Emerging frontiers in Chronic Traumatic Encephalopathy: early diagnosis and implications for neurotherapeutic interventions.

INTRODUCTION: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disorder associated with repetitive head trauma. Historically, the diagnosis has been primarily clinical, which has hindered definitive early diagnosis and proactive intervention. AREAS COVERED: The authors analyze the recent advancements in early diagnosis of CTE by examining biomarkers, imaging, and clinical decision tools. They discuss the identification of neuropathologies - such as tau aggregates - through novel techniques ranging from blood sampling and to brain density scanning. The reader will walk away with a better understanding of current advancements in early detection and be better equipped to deal with encephalopathies secondary to trauma in clinical practice. EXPERT OPINION: Tremendous progress has been made in understanding the pathophysiology of CTE. Despite these advancements, CTE treatment is still primarily symptomatic rather than underlying disease. Future research should focus on integrating current understanding of CTE pathophysiology with treatment modalities.

The underpinning of meaningful activities by brain correlates: a systematic review.

Introduction: Engaging in meaningful activities contributes to health and wellbeing. Research identifies meaningfulness by analysing retrospective and subjective data such as personal experiences in activities. Objectively measuring meaningful activities by registering the brain (fNIRS, EEG, PET, fMRI) remains poorly investigated. Methods: A systematic review using PubMed, Web of Science, CINAHL, and Cochrane Library. Findings: Thirty-one studies investigating the correlations between daily activities in adults, their degree of meaningfulness for the participant, and the brain areas involved, were identified. The activities could be classified according to the degree of meaningfulness, using the attributes of meaningfulness described in the literature. Eleven study activities contained all attributes, which means that these can be assumed to be meaningful for the participant. Brain areas involved in these activities were generally related to emotional and affective processing, motivation, and reward. Conclusion: Although it is demonstrated that neural correlates of meaningful activities can be measured objectively by neurophysiological registration techniques, "meaning" as such has not yet been investigated explicitly. Further neurophysiological research for objective monitoring of meaningful activities is recommended.

Transdiagnostic Connectome-Based Prediction of Craving.

OBJECTIVE: Craving is a central construct in the study of motivation and human behavior and is also a clinical symptom of substance and non-substance-related addictive disorders. Thus, craving represents a target for transdiagnostic modeling. METHODS: The authors applied connectome-based predictive modeling (CPM) to functional connectivity data in a large (N=274) transdiagnostic sample of individuals with and without substance use-related conditions, to predict self-reported craving. Functional connectomes derived from three guided imagery conditions of personalized appetitive, stress, and neutral-relaxing experiences were used to predict craving rated before and after each imagery condition. The generalizability of the "craving network" was tested in an independent sample using functional connectomes derived from a cue-induced craving task collected before and after fasting to predict craving rated during fasting. RESULTS: CPM successfully predicted craving, thereby identifying a transdiagnostic "craving network." Anatomical localization of model contribution suggested that the strongest predictors of craving were regions of the salience, subcortical, and default mode networks. As external validation, in an independent sample, the "craving network" predicted food craving during fasting using data from a cue-induced craving task. CONCLUSIONS: These data provide a transdiagnostic perspective to a key phenomenological feature of addictive disorders-craving-and identify a common "craving network" across individuals with and without substance use-related disorders, thereby suggesting a neural signature for craving or urge for motivated behaviors.

The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression.

OBJECTIVE: The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. METHODS: Using a novel deep learning framework trained to predict biological sex based on T1-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T1-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age). RESULTS: Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy in autism were not observed in individuals with ADHD. In autistic females, the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also associated with gene expression patterns of midgestational cell types. CONCLUSIONS: The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.

Preclinical and clinical evidence on the approach-avoidance conflict evaluation as an integrative tool for psychopathology.

The approach-avoidance conflict (AAC), i.e. the competing tendencies to undertake goal-directed actions or to withdraw from everyday life challenges, stands at the basis of humans' existence defining behavioural and personality domains. Gray's Reinforcement Sensitivity Theory posits that a stable bias toward approach or avoidance represents a psychopathological trait associated with excessive sensitivity to reward or punishment. Optogenetic studies in rodents and imaging studies in humans associated with cross-species AAC paradigms granted new emphasis to the hippocampus as a hub of behavioural inhibition. For instance, recent functional neuroimaging studies show that functional brain activity in the human hippocampus correlates with threat perception and seems to underlie passive avoidance. Therefore, our commentary aims to (i) discuss the inhibitory role of the hippocampus in approach-related behaviours and (ii) promote the integration of functional neuroimaging with cross-species AAC paradigms as a means of diagnostic, therapeutic, follow up and prognosis refinement in psychiatric populations.

Neural Signatures of Pain Modulation in Short-Term and Long-Term Mindfulness Training: A Randomized Active-Control Trial.

