Blood Pressure

Blood pressure is an important topic for psychiatrists and all physicians.  The prevalence of blood pressure problems especially hypertension is high in the United States and has significant associated mortality and morbidity.  Many psychiatric medications affect blood pressure and some blood pressure medications like beta adrenergic receptor blockers, central alpha adrenergic receptor agonists, and alpha-1 adrenergic receptor inverse agonists have psychiatric applications.  In addition, blood pressure irregularities are noted in major toxic reactions to psychiatric medications like serotonin syndrome and neuroleptic malignant syndrome.  Hypertension is a contraindication to the use of some psychiatric medications and parameters need to be placed for their use.  All of these considerations would seem to make it obvious that frequent and consistent blood pressure measurements should be a part of psychiatric practice - but they are not.

Various problems with obtaining blood pressures occur in psychiatric practice.  Practice settings are part of the problem.  In some clinics, depending on the resources blood pressures may not be measured at all. I have received patients from some of these clinics who were treated with medications that cause hypertension or hypotension and found that their blood pressures were never checked.  I have worked in clinics where the only way that I could obtain a blood pressure or pulse reading was if I took it myself.  I have worked in other settings where blood pressures were taken, but I had no confidence in the numbers.  I found myself interviewing the patient and trying to piece together why their blood pressure and heart rates were elevated at some times but normal in others.  The only adequate assessment of the situation is that attention to blood pressure and its measurement in psychiatric settings is uneven and may be uniformly poor.

That is why an article in The Journal of Clinical Hypertension (1) caught my eye.  In the student the authors looked at 159 medical students and how they measured the blood pressure of a simulated patient against an 11-element skillset on BP measurement.  Only one student out of the 159 demonstrated all 11 skills in simulation.  The specific tasks are listed in the article and have to do with patient preparation, positioning, and the actual measurement task itself.  Some common errors in any of these areas can lead to significant differences in systolic and diastolic blood pressure measurements.  Those errors alone especially those in cuff size selection, arm positioning and patient readiness can lead to consistent false measurements in blood pressure.  As an example, I have assessed a week or two of blood pressure measurements in the mild hypertension range and after correcting the measurement techniques found that the subsequent week was all in the normal range.  This study illustrates an unacceptably high variation in these skillsets in medical students.  I am not aware of similar studies in practicing physicians.

The second article (2) is an encyclopedic reference that is a scientific consensus statement by the American Heart Association on High Blood Pressure Research.  This reference will answer any possible question about blood pressure measurement. A valuable resource from this site was a resource that provides a very extensive list of validated home blood pressure devices. It is possible to make recommendations for accurate and cost effective devices or provide the link to patients who want to explore the possibilities.

I encourage psychiatrists everywhere to make sure that blood pressures and pulses are being taken regularly and accurately.  The buck stops with the physician doing the assessment and treatment and in my opinion it is impossible to practice psychiatry without regular blood pressure measurements.  In addition to monitoring the cardiovascular status of the patient and the response to prescribed medications it provides the opportunity to diagnose a disorder that causes significant cardiovascular and cerebrovascular disease and reverse that process.

Know the 11-element skillset on blood pressure measurement.


George Dawson, MD, DFAPA


References:

1: Rakotz MK, Townsend RR, Yang J, Alpert BS, Heneghan KA, Wynia M, Wozniak GD.Medical students and measuring blood pressure: Results from the American Medical Association Blood Pressure Check Challenge. J Clin Hypertens (Greenwich). 2017 Jun;19(6):614-619. doi: 10.1111/jch.13018. Epub 2017 Apr 28. PubMed PMID: 28452119

2: Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW,Kurtz T, Sheps SG, Roccella EJ; Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Recommendations for blood pressure measurement in humans and experimental animals: Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension. 2005 Jan;45(1):142-61. Epub 2004 Dec 20. PubMed PMID: 15611362

Both of the above links are full text.



          

Dementia Prevention And Substance Use Disorders

Dementia from Addictive Compounds

As a geriatric psychiatrist and an addiction psychiatrist, what I see happening in both professional literature and lay literature is mind boggling.  There is a clear bias advocating for the benign and even therapeutic effects of alcohol and addicting drugs.  What most articles omit is that the health effects of alcohol are limited to no more than two standard drinks per day for men and one drink per day for women.  The drinks cannot be all taken on the same day.  The limits are per day not per week.  Most of the evidence also suggests that the alcoholic beverage should be wine rather than beer or distilled spirits.  Recent studies suggest that of the 70% of Americans who drink - about 1/3 of them are probably drinking in excess of those amounts.  Doing the arithmetic that amounts to about 56 million people.  Even a low percentage of brain injury will result in a significant number of cases od dementia. Moderate to heavy drinking (3-12+ drinks/day) carries the associated risks of high carbohydrate intake and sedentary life style.  It is very common to find that moderate to heavy drinkers stop their usual outdoor activities and exercise and spend a lot of time watching television.  This can lead to obesity, glucose intolerance and dyslipidemia and in the worst case scenario metabolic syndrome.  All of those consequences lead to increased risk of cardiovascular and cerebrovascular disease.  

There are addiction risks with alcohol consumption apart from atherosclerotic heart disease. Alcohol is proarrhythmic and doubles the risk for arrhythmia.  In one large Danish study (11) they noted that alcohol intake and a history of atrial fibrillation was a risk factor for ventricular fibrillation.  Some authors view alcohol use a risk factor in preventable atrial fibrillation.  In clinical practice it is very common to interview patients with atrial fibrillation who notice that during times of heavy alcohol use they can sense that they are in atrial fibrillation and they spontaneously convert to sinus rhythm as their blood alcohol levels drop.  Atrial fibrillation is a causative mechanism for embolic stroke and associated cognitive disorders.

The direct toxic effect of alcohol on the brain has been debated for years. Amnesia from Wernicke-Korsakoff syndrome is a known diagnostic entity related to thiamine deficiency associated with excessive alcohol use.  It is probably underdiagnosed in most populations compared with postmortem diagnoses of the specific lesions consistent with Wernicke-Korsakoff syndrome (WKS).  A large number of people with alcohol use problems have demonstrable cognitive effects on testing as well as structural and functional brain imaging brain imaging studies suggest some effect on brain structure.  The lack of a pathological lesion has led some to suggest that this is a non-specific effect, but it is very likely that there are several variants of cognitive dysfunction related to alcohol use that are not associated with WKS (12).  On a clinical basis it is very common to see patients with subjective cognitive impairment that typically involves working memory, declarative memory, and executive function.  In treatment setting where abstinence from alcohol is assured many of these problems seem to clear up after about 60 days of abstinence.  But there are also populations of people with varying degrees of anterograde and retrograde amnesia that is not as dense as expected with full WKS.  Many of these patients are seen in treatment settings and never referred for comprehensive assessments of their cognitive disorder.  To my knowledge there have been no studies looking at the issue of whether or not partial amnestic states correlate with WKS lesions at autopsy.        

