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Tuesday, April 28, 2009

Hemispherectomies, Brain Plasticity & The Mind

Hemispherectomy strikes us as a radical procedure. It chillingly reminds us of the lobectomies performed in the 1940s and 1950s. Lobectomies impacted the patients' personality so profoundly that they were quickly abandoned.

The case of Henry Gustav Molaison is one example. He underwent this procedure at the age of sixteen to subdue deleteriously frequent bouts of epilepsy. Epileptic seizures are produced by bursts of electrical signals from nerve cells clustered in small discrete brain regions known as epileptic foci. The bursts send waves of hyper-excitation through the cerebral cortex that lead to loss of consciousness and uncontrollable limb movements. Henry Molaison's surgeon, William Scoville, found reasons to believe that Henry had such foci on each cerebral hemisphere and, therefore, removed parts of the medial temporal lobe on both sides.

Indeed, the surgery freed Henry from his violent seizures. He suffered very few mild attacks in his later years. However, he could not remember anymore who he was. Known only by the initials H.M. until his death last year, he volunteered for numerous psychological studies, offering crucial insights into the workings of memory. I have written about him in my post dated Feb. 20, 2009. Scoville would never use the technique again.

After such discouraging results, lobectomies were replaced with surgical procedures that aimed to block seizures more discretely. Already in the 1940s, the neurosurgeon William Van Wagenen had pioneered a procedure that consisted of the transection of the nerve cell connections between the cerebral hemispheres. He cut the structure containing the nerve cell fibers of these connections, called corpus callosum, at the midline between the hemispheres, leaving the latter unharmed. If the epileptic foci were located in only one hemisphere, the transection of the interhemispheric connections would prevent the waves of excitation from crossing to the other hemisphere devoid of foci. The procedure was successful in eliminating seizures and became known as callosotomy (Mathews and others, 2008).

The Nobel Prize-laureate Roger Sperry had spent years of research on the transfer of information from one cerebral hemisphere to the other and had the opportunity of studying some of Van Wagenen's patients.  Based on this experience, Sperry and his colleagues at the California Institute of Technology, began to perform callosotomies in the early 1960s. The neurophysiologist and neurosurgeon Joseph Bogen pioneered and refined the procedure. The callosotomies, while successfully suppressing seizures, produced utterly subtle mental changes. The team began a long series of elaborate psychological tests to examine the patients' differences in behavior. The studies became widely known as the split brain experiments and provided fundamental insights into differences in function of the cortical hemispheres and their interactions.

In very severe cases of epilepsy like Rasmussen syndrome, however, callosotomies alone have proven ineffective, and hemispherectomies have shown superior results. Complete hemispherectomies were performed only early in the 20th century. They affected the patients' mental capabilities gravely, and the method was abandoned.  In the 1960s, however, the procedure was revived in a more refined and restricted fashion. The pediatric neurosurgeon Benjamin Carson at the Johns Hopkins University School of Medicine became a pioneer in this field. He achieved the effective suppression of seizures of the severest nature with hemidecortications and  functional hemispherectomies (Carson and others, 1996).

Hemidecortications comprise the temporal, frontal, parietal and occipital lobes of the cerebral hemisphere with the epileptic foci. The cortical gray matter is removed, while leaving the underlying white matter in tact as much as possible. Functional hemispherectomies, on the other hand, entail the removal of the temporal lobe and the complete transection of the corpus callosum. In both types of surgery, brain structures under the cerebral cortex are left intact.

The surgeries are preferably performed in young children. Depending on their age, the resulting long-term disabilities can be small. Except the limited use of the arm on the opposite side of a hemidecortication, behavioral differences may be difficult to notice (ScienceDaily reports in a post dated Oct. 16, 2003).

Roughly the same cortical functions are mapped symmetrically on both cerebral hemispheres. Differences develop during the first years of life. One major difference is that language is processed on the left hemisphere in all right-handed and most left-handed adults. Early in life, however, nerve cell connections are still forming in exuberance. That is, cortical nerve cells grow transitory endings into several regions of cortex on the same hemisphere and on the other hemisphere, into subcortical brain structures and into the spinal cord. Used connections stabilize; unused ones are pruned. Similar exuberance and elimination has been observed in the pathways that provide sensory input to cerebral cortex.

