A randomised controlled feasibility trial of intermittent theta burst stimulation with an open longer-term follow-up for young people with persistent anorexia nervosa (RaISE): Study protocol.

OBJECTIVE: We present the protocol of a feasibility randomised controlled trial (RCT) of intermittent theta burst stimulation (iTBS) for young people with anorexia nervosa (AN). Effective first-line psychological therapies exist for young people with AN, but little is known about how to treat those who do not respond. Non-invasive neuromodulation, such as iTBS, could address unmet treatment needs by targeting neurocircuitry associated with the development and/or maintenance of AN. DESIGN: Sixty-six young people (aged 13-30 years) with persistent AN will be randomly allocated to receive 20 sessions of real or sham iTBS over the left dorsolateral prefrontal cortex in addition to their usual treatment. Outcomes will be measured at baseline, post-treatment (1-month post-randomisation) and 4-months post-randomisation (when unblinding will occur). Additional open follow-ups will be conducted at 12- and 24-months post-randomisation. The primary feasibility outcome is the proportion of participants retained in the study at 4-months. Secondary outcomes include AN symptomatology, other psychopathology, quality of life, service utilisation, neurocognitive processes, and neuroimaging measures. DISCUSSION: Findings will inform the development of a future large-scale RCT. They will also provide exploratory data on treatment efficacy, and neural and neurocognitive predictors and correlates of treatment response to iTBS in AN.

A randomised controlled feasibility study of food-related computerised attention training versus mindfulness training and waiting-list control for adults with overweight or obesity: the FOCUS study.

BACKGROUND: In a feasibility randomised controlled trial in people with overweight/obesity with and without binge eating disorder (BED) symptoms, we assessed eight weekly sessions of attention bias modification training (ABMT) and mindfulness training (MT) versus waiting list (WL) and explored potential mechanisms. METHODS: 45 participants were randomly allocated to one of three trial arms. Primary outcomes were recruitment, retention and treatment adherence rates. Secondary outcomes included measures of eating behaviour, mood, attention and treatment acceptability. Assessments were conducted at baseline, post-intervention (week 8), and follow-up (week 12). RESULTS: Participant retention at follow-up was 84.5% across groups. Session completion rates in the laboratory were 87% for ABMT and 94% for MT, but home practice was much poorer for ABMT. Changes in BMI and body composition were small between groups and there was a medium size BMI reduction in the MT group at follow-up. Effect sizes of eating disorder symptom changes were not greater for either intervention group compared to WL, but favoured ABMT compared to MT. Hedonic hunger and mindful eating scores favoured MT compared to ABMT and WL. ABMT reduced attention biases towards high-calorie food cues, which correlated with lower objective binge eating days at post-intervention. No significant changes were observed in the MT, or WL conditions. CONCLUSIONS: Both ABMT and MT have potential value as adjuncts in the treatment of obesity and BED, and a larger clinical trial appears feasible and indicated. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN15745838. Registered on 22 May 2018.

In this small research study, people who were classified as overweight or living with obesity (with or without symptoms of binge eating disorder) received either a mindfulness intervention, a "subconscious" attention-based intervention called attention bias modification training (ABMT) or were put on a waiting list for 8 weeks. People in the mindfulness group experienced improvements in emotional eating, mindful eating, and "impulsive" eating. Those who received the attention-based training paid less attention to highly caloric food after the intervention which correlated with fewer binge eating episodes. Results from this study suggest that both types of interventions have potential as add-on treatments for obesity and binge eating disorder, but larger studies are necessary to assess their clinical impact.

Effects of transcranial direct current stimulation in children and young people with psychiatric disorders: a systematic review.