The problems with recognizing and treating cognitive disorders associated with substance use problems are exemplified in the first few paragraphs about alcohol.  They are no less important for other commonly abused substances.  In the case of stimulants, amphetamine analogues are known neurotoxins.  Studies by Volkow and others have shown persistent changes in dopaminergic neurons up to 15 months after the last use.  This may correlate with a persistent attentional deficit that leads patients to conclude that they now have attention deficit disorder.  Additional brain insults from hemorrhagic strokes and cardiovascular problems associated with long term stimulant use are common.  Stimulants are well known precipitants of acute myocardial ischemia and brain complications from hypoperfusion and emboli.  Acute hypertension and tachycardia are part of the acute intoxication syndrome that can lead to hypertension and hemorrhagic stroke.  This recurrent cycle leads to commonly observed complications of cardiomyopathy in the 4th and 5th decades of life and heightened risk of ventricular arrhythmias and cardiac arrest.

The graphic at that top of this post is not exhaustive - but point out some significant acute and chronic complications of drug use that can lead to permanent brain injury.  These mechanisms cannot be overlooked as avoidable causes of dementia.  I will be trying to elaborate on this graphic in the future to look at developing a review in this area.  Any acute acre and addiction psychiatrist is probably more aware of these syndromes and complications because they are encountered in clinical practice.  I have not seen any formal estimates of the fraction of dementia cases are preventable by avoiding these compounds.  The largest fraction of dementia cases would likely be attributable to the most commonly used drugs - tobacco and alcohol.  Drugs that kill more people acutely on a proportional basis like stimulants and opioids probably leave fewer survivors with dementia as a complication.  

Contrary to the conventional wisdom these days - avoiding dementia is another strong argument for a sober life style.


George Dawson, MD, DFAPA


References:

1: de Gaetano G, Costanzo S, Di Castelnuovo A, Badimon L, Bejko D, Alkerwi A,Chiva-Blanch G, Estruch R, La Vecchia C, Panico S, Pounis G, Sofi F, Stranges S, Trevisan M, Ursini F, Cerletti C, Donati MB, Iacoviello L. Effects of moderate beer consumption on health and disease: A consensus document. Nutr Metab Cardiovasc Dis. 2016 Jun;26(6):443-67. doi: 10.1016/j.numecd.2016.03.007. Epub 2016 Mar 31. Review. PubMed PMID: 27118108.

Moderate consumption is defined as 1 drink per day in women and 2 drinks per day  for men in a non-binge drinking pattern. J-shaped dose-response curve

2: Fernández-Solà J. Cardiovascular risks and benefits of moderate and heavy alcohol consumption. Nat Rev Cardiol. 2015 Oct;12(10):576-87. doi: 10.1038/nrcardio.2015.91. Epub 2015 Jun 23. Review. PubMed PMID: 26099843.

U-Shaped dose-response curve

3: Matsumoto C, Miedema MD, Ofman P, Gaziano JM, Sesso HD. An expanding knowledge of the mechanisms and effects of alcohol consumption on cardiovascular disease. J Cardiopulm Rehabil Prev. 2014 May-Jun;34(3):159-71. doi: 10.1097/HCR.0000000000000042. Review. PubMed PMID: 24667667.

4: Graff-Iversen S, Jansen MD, Hoff DA, Høiseth G, Knudsen GP, Magnus P, Mørland J, Normann PT, Næss OE, Tambs K. Divergent associations of drinking frequency and binge consumption of alcohol with mortality within the same cohort. J Epidemiol Community Health. 2013 Apr;67(4):350-7. doi: 10.1136/jech-2012-201564. Epub 2012 Dec 12. PubMed PMID: 23235547.

5: Weyerer S, Schäufele M, Wiese B, Maier W, Tebarth F, van den Bussche H,Pentzek M, Bickel H, Luppa M, Riedel-Heller SG; German AgeCoDe Study group (German Study on Ageing, Cognition and Dementia in Primary Care Patients). Current alcohol consumption and its relationship to incident dementia: results from a 3-year follow-up study among primary care attenders aged 75 years and older. Age Ageing. 2011 Jul;40(4):456-63. doi: 10.1093/ageing/afr007. Epub 2011 Mar 2. PubMed PMID: 21367764.

6: Bathla M, Singh M, Anjum S, Kulhara P, Jangli S IIIrd. Metabolic syndrome indrug naïve patients with substance use disorder. Diabetes Metab Syndr. 2016 Sep 3. pii: S1871-4021(16)30183-7. doi: 10.1016/j.dsx.2016.08.022. [Epub ahead of print] PubMed PMID: 27618517

Alcohol was the main substance used by patients meeting WHO criteria for Metabolic Syndrome.

7: Vancampfort D, Hallgren M, Mugisha J, De Hert M, Probst M, Monsieur D, Stubbs B. The Prevalence of Metabolic Syndrome in Alcohol Use Disorders: A Systematic Review and Meta-analysis. Alcohol Alcohol. 2016 Sep;51(5):515-21. doi: 10.1093/alcalc/agw040. Epub 2016 Jun 23. Review. PubMed PMID: 27337988. 

1 person in 5 with alcohol use disorder has metabolic syndrome.

8: Wakabayashi I. Frequency of heavy alcohol drinking and risk of metabolicsyndrome in middle-aged men. Alcohol Clin Exp Res. 2014 Jun;38(6):1689-96. doi: 10.1111/acer.12425. Epub 2014 May 12. PubMed PMID: 24818654.

Positive correlation between heavy drinking and metabolic syndrome.

9: Yousefzadeh G, Shokoohi M, Najafipour H, Eslami M, Salehi F. Association between opium use and metabolic syndrome among an urban population in Southern Iran: Results of the Kerman Coronary Artery Disease Risk Factor Study (KERCADRS). ARYA Atheroscler. 2015 Jan;11(1):14-20. PubMed PMID: 26089926; PubMed Central PMCID: PMC4460348.

Current opioid users had the highest prevalence of metabolic syndrome (39.6%) but the study was confounded by a high baseline rate in the controls (37.2%).

