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The faster a drug enters the brain, the greater its addictive potential, yet the brain circuits underlying the rate dependency to drug reward remain unresolved. With simultaneous PET-fMRI we linked dynamics of dopamine signaling, brain activity/connectivity, and self-reported ‘high’ in 20 adults receiving methylphenidate orally (results in slow delivery) and intravenously (results in fast delivery) (trial NCT03326245). We estimated speed of striatal dopamine increases to oral and IV methylphenidate and then tested where brain activity was associated with slow and fast dopamine dynamics (primary endpoint). We then tested whether these brain circuits were temporally associated with individual ‘high’ ratings to methylphenidate (secondary endpoint). A corticostriatal circuit comprising the dorsal anterior cingulate cortex and insula and their connections with dorsal caudate was activated by fast (but not slow) dopamine increases and paralleled ‘high’ ratings. These data provide evidence in humans for a link between dACC/insula activation and fast but not slow dopamine increases and document a critical role of the salience network in drug reward. The faster a drug enters the brain, the greater its addictive potential. Using simultaneous PET-fMRI in humans, here the authors report a neural circuit responding to fast but not slow dopamine increases from intravenous versus oral methylphenidate delivery.

Substance use disorders (SUDs) and anxiety disorders (ADs) are highly comorbid, a co-occurrence linked to worse clinical outcomes than either condition alone. While the neurobiological mechanisms involved in SUDs and anxiety disorders are intensively studied separately, the mechanisms underlying their comorbidity remain an emerging area of interest. This narrative review explores the neurobiological processes underlying this comorbidity, using the Research Domain Criteria (RDoC) framework to map disruptions in positive valence, negative valence, and cognitive systems across the three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Anxiety and substance use play a reciprocal role at each stage of addiction, marked by significant psychosocial impairment and dysregulation in the brain. A more thorough understanding of the neural underpinnings involved in comorbid SUDs and anxiety disorders will contribute to more tailored and effective therapeutic interventions and assessments.

Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate’s brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [ 11 C]raclopride’s binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [ 11 C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of “high”. We show for the first time that the “high” is associated with the fast dopamine increases induced by methylphenidate. Combined PET imaging and mathematical simulations reveal that the rate of dopamine increase in the striatum underlies self-reports of drug “high” in response to oral and intravenous methylphenidate challenges in humans

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [ 11 C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = −0.54, p spin  < 0.001). GBC showed “fast>slow” associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and “slow>fast” associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex ( p FDR  < 0.05). “Fast>slow” GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [ 11 C]SCH23390 binding; rho = 0.22, p spin  < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported ‘high’ ratings to intravenous MP across individuals ( r ( 19)  = −0.68, p bonferroni  = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Sleep and circadian disruptions are highly prevalent in opioid use disorder (OUD) and are a barrier to successful treatment and recovery; yet few objective data are available, especially for individuals in OUD treatment with opioid agonist therapy. If disruptions remain present despite OUD treatment, this information would yield potential new targets for adjunctive therapy. To systematically investigate different aspects of rest-activity rhythms (RAR), including sleep, physical activity, circadian rhythmicity, and brain functional correlates in individuals with OUD. This cross-sectional study conducted from October 12, 2017, through January 11, 2024, recruited participants with OUD from treatment programs or the community in the District of Columbia, Maryland, and Virginia area. Participants included individuals with OUD treated with methadone or buprenorphine, individuals with OUD who remained abstinent without medications, and healthy controls (HCs). Healthy participants were recruited from advertisements. Statistical analyses were conducted between March 1 and May 31, 2024. In total, 21 RAR features were derived from 1-week actigraphy data, and principal components were used to extract independent RAR components. Modulators and brain and clinical correlates of RAR were also examined. This study included 73 participants (46 [63%] male; mean [SD] age, 43.5 [11.3] years). Among 42 patients with OUD (16 [38%] female; mean [SD] age, 42.7 [11.4] years), 33 receiving medications for opioid use disorder (MOUD) exhibited greater sleep-wake irregularity than 9 patients without MOUD (mean difference, 0.85 [95% CI, 0.00-1.69]) or 31 age- and sex-matched HCs (11 [36%] female; mean [SD] age, 44.5 [11.3] years; mean difference, 0.75 [95% CI, 0.19-1.31). Among participants receiving MOUD, greater sleep irregularity was associated with longer heroin use history (r26 = 0.45; P = .02) and lower daytime light exposure (r33 = -0.57; P < .001). Compared with HCs, participants with OUD exhibited lower fractional occupancy (percentage of occurrence) in a default mode network-dominated brain state, with individuals experiencing more pronounced sleep-wake irregularities displaying exacerbated impairments (r23 = -0.55; P = .007). Findings of this cross-sectional study showed that sleep irregularity in participants with OUD receiving opioid agonist medications correlated with years of opioid misuse and shorter daylight exposures and was associated with impaired brain state dynamics. These findings suggest that interventions increasing light exposure may improve sleep-wake irregularity and brain functional network dynamics in individuals with OUD receiving opioid agonist medications.

Dopaminergic signaling shapes large-scale brain network architecture, constraining neural communication along a principal gradient that spans unimodal sensorimotor to transmodal association cortices. While more differentiated gradients are typically linked to enhanced cognition, it remains unclear whether dopamine-enhancing psychostimulants, such as methylphenidate (MP), amplify or compress this functional hierarchy to support attention. Across two double-blind, placebo-controlled studies in healthy adults (n = 38 and n = 20), we combined 60 mg oral MP with PET and fMRI to assess striatal dopamine function and cortical organization. MP consistently compressed the principal gradient, reducing segregation between sensory and association areas. The degree of compression predicted individual variation in striatal D1 and D2 receptor availability. MP-induced gradient compression in inferior parietal cortex tracked attention improvements. Critically, we validated key findings in a large, independent cohort from the Adolescent Brain Cognitive Development (ABCD) study (n = 4,958). These results highlight a dopamine-sensitive mechanism linking cortical functional reorganization with cognitive performance.