Repetitive Transcranial Magnetic Stimulation Strategies in the Treatment of Anorexia Nervosa: A Literature Review
Abstract
Objective:
This literature review summarizes the recent treatment approach of neural circuit manipulation with repetitive transcranial magnetic stimulation (rTMS) in the treatment of anorexia nervosa.
Methods:
A PubMed query was conducted with the search terms “anorexia nervosa” and “transcranial magnetic stimulation.” Three authors systematically evaluated the search results to determine eligibility for inclusion.
Results:
Of 33 studies identified in the search, 16 primary studies were eligible for inclusion. The application of rTMS to the dorsolateral prefrontal cortex, the dorsomedial prefrontal cortex, and the insula were investigated in 11, four, and one of the studies, respectively.
Conclusions:
Findings indicated that rTMS is safe for patients with anorexia nervosa and well tolerated, but large randomized controlled trials comparing real versus sham rTMS of various brain regions are needed.
Anorexia nervosa (AN) is a devastating eating disorder that presents with excessive restriction of calorie intake and intense fear of weight gain. Although AN is associated with one of the highest rates of mortality among all psychiatric illnesses, the etiology and neurobiology of AN remain unclear. Furthermore, the U.S. Food and Drug Administration has not approved any medications for the treatment of AN. A variety of psychotropic medications, including antidepressants and antipsychotics, have been studied for patients with AN, with limited success (1).
Because pharmacological options have shown limited efficacy for treating AN, neuromodulation, including deep brain stimulation and repetitive transcranial magnetic stimulation (rTMS), has recently garnered significant interest as a potential treatment modality for AN. Variations in pulse frequency and targeted cortical regions offer additional control over the neurophysiological and clinical effects of rTMS. The U.S. Food and Drug Administration has approved rTMS to safely treat obsessive-compulsive disorder, major depressive disorder, and migraine, and recent studies have begun investigating the safety profile and potential efficacy of rTMS in aiding the treatment of AN (2). In this overview, we summarize the recent treatment approach of neural circuit manipulation with rTMS in the treatment of AN.
Methods
A PubMed query was conducted with the search terms “anorexia nervosa” and “transcranial magnetic stimulation” without additional search restrictions, which identified publications that contained both terms anywhere in the articles. The articles were systematically evaluated by three independent researchers (J.K., S.K., and S.K.) to determine eligibility for inclusion. Articles were included if they were primary studies, including pilot studies, case series, and case reports, that used rTMS to treat individuals with AN. Articles were excluded if they did not present an original research study with new data.
Results
Of 33 articles identified with the search terms, 16 primary studies met the inclusion criteria. Most of these studies (N=11) investigated the application of rTMS to the dorsolateral prefrontal cortex (DLPFC). Of the remaining studies, rTMS applied to the dorsomedial prefrontal cortex (DMPFC) was examined in four studies, and one study evaluated deep rTMS of the insula. Study participants were primarily female adults. These 16 primary studies, published between 2012 and 2021, included six case reports and series, six pilot studies, and four randomized controlled trials (RCTs) (Table 1). Most studies were conducted in the United Kingdom and Canada, with a few studies conducted in the Czech Republic and India.