10:   Brunner S, Herbel R, Drobesch C, Peters A, Massberg S, Kääb S, Sinner MF.Alcohol consumption, sinus tachycardia, and cardiac arrhythmias at the Munich Octoberfest: results from the Munich Beer Related Electrocardiogram Workup Study (MunichBREW). Eur Heart J. 2017 Apr 25. doi: 10.1093/eurheartj/ehx156. [Epub ahead of print] PubMed PMID: 28449090.

11: Jabbari R. Ventricular fibrillation and sudden cardiac death during myocardialinfarction. Dan Med J. 2016 May;63(5). pii: B5246. Review. PubMed PMID: 2712702.

12: Ridley NJ, Draper B, Withall A. Alcohol-related dementia: an update of the evidence. Alzheimers Res Ther. 2013 Jan 25;5(1):3. doi: 10.1186/alzrt157. eCollection 2013. Review. PubMed PMID: 23347747.


Supplementary:

The calculation for the following observation:

Recent studies suggest that of the 70% of Americans who drink - about 1/3 of them are probably drinking in excess of those amounts.  Doing the arithmetic that amounts to about 56 million people.

321M(current US population) - 80M (population less than drinking age) x 0.7 (percentage of population that drinks) x 0.3 percentage of excess drinkers = 56 million people.

 

Infection Disease Docs - Treating Addiction

There was a very interesting commentary in this week's New England Journal of Medicine.  In it the authors describe a case from their infection disease practice of a young man with infectious complications of intravenous heroin use ( Staph. aureus tricuspid valve endocarditis, septic arthritis, and empyema).  He had a history of doing well on buprenorphine maintenance in the past and was offered that treatment again by the Infectious Disease (ID) team as he was leaving inpatient hospital.  They completed the induction phase on the afternoon of discharge and he was discharged on buprenorphine-naloxone (Suboxone).  The ID  faculty at Beth Israel Deaconess Medical Center, a large tertiary care hospital in Boston have all been certified as buprenorphine prescribers and present this as an option to all of their patients with infectious complications of  intravenous substance use.  In addition to the buprenorphine they also provide rescue naloxone to treat acute opioid overdoses, discussions about harm reduction, injection practices, and cravings.  In the case that was presented, there was a discussion of the relapse risk and risk of recurrent infection or death from an accidental overdose.

This group of physicians has provided an outstanding example of what can be done when you are working with a highly motivated group who seizes the opportunity to make a significant difference. Part of their discussion is in terms of expanding their practice outside of the traditional role and expecting some pushback on that.   As I read their report, I thought about how this process might occur within the usual hospital setting.  A psychiatric consultation would be placed.  In tertiary centers a psychiatrist would see the patient, make a detailed assessment and recommend outpatient care somewhere.  That psychiatrist may or may not have a buprenorphine license.  Depending on location, there may not be a buprenorphine provider to refer the patient to.  In the case of intravenous heroin use that practically guarantees a relapse to heroin at the time of discharge with the attendant mortality and morbidity.  In this case the patient is familiar with the same treatment team that discusses the issue with him and gets him on Suboxone prior to discharge.  In today's world of rationed medical care - I cannot think of a more perfect intervention for high risk patients from an addiction standpoint.

The use of buprenorphine to treat opioids use disorders is not a perfect solution but it helps a large number of patients remain abstinent in general treatment populations.  The patient described in this paper was perhaps more highly motivated than most due to his complicated illnesses.  The authors experience reflects the fact that they clearly know the treatment process is complicated but view what they are doing as a bridge to long term care for opioid use disorders.  I agree with them completely.

There are a few considerations that they did not touch on that I think are important.  The personal characteristics of the physicians in this group is a major factor.   They discuss the history of their specialty as one that values social justice and public health.  They suggest this was a primary factor in allowing them to not get caught up in the stigma of treating addicts and the associated lack of resources.  I witnessed this first hand in the 1980s and 1990s when ID physicians and clinic staff were dealing with the HIV epidemic.  That went on for years before there was adequate treatment and the death toll was high.  Many ID clinics provided critical support to patient and their families during that  time.  I don't think that they ever got any recognition for that role.  Treating addiction above all else takes emotional neutrality and that was a characteristic I observed first hand in HIV clinics.        

I certainly hope that this group gets the credit for innovation and hard work that goes with this approach.  They mention a couple of other groups who have picked up on this approach.  At the same time I have concerns about how other groups may view this article.  The billing and coding system and clinic structures are generally not setup to allocate enough time to deal with two very complicated problems.  In the outpatient setting, sober homes set up to deal with the substance use and medical complications are extremely rare.  In some cases, sober homes and halfway houses refuse to accept patients taking Suboxone or other potentially addictive drugs.  It takes dedicated social work or case management staff to negotiate those problems.  It also takes some level of administrative support to know that discharging a patient as soon as possible when they are in opioid withdrawal makes little sense.

Time and burnout are also relevant factors.  The primitive state of productivity based medical administration needs to be able to accommodate this level of complex care and allot physicians enough time to provide both medical and addiction services.  I have over 20 years of experience in providing both medical and psychiatric services on inpatient settings.  Even though I enjoyed doing it - there was a tremendous time penalty associated with the additional work and that can easily lead to burnout.  If addiction care expands among specialists and generalists - they need the additional times and reimbursement to provide this level of care.

None of these considerations detracts from the accomplishment of this department of infectious disease doctors.  Taking on this additional role is especially striking in an era where patients are told that they can only discuss one problem per clinic visit with their doctors.  This approach is a shining example of the highest level of medical professionalism and my hat is off to them.


George Dawson, MD, DFAPA

1: Rapoport AB, Rowley CF. Stretching the Scope - Becoming Frontline Addiction-Medicine Providers. N Engl J Med. 2017 Aug 24;377(8):705-707. doi: 10.1056/NEJMp1706492. PubMed PMID: 28834479. (free full text).

Mind Your Back

This is one of my occasional public service announcements.  I have at least one previous post on spinal health on this blog.  Some might wonder why a psychiatrist is interested in the spine.  I had an early interest in neurosurgery and over the years have talked with people who have sustained various spinal injuries that they have recovered from or been disabled by.  These injuries are very common and can occur along any number of trajectories. They can be associated with chronic pain and result in numerous surgical or pain intervention procedures that have varying degrees of success.  Once a chronic pain state has been established it is unlikely to be resolved completely at any time in the future.

