Regional cerebral metabolism alterations and functional connectivity in individuals with opioid use disorder: An integrated resting-state PET/fMRI study.

Individuals with opioid use disorder (OUD) have been reported to show abnormal brain metabolism and impaired coupling among brain networks such as the default mode network (DMN), salience network (SN), and executive control network (ECN). However, the characteristics of brain glucose metabolism and its related functions in the brain networks in individuals with OUD remain unknown. Thirty-six individuals with OUD and thirty matched healthy controls (HCs) were recruited in this integrated positron emission tomography/magnetic resonance imaging (PET/MRI) study. Differences in glucose metabolism were analyzed by using 18F-fluorodeoxyglucose (18F-FDG), and the corresponding coupling characteristics of the individuals with OUD were also analyzed. The individuals with OUD showed widespread bilateral hypometabolism in the middle temporal gyrus (MTG), superior temporal gyrus, angular gyrus, supramarginal gyrus, inferior parietal lobe, Rolandic operculum, and left insula, but obvious hypermetabolism in the brainstem and left cerebellum. Meanwhile, in individuals with OUD, the hypometabolism of right MTG which is included in the DMN was accompanied by decreased coupling with the left superior frontal gyrus and right superior parietal gyrus which are included in the ECN. Furthermore, individuals with OUD showed a positive correlation between the duration of heroin use and glucose metabolism of the left MTG. The individuals with OUD were characterized by widespread bilateral hypometabolism in the temporal and parietal regions but obvious hypermetabolism in the brainstem and left cerebellum. The results suggest that the hypometabolism in the temporal and parietal regions might be related to DMN dysfunction and the hypermetabolism in the brainstem and left cerebellum may be compensate for other brain regions showing hypometabolism. In particular, hypometabolism in the self-referential-related DMN regions in OUD might attenuate their relationships with the inhibitory-control-related ECN regions. These findings highlight the importance of evaluating the metabolic and functional profiles of the right MTG in future studies on the treatment of OUD.

Hippocampal volume loss in individuals with a history of non-fatal opioid overdose.

Incidence of opioid-related overdoses in the United States has increased dramatically over the past two decades. Despite public emphasis on overdose fatalities, most overdose cases are not fatal. Although there are case reports of amnestic syndromes and acute injury to the hippocampus following non-fatal opioid overdose, the effects of such overdoses on brain structure are poorly understood. Here, we investigated the neuroanatomical correlates of non-fatal opioid overdoses by comparing hippocampal volume in opioid use disorder (OUD) patients who had experienced an opioid overdose (OD; N = 17) with those who had not (NOD; N = 32). Voxel-based morphometry showed lower hippocampal volume in the OD group than in the NOD group, which on post hoc analysis was evident in the left but not the right hippocampus. These findings strengthen the evidence that hippocampal injury is associated with non-fatal opioid overdose, which is hypothesized to underlie overdose-related amnestic syndrome.

Longitudinal Imaging in a Patient With Opioid-associated Amnestic Syndrome.

Since 2012, individuals with a history of opioid misuse have infrequently been observed to develop a sudden-onset amnestic syndrome associated with bilateral hippocampal-restricted diffusion on MRI. Follow-up imaging of this opioid-associated amnestic syndrome (OAS) has revealed persistent hippocampal abnormalities. Given these observations, as well as neuropathological studies demonstrating excessive tau deposition in the hippocampi and other brain regions of individuals with opioid misuse, we describe longitudinal imaging of a patient with a history of OAS from presentation through 53 months later, when tau positron emission tomography (PET) was performed. Our patient was a 21-year-old woman with a history of attention-deficit hyperactivity disorder and substance use disorder, including opioids (intravenous heroin), who was hospitalized for acute-onset, dense anterograde amnesia. Her urine toxicology screen was positive for opiates. On presentation, her brain MRI showed restricted diffusion as well as T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensity of the hippocampi and globi pallidi. On day 3, magnetic resonance spectroscopy of a right hippocampal region of interest showed a mild reduction of N-acetyl aspartate/creatine, slight elevation of choline/creatine, and the appearance of lactate/lipid and glutamate/glutamine peaks. At 4.5 months, there was resolution of restricted diffusion on MRI, although a minimal anterior T2 and FLAIR hyperintense signal in the right hippocampus persisted. However, by 53 months, when mild memory loss was reported, the hippocampi appeared normal on MRI, and [ 18 F]T807 (tau) PET showed no uptake suggestive of tau deposition. This case report supports the investigation into the hypothesis that OAS may follow a trajectory of reversible metabolic injury.