| Study and year | Type | TMS target and type | Design | Key findings |
|---|---|---|---|---|
| Downar et al., 2012 (6) | Case report | DMPFC, rTMS | Patient (age 43) with AN; binge-eating and purging behavior and depressive symptoms measured at baseline and 11 weekly postintervention follow-ups | Full remission from binge-eating and purging behaviors and depression symptoms for more than 2 months after the intervention |
| McClelland et al., 2013 (7) | Case report | Left DLPFC, rTMS | Two patients (ages 23 and 52) with treatment-resistant AN; eating disorder symptoms, weight, and mood measured before, immediately after, and 1 month after the intervention | Improvements in eating disorder symptoms and mood that persisted 1 month after the intervention |
| Choudhary et al., 2017 (5) | Case report | Left DLPFC, rTMS | Patient (age 23) with AN partially responsive to cognitive-behavioral therapy and pharmacological treatment who received rTMS; BMI and body image attitude changes measured | Marked improvement in BMI and body image attitude and reduction in laxative abuse behavior |
| Jaššová et al., 2018 (8) | Case report | Left DLPFC, rTMS | Patient (age 29) with treatment-resistant AN; BMI, eating behavior, and anxiety and depressive symptoms measured before and after the intervention | Negligible changes in weight, anxiety and depressive symptoms, and eating behavior immediately and 2 years after the intervention |
| McClelland et al., 2016 (4) | Case series | Left DLPFC, rTMS | Five patients (age range, 23–52; median age, 32) with SE-AN; eating disorder symptoms, mood, and anxiety and depressive symptoms measured before and after intervention, with 6- and 12-month follow-ups | BMI remained stable, but eating disorder symptoms significantly improved immediately after the intervention; improvement in mood and eating disorder symptoms maintained at 6-month follow-up, but BMI fell by 12-month follow-up. |
| Woodside et al., 2017 (3) | Case series | DMPFC, rTMS | 14 patients (mean age, 40) with an eating disorder (including AN, bulimia nervosa, and eating disorder not otherwise specified) and comorbid PTSD; PTSD symptoms and emotional regulation score measured after the intervention | Significant improvements in PTSD symptoms and emotional regulation after the intervention; fewer improvements for those with severely low BMI |
| Van den Eynde et al., 2013 (14) | Pilot study | Left DLPFC, rTMS | 10 participants with AN (age range, 8–44; median age, 25); eating disorder symptoms assessed before and after one session of rTMS to DLPFC in the context of visual and real food stimuli | Well tolerated and safe; effective in reducing satiety and anxiety |
| Dunlop et al., 2015 (13) | Pilot study | DMPFC, rTMS | 28 patients (age range, 20–56; mean age, 25) with AN or bulimia nervosa; resting-state fMRI data and eating disorder symptoms collected before and after the intervention | Decrease in purge frequency, especially among patients with lower connectivity from the DMPFC to the bilateral temporal poles, OFC, and right posterior insula |
| Knyahnytska et al., 2019 (12) | Pilot study | Insula, dTMS with the Hesed coil | Eight participants (mean age, 33) with restricting or binge-purging AN; safety, feasibility, and change in AN-specific symptoms measured | Safe and well tolerated; decreased severity of AN-related obsessions and compulsions around food and weight and anxiety and depression scores |
| Dalton et al., 2021 (10) | Pilot study | Left DLPFC, rTMS | 34 participants with AN (mean age, 29) and 30 without AN (mean age, 26); changes in BMI, eating disorder symptoms, and regional cerebral blood flow (using fMRI) measured before and after sham or real rTMS | Greater postintervention reduction in amygdala cerebral blood flow associated with greater long-term weight gain at 10-month follow-up |
| Dalton et al., 2021 (9) | Pilot study | Left DLPFC, rTMS | 26 patients with SE-AN (16 taking antidepressants; mean age, 30; 10 not taking antidepressants; mean age, 33); between-group comparison of outcomes | Antidepressant medication appeared to enhance response to rTMS with respect to eating disorder symptoms but not affective symptoms. |
| Woodside et al., 2021 (11) | Pilot study | DMPFC, rTMS | 19 patients (age range, 21–56; mean age, 31); core AN pathology and functional connectivity examined | Significant improvements on inventories of anxiety, depression, and concern for weight and shape; greatest improvements among those with lower baseline DMPFC functional connectivity to the right frontal pole and left angular gyrus |
| McClelland et al., 2016 (15) | Randomized controlled trial | Left DLPFC, rTMS | 21 patients with AN (mean age, 25) received rTMS and 28 patients with AN (mean age, 28) received sham rTMS; double-blind parallel-group study measuring core AN symptoms and performance in a temporal discounting task before and after intervention | 49 of 60 patients completed study; reduced core AN symptoms and rates of temporal discounting in real rTMS group compared with sham stimulation group, after analysis controlled for pre-rTMS scores; safe, well tolerated, and considered an acceptable intervention |