Mapped onto that landscape of acute injuries are injuries to the aging spine.  For various reasons aging has an impact on every persons spine.  Degenerative disk disease is a normative finding on imaging studies as a person ages.  Acute injuries can make a spine image appear to be older because it looks like age-related changes.  For example, I have had athletes who injured their back tell me that their physician told them that after a certain injury their x-ray "looked like a the x-ray of a 70 year old man."  Older spines may not be as dense and I have seen many people diagnosed with acute compression fractures that were either spontaneous or they occurred after a fall.  I have talked with people who had a compression fracture as a first sign of cancer from metastatic disease but I want to emphasize that this is a rare cause of acute back pain.  The commonest cause of back pain and back injury are acute accidents and per my example - acute injury to the aging spine.

Let me give a clear example.  Consider the theoretical case of Bob X.  For 35 years Bob has worked on a railroad section crew.  Even though there is a lot of mechanization on the railroad these days, Bob's strength was legendary in terms of what he could lift off the ground.  He retired at age 66 and became relatively sedentary.  He gained a substantial amount of weight and spend most of his day watching television.  He happened to be out in his yard one afternoon and his neighbor asked him  to help him lift a mower onto trailer.  Bob looked at the mower and figured it was much less than what he was used to lifting on the railroad.  He decided to lift it up by himself and set it on the trailer.  He noticed almost immediate lower back pain and then some pain radiating down his left leg.  After persistent pain for a few days he went in to see his physician and an MRI scan of the lumbar spine was done showing a minor facet fracture and an L4-5 disk herniation.  In this case we have a man who has a physically demanding job and probably became deconditioned after retirement.  He became injured when handling a load that he estimated he could easily handle based on past experience and did not factor in the conditioning aspects.

That brings me to today's example.  I needed to grease the front axles of my riding lawn mower.  It is a large Toro model and the front end is weighted for stability.  The mower weighs about 550 pounds.  I typically pick up the front end and place it on an inverted 10 gallon plastic pail.  That is essentially a dead lift of at least a foot with a weight of about 100+ pounds.  Even though I have done spinal exercises every day for the past 15 years this is a setup for an injury.  Today I started to think about mechanical advantage and remembered a brief job I had during my youth.  I helped a guy change very large earthmover tires. In the process we used a small hydraulic jack to break the beads on these tires so that we could get them off the rim.  I decided to purchase a jack to do the job.  At the store, there were a great many jacks with different capacities.  I got one with a jack stand built right into it and it also had a wide stable base.

After placing the jack under the mower I moved it into the exact position I needed by pumping the jack about three times with three fingers.  No back strain at all.  

Today's take home message is that you need to protect your spine, especially if you are aging.  Aging is associated with a number of factors that decreases the ability of the spine to sustain a load and lift effectively.  Workers and athletes who are used to sustaining high loads on their spines need to reconsider that and slow down or stop as they age.  Practically everyone has degenerative disk disease and that leads to a characteristic radiographic appearance and generally some degree of chronic back pain.  I think that a reasonable approach with aging is to exercise your back in a manner consistent with maintaining adequate conditioning of the perispinal muscles and adequate density of the vertebrae.   Those programs need to be individualized especially if there is a prior spinal problem or illness affecting the spine.  Your physician should be able to recommend a specialty program or physical therapy who can provide the exercise regimen to maintain conditioning and flexibility.  That approach can also result in significant pain relief.  Many of these programs also have individualized programs on techniques to avoid lifting injuries.

Shortcuts at home to alleviate load on the spine like the hydraulic jack in the example should be considered. There are a number of useful products like small hand trucks designed to pick up plant pots that can also be useful.  Innovation in this area is needed as the population ages.  Small assistive devices for the home need to be designed for moving the 10-50 pound loads that homeowners typically have to move around.  The goal is avoiding a spinal or musculoskeletal injury that leads to further deconditioning and risk of future injury.

There is not enough advice and information out there on how to prevent these injuries. Once they occur, trying to get the right help can be confusing and limited to medications rather than the needed physical therapy. More importantly - these injuries can result in a marked lifestyle change and decreased physical activity required to maintain general health.  Spinal health is also a part of mental health.  About 20% of people with acute back pain develop chronic pain.  Chronic pain syndromes are typically associated with anxiety, depression, insomnia and in some cases substance use disorders. That is how psychiatrists end up seeing people with chronic back pain.

Preventing back injury and chronic low back pain will also prevent all of these psychiatric comorbidities.



George Dawson, MD, DFAPA      



Disclaimer:  This is a non-commercial blog.  The pictures here depict the equipment that I have purchased and am really using.  There is no promotional consideration.




            

Making Sense of Alcohol Consumption in the USA

I don't know how many people are aware of it but a crisis of alcohol use was declared about a week ago (1) by Marc Schuckit, MD.  Dr. Schuckit is one of the top psychiatric experts in alcohol use disorders and I have been reading his work for the past 35 years.  His commentary was based on an article (2) in that same issue of JAMA Psychiatry  on the epidemiology of alcohol use in the United states in the 21st century.

Most of the researchers listed as authors of this paper are affiliated with the Epidemiology and Biometry Branch of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).  They are analyzing data collected in the National  Epidemiological Survey on Alcohol and Related Conditions (NESARC and NESARC-III)) during two different time points: 2001-2002 (N=43,093) and 2012-2013 (N=36,309).  Typical response rates were noted for both the initial selections and the individual response rates for the face-to-face interviews.  Both surveys were designed to be nationally representative samples adjusted to account for sampling error and non-response.  I interpret that to mean that the percentages listed in the following table to represent population wide numbers based on these samples. Respondents were paid $90 for participation.  The specific sampling strategies were listed in the paper.

