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Anxiety, a condition characterized by intense fear and persistent worry, affects millions each year and, when severe, is distressing and functionally impairing. Numerous machine learning frameworks have been developed and tested to predict features of anxiety and anxiety traits. This study extended these approaches by using a small set of interpretable judgment variables (n = 15) and contextual variables (demographics, perceived loneliness, COVID-19 history) to (1) understand the relationships between these variables and (2) develop a framework to predict anxiety levels [derived from the State Trait Anxiety Inventory (STAI)]. This set of 15 judgment variables, including loss aversion and risk aversion, models biases in reward/aversion judgments extracted from an unsupervised, short (2-3 min) picture rating task (using the International Affective Picture System) that can be completed on a smartphone. The study cohort consisted of 3476 de-identified adult participants from across the United States who were recruited using an email survey database. Using a balanced Random Forest approach with these judgment and contextual variables, STAI-derived anxiety levels were predicted with up to 81% accuracy and 0.71 AUC ROC. Normalized Gini scores showed that the most important predictors (age, loneliness, household income, employment status) contributed a total of 29-31% of the cumulative relative importance and up to 61% was contributed by judgment variables. Mediation/moderation statistics revealed that the interactions between judgment and contextual variables appears to be important for accurately predicting anxiety levels. Median shifts in judgment variables described a behavioral profile for individuals with higher anxiety levels that was characterized by less resilience, more avoidance, and more indifference behavior. This study supports the hypothesis that distinct constellations of 15 interpretable judgment variables, along with contextual variables, could yield an efficient and highly scalable system for mental health assessment. These results contribute to our understanding of underlying psychological processes that are necessary to characterize what causes variance in anxiety conditions and its behaviors, which can impact treatment development and efficacy., (© 2024. The Author(s).)

Background: Despite COVID-19 vaccine mandates, many chose to forgo vaccination, raising questions about the psychology underlying how judgment affects these choices. Research shows that reward and aversion judgments are important for vaccination choice; however, no studies have integrated such cognitive science with machine learning to predict COVID-19 vaccine uptake., Objective: This study aims to determine the predictive power of a small but interpretable set of judgment variables using 3 machine learning algorithms to predict COVID-19 vaccine uptake and interpret what profile of judgment variables was important for prediction., Methods: We surveyed 3476 adults across the United States in December 2021. Participants answered demographic, COVID-19 vaccine uptake (ie, whether participants were fully vaccinated), and COVID-19 precaution questions. Participants also completed a picture-rating task using images from the International Affective Picture System. Images were rated on a Likert-type scale to calibrate the degree of liking and disliking. Ratings were computationally modeled using relative preference theory to produce a set of graphs for each participant (minimum R 2 >0.8). In total, 15 judgment features were extracted from these graphs, 2 being analogous to risk and loss aversion from behavioral economics. These judgment variables, along with demographics, were compared between those who were fully vaccinated and those who were not. In total, 3 machine learning approaches (random forest, balanced random forest [BRF], and logistic regression) were used to test how well judgment, demographic, and COVID-19 precaution variables predicted vaccine uptake. Mediation and moderation were implemented to assess statistical mechanisms underlying successful prediction., Results: Age, income, marital status, employment status, ethnicity, educational level, and sex differed by vaccine uptake (Wilcoxon rank sum and chi-square P<.001). Most judgment variables also differed by vaccine uptake (Wilcoxon rank sum P<.05). A similar area under the receiver operating characteristic curve (AUROC) was achieved by the 3 machine learning frameworks, although random forest and logistic regression produced specificities between 30% and 38% (vs 74.2% for BRF), indicating a lower performance in predicting unvaccinated participants. BRF achieved high precision (87.8%) and AUROC (79%) with moderate to high accuracy (70.8%) and balanced recall (69.6%) and specificity (74.2%). It should be noted that, for BRF, the negative predictive value was <50% despite good specificity. For BRF and random forest, 63% to 75% of the feature importance came from the 15 judgment variables. Furthermore, age, income, and educational level mediated relationships between judgment variables and vaccine uptake., Conclusions: The findings demonstrate the underlying importance of judgment variables for vaccine choice and uptake, suggesting that vaccine education and messaging might target varying judgment profiles to improve uptake. These methods could also be used to aid vaccine rollouts and health care preparedness by providing location-specific details (eg, identifying areas that may experience low vaccination and high hospitalization)., (©Nicole L Vike, Sumra Bari, Leandros Stefanopoulos, Shamal Lalvani, Byoung Woo Kim, Nicos Maglaveras, Martin Block, Hans C Breiter, Aggelos K Katsaggelos. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 18.03.2024.)

Background: Rates of depression and addiction have risen drastically over the past decade, but the lack of integrative techniques remains a barrier to accurate diagnoses of these mental illnesses. Changes in reward/aversion behavior and corresponding brain structures have been identified in those with major depressive disorder (MDD) and cocaine-dependence polysubstance abuse disorder (CD). Assessment of statistical interactions between computational behavior and brain structure may quantitatively segregate MDD and CD., Methods: Here, 111 participants [40 controls (CTRL), 25 MDD, 46 CD] underwent structural brain MRI and completed an operant keypress task to produce computational judgment metrics. Three analyses were performed: (1) linear regression to evaluate groupwise (CTRL v. MDD v. CD) differences in structure-behavior associations, (2) qualitative and quantitative heatmap assessment of structure-behavior association patterns, and (3) the k-nearest neighbor machine learning approach using brain structure and keypress variable inputs to discriminate groups., Results: This study yielded three primary findings. First, CTRL, MDD, and CD participants had distinct structure-behavior linear relationships, with only 7.8% of associations overlapping between any two groups. Second, the three groups had statistically distinct slopes and qualitatively distinct association patterns. Third, a machine learning approach could discriminate between CTRL and CD, but not MDD participants., Conclusions: These findings demonstrate that variable interactions between computational behavior and brain structure, and the patterns of these interactions, segregate MDD and CD. This work raises the hypothesis that analysis of interactions between operant tasks and structural neuroimaging might aide in the objective classification of MDD, CD and other mental health conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vike et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cortico-striato-thalamo-cortical (CSTC) loops are fundamental organizing units in mammalian brains. CSTCs process limbic, associative, and sensorimotor information in largely separated but interacting networks. CTSC loops pass through paired striatal compartments, striosome (aka patch) and matrix, segregated pools of medium spiny projection neurons with distinct embryologic origins, cortical/subcortical structural connectivity, susceptibility to injury, and roles in behaviors and diseases. Similarly, striatal dopamine modulates activity in striosome and matrix in opposite directions. Routing CSTCs through one compartment may be an anatomical basis for regulating discrete functions. We used differential structural connectivity, identified through probabilistic diffusion tractography, to distinguish the striatal compartments (striosome-like and matrix-like voxels) in living humans. We then mapped compartment-specific projections and quantified structural connectivity between each striatal compartment, the globus pallidus interna (GPi), and 20 thalamic nuclei in 221 healthy adults. We found that striosome-originating and matrix-originating streamlines were segregated within the GPi: striosome-like connectivity was significantly more rostral, ventral, and medial. Striato-pallido-thalamic streamline bundles that were seeded from striosome-like and matrix-like voxels transited spatially distinct portions of the white matter. Matrix-like streamlines were 5.7-fold more likely to reach the GPi, replicating animal tract-tracing studies. Striosome-like connectivity dominated in six thalamic nuclei (anteroventral, central lateral, laterodorsal, lateral posterior, mediodorsal-medial, and medial geniculate). Matrix-like connectivity dominated in seven thalamic nuclei (centromedian, parafascicular, pulvinar-anterior, pulvinar-lateral, ventral lateral-anterior, ventral lateral-posterior, ventral posterolateral). Though we mapped all thalamic nuclei independently, functionally-related nuclei were matched for compartment-level bias. We validated these results with prior thalamostriate tract tracing studies in non-human primates and other species; where reliable data was available, all agreed with our measures of structural connectivity. Matrix-like connectivity was lateralized (left > right hemisphere) in 18 thalamic nuclei, independent of handedness, diffusion protocol, sex, or whether the nucleus was striosome-dominated or matrix-dominated. Compartment-specific biases in striato-pallido-thalamic structural connectivity suggest that routing CSTC loops through striosome-like or matrix-like voxels is a fundamental mechanism for organizing and regulating brain networks. Our MRI-based assessments of striato-thalamic connectivity in humans match and extend the results of prior tract tracing studies in animals. Compartment-level characterization may improve localization of human neuropathologies and improve neurosurgical targeting in the GPi and thalamus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Funk, Hassan, Brüggemann, Sharma, Breiter, Blood and Waugh.)

