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.

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.

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.

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.

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.

Altered functional network activities for behavioral adjustments and Bayesian learning in young men with Internet gaming disorder.

BACKGROUND AND AIMS: Deficits in cognitive control represent a core feature of addiction. Internet Gaming Disorder (IGD) offers an ideal model to study the mechanisms underlying cognitive control deficits in addiction, eliminating the confounding effects of substance use. Studies have reported behavioral and neural deficits in reactive control in IGD, but it remains unclear whether individuals with IGD are compromised in proactive control or behavioral adjustment by learning from the changing contexts. METHODS: Here, fMRI data of 21 male young adults with IGD and 21 matched healthy controls (HC) were collected during a stop-signal task. We employed group independent component analysis to investigate group differences in temporally coherent, large-scale functional network activities during post-error slowing, the typical type of behavioral adjustments. We also employed a Bayesian belief model to quantify the trial-by-trial learning of the likelihood of stop signal - P(Stop) - a broader process underlying behavioral adjustment, and identified the alterations in functional network responses to P(Stop). RESULTS: The results showed diminished engagement of the fronto-parietal network during post-error slowing, and weaker activity in the ventral attention and anterior default mode network in response to P(Stop) in IGD relative to HC. DISCUSSION AND CONCLUSIONS: These results add to the literatures by suggesting deficits in updating and anticipating conflicts as well as in behavioral adjustment according to contextual information in individuals with IGD.

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.

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.

Multimodal investigation of dopamine D2/D3 receptors, default mode network suppression, and cognitive control in cocaine-use disorder.

Stimulant-use disorders have been associated with lower availability of dopamine type-2 receptors (D2R) and greater availability of type-3 receptors (D3R). Links between D2R levels, cognitive performance, and suppression of the default mode network (DMN) during executive functioning have been observed in healthy and addicted populations; however, there is limited evidence regarding a potential role of elevated D3R in influencing cognitive control processes in groups with and without addictions. Sixteen individuals with cocaine-use disorder (CUD) and 16 healthy comparison (HC) participants completed [11C]-(+)-PHNO PET imaging of D2R and D3R availability and fMRI during a Stroop task of cognitive control. Independent component analysis was performed on fMRI data to assess DMN suppression during Stroop performance. In HC individuals, lower D2R-related binding in the dorsal putamen was associated with improved task performance and greater DMN suppression. By comparison, in individuals with CUD, greater D3R-related binding in the substantia nigra was associated with improved performance and greater DMN suppression. Exploratory moderated-mediation analyses indicated that DMN suppression was associated with Stroop performance indirectly through D2R in HC and D3R in CUD participants, and these indirect effects were different between groups. To our knowledge, this is the first evidence of a dissociative and potentially beneficial role of elevated D3R availability in executive functioning in cocaine-use disorder.

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.

Is monetary reward processing altered in drug-naïve youth with a behavioral addiction? Findings from internet gaming disorder.

Current models of addiction biology highlight altered neural responses to non-drug rewards as a central feature of addiction. However, given that drugs of abuse can directly impact reward-related dopamine circuitry, it is difficult to determine the extent to which reward processing alterations are a trait feature of individuals with addictions, or primarily a consequence of exogenous drug exposure. Examining individuals with behavioral addictions is one promising approach for disentangling neural features of addiction from the direct effects of substance exposure. The current fMRI study compared neural responses during monetary reward processing between drug naïve young adults with a behavioral addiction, internet gaming disorder (IGD; n = 22), and healthy controls (n = 27) using a monetary incentive delay task. Relative to controls, individuals with IGD exhibited blunted caudate activity associated with loss magnitude at the outcome stage, but did not differ from controls in neural activity at other stages. These findings suggest that decreased loss sensitivity might be a critical feature of IGD, whereas alterations in gain processing may be less characteristic of individuals with IGD, relative to those with substance use disorders. Therefore, classic theories of altered reward processing in substance use disorders should be translated to behavioral addictions with caution.

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.

Differential responses to infant faces in relation to maternal substance use: An exploratory study.

BACKGROUND: Maternal substance use and addiction has been associated with negative consequences for parenting and may increase addiction vulnerability in the developing child. Neuroimaging research suggests that substance use may decrease the reward of caring for infants and heighten stress reactivity to affective infant cues. METHODS: Thirty-two substance-using mothers and twenty-two non-substance-using mothers were presented with emotional face and cry stimuli generated from their own and a demographically matched unknown infant during fMRI scanning. Between-group differences in neural activity during task performance were assessed using whole-brain, mixed-effects models corrected for multiple comparisons (voxel-level p < 0.001, pFWE<0.05). RESULTS: Relative to non-substance-using mothers, substance-using mothers exhibited greater activation when viewing their own infant's face as compared to an unknown infant's face across multiple brain regions, including superior medial frontal, inferior parietal, and middle temporal regions. Substance-using mothers also had a decreased response to sad infant faces in the ventral striatum relative to the non-substance-using mothers. Neural responses to own vs. unknown infant cries did not significantly differ between substance-using and non-substance-using mothers. CONCLUSIONS: Findings suggest overlapping cortical and subcortical brain regions implicated in responding to infant faces, with activation differences related to infant familiarity, emotional expression, and maternal substance use. While prior work has focused on attenuated neural responses to infant cues, greater attention is needed toward understanding the increased reactivity to affective infant cues observed in substance-using mothers.

