Coffee Shop Neuroscience

I went into my favorite coffee shop the other day for my usual mocha.  They typically post a trivia question of the day that gives you a 10 cent discount on the coffee.  After a conference with a recent focus on neuroscience it was interesting to see a question about the number of thoughts per day.  My wife ventured a guess.  I asked the barista for the source and all that she could tell me was: "We get it off the Internet like most of our questions."  No footnote or reference available.  The source was not difficult to find.  It was a typical Internet site that has never impressed me as a knowledge source, but it did have a link to the original paper.  It turns out to be a neuroscience site - The Laboratory of Neuroimaging (LONI) at UCLA.  Read the fine print at the bottom of this page for qualifiers on what counts as a thought.  I looked for any papers on this estimate on the web site as well as Medline and did not come up with anything.

Irrespective of the methodology the question poses interesting questions for clinical psychiatrists if they are comfortable outside the confines of the DSM.  How much attention is being paid the the baseline conscious state of the patient and why might that be important?  What is their stream of consciousness every day?  Is it disrupted by mental illness or addiction?  To what extent is that stream of consciousness broken up into daydreams, memories, and fantasies?  To what extent is it impacted by a process that is not even suggested by the DSM?  The best example that I can think of is boredom.  Being easily bored can be a diagnostic criterion, but it seems to be an uneasy mental state on its own.  People who are bored get driven to do things to alleviate boredom and sometimes those activities are very risky.  Are the thoughts mentioned in the coffee shop question memories, fantasies, or daydreams? Why the large number?  I am not aware of brief frequent thoughts.  My stream of conscious thought is comprised of more coherent stories or images.

I did a Grand Rounds on fantasy and daydreaming about 15 years ago.  There has never been much quantitative work on fantasy.  There were some new research approaches to daydreaming being used at the time and I incorporated some of those references into the presentation.  I don't recall the exact number of daydreams per day but they were considerably less than 100.  The only research approximating the numbers of thoughts per day may be the research on the exact number of spoken words per day.  This research has generally been a comparison between men and women and a test of which sex speaks the most words.  Those numbers across different cultures and sampling periods range from 12,867 to 24,051 words per day (5).  Standard deviation were large and the authors conclude that on the average both sexes spoke about 16,000 words per day.  To me speech and language is unconsciously processed thought, but even counting all of those words does not get us to the level of the coffee shop question.  Do the authors believe that they have a way to capture tens of thousands of unconsciously processed thoughts?  I am very interested in hearing how they arrive at these figures.

The research in this area has since moved into the area of the wandering mind.  Wandering mind is defined as a cognitive focus on information unrelated to the immediate sensory input or task on hand.   It would include daydreams, fantasies, and the typical stream of consciousness that every person experiences at times throughout the day.  The critical research questions include when is mindwandering adaptive as is the case of generative fantasies and when it is maladaptive?  Smallwood, et al (7) have written an excellent brief review of how mindwandering can negatively impact medical decision making and the cognitive performance of physicians.  They point out that fatigue, depression, and circadian rhythm disturbances can lead to increased mindwadering with negative consequences by decoupling attention to the external environment from the necessary memories, patterns and access to decision-making that are the physician's cognitive set.      
    
The question also involves neuroscience.  Is there a physical representation of this process in the brain and what is it?  Neuroscience tells us that the brain has a Default Mode Network (DMN).  It was initially noted to be a network of brain regions that remain active during functional brain imaging studies in the absence of an external task.  These studies typically involve an active task for the research subject and the resulting brain image is analyzed as a response to that stimulus.  It was determined that this DMN comprises the system that allows for internal dialogue and stimulus-independent thought.  The physical representation includes a primary system comprised of the anterior medial prefrontal cortex (aMPFC) and the medial posterior cingulate cortex (PCC) communicating with two subsystems.  The medial temporal lobe subsystem is comprised by the retrosplenial cortex (RSP), parahippocampal cortex (PHC), hippocampal formation (HF), the ventral medial prefrontal cortex (vmPFC), and the posterior inferior parietal lobule (pIPL).  The dorsal medical prefrontal cortex subsystem is comprised of the temporal pole (TempP), the lateral temporal cortex (LTC), the temporoparietal junction (TPJ), and the dorsal medial prefrontal cortex) (1).  Some groups differ on the physical representation of this system and some groups use Brodmann area designations.  I drew a slightly different model based on Sporn's text (6) with some obvious distortion due to the lack of a three dimensional representation (the rTC should be folded over to the right temporal area away for the medial view):

