December 2007

VOL.80 NO.10 December 2007 $5.00

SAN FRANCISCO MEDICINE JOURNAL OF THE SAN FRANCISCO MEDICAL SOCIETY

Neuroscience 

The Mind

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CONTENTS SAN FRANCISCO MEDICINE December 2007 Volume 80, Number 10 Neuroscience and the Mind FEATURE ARTICLES

MONTHLY COLUMNS

10 Neuroscience and the Mind Mike Denney, MD, PhD

4 On Your Behalf 5 SFMS Election Results

12 Psychoanalysis and Neuroscience Charles Fisher, MD 15 The Female Brain Louann Brizendine, MD

7 President’s Message Steve Follansbee, MD 9 Editorial Mike Denney, MD, PhD

18 The Brain That Changes Itself Norman Doidge, MD

32 Hospital News

19 Why God Won’t Go Away Mike Denney, MD, PhD

35 In Memoriam Nancy Thomson, MD

20 A Novelist on the Brain Steve Heilig, MPH

35 Classified Ad

23 Neuroscience, Menopause, and the Mind Ricki Pollycove, MD, MHS, FACOG 24 Emotion, Stress, and Traumatic Reactions Mardi J. Horowitz, MD

Editorial and Advertising Offices 1003 A O’Reilly

25 The Neuroscience of Addiction Jeff Miller 27 Major Depression Revisited Owen M. Wolkowitz, MD; Synthia Mellon, PhD; and Elissa S. Epel, PhD

San Francisco, CA 94129 Phone: 415.561.0850 ext.261 Fax: 415.561.0833 Email: adenz@sfms.org Web: www.sfms.org Subscriptions:

29 Detecting Awareness in a Vegetative State Adrian M. Owen, et al.

30 Neurodegenerative Diseases Michael Weiner, MD

$45 per year; $5 per issue Advertising information is available on our website, www.sfms.org, or can be sent upon request.

Printing: Sundance Press

31 Neurotechnology Zach Lynch

www.sfms.org

P.O. Box 26605 Tuscon, AZ 85726-6605

december 2007 San Francisco Medicine

ON YOUR BEHALF

December 2007 Volume 80, Number 10

A sampling of activities and actions of interest to SFMS members Editor Mike Denney Managing Editor Amanda Denz Copy Editor Mary VanClay

Notes from the Membership Department

Cover Artist Amanda Denz Editorial Board

Save the Date!

Chairman Mike Denney

Shieva Khayam-Bashi

January 24, 2008 SFMS Annual Dinner The dinner will be held again at the Concordia-Argonaut. Steven H. Fugaro, MD, will be installed as the 2008 President.

Steven A. Schroeder, MD, will be our keynote speaker. Please watch your mailbox for your invitation and RSVP card.

SFMS Officers

SFMS Nutcracker Night

President Stephen E. Follansbee

A NEW member event and a perfect way to unwind after the holidays! San Francisco Medical Society will enjoy its first Nutcracker Night on Saturday, December 29. This fun, family-friendly event will feature a festive reception with appetizers, sweet treats, and beverages at 5:30 p.m. followed by a performance of the San Francisco Ballet’s glorious new production of The Nutcracker at 7:00 p.m. Tickets are $55, inclusive of the reception. Space is limited, so plan on purchasing your tickets

by December 17 at the latest. If you have any questions, please contact Therese Porter in the Membership Department at (415) 5610850 extension 268 or tporter@sfms.org.

Obituarist Nancy Thomson Stephen Askin

Arthur Lyons

Toni Brayer

Terri Pickering

Gordon Fung

Ricki Pollycove

Erica Goode

Kathleen Unger

Gretchen Gooding

Stephen Walsh

President-Elect Stephen H. Fugaro Secretary Michael Rokeach Treasurer Charles J. Wibbelsman Editor Mike Denney Immediate Past President Gordon L. Fung SFMS Executive Staff Executive Director Mary Lou Licwinko Director of Public Health & Education Steve Heilig Director of Administration Posi Lyon Director of Membership Therese Porter Director of Communications Amanda Denz Board of Directors Term:

Carolyn D. Mar

Jan 2007-Dec 2009

Rodman S. Rogers

Brian T. Andrews

John B. Sikorski

Lucy S. Crain

Peter W. Sullivan

Jane M. Hightower

John I. Umekubo

Donald C. Kitt

Term:

Jordan Shlain

Jan 2005-Dec 2007

Lily M. Tan

Gary L. Chan

Shannon Udovic-

George A. Fouras

Constant

Jeffrey Newman

Term:

Thomas J. Peitz

Jan 2006-Dec 2008

John W. Pierce

Mei-Ling E. Fong

Daniel M. Raybin

Thomas H. Lee

Michael H. Siu

CMA Trustee Robert J. Margolin AMA Representatives H. Hugh Vincent, Delegate Judith L. Mates, Alternate Delegate

The Great Dickens Christmas Fair Let Christmas Past be your Christmas present! Join 500 costumed performers in this 100,000-square-foot, theatrically lit recreation of Victorian London. Discover six stages of continuous entertainment from the spectacular Christmas Pantomime to the saucy French Postcard Review. Indulge in gourmet foods, fine wines, and authentic English ales. Try your hand at challenging games of skill and chance, from billiards and darts to fencing lessons. Shop for one-of-a-kind ceramics, fine clothing, rare books, exquisite jewelry, stained glass, feather masks, and children’s toys. Capture the magic

San Francisco Medicine december 2007

of the holidays with puppet shows, carousels, and a personal audience with Father Christmas or tea with Alice in Wonderland. For five weekends, 11:00 a.m. to 7:00 p.m. at the Cow Palace Exhibition Halls, November 23 through December 23.

SFMS has arranged with the Dickens Fair for members to purchase individual tickets at their group discount price through a dedicated webpage with shopping cart. Adult tickets are $15 each—$7 off the gate price. Please note that children’s tickets ($10) are not discounted but are available when ordering. Additionally, there is a $2 handling fee per order. One thing to note is that they do not have the ability to mail tickets in advance, but patrons are to pick them up at Will Call any day of the event.

The link is www.dickensfair.com/ sfms.html. There is one caveat: This link is available only to our membership.

It is not for the general public and may not be forwarded to outside friends and family.

Coming Next Year 2008 is going to be a great year for San Francisco Medical Society member events!

Watch for the return of the Tennis Mixer in January, Gallery events, the Night at the Symphony, and much more! Nonmembers and guests are welcome at most of our social events. These member events are a great way to introduce your physician peers to the San Francisco Medical Society.

New Resource on Drug Abuse The National Institute on Drug Abuse (NIDA) has launched a new website to provide physicians and other health professionals with the latest science on drug abuse and addiction. To learn more, please visit www.nida.nih.gov/medstaff.html.

Free HPV/Cervical Cancer Tool Kit A new tool kit on HPV and cervical www.sfms.org

cancer is available free of charge to physicians from the California Medical Association Foundation. The tool kit includes provider and patient information in multiple languages, vaccination and screening guidelines, newsletter articles, CME, and more. It is available online and on CD. See www.calmedfoundation.org/projects/HPV/ index.aspx for more information.

Volunteer to Give a Second Opinion to Cancer Patients Thesecondopinion, provided by the Regional Cancer Foundation, is a nonprofit organization that provides multidisciplinary second opinions to adults in California who have been diagnosed with new or recurring cancer. They are currently looking for volunteers to serve on the review board. If you are interested in helping out, please see www.thesecondopinion.org.

Protecting Your Prescribing Privacy The AMA Physician Masterfile maintains current data on all physicians, whether AMA members or not. These data can be combined with individual prescribing data. The compiled database is then sold to interested parties, including pharmaceutical companies. Prescribing data are used to develop a sales pitch to the individual physician prescriber.

The AMA has insisted on an “opt-out” program, the Physician Data Restriction Program. In order to opt out of sharing your prescribing data with pharmaceutical representatives, please go to: www.ama-assn. org/ama/pub/category/12054.html.

Autism Conference February 8, 2008 Medical Approaches in Autism: Clinical Implications of Environmental Toxicology for Children’s Neurodevelopment in Autism 8:00 a.m. to 5:00 p.m. at the UCSF Laurel Heights Conference Center, 3333 California St., San Francisco, California.

For questions or additional information, please email the NPART Symposium Coordinator at aut_sym@mac.com.

www.sfms.org

2007 SFMS Election Results 2008 Officers (one-year term) President-Elect: Charles J. Wibbelsman, MD Secretary: Gary L. Chan, MD Treasurer: Michael Rokeach, MD Editor: Mike Denney, MD Board of Directors (seven elected for three-year term 2008-2010): George A. Fouras, MD Keith Loring, MD William A. Miller, MD Jeffrey Newman, MD Thomas J. Peitz, MD Daniel M. Raybin, MD Michael H. Siu, MD Nominations Committee (four elected for two-year term 2008-2009): Mark A. Alderdice, MD Donald C. Kitt, MD Richard B. Ward, MD Angela Wong, MD American Medical Association Delegate (two-year term 2008-2009): H. Hugh Vincent, MD American Medical Association Alternate (two-year term 2008-2009): Robert J. Margolin, MD Young Physicians Section Delegate (two-year term 2008-2009): Lily M. Tan, MD Young Physicians Section Alternate (two-year term 2008-2009): Lawrence Cheung, MD Delegates to the CMA House of Delegates (First four are delegates; next five are alternates. Charles J. Wibbelsman, President-Elect, will serve as the fifth delegate according to the SFMS Bylaws. Two-year term 2008-2009): Delegates Stephen E. Follansbee, MD Peter W. Sullivan, MD George P. Susens, MD John I. Umekubo, MD

Alternates Gary L. Chan, MD Rita Melkonian, MD Rodman S. Rogers, MD Jordan Shlain, MD Rachel H.C. Shu, MD

The proposed amendments to the Bylaws were approved. december 2007 San Francisco Medicine

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president’s Message Stephen Follansbee, MD

Science of the Mind

I

find that my last column as the 2007 President of the SFMS addresses a subject I find compelling for a number of reasons.

But first let me admit that, of all the responsibilities I faced as the incoming President, writing this column was the most daunting. I was nervous about the added responsibility. I was particularly nervous about whether I would have anything to say. I now can admit freely that writing this column has been a joy. Why is that?

The answer relates directly to the subject of this issue.

For me, what makes us human is our minds. What makes medicine challenging and rewarding is that we use our minds constantly. We are always questioning our assumptions and taking a fresh approach to our patients, reconsidering their health problems.

No two patients are alike, and it is our intellect that recognizes this and encourages us to continue to learn and to challenge what we have already concluded. (A corollary to this is that I am clear that if I lose my mind, be it through trauma, Alzheimer’s, or another process or condition, I do not want to continue to live. I will have lost what is me.)

In writing this column for every issue, I have had to put my mind to work. And I have enjoyed the challenge of facing topics that I do not think about every day. It has encouraged me to consider the issues, do some research, and formulate some ideas into the written word. That process has brought me joy.

Arguably, the science of the mind is the last great frontier in medicine. From an infectious diseases point of view, the brain and central nervous system have always constituted something of a protected sanctuary, relatively resistant to infection. However, once infected, the consequences can be among the most devastating to the individual. Improvements in treatment must not only include new anti-infectives, particularly against viruses, that penetrate the intact blood-brain barrier. New treatments must also stimulate and enhance the immune response to infection at the same time that they interrupt the inflammatory response that may lead to permanent brain damage.

The challenges to advancing the science of the mind are great.

Since our minds make us human, we need to study humans. Animal models may be appropriate for certain questions, but they do not seem relevant to the functions we value as “human.” A recent single-patient report and discussion on localizing the out-of-body www.sfms.org

experience or disembodiment sensation (without autoscopy) is fascinating.1 The observations resulted from localized electrical stimulation of the posterior part of the right superior temporal gyrus in an attempt to suppress unilateral tinnitus. PET scanning data were collected to map the important area. The article suggests the anatomic location for integration of complex vestibular and somatosensory, predominantly proprioception, input.

In addition to the necessity of studying humans, scientists need to integrate not only the electrical and vascular perfusion data precisely but also take into account genetics, cultural and ethnic issues, and biochemical markers and neurotransmitters. Treatment will not only involve new and targeted medications but also new modalities for brain retraining and reconditioning.

This is a fascinating issue of San Francisco Medicine. It is a privilege to have contributed a small part to this issue, and it has been a privilege to have been your 2007 President. May we all use our fullest mental capacities to bring to medicine, our profession and our passion, the best of our talents.

De Ridder D, K van Laere, P Dupont, et al. Visualizing out-ofbody experience in the brain. N Engl J Med 2007;357:1829–33.

Save the Date!