Relationships between drinking quantity and frequency and behavioral and hippocampal BOLD responses during working memory performance involving allocentric spatial navigation in college students.

BACKGROUND: Quantity and frequency of drinking may be used to effectively quantify the severity of alcohol-use. Drinking-severity has been related to neurocognitive impairments in such domains as spatial working memory (SWM). Youth drinking has been associated with altered neurofunctional underpinnings of SWM. The current study examined the relationship between drinking-severity and SWM processing. METHODS: One-hundred-and-seventy college drinkers reported the maximum number of drinks in a 24 -h period in the last six-months (quantity) and average number of drinking weeks in the last six-months (frequency). All participants performed a virtual Morris Water Task during fMRI which included trials where the target platform was visible or hidden. RESULTS: Greater quantity was associated with reduced SWM-related activity in the dorsolateral prefrontal cortex (F(1, 167) = 4.15, p = .04). Greater frequency was associated with reduced SWM-related activity in the hippocampus (F(1, 167) = 4.34, p = 0.039). Greater quantity was associated with longer search times (r = 0.21, p = .005) and greater platforms found (r = 0.19, p = .01) in VISIBLE trials. We did not find a relationship between drinking quantity or frequency and gender on SWM-related activity, although men found more platforms in both HIDDEN (F(1, 168) = 11.7, p = 0.0008) and VISIBLE (F(1, 168) = 23.0, p < .0001) trials compared to women. CONCLUSIONS: Altered SWM-related hippocampal function relating to alcohol use in young adults raises questions regarding the impact on young adult health and the nature of the findings. Future studies should examine whether these differences may lead to cognitive deficits later in life.

Alterations in functional networks during cue-reactivity in Internet gaming disorder.

BACKGROUND: Cue-induced brain reactivity has been suggested to be a fundamental and important mechanism explaining the development, maintenance, and relapse of addiction, including Internet gaming disorder (IGD). Altered activity in addiction-related brain regions has been found during cue-reactivity in IGD using functional magnetic resonance imaging (fMRI), but less is known regarding the alterations of coordinated whole brain activity patterns in IGD. METHODS: To investigate the activity of temporally coherent, large-scale functional brain networks (FNs) during cue-reactivity in IGD, independent component analysis was applied to fMRI data from 29 male subjects with IGD and 23 matched healthy controls (HC) performing a cue-reactivity task involving Internet gaming stimuli (i.e., game cues) and general Internet surfing-related stimuli (i.e., control cues). RESULTS: Four FNs were identified that were related to the response to game cues relative to control cues and that showed altered engagement/disengagement in IGD compared with HC. These FNs included temporo-occipital and temporo-insula networks associated with sensory processing, a frontoparietal network involved in memory and executive functioning, and a dorsal-limbic network implicated in reward and motivation processing. Within IGD, game versus control engagement of the temporo-occipital and frontoparietal networks were positively correlated with IGD severity. Similarly, disengagement of temporo-insula network was negatively correlated with higher game-craving. DISCUSSION: These findings are consistent with altered cue-reactivity brain regions reported in substance-related addictions, providing evidence that IGD may represent a type of addiction. The identification of the networks might shed light on the mechanisms of the cue-induced craving and addictive Internet gaming behaviors.

Gradient theories of brain activation: A novel application to studying the parental brain.

PURPOSE OF REVIEW: Parental brain research primarily employs general-linear-model-based (GLM-based) analyses to assess blood-oxygenation-level-dependent responses to infant auditory and visual cues, reporting common responses in shared cortical and subcortical structures. However, this approach does not reveal intermixed neural substrates related to different sensory modalities. We consider this notion in studying the parental brain. RECENT FINDINGS: Spatial independent component analysis (sICA) has been used to separate mixed source signals from overlapping functional networks. We explore relative differences between GLM-based analysis and sICA as applied to an fMRI dataset acquired from women while they listened to infant cries or viewed infant sad faces. SUMMARY: There is growing appreciation for the value of moving beyond GLM-based analyses to consider brain functional organization as continuous, distributive, and overlapping gradients of neural substrates related to different sensory modalities. Preliminary findings suggest sICA can be applied to the study of the parental brain.