If cortical tissue is removed on one hemisphere in this sensitive period, nerve cells that would have innervated the removed tissue may stabilize connections with the other hemisphere, and the latter may compensate the loss of function (Holloway and others, 2000). The extraordinary extent of the compensation is evident in the young man featured in the second installment of the Public Broadcasting Service series "The Secret Life of the Brain" which premiered in 2002. Another child is portrayed in the report by WBFF Channel 45 Fox News from 1997 below:


Pulsifer and others (2004) examined the cognitive abilities of 71 children before and after the surgery. Most parents were satisfied with the outcome and most children were able to attend mainstream schools at the time of the study, though more than half needed support. If we were asked to select these children's brain scans among the scans of their classmates in school, we would pick the correct ones without hesitation. If we were to pick out the children mingling with their peers during recess, we were likely to fail.

Addendum
  • I have written extensively about differences in brain plasticity between the developing and the mature brain in my post with the title "Brain Plasticity & The Mind" published Jan. 7, 2011. During development nerve cell connections undergo a period of exuberance followed by elimination. That is, underutilized connections are pruned and used connections strengthen. In the adult brain, ascending sensory pathways to the cerebral cortex and the descending motor pathways are crossed. The degree of decussation varies. While half of the optic nerve fibers cross at the optic chiasm in the visual system, in the motor system 80-85 percent decussate. However, transitory uncrossed nerve cell projections have been observed in equal proportion with the crossed projections during early brain development. Tolbert and others (1984) provide an example. Possibly, such connections are stabilized after an early hemispherectomy and may account for the observed recovery of motor functions (03/ 03/11).
References
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Saturday, April 25, 2009

Academic Institutions & Profitability

The effects of the unfolding economic crisis on the finances of American academic institutions I have monitored in my post dated Dec. 9, 2008, indicate that a number of non-profit private research universities overextended themselves financially in the past ten years. For example,  Vanderbilt University spent roughly the equivalent of its current endowment on the expansion of its infrastructure. The sudden economic crisis has produced unforeseen, painful shortfalls of funds the institutions had relied upon to cover their daily expenses. Now, these universities are vigorously seeking new avenues to finance operations and contractual obligations.

One solution that research universities seem to embrace entails identifying ventures that show earning potential, insulating them financially from the mother institution, and converting them into university-owned independent enterprises. The mother university is transformed into a holding in private equity. Particularly, ventures in drug development and individualized health care using genomics and proteomics as well as management of electronic medical records lend themselves to this process. The strategy resonates in an interview entitled "Balser looks ahead to role as Medical Center leader" that the incoming Vice-Chancellor of Health Affairs gave to the Vanderbilt University Medical Center Reporter on Apr. 17, 2009.

There is precedence for such strategy. Large enterprises have pursued corporate disintegration for the sake of profitability in the recent past. The German chemical conglomerate Hoechst AG that once employed 150,000 people worldwide, was unwound into profitable spinoffs twenty years ago. Profitable businesses within the conglomerate were identified with the help of a world-renowned consulting firm whose representatives wore distinct dress code including bowler hats and umbrellas. Subsequently, the profitable businesses were pared from the conglomerate, reincorporated as independent companies, releasing them from any existing union contracts, and sold. In this country, General Motors and Chrysler have been in a similar process. At not-for-profit academic institutions, the strategy may erode the support for teaching and services to the underinsured and uninsured.

