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OBJECTIVE: Increased amygdala reactivity during processing of certain types of emotional stimuli (e.g., fear, anger) has been observed in patients with anxiety disorders such as social phobia and posttraumatic stress disorder (PTSD). It is uncertain whether this heightened amygdala reactivity is specific to treatment-seeking patients with anxiety disorders or is a general feature of individuals with increased anxiety-related temperamental traits. METHOD: Thirty-two physically healthy subjects 18-21 years old were recruited from a large pool of college students. Of these, 16 were chosen on the basis of scoring in the upper-15th percentile on a measure of trait anxiety (anxiety-prone group), and 16 were chosen on the basis of scoring in the normative range (40th-60th percentile). Subjects participated in functional magnetic resonance imaging (fMRI) during an emotion face assessment task that has been shown to reliably engage amygdala and associated limbic structures. RESULTS: Anxiety-prone subjects had significantly greater bilateral amygdala and insula activation to emotional faces than did the anxiety-normative comparison subjects. Higher scores on several measures assessing anxiety proneness (e.g., neuroticism, trait anxiety, and anxiety sensitivity) were associated with greater activation of the amygdala (predominantly left-sided) and the anterior insula (bilateral). CONCLUSIONS: Increased amygdala and insula reactivity to certain types of emotional processing is seen in young adults with increased anxiety-related temperamental traits. Therefore, this brain emotion-processing profile may be a functional endophenotype for proneness to (certain kinds of) anxiety disorders. [ABSTRACT FROM AUTHOR]

Noninvasive brain stimulation technologies such as transcranial electrical and magnetic stimulation (tES and TMS) are emerging neuromodulation therapies that are being used to target the neural substrates of substance use disorders. By the end of 2022, 205 trials of tES or TMS in the treatment of substance use disorders had been published, with heterogeneous results, and there is still no consensus on the optimal target brain region. Recent work may help clarify where and how to apply stimulation, owing to expanding databases of neuroimaging studies, new systematic reviews, and improved methods for causal brain mapping. Whereas most previous clinical trials targeted the dorsolateral prefrontal cortex, accumulating data highlight the frontopolar cortex as a promising therapeutic target for transcranial brain stimulation in substance use disorders. This approach is supported by converging multimodal evidence, including lesion-based maps, functional MRI-based maps, tES studies, TMS studies, and dose-response relationships. This review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials., Competing Interests: Dr. Joutsa has received grants from the Finnish Foundation for Alcohol Studies, the Finnish Medical Foundation, the Instrumentarium Research Foundation, the Sigrid Juselius Foundation, Turku University Hospital (VTR funds), and University of Turku, congress travel support from Abbott and AbbVie, and lecturer honoraria from Lundbeck and Novartis, and he has served as consultant for Adamant Health and Summaryx. Dr. Siddiqi has served as a scientific consultant for Magnus Medical and as a clinical consultant for Acacia Mental Health, Boston Precision Neurotherapeutics, and Kaizen Brain Center; he has received investigator-initiated research funding from BrainsWay and Neuronetics; he has served as a speaker for BrainsWay and for PsychU.org (sponsored by Otsuka); he owns intellectual property involving the use of functional connectivity to target TMS; and he owns stock in BrainsWay and Magnus Medical. Dr. Bikson has served as a consultant for, received grants from, served on scientific advisory boards, or has invention assignment agreements with Allergan (AbbVie), Apple, Biovisics, Boston Scientific, Ceragem, GlaxoSmithKline, Google X, Halo Neuroscience, Humm, i-Lumen, Lumenis, Mecta, SafeToddles, and Ybrain; he is an inventor on a patent on brain stimulation held by City University of New York; and he has equity in Soterix Medical. Dr. Paulus has served as an adviser for Hoffmann–La Roche and Spring Care, and he has received royalties from UpToDate. Dr. Fox holds intellectual property on the use of brain connectivity imaging to analyze lesions and guide brain stimulation; he has served as a consultant for Abbott, Boston Scientific, Magnus Medical, and Soterix; and he has received investigator-initiated research funding from Neuronetics. Dr. Hanlon is employed by and has financial interests in BrainsWay. Dr. Ekhtiari has received honoraria from Indivior for speaking at educational events. The other authors report no financial relationships with commercial interests.

