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Wednesday, August 27, 2008

Continuity of the Mind

Today the National Convention of the Democratic Party nominated Senator Barack Obama as candidate for the election to the highest office in the United States. His campaign for candidacy took about two years. Though conditions and means have changed decisively, the challenges that have to be met by the hopefuls for this type of position have remained remarkably similar over the past millenium.

Roughly 800 years ago an ambitious young man set out from his home in the pursuit of the highest office of his nation. It was the beginning of a long campaign trail that took him thousands of miles across the land he aspired to govern, learning about differences in culture of a diverse people and gaining insights into their daily problems. The journey was cumbersome and needed elaborate organization. Several hundred aids accompanied him. They had to set up camp, see to his security, and prepare the next moves. His message had to go out. It had to resonate. He had to convey that he understood the people's needs and that, once elected, he was going to help them. The locals had to be entertained. Vast sums of money were spent. Promises were made. Though his journey was educational, the main purpose of the endeavor was to rally support for his cause. He had a powerful and influential opponent and needed the overwhelming endorsement from people of all walks of life in order to win.

He had the professional credentials. He was formally educated to stand up to the challenges of government. He was well prepared in public administration and law. He was fluent in the legal language of his time and proficient in several other languages. However, he needed to learn the language instrumental in his struggle for national leadership: German. The majority of the people in the nation spoke German. The members of the Electoral Council considered themselves German. They met in a German city to elect the new head of state and government, and they wanted a popular leader.

This was a great disadvantage for our candidate. He had grown up in Southern Italy. He was considered a minority, an outsider. His mother was Norman. Though his father was German, our candidate conversed poorly in the high language. A superb command of German was imperative. Therefore, he campaigned much in Germany and made a great effort to learn the language. Eventually, he mastered it so well that he could write poetry. His was a brilliant mind. He dazzled those who met him. He was gregarious, smart and engaging. His sophistication impressed. He had a great gift of endearment. He attained wide popularity, becoming known as the Kid from Apulia after his birthplace in Italy where he would continue to live for many years. Apulia is quite deforested and arid today. In the our candidate's time, the landscape could have easily resembled Turner's vision.

His popularity would eventually give our candidate the edge in the election. His opponent struck a rather dull pose, though he could impress with a fabled pedigree. He was the member of a Saxon dynasty, known as the Wolves. They counted several figures of worldwide acclaim in their ranks. Alas, the Saxon did not show much political skill, reveled in military prowess and was given to adventure. On election day, the Kid from Apulia carried the vote. Though the Council of Electors had only seven members, the effort on our candidate's part was tremendous. Three electors were clergy. Our candidate had a complicated relationship with the Church. He and the Holy See held diametrically opposed views on the separation of church and state and the prerogatives of the two branches. He was to assume a difficult position.

Although he became nominally head of the nation, his governance was riddled with problems. Revenue was hard to collect. Resources beyond his own were never certain. Any decision of national importance needed the support of powerful locals who pursued their own special interests. He spent much time on the road to negotiate support for his ideas. Alliances were ever shifting, and the Holy See never seized to challenge his claims to power. The struggle would consume much of his energy and almost cost him his life. But, ultimately the Kid from Apulia is not remembered for his political achievements, but for his scholarly writings, the poetry he left behind, and his philanthropy.

He founded one of the first universities in continental Europe, the University of Naples. He enjoyed falconry. Some of his accounts on falcon behavior and training are preserved. His modern-minded examination of the subject strikes today's reader in awe. This man was determined, yet flexible. He had excellent observation skills and a brilliant analytical mind. He kept his mind open, willing to learn and embrace the unanticipated and unknown. He understood that even the most powerful can ill afford ignorance. Hopefully, the next President of the United States will be blessed with such abilities.

Who was this man? His name was Frederic. He was crowned Frederic II, Emperor of the Holy Roman Empire of German Nations in A.D. 1220. We do not know much about his looks. Some believe that the horseman statue in the Cathedral of Bamberg is sculpted in his likeness. We are left with a bronze of his beloved hunting companions and his writings about them. The bronze is on display at the Cloisters in New York City. Pages of his treatise on falcon behavior can be seen in the Vatican Library.

