Neocortical modularity and the cell minicolumn

Manuel F. Casanova, editor. Now available from Nova Science Publishers.

Table of contents

Introduction

Author: Manuel F. Casanova

1. Vernon B. Mountcastle: A life that transformed the neurosciences

Author: Manuel F. Casanova

2. Vernon B. Mountcastle: Scientific achievements

Authors: Juan Trippe II and Manuel F. Casanova

3. An apologia for a paradigm shift in the neurosciences

Author: Manuel F. Casanova

4. Reflections on the structure of the cortical minicolumn

Author: Javier DeFelipe

5. The cell column in comparative anatomy

Authors: Daniel Buxhoeveden and Manuel F. Casanova

6. Encephalization, minicolumns, and hominid evolution

Authors: Daniel Buxhoeveden and Manuel F. Casanova

7. The generation and migration of cortical interneurons

Author: John G. Parnavelas

8. Minicolumnar patterns in the global cortical response to sensory stimulation

Authors: Mark Tommerdahl, Joannellyn Chiu, Barry L. Whitsel, and Oleg V. Favorov

9. Minicolumnar morphometry: Computerized image analysis

Authors: Manuel F. Casanova and Andrew E. Switala

10. The verticality index: A quantitative approach to the analysis of the columnar arrangement of neurons in the primate neocortex

Authors: Axel Schleicher and Karl Zilles

11. Mountcastle principle of columnar cortex as basis for theory of higher brain function: Clinical relevance

Authors: Gordon L. Shaw and Mark Bodner

Introduction

Manuel F. Casanova

Copyright © 2004 Nova Science Publishers

“For certainly much of what I have accomplished has been by the good fortune of being in a great institution and having first class colleagues…I think the answer is that given a certain level of competence, one has to be totally dedicated—and lucky!” —Vernon Mountcastle, regarding his success in neurosciences (personal communication, 2004).

Many years ago the chess grandmaster Jose Raul Capablanca wrote an introductory textbook for his game. Contrary to previous authors who belabored the opening of the game, he emphasized the ending from the very first chapter. This approach received mixed reviews, as in this stage of the game, the outcome had usually been already decided. Mr. Capablanca, however, defended his approach. He explained that the endgame was purified to such an extent that only the essential elements remained, making piece–piece interactions more easily understood by the novice. Like Capablanca, neuropathologists approach their craft by learning the properties of the basic units before tackling more complicated tissue reactions. In effect, there is a covert understanding that observations on the morphology of cells provide a window to physiology in both health and disease.

Nature in its wisdom has simplified the job of the neuropathologist by limiting the number of ways a neuron may react to injury. Neurons are the most highly specialized cells of the body. Specialization, however, carries with it some dubious distinctions. As a jack–of–all–trades, the neuron ends up master of none. It may be said that a neuron has been so intensively “inbred” that it has lost some of its natural resistance to disease. Neurons therefore need help from outside sources to cope effectively with environmental exigencies. Among neurons’ coping mechanisms are the blood brain barrier and the capacity of astrocytes to dispose of certain toxins. Furthermore, a neuron can only process information efficiently by deleting a large number of otherwise extraneous activities. Only primitive cells (e.g., tumor cells) exhibit such a variety of processes that confuses their internal logic and makes them react erratically.

In the case of the brain, many different lesions manifest the same patterns of cellular and tissue disruption. Hypoxia, hypoglycemia, infections, and trauma often produce homogenization (so called ischemic changes) of neurons. These cells stain more darkly, obscuring their individual elements. As a primary attempt to adapt to a particular stressor, the cell will repress its more highly differentiated functions, those that usually require a major amount of energy expenditure. The incapacitated cell becomes smaller (atrophic), somewhat triangular and shriveled. The neuropil, or the background of the gray matter, is pale staining. These changes, following dissimilar injuries, bear a temporal profile. After the first few hours of an insult, properly fixed neurons will exhibit microvacuolation of their somas. Homogenization of the cellular constituents is evident during the first day while an increase in microglia and early neuronophagia occurs after 48 hours. The end result is atrophy, cell loss, and gliosis. None of these changes characterize the pathology of mental illnesses.

Our everyday view of the world may not necessarily be the most comprehensive one. In this regard neuropathologists should temper opinions based on a limited representation of reality. Microscopy freezes in time a two-dimensional representation of a minute histological process. One must acquire knowledge of the physiology of the lesion before reaching a multidimensional diagnosis. In the case of mental disorders, the modular organization of the cortex may offer some clues to underlying etiology. It is tissue, rather than individual cells, that provides for the phenomena of perceptual binding and gamma frequencies. It is the continuous reentry of excitation into neuronal networks that provides for selective attention. The basis for language and its semantic content resides in the conjoint activation of topographically diverse brain regions. We may conclude that although molecular biologists placed the neuron on the rack and forced it to reveal its secrets, they learned very little about mental disorders.

