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.

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

• Christensen HC, Schüz J, Kosteljanetz M, Poulsen HS, Thomsen J, Johansen C (2004) Cellular telephone use and risk of acoustic neuroma. Am J Epidemiol 159: 277-283.
• Hardell L, Carlberg M, Hansson Mild K (2005) Case-control study on cellular and cordless telephones and the risk for acoustic neuroma or meningioma in patients diagnosed 2000–2003. Neuroepidemiology 25: 120-128.
• The INTERPHONE Study Group (2010) Brain tumour risk in relation to mobile telephone use: results of the INTERPHONE international case–control study. Int J Epidemiol 39: 675-694.
• Volkow ND, Tomasi D, Gene-Jack Wang G-J, Vaska P, Fowler JS, Telang F, Alexoff D, Logan J, Wong C (2011) Effects of cell phone radiofrequency signal exposure on brain glucose metabolism. JAMA 305: 808-813.

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):

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

• Chugani HT, Phelps ME, Mazziotta JC.
  
  
  Positron emission tomography study of human brain functional development.
  Ann Neurol. 1987 Oct;22(4):487-97.
• Gogtay N.
  
  
  Cortical brain development in schizophrenia: insights from neuroimaging studies in childhood-onset schizophrenia.
  Schizophr Bull. 2008 Jan;34(1):30-6.
  
• Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF 3rd, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM.
  
  
  Dynamic mapping of human cortical development during childhood through early adulthood.
  Proc Natl Acad Sci U S A. 2004 May 25;101(21):8174-9.
  
• Huttenlocher PR, De Courten C, Garey LJ, van der Loos H.
  
  
  Synaptic development in human cerebral cortex.
  Int J Neurol. 1982-1983;16-17:144-54.
  
• Innocenti GM.
  
  
  Exuberant development of connections, and its possible permissive role in cortical evolution.
  Trends Neurosci. 1995 Sep;18(9):397-402.
  
• LeVay S, Wiesel TN, Hubel DH.
  
  
  The development of ocular dominance columns in normal and visually deprived monkeys.
  J Comp Neurol. 1980 May 1;191(1):1-51.
  
• Markham JA, Greenough WT.
  
  
  Experience-driven brain plasticity: beyond the synapse.
  Neuron Glia Biol. 2004 Nov;1(4):351-363.
• Melzer P, Crane AM, Smith CB.
  
  
  Mouse barrel cortex functionally compensates for deprivation produced by neonatal lesion of whisker follicles.
  Eur J Neurosci. 1993 Dec 1;5(12):1638-52.
• Melzer P, Morgan VL, Pickens DR, Price RR, Wall RS, Ebner FF.
  
  
  Cortical activation during Braille reading is influenced by early visual experience in subjects with severe visual disability: a correlational fMRI study.
  Hum Brain Mapp. 2001 Nov;14(3):186-95.
• Rakic P, Bourgeois JP, Goldman-Rakic PS.
  
  
  Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness.
  Prog Brain Res. 1994;102:227-43.
  
• Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW.
  
  
  Longitudinal mapping of cortical thickness and brain growth in normal children.
  J Neurosci. 2004 Sep 22;24(38):8223-31.
• Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J, Nicolson R, Toga AW, Rapoport JL.
  
  
  Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia.
  Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11650-5.