January 24, 2008 SFMS Annual Dinner Please watch your mailbox for more information, including your invitation and RSVP card. Contact Posi Lyon with any questions, plyon@sfms.org, (415) 561-0850 extension 260.

december 2007 San Francisco Medicine

Get Paid What You’re Worth

All around California, physicians are being pressured by giant PPOs to accept lower reimbursement rates in exchange for patient volume. It’s a tough choice, but one fact stands clear: Every time you lower your rates, you have to work longer hours for less pay.

The Pacific Foundation for Medical Care offers you a better choice.

Since 1957, we have reimbursed physicians at generous rates that maximize your income—not ours. We’re nonprofit, and we’re governed by physicians. Our Mission is simple: To pay you what you’re worth.

Pacific Foundation for Medical Care To learn more about PFMC, or for a membership application, visit www.pfmc.org or call Kathy Pass at 800-548-7677, Ext. 115

Editorial Mike Denney, MD, PhD

The Wizard and the Scarecrow

T

he wonderful book The Wizard of Oz, written by L. Frank Baum, was published in the year 1900 during an era of cultural shift away from linear, orderly, and traditional ways of thinking and toward twentieth-century discontinuity and paradox in the arts and sciences. As though living in this paradigm shift, Dorothy, an orphan, is magically transported by a cyclone from the farm of Uncle Henry and Aunt Em in Kansas to the enchanted Land of Oz, where she soon meets Scarecrow who has no brains, Tin Woodman who has no heart, and Cowardly Lion who has no courage. Together they discuss their plight and formulate a plan to follow the yellow brick road to the Emerald City, where they hope to find the Great Wizard who can implant their missing parts and help Dorothy return to Kansas.

We can readily grasp the scheme of these four characters as they try to fulfill the wishes of Dorothy, the Tin Woodman, and the Cowardly Lion. However, it is Scarecrow, made of straw, who captures our curiosity in the spirit of the discontinuity and paradox of the year 1900. Scarecrow, though without a brain, obviously has a mind—he engages in cognition, reasoning, meaningful conversation, rational thought, and complex agreements with the others. Paradoxically, he has no brain—yet he has a mind. It is as though the straw itself is capable of conscious thought.

This enigma surrounding the relationship of brain (objective) to mind (subjective) has been pondered by philosophers over the centuries. René Descartes (1596–1650) said, “I think, therefore I am,” thereby separating the mind from the body (brain). Immanuel Kant (1724–1804) carried this idea further by noting that the human mind cannot objectively know “the thing in itself” but can only know its own subjective experience of things. Nowadays, this question about the relationship of the mind to the brain can be envisioned in the theories of materialism, panpsychism, or mysterianism.

Materialism postulates that somehow the mind arises as an epiphenomenon of the brain (spirit from matter), a concept that began with Aristotle and remains inherent in our present-day objective science. Panpsychism, first proposed by Pythagoras and Plotinus, suggests that, throughout the cosmos, consciousness is immanent in all things, and some modern philosophers propose that consciousness was the source of the “big bang” and thus itself actually gave rise to matter—Scarecrow’s straw does have a mind. And mysterianism, as www.sfms.org

explained by Rutgers philosopher Colin McGinn in his book The Mysterious Flame (Penguin, 1999), asserts that the mind can indeed arise from the material brain, but that the brain lacks the capacity to comprehend how this can be possible, and thus the question will remain forever unanswered.

As in this issue of San Francisco Medicine we contemplate our theme of neuroscience and the mind, we notice that our biomedical science is inherently based upon materialism—our methods presuppose that EEGs, PET scans, and MRIs somehow represent not only the objective function of the brain but also the subjective experience of the person. We assume that the anatomical and physiological findings on the images represent not only change in brain tissue but also the subjective cognition of the human being. Carrying this perspective to the extreme, in a University of Pennsylvania study of praying Franciscan nuns and meditating Tibetan monks, researchers Andrew Newberg, MD, and Eugene d’Aquili, MD, PhD, conclude that the highlighted areas on brain SPECTscans in the posterior superior segment of the parietal lobe are “images of God,” somehow depicting the subjects’ personal experiences of the divine.

On the other hand, in the spirit of discontinuity and paradox in this question of matter and mind, we might notice that it was in the year 1900 that the philosopher Edmund Husserl, founder of phenomenology, completed his book Logical Investigations, which pointed out a profound self-referential paradox: The only way that we can contemplate the mind is by using the mind. Moreover, in his book The First Moderns (University of Chicago Press, 1997), narrative historian William R. Everdell says that the mathematical discoveries of the early twentieth century indicate that “there is embedded in every system for arriving at truth a recursive or self-reference that automatically undermines the consistency of the system.”

We may need a cultural shift to a new paradoxical science if we are ever to understand the relationship of neuroscience and the mind.

Our ordinary empirical science seems inadequate to the task. Indeed, we might remember that when Dorothy, Scarecrow, Tin Woodman, and Cowardly Lion are finally allowed into the Throne Room, the little dog Toto knocks down the screen and the great Wizard of Oz is exposed to be nothing but a humbug who hasn’t any realistic idea of how to get Dorothy back to Kansas, and who can offer no explanation of how Scarecrow can have a mind without a brain. december 2007 San Francisco Medicine

Neuroscience and the Mind

Neuroscience and the Mind Discontinuity, Paradox, and the Magical Year of 1900 Mike Denney, MD, PhD

I

n the year 1900, the Modern artist Edvard Munch painted a picture of his sister, Laura. The painting was later named Melancholy because Laura suffered severe mental illness and was considered to be chronically insane. At the time, little was known about the anatomy and physiology of the brain, and most emotionally disturbed or mentally ill patients were simply separated from society and confined in insane asylums, where they were sometimes studied by doctors and scientists who wished to learn more about neuroscience and the mind.

Munch, whose most famous painting is The Scream (1893), was only one among many creative artists in that cultural transformation from the fin de siècle to the Belle Epoque of the late nineteenth to the early twentieth centuries. The discontinuity and paradox of this magical era took the form of such artistic manifestations as impressionistic and abstract painting by Claude Monet and Paul Cézanne, rhymeless and meterless poetry by Arthur Rimbaud and Jules LaForge, atonal and discordant music

by Arnold Schoenberg and Igor Stravinsky, dream and fantasy theater by August Strindberg and Henrik Ibsen, and fantastic stream-of-consciousness literature by James Joyce and Virginia Woolf.

This fascinating cultural transformation was also expressed in neuroscience.

In the foreground of Munch’s painting of Laura, in the form of an oddly-shaped little table, is a strange image. It is in the colors of histological tissue stains. On further scrutiny, the informed viewer can detect that this image actually may be a replication of a drawing taken from the sketchbook of the Spanish physician and neurohistologist Santiago Ramón y Cajal. It is an image of the structure of the human cerebral cortex.

By 1900, after modifying the silver chromate tissue staining technique of Golgi, Cajal had discovered in human brain tissue, and illustrated in his drawings, delicate squiggly lines or fibrils with a tangled appearance, with pyramidal-shaped cells from which extend long, delicate vertical strands that then branch horizontally in a complex, intertwined network. Cajal demonstrated that the central nervous system in human beings is not made up of linear and continuous fibers but is composed of billions of individual neurons that are separated by delicate synapses. These synapses were later shown to be polarized communication centers across which electrical impulses transmit signals. For this neuron doctrine he was awarded the Nobel Prize in Medicine in 1906. Cajal had demonstrated that, like modern art, the structure of the human brain is also discontinuous and paradoxical.

As an extension of nineteenth-century neurological discoveries such as observing reflexes, localizing brain areas by electrical stimulation and ablation, demonstrating low-level electrical activity in the resting brain, and Helmholtz’s measuring of the speed of nerve transmission, scientists became focused upon the mind as well as the brain. In 1887, Charles Richet, MD, of the Faculté de Médecine in Paris, best known for his discovery of anaphylaxis (for which he won the Nobel Prize), published his book Essai de psychologie générale, in which he advocates that the physiology of the brain and the psychological attitudes, emotions, thoughts, and behavior within humans are all aspects of the same science.

Meanwhile, in another part of Paris, neurologist Jean Louis Martin Charcot, the “Napoleon of Neuroses” at the Sâlpetrière clinic, was clarifying general paralysis, neu-

10 San Francisco Medicine december 2007

ralgias, epileptic seizures, muscle spasticity, tabes dorsalis, and Parkinson’s disease—but his favorite subject was psychological hysteria in women. In 1885, Sigmund Freud studied with Charcot and later collaborated with Eugen Bleuler in the treatment of “Anna O,” a patient with psychosomatic paralysis.

In the year 1900, Freud published Interpretation of Dreams, which was the beginning of dynamic psychiatry, a discipline derived from the connection of body to emotions, brain to mind, of Anna O. It was in that same extraordinary year of 1900, at the state asylum in Frankfurt am Main, that the neuropathologist Alois Alzheimer attended a fifty-one-year-old woman named Auguste D, who had memory loss, disorientation, and hallucinations, and who died four years later. Studying this “unusual disease of the cerebral cortex,” Alzheimer went on to elucidate this ailment and to demonstrate associated plaques and neurofibril tangles in the brain.

Soon neurochemistry began to bring new understanding of the relationship of the brain and the mind. Adrenalin was identified in 1901, oxytocin in1909, and histamine in 1910. In 1921, Otto Loewi, professor of pharmacology at Graz, awakened at 3 a.m. from a dream that vividly described a simple experiment with which he could prove his theory that nerve impulses are mediated by chemical transmission. Loewi got out of bed, went to his laboratory, and performed the simple experiment: He immersed in a Ringer’s solution two frog hearts, one with the vagus nerve intact and the other with the vagus nerve severed. When he stimulated the vagus nerve to the intact heart, the other heart also slowed its rate. A chemical, diffused across the Ringer’s solution, must have been responsible for the effect. In www.sfms.org

1933, acetylcholine was found to be that chemical, a finding that was forerunner to our current understanding of the balance of oxytocin, dopamine, and serotonin in the brain and to the development of psychotropic medicines.

One of the most important events of the year 1900 brought mind-stretching new dimensions to the discontinuity and paradox of neuroscience and the mind. In December of that year, philosopher Bertrand Russell discovered in his Principia Mathematica a recursive or self-referential paradox that permeated the entire work. After describing it with intricate mathematics, he spoke in the vernacular, “What man shaves the barber in a town in which the barber shaves those men who do not shave themselves?” When, in 1931, Kurt Godel sought to explain this paradox, he discovered that it was inherent in mathematics and could be expressed in the form of his Incompleteness Theorem, which clarifies that mathematics, the basis of logic, will be forever incomplete, locked in a self-referential paradox.

Soon, it was recognized that this mysterious hole in mathematics would never go away but instead formed the basis for chaos and complexity theory. John H. Holland, professor of psychology, electrical engineering, and computer science at the University of Michigan, in his book Emergence (Perseus Books, 1998), clarifies that simple parameters can result in highly complex systems in which novel properties emerge that are unpredictable by ordinary science.

In his book Mind and Emergence (Oxford University Press, 2004), Philip Clayton, professor of philosophy and religion at Claremont Graduate University, carries these ideas into neuroscience, asserting that the human brain is the most complex interconnected entity we know of in the universe, and that the mind itself may be an emergent phenomenon arising from the brain. Clayton says, “What emerges in the human case is a particular psychosomatic unity, an organism that can do things both mentally and physically.”

The most magical aspect of the year 1900 imposed a monumental paradigm shift in neuroscience. It was embodied in three unlikely individuals: Max Planck, Carl G. Jung, and Wolfgang Pauli. In that www.sfms.org

year, physicist Max Planck found an answer to the problem of why heated black metal glows red by writing a formula that included a symbol for a quantum, the smallest unit of energy or matter; Carl G. Jung decided against an internal medicine residency and instead entered the Burghölzli Clinic in Zurich to become an psychoanalyst; and Wolfgang Pauli was born.

Planck saw his theory of quantum developed to be the most reliable description

“One of the most important events of the year 1900 brought mind-stretching new dimensions to the discontinuity and paradox of neuroscience and the mind.” of reality ever known even as it demonstrated that subatomic particles can be in two places at the same time, cannot be said to exist in space/time reality until they are observed, and can affect one another acausally at a distance. Jung developed a theory in psychology of archetypes and synchronicity, images and processes in the mind that seemed to behave like quantum particles.

Pauli grew up a child genius and later earned the Nobel Prize in physics for his exclusion principle, which essentially demonstrated that the weird behavior of quantum particles is the nature of matter. Later, in a long-term collaboration, Jung and Pauli agreed that, indeed, the human mind and the matter of the universe are as one.