Objective: Anorexia nervosa has the highest mortality rate of any psychiatric condition, yet the pathophysiology of this disorder and its primary symptom, extreme dietary restriction, remains poorly understood. In states of hunger relative to satiety, the rewarding value of food stimuli normally increases to promote eating, yet individuals with anorexia nervosa avoid food despite emaciation. This study's aim was to examine potential neural insensitivity to these effects of hunger in anorexia nervosa., Methods: At two scanning sessions scheduled 24 hours apart, one after a 16-hour fast and one after a standardized meal, 26 women who were in remission from anorexia nervosa (to avoid the confounding effects of malnutrition) and 22 matched control women received tastes of sucrose solution or ionic water while functional MRI data were acquired. Within a network of interest responsible for food valuation and transforming taste signals into motivation to eat, the authors compared groups across conditions on blood-oxygen-level-dependent (BOLD) signal and task-based functional connectivity., Results: Participants in the two groups had similar BOLD responses to sucrose and water tastants. A group-by-condition interaction in the ventral caudal putamen indicated that hunger had opposite effects on tastant response in the control group and the remitted anorexia nervosa group, with an increase and a decrease, respectively, in BOLD response when hungry. Hunger had a similar opposite effect on insula-to-ventral caudal putamen functional connectivity in the remitted anorexia nervosa group compared with the control group. Exploratory analyses indicated that lower caudate response to tastants when hungry was associated with higher scores on harm avoidance among participants in the remitted anorexia nervosa group., Conclusions: Reduced recruitment of neural circuitry that translates taste stimulation to motivated eating behavior when hungry may facilitate food avoidance and prolonged periods of extremely restricted food intake in anorexia nervosa.

Objective: Although lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes., Method: Brain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings., Results: Lower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects., Conclusions: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.

Objective: Underage drinking is widely recognized as a leading public health and social problem for adolescents in the United States. Being able to identify at-risk adolescents before they initiate heavy alcohol use could have important clinical and public health implications; however, few investigations have explored individual-level precursors of adolescent substance use. This prospective investigation used machine learning with demographic, neurocognitive, and neuroimaging data in substance-naive adolescents to identify predictors of alcohol use initiation by age 18., Method: Participants (N=137) were healthy substance-naive adolescents (ages 12-14) who underwent neuropsychological testing and structural and functional magnetic resonance imaging (sMRI and fMRI), and then were followed annually. By age 18, 70 youths (51%) initiated moderate to heavy alcohol use, and 67 remained nonusers. Random forest classification models identified the most important predictors of alcohol use from a large set of demographic, neuropsychological, sMRI, and fMRI variables., Results: Random forest models identified 34 predictors contributing to alcohol use by age 18, including several demographic and behavioral factors (being male, higher socioeconomic status, early dating, more externalizing behaviors, positive alcohol expectancies), worse executive functioning, and thinner cortices and less brain activation in diffusely distributed regions of the brain., Conclusions: Incorporating a mix of demographic, behavioral, neuropsychological, and neuroimaging data may be the best strategy for identifying youths at risk for initiating alcohol use during adolescence. The identified risk factors will be useful for alcohol prevention efforts and in research to address brain mechanisms that may contribute to early drinking.

Objective: Military deployment can have profound effects on physical and mental health. Few studies have examined whether interventions prior to deployment can improve mechanisms underlying resilience. Mindfulness-based techniques have been shown to aid recovery from stress and may affect brain-behavior relationships prior to deployment. The authors examined the effect of mindfulness training on resilience mechanisms in active-duty Marines preparing for deployment., Method: Eight Marine infantry platoons (N=281) were randomly selected. Four platoons were assigned to receive mindfulness training (N=147) and four were assigned to a training-as-usual control condition (N=134). Platoons were assessed at baseline, 8 weeks after baseline, and during and after a stressful combat training session approximately 9 weeks after baseline. The mindfulness training condition was delivered in the form of 8 weeks of Mindfulness-Based Mind Fitness Training (MMFT), a program comprising 20 hours of classroom instruction plus daily homework exercises. MMFT emphasizes interoceptive awareness, attentional control, and tolerance of present-moment experiences. The main outcome measures were heart rate, breathing rate, plasma neuropeptide Y concentration, score on the Response to Stressful Experiences Scale, and brain activation as measured by functional MRI., Results: Marines who received MMFT showed greater reactivity (heart rate [d=0.43]) and enhanced recovery (heart rate [d=0.67], breathing rate [d=0.93]) after stressful training; lower plasma neuropeptide Y concentration after stressful training (d=0.38); and attenuated blood-oxygen-level-dependent signal in the right insula and anterior cingulate., Conclusions: The results show that mechanisms related to stress recovery can be modified in healthy individuals prior to stress exposure, with important implications for evidence-based mental health research and treatment.