Transcranial direct current stimulation (tDCS) has demonstrated benefits in adults with various psychiatric disorders, but its clinical utility in children and young people (CYP) remains unclear. This PRISMA systematic review used published and ongoing studies to examine the effects of tDCS on disorder-specific symptoms, mood and neurocognition in CYP with psychiatric disorders. We searched Medline via PubMed, Embase, PsychINFO via OVID, and Clinicaltrials.gov up to December 2022. Eligible studies involved multiple session (i.e., treatment) tDCS in CYP (≤ 25 years old) with psychiatric disorders. Two independent raters assessed the eligibility of studies and extracted data using a custom-built form. Of 33 eligible studies (participant N = 517), the majority (n = 27) reported an improvement in at least one outcome measure of disorder-specific symptoms. Few studies (n = 13) examined tDCS effects on mood and/or neurocognition, but findings were mainly positive. Overall, tDCS was well tolerated with minimal side effects. Of 11 eligible ongoing studies, many are sham-controlled RCTs (n = 9) with better blinding techniques and a larger estimated participant enrolment (M = 79.7; range 15-172) than published studies. Although encouraging, the evidence to date is insufficient to firmly conclude that tDCS can improve clinical symptoms, mood, or cognition in CYP with psychiatric disorders. Ongoing studies appear of improved methodological quality; however, future studies should broaden outcome measures to more comprehensively assess the effects of tDCS and develop dosage guidance (i.e., treatment regimens).

EDIFY (Eating Disorders: Delineating Illness and Recovery Trajectories to Inform Personalised Prevention and Early Intervention in Young People): project outline.

EDIFY (Eating Disorders: Delineating Illness and Recovery Trajectories to Inform Personalised Prevention and Early Intervention in Young People) is an ambitious research project aiming to revolutionise how eating disorders are perceived, prevented and treated. Six integrated workstreams will address key questions, including: What are young people's experiences of eating disorders and recovery? What are the unique and shared risk factors in different groups? What helps or hinders recovery? How do the brain and behaviour change from early- to later-stage illness? How can we intervene earlier, quicker and in a more personalised way? This 4-year project, involving over 1000 participants, integrates arts, design and humanities with advanced neurobiological, psychosocial and bioinformatics approaches. Young people with lived experience of eating disorders are at the heart of EDIFY, serving as advisors and co-producers throughout. Ultimately, this work will expand public and professional perceptions of eating disorders, uplift under-represented voices and stimulate much-needed advances in policy and practice.

Associations between bone mineral density, body composition and amenorrhoea in females with eating disorders: a systematic review and meta-analysis.

BACKGROUND: Lower bone mineral density (BMD) increases the risk of osteoporosis in individuals with eating disorders (EDs), particularly women with anorexia nervosa (AN), making them susceptible to pain and fractures throughout adulthood. In AN, low weight, hypothalamic amenorrhoea, and longer illness duration are established risk factors for low BMD, and in people with other EDs a history of AN seems to be an important risk factor for low BMD. PURPOSE: To conduct a systematic review and meta-analysis of BMD in individuals with EDs, including AN, bulimia nervosa (BN), binge-eating disorder (BED) and other specified feeding or eating disorders (OSFED) compared to healthy controls (HC). METHODS: Following PRISMA guidelines, electronic databases were reviewed and supplemented with a literature search until 2/2022 of publications measuring BMD (dual-energy X-ray absorptiometry or dual photon absorptiometry) in females with any current ED diagnosis and a HC group. Primary outcomes were spine, hip, femur and total body BMD. Explanatory variables were fat mass, lean mass and ED clinical characteristics (age, illness duration, body mass index (BMI), amenorrhoea occurrence and duration, and oral contraceptives use). RESULTS: Forty-three studies were identified (N = 4163 women, mean age 23.4 years, min: 14.0, max: 37.4). No study with individuals with BED met the inclusion criteria. BMD in individuals with AN (total body, spine, hip, and femur), with BN (total body and spine) and with OSFED (spine) was lower than in HC. Meta-regression analyses of women with any ED (AN, BN or OSFED) (N = 2058) showed low BMI, low fat mass, low lean mass and being amenorrhoeic significantly associated with lower total body and spine BMD. In AN, only low fat mass was significantly associated with low total body BMD. CONCLUSION: Predictors of low BMD were low BMI, low fat mass, low lean mass and amenorrhoea, but not age or illness duration. In people with EDs, body composition measurement and menstrual status, in addition to BMI, are likely to provide a more accurate assessment of individual risk to low BMD and osteoporosis.