Background: The COVID-19 pandemic has heightened mental health concerns, but the temporal relationship between mental health conditions and SARS-CoV-2 infection has not yet been investigated. Specifically, psychological issues, violent behaviors, and substance use were reported more during the COVID-19 pandemic than before the pandemic. However, it is unknown whether a prepandemic history of these conditions increases an individual's susceptibility to SARS-CoV-2., Objective: This study aimed to better understand the psychological risks underlying COVID-19, as it is important to investigate how destructive and risky behaviors may increase a person's susceptibility to COVID-19., Methods: In this study, we analyzed data from a survey of 366 adults across the United States (aged 18 to 70 years); this survey was administered between February and March of 2021. The participants were asked to complete the Global Appraisal of Individual Needs-Short Screener (GAIN-SS) questionnaire, which indicates an individual's history of high-risk and destructive behaviors and likelihood of meeting diagnostic criteria. The GAIN-SS includes 7 questions related to externalizing behaviors, 8 related to substance use, and 5 related to crime and violence; responses were given on a temporal scale. The participants were also asked whether they ever tested positive for COVID-19 and whether they ever received a clinical diagnosis of COVID-19. GAIN-SS responses were compared between those who reported and those who did not report COVID-19 to determine if those who reported COVID-19 also reported GAIN-SS behaviors (Wilcoxon rank sum test, α=.05). In total, 3 hypotheses surrounding the temporal relationships between the recency of GAIN-SS behaviors and COVID-19 infection were tested using proportion tests (α=.05). GAIN-SS behaviors that significantly differed (proportion tests, α=.05) between COVID-19 responses were included as independent variables in multivariable logistic regression models with iterative downsampling. This was performed to assess how well a history of GAIN-SS behaviors statistically discriminated between those who reported and those who did not report COVID-19., Results: Those who reported COVID-19 more frequently indicated past GAIN-SS behaviors (Q<0.05). Furthermore, the proportion of those who reported COVID-19 was higher (Q<0.05) among those who reported a history of GAIN-SS behaviors; specifically, gambling and selling drugs were common across the 3 proportion tests. Multivariable logistic regression revealed that GAIN-SS behaviors, particularly gambling, selling drugs, and attention problems, accurately modeled self-reported COVID-19, with model accuracies ranging from 77.42% to 99.55%. That is, those who exhibited destructive and high-risk behaviors before and during the pandemic could be discriminated from those who did not exhibit these behaviors when modeling self-reported COVID-19., Conclusions: This preliminary study provides insights into how a history of destructive and risky behaviors influences infection susceptibility, offering possible explanations for why some persons may be more susceptible to COVID-19, potentially in relation to reduced adherence to prevention guidelines or not seeking vaccination., (©Nicole L Vike, Sumra Bari, Khrystyna Stetsiv, Sean Woodward, Shamal Lalvani, Leandros Stefanopoulos, Byoung Woo Kim, Nicos Maglaveras, Aggelos K Katsaggelos, Hans C Breiter. Originally published in JMIR Formative Research (https://formative.jmir.org), 14.04.2023.)

The relationship of human brain structure to cognitive function is complex, and how this relationship differs between childhood and adulthood is poorly understood. One strong hypothesis suggests the cognitive function of Fluid Intelligence (Gf) is dependent on prefrontal cortex and parietal cortex. In this work, we developed a novel graph convolutional neural networks (gCNNs) for the analysis of localized anatomic shape and prediction of Gf. Morphologic information of the cortical ribbons and subcortical structures was extracted from T1-weighted MRIs within two independent cohorts, the Adolescent Brain Cognitive Development Study (ABCD; age: 9.93 ± 0.62 years) of children and the Human Connectome Project (HCP; age: 28.81 ± 3.70 years). Prediction combining cortical and subcortical surfaces together yielded the highest accuracy of Gf for both ABCD (R = 0.314) and HCP datasets (R = 0.454), outperforming the state-of-the-art prediction of Gf from any other brain measures in the literature. Across both datasets, the morphology of the amygdala, hippocampus, and nucleus accumbens, along with temporal, parietal and cingulate cortex consistently drove the prediction of Gf, suggesting a significant reframing of the relationship between brain morphology and Gf to include systems involved with reward/aversion processing, judgment and decision-making, motivation, and emotion., (© 2022. The Author(s).)

Background: The COVID-19 disease results from infection by the SARS-CoV-2 virus to produce a range of mild to severe physical, neurological, and mental health symptoms. The COVID-19 pandemic has indirectly caused significant emotional distress, triggering the emergence of mental health symptoms in individuals who were not previously affected or exacerbating symptoms in those with existing mental health conditions. Emotional distress and certain mental health conditions can lead to violent ideation and disruptive behavior, including aggression, threatening acts, deliberate harm toward other people or animals, and inattention to or noncompliance with education or workplace rules. Of the many mental health conditions that can be associated with violent ideation and disruptive behavior, psychosis can evidence greater vulnerability to unpredictable changes and being at a greater risk for them. Individuals with psychosis can also be more susceptible to contracting COVID-19 disease., Objective: This study aimed to investigate whether violent ideation, disruptive behavior, or psychotic symptoms were more prevalent in a population with COVID-19 and did not precede the pandemic., Methods: In this preliminary study, we analyzed questionnaire responses from a population sample (N=366), received between the end of February 2021 and the start of March 2021 (1 year into the COVID-19 pandemic), regarding COVID-19 illness, violent ideation, disruptive behavior, and psychotic symptoms. Using the Wilcoxon rank sum test followed by multiple comparisons correction, we compared the self-reported frequency of these variables for 3 time windows related to the past 1 month, past 1 month to 1 year, and >1 year ago among the distributions of people who answered whether they tested positive or were diagnosed with COVID-19 by a clinician. We also used multivariable logistic regression with iterative resampling to investigate the relationship between these variables occurring >1 year ago (ie, before the pandemic) and the likelihood of contracting COVID-19., Results: We observed a significantly higher frequency of self-reported violent ideation, disruptive behavior, and psychotic symptoms, for all 3 time windows of people who tested positive or were diagnosed with COVID-19 by a clinician. Using multivariable logistic regression, we observed 72% to 94% model accuracy for an increased incidence of COVID-19 in participants who reported violent ideation, disruptive behavior, or psychotic symptoms >1 year ago., Conclusions: This preliminary study found that people who reported a test or clinician diagnosis of COVID-19 also reported higher frequencies of violent ideation, disruptive behavior, or psychotic symptoms across multiple time windows, indicating that they were not likely to be the result of COVID-19. In parallel, participants who reported these behaviors >1 year ago (ie, before the pandemic) were more likely to be diagnosed with COVID-19, suggesting that violent ideation, disruptive behavior, in addition to psychotic symptoms, were associated with COVID-19 with an approximately 70% to 90% likelihood., (©Sumra Bari, Nicole L Vike, Khrystyna Stetsiv, Sean Woodward, Shamal Lalvani, Leandros Stefanopoulos, Byoung Woo Kim, Nicos Maglaveras, Hans C Breiter, Aggelos K Katsaggelos. Originally published in JMIR Formative Research (https://formative.jmir.org), 16.08.2022.)