| Dalton et al., 2018 (17) | Randomized controlled trial | Left DLPFC, rTMS | 34 participants with AN (mean age, 30); double-blind, sham-controlled trial with safety, tolerability, BMI, and mood and eating disorder symptoms measured at baseline and at 0, 1, and 4 months after the intervention. | Feasible and well accepted; mood symptoms showed greater improvement in real rTMS group; small between-group effect sizes of change scores with BMI and eating disorder symptoms |
| Dalton et al., 2020 (16) | Randomized controlled trial | Left DLPFC, rTMS | 34 participants with SE-AN (mean age, 30); double-blind, sham-controlled trial with food preference and selection habits measured at baseline and 4 months after the intervention | No change in SE-AN participants’ preference for low-fat food; after intervention, SE-AN participants showed decreased self-control over tasty-unhealthy food items. |
| Dalton et al., 2020 (18) | Randomized controlled trial | Left DLPFC, rTMS | 24 participants (mean age, 34) with SE-AN; 12 received real rTMS and 10 of 12 receiving sham rTMS received real rTMS during the open, 18-month follow-up period; BMI and eating disorder and mood symptoms measured | Improvements in eating disorder and mood symptoms sustained at 18-month follow-up, with catch-up effects in sham group that eventually received real rTMS |
TABLE 1. Summaries of 16 studies in which repetitive transcranial magnetic stimulation (rTMS) was used in the treatment of anorexia nervosa (AN)a
Case Reports
Because of the novelty of applying neuromodulation techniques in the treatment of eating disorders, case reports and case series make up the primary literature on this topic and provide a valuable foundation for the development of treatment strategies and future studies. As clinicians have explored the potential of therapeutic rTMS for patients with AN, detailed profiles of patient characteristics, comorbid conditions, and outcomes after treatment have been described. Most of the case reports and series demonstrated that implementing rTMS therapy to the left DLPFC or DMPFC of patients with treatment-resistant AN resulted in improvements in satiety, body mass index (BMI), mood or anxiety symptoms, or eating disorder symptoms up to 1 month after the intervention (3–7). Despite the overall favorable evidence for rTMS, one case report described a patient with AN who experienced negligible changes in weight, anxiety and depressive symptoms, and eating behavior after rTMS to the left DLPFC in both immediate and 2-year postintervention follow-ups (8).
Pilot Studies
Building on the evidence from case studies, the pilot studies generally demonstrated that rTMS therapy is safe and well tolerated, and it is effective in improving weight gain, anxiety, or eating disorder behaviors, with mostly moderate-to-large effect sizes among small groups of participants with AN; sample sizes ranged from eight to 34 participants (9–14). Unlike all other studies reviewed here that used rTMS to stimulate the DMPFC or DLPFC, one of the pilot studies used deep rTMS (dTMS) to target the insula and demonstrated that dTMS was safe and well tolerated among patients with AN (12).
RCTs
Although RCTs directly comparing rTMS to a control treatment are limited, the few studies that have been conducted established different levels of efficacy for DLPFC rTMS on AN symptomatology that depend on the number of rTMS sessions and the length of follow-up time. When RCTs were limited to short-term follow-up and a single rTMS session, the effects appeared mostly insignificant or at best modest. One RCT showed no difference between groups receiving sham rTMS and real rTMS on measures of subjective AN-related experiences, such as the urge to restrict food intake and levels of feeling fat, in the 24 hours following one session of DLPFC rTMS (15). However, longer-term RCTs that included more sessions of rTMS showed larger differences between control and treatment groups. A 4-month follow-up study of patients with severe, enduring AN showed decreased self-regulation of food choices, including an increased selection of tasty yet unhealthy foods, relative to baseline for those who received real rTMS to the DLPFC, whereas those who received sham rTMS did not show these improvements (16, 17). At the 18-month follow-up, patients who had undergone real rTMS in the original study showed better outcomes, compared with those who had originally received sham rTMS. For five participants from the original group that received real rTMS, weight was recovered to a BMI ≥18.5, compared with only one participant showing such recovery in the original group that received sham treatment (18). Results from these RCTs establish strong evidence for DLPFC rTMS in improving certain aspects of AN symptomatology and clarify a particular dose- and time-dependent role of rTMS therapy in these improvements.
