Modeling social cognition in alcohol use disorder: lessons from schizophrenia.

A better understanding of social deficits in alcohol use disorder (AUD) has the potential to improve our understanding of the disorder. Clinical research shows that AUD is associated with interpersonal problems and the loss of a social network which impedes response to treatment. Translational research between animal models and clinical research may benefit from a discussion of the models and methods that currently guide research into social cognition in AUD. We propose that research in AUD should harness recent technological developments to improve ecological validity while maintaining experimental control. Novel methods allow us to parse naturalistic social cognition into tangible components, and to investigate previously neglected aspects of social cognition. Furthermore, to incorporate social cognition as a defining element of AUD, it is critical to clarify the timing of these social disturbances. Currently, there is limited evidence to distinguish factors that influence social cognition as a consequence of AUD, and those that precede the onset of the disorder. Both increasing the focus on operationalization of social cognition into objective components and adopting a perspective that spans the clinical spectrum will improve our understanding in humans, but also possibly increase methodological consistency and translational dialogue across species. This commentary underscores current challenges and perspectives in this area of research.

Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial.

The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values ≥ 4.21, p-values ≤ 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.

PREFRONTAL CORRELATES OF FEAR GENERALIZATION DURING ENDOCANNABINOID DEPLETION.

Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging from a childhood maltreatment exposed and non-exposed mixed population combined with human and rodent fear conditioning models. Here we show that 2-AG levels are inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increases the proportion of neurons, and the similarity between neuronal representations, of threat-predictive and neutral stimuli within prelimbic prefrontal cortex ensembles. In humans, increased dorsolateral prefrontal cortical-amygdala resting state connectivity is inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and suggest 2-AG deficiency could represent a trauma-related disorder susceptibility endophenotype.

Repetitive deep TMS in alcohol dependent patients halts progression of white matter changes in early abstinence.

AIM: Alcohol use disorder (AUD) is the most prevalent form of addiction, with a great burden on society and limited treatment options. A recent clinical trial reported significant clinical benefits of deep transcranial magnetic stimulations (Deep TMS) targeting midline frontocortical areas. However, the underlying biological substrate remained elusive. Here, we report the effect of Deep TMS on the microstructure of white matter. METHODS: A total of 37 (14 females) AUD treatment-seeking patients were randomized to sham or active Deep TMS. Twenty (six females) age-matched healthy controls were included. White matter integrity was evaluated by fractional anisotropy (FA). Secondary measures included brain functional connectivity and self-reports of craving and drinking units in the 3 months of follow-up period. RESULTS: White matter integrity was compromised in patients with AUD relative to healthy controls, as reflected by the widespread reduction in FA. This alteration progressed during early abstinence (3 weeks) in the absence of Deep TMS. However, stimulation of midline frontocortical areas arrested the progression of FA changes in association with decreased craving and relapse scores. Reconstruction of axonal tracts from white-matter regions showing preserved FA values identified cortical regions in the posterior cingulate and dorsomedial prefrontal cortices where functional connectivity was persistently modulated. These effects were absent in the sham-stimulated group. CONCLUSIONS: By integrating brain structure and function to characterize the alcohol-dependent brain, this study provides mechanistic insights into the TMS effect, pointing to myelin plasticity as a possible mediator.

Assessing Childhood Maltreatment Exposure in Patients Without and With a Diagnosis of Substance Use Disorder.

OBJECTIVES: Childhood maltreatment (CM), widely held as a risk factor for substance use disorders (SUDs), is commonly assessed using the Childhood Trauma Questionnaire (CTQ). Retrospective self-reports are, however, potentially subject to bias. We used a unique patient sample with prospectively documented CM to examine the performance of the CTQ and how this is affected by the presence of SUD. METHODS: Analysis was based on a total of 104 individuals. Subjects with prospectively recorded CM were identified from a specialized childhood trauma unit in Linköping, Sweden (n = 55; 31 with SUD, 61% females; 24 without SUD, 71% females). Clinical controls had SUD but no CM (n = 25, 48% females). Healthy controls had neither SUD nor CM (n = 24, 54% females). We analyzed the agreement between retrospective CTQ scores and prospectively documented CM by κ analysis and assessed the performance of the CTQ to identify CM exposure using receiver operating characteristic (ROC) analysis. RESULTS: Agreement between prospectively and retrospectively recorded CM exposure was poor for sexual abuse (36.6%, Cohen κ = 0.32, P = 0.008) and physical abuse (67.3%, κ = 0.35, P = 0.007). Overall CTQ performance was fair (ROC: area under the ROC curve = 0.78, optimal cutoff = 36.5, sensitivity = 0.65, specificity = 0.75). However, performance was excellent in the absence of SUD (area under the ROC curve = 0.93, cutoff = 32.0, sensitivity = 0.88, specificity = 0.88), but poor in participants with lifetime SUD (area under the ROC curve = 0.62, cutoff = 42.0, sensitivity = 0.60, specificity = 0.36). CONCLUSIONS: These data support the CTQ as a tool to assess CM exposure but suggest that it may be less useful in patients with SUD.

