The Neural Signature of Impaired Inhibitory Control in Individuals with Heroin Use Disorder.

Heroin addiction imposes a devastating toll on society, with little known about its neurobiology. Excessive salience attribution to drug over nondrug cues/reinforcers, with concomitant inhibitory control decreases, are common mechanisms underlying drug addiction. Although inhibitory control alterations generally culminate in prefrontal cortex (PFC) hypoactivations across drugs of abuse, patterns in individuals with heroin addiction (iHUDs) remain unknown. We used a stop-signal fMRI task designed to meet recent consensus guidelines in mapping inhibitory control in 41 iHUDs and 24 age- and sex-matched healthy controls (HCs). Despite group similarities in the stop-signal response time (SSRT; the classic inhibitory control measure), compared with HCs, iHUDs exhibited impaired target detection sensitivity (proportion of hits in go vs false alarms in stop trials; p = 0.003). Additionally, iHUDs exhibited lower right anterior PFC (aPFC) and dorsolateral PFC (dlPFC) activity during successful versus failed stops (the hallmark inhibitory control contrast). Lower left dlPFC/supplementary motor area (SMA) activity was associated with slower SSRT specifically in iHUDs and lower left aPFC activity with worse target sensitivity across all participants (p < 0.05 corrected). Importantly, in iHUDs, lower left SMA and aPFC activity during inhibitory control was associated with shorter time since last use and higher severity of dependence, respectively (p < 0.05 corrected). Together, results revealed lower perceptual sensitivity and hypoactivations during inhibitory control in cognitive control regions (e.g., aPFC, dlPFC, SMA) as associated with task performance and heroin use severity measures in iHUDs. Such neurobehavioral inhibitory control deficits may contribute to self-control lapses in heroin addiction, constituting targets for prevention and intervention efforts to enhance recovery.SIGNIFICANCE STATEMENT Heroin addiction continues its deadly impact, with little known about the neurobiology of this disorder. Although behavioral and prefrontal cortical impairments in inhibitory control characterize addiction across drugs of abuse, these patterns remain underexplored in heroin addiction. Here, we illustrate a significant behavioral impairment in target discrimination in individuals with heroin addiction compared with matched healthy controls. We further show lower engagement during inhibitory control in the anterior and dorsolateral prefrontal cortex (key regions that regulate cognitive control) as associated with slower stopping, worse discrimination, and heroin use measures. Mapping the neurobiology of inhibitory control in heroin addiction for the first time, we identify potential treatment targets inclusive of prefrontal cortex-mediated cognitive control amenable for neuromodulation en route to recovery.

Whole-brain white matter abnormalities in human cocaine and heroin use disorders: association with craving, recency, and cumulative use.

Neuroimaging studies in substance use disorder have shown widespread impairments in white matter (WM) microstructure suggesting demyelination and axonal damage. However, substantially fewer studies explored the generalized vs. the acute and/or specific drug effects on WM. Our study assessed whole-brain WM integrity in three subgroups of individuals addicted to drugs, encompassing those with cocaine (CUD) or heroin (HUD) use disorder, compared to healthy controls (CTL). Diffusion MRI was acquired in 58 CTL, 28 current cocaine users/CUD+, 32 abstinent cocaine users/CUD-, and 30 individuals with HUD (urine was positive for cocaine in CUD+ and opiates used for treatment in HUD). Tract-Based Spatial Statistics allowed voxelwise analyses of diffusion metrics [fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD)]. Permutation statistics (p-corrected < 0.05) were used for between-group t-tests. Compared to CTL, all individuals with addiction showed widespread decreases in FA, and increases in MD, RD, and AD (19-57% of WM skeleton, p < 0.05). The HUD group showed the most impairments, followed by the CUD+, with only minor FA reductions in CUD- (<0.2% of WM skeleton, p = 0.05). Longer periods of regular use were associated with decreased FA and AD, and higher subjective craving was associated with increased MD, RD, and AD, across all individuals with drug addiction (p < 0.05). These findings demonstrate extensive WM impairments in individuals with drug addiction characterized by decreased anisotropy and increased diffusivity, thought to reflect demyelination and lower axonal packing. Extensive abnormalities in both groups with positive urine status (CUD+ and HUD), and correlations with craving, suggest greater WM impairments with more recent use. Results in CUD-, and correlations with regular use, further imply cumulative and/or persistent WM damage.

