Age, gender and body-mass-index relationships with in vivo CB1 receptor availability in healthy humans measured with [11C]OMAR PET.

Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18-55 years; 44 male; BMI=27.01±5.56), the largest cohort of subjects studied to date using the CB1R PET ligand [11C]OMAR. There was a significant decline in CB1R availability (VT) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in VT remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using [11C]OMAR and other radioligands such as [18F]FMPEP-d2 and [18F]MK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both [11C]OMAR and [18F]FMPEP-d2 within the same cohort of subjects.

Multimodal neuroimaging of metabotropic glutamate 5 receptors and functional connectivity in alcohol use disorder.

BACKGROUND: People recovering from alcohol use disorder (AUD) show altered resting brain connectivity. The metabotropic glutamate 5 (mGlu5) receptor is an important regulator of synaptic plasticity potentially linked with synchronized brain activity and a target of interest in treating AUD. The goal of this work was to assess potential relationships of brain connectivity at rest with mGlu5 receptor availability in people with AUD at two time points early in abstinence. METHODS: Forty-eight image data sets were acquired with a multimodal neuroimaging battery that included resting-state functional magnetic resonance imaging (fMRI) and mGlu5 receptor positron emission tomography (PET) with the radiotracer [18 F]FPEB. Participants with AUD (n = 14) were scanned twice, at approximately 1 and 4 weeks after beginning supervised abstinence. [18 F]FPEB PET results were published previously. Primary comparisons of fMRI outcomes were performed between the AUD group and healthy controls (HCs; n = 23) and assessed changes over time within the AUD group. Relationships between resting-state connectivity measures and mGlu5 receptor availability were explored within groups. RESULTS: Compared to HCs, global functional connectivity of the orbitofrontal cortex was higher in the AUD group at 4 weeks of abstinence (p = 0.003), while network-level functional connectivity within the default mode network (DMN) was lower (p < 0.04). Exploratory multimodal analyses showed that mGlu5 receptor availability was correlated with global connectivity across all brain regions (HCs, r = 0.41; AUD group at 1 week of abstinence, r = 0.50 and at 4 weeks, r = 0.46; all p < 0.0001). Furthermore, a component of cortical and striatal mGlu5 availability was correlated with connectivity between the DMN and salience networks in HCs (r = 0.60, p = 0.003) but not in the AUD group (p > 0.3). CONCLUSIONS: These preliminary findings of altered global and network connectivity during the first month of abstinence from drinking may reflect the loss of efficient network function, while exploratory relationships with mGlu5 receptor availability suggest a potential glutamatergic relationship with network coherence.

Lower prefrontal cortical synaptic vesicle binding in cocaine use disorder: An exploratory 11 C-UCB-J positron emission tomography study in humans.

Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single 11 C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (VT ) and the plasma-free fraction-corrected form of the total volume of distribution (VT /fP ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for VT and VT /fP . Post hoc analyses revealed no differences on VT , while for VT /fP showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional VT /fP values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.

Identifying brain networks in synaptic density PET (11C-UCB-J) with independent component analysis.

BACKGROUND: The human brain is inherently organized into distinct networks, as reported widely by resting-state functional magnetic resonance imaging (rs-fMRI), which are based on blood-oxygen-level-dependent (BOLD) signal fluctuations. 11C-UCB-J PET maps synaptic density via synaptic vesicle protein 2A, which is a more direct structural measure underlying brain networks than BOLD rs-fMRI. METHODS: The aim of this study was to identify maximally independent brain source networks, i.e., "spatial patterns with common covariance across subjects", in 11C-UCB-J data using independent component analysis (ICA), a data-driven analysis method. Using a population of 80 healthy controls, we applied ICA to two 40-sample subsets and compared source network replication across samples. We examined the identified source networks at multiple model orders, as the ideal number of maximally independent components (IC) is unknown. In addition, we investigated the relationship between the strength of the loading weights for each source network and age and sex. RESULTS: Thirteen source networks replicated across both samples. We determined that a model order of 18 components provided stable, replicable components, whereas estimations above 18 were not stable. Effects of sex were found in two ICs. Nine ICs showed age-related change, with 4 remaining significant after correction for multiple comparison. CONCLUSION: This study provides the first evidence that human brain synaptic density can be characterized into organized covariance patterns. Furthermore, we demonstrated that multiple synaptic density source networks are associated with age, which supports the potential utility of ICA to identify biologically relevant synaptic density source networks.