The structured interview was the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version (AUDADIS-IV) in NESARC and AUDADIS-V in NESARC-III.  The definitions of high risk drinking are noted in the table.  DSM-IV diagnoses of alcohol abuse or dependence were given according to the suggested criteria match.  Various measures of reliability and validity of the structured interview are referenced as being fair to high.  All of the demographic variables noted in the test subjects are noted in the article as well as some discussion of how subgroups varied.  For example very  large increases were noted in practically all subgroups for 12-month DSM-IV AUD diagnoses with subjects in the 65 years and older increased by 106.7%  

Metric	NESARC (2001-2003)	NESARC III (2012-2013)	Percentage Increase
12-month alcohol use	65.4%	72.7%	11.2%
12-month high-risk drinking	9.7%	12.6%	29.9%
12-month DSM-IV AUD diagnosis	8.5%	12.7%	49.4%
12-month DSM-IV AUD among 12-month alcohol users	12.9%	17.5%	35.7%
12-month DSM-IV AUD among 12 month high-risk drinkers	46.5%	54.5%	17.2%

The trend according to this study is only in the upward direction.  The authors speculate about socioeconomic etiologies (unemployment, discrimination, income disparities, stigma of alcoholism) and increased permissiveness in what is acceptable drinking for women.  Subgroup analysis shows these groups had the highest increases in alcohol use.  The authors also point out that there are primary and secondary effects in these groups that can significantly increase the known morbidity and mortality associated with drinking such as more significant alcohol related illnesses in women for the same dose of alcohol due to decreased metabolic clearance and increased likelihood of adverse drug effects due to polypharmacy in both women and the elderly.  They also point out that alcohol related problems seem to have gone under the radar with higher visibility of less commonly used intoxicants like cannabis and hallucinogens.  I would add that permissiveness of intoxicant use in general is a cultural phenomenon and it probably not too surprising that the widespread legalization and hype about cannabis would be associated with increased alcohol consumption.  There are certainly many people with the belief that alcohol alleviates chronic pain, insomnia, anxiety, and depression as well as cannabis.  The popular notion that alcohol is a healthy beverage that provides protection against heart attacks and stroke is undoubtedly another factor.  Few people realize that the maximum number of drinks per day for men and women (2 and 1 respectively) was based on the fact that above that level the risks for cardiovascular disease and cancer increase significantly.

The new study also has some implications for other large scale estimates of alcohol use and the associated morbidity and mortality.  As an example, the World Health Organization came out with a large study in 2014 that reported on data from 2010 and 2012.  Comparison with the NESARC data shows that 12-month alcohol use (WHO v. NESARC III) is fairly close at 68.9 v. 72.7%.  Comparison of 12-month high risk drinking uses different measures.  For WHO, high-risk drinking is defined as at least 60 grams of alcohol in a single day in any 30 day period.  For NESARC III, the definition is 4 or more standard drinks on any day for women and 5 or more standard drinks on any day for men.  In the US, a standard drink is considered 14 g of pure alcohol.  That results in 16.2% of American drinkers being classified as heavy episodic drinkers and 12.6% classified as 12-month high risk drinkers.  From a diagnostic standpoint, WHO estimates that the prevalence of 12-month alcohol use disorders is 7.4% and NESARC III gives and estimate of 12.7%.  It is likely that different methodologies explain the marked difference in prevalence estimate for alcohol use disorders.  The WHO estimate was based on ICD alcohol use disorders as well as disorders representing harmful use of alcohol.  The NESARC III estimate was lay interviewers using a standard interview format to provide as DSM-IV diagnosis.  That means that the WHO estimate for alcohol use disorders based on the NESARC III data would be 20-30% higher than the 12.7% estimate.  A further note on the heavy episodic or high-risk drinking.  In treatment centers it is very common for people seeking admission to be drinking in excess of those rates on a daily basis.

A closely related phenomenon to high risk drinking is binge-drinking.  The CDC uses the same volume definition for high risk drinking but states that it occurs in an unspecified short period of time to elevate blood alcohol content above 0.08 g/dL.  According to their reviews the average binge drinker consumes 8 drinks per episode.  The main risk is alcohol poisoning.  Six people a day die of alcohol poisoning in the US, most of them are white men between the ages of 35 and 64.  Binge drinking carries with it all of the related risks of acute intoxication.

In his commentary, Dr. Schuckit reviews his concerns about the potential implications of alcohol use increases in both women and the elderly.  He points out that elderly patients almost always have co-morbid medical illnesses that will be exacerbated by drinking.  He discussed an intervention that his group did with 500 college freshmen as 4 - 50 minute internet-based videos.  The course was designed to help them recognize their vulnerability to heavy drinking.  The intervention was effective at both 6 and 12 months.  He concludes by focusing in on the threats to research funding in this area - specifically with the proposed cuts to the National Institutes of Health budget.  He suggests that supporting politicians who recognize the importance of research, identifying health crisis, and addressing them.

I think there is a lot of room to be a lot more proactive in our society.  Apart from the cultural myths that I already mentioned, a dangerous one is: "I am not an alcoholic and therefore I don't have any problems with alcohol."  The above research and others point out that it is possible to be a high risk drinker and not have a 12-month diagnosis of an alcohol use disorder.  Psychiatrists see variations of this pattern over the course of their careers.  They may be called on to assess the teenager in the ICU after they had an episode of acute alcohol poisoning after voluntarily drinking too much.  They may be called on to assess people who were violent or victimized when they drank too much.  They may have to do specialized assessments on professionals who engaged in high risk drinking for some reason and ended up placing their credentials and licensure at risk.

It is time to realize that there is much more to alcohol use than being an alcoholic or technically having a diagnosis of an alcohol use disorder.  Even one episode of high risk drinking may end or permanently alter a persons life.  Education on alcohol use is needed to dispel these popular myths and help people negotiate what is commonly a difficult decision in their life.  


George Dawson, MD, DFAPA






References:

1: Schuckit MA. Remarkable Increases in Alcohol Use Disorders. JAMA Psychiatry.2017 Aug 9. doi: 10.1001/jamapsychiatry.2017.1981. [Epub ahead of print] PubMed PMID: 28793142.

2:  Grant BF, Chou SP, Saha TD, Pickering RP, Kerridge BT, Ruan WJ, Huang B, Jung J, Zhang H, Fan A, Hasin DS. Prevalence of 12-Month Alcohol Use, High-Risk Drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: Results From the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry. 2017 Aug 9. doi: 10.1001/jamapsychiatry.2017.2161. [Epub ahead of print] PubMed PMID: 28793133.

3:  World Health Organization.  Global Status Report On Alcohol and Health, 2014 edition. 

4:  CDC Press Release November 20, 2014.  Most people who drink excessively are not alcohol dependent. 

5: Quinn AE, Brolin M, Stewart MT, Evans B, Horgan C. Reducing Risky Alcohol Use: What Health Care Systems Can Do. Issue Brief (Mass Health Policy Forum). 2016 Apr 27;(46):1-50. PubMed PMID: 27911073.

6: Stahre M, Roeber J, Kanny D, Brewer RD, Zhang X. Contribution of excessive alcohol consumption to deaths and years of potential life lost in the United States. Prev Chronic Dis. 2014 Jun 26;11:E109. doi: 10.5888/pcd11.130293. PubMed PMID: 24967831; PubMed Central PMCID: PMC4075492. 