[Functional impairments in large-scale brain projects in opioid addiction]. / Funktsional'nye narusheniya v krupnomasshtabnykh setyakh pokoya golovnogo mozga pri opioidnoi narkomanii.

OBJECTIVE: To assess the functional state of large-scale resting networks of the brain in patients with opioid intoxication. MATERIAL AND METHODS: Thirty-one male subjects, aged 27.4+5.1 years, were studied. Resting state functional MRI was performed in 12 patients with heroin intoxication aged 29.1+5.9 years. The control group consisted of 16 healthy volunteers without bad habits aged 26.2+4.2 years. RESULTS: In the group of opioids intoxication, there is a decrease in the functional activity of the salience network with the executive control network and the default mode network of the brain (p<0.05) compared to the control group. A positive correlation of functional connections is found between the anterior cingulate cortex and the medial prefrontal cortex (T=2.74; p=0.041), which is not recorded in the control group. The functional connections between the default mode network and executive control are more highly represented in opioid intoxication in comparison with the control group (medial prefrontal cortex - left posterior parietal cortex T=7.5; p=0.001; medial prefrontal cortex - right posterior parietal cortex T=3.71; p=0.014; posterior cingulate cortex - left posterior parietal cortex T=6.15; p=0.002; posterior cingulate cortex - right posterior parietal cortex T=3.25; p=0.023; posterior cingulate cortex - right dorsolateral prefrontal cortex T=2.83; p=0.037). CONCLUSION: The results indicate that functional connections in large-scale resting networks are disrupted during opioid intoxication, which indicates a disturbance of the normal functional architectonics of the brain.

Relationship between optical coherence tomography findings and clinical variables in patients with opiate use disorder / Relação entre os achados da tomografia de coerência óptica e as variáveis clínicas em pacientes com transtorno por uso de opiáceos

ABSTRACT Purpose: This study aimed to examine optical coherence tomography findings in patients with opiate use disorder by comparing them with healthy controls. Methods: The study included 30 opiate use disorder patients and 30 controls. The participants' detailed biomicroscopic examinations, visual acuity, intraocular pressure, and both eye examinations were evaluated. A total of 120 eyes were evaluated using optical coherence tomography, measuring the central macular thickness, mean macular thickness, mean macular volume and retinal nerve fiber layer thickness. Moreover, all participants filled in the demographic data form and Barratt Impulsiveness Scale. Results: Upon examination of the optical coherence tomography findings, central macular thickness, mean macular thickness, and mean macular volume were thinner in both eyes in patients with opiate use disorder (p<0.01 in all measurements in both eyes). Similarly, the total values of the superior quadrant and retinal nerve fiber layer thickness were statistically significant in both eyes compared to that in the control group (p=0.007, p=0.002; p=0.049, p=0.007, in the right and left eyes, respectively). Only the left eye was positively correlated with retinal nerve fiber layer superior quadrant measurement and hospitalization (r=0.380, p=0.039). Conclusion: Our results revealed that the patients' central macular thickness, mean macular thickness, and mean macular volume values were thinner. Increase in the retinal nerve fiber layer thickness superior quadrant thickness and total value was also observed. Further studies with larger sampling groups that evaluate neuroimaging findings should be conducted.

RESUMO Objetivo: O objetivo foi investigar foi, os achados da tomografia de coerência óptica em pacientes com transtorno do uso de opiáceos, comparando-os com controles saudáveis. Métodos: O estudo incluiu 30 pacientes com transtorno do uso de opiáceos e 30 controles. Os exames biomicroscópicos detalhados de todos os participantes, acuidade visual, pressão intraocular e ambos os exames oculares foram avaliados com tomografia de coerência óptica. Um total de 120 olhos foram avaliados usando tomografia de coerência óptica, e a espessura macular central, espessura macular média, volume macular médio e a espessura da camada de fibra nervosa da retina dos participantes foram medidos. Além disso, todos os participantes preencheram o Formulário de Dados Demográficos e a Escala de Impulsividade Barratt (BIS-11). Resultados: Quando os achados de tomografia de coerência óptica foram examinados, espessura macular central, espessura macular média e volume macular médio eram mais finos de acordo com controles saudáveis em ambos os olhos em pacientes com transtorno do uso de opiáceos (p<0,01 em todas as medições em ambos os olhos). Da mesma forma, os valores totais do quadrante superior e espessura da camada de fibra nervosa da retina estavam mais em níveis estatisticamente significativos em ambos os olhos em comparação com o grupo controle (p=0,007, p=0,002; p=0,049, p=0,007, no olho direito e esquerdo, respectivamente). Estar internado em hospital e apenas a medida do quadrante superior da espessura da camada de fibra nervosa da retina do olho esquerdo associou-se positivamente (r=0,380, p=0,039). Conclusão: Em nossos resultados, descobrimos que os valores de espessura macular central, espessura macular média e volume macular médio dos pacientes eram mais finos. Verificamos também espessamento no quadrante superior e valor total da espessura da camada de fibra nervosa da retina. Nosso estudo deve ser apoiado por novos estudos com grupos de amostragem maiores, nos quais os achados de neuroimagem são avaliados.