Objective: Recent studies suggest that altered function of higher-order appetitive neural circuitry may contribute to restricted eating in anorexia nervosa and overeating in bulimia nervosa. This study used sweet tastes to interrogate gustatory neurocircuitry involving the anterior insula and related regions that modulate sensory-interoceptive-reward signals in response to palatable foods., Method: Participants who had recovered from anorexia nervosa and bulimia nervosa were studied to avoid confounding effects of altered nutritional state. Functional MRI measured brain response to repeated tastes of sucrose and sucralose to disentangle neural processing of caloric and noncaloric sweet tastes. Whole-brain functional analysis was constrained to anatomical regions of interest., Results: Relative to matched comparison women (N=14), women recovered from anorexia nervosa (N=14) had significantly diminished and women recovered from bulimia nervosa (N=14) had significantly elevated hemodynamic response to tastes of sucrose in the right anterior insula. Anterior insula response to sucrose compared with sucralose was exaggerated in the recovered group (lower in women recovered from anorexia nervosa and higher in women recovered from bulimia nervosa)., Conclusions: The anterior insula integrates sensory reward aspects of taste in the service of nutritional homeostasis. One possibility is that restricted eating and weight loss occur in anorexia nervosa because of a failure to accurately recognize hunger signals, whereas overeating in bulimia nervosa could represent an exaggerated perception of hunger signals. This response may reflect the altered calibration of signals related to sweet taste and the caloric content of food and may offer a pathway to novel and more effective treatments.

Objective: The authors' goal was to evaluate the association between impairment in daily function and subsyndromal depressive symptoms as well as major depression to determine the economic and societal significance of these conditions., Method: Using 12-month prevalence data gathered by the National Institute of Mental Health (NIMH) Epidemiologic Catchment Area Program (ECA), based on responses to the NIMH Diagnostic Interview Schedule, the authors divided the 2,393 subjects from the Los Angeles ECA site into three groups: subjects with subsyndromal depressive symptoms (N = 270), major depression (N = 102), and no depressive disorder or symptoms (N = 2,021). The groups were compared on 10 domains of functional outcome and well-being., Results: Significantly more subjects with depressive symptoms than subjects who had no disorder reported high levels of household strain, social irritability, and financial strain as well as limitations in physical or job functioning, restricted activity days, bed days, and poor health status. Significantly more subjects with major depression than subjects with no disorder reported major financial losses, bed days, high levels of financial strain, limitations in physical or job functioning, and poor health status. Except for lower self-ratings of health status, no significant differences were found between subjects with subsyndromal symptoms and those with major depression., Conclusions: Significantly more people with subsyndromal depressive symptoms or major depression reported impairment in eight of 10 functional domains than did subjects with no disorder. The high 1-year prevalence of subsyndromal depressive symptoms, combined with the associated functional impairment, emphasizes the clinical and public health importance and need for additional investigations into these symptoms.

Objective: This study aimed to quantify the complexity of behavioral sequences of patients with schizophrenia and comparison subjects by using methods from nonlinear dynamical systems theory., Method: A simple choice task consisting of predicting 500 random right or left appearances of a stimulus was used to obtain binary response sequences in 22 patients with schizophrenia and 16 comparison subjects. Dynamical entropy was measured and the fluctuation spectrum of local subsequence entropies calculated to quantify the degree of interdependency between consecutive responses of patients and comparison subjects., Results: The response sequences generated by the schizophrenic patients exhibited a higher degree of interdependency than those of comparison subjects. Moreover, schizophrenic patients exhibited significantly less consistency in their response selection and ordering, characterized by a greater contribution of both highly perseverative and highly unpredictable subsequences of responses within a test session., Conclusions: The result of the biological abnormality underlying schizophrenia may not be a simple increase or decrease of neuropsychological or neurobiological functions. Instead, the observed abnormalities in behavioral patterns reflect a quantifiable dysregulation and disorganization of these functions.