Crossing An Invisible Line– When One Is Too Many

…pickled, not wet

Each culture has in its infinite wisdom, vastly contributed to the field of how to best nurse our dehydrated brains.  Reportedly, it is in part from this effect that the terrible headaches and other overly self-investigated side effects of a good night out can emerge.  For that reason Japanese have Genmaicha a brown rice tea, in Anglosphere countries a hair of the dog intervention is sometimes suggested, namely having one or two not long after waking up, Germans have rollmops, a sweet pickles rolled in herring, while in other places partygoers end their night with a hearty meat soup for breakfast before sleep on Sundays.

The Invisible Line

However interesting home remedies can be, let’s instead take a closer look into folks who are clearly further down the line.  And it shouldn’t take much to spot one around town because after all, “The third leading risk for burden of disease in Europe is alcohol use, and alcohol consumption is almost double the global average” (World Health Organization, 2013).  Alcohol Use Disorder (AUD) was incorporated into the Diagnostic Statistical Manual of Mental Disorders 5th edition, to integrate both alcohol abuse and dependency.

Although there are some disagreements in terms of how to best identify individuals afflicted with this poorly understood, somewhat unbeatable and largely untreated ailment, we can generally say that it is characterized by sensitization and tolerance through prolonged exposure as well as withdrawal after discontinuing intake.  It is safe to say that most people do not transition into dependence.  For that to happen, we must also include into the aforementioned three qualifiers, negative reinforcement through self-medication of other mental disorders.

Infograph-risk-deaths-alcohol.jpg
WHO, with permission.

Alcohol consumption increases activity of neurotransmitters such as GABA, glycine, serotonin and nicotinic acetylcholine directly, while indirectly it increases dopamine, opioid and endocannabinoid activity and limits glutamate.  As expected, loads of genetic studies have pinpointed common themes, a favorite being the aldehyde dehydrogenase ALDH2 gene, which by contrast decreases risk and is mainly carried by Asian populations.  However, it is suggested we only understand 1% of the genetic contribution and “higher powered genome-wide association studies […] across large numbers of single-nucleotide polymorphisms”, linking many specific genes known to be partially involved are still required (Connor, 2015).

Given alcohol’s pleasurable effect, the reward circuitry is clearly involved and not surprisingly that lends to nucleus accumbens and dopamine.  Interestingly, dopamine influences intrinsic motivation and levels are lower at withdrawal, referring to the effects of abruptly stopping or lowering intake in a dependent person.  This could, together with a greater propensity to revert to conditioned behavior through background stimuli, offer a partial explanation for low success rates of treatment.  Research has shown that nucleus accumbens activity, was heightened in AUD participants who relapsed more often.

Glück’ wine

Since we have already kicked off the holidays, we might want to give thought to why some will push through with their New Year’s resolutions, while other will make for hospital.  As for neuroimaging studies, Dupuy and Chanraud have recently published a chapter devoted to AUD.  What they observed is termed disconnection syndrome, meaning brain areas in patients cannot be equally recruited as those for healthy folks.  And although this was previously reported under pathophysiology studies, it is now thoroughly supported by imaging research on functional connectivity.

We previously mentioned the reward system but other important players are the default mode network (DMN) active when attending to the outside world and representing our resting state; the entorhinal cortex (EC) area used in memory and navigation; and salience area (SA), used in defining key attributes as well as recruiting other networks.

The authors explain that “[f]or DMN, SA, reward and EC networks, both greater within-network and expanded outside-network connectivity correlated with poor performance and altered mood” (Dupuy & Chanraud, 2015).  The DMN of patients proved to be less synchronized, which possibly interferes with the allocation of mental resources to other areas.  Prolonged abstinence increases entorhinal connectivity and enhances cognitive abilities while short abstinence leads to increased activity in reward centers.  fMRI work has also been done in less studied frequency oscillations, for which differences were reported in all 56 subjects versus controls. Taken together, these studies show that an alcoholic’s brain relies more on alternative networks; put simply it takes more effort to accomplish a same goal.

Another key component for differences observed in patients comes from a work around glial cells (those that are usually attributed a role of support and protection in the nervous system).  Research has shown that Ibudilast, a drug that acts to inhibit microglia, resulted in lower stress and cue induced cravings.  Other more widely accepted medications include Naltrexone, used in the U.S. and another opioid antagonist Nalmefene, approved only in Europe.  It turns out that the immune system creates peripheral signals from drinking which can last months and are possibly further potentiated by microglia eventually leading to cell death.  Alterations to these, also create compounds that mimic neurotransmitter glutamate and increase cravings.

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Benefits of alcohol. (WikiCommons) (CC0 1.0)

Clean or old fashioned?

A popular topic in neuroscience and a major focus for this department is decision-making, something we certainly question in heavy drinkers and those that fall off the wagon.  A two-step decision task in a study will include a model-free (state transitions or changes are not so important) and a model-based (takes more into account reward in transition) scenario, where responses in about 70% of trials are common and in 30% rare.

This means that the participant cannot definitely anticipate a correct answer but the approach taken allows for a detailed study of the mechanism or algorithms that describe how individuals are operating at each stage.  When using this type of task with AUD patients researchers explained that, “[…] alcohol-dependent patients appeared to have difficulties repeating an action that is generally more rewarded, but was punished during the most recently pursued action”, and suggest impaired regulation of dopamine is involved (Heinz, 2017). 

Furthermore, it’s not just cues or triggers and exposure to even small doses that insult equilibrium in treated patients, stress also plays a key role.  Stress is known to deplete serotonin and dopamine and affect the immune system (including glial cells).  During withdrawal and while drinking, cortisol is released and impairs the pre-frontal cortex, an area proven to be involved in decision-making.

Spiritus Bacchus

Taking these facts into consideration, it is apparent why AUD is a progressive and degenerative.  After all, many neurological aspects make further consumption easier through reward habituation and relapse through interference with instrumental learning.  Recently, after being allowed visitation to a detox support group at a local hospital it was clear that even after sharing their tragic accounts, some patients felt they were there by mistake, too eager maybe for the next drink.  Hard as it may be, the fact is that they seemed to measured consequences with a different stick and even while confined to a ward, the question whether alcoholism can be considered a disease remains for many.

Some health professionals suggest seeing it as a framework or condition as is the case of diabetes, for which patients can take precautions and avoid major complications.  Unfortunately to date, the available medication is for short-term, for deterrence and is maybe too specific to treat any causes.  Therapy continues to grant the best results, but co-occurring mental disorders can only be addressed once the fog of drink is lifted and for that willingness is sometimes not enough.  Then again, if decision-making is so compromised, wouldn’t that confer greater responsibility to society?  Apparently some countries think so, which is why taxes and policies vary so greatly.

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