Allen Brain Atlas Is A Serious Upgrade

© 2010 Allen Institute for Brain Science. Allen Human Brain Atlas. Available from: human.brain-map.org

I have been studying neuroanatomy for the past 37 years.  When I started out there was no Powerpoint.  All of the presentations and lectures were projections of actual sectioned or stained specimens, photographs, or combinations of images from journal articles.  The lecture notes were generally a patchwork of similar figures.  The texts were a self study manual by Sidman and Sidman (2) and Carpenter's Human Neuroanatomy (1).   My original neuroanatomy course focused primarily on functional neuroanatomy that focused on clinical syndromes that had to do with identifying cranial nerve, midbrain, and hindbrain lesions and the general organization of the central and peripheral nervous systems.  Some systems were discussed.  Papez version of the limbic circuit for example but there was very little aphasiology or behavioral neurology.  There was very little cortical localization for that matter.  Mt speculation is that the neuroanatomists of the time thought that most medical students would pick it up in clinical neurology.  In terms of motor function, there was an emphasis on the dorsal striatum and a discussion of the usual clinicopathological correlates - Wilson's Disease, Huntington's Disease and Parkinson's Disease.  There was not discussion of the broad array of movement disorders.

Those early days of neuroanatomy were far from perfect.  There was no focus on the ventral striatum. despite the fact that Olds had discovered the median forebrain bundle and the reward system about 20 years earlier.   Diagrams about mesolimbic dopaminergic systems, even in pharmaceutical company literature were labelled according to conventions established in laboratory rats rather than the human brain.  There were a lot of deficiencies for anyone who learned neuroanatomy in the last two decades of the 20th century.  That is at least as far as I can tell.  I routinely teach a course on the neurobiology of addiction to physicians and residents where I usually say something like: "When I was in medical school most of the focus was on the dorsal striatum and the disease correlates.  Now we know that there is a ventral striatum that hang off the anterior and inferior aspect of the dorsal striatum.  I assume that you all have learned about these structures?"  That is generally followed by dead silence.  I am still uncertain about what that silence means.          

You can't really study neuroscience as it relates to psychiatry without knowing a great deal of neuroanatomy.  Finding the right sources is critical.  There was a progression of neuroanatomy texts  for medical school but in my opinion none of them is better than Hal Blumenfled's text (3).  His text has excellent graphics that are organized to illustrate concepts.  The best example I can think of is Figure 14.10 in this text entitled Dopaminergic Projection Systems.  The diagram illustrates the striatum (dorsal striatum), limbic system, and prefrontal cortex and their connections to the midbrain structures via the mesolimbic, mesostriatal and mesocortical pathways.   The origins of these pathways in the substantia nigra pars compacta, ventral tegmental area, and ventral tegmental area plus ventral tegmental area are illustrated in the same diagram.  It is one of the best conceptual diagrams I have seen in the field.  When it comes to illustrations of the ventral striatum and nucleus accumbens the text depends on a photograph of a coronal section (fig. 18.4) through the nucleus accumbens very similar to the one illustrated below from the University of Michigan.

The anatomy of this area of the brain is critical.  There are connections to the limbic system and hypothalamus.  Most medical school neuroanatomy texts lack both granularity and specific detail when is comes to the connectivity in this area.  A lot of the lack of granularity is based on the photographs and staining characteristics of the sections.  Blumenfeld's text talks about important structure in the area, neurotransmitter characteristics of some of those nuclei

Paxinos, Mai, and co-authors offer a detailed text (4), a detailed human brain atlas (5), and an online site (6).  I am still using the second edition of the text and the atlas and there are third and fourth editions available at this time.  These texts were recommended to me by Dr. Heimer when I corresponded with him after taking his course on brain dissection.  There is probably no better paragraph illustrating the significant advance in the neuroanatomy of this area than in Chapter 21 of this edition on page 682.  It is the only page in the text that refers to the nucleus accumbens:

".....The ventral region, which has been included in the term, the "substantia innominata," has now been histochemically identified as the ventral extension of the striatum.  In addition, the olfactory tubercle and the rostrolateral portion of the anterior perforated space adjacent to the lateral olfactory tract in primates are also included in the ventral striatum (Heimer, et al., 1999).  The remainder of the anterior perforated space appears to be a mixed area with elements of the putamen, extended amydala, the corticopetal cell complex, and the ventral extension of the pallidum."