To carry neuroscience into the future comes now Jeffrey Satinover, a Jungian analyst and former Fellow in psychiatry at Yale and William James lecturer at Harvard, who, in his book The Quantum Brain (John Wiley & Sons, 2001), points out that the human neocortex contains roughly 20 billion neurons, and that each of these has thousands of connections through synapses, and that these also contain multiple feedback loops in an incomprehensible degree of complexity. The emergence of a phenomenon called mind is, indeed, plau-

sible. Not only that, Satinover notices that the electrochemical activity at the synapse results in some tiny oscillations of quantum uncertainty and that these are then amplified upward by chaos and emergence. From brain to mind is a quantum leap, resulting in conceptual thought, imagination, and metaphoric images, which, like quantum particles, can be in two places at the same time, are not present until they are observed, and can affect one another at a distance.

In the story of neuroscience and the mind, the art, anatomy, and physiology all come together at the mysterious synapse, that chaotic and quantum space between neurons that was identified by Santiago Ramón y Cajal during the era of discontinuity and paradox in the magical year of 1900.

Send Your Message to 2,500 Health Care Professionals The San Francisco Medical Society offers multiple advertising opportunities ranging from full-page, 4-color display ads to classified ads with discounted rates for members.

Please contact Ashley Skabar for more information, (415) 561-0850 extension 240 or askabar@sfms.org.

december 2007 San Francisco Medicine 11

Neuroscience and the Mind

Psychoanalysis and Neuroscience How the Mind Affects the Brain Charles Fisher, MD

P

sychoanalysis is a composite discipline. It is a technical approach to the treatment of emotional distress and dysfunction, a tool for self-understanding, and a window to the science of the mind.

Because it deals with the underlying causes of self-defeating patterns of behavior, it is a powerful method for bringing about change. As a form of treatment, psychoanalysis raises complex questions of human value and meaning at every step of the way. Therefore the field will always be a composite one, belonging simultaneously to the worlds of natural science, social science, and healing art.

Currently, the scientific base of psychoanalysis is growing rapidly. This short review will focus on the intersection of psychoanalysis and neuroscience. (For a review of empirical studies of the process and outcome of psychoanalytic treatment, see www.ipa.org.uk/research/research_toc.asp.

For further information about psychoanalysis from a clinical point of view, see the website of the American Psychoanalytic Association at www.apsa.org/ and click on “About Psychoanalysis” at the top the page.)

Historical Background In 1891, the year that Sigmund Freud published his manuscript On Aphasia, H.W.G. Waldeyer published his breakthrough Neuron Theory. Freud, a prominent neurologist in his own right at that time, had theorized in his lecture “The Structure of the Elements of the Nervous System” that the system was composed of fibrillary structures. In fact, Freud came close to being the first person to describe the neuron theory of the central nervous system.

Freud made use of the neuron theory in his 1895 work Project for a Scientific Psychology, which was “one of the first comprehensive neuroscientific models to integrate brain

and mind” (Norman Doidge, The Brain That Changes Itself, p. 223). In this work, Freud anticipated Hebb’s law that “neurons that fire together wire together,” thus introducing an

“New tools make it possible to move from the study of synapses and neurons to the investigation of complex phenomena, such as memory, motivation, language, perception, empathy, self-knowledge, and processes of personal growth and change.” early version of the concept of neuroplasticity, or changes in the brain due to experience.

But the neuroscience of the late nineteenth and early twentieth centuries was not advanced enough to carry the integration much further. Though Freud always held out hope for an eventual integration of psychoanalysis and neuroscience, his own work in psychoanalysis from the late 1890s onward focused on the methods of free association and interpretation, which explored the conscious and unconscious phenomenology of mental life without specifying accompanying processes in the brain.

Freud’s work, and that of other psychoanalysts over the past century, helped explain the regulation of emotional states by higherlevel processes (“executive control,” in the language of contemporary neuroscience), which makes us civilized creatures and is the basic substrate of all psychotherapy.

12 San Francisco Medicine december 2007

Contemporary Tools of Neuroscience In our time, we are seeing spectacular advances in brain science. Neuroimaging techniques—functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and various forms of electroencephalography (EEG)—allow us to visualize, locate, and measure certain aspects of brain function in an individual performing specific mental functions. Transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) allow us to selectively and reversibly stimulate or inhibit particular regions of the brain without breaking the skin. This makes it possible to demonstrate that a particular brain region is causally involved in a specific brain function.

Genetic studies and molecular biology are additional contemporary tools for exploring interactions between the brain and mental life. Researchers have demonstrated that genes affect mental life in numerous ways. The Nobel Prize winner for Physiology or Medicine for 2000, Eric Kandel, MD, has shown that behavior itself can modify gene expression, and that altered gene expression can lead to structural alterations in neural circuits of the brain, stabilizing learned changes in mental processes. Another Nobel Prize winner, Gerald Edelman, MD, PhD (Physiology or Medicine, 1972), has addressed the mechanisms by which higher-order mental processes (concepts about concepts) organize and coordinate neural plasticity. These findings show powerful correlations among thoughts, changes in neuronal circuits, and events at a molecular level, thus connecting the data of subjective experience with the data of basic science.

One of the most powerful methods www.sfms.org

of investigation of interactions between brain and mind is not so new. It is the clinico-anatomical method, as refined by the great Russian neuropsychologist A.R. Luria (1902–1977). His method of “dynamic localization” involved thorough analysis of the inner structure of a neurological symptom followed by syndrome analysis to determine how the syndrome was linked to a functional neurological system. Rather than linking a single symptom to a single brain location, he studied the more complex relation of a complete syndrome to an integrated circuit in the brain. This method has been used with great success by the contemporary neuropsychologist and psychoanalyst Mark Solms, to study the neuropsychology of dreams (see below).

Brain Changes in Response to Psychotherapy Multiple studies illustrate the fact that psychotherapy is a biological intervention with effects on both brain and mind. Baxter and colleagues (Archives of General Psychiatry, 1992;49:681–689) used PET scanning to demonstrate changes in the head of the right caudate nucleus in patients with obsessivecompulsive disorder successfully treated with behavior therapy. These changes correlated with positive response to treatment. Similar changes were observed in patients who improved with medication. These findings have been replicated many times over, with obsessive-compulsive patients, patients with social phobia, and depressed patients. Several different forms of psychotherapy were used in the various studies, and different areas of the brain were affected according to the diagnostic category of patients being studied.

A key study by Goldapple and colleagues (Archives of General Psychiatry, 2004; 61:34–41) found changes in specific sites in the brain in patients with major depression treated with psychotherapy. Significantly, these brain changes were different from those seen in a comparable group of depressed patients who improved on medication.

These findings suggest that psychotherapy and medication help depressed patients via distinct mechanisms.

In an important review article, “Toward a Neurobiology of Psychotherapy: Basic Science and Clinical Applications,” Etkin, www.sfms.org

Kandel, and colleagues (The Journal of Neuropsychiatry and Clinical Neurosciences, 2005; 17:145–158) proposed that in the conditions studied by these and other investigators, there are brain changes associated with clinical improvement per se, whether due to psychotherapy or medication. In addition, there are other changes that differ according to the treatment modality. These changes are associated with specific mechanisms by which psychotherapies or medications are helpful to patients. They concluded that “most theories of psychopathology, both psychodynamic and cognitive, emphasize the importance of unconscious mental processes,” particularly in anxiety disorders. Elaborating this point, they wrote: “Distinguishing between conscious and unconscious processes may be essential for understanding both psychopathology and psychotherapy. Thus, neuroimaging can help distinguish conscious from unconscious brain changes and identify which particular brain changes are responsible for the behavioral improvement.”

These principles are being used to study the mechanisms by which psychoanalysis can exert a specific impact on the biology of the brain. For example, David Silbersweig and colleagues at Cornell are using fMRI to investigate whether transference-focused psychotherapy (a form of psychoanalytic psychotherapy) for borderline personality disorder patients operates by way of different brain mechanisms than does dialectical behavior therapy.

Mirror Neurons Vittorio Gallese, at the School of Medicine of the University of Parma, received the 2007 Grawemeyer International Psychology Award for the discovery of mirror neurons.

Mirror neurons are a system of brain cells in monkeys and humans that discharge in identical fashion when we perform an action and also when we perceive similar behavior in others. This discovery may explain how we empathize and communicate, and why we learn by seeing as well as doing. In a recent publication, Gallese writes (Journal of the American Psychoanalytic Association, 2006;54:47–57), “Neuroscience and psychoanalysis are in part tackling the same issues.”

He explains that “one of the most relevant developments in psychoanalysis in recent

decades is a renewed interest in interpersonal relations and in conceptualizations of the relationship between self and others…. The mirror neuron systems in our brain mediate between the personal experiential knowledge we hold of our lived body, and the implicit certainties we simultaneously hold about others.”

Unconscious Mental Processes and Repression It is now well established among neuroscientists that most of mental life operates outside of awareness—that is to say, most mental processes are unconscious. Eric Kandel (American Journal of Psychiatry, 1999; 156:505–524) describes procedural memories as, “completely unconscious and … evident only in performance rather than in conscious recall.” Kandel makes the point that this kind of unconscious mental life is not the same as Freud’s repressed unconscious, in which unwanted memories and thoughts are actively excluded from awareness because of their objectionable content.

However, more recent neuroscience research has begun to demonstrate the brain mechanisms underlying repression. Michael Anderson and Collin Green rigorously demonstrated active memory suppression as an executive control process in neurologically normal college students (Nature, 2001;410:366–369). In a subsequent article entitled “Neural Systems Underlying the Suppression of Unwanted Memories” (Science, 2004;303:232–235), Anderson and colleagues used fMRI to demonstrate specific brain changes accompanying active suppression of unwanted memories.

Memory Retrieval and Reconsolidation Long-term memories are not permanently engraved in the mind but are retranscribed and reconsolidated each time they are activated. Recent work by Karim Nader, Glenn Schafe, and Joseph Le Doux (Nature, 2000;406:722–726) showed that fear memories in rats enter a labile state when they are activated. New protein synthesis in the amygdala is necessary in order for the memory to be consolidated and stored. This finding may point to a biological mechanism Continued on Following Page...

december 2007 San Francisco Medicine 13

Psychoanalysis and Neuroscience Continued from Previous Page...

supports hypotheses related to psychoanalytic theories of dreaming.

new questions and new areas of study for neuroscience.

accompanying the modification of memory and emotion (particularly fear) when patients in psychoanalysis or psychotherapy reactivate disturbing memories.

Implications for Psychoanalysis and Neuroscience

Resources for Study

Dreams Pursuing A.R. Luria’s method of dynamic localization, Mark Solms (The Neuropsychology of Dreams, 1996) studied the dreams of 332 patients with focal brain lesions that caused disturbances in dreaming.

Solms used clinical interviews to identify changes in dreaming and a variety of standard methods, including CT and MRI imaging as well as surgical observation, to identify lesions. He found that dreaming is disturbed in different ways by damage to six different parts of the brain.

Surprisingly, he found preservation of dreaming in patients with deep brainstem lesions that prevented rapid eye movement (REM) sleep. This finding contradicted the then-popular hypothesis that dreams are an epiphenomenon of brain activation in REM sleep. In contrast, Solms found cessation of dreaming in two groups of patients with lesions in higher cortical regions of the brain involved in symbolization, spatial thought, and inhibitory mental control. These, too, were surprising findings suggesting intrinsic connections between higher mental functioning and dreaming. Syndromes involving other parts of the brain caused such disturbances in dreaming as nonvisual dreaming, the inability to distinguish dreams from reality, and recurring stereotypical nightmares.

Solms concluded, “Dreams and REM appear to unfold over different anatomical structures, and they involve different psychological mechanisms.” Instead of REM activation, dreams appear to be stimulated most specifically by a system involved with motivation in the brain. This system, named the SEEKING system by Jaak Panksepp, at Bowling Green State University (in Affective Neuroscience: The Foundations of Human and Animal Emotions, 1998), closely parallels Sigmund Freud’s concept of motivational drive. In summary, Mark Solms’s work challenges the thesis that dreams are meaningless by-products of sleep physiology and closely

Psychoanalysis, in the words of Eric Kandel, “outlined by far the most coherent, interesting, and nuanced view of the human mind” (Autobiography, 2000). Currently, psychoanalysis is in ferment, stimulated by sweeping changes in the cultural and scientific landscape and challenged by economic and intellectual competition. These developments are exhilarating as well as unsettling to psychoanalysts. They point to a path for further growth and maturation in psychoanalysis as a discipline.

Contemporary neuroscience, like psychoanalysis, is comprehensive in its approach. Its new tools make it possible to formulate and study remarkable new hypotheses about the human brain. In doing so, we move from the study of synapses and neurons to the investigation of complex phenomena, such as memory, motivation, language, perception, empathy, self-knowledge, and processes of personal growth and change.

As I have sketched in this article, a number of discoveries in neuroscience support the basic intellectual premises of psychoanalysis—unconscious mental processing, active inhibition of unwanted memories, and motivational drive in relation to dreaming. Other kinds of work in contemporary neuroscience inform us about the biological processes that accompany change in psychotherapy.