Common and distinct fronto-striatal volumetric changes in heroin and cocaine use disorders.

Different drugs of abuse impact the morphology of fronto-striatal dopaminergic targets in both common and unique ways. While dorsal striatal volume tracks with addiction severity across drug classes, opiates impact ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAcc) neuroplasticity in preclinical models, and psychostimulants alter inhibitory control, rooted in cortical regions such as the inferior frontal gyrus (IFG). We hypothesized parallel grey matter volume changes associated with human heroin or cocaine use disorder: lower grey matter volume of vmPFC/NAcc in heroin use disorder and IFG in cocaine use disorder, and putamen grey matter volume to be associated with addiction severity measures (including craving) across both. In this cross-sectional study, we quantified grey matter volume (P < 0.05-corrected) in age/sex/IQ-matched individuals with heroin use disorder (n = 32, seven females), cocaine use disorder (n = 32, six females) and healthy controls (n = 32, six females) and compared fronto-striatal volume between groups using voxel-wise general linear models and non-parametric permutation-based tests. Overall, individuals with heroin use disorder had smaller vmPFC and NAcc/putamen volumes than healthy controls. Bilateral lower IFG grey matter volume patterns were specifically evident in cocaine versus heroin use disorders. Correlations between addiction severity measures and putamen grey matter volume did not reach nominal significance level in this sample. These results indicate alterations in dopamine-innervated regions (in the vmPFC and NAcc) in heroin addiction. For the first time we demonstrate lower IFG grey matter volume specifically in cocaine compared with heroin use disorder, suggesting a signature of reduced inhibitory control, which remains to be tested directly using select behavioural measures. Overall, results suggest substance-specific volumetric changes in human psychostimulant or opiate addiction, with implications for fine-tuning biomarker and treatment identification by primary drug of abuse.

Emotional Expression on Social Media Support Forums for Substance Cessation: Observational Study of Text-Based Reddit Posts.

BACKGROUND: Substance use disorder is characterized by distinct cognitive processes involved in emotion regulation as well as unique emotional experiences related to the relapsing cycle of drug use and recovery. Web-based communities and the posts they generate represent an unprecedented resource for studying subjective emotional experiences, capturing population types and sizes not typically available in the laboratory. Here, we mined text data from Reddit, a social media website that hosts discussions from pseudonymous users on specific topic forums, including forums for individuals who are trying to abstain from using drugs, to explore the putative specificity of the emotional experience of substance cessation. OBJECTIVE: An important motivation for this study was to investigate transdiagnostic clues that could ultimately be used for mental health outreach. Specifically, we aimed to characterize the emotions associated with cessation of 3 major substances and compare them to emotional experiences reported in nonsubstance cessation posts, including on forums related to psychiatric conditions of high comorbidity with addiction. METHODS: Raw text from 2 million posts made, respectively, in the fall of 2020 (discovery data set) and fall of 2019 (replication data set) were obtained from 394 forums hosted by Reddit through the application programming interface. We quantified emotion word frequencies in 3 substance cessation forums for alcohol, nicotine, and cannabis topic categories and performed comparisons with general forums. Emotion word frequencies were classified into distinct categories and represented as a multidimensional emotion vector for each forum. We further quantified the degree of emotional resemblance between different forums by computing cosine similarity on these vectorized representations. For substance cessation posts with self-reported time since last use, we explored changes in the use of emotion words as a function of abstinence duration. RESULTS: Compared to posts from general forums, substance cessation posts showed more expressions of anxiety, disgust, pride, and gratitude words. "Anxiety" emotion words were attenuated for abstinence durations >100 days compared to shorter durations (t12=3.08, 2-tailed; P=.001). The cosine similarity analysis identified an emotion profile preferentially expressed in the cessation posts across substances, with lesser but still prominent similarities to posts about social anxiety and attention-deficit/hyperactivity disorder. These results were replicated in the 2019 (pre-COVID-19) data and were distinct from control analyses using nonemotion words. CONCLUSIONS: We identified a unique subjective experience phenotype of emotions associated with the cessation of 3 major substances, replicable across 2 time periods, with changes as a function of abstinence duration. Although to a lesser extent, this phenotype also quantifiably resembled the emotion phenomenology of other relevant subjective experiences (social anxiety and attention-deficit/hyperactivity disorder). Taken together, these transdiagnostic results suggest a novel approach for the future identification of at-risk populations, allowing for the development and deployment of specific and timely interventions.