Addenda

  • Today, the President nominated the geneticist Francis Collins for the post of Director of the National Institutes of Health (NIH). At the end of Gardiner Harris' report entitled "Pick to Lead Health Agency Draws Praise and some Concern" on the nomination published in The New York Times today, Dr. Alan I. Leshner, now chief executive of the American Association for the Advancement of Science, formerly of the NIH, is quoted saying that it was “an excellent idea to have a very credible geneticist heading N.I.H. at a time when we are pursuing so vigorously the promise of personalized medicine based on genomics." Vanderbilt University's health sciences appear well attuned to the future goals of the federal agency that funds most of biomedical research in this country (07/09/09).
  • Today, Janell Ross describes in her front page article for The Tennessean entitled "Medical debts compound pain" the lives of Tennesseans who cannot afford to pay their medical bills (new title in web site archive: "Imagine getting sick, getting bills you can't pay, then being sent to jail"). On page 4A, she notes that in fiscal year 2009 Vanderbilt University was owed 274.3 million dollars in unpaid bills for medical services, of which the institution absorbed 197.9 million dollars. One may wonder who covers the loss (09/27/09). According to Blake Farmer's report entitled "Uncompensated Care Heads to VUMC, Rise Smaller than Predicted" on National Public Radio's WPLN yesterday, Vanderbilt's unrecoverable loss from unpaid medical bills has risen to 228 million dollars (11/12/09).
  • The idea of personalized medicine entails the sequencing of our individual genomes to uncover differences that may potentially lead to future illness. The results could be used to take preemptive measures. To date, sequencing the human genome has been prohibitively expensive, costing between 5,000.- and 50,000.- dollars. However,  John Markoff reported in his post entitled "I.B.M. Joins Pursuit of $1,000 Personal Genome" for The New York Times yesterday that technological advances in genetic sequencing may  possibly bring down the cost to a thousand dollars in the near future. Even a mere 100.- dollars seem feasible.  In specific cases, e.g. when diseases run in families, personalized genomic sequencing may certainly benefit the concerned. However, whether ubiquitous screening will improve health care remains an open question (10/06/09).
  • Perhaps  Columbia/HCA represents an apt partner for converting not-for-profit health care into for-profit enterprises. Listen to yesterday's interview of National Public Radio's WPLN with Columbia/HCA's CEO Richard M. Bracken in a segment entitled "HCA Earnings Soar, Acquiring Struggling Non-Profits Emerges as Growth Option". I recall hearing similar pronouncements a dozen years ago, when then CEO Richard L. Scott unleashed a similar wave of acquisitions. After such take overs, teachers and basic scientists may quickly become an endangered species as the fate of Allegheny University of  Health Sciences, a merger of Hahnemann University and Medical College of Pennsylvania, illustrates (11/06/09).
  • The current revenue shortfall will force states to diminish their spending on Medicaid programs in the near future, diminishing income particularly at not-for-profit hospitals. Tennessee considers cuts in its Medicaid program of up to 7 percent, According to Getahn Ward's article entitled "Nashville hospitals' banner year may not tell full story" in The Tennessean today, Vanderbilt University anticipates a loss of 50 to 70 million dollars because of the anticipated reduction in Medicaid payments in the new year. Inevitably, this will only add to the hundreds of millions of dollars in unpaid services that the institution already must absorb (11/29/09).
  • According to Madison Park's post on CNN entitled "Walgreens postpones plans to sell personal genetic tests" today, Walgreens had planned to offer saliva tests for at risk genes for less than $270.-.