Discussion
The DLPFC has been the brain region targeted in most investigations of rTMS and neuromodulation in the treatment of AN, largely because of the established role of this region in mechanisms of self-regulation and self-control. The DLPFC is interconnected with limbic regions, including the amygdala and insula, and dysregulation in this frontolimbic circuitry has been associated with behavioral and emotional regulation in AN (19). Taken together, targeting the left DLPFC with rTMS may alter the top-down control of the DLPFC over frontolimbic regions associated with maladaptive emotion regulation strategies (e.g., dietary restraint) and subsequently improve eating disorder symptoms and affective symptoms. Although the DLPFC has been the primary region of interest, the DMPFC has also been increasingly investigated in the treatment of AN using rTMS because of the role of the DMPFC in various tasks of self-regulation, including suppression of emotional responses to impulse control (13).
Beyond application to the prefrontal cortices, modulation of the deep prefrontal and subcortical brain regions that are also implicated in the pathophysiology of AN, such as the cingulate gyrus, the thalamus, and the insula, is being explored using these interventional methods. Brain imaging studies that involve presenting pictures of food to individuals with chronic AN revealed altered activity in the insula and the orbitofrontal cortex (20). Thus, rTMS modulation of the insula has been of particular interest because of aberrant insular activity in malnourished patients with AN during functional magnetic resonance imaging and the role of the insula in feeding behavior, self-awareness, and homeostatic mechanisms (12).
As evidenced by the studies described here, a significant consideration in the use of rTMS is the appropriateness of the treatment for varying presentations of AN. Although rTMS has proven to be a much-needed breakthrough therapy for some patients with AN, studies have also revealed a subset of patients who do not respond as well to rTMS. An open-label case series on the effects of rTMS of the DMPFC of patients with an eating disorder comorbid with PTSD demonstrated that the patients with severely low BMI showed less improvement in PTSD symptoms and emotional regulation after rTMS, compared with those with higher BMIs (3). This finding suggests that patients with AN may have a decreased response to rTMS, compared with patients with other eating disorders, and that undergoing a nutritional rehabilitation program beforehand could augment the effects of rTMS for these patients. Similarly, a pilot trial of rTMS applied to the DMPFC in patients with AN showed that those with lower baseline functional connectivity from the DMPFC to the right frontal pole and to the left angular gyrus showed significantly greater improvements in eating disorder symptoms, compared with participants with higher baseline functional connectivity between these regions (11).
Most follow-up assessments are conducted less than 12 months after the intervention, and thus long-term follow-up studies are necessary to accurately evaluate the lasting effects of rTMS and to assess the need for rTMS maintenance therapy. Furthermore, the heterogeneous nature of AN requires nuanced investigation into the characteristics that may make rTMS a more effective tool for some patients than for others. A limitation of this review was using PubMed as the sole database, which may have missed some studies.
Conclusions
Although rTMS has been a breakthrough therapy for some patients with AN, studies have also revealed a subset of patients for whom it is not effective. Further brain mapping analyses and genomic studies would be useful to deduce specific targets for treatment that take into account the underlying variability in structural connectivity among patient populations with AN. Overall, the existing literature indicates that rTMS is safe and well tolerated and may be an effective treatment for patients with AN. However, large RCTs comparing real and sham rTMS treatment of various brain regions and in different populations of patients with AN are needed to develop evidence-based recommendations to optimize outcomes.
Key Points/Clinical Pearls
Because current pharmacological options have shown limited efficacy in the treatment of anorexia nervosa, neuromodulation has recently garnered significant interest as a potential treatment modality for the disorder.
Findings published in the past 10 years indicate that repetitive transcranial magnetic stimulation is safe and well tolerated and may be an effective treatment for patients with anorexia nervosa.
Although repetitive transcranial magnetic stimulation has been a breakthrough therapy for some patients with anorexia nervosa, studies have also revealed a subset of patients for whom it is not effective.
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