Contact sports participation has been shown to have both beneficial and detrimental effects on health, however little is known about the metabolic sequelae of these effects. We aimed to identify metabolite alterations across a collegiate American football season. Serum was collected from 23 male collegiate football athletes before the athletic season (Pre) and after the last game (Post). Samples underwent nontargeted metabolomic profiling and 1131 metabolites were included for univariate, pathway enrichment, and multivariate analyses. Significant metabolites were assessed against head acceleration events (HAEs). 200 metabolites changed from Pre to Post (P < 0.05 and Q < 0.05); 160 had known identity and mapped to one of 57 pre-defined biological pathways. There was significant enrichment of metabolites belonging to five pathways (P < 0.05): xanthine, fatty acid (acyl choline), medium chain fatty acid, primary bile acid, and glycolysis, gluconeogenesis, and pyruvate metabolism. A set of 12 metabolites was sufficient to discriminate Pre from Post status, and changes in 64 of the 200 metabolites were also associated with HAEs (P < 0.05). In summary, the identified metabolites, and candidate pathways, argue there are metabolic consequences of both physical training and head impacts with football participation. These findings additionally identify a potential set of objective biomarkers of repetitive head injury., (© 2022. The Author(s).)

Research suggests contact sports affect neurological health. This study used permutation-based mediation statistics to integrate measures of metabolomics, neuroinflammatory miRNAs, and virtual reality (VR)-based motor control to investigate multi-scale relationships across a season of collegiate American football. Fourteen significant mediations (six pre-season, eight across-season) were observed where metabolites always mediated the statistical relationship between miRNAs and VR-based motor control ( p S o b e l p e r m ≤ 0.05; total effect > 50%), suggesting a hypothesis that metabolites sit in the statistical pathway between transcriptome and behavior. Three results further supported a model of chronic neuroinflammation, consistent with mitochondrial dysfunction: (1) Mediating metabolites were consistently medium-to-long chain fatty acids, (2) tricarboxylic acid cycle metabolites decreased across-season, and (3) accumulated head acceleration events statistically moderated pre-season metabolite levels to directionally model post-season metabolite levels. These preliminary findings implicate potential mitochondrial dysfunction and highlight probable peripheral blood biomarkers underlying repetitive head impacts in otherwise healthy collegiate football athletes., Competing Interests: Dr. Papa is an inventor of a US patent application filed by Uniformed Services University of the Health Sciences (USUHS) regarding the potential utilities of selected miRNAs as diagnostic biomarkers for TBI. The other authors declare they have no financial or other conflicts of interest with regard to the data and analyses presented herein. The opinions expressed herein are those of the authors and are not necessarily representative of those from their respective institutions., (© 2021 The Authors.)

Although neuroimaging studies of collision (COLL) sport athletes demonstrate alterations in brain structure and function from pre- to post-season, reliable tools to detect behavioral/cognitive change relevant to functional networks associated with participation in collision sports are lacking. This study evaluated the use of eye-movement testing to detect change in cognitive and sensorimotor processing among male club collegiate athletes after one season of participation in collision sports of variable exposure. We predicted that COLL (High Dose [hockey], n  = 8; Low Dose [rugby], n  = 9) would demonstrate longer reaction times (antisaccade and memory-guided saccade [MGS] latencies), increased inhibitory errors (antisaccade error rate), and poorer spatial working memory (MGS spatial accuracy) at post-season, relative to pre-season, whereas non-collision collegiate athletes (NON-COLL; n  = 17) would remain stable. We also predicted that whereas eye-movement performance would detect pre- to post-season change, ImPACT (Immediate Post-Concussion Assessment and Cognitive Test) performance would remain stable. Our data showed that NON-COLL had shorter (improved performance) post- versus pre-season antisaccade and MGS latencies, whereas COLL groups showed stable, longer, or attenuated reduction in latency ( p s ≤ 0.001). Groups did not differ in antisaccade error rate. On the MGS task, NON-COLL demonstrated improved spatial accuracy over time, whereas COLL groups showed reduced spatial accuracy ( p  < 0.05, uncorrected). No differential change was observed on ImPACT. This study provides preliminary evidence for eye-movement testing as a sensitive marker of subtle changes in attentional control and working memory resulting from participation in sports with varying levels of subconcussive exposure., Competing Interests: No competing financial interests exist., (© Virginia T. Gallagher et al., 2021; Published by Mary Ann Liebert, Inc.)

Female athletes are under-studied in the field of concussion research, despite evidence of higher injury prevalence and longer recovery time. Hormonal fluctuations caused by the natural menstrual cycle (MC) or hormonal contraceptive (HC) use impact both post-injury symptoms and neuroimaging findings, but the relationships among hormone, symptoms, and brain-based measures have not been jointly considered in concussion studies. In this preliminary study, we compared cerebral blood flow (CBF) measured with arterial spin labeling between concussed female club athletes 3-10 days after mild traumatic brain injury (mTBI) and demographic, HC/MC matched controls (CON). We tested whether CBF statistically mediates the relationship between progesterone serum levels and post-injury symptoms, which may support a hypothesis for progesterone's role in neuroprotection. We found a significant three-way relationship among progesterone, CBF, and perceived stress score (PSS) in the left middle temporal gyrus for the mTBI group. Higher progesterone was associated with lower (more normative) PSS, as well as higher (more normative) CBF. CBF mediates 100% of the relationship between progesterone and PSS (Sobel p value = 0.017). These findings support a hypothesis for progesterone having a neuroprotective role after concussion and highlight the importance of controlling for the effects of sex hormones in future concussion studies.

Neuroimaging demonstrates that athletes of collision sports can suffer significant changes to their brain in the absence of concussion, attributable to head acceleration event (HAE) exposure. In a sample of 24 male Division I collegiate football players, we examine the relationships between tryptophan hydroxylase 2 ( TPH2 ), a gene involved in neurovascular function, regional cerebral blood flow (rCBF) measured by arterial spin labeling, and virtual reality (VR) motor performance, both pre-season and across a single football season. For the pre-season, TPH2 T-carriers showed lower rCBF in two left hemisphere foci (fusiform gyrus/thalamus/hippocampus and cerebellum) in association with higher (better performance) VR Reaction Time, a dynamic measure of sensory-motor reactivity and efficiency of visual-spatial processing. For TPH2 CC homozygotes, higher pre-season rCBF in these foci was associated with better performance on VR Reaction Time. A similar relationship was observed across the season, where TPH2 T-carriers showed improved VR Reaction Time associated with decreases in rCBF in the right hippocampus/amygdala, left middle temporal lobe, and left insula/putamen/pallidum. In contrast, TPH2 CC homozygotes showed improved VR Reaction Time associated with increases in rCBF in the same three clusters. These findings show that TPH2 T-carriers have an abnormal relationship between rCBF and the efficiency of visual-spatial processing that is exacerbated after a season of high-impact sports in the absence of diagnosable concussion. Such gene-environment interactions associated with behavioral changes after exposure to repetitive HAEs have been unrecognized with current clinical analytical tools and warrant further investigation. Our results demonstrate the importance of considering neurovascular factors along with traumatic axonal injury to study long-term effects of repetitive HAEs.

