controls and SCD patients; however, activation seems stronger in SCD patients. Activation in the striatum regions was also observed in microstates for SCD patients, but not for healthy controls. These results show that the insula and striatum regions have greater activation in SCD patients compared to controls, and that patients have altered brain connectivity during resting state. Insula activation could be related to the salience network, a resting state network that is responsible for processing external input, or to pain processing. The insula and striatum are some of the common brain regions that have been shown to be active during painful stimuli. This altered activation could be caused by sickle pain and could be a potential biomarker of pain intensity. Due to the non-invasive nature of these quantitative data, this method can have applications in the unbiased objective quantification of pain and treatment outcomes. Altered connectivity observed in SCD patients can also be used to help better understand the neural pathophysiology of sickle pain and can lead to better management strategies for these patients. This work was supported in part by NIH grant U01-HL117664 and NSF IGERT grant DGE-1069104. Disclosures No relevant conflicts of interest to declare.

Chronic pain is an important public health issue. Moreover, its adequate management is still considered a major clinical problem, mainly due to its incredible complexity and still poorly understood pathophysiology. Recent scientific evidence coming from neuroimaging research, particularly functional magnetic resonance (fMRI) and positron emission tomography (PET) studies, indicates that chronic pain is associated with structural and functional changes in several brain structures that integrate antinociceptive pathways and endogenous modulatory systems. Furthermore, the last two decades have witnessed a huge increase in the number of studies evaluating the clinical effects of noninvasive neuromodulatory methods, especially transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), which have been proved to effectively modulate the cortical excitability, resulting in satisfactory analgesic effects with minimal adverse events. Nevertheless, the precise neuromechanisms whereby such methods provide pain control are still largely unexplored. Recent studies have brought valuable information regarding the recruitment of different modulatory systems and related neurotransmitters, including glutamate, dopamine, and endogenous opioids. However, the specific neurocircuits involved in the analgesia produced by those therapies have not been fully elucidated. This review focuses on the current literature correlating the clinical effects of noninvasive methods of brain stimulation to the changes in the activity of endogenous modulatory systems.