Still other findings challenge long-held assumptions about the mind. Contemporary philosophy is challenged in ever more pointed ways to account for the existence of consciousness and the phenomenology of mind and brain. Are mind and brain separate realms? If so, do they interact? Are they separate manifestations of a single realm? If so, what is its essential nature? These questions are beyond the scope of either field, and yet they inevitably arise when we try to put the fields of psychoanalysis and neuroscience together. For now, it may be sufficient to say that findings in each field can stimulate inquiry in the other. Just as the data of neuroscience stimulate new questions in psychoanalysis, the phenomenological and subjective data of psychoanalysis stimulate

14 San Francisco Medicine december 2007

For those who are interested in learning more about the intersection of psychoanalysis and neuroscience, I can recommend two books and a journal: Norman Doidge’s book The Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science, Penguin Books, 2007, is a highly readable account of the phenomenology and science of neuroplasticity—changes in the organization of the brain brought about by the application of novel and sometimes startling methods.

Mark Solms and Oliver Turnbull’s book The Brain and the Inner World: An Introduction to the Neuroscience of Subjective Experience, Other Press, 2003, is just what its title suggests: It is part textbook, part comprehensive theory, and overall quite readable.

The journal Neuro-Psychoanalysis, published twice annually by the International Neuropsychoanalysis Centre and Society in London, has a distinguished editorial board of psychoanalysts and neuroscientists. It is an excellent resource for this topic.

As a bonus, I might recommend an astonishing book, The Center Cannot Hold,

by Elyn R. Saks, Associate Dean and Orrin B. Evans Professor of Law, Psychology, and Psychiatry and the Behavioral Sciences at the University of Southern California Gould School of Law (Hyperion, 2007). It describes Professor Saks’s remarkable success in overcoming schizophrenia through the use of medications and psychoanalysis.

Charles P. Fisher, MD, is a Training and Supervising Analyst and faculty member at the San Francisco Center for Psychoanalysis, a Personal and Supervising Analyst at the Psychoanalytic Center of Northern California, Associate Clinical Professor of Psychiatry at the University of California San Francisco, and former Psychiatry Residency Training Director at California Pacific Medical Center. He has had a long-standing interest in the relationship of mind and brain.

www.sfms.org

Neuroscience and the Mind

The Female Brain The Neuroscience of Gender Louann Brizendine, MD

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eila was a busy little bee, flitting around the playground, connecting with the other children whether or not she knew them. On the verge of speaking in two- and three-word phrases, she mostly used her contagious smile and emphatic nods of her head to communicate, and communicate she did. So did the other little girls. “Dolly,” said one. “Shopping,” said another. There was a pint-size community forming, abuzz with chatter, games, and imaginary families.

Leila was always happy to see her cousin Joseph when he joined her on the playground, but her joy never lasted long. Joseph grabbed the blocks she and her friends were using to make a house. He wanted to build a rocket, and build it by himself. His pals would wreck anything that Leila and her friends had created. The boys pushed the girls around, refused to take turns, and would ignore a girl’s request to stop or give the toy back. By the end of the morning, Leila had retreated to the other end of the play area with the girls. They wanted to play house quietly together.

Common sense tells us that boys and girls behave differently. We see it every day at home, on the playground, and in classrooms. But what the culture hasn’t told us is that the brain dictates these divergent behaviors. The impulses of children are so innate that they kick in even if we adults try to nudge them in another direction.

One of my patients gave her three-and-ahalf-year-old daughter many unisex toys, including a bright red fire truck instead of a doll. She walked into her daughter’s room one afternoon to find her cuddling the truck in a baby blanket, rocking it back and forth saying, “Don’t worry, little truckie, everything will be all right.” www.sfms.org

This isn’t socialization. This little girl didn’t cuddle her “truckie” because her environment molded her unisex brain. There is no unisex brain. She was born with a

“Common sense tells us that boys and girls behave differently. We see it every day at home, on the playground, and in classrooms. But what the culture hasn’t told us is that the brain dictates these divergent behaviors.” female brain, which came complete with its own impulses. Girls arrive already wired as girls, and boys arrive already wired as boys.

Their brains are different by the time they’re born, and their brains are what drive their impulses, values, and their very reality.

The brain shapes the way we see, hear, smell, and taste. Nerves run from our sense organs directly to the brain, and the brain does all the interpreting. A good conk on the head in the right place can mean that you won’t be able to smell or taste. But the brain does more than that. It profoundly affects how we conceptualize the world—whether we think a person is good or bad, if we like the weather today or it makes us unhappy, or whether we’re inclined to take care of the day’s business. You don’t have to be a neuroscientist to know this. If you’re feeling a little down and have a nice glass of wine or a lovely piece of chocolate, your attitude can shift. A gray, cloudy day can turn bright,

or irritation with a loved one can evaporate because of the way the chemicals in those substances affect the brain. Your immediate reality can change in an instant.

If chemicals acting on the brain can create different realities, what happens when two brains have different structures?

There’s no question that their realities will be different. Brain damage, strokes, prefrontal lobotomies, and head injuries can change what’s important to a person. They can even change one’s personality from aggressive to meek or from kind to grumpy.

But it’s not as if we all start out with the same brain structure. Males’ and females’ brains are different by nature. Think about this. What if the communication center is bigger in one brain than in the other?

What if the emotional memory center is bigger in one than in the other? What if one brain develops a greater ability to read cues in people than does the other? In this case, you would have a person whose reality dictated that communication, connection, emotional sensitivity, and responsiveness were the primary values. This person would prize these qualities above all others and be baffled by a person with a brain that didn’t grasp the importance of these qualities. In essence, you would have someone with a female brain.

We, meaning doctors and scientists, used to think that gender was culturally created for humans but not for animals.

When I was in medical school in the 1970s and 1980s, it had already been discovered that male and female animal brains started developing differently in utero, suggesting that impulses such as mating and bearing and rearing young are hardwired into the animal brain. But we were taught that for Continued on Following Page...

december 2007 San Francisco Medicine 15

The Female Brain Continued from Previous Page... humans, sex differences mostly came from how one’s parents raised one as a boy or a girl. Now we know that’s not completely true, and if we go back to where it all started, the picture becomes abundantly clear.

Imagine for a moment that you are in a microcapsule speeding up the vaginal canal, hitting warp drive through the cervix ahead of the tsunami of sperm. Once inside the uterus, you’ll see a giant, undulating egg waiting for that lucky tadpole with enough moxie to penetrate the surface. Let’s say the sperm that led the charge carries an X and not a Y chromosome. Voilà, the fertilized egg is a girl.

In the span of just thirty-eight weeks, we would see this girl grow from a group of cells that could fit on the head of a pin to an infant who weighs the average of seven and a half pounds and possesses the machinery she needs to live outside her mother’s body.

But the majority of the brain development that determines her sex-specific circuits happened during the first eighteen weeks of her mother’s pregnancy.

Until eight weeks old, every fetal brain looks female—female is nature’s default gender setting. If you were to watch a female and a male brain developing via time-lapse photography, you would see their circuit diagrams being laid down according to the blueprint drafted by both genes and sex hormones. A huge testosterone surge beginning in the eighth week will turn this unisex brain male by killing off some cells in the communication centers and growing more cells in the sex and aggression centers.

If the testosterone surge doesn’t happen, the female brain continues to grow unperturbed.

The fetal girl’s brain cells sprout more connections in the communication centers and areas that process emotion. How does this fetal fork in the road affect us? For one thing, because of her larger communication center, this girl will grow up to be more talkative than her brother. Men use about seven thousand words per day. Women use about twenty thousand. For another, it defines our innate biological destiny, coloring the lens through which each of us views and engages the world.

Reading Emotion Means Reading Reality Just about the first thing the female brain compels a baby to do is study faces.

Cara, a former student of mine, brought

“Baby girls are born interested in emotional expression. They take meaning about themselves from a look, a touch, every reaction from the people they come into contact with.

From these cues they discover whether they are worthy, lovable, or annoying. ” her baby Leila in to see us for regular visits.

We loved watching how Leila changed as she grew up, and we saw her pretty much from birth through kindergarten. At a few weeks old, Leila was studying every face that appeared in front of her. My staff and I made plenty of eye contact, and soon she was smiling back at us. We mirrored each other’s faces and sounds, and it was fun bonding with her. I wanted to take her home with me, particularly because I hadn’t had the same experience with my son.

I loved that this baby girl wanted to look at me, and I wished my son had been so interested in my face. He was just the opposite. He wanted to look at everything else—mobiles, lights, and doorknobs—but not me. Making eye contact was at the bottom of his list of interesting things to do. I was taught in medical school that all babies are born with the need for mutual gazing because it is the key to developing the mother-infant bond, and for months I thought something was terribly wrong with my son. They didn’t know back then about the many sex-specific differences in the brain. All babies were thought to be hardwired to gaze at faces, but it turns out that theories of the earliest stages of child development were female-biased. Girls, not

16 San Francisco Medicine december 2007

boys, come out wired for mutual gazing. Girls do not experience the testosterone surge in utero that shrinks the centers for communication, observation, and processing of emotion, so their potential to develop skills in these areas are better at birth than boys’. Over the first three months of life, a baby girl’s skills in eye contact and mutual facial gazing will increase by more than 400 percent, whereas facial gazing skills in a boy during this time will not increase at all.

Baby girls are born interested in emotional expression. They take meaning about themselves from a look, a touch, every reaction from the people they come into contact with. From these cues they discover whether they are worthy, lovable, or annoying. But take away the signposts that an expressive face provides and you’ve taken away the female brain’s main touchstone for reality.

Watch a little girl as she approaches a mime.

She’ll try with everything she has to elicit an expression. Little girls do not tolerate flat faces. They interpret an emotionless face that’s turned toward them as a signal they are not doing something right. Like dogs chasing Frisbees, little girls will go after the face until they get a response. The girls will think that if they do it just right, they’ll get the reaction they expect. It’s the same kind of instinct that keeps a grown woman going after a narcissistic or otherwise emotionally unavailable man—“If I just do it right, he’ll love me.” You can imagine, then, the negative impact on a little girl’s developing sense of self of the unresponsive, flat face of a depressed mother—or even one that’s had too many Botox injections. The lack of facial expression is very confusing to a girl, and she may come to believe, because she can’t get the expected reaction to a plea for attention or a gesture of affection, that her mother doesn’t really like her. She will eventually turn her efforts to faces that are more responsive.

Anyone who has raised boys and girls or watched them grow up can see that they develop differently, especially that baby girls will connect emotionally in ways that baby boys don’t. But psychoanalytic theory misrepresented this sex difference and made the assumption that greater facial gazing and the impulse to connect meant that girls were more “needy” of symbiosis with their www.sfms.org

mothers. The greater facial gazing doesn’t indicate a need; it indicates an innate skill in observation. It’s a skill that comes with a brain that is more mature at birth than a boy’s brain and develops faster, by one to two years.

broader range of sound frequency and tones in the human voice than can boys. Even as an infant, all a girl needs to hear is a slight tightening in her mother’s voice to know she should not be opening the drawer with the fancy wrapping paper in it. But you will

Hearing, Approval, and Being Heard

“Because their brains did not undergo a testosterone marination in utero and their communication and emotion centers were left intact, girls also arrive in the world better at reading faces and hearing human vocal tones.”

Girls’ well-developed brain circuits for gathering meaning from faces and tone of voice also push them to comprehend the social approval of others very early. Cara was surprised that she was able to take Leila out into public. “It’s amazing. We can sit at a restaurant, and Leila knows, at eighteen months, that if I raise my hand she should stop reaching for my glass of wine. And I noticed that if her dad and I are arguing, she’ll eat with her fingers until one of us looks over at her. Then she’ll go back to struggling with a fork.”

These brief interactions show Leila picking up cues from her parents’ faces that her cousin Joseph likely wouldn’t have looked for. A University of Texas study of twelve-month-old girls and boys showed the difference in desire and ability to observe.

In this case, the child and mother were brought into a room, left alone together, and instructed not to touch an object. The mother stood off to the side. Every move, glance, and utterance was videotaped.

Very few of the girls touched the forbidden object, even though their mothers never explicitly told them not to. The girls looked back at their mothers’ faces ten to twenty times more than did the boys, checking for signs of approval or disapproval. The boys, by contrast, moved around the room and rarely glanced at their mothers’ faces. They frequently touched the forbidden object, even though their mothers shouted, “No!” The one-year-old boys, driven by their testosterone-formed male brains, are compelled to investigate their environment, even those elements of it they are forbidden to touch.

Because their brains did not undergo a testosterone marination in utero and their communication and emotion centers were left intact, girls also arrive in the world better at reading faces and hearing human vocal tones. Just as bats can hear sounds that even cats and dogs cannot, girls can hear a www.sfms.org

have to restrain the boy physically to keep him from destroying next Christmas’s packages. It’s not that he’s ignoring his mother.