7: Landen M, Roeber J, Naimi T, Nielsen L, Sewell M. Alcohol-attributable mortality among American Indians and Alaska Natives in the United States, 1999-2009. Am J Public Health. 2014 Jun;104 Suppl 3:S343-9. doi: 10.2105/AJPH.2013.301648. Epub 2014 Apr 22. PubMed PMID: 24754661; PubMed Central PMCID: PMC4035890. 

8: Gonzales K, Roeber J, Kanny D, Tran A, Saiki C, Johnson H, Yeoman K, Safranek T, Creppage K, Lepp A, Miller T, Tarkhashvili N, Lynch KE, Watson JR, Henderson D, Christenson M, Geiger SD; Centers for Disease Control and Prevention (CDC). Alcohol-attributable deaths and years of potential life lost--11 States, 2006-2010. MMWR Morb Mortal Wkly Rep. 2014 Mar 14;63(10):213-6. PubMed PMID: 24622285. 

9: Sacks JJ, Roeber J, Bouchery EE, Gonzales K, Chaloupka FJ, Brewer RD. State costs of excessive alcohol consumption, 2006. Am J Prev Med. 2013 Oct;45(4):474-85. doi: 10.1016/j.amepre.2013.06.004. PubMed PMID: 24050424. 

10: Nelson DE, Naimi TS, Brewer RD, Roeber J. US state alcohol sales compared to survey data, 1993-2006. Addiction. 2010 Sep;105(9):1589-96. doi: 10.1111/j.1360-0443.2010.03007.x. Epub 2010 Jul 9. PubMed PMID: 20626370. 

11: Woerle S, Roeber J, Landen MG. Prevalence of alcohol dependence among excessive drinkers in New Mexico. Alcohol Clin Exp Res. 2007 Feb;31(2):293-8. PubMed PMID: 17250622.

12:  WHO Global Information System On Alcohol and Health: http://www.who.int/gho/alcohol/en/


Supplementary:

Click to enlarge and clarify the graphic at the top of this post.

Supplementary:

This article was published after the original post and is presumptive evidence that the trend in consumption is real:

Death Rates for Chronic Liver Disease and Cirrhosis, by Sex and Age Group — National Vital Statistics System, United States, 2000 and 2015. MMWR Morb Mortal Wkly Rep 2017;66:1031. DOI: http://dx.doi.org/10.15585/mmwr.mm6638a9

The Google Memo

I decided to comment on the now famous (or at least viral) Google memo as an anchor point for social media on the blog. After making its way through the social media and into the mainstream media, I don’t think that it is necessary to say much about it other than it was written by a Google software engineer James Damore who was subsequently fired for the effort. I qualify my statements by saying that I do not know this engineer or anything about the corporate culture at Google other than what was written in his long memo. I do have 33 years of experience steeped in every aspect of medical culture. That includes working for corporations that have implemented many of the initiatives discussed in the memo. My overall take is that corporate politics can be dangerous to your health, but not because of major party politics.

The Memo presents a confusing introduction. The author states that he does not believe in stereotypes but proceeds to argue from that viewpoint. He discusses the predominate liberal atmosphere at Google and what that means in terms of liberal stereotypes. He refers to himself as a classic liberal, but at the same time complains about and refers to being discriminated against as a conservative. Despite the ample qualifiers, there is an implicit suggestion that due to inherently different characteristics – it may not be possible for a substantially male population in coding to be altered in material ways and that the programs in place to do an end run around this issue are not cost effective for the company. It is a strong argument to maintain the status quo.

As a kid growing up in the 1960s, female physicians were unheard of.  In the subsequent decades all of that changed drastically.  When I started in medical school, about half of the class was women, but women were substantially underrepresented in largely surgical specialties. There were clear problems with the transition. I can recall rounding where there were open arguments and verbal attacks based on gender by people at the same level of training. As a medical student I was privy to the private conversations of both sides and in those days it was all about gender. But thankfully only in a few areas. I had the opportunity to train with attendings and residents who were women and who were first rate physicians and academicians. Because of the gender based undercurrent, I also felt the backlash. Being an introvert is like being a projective test for some people. I got feedback from a male resident that the female attending on one of my rotations thought that I did not like women and that was just inaccurate. I attributed it and some other attitudes from a few women I encountered to biases they may have encountered along the way. I won’t say that did not have an effect on me – but it did not adversely impact my progress on the path to being a physician.

By the time I became a resident, half of my class was women. I viewed them as colleagues. They were all clearly as bright as I was. The farther I got into psychiatry, the more remote the gender biases seemed to be. I was eventually hired into a department that was largely women. It had a collegial atmosphere. In all areas of patient care, I never doubted that the work they were doing was at the level of my work. I would not hesitate to refer people to them or consult with them in tough situations and do so even today. In psychiatry, women are well represented in professional societies, scientific meetings and publications. I have never heard a male psychiatrist utter a word about women being less skilled or professional in psychiatry. It would be taken as an absurd statement.

The brief recap of my experience of gender representation in psychiatry has its limitations. It is my experience over 30 years in the field. It is in a field that is in short supply and may be dying – rationed out of existence by the government and managed care companies. For many years, interest in psychiatry was low. The problem has never been studied to my knowledge but my speculation is that enrollment by women in both medical school and psychiatric residency programs probably averted a much greater crisis. I can’t speak to the initiatives that got the enrollment in medical schools to go higher, but whatever it was – consider it highly successful.

That does not mean it was an easy transition.  Although I never personally witnessed it, I have no doubt that women and minority students were treated badly at some point in their medical training.  I base this on my own experience of being treated badly.  There were clearly attending physicians who were not interested in the education of medical students and were openly hostile.  I was ridiculed in front of one of my teams by the attending physician when he learned that I was going into psychiatry.  "You don't want to work Dawson?  Psychiatrists don't work as hard as other physicians and if I needed counseling I wouldn't see a psychiatrist".  All of that was presented with a congruent sneer. I held back at that time at the time, and did not tell him it would probably take years of psychoanalysis rather than a few counseling sessions.  

I observed in those days that the abusive cultures seemed to be localized in private institutions.  I naturally gravitated to the public ones - the County Hospital and Veteran's Administration Medical Center.  In these places there was a certain  esprit de corps.  There was a lot of work.  The staff were interested in caring for very ill patients with limited resources being available.  There was generally a wide sampling of specialists and everyone seemed accepting of medical students and residents as long as they pulled their own weight.  I met some of the best attendings and teachers in these settings.