FRONTAL WHITE MATTER CHANGES INDICATE RECOVERY WITH INPATIENT TREATMENT IN HEROIN ADDICTION.

Importance: Amidst an unprecedented opioid epidemic, identifying neurobiological correlates of change with medication-assisted treatment of heroin use disorder is imperative. Distributed white matter (WM) impairments in individuals with heroin use disorder (iHUD) have been associated with increased drug craving, a reliable predictor of treatment outcomes. However, little is known about the extent of whole-brain structural connectivity changes with inpatient treatment and abstinence in iHUD. Objective: To assess WM microstructure and associations with drug craving changes with inpatient treatment in iHUD (effects of time/re-scan compared to controls; CTL). Design: Longitudinal cohort study (12/2020-09/2022) where iHUD and CTL underwent baseline magnetic resonance imaging (MRI#1) and follow-up (MRI#2) scans, (mean interval of 13.9 weeks in all participants combined). Setting: The iHUD and CTL were recruited from urban inpatient treatment facilities and surrounding communities, respectively. Participants: Thirty-four iHUD (42.1yo; 7 women), 25 age-/sex-matched CTL (40.5yo; 9 women). Intervention: Between scans, inpatient iHUD continued their medically-assisted treatment and related clinical interventions. CTL participants were scanned at similar time intervals. Main Outcomes and Measures: Changes in white matter diffusion metrics [fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivities (RD)] in addition to baseline and cue-induced drug craving, and other clinical outcome variables (mood, sleep, affect, perceived stress, and therapy attendance). Results: Main findings showed HUD-specific WM microstructure changes encompassing mostly frontal major callosal, projection, and association tracts, characterized by increased FA (.949<1-p<.986) and decreased MD (.949<1-p<.997) and RD (.949<1-p<.999). The increased FA (r=-0.72, p<.00001) and decreased MD (r=0.69, p<.00001) and RD (r=0.67, p<.0001) in the genu and body of the corpus callosum and the left anterior corona radiata in iHUD were correlated with a reduction in baseline craving (.949<1-p<.999). No other WM correlations with outcome variables reached significance. Conclusions and Relevance: Our findings suggest whole-brain normalization of structural connectivity with inpatient medically-assisted treatment in iHUD encompassing recovery in frontal WM pathways implicated in emotional regulation and top-down executive control. The association with decreases in baseline craving further supports the relevance of these WM markers to a major symptom in drug addiction, with implications for monitoring clinical outcomes.

Naturalistic drug cue reactivity in heroin use disorder: orbitofrontal synchronization as a marker of craving and recovery.

Movies captivate groups of individuals (the audience), especially if they contain themes of common motivational interest to the group. In drug addiction, a key mechanism is maladaptive motivational salience attribution whereby drug cues outcompete other reinforcers within the same environment or context. We predicted that while watching a drug-themed movie, where cues for drugs and other reinforcers share a continuous narrative context, fMRI responses in individuals with heroin use disorder (iHUD) will preferentially synchronize during drug scenes. Results revealed such drug-biased synchronization in the orbitofrontal cortex (OFC), ventromedial and ventrolateral prefrontal cortex, and insula. After 15 weeks of inpatient treatment, there was a significant reduction in this drug-biased shared response in the OFC, which correlated with a concomitant reduction in dynamically-measured craving, suggesting synchronized OFC responses to a drug-themed movie as a neural marker of craving and recovery in iHUD.

Recovery of inhibitory control prefrontal cortex function in inpatients with heroin use disorder: a 15-week longitudinal fMRI study.

