Neurobiology of Pathological Gambling

Presentation on theme: "Neurobiology of Pathological Gambling"— Presentation transcript:

1 Neurobiology of Pathological Gambling
충남대학교병원 정신건강의학과 김현진

2 Pathological gambling & Addiction
ICD-9(WHO, 1977) : Excessive gambling DSM-III(APA, 1980) : Impulse Control Disorder DSM-IV(APA, 1994) : Pathological Gambling similarity to substance dependence : ‘repeated unsuccessful attempts to control, cut back or stop gambling’ DSM-5(APA, 2013) ICD category -> Substance related and Addictive Disorders (‘SAD’) only non-substance related disorder in the SAD category. so-called “behavioral addictions” is a pivotal step genetic predisposition, treatment response, clinical characteristics, cognitive deficits and underlying neurobiological mechanisms Obsessive-compulsive-related Disorders & Substance-related Disorders working group의 의견

3 Arguments? Addiction! Reward processing 증가된 salience of stimuli
ICD : based on negative reinforcement Gambling: positive reinforcement(early stage) 증가된 salience of stimuli hypo-responsive reward circuitry similar diagnostic characteristics, and comorbidity rates Shared genetic vulnerabilities overlap in pharmacological and behavioral treatments Similar neurobiological underpinnings of brain function and cognitive features

4 중요한 뇌 구조물이 각각 inferior frontal cortex <-> Prefrontal cortex – struatum, dorsal striatum 이라는 측면에서 분명한 차이를 보이고 있다는 부분이 많은 영향을 주었을것으로 생각됨. Fauth‐Bühler, M., et al. (2016). "Pathological gambling: a review of the neurobiological evidence relevant for its classification as an addictive disorder." Addiction biology.

5 1.Potenza MN. The neural bases of cognitive processes in gambling disorder. Trends in cognitive sciences. 2014;18(8):

6 Key neural systems The Impulsive system The Reflective System
hyperactive, amygdala-striatum dependent promotes automatic and habitual actions The Reflective System hypoactive, prefrontal cortex dependent decision-making, forecasting the future consequences of a behavior, inhibitory control, and self-awareness The Insula intensify motivation and weaken control of behavior translates bottom-up, interoceptive signals into subjective output (e.g., craving)

7 The impulsive system Automatic motivational and behavioral aspects of drug seeking. The amygdala-striatal (dopamine dependent) neural system Rewards -> Increased mesolimbic dopamine activity Goal-directed and compulsive behaviors Synaptic structural plasticity in both dorsal and ventral striatal regions Sensitization of dopaminergic systems Cognitive processing level(Incentive sensitization theory) Continued drug use -> strengthening of implicit ‘wanting’ motivation-relevant associative memories Addiction-related cues -> generate automatic approach tendencies 유발-감작모델

8 The Reflective System 어떻게 habit (or impulsive) system을 control 하고 long- term goals에 flexible한 접근을 가능하게 하는가? ‘cool’ and ‘hot’ executive functions system lateral inferior and dorsolateral frontostriatal and frontoparietal networks basic working memory operations maintenance and updating of relevant information (‘updating’) inhibition of prepotent impulses (‘inhibition’) Mental set shifting (‘shifting’) Paralimbic orbitomedial and ventromedial frontolimbic structures triggering somatic states from memories, knowledge, and cognition positive or negative signal emerges (somatic marker hypothesis) cognitive (‘cool’ executive functions) and affective (‘hot’ executive functions) systems

9 The Insula interoceptive signals(homeostatic imbalance, deprivation state, stress, sleep deprivation, etc.)을 통해 행동의 동기를 강화하고 조절을 약화시킴. translation of interoceptive signals by sensitizing or exacerbating the activity of the habit/impulsive system by subverting the mechanisms of the PFC for attention, reasoning, planning, and decision-making processes ‘hijack’ the cognitive resources disabling (or ‘hijacking’) activity of the prefrontal (control/reflective) system self-awareness (lack of insight) Dissociations between self-perception and actual behavior Insular에 손상이 있는 smokers ability to quit smoking easily and immediately, without relapse, and without a persistence of the urge to smoke 몸을 일정하게 유지하는 기초적 감각과 관련된 역할 -> 감정은 동기를 유발하게 하는 감각이기 때문에 모든 포유류는 감정을 가진다. 그런데 침팬지와 오랑우탄 같은 몇몇 대형 영장류와 인간의 경우, 나는 자기 보존을 위한 감정뿐만 아니라 고차원적인 배역도 맡는다. 

10 1. Noël X, Brevers D, Bechara A
1.Noël X, Brevers D, Bechara A. A neurocognitive approach to understanding the neurobiology of addiction. Current opinion in neurobiology. 2013;23(4):632-8.

11 Neurochemistry of Gambling
Adrenergic systems : arousal and excitement Serotonin : impulse control Dopamine : rewarding and reinforcing aspects Opioids : pleasure/urges Cortisol : stress responsiveness Glutamate : cognitive functioning(cognitive flexibility)

12 Serotonergic Function
Emotion, mood and cognition -> Behavioral initiation & cessation(Impulse control) Low levels of serotonin increased motivation to satisfy urges impairment in inhibition or reward processing -> difficulty controlling their desires Low Platelet MAO activity Severe PG : MAO-A gene Polymorphism 이상 Serotonergic receptor hyposensitivity or hypersensitivity? tryptophan hydroxylase(TPH) gene & tryptophan 2,3- dioxygenase(TDO2) gene Low Platelet MAO activity : serotonin Pph index

13 Dopaminergic function
Reward processing, Reward-Based Learning, Reinforcement Mesolimbic Pathway ventral tegmental area (VTA) -> basal ganglia(Nucleus Accumbens) “Reward deficiency syndrome” crave environmental stimuli to compensate

14 Dopaminergic function(cont’)
Dopamine metabolite 증가 : 3,4- dihydroxyphenylacetic acid(DOPAC), homovanilic acid(HVA) dopamine D2(DRD2)와 dopamine D4(DRD4) gene, dopamine transporter(DAT1) gene

15 The Great Brain Experiment
노년층은 청년층보다 리스크가 적은 옵션 선택 -> 노년층은 큰 이익을 얻기 위해 리스 크를 감수하는 옵션을 선택하는 비율 이 청년층보다 낮았으나 손실 관련 청 년층과 노년층간 차이는 없음 노화에 따른 도파민 분비량 감소에 영향?