<p><strong>List of abstracts and authors:</strong></p><p><strong>1. Bipolar disorder not otherwise specified -overdiagnosed or underdiagnosed?</strong></p><p>E Allers</p><p><strong>2. The prognosis of major depression untreated and treated: Does the data reflect the true picture of the prognosis of this very common disorder?</strong></p><p>E Allers</p><p><strong>3. Can we prolong our patients' life expectancy? Providing a better quality of life for patients with severe mental illness</strong></p><p>O A Betencourt</p><p><strong>4. The scope of ECT practice in South Africa</strong></p><p>J Benson-Martin, P Milligan</p><p><strong>5. Biomarkers for schizophrenia: Can we evolve like cancer therapeutics?</strong></p><p>P Buckley<strong></strong></p><p><strong>6. Relapse in schizophrenis: Major challenges in prediction and prevention</strong></p><p>P Buckley</p><p><strong>7. Informed consent in biological treatments: The right to know the duty to inform</strong></p><p><strong></strong>I Chetty</p><p><strong>8. Effectiveness of a long-acting injectable antipsychotic plus an assertive monitoring programme in first-episode schizophrenia</strong></p><p><strong></strong>B Chiliza, L Asmal, O Esan, A Ojagbemi, O Gureje, R Emsley</p><p><strong>9. Name, shame, fame</strong></p><p>P Cilliers</p><p><strong>10. Can we manage the increasing incidence of violent raging children? We have to!</strong></p><p>H Clark</p><p><strong>11. Serotonin, depression and antidepressant action</strong></p><p>P Cowen</p><p><strong>12. Prevalence and correlates of comorbid psychiatris illness in patients with heroin use disorder admitted to Stikland Opioid Detoxification Unit</strong></p><p>L Dannatt, K J Cloete, M Kidd, L Weich</p><p><strong>13. Investigating the association between diabetes mellitus, depression and psychological distress in a cohort of South African teachers</strong></p><p>A K Domingo, S Seedat, T M Esterhuizen, C Laurence, J Volmink, L Asmal</p><p><strong>14. Neuropeptide S -emerging evidence for a role in anxiety</strong></p><p>K Domschke</p><p><strong>15. Pathogenetics of anxiety</strong></p><p>K Domschke</p><p><strong>16. The effects of HIV on the fronto-striatal system</strong></p><p>S du Plessis, M Vink, J Joska, E Koutsilieri, C Scheller, B Spottiswoode, D Stein, R Emsley</p><p><strong>17. Effects of acute antipsychotic treatment on brain morphology in schizophrenia</strong></p><p>R Emsley, L Asmal, B Chiliza, S du Plessis, J Carr, A Goosen, M Kidd, M Vink, R Kahn</p><p><strong>18. Development of a genetic database resource for monitoring of breast cancer patients at risk of physical and psychological complications</strong></p><p>K Grant, F J Cronje, K Botha, J P Apffelstaedt, M J Kotze</p><p><strong>19. Unipolar mania reconsidered: Evidence from a South African study</strong></p><p><strong></strong>C Grobler</p><p><strong>20. Antipsychotic-induced movement disorders: Occurence and management</strong></p><p>P Haddad</p><p><strong>21. The place of observational studies in assessing the effectiveness of long-acting injectable antipsychotics</strong></p><p>P Haddad</p><p><strong>22. Molecular mechanisms of d-cycloserine in fear extinction: Insights from RNS sequencing</strong></p><p>S Hemmings, S Malan-Muller, L Fairbairn, M Jalali, E J Oakeley, J Gamieldien, M Kidd, S Seedat</p><p><strong>23. Schizophrenia: The role of inflammation</strong></p><p>DC Henderson</p><p><strong>24. Addictions: Emergent trends and innovations</strong></p><p>V Hitzeroth</p><p><strong>25. The socio-cultural-religious context of biological psychiatric practice</strong></p><p>B Janse van Rensburg</p><p><strong>26. Biochemical markers for identifying risk factors for disability progression in multiple sclerosis</strong></p><p><strong></strong>S Janse van Rensburg, M J Kotze, F J Cronje, W Davis, K Moremi, M Jalali Sefid Dashti, J Gamieldien, D Geiger, M Rensburg, R van Toorn, M J de Klerk, G M Hon, T Matsha, S Hassan, R T Erasmus</p><p><strong>27. Alcohol-induced psychotic disorder: Brain perfusion and psychopathology - before and after antipsychotic treatment</strong></p><p>G Jordaan, J M Warwick, D G Nel, R Hewlett, R Emsley</p><p><strong>28.'Pump and dump': Harm reduction strategies for breastfeeding while using substances</strong></p><p>L Kramer</p><p><strong>29. Adolescent neuropsychiatry - an emerging field in South African adolescent psychiatric services</strong></p><p>A Lachman</p><p><strong>30. Recovery versus remission, or what it means to be healthy for a psychiatric patient?</strong></p><p>B Latecki</p><p><strong>31. Holistic methods utilised to normalise behaviours in youth diagnosed with neuro-biochemical disorders</strong></p><p>P Macqueen</p><p><strong>32. Candidate genes and novel polymorphisms for anxiety disorder in a South African cohort</strong></p><p>N McGregor, J Dimatelis, S M J Hemmings, C J Kinnear, D Stein, V Russel, C Lochner</p><p><strong>33. Higher visual functioning</strong></p><p>A Moodley</p><p><strong>34. The effects of prenatal methylmercury exposure on trace element and antioxidant levels in rat offspring following 6-hydroxydopamine-induced neuronal insult</strong></p><p>Z M Moosa, W M U Daniels, M V Mabandla</p><p><strong>35. Paediatric neuropsychiatric movement disorders</strong></p><p>L Mubaiwa</p><p><strong>36. The South African national female offenders study</strong></p><p>M Nagdee, L Artz, C de Clercq, P de Wet, H Erlacher, S Kaliski, C Kotze, L Kowalski, J Naidoo, S Naidoo, J Pretorius, M Roffey, F Sokudela, U Subramaney</p><p><strong>37. Neurobiological consequences of child abuse</strong></p><p>C Nemeroff</p><p><strong>38. What do Stellenbosch Unviversity medical students think about psychiatry - and why should we care?</strong></p><p>G Nortje, S Suliman, K Seed, G Lydall, S Seedat</p><p><strong>39. Neurological soft skins in Nigerian Africans with first episode schizophrenia: Factor structure and clinical correlates</strong></p><p><strong></strong>A Ojagbemi, O Esan, O Gureje, R Emsley</p><p><strong>40. Should psychiatric patients know their MTHFR status?</strong></p><p>E Peter</p><p><strong>41. Clinical and functional outcome of treatment refractory first-episode schizophrenia</strong></p><p>L Phahladira, R Emsley, L Asmal, B Chiliza</p><p><strong>42. Bioethics by case discussion</strong></p><p>W Pienaar</p><p><strong>43. Reviewing our social contract pertaining to psychiatric research in children, research in developing countries and distributive justice in pharmacy</strong></p><p>W Pienaar</p><p><strong>44. The performance of the MMSE in a heterogenous elderly South African population</strong></p><p>S Ramlall, J Chipps, A I Bhigjee, B J Pillay</p><p><strong>45. Biological basis addiction (alocohol and drug addiction)</strong></p><p>S Rataemane</p><p><strong>46. Volumetric brain changes in prenatal methamphetamine-exposed children compared with healthy unexposed controls</strong></p><p><strong></strong>A Roos, K Donald, G Jones, D J Stein</p><p><strong>47. Single voxel proton magnetic resonance spectroscopy of the amygdala in social anxiety disorder in the context of early developmental trauma</strong></p><p>D Rosenstein, A Hess, S Seedat, E Meintjies</p><p><strong>48. Discussion of HDAC inhibitors, with specific reference to supliride and its use during breastfeeding</strong></p><p>J Roux</p><p><strong>49. Prevalence and clinical correlates of police contact prior to a first diagnosis of schizophrenia</strong></p><p>C Schumann, L Asmal, K Cloete, B Chiliza, R Emsley</p><p><strong>50. Are dreams meaningless?</strong></p><p>M Solms</p><p><strong>51. The conscious id</strong></p><p>M Solms<strong></strong></p><p><strong>52. Depression and resilience in HIV-infected women with early life stress: Does trauma play a mediating role?</strong></p><p>G Spies, S Seedat</p><p><strong>53. State of affairs analysis for forensic psychiatry in SA</strong></p><p>U Subramaney</p><p><strong>54. Escitalopram in the prevention of post-traumatic stress disorder: A pilot randomised controlled trial</strong></p><p>S Suliman, S Seedat, J Pingo, T Sutherland, J Zohar, D J Stein</p><p><strong>55. Epigenetic consequences of adverse early social experiences in primates</strong></p><p>S Suomi</p><p><strong>56. Risk, resilience, and gene x environment interactions in primates</strong></p><p>S Suomi</p><p><strong>57. Biological aspects of anorexia nervosa</strong></p><p>C Szabo</p><p><strong>58. Agents used and profiles of non-fatal suicidal behaviour in East London</strong></p><p>H Uys</p><p><strong>59. The contributions of G-protein coupled receptor signalling to opioid dependence</strong></p><p>J van Tonder</p><p><strong>60. Emerging trend and innovation in PTSD and OCD</strong></p><p>J Zohar</p><p><strong>61. Making the SASOP treatment guidelines operational</strong></p><p>E Allers</p><p><strong>Poster Presentations</strong></p><p><strong>62. Neuropsychological deficits in social anxiety disorder in the context of early developmental trauma</strong></p><p><strong></strong>S Bakelaar, D Rosenstein, S Seedat</p><p><strong>63.Social anxiety disorder in patients with or without early childhood trauma: Relationship to behavioral inhibition and activation and quality of life</strong></p><p><strong></strong>S Bakelaar, C Bruijnen, A Sambeth, S Seedat</p><p><strong>64. Exploring altered affective processing in obssessive compulsive disorder symptom subtypes</strong></p><p>E Breet, J Ipser, D Stein, C Lochner<strong><br /></strong></p><p><strong>65. To investigate the bias toward recognising the facial expression of disgust in obsessive compulsive disorder as well as the effect of escitalopram</strong></p><p>E Breet, J Ipser, D Stein, C Lochner</p><p><strong>66. A fatal-case of nevirapine-induced Stevens-Johnson's syndrome in HIV mania</strong></p><p>A Bronkhorst, Z Zingela, W M Qwesha, B P Magigaba<strong></strong></p><p><strong>67. Association of the COMT G472A (met/met) genotype with lower disability in people diagnosed with multiple sclerosis</strong></p><p>W Davis, S J van Rensburg, L Fisher, F J Cronje, D Geiger, M J Kotze</p><p><strong>68. Homocycsteine levels are associated with the fat mass and obesity associated gene FTO(intron 1 T&gt;A) polymorphism in MS patients</strong></p><p>W Davis, S J Van Rensburg, M J Kotze, L Fisher, M Jalali, F J Cronje, K Moremi, J Gamieldien, D Geiger, M Rensburg, R van Toorn, M J de Klerk, G M Hon, T Matsha, S Hassan, R T Erasmus</p><p><strong>69. Analysis of the COMT 472 G&gt;A (rs4680) polymorphism in relation to environmental influences as contributing factors in patients with schizophrenia</strong></p><p>D de Klerk, S J van Rensburg, R A Emsley, D Geiger, M Rensburg, R T Erasmus, M J Kotze</p><p><strong>70. Dietary folate intake, homocysteine levels and MTHFR mutation detection in South African patients with depression: Test development for clinical application </strong></p><p>D Delport, N vand der Merwe, R Schoeman, M J Kotze</p><p><strong>71. The use ofexome sequencing for antipsychotic pharmacogenomic applications in South African schizophrenia patients</strong></p><p>B Drogmoller, D Niehaus, G Wright, B Chiliza, L Asmal, R Emsley, L Warnich</p><p><strong>72. The effects of HIV on the ventral-striatal reward system</strong></p><p>S du Plessis, M Vink, J Joska, E Koutsilieri, C Scheller, B Spottiswoode, D Stein, R Emsley</p><p><strong>73. Xenomelia relates to asymmetrical insular activity: A case study of fMRI</strong></p><p>S du Plessis, M Vink, L Asmal</p><p><strong>74. Maternal mental helath: A prospective naturalistic study of the outcome of pregancy in women with major psychiatric disorders in an African country</strong></p><p>E du Toit, L Koen, D Niehaus, B Vythilingum, E Jordaan, J Leppanen</p><p><strong>75. Prefrontal cortical thinning and subcortical volume decrease in HIV-positive children with encephalopathy</strong></p><p>J P Fouche, B Spottiswoode, K Donald, D Stein, J Hoare</p><p><strong>76. H-magnetic resonance spectroscopy metabolites in schizophrenia</strong></p><p>F Howells, J Hsieh, H Temmingh, D J Stein</p><p><strong>77. Hypothesis for the development of persistent methamphetamine-induced psychosis</strong></p><p><strong></strong> J Hsieh, D J Stein, F M Howells</p><p><strong>78. Culture, religion, spirituality and psychiatric practice: The SASOP Spirituality and Psychiatry Special Interest Group Action Plan for 2012-2014</strong></p><p>B Janse van Rensburg</p><p><strong>79. Cocaine reduces the efficiency of dopamine uptake in a rodent model of attention-deficit/hyperactivity disorder: An <em>in vivo</em> electrochemical study</strong></p><p><strong></strong>L Kellaway, J S Womersley, D J Stein, G A Gerhardt, V A Russell</p><p><strong>80. Kleine-Levin syndrome: Case in an adolescent psychiatric unit</strong></p><p>A Lachman</p><p><strong>81. Increased inflammatory stress specific clinical, lifestyle and therapeutic variables in patients receiving treatment for stress, anxiety or depressive symptoms</strong></p><p>H Luckhoff, M Kotze, S Janse van Rensburg, D Geiger</p><p><strong>82. Catatonia: An eight-case series report</strong></p><p>M Mabenge, Z Zingela, S van Wyk</p><p><strong>83. Relationship between anxiety sensitivity and childhood trauma in a random sample of adolescents from secondary schools in Cape Town</strong></p><p>L Martin, M Viljoen, S Seedat</p><p><strong>84. 'Making ethics real'. An overview of an ethics course presented by Fraser Health Ethics Services, BC, Canada</strong></p><p>JJ McCallaghan</p><p><strong>85. Clozapine discontinuation rates in a public healthcare setting</strong></p><p>M Moolman, W Esterhuysen, R Joubert, J C Lamprecht, M S Lubbe</p><p><strong>86. Retrospective review of clozapine monitoring in a publica sector psychiatric hospital and associated clinics</strong></p><p>M Moolman, W Esterhuysen, R Joubert, J C Lamprecht, M S Lubbe</p><p><strong>87. Association of an iron-related TMPRSS6 genetic variant c.2007 C&gt;7 (rs855791) with functional iron deficiency and its effect on multiple sclerosis risk in the South African population</strong></p><p>K Moremi, S J van Rensburg, L R Fisher, W Davis, F J Cronje, M Jalali Sefid Dashti, J Gamieldien, D Geiger, M Rensburg, R van Toorn, M J de Klerk, G M Hon, T Matsha, S Hassan, R T Erasmus, M Kidd, M J Kotze</p><p><strong>88. Identifying molecular mechanisms of apormophine-induced addictive behaviours</strong></p><p>Z Ndlazi, W Daniels, M Mabandla</p><p><strong>89. Effects of lifestyle factors and biochemistry on the major neck blood vessels in patients with mutiple sclerosis</strong></p><p>M Nelson, S J van Rensburg, M J Kotze, F Isaacs, S Hassan</p><p><strong>90. Nicotine protects against dopamine neurodegenration and improves motor deficits in a Parkinsonian rat model</strong></p><p>N Ngema, P Ngema, M Mabandla, W Daniels</p><p><strong>91. Cognition: Probing anatomical substrates</strong></p><p>H Nowbath</p><p><strong>92. Chronic exposure to light reverses the effects of maternal separation on the rat prefrontal cortex</strong></p><p>V Russel, J Dimatelis</p><p><strong>93. Evaluating a new drug to combat Alzheimer's disease</strong></p><p>S Sibiya, W M U Daniels, M V Mabandla</p><p><strong>94. Structural brain changes in HIV-infected women with and without childhood trauma</strong></p><p>G Spies, F Ahmed, C Fennema-Notestine, S Archibald, S Seedat</p><p><strong>95. Nicotine-stimulated release of hippocampal norepinephrine is reduced in an animal model of attention-deficit/ hyperactivity disorder: the spontaneously hypertensive rat</strong></p><p>T Sterley</p><p><strong>96. Brain-derive neurotrophic factor (BDNF) protein levels in anxiety disorders: Systematic review and meta-regression analysis</strong></p><p>S Suliman, S M J Hemmings, S Seedat</p><p><strong>97. A 12-month retrospective audit of the demographic and clinical profile of mental healthcare users admitted to a district level hospital in the Western Cape, South Africa</strong></p><p>E Thomas, K J Cloete, M Kidd, H Lategan</p><p><strong>98. Magnesium recurarization: A comparison between reversal of neuromuscular block with sugammadex v. neostigmine/ glycopyrrolate in an <em>in vivo</em> rat model</strong></p><p><strong></strong>M van den Berg, M F M James, L A Kellaway</p><p><strong>99. Identification of breast cancer patients at increased risk of 'chemobrain': Case study and review of the literature</strong></p><p>N van der Merwe, R Pienaar, S J van Rensburg, J Bezuidenhout, M J Kotze</p><p><strong>100. The protective role of HAART and NAZA in HIV Tat protein-induced hippocampal cell death</strong></p><p>S Zulu, W M U Daniels, M V Mabandla</p>