Importance: Heroin addiction and related mortality impose a devastating toll on society, with little known about the neurobiology of this disease or its treatment. Poor inhibitory control is a common manifestation of prefrontal cortex (PFC) impairments in addiction, and its potential recovery following treatment is largely unknown in heroin (or any drug) addiction. Objective: To study inhibitory control brain activity in iHUD and HC, before and after 15 weeks of inpatient treatment in the former. Design: A longitudinal cohort study (11/2020-03/2022) where iHUD and HC underwent baseline and follow-up fMRI scans. Average follow-up duration: 15 weeks. Setting: The iHUD and HC were recruited from treatment facilities and surrounding neighborhoods, respectively. Participants: Twenty-six iHUD [40.6±10.1 years; 7 (29.2%) women] and 24 age-/sex-matched HC [41.1±9.9 years; 9 (37.5%) women]. Intervention: Following the baseline scan, inpatient iHUD continued to participate in a medically-assisted program for an average of 15 weeks (abstinence increased from an initial 183±236 days by 65±82 days). The HC were scanned at similar time intervals. Main Outcomes and Measures: Behavioral performance as measured by the stop-signal response time (SSRT), target detection sensitivity (d', proportion of hits in go vs. false-alarms in stop trials), and brain activity (blood-oxygen level dependent signal differences) during successful vs. failed stops in the stop signal task. Results: As we previously reported, at time 1 and as compared to HC, iHUD exhibited similar SSRT but impaired d' [t(38.7)=2.37, p=.023], and lower anterior and dorsolateral PFC (aPFC, dlPFC) activity (p<.001). Importantly, at time 2, there were significant gains in aPFC and dlPFC activity in the iHUD (group*session interaction, p=.002); the former significantly correlated with increases in d' specifically in iHUD (p=.012). Conclusions and Relevance: Compared to HC, the aPFC and dlPFC impairments in the iHUD at time 1 were normalized at time 2, which was associated with individual differences in improvements in target detection sensitivity. For the first time in any drug addiction, these results indicate a treatment-mediated inhibitory control brain activity recovery. These neurobehavioral results highlight the aPFC and dlPFC as targets for intervention with a potential to enhance self-control recovery in heroin addiction.

Prefrontal-habenular microstructural impairments in human cocaine and heroin addiction.

The habenula (Hb) is central to adaptive reward- and aversion-driven behaviors, comprising a hub for higher-order processing networks involving the prefrontal cortex (PFC). Despite an established role in preclinical models of cocaine addiction, the translational significance of the Hb and its connectivity with the PFC in humans is unclear. Using diffusion tractography, we detailed PFC structural connectivity with the Hb and two control regions, quantifying tract-specific microstructural features in healthy and cocaine-addicted individuals. White matter was uniquely impaired in PFC-Hb projections in both short-term abstainers and current cocaine users. Abnormalities in this tract further generalized to an independent sample of heroin-addicted individuals and were associated, in an exploratory analysis, with earlier onset of drug use across the addiction subgroups, potentially serving as a predisposing marker amenable for early intervention. Importantly, these findings contextualize a plausible PFC-Hb circuit in the human brain, supporting preclinical evidence for its impairment in cocaine addiction.

Translationally Relevant Magnetic Resonance Imaging Markers in a Ferret Model of Closed Head Injury.

Pre-clinical models of traumatic brain injury (TBI) have been the primary experimental tool for understanding the potential mechanisms and cellular alterations that follow brain injury, but the human relevance and translational value of these models are often called into question. Efforts to better recapitulate injury biomechanics and the use of non-rodent species with neuroanatomical similarities to humans may address these concerns and promise to advance experimental studies toward clinical impact. In addition to improving translational aspects of animal models, it is also advantageous to establish pre-clinical outcomes that can be directly compared with the same outcomes in humans. Non-invasive imaging and particularly MRI is promising for this purpose given that MRI is a primary tool for clinical diagnosis and at the same time increasingly available at the pre-clinical level. The objective of this study was to identify which commonly used radiologic markers of TBI outcomes can be found also in a translationally relevant pre-clinical model of TBI. The ferret was selected as a human relevant species for this study with folded cortical geometry and relatively high white matter content and the closed head injury model of engineered rotation and acceleration (CHIMERA) TBI model was selected for biomechanical similarities to human injury. A comprehensive battery of MRI protocols based on common data elements (CDEs) for human TBI was collected longitudinally for the identification of MRI markers and voxelwise analysis of T2, contrast enhancement and diffusion tensor MRI values. The most prominent MRI findings were consistent with focal hemorrhage and edema in the brain stem region following high severity injury as well as vascular and meningeal injury evident by contrast enhancement. While conventional MRI outcomes were not highly conspicuous in less severe cases, quantitative voxelwise analysis indicated diffusivity and anisotropy alterations in the acute and chronic periods after TBI. The main conclusions of this study support the translational relevance of closed head TBI models in intermediate species and identify brain stem and meningeal vulnerability. Additionally, the MRI findings highlight a subset of CDEs with promise to bridge pre-clinical studies with human TBI outcomes.