Individuals with eating disorders (EDs) have an increased risk for developing osteoporosis and suffering fractures. To better understand this problem, we conducted a systematic review and meta-analysis comparing bone mineral density (BMD) of females with EDs with that of healthy people without an ED. We also tried to identify key factors linked with reduced bone mass in EDs. We included studies reporting BMD of individuals with anorexia nervosa (AN), bulimia nervosa (BN), binge-eating (BED) or other non-specified ED (OSFED), and of healthy controls. We found that people with AN had overall lower BMD than controls and also in the spine, hip, and femur. In people with BN, there was lower BMD overall and in the spine, but that must be only in those who previously had AN. In people with OSFED, BMD was lower in the spine. Having a low BMI, low fat mass, low lean mass and not having menstrual periods seem to negatively affect BMD. Therefore, this systematic review supports the idea that people with current or past AN, irrespective of their current ED diagnosis, should have their bone health assessed. For early identification of those most at risk, body composition measurements, current menstrual status, duration of amenorrhoea and presence or absence of a history of AN should be considered in clinical practice.

Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa: A Coordinated Analysis by the ENIGMA Eating Disorders Working Group.

BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.

'My dad was like "it's your brain, what are you doing?"': Participant experiences of repetitive transcranial magnetic stimulation treatment in severe enduring anorexia nervosa.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a promising emerging treatment for anorexia nervosa (AN). However, to date, patients' views and experiences of this treatment have not been fully explored. To assess these, we integrated a qualitative study into a feasibility randomised controlled trial of rTMS in individuals with severe enduring AN. METHOD: Twenty-nine (of 34) trial participants contributed to this study. Semi-structured interviews were conducted 3-months following the completion of rTMS treatment (4-months post-randomisation), prior to unblinding. Transcripts were analysed using content analysis. RESULTS: rTMS was deemed an acceptable but time-consuming treatment. Many emphasised how their lives had changed to some extent during, but mainly after treatment by making them more positive, open-minded, flexible and willing to try new things in relation to their AN and other aspects of their lives. CONCLUSIONS: These qualitative data will be valuable in shaping participant information, recruitment and planning of future large-scale trials of rTMS in AN. TRIAL REGISTRATION: ISRCTN14329415, registered 23rd July 2015, https://www.isrctn.com/ISRCTN14329415.

Participant Experiences of Transcranial Direct Current Stimulation (tDCS) as a Treatment for Antipsychotic Medication Induced Weight Gain.

Background: Despite the growing number of studies on the use of non-invasive brain stimulation in people with schizophrenia, there is limited research on participant views of such treatment methods. Aim: Explore participant experiences and perceptions of transcranial direct current stimulation (tDCS). Methods: Twelve people with schizophrenia took part in semi-structured interviews after having completed 5 sessions of tDCS. Thematic analysis was used to identify codes and themes. Results: Five themes were identified: (1) motivation for study enrolment; (2) concerns about tDCS; (3) factors reducing the fear of tDCS; (4) experience of tDCS; (5) perceived effects of tDCS. Conclusions: The study provides insight into the perceptions and experiences of each individual. Participants were concerned about the safety of tDCS and associated it with invasive procedures such as electroconvulsive therapy and lobotomy. Educational materials and a good relationship with the researcher played an important role in reducing the fear of brain stimulation. All participants described tDCS as uncomfortable, however, agreed that unpleasant sensations only lasted for a short while (20 s-5 min). After the first session, participants no longer felt anxious about the remaining ones. Strategies to improve treatment experience and study recruitment have been identified.

