Download Neurobiology of pathological gambling

Neurobiology of Pathological
Gambling
충남대학교병원
정신건강의학과
김현진
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
Arguments? Addiction!
• Reward processing
• ICD : based on negative reinforcement
• Gambling: positive reinforcement(early stage)
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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
Fauth‐Bühler, M., et al. (2016). "Pathological gambling: a review of the neurobiological
evidence relevant for its classification as an addictive disorder." Addiction biology.
1.Potenza MN. The neural bases of cognitive processes in gambling disorder. Trends in cognitive sciences. 2014;18(8):429-38.
Key neural systems
1. The Impulsive system
• hyperactive, amygdala-striatum dependent
• promotes automatic and habitual actions
2. The Reflective System
• hypoactive, prefrontal cortex dependent
• decision-making, forecasting the future consequences of a
behavior, inhibitory control, and self-awareness
3. The Insula
• intensify motivation and weaken control of behavior
• translates bottom-up, interoceptive signals into subjective
output (e.g., craving)
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
The Reflective System
• 어떻게 habit (or impulsive) system을 control 하고 longterm 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
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
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.
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)
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 2,3dioxygenase(TDO2) gene
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
Dopaminergic function(cont’)
• Dopamine metabolite 증가 : 3,4dihydroxyphenylacetic acid(DOPAC), homovanilic
acid(HVA)
• dopamine D2(DRD2)와 dopamine D4(DRD4) gene,
dopamine transporter(DAT1) gene
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?
http://www.thegreatbrainexperiment.com/
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
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
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)
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 “nearmiss”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)
Cognitive-emotional processes
1. Reward and punishment processing, and its
relation to behavioral conditioning
2. Increased sensitivity to gambling cues
• strong urges or cravings for gambling
3. Impulsivity
• vulnerability trait for acquiring pathological gambling
4. Continuation of gambling despite severe negative
consequences(diminished decision-making
abilities)
Reward & Punishment sensitivity
• PG에서 rewarding & punishing
events 중에 mesolimbicprefrontal 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
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...?
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)
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