Placental volume in pregnant women with opioid use: prenatal MRI assessment.

OBJECTIVE: Opioid use in pregnant women is a growing public health concern and is shown to be associated with lower infant birth weights. Placental volume changes in prior studies correlated with various maternal and fetal conditions. We aimed to identify differences between placental volumes in pregnant women with opioid use, and control pregnant women without drug use. METHODS: We prospectively recruited 27 healthy pregnant women and 17 pregnant women with opioid use disorder who were on medication-assisted treatment (MAT). All women underwent placenta/fetal MRI at 27-39 weeks gestation on a 3 Tesla MR scanner. Placental volumes were measured in a blinded fashion using a previously validated technique. Multiple linear regression was used to identify associations of placental volume with multiple maternal and fetal clinical factors. The significance threshold was set at p < .05. RESULTS: Placental volume was significantly associated with gestational age at MRI (p < .0001), fetal sex (p = .027), MAT with smoking (p = .0008), MAT with polysubstance use (p = .01), and maternal BMI (p = .032). Placental volume was not associated with opioid MAT alone in our cohort. CONCLUSION: For pregnant women on medication-assisted treatment for opioid use disorder, there was no significant difference in placental volume compared to healthy pregnant women. However, concomitant smoking and polysubstance use in the setting of medication-assisted treatment may be detrimental to placental health. To our knowledge, this is the first study assessing placental volume in opioid use on prenatal MRI. These results support the benefit of medication-assisted treatment during pregnancy; however additional studies are needed to further elucidate the impact of opioid use on placental and fetal development and postnatal outcomes.

Relationship between optical coherence tomography findings and clinical variables in patients with opiate use disorder.

PURPOSE: This study aimed to examine optical coherence tomography findings in patients with opiate use disorder by comparing them with healthy controls. METHODS: The study included 30 opiate use disorder patients and 30 controls. The participants' detailed biomicroscopic examinations, visual acuity, intraocular pressure, and both eye examinations were evaluated. A total of 120 eyes were evaluated using optical coherence tomography, measuring the central macular thickness, mean macular thickness, mean macular volume and retinal nerve fiber layer thickness. Moreover, all participants filled in the demographic data form and Barratt Impulsiveness Scale. RESULTS: Upon examination of the optical coherence tomography findings, central macular thickness, mean macular thickness, and mean macular volume were thinner in both eyes in patients with opiate use disorder (p<0.01 in all measurements in both eyes). Similarly, the total values of the superior quadrant and retinal nerve fiber layer thickness were statistically significant in both eyes compared to that in the control group (p=0.007, p=0.002; p=0.049, p=0.007, in the right and left eyes, respectively). Only the left eye was positively correlated with retinal nerve fiber layer superior quadrant measurement and hospitalization (r=0.380, p=0.039). CONCLUSION: Our results revealed that the patients' central macular thickness, mean macular thickness, and mean macular volume values were thinner. Increase in the retinal nerve fiber layer thickness superior quadrant thickness and total value was also observed. Further studies with larger sampling groups that evaluate neuroimaging findings should be conducted.

Effects of Mindfulness-Based Interventions on Gray Matter Volume in Patients with Opioid Dependence.