A randomized controlled experimental medicine study of ghrelin in value-based decision making.

BACKGROUNDThe stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug reward using monetary rewards.METHODSThirty participants (50% women and 50% men) underwent 2 fMRI scans while receiving i.v. ghrelin or saline in a randomized counterbalanced order.RESULTSStriatal representations of reward anticipation were unaffected by ghrelin, while activity during anticipation of losses was attenuated. Temporal discounting rates of monetary reward were lower overall in the ghrelin condition, an effect driven by women. Discounting rates were inversely correlated with neural activity in a large cluster within the left parietal lobule that included the angular gyrus. Activity in an overlapping cluster was related to behavioral choices and was suppressed by ghrelin.CONCLUSIONThis is, to our knowledge, the first human study to extend the understanding of ghrelin's significance beyond the canonical feeding domain or in relation to addictive substances. Contrary to our hypothesis, we found that ghrelin did not affect sensitivity to monetary reward anticipation, but rather resulted in attenuated loss aversion and lower discounting rates for these rewards. Ghrelin may cause a motivational shift toward caloric reward rather than globally promoting the value of reward.TRIAL REGISTRATIONEudraCT 2018-004829-82.FUNDINGSwedish Research Council (2013-07434), Marcus and Marianne Wallenberg foundation (2014.0187) and National Institute on Drug Abuse/National Institute on Alcohol Abuse and Alcoholism Intramural Research Program.

Resilience to substance use disorder following childhood maltreatment: association with peripheral biomarkers of endocannabinoid function and neural indices of emotion regulation.

Childhood maltreatment (CM) is a risk factor for substance use disorders (SUD) in adulthood. Understanding the mechanisms by which people are susceptible or resilient to developing SUD after exposure to CM is important for improving intervention. This case-control study investigated the impact of prospectively assessed CM on biomarkers of endocannabinoid function and emotion regulation in relation to the susceptibility or resilience to developing SUD. Four groups were defined across the dimensions of CM and lifetime SUD (N = 101 in total). After screening, participants completed two experimental sessions on separate days, aimed at assessing the behavioral, physiological, and neural mechanisms involved in emotion regulation. In the first session, participants engaged in tasks assessing biochemical (i.e., cortisol, endocannabinoids), behavioral, and psychophysiological indices of stress and affective reactivity. During the second session, the behavioral and brain mechanisms associated with emotion regulation and negative affect were investigated using magnetic resonance imaging. CM-exposed adults who did not develop SUD, operationally defined as resilient to developing SUD, had higher peripheral levels of the endocannabinoid anandamide at baseline and during stress exposure, compared to controls. Similarly, this group had increased activity in salience and emotion regulation regions in task-based measures of emotion regulation compared to controls, and CM-exposed adults with lifetime SUD. At rest, the resilient group also showed significantly greater negative connectivity between ventromedial prefrontal cortex and anterior insula compared to controls and CM-exposed adults with lifetime SUD. Collectively, these peripheral and central findings point to mechanisms of potential resilience to developing SUD after documented CM exposure.

Neural processing of self-touch and other-touch in anorexia nervosa and autism spectrum condition.

INTRODUCTION: The tactile sense plays a crucial role in the development and maintenance of a functional bodily self. The ability to differentiate between self- and nonself-generated touch contributes to the perception of the bodies' boundaries and more generally to self-other-distinction, both of which are thought be altered in anorexia nervosa (AN) and autism spectrum condition (AS). While it has been suggested that AN and AS are characterized by overlapping symptomatology, they might differ regarding body perception and self-other-distinction. METHODS: Participants with a diagnosis of AN (n = 25), AS (n = 29), and a comparison group without diagnoses (n = 57) performed a self-other-touch task during functional brain imaging. In the experimental conditions, they stroked their own arm or were stroked on the arm by an experimenter. RESULTS: As shown previously, the CG group showed lower activation or deactivation in response to self-touch compared to social touch from someone else. A main group effect was found in areas including somatosensory cortex, frontal and temporal gyri, insula, and subcortical regions. This was driven by increased activations in participants with AN, while participants in the AS group showed mostly comparable activations to the comparison group. CONCLUSIONS: AN diagnosis was associated with an increased neural activity in response to both self-touch and social touch. Failure to attenuate self-touch might relate to altered predictions regarding the own body and reduced perception of bodily boundaries. Participants with an AS diagnosis were mostly comparable to the comparison group, potentially indicating unaltered tactile self-other-distinction.