Drinking and responses to antidrinking messages among young adults: An fMRI study.

Young adults consume most of their alcohol by binge drinking, and more than one-third report binge drinking in the past month. Some will transition out of excessive drinking, while others will maintain or increase alcohol use into adulthood. Public health campaigns depicting negative consequences of drinking have shown some efficacy at reducing this behavior. However, substance use in dependent individuals is governed in part by automatic or habitual responses to drug cues rather than the consequences. This study used functional magnetic resonance imaging to measure neural responses to drinking cues and drinking cues paired with antidrinking messages among young adults who binge drink (N = 30). This study also explored responses to smoking cues and antismoking messages. Neural responses were also compared between drinking/smoking and neutral cues. Self-reported drinking and smoking were collected at baseline, postscan, and 1 month. Results indicate that activity in the ventral striatum-implicated in reward processing-was lower for drinking cues paired with antidrinking messages than drinking cues. This difference was less pronounced in young adults who reported greater baseline past month drinking quantity. Past month drinking quantity decreased from baseline to 1 month. Further, young adults who showed higher activity during antidrinking messages in the medial prefrontal cortex-implicated in processing message self-relevance- reported a greater decrease in past month drinking frequency from baseline to 1 month. Findings may help to identify young adults who are at risk for continued heavy drinking in adulthood and inform interventions aimed to reduce drinking and reward in young adults.

Separating dopamine D2 and D3 receptor sources of [11C]-(+)-PHNO binding potential: Independent component analysis of competitive binding.

Development of medications selective for dopamine D2 or D3 receptors is an active area of research in numerous neuropsychiatric disorders including addiction and Parkinson's disease. The positron emission tomography (PET) radiotracer [11C]-(+)-PHNO, an agonist that binds with high affinity to both D2 and D3 receptors, has been used to estimate relative receptor subtype occupancy by drugs based on a priori knowledge of regional variation in the expression of D2 and D3 receptors. The objective of this work was to use a data-driven independent component analysis (ICA) of receptor blocking scans to separate D2-and D3-related signal in [11C]-(+)-PHNO binding data in order to improve the precision of subtype specific measurements of binding and occupancy. Eight healthy volunteers underwent [11C]-(+)-PHNO PET scans at baseline and at two time points following administration of the D3-preferring antagonist ABT-728 (150-1000 â€‹mg). Parametric binding potential (BPND) images were analyzed as four-dimensional image series using ICA to extract two independent sources of variation in [11C]-(+)-PHNO BPND. Spatial source maps for each component were consistent with respective regional patterns of D2-and D3-related binding. ICA-derived occupancy estimates from each component were similar to D2-and D3-specific occupancy estimated from a region-based approach (intraclass correlation coefficients â€‹> â€‹0.95). ICA-derived estimates of D3 receptor occupancy improved quality of fit to a single site binding model. Furthermore, ICA-derived estimates of the regional fraction of [11C]-(+)-PHNO binding related to D3 receptors was generated for each subject and values showed good agreement with region-based model estimates and prior literature values. In summary, ICA successfully separated D2-and D3-related components of the [11C]-(+)-PHNO binding signal, establishing this approach as a powerful data-driven method to quantify distinct biological features from PET data composed of mixed data sources.

Neurofunctional Differences Related to Methamphetamine and Sexual Cues in Men With Shorter and Longer Term Abstinence Methamphetamine Dependence.

BACKGROUND: Stimulant use and sexual behaviors have been linked in behavioral and epidemiological studies. Although methamphetamine-related neurofunctional differences have been investigated, few studies have examined neural responses to drug and sexual cues with respect to shorter or longer term methamphetamine abstinence in individuals with methamphetamine dependence. METHODS: Forty-nine men with shorter term methamphetamine abstinence, 50 men with longer term methamphetamine abstinence, and 47 non-drug-using healthy comparison men completed a functional magnetic resonance imaging cue-reactivity task consisting of methamphetamine, sexual, and neutral visual cues. RESULTS: Region-of-interest analyses revealed greater methamphetamine cue-related activation in shorter term methamphetamine abstinence and longer term methamphetamine abstinence individuals relative to healthy comparison men in the ventromedial prefrontal cortex. A significant interaction of group and condition in the anterior insula was found. Relative to healthy comparison participants, both shorter term methamphetamine abstinence and longer term methamphetamine abstinence groups displayed greater sexual cue-related anterior insula activation relative to methamphetamine cues and neutral cues, but there were no differences between shorter term methamphetamine abstinence and longer term methamphetamine abstinence groups in anterior insula responses. Subsequent whole-brain analyses indicated a group-by-condition interaction with longer term methamphetamine abstinence participants showing greater sexual-related activation in the left superior frontal cortex relative to healthy comparison men. Shorter term methamphetamine abstinence participants showed greater superior frontal cortex activation to sexual relative to neutral cues, and longer term methamphetamine abstinence participants showed greater superior frontal cortex activation to sexual relative to neutral and methamphetamine cues. CONCLUSIONS: The findings suggest that abstinence from methamphetamine may alter how individuals respond to drug and sexual cues and thus may influence drug use and sexual behaviors. Given the use of methamphetamine for sexual purposes and responses to natural vs drug rewards for addiction recovery, the findings may have particular clinical relevance.