He physically cannot hear the same tone of warning.

A girl is also astute at reading from facial expression whether or not she’s being listened to. At eighteen months, Leila could not be kept quiet. We couldn’t understand anything she was trying to tell us, but she waddled up to each person in the office and unloosed a stream of words that seemed very important to her. She tested for agreement in each of us. If we appeared even the tiniest bit disinterested, or broke eye contact for a second, she put her hands on her hips, stomped her foot, and grunted in indignation. “Listen!” she yelled. No eye contact meant to her that we were not listening.

Cara and her husband, Charles, were worried that Leila seemed to insist on being included in any conversation at home. She was so demanding that they thought they had spoiled her. But they hadn’t. It was just their daughter’s brain searching for a way to validate her sense of self.

Whether or not she is being listened to will tell a young girl if others take her seriously, which in turn goes to the growth of her sense of a successful self. Even though her language skills aren’t developed, she understands more than she expresses, and she knows—before you do—if your mind has

wandered for an instant. She can tell if the adult understands her. If the adult gets on the same wavelength, it actually creates her sense of self as being successful or important.

If she doesn’t connect, her sense is of an unsuccessful self. Charles in particular was surprised by how much focus it took to keep up the relationship with his daughter. But he saw that, when he listened attentively, she began to develop more confidence.

Louann Brizendine, MD, completed her degree in Neurobiology at University of California at Berkeley, graduated from Yale School of Medicine, and did her internship and residency at Harvard Medical School. She has also served on both the faculties of Harvard University and University of California at San Francisco. Now at UCSF, Dr. Brizendine pursues active clinical, teaching, writing, and research activities.

She founded the UCSF Women’s Mood and Hormone Clinic in 1994 and continues to serve as the clinic’s director. To learn more about her work, visit www.louannbrizendine.com.

From the book The Female Brain, by Louann Brizendine, MD, published by Broadway Books, a division of Random House, Inc. Reprinted with permission. Copyright © 2006

by Louann Brizendine, MD.

december 2007 San Francisco Medicine 17

Neuroscience and the Mind

The Brain That Changes Itself Neuroplasticity Defined Norman Doidge, MD

T

he Brain That Changes Itself: Stories of Personal Triumph from the Frontiers of Brain Science is about the revolutionary discovery that the human brain can change itself, as told through the stories of the scientists, doctors, and patients who have together brought about these astonishing transformations.

Without operations or medications, they have made use of the brain’s hitherto unknown ability to change. Some were patients who had what were thought to be incurable brain problems; others were people without specific problems who simply wanted to improve the functioning of their brains or preserve them as they aged. For four hundred years this venture would have been inconceivable because mainstream medicine and science believed that brain anatomy was fixed. The common wisdom was that after childhood the brain changed only when it began the long process of decline; that when brain cells failed to develop properly, or were injured, or died, they could not be replaced. Nor could the brain ever alter its structure and find a new way to function if part of it was damaged.

The theory of the unchanging brain decreed that people who were born with brain or mental limitations, or who sustained brain damage, would be limited or damaged for life. Scientists who wondered if the healthy brain might be improved or preserved through activity or mental exercise were told not to waste their time.

A neurological nihilism—a sense that treatment for many brain problems was ineffective or even unwarranted—had taken hold, and it spread through our culture, even stunting our overall view of human nature. Since the brain could not change, human nature, which emerges from it,

seemed necessarily fixed and unalterable as well. The belief that the brain could not change had three major sources: the fact that brain-damaged patients could so rarely

“[These scientists] showed that children are not always stuck with the mental abilities they are born with; that the damaged brain can often reorganize itself so that when one part fails, another can substitute; that if brain cells die, they can at times be replaced; that many ‘circuits’ and even basic reflexes that we think are hardwired are not.” make full recoveries; our inability to observe the living brain’s microscopic activities; and the idea—dating back to the beginnings of modern science—that the brain is like a glorious machine. And while machines do many extraordinary things, they don’t change and grow.

I became interested in the idea of a changing brain because of my work as a research psychiatrist and psychoanalyst.

When patients did not progress psychologically as much as hoped, often the conventional medical wisdom was that their problems were deeply “hardwired” into an unchangeable brain. “Hardwiring” was another machine metaphor coming from

18 San Francisco Medicine december 2007

the idea of the brain as computer hardware, with permanently connected circuits, each designed to perform a specific, unchangeable function.

When I first heard news that the human brain might not be hardwired, I had to investigate and weigh the evidence for myself. These investigations took me far from my consulting room.

I began a series of travels, and in the process I met a band of brilliant scientists, at the frontiers of brain science, who had, in the late 1960s or early 1970s, made a series of unexpected discoveries. They showed that the brain changed its very structure with each different activity it performed, perfecting its circuits so it was better suited to the task at hand. If certain “parts” failed, then other parts could sometimes take over.

The machine metaphor, of the brain as an organ with specialized parts, could not fully account for changes the scientists were seeing. They began to call this fundamental brain property “neuroplasticity.”

Neuro is for “neuron,” the nerve cells in our brains and nervous systems. Plastic is for “changeable, malleable, modifiable.” At first many of the scientists didn’t dare use the word “neuroplasticity” in their publications, and their peers belittled them for promoting a fanciful notion. Yet they persisted, slowly overturning the doctrine of the unchanging brain. They showed that children are not always stuck with the mental abilities they are born with; that the damaged brain can often reorganize itself so that when one part fails, another can substitute; that if brain cells die, they can at times be replaced; that many “circuits” and even basic reflexes that we think are hardwired are not. One of these scientists even showed that thinking, Continued on Page 22... www.sfms.org

Neuroscience and the Mind

Why God Won’t Go Away Neuroscience, Brain Scans, and the Divine Mike Denney, MD, PhD

S

ince physicist Fritjof Capra published his book The Tao of Physics in 1975 and Paul Davies followed with God and the New Physics in 1983, scientist-writers have increasingly sought a credible connection between new science and the divine. Recently, this trend has found a home in the field of neuroscience, through which a few advanced researchers offer evidence for an inherent biological presence in the brain for the capacity of human beings to experience God. Such scientific and metaphysical thinking results in a kind of biology of belief where religion and neuroscience meet.

The most recent offering in this genre is Why God Won’t Go Away, by radiologist Andrew Newberg, MD, and the late psychiatrist Eugene D’Aquili, MD, both of the University of Pennsylvania; and freelance journalist Vince Rause. In this intriguing book, the authors report on research using SPECT, single-photon emission computed tomography, which can produce color images that illuminate areas of the brain that are active.

Performing their tests first upon Tibetan Buddhist meditators and later upon a group of Franciscan nuns, the researchers noted an area in the left posterior superior parietal lobe of the brain that consistently demonstrated decreased activity when the subjects experienced a closeness or oneness with a transcendent absolute unitary being, or God. The authors call this part of the brain the OAA, or orientation association area, an area which ordinarily produces scans showing very active, vibrant bursts of brilliant reds and yellows as it busily monitors individuals’ relationships with their surroundings. But its activity becomes dark blotches of cool greens and blues, www.sfms.org

indicating reduced activity, during peak spiritual experiences. Noting this direct correlation of brain physiology with the spiritual, Newberg and D’Aquili conclude, “In other words, mystical experience is biologically, observably, and scientifically real.” The authors go on to cite their findings as evidence of how neurobiology results in mind, how the brain’s architecture results in religious ritual and myth, and how the mind’s need to understand creates religion and belief. They suggest that during the subjective experience of the divine, the brain can produce scan images that may be “photographs of God.” In an earlier book, The Humanizing Brain, authors James B. Ashbrook and Carol Rausch Albright, both experts at the interface of neuroscience and theology at the Chicago Center for Religion and Science, offer striking parallels as they compare neuroanatomy and neurophysiology with religious and mystical writings. The authors suggest that each level of the triune brain, reptilian or thalamic, paleomammalian or limbic, and neomammalian or cortical, has a specific role in the experience of the divine in human consciousness. Furthermore, Ashbrook and Albright explore the frontal lobes and the relationships of the right and left brain through the corpus callosum as important factors in the neurobiology of faith.

This fascinating book carries us dizzyingly from the brain stem to a nurturing God, from the limbic system to a meaning-making God, and from the cortex to a versatile God. In doing so, it offers new insights for those who seek understanding of the relationship of the body with the mind and of human beings with the divine.

As scientifically educated and trained physicians, our first impulse might be to dis-

miss such books because the data is limited, there are no controls, and the conclusions therefore cannot be statistically valid. Such is the reaction of Jerome Groopman, MD, Professor of Medicine at Harvard, in his review of these books in the September 17, 2001, edition of The New Yorker. Groopman complains that Newberg and D’Aquili, as well as Albright and Ashcroft, have not engaged in rigorously designed experiments, that their arguments are dubious because they do not have a control such as “an experience totally detached from the divine,” and that they commit the “cardinal error of neurotheology: mixing terms and methods of science and religion in an attempt to confer the former’s authority on the latter.” Groopman decries that anyone would suggest that a scan image could be a “photograph of God.” Obviously, such criticism is valid only if we restrict our path toward understanding and enlightenment to a rigorous, empirical, statistical scientific method. But books like Why God Won’t Go Away and The Humanizing Brain are not offered as rigorous scientific data. They are insights into a world of intrigue, mystery, and enchantment. Newberg and D’Aquili point out that the subjective experiences of God within their experimental subjects, as has occurred throughout the ages in saints and mystics of all religions, were profoundly real yet metaphorical, beyond the measurement of ordinary science. Similarly, Ashbrook’s and Albright’s approach parallels that of Jewish mystic Martin Buber, who once wrote, “Man cannot approach the divine by reaching beyond the human: he can approach it through becoming human.”

The very least these books have to Continued on Page 22...

december 2007 San Francisco Medicine 19

Neuroscience and the Mind

A Novelist on the Brain A Conversation with Tom Wolfe on Neuroscience, Language, and Nature versus Nurture Steve Heilig, MPH

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esides being one of the pioneers of what came to be known as the “New Journalism” in the 1960s, Tom Wolfe is a renowned author. His bestselling books include The Right Stuff, The Bonfire of the Vanities, The Electric Kool-Aid Acid Test, The Pump House Gang, The Painted Word, A Man in Full, and I Am Charlotte Simmons. Wolfian terms like “the right stuff,” “radical chic,” “the Me Decade” or “Me Generation,” and “good ol’ boy” have all become popular phrases even among those who have never read his works.

He’s been called “America’s greatest living novelist.” Wolfe has been widely published in leading magazines, and in 1996 he wrote about emerging controversies in neuroscience for Forbes. He is at work on a new book related to the topics in that article and agreed to talk about some of his further reflections on neuroscience over the past decade.

SFM: In your 1996 essay you wrote that if you were in college today, you would likely go into neuroscience instead of getting a PhD in American Studies at Yale and becoming a writer. Is that still true?

Tom Wolfe: I’d certainly still be drawn to it, because it’s the field that contains the greatest mysteries in all of science. The findings could fundamentally change the way people think about themselves—but we don’t know that yet.

been impossible for Delgado to get out of the way, he pressed a button and the bull came to a shuddering stop. That was the acid test of a man who knew his brain physiology.

His son José Maria Delgado, also a brain physiologist, said that the problem is not that the brain has millions of neurons but that it has distinct types of neurons, and we have no idea what they do. “All the rest,” he said, “is literature, not science.” And by “literature” he was talking about all the speculation by people such as Edward O. Wilson, Richard Dawkins, and the like, who today have all sorts of theories about the nature of the human brain but all of whom know practically nothing about the human brain. They are writing Tom Wolfe literature, which doesn’t mean they are wrong—but they don’t SFM: What are the questions that fascinate have a scientific leg to stand on. Their theoyou the most? ries are sometimes called “materialism” by philosophers, but the theories aren’t really Wolfe: Well, the most famous brain physi- complex enough to rate an “ism.” ologist—what we now call a neuroscientist—was Dr. José M.R. Delgado, a Spaniard, SFM: It sounds like you think they’re dressing who achieved fame for his stereotaxic needle up old deterministic thinking into pseudoimplants in the brains of animals, through scientific garb. which he discovered some of the areas of the brain that controlled certain functions. Wolfe: Yes. All of their writing boils down He became famous when he stood in a bull to this: In order to have a “mind,” all we ring with nothing but a radio transmitter in have is the brain and parts of the central his hand and allowed himself to be charged nervous system. It is a mechanism with by a raging bull in whose brain he had no “ghost in the machine” or “soul”—the implanted those tiny needles. When the brain runs on the molecular level, which bull came into a range where it would have means that, like any machine, the brain

20 San Francisco Medicine december 2007

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has no choice but to act in the way it is programmed. In their minds it is programmed wholly by genes. Wilson once said the brain is born not as a tabula rasa to be filled in by experience, but as a as a film to be slipped into developing fluid—it can be developed well or poorly, but either way you’re only going to get what was on the film to start with. So while you may think you’re making decisions, you’re actually not and you will react in a certain way in any given situation.