Chronic pain coincides with myriad functional alterations throughout the brain and spinal cord. While spinal cord mechanisms of chronic pain have been extensively characterized in animal models and in vitro, to date, research in patients with chronic pain has focused only very minimally on the spinal cord. Previously, spinal cord functional magnetic resonance imaging (fMRI) identified regional alterations in spinal cord activity in patients (who were not taking opioids) with fibromyalgia, a chronic pain condition. Here, in patients with fibromyalgia who take opioids (N = 15), we compared spinal cord resting-state fMRI data vs. patients with fibromyalgia not taking opioids (N = 15) and healthy controls (N = 14). We hypothesized that the opioid (vs. non-opioid) patient group would show greater regional alterations in spinal cord activity (i.e., the amplitude of low frequency fluctuations or ALFF, a measure of regional spinal cord activity). However, we found that regional spinal cord activity in the opioid group was more similar to healthy controls, while regional spinal cord activity in the non-opioid group showed more pronounced differences (i.e., ventral increases and dorsal decreases in regional ALFF) vs. healthy controls. Across patient groups, self-reported fatigue correlated with regional differences in spinal cord activity. Additionally, spinal cord functional connectivity and graph metrics did not differ among groups. Our findings suggest that, contrary to our main hypothesis, patients with fibromyalgia who take opioids do not have greater alterations in regional spinal cord activity. Thus, regional spinal cord activity may be less imbalanced in patients taking opioids compared to patients not taking opioids.