Gray-matter relationships to diagnostic and transdiagnostic features of drug and behavioral addictions.

Alterations in neural structure have been reported in both cocaine-use disorder and gambling disorder, separately, suggesting similarities across addiction diagnoses. Individual variation in neural structure has also been associated with impulsivity, a dimensional construct implicated in addictions. This study combines categorical (diagnosis-based) and dimensional (transdiagnostic) approaches to identify neural structural alterations linked to addiction subtypes and trait impulsivity, respectively, across individuals with gambling disorder (n = 35), individuals with cocaine-use disorder (n = 37) and healthy comparison individuals (n = 37). High-resolution T1-weighted data were analyzed using modulated voxel-based morphometry (VBM). Statistical analyses were conducted using whole-brain general-linear models, corrected for family-wise error (pFWE < .05). Categorical analyses indicated a main effect of diagnostic group on prefrontal (dorsal anterior cingulate and ventromedial prefrontal cortex) gray matter volumes (GMVs), involving decreased GMVs among cocaine-use disorder participants only. Dimensional analyses indicated a negative association between trait impulsivity and cortical (insula) and subcortical (amygdala and hippocampus) GMVs across all participants. Conjunction analysis indicated little anatomical overlap between regions identified as differentiating diagnostic groups and regions covarying with impulsivity. These data provide first evidence of neural structural differences between gambling disorder and an illicit substance-use disorder. They further indicate dissociable effects of diagnostic groupings and trait impulsivity on neural structure among individuals with behavioral and drug addictions. Study findings highlight the importance of considering both categorical and dimensional (e.g. Research Domain Criteria; RDoC) analysis approaches within the context of addictions research.

An Initial Investigation of Individual Rate-of-Play Preferences and Associations with EGM Gambling Behavior.

Electronic gambling machines (EGMs) show a strong association with gambling problems. The high speed of gaming offered by modern EGMs allows playing numerous games in a short span of time, which is thought to contribute to attentional distraction, increased spending and prolonged play. However, the relationship between EGM speeds and potentially risk-related gambling behavior remains unclear. We introduce a novel approach to investigating the role of gaming speed in EGM gambling behavior by examining 'individual rate-of-play' (I-ROP) during simulated EGM gambling. A community sample of male regular gamblers (N = 72) played virtual slot machines in pairs offering sequentially adjusted game speeds towards the estimation of a behaviorally expressed preference speed, or I-ROP. This initial experiment aimed to explore the variability of I-ROPs during simulated EGM gambling, and examine behavior while playing EGMs at speeds relative to their I-ROP. Estimated I-ROPs ranged from less than one half second to over seven seconds and were negatively associated with cognitive ability, but not related to problem gambling severity, impulsiveness, or gambling-related cognitions. Subsequent gambling sessions on EGMs offering individually calibrated faster and slower gaming speeds were associated with greater and reduced risk-related gambling behaviors respectively. I-ROPs represent a potentially informative construct for exploring influences of gaming speed on gambling behavior, and may lend insight into potential risk-related behavior an individual vulnerability with respect to commercially available EGMs that warrants additional research.

Regional and source-based patterns of [11C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D2 and D3 receptor availability in cocaine-use disorder.

Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BPND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lower BPND in CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BPND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions of BPND (calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BPND in the D2R-rich dorsal striatum and greater BPND in the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BPND that were correlated with regional estimates of D2R-related and D3R-related proportions of BPND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration.

A pilot study linking reduced fronto-Striatal recruitment during reward processing to persistent bingeing following treatment for binge-eating disorder.

