Illuminating The Functional Architecture Of The Broken Brain

The term ‘phrenology’ conjures up images of nineteenth century medics examining bumps on people’s heads as a means of enciphering key aspects of their character (1).  The arch-phrenologist was a man by the name of Franz Josef Gall whose suggestion that “mental faculties might be reflected in the shape of the brain, and hence the skull” kept many a head-feeler on the look out for supportive evidence (1).  But soon recognized for the fraud that it was, phrenology lost traction as a discipline worthy of attention by any serious-minded medical practitioner (1).

Between 1861 and 1874 however the French anatomist Pierre-Paul Broca and German physician Carl Wernicke brought respectability to the idea of functional compartmentalization within the brain by showing how the aphasias—disorders that adversely reduce the capacity for language and speech be it in verbal articulation or comprehension—were attributable to lesions in the left frontal and temporal lobes (2).  Broca’s area is located just in front of another region that brings about motor movements of speech in the face, tongue, lips, palate and vocal chords (2).

Several high profile cases of sustained head injuries that were followed by long-term distortions of personality and behavior stand out in the history of western medicine (3).  On the 13th of September, 1848, the skull of an American railroad foreman by the name of Phineas Gage was pierced by a 3 cm tamping iron as he worked with explosives to level the land prior to laying down railway tracks (3,4).  The description of what followed fits more with what one might expect from a fist blow to the face than a full-force lesioning of the brain:

“Gage was momentarily stunned but regained full consciousness immediately thereafter.  He was able to talk and even walk with the help of his men” (3)

But to those who knew him well there was an observably dramatic change in personality that would in time drive a rift between him and others whose social connection he had once enjoyed.  Cognitive experts recount how the abundance of profanity in his speech and the blatant disregards for “social conventions” were at the apex of personality changes that would mar relationships for the remaining 12 years of his life (3,4).  In short, Gage had become somewhat of a societal hellion.

Although poorly appreciated at the time, the psychological manifestations so apparent in the Gage case offered an unprecedented opportunity to understand the brain’s functional ‘division of labor’ (3,4).  When the husband and wife neurology team of Antonio and Hanna Damasio from the University of Southern California and their entourage of prominent neurologists secured access to Gage’s skull in the 1990s, they painstakingly worked to deduce the likely trajectories of the tamping iron (3).  What they found correlated well with the observations made at the time of the accident.  While the Broca area and the motor cortices of the brain had remained intact, the left hemispherical frontal lobe- the center of “emotional processing and social cognition and behavior”- had been irremediably damaged (3).  Devotees of British Royal Family history may at once see the resemblance between the Gage case and that of Henry VIII whose jousting mishaps are believed to have transformed him from “sporty, promising, generous young prince” to “cruel, paranoid and vicious tyrant” in his later years (5).

There clearly exists a healthy fascination amongst the general public over medical cases such as Gage that yield crucial information on what exactly goes on under our skulls.  An eight-page long dissection of the life of one Henry Molaison in the popular magazine Esquire for example laid out the bare bones of, what has been touted as “the most important brain-research subject of our time” (6).  At the tender age of seven Molaison suffered a bicycling collision that created a deep gash in his forehead and set in motion a lifetime of epileptic seizures (6).  Desperate for a solution, Molaison’s parents sought the aid of a neurosurgeon by the name of William Beecher Scoville who in 1953 removed Molaison’s entire hippocampus on the grounds that this seahorse-shaped organ had been loosely implicated in epilepsy (6).  In so doing they created in Molaison the “exactness of a planned experiment” for studying memory dysfunction.  Molaison’s life was irretrievably blemished by severe short term memory loss and thus became a closely-guarded ‘template’ for studying psychiatric disease (6).

Epilepsy was also at the heart of Nobel Prize winner Roger Wolcott Sperry’s experiments that would ultimately uncover the brain’s hemispherical partitioning (7).  During the 1960s the physical severing of the corpus callosum, a neurological bridge of sorts that links the brain’s left and right side, through a procedure called a commissurotomy became the most effective treatment for epileptic patients (7,8).  In effect such a drastic removal restricted the spread of the ‘neurological storm’ that so devastatingly characterizes epileptic seizures (7).  But earlier studies with animals produced some striking observations that suggested a role for the corpus callosum in inter-hemispheric memory transfer (8).  In the words of one of Sperry’s students: “restriction of sensory input to one brain half in commissurotomized animals was shown to limit the learning of various tasks to that hemisphere” (8).  Such animals required that each side of the brain be trained independently on how to perform rudimentary tasks (8).

Commissurotomies in humans also exposed the preferential task-weighting of each hemisphere.  The left half was found to be superior to the right in “tasks involving analytical, sequential, and linguistic processing” while the right performed better in “wholistic, parallel, and spatial abilities” (8).