While the prevalence of opioid use disorder (OUD) among pregnant women has multiplied in the United States in the last decade, buprenorphine treatment (BT) for peripartum women with OUD has been administered to reduce risks of repeated cycles of craving and withdrawal. However, the maternal behavior and bonding in mothers with OUD may be altered as the underlying maternal behavior neurocircuit (MBN) is opioid sensitive. In the regulation of rodent maternal behaviors such as licking and grooming, a series of opioid-sensitive brain regions are functionally connected, including the ventral pallidum (VP). In humans, these brain regions, interact with the supplementary motor area (SMA) to regulate maternal behaviors and are functionally dysregulated by opioids. It is unclear how these brain regions respond to the emotions of their child for mothers receiving BT. In this functional magnetic resonance imaging (fMRI) pilot study in 22 mothers within the first postpartum year, including six mothers receiving BT and 16 non-OUD mothers as a comparison group (CG), we devised a child face mirroring task in fMRI settings to assess maternal responses to pictures of facial expressions of own child and an unknown child in an empathic mirroring condition (Join) and a non-mirroring observation condition (Observe). In each condition, faces of neutral, ambiguous, distressed, and joyful expressions of each child were repeatedly displayed in a random order. The response of SMA during empathic mirroring (Join) vs. non-mirroring (Observe) of own child was reduced among BT/OUD vs. CG. Within MBN, the left VP, critical for parental sensitivity, had a similar deficit. This study outlines potential mechanisms for investigating the risks of deficits in the neural responses to actual maternal sensitivity and parenting behavior in mothers with OUD, and potential targets for interventions that reduce stress and augment maternal behavior and child outcome.

Both unexpected pain and unexpected pain absence can drive avoidance learning, but whether they do so via shared or separate neural and neurochemical systems is largely unknown. To address this issue, we combined an instrumental pain-avoidance learning task with computational modeling, functional magnetic resonance imaging (fMRI), and pharmacological manipulations of the dopaminergic (100 mg levodopa) and opioidergic (50 mg naltrexone) systems (N = 83). Computational modeling provided evidence that untreated participants learned more from received than avoided pain. Our dopamine and opioid manipulations negated this learning asymmetry by selectively increasing learning rates for avoided pain. Furthermore, our fMRI analyses revealed that pain prediction errors were encoded in subcortical and limbic brain regions, whereas no-pain prediction errors were encoded in frontal and parietal cortical regions. However, we found no effects of our pharmacological manipulations on the neural encoding of prediction errors. Together, our results suggest that human pain-avoidance learning is supported by separate threat- and safety-learning systems, and that dopamine and endogenous opioids specifically regulate learning from successfully avoided pain.