INTRODUCTION: Recently, several mindfulness-based programs showed promising clinical effects in the treatment of psychiatric disorders including substance use disorders. However, very little is known about the effects of mindfulness-based interventions (MBIs) on brain structure in such patients. METHODS: This study aimed to detect changes in gray matter volume (GMV) in opioid-dependent patients receiving MBI during their first month of treatment. Thirty patients were assigned to either 3 weeks of MBI (n = 16) or treatment as usual (TAU, n = 14) and were investigated using structural magnetic resonance imaging before and after treatment. Longitudinal pipeline of the Computational Anatomy Toolbox for SPM (CAT12) was used to detect significant treatment-related changes over time. The identified GMV changes following treatment were related to clinically relevant measures such as impulsivity, distress tolerance, and mindfulness. RESULTS: After treatment, increased mindfulness scores were found in individuals receiving MBI compared to TAU. In the MBI group, there were also significant differences with respect to distress tolerance and impulsivity. Effects on mindfulness, distress tolerance, and impulsivity were also found in the TAU group. Longitudinal within-group analysis revealed increased left anterior insula GMV in individuals receiving MBI. Anterior insula volume increase was associated with decreased impulsivity levels. In the TAU group, significant GMV changes were found in the right lingual gyrus and right entorhinal cortex. DISCUSSION/CONCLUSION: MBI can yield significant clinical effects during early abstinence from opioid dependence. MBI is particularly associated with increased insula GMV, supporting an important role of this region in the context of MBI-induced neural changes.

Association of Project ECHO Training With Buprenorphine Prescribing by Primary Care Clinicians in Minnesota for Treating Opioid Use Disorder.

Importance: Buprenorphine is an approved medication for opioid use disorder (MOUD); however, prescribing buprenorphine is limited by a requirement to obtain a waiver to prescribe it (hereinafter, "DATA [Drug Abuse Treatment Act]-waiver") and a lack of knowledge of the best practices among clinicians. Objective: To examine how Project ECHO (Extension for Community Healthcare Outcomes) telementoring is associated with changes in DATA-waiver attainment and buprenorphine prescribing among primary care clinicians in Minnesota. Design, Setting, and Participants: In this retrospective matched-cohort study of 918 clinicians, ECHO-trained clinicians were enrolled on the date they first attended ECHO (January 3, 2018, to June 11, 2020); comparison clinicians were assigned an enrollment date from the distribution of the first ECHO sessions. The baseline period was 12 months preceding enrollment, with follow-up for 18 months or until June 30, 2020. The ECHO-trained clinicians were a population-based sample of primary care clinicians who treated Medicaid patients in Minnesota 12 months prior to the initiation of ECHO training. This analysis used propensity score matching to select comparison clinicians who were similar across demographic and clinical practice characteristics at baseline in a 2:1 ratio. Follow-up was available for 167 ECHO-trained clinicians (54.6%) and 330 comparison clinicians (53.9%) at 18 months. Exposures: ECHO-trained clinicians attended at least 1 weekly, hour-long ECHO session. Comparison clinicians never participated in any ECHO sessions. Main Outcomes and Measures: DATA-waiver attainment, any buprenorphine prescribing, and the percentage of patients with opioid use disorder (OUD) who were prescribed buprenorphine. Results: The final sample included 918 clinicians (ECHO-trained [306]; comparison [612]), of whom 620 (67.5%) practiced outside the metropolitan Twin Cities (Minneapolis-St Paul) region. The mean (SD) age of the ECHO-trained clinicians was 46.0 (12.1) years and that of the comparison clinicians was 45.7 (12.3) years. Relative to the changes among the matched comparison clinicians, the ECHO-trained clinicians were more likely to obtain a DATA-waiver (difference-in-differences, 22.7 percentage points; 95% CI, 15.5-29.9 percentage points; P < .001) and prescribe any buprenorphine (16.5 percentage points; 95% CI, 10.4-22.5 percentage points; P < .001) after 6 quarters of follow-up. ECHO-trained clinicians prescribed buprenorphine to a greater share of patients with OUD (a difference of 7.6 percentage points per month; 95% CI, 4.6-10.6 percentage points per month; P < .001), relative to that prescribed by the comparison clinicians. Conclusions and Relevance: According to the findings of this matched-cohort study, ECHO telementoring may be associated with greater prescribing of buprenorphine by primary care clinicians. These findings suggest that Project ECHO training could be a useful tool for expanding access to MOUD.

Longitudinal resting-state functional connectivity changes in the insular subdivisions of abstinent individuals with opioid use disorder.