Thursday, August 21, 2008

Cell Phones & Brain Cancer

Remember Jon Krakauer's account of tragedy on Mt. Everest? We have an irrational perception of acceptable risk. For sheer enjoyment, we frequently are willing to expose ourselves knowingly to the possibility of severe injury. Just three weeks ago about a dozen climbers succombed to an ice fall on K2. In any good summer, roughly 100 people perish in mountaineering accidents in the Swiss Alps alone. V. Lischke and others report 462 fatalities for 1997 Europe-wide. According to the U.S. Dept. of Transportation, 4,810 Americans perished on motor bikes in 2005, translating into 73 riders per 100,000 bike registrations. The fatalities continue to rise. Last year 5,154 Americans died on their bike.

By contrast, according to wrongdiagnosis.com every year fewer than 50 in 100,000 Americans battle glioblastoma multiforme, that is the most aggressive and fatal type of brain cancer. Recent research studies link brain cancer with electromagnetic radiation from cell phones. A discussion of some studies can be found here. The debate has become ever more intense since Senator Edward Kennedy was diagnosed with malignant glioma, probably a glioblastoma multiforme. I discussed this type of brain cancer in my post dated June 3, 2008.

Prudence is advised in the debate on a possible association between cell phone-related electromagnetic radiation and brain cancer. The energy of electromagnetic waves is directly proportional to their frequency. The spectrum of the frequencies ranges from meter-long radio waves via the nanometer-long waves of visible light to atom-sized gamma rays. The shorter the wave length, the higher the frequency and the greater the energy that potentially can harm our genes. DNA may be altered directly through the absorption of radiation energy or indirectly through radiation-produced free radicals that may react chemically with the DNA. Even low amounts of energy can damage DNA and may theoretically result in uncontrolled cancerous cell proliferation. However, our cells are provided with DNA repair mechanisms. Commonly many hits are needed to overcome the defenses and cause noticeable damage. Alas, the defenses appear to wear out with advancing age and we may become more susceptible to cancer.

To determine thresholds for harm from electromagnetic radiation, epidemiological studies are conducted that compare the health records of people with known exposure to those of people who match this group in all aspects, except the exposure. Professionals with job-related extraordinarily high exposure are frequently enrolled in the group of the potentially affected to improve the chances of discovery. Hardell and others (2005) observed that Swedish long-term users of analogue mobile (NMT) phones like the now obsolete car phones developed a significantly higher risk for auditory nerve tumors (acoustic neuromas) on the side of phone use. Digital mobile (GSM) phones like our modern cell and cordless phones did not increase this risk consistent with findings in Denmark (Christensen and others, 2004). The prevalence of acoustic neuroma in the U.S. is low. Less than 1 in 1000 Americans is affected. According to ctia.org, roughly 264 million wireless subscriptions are active at present.

Though the results of such studies provide important leads on the type of the potential harm to our health and may be instrumental for safety considerations at the work place, they cannot be easily extrapolated to regular phone users. The amount of radiation energy deposited in the auditory nerve can only be estimated. Moreover, the effects cannot be ascertained with the data collected at higher doses because of the non-linearity of the relationship between dose and effect and the increasing scatter of the observations at progressively lower doses. The concerned may opt to use plug-in extensions for ear and mouth pieces or voice-activation as precaution.