Some of the younger theorists believe that if they had sophisticated enough technology, they could predict what you’re going to do five seconds from now or even out to one month. They run into a problem with reflexivity, which is to say that if any given brain has no choice or free will, then even the neuroscientist himself has no choice in what he says.

SFM: You are speaking on this with skepticism—what is your own theory?

Wolfe: Here’s an area about which I do know a great deal—the properties of words. I submit that evolution explains the animals, plants, and man—or rather, the caveman—up until about 11,000 years ago. Paleontologists agree that farming began about 9,000 B.C., and that means speech evolved at least that long ago, since you cannot have agriculture without speech. Think about it—you can’t even count to ten inside your head without using words. Speech is the taking of raw sounds and turning them not only into a means of communication but also of memorization. Of the two, memorization is probably the more important, especially in the form of print, film, video, or, for that matter, blueprints, diagrams, and all forms of mathematics and formulas.

Once you have speech, you don’t have to wait for natural selection! If you want more strength, you build a stealth bomber; if you don’t like bacteria, you invent penicillin; if you want to communicate faster, you invent the Internet. Once speech evolved, all of human life changed. “In the beginning was the Word; and the Word was with God; and the Word was God.” And Word then also meant wisdom. I’m guessing that one of the first questions humans asked once they had speech was, “Hey, why are we here, and www.sfms.org

who made all this?” “Why” is a question no animal can ask, because both the question and answers require speech.

SFM: So culture, and communication, is now much more important than genes?

Wolfe: Exactly: culture, communication, memorization, and history. I’m willing to say OK, we may have no free will, but speech creates so many variables that it doesn’t really matter. No machines will ever truly fully figure the brain out, because the brain’s performance is constantly altered or else constrained by this inanimate, rogue artifact you can’t control: namely, speech. Laws you obey, scientific findings you assume to be correct, creeds you believe in, existing plans you go by, history is as you understand it—these artifacts, once accepted, will affect your thoughts and behavior and use you more than you use them.

SFM: You wrote of humans trying to fully understand ourselves as being “as if a group of dogs were to call a conference to try to understand The Dog.” But people are still going to try. So are we machines, or something else?

Wolfe: There’s no question that our brains are machines, but I must keep stressing that speech and the property of words are what really matter.

SFM: Somebody else must have already given you the rejoinder that you believe this because you are a writer.

Wolfe: It’s fortunate that I am a writer, because that has helped me understand the properties of words. They are what have made life complex. In the battle for status in the animal kingdom, power and aggressiveness have been all-important. But among humans, once they acquired speech, all that changed. I don’t know of any political leader today with status on the level of say, Elvis Presley’s and Albert Einstein’s.

SFM: The determinists have posited that IQ is also set at birth. What do you think?

Wolfe: That subject is dynamite. If you speak privately to genetic theorists, they

will all say intelligence is inherited, but they won’t say it publicly as it will only get them into trouble. Real neuroscientists are more circumspect and admit we just don’t know enough to put out half-cocked theories of intelligence, gender, and so on.

SFM: As a renowned observer of intellectual fashion, where do you think neuroscience will take us?

Wolfe: There have been a series of revolutions in thought about human beings. Darwin didn’t even have a university attachment when he developed his theories, but with the sheer power of his words, he changed the way most educated humans regard themselves and their lives. As Nietzsche observed, most regard themselves as smarter versions of other beasts. And then there was Marx, sitting alone in a library, not a very pleasant man, whose premises, even when proven absolutely wrong, have implanted ideas that are still very hard to get rid of. And Freud has now been proven to be a complete quack with regard to how the brain works, but his notion of the need for sexual release no doubt accounts for millions of extra orgasms a day even now. It remains to be seen where the next literary theory of life will lead us. Nietzsche predicted—in the 1880s—that in this century, the twentyfirst, would come the total eclipse of all values, a development more painful than man can possibly imagine beforehand. As I wrote in 1996, genetic theory certainly tilts in that direction.

SFM: If you were to recommend any one book in this area, what would it be?

Wolfe: That would still be the elder José Delgado’s Physical Control of the Mind.

SFM: In closing, what are you working on now?

Wolfe: Among other things, a book on this very topic of the brain. It will be called The Human Beast. That was originally the title of a book by Emile Zola published in 1890, influenced directly by Darwin’s doctrine, which was then barely thirty years old.

december 2007 San Francisco Medicine 21

The Brain That Changes Itself Continued from Page 18... learning, and acting can turn our genes on or off, thus shaping our brain anatomy and our behavior—surely one of the most extraordinary discoveries of the twentieth century. In the course of my travels I met a scientist who enabled people who had been blind since birth to begin to see, another who enabled the deaf to hear; I spoke with people who had had strokes decades before and had been declared incurable, who were helped to recover with neuroplastic treatments; I met people whose learning disorders were cured and whose IQs were raised; I saw evidence that it is possible for eighty-yearolds to sharpen their memories to function the way they did when they were fifty-five.

I saw people rewire their brains with their thoughts, to cure previously incurable obsessions and traumas. I spoke with Nobel laureates who were hotly debating how we must rethink our model of the brain now that we know it is ever changing.

The idea that the brain can change its own structure and function through thought and activity is, I believe, the most important alteration in our view of the brain since we first sketched out its basic anatomy and the workings of its basic component, the neuron. Like all revolutions, this one will have profound effects. The neuroplastic revolution has implications for, among other things, our understanding of how love, sex, grief, relationships, learning, addictions, culture, technology, and psychotherapies change our brains. All of the humanities,

social sciences, and physical sciences, insofar as they deal with human nature, are affected, as are all forms of training. All of these disciplines will have to come to terms with the fact of the self-changing brain and with the realization that the architecture of the brain differs from one person to the next and that it changes in the course of our individual lives. While the human brain has apparently underestimated itself, neuroplasticity isn’t all good news; it renders our brains not only more resourceful but also more vulnerable to outside influences. Neuroplasticity has the power to produce more flexible but also more rigid behaviors—a phenomenon I call “the plastic paradox.”

Ironically, some of our most stubborn habits and disorders are products of our plasticity. Once a particular plastic change occurs in the brain and becomes well established, it can prevent other changes from occurring. It is by understanding both the positive and negative effects of plasticity that we can truly understand the extent of human possibilities.

Norman Doidge, MD, is a psychiatrist, psychoanalyst, researcher, author, essayist, and poet. He is on the research faculty at the Columbia University Center for Psychoanalytic Training and Research, in New York, and is a professor in the University of Toronto’s Department of Psychiatry. To learn more, visit his website www.normandoidge.com.

Reprinted by arrangement with Penguin Books, a member of Penguin Group (USA) Inc., from The Brain That Changes Itself,

by Norman Doidge. Copyright © 2007 by Norman Doidge.

22 San Francisco Medicine december 2007

Why God Won’t Go Away Continued from Page 19... offer is that, to date, neuroscience cannot disprove God. So, in reading them we might remember that a scan image is like any other image—it can open our minds to imagine. Indeed, these books may be yet another reminder that if we are ever to find a meaningful connection between science and spirituality, we must first find a way within ourselves to unite cognition with intuition, the literal with the poetic.

Why God Won’t Go Away Andrew Newberg, MD, Eugene D’Aquili, MD, PhD, and Vince Rause New York: Ballantine, 2001 The Humanizing Brain James B. Ashbrook and Carol Rausch Albright Cleveland, Ohio: The Pilgrim Press, 1997

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Neuroscience and the Mind

Neuroscience, Menopause, and the Mind Hormone Replacement Therapy and Alzheimer’s Disease in Women Ricki Pollycove, MD, MHS, FACOG

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ur human experience is the product of both a biologically evolved physical body and an expanding consciousness. Whether one views human beings as products of divine creation or Darwinian evolution—or a combination of the two that might be called divine evolution—our opportunity to use our minds to understand ourselves is remarkable. Both aspects of our evolution are miraculous: our exquisite, intricate bodies with biologic clocks that are set on decades for major reproductive capacity, and our consciousness in cultural, social, ideological, philosophical, intellectual, artistic, and spiritual realms.

These changes can be accompanied by the emergence of greater wisdom, freedom of choice with diminishing demands of child rearing, and—often—less of a struggle to achieve a balance between career and family. There can be more time for contemplation and reflection, more time for leadership roles and supporting other family members, more time for caring for grandchildren or aging parents. Women often say that they “find their voice” and are better able to express their authentic opinions and “stick up for themselves” after menopause. These psychological and emotional shifts may result from a sense of urgency that there is no time to waste in the second half of life.

Yet this opportunity to expand consciousness is wholly dependent upon a healthy and vigorous body. For women, menopause plays a major role in that health and vigor. Most women experience the physiologic changes of menopause whether they want them or not—insomnia, joint stiffness, inability to concentrate or retrieve memories, depressed mood, and hot flashes and night sweats.

The lack of estrogen, however, may www.sfms.org

also affect those intellectual, artistic, and spiritual realms, as reflected in the comparative statistics regarding the incidence of Alzheimer’s disease in women who do or do not take hormones over a significant period of time. A study done over twenty-five years compared groups of men to groups of women who used estrogen supplementation for varying lengths of time, to determine their risk for Alzheimer’s disease (P.P. Zandi et al, JAMA 2002;288:2123–2129). The highest rates of diagnosis of Alzheimer’s disease occurred in the women who used estrogen not at all or only for short lengths of time. The lowest risk for Alzheimer’s disease was in men and in those women who used estrogen from the onset of menopause and for greater than ten years.

This population study by Zandi et al echoes the physiological research done in brain cells in tissue culture, in brains of animals under various conditions of estrogen deprivation, and in human brain autopsies of sixty-five-year-old women who died in auto accidents and had their brains examined microscopically. These “necropsy” studies show healthy, youthful brain details in the estrogen users as compared to the nonusers fifteen years postmenopausal.

Neuroscientists have published frequent studies supporting these positive functions of estrogen in the brain.

The biologic truth is that both women’s bodily physiology and their potential for psychological and spiritual growth are steadily disadvantageous as estrogen levels fall in menopause. It is well established that diseases such as osteoporosis, high blood pressure, occlusive cardiovascular disease, macular degeneration, deafness, and dementia are all accelerated in women as compared to men after menopause sets in. Lowered

estrogen levels result in decreased strength, lowered metabolic rates, and increase in fat mass, frailty, and fractures. These symptoms and diseases, both physical and mental, can be dramatically relieved with hormone replacement therapy.

As dementia becomes an increasingly threatening problem with our aging population, data such as these are important to share. Many physicians and many women themselves view menopause as a natural biologic event. This prevailing Western medical paradigm of inexorable menopause has resulted in a public health dilemma. In 1800, the average life expectancy for women was thirty-two years. Nowadays, it averages ninety years. Demographers say that more than half of us will live well past eighty, ninety, or even 100 if we have had no major life-threatening illness before the age of fiftyfive. Yet in the face of these statistics, men and women alike fear and dread a decrepit old age of infirmity and dependency. They deeply desire to have their minds intact and their physical bodies healthy in order to be productive “until the very end.”

Clearly, the natural consequences of sustained low estrogen levels in menopausal women, as quantified by Western science, take a toll on virtually every organ system measured, including the brain. We are at the crossroads of knowledge and tradition in attempting to synthesize a better approach to healthy aging for women.

Ricki Pollycove, MD, MHS, FACOG, has practiced obstetrics and gynecology privately in San Francisco since 1981, with an increasing emphasis on menopause management. With a research background in the immunology of breast cancer, she continues to devote a significant portion of her practice to the special concerns of cancer survivors and women with multiple medical problems.

december 2007 San Francisco Medicine 23

Neuroscience and the Mind

Emotion, Stress, and Traumatic Reactions The Neuroscience of Psychological Trauma Mardi J. Horowitz, MD

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n 1976, my book Stress Response Syndromes was published, containing what turned out to be an influential information processing model of how we assimilate or develop problems after psychologically traumatic experiences. This work and related papers by myself, colleagues, and other investigators led to the 1980 addition of the diagnosis of Posttraumatic Stress Disorder in the official psychiatric nomenclature.

The emphasis was on symptoms of intrusive thinking and pangs of intense alarm, as well as its seeming opposite, extremes of denial and emotional numbing. Back then, the explanatory theory involved mostly psychological processes of memory, peremptory memory return, and reactive emotion. We were also aware of the worsened psychological effects when, socially, a victim was somehow stigmatized for being a victim. Now we know much more about how the brain is involved as well. We are fleshing out a biopsychosocial model of trauma and loss.