Today, Walgreens halted its plans until further notice after the FDA intervened. I quote from her post: "Many of these markers are not understood, even what genes they are affecting right now," said Dr. Kenneth Offit, chief of clinical genetics service at Memorial Sloan-Kettering Cancer Center in New York. "It's a very, very early stage in this level of genomic research." Affordable personalized medicine for everyone seems still way off in the future (05/13/10).
  • The Nobel-laureate and scientific adviser to the U.S. president Harold Varmus, who served as Director of the National Institutes of Health and soon will head the National Cancer Institute, appears to have changed his mind on the immediate promises of personalized medicine. In Nicholas Wade's report for The New York Times with the title "A Decade Later, Genetic Map Yields Few New Cures" dated Jun 10, 2010, Varmus is quoted saying: "Genomics is a way to do science, not medicine" (06/14/10).
  • Christina E. Sanchez reports in her article entitled "Vanderbilt takes care personally" in today's Tennessean on the university's recent initiative in personalized medicine. She uses targeted therapies in the treatment of cancer to demonstrate the potential of this new avenue of care. The article does not detail therapies, but particularly mentions new treatments for lung cancer that entail the screening of patients' tumor tissue for modified genes. Recent studies uncovered a modification of the gene ALK in people with non-small cell lung cancer. ALK encodes the enzyme anaplastic lymphoma receptor tyrosine kinase. The fusion of this gene with the gene EML4 renders a tyrosine kinase persistently active that prevents programmed cell death from curtailing neoplastic growth.  Aaron Saenz describes a potential drug treatment using this important finding in his post entitled "Crizotinib Targets Gene To Stop Lung Cancer Tumors in 90% of Treated Patients" on Singularity Hub dated Jun. 9, 2010. No doubt, the development of drugs specifically targeting such cellular malfunction is highly desirable. However, less than four percent of lung cancer patients carry the EML4-ALK fusion, and the drugs tested to date only slow the progress of the disease. Personalized medicine definitely needs more research, time and money to come to fruition (08/04/10).
  • More than a decade of expansion have come to an end: Vanderbilt University is in the process of eliminating more than 1,000 jobs in mass lay-offs at its medical center this fiscal year. Vice Chancellor of Health Affairs, Dean of the Medical School and CEO Jeffrey Balser chose not to mince words. According to The Tennessean's post with the title "Vanderbilt University Medical Center eliminates 275 jobs of 1,000 to be cut" published online Sep. 20, 2013, Balser noted: “Some have been concerned that VUMC has been ‘too transparent’ about the need to reduce staffing,...” At the end of the day for-profit TriStar Centennial Health may stand ready to absorb Vanderbilt's operation at a good price, while the current leadership will be rewarded with golden parachutes(02/21/2013).

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Sunday, April 19, 2009

Gustav Fechner & Functional Brain Imaging

Today we celebrate the birthday of Gustav Theodor Fechner. He was born in 1801. Anecdotes have it that he was a late-night owl and that, as a young student, he liked to stay in bed daydreaming in the mornings and was notoriously tardy even for ten-o'clock c.t. lectures (Boring EG, 1970). In the German academic system, the suffix c.t. stands for cum tempore and means that the lecture actually begins fifteen minute past the hour.

He must have spent his time with the right thoughts. At the age of 34, he had completed his M.D. and Ph.D. degrees and was tenured as full professor on his way to become one of the first and most eminent experimental psychologists. He believed that the physical world and our perception of it were complementary and set out to find a mathematical relationship between the physical world and its mental image.

While Fechner began to explore methods to quantify mental work, he became aware of Ernst Heinrich Weber's studies. Weber had asked blindfolded participants to compare packages of differing weight placed in each hand. He observed that the smallest weight that could be judged as different changed in fixed proportion with the weight of reference. The heavier the reference weight, the greater the difference in weight had to be to be noticed. The reported change in sensation Δs was a function of the ratio between the difference in weight Δw and the reference weight W multiplied by a factor r:

(1)    f(Δs) = r x  Δw/W

Integrating function (1) and substituting weight for stimulus R results in:

(2)    f(S) = r x ln(R) + Smin

where sensation S is a function of the natural logarithm of stimulus R multiplied by factor r plus a constant Smin which constitutes the smallest noticeable difference in R. Hence, sensation S increases in direct proportion with the logarithm of stimulus R with the slope of factor r. Consequently, stimulus magnitude had to be doubled for the increase to be noticed.

In reverence of Weber's work, Fechner called the direct proportionality between sensation and the logarithm of stimulus strength Weber's law, proposing that the relationship may apply to all senses. Confirming his hypothesis, he could provide evidence that Weber's law adequately described the relationship between perceived luminosity and the brightness of stars. He believed that the law might open ways to indirectly measure mental processes, trailblazing a science of quantifying mental activity. Alas mind work remained inferred from the participants' judgment. In acknowledgment of the pioneering contributions to experimental psychology of both men, the law is known as Weber-Fechner law today.

One hundred-fifty years later, the direct measurement of mental processes remains elusive. However, methods have been found to measure cerebral work. Brain cells utilize glucose and oxygen to process information. Both have to be supplied by blood flow on demand, since they cannot be stored in the brain tissue. Thus, local cerebral blood flow increases with the increase in nerve cell activity.

Since the 1940's, Seymour Kety, Lou Sokoloff, and others were working out methods to measure local cerebral blood flow with radioactive tracers, initially at the University of Pennsylvania and later at the National Institutes of Health (Sokoloff, 2000). Around 1970, Lou Sokoloff and others succeeded in developing a method with which the rates of local cerebral glucose utilization could be determined in animals (Sokoloff and others, 1977).