Subsequent research has shown that the DMN may be implicated in several psychiatric disorders (2). Several functions for the DMN have been proposed that cut across a number of disorders including mind-wandering when no specific external stimulus is present, memory consolidation, to possibly maintain a baseline level of arousal, to divide attention across tasks and for continuity across time (3).  Disruptions and functional disconnects to the DMN have been studied for a number of psychiatric disorders.  If the conceptualization is correct it is useful to think about the implications of functional or anatomic disconnects or hyperconnects to other systems.

How is all of this relevant to psychiatry?  Consider the case of two patients with severe depression.  They both have insomnia, anhedonia and decreased appetite.  They both have typical depressogenic thought patterns including abundant self criticism, hopelessness, and suicidal thoughts without intent to harm themselves.  The only difference is that one of these patients has intense rumination about a job loss.  This patient was downsized along with 50 other people.  The job loss was a straight business decision rather than any performance deficiency.  The patient without rumination is treated with standard methods and recovers.  The patient with intense rumination does not.  The depression and rumination persists despite multiple antidepressant trials.  The degree of disability persists.  There is not much guidance about how to treat this person from a biological standpoint.  It comes down to empirical drug trials and additional treatment for what has been considered anxiety, psychosis, or possible obsessive compulsive disorder.  I have seen these patients recover with detoxification from drugs or alcohol, treatment with antipsychotics, treatment with electroconvulsive therapy, but not treatment with benzodiazepines.  Will the cognitive neuroscience that incorporates models of the wandering mind and default mode network offer fast and more effective treatments?  I think that we may already be seeing that.  Mayberg's classic 2005 article (8) explicitly testing the network hypotheses about treatment resistant depression with deep brain stimulation was a start.  That literature has greatly expanded since that point.

There has been an explosion of network based theories of both psychopathology and normal conscious thought in the past decade.  These models are increasingly relevant as psychiatry is dragged out of a receptor and reuptake protein based discipline, where the practitioners may have a vague idea of where those receptors are located and what they really might be doing.  It was a necessary second step, but only neuroscience will get us to better models and models that we can apply to the treatment of unique individuals.  Psychiatrists have a critical decision to make at this point.  Are we going to remain stuck in a diagnostic and treatment paradigm that clearly applies to a minority of the people with mental illness or are we going to embrace the science that will both allow us to treat everyone better and give us a more complete understanding of human consciousness?

Learning about the Default Mode Network is a good starting point.  


George Dawson, MD, DFAPA



References:

1;  Barron, DS, Yarnell S.  Default Mode Network: the basics for psychiatrists.  Fundamentals of neuroscience in psychiatry.  National Neuroscience Curriculum Initiative.

2:  Mohan A, Roberto AJ, Mohan A, Lorenzo A, Jones K, Carney MJ, Liogier-Weyback L, Hwang S, Lapidus KA. The Significance of the Default Mode Network (DMN) in Neurological and Neuropsychiatric Disorders: A Review. Yale J Biol Med. 2016 Mar 24;89(1):49-57. eCollection 2016 Mar. Review. PubMed PMID: 27505016; PubMed Central PMCID: PMC4797836

3: Mason MF, Norton MI, Van Horn JD, Wegner DM, Grafton ST, Macrae CN. Wandering minds: the default network and stimulus-independent thought. Science. 2007 Jan 19;315(5810):393-5. PubMed PMID: 17234951; PubMed Central PMCID: PMC1821121.