Addenda

  • National Public Radio's All Things Considered ran an interesting update on this issue today. You may wish to read the report and listen to the podcast by Allison Aubrey entitled "Doctors Urge Research On Cell Phone-Cancer Issue" (09/25/08).
  • On Aug. 24, an ice fall swept away a party of twelve on the Mont Blanc du Tacul, a smaller brother of the White Lady. Eight are missing. I once stood on this mountain at a different time in the year. I was fortunate to have a friend as guide who understood risk well (10/21/08).
  • Maggie Fox reports in her post with the title "U.S. senator promises look into cellphone-cancer link" published online on Reuters today that Senator Tom Harkin, chairman of the Committee for Health, Education, Labor and Pensions, plans to encourage more research to examine whether the use of cellphones may cause cancer. The fear persists (09/14/09)!
  • The environmental working group lists the head-absorbed power [W/kg] of the radio waves emitted from a number of cell phones in this table (06/16/2010).
  • Volkow and others (2011) report in this week's issue of the Journal of the American Medical Association that cell phone radiation is statistically significantly associated with an acute increase of glucose metabolism in the temporal and frontal lobes of the cerebral cortex by, on average, 7.2 percent on the side the active, but muted, phone was held for 50 minutes. The researchers used the [18F]fluorodeoxyglucose method and positron emission tomography (PET) to determine regional cerebral glucose utilization rates in 47 healthy volunteers. They conclude in the abstract of their communication that “this finding is of unknown clinical significance.” Indeed, the finding does not provide any insight into the cellular mechanisms underlying the observed increase. Under healthy physiological conditions, brain glucose metabolism does not rise to levels posing a health hazard. I have written on this topic in my post with the title "Good News for Brain Energy Use" published Sep. 12, 2009. If the sole aim of this study had been to investigate the potential influence of modern-day cell phone radiation on brain energy metabolism, the study could have been conducted with mice at lower cost, sparing the participants unnecessary exposure to ionizing radiation from PET (02/24/11).
  • Epidemiologists have recently come to discrepant conclusions on the risk of cancer associated with cell phone use. According to Scott Hensley's report with the title "Cellphone Use May Be A Cancer Risk After All" on National Public Radio's All Things Considered today, a recent World Health Organization review conducted by 31 experts from 14 countries found sufficient evidence that may support a correlation between cellphone use and gliomas and acoustic neuromas. The study will be published in the July issue of the journal The Lancet Oncology. By contrast, a comprehensive case–control study with 2708 glioma and 2409 meningioma cases and matched controls from 13 countries published last year by The INTERPHONE Study Group (2010) could not establish any elevated risks with mobile phone use with certainty (05/31/10).
References



As the eminent film director Werner Herzog so aptly documents in his recent public service announcement video below with the title "‪From One Second To The Next‬", cell phone use may pose other, more prevalent effects proven to be absolutely devastating to our health (08/20/2013):

Thursday, August 14, 2008

Cortical Development & Schizophrenia

In its Health Guide section of June 13, 2008, The New York Times published a comprehensive article entitled "Schizophrenia and the Brain" (the article has been found irretrievable on Jan. 29, 2011, but the animations can be found in the NIMH Science Update of Oct. 30, 2008, with the title "Brain's Wiring Stunted, Lopsided in Childhood Onset Schizophrenia"). The article includes a series of fascinating time lapse movies showing the maturation of cerebral cortex from early childhood (4 years of age) to young adulthood (21 years of age). The normal developmental profile was compared to that of people with early-childhood schizophrenia, the symptoms of which can manifest themselves as early as 8 years of age. A commentator explains the changes in the movies and an accompanying interview with P.M. Thompson, a principal investigator of this research, provides further perspective on the findings. The intriguing dynamics of cortical maturation shown in the time-lapse movies give pause to the close observer and evoke the desire for more information.

The human cerebrum consists of gray and white matter in roughly equal proportions. The gray matter comprises deep structures as well as the cerebral cortex containing the nerve cells and nerve cell processes that connect these cells locally. The cerebral white matter underlying the cortex is composed of the nerve cell processes known as axons that connect the cortical cells with distant regions in the same hemisphere, the other hemisphere, the deep gray matter structures and the spinal cord. It also contains the axons of ascending projections that terminate in the cerebral cortex. The axons are wrapped in sheeths of a fatty substance known as myelin. The myelination gives the white matter the color of cream.

Dr. Thompson and his colleagues measured the density of cortical gray matter repeatedly in the same people with nuclear resonance imaging in two-year intervals. The changes across the samples are projected in false colors and time lapse on virtual reconstructions of cerebral cortex. The studies providing the data for normal development have been described in detail by Gogtay and others (2004) and for early-onset schizophrenia by Gogtay (2008) and Thompson and others (2001). Some of the cited studies can be accessed for free, others need a subscription.
Dr. Thompson and his colleagues attribute the diminutions in gray matter density to enhanced myelination in the white matter and/or the loss of nerve cells, nerve cell processes known as neuropil and nerve cell contacts known as synapses in the gray matter. Myelination of axons accelerates nerve cell signal conduction at increased efficiency and is believed to continue into advanced age. The loss of synapses in the cerebral cortex may result from the pruning of neural networks in which used nerve cell connections are spared whereas idle connections are eliminated.