There are several key neuroscience findings. All have to do with the modularity of brain systems. These stem from the reptilian midbrain, as we call it metaphorically, through the limbic systems, and on to the higher cortical functions. Some research has suggested that trauma can damage the hippocampus through overload of stress hormones and other excessive stimulations and exhaustions. The roles of the amygdalae, cingulated gyrus, and orbitofrontal cortex have also been examined, and an interactive theory has led to improvement in our psychological theories of stress and trauma.

The crucial brain modularity issues have to do with substrates for storage of traumainduced primitive fear and alarm designations for certain specific stimuli. These take place in the slowly processing dorsal systems of the

cortex, leading to complex memories and fantasies about what traumas mean for affiliations, attachments, and personal roles in coping or decompensating. These also take place in rapid neuronal processing of perceptions, which occurs at the level of the amygdalae and other ventral systems. The function of the lower road of information processing signals now seems clear: at the synaptic level there is altered reactivity, so that danger signals are created and attention is drawn by the power of emotional motivation to a conditionally learned source of threat. When we use psychotherapy techniques of relaxation, guided imagery, and emotional exposure in safe circumstances, we are attempting to reprogram these lower-road circuits, to desensitize and extinguish the alarm tendencies.

When we use psychotherapy techniques of support, advice, education, clarification, and interpretation, we are addressing the more complex associational networks of the dorsal systems—especially those in the prefrontal cortex, which exert a downward control on such lower systems as the amygdalae.

Slower processes occur at higher cortical levels, but they have greater complexity and function to control, moderate, or inhibit actions based on the faster, lower levels of alarm reactions based on traumatic conditioning. The higher levels involve the meaning of perceptual or mnemic stimuli to the self and to affiliations of the self to the larger world. These are the levels that gradually change during more complex processes, such as mourning a loss and learning to cope with threats. Important among these modules are the prefrontal cortex and other dorsal systems. These symptoms can either process information, leading to plans to not be startled by certain stimuli, or they can dampen information, leading perhaps to such

24 San Francisco Medicine december 2007

experiences as indifference or pathological denial of the meaning of such stimuli.

The low road of processing, as through the amygdalae, is one that can be moderated not only by behavioral techniques such as gradual exposure to feared types of perceptual stimuli, but by medications. The high road of processing may be dampened by sedative medications. This may all reduce anxiety and fear responses, but at a price. It could impede the gradual psychological work of the type we know to occur in mourning a loss: a process that takes months.

The brain/mind is complex. The mind, as when mourning a loss, can influence physical health directly and indirectly, as in noncompliance with healthy lifestyles or increases in smoking and alcohol use.

The brain, if fatigued or damaged (as in the closed-head injuries of Iraqi veterans), not only records the trauma but may, if impaired, reduce the mind’s capacity to assimilate and accommodate to what has happened.

For such reasons, people who sustain trauma-induced psychological disorders, and those with complicated responses to severe losses, require a careful biopsychosocial workup, one that looks at interactions between each point of view. There is no quick fix through medications, and combined treatments over an extended period of time need to be based on such biopsychosocial formulations.

Mardi J. Horowitz, MD, is professor in the Department of Psychiatry, University of California at San Francisco; and Director, Second Opinion on Psychotherapy Consultation Group, Langley Porter Psychiatric Institute.

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Neuroscience and the Mind

The Neuroscience of Addiction An Interview with Howard Fields Jeff Miller

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euroscientist Howard Fields, MD, PhD—a senior researcher at the UCSF-affiliated Ernest Gallo Clinic and Research Center and director of UCSF’s Wheeler Center for the Neurobiology of Addiction—wonders why we punish addicts.

“If you listen to addicts, they say, ‘I’m out of control. I can’t help it. I can’t stop myself. I know I need help.’ That’s what everyone needs to understand,” Fields says.

“Most alcoholics would like to cut back on their drinking. But some unconscious force makes them take that fifth or sixth drink even when they know they shouldn’t.”

Finding that unconscious force inside the human brain is the Holy Grail of Fields’ research. It’s a quest that has little use for the magic wand called willpower that society waves over the addiction problem as both an explanation and a solution. “Blaming a person’s lack of willpower is another way of saying it’s your fault, that you had a choice,” says Fields. “But who chooses to be an addict? And what is willpower but just another manifestation of nerve cell activity?”

It’s a fascinating neurobiological conundrum that all of us either witness or participate in daily. Think about it for a moment. At some point in our lives, almost everyone is exposed to alcohol. Yet most people do not become alcoholics, even those who drink small or moderate amounts daily.

For perhaps 5 percent to 10 percent of us, though, and for reasons as yet unexplained, drinking alcohol becomes an addiction with often disastrous consequences for our health, our freedom, and the lives of others.

“What is going on inside the heads of these people?” society asks with both contempt and rage. Fields has an answer of sorts: “When you compare alcoholics www.sfms.org

and controls as they decide between an immediate reward and a delayed one, you see that chronic alcoholics are much more impulsive.” Which came first, the drinking or the impulsivity? It’s not an idle question, and it’s one that Fields cannot yet answer.

“We don’t know if drinking causes impulsiveness or if innate impulsiveness makes alcoholics drink more.”

Still, some of the neuroscientific murkiness is beginning to clear. For example, Fields and his colleagues have found that for those who prefer the delayed reward, there is activity in different regions of the brain than if you prefer the immediate reward.

“You can think of it as the neural correlates of the ego (immediate gratification) and superego (long-term benefit),” Fields remarks.

The key point is that if there are different paths for processing immediate and delayed gratification, then the underlying neural mechanism and biochemistry must be different as well. And if you understand these differences, you are closer to understanding what makes alcoholics different. The main point is that their brains are different, and that is why they cannot stop drinking once they start.

The Role of Receptors Kappa delta mu sounds like a college fraternity. And if you associate college with sometimes fatal outbursts of binge drinking, the Greek letters might be a fitting label.

For neuroscientists, though, kappa, delta, and mu refer to opioid receptors, large molecules found on the surface of neurons. Opioids, literally “resembling opium”—which stems from the Greek word opion, or “poppy juice”—are a group of natural substances produced by the opium poppy plant. Substances that act similarly

are also produced by the body when we are stressed or when we are anticipating reward.

Think endorphins. Fields believes that small differences in receptor activity might be a major culprit in alcoholism.

Fields acknowledges that the opioid receptor hypothesis is only one of many, and none are yet proven. In addition to opioids, some scientists favor the GABA receptor theory; GABA, short for gammaamino butyric acid, is a neurotransmitter, a substance that governs how electrical signals pass between cells.

“There are some scientists,” says Fields, “who think alcohol is addicting primarily through a direct action on GABA receptors that indirectly activates dopamine neurons.

It’s true that alcohol does produce an increase in dopamine concentration in the brain, where we know that feelings of reward originate. And we know that rats bred to like alcohol will choose a lever to deliver alcohol directly into the region of their brains where there are dopamine neurons.”

Yet there is another principle at work that Fields finds equally fascinating. It involves satiety, or—more accurately—the failure of satiety to literally signal that “enough is enough.”

Animal models reveal that endorphins acting at the mu subtype of opioid receptor promote eating and suppress satiety. What if alcoholism is a failure of satiety? What if alcoholics keep drinking because they never feel like they’ve had enough? Conversely, endorphins activating the kappa receptor promote satiety. So what about the endorphins released in the brain when someone drinks alcohol? Where do they go? Fields asks, “Do different endogenous opioids act on mu and kappa receptors? Is the balance Continued on Following Page...

december 2007 San Francisco Medicine 25

The Neuroscience of Addiction Continued from Previous Page... between a mu receptor that promotes drinking and a kappa receptor that suppresses drinking at least partially responsible for how much you drink?”

The answers might finally pinpoint where exactly alcohol acts to produce its powerful sense of reward. That region—or the molecular activity within it—then becomes a potential drug target. In Fields’ mind, it boils down to this: “What we’re doing in my lab is using animals to find out what would be the ideal combination of receptor agonists and antagonists to maximally reduce drinking, then try to design a molecule that would have those properties.”

Naltrexone remains one of the few effective drugs for treating alcohol addiction. The operative word here is treat, not cure. “Naltrexone is effective,” says Fields.

“It reduces the amount you’ll drink, which means that for many people, it’s the difference between two drinks and five drinks.

But getting people to stay on it is tough.

And it might not work for everyone, maybe because it blocks both the delta and kappa receptors. Activated kappa receptors suppress alcohol intake. So if you block them, as some have done in animal studies, you could be creating conditions where some

people drink more while taking naltrexone instead of less.”

Another drug, called rimonabant (Acomplia), now being sold in various European countries as an antiobesity drug, also seems to reduce both cigarette smoking and alcohol intake, although its increased risk of depression has made the U.S. Food and Drug Administration wary. Nonetheless, if approved, rimonabant’s off-label use could rival its primary purpose.

Fields wouldn’t mind the competition.

“Based on the research going on here and other places in the U.S. and around the world, I would say that in the next five to ten years, addiction treatment is going to be markedly improved by the introduction of new pharmacological agents.”

The Role of Willpower “Most treatment programs for alcoholics don’t use a lot of medication,” Fields continues. “They use detoxification and cognitive behavioral transformation, like the twelve-steps of Alcoholics Anonymous (AA). This is fine. Many people are helped—but relapse is very common. What I’d like to see is more clinical research. The biggest hurdle is that not everyone in the medical profession has yet to buy into the fact that addiction is really a disease of the nervous system. It’s exciting, of course, that all the science is inevitably going to lead to

some new treatments.”

Is the vigilance and “self-awakening” inherent in AA’s twelve-step therapy is a cure in itself? Probably not. When it comes to addiction, cure is a big and misleading word. The brain simply “learns” to like addictive substances too much, even filing away a menu of environmental triggers—a particular street corner, money, a sound, a smell—to queue up the urge. In short, abstinence is a daily battle.

So what to make of other studies confirming that twelve-step therapy can be superior to cognitive behavioral therapy when total abstinence is the desired outcome? Does this prove the case for moral fiber? After all, if some addicts can control the urge to abuse drugs or drink excessively without relying on any antiaddiction drugs, isn’t this a victory of the will?

Fields thinks not. “In my mind, any change in behavior is secondary to a change in the brain. Willpower does exist, but it’s biologically based and can be influenced by drugs for better or worse. If drugs can dissolve your willpower, it follows that other drugs can restore it.” Still, neuroscience suggests, something very human—if as yet uncharted in the brain—can contribute to sustained behavioral change.

Reprinted with permission from UCSF’s online publication Science Cafe, www.ucsf. edu/sciencecafe.

Welcome New Members!

The San Francisco Medical Society would like to welcome the following new members:

ACTIVE REGULAR MEMBERS Inder Dhillhon, MD, The Permanente Medical Group—Referred by Suketu Sanghvi, MD Catherine Frenette, MD, California Pacific Medical Center—Referred by Robert Gish, MD Alexandra L. Haessler, MD, California Pacific Medical Center Kenneth C. Ip, MD, The Permanente Medical Group—Referred by Suketu Sanghvi, MD George V. Janku, MD, The Permanente Medical Group—Referred by Suketu Sanghvi, MD Ramey D. Littell, MD, The Permanente Medical Group—Referred by Stephen Follansbee, MD Michelle Y. Morrill, MD, The Permanente Medical Group—Referred by Suketu Sanghvi, MD Marybeth Mulcahy, MD, The Permanente Medical Group—Referred by Suketu Sanghvi, MD Todd C. Pope, MD, The Permanente Medical Group

HOUSE OFFICER/RESIDENT Namita Kansal, MD, Internal Medicine 26 San Francisco Medicine december 2007

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Neuroscience and the Mind

Major Depression Revisited The Role of Stress, Cell Aging, and Neurotrophic Factors Owen M. Wolkowitz, MD; Synthia Mellon, PhD; and Elissa S. Epel, PhD

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dvances in neuroscience are dramatically altering our understanding of depression. Major depression affects approximately 15 percent of the population at some point, and it is the leading cause of disability in North America. Underscoring its health significance, depression is associated with significantly higher rates of diabetes, metabolic syndrome, osteoporosis, cardiovascular and cerebrovascular disease, pathological cognitive aging, Alzheimer’s disease, and other dementias. Major depression is also associated with increased mortality following myocardial infarction, and depression is an independent risk factor for early mortality in general, even after accounting for sociodemographic factors, suicide, and biological and behavioral risk factors such as smoking, alcohol, and physical illness. The reasons for this increased risk of medical comorbidities have remained elusive.

Decades of research into the biology and pharmacologic treatment of depression have yielded safer, more tolerable medications, such as SSRI’s. However, the proportion of patients remitting with the newest antidepressants is no better than with the very first tricyclic antidepressants.

Since virtually all current antidepressants work via similar mechanisms (targeting central nervous system serotonin and/or catecholamine pathways), future advances might require the identification and targeting of new pathogenic mechanisms. For example, emerging theories of depression are highlighting an imbalance between neurodegenerative and neuroprotective processes as well as increases in the rates of cellular aging.

