University of California at San Francisco ARC Departm ent of - - PowerPoint PPT Presentation

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University of California at San Francisco ARC Departm ent of - - PowerPoint PPT Presentation

Jun 03, 2023 468 likes •1.52k views

W here do harm ful drinking urges com e from ? W oody Hopf, Ph.D . University of California at San Francisco ARC Departm ent of Neurology W hat is harm ful drinking? W hat m akes it harm ful? How m uch alcohol is safe? Apologize

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W here do harm ful drinking urges com e from ?

W oody Hopf, Ph.D.

Departm ent of Neurology University of California at San Francisco ARC

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W hat is harm ful drinking? W hat m akes it “harm ful?” How m uch alcohol is “safe?” Apologize ahead of tim e for bringing up uncom fortable observations

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W hat is harm ful drinking? W hat m akes it “harm ful?” How m uch alcohol is “safe?” Apologize ahead of tim e for bringing up uncom fortable observations

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??

*

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Social alcohol drinking

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Social alcohol drinking Binge alcohol drinking

Moderate drinkers becom e binge drinkers

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Binge alcohol drinking

Binge drinking: 4 -5 drinks in 2 hours

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Binge alcohol drinking

Binge drinking: 4 -5 drinks in 2 hours

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The Cost of AUD ( Alcohol Use Disorder) > $ 2 5 0 billion and ~ 9 0 ,0 0 0 preventable deaths in the US every year

CDC, 2014 Health, Social, Fam ily, Legal, Econom ic, Dom estic Violence, Collisions w hile Driving

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The Cost of Binging > $ 2 5 0 billion and ~ 9 0 ,0 0 0 preventable deaths in the US every year

CDC, 2014

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The 1 / 7 th of US adults that are binge drinkers consum e 3 / 4 th

  • f the cost

The Cost of Binging > $ 2 5 0 billion and ~ 9 0 ,0 0 0 preventable deaths in the US every year

CDC, 2014

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Betw een 2 0 0 2 and 2 0 1 3 , fem ale alcoholism increased by 8 4 %

National I nstitute on Alcohol Abuse and Alcoholism , 2 0 1 7

https://www.niaaa.nih.gov/

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https://pubs.niaaa.nih.gov/publications/surveillance101/Underage13.htm

Young people are drinking less

1992 2012 Red: females Blue: males 1992 2012

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Binge alcohol drinking

Binge drinking

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Binge alcohol drinking Compulsive alcohol drinking

Com pulsive alcohol drinking:

I ntake despite bad consequences

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Binge alcohol drinking Compulsive alcohol drinking

Com pulsive alcohol drinking:

I ntake despite bad consequences

Bingers becom e com pulsive drinkers

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Binge alcohol drinking Compulsive alcohol drinking

Com pulsive alcohol drinking:

I ntake despite bad consequences

Bingers becom e com pulsive drinkers

I know I shouldn’t but I do it anyways

moderate to high risk of harm

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Binge alcohol drinking Compulsive alcohol drinking

DSM-V: Addiction defined as “Choice to drink despite know n cost”

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Binge alcohol drinking Compulsive alcohol drinking

“Choice to drink despite cost” drives addiction

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Binge alcohol drinking Compulsive alcohol drinking

“Choice to drink despite cost” allow s addiction

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How do w e “put things out of our m inds”

  • r “avert our eyes”
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W here does “Choice to drink despite cost” com e from in the brain?

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Can we use rats/ mice to help identify key addiction-driving (1) brain areas, (2) molecules, and (3) “psychological” mechanisms (thoughts, mindstates) and Develop new therapies (behavioral and drug-based) W here does “Choice to drink despite cost” com e from in the brain?

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Drinking alcohol from a bottle:

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Wise, 1973, Simms et al., 2008; Hopf et al., 2010 Monday afternoon to Tuesday afternoon

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I nterm ittent Access to Alcohol, 2 -bottle choice

Alcohol Drinking Model

Alcohol Intake

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I nterm ittent Access to Alcohol, 2 -bottle choice

Alcohol Drinking Model

Sw itch to 2 0 m in/ d

Alcohol Intake

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ACT!

Brain Areas that m ediate Com pulsive Drives for Alcohol?

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ACT!