Over 100 million Americans suffer from chronic pain (CP), which causes more disability than any other medical condition in the United States at a cost of $560–$635 billion per year (Institute of Medicine, 2011). Opioid analgesics are frequently used to treat CP. However, long term use of opioids can cause brain changes such as opioid-induced hyperalgesia that, over time, increase pain sensation. Also, opioids fail to treat complex psychological factors that worsen pain-related disability, including beliefs about and emotional responses to pain. Cognitive behavioral therapy (CBT) can be efficacious for CP. However, CBT generally does not focus on important factors needed for long-term functional improvement, including attainment of personal goals and the psychological flexibility to choose responses to pain. Acceptance and Commitment Therapy (ACT) has been recognized as an effective, non-pharmacologic treatment for a variety of CP conditions (Gutierrez et al., 2004). However, little is known about the neurologic mechanisms underlying ACT. We conducted an ACT intervention in women (n = 9) with chronic musculoskeletal pain. Functional magnetic resonance imaging (fMRI) data were collected pre- and post-ACT, and changes in functional connectivity (FC) were measured using Network-Based Statistics (NBS). Behavioral outcomes were measured using validated assessments such as the Acceptance and Action Questionnaire (AAQ-II), the Chronic Pain Acceptance Questionnaire (CPAQ), the Center for Epidemiologic Studies Depression Scale (CES-D), and the NIH Toolbox Neuro-QoLTM (Quality of Life in Neurological Disorders) scales. Results suggest that, following the 4-week ACT intervention, participants exhibited reductions in brain activation within and between key networks including self-reflection (default mode, DMN), emotion (salience, SN), and cognitive control (frontal parietal, FPN). These changes in connectivity strength were correlated with changes in behavioral outcomes including decreased depression and pain interference, and increased participation in social roles. This study is one of the first to demonstrate that improved function across the DMN, SN, and FPN may drive the positive outcomes associated with ACT. This study contributes to the emerging evidence supporting the use of neurophysiological indices to characterize treatment effects of alternative and complementary mind-body therapies.

Painful diabetic neuropathy (DN) is a common and distressing complication. New approaches are required to identify novel targets that will serve as a catalyst for future drug discovery programmes. We have demonstrated that responders to neuropathic pain treatment have greater functional connectivity between the insula cortex and the corticolimbic system compared to non-responders. Activity within these networks is mediated by endogenous opioid receptor systems and may hold clues to possible future treatment targets. Methods: 43 painful-DN subjects [responders (VAS&lt;4; n=29) and non-responders (VAS≥4; n=14) ] underwent detailed clinical and neurophysiological assessment, and RS-fMRI. Data analysis was performed using the NITRC Functional ConnectivityToolbox and SPM8 in MatLab. RS-fMRI data was masked and binarised using an opioid receptor atlas to restrict the analysis to the voxels with high receptor density. Subject-specific spatial maps of responders and non-responders were compared. Results: Compared to painful-DN non-responders, responders had greater functional connectivity between the corticolimbic system with the opioid receptor networks [F (2) (41) =43.53;intensity=128.7; R-amygdala beta=0.48; p-FDR&lt;0.0001; R-putamen beta=0.3; p-FDR&lt;0.0001; dorsal lateral prefrontal cortex beta=0.25; p-FDR=0.0002 and the posterior parietal cortex networks beta0.25; p-FDR=0.0002]. Conclusion: Painful DN treatment responders have better target engagement of opioid receptors systems compared to non-responders. This indicates that a functioning/intact descending pain inhibition network is crucial for a better pain response. Interventions targeted at this network could provide better pain relief in non-responders to neuropathic pain treatment. Disclosure K.Teh: None. G.P.Sloan: None. I.D.Wilkinson: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH & Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc. D.Selvarajah: None. Funding National Institute of Health Research EME grant; European Foundation for the Study of Diabetes

AbstractD2-like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we investigate the relationship between the fronto-striatal D2/D3 dopamine receptor availability and response inhibition in a selected population of healthy OPRM1 G-allele carriers. Twenty-two participants successively underwent blood-oxygen level dependent functional magnetic resonance imaging (fMRI) while performing a stop-signal task and a separate positron emission tomography (PET) scan. Striatal and extrastriatal D2/D3 dopamine receptor availability was measured using the radiotracer [18F]fallypride. Caudate D2/D3 dopamine receptor availability positively correlated with stopping-related fronto-striatal fMRI activation. In addition, right prefrontal D2/D3 dopamine receptor availability correlated positively with stopping-related striatal fMRI BOLD signal. Our study partially replicates previous findings on correlations between striatal D2/D3 dopamine receptor availability and response inhibition in a population selected for its genetic determination of dopamine response to alcohol and as a modulator of impulse control via the endogenous opioid system. We confirm the important role of D2/D3 dopamine receptor availability in the fronto-striatal neural circuit for response inhibition. Moreover, we extend previous findings suggesting that dopamine receptor availability in the right inferior frontal cortex, a crucial region of the stopping network, is also strongly associated with stopping-related striatal fMRI activity in healthy OPRM1 G-allele carriers.

Background/Objective: Prenatal opioid exposure (POE) is a growing public health issue that can result in premature birth, Neonatal Abstinence Syndrome (NAS), and adverse neurodevelopmental outcomes. However, the neural basis for these findings remains relatively unknown. In this study, we aimed to investigate the neural correlates of POE based on neonatal thalamocortical functional connectivity using resting state functional magnetic resonance imaging (rs-fMRI). Methods: In this prospective, IRB-approved study, nineteen neonates with POE and twenty opioid naive (ON) controls underwent non-invasive MRI during natural sleep at mean post-menstrual age (PMA) of 44.7 ± 2.6 and 44.6 ± 2.6 weeks respectively. MR imaging included anatomic T2-weighted images and rs-fMRI. General Linear Model (GLM) seed-based whole brain functional connectivity analysis was performed for each subject, with the right and left thalamus as distinct seed regions. Unpaired mixed-effects group analyses between POE and ON groups were conducted for each seed region corrected for PMA and sex. Results: Thalamic connectivity to cortical and subcortical structures differed in the POE group compared to the ON control group. The POE group exhibited higher functional connectivity to deep gray structures, frontal, medial prefrontal, parietal, occipital, and anterior temporal cortices compared to controls. The POE group exhibited lower connectivity to the nuclei accumbentes, bilateral caudate nuclei, posterior cingulate gyri, superior frontal gyri, insular, and dorsolateral prefrontal cortices. Conclusion and Potential Impact: Overall, these novel results suggest the presence of opioid exposure-related alterations in thalamic functional connectivity. Given that the thalamus plays a crucial role in early brain development, the described alterations in thalamocortical and thalamic-subcortical connectivity may have implications in stratifying risk and informing treatment for the adverse neurodevelopmental outcomes associated with POE. Future studies should explore the relationship between POE-associated disruptions in thalamic connectivity and developmental outcomes.