Based on his observations on animal behavior in the 1940s, the psychologist Donald O. Hebb was the first to suggest that the strengthening of synapses that are activated together may provide a neural mechanism for learning and memory. In the 1960s and 1970s, the Nobel Prize-laureates T. Wiesel, D. Hubel and their colleagues observed that the arbors of the endings of inputs to visual cortex from the eyes overlap at first, but separate into distinct, eye-specific domains during brain maturation (LeVail and others, 1980). As an important affirmation of the validity of Hebb's hypothesis, the development of the ocular dominance domains was plastic and depended on active input. When input from one eye was deprived, most endings of the idled input were pruned, whereas the endings of the functional, active input remained extended, claiming the cortical territory of the deprived eye. During a critical period the effect could be reversed when the inputs from the intact eye were deprived and the hitherto deprived inputs were reactivated. The experiments demonstrated elegantly that the development of connections between nerve cells can be highly dynamic and particularly sensitive to sensory stimulation during a critical period. 

In the 1980s, Hebb's hypothesis was validated on the cellular level with the discovery that repeated stimulation of the input of particular types of cortical nerve cells strengthened their response to stimulation. The effect is known as long-term potentiation or LTP for short. Subsequently, researchers identified the molecular mechanism for LTP. A particular type of receptor for the excitatory neurotransmitter glutamate plays a key role. Glutamatergic synapses are the most abundant in cerebral cortex. The receptor involved in LTP is known as N-methyl-D-aspartic acid receptor or NMDA-receptor for short. The receptor channels positively charged ions through the nerve cell membrane, increasing the the postsynaptic excitatory potential or EPSP for short. This voltage initiates electric spiking known as action potentials in the nerve cell's axon. The action potentials travel along the axon to the nerve cell endings and trigger the release of neurotransmitter into the cleft of the next synapse. NMDA-receptors can enhance synaptic transmission and thereby strengthen synapses because the opening of the ion channels is voltage dependent and multiple receptor activation facilitates the opening of disproportionately more channels. It is widely accepted today that via this mechanism Hebb's rule applies to the experience-dependent strengthening of glutamatergic synapses, and synaptic stabilization and loss are understood as basic mechanisms for the refinement of cortical nerve cell circuitry. 

In support of this concept, nerve cell connections between and within the cortical hemispheres have been shown to develop in steps of exuberance and elimination (for review see Innocenti, 1995). In harmony, P.R. Huttenlocher was the first to report a waxing and waning of nerve cell contact density in the maturing human cerebral cortex (see Huttenlocher and others, 1982-83). The exact time course appeared to differ among cortical areas. In accord, local peaks of energy metabolism were observed (Chugani and others, 1987). Eventually, comprehensive synaptic counts in the cortex of non-human primates affirmed the initial increase and the subsequent decrease in the number of synapses as fundamental steps in the maturation of cerebral cortex (Rakic and others, 1994).

In the time-lapse movies shown in The New York Times, Dr. Thompson and his colleagues use measurements of gray matter density to track the maturation of cerebral cortex. Gray matter density may indeed be closely associated with synaptic density. W.T. Greenough and colleagues showed that exposure to an enriched environment and the ensuing enhanced sensory stimulation increases myelination, cortical synaptic density and, notably, cortical thickness in rats (for review see Markham and Greenough, 2004).  In separate studies, Thompson and colleagues could establish that cortical gray matter density tightly correlates with cortical thickness (Sowell and others, 2004). The thickness varies regionally between 1.5 and 5.5 mm and diminished by as much as 0.3 mm in a year during development. In accord, the time-lapse movies on normal development show that the gray matter density in cerebral cortex diminishes on both hemispheres with advancing age. The diminution progresses in waves originating in the parietal lobes and sweeping toward the frontal lobes.