Data on functional mapping of the brain has emerged from a number of different lesion types.  While being somewhat informative brain tumors are, in the assessment of the late behavioral neurologist Norman Geschwind, of dubitable value simply because they exert long range effects across numerous regions of the brain (2).  Penetrative blows like that suffered by Phineas Gage can often be similarly befuddling due to imprecise documentation on trajectories and inaccurate post-mortem evaluations (2).  According to Geschwind the most informative data has come from patients who have experienced blood vessel occlusion- blood flow deficiencies that allow clinicians to tie functional loss with very precise regions of the brain (2).

The molecular revolution has also brought about a deeper understanding of many of the cellular processes that characterize our psychological experiences.  Fear is a case in point.  The fear response center of the brain, the amygdala, is divided into a Central (CA) and Lateral (LA) Nucleus each of which respectively controls the expression of conditioned and unconditioned fear (9).  Fear conditioning is the process by which the brain learns to associate an unpleasant stimulus, say an electric shock, with a particular setting or context.  The CA is divided into two neuron subdivisions: (i) the CEm that drives the output of conditioned fear by orchestrating appropriate “autonomic and motor responses” such as physical ‘freezing’ and (ii) the CEI that regulates the CEm output (9). 

The molecular basis for CEI-based regulation has been dissected and found to correlate with the activity of an enzyme called PKC-delta (10).  PKC-delta expression is observed in approximately half of the CEI neurons, in agreement with data that point to two distinct types of CEI cell populations that either do or do not confer (CEI-on or CEI-off) an inhibitory effect on CEm in response to the ‘tone’ of conditioned fear (9,10).  Viral tracing has thrown into clear view the existence of a negative feedback loop between CEI-on and CEI-off cells (10).  Such results hint at one possible avenue for therapeutic treatments of anxiety disorders that might involve targeting specific cell populations within the brain (11).

The most glaring revelation of modern neuroscience has to be that none of our cerebral faculties act in isolation.  The responses I have outlined above feed off each other in interconnected circuits that shape our experiences and mold how we interface with the outside world.  It is of course a tragedy of the highest order that disease and adversity are the costs that some have had to pay for our ever-deepening knowledge of our inner-wiring. But one can take at least some comfort in knowing that it is through the brain’s broken state that we have garnered some of the greatest insights on the functional architecture of this remarkable organ.
Further Reading

  1. Helen Power (2001) Mapping Speech, appears in The Science Book, ed. Peter Tallack, Weidenfeld And Nicolson Publishers, London, p.182
  2. Norman Geschwind (1970) The Organization Of Language And the Brain, Science, Vol 170, pp.940-944
  3. Hanna Damasio, Thomas Grabowski, Randall Frank, Albert M. Galaburda and Antonio R. Damasio (1994) The return of Phineas Gage: clues about the brain from the skull of a famous patient, Science, Vol. 264, pp.1102
  4. Thomas C. Neylan (1999) Frontal Lobe Function: Mr. Phineas Gage’s Famous Injury, J. Neuropsychiatry Clin Neurosci, Vol 11, pp.280-281, See
  5. Michael McCarthy (2009) The jousting accident that turned Henry VIII into a tyrant, The Independent, Saturday, 18 April 2009, See
  6. Luke Dittrich (2010) The Brain That Changed Everything, Esquire, October 25th, 2010, See
  7. The ‘Split Brain’ Experiments, See
  8. Theodore Voneida, The National Adademies Press, Biographical Memoirs, Roger Wolcott Sperry, August 20, 1913 — April 17, 1994, See

  10. Ciocchi S, Herry C, Grenier F, Wolff SB, Letzkus JJ, Vlachos I, Ehrlich I, Sprengel R, Deisseroth K, Stadler MB, Müller C, & Lüthi A (2010). Encoding of conditioned fear in central amygdala inhibitory circuits. Nature, 468 (7321), 277-82 PMID: 21068837
  11. Haubensak W, Kunwar PS, Cai H, Ciocchi S, Wall NR, Ponnusamy R, Biag J, Dong HW, Deisseroth K, Callaway EM, Fanselow MS, Lüthi A, & Anderson DJ (2010). Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature, 468 (7321), 270-6 PMID: 21068836
  12. Megan Scudellari (2010) How fear flows through the mind, The Scientist, 10th November, See
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Robert Deyes

Robert has been a Technical Services Scientist at Promega for over 10 years. He also worked for two years as a Technical Advisor at the Paisley, Scotland facility of Life Technologies Inc. After earning his Masters in Medical Genetics from the University of Glasgow, he spent 18 months at the Université Louis Pasteur in Strasbourg, France where he did research into the molecular basis of the inherited disorder Spinal Muscular Atrophy. He also holds a BSc from the University of Portsmouth in England.

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