Transcriptomics, regional cerebral blood flow (rCBF), and a virtual reality-based spatial motor task were integrated using mediation analysis in a novel demonstration of "imaging omics." Data collected in National Collegiate Athletic Association (NCAA) Division I football athletes cleared for play before in-season training showed significant relationships in 1) elevated levels of miR-30d and miR-92a to elevated putamen rCBF, 2) elevated putamen rCBF to compromised Balance scores, and 3) compromised Balance scores to elevated microRNA (miRNA) levels. rCBF acted as a consistent mediator variable (Sobel's test P  < 0.05) between abnormal miRNA levels and compromised Balance scores. Given the involvement of these miRNAs in inflammation and immune function and that vascular perfusion is a component of the inflammatory response, these findings support a chronic inflammatory model in these athletes with 11 years of average football exposure. rCBF, a systems biology measure, was necessary for miRNA to affect behavior., (© The Author(s) 2020. Published by Oxford University Press.)

Synopsis: Mild traumatic brain injury, or concussion, is a common sports injury. Concussion involves physical injury to brain tissue and vascular and axonal damage that manifests as transient and often nonspecific clinical symptoms. Concussion diagnosis is challenging, and the relationship between brain injury and clinical symptoms is unclear. The purpose of this commentary was to translate cutting-edge neuroscience to rehabilitation practice. We (1) highlight potential biomarkers that may improve our understanding of concussion and its recovery, (2) explain why researchers must address the paucity of concussion research in female athletes, and (3) present female-specific factors that should be accounted for in future studies. Integrating objective, quantitative measures of concussion pathophysiology with concussion history, genetics, and genomics will help caregivers identify concussed athletes, tailor recovery protocols, and protect athletes from potential long-term effects of cumulative head impact. J Orthop Sports Phys Ther 2019;49(11):811-818. Epub 1 Jun 2019. doi:10.2519/jospt.2019.8884 .

This prospective controlled observational cohort study assessed the performance of a novel panel of serum microRNA (miRNA) biomarkers on indicators of concussion, subconcussive impacts, and neurocognitive function in collegiate football players over the playing season. Male collegiate student football athletes participating in a Division I Football Bowl Subdivision of the National Collegiate Athletic Association (NCAA) were enrolled. There were a total of 53 participants included in the study, 30 non-athlete control subjects and 23 male collegiate student football athletes. Neurocognitive assessments and blood samples were taken within the week before the athletic season began and within the week after the last game of the season and measured for a panel of pre-selected miRNA biomarkers. All the athletes had elevated levels of circulating miRNAs at the beginning of the season compared with control subjects (p < 0.001). Athletes with the lowest standard assessment of concussion (SAC) scores at the beginning of the season had the highest levels of miRNAs. The area under the curve (AUC) for predicting pre-season SAC scores were miR-195 (0.90), miR-20a (0.89), miR-151-5p (0.86), miR-505* (0.85), miR-9-3p (0.77), and miR-362-3p (0.76). In athletes with declining neurocognitive function over the season, concentrations of miRNAs increased over same period. There were significant negative correlations with miR-505* (p = 0.011), miR-30d (p = 0.007), miR-92 (p = 0.033), and (p = 0.008). The miRNAs correlating with balance problems were miR-505* (p = 0.007), miR-30d (p = 0.028), and miR-151-5p (p = 0.023). Those correlating with poor reaction times were miR-20a (0.043), miR-505* (p = 0.049), miR-30d (p = 0.031), miR-92 (p = 0.015), and miR-151-5p (p = 0.044). Select miRNAs were associated with baseline concussion assessments at the beginning of the season and with neurocognitive changes from pre to post-season in collegiate football players. Should these findings be replicated in a larger cohort of athletes, these markers could potentially serve as measures of neurocognitive status in athletes at risk for concussion and subconcussive injuries.

In a previous report showing white matter microstructural hemispheric asymmetries medial to the pallidum in focal dystonias, we showed preliminary evidence that this abnormality was reduced 4 weeks after botulinum toxin (BTX) injections. In the current study we report the completed treatment study in a full-size cohort of CD patients ( n = 14). In addition to showing a shift toward normalization of the hemispheric asymmetry, we evaluated clinical relevance of these findings by relating white matter changes to degree of symptom improvement. We also evaluated whether the magnitude of the white matter asymmetry before treatment was related to severity, laterality, duration of dystonia, and/or number of previous BTX injections. Our results confirm the findings of our preliminary report: we observed significant fractional anisotropy (FA) changes medial to the pallidum 4 weeks after BTX in CD participants that were not observed in controls scanned at the same interval. There was a significant relationship between magnitude of hemispheric asymmetry and dystonia symptom improvement, as measured by percent reduction in dystonia scale scores. There was also a trend toward a relationship between magnitude of pre-injection white matter asymmetry and symptom severity, but not symptom laterality, disorder duration, or number of previous BTX injections. Post-hoc analyses suggested the FA changes at least partially reflected changes in pathophysiology, but a dissociation between patient perception of benefit from injections and FA changes suggested the changes did not reflect changes to the primary "driver" of the dystonia. In contrast, there were no changes or group differences in DTI diffusivity measures, suggesting the hemispheric asymmetry in CD does not reflect irreversible white matter tissue loss. These findings support the hypothesis that central nervous system white matter changes are involved in the mechanism by which BTX exerts clinical benefit.

This candidate gene study evaluated the relationship of a past history of concussion with single nucleotide polymorphisms (SNPs) in nine genes in a small cohort (N = 87) of a nationally ranked Division I football team. Genes and SNPs studied were selected based on their published connection to brain injury and brain development, as well as impulsivity. We used multinomial logistic regression analysis (MLRA) to quantify how well genotype predicted the number of previously diagnosed concussions (three categories: none, one, two or more), while covarying race and number of years participating in football. The rs4504469 SNP for KIAA0319 was the only locus that significantly predicted number of previously diagnosed concussions (p = 0.005, meeting Bonferroni correction for multiple comparisons). The KIAA0319 results raise the hypothesis that having the CT or TT genotype of KIAA0319 may be predictive of a lower incidence of previously diagnosed concussion. This finding raises a number of hypotheses for future pre-clinical research, particularly whether alterations in neural organization related to KIAA0319 rs4504469 lead to reduced susceptibility for lasting head trauma, or greater resilience in the face of repeated subconcussive injury.

Objective: Research typically characterizes cannabis use by self-report of cannabis intake frequency. In an effort to better understand relationships between measures of cannabis use, we evaluated if Δ-9-tetrahydrocannabinol (THC) and metabolite concentrations (biometrics) were associated with a calibrated timeline followback (TLFB) assessment of cannabis use., Method: Participants were 35 young adult male cannabis users who completed a calibrated TLFB measure of cannabis use over the past 30 days, including time of last use. The calibration required participants handling four plastic bags of a cannabis substitute (0.25, 0.5, 1.0, and 3.5 grams) to quantify cannabis consumed. Participants provided blood and urine samples for analysis of THC and metabolites, at two independent laboratories. Participants abstained from cannabis use on the day of sample collection. We tested Pearson correlations between the calibrated TLFB measures and cannabis biometrics., Results: Strong correlations were seen between urine and blood biometrics (all r > .73, all p < .001). TLFB measures of times of use and grams of cannabis consumed were significantly related to each biometric, including urine 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) and blood THC, 11-hydroxy-THC (11-OH-THC), THCCOOH, THCCOOH-glucuronide (times of use: r > .48-.61, all p < .05; grams: r > .40-.49, all p < .05)., Conclusions: This study extends prior work to show TLFB methods significantly relate to an extended array of cannabis biometrics. The calibration of cannabis intake in grams was associated with each biometric, although the simple TLFB measure of times of use produced the strongest relationships with all five biometrics. These findings suggest that combined self-report and biometric data together convey the complexity of cannabis use, but allow that either the use of calibrated TLFB measures or biometrics may be sufficient for assessment of cannabis use in research.