Exuberance of synapses in human cortex commonly peaks before the age of 4 years and the range of the time-lapse movies may not cover the synaptic build up. However, taking the findings reviewed above into consideration, it is reasonable to suggest that the reductions in gray matter density reflect synaptic elimination following exuberance and the dynamic in the movies may be accurately labeled as cortical maturation. By contrast, the changes in gray matter density visible in the time-lapse movie shown for childhood-onset schizophrenia are more complex. The color scale of maturation seems inverse. Despite the bright colors, the changes seem subtle. Thompson and others (2001) report that they observed more rapid and, in some areas, greater than normal decreases in gray matter density on both cortical hemispheres, suggesting a loss of synapses in addition to the normal pruning of underutilized connections.

The most striking diminutions of gray matter density were found in the parietal lobes. Large swaths of parietal cortex receive multi-modal sensory input. The information from multiple senses is integrated here. In humans, parietal areas process language. In my studies on cortical responses to Braille reading, distinct foci of activation were found in posterior parietal cortex near the borders of regions that predominantly receive visual, auditory or somatic sensory input (Melzer and others, 2001). Information that establishes our  identity may be processed in parietal cortex. In order to be able to interpret the gray matter density decrease in early-childhood schizophrenia more rigorously, it is essential to disambiguate the causes for the diminution and perhaps establish a relationship with synapse formation.

In my own research on developmental plasticity in mice, I observed considerable thinning of somatic sensory cortex in addition to cytoarchitectonic alterations after the deprivation of tactile input by neonatal whisker follicle removal (Melzer and others, 1993). The cortical layer that shrank the most normally receives the densest tactile input and synapses are lost when the input is disrupted. The cortex was not fully developed at the time of follicle removal. It takes the entire first week after birth for somatic sensory cortex to mature to a degree that the structural alterations visibly manifest themselves. Mouse somatic sensory cortex is considered fully mature three weeks after birth. That is, the effects of the deprivation of input take about the third of time for postnatal maturation to become obvious. In analogy, the cause for the gray matter loss observed in schizophrenia most likely affects cortical development well in advance of the manifestation of the loss.

In the search for the mechanisms underlying the gray matter loss, the time-lapse movies on the development of cortical gray matter density provide invaluable information. They allow us to begin the search in the cortical areas with the greatest loss. The movies represent group results. In order to select the best suited areas, it would be helpful to examine whether some cases in the sample contribute substantially more to the mapped averages of gray matter density loss than the rest of the sample and whether those cases share common factors in their medical histories.

References


Friday, August 1, 2008

Auguste Forel & Brain Plasticity

Today the Swiss celebrate the founding of their confederation. The Swiss Confederation was conceived in a tax revolt more than 700 years ago, making Switzerland today's oldest post-classical European democratic republic governed on federal principles. I take this occasion to commemorate some of the achievements of the Switzerland's most eminent physician neuroscientist Auguste-Henri Forel. A summary of his contributions to neuroscience can be found at whonamedit.com.

Auguste-Henri Forel was born on September 1, 1848, in the wine country on the banks of Lake Geneva outside Lausanne. He attended secondary schools in Lausanne, but turned to the University of Zürich, when the time came to enroll for medical school. Young Forel loathed the decision. The move to Zürich entailed crossing the language barrier. It meant studying and being taught in German and living with people who speak a German dialect that is difficult to acquire. Even today, the francophonic region of Switzerland boasts only two full-track medical schools. Competition for posts is stiff and the pressure to conform is high. Auguste Forel apparently was made to realize early that he would not fit in. Besides, German universities were famous for the great scientific discoveries of the time, appealing strongly to the young inquisitive mind.

The sacrifice of home paid off for Forel. In the Teutonic sphere, he enjoyed an outstanding career as a psychiatrist and neuro-anatomist, working with a number of highly-respected researchers of the 19th century. He helped to establish a theory of the neuron still valid today. His was the first theory that recognized the role of the nerve cells as independent fundamental building blocks of the networks that process information in the brain. He was appointed director of one of the earliest psychiatric research hospitals in continental Europe. At this institution, he examined the effects of alcoholism on the brain. He was one of the first psychiatrists to study human sexuality with scientific methods. In his book on this subject, he did not shy away from discussing homosexuality and other cultural taboos of his time. He wrote legal opinions on the implications of mental illness for criminal code. He understood that every act of our mind had a molecular mechanism in the brain. An account of his writings on the human condition and the ensuing controversies can be found at Humbolt University's Archive for Sexology.