Aberrant resting-state connectivity of auditory, ventral attention/salience and default-mode networks in adults with attention deficit hyperactivity disorder.

Background: Numerous resting-state studies on attention deficit hyperactivity disorder (ADHD) have reported aberrant functional connectivity (FC) between the default-mode network (DMN) and the ventral attention/salience network (VA/SN). This finding has commonly been interpreted as an index of poorer DMN regulation associated with symptoms of mind wandering in ADHD literature. However, a competing perspective suggests that dysfunctional organization of the DMN and VA/SN may additionally index increased sensitivity to the external environment. The goal of the current study was to test this latter perspective in relation to auditory distraction by investigating whether ADHD-adults exhibit aberrant FC between DMN, VA/SN, and auditory networks. Methods: Twelve minutes of resting-state fMRI data was collected from two adult groups: ADHD (n = 17) and controls (n = 17); from which the FC between predefined regions comprising the DMN, VA/SN, and auditory networks were analyzed. Results: A weaker anticorrelation between the VA/SN and DMN was observed in ADHD. DMN and VA/SN hubs also exhibited aberrant FC with the auditory network in ADHD. Additionally, participants who displayed a stronger anticorrelation between the VA/SN and auditory network at rest, also performed better on a cognitively demanding behavioral task that involved ignoring a distracting auditory stimulus. Conclusion: Results are consistent with the hypothesis that auditory distraction in ADHD is linked to aberrant interactions between DMN, VA/SN, and auditory systems. Our findings support models that implicate dysfunctional organization of the DMN and VA/SN in the disorder and encourage more research into sensory interactions with these major networks.

A methodological checklist for fMRI drug cue reactivity studies: development and expert consensus.

Cue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participants' characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work are difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting and review the FDCR literature to assess the reporting of items that are deemed important. Forty-five FDCR scientists from around the world participated in this study. First, an initial checklist of items deemed important in FDCR studies was developed by several members of the Enhanced NeuroImaging Genetics through Meta-Analyses (ENIGMA) Addiction working group on the basis of a systematic review. Using a modified Delphi consensus method, all experts were asked to comment on, revise or add items to the initial checklist, and then to rate the importance of each item in subsequent rounds. The reporting status of the items in the final checklist was investigated in 108 recently published FDCR studies identified through a systematic review. By the final round, 38 items reached the consensus threshold and were classified under seven major categories: 'Participants' Characteristics', 'General fMRI Information', 'General Task Information', 'Cue Information', 'Craving Assessment Inside Scanner', 'Craving Assessment Outside Scanner' and 'Pre- and Post-Scanning Considerations'. The review of the 108 FDCR papers revealed significant gaps in the reporting of the items considered important by the experts. For instance, whereas items in the 'General fMRI Information' category were reported in 90.5% of the reviewed papers, items in the 'Pre- and Post-Scanning Considerations' category were reported by only 44.7% of reviewed FDCR studies. Considering the notable and sometimes unexpected gaps in the reporting of items deemed to be important by experts in any FDCR study, the protocols could benefit from the adoption of reporting standards. This checklist, a living document to be updated as the field and its methods advance, can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI.

Repetitive Transcranial Magnetic Stimulation in Alcohol Dependence: A Randomized, Double-Blind, Sham-Controlled Proof-of-Concept Trial Targeting the Medial Prefrontal and Anterior Cingulate Cortices.