Purpose: Infants of mothers with opioid and substance use can present with postnatal withdrawal symptoms and are at risk of poor neurodevelopmental outcomes in later childhood. Identifying methods to evaluate the consequences of substance exposure on the developing brain can help initiate proactive therapies to improve outcomes for opioid-exposed neonates. Additionally, early brain imaging in infancy has the potential to identify early brain developmental alterations that could prognosticate neurodevelopmental outcomes in these children. In this study, we aim to identify differences in global brain network connectivity in infants with prenatal opioid exposure compared to healthy control infants, using resting-state functional MRI performed at less than 2 months completed gestational age. Materials and Methods: In this prospective, IRB-approved study, we recruited 20 infants with prenatal opioid exposure and 20 healthy, opioid naïve infants. Anatomic imaging and resting-state functional MRI were performed at less than 48 weeks corrected gestational age, and rs-fMRI images were co-registered to the UNC neonate brain template and 90 anatomic atlas-labelled regions. Covariate Assisted Principal (CAP) regression was performed to identify brain network functional connectivity that was significantly different among infants with prenatal opioid exposure compared to healthy neonates. Results: Of the 5 significantly different CAP components identified, the most distinct component (CAP5, p= 3.86 x 10-6) spanned several brain regions, including the right inferior temporal gyrus, bilateral Hesch’s gyrus, left thalamus, left supramarginal gyrus, left inferior parietal lobule, left superior parietal gyrus, right anterior cingulate gyrus, right gyrus rectus, left supplementary motor area, and left pars triangularis. Functional connectivity in this network was lower in the infants with prenatal opioid exposure compared to non-opioid exposed infants. Conclusion: This study demonstrates global network alterations in infants with prenatal opioid exposure compared to non-opioid exposed infants. Future studies should be aimed at identifying clinical significance of this altered connectivity.

Abstract Objective Standard of care for opioid use disorder (OUD) includes medication and counseling. However, there is an unmet need for complementary approaches to treat OUD patients coping with pain; furthermore, few studies have probed neurobiological features of pain or its management during OUD treatment. This preliminary study examines neurobiological and behavioral effects of a virtual reality-based meditative intervention in patients undergoing methadone maintenance treatment (MMT). Design Prospective, non-blinded, single-arm, 12-week intervention with standardized assessments. Setting Academic research laboratory affiliated with an on-site MMT clinic. Methods Fifteen (11 female) MMT patients completed a virtual reality, therapist-guided meditative intervention that included breathing and relaxation exercisessessions were scheduled twice weekly. Assessments included functional magnetic resonance imaging (fMRI) of pain neuromatrix activation and connectivity (pre- and post-intervention), saliva cortisol and C-reactive protein (CRP) at baseline and weeks 4, 8 and 12; and self-reported pain and affective symptoms before and after each intervention session. Results After each intervention session (relative to pre-session), ratings of pain, opioid craving, anxiety and depression (but not anger) decreased. Saliva cortisol (but not CRP) levels decreased from pre- to post-session. From pre- to post-intervention fMRI assessments, pain task-related left postcentral gyrus (PCG) activation decreased. At baseline, PCG showed positive connectivity with other regions of the pain neuromatrix, but this pattern changed post-intervention. Conclusions These preliminary findings demonstrate feasibility, therapeutic promise, and brain basis of a meditative intervention for OUD patients undergoing MMT.

Laughter is a contagious prosocial signal that conveys bonding motivation; adult crying conversely communicates desire for social proximity by signalling distress. Endogenous mu-opioid receptors (MORs) modulate sociability in humans and non-human primates. In this combined PET–fMRI study ( n = 17), we tested whether central MOR tone is associated with regional brain responses to social signals of laughter and crying. MOR availability was measured with positron emission tomography (PET) using the high-affinity agonist radioligand [ 11 C]carfentanil. Haemodynamic responses to social laughter and crying vocalizations were measured using functional magnetic resonance imaging (fMRI). Social laughter evoked activation in the auditory cortex, insula, cingulate cortex, amygdala, primary and secondary somatosensory cortex, and primary and secondary motor cortex; crying sounds led to more restricted activation in the auditory cortex and nearby areas. MOR availability was negatively correlated with the haemodynamic responses to social laughter in the primary and secondary somatosensory cortex, primary and secondary motor cortex, posterior insula, posterior cingulate cortex, precuneus, cuneus, temporal gyri and lingual gyrus. For crying-evoked activations, MOR availability was negatively correlated with medial and lateral prefrontal haemodynamic responses. Altogether our findings highlight the role of the MOR system in modulating acute brain responses to both positive and negative social signals. This article is part of the theme issue ‘Cracking the laugh code: laughter through the lens of biology, psychology and neuroscience’.