4: Stafford JM, Jarrett BR, Miranda-Dominguez O, Mills BD, Cain N, Mihalas S,Lahvis GP, Lattal KM, Mitchell SH, David SV, Fryer JD, Nigg JT, Fair DA. Large-scale topology and the default mode network in the mouse connectome. Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18745-50. doi: 10.1073/pnas.1404346111. Epub 2014 Dec 15. PubMed PMID: 25512496

5: Mehl MR, Vazire S, Ramírez-Esparza N, Slatcher RB, Pennebaker JW. Are women really more talkative than men? Science. 2007 Jul 6;317(5834):82. PubMed PMID:17615349.

6: Olaf Sporns.  Networks of the Brain.  MIT Press.  Cambridge, Massachusetts, 2011.

7: Smallwood J, Mrazek MD, Schooler JW. Medicine for the wandering mind: mindwandering in medical practice. Med Educ. 2011 Nov;45(11):1072-80. doi: 10.1111/j.1365-2923.2011.04074.x. PubMed PMID: 21988623. (link to free full text).

8: Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM,Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron. 2005 Mar 3;45(5):651-60. PubMed PMID: 15748841.

9: Christoff K, Irving ZC, Fox KC, Spreng RN, Andrews-Hanna JR. Mind-wandering asspontaneous thought: a dynamic framework. Nat Rev Neurosci. 2016 Nov;17(11):718-731. doi: 10.1038/nrn.2016.113. PubMed PMID: 27654862


Supplementary 1:

Olaf Sporn's book Networks of the Brain is an excellent resource to study this topic and to try to catch up on a decade of research:

Supplementary 2:

Default Mode Network links that are relevant for psychiatrists (unedited):

"default mode network" dementia

"default mode network" addiction

"default mode network" "bipolar disorder"

"default mode network" schizophrenia"

"default mode network" ADHD 

"default mode network" depression

"default mode network" anxiety

"default mode network" mind-wandering

"default mode network" day dreaming


Supplementary 3:

The answer to the coffee shop question is a.

UW 3rd Annual Update - Treatment Resistant Depression

There were two presentations relevant to depression that were given at the UW conference this year.  The first was from Karen Dineen Wagner, MD, PhD from the University of Texas Medical Branch in Galveston, Texas.  Her message was a mix of the old and the new.  The old is the state of pharmacology of depressed children seems to have changed very little over the past 20 years.  This seem largely due to the fact that there have been few successful antidepressant trials in children.  This has led to the state where there are only two FDA approved medications fluoxetine and escitalopram based on a total of 4 clinical trials.  She  showed an additional 14 clinical trials of typical antidepressants including 3 that were positive for citalopram and sertraline but an additional negative study for the FDA approved medication escitalopram.  The difficulty in many of these trials is a high placebo response rate in the trials (40% greater than in adult clinical trials).  She recommended an informed consent approach explaining to the parents any time an off label approach was being used and the rationale for using any medication based approach.  She also recommended starting with the FDA approved medications for pediatric depression.

Her suggested approach to depression in children and adolescents is to start out with an FDA approved SSRI plus cognitive behavior therapy (CBT).  This is the most evidence based approach with the evidence rapidly disappearing at subsequent levels where the usual augmentation and substitution steps that are typically used in adults were suggested.  The Treatment for Adolescents with Depression (TADS) study was presented with the recovery rates for fluoxetine, fluoxetine + CBT, and CBT alone at 12, 18, and 36 weeks were presented.  The fluoxetine + CBT arm had superior results at 12 and 18 weeks but at 36 weeks the recovery rates were similar at 86% versus 81%.  Those are good results for any antidepressant trial and the placebo response rate in this study was more similar to the adult placebo response rate.  The results of this study were presented as a rationale for using antidepressants in adolescents with severe depression and/or suicidal ideation since the response rate for fluoxetine + CBT were faster than fluoxetine or CBT alone at 12 and 18 weeks and essentially the same at 18 and 36 weeks.