In addition to research on the human brain and mind, Forel developed a passion for the behavior of social insects at an early age and became a reputed specialist in ant taxonomy. After retiring from his duties as hospital director, he returned to the vineyards of francophonic Switzerland. The village where he settled, Yvorne, is located in the Rhone valley upstream from Lake Geneva about an hour's drive from his birth place. His residence became known as the Ant Hill. He devoted his time completely to the study of ants until his death at age 84, though he remained passionate about the curse of alcoholism and other human causes.

The locals remember him as an oddball ant lover who walked through their vineyards ranting and raving about their drinking habits. Obviously, the condemnation of wine consumption was at odds with the vintners' idea of their pleasurable products for refined tastes that constituted their livelihoods. Otherwise, they got along fine. Alas, the most prominent inhabitant of the village did not affect life in the village one single bit. Now as then, the smell of freshly pressed grapes permeates the air every September.

Moreover, Forel never managed to become truly accepted by the academic establishment of his francophonic homeland. He had to go through great troubles to obtain a medical license for this region and was never offered an academic appointment, regardless of his extraordinary scientific achievements and international acclaim. Only the burghers of Lausanne and Geneva know the reasons. Jean Calvin's ideals loom large there. Perhaps, Forel was too famous for them. By contrast, on the national level Auguste-Henri Forel was held in highest esteem. He was honored with a portrait on the largest denomination of the Swiss currency worth approximately $1,000.-. The banknote was in circulation until the year 2000. It was withdrawn because of counterfeiting. Its backside featured engravings of a neuron and an ant. I do not know of any other banknote dedicated to the brain and behavioral sciences.

I learned about Forel's research when I was working at the Institute of Anatomy of the University of Lausanne medical school. My colleagues and I were studying the influence of sensory input on brain development. I used the mouse somatic sensory system as a model. I already described the peculiarities of this system in my post dated May 15, 2008. The whiskers on the mouse's snout are represented topographically in the cerebral cortex of the brain by cytoarchitectonic units called barrels. The fifth cranial nerve, also known as the trigeminal nerve, innervates the face. Sensory trigeminal nerve fibers connect the pressure-sensitive receptor cells in the whisker follicles to the trigeminal sensory brainstem. From the brainstem the pathway crosses over to the other side and the input is relayed via the somatic sensory thalamus to the appropriate barrels in a one whisker-to-one barrel fashion.

Barrels develop in the first week after birth. When whisker follicles are removed at birth the corresponding barrels do not develop and the neighboring barrels enlarge. The critical period in which the barrels are plastic ceases once they are formed. The topographic order of the whisker input to somatic sensory cortex and its plasticity make the mouse whisker-to-barrel pathway a particularly useful model to examine the instructive power of sensory input on the development of sensory representation in the brain.

I set out to compare functional whisker representations in somatic sensory cortex, that is the areas whisker deflection activates in metabolic imaging, with the barrels. The follicles of select whiskers were removed in the critical period of brain development and in maturity. Early in his career, Auguste Forel conducted experiments, the results of which were instrumental to the hypotheses in my research.


The pictures above show a view of Yvorne (top, left), Forel at work in the Ant Hill (top, right), microscopic drawings of sections through the brainstem stained for nerve cells and fibers (bottom, left), and his description of the findings (bottom, right). He had examined in rabbits the consequences of cutting the trigeminal nerve at the root where it enters the brain. The microscopic drawings above show the nerve cells receiving the sensory trigeminal input (pink) and bundles of incoming trigeminal nerve fibers (brown) in the brainstem with an unperturbed trigeminal nerve (left) and after a nerve cut (right). Forel was probably the first to document a glial reaction to injury in the nervous system. Glia are types of brain cells distinct from nerve cells. They provide maintenance and support the immune response in the brain. I have written about this discovery in my post dated Dec. 16, 2007.