The corporate takeover of medicine facilitated by the federal government created a hostile and authoritarian atmosphere.  Instead of being responsible for your own knowledge and how you took care of patients you were now burdened with totally subjective administrative standards.  The first was the new billing and coding standards.  Miss a bullet point in the document and get accused of fraudulent billing.  Send that bill in the mail and get accused of racketeering and go to Leavenworth.  People may find that humorous now, but I can assure you that in about 1996, every physician in my organization had to attend a seminar and that is part of what we were told.  As the feds transferred their power to intimidate to managed care organizations a whole new set of rules to intimidate and control physicians was put into place.  The "disruptive physician" concept was suddenly co-opted from physicians with clear personality disorders to just about anything that a physician did that somebody did not like.  In some institutions the accusations did not have to be witnessed or even factual.  Some institutions just adapted a "three strikes and you are out" policy.  In other words, if they collect 3 unsubstantiated, unwitnessed and (according to their rules) uncontested complaints - the physician could be fired.  That was a discretionary rule, I have seen physicians fired for just one complaint.  By the time the corporations had taken over, these rules were equally applied regardless of gender or race.  I personally know male and female physicians who were fired or who just collected a strike or two.  Equal oppression by the corporation may be the ultimate sign of egalitarianism.            

I am going to digress for a minute on the science of the memo, because the author seems to invoke this theme several times, even to the point of offering to send more references.  This memo is not a scientific endeavor, it is a political one.  In that process, even the extremes of liberalism and conservatism will be able to come up with scientific papers to support their extreme positions.  Even though there is a general consensus on climate change this is an example.  Not everyone agreed with Einstein's revolutionary theory and at the time his work was highly politicized based in part on his ethnicity.  The process of science is not designed to be taken in a political context.  The other aspect of the science of the memo has to do with measurement.  Measurement in the social sciences is a very approximate matter.  It requires individualized expert interpretation in a highly specific context.  I have lost count of the number of professional people that I know who were told by guidance counselors that they would never make it in college.  Measures of personality and intelligence have significant limitations.  They are not qualitative by any means.  One interesting conceptualization of the problem is Massimo Pigliucci's graph of empirical knowledge versus theoretical understanding.  On this graph, theoretical understanding of social sciences is definitely lagging.  Even though there is a well publicized reproducibility problem in social sciences, I consider that to be expected rather than a problem that needs to be solved.  In situations where the human conscious states is the subject of analysis, it is necessary to keep in mind that we have no adequate analysis of a very large number of possible states and how they overlap between men and women.  There is nothing to suggest that interracial differences at this level are significant.  Everyone has a somewhat heritable biological substrate, but in the case of the brain we have an infinitely plastic and complex organ that we are just beginning to understand.  It is easy to mistake the positive and negative effects of socialization for a biologically inherent trait.      

My experience in the workplace, at various levels of medical and scientific endeavor has made it very clear - irrespective of socialization or biology - men and women can function interchangeably doing the same tasks. The idea that one sex is intellectually superior or has personality characteristics that can lead to inherently better performance in the workplace is just plain wrong. I certainly can't speak to the workplace or political environment at Google, but I can say that the political environment in most real workplaces these days is dominated by corporate rather than major party politics. That corporate approach opens a number of avenues for the corporation to demand specific compliant behaviors from employees with possible penalties right up to termination.   Squabbling about major party politics at the water cooler pales in comparison.

It turns out that every corporation is an "ideological echo chamber" but that ideology originates at the level of the executives and the board of directors.  It is overwhelmingly focused on the best interests of the corporation and not the employees.  Attempting to impact that with a generally released memo like this one is a naive mistake and it misses the mark for many reasons.  The commentary from outside of the organization is predictable given the source, and of course entirely irrelevant to the intended purpose of the memo. And lastly, Damore's ideas about why men make superior software engineers is possibly accurate but I doubt it.  The women I have gone to school with and worked with were very bit as good as the men in those settings.  Engineers may be tempted to say that medicine is not software engineering and that is true, but for some of us there are a significant number of quantitative sciences and mathematics courses long the way.

And it was always obvious to me that we need as many women in those classes and professional schools as possible.



George Dawson, MD, DFAPA

Supplementary 1:  I could not work this into the main body of the post but the social media spin on this memo has been intense.  Spins saying that it has the science right and spin saying that it has the science wrong.  The author having to defend himself on the issue of whether or not he supports the alt-right.  He said that women aren't good at tech and he has said that there are women who are good coders at Google.  The reality is that women can do what men do and at no point in our history has there been more proof of that.  That is a much different issue from corporate governance or politics.

  

Reference:

1:  James Damore.  Google's Ideological Echo Chamber.  July 2017.

      It is available from several sites on the Internet.    

Computational Psychiatry

From Reference 1

In the 1970s I was reading a lot of science fiction in the Peace Corps. One of those books had a story about a scientist who had figured out all of the mathematical equations for human behavior. Although it was clearly fiction that thought stayed in my mind over the decades. When I was doing quantitative EEG work in the 1990s, I thought about it but it was apparent that the statistical models being used for that work were not remotely related to the observed behaviors that these devices were trying to classify – and there was always some clinical variable (eg. Did the subject have an alcohol problem or traumatic brain injury?) – that seemed to make the equations even more approximate. An electrical engineer that I was working with was able to apply a complexity measure to the output from a single electrode from an EEG and demonstrate the expected decrease in complexity with neural networks in Alzheimer’s Disease. That metric was interesting but not at the level where second to second behaviors could be examined. It was more of a brain state function.

That brings me to the recent article in JAMA Psychiatry entitled “Association of Neural and Emotional Impacts of Reward Prediction Errors With Major Depression”. Reward prediction errors are the difference between experienced and predicted rewards. The authors note that if the reward exceeds the expectation then “the value associated with the chosen option is increased, making it more likely to be chosen again.” As I read this, I thought about the case of chronic addiction where that is no longer the case and the maladaptive choice is made over and over again. I also thought about the subtler case of low frequency unexpected rewards. A common experience would be the “Aha” experience that universally occurs when problems are suddenly solved and exam questions answered after a unique insight is realized. As I tell my students, there is good evidence that if we put the person’s head into an fMRI scanner right at that instant that their nucleus accumbens would be lighting up. There does appear to be a lot more going on that the difference between experienced rewards and expected rewards.

This study looked at the issue of whether depression attenuates ventral striatal reward prediction errors (RPEs) in a task that did not involve a significant learning component. It was already known that there were attenuated RPE signals in the ventral striatum of people with depression during reinforced learning. It was also known that in healthy controls RPE variation explains momentary mood fluctuations.