The insular cortex plays a critical role in reward circuitry involved with drug craving in substance use disorders. This study aimed to investigate whether opioid use disorder exhibit functional alterations in the insular circuitry after abstinence. Sixty-one opioid use disorder underwent resting-state and 3D-T1-weighted magnetic resonance imaging and completed craving questionnaires at baseline and after 8 months of abstinence. Changes in resting-state functional connectivity in the insular cortex and their correlations with craving were analyzed. Craving was reduced at follow-up compared with baseline. Compared with that at baseline, there was significantly increased resting-state functional connectivity between the right insular cortex and the superior frontal gyrus/anterior cingulate gyrus (family-wise error corrected) at follow-up. Changes in the functional connectivity of the right dorsal anterior insula/posterior insula with the bilateral superior frontal gyrus were negatively correlated with changes in craving. Our results demonstrated the presence of changes in functional connectivity of the insula in opioid use disorder after protracted abstinence, providing novel evidence of a correlation between craving changes and changes in the neurocircuitry of insular cortex subdivision after abstinence. This study reveals the possibility of neuroplasticity after protracted abstinence, providing insight for future abstinence therapies and rehabilitation procedures for patients with substance use disorders.

Unique and joint associations of polygenic risk for major depression and opioid use disorder with endogenous opioid system function.

Major depressive disorder (MDD) and opioid use disorder (OUD) are common, potentially fatal, polygenic disorders that are moderately heritable and often co-occur. We examined the unique and shared associations of polygenic risk scores (PRS) for these disorders with µ-opioid receptor (MOR) concentration and endogenous opioid response during a stressful stimulus. Participants were 144 healthy European-ancestry (EA) subjects (88 females) who underwent MOR quantification scans with [11C]carfentanil and PET and provided DNA for genotyping. MOR non-displaceable binding potential (BPND) was measured in 5 regions of interest (ROIs) related to mood and addiction. We examined associations of PRS both at baseline and following opioid release calculated as the ratio of baseline and stress-challenge scans, first in the entire sample and then separately by sex. MOR availability at baseline was positively associated with MDD PRS in the amygdala and ventral pallidum. MDD and OUD PRS were significantly associated with stress-induced opioid system activation in multiple ROIs, accounting for up to 14.5% and 5.4%, respectively, of the variance in regional activation. The associations were most robust among females, where combined they accounted for up to 25.0% of the variance among the ROIs. We conclude that there is a pathophysiologic link between polygenic risk for MDD and OUD and opioid system activity, as evidenced by PRS with unique and overlapping regional associations with this neurotransmitter system. This link could help to explain the high rate of comorbidity of MDD and OUD and suggests that opioid-modulating interventions could be useful in treating MDD and OUD, both individually and jointly.

Evidence for the Normalization Effects of Medication for Opioid Use Disorder on Functional Connectivity in Neonates with Prenatal Opioid Exposure.

Altered functional connectivity has been reported in infants with prenatal exposure to opioids, which significantly interrupts and influences endogenous neurotransmitter/receptor signaling during fetal programming. Better birth outcomes and long-term developmental outcomes are associated with medication for opioid use disorder (MOUD) during pregnancy, but the neural mechanisms underlying these benefits are largely unknown. We aimed to characterize effects of prenatal opioid/other drug exposure (PODE) and the neural basis for the reported beneficial effects of MOUD by examining neonatal brain functional organization. A cohort of 109 human newborns, 42 PODE, 39 with prenatal exposure to drugs excluding opioids (PDE), 28 drug-free controls (males and females) underwent resting-state fMRI at 2 weeks of age. To examine neural effects of MOUD, PODE infants were separated into subgroups based on whether mothers received MOUD (n = 31) or no treatment (n = 11). A novel heatmap analysis was designed to characterize PODE-associated functional connectivity alterations and MOUD-related effects, and permutation testing identified regions of interest with significant effects. PODE neonates showed alterations beyond those associated with PDE, particularly in reward-related frontal-sensory connectivity. MOUD was associated with a significant reduction of PODE-related alterations in key regions of endogenous opioid pathways including limbic and frontal connections. However, significant residual effects in limbic and subcortical circuitry were observed. These findings confirm altered brain functional organization associated with PODE. Importantly, widespread normalization effects associated with MOUD reveal, for the first time, the potential brain basis of the beneficial effects of MOUD on the developing brain and underscore the importance of this treatment intervention for better developmental outcomes.SIGNIFICANCE STATEMENT This is the first study to reveal the potential neural mechanisms underlying the beneficial effects on the neonate brain associated with MOUD during pregnancy. We identified both normalization and residual effects of MOUD on brain functional architecture by directly comparing neonates prenatally exposed to opioids with MOUD and those exposed to opioids but without MOUD. Our findings confirm altered brain functional organization associated with prenatal opioid exposure and demonstrate that although significant residual effects remain in reward circuitry, MOUD confers significant normalization effects on functional connectivity of regions associated with socioemotional development and reward processing. Together, our results highlight the importance of MOUD intervention for better neurodevelopmental outcomes.