16 Endogenous opioids Endorphins : Pleasure, Urges
Feeling of well-being and lessen feelings of pain. GABA -> Dopamine in VTA -> Control mesocorticolimbic dopamine activity altered opioidergic systems engaging in rewarding behaviors -> intense euphoric feelings experienced -> difficulty controlling desires -> continue an addictive behavior Opioid antagonists(naltrexone and nalmefene) efficacy in treating PG 83명의 병적도박군에 11주간 naltrexone을 투여한 결과 placebo군보다 유의하게 병적도박의 증상을 호전시킨다는 결과를 보고하였다

17 Noradrenergic Function
Arousal & Excitement High 3-methoxy-4-hydroxyphenylglycol(MHPG)(in CSF) High norepinephrine & vanillymandelic acid(in urine) -> related sensation-seeking behaviors alpha2c receptors(ADRA2C) gene

18 Other NC Stress and Stress Hormones : Cortisol
Stress reaction after participating in gambling activities -> Higher levels of cortisol and adrenaline possibility of stress pathway involvement in gambling Glutamate : Compulsive, Cognitive inflexibility glutamatergic drugs(n-acetyl cysteine, memantine)

19 NE : 흥분/각성 -> NE level 증가,

20 Cognitive deficits PG >> substance addictions
Normal range on intelligence tests highly on measures of impulsiveness and low on measures of self-control relating to multiple cognitive domains cognitive control, decision-making, reward/loss and “near- miss”processing, delay and probabilistic discounting, reversal learning, alternation learning, and risk-taking diminished activation of the prefrontal cortex (particularly ventromedial but also ventrolateral and orbitofrontal) and subcortical regions (particularly the ventral striatum)

21 Cognitive-emotional processes
Reward and punishment processing, and its relation to behavioral conditioning Increased sensitivity to gambling cues strong urges or cravings for gambling Impulsivity vulnerability trait for acquiring pathological gambling Continuation of gambling despite severe negative consequences(diminished decision-making abilities)

22 Reward & Punishment sensitivity
PG에서 rewarding & punishing events 중에 mesolimbic- prefrontal cortex activation의 감소 brain’s reward system associated with dopamine insensitivity of the reward system -> more likely to seek rewarding events. 금전을 따고 잃는것에 대한 ‘위 험’에 관련된 뇌기능의 비정상 적 작동 substance use disorders와 유사 한 결과 de Ruiter et al., 2009 and Reuter et al.,2005

23 Cue Reactivity strong urge to gamble -> relapse in gambling behavior gambling-related stimuli(dramatic portrayals, casino images, descriptions) Increased activity in the mesolimbic-prefrontal cortex...?

24 Impulsivity Choices between immediate, smaller rewards and larger, delayed rewards cognitive or decision-making impulsivity(choice) immediate (smaller, sooner) rewards >> long-term (larger, later) rewards Cambridge Gambling Task, Iowa Gambling Task motor or response impulsivity(action) ability to inhibit motor responses. Go/No-Go Tasks, continuous performance Tests, stop-signal tasks 병적 도박자에서 several inhibitory processes의 손상이 나 타남. The Stroop interference(Potenza, Leung et al., 2003). Fronto-striatal circuits striatal component : ventral striatum Prefrontal component : anterior cingulate cortex/ventromedial prefrontal cortex (VMPFC)

25 Decision-Making process
IOWA Gambling Task(IGT) Impulsivity, risk-taking, experiencing and evaluating immediate and delayed wins and losses. 즉각적인 만족을 얻기위 해 장기간의 부정적인 결 과에 대한 무시 (Goudriaan, 2004). Ventromedial Prefrontal cortex이 손상된 환자와 비슷한 행동양상이 관찰 IOWA Gambling Task(IGT) : 참가자는 컴퓨터 화면을 통해 가상의 카드 4벌을 보게 된다. 참가자는 뒤집어진 카드 4장 중 한장을 선택해야 한다. 각 카드에는 상금과 벌금이 있다. 이 중 특정 위치에 놓인 카드는 항상 높은 수익과 높은 위험(돈을 크게 잃는 경우, Bad deck)이 공존한다. 반면 나머지 두 위치에 놓인 카드는 항상 낮은 수익과 낮은 위험(그러나 평균 이득은 위험이 높은 카드보다 높다, Good deck)을 가지고 있다. -> 일반인들의 경우 40-50회 정도 카드를 뽑고 난 다음에는 '좋은 패'가 나오는 위치에서만 카드를 뽑는 경향을 보였다. 그러나 안와전두엽(orbitofrontal cortex, OFC)에 손상을 입은 환자는 계속해서 '나쁜 패'가 나오는 위치를 고수했다. 이들은 이 위치에서 카드를 뽑으면 결과적으로 손해를 본다는 사실을 알고 있음에도 이처럼 행동했다.

26

27