Brain Areas that m ediate Com pulsive Drives for Alcohol?

mPFC Insula striatum

ventral

Ambroggi et al. 2010, McGinty et al. 2013

Seif et al. 2013, 2015, Darevsky et al. 2018, in prep

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ACT!

Brain Areas that m ediate Com pulsive Drives for Alcohol?

mPFC Insula striatum

ventral

Ambroggi et al. 2010, McGinty et al. 2013

Seif et al. 2013, 2015, Darevsky et al. 2018, in prep

mPFC: medial prefrontal cortex

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ACT!

Insula striatum

ventral

Ambroggi et al. 2010, McGinty et al. 2013

Seif et al. 2013, 2015, Darevsky et al. 2018, in prep

The “I nsula I nput” to Striatum

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ACT!

mPFC striatum

ventral

Ambroggi et al. 2010, McGinty et al. 2013

Seif et al. 2013, 2015, Darevsky et al. 2018, in prep

mPFC: medial prefrontal cortex

The “m PFC I nput” to Striatum

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Channelrhodopsin: Light excites cells Halorhodopsin: Light inhibits cells

Optogenetics Tools to inhibit or activate specific connections in the brain

Stuber and Mason 2013

532 nm

Protein developed by bacteria in sun-baked salt/ m udflats ( Death Valley) Absorb light, be less active Survive in the sun better

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Insula Striatum

I nfect I nsula neurons w ith a virus containing the gene for halorhodopsin

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I nfect I nsula cells w ith halorhodopsin Target a fiber-optic cable into the Striatum

Insula Striatum

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Attach cable to laser before behavior test

Insula Striatum

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Laser Light I nhibits I nsula I nputs!

Insula Striatum

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I nsula input

Needed for Com pulsion-Like Alcohol Drinking

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Amount of challenge in alcohol: 0 no challenge, 30 tastes bad Alcohol Intake

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Alcohol Intake

Laser light turned on or not

Amount of challenge in alcohol: 0 no challenge, 30 tastes bad

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Alcohol Intake

I nsula input

Insula-Striatum Inputs are inhibited or not

Amount of challenge in alcohol: 0 no challenge, 30 tastes bad

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Alcohol Intake

Regular, Alcohol-Only Drinking

Amount of challenge in alcohol: 0 no challenge, 30 tastes bad

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Alcohol Intake

Regular, Alcohol-Only Drinking

Amount of challenge in alcohol: 0 no challenge, 30 tastes bad

NO CHANGE!!

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Alcohol Intake

Compulsive Drinking

Amount of challenge in alcohol: 0 no challenge, 30 tastes bad

Reduced w hen I nhibit I nsula-Striatum inputs

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m PFC input

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I nsula input

* *

Seif et al., 2013 Seif et al., Nat Neurosci, 2013

Needed for Com pulsion-Like Alcohol Drinking

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W hat about for a different bad consequence? ( shock)

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Seif et al., Nature Neuroscience, 2013

∗ ∗

Seif et al., Nat Neurosci, 2013

Seif et al., Nat Neurosci, 2013

m PFC input I nsula input

Needed for Com pulsion-Like Alcohol Drinking

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Both Inputs (Insula & mPFC) drive alcohol drinking that continues despite both types of badness (taste, shock) A common mechanism for consequence-resistant action?

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Yay for Rats, but w hat about Hum ans?

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Com pulsion-like drinking in rodents Keep drinking despite shock/ bad taste These consequences are m ore im m ediate I s this like a hum an alcoholic?

No: Shots now , lose your job tom orrow Yes: Treatm ent Seekers: negative consequences are m ore im m ediate: W hen they think about going in the bar, ot Look at beer glass

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Com pulsion-like drinking in rodents Keep drinking despite shock/ bad taste These consequences are m ore im m ediate I s this like a hum an alcoholic?

No: Drink now , lose your job tom orrow Yes: Treatm ent Seekers: negative consequences are m ore im m ediate W hen they think about going in the bar, or They look at beer glass

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I nsula-m PFC-Striatum Circuit: Com pulsive Action for Alcohol in Rats and Hum ans?