It has been hypothesized that the pleasure of a reward in humans is mediated by an opioidergic system involving the hypothalamus, nucleus accumbens and the amygdala. Importantly, enjoying the pleasure of a reward is distinct from incentive salience induced by cues predicting the reward. We investigated this issue using a within subject, pharmacological challenge design with the opioid receptor antagonist naloxone and fMRI. Our data show that blocking opioid receptors reduced pleasure associated with viewing erotic pictures more than viewing symbols of reward such as money. This was paralleled by a reduction of activation in the ventral striatum, lateral orbitofrontal cortex, amygdala, hypothalamus and medial prefrontal cortex. Crucially, the naloxone induced activation decrease was observed at reward delivery, but not during reward anticipation, indicating that blocking opioid receptors decreases the pleasure of rewards in humans.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

The opioid epidemic is an ongoing public health crisis, and children born following prenatal opioid exposure (POE) have increased risk of long-term cognitive and behavioral sequelae. Clinical studies have identified reduced gray matter volume and abnormal white matter microstructure in children with POE but impacts on whole-brain functional brain connectivity (FC) have not been reported. To define effects of POE on whole brain FC and white matter injury in adult animals, we performed quantitative whole-brain structural and functional MRI. We used an established rat model of POE in which we have previously reported impaired executive function in adult rats analogous to persistent neurocognitive symptoms described in humans with POE. Pregnant Sprague-Dawley rat dams received continuous methadone (12 mg/kg/day) vs. saline infusion for 28 days via osmotic mini-pumps, exposing rats to pre- and postnatal opioid until weaning. At young adult age (P60), POE and saline exposed offspring underwent in vivo MRI included diffusion tensor imaging and functional MRI (fMRI). Results indicate that fractional anisotropy (FA) was decreased in adult animals with POE [n = 11] compared to animals that received saline [n = 9] in major white matter tracts, including the corpus callosum (p &lt; 0.001) and external capsule (p &lt; 0.01). This change in FA was concomitant with reduced axial diffusivity in the external capsule (p &lt; 0.01) and increased radial diffusivity in the corpus callosum (p &lt; 0.01). fMRI analyses reveal brainwide FC was diffusely lower in POE (p &lt; 10−6; 10% of variance explained by group). Decreased connectivity in cortical-cortical and cortico-basal ganglia circuitry was particularly prominent with large effect sizes (Glass's Δ &gt; 1). Taken together, these data confirm POE reduces brainwide functional connectivity as well as microstructural integrity of major white matter tracts. Altered neural circuitry, dysregulated network refinement, and diffuse network dysfunction have been implicated in executive function deficits that are common in children with POE. FC may serve as a translatable biomarker in children with POE.

Previous studies have identified altered brain changes in chronic pain patients, however, it remains unclear whether these changes are reversible. We summarized the neural and molecular changes in patients with chronic pain and employed a meta-analysis approach to quantify the changes. We included 75 studies and 11 of these 75 studies were included in the activation likelihood estimation (ALE) analysis. In the 62 functional magnetic resonance imaging (fMRI) studies, the primary somatosensory and motor cortex (SI and MI), thalamus, insula, and anterior cingulate cortex (ACC) showed significantly decreased activity after the treatments compared to baseline. In the 13 positron emission tomography (PET) studies, the SI, MI, thalamus, and insula showed significantly increased glucose uptake, blood flow, and opioid-receptor binding potentials after the treatments compared to baseline. A meta-analysis of fMRI studies in patients with chronic pain, during pain-related tasks, showed a significant deactivation likelihood cluster in the left medial posterior thalamus. Further studies are warranted to understand brain reorganization in patients with chronic pain compared to the normal state, in terms of its relationship with symptom reduction and baseline conditions.

ObjectivePlacebo as well as nocebo responses are widely found in scientific research and clinical practice. Growing evidence suggests sex differences in placebo as well as nocebo responses. However, data concerning this question are still insufficient. This study examined whether the BOLD signals of two responses, as measured with functional MRI (fMRI), differ by sex under conditions of equivalent experimental pain perception.MethodThirty-one healthy volunteers (14 female) underwent two fMRI scans, once during a placebo intervention and once during a nocebo intervention, pseudorandomly ordered, in an acute lower back pain (ALBP) model. We collected visual analog scale (VAS) data after each scanning. fMRI data from different sex groups were subjected to functional connectivity (FC) analysis and behavioral correlation analysis (BCA).ResultsThe results showed statistical differences in VAS scores between male and female participants, in both placebo and nocebo responses. Both groups also showed reduced FC in the pain-associated network of the placebo response and elevated FC in the pain-related network of the nocebo response. However, in the placebo condition, male participants displayed increased FC in the ventromedial prefrontal cortex, parahippocampal gyrus (PHP), and posterior cingulate cortex (PCC), while female participants showed increased FC in the dorsolateral prefrontal cortex, hippocampal gyrus (HP), and insular cortex (IC). In the nocebo condition, male participants showed decreased FC in the PCC and HP, while female participants displayed decreased FC in the mid-cingulate cortex, thalamus (THS), and HP. The BCA results of the two groups were also different.ConclusionWe found that the endogenous opioid system and reward circuit play a key role in sex differences of placebo response and that anxiety and its secondary reactions may cause the sex differences of nocebo response.

Pain perception is decreased by shifting attentional focus away from a threatening event. This attentional analgesia engages parallel descending control pathways from anterior cingulate (ACC) to locus coeruleus, and ACC to periaqueductal grey (PAG) – rostral ventromedial medulla (RVM), indicating possible roles for noradrenergic or opioidergic neuromodulators. To determine which pathway modulates nociceptive activity in humans, we used simultaneous whole brain-spinal cord pharmacological-fMRI (N = 39) across three sessions. Noxious thermal forearm stimulation generated somatotopic-activation of dorsal horn (DH) whose activity correlated with pain report and mirrored attentional pain modulation. Activity in an adjacent cluster reported the interaction between task and noxious stimulus. Effective connectivity analysis revealed that ACC interacts with PAG and RVM to modulate spinal cord activity. Blocking endogenous opioids with Naltrexone impairs attentional analgesia and disrupts RVM-spinal and ACC-PAG connectivity. Noradrenergic augmentation with Reboxetine did not alter attentional analgesia. Cognitive pain modulation involves opioidergic ACC-PAG-RVM descending control which suppresses spinal nociceptive activity.