With the advent of Positron Emission Tomography (PET), both methods became widely used in humans. Since then, numerous studies have demonstrated that brain work and blood flow indeed increase in logarithmic proportion with the magnitude of stimulation. Electrical nerve cell discharges known as spikes encode stimulus magnitude. My colleagues and I observed with micro-electrode recordings from nerve cells in the cerebral cortex that the cells are limited in their ability to increase the spike rate with increasing frequency of stimulation. Instead, they dynamically scale down their responsiveness with increasing frequency, while continuing to respond time-locked to the stimuli (Melzer and others, 2006). This ability, known as gain control, may underlie the logarithmic relationship between sensory stimulus, brain cell response and mental perception.

Combining PET with functional magnetic resonance imaging (fMRI), Dettmers and others (1996) were able to show a tight association between stimulus-related increases in local cerebral blood flow measured with PET and the blood oxygen level-dependent (BOLD) signal measured with fMRI. Hence, modern non-invasive tomographic brain imaging methods support that the law of Weber and Fechner may apply to brain work. This is not exactly the outcome Professor Fechner had in mind, but he would certainly find the findings exciting, were he still alive today.

References

Monday, April 13, 2009

Chess & Mind

Chess, the game of queens and kings, is a truly royal game. Playing chess requires great focus of mind. The player needs to consider defensive and offensive moves simultaneously. She/he must be able to imagine the development of the game many steps in advance. Mind games like chess are quite similar to physical sports. You have to keep at it persistently in order to progress and learn from friends more experienced than you. Chess is a great after-school activity for children. It may result in crushed egos. Crushed bones need not be feared.

Two weekends ago, my son attended the Fourth SuperNational K-6 Chess Championship convention held here in Nashville at the Opryland Hotel. Dylan Loeb McClain covered the event for The New York Times in his post dated Apr. 11, 2009. Several thousand children from all over the nation with their parents descended on Nashville to play two days and a half-worth of chess. It was our first time.

I attended many professional conventions in my life. None I experienced like this. Commonly, people convene to exchange information verbally. As a result, the convention floor is filled with the chatter and hum of many voices. Attendees present posters. Potential customers talk about business at exhibitors' booths. Orders are accepted. Deals are struck. Talks are given at symposia,  sessions and workshops. Luminaries present evening lectures amplified and broadcast to thousands of listeners in the audience.

By contrast, the SuperNationals are conducted in absolute silence. The huge hall is filled with thousands of conventioneers, but no one is uttering a single word. The players communicate through their moves on the board.The only noise consists of the plops of the pieces on the board and the taps on the timers.

Fourth SuperNational K-6 Chess Championship, Nashville, TN, 2009.
The experience may be extraordinary to spectators, resembling an out-of-body experience. To the players, it is extremely taxing. While I enjoyed the splendid variety of beautiful orchids around the waterfalls in the tropical rain forest bubble of the hotel, my son played five rounds. His longest round took three hours and a half. He won. When it was over, his opponent gave him a small present. We must take some tokens of appreciation for the others next time.

My son won most of his games, finished 78th, and qualified for a trophy. His school, Meigs Magnet Middle School, ranked 12th in the final standing. We returned home in high spirits. I hope the royal game will continue to provide him with a fulfilling past time in the future, strengthening his mind's focus.


Addenda
  • Hopefully this research study will affirm that playing chess helps stave off dementia as we age (12/09/10):
  • Look at these beautifully carved medieval ivory chessmen discussed in Ken Johnson's The New York Times art review with the title "Medieval Foes With Whimsy" published online yesterday (11/18/2011):

Wednesday, April 8, 2009

Recent Advances in Parkinson's Disease

Two days ago, National Public Radio's  All Things Considered broadcast a segment in its series This I believe with Mohammed Ali's contribution entitled "I Am Still The Greatest". The great boxing champion is suffering from Parkinson's disease. But that did not stop him to deliver his testimonial. Despite his condition, Muhammad Ali has risen to even greater championship after his boxing career ended, becoming a relentless ambassador for humanitarian causes and for more research in better treatments for this horribly destructive disease.