There have been some major developments along the way such as Heimer's formulation of the extended amygdala (8).  His work was based on an advancement in technology that allowed for clearer visualization of the connections between the basal forebrain and the amygdala (9).

Enter the Allen Brain Atlas.  I have my favorite coronal section displayed at the top of this page per the Allen Brain Atlas terms of non-commercial use.  It is section 21 of 106 (numbered from the frontal pole).  I encourage anyone with an interest in human brain anatomy to go to the web site and look at coronal sections of the human brain.  Every coronal section has a smaller image of the location of the section on a lateral view of the brain. The image here is a standard image file (.jpg) and does not have the functionality of the web site.  As an example, on the web site there is a rollover feature that tells the exact structure under the cursor.  This is a very useful feature when studying the basal forebrain area and relationships between the nucleus accumbens, amygdala, and hypothalamus.

The only other text that I have found to be very useful in the clinical applications of neuroanatomy is Scott Atlas text on the MRI of the brain and spine (10).  The graphics on the accompanying CD are excellent and very useful as orientation to MRI scanning.

One of the problems with expensive texts is that they are not very useful or practical for teaching purposes.  I have tried to get permission from several texts to use the occasional graphic on this blog or for teaching purposes only to be confronted with very steep fees.  By steep, I mean on the order of a thousand dollars per graphic.  I consider that to be outrageous based in some cases on the publication date and the use for noncommercial not-for-profit teaching purposes.  In the case of reasonable fees, the licensing arrangement seems impractical.  As an example, I had a licensing arrangement at a reasonable rate but it involved me counting the number of PowerPoint slides for the number of students and submitting that fee on a regular basis.  I have no doubt that many lecturers are more organized than I am, but at 15-20 neuroanatomy based lectures per year to groups of various sizes I eventually gave it up and used publicly available material.

The good news for psychiatrists is that neuroanatomy has never been more relevant.  It has become a clear basis for addiction psychiatry and neuropsychiatry.  The amount of material that is openly accessed for teaching purposes has never been better.  In clinical work, one of the few good features of the electronic health record (EHR) has been access to imaging in the digital format.  I used to have to go down to Radiology and trace abnormal images on note cards and occasionally reproduce them in the handwritten record.  In many systems it is possible to cut and paste the image of interest into EHR progress notes.



George Dawson, MD, DFAPA



References:


1:  Carpenter, Malcolm B.  Human Neuroanatomy.  7th ed.  Baltimore, MD: The Williams & Wilkins Company, 1976.

2:  Sidman RL, Sidman M.  Neuroanatomy A Programmed Text: 1st ed. Baltimore, Maryland: Lippincott, Williams, and Wilkins, 1965.

3:  Blumenfeld, Hal. Neuroanatomy Through Clinical Cases: 1st ed. Sunderland, MA: Sinauer Associates, 2002: p 595.

4:  Paxinos G, Mai JK, eds. The Human Nervous System: 2nd ed. San Diego, California: Elsevier Academic Press, 2004.

5:  Mai JK, Assheuer J, Paxinos G.  Atlas of the Human Brain: 2nd ed.  Amsterdam, Netherlands: Elsevier Academic Press, 2004.