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2018

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Pressing for alcohol in the face of shock

Grodin, Momenan et al., 2018 Red border: higher threat of shock, when pressing to get alcohol

  • r other reward

Green border: Safe (no shock)

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Lots of pressing w hen it is Safe ( green bars)

Grodin, Momenan et al., 2018

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Heavy hum an drinkers: m ore w illing to press for alcohol in the face of threat

Grodin, Momenan et al., 2018

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HEAVY DRI NKERS:

I nsula/ m PFC/ Striatum Alcohol response despite bad consequences

More I nsula-Striatum connection correlates with

  • m ore com pulsive responding
  • greater self-reported com pulsivity
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Sam e Brain Circuit m ediates Com pulsive Action for Alcohol in Hum ans and Rats!

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Sam e Brain Circuit m ediates Com pulsive Action for Alcohol in Hum ans and Rats!

W hy these regions? W hat are they “doing?”

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W hy do I nsula-Striatum only regulate Com pulsive Drinking?

*

I nsula

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Com pulsive intake: Automatic, habitual intake with actual challenge Habitual intake: Automatic, habitual intakestriatal, less cortical areas

W hy do I nsula-Striatum only regulate Com pulsive Drinking?

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Com pulsive intake: Conflict Recruits Cortical Circuits Habitual intake: No Conflict, recruits more striatal, less cortical areas

Tiffany and Conklin, 2000; Naqvi and Bechara, 2010

W hy do I nsula-Striatum only regulate Com pulsive Drinking?

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Com pulsive intake: Conflict Recruits Cortical Circuits Habitual intake: No Conflict, recruits more striatal, less cortical areas

Com pulsion: not giving in to “bad consequences” Cost of not drinking w orse than harm s associated w ith drinking

W hy do I nsula-Striatum only regulate Com pulsive Drinking?

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Com pulsive intake: Conflict Recruits Cortical Circuits Habitual intake: No Conflict, recruits more striatal, less cortical areas

Different brain circuits drive your drinking depending on your m indset ( conflict-ignoring or non-conflicted) This can change from m om ent to m om ent

W hy do I nsula-Striatum only regulate Com pulsive Drinking?

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Com pulsive intake: Conflict Recruits Cortical Circuits Habitual intake: No Conflict, recruits more striatal, less cortical areas

Our therapies target “Mom ents of Crisis” ( at risk of relapsing)

I f one has no conflict, then the therapy w on’t do anything

W hy do I nsula-Striatum only regulate Com pulsive Drinking?

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Our therapies target “Mom ents of Crisis” ( at risk of relapsing)

I f one has no conflict, then the therapy w on’t do anything

Com pulsive intake: Conflict Recruits Cortical Circuits Habitual intake: No Conflict, recruits more striatal, less cortical areas

I f one has no conflict, then the therapy w on’t do anything

W hy do I nsula-Striatum only regulate Com pulsive Drinking?

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W hat does I nsula “do norm ally?”

( Not there just to let us get addicted)

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How to Deal w ith Challenges that get in the w ay of Rew ard

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Challenges are I m portant! The Salience Netw ork m ediates im portant events

Seeley et al., 2007

mPFC

I nsula

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Short im portant things

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Alcohol cues prom ote drinking Activity in aI NS and friends PREDI CTS future intake and relapse

Myrick 2004; Filbery 2008; Claus 2013

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Heavy social drinkers Heavy social drinkers

I nsula

m PFC Striatum

Alcohol cues prom ote drinking I nsula activity PREDI CTS real-w orld intake and relapse

Myrick 2004; Filbery 2008; Claus 2013

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Heavy social drinkers Heavy social drinkers

I nsula

m PFC Striatum

Alcohol cue “autom atically captures attention”

Myrick 2004; Filbery 2008; Claus 2013

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I f you gam ble and “alm ost w in” I nsula activation predicts the desire to gam ble m ore

Luke 2011 Greater desire to keep gambling Greater Insula activity for almost win

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Partial I nsula Stroke: Give up smoking without effort

Quitting was easy Quitting was hard Naqvi and Bechara 2007 Science

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Long im portant things

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Guillem et al., 2010

I nsula cells active for 3 hours

( pressing a lever to get cocaine)

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Guillem et al., 2010

I nsula cells active for 3 hours

( pressing a lever to get cocaine)

Being “on”

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I nsula key for anxiety:

  • Overvalue negative info
  • Sustained attention
  • Relief Seeking w hen bad feeling aw akened

( subconscious and conscious levels)

Paulus and Stein 2006

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Critchley et al., 2004

A gam e: is m y heart beat in tim e w ith m usic rhythm ?