Researchers may still wait to apply their molecular trade to single gene-dependent neuropsychiatric disorders. However, in clinical practice conditions such as Huntington’s disease, familial Alzheimer’s, and Zellweger’s syndrome are few and far between. Still these conditions are not completely determined at the DNA level. Placing mice carrying the Huntington’s gene in an enriched environment delays the onset of symptomatology. In similar fashion physical and mental exercise appears to protect against the ravaging effects of Alzheimer’s disease. Possibly the most inheritable mental disorder is autism, with 92 % of monozygotic twins having a condition within the DSM spectrum of related disorders. Studies on the inheritance of autism suggest the involvement of three to ten genes. It has been proposed that mutations surpassing a threshold number of genes could cause classical autism, while a smaller number provides less significant deficits, e.g., social shyness or delays in language acquisition. It is mind-boggling the number of permutations (extreme coincidences) scientists quote to explain a condition as being completely determined by genes. There is something unsavory and inchoate about attempts to understand the brain/mind relationship based on complex statistical relationships between genes. These mathematical manipulations are subsumed under the euphemism of “genetic complexity,” a clear evolutionary step from its predecessor the “Oh GOD” principle (One Gene, One Disease) and its parodies (one gene, one enzyme and one molecule, one postdoc). Genetic complexity views psychiatric illnesses as chimeras of molecular events. However, most neuropsychiatric conditions fall within the psychobiosocial framework of which genetics is only one aspect. Adolf Meyer would have stressed that mental conditions involve the whole person along with his/her environment.

Researchers should learn from the difficulty in targeting genes to create animal models with specific phenotypes. Generally, it is impossible to assess the impact of specific gene deletions on the phenotype/behavior of the animal. One of my favorite observations is the fact that within aligned regions, the genomes of chimpanzees and humans are almost identical. However, phenotypic and behavioral differences between these species are quite obvious. In surmising the recent surge of research in molecular biology and the corresponding scarcity of results, a geneticist may say that you need to break a few eggshells to make an omelet. Thus far we have been walking on egg shells and lost sight of the omelet.

Token physicalism is the view that each and every mental event is the result of a physical event, usually at the cellular or molecular level. It assumes that for every mental state there exists a set of physical causes that taken together produce that effect or even necessitate the same. The impracticability of such a view has only recently been realized. Take for example the paradigm shift in our perception of neuropharmacological interventions. With newer drugs only a small fraction of a given receptor occupancy correlates with maximum clinical response. The initial strategy of drug design based on targeting specific receptors has therefore yielded drugs that affect various combinations of adrenergic, dopaminergic, serotonergic, and histaminergic receptors. Thus, the systemic approach that escapes the molecular level of resolution has proven to be more successful in neuropharmacology. The relevance of a molecular event to the clinical applications of a specific disease may be of use in conditions due to bacteria and viruses. Thus far this medical model has failed to explain psychiatric disorders.

I have never heard a psychiatric patient complain of abnormalities in his/her dopamine receptor or second messenger system. I have never heard of a psychiatrist treating a patient based on the insertion of double-stranded DNA into a plasmid. Outside of psychiatry, even the 20 or so clinical trials of gene therapy in cystic fibrosis have found no or little effect of the inserted gene. The vectors used in these experiments have produced more side effects than benefits. However, both the failures and side effects may all be related to genetic engineering problems that may be overcome in the future. The problem is whether we have learned enough from these trials and at what expense. Figure 1

Higher levels of resolution simplify the analysis of molecular interactions but fail to reflect the complexity ingrained in psychiatric symptoms. An intermediate level of resolution lying between the realm of cells and organs (Figure 1) may more suitably explain complex and disturbing behaviors. Unfortunately, neuroscience textbooks cover only half of the field, emphasizing manifestations within a reductionistic scale. Different chapters offer a collage of molecular events, scattered attention to neuronal nets, and hardly a mention of either mini- or macrocolumns. The attention paid to the neuron at the expense of modular arrangements is an atavism tantamount to chronological snobbery. This lack of acknowledgment is more perplexing when considering the range of complexity exhibited by the arrangement between and within cortical modules. In effect, modular abnormalities could explain a cornucopia of pathologies capable of dwarfing the limited response of the single neuron. It is by looking outside of the neuron that we may answer the pathological riddle of mental disorders.

It has been my intent in editing this book to focus on the lowest hierarchical element within the modular organization of the brain: the cell minicolumn. The minicolumn is a self-contained ecosystem of neurons and their connections that repeats itself throughout the extent of the neocortex. Although a few neuroanatomists at the turn of the century called attention to the vertical arrangement of the cortex, Vernon Mountcastle provided physiological proof in the 1950’s for its existence and its role in perception. I feel an affinity for Dr. Mountcastle. We constantly deal in our writings with similar problems but from different perspectives. Initially, reading Mountcastle was akin to performing mental gymnastics. You do not read Mountcastle in a hurry. You have to be prepared to frequently reread a paragraph. Over time, however, my understanding of Mountcastle’s work has flourished into reverence. My appreciation of minicolumns is now a mosaic of facts that makes sense of most neuroscience. A deaf person can’t appreciate the beauty of Beethoven’s symphonies anymore than minicolumnar illiterates can understand neuroscience.

Mountcastle is an outsized character that marched to his own beat. Never the person he “ought” to be, he was never boxed into preconceived ideas. This character trait was of immense help throughout his research career: Having no shoulders to stand on, he set his own goals and built upon his strengths. He aspired to an objective truth, the Holy Grail of neurosciences. In his search he overcame narrowness of scientific vision and became an heir to Socrates. While others went for easily accessible and exploitable prizes, Mountcastle claimed no glory, no acclaim. Personally he treated others by the categorical imperative: with respect and dignity as ends in themselves. He is a unique individual: We can’t exchange Mountcastle for someone else and have an equal. At 85 years of age he presently pursues research with the same enthusiasm of his younger days. Therefore, I have devoted this book to Mountcastle, his life and scientific work.

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