OBJECTIVE: The primary purpose of this study was to examine neurobiological underpinnings of reward processing that may relate to treatment outcome for binge-eating disorder (BED). METHOD: Prior to starting treatment, 19 obese persons seeking treatment for BED performed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Analyses examined how the neural correlates of reward processing related to binge-eating status after 4-months of treatment. RESULTS: Ten individuals continued to report binge-eating (BEpost-tx ) following treatment and 9 individuals did not (NBEpost-tx ). The groups did not differ in body mass index. The BEpost-tx group relative to the NBEpost-tx group showed diminished recruitment of the ventral striatum and the inferior frontal gyrus during the anticipatory phase of reward processing and reduced activity in the medial prefrontal cortex during the outcome phase of reward processing. DISCUSSION: These results link brain reward circuitry to treatment outcome in BED and suggest that specific brain regions underlying reward processing may represent important therapeutic targets in BED.

Meditation experience is associated with differences in default mode network activity and connectivity.

Many philosophical and contemplative traditions teach that "living in the moment" increases happiness. However, the default mode of humans appears to be that of mind-wandering, which correlates with unhappiness, and with activation in a network of brain areas associated with self-referential processing. We investigated brain activity in experienced meditators and matched meditation-naive controls as they performed several different meditations (Concentration, Loving-Kindness, Choiceless Awareness). We found that the main nodes of the default-mode network (medial prefrontal and posterior cingulate cortices) were relatively deactivated in experienced meditators across all meditation types. Furthermore, functional connectivity analysis revealed stronger coupling in experienced meditators between the posterior cingulate, dorsal anterior cingulate, and dorsolateral prefrontal cortices (regions previously implicated in self-monitoring and cognitive control), both at baseline and during meditation. Our findings demonstrate differences in the default-mode network that are consistent with decreased mind-wandering. As such, these provide a unique understanding of possible neural mechanisms of meditation.

Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder.

BACKGROUND: Elucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD. METHODS: Positron emission tomography (PET) with [18F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25). RESULTS: Consistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028). LIMITATIONS: The modest sample size is the primary limitation. CONCLUSIONS: Deficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights.

Neural correlates of altered emotional responsivity to infant stimuli in mothers who use substances.

Mothers who use substances during pregnancy and postpartum may have altered maternal behavior towards their infants, which can have negative consequences on infant social-emotional development. Since maternal substance use has been associated with difficulties in recognizing and responding to infant emotional expressions, investigating mothers' subjective responses to emotional infant stimuli may provide insight into the neural and psychological processes underlying these differences in maternal behavior. In this study, 39 mothers who used substances during the perinatal period and 42 mothers who did not underwent functional magnetic resonance imaging while viewing infant faces and hearing infant cries. Afterwards, they rated the emotional intensity they thought each infant felt ('think'-rating), and how intensely they felt in response to each infant stimulus ('feel'-rating). Mothers who used substances had lower 'feel'-ratings of infant stimuli compared to mothers who did not. Brain regions implicated in affective processing (e.g., insula, inferior frontal gyrus) were less active in response to infant stimuli, and activity in these brain regions statistically predicted maternal substance-use status. Interestingly, 'think'-ratings and activation in brain regions related to cognitive processing (e.g., medial prefrontal cortex) were comparable between the two groups of mothers. Taken together, these results suggest specific neural and psychological processes related to emotional responsivity to infant stimuli may reflect differences in maternal affective processing and may contribute to differences in maternal behavior in mothers who use substances compared to mothers who do not. The findings suggest potential neural targets for increasing maternal emotional responsivity and improving child outcomes.

Task-related concurrent but opposite modulations of overlapping functional networks as revealed by spatial ICA.

Animal studies indicate that different functional networks (FNs), each with a unique timecourse, may overlap at common brain regions. For understanding how different FNs overlap in the human brain and how the timecourses of overlapping FNs are modulated by cognitive tasks, we applied spatial independent component analysis (sICA) to functional magnetic resonance imaging (fMRI) data. These data were acquired from healthy participants while they performed a visual task with parametric loads of attention and working memory. sICA identified a total of 14 FNs, and they showed different extents of overlap at a majority of brain regions exhibiting any functional activity. More FNs overlapped at the higher-order association cortex including the anterior and posterior cingulate, precuneus, insula, and lateral and medial frontoparietal cortices (FPCs) than at the primary sensorimotor cortex. Furthermore, overlapping FNs exhibited concurrent but different task-related modulations of timecourses. FNs showing task-related up- vs. down-modulation of timecourses overlapped at both the lateral and medial FPCs and subcortical structures including the thalamus, striatum, and midbrain ventral tegmental area (VTA). Such task-related, concurrent, but opposite changes in timecourses in the same brain regions may not be detected by current analyses based on General-Linear-Model (GLM). The present findings indicate that multiple cognitive processes may associate with common brain regions and exhibit simultaneous but different modulations in timecourses during cognitive tasks.