OBJECTIVE: Mindfulness-based interventions are widely used to target pain, yet their neural mechanisms of action are insufficiently understood. The authors studied neural and subjective pain response in a randomized active-control trial of mindfulness-based stress reduction (MBSR) alongside long-term meditation practitioners. METHODS: Healthy participants (N=115) underwent functional neuroimaging during a thermal acute pain task before and after random assignment to MBSR (N=28), an active control condition (health enhancement program [HEP]) (N=32), or a waiting list control condition (N=31). Long-term meditators (N=30) completed the same neuroimaging paradigm. Pain response was measured via self-reported intensity and unpleasantness, and neurally via two multivoxel machine-learning-derived signatures: the neurologic pain signature (NPS), emphasizing nociceptive pain processing, and the stimulus intensity independent pain signature-1 (SIIPS1), emphasizing stimulus-independent neuromodulatory processes. RESULTS: The MBSR group showed a significant decrease in NPS response relative to the HEP group (Cohen's d=-0.43) and from pre- to postintervention assessment (d=-0.47). The MBSR group showed small, marginal decreases in NPS relative to the waiting list group (d=-0.36), and in SIIPS1 relative to both groups (HEP group, d=-0.37; waiting list group, d=-0.37). In subjective unpleasantness, the MBSR and HEP groups also showed modest significant reductions compared with the waiting list group (d=-0.45 and d=-0.55). Long-term meditators reported significantly lower pain than nonmeditators but did not differ in neural response. Within the long-term meditator group, cumulative practice during intensive retreat was significantly associated with reduced SIIPS1 (r=-0.65), whereas daily practice was not. CONCLUSIONS: Mindfulness training showed associations with pain reduction that implicate differing neural pathways depending on extent and context of practice. Use of neural pain signatures in randomized trials offers promise for guiding the application of mindfulness interventions to pain treatment.

Toward a Better Understanding of the Mechanisms and Pathophysiology of Anhedonia: Are We Ready for Translation?

Anhedonia-the loss of pleasure or lack of reactivity to pleasurable stimuli-remains a formidable treatment challenge across neuropsychiatric disorders. In major depressive disorder, anhedonia has been linked to poor disease course, worse response to psychological, pharmacological, and neurostimulation treatments, and increased suicide risk. Moreover, although some neural abnormalities linked to anhedonia normalize after successful treatment, several persist-for example, blunted activation of the ventral striatum to reward-related cues and reduced functional connectivity involving the ventral striatum. Critically, some of these abnormalities have also been identified in unaffected, never-depressed children of parents with major depressive disorder and have been found to prospectively predict the first onset of major depression. Thus, neural abnormalities linked to anhedonia may be promising targets for prevention. Despite increased appreciation of the clinical importance of anhedonia and its underlying neural mechanisms, important gaps remain. In this overview, the author first summarizes the extant knowledge about the pathophysiology of anhedonia, which may provide a road map toward novel treatment and prevention strategies, and then highlights several priorities to facilitate clinically meaningful breakthroughs. These include a need for 1) appropriately controlled clinical trials, especially those embracing an experimental therapeutics approach to probe target engagement; 2) novel preclinical models relevant to anhedonia, with stronger translational value; and 3) clinical scales that incorporate neuroscientific advances in our understanding of anhedonia. The author concludes by highlighting important future directions, emphasizing the need for an integrated, collaborative, cross-species, and multilevel approach to tackling anhedonic phenotypes.

Predictive Value of Acute Neuroplastic Response to rTMS in Treatment Outcome in Depression: A Concurrent TMS-fMRI Trial.

OBJECTIVE: The study objective was to investigate the predictive value of functional connectivity changes induced by acute repetitive transcranial magnetic stimulation (rTMS) for clinical response in treatment-resistant depression. METHODS: Cross-sectional changes in functional connectivity induced by a single concurrent rTMS-fMRI session were assessed in 38 outpatients with treatment-resistant depression (26 of them female; mean age, 41.87 years) who subsequently underwent a 4-week course of rTMS. rTMS was delivered at 1 Hz over the right dorsolateral prefrontal cortex. Acute rTMS-induced functional connectivity changes were computed and subjected to connectome-based predictive modeling to test their association with changes in score on the Montgomery-Åsberg Depression Rating Scale (MADRS) after rTMS treatment. RESULTS: TMS-fMRI induced widespread, acute, and transient alterations in functional connectivity. The rTMS-induced connectivity changes predicted about 30% of the variance of improvement in the MADRS score. The most robust predictive associations involved connections between prefrontal regions and motor, parietal, and insular cortices and between bilateral regions of the thalamus. CONCLUSIONS: Acute rTMS-induced connectivity changes in patients with treatment-resistant depression may index macro-level neuroplasticity, relevant to interindividual variability in rTMS treatment response. Large-scale network phenomena occurring during rTMS might be used to inform prospective clinical trials.

Association of Childhood Maltreatment With Interpersonal Distance and Social Touch Preferences in Adulthood.

OBJECTIVE: Childhood maltreatment is a major risk factor for psychopathology associated with interpersonal problems in adulthood, but the etiological pathways involved are still unclear. The authors propose that childhood maltreatment confers risk for dysfunctional behavior in social interactions by altering interpersonal distance preference and the processing of social touch. METHODS: Ninety-two medication-free adults (64 of them female) with low, medium, and high levels of childhood maltreatment were tested with an interpersonal distance paradigm and subsequently underwent a social touch functional MRI task during which they rated the perceived comfort of slow touch (C-tactile [CT] optimal speed; 5 cm/s) and fast touch (non-CT-optimal speed; 20 cm/s). RESULTS: Participants with high childhood maltreatment levels preferred a larger interpersonal distance and experienced fast touch as less comforting compared with participants with no or moderate childhood maltreatment experiences. On the neural level, participants with severe childhood maltreatment exhibited exaggerated responses to fast touch in the right somatosensory and posterior insular cortex, which correlated with lower comfort ratings. Severe childhood maltreatment was associated with decreased activation in the right hippocampus in response to slow touch. This response pattern was not moderated or mediated by childhood maltreatment-associated region-specific reductions in gray matter volume. CONCLUSIONS: The study findings suggest that higher childhood maltreatment levels are associated with hypersensitivity characterized by a preference for larger interpersonal distance and discomfort of fast touch. These dysregulations were manifested in a sensory cortical hyperreactivity and limbic CT-related hypoactivation. These results may shed light on why individuals with severe childhood maltreatment exhibit an increased susceptibility to interpersonal dysfunctions and psychiatric disorders in adulthood.