BACKGROUND: Alcohol addiction is associated with a high disease burden, and treatment options are limited. In a proof-of-concept study, we used deep repetitive transcranial magnetic stimulation (dTMS) to target circuitry associated with the pathophysiology of alcohol addiction. We evaluated clinical outcomes and explored associated neural signatures using functional magnetic resonance imaging. METHODS: This was a double-blind, randomized, sham-controlled trial. A total of 51 recently abstinent treatment-seeking patients with alcohol use disorder (moderate to severe) were randomized to sham or active dTMS, using an H7 coil targeting midline frontocortical areas, including the medial prefrontal and anterior cingulate cortices. Treatment included 15 sessions over 3 weeks, followed by five sessions over 3 months of follow-up. Each session delivered 100 trains of 30 pulses at 10 Hz. The primary predefined outcome was reduction in percentage of heavy drinking days, obtained using timeline follow-back interviews. Secondary analyses included self-reports of craving, ethyl glucuronide in urine, and brain imaging measures. RESULTS: Both craving after treatment and percentage of heavy drinking days during follow-up were significantly lower in the active versus sham control group (percentage of heavy drinking days = 2.9 ± 0.8% vs. 10.6 ± 1.9%, p = .037). Active dTMS was associated with decreased resting-state functional connectivity of the dorsal anterior cingulate cortex with the caudate nucleus and decreased connectivity of the medial prefrontal cortex to the subgenual anterior cingulate cortex. CONCLUSIONS: We provide initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction. These data strongly support a rationale for a full-scale confirmatory multicenter trial. Therapeutic benefits of dTMS appear to be associated with persistent changes in brain network activity.

Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.

Acute effects of alcohol on social and personal decision making.

Social drinking is common, but it is unclear how moderate levels of alcohol influence decision making. Most prior studies have focused on adverse long-term effects on cognitive and executive function in people with alcohol use disorders (AUD). Some studies have investigated the acute effects of alcohol on decision making in healthy people, but have predominantly used small samples and focused on a narrow selection of tasks related to personal decision making, e.g., delay or probability discounting. Here, we conducted a large (n = 264), preregistered randomized placebo-controlled study (RCT) using a parallel group design, to systematically assess the acute effects of alcohol on measures of decision making in both personal and social domains. We found a robust effect of a 0.6 g/kg dose of alcohol on both moral judgment and altruistic behavior, but no effects on several measures of risk taking or waiting impulsivity. These findings suggest that alcohol at low to moderate doses selectively moderates decision making in the social domain, and promotes utilitarian decisions over those dictated by rule-based ethical principles (deontological). This is consistent with existing theory that emphasizes the dual roles of shortsighted information processing and salient social cues in shaping decisions made under the influence of alcohol. A better understanding of these effects is important to understand altered social functioning during alcohol intoxication.

Social Acts and Anticipation of Social Feedback.

Socialization happens so regularly in humans that it can be perceived as an effortless activity. However, it reflects a sophisticated behavior, pervaded by anticipation and emotion. The fast-paced social interplay, strongly mediated by facial expressions, can be considered one of the most frequent high-order motor acts within the human behavioral repertoire. The ability to adequately process social feedback is critical for appropriate socialization and affects well-being. The social difficulties often observed in psychiatric patients highlight the link between mental health and successful socialization and the importance of characterizing the behavioral and neural mechanisms of social interaction. This chapter will present some cross-species evidence on the cortical regions engaged during social interactions including facial expressions, and the impact of induced or perceived social stress on the experience of social interactions.

Negative self-evaluation induced by acute stress indexed using facial EMG.

Maladaptive stress responses are a key feature of several psychiatric disorders, but findings of stress effects on social behavior are inconsistent. Using a within-subject design, we investigated, in 35 healthy participants, the effects of acute stress on psychophysiological and behavioral responses during a simulated online social interaction task. Participants were exposed to established stress and non-stress exposure procedures in two separate sessions. During the task, participants liked or disliked pictures of other putative players and, similarly, saw their own picture being judged by others. After stress exposure, corrugator muscle activity (frowning) was significantly increased when participants saw their own picture while anticipating feedback from others. Consistently, zygomatic muscle activity (smiling) for self-evaluation was lower after stress than in the non-stress session. We found self-report of stress to be a significant predictor of corrugator activity in both sessions, indicating that higher levels of subjective stress overall were accompanied by increased negative self-evaluation. Surprisingly, no stress effects were found on behavioral measures of other-evaluation (i.e., percentage of dislikes to others), but corrugator response significantly predicted the percentage of dislikes during the stress session only. Overall, our findings suggest that stress increases negative self-evaluation as indexed by elevated corrugator activity. Furthermore, stress might sharpen the consistency between corrugator activity and negative evaluation of others. Our results indicate that negative self-evaluation might be a useful therapeutic target in patients with stress-related psychiatric disorders. In this context, facial muscle activity may be an adequate biomarker for identifying stress-related differences in self-evaluation.