Real-time fMRI links subjective experience with brain activity during focused attention.

Recent advances in brain imaging have improved the measure of neural processes related to perceptual, cognitive and affective functions, yet the relation between brain activity and subjective experience remains poorly characterized. In part, it is a challenge to obtain reliable accounts of participant's experience in such studies. Here we addressed this limitation by utilizing experienced meditators who are expert in introspection. We tested a novel method to link objective and subjective data, using real-time fMRI (rt-fMRI) to provide participants with feedback of their own brain activity during an ongoing task. We provided real-time feedback during a focused attention task from the posterior cingulate cortex, a hub of the default mode network shown to be activated during mind-wandering and deactivated during meditation. In a first experiment, both meditators and non-meditators reported significant correspondence between the feedback graph and their subjective experience of focused attention and mind-wandering. When instructed to volitionally decrease the feedback graph, meditators, but not non-meditators, showed significant deactivation of the posterior cingulate cortex. We were able to replicate these results in a separate group of meditators using a novel step-wise rt-fMRI discovery protocol in which participants were not provided with prior knowledge of the expected relationship between their experience and the feedback graph (i.e., focused attention versus mind-wandering). These findings support the feasibility of using rt-fMRI to link objective measures of brain activity with reports of ongoing subjective experience in cognitive neuroscience research, and demonstrate the generalization of expertise in introspective awareness to novel contexts.

Linking resting-state network fluctuations with systems of coherent synaptic density: A multimodal fMRI and 11C-UCB-J PET study.

Introduction: Resting-state network (RSN) connectivity is a widely used measure of the brain's functional organization in health and disease; however, little is known regarding the underlying neurophysiology of RSNs. The aim of the current study was to investigate associations between RSN connectivity and synaptic density assessed using the synaptic vesicle glycoprotein 2A radioligand 11C-UCB-J PET. Methods: Independent component analyses (ICA) were performed on resting-state fMRI and PET data from 34 healthy adult participants (16F, mean age: 46 ± 15 years) to identify a priori RSNs of interest (default-mode, right frontoparietal executive-control, salience, and sensorimotor networks) and select sources of 11C-UCB-J variability (medial prefrontal, striatal, and medial parietal). Pairwise correlations were performed to examine potential intermodal associations between the fractional amplitude of low-frequency fluctuations (fALFF) of RSNs and subject loadings of 11C-UCB-J source networks both locally and along known anatomical and functional pathways. Results: Greater medial prefrontal synaptic density was associated with greater fALFF of the anterior default-mode, posterior default-mode, and executive-control networks. Greater striatal synaptic density was associated with greater fALFF of the anterior default-mode and salience networks. Post-hoc mediation analyses exploring relationships between aging, synaptic density, and RSN activity revealed a significant indirect effect of greater age on fALFF of the anterior default-mode network mediated by the medial prefrontal 11C-UCB-J source. Discussion: RSN functional connectivity may be linked to synaptic architecture through multiple local and circuit-based associations. Findings regarding healthy aging, lower prefrontal synaptic density, and lower default-mode activity provide initial evidence of a neurophysiological link between RSN activity and local synaptic density, which may have relevance in neurodegenerative and psychiatric disorders.

Identification and Validation of Distinct Latent Neurodevelopmental Profiles in the Adolescent Brain and Cognitive Development Study.