A pilot study exploring the effect of repetitive transcranial magnetic stimulation (rTMS) treatment on cerebral blood flow and its relation to clinical outcomes in severe enduring anorexia nervosa.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment option for people with severe enduring anorexia nervosa (SE-AN), but associated neurobiological changes are poorly understood. This study investigated the effect of rTMS treatment on regional cerebral blood flow (CBF) and whether any observed changes in CBF are associated with changes in clinical outcomes in people with SE-AN. METHODS: As part of a randomised sham-controlled feasibility trial of 20 sessions of high-frequency rTMS to the left dorsolateral prefrontal cortex, 26 of 34 trial participants completed arterial spin labelling (ASL) functional magnetic resonance imaging (fMRI) to quantify regional and global resting state CBF before (pre-randomisation baseline) and after real or sham treatment (1-month post-randomisation). A group of healthy females (n = 30) were recruited for baseline comparison. Clinical outcomes, including BMI, and depression and anxiety symptoms, were assessed at baseline, 1-, 4-, and 18-months post-randomisation. RESULTS: No group differences in regional CBF were identified between the SE-AN and healthy comparison participants. A significant treatment-by-time interaction in a medial temporal lobe cluster with the maximal peak in the right amygdala was identified, reflecting a greater reduction in amygdala CBF following real rTMS compared to sham. Participants with the greatest rTMS-related reduction in amygdala CBF (i.e., between baseline and 1-month post-randomisation) showed the greatest sustained weight gain at 18-months post-randomisation. Higher baseline CBF in the insula predicted greater weight gain between baseline and 1-month post-randomisation and between baseline and 4-months post-randomisation. CONCLUSIONS: This exploratory pilot study identified rTMS treatment related changes in CBF in adults with SE-AN and these were associated with changes in weight. Our preliminary findings also suggest that CBF (as measured by ASL fMRI) may be a marker of rTMS treatment response in this patient group. Future rTMS studies in AN should employ longitudinal neuroimaging to further explore the neurobiological changes related to rTMS treatment. TRIAL REGISTRATION: ISRCTN14329415 , registered 23rd July 2015.

Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment option for people with severe enduring anorexia nervosa (SE-AN). However, little is known about the neurobiological effects of this treatment. This study explored the effect of rTMS treatment on regional cerebral blood flow (CBF) and whether any observed changes in CBF are associated with changes in clinical outcomes in people with SE-AN. Participants completed arterial spin labelling (ASL) functional magnetic resonance imaging (fMRI) before and after receiving 20 sessions (over 4 weeks) of real or sham rTMS. We found a greater reduction in amygdala CBF following real rTMS compared to sham rTMS. Participants with the greatest rTMS-related reduction in amygdala CBF showed the greatest sustained weight gain at an 18-month follow-up. Higher baseline CBF in the insula predicted greater weight gain during treatment and at a 4-month follow-up. This suggests that CBF (as measured by ASL fMRI) may be a marker of rTMS treatment response in this patient group. Future rTMS studies in AN should use longitudinal neuroimaging to further explore the neurobiological changes related to rTMS treatment.

The outcomes of mindfulness-based interventions for Obesity and Binge Eating Disorder: A meta-analysis of randomised controlled trials.

BACKGROUND: Mindfulness Based Interventions (MBIs) for weight loss and overeating-related behaviours have recently gained popularity. Previous systematic reviews and meta-analyses included studies of variable quality, which hinders interpretation of results. This meta-analysis examined only randomised controlled trials (RCTs) comparing the efficacy of MBIs with control groups primarily encouraging either dietary or exercise-based behavioural change in individuals with overweight/obesity and/or binge eating disorder (BED). METHODS: Using PRISMA guidelines, we systematically reviewed relevant articles in Medline, Psychinfo and EMBASE. Twelve eligible RCTs were identified, with three random-effects meta-analyses conducted on primary outcome measures of body mass (N = 11), mindfulness (N = 7) and BED symptoms (N = 3). RESULTS: MBIs were more efficacious than control in increasing mindfulness scores and decreasing BED symptoms from pre-to post-treatment. However, they were no more efficacious than control in reducing body mass which may be attributed to variability in the duration of interventions. Based on intervention duration, exploratory cumulative meta-analyses revealed that while shorter interventions (i.e., 6 weeks) showed greater reductions in body mass compared to longer interventions (i.e., 24 weeks), longer interventions led to greater improvements in mindfulness scores and BED symptoms. CONCLUSIONS: These results highlight the potential of MBIs to improve obesity-related behaviours compared to lifestyle interventions, but their effects on short-term weight loss remain unclear. Future research with a rigorous methodology should consider long-term follow-ups including body mass and mindfulness-related outcome measures in order to establish the clinical potential of MBIs.

