Deep brain stimulation for Obesity

Alexander Taghva, M.D.Orange County Neurosurgical AssociatesOhio State UniversityDecember 6, 2012Deep brain stimulation for AddictionDisclosuresMedtronic fellow in neuromodulation at Ohio State University 2010-2011Objectives1. Discuss quantifiable behavioral aspects of substance-dependent individuals, especially delay discounting.2. Propose a neurobiological explanation for these deficits to support a role for deep brain stimulation .3. Briefly review available clinical data on DBS for addiction.Ongoing research at OSU: TBI, obesity, AlzheimersOngoing Phase I trials for neurobehavioral deficits for Alzheimers, traumatic brain injury, obesityMany of these patients have problems with behavioral self-regulation, including addictionsToo soon to make claims, but anecdotally, behavioral self-regulation improves in some of these patients with DBS

Claims I will try to support (simplified)Addiction is essentially a disorder of increased impulsivity. Prefer immediate gratification despite long-term consequencesDifferent brain regions respond differently to immediate versus delayed rewardsVentral and dorsal CSPTC circuitsAddiction arises from imbalances or dysfunction of these circuitsAddiction can be seen as a disorder of increased impulsivity(Claim 1)NeuroeconomicsNeuroeconomics studies the calculations involved in decision makingDelay-discounting refers to the process by which immediate rewards are worth more than delayed rewards.This can be quantified by the indifference point.

7Example: Delay discountingIf I offer you $1000 right now versus giving you $1000 one month from now, you would take the money nowWhat if I offer you $900 now versus $1000 in one month? How about $800, etc.?Normal people will do this based on some interest calculation where as SDP individuals will tend to be more impulsive8Example: Indifference pointIf the preference switches to take $1000 in one month versus $800 now, the amount discounted in one month is 20%.That is, the indifference point is 80%

Increased discounting in addictive behaviorsDrug addicts, gamblers, alcoholics tend to discount more than non-afflicted peopleThis is also the case with obese individuals.In other words, lower-value immediate rewards are more valuable than higher value rewards later. Translates to impulsive behaviorHeroin abusers

Top line is a control group. Y axis is the value of money now versus $100 at the time delay of x-axis11Smokers and EtOH discount more than controls (Businelle et al 2010)

Obese women discount more (higher impulsivity) than control women. (Weller et al. 2008, Appetite)Different brain regions respond differently to immediate vs. delayed rewards(Claim 2)Immediate versus delayed rewardsMcClure et al in 2004 demonstrated that certain brain circuits react differently to immediate rewards versus delayed rewards.Immediate-reward (limbic) circuit consists of ventromedially placed structures VTA, ventral striatum, ventral pallidum, nucleus accumbens, amygdala, anterior and subgenual cingulate gyrus, medial OFCImmediate reward (McClure 2004)

Delayed-reward (associative) circuitsStructures involved in response to delayed-rewards are more dorsolaterally placedDorsolateral prefrontal cortex (DLPFC), lateral orbitofrontal cortex (lOFC), central striatumDelayed-reward structures

These structures respond to reward, but dont differentiate between delayed versus immediate18Limbic CSPTC loopCorticostriatal circuits exist for limbic, cognitive, and motor circuits.

Limbic emotional value

Cognitive control of emotions

Motor complete action

These circuits interface at ventral striatum (and other cortical regions) to provide a link from emotion to action.

Cognitive or Associative circuitProvides top-down control of impulses

Ventral striatum limbic to motor(Haber et al 2000)

Overlap in ventral striatumAnatomic basis for interface between different circuits (Haber and Knutson)

Areas of interaction of dorsolateral circuits with ventromedial circuits

The reward circuit: linking primate anatomy and human imaging.Haber SN, Knutson B.Neuropsychopharmacology. 2010 Jan;35(1):4-26. Epub . Review.

Frontostriatal DTI predicts impulsive behavior

Olson EA et al. White matter integrity predicts delay discounting behavior in 9- to 23-year-olds: a diffusion tensor imaging study. J Cogn Neurosci. 2009 Jul;21(7):1406-21.Addiction results from imbalance or dysfunction of these circuitsClaim 3Magnitude of reward vs. delay

Impulsive individuals have more cortical deactivation to delay and less mesolimbic activation to delayed rewards. (Ballard and Knutson 2008)

Impulsive individuals have more cortical deactivation to delay and less mesolimbic activation to delayed rewards.26This dysfunction is also seen in drug abusers

NIAAANot only the balance but magnitude of activation given a delay may be dysfunctional. Complex picture.Delayed reward in drug abuse

NIAAAIncreased limbic activity to reward (Bjork et al 2008)

Decreased dorsal activation with risk taking in drug abuse

Bjork 2008Imaging from obesityNeuroimaging also supports the fact that delayed-reward circuits are underactive as compared to immediate reward circuits in obesityIncreased activation of reward circuitry in obesity L.E. Stoeckel et al. / Brain Research Bulletin 79 (2009) 388395

Decreased dorsal activation proportional to BMI (Batterink et al)

Decreased dorsal activation proportional to BMI (Batterink et al)

The emotional brain overrides the rational brain

(Arnsten 2009)PTSD, OCD, AN, MDD have dysfunctions in balance.35Animal dataDBS of NAcc shell attenuates cocaine reinstatementDBS of shell attenuates reinstatement of cocaine

DBS of dorsal striatum does not work

DBS NAcc decreases alcohol consumption in ratsCurrent through shell of nucleus accumbens had dose dependent response

DBS decreases EtOH consumption in rats

Clinical data on DBS AddictionTarget primarily used is nucleus accumbensSmoking cessation and weight loss DBS Nucleus accumbens

Mantione et al Neurosurgery 2010Case reports on treatment of other disorders41

Lesioning study

5-year nonrelapse rate 58%

Side effects lack of sexual desire, poor concentration, loss of interest

Lesioning of nucleus accumbens attenuates opiate addictionDBS leading to smoking cessation in anxiety population

Improvement in craving for EtOH addiction

Mechanisms of Action of DBSLocal inhibitionLocal excitationRegulation of impulsesDesynchronization of impulsesChanges in gene expressionFrontostriatal modulation occursBut the data are somewhat hard to interpret.

(Bourne et al 2012)

Activation of DLPFC in loss situation with DBS on. Leads to better decision making?48

Increase in error related negativity on EEG

Anterior mid-cingulate cortex implicatedThank you.Questions?