BACKGROUND: Regardless of the precise mechanism, all neurodevelopmental models of risk assume that, at the population level, there exist subgroups of individuals that share similar patterns of neural function and development-and that these subgroups somehow relate to psychiatric risk. However, the existence of multiple neurodevelopmental subgroups at the population level has not been assessed previously. METHODS: In the current study, cross-validated latent profile analysis was used to test for the presence of empirically derived, brain-based developmental subgroups using functional magnetic resonance imaging data from 6758 individuals (49.4% female; mean age = 9.94 years) in the Adolescent Brain and Cognitive Development (ABCD) study wave 1 release. Data were randomly split into training and testing samples. RESULTS: Analyses in the training sample (n = 3379) identified a seven-profile solution (entropy = 0.880) that was replicated in the held-out testing data (n = 3379, entropy = 0.890). Identified subgroups included a moderate group (66.8%), high reward (4.3%) and low reward (4.0%) groups, high inhibition (9.8%) and low inhibition (6.7%) groups, and high emotion regulation (4.0%) and low emotion regulation (4.3%) groups. Relative to the moderate group, other subgroups were characterized by more males (χ2 = 24.10, p = .0005), higher proportions of individuals from lower-income households (χ2 = 122.17, p < .0001), poorer cognitive performance (ps < .0001), more screen time (F = 6.80, p < .0001), heightened impulsivity (ps < .006), and higher rates of neurodevelopmental disorders (χ2 = 26.20, p = .0002). CONCLUSIONS: These data demonstrate the existence of multiple, distinct neurodevelopmental subgroups at the population level. They indicate that these empirically derived, brain-based developmental profiles relate to differences in clinical features, even at a young age, and prior to the peak period of risk for the development of psychopathology.

Longitudinal changes in network engagement during cognitive control in cocaine use disorder.

BACKGROUND: Cocaine use disorder (CUD) is characterized by poor cognitive control and has limited empirically supported treatment options. Furthermore, an understanding of brain mechanisms underlying CUD is at a relatively early stage. Thus, this study aimed to investigate longitudinal alterations in functional neural networks associated with cognitive control in cocaine use disorder (CUD). METHODS: Secondary analysis was performed on data from 44 individuals who participated in three randomized clinical trials for CUD and completed an fMRI Stroop task both at baseline and post-treatment. Independent component analysis (ICA) was performed to assess changes in functional network engagement and investigate associations with cocaine-use behaviors. Mixed linear models were performed to test for longitudinal effects on network engagement and relationships with baseline patterns of cocaine use (i.e., past-month frequency and lifetime years of use) and periods of abstinence/use between scans (i.e., percent negative urine toxicology and maximum days of contiguous abstinence). RESULTS: Six functional networks were identified as being related to cognitive control and/or exhibiting changes in engagement following treatment. Results indicated that engagement of amygdala-striatal, middle frontal and right-frontoparietal networks were reduced over time in CUD. Less change in the amygdala-striatal network was associated with greater lifetime years of cocaine use. Additional analyses revealed that negative toxicology results and achievement of continuous abstinence were associated with greater engagement of the right-frontoparietal network. CONCLUSIONS: Neural systems that underlie cognitive control may change over time in individuals with CUD. A longer history of cocaine-use may hinder changes in network activity, potentially impeding recovery.

GABAergic polygenic risk for cocaine use disorder is negatively correlated with precuneus activity during cognitive control in African American individuals.

Impaired cognitive control has been implicated in cocaine use disorder (CUD). GABAergic treatments have been proposed for CUD. Here we examined relationships between GABAergic genes and neural correlates of cognitive control in CUD. We analyzed two independent African American cohorts: one of >3000 genomewide-genotyped subjects with substance dependence and another of 40 CUD and 22 healthy control (HC) subjects who were exome-array genotyped and completed an fMRI Stroop task. We used five association thresholds to select variants of GABAergic genes in the reference cohort, yielding five polygenic risk scores (i.e., CUD-GABA-PRSs) for the fMRI cohort. At p < 0.005, the CUD-GABA-PRSs, which aggregated relative risks of CUD from 89 variants harboring in 16 genes, differed between CUD and HC individuals in the fMRI sample (p = 0.013). This CUD-GABA-PRS correlated inversely with Stroop-related activity in the left precuneus in CUD (r = -80.58, pFWE < 0.05) but not HC participants. Post-hoc seed-based connectivity analysis of the left precuneus identified reduced functional connectivity to the posterior cingulate cortex (PCC) in CUD compared to HC subjects (p = 0.0062) and the degree of connectivity correlated with CUD-GABA-PRSs in CUD individuals (r = 0.287, p = 0.036). Our findings suggest that the GABAergic genetic risk of CUD in African Americans relates to precuneus/PCC functional connectivity during cognitive control. Identification of these GABAergic processes may be relevant targets in CUD treatment. The novel identification of 16 GABAergic genes may be investigated further to inform treatment development efforts for this condition that currently has no medication with a formal indication for its treatment.