Preliminary evidence from postmortem studies of X-linked dystonia-parkinsonism (XDP) suggests tissue loss may occur first and/or most severely in the striatal striosome compartment, followed later by cell loss in the matrix compartment. However, little is known about how this relates to pathogenesis and pathophysiology. While MRI cannot visualize these striatal compartments directly in humans, differences in relative gradients of afferent cortical connectivity across compartments (weighted toward paralimbic versus sensorimotor cortex, respectively) can be used to infer potential selective loss in vivo. In the current study we evaluated relative connectivity of paralimbic versus sensorimotor cortex with the caudate and putamen in 17 individuals with XDP and 17 matched controls. Although caudate and putamen volumes were reduced in XDP, there were no significant reductions in either "matrix-weighted", or "striosome-weighted" connectivity. In fact, paralimbic connectivity with the putamen was elevated, rather than reduced, in XDP. This was driven most strongly by elevated putamen connectivity with the anterior insula. There was no relationship of these findings to disease duration or striatal volume, suggesting insula and/or paralimbic connectivity in XDP may develop abnormally and/or increase in the years before symptom onset.

Musical preference is highly individualized and is an area of active study to develop methods for its quantification. Recently, preference-based behavior, associated with activity in brain reward circuitry, has been shown to follow lawful, quantifiable patterns, despite broad variation across individuals. These patterns, observed using a keypress paradigm with visual stimuli, form the basis for relative preference theory (RPT). Here, we sought to determine if such patterns extend to non-visual domains (i.e., audition) and dynamic stimuli, potentially providing a method to supplement psychometric, physiological, and neuroimaging approaches to preference quantification. For this study, we adapted our keypress paradigm to two sets of stimuli consisting of seventeenth to twenty-first century western art music (Classical) and twentieth to twenty-first century jazz and popular music (Popular). We studied a pilot sample and then a separate primary experimental sample with this paradigm, and used iterative mathematical modeling to determine if RPT relationships were observed with high R 2 fits. We further assessed the extent of heterogeneity in the rank ordering of keypress-based responses across subjects. As expected, individual rank orderings of preferences were quite heterogeneous, yet we observed mathematical patterns fitting these data similar to those observed previously with visual stimuli. These patterns in music preference were recurrent across two cohorts and two stimulus sets, and scaled between individual and group data, adhering to the requirements for lawfulness. Our findings suggest a general neuroscience framework that predicts human approach/avoidance behavior, while also allowing for individual differences and the broad diversity of human choices; the resulting framework may offer novel approaches to advancing music neuroscience, or its applications to medicine and recommendation systems.

The cumulative effect of repetitive subconcussive collisions on the structural and functional integrity of the brain remains largely unknown. Athletes in collision sports, like football, experience a large number of impacts across a single season of play. The majority of these impacts, however, are generally overlooked, and their long-term consequences remain poorly understood. This study sought to examine the effects of repetitive collisions across a single competitive season in NCAA Football Bowl Subdivision athletes using advanced neuroimaging approaches. Players were evaluated before and after the season using multiple MRI sequences, including T 1 -weighted imaging, diffusion tensor imaging (DTI), arterial spin labeling (ASL), resting-state functional MRI (rs-fMRI), and susceptibility weighted imaging (SWI). While no significant differences were found between pre- and post-season for DTI metrics or cortical volumes, seed-based analysis of rs-fMRI revealed significant ( p  < 0.05) changes in functional connections to right isthmus of the cingulate cortex (ICC), left ICC, and left hippocampus. ASL data revealed significant ( p  < 0.05) increases in global cerebral blood flow (CBF), with a specific regional increase in right postcentral gyrus. SWI data revealed that 44% of the players exhibited outlier rates ( p  < 0.05) of regional decreases in SWI signal. Of key interest, athletes in whom changes in rs-fMRI, CBF and SWI were observed were more likely to have experienced high G impacts on a daily basis. These findings are indicative of potential pathophysiological changes in brain integrity arising from only a single season of participation in the NCAA Football Bowl Subdivision, even in the absence of clinical symptoms or a diagnosis of concussion. Whether these changes reflect compensatory adaptation to cumulative head impacts or more lasting alteration of brain integrity remains to be further explored.

This study examines how the domains of reward and attention, which are often studied as independent processes, in fact interact at a systems level. We operationalize divided attention with a continuous performance task and variables from signal detection theory (SDT), and reward/aversion with a keypress task measuring approach/avoidance in the framework of relative preference theory (RPT). Independent experiments with the same subjects showed a significant association between one SDT and two RPT variables, visualized as a three-dimensional structure. Holding one of these three variables constant, further showed a significant relationship between a loss aversion-like metric from the approach/avoidance task, and the response bias observed during the divided attention task. These results indicate that a more liberal response bias under signal detection (i.e., a higher tolerance for noise, resulting in a greater proportion of false alarms) is associated with higher "loss aversion." Furthermore, our functional model suggests a mechanism for processing constraints with divided attention and reward/aversion. Together, our results argue for a systematic relationship between divided attention and reward/aversion processing in humans.

Background: Dystonia, a debilitating movement disorder characterized by abnormal fixed positions and/or twisting postures, is associated with dysfunction of motor control networks. While gross brain lesions can produce secondary dystonias, advanced neuroimaging techniques have been required to identify network abnormalities in primary dystonias. Prior neuroimaging studies have provided valuable insights into the pathophysiology of dystonia, but few directly assessed the gross volume of motor control regions, and to our knowledge, none identified abnormalities common to multiple types of idiopathic focal dystonia., Methods: We used two gross volumetric segmentation techniques and one voxelwise volumetric technique (voxel based morphometry, VBM) to compare regional volume between matched healthy controls and patients with idiopathic primary focal dystonia (cervical, n = 17, laryngeal, n = 7). We used (1) automated gross volume measures of eight motor control regions using the FreeSurfer analysis package; (2) blinded, anatomist-supervised manual segmentation of the whole thalamus (also gross volume); and (3) voxel based morphometry, which measures local T1-weighted signal intensity and estimates gray matter density or volume at the level of single voxels, for both whole-brain and thalamus., Results: Using both automated and manual gross volumetry, we found a significant volume decrease only in the thalamus in two focal dystonias. Decreases in whole-thalamic volume were independent of head and brain size, laterality of symptoms, and duration. VBM measures did not differ between dystonia and control groups in any motor control region., Conclusions: Reduced thalamic gross volume, detected in two independent analyses, suggests a common anatomical abnormality in cervical dystonia and spasmodic dysphonia. Defining the structural underpinnings of dystonia may require such complementary approaches.

Introduction: Decades of research have demonstrated the importance of social influence in initiation and maintenance of drug use, but little is known about neural mechanisms underlying social influence in young adults who use recreational drugs., Methods: To better understand whether the neural and/or behavioral response to social influence differs in young adults using illicit drugs, 20 marijuana-using young adults (MJ) aged 18-25, and 20 controls (CON) performed a decision-making task in the context of social influence, while they underwent functional magnetic resonance imaging scans. A priori analyses focused on the nucleus accumbens (NAc), with post hoc analyses in the rest of the striatum. In this task, participants could choose to either follow or go against group influence., Results: When subjects applied social information to response choice selection (independent of following or going against group influence), we observed activation in the middle striatum (caudate), in the MJ group only, that extended ventrally into the NAc. MJ users but not CON showed greater activation in the NAc but not the caudate while making choices congruent with group influence as opposed to choices going against group influence. Activation in the NAc when following social influence was associated with amount of drug use reported. In contrast, during the feedback phase of the task we observed significant NAc activation in both MJ and CON, along with dorsal caudate activation only in MJ participants. This NAc activation did not correlate with drug use., Conclusions: This study shows that MJ users, but not CON, show differential brain activation across striatal subregions when applying social information to make a decision, following versus going against a group of peers, or receiving positive feedback. The current work suggests that differential neural sensitivity to social influence in regions such as the striatum may contribute to the development and/or maintenance of marijuana use.

Individuals tend to give losses approximately 2-fold the weight that they give gains. Such approximations of loss aversion (LA) are almost always measured in the stimulus domain of money, rather than objects or pictures. Recent work on preference-based decision-making with a schedule-less keypress task (relative preference theory, RPT) has provided a mathematical formulation for LA similar to that in prospect theory (PT), but makes no parametric assumptions in the computation of LA, uses a variable tied to communication theory (i.e., the Shannon entropy or information), and works readily with non-monetary stimuli. We evaluated if these distinct frameworks described similar LA in healthy subjects, and found that LA during the anticipation phase of the PT-based task correlated significantly with LA related to the RPT-based task. Given the ease with which non-monetary stimuli can be used on the Internet, or in animal studies, these findings open an extensive range of applications for the study of loss aversion. Furthermore, the emergence of methodology that can be used to measure preference for both social stimuli and money brings a common framework to the evaluation of preference in both social psychology and behavioral economics.

Cannabis use has been associated with episodic memory (EM) impairments and abnormal hippocampus morphology among both healthy individuals and schizophrenia subjects. Considering the hippocampus' role in EM, research is needed to evaluate the relationship between cannabis-related hippocampal morphology and EM among healthy and clinical groups. We examined differences in hippocampus morphology between control and schizophrenia subjects with and without a past (not current) cannabis use disorder (CUD). Subjects group-matched on demographics included 44 healthy controls (CON), 10 subjects with a CUD history (CON-CUD), 28 schizophrenia subjects with no history of substance use disorders (SCZ), and 15 schizophrenia subjects with a CUD history (SCZ-CUD). Large-deformation, high-dimensional brain mapping with MRI produced surface-based representations of the hippocampus that were compared across all four groups and correlated with EM and CUD history. Surface maps of the hippocampus were generated to visualize morphological differences. CON-CUD and SCZ-CUD were characterized by distinct cannabis-related hippocampal shape differences and parametric deficits in EM performance. Shape differences observed in CON-CUD were associated with poorer EM performance, while shape differences observed in SCZ-CUD were associated with a longer duration of CUD and shorter duration of CUD remission. A past history of CUD may be associated with notable differences in hippocampal morphology and EM impairments among adults with and without schizophrenia. Although the results may be compatible with a causal hypothesis, we must consider that the observed cannabis-related shape differences in the hippocampus could also be explained as biomarkers of a neurobiological susceptibility to poor memory or the effects of cannabis., (© 2015 Wiley Periodicals, Inc.)

Loss aversion (LA), the idea that negative valuations have a higher psychological impact than positive ones, is considered an important variable in consumer research. The literature on aging and behavior suggests older individuals may show more LA, although it is not clear if this is an effect of aging in general (as in the continuum from age 20 and 50 years), or of the state of older age (e.g., past age 65 years). We also have not yet identified the potential biological effects of aging on the neural processing of LA. In the current study we used a cohort of subjects with a 30 year range of ages, and performed whole brain functional MRI (fMRI) to examine the ventral striatum/nucleus accumbens (VS/NAc) response during a passive viewing of affective faces with model-based fMRI analysis incorporating behavioral data from a validated approach/avoidance task with the same stimuli. Our a priori focus on the VS/NAc was based on (1) the VS/NAc being a central region for reward/aversion processing; (2) its activation to both positive and negative stimuli; (3) its reported involvement with tracking LA. LA from approach/avoidance to affective faces showed excellent fidelity to published measures of LA. Imaging results were then compared to the behavioral measure of LA using the same affective faces. Although there was no relationship between age and LA, we observed increasing neural differential sensitivity (NDS) of the VS/NAc to avoidance responses (negative valuations) relative to approach responses (positive valuations) with increasing age. These findings suggest that a central region for reward/aversion processing changes with age, and may require more activation to produce the same LA behavior as in younger individuals, consistent with the idea of neural efficiency observed with high IQ individuals showing less brain activation to complete the same task.

Multiple transformative forces target marketing, many of which derive from new technologies that allow us to sample thinking in real time (i.e., brain imaging), or to look at large aggregations of decisions (i.e., big data). There has been an inclination to refer to the intersection of these technologies with the general topic of marketing as "neuromarketing". There has not been a serious effort to frame neuromarketing, which is the goal of this paper. Neuromarketing can be compared to neuroeconomics, wherein neuroeconomics is generally focused on how individuals make "choices", and represent distributions of choices. Neuromarketing, in contrast, focuses on how a distribution of choices can be shifted or "influenced", which can occur at multiple "scales" of behavior (e.g., individual, group, or market/society). Given influence can affect choice through many cognitive modalities, and not just that of valuation of choice options, a science of influence also implies a need to develop a model of cognitive function integrating attention, memory, and reward/aversion function. The paper concludes with a brief description of three domains of neuromarketing application for studying influence, and their caveats.

Impaired cognitive empathy (ie, understanding the emotional experiences of others) is associated with poor social functioning in schizophrenia. However, it is unclear whether the neural activity underlying cognitive empathy relates to social functioning. This study examined the neural activation supporting cognitive empathy performance and whether empathy-related activation during correctly performed trials was associated with self-reported cognitive empathy and measures of social functioning. Thirty schizophrenia outpatients and 24 controls completed a cognitive empathy paradigm during functional magnetic resonance imaging. Neural activity corresponding to correct judgments about the expected emotional expression in a social interaction was compared in schizophrenia subjects relative to control subjects. Participants also completed a self-report measure of empathy and 2 social functioning measures (social competence and social attainment). Schizophrenia subjects demonstrated significantly lower accuracy in task performance and were characterized by hypoactivation in empathy-related frontal, temporal, and parietal regions as well as hyperactivation in occipital regions compared with control subjects during accurate cognitive empathy trials. A cluster with peak activation in the supplementary motor area (SMA) extending to the anterior midcingulate cortex (aMCC) correlated with social competence and social attainment in schizophrenia subjects but not controls. These results suggest that neural correlates of cognitive empathy may be promising targets for interventions aiming to improve social functioning and that brain activation in the SMA/aMCC region could be used as a biomarker for monitoring treatment response., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Depression is a debilitating condition that adversely affects many aspects of a person's life and general health. Earlier work has supported the idea that there may be a relationship between the use of certain media and depression. In this study, we tested if self-report of depression (SRD), which is not a clinically based diagnosis, was associated with increased internet, television, and social media usage by using data collected in the Media Behavior and Influence Study (MBIS) database (N = 19,776 subjects). We further assessed the relationship of demographic variables to this association. These analyses found that SRD rates were in the range of published rates of clinically diagnosed major depression. It found that those who tended to use more media also tended to be more depressed, and that segmentation of SRD subjects was weighted toward internet and television usage, which was not the case with non-SRD subjects, who were segmented along social media use. This study found that those who have suffered either economic or physical life setbacks are orders of magnitude more likely to be depressed, even without disproportionately high levels of media use. However, among those that have suffered major life setbacks, high media users-particularly television watchers-were even more likely to report experiencing depression, which suggests that these effects were not just due to individuals having more time for media consumption. These findings provide an example of how Big Data can be used for medical and mental health research, helping to elucidate issues not traditionally tested in the fields of psychiatry or experimental psychology.

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1β in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management., (Copyright © 2014 the authors 0270-6474/14/349779-10$15.00/0.)

While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health, the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders.

Empathic deficits have been linked to poor functioning in schizophrenia, but this work is mostly limited to self-report data. This study examined whether performance-based empathy measures account for incremental variance in social competence and social attainment above and beyond self-reported empathy, neurocognition, and clinical symptoms. Given the importance of working memory in theoretical models of empathy and in the prediction of functioning in schizophrenia, we also examined whether empathy mediates the relationship between working memory and functioning. Sixty outpatients and 45 healthy controls were compared on performance-based measures of 3 key components of empathic responding, including facial affect perception, emotional empathy (affective responsiveness), and cognitive empathy (emotional perspective-taking). Participants also completed measures of self-reported empathy, neurocognition, clinical symptoms, and social competence and attainment. Patients demonstrated lower accuracy than controls across the 3 performance-based empathy measures. Among patients, these measures showed minimal relations to self-reported empathy but significantly correlated with working memory and other neurocognitive functions as well as symptom levels. Furthermore, cognitive empathy explained significant incremental variance in social competence (∆R (2) = .07, P < .05) and was found to mediate the relation between working memory and social competence. Performance-based measures of empathy were sensitive to functionally relevant disturbances in schizophrenia. Working memory deficits appear to have an important effect on these disruptions in empathy. Empathy is emerging as a promising new area for social cognitive research and for novel recovery-oriented treatment development., (© The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization.

Cannabis use is associated with working memory (WM) impairments; however, the relationship between cannabis use and WM neural circuitry is unclear. We examined whether a cannabis use disorder (CUD) was associated with differences in brain morphology between control subjects with and without a CUD and between schizophrenia subjects with and without a CUD, and whether these differences related to WM and CUD history. Subjects group-matched on demographics included 44 healthy controls, 10 subjects with a CUD history, 28 schizophrenia subjects with no history of substance use disorders, and 15 schizophrenia subjects with a CUD history. Large-deformation high-dimensional brain mapping with magnetic resonance imaging was used to obtain surface-based representations of the striatum, globus pallidus, and thalamus, compared across groups, and correlated with WM and CUD history. Surface maps were generated to visualize morphological differences. There were significant cannabis-related parametric decreases in WM across groups. Similar cannabis-related shape differences were observed in the striatum, globus pallidus, and thalamus in controls and schizophrenia subjects. Cannabis-related striatal and thalamic shape differences correlated with poorer WM and younger age of CUD onset in both groups. Schizophrenia subjects demonstrated cannabis-related neuroanatomical differences that were consistent and exaggerated compared with cannabis-related differences found in controls. The cross-sectional results suggest that both CUD groups were characterized by WM deficits and subcortical neuroanatomical differences. Future longitudinal studies could help determine whether cannabis use contributes to these observed shape differences or whether they are biomarkers of a vulnerability to the effects of cannabis that predate its misuse.

In the last decade, there has been an upsurge of interest in understanding the mechanisms of behavior change (MOBC) and effective behavioral interventions as a strategy to improve addiction-treatment efficacy. However, there remains considerable uncertainty about how treatment research should proceed to address the MOBC issue. In this article, we argue that limitations in the underlying models of addiction that inform behavioral treatment pose an obstacle to elucidating MOBC. We consider how advances in the cognitive neuroscience of addiction offer an alternative conceptual and methodological approach to studying the psychological processes that characterize addiction, and how such advances could inform treatment process research. In addition, we review neuroimaging studies that have tested aspects of neurocognitive theories as a strategy to inform addiction therapies and discuss future directions for transdisciplinary collaborations across cognitive neuroscience and MOBC research., (2013 APA, all rights reserved)

Objectives: The search for predictors of schizophrenia has accelerated with a growing focus on early intervention and prevention of psychotic illness. Studying nonpsychotic relatives of individuals with schizophrenia enables identification of markers of vulnerability for the illness independent of confounds associated with psychosis. The goal of these studies was to develop new auditory continuous performance tests (ACPTs) and evaluate their effects in individuals with schizophrenia and their relatives., Methods: We carried out two studies of auditory vigilance with tasks involving working memory (WM) and interference control with increasing levels of cognitive load to discern the information-processing vulnerabilities in a sample of schizophrenia patients, and two samples of nonpsychotic relatives of individuals with schizophrenia and controls. Study 1 assessed adults (mean age = 41), and Study 2 assessed teenagers and young adults age 13-25 (M = 19)., Results: Patients with schizophrenia were impaired on all five versions of the ACPTs, whereas relatives were impaired only on WM tasks, particularly the two interference tasks that maximize cognitive load. Across all groups, the interference tasks were more difficult to perform than the other tasks. Schizophrenia patients performed worse than relatives, who performed worse than controls. For patients, the effect sizes were large (Cohen's d = 1.5), whereas for relatives they were moderate (d = ~0.40-0.50). There was no age by group interaction in the relatives-control comparison except for participants <31 years of age., Conclusions: Novel WM tasks that manipulate cognitive load and interference control index an important component of the vulnerability to schizophrenia.

Background: There has been increasing interest in the interaction of the basal ganglia with the cerebellum and the brainstem in motor control and movement disorders. In addition, it has been suggested that these subcortical connections with the basal ganglia may help to coordinate a network of regions involved in mediating posture and stabilization. While studies in animal models support a role for this circuitry in the pathophysiology of the movement disorder dystonia, thus far, there is only indirect evidence for this in humans with dystonia., Methodology/principal Findings: In the current study we investigated probabilistic diffusion tractography in DYT1-negative patients with cervical dystonia and matched healthy control subjects, with the goal of showing that patients exhibit altered microstructure in the connectivity between the pallidum and brainstem. The brainstem regions investigated included nuclei that are known to exhibit strong connections with the cerebellum. We observed large clusters of tractography differences in patients relative to healthy controls, between the pallidum and the brainstem. Tractography was decreased in the left hemisphere and increased in the right hemisphere in patients, suggesting a potential basis for the left/right white matter asymmetry we previously observed in focal dystonia patients., Conclusions/significance: These findings support the hypothesis that connections between the basal ganglia and brainstem play a role in the pathophysiology of dystonia.

Background: Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB)., Methodology/principal Findings: We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity., Conclusions/significance: These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression.

Background: Approach and avoidance behavior provide a means for assessing the rewarding or aversive value of stimuli, and can be quantified by a keypress procedure whereby subjects work to increase (approach), decrease (avoid), or do nothing about time of exposure to a rewarding/aversive stimulus. To investigate whether approach/avoidance behavior might be governed by quantitative principles that meet engineering criteria for lawfulness and that encode known features of reward/aversion function, we evaluated whether keypress responses toward pictures with potential motivational value produced any regular patterns, such as a trade-off between approach and avoidance, or recurrent lawful patterns as observed with prospect theory., Methodology/principal Findings: Three sets of experiments employed this task with beautiful face images, a standardized set of affective photographs, and pictures of food during controlled states of hunger and satiety. An iterative modeling approach to data identified multiple law-like patterns, based on variables grounded in the individual. These patterns were consistent across stimulus types, robust to noise, describable by a simple power law, and scalable between individuals and groups. Patterns included: (i) a preference trade-off counterbalancing approach and avoidance, (ii) a value function linking preference intensity to uncertainty about preference, and (iii) a saturation function linking preference intensity to its standard deviation, thereby setting limits to both., Conclusions/significance: These law-like patterns were compatible with critical features of prospect theory, the matching law, and alliesthesia. Furthermore, they appeared consistent with both mean-variance and expected utility approaches to the assessment of risk. Ordering of responses across categories of stimuli demonstrated three properties thought to be relevant for preference-based choice, suggesting these patterns might be grouped together as a relative preference theory. Since variables in these patterns have been associated with reward circuitry structure and function, they may provide a method for quantitative phenotyping of normative and pathological function (e.g., psychiatric illness).

Brain derived neurotrophic factor (BDNF) regulates neural development and synaptic transmission. We have tested the hypothesis that functional variation in the BDNF gene (Val66Met polymorphism, rs6265) affects brain reward circuitry encoding human judgment and decision-making regarding relative preference. We quantified relative preference among faces with emotional expressions (angry, fearful, sad, neutral, and happy) by a keypress procedure performed offline to measure effort traded for viewing time. Keypress-based relative preferences across the ensemble of faces were mirrored significantly by fMRI signal in the orbitofrontal cortex, amygdala, and hippocampus when passively viewing these faces. For these three brain regions, there was also a statistically significant group difference by BDNF genotype in the fMRI responses to the emotional expressions. In comparison with Val/Met heterozygotes, Val/Val individuals preferentially sought exposure to positive emotions (e.g., happy faces) and had stronger regional fMRI activation to aversive stimuli (e.g., angry, fearful, and sad faces). BDNF genotype accounted for approximately 30% of the variance in fMRI signal that mirrors keypress responses to these stimuli. This study demonstrates that functional allelic variation in BDNF modulates human brain circuits processing reward/aversion information and relative preference transactions., ((c) 2009 Wiley-Liss, Inc.)

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

The structural effects of cocaine on neural systems mediating cognition and motivation are not well known. By comparing the thickness of neocortical and paralimbic brain regions between cocaine-dependent and matched control subjects, we found that four of 18 a priori regions involved with executive regulation of reward and attention were significantly thinner in addicts. Correlations were significant between thinner prefrontal cortex and reduced keypresses during judgment and decision making of relative preference in addicts, suggesting one basis for restricted behavioral repertoires in drug dependence. Reduced effortful attention performance in addicts also correlated with thinner paralimbic cortices. Some thickness differences in addicts were correlated with cocaine use independent of nicotine and alcohol, but addicts also showed diminished thickness heterogeneity and altered hemispheric thickness asymmetry. These observations suggest that brain structure abnormalities in addicts are related in part to drug use and in part to predisposition toward addiction.

Objective: Amygdala volume has been associated with drug craving in cocaine addicts, and amygdala volume reduction is observed in some alcohol-dependent subjects. This study sought an association in alcohol-dependent subjects between volumes of reward-related brain regions, alcohol craving, and the risk of relapse., Method: Besides alcohol craving, the authors assessed amygdala, hippocampus, and ventral striatum volumes in 51 alcohol-dependent subjects and 52 age- and education-matched healthy comparison subjects after detoxification. After imaging and clinical assessment, patients were followed for 6 months and alcohol intake was recorded., Results: Alcohol-dependent subjects showed reduced amygdala, hippocampus, and ventral striatum volumes and reported stronger craving in relation to healthy comparison subjects. However, only amygdala volume and craving differentiated between subsequent relapsers and abstainers. A significant decrease of amygdala volume in alcohol-dependent subjects was associated with increased alcohol craving before imaging and an increased alcohol intake during the 6-month follow-up period., Conclusions: These findings suggest a relationship between amygdala volume reduction, alcohol craving, and prospective relapse into alcohol consumption.

Several genes of the dopaminergic and glutamatergic neurotransmitter systems have been found to be associated with alcohol disease and related intermediate phenotypes. Here, we evaluated genetic variants of the catechol-O-methyltransferase (COMT) and the metabotropic glutamate receptor 3 (mGluR3) genes in alcohol-dependent patients and their association with volumetric measurements of brain structures. By combined analysis of imaging data and genotyping results, large numbers of variables are produced that overstrain conventional statistical methods based on tests for group differences. Limitations in assessment of epistatic effects and multiple testing problems are encountered. Therefore, we introduce a novel method for detecting associations between a set of genetic markers and phenotypical measurements based on machine learning techniques. Hippocampal volume was found to be associated with epistatic effects of the COMT-mGluR3 genes in alcohol-dependent patients but not in controls. These data are in line with prior studies supporting a role for dopamine-glutamate interaction in modulation of alcohol disease.

Context: Previous functional neuroimaging studies have identified a network of brain regions that process aversive stimuli, including anger. A polymorphism near the cyclic adenosine monophosphate response element binding protein gene (CREB1) has recently been associated with greater self-reported effort at anger control as well as risk for antidepressant treatment-emergent suicidality in men with major depressive disorder, but its functional effects have not been studied., Objective: To determine whether this genetic variant is associated with altered brain processing of and behavioral avoidance responses to angry facial expressions., Design and Participants: A total of 28 white participants (mean age, 29.2 years; 13 women) were screened using the Structured Clinical Interview for DSM-IV to exclude any lifetime Axis I psychiatric disorder and were genotyped for rs4675690, a single-nucleotide polymorphism near CREB1., Main Outcome Measures: Blood oxygenation level-dependent signal by functional magnetic resonance imaging in the amygdala, insula, anterior cingulate, and orbitofrontal cortex during passive viewing of photographs of faces with emotional expressions. To measure approach and avoidance responses to anger, an off-line key-press task that traded effort for viewing time assessed valuation of angry faces compared with other expressions., Results: The CREB1-linked single-nucleotide polymorphism was associated with significant differential activation in an extended neural network responding to angry and other facial expressions. The CREB1-associated insular activation was coincident with activation associated with behavioral avoidance of angry faces., Conclusions: A polymorphism near CREB1 is associated with responsiveness to angry faces in a brain network implicated in processing aversion. Coincident activation in the left insula is further associated with behavioral avoidance of these stimuli.

Background: Reinforcement of behavioral responses involves a complex cerebral circuit engaging specific neuronal networks that are modulated by cortical oversight systems affiliated with emotion, memory, judgment, and decision making (collectively referred to in this study as the "extended reward and oversight system" or "reward network"). We examined whether reward-network brain volumes are reduced in alcoholics and how volumes of subcomponents within this system are correlated with memory and drinking history., Methods: Morphometric analysis was performed on magnetic resonance brain scans in 21 abstinent long-term chronic alcoholic men and 21 healthy control men, group-matched on age, verbal IQ, and education. We derived volumes of total brain and volumes of cortical and subcortical reward-related structures including the dorsolateral-prefrontal, orbitofrontal, cingulate cortices, and the insula, as well as the amygdala, hippocampus, nucleus accumbens septi (NAc), and ventral diencephalon., Results: Morphometric analyses of reward-related regions revealed decreased total reward-network volume in alcoholic subjects. Volume reduction was most pronounced in right dorsolateral-prefrontal cortex, right anterior insula, and right NAc, as well as left amygdala. In alcoholics, NAc and anterior insula volumes increased with length of abstinence, and total reward-network and amygdala volumes correlated positively with memory scores., Conclusions: The observation of decreased reward-network volume suggests that alcoholism is associated with alterations in this neural reward system. These structural reward system deficits and their correlation with memory scores elucidate underlying structural-functional relationships between alcoholism and emotional and cognitive processes.

Functional imaging studies of sex effects in working memory (WMEM) are few, despite significant normal sex differences in brain regions implicated in WMEM. This functional MRI (fMRI) study tested for sex effects in an auditory verbal WMEM task in prefrontal, parietal, cingulate, and insula regions. Fourteen healthy, right-handed community subjects were comparable between the sexes, including on WMEM performance. Per statistical parametric mapping, women exhibited greater signal intensity changes in middle, inferior, and orbital prefrontal cortices than men (corrected for multiple comparisons). A test of mixed-sex groups, comparable on performance, showed no significant differences in the hypothesized regions, providing evidence for discriminant validity for significant sex differences. The findings suggest that combining men and women in fMRI studies of cognition may obscure or bias results., (((c) 2005 APA, all rights reserved).)