The issue of strategies for addressing SSRI resistant depression were presented in the form of a previous trial where 334 adolescents with SSRI treatment failures were randomized to a different SSRI or venlafaxine or SSRI + CBT or venlafaxine + CBT.  The trial done by Brent, et al showed that there was no difference in response rates switching to another SSRI or venlafaxine but switching antidepressants and adding CBT produced superior results.  Sides effects were greater for the venlafaxine arm with a slight increase in diastolic blood pressure and heart rate and a four fold increase in skin rashes - a complication that I have rarely seen in adults.  The overall impression was that CBT was the most effective intervention for adolescent depression but I am sure that most psychiatrists in the crowd were left wondering: "If I can't find CBT therapists for my adult patients with depression - what are the odds I can find them for my adolescent patients?  To me that has always been the critical shortage in psychiatry - not the number of people who can prescribe medications.

Others trials of medical interventions (omega-3 fatty acids, ECT, TMS, bright light therapy), psychotherapies (Interpersonal Therapy(IPT), family based IPT), and exercise were sparse.  Computer-based CBT has always been an underutilized modality and it showed that there were similar response rates between treatment-as-usual and an interactive fantasy based CBT called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts).  In the game the child chooses an avatar and the goal is to restore balance in a fantasy world dominated by GNATS (Gloomy Negative Automatic Thoughts).  The SPARX game is available free online to residents of New Zealand.  New Zealand and Australia have been pioneers in the area of online CBT.  To find resources just Google "SPARX virtual therapy for depression".

Paul Holtzheimer, MD provided the adult perspective in the topic Management of Treatment Resistant Depression in Adults.  He made the epidemiological point that treatment resistant depression (TRD) is present in 10-33% of patients with major depressive disorder and in the U.S. that is about 1-3% of the population.  He had a fairly comprehensive agenda covering pharmacotherapy and augmentation strategies, electroconvulsive therapy, more recent non-invasive electromagnetic therapies and deep brain stimulation.  There was nothing new on the medication front.  After reviewing the basic medication groups, he suggested that the newest antidepressants offered no advantage over earlier medication.  He suggested that monoamine oxidase inhibitors (MAOIs) were being underutilized as a treatment for depression unresponsive to standard agents.  In the moderated discussion Ned Kalin, MD - the head of the department of psychiatry at the University of Wisconsin agreed.  The speaker said that he typically used phenelzine and tranylcypromine.  I personally have not prescribed either of these agents in some time.  I recall using them in situations where the person has treatment resistant depression and did not have any responders.  In those situations, response rates tend to be low anyway.  The other problem is that you have to think that your chronically depressed patient is going to be motivated and cognitively intact enough to adhere to the necessary diet, report what could be significant side effects and not try to kill themselves with the medication.  During the discussion there was a report of one patient who decided to eat high tyramine content food (prohibited on this diet due to a the risk of a hypertensive reaction) - have a stroke and die.  The patient in this case did have a stroke but did not die.  I personally know of situations where strokes have occurred, so this strategy is not without risk.

The augmentation strategies discussed were right out of STAR*D with the exception of using atypical antipsychotics with antidepressants.  Dr. Holtzheimer said that this was probably the most common augmentation strategy and the risks were discussed.  He and Dr. Kalin were advocates of augmentation with lithium and triiodothyronine (T3).  There were three slides on STAR*D showing cumulative remission and remission rates across all levels of care.  Those rates were 33% with initial monotherapy and 66% after 4 treatments and as expected less remission rates at each level of treatment change.  Dr. Holtzheimer made the point that the current rates of remission with medication and psychotherapy have really not changed since the 1950s and that makes electroconvulsive therapy (ECT) the most effective antidepressant treatment with a 50-75% remission rates and a >50% relapse rate in the first 6 months.  He touched on novel pharmacological agents categorized by neurotransmitter, neuroendocrine, or immunological systems.  He did not say much about ketamine (there is an intranasal preparation in clinical trials right now) but did mention that there is a IL-6 (cytokine) antibody trial going on right now.