Parkinson's Disease is a degenerative disease of the central nervous system, resulting in severe tremor of limbs, motor arrest, and disruption of speech. Its cause is unknown, though a subset of people with the disease are known to carry an inherited genetic mutation that may predispose degeneration.

Nerve cells located in the basal ganglia, a group of forebrain structures situated nose-ward under the cerebral cortex, control our fine movements. They provide feedback to the nerve cells in the motor areas of the cerebral cortex that connect with nerve cells in the ventral horn of the spinal cord. The spinal nerve cells, known as motor neurons, innervate muscle fibers and control limb movement.

Basal ganglia functionality depends on a set of nerve cells located in a structure behind the basal ganglia, known as substantia nigra. In Parkinson's disease, the substantia nigra cells degenerate over decades and eventually die. The loss of their input to the basal ganglia perturbs motor control.

The nerve cells in the substantia nigra use the neurotransmitter dopamine to communicate with the nerve cells in the basal ganglia. Replacing the lost dopamine with the systemic administration of the drug levodopa ameliorates the symptoms. However, over time the brain develops increasing tolerance to the drug, and even high doses cannot control tremors anymore. Efforts pioneered by A. Björklund at the University of Lund in Sweden at grafting into the brain undifferentiated cells induced to produce dopamine showed promising results in animal studies, but grafts with fetal ventral mesencephalic tissue, rich in dopaminergic neuroblasts, have not proved unequivocally successful in humans (Kefalopoulou and others, 2014).

When medication eventually fails, surgically removing specific parts of the basal ganglia or inter-brain structures also involved in fine motor control may improve the condition (Çoban and others, 2009). In the last decade, however, deep brain stimulation has gained popularity. The method is less invasive and has produced superb outcome. It entails electrical stimulation of nerve cells in the basal ganglia or the inter-brain using thin implanted micro-electrode wires. The electrical impulses are thought to disrupt the persistent nerve cell activity causing the tremors. As a potential further improvement of this procedure, a research study published recently in the journal Science showed that the electrical stimulation of spinal cord nerve fibers with micro-electrodes, threaded between the vertebrae to touch the outer spinal cord where bundles of nerve fibers run that convey sensory information to the brain, may suffice to subdue tremors in Parkinsonian mice (Fuentes and others, 2009). The promising findings were reported on Mar. 19, 2009, in Julie Steenhuysen's post entitled "Spinal cord device helped mice with Parkinson's" on Reuters and Sandra Blakeslee's article entitled "Spinal Shocks Ease Parkinson’s in Mice" in The New York Times. If this procedure proved successful in people, brain surgery would be rendered unnecessary.

If Parkinson's disease runs in your family, you may be interested in gene chip tests for a predisposition available from 23andMe.

Addenda

  • Some patients with Parkinson's Disease benefitted from having fetal midbrain tissue rich in dopamine-producing nerve cells grafted into the dopamine-depleted basal ganglion known as striatum. However, dyskinesias, that is severe bouts of involuntary movements, hampered recovery despite major improvements in motor control. Using radioactively labeled markers and Positron Emission Tomography, Politis and others (2010) recently showed that the grafts produce extraordinary amounts of the neurotransmitter serotonin, suggesting that excessive serotonergic innervation of the striatum causes the dyskinesias. Hence, medication with long-lasting serotonin antagonists may subdue the undesired effect in grafted patients, and the use of grafts that lack great amounts of serotonergic nerve cells in future surgery may improve outcome in implantation therapy (07/03/10).
  • If you are considering stem cell therapy, you may find the information on the International Society for Stem Cell Research site helpful (07/26/10).
  • Today, Diane Rehm interviewed Miguel Nicolelis on her show with the title "Miguel Nicolelis: 'Beyond Boundaries'". Dr. Nicolelis is a lead investigator in this research and discusses his fascinating insights (03/16/11).
  • Kefalopoulou and others (2014) report that 2 of the 18 patients who volunteered for the University of Lund trial implanting grafts of fetal ventral mesencephalic tissue 15 and 18 years ago showed significant, persistent behavioral improvements (04/09/2014).
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