Among the first (and most obvious) signposts along the way to a new model of www.sfms.org

depression were the findings that depressive episodes, especially initial ones, are often preceded by major life stresses, and that depressed individuals often have elevated

“Major depression affects approximately 15 percent of the population at some point, and it is the leading cause of disability in North America.” levels of the stress hormone cortisol. Soon after these discoveries were made, Robert Sapolsky at Stanford and others discovered that prolonged exposure to excessive levels of glucocorticoid hormones (such as cortisol in primates and corticosterone in lower animals) could jeopardize or damage cells in the hippocampus. The hippocampus is part of an important fronto-limbic brain circuit that mediates mood, memory, behavior, and arousal as well as activity of the hypothalamic-pitutary-adrenal axis. Although a primary role of the hippocampus in depression has not been proven, high-resolution brain magnetic resonance imaging scans have often noted small but statistically significant decreases in hippocampal volume (even accounting for overall brain volume) in depressed patients. The loss of hippocampal volume in depressed individuals may be progressive, becoming more pronounced with greater lifetime exposure to untreated depression. This latter observation highlights the importance of early and effective treatment of depression.

How might stress or stress hormones damage the hippocampus? In Sapolsky’s original model, prolonged glucocorticoid

excess leads to a “glucocorticoid cascade” with ever-progressing brain damage. High glucocorticoid levels lead to elevated circulating glucose levels (making energy more available for “fight or flight” responses), but this is at the expense of inducing intracellular glucose deprivation in certain energy-intensive cells, such as neurons. This can lead to an “energetic crisis” in those cells, which in turn leads to difficulty clearing synaptic glutamate and to increases in intra-cytoplasmic calcium levels. These can, in turn, lead to excitotoxic and oxidative damage, both of which can damage neurons and glial cells in the brain. A vital link in this story, discovered by Bruce McEwen at Rockefeller University and by Sapolsky and others, was that the hippocampus has the highest concentration of glucocorticoid receptors in the brain, making it particularly susceptible to such neurotoxic effects.

The next advance occurred in the late 1990s, when Robert Duman of Yale University and others built upon the previous work of Princeton’s Elizabeth Gould to formulate the “neurotrophin hypothesis” of depression. Gould had previously found that certain neurons in the adult primate brain maintain regenerative capacity.

Previous dogma had held that, beyond a certain point in late adolescence, brains lose plasticity and recovery from neuronal death was impossible. It was discovered, though, that stem cells in certain discrete regions of the brain (e.g., the subgranular zone of the hippocampus’s dentate gyrus and the subventricular zone, which projects axons to portions of the prefrontal cortex) maintain plasticity and the ability to form new neurons and glial cells throughout the life of the organism. Importantly, though, Continued on Following Page...

december 2007 San Francisco Medicine 27

Major Depression Revisited Continued from Previous Page... this plasticity and growth is dependent upon the availability of growth factors such as brain-derived neurotrophic factor (BDNF).

In the absence of BDNF, stem cells fail to proliferate, mature, and survive. Duman and colleagues found that stress, and even the administration of glucocorticoids in the absence of stress, significantly decreased brain BDNF levels, inhibited neurogenesis, and led to nerve cell damage in laboratory animals. The previously loose threads of stress, high cortisol levels, and small hippocampal volume that were reported in some depressed individuals were being stitched together to suggest a new model of depression.

Specifically, stress hormones, oxidative and excitatory amino acid toxicity, decreases in neurotrophic factors, and impairment or death of hippocampal nerve cells all may play a role in depressive illness. This theory was supported by Duman and colleagues’ findings that antidepressant treatments (regardless of proximal mechanism of action: serotonin specific reuptake inhibitors, catecholamine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and even electroconvulsive therapy) all increase hippocampal neurogenesis and levels of BDNF. It was thus proposed that antidepressant-induced activation of BDNF expression might be a critical aspect of its therapeutic efficacy.

Coming on the heels of these discoveries, a new (but perhaps related) theory is now being advanced about the pathophysiology of major depression. Hearkening back to the original observation that depression often follows major life stressors, Epel and colleagues at UCSF found that chronic psychological stress, even among nondepressed individuals (such as mothers of chronically ill children or caregivers of spouses with dementia), is associated with significantly accelerated aging at the cellular level. One of the best biomarkers of “biological,” as opposed to “chronological,” aging is the length of cells’ telomeres. Telomeres are the “end caps” that protect the ends of DNA strands from damage, such as fraying and end-to-end fusions. In mitotic cells, each cell division results in incomplete replication of the telo-

mere ends, resulting in progressive telomere shortening. When telomeres reach a critically short length, cells become susceptible to apoptosis and death. Fortunately, the enzyme telomerase can effectively protect and even lengthen telomere ends, thereby prolonging cell survival. Epel and colleagues examined telomere lengths and telomerase activities in peripheral blood mononuclear cells (PBMCs) and found that not only were telomere lengths decreased in stressed women, but telomerase activity was lowered.

The magnitude of the telomere shortening in the stressed individuals was not trivial; it was, on average, the equivalent of nine to seventeen years of accelerated aging (based on an estimated loss of thirty-one to sixtythree base pairs of telomeric length per year in adults)! In 2006, Natalie Simon and colleagues at Harvard reported preliminary data suggesting that individuals with major depression also had shortened PBMC telomeres. It remains unknown if and how PBMC aging relates to brain cell (especially hippocampal cell) aging, but PBMC telomere shortening has been related to various indices of organismic aging in humans, e.g., atherosclerosis, heart disease, dementia, etc., and to early mortality. Even if PBMC aging does not directly bear upon brain processes relevant to depression, it could significantly contribute to the high comorbidity of heart disease, stroke, dementia, and other serious illnesses seen in depressed individuals.

In our current studies at UCSF, we are further exploring the possibility that cellular aging is accelerated in depressed and stressed individuals, and we are examining possible biochemical mediators of this effect. Among the more promising leads we are investigating are: chronically increased levels of stress hormones such as cortisol, increased oxidative stress, increased proinflammatory cytokine activity, and decreased BDNF levels. Perturbations in these systems could underlie a plausible link between stress and brain cell damage, and between vulnerability to medical illness and depression. It could also link together the “glucocorticoid cascade hypothesis” and the “neurotrophin hypothesis” of depression with the recent findings of cell aging in depression. We are working with researchers at the San Francisco V.A. Medical Center (Michael

28 San Francisco Medicine december 2007

Weiner and Susanne Mueller) to apply ultra-high-resolution brain MRI scanning techniques to identify region-specific areas of brain damage in depressed individuals, which may be related to these biochemical perturbations.

The novel pathways and hypotheses we have outlined here do not supplant the current “monoamine hypothesis” of depression (which forms the basis of nearly all current antidepressant treatments), but—if confirmed— may modify, enrich, and extend it.

This is a time of great energy and enthusiasm among depression researchers. With new biological models to guide us, we are hopeful that novel, rational, and mechanism-based treatments will soon be in the offing.

Owen Wolkowitz, MD, is a professor in the Department of Psychiatry at UCSF and Director of the Psychopharmacology Assessment Clinic at Langley Porter Psychiatric Institute. His clinical and teaching interests are the psychopharmacology of depression, and his research revolves around depression and the effects of stress hormones on the brain.

Synthia Mellon, PhD, is a professor and Vice Chair of the Department of OB/GYN and Reproductive Endocrinology at UCSF. Her research expertise includes the biochemistry of neurosteroid hormones.

Elissa Epel, PhD, is an assistant professor in the Department of Psychiatry at UCSF and is Director of Research at the UCSF Center for Obesity Assessment, Study, and Treatment (COAST). She, along with colleagues including Drs. Elizabeth Blackburn and Jue Lin at UCSF, was the first to demonstrate accelerated cell aging in individuals with chronic psychological stress.

Studies at UCSF are enrolling subjects who are dementia caregivers or who are unmedicated and depressed. Some of these studies involve free antidepressant treatment and MRI scans. Interested individuals may contact the Study Coordinators at (415) 476-7254 or (415) 476-7634.

For a full list of references, visit www. sfms.org.

www.sfms.org

Neuroscience and the Mind

Detecting Awareness in a Vegetative State Methods for Detecting Consciousness Adrian M. Owen, et al

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he vegetative state is one of the least understood and most ethically troublesome conditions in modern medicine. The term describes a unique disorder in which patients who emerge from coma appear to be awake but show no signs of awareness. Although the diagnosis depends crucially on there being no reproducible evidence of purposeful behavior in response to external stimulation, recent functional neuroimaging studies have suggested that “islands” of preserved brain function may exist in a small percentage of patients who have been diagnosed as vegetative (Schiff, et al, 2002). On this basis, we hypothesized that this technique also may provide a means for detecting conscious awareness in patients who are assumed to be vegetative yet retain cognitive abilities that have evaded detection using standard clinical methods.

In July 2005, a twenty-three-year-old woman sustained a severe traumatic brain injury as a result of a road traffic accident.

Five months later, she remained unresponsive with preserved sleep-wake cycles. Clinical assessment by a multidisciplinary team concluded that she fulfilled all of the criteria for a diagnosis of vegetative state according to international guidelines.

We used functional magnetic resonance imaging (fMRI) to measure her neural responses during the presentation of spoken sentences (e.g., “There was milk and sugar in his coffee”), which were compared with responses to acoustically matched noise sequences.* Speech-specific activity was observed bilaterally in the middle and superior temporal gyri, equivalent to that observed in healthy volunteers listening to the same stimuli. Furthermore, sentences that contained ambiguous words (italicized) www.sfms.org

(e.g., “The creak came from a beam in the ceiling”) produced an additional significant response in a left inferior frontal region, similar to that observed for normal volun-

“The vegetative state is one of the least understood and most ethically troublesome conditions in modern medicine.” teers. This increased activity for ambiguous sentences reflects the operation of semantic processes that are critical for speech comprehension.

An appropriate neural response to the meaning of spoken sentences, although suggestive, is not unequivocal evidence that a person is consciously aware. For example, many studies of implicit learning and priming, as well as studies of learning during anesthesia and sleep, have demonstrated that aspects of human cognition, including speech perception and semantic processing, can go on in the absence of conscious awareness.

To address this question of conscious awareness, we conducted a second fMRI study during which the patient was given spoken instructions to perform two mental imagery tasks at specific points during the scan. One task involved imagining playing a game of tennis and the other involved imagining visiting all of the rooms of her house, starting from the front door. During the periods that she was asked to imagine playing tennis, significant activity was observed in the supplementary motor area. In contrast, when she was asked to imagine walking

through her home, significant activity was observed in the parahippocampal gyrus, the posterior parietal cortex, and the lateral premotor cortex. Her neural responses were indistinguishable from those observed in healthy volunteers performing the same imagery tasks in the scanner.

These results confirm that, despite fulfilling the clinical criteria for a diagnosis of vegetative state, this patient retained the ability to understand spoken commands and to respond to them through her brain activity, rather than through speech or movement. Moreover, her decision to cooperate with the authors by imagining particular tasks when asked to do so represents a clear act of intention, which confirmed beyond any doubt that she was consciously aware of herself and her surroundings. Of course, negative findings in such patients cannot be used as evidence for lack of awareness, because false negative findings in functional neuroimaging studies are common, even in healthy volunteers. However, in the case described here, the presence of reproducible and robust task-dependent responses to command without the need for any practice or training suggests a method by which some noncommunicative patients, including those diagnosed as vegetative, minimally conscious, or locked in, may be able to use their residual cognitive capabilities to communicate their thoughts to those around them by modulating their own neural activity.

From Science Magazine, September 2006, Volume 313, reprinted with permission from AAAS. *Materials and methods are available as supporting material on www.sciencemag.org.

december 2007 San Francisco Medicine 29

Neuroscience and the Mind

Neurodegenerative Diseases Advanced Neuroimaging at UCSF and the San Francisco V.A. Hospital Michael Weiner, MD

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uring the last decade, interest in MRI of neurodegenerative diseases has been rapidly rising. Much of this increased interest is due to the rising incidence and prevalence of these diseases, caused by the increase in lifespan in the populations of the U.S., Europe, and Japan. As a result, imaging techniques have become more refined, especially due to the development of computer-assisted image processing tools that also quantify the volumes of brain structures. Additionally, improved knowledge concerning the pathophysiological mechanisms of neurodegenerative diseases, especially Alzheimer’s disease, has led to the development of putative treatments that are entering clinical trials. The pharmaceutical companies have recognized that imaging techniques, especially MRI and PET, provide “surrogate” information concerning the pattern and rate of neurodegeneration, which can be used to monitor the effects of treatments that slow the progression of neurodegeneration. All of these factors have led to an explosion of interest in imaging of neurodegenerative diseases, culminating in the funding of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which is a multisite study using MRI, PET, and biomