A systematic review of sex/gender differences in the multi-dimensional neurobiological mechanisms in addiction and their relevance to impulsivity.

Purpose of Review: Addiction may be characterized along three functional domains: Approach Behavior, Executive Function, and Negative Emotionality. Constructs underlying impulsivity thought to be relevant in addiction map on to these three functional domains. The purpose of the present review was to evaluate the extant research regarding sex/gender differences in the multi-dimensional domains of addiction using human neuroimaging and discuss their relevance to impulsivity. Recent Findings: Few papers over the past two decades have used human neuroimaging to test sex/gender differences in addiction. There is therefore a significant gap in the literature regarding sex/gender differences in the neurobiological mechanisms driving the multi-dimensionality of addiction and their implications to impulsivity. Summary: Of the 34 reviewed papers, the orbitofrontal cortex/ventromedial prefrontal cortex (OFC/vmPFC) was the most frequently reported brain region to evidence a sex/gender difference during fMRI tasks probing Approach Behavior and Negative Emotionality. This finding suggests potential sex/gender-specific patterns of subjective valuation in substance misuse, driven by OFC/vmPFC dysregulation.

Current Approaches in Computational Psychiatry for the Data-Driven Identification of Brain-Based Subtypes.

The ability of our current psychiatric nosology to accurately delineate clinical populations and inform effective treatment plans has reached a critical point with only moderately successful interventions and high relapse rates. These challenges continue to motivate the search for approaches to better stratify clinical populations into more homogeneous delineations, to better inform diagnosis and disease evaluation, and prescribe and develop more precise treatment plans. The promise of brain-based subtyping based on neuroimaging data is that finding subgroups of individuals with a common biological signature will facilitate the development of biologically grounded, targeted treatments. This review provides a snapshot of the current state of the field in empirical brain-based subtyping studies in child, adolescent, and adult psychiatric populations published between 2019 and March 2022. We found that there is vast methodological exploration and a surprising number of new methods being created for the specific purpose of brain-based subtyping. However, this methodological exploration and advancement is not being met with rigorous validation approaches that assess both reproducibility and clinical utility of the discovered brain-based subtypes. We also found evidence for a collaboration crisis, in which methodological exploration and advancements are not clearly grounded in clinical goals. We propose several steps that we believe are crucial to address these shortcomings in the field. We conclude, and agree with the authors of the reviewed studies, that the discovery of biologically grounded subtypes would be a significant advancement for treatment development in psychiatry.

Subtypes in addiction and their neurobehavioral profiles across three functional domains.

Rates of return to use in addiction treatment remain high. We argue that the development of improved treatment options will require advanced understanding of individual heterogeneity in Substance Use Disorders (SUDs). We hypothesized that considerable individual differences exist in the three functional domains underlying addiction-approach-related behavior, executive function, and negative emotionality. We included N = 593 participants from the enhanced Nathan Kline Institute-Rockland Sample community sample (ages 18-59, 67% female) that included N = 420 Controls and N = 173 with past SUDs [54% female; N = 75 Alcohol Use Disorder (AUD) only, N = 30 Cannabis Use Disorder (CUD) only, and N = 68 Multiple SUDs]. To test our a priori hypothesis that distinct neuro-behavioral subtypes exist within individuals with past SUDs, we conducted a latent profile analysis with all available phenotypic data as input (74 subscales from 18 measures), and then characterized resting-state brain function for each discovered subtype. Three subtypes with distinct neurobehavioral profiles were recovered (p < 0.05, Cohen's D: 0.4-2.8): a "Reward type" with higher approach-related behavior (N = 69); a "Cognitive type" with lower executive function (N = 70); and a "Relief type" with high negative emotionality (N = 34). For those in the Reward type, substance use mapped onto resting-state connectivity in the Value/Reward, Ventral-Frontoparietal and Salience networks; for the Cognitive type in the Auditory, Parietal Association, Frontoparietal and Salience networks; and for the Relief type in the Parietal Association, Higher Visual and Salience networks (pFDR < 0.05). Subtypes were equally distributed amongst individuals with different primary SUDs (χ2 = 4.71, p = 0.32) and gender (χ2 = 3.44, p = 0.18). Results support functionally derived subtypes, demonstrating considerable individual heterogeneity in the multi-dimensional impairments in addiction. This confirms the need for mechanism-based subtyping to inform the development of personalized addiction medicine approaches.

Explainable machine learning analysis reveals sex and gender differences in the phenotypic and neurobiological markers of Cannabis Use Disorder.

Cannabis Use Disorder (CUD) has been linked to a complex set of neuro-behavioral risk factors. While many studies have revealed sex and gender differences, the relative importance of these risk factors by sex and gender has not been described. We used an "explainable" machine learning approach that combined decision trees [gradient tree boosting, XGBoost] with factor ranking tools [SHapley's Additive exPlanations (SHAP)] to investigate sex and gender differences in CUD. We confirmed that previously identified environmental, personality, mental health, neurocognitive, and brain factors highly contributed to the classification of cannabis use levels and diagnostic status. Risk factors with larger effect sizes in men included personality (high openness), mental health (high externalizing, high childhood conduct disorder, high fear somaticism), neurocognitive (impulsive delay discounting, slow working memory performance) and brain (low hippocampal volume) factors. Conversely, risk factors with larger effect sizes in women included environmental (low education level, low instrumental support) factors. In summary, environmental factors contributed more strongly to CUD in women, whereas individual factors had a larger importance in men.