6:  Mai JK, Paxinos G, Voxx T.  Atlas of the Human Brain: 3rd ed.  Elsevier Science, 2007.
This text is listed as the source material for http://teaching.thehumanbrain.info/ an open access neuroanatomy site that uses photographs from the book and other materials and is licensed for non-commercial use and teaching purposes by a Creative Commons 3.0 license - Attribution Non-Commerical - No Derivatives 3.0 Germany.

7:  Haber SN, Gdowski MJ.  The basal ganglia. In: Paxinos G, Mai JK, eds. The Human Nervous System: 2nd ed. San Diego, California: Elsevier Academic Press, 2004:  676-738.

8:  Heimer L. A new anatomical framework for neuropsychiatric disorders and drug abuse. Am J Psychiatry. 2003 Oct;160(10):1726-39. Review. Erratum in: Am J Psychiatry. 2003 Dec;160(12):2258. PubMed PMID: 14514480.

9:  Elias WJ, Ray DK, Jane JA. Lennart Heimer: concepts of the ventral striatum and extended amygdala. Neurosurg Focus. 2008;25(1):E8. doi: 10.3171/FOC/2008/25/7/E8. PubMed PMID: 18590385.

10:  Atlas SW, ed.  Magnetic Resonance Imaging of the Brain and Spine.  3rd ed.  Philadelphia, Pennsylvania: Lippincott Williams, and Wilkins, 2002.

A Head Full Of Prior Probabilities

I read an article in Science recently that reminded me of why I am a subscriber.  The article had to do with a model of rational thinking based on the neurobiology of the several critical brain structures, the prefrontal cortex (PFC), dorsal striatum, ventral striatum, and anterior cingulate cortex.  The interesting aspect of this model is that is also takes into account Bayesian analysis and uses that to build a model for how the can make use of these unique neuroanatomical local structures and come up with novel solutions in uncertain environments.

For about 15 years I taught a course that was designed to minimize diagnostic errors when physicians consider the question:  "Is this a medical condition or a psychiatric disorder?"  On of the first cases I would use is a hypothetical case of a teenage girl admitted to a hospital for dehydration secondary to acute gastroenteritis.  In this case the psychiatrist is consulted because the patient began to manifest acute agitation.  This was an acute behavioral change and that was confirmed by family members who had never seen the patient like this before.  The consult to the psychiatrist read: "Please see to assess and treat hysterical behavior."

On the diagnostic side there are several prior probabilities to consider.  In medicine, I like to consider prior probabilities as those of a particular finding or condition that exists is a particular population in the wild.  In this case a few to consider would be:

1.  The prior probability of "hysteria" in teenage girls with no previous behavior problems.  What is hysteria?

2.  The prior probability of acute mental status changes in teenagers with no medical conditions.

3.  The prior probability of teenage girls with no medical problems being in a hospital bed being rehydrated with I.V. fluid therapy.

4.  The prior probability of acute mental status changes in teenagers with no psychiatric or substance use disorders.

Considering 1-> 4, it should be evident that all of the corresponding probabilities are very low.  It would difficult to rank order them on that basis and it suggests the need for more hypothesis generation or data acquisition.   As we examine the patient we realize that cannot produce any meaningful verbal response, she has opisthotonic posturing and decorticate posturing on the left in response to painful stimuli.  The next set of prior probabilities is more declarative:

1.  The posterior probability of a brain problem with opisthotonic posturing and findings 1 - 4.

2.  The posterior probability of an acute brain problem with decorticate posturing and findings 1 - 4.

Suddenly with the examination findings - one specific and the other not - the probabilities of a severe life threatening brain problem have gone through the roof.  The patient appears to be acutely encephalopathic with an impending brain stem herniation syndrome.  This is no longer a patient who should be in a non-acute care bed in the hospital or a patient who needs acute psychiatric care.  She belongs in an intensive care unit, hopefully one that specializes in treating acute, life-threatening neurological disorders so that the problem of increased intracranial pressure can be addressed.  That important decision is made with a two minute examination of the patient at the bedside.  She is transferred to a neurological ICU for more appropriate care.