Multivariate pattern analysis links drug use severity to distributed cortical hypoactivity during emotional inhibitory control in opioid use disorder.

Opioid use disorder (OUD) is characterized by emotional and cognitive impairements that are associated with poor treatment outcomes. The present study investigated the neural mechanism underlying emotion evaluation and inhibitory control using an affective go/no-go (AGN) task and its association with drug use severity and craving in patients with OUD. Twenty-six recently detoxified patients with OUD underwent functional magnetic resonance imaging (fMRI) while performing the AGN task that required response to frequently presented appetitive stimuli ("go") and inhibition of response to infrequently presented aversive stimuli ("no-go"). The fMRI session was immediately followed by an injection of extended-release opioid antagonist naltrexone (XR-NTX). Participants' opioid craving was assessed immediately before fMRI and 10 ± 2 days after XR-NTX injection. Multivariate pattern analysis (MVPA) showed that drug use severity was associated with distributed brain hypoactivity in response to aversive no-go stimuli, with particularly large negative contributions from the cognitive control and dorsal attention brain networks. While drug use severity and its associated MVPA brain response pattern were both correlated with opioid craving at baseline, only the brain response pattern predicted craving during XR-NTX treatment. Our findings point to widespread functional hypoactivity in the brain networks underlying emotional inhibitory control in OUD. Such a distributed pattern is consistent with the multifaceted nature of OUD, which affects multiple brain networks. It also highlights the utility of the multivariate approach in uncovering large-scale cortical substrates associated with clinical severity in complex psychiatric disorders and in predicting treatment response.

Characteristic changes in EEG spectral powers of patients with opioid-use disorder as compared with those with methamphetamine- and alcohol-use disorders.

Electroencephalography (EEG) likely reflects activity of cortical neurocircuits, making it an insightful estimation for mental health in patients with substance use disorder (SUD). EEG signals are recorded as sinusoidal waves, containing spectral amplitudes across several frequency bands with high spatio-temporal resolution. Prior work on EEG signal analysis has been made mainly at individual electrodes. These signals can be evaluated from advanced aspects, including sub-regional and hemispheric analyses. Due to limitation of computational techniques, few studies in earlier work could conduct data analyses from these aspects. Therefore, EEG in patients with SUD is not fully understood. In the present retrospective study, spectral powers from a data house containing opioid (OUD), methamphetamine/stimulants (MUD), and alcohol use disorder (AUD) were extracted, and then converted into five distinct topographic data (i.e., electrode-based, cortical subregion-based, left-right hemispheric, anterior-posterior based, and total cortex-based analyses). We found that data conversion and reorganization in the topographic way had an impact on EEG spectral powers in patients with OUD significantly different from those with MUD or AUD. Differential changes were observed from multiple perspectives, including individual electrodes, subregions, hemispheres, anterior-posterior cortices, and across the cortex as a whole. Understanding the differential changes in EEG signals may be useful for future work with machine learning and artificial intelligence (AI), not only for diagnostic but also for prognostic purposes in patients with SUD.

It is never as good the second time around: Brain areas involved in salience processing habituate during repeated drug cue exposure in treatment engaged abstinent methamphetamine and opioid users.

