The possibility of deep brain stimulation to treat eating disorders.

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1 The possibility of deep brain stimulation to treat eating disorders. Andres M Lozano MD PhD Professor and Dan Family Chair of Neurosurgery Canada Research Chair in Neuroscience Toronto Western Hospital University of Toronto

2 Brain Functions are localized within specific circuits. Dysfunction in circuits leads to Neurologic and Psychiatric disorders

3 Interventions Drive the activity in underperforming circuitse.g. Alzheimer's Eliminate/Block/Neutralizeabnormal activity Tremor, Epilepsy, Pain, Hallucinations

4 Neuromodulation Techniques TENS PNS VNS TMS TDCS CORTEX DBS DRUG DELIVERY SPINAL STIMULATION

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7 Neuron 2013 > 30 Published Indications for DBS (established, Investigational, Proposed) Parkinson s Disease Essential and other tremors (post-traumatic, Holmes, MS, etc..) Dystonias Chorea Chronic pain Cluster headache Epilepsy Gilles de la Tourette OCD Major Depression Bipolar disorder Aggressivity /violence Anorexia nervosa Obesity Drug/alcohol/nicotine Addiction Alzheimer Cognitive impairment in PD Minimally conscious state Tinnitus Post-traumatic stress disorder Enhancements (memory) Pleasure Antisocial behaviour / Abnormal morality

8 Obesity Regulation of Feeding Appetite Hunger Satiety Hypothalamus and Brainstem Behavioral Reward/Salience Motivation/Drive Learning/Memory Self control

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10 OBESITY Appetite control in hypothalamus Ventral medial nucleus satiety Ventrolateral nucleus hunger Animal experiments show hypothalamic stimulation influences feeding behavior Experience with hypothalamotomy for obesity in humans Quaade F. Lancet Feb 16;1(7851):267. Stereotaxy for obesity.

11 LETTER: STEREOTAXY FOR OBESITY QUAADE F. Lancet Feb 16;1(7851):267.

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14 DBS IMPLANTATION 53 yo male with lifelong history of morbid obesity (420 lbs, BMI 55.1 kg/m2) DBS electrodes implanted bilaterally in medial or lateral hypothalamus To identify the best site to suppress appetite, the effect of stimulation at each of the 4 four contacts of each of these electrodes was tested in the operating room.

15 DBS ELECTRODE POSITION

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22 World Neurosurg Sep-Oct;80(3-4):S28.e21-31.

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26 One patient with SCC DBS for depression and co-morbid anorexia Significant improvement in depression Improvement in anorexia symptoms Weight restoration

27 What else do we know about Cg25? local connections SERT S1A S2A D3 GABA Hypothalamus sleep-appetite cortisol Amygdala Motivation Drive anhedonia OMPFC NA Cd-P DLPFC MOTOR Thal Brainstem 5HT, NE, opiates Sleep, Pain, Diffuse Projections Stress responses Circadian regulation Emotional reactivity Ongur and Price. JCN 1998 VTA SN Haber, J. Neuroscience 2000 Changes in Cg25 may have local and Remote effects throughout the Brain

28 Study Rationale DBS for anorexia 1. Psychiatric condition with highest mortality rate affecting predominantly young females 2. No effective treatments for most chronic, refractory cases 3. Body of neuroscientific literature pointing at dysfunctional circuits and structures in AN brains 4. Promising experience with deep brain stimulation in conditions such as Depression and Obsessive-Compulsive Disorder 5. Targeting mood and anxiety may be a foot-in-the-door in otherwise treatment refractory patients, helping to convert treatment-nonresponders into treatment-responders

29 Pilot Trial 2013

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31 Refusal, Fear, Image

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33 Anorexia patient. Stimulation of Left area 25

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36 The Lancet Psychiatry. Feb 24, 2017

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41 Symptom Counts Graphs show total number of binges and purges in previous 28 days at each time point Some patients are pure restrictors or in program at the time Means: Baseline Binges Binges 1m Binges 3m Binges 6m Binges 12m Baseline Purges Purges 1m Purges 3m Purges 6m Purges 12m

42 FDG PET in 6 Patients with Anorexia. Changes over 6 months.

43 Summary study of DBS in chronic anorexia nervosa, suggests that DBS is safe and well-tolerated in these patients DBS is associated with beneficial effects on mood, anxiety and affective regulation DBS influences the metabolism in structures believed to be involved in AN circuitry First study that directly influences AN circuitry Decreased subcallosal and insular activity at 6 months Increased parietal activity at 6 and 12m

44 Brain targets for Obesity/Anorexia Multiple theoretical targets possible Emphasized DBS but need to consider more targeted and non-electrical approaches drug infusion, gene therapy, other biogical therapies, non-invasive stimulation, optical and magnetic stimulation are possible Single approach/target unlikely to succeed Multiple strategies can be considered who, where and how needs to be determined

45 Conclusion Brain circuits are accessible and modifiable Neuromodulation changes brain function Opportunity to learn, to test, to discover Multidisciplinary work essential The hope is to help more patients.