Recurrent neural network-based acute concussion classifier using raw resting state EEG data.

Concussion is a global health concern. Despite its high prevalence, a sound understanding of the mechanisms underlying this type of diffuse brain injury remains elusive. It is, however, well established that concussions cause significant functional deficits; that children and youths are disproportionately affected and have longer recovery time than adults; and that individuals suffering from a concussion are more prone to experience additional concussions, with each successive injury increasing the risk of long term neurological and mental health complications. Currently, the most significant challenge in concussion management is the lack of objective, clinically- accepted, brain-based approaches for determining whether an athlete has suffered a concussion. Here, we report on our efforts to address this challenge. Specifically, we introduce a deep learning long short-term memory (LSTM)-based recurrent neural network that is able to distinguish between non-concussed and acute post-concussed adolescent athletes using only short (i.e. 90 s long) samples of resting state EEG data as input. The athletes were neither required to perform a specific task nor expected to respond to a stimulus during data collection. The acquired EEG data were neither filtered, cleaned of artefacts, nor subjected to explicit feature extraction. The LSTM network was trained and validated using data from 27 male, adolescent athletes with sports related concussion, benchmarked against 35 non-concussed adolescent athletes. During rigorous testing, the classifier consistently identified concussions with an accuracy of > 90% and achieved an ensemble median Area Under the Receiver Operating Characteristic Curve (ROC/AUC) equal to 0.971. This is the first instance of a high-performing classifier that relies only on easy-to-acquire resting state, raw EEG data. Our concussion classifier represents a promising first step towards the development of an easy-to-use, objective, brain-based, automatic classification of concussion at an individual level.

Myelin water fraction decrease in individuals with chronic mild traumatic brain injury and persistent symptoms.

The diffuse and continually evolving secondary changes after mild traumatic brain injury (mTBI) make it challenging to assess alterations in brain-behaviour relationships. In this study we used myelin water imaging to evaluate changes in myelin water fraction (MWF) in individuals with chronic mTBI and persistent symptoms and measured their cognitive status using the NIH Toolbox Cognitive Battery. Fifteen adults with mTBI with persistent symptoms and twelve age, gender and education matched healthy controls took part in this study. We found a significant decrease in global white matter MWF in patients compared to the healthy controls. Significantly lower MWF was evident in most white matter region of interest (ROIs) examined including the corpus callosum (separated into genu, body and splenium), minor forceps, right anterior thalamic radiation, left inferior longitudinal fasciculus; and right and left superior longitudinal fasciculus and corticospinal tract. Although patients showed lower cognitive functioning, no significant correlations were found between MWF and cognitive measures. These results suggest that individuals with chronic mTBI who have persistent symptoms have reduced MWF.

Disrupted Information Flow in Resting-State in Adolescents With Sports Related Concussion.

Children and youths are at a greater risk of concussions than adults, and once injured, take longer to recover. A key feature of concussion is an increase in functional connectivity, yet it remains unclear how changes in functional connectivity relate to the patterns of information flow within resting state networks following concussion and how these relate to brain function. We applied a data-driven measure of directed effective brain connectivity to compare the patterns of information flow in healthy adolescents and adolescents with subacute concussion during the resting state condition. Data from 32 healthy adolescents (mean age =16 years) and 21 concussed adolescents (mean age = 15 years) within 1 week of injury were included in the study. Five minutes of resting state data EEG were collected while participants sat quietly with their eyes closed. We applied the information flow rate to measure the transfer of information between the EEG time series of each individual at different source locations, and therefore between different brain regions. Based on the ensemble means of the magnitude of normalized information flow rate, our analysis shows that the dominant nexus of information flow in healthy adolescents is primarily left lateralized and anterior-centric, characterized by strong bidirectional information exchange between the frontal regions, and between the frontal and the central/temporal regions. In contrast, adolescents with concussion show distinct differences in information flow marked by a more left-right symmetrical, albeit still primarily anterior-centric, pattern of connections, diminished activity along the central-parietal midline axis, and the emergence of inter-hemispheric connections between the left and right frontal and the left and right temporal regions of the brain. We also find that the statistical distribution of the normalized information flow rates in each group (control and concussed) is significantly different. This paper is the first to describe the characteristics of the source space information flow and the effective connectivity patterns between brain regions in healthy adolescents in juxtaposition with the altered spatial pattern of information flow in adolescents with concussion, statistically quantifying the differences in the distribution of the information flow rate between the two populations. We hypothesize that the observed changes in information flow in the concussed group indicate functional reorganization of resting state networks in response to brain injury.