The brain response to drug-related cues is an important marker in addiction-medicine. However, the temporal dynamics of this response in repeated exposure to cues are not well known. In an fMRI drug cue-reactivity task, the presence of rapid habituation or sensitization was investigated by modeling time and its interaction with condition (drug>neutral) using an initial discovery-sample. Replication of this temporal response was tested in two other clinical populations all abstinent during their early recovery (treatment). Sixty-five male participants (35.8 ± 8.4 years-old) with methamphetamine use disorder (MUD) were recruited as the discovery-sample from an abstinence-based residential treatment program. A linear mixed effects model was used to identify areas with a time-by-condition interaction in the discovery-sample. Replication of these effects was tested in two other samples (29 female with MUD from a different residential program and 22 male with opioid use disorder from the same residential program as the discovery sample). The second replication sample was re-tested within two weeks. In the discovery-sample, clusters within the VMPFC, amygdala and ventral striatum showed both a main effect of condition and a condition-by-time interaction, indicating a habituating response to drug-related but not neutral cues. The estimates for the main effects and interactions were generally consistent between the discovery and replication-samples across all clusters. The re-test data showed a consistent lack of drug > neutral and habituation response within all selected clusters in the second cue-exposure session. The VMPFC, amygdala and ventral striatum show habituation in response to drug-related cues which is consistent among different clinical populations. This habituated response in the first session of cue-exposure and lack of reactivity in the second session of exposure may be important for informing the development of cue-desensitization interventions.

Structural MRI and functional connectivity features predict current clinical status and persistence behavior in prescription opioid users.

Prescription opioid use disorder (POUD) has reached epidemic proportions in the United States, raising an urgent need for diagnostic biological tools that can improve predictions of disease characteristics. The use of neuroimaging methods to develop such biomarkers have yielded promising results when applied to neurodegenerative and psychiatric disorders, yet have not been extended to prescription opioid addiction. With this long-term goal in mind, we conducted a preliminary study in this understudied clinical group. Univariate and multivariate approaches to distinguishing between POUD (n = 26) and healthy controls (n = 21) were investigated, on the basis of structural MRI (sMRI) and resting-state functional connectivity (restFC) features. Univariate approaches revealed reduced structural integrity in the subcortical extent of a previously reported addiction-related network in POUD subjects. No reliable univariate between-group differences in cortical structure or edgewise restFC were observed. Contrasting these mixed univariate results, multivariate machine learning classification approaches recovered more statistically reliable group differences, especially when sMRI and restFC features were combined in a multi-modal model (classification accuracy = 66.7%, p < .001). The same multivariate multi-modal approach also yielded reliable prediction of individual differences in a clinically relevant behavioral measure (persistence behavior; predicted-to-actual overlap r = 0.42, p = .009). Our findings suggest that sMRI and restFC measures can be used to reliably distinguish the neural effects of long-term opioid use, and that this endeavor numerically benefits from multivariate predictive approaches and multi-modal feature sets. This can serve as theoretical proof-of-concept for future longitudinal modeling of prognostic POUD characteristics from neuroimaging features, which would have clearer clinical utility.

Dissociable neural substrates of opioid and cocaine use identified via connectome-based modelling.

Opioid use disorder is a major public health crisis. While effective treatments are available, outcomes vary widely across individuals and relapse rates remain high. Understanding neural mechanisms of treatment response may facilitate the development of personalized and/or novel treatment approaches. Methadone-maintained, polysubstance-using individuals (n = 53) participated in fMRI scanning before and after substance-use treatment. Connectome-based predictive modeling (CPM)-a recently developed, whole-brain approach-was used to identify pretreatment connections associated with abstinence during the 3-month treatment. Follow-up analyses were conducted to determine the specificity of the identified opioid abstinence network across different brain states (cognitive vs. reward task vs. resting-state) and different substance use outcomes (opioid vs. cocaine abstinence). Posttreatment fMRI data were used to assess network changes over time and within-subject replication. To determine further clinical relevance, opioid abstinence network strength was compared with healthy subjects (n = 38). CPM identified an opioid abstinence network (p = 0.018), characterized by stronger within-network motor/sensory connectivity, and reduced connectivity between the motor/sensory network and medial frontal, default mode, and frontoparietal networks. This opioid abstinence network was anatomically distinct from a previously identified cocaine abstinence network. Relationships between abstinence and opioid and cocaine abstinence networks replicated across multiple brain states but did not generalize across substances. Network connectivity measured at posttreatment related to abstinence at 6-month follow-up (p < 0.009). Healthy comparison subjects displayed intermediate network strengths relative to treatment responders and nonresponders. These data indicate dissociable anatomical substrates of opioid vs. cocaine abstinence. Results may inform the development of novel opioid-specific treatment approaches to combat the opioid epidemic.

Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities.