Without going into too many details about Bayesian inference other than this example, I have never really seen it referred to from a neurobiological perspective.  The new paper by Donoso, et al makes the connection in the introductory paragraphs:

"Human reasoning subserves adaptive behavior and has evolved facing the uncertainty of everyday environments. In such situations, probabilistic inferential processes (i.e., Bayesian inferences) make optimal use of available information for making decisions. Human reasoning involves Bayesian inferences accounting for human responses that often deviate from formal logic (1). Bayesian inferences also operate in the prefrontal cortex (PFC) and guide behavioral choices (2, 3). Everyday environments, however, are changing and open-ended, so that the range of uncertain situations and associated behavioral strategies (i.e., internal maps linking stimuli, actions, and expected outcomes) becomes potentially infinite."


The Wisconsin Card Sorting Test (WCST), a well known neuropsychological measure of frontal lobe mental flexibility.  In the test the subject's task is to sort cards based on shapes, colors, or the number of objects per card.  The sorting paradigm is not made explicit and every time the examiner changes it, the test subject needs to figure it out and start sorting cards according to that new paradigm.  Results can be correct, exploratory, incorrect or perseverative.  Perseverative can be defined as a continuous repetitive sorting error that does not take into account the need for error correction - continuing to use a response that was at one point correct.

At this point there are many imaging studies that look at correlates between functional brain scans and performance on the WCST.  In this study the authors look at a custom variation of the sorting tests where subjects were looking for digit combinations by trial and error and produce a response that was exploratory, perseverative or correct based on feedback about the correctness of choices.  All subject were young (18-26 years old) and screened for medical, neurological, and psychiatric disorders).  There were a total of 40 test subjects equally split by sex.  The article contains a detailed discussion of the subjects response patterns relative to a theoretical model, but I am most interested in the brain imaging results and the implications of those results.

Working in the addiction field, it is fairly common these days to read research studies that look at activation of the ventral striatum.  There are also theories about which neural circuits are responsible for most aspects of addiction including the initial euphorigenic effects,  acute behaviors involving positive reinforcement, and chronic compulsive effects associated with negative reinforcement.  I think that there is an general conceptualization that there are varying levels of euphoria associated with activation of the ventral striatum whether that is from an addictive drug or what has been considered to be "natural" activators of the ventral striatum including food, water, sexual behavior, and social affiliation.  This is the first study that I have seen showing that activation of the ventral striatum is associated with the cognitive aspects of life.  In correspondence with the lead author Etienne Koechlin his group refers to this as the "Eureka Response".  He suggests that the ventral striatum adds and affective valence to a cognitive strategy that has been selected by the frontal cortex as a correct strategy and that  valence contributes to consolidation in long term memory.  He points out that the cognitive system needs the affective role of the ventral striatum to run properly.

If this paper can be replicated this is really landmark work.  It provides a neurobiological explanation for why we can choose among several prior probabilities in important situations.  In terms of clinical decision making it may be why senior clinicians have immediate associations to critical cases when they are involved in subsequent clinical decision making.  That process has been looked at in terms of pattern matching and pattern completion in the past but an affective valence adds another important dimension.

This is potentially one of the most important papers and theories I have seen in recent times.  It has broad implications for psychiatry, addiction, cognitive psychology, and many other fields.  An affective valence from the ventral striatum may make living with a head full of prior probabilities - a lot easier.


George Dawson, MD, DFAPA



Supplementary 1:  The following table lists the common neuroanatomical abbreviations used in this paper:

References:

1: 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.


2:  Albert DA, Munson R, Resnick MD.  Reasoning in Medicine: An Introduction To Clinical Inference.  The Johns Hopkins University Press.  Baltimore. 1988.

"Our aim is to dig deep into the clinical mind and lay bare the processes of reasoning and inference that are (or can be) involved in arriving at and in justifying clinical decisions."