Deep Brain Stimulation as therapeutic approach in animal models of obesity

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1 Deep Brain Stimulation as therapeutic approach in animal models of obesity Lukas Maurer - Endokrinologie Medizinische Klinik mit SP Endokrinologie, Diabetes und Ernährungsmedizin Joachim Spranger Klinik für Neurologie Andrea Kühn Matthias Endres

2 Last-Ditch Obesity Treatment? Medical Frontier: Brain Surgery for Weight Loss Can't resist that doughnut? An electric shock to the brain could stop people from binge eating Control the brain - control the gain

3 Bariatric Surgery Swedish Obesity Subjets Study- Sjöström et al.2007 Weight gain after short- and long-limb gastric bypass in patients followed longer than 10 years - Christou et al.2006

4 Neuromodulation Movement Disorders Parkinson s Disease Dystonia Essentiell Tremor Neuropsych. Disorders Major Depression Obsessive-Compulsive Disorder Addiction Deep Brain Stimulation for Parkinson s Disease. Okun et al. 2012

5 Energy Homeostasis Ventromedial Hypothalamus Lateral Hypothalamus

6 Lateral Hypthalamus acute electrical stimulation of the LH increases food intake Delgado et al Stephan et al Mogenson et al Halperin et al stimulation paradigm: 60 Hz; pulse duration 0.2 msec. ; 1 to 5 V.

7 Lateraler Hypothalamus

8 Lateral Hypthalamus Deep brain stimulation of LH for treatment of obesity in rats - Sani et al Sprague Dawley rats - free access to a high-fat diet bilaterally stimulation of the LH (2.0 V, pulse width 100 msec, frequency Hz)

9 Lateral Hypothalamus DBS in the LH Area in a Rat Model of Obesity: In Vivo Assessment of Brain Glucose Metabolism Soto-Montenegro et al obese Zucker (fa/fa-) rats 130 Hz and 300 µa with a pulse width of 60 µs; for 1 h per day for 15 days

10 Lateraler Hypothalamus Bl6/C57 mice, free access high fat diet DBS LHA 130Hz, 100µA, 60 µs - Unpublished data

11 Pilot Study - LHA Lateral hypothalamic area deep brain stimulation for refractory obesity - Whiting et al 2013 DBS LHA Frequency185Hz Pulse width 90µs Voltage 7V

12 Ventromedial Hypothalamus acute electrical stimulation of the VMH decreases food intake Beltt et al Brown et al Stenger et al Bielajew et al Ruffin et al sham stimulation unilateral VMH 15 min burst stimulation 30s/30s constant current square wave pulses 100Hz, current 15 µa to 5 µa

13 Ventromedial Hypothalamus Hypothalamic Deep Brain Stimulation Reduces Weight Gain in Female Göttingen minipigs - Melega et al Body fat and body weight reduction following hypothalamic deep brain stimulation in monkeys: an intraventricular approach - Torres et al DBS (50 Hz, 0.5 ma, 500 µs) Reduced weight gain, no effect on food intake at Near ad libitum diet DBS (80 Hz, individual setup) 8 weeks Reduced food intake, 8% weight loss

14 Clinical Data on VMH Memory enhancement perifornical DBS - Hamani et al Induction of panic attack by stimulation of the ventromedial hypothalamus - Wilent et al. 2009

15 Food Related Reward Fulton S. et al. 2009

16 Functional Imaging in Obesity Weight Gain Is Associated with Reduced Striatal Response to Palatable Food Stice et al Striatal dopamine D2-like receptor correlation patterns with human obesity and opportunistic eating behavior Guo et al. 2014

17 Nucleus accumbens Deep Brain Stimulation Reveals a Dissociation of Consummatory and Motivated Behaviour in the Medial and Lateral Nucleus Accumbens Shell of the Rat - Van der Plasse et al DBS (130 Hz, 100µA, 60µs) 1 hour mshell increased food intake lshell stimulation reduced response to sucrose Sucrose Preference Food Intake

18 Nucleus accumbens Amelioration of Binge Eating by Nucleus Accumbens Shell Deep Brain Stimulation in Mice Involves D2 Receptor Modulation - Halpern et al DBS (160Hz, 150µA, 60µs) Acute 1h: suppression of binge eating but not caloric intake over 24h from chow, attenuated by D2 blockade Chronic 4d: decreased food intake on day 1, decrease in body weight

19 Nucleus accumbens Alterations in blood glucose and plasma glucagon concentrations during deep brain stimulation in the shell region of the nucleus accumbens in rats Diepenbroek et al DBS (130 Hz, 100µA, 60µs) 1 hour rapid increase in plasma concentrations of glucagon and glucose

20 Nucleus Accumbens Bl6/C57 mice, free access high fat diet DBS (130Hz & 20 Hz, 100µa, 60µs) - Unpublished data

21 Nucleus accumbens Deep brain stimulation of the nucleus accumbens shell induces anti-obesity effects in obese rats with alteration of dopamine neurotransmission Zhang et al DBS (130Hz, 500µA, 90µs) reductions in total energy intake and weight gain D2R expression & DA levels reduced in DIO rats DBS increased D2R expression & DA levels in DIO rats

22 Case Report - Nucleus accumbens Smoking Cessation and Weight Loss After Chronic Deep Brain Stimulation of the Nucleus Accumbens: Therapeutic and Research Implications: Case Report Mantione et al DBS 185 Hz, 3.5 V, 90µs Weight loss of 44 kg in 10 months without any effort and reached her goal of 71 kg (stable at 2 year follow up)

23 Clinical trials

24 Open Questions Stimulation paradigm? Target? Model? High vs. Low Frequency Theta Burst Coordinated Reset Closed loop Diet induced obesity Genetic obesity models Food intake / Body weight Food preferences & reward values