Pain medication plays an important role in the treatment of acute and chronic pain conditions, but some drugs, opioids in particular, have been overprescribed or prescribed without adequate safeguards, leading to an alarming rise in medication-related overdose deaths. The NIH Helping to End Addiction Long-term (HEAL) Initiative is a trans-agency effort to provide scientific solutions to stem the opioid crisis. One component of the initiative is to support biomarker discovery and rigorous validation in collaboration with industry leaders to accelerate high-quality clinical research into neurotherapeutics and pain. The use of objective biomarkers and clinical trial end points throughout the drug discovery and development process is crucial to help define pathophysiological subsets of pain, evaluate target engagement of new drugs and predict the analgesic efficacy of new drugs. In 2018, the NIH-led Discovery and Validation of Biomarkers to Develop Non-Addictive Therapeutics for Pain workshop convened scientific leaders from academia, industry, government and patient advocacy groups to discuss progress, challenges, gaps and ideas to facilitate the development of biomarkers and end points for pain. The outcomes of this workshop are outlined in this Consensus Statement.

Methamphetamine and Opioid Cue Database (MOCD): Development and Validation.

INTRODUCTION: Drug cue reactivity (DCR) is widely used in experimental settings for both assessment and intervention. There is no validated database of pictorial cues available for methamphetamine and opioids. METHODS: 360 images in three-groups (methamphetamine, opioid and neutral (control)) matched for their content (objects, hands, faces and actions) were selected in an initial development phase. 28 participants with a history of both methamphetamine and opioid use (37.71 ± 8.11 years old, 12 female) with over six months of abstinence were asked to rate images for craving, valence, arousal, typicality and relatedness. RESULTS: All drug images were differentiated from neutral images. Drug related images received higher arousal and lower valence ratings compared to neutral images (craving (0-100) for neutral (11.5 ± 21.9), opioid (87.7 ± 18.5) and methamphetamine (88 ± 18), arousal (1-9) for neutral (2.4 ± 1.9), opioid (4.6 ± 2.7) and methamphetamine (4.6 ± 2.6), and valence (1-9) for neutral (4.8 ± 1.3), opioid (4.4 ± 1.9) and methamphetamine (4.4 ± 1.8)). There is no difference between methamphetamine and opioid images in craving, arousal and valence. There is a significant positive relationship between the amount of time that participants spent on drug-related images and the craving they reported for the image. Every 10 points of craving were associated with an increased response time of 383 ms. Three image sets were automatically selected for equivalent fMRI tasks (methamphetamine and opioids) from the database (tasks are available at github). CONCLUSION: The methamphetamine and opioid cue database (MOCD) provides a resource of validated images/tasks for future DCR studies. Additionally, researchers can select several sets of unique but equivalent images based-on their psychological/physical characteristics for multiple assessments/interventions.

Prefrontal GABA and glutamate levels correlate with impulsivity and cognitive function of prescription opioid addicts: A 1 H-magnetic resonance spectroscopy study.

AIM: Prescription opioids are psychoactive substances that can elicit many neuropsychological effects. There are no studies that directly demonstrate the effects of prescription opioid addiction (POA) on the human brain. This study aimed to quantify γ-aminobutyric acid (GABA) and glutamate (Glu) levels in the prefrontal cortex (PFC) of POA patients using proton magnetic resonance spectroscopy (1 H-MRS), and to explore their association with impulsive behavior and cognitive impairment. METHODS: Thirty-five patients with a definitive clinical diagnosis of codeine-containing cough syrup dependence and 35 matched healthy controls underwent neuropsychological assessments, namely the Barratt Impulsiveness Scale (BIS-11) and the Montreal Cognitive Assessment Scale (MoCA). Point-resolved spectroscopy was performed to detect GABA and glutamate within the medial PFC, and the corresponding levels were estimated using jMRUI and corrected for fraction of cerebrospinal fluid in the 1 H-MRS voxel. The difference in metabolite levels between groups and the correlation between metabolite levels and psychometric scores in patients were analyzed statistically. RESULTS: The peak level predominantly consisting of GABA with a relatively small influence of other chemicals (GABA+) was lower and that of glutamate was higher in the PFC of POA patients than in healthy controls. GABA+ levels correlated negatively with BIS-11 scores but correlated positively with MoCA scores. In contrast, glutamate levels showed a positive correlation with BIS-11 scores but no significant correlation with MoCA scores. CONCLUSION: The quantitative in vivo measurement of GABA and glutamate levels in the PFC by 1 H-MRS could be a reliable way to evaluate impulsivity and cognitive function of POA.