The experiment itself consisted of two phases. In the first, a laboratory study looked at 34 subjects and 10 controls with diagnoses of depression after fairly rigorous exclusion criteria were applied at the clinical and fMRI level. The majority of the experimental group and half of the controls were women. It appears that all of the depressed patients were taking antidepressant medication. The subjects completed a risk decision task that did not require any learning and was designed so that performance by the depressed patients and controls was the same. The task consisted of 160 trials where the subject was asked to choose monetary gambles with two outcomes. The outcomes were given in real money. They were then asked to rate their happiness on an analog scale in response to the question: “How happy are you at this moment?” During the tasks, fMRI blood oxygen level dependent (BOLD) activity was measured. The MRI plane was optimized to view the ventral striatum. In the graphics both transverse and coronal MRI planes are depicted with the pixelated areas of interest in the ventral striatum.

In the second phase of the experiment, the risky decision tasks was translated to a smartphone app, The Great Brain Experiment (http://www.thegreatbrainexperiment.com). A total of 1833 participants completed 30 choice trials and 12 ratings. They were not compensated.

In terms of results, the depressed group and controls had similar earning on the probabilistic reward task ($7.75). Median reaction times and choice accuracy were also similar. Ventral striatal BOLD activity on the fMRI correlated with reward magnitude and did not differ between depressed subjects and controls. A lack of difference between these groups was also examined across reward magnitude, anhedonia, and antidepressant use and no differences were found.

In the smartphone sample, the momentary mood computational model (see above equation) correlated with happiness ratings. The model worked better is severe forms of depression. Anhedonia did not correlate with the impact of RPEs but other depression questions on the Beck Depression Inventory-II did.

The authors conclude that their results demonstrate that there is no impairment in “basic reward-related neural and emotional processes in depression in a non-learning context”. The dopaminergic RPE signal was the same in the depressed group and controls. They make the further arguments that dopamine signaling in the ventral striatum is complex and other factors are involved. They discuss a model from the literature that discusses the cognitive deficit in depression as one of goal directed reasoning based on a model of the causal structure of the world. They imply that dopamine at least in the studied reward systems may not have a central role in depression.

The authors discuss a major limitation of their study in that only 9/32 subjects with depression were unmedicated. They discuss how they examined some parameters that suggests this effect was not significant. An ideal study would look at both the effects of severe depression (PHQ-9 score here was 15.8 [SD 4.7]) , no medications, and patients who have never been medicated. It might be useful to consider more rigorous elimination of other disorders affecting the ventral striatum. All things considered it is a useful look at an experimental paradigm that demonstrates the utility of brain imaging in applications that can be used on a wider population basis and whether or not they may be valid.

The accompanying editorial by Rabinovich and Varona was interesting.  They make the argument that the global conscious state is too complex to be described by mathematical equations but various components are not.  They go on to describe their own model of global brain networks and how they interact with one another.  They suggest that brain networks are very similar and vary only in content and the complexity of their content.  As an example in the creativity process, the channels stay the same whether the process involves music, poetry, or mathematics.  They suggest the same processes are active in psychiatric disorders and illustrate cognitive and ritual heteroclinic channels in obsessive-compulsive disorder.  They suggest that these dynamic systems in the brain can be determined and can be quantitatively characterized by various means like the value of the Kolmogorov-Sinai entropy. Mathematically modeling the brain as dynamic systems has been around for some time.  I will have to review this work but it seems that it may not incorporate enough of the physical characteristics of the systems into the mathematics.

Finally, I would be remiss if I did not mention the excellent review by Wang and Krystal (3) and well as many of their other articles on computational psychiatry.  Their definition of computation psychiatry is a discipline that seeks to incorporate the computational mechanism from a real neural network into its role in psychiatric disorders and the way a person actually functions.  This is an exciting approach because it represents the ultimate integration of all of the anatomy, physiology and pharmacology that we study into a real working system. It is exactly where the field needs to be heading.  I think there is a natural overlap with the study of human consciousness.

These are exciting times and computational psychiatry is adding to that mix. 

George Dawson, MD, DFAPA

References:

1:  Rutledge RB, Moutoussis M, Smittenaar P, Zeidman P, Taylor T, Hrynkiewicz L, Lam J, Skandali N, Siegel JZ, Ousdal OT, Prabhu G, Dayan P, Fonagy P, Dolan RJ. Association of Neural and Emotional Impacts of Reward Prediction Errors With Major Depression. JAMA Psychiatry. 2017 Aug 1;74(8):790-797. doi: 10.1001/jamapsychiatry.2017.1713. PubMed PMID: 28678984.

2:  Rabinovich MI, Varona P. Consciousness as Sequential Dynamics, Robustness, andMental Disorders. JAMA Psychiatry. 2017 Aug 1;74(8):771-772. doi: 10.1001/jamapsychiatry.2017.0273. PubMed PMID: 28564683

3:  Wang XJ, Krystal JH. Computational psychiatry. Neuron. 2014 Nov5;84(3):638-54. doi: 10.1016/j.neuron.2014.10.018. Epub 2014 Nov 5. Review. PubMed PMID: 25442941

4: Keller K, Mangold T, Stolz I, Werne J. Permutation entropy: new ideas and challenges. Entropy 2017, 19(3), 134; doi:10.3390/e19030134

Contains a section on Kolmogorov-Sinai Entropy and a discussion of EEG applications.

5: Donoso M, Collins AG, Koechlin E. Human cognition. Foundations of human reasoning in the prefrontal cortex. Science. 2014 Jun 27;344(6191):1481-6. doi: 10.1126/science.1252254. Epub 2014 May 29. PubMed PMID: 24876345

I included this reference as a great example of the network in the frontal cortex that are active in reasoning and activation of the ventral striatum during good decisions (the "aha effect").

6: Piray P, Toni I, Cools R. Human Choice Strategy Varies with Anatomical Projections from Ventromedial Prefrontal Cortex to Medial Striatum. J Neurosci. 2016 Mar 9;36(10):2857-67. doi: 10.1523/JNEUROSCI.2033-15.2016. PubMed PMID:26961942.

7: Jarbo K, Verstynen TD. Converging structural and functional connectivity oforbitofrontal, dorsolateral prefrontal, and posterior parietal cortex in the human striatum. J Neurosci. 2015 Mar 4;35(9):3865-78. doi: 10.1523/JNEUROSCI.2636-14.2015. PubMed PMID: 25740516.