Background and Objective: Placebo and nocebo responses are widely observed. Herein, we investigated the nocebo hyperalgesia and placebo analgesia responses in brain network in acute lower back pain (ALBP) model using multivariate Granger causality analysis (GCA). This approach analyses functional magnetic resonance imaging (fMRI) data for lagged-temporal correlation between different brain areas.Method: After completing the ALBP model, 20 healthy subjects were given two interventions, once during a placebo intervention and once during a nocebo intervention, pseudo-randomly ordered. fMRI scans were performed synchronously during each intervention, and visual analog scale (VAS) scores were collected at the end of each intervention. The fMRI data were then analyzed using multivariate GCA.Results: Our results found statistically significant differences in VAS scores from baseline (pain status) for both placebo and nocebo interventions, as well as between placebo and nocebo interventions. In placebo network, we found a negative lagged-temporal correlation between multiple brain areas, including the dorsolateral prefrontal cortex (DLPFC), secondary somatosensory cortex area, anterior cingulate cortex (ACC), and insular cortex (IC); and a positive lagged-temporal correlation between multiple brain areas, including IC, thalamus, ACC, as well as the supplementary motor area (SMA). In the nocebo network, we also found a positive lagged-temporal correlation between multiple brain areas, including the primary somatosensory cortex area, caudate, DLPFC and SMA.Conclusion: The results of this study suggest that both pain-related network and reward system are involved in placebo and nocebo responses. The placebo response mainly works by activating the reward system and inhibiting pain-related network, while the nocebo response is the opposite. Placebo network also involves the activation of opioid-mediated analgesia system (OMAS) and emotion pathway, while nocebo network involves the deactivation of emotional control. At the same time, through the construction of the GC network, we verified our hypothesis that nocebo and placebo networks share part of the same brain regions, but the two networks also have their own unique structural features.

Substance use disorders (SUD) have been shown to be associated with gray matter (GM) loss, particularly in the frontal cortex. However, unclear is to what degree these regional GM alterations are substance-specific or shared across different substances, and if these regional GM alterations are independent of each other or the result of system-level processes at the intrinsic connectivity network level. The T1 weighted MRI data of 65 treated patients with alcohol use disorder (AUD), 27 patients with opioid use disorder (OUD) on maintenance therapy, 21 treated patients with stimulant use disorder comorbid with alcohol use disorder (polysubstance use disorder patients, PSU), and 21 healthy controls were examined via data-driven vertex-wise and voxel-wise GM analyses. Then, structural covariance analyses and open-access fMRI database analyses were used to map the cortical thinning patterns found in the three SUD groups onto intrinsic functional systems. Among AUD and OUD, we identified both common cortical thinning in right anterior brain regions as well as SUD-specific regional GM alterations that were not present in the PSU group. Furthermore, AUD patients had not only the most extended regional thinning but also significantly smaller subcortical structures and cerebellum relative to controls, OUD and PSU individuals. The system-level analyses revealed that AUD and OUD showed cortical thinning in several functional systems. In the AUD group the default mode network was clearly most affected, followed by the salience and executive control networks, whereas the salience and somatomotor network were highlighted as critical for understanding OUD. Structural brain alterations in groups with different SUDs are largely unique in their spatial extent and functional network correlates.

AbstractOpioid use disorder (OUD) affects more than 27 million people globally accounting for more than 300,000 deaths annually. Protracted abstinence among individuals with OUD is rare due to a high relapse rate among those not receiving medications for OUD. Extensive preclinical studies form the basis of the allostasis theory, which proposes long-lasting functional brain abnormalities that persist after opioid withdrawal and contribute to relapse. Few studies have tested the allostasis theory in humans using neuroimaging. Here, we used fMRI and an instrumental learning task to test allostasis theory predictions (ATP) of functional abnormalities in both positive valence (PVS) and negative valence (NVS) accumbens systems in OUD patients with protracted abstinence (n = 15), comparing them with OUD patients receiving methadone treatment (MT) (n = 33), and with healthy controls (n = 23). As hypothesized, protracted abstinence OUD patients showed incomplete recovery of nucleus accumbens function, as evidenced by the blunted response to aversive events (NVS) during negative reinforcement, as observed in MT patients. In contrast, their accumbens response to rewarding events (PVS) during positive reinforcement was similar to that of controls and different from that in MT patients whose response was blunted. Protracted abstinence OUD patients also showed improvements in depression symptoms compared to MT patients. Residual depressive symptoms and pre-MT intravenous drug measures were associated with worse accumbens function in protracted abstinence. These results support the ATP of long-lasting dysfunction of NVS after withdrawal and show preliminary evidence of recovery of PVS function with protracted withdrawal. Therapeutic strategies that target NVS may facilitate recovery.

BackgroundPain continues to be underrecognized and undertreated in people with Alzheimer's disease (AD). The periaqueductal gray (PAG) is essential to pain processing and modulation yet is damaged by AD. While evidence exists of altered neural processing of pain in AD, there has not been a focused investigation of the PAG during pain in people with AD.PurposeTo investigate the role of the PAG in sensory and affective pain processing for people living with AD.MethodsParticipants from a larger study completed pain psychophysics assessments and then a perceptually-matched heat pain task (warmth, mild, and moderate pain) during a functional MRI scan. In this cross-sectional study, we examined blood oxygenation level-dependent (BOLD) responses in the PAG and other pain-related regions in participants with AD (n = 18) and cognitively intact older adults (age- and sex-matched, n = 18). Associations of BOLD percent signal change and psychophysics were also examined.ResultsThere were significant main effects of AD status on the temperature needed to reach each perception of warmth or pain, where people with AD reached higher temperatures. Furthermore, participants with AD rated mild and moderate pain as more unpleasant than controls. PAG BOLD activation was greater in AD relative to controls during warmth and mild pain percepts. No significant differences were found for moderate pain or in other regions of interest. Greater PAG activation during mild pain was associated with higher affective/unpleasantness ratings of mild pain in participants with AD but not in controls.ConclusionResults suggest a role for the PAG in altered pain responses in people with AD. The PAG is the primary source of endogenous opioid pain inhibition in the neuroaxis, thus, altered PAG function in AD suggests possible changes in descending pain inhibitory circuits. People with AD may have a greater risk of suffering from pain compared to cognitively intact older adults.