Cytokines and Water Distribution in Anorexia Nervosa.

In patients with anorexia nervosa (AN), decreased intracellular (ICW), extracellular (ECW), and total body water (TBW) as well as changes in serum cytokine concentrations have been reported. In this exploratory study, we measured body composition and serum cytokine levels in patients with AN (n = 27) and healthy controls (HCs; n = 13). Eating disorder symptom severity was assessed using the Eating Disorder Examination-Questionnaire (EDE-Q). Body composition was determined by bioimpedance analysis (BIA) which provided information on ICW, ECW, and TBW. Following blood collection, 27 cytokines and chemokines were quantified using multiplex ELISA-based technology: Eotaxin, Eotaxin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon- (IFN-) γ, interleukin- (IL-) 1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-12p70, IL-13, IL-15, IL-16, IL-17A, interferon γ-induced protein- (IP-) 10, macrophage inflammatory protein- (MIP-) 1α, MIP-1ß, monocyte chemoattractant protein- (MCP-) 1, MCP-4, thymus and activation-regulated chemokine (TARC), TNF-α, and TNF-ß. ICW, ECW, and TBW volumes were significantly lower in patients with AN than in HCs. In the whole sample, GM-CSF, MCP-4, and IL-4 were positively, whereas IFN-γ, IL-6, and IL-10 were negatively associated with all three parameters of body water. In AN participants, we found a statistically significant negative correlation of IL-10 with ICW, ECW, and TBW. Our results suggest an interaction between body water and the cytokine system. Underlying mechanisms are unclear but may involve a loss of water from the gut, kidneys, or skin due to AN-associated inflammatory processes.

Effects of non-invasive brain stimulation in children and young people with psychiatric disorders: a protocol for a systematic review.

BACKGROUND: Most psychiatric disorders have their onset in childhood or adolescence, and if not fully treated have the potential for causing life-long psycho-social and physical sequelae. Effective psychotherapeutic and medication treatments exist, but a significant proportion of children and young people do not make a full recovery. Thus, novel, safe, brain-based alternatives or adjuncts to conventional treatments are needed. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive brain stimulation (NIBS) techniques which have shown clinical benefits in adult psychiatric conditions. However, in children and young people their efficacy is not well established. The objective of this study will be to systematically evaluate the evidence on clinical effects of NIBS in children and young people with psychiatric disorders, assessing disorder-specific symptoms, mood and neurocognitive functions. METHODS: We designed and registered a study protocol for a systematic review. We will include randomised and non-randomised controlled trials and observational studies (e.g. cohort, case-control, case series) assessing the effects of NIBS in children and young people (aged ≤ 24 years old) for psychiatric disorders. The primary outcome will be reduction of disorder-specific symptoms. Secondary outcomes will include effects on mood and cognition. A comprehensive search from database inception onwards will be conducted in MEDLINE, EMBASE and PsycINFO. Grey literature will be identified through searching multiple clinical trial registries. Two reviewers will independently screen all citations, full-text articles and abstract data. The methodological quality of the studies will be appraised using appropriate tools. We will provide a narrative synthesis of the evidence and according to heterogeneity will conduct an appropriate meta-analysis. Additional analyses will be conducted to explore the potential sources of heterogeneity. DISCUSSION: This systematic review will provide a broad and comprehensive evaluation of the evidence on clinical effects of NIBS in children and young people with psychiatric disorders. Our findings will be reported according to the PRISMA guidelines and will be of interest to multiple audiences (including patients, researchers, healthcare professionals and policy-makers). Results will be published in a peer-reviewed journal. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019158957.

A preliminary exploration of the effect of concurrent antidepressant medication on responses to high-frequency repetitive transcranial magnetic stimulation (rTMS) in severe, enduring anorexia nervosa.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment option for people with severe, enduring anorexia nervosa (SE-AN). As depression is often comorbid with AN, antidepressant medication is commonly prescribed to this patient group. Concurrent antidepressant medications may affect the rTMS treatment response. Therefore, in a secondary analysis of data from a feasibility trial, we explored the effect of antidepressant medication on responses to rTMS in people with SE-AN. METHODS: Twenty-six participants with SE-AN received 20 sessions (over 4 weeks) of neuronavigated high-frequency real rTMS to the left dorsolateral prefrontal cortex. Eating disorder (ED) and general psychopathology symptoms were assessed at baseline, post-treatment and at a 4-month follow-up. RESULTS: Participants taking antidepressants (n = 16) for the duration of the rTMS treatment had a greater reduction in ED symptoms at the 4-month follow-up, compared to those not taking antidepressants (n = 10). Antidepressant status was not however associated with significant changes in mood outcomes. CONCLUSIONS: In people with SE-AN receiving rTMS treatment, preliminary findings suggest a potential synergistic effect of antidepressant medication in reducing ED symptomatology. There was however no associated reduction in affective symptoms i.e., the effect does not seem to be related to changes in mood. The sample in this exploratory study was small and heterogenous. However, the preliminary results provide a basis for hypothesis generation for future studies.

Clinicians' views on neuromodulation as a treatment for eating disorders: A qualitative study.

BACKGROUND: Neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS), are emerging as promising treatment options in eating disorders (EDs). To date, the views of ED clinicians regarding these interventions have not been explored. METHODS: Eighteen clinicians were recruited from a specialist ED Service in London, UK. Following a short educational presentation on rTMS, tDCS and DBS, they completed a semi-structured interview to explore their views on the use of these treatment options in EDs. RESULTS: Clinician knowledge of neuromodulation techniques was low. They raised safety and ethical (particularly capacity to consent) concerns mainly with regard to DBS. Neuromodulation treatments were considered most appropriate as an adjunct to psychotherapy and for patients with severe, enduring illness (who had completed previous psychological treatments). CONCLUSIONS: Improving clinicians' knowledge and understanding of neuromodulation is fundamental for bridging the gap between research and clinical work. This is especially so given the predominance of psychological theory and practice in the treatment of EDs.

Repetitive transcranial magnetic stimulation treatment in severe, enduring anorexia nervosa: An open longer-term follow-up.

OBJECTIVE: This study assessed longer-term outcomes from a randomised controlled feasibility trial of 20 sessions of real versus sham high-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex in adults with severe, enduring anorexia nervosa (SE-AN). METHODS: Thirty participants who completed the original study protocol were invited to take part in an open follow-up (18-months post-randomisation), assessing body mass index (BMI), eating disorder (ED) symptoms and other psychopathology. RESULTS: Twenty-four participants (12 each originally allocated to real/sham) completed the 18-month follow-up. Ten of 12 participants who originally received sham treatment had real rTMS at some stage during the follow-up. A medium between-group effect size was seen for BMI change from baseline to 18-months, favouring those originally allocated to real rTMS. In this group at 18-months, five participants were weight recovered (BMI ≥18.5 kg/m2 ), compared with one participant in the original sham group. Both groups showed further improvement in ED symptoms during the follow-up. Effects on mood were largely maintained at follow-up, with catch-up effects in the original sham group. CONCLUSIONS: Findings suggest that rTMS treatment effects on mood are durable and that BMI and ED symptom improvements need time to emerge. Large-scale trials are needed.

Exposure to food in anorexia nervosa and brain correlates of food-related anxiety: findings from a pilot study.

BACKGROUND: Although the primary target of treatment for anorexia nervosa (AN) is weight gain, established psychological interventions focus on maintaining factors of AN, and do not specifically address eating behaviours. We have previously reported results of a case series investigating in-vivo food exposure in AN, demonstrating the feasibility and acceptability of this treatment together with evidence of significant clinical change (Cardi, Leppanen, Mataix-Cols, Campbell, & Treasure, 2019). The current study examined the neural circuitry of food-related anxiety. METHODS: We examined neural reactivity (fMRI) to food images pre- and post-food exposure therapy (n=16), and compared it to a group of healthy control participants (HC n=21) who were scanned on two occasions. RESULTS: Prior to treatment, the AN group (compared to HC) showed less reactivity in the anterior cingulate cortex (ACC). Following exposure treatment, patients (compared to HC), show increased activity in the dorsolateral prefrontal cortex, decreased activity in the superior parietal lobe and no differences in the ACC. The level of activation of the insula (pre-treatment) predicted the degree of post-treatment reduction in self-reported food anxiety in AN. Changes in food-related anxiety were also associated with changes in neural activation in a cluster located in the middle temporal gyrus/lateral parietal cortex. LIMITATIONS: The primary limitations of this work are the small sample size and lack of patient comparison group. CONCLUSIONS: Exposure to food in AN may be associated with changes in neural circuitries implicated in emotion regulation and attentional processes. However, these findings need replication in larger and controlled studies.

Brain white matter microstructure in obese women with binge eating disorder.

OBJECTIVE: Research on potential brain circuit abnormalities in binge eating disorder (BED) is limited. Here, we assess white matter (WM) microstructure in obese women with BED. METHOD: Diffusion tensor imaging data were acquired, and tract-based spatial statistics used to examine WM in women with BED who were obese (n = 17) compared to normal-weight (NWC) (n = 17) and to women who were obese (OBC) (n = 13). Body mass index (BMI) was a covariate in the analyses. RESULTS: The BED group (vs. NWC) had greater axial diffusion (AD) in the forceps minor, anterior thalamic radiation, superior and inferior longitudinal fasciculus, that is, in pathways connecting fronto-limbic regions. Microstructures differences in AD between the BED and OBC groups were seen in fronto-limbic pathways extending to temporoparietal pathways. The BED (vs. OBC) group had greater fractional anisotropy in the forceps minor and greater AD in the superior longitudinal fasciculus, cingulate gyrus, and corpus callosum, consistent with fronto-tempoparietal pathways. CONCLUSION: Women with BED show WM alterations in AD in fronto-limbic and parietal pathways that are important in decision-making processes. As BMI was a covariate in the analyses, alterations in BED may be part of the pathology, but whether they are a cause or effect of illness is unclear.

Reported and Recorded Sleepiness in Obesity and Depression.

BACKGROUND: Obesity and depression are both associated with changes in sleep/wake regulation, with potential implications for individualized treatment especially in comorbid individuals suffering from both. However, the associations between obesity, depression, and subjective, questionnaire-based and objective, EEG-based measurements of sleepiness used to assess disturbed sleep/wake regulation in clinical practice are not well known. OBJECTIVES: The study investigates associations between sleep/wake regulation measures based on self-reported subjective questionnaires and EEG-derived measurements of sleep/wake regulation patterns with depression and obesity and how/whether depression and/or obesity affect associations between such self-reported subjective questionnaires and EEG-derived measurements. METHODS: Healthy controls (HC, NHC = 66), normal-weighted depressed (DEP, NDEP = 16), non-depressed obese (OB, NOB = 68), and obese depressed patients (OBDEP, NOBDEP = 43) were included from the OBDEP (Obesity and Depression, University Leipzig, Germany) study. All subjects completed standardized questionnaires related to daytime sleepiness (ESS), sleep quality and sleep duration once as well as questionnaires related to situational sleepiness (KSS, SSS, VAS) before and after a 20 min resting state EEG in eyes-closed condition. EEG-based measurements of objective sleepiness were extracted by the VIGALL algorithm. Associations of subjective sleepiness with objective sleepiness and moderating effects of obesity, depression, and additional confounders were investigated by correlation analyses and regression analyses. RESULTS: Depressed and non-depressed subgroups differed significantly in most subjective sleepiness measures, while obese and non-obese subgroups only differed significantly in few. Objective sleepiness measures did not differ significantly between the subgroups. Moderating effects of obesity and/or depression on the associations between subjective and objective measures of sleepiness were rarely significant, but associations between subjective and objective measures of sleepiness in the depressed subgroup were systematically weaker when patients comorbidly suffered from obesity than when they did not. CONCLUSION: This study provides some evidence that both depression and obesity can affect the association between objective and subjective sleepiness. If confirmed, this insight may have implications for individualized diagnosis and treatment approaches in comorbid depression and obesity.

The effect of repetitive transcranial magnetic stimulation on food choice-related self-control in patients with severe, enduring anorexia nervosa.

OBJECTIVE: Individuals with anorexia nervosa (AN) pursue low-fat, low-calorie diets even when in a state of emaciation. These maladaptive food choices may involve fronto-limbic circuitry associated with cognitive control, habit, and reward. We assessed whether high-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (DLPFC) influenced food-related choice behavior in patients with severe, enduring (SE)-AN. METHOD: Thirty-four females with SE-AN completed a Food Choice Task before and after 20 sessions of real or sham rTMS treatment and at a 4-month follow-up. During the task, participants rated high- and low-fat food items for healthiness and tastiness and then made a series of choices between a neutral-rated food and high- and low-fat foods. Outcomes included the proportion of high-fat and self-controlled choices made. A comparison group of 30 healthy women completed the task at baseline only. RESULTS: Baseline data were consistent with previous findings: relative to healthy controls, SE-AN participants showed a preference for low-fat foods and exercised self-control on a greater proportion of trials. There was no significant effect of rTMS treatment nor time on food choices related to fat content. However, among SE-AN participants who received real rTMS, there was a decrease in self-controlled food choices at post-treatment, relative to baseline. Specifically, there was an increase in the selection of tasty-unhealthy foods. DISCUSSION: In SE-AN, rTMS may promote more flexibility in relation to food choice. This may result from neuroplastic changes in the DLPFC and/or in associated brain areas.

Effects of Transcranial Direct Current Stimulation (tDCS) and Approach Bias Modification (ABM) training on food cravings in people taking antipsychotic medication.

BACKGROUND: Antipsychotic drug-induced weight gain puts individuals with schizophrenia at increased cardiometabolic risk. As a potential intervention for this problem, we describe the theoretical background and a protocol for a feasibility randomised controlled trial (RCT) of approach bias modification (ABM) training combined with real versus sham (placebo) transcranial direct current stimulation (tDCS). The primary aim of this trial is to obtain information that will guide decision making and protocol development in relation to a future large-scale RCT of ABM and tDCS in this group of participants. Second, the study will assess the preliminary efficacy of ABM + tDCS in reducing food cravings in people who take antipsychotic medication. METHODS: Thirty adults with a DSM-V diagnosis of schizophrenia or schizoaffective disorder treated with anti-psychotic medication will be randomly allocated to receive five sessions that will combine ABM and real or sham tDCS, in a parallel group design. In this feasibility study, a broad range of outcome variables will be examined. Measures will include food craving, psychopathology (e.g. symptoms of schizophrenia and depression), neuropsychological processes (such as attentional bias and impulsiveness), and the tolerability and acceptability of tDCS. The feasibility of conducting a large-scale RCT of ABM + tDCS and appropriateness of tDCS as a treatment for antipsychotic drug-induced weight gain will be evaluated by assessment of recruitment and retention rates, acceptability of random allocation, blinding success (allocation concealment), completion of treatment sessions and research assessments (baseline, post-treatment and follow-up). DISCUSSION: The effect sizes generated and other findings from this trial will inform a future large-scale RCT with respect to decisions on primary outcome measures and other aspects of protocol development. In addition, results from this study will provide a preliminary indication of the efficacy of ABM + tDCS treatment for antipsychotic drug-induced weight gain. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN13280178. Registered on 16 October 2018.