He moved on to talk about more invasive therapies.  He presented a graphic that was a drawing by Papez.  To anyone trained in neuroanatomy around the time I was in medical school, many anatomy professors would present a saggital section of the brain and refer to the limbic structures as the Papez circuit.  At first I thought the drawing had a surprising amount of detail for a 1937 publication but then I went to the original article online (AMA web site) and found that the original drawing was not used.  The 1937 drawing had the surface anatomy correct but no tracts.  Papez mentions the amygdala three times in the last few paragraphs of his article but does not label it in the drawing.  Dr. Holtzheimer used this slide as a prelude to an article by Mayberg (3) providing a rational for deep brain stimulation as treatment for depression.  I plan to come up with a separate post in this technology based on several sources but right now there are a number of centers looking a deep brain stimulation for depression and addiction.  Dr. Holtzheimer briefly commented on transmagnetic stimulation (TMS).  There are apparently 4 FDA approved devices, use is expanding and insurance reimbursement is expanding.  He said it was 50% effective for treatment resistant depression.  I am highly skeptical of that number based on the people I see, but I also realize that I am seeing a highly treatment resistant with multiple comorbidities.  Seizure risk was listed as the most significant side effect.

Vagus nerve stimulation (VNS) has been around for about a decade.  I have seen a few of these patients and never referred anyone for placement of this device.  There is limited third part reimbursement and in my opinion waning enthusiasm for this technology.  The last time I interviewed a person with VNS, their speech quality changed every time the stimulator was active.  That is a significant side effect and I don't know if that has been addressed with current technology.   Transcranial direct current stimulation (tDCS), transcutaneous vagus nerve stimulation, and cranial electrical stimulation were all listed as having limited data.

Deep brain stimulation (DBS) was clearly the main focus of Dr. Holtzheimer's presentation.  The first article suggesting that it may be effective for obsessive compulsive disorder (OCD) was in the Lancet in 1999.  Based on that research DBS of the anterior internal capsule is an FDA approved indication for DBS.  An open label study suggested that it may also be effective for TRD and there were no adverse effects or neuropsychological effects.  Three additional pilot studies of DBS to the nucleus accumbens suggested that it may be useful for TRD and features of TRD like anxiety and anhedonia.  Since then there have been two randomized controlled trials of DBS to the ventral striatum subcallosal cingulate gyrus (SCC).  The first study (ventral striatum) was negative and the second (SCC) was stopped after a futility analysis.

The overall conclusion had to be that TRD was still a common and disabling condition.  The mainstays of treatment at this point are still the medications and ECT that we have had throughout my career.  My experience is that I can help most people get well, but there are significant obstacles even to standard care.  Every lecturer here emphasized the utility of cognitive behavioral therapy.  Like most psychiatrists, I can do cognitive behavioral therapy but by myself I can't meet the demand.  The people responsible for mental health policy and insurance standards certainly do not want to fund the recommended research courses of CBT for chronic depression.  There is no distinction for TRD versus non-TRD depression and no differential resource allocation.  That leaves most patients with TRD and non-TRD depression looking for "prescribers" who can see them for 10-30 minute appointments to get advice on how to recover and try various prescriptions.  None of the available care matches what top researchers recommend in these CME seminars, in articles, or in books.

We could do a lot better trying to live up to that standard while additional diagnostic and treatment strategies are developed.          


George Dawson, MD, DFAPA

References:

1:  David Brent Adolescent depression references  

2:  Papez JW. A proposed mechanism of emotion. 1937. J Neuropsychiatry ClinNeurosci. 1995          Winter;7(1):103-12. PubMed PMID: 7711480.

3: Mayberg HS. Targeted electrode-based modulation of neural circuits for depression. J Clin Invest. 2009 Apr;119(4):717-25. doi: 10.1172/JCI38454. Review. PubMed PMID: 19339763