Important to his theory of the neuron, Forel noted that the incoming nerve fibers considerably diminished in number after the cut, whereas the density of nerve cells appeared increased. Careful, subsequent analysis showed that the increase in density resulted from tissue shrinkage. The number of nerve cells actually remained unchanged. This finding suggested that the cells of the nervous system were not fused into a continuous web as some scientists believed at the time. By contrast, the cells constituted independent members of an indirectly-connected network. In this network, no single member needed to show all functional attributes of the whole inasmuch as the behavior of a single ant does not reveal the destiny of the colony. The Gestalt psychologists would pick up on this idea and propose that in matters of brain and mind the whole was more than the mere sum of the pieces. I wrote about this school of thought in my post dated June 6, 2008. The cellular structure that permits communication between nerve cells without fusion is known as synapse today and was discovered only with the advent of the electron microscope half a century later.

The cell bodies of the trigeminal nerve fibers lie between the nerve's root at the brain and the nerve's endings in the skin. Forel cut the nerve at the root resulting in the degeneration of the projections that innervate the brainstem of the central nervous system. The severed central projections do not regenerate. By contrast, the removal of whisker follicles in my studies disrupted the peripheral trigeminal sensory projections innervating the mouse's face. Peripherally projecting nerve fibers regrow vigorously and attempt to find targets in the skin, particularly in the mature nervous system. Properly guided, they are able to restore functional innervation. I experienced the potential of restoration myself in two instances with opposite outcomes.

In addition to the face's skin, the trigeminal nerve innervates our teeth. At one time, I had to undergo orthodontic surgery to treat an inflammation in a root canal. During the procedure the branch of the trigeminal nerve that innervates the lower jaw and lower lip was crushed. My cheek and half of the lip remained numb after the anesthesia had worn off. But within six weeks, sensation returned successively, progressing toward the tip of the lip. I still vividly recall the moment when the numbness on the lip vanished with a slight tingling sensation and my sense of touch was completely restored. Apparently, the regenerating nerve fibers had successfully found their targets.

I was less fortunate on another occasion. I accidentally cut myself deep in the palmar surface of the right index finger, partially severing its sensory innervation. The accident happened 30 years ago. Half of my finger remains numb today. I have to be careful when I open bottles with twist caps, because I do not feel the pain before it is too late. Obviously, the regrowing nerve fibers were not able to bridge the injury and re-innervate the skin. They lacked the guide of the sheeth wrapping the nerve. The nerve stumps had become separated and misaligned in the accident. Today, surgeons are careful to reconnect nerve sheeths in reconstructive procedures to ensure optimal restoration of innervation.

Forel's insights into the relationships between ants and nerve cells spawned a number of hypotheses in my work about possible nerve cell responses to the loss of sensory input. I imagined the ensemble of nerve cells interacting in the brain in analogy to an orchestra of ants, the Orchestre de Mille Francs, OMF for short. The members of the OMF grow up and learn to play music together. Each member must play their instrument in context of the music the other members play. Though the members are independent players, they need to listen to one another and coordinate their actions in order to perform in meaningful symphony. What would happen if members break their instrument? What would happen if they break a limb? Can the remaining members substitute? Does it depend on the kind of instrument the member was playing? Would the music change? Could the melody be restored? Did the changes depend on the proficiency of the players? Was the potential for change greater with beginners than with seasoned virtuosos? The drawings shown below helped flesh out possible scenarios.

L'orchestre de mille Francs

One intriguing finding of my mouse studies was that the functional cortical representations of the intact whiskers adjacent to the removed ones enlarged into the territory left vacant by the removal. The functional whisker representations were modified even when whisker follicles were removed in adult mice long after the critical period for barrels had ended. This plasticity of functional sensory representation may provide a basis for the perception of a continuous tactile field while the sensory nerve fibers in the facial skin reorganize. The regeneration of peripheral innervation is particularly strong when the nervous system is mature. My studies and the studies of others showed that whisker follicles remaining in the skin attract the newly regenerated nerve fibers and are innervated by them within three months. The findings suggest that it may be worthwhile to surgically provide guides for regrowing nerve endings months after the disruption of innervation. An extended program of exercises providing continued sensory stimulation may help boost new functionality.

Addendum