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Critchley et al., 2004

A gam e: is m y heart beat in tim e w ith m usic rhythm ?

Better ability to feel body More basal anxiety

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Critchley et al., 2004

Aw areness innately com es w ith som e anxiety

Better ability to feel body More basal anxiety

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Craig, 2009

pleasant music

Insula

smile self-recognition time perception happy voices maternal affiliation “Feeling of knowing” Moment of recognizing Decision making Most singular sense

  • f Self in the moment
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Mindfulness as a therapy:

Likely effective because it reprograms “fast reactivity to importance” memories Both (1) being reactive, and (2) learning to be less reactive, mediated through the Insula The Insula is all about having awareness and using awareness to impact what happens Sim ply being aw are reprogram s I nsula at it’s m ost basic substance

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Mindfulness as a therapy:

Likely effective because it reprograms “fast reactivity to importance” memories Both (1) being reactive, and (2) learning to be less reactive, mediated through the Insula The Insula is all about having awareness and using awareness of importance to impact what happens

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Insula: critical for important things Balancing awareness and non-awareness to help carry out importance-directed actions This system regulates both positive and negative situations Addiction takes over the system : Alcohol becom es the m ost im portant thing

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W hat is harm ful drinking? W hy do w e call it “harm ful?” How m uch alcohol is harm ful? Apologize ahead of tim e for bringing up uncom fortable observations

Binging

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W hat is harm ful drinking? W hy do w e call it “harm ful?” How m uch alcohol is harm ful? Apologize ahead of tim e for bringing up uncom fortable observations

Thoughts/ urges/ cues w hich “autom atically” push one forw ard

Binging

Repeated practice in “giving in to urges” I know I shouldn’t do it but I do it anyways

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W hat is harm ful drinking? W hy do w e call it “harm ful?” How m uch alcohol is harm ful? Apologize ahead of tim e for bringing up uncom fortable observations

Thoughts/ urges/ cues w hich “autom atically” push one forw ard

Binging

Repeated practice in “giving in to urges” I know I shouldn’t do it but I do it anyways

Costs:

  • Becom es “habitual”
  • Pay less attention to negative info (“it’ll be fine” becomes habit)
  • Can’t m uster as m uch w ill to overcom e (gotten good at giving in)

Costs:

  • Organ Dam age
  • Harm to Others

And Self

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How m uch alcohol is harm ful? ( and is there a “healthy” level?)

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A lot of alcohol

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Risk is Proportional to I ntake

Binge drinking is harmful at multiple levels (Health, Social, Family, Job, Legal Costs)

  • Disease risk in multiple organs
  • Injury to self and others
  • Lost wages and productivity
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Excessive intake prom otes liver disease

Zakhari & Li 2007

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Binge-level alcohol increases leakage of bacterial factors from gut into blood

Bala et al. 2014

Bacterial toxins Bacterial DNA

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Alcohol seen as such a toxin by the body: W illing to turn it into form aldehye to get rid of it ALDH2 m utation: ~ 5 6 0 m illion people w ith alcohol “flush response” Higher risk of m any diseases But also Likely m any adaptations for alcohol: Earliest m am m als like alcohol- living shrew s Even archebacteria have strong ALDH2

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Alcohol seen as such a toxin by the body: W illing to turn it into form aldehye to get rid of it ALDH2 m utation: ~ 5 6 0 m illion people w ith alcohol “flush response” Higher risk of m any diseases But also Likely m any adaptations for alcohol: Earliest m am m als like alcohol- living shrew s Even archebacteria have strong ALDH2

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Moderate alcohol

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Risk of Harm

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1 drink per day

Risk of Harm

5 drinks per day Possible benefit of

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1 drink per day 5 drinks per day

Risk of Harm

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1 drink per day 5 drinks per day

Risk of Harm

Could Doctors Prescribe Alcohol? Difference betw een studying people at the Aggregate vs I ndividual Level

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1 drink per day 5 drinks per day

Risk of Harm

Drink Responsibly Just Don’t Binge

https://pubs.niaaa.nih.gov/publications/surveillance101/Underage13.htm

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1992 to 2012 1 drink per day 5 drinks per day

Risk of Harm

Just Don’t Binge

https://pubs.niaaa.nih.gov/publications/surveillance101/Underage13.htm

Drink Responsibly