Altered relationship between subjective perception and central representation of touch hedonics in adolescents with autism-spectrum disorder.

An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affective touch is an important means of social interaction, and C-Tactile (CT) afferents are thought to play a key role in the peripheral detection and encoding of these stimuli. Exploring the neural and behavioral mechanisms for processing CT-optimal touch (~3 cm/s) may therefore provide useful insights into the pathophysiology of ASD. We examined the relationship between touch hedonics (i.e. the subjective pleasantness with which affective touch stimuli are perceived) and neural processing in the posterior superior temporal sulcus (pSTS). This region is less activated to affective touch in individuals with ASD, and, in typically developing individuals (TD), is correlated positively with touch pleasantness. TD and ASD participants received brushing stimuli at CT-optimal, and CT-non-optimal speeds during fMRI. Touch pleasantness and intensity ratings were collected, and affective touch awareness, a measure of general touch hedonics was calculated. As expected, slow touch was perceived as more pleasant and less intense than fast touch in both groups, whereas affective touch awareness was moderately higher in TD compared to ASD. There was a strong, positive correlation between right pSTS activation and affective touch awareness in TD, but not in ASD. Our findings suggest that altered neural coupling between right pSTS and touch hedonics in ASD may be associated with social touch avoidance in ASD.

Psychophysiological and Neural Support for Enhanced Emotional Reactivity in Female Adolescents With Nonsuicidal Self-injury.

BACKGROUND: Nonsuicidal self-injury (NSSI) is prevalent in adolescent populations worldwide. Emotion dysregulation is believed to contribute to NSSI, but underlying mechanisms are less known. We combined psychophysiological and neural data with subjective self-report in close temporal proximity to examine the mechanisms underlying emotion processing in adolescents with NSSI relative to control adolescents without a psychiatric diagnosis. METHODS: Thirty female adolescents with NSSI and 30 age-matched female control subjects were included in this case-control study. Participants were presented with negative affective pictures during a functional magnetic resonance imaging scan. In a separate facial electromyography session, the same participants were shown positive and negative affective images and also provided ratings of valence and arousal. RESULTS: Participants with NSSI responded to affective images with greater positive (e.g., zygomatic) and greater negative (e.g., corrugator) reactivity. We found no differences in self-reported affect in response to the images. Analyses of the negative picture-viewing functional magnetic resonance imaging data showed a significant positive correlation between anterior insula response and the averaged electromyography magnitude in NSSI, but not in control subjects. CONCLUSIONS: Adolescents with NSSI show enhanced emotional reactivity that is associated with anterior insula responding, but no abnormalities in self-reported affect. This discrepancy between self-report and objective measures of emotional reactivity potentially indicates a suppression of the emotional reaction in adolescents with NSSI. Moreover, the current data suggest potential targets for novel therapeutic approaches that can be combined with existing clinical treatment, such as real-time electromyography-based biofeedback focusing on emotional awareness, labeling, and expressing emotional experiences.

Nonsuicidal Self-Injury Disorder in Adolescents: Clinical Utility of the Diagnosis Using the Clinical Assessment of Nonsuicidal Self-Injury Disorder Index.

Nonsuicidal self-injury disorder (NSSID) is a condition in need of further study, especially in adolescent and clinical populations where it is particularly prevalent and studies are limited. Twenty-nine clinical self-injuring adolescents were included in the study. The Clinical Assessment of Nonsuicidal Self-Injury Disorder Index (CANDI) was used to assess prevalence of NSSID. The NSSID diagnosis criteria were met by 62.1% of adolescents. The impairment or distress criterion was least often met. Criteria B and C (assessing reasons for NSSI and cognitions/emotions prior to NSSI) were confirmed by 96-100% of all participants. Adolescents with NSSI in this clinical sample had several comorbidities and high levels of psychopathology. NSSID occurred both in combination with and independently of borderline personality disorder traits as well as suicide plans and attempts. Those with NSSID had a significantly higher cutting frequency than those not meeting full NSSID criteria. Other NSSI characteristics, comorbidity, psychopathology, and trauma experiences did not differ between groups. CANDI was a feasible tool to assess NSSID in adolescents. It is important to use structured measures to assess the validity of the NSSID diagnosis across development in both community and clinical samples. The clinical utility of the NSSID diagnosis is discussed.

Repetitive transcranial magnetic stimulation targeting the insular cortex for reduction of heavy drinking in treatment-seeking alcohol-dependent subjects: a randomized controlled trial.

Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatment-seeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction.