Neuromodulation and Eating Disorders.

PURPOSE OF REVIEW: We review recent evidence on the use of neuromodulation for treating eating disorders (EDs), including anorexia nervosa, bulimia nervosa and binge eating disorder. We evaluate studies on (a) modern non-invasive methods of brain stimulation, such as transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), (b) electroconvulsive therapy (ECT) and (c) more invasive techniques, including deep brain stimulation (DBS). RECENT FINDINGS: Most reports on the clinical applications of neuromodulation in EDs are limited to case studies, case series and small clinical trials. The majority have focused on severe, enduring and hard-to-treat cases of AN. In this population, data suggest that both rTMS and DBS have therapeutic potential and are safe and acceptable. High-quality clinical trials in different ED populations are needed which investigate different stimulation methods, sites and parameters, the use of neuromodulation as stand-alone and/or adjunctive treatment, as well as the mechanisms of action.

The impact of an emotionally expressive writing intervention on eating pathology in female students.

Introduction: Previous research demonstrating emotional influences on eating and weight suggest that emotionally expressive writing may have a significant impact on reducing risk of eating pathology. This study examined the effects of writing about Intensely Positive Experiences on weight and disordered eating during a naturalistic stressor. Method: Seventy-one female students completed an expressive or a control writing task before a period of exams. Both groups were compared on BMI (kg/m2) and the Eating Disorder Examination - Questionnaire (EDE-Q) before the writing task and at 8-week follow-up. A number of secondary analyses were also examined (to identify potential mediators) including measures of attachment, social rank, self-criticism and self-reassurance, stress and mood. Results: There was a significant effect of intervention on changes in the subscales of the EDE-Q (p = .03). Specifically, expressive writers significantly reduced their dietary restraint while those in the control group did not. There was no significant effect of the intervention on changes in BMI or the other subscales of the EDE-Q (Eating, Weight and Shape Concern). There was also no effect of writing on any of the potential mediators in the secondary analyses. Discussion: Emotionally expressive writing may reduce the risk of dietary restraint in women but these findings should be accepted with caution. It is a simple and light touch intervention that has the potential to be widely applied. However, it remains for future research to replicate these results and to identify the mechanisms of action.

Affect systems, changes in body mass index, disordered eating and stress: an 18-month longitudinal study in women.

Background: Evidence suggests that stress plays a role in changes in body weight and disordered eating. The present study examined the effect of mood, affect systems (attachment and social rank) and affect regulatory processes (self-criticism, self-reassurance) on the stress process and how this impacts on changes in weight and disordered eating. Methods: A large sample of women participated in a community-based prospective, longitudinal online study in which measures of body mass index (BMI), disordered eating, perceived stress, attachment, social rank, mood and self-criticism/reassurance were measured at 6-monthly intervals over an 18-month period. Results: Latent Growth Curve Modelling showed that BMI increased over 18 months while stress and disordered eating decreased and that these changes were predicted by high baseline levels of these constructs. Independently of this, however, increases in stress predicted a reduction in BMI which was, itself, predicted by baseline levels of self-hatred and unfavourable social comparison. Conclusions: This study adds support to the evidence that stress is important in weight change. In addition, this is the first study to show in a longitudinal design, that social rank and self-criticism (as opposed to self-reassurance) at times of difficulty predict increases in stress and, thus, suggests a role for these constructs in weight regulation.

Repetitive transcranial magnetic stimulation in anorexia nervosa: a pilot study.

The search for new treatments to improve outcome in people with anorexia nervosa continues. This pilot study investigated whether one session of high frequency repetitive transcranial magnetic stimulation (rTMS) delivered to the left dorsolateral prefrontal cortex reduces eating disorder related symptoms following exposure to visual and real food stimuli. Safety and tolerability were also assessed. Ten right-handed people with anorexia nervosa underwent one session of rTMS. Subjective experiences related to the eating disorder (e.g. urge to restrict, feeling full etc.) were assessed before and after rTMS. Non-parametric repeated measures tests were used. rTMS was safe and well-tolerated, and resulted in reduced levels of feeling full, feeling fat and feeling anxious. Thus, rTMS may reduce core symptoms of anorexia nervosa. Future research should establish the therapeutic potential of rTMS in anorexia nervosa.

Handedness, repetitive transcranial magnetic stimulation and bulimic disorders.

Repetitive Transcranial Magnetic Stimulation (rTMS) research in psychiatry mostly excludes left-handed participants. We recruited left-handed people with a bulimic disorder and found that stimulation of the left prefrontal cortex may result in different effects in left- and right-handed people. This highlights the importance of handedness and cortex lateralisation for rTMS.

Social appearance anxiety and bulimia nervosa.

Social appearance anxiety is an unexplored concept in eating disorders (ED). It refers to social anxiety surrounding overall appearance, including body shape, and fear of negative evaluation by others. It is potentially relevant to those with bulimia nervosa (BN) as both social anxiety and body image disturbance are commonly experienced by patients. Thirty women with BN and forty healthy controls (HC) completed the Social Appearance Anxiety Scale (SAAS), a 16-item self-report questionnaire. ED cognitions and behaviours were assessed with the Eating Disorders Examination-Questionnaire. Women with BN have significantly higher SAAS scores than HC (z=-6.79, p<0.001). In BN, SAAS scores show significant positive correlation with global ED subscales and dietary restraint. In HC, SAAS scores are correlated with shape, weight, eating concern, and global eating disturbance subscales. Preliminary findings suggest the SAAS is potentially useful in future research concerning overall risk factors for eating disturbance and treatment outcome in BN.

Immediate cognitive effects of repetitive Transcranial Magnetic Stimulation in eating disorders: a pilot study.

OBJECTIVE: The aim of this study was to evaluate the effects of high frequency repetitive Transcranial Magnetic Stimulation (rTMS), delivered to the dorsolateral prefrontal cortex, on selective attention in people with a bulimic disorder. METHOD: Participants (N=33) were randomised to a single session of real or sham rTMS. They performed a Stroop colour word task before and after the rTMS intervention. Interference scores were calculated as the time difference between completing cards with congruent and incongruent stimuli. RESULTS: Analysis of covariance comparing the interference scores post-rTMS with the pre-rTMS scores as covariates showed no differences between the real and sham groups [F(1,32)=1.110; p=0.301]. DISCUSSION: While methodological issues warrant a cautious interpretation, these pilot data suggest that selective attention is unaffected by a single session of rTMS.

Neurocognition in bulimic eating disorders: a systematic review.

UNLABELLED: Van den Eynde F, Guillaume S, Broadbent H, Stahl D, Campbell IC, Schmidt U, Tchanturia K. Neurocognition in bulimic eating disorders: a systematic review. OBJECTIVE: The aim of this study was to review the literature on neurocognition comparing people with a bulimic eating disorder in the acute phase of the illness with healthy controls (HC). METHOD: The review follows the PRISMA (preferred reporting items for systematic reviews and meta-analysis) statement guidelines. Three databases (Medline, Web of Science, and Scopus) were searched combining the search terms 'bulimic disorder', 'bulimia nervosa (BN)', 'binge-eating disorder (BED)' with terms referring to cognitive domains (e.g. 'executive functions'). RESULTS: Thirty-seven studies on people with BN and four on people with BED were selected for review. Overall, sample sizes were relatively small [bulimic disorders: median and range 22 (12-83); HC: 27 (13-172)]. The diversity in methodology precluded a meta-analytical approach. People with a bulimic disorder did not present with a clear neurocognitive profile. Inclusion of salient, disorder-related stimuli (e.g. body weight/shape words) in the neurocognitive paradigms tended to generate differences between people with a bulimic disorder and HC. CONCLUSION: Neurocognition in bulimic eating disorders is under researched, and the available evidence is inconclusive. This review outlines strategies for further research in this area.

Repetitive transcranial magnetic stimulation reduces cortisol concentrations in bulimic disorders.

BACKGROUND: In people with bulimic eating disorders, exposure to high-calorie foods can result in increases in food craving, raised subjective stress and salivary cortisol concentrations. This cue-induced food craving can be reduced by repetitive transcranial magnetic stimulation (rTMS). We investigated whether rTMS has a similar effect on salivary cortisol concentrations, a measure of hypothalamic-pituitary-adrenal axis (HPAA) activity. METHOD: We enrolled twenty-two female participants who took part in a double-blind randomized sham-controlled trial on the effects of rTMS on food craving. Per group, eleven participants were randomized to the real or sham rTMS condition. The intervention consisted of one session of high-frequency rTMS delivered to the left dorsolateral prefrontal cortex (DLPFC). Salivary cortisol concentrations were assessed at four time points throughout the 90-min trial. To investigate differences in post-rTMS concentrations between the real and sham rTMS groups, a random-effects model including the pre-rTMS cortisol concentrations as covariates was used. RESULTS: Salivary cortisol concentrations following real rTMS were significantly lower compared with those following sham rTMS. In this sample, there was also a trend for real rTMS to reduce food craving more than sham rTMS. CONCLUSIONS: These results suggest that rTMS applied to the left DLPFC alters HPAA activity in people with a bulimic disorder.

Chromosomal mapping of excessive physical activity in mice in response to a restricted feeding schedule.

Excessive physical activity plays an important role in the progression of anorexia nervosa (AN) by accelerating weight loss during dietary restriction. To search for mechanisms underlying this trait, a panel of mouse chromosome substitution strains derived from C57BL/6J and A/J strains was exposed to a scheduled feeding paradigm and to voluntary running wheel (RW) access. Here, we showed that A/J chromosomes 4, 12 and 13 contribute to the development of a disrupted RW activity in response to daily restricted feeding. This pattern is characterized by intense RW activity during the habitual rest phase and leads to accelerated body weight loss. Regions on mouse chromosomes 4, 12 and 13 display homology with regions on human chromosomes linked with anxiety and obsessionality in AN cohorts. Therefore, our data open new roads for interspecies genetic studies of AN and for unraveling novel mechanisms and potential effective treatment strategies for these neurobehavioral traits.

Multidimensional self reports as a measure of characteristics in people with eating disorders.

This study used multidimensional self report assessments to measure perfectionism, impulsivity and obsessive compulsive characteristics in females with anorexia nervosa (AN), bulimia nervosa (BN) and in matched healthy controls (HC). The Frost Multidimensional Perfectionism Scale (FMPS), Barrett Impulsivity Scale (BIS) and Obsessive Compulsive Inventory-Revised (OCI-R) scale were completed by 107 participants (AN=30, BN=26, HC=51), in parallel with clinical measures. Results show that people with AN have the highest scores on the dimensions of the FMPS as well as on the overall score; the AN and BN groups have the highest scores on the dimensions and on the overall score of the OCI-R; on the BIS, the AN and BN groups have the highest scores on the attention subscale, but there are no group differences on the overall BIS scores. In relation to the FMPS, the global score, and the subscales 'concern over mistakes' and 'doubts about actions' are all highly correlated with both eating pathology (Eating Disorder Examination Questionnaire, EDE-Q) and low global functioning (Structured Clinical Interview for DSM IV, SCID). The subscale 'obsessing' on the OCI-R shows a strong correlation with eating pathology. The overall score and also the subscales of the BIS do not show strong correlations with eating pathology or poor global functioning. In conclusion, therapies should seek to address these specific areas which are highly correlated with eating disorder pathology.

Brain-derived neurotrophic factor (BDNF) and set-shifting in currently ill and recovered anorexia nervosa (AN) patients.

BACKGROUND: Studies of patients with anorexia nervosa (AN) have shown that they do not perform well in set-shifting tasks but little is known about the neurobiological correlates of this aspect of executive function. The aim of this study was to measure serum brain-derived neurotrophic factor (BDNF) and to establish whether set-shifting difficulties are present in people with current AN and in those recovered from AN, and whether serum BDNF concentrations are correlated with set-shifting ability. METHOD: Serum BDNF concentrations were measured in 29 women with current AN (AN group), 18 women who had recovered from AN (ANRec group) and 28 age-matched healthy controls (HC group). Set-shifting was measured using the Wisconsin Card Sorting Test (WCST). Eating-related psychopathology and depressive, anxiety and obsessive-compulsive symptomatology were evaluated using the Eating Disorder Examination Questionnaire (EDEQ), the Hospital Anxiety and Depression Scale (HADS), and the Maudsley Obsessive-Compulsive Inventory (MOCI) respectively. RESULTS: Serum BDNF concentrations (mean+/-s.d.) were significantly lower in the AN group (11.7+/-4.9 ng/ml) compared to the HC group (15.1+/-5.5 ng/ml, p=0.04) and also compared to the ANRec group (17.6+/-4.8 ng/ml, p=0.001). The AN group made significantly more errors (total and perseverative) in the WCST relative to the HC group. There was no significant correlation between serum BDNF concentrations and performance on the WCST. CONCLUSIONS: Serum BDNF may be a biological marker for eating-related psychopathology and of recovery in AN. Longitudinal studies are needed to explore possible associations between serum BDNF concentrations, illness and recovery and neuropsychological traits.

The inability to ignore: distractibility in women with restricting anorexia nervosa.

BACKGROUND: Attentional difficulties reported in individuals with anorexia nervosa (AN) may be due to preferential processing of disease-salient stimuli at a pre-attentive or at a conscious level or to a general problem in attention. Attentional difficulties may be associated with duration of illness. METHOD: Female participants with AN (restricting subtype; n=24) and healthy comparison women (n=24) were randomly allocated to subliminal or supraliminal exposure to visual stimuli (food, neutral and aversive images) while performing the 1-back and 2-back working-memory tasks. RESULTS: Participants with AN made fewer errors than the healthy comparison group in the subliminal condition but significantly more errors in the supraliminal condition [condition x group interaction, F(1, 44)=6.82, p<0.01]: this was irrespective of stimulus type (food, neutral and aversive) and task (1-back or 2-back). The total number of errors made correlated positively with the duration of the AN for both the 1-back task (rs=0.46, p<0.05) and for the 2-back task (rs=0.53, p<0.01). CONCLUSIONS: Decreased ability to concentrate in the presence of explicit distracters is a feature of AN and is associated with longer duration of illness. This phenomenon could be addressed in psychological interventions.

Dopaminergic and brain-derived neurotrophic factor signalling in inbred mice exposed to a restricted feeding schedule.

Increased physical activity and decreased motivation to eat are common features in anorexia nervosa. We investigated the development of these features and the potential implication of brain-derived neurotrophic factor (BDNF) and dopaminergic signalling in their development in C57BL/6J and A/J inbred mice, using the 'activity-based anorexia' model. In this model, mice on a restricted-feeding schedule are given unlimited access to running wheels. We measured dopamine receptor D2 and BDNF expression levels in the caudate putamen and the hippocampus, respectively, using in situ hybridization. We found that in response to scheduled feeding, C57BL/6J mice reduced their running wheel activity and displayed food anticipatory activity prior to food intake from day 2 of scheduled feeding as an indication of motivation to eat. In contrast, A/J mice increased running wheel activity during scheduled feeding and lacked food anticipatory activity. These were accompanied by increased dopamine receptor D2 expression in the caudate putamen and reduced BDNF expression in the hippocampus. Consistent with human linkage and association studies on BDNF and dopamine receptor D2 in anorexia nervosa, our study shows that dopaminergic and BDNF signalling are altered as a function of susceptibility to activity-based anorexia. Differences in gene expression and behaviour between A/J and C57BL/6J mice indicate that mouse genetic mapping populations based on these progenitor lines are valuable for identifying molecular determinants of anorexia-related traits.

Menstrual cycle effects on hypothalamic dopamine receptor function in women with a history of puerperal bipolar disorder.

Neuroendocrine challenge tests of hypothalamic dopamine receptor function in the early postpartum period suggest that the sensitivity of these receptors is increased in women with a history of bipolar disorder after childbirth. We tested the hypothesis that, in women predisposed to bipolar disorder in the puerperium, hypothalamic dopamine receptor function is more sensitive to changes in circulating ovarian hormone concentrations than in women without such histories. Eight fully recovered and drug-free women who had had at least one episode of bipolar illness following childbirth were compared with nine normal controls. Growth hormone (GH) responses to apomorphine (APO 0.005 mg s.c.) were measured in the early follicular phase, when plasma concentrations of ovarian hormones are low, and in the mid-luteal phase, when they are relatively high. The recovered bipolar subjects and the controls did not differ from each other in their follicular and midluteal oestrogen and progesterone concentrations. In the midluteal phase, both groups had increased oestrogen and progesterone levels. The recovered bipolar subjects did not differ from controls in baseline concentrations of GH in either of the menstrual phases. The APO-GH responses of the two groups did not differ in the follicular phase, but in the midluteal phase, when female sex steroids are relatively increased, the recovered group had significantly enhanced APO-GH responses [MANOVA for repeated measures: (i) area under the curve, group by phase effect: p < 0.04; (ii) GH peak rise after APO, group by phase effect: p < 0.056] and the responses were not related to concurrent measures of mood. The results of this small study of women predisposed to bipolar disorder in the puerperium shows an increased dopaminergic receptor sensitivity in the luteal phase of the menstrual cycle. It suggests that their dopaminergic systems have increased sensitivity to changes in circulating female sex steroids. This may be aetiologically relevant to the pathogenesis of puerperal bipolar disorder.

Evidence for long-term pancreatic damage caused by laxative abuse in subjects recovered from anorexia nervosa.

OBJECTIVE: This study examined whether a prior history of laxative abuse results in long-term changes in gastrointestinal function. METHOD: The functioning of the enteroinsular axis was examined by measuring the insulin response to a standard meal. The study involved 18 subjects who had fully recovered from anorexia nervosa (AN) and an age and weight-matched control group. In the recovered group, 10 of 18 subjects had a history of laxative abuse. RESULTS: Subjects with a prior history of laxative abuse show a more gradual increase and decrease in insulin secretion, but no differences in glucose response or hunger ratings. DISCUSSION: Because there are no differences in the glucose response to the meal, it is hypothesized that the difference in insulin response is due to changes in the enteroinsular axis. These data indicate that chronic laxative abuse induces long-term changes in gastrointestinal function.

Changes in neurite outgrowth but not in cell division induced by low EMF exposure: influence of field strength and culture conditions on responses in rat PC12 pheochromocytoma cells.

The effects of low electromagnetic field (EMF) exposure (4.5-15.8 microT, 50 Hz AC) on neurite outgrowth and cell division in rat PC12 pheochromocytoma cells were examined. The study involved two separate experimental series in which culture conditions during exposure to the magnetic fields differed. In series 1 (14 experiments in which culture conditions were not strongly conducive to cell differentiation [15% serum]), exposure to 4.5-8.25 microT for 23 h significantly inhibited neurite outgrowth by 21.5 +/- 1.3% (by Manova, p = 0.003). In contrast, in series 2 (12 experiments in which culture conditions promoted cellular differentiation [4% serum]), exposure to 4.35-8.25 microT for 23 h significantly stimulated neurite outgrowth by 16.9 +/- 1.1% (by Manova, p = 0.009). Thus, in both series, exposure to a narrow range of low EMF has significant, but opposite effects on neurite outgrowth. Exposure to higher fields, 8.25-12.5 microT (series 1) and 8.25-15.8 microT (series 2) had no significant effect on neurite outgrowth. These data, when considered with other reports, suggest that neuronal differentiation can be altered by low level EMF exposure. While this may not be detrimental, it merits further research. At present, the reasons for the significant changes in neurite outgrowth being confined to the same narrow field strength are unclear. As stated above, culture conditions in series 2 were more conducive to cell differentiation than those in series 1. This is reflected in the lower number of cells in control samples in series 2, at the end of the 23-h incubation, than in series 1 (- 16.9 +/- 1.7%, p = 0.003). As the same numbers were plated in both series, the medium used in series 1 allows more of the PC12 cells to divide; this is consistent with some cells reverting to a non-neuronal adrenal chromaffin phenotype [L. Greene, A. Tischler. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. U. S. A., 73 (1976) 2424-2426]. Exposure to both ranges of magnetic fields (4.35-8.25 and 8.25-15.8 microT) has no effect on cell division. Thus, there is no evidence in this study that there is a mitogenic effect arising from low EMF exposure.

A mathematical model for assessing changes in neurofilament protein levels in neurites and cell bodies of differentiating neuroblastoma cells.

A mathematical model which allows the calculation of the level of neurofilament protein in the cell body (x) and in the neurites (y) of differentiating SK-N-SH cells is presented. The model considers the changes in cell number (proliferating cells) and the number of cells with neurites (differentiating cells). It takes into account the fact that (i) when cells are cultured in differentiating conditions, an increase in cell number is initially observed and (ii) in a non-synchronized population of differentiating cells, the length of neurite extended by individual cells varies within the population. Total neurofilament protein levels in a population of cells were measured by enzyme-linked immunoabsorbant assay and application of the model to the data allowed values for x and y to be calculated. The validity of the model is supported by the fact that the predicted total neurofilament protein levels are highly correlated with the experimentally derived neurofilament protein levels. The model should be of use in temporal studies of cytoskeletal proteins involved in neuronal growth/differentiation and also in studies in which the system is a target of toxic insult.

Recombinant nef HIV-IIIB protein is toxic to human neurons in culture.

The expression of HIV-1 negative factor (nef) has been positively correlated with HIV disease progression [Z. Hanna, D.G. Kay, N. Rebai, A. Guimond, S. Jothy, P. Jocicoeur, Nef harbors a makor determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice. Cell 95 (1998) 163-175]. Nef expression has been detected in HIV infected human brains with neuronal damage [A. Ranki, M. Nyberg, V. Ovod, M. Haltia, I. Elovaara, R. Raininko, H. Haapsalo, K. Krohn, Abundant expression of HIV Nef and Rev proteins in brain astrocytes in associated with dementia, AIDS 9(9) (1995) 1001-1008; Y. Saito, L.R. Sharer, M.G. Epstein, J. Michaels, M. Mintz, M. Londer, K. Golding, B.M. Blumberg, Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmorten paediatric central tissues, Neurology 14 (1994) 474-480]. It is postulated that nef may contribute to the neuronal damage observed in the brain of those with late HIV disease. To test this, the potential toxicity of recombinant nef (from HIV-1 IIIB) was compared to the neurotoxin human tumour necrosis alpha (TNFalpha) on human brain cells in culture. SK-N-SH neuroblastoma, primary human neurons and glial cells were exposed to recombinant nef or TNFalpha protein for 3 days or twice over 6 days. Cell viability was assessed by Trypan Blue, lactate dehydrogenase (LDH) release and MTT assays. Nuclear fragmentation was detected using the Hoechst Blue nuclear dye assay. Both nef and TNFalpha (100 ng/ml) caused a significant 30% reduction of SK-N-SH cell numbers after 3 days exposure (P=0. 001). At this time, exposure to nef caused evident fragmented nuclei in these cultures. Human neuronal cultures had a 32 and 33% decrease in cell number after 6 days exposure to either nef or TNFalpha, respectively (P<0.001). Furthermore, as previously shown [J. He, C.M. DeCastro, G.R. Vandenbark, J. Busciglio, D. Gabuzda, Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protoonocogene, Proc. Natl. Acad. Sci. 94 (1997) 3954-3959], a 3-day exposure to nef significantly reduced human glial cell number by 25% (P=0.001). Recombinant nef and TNFalpha compromise human neurons in culture. Thus, like other virotoxins, it is shown for the first time that nef may also contribute to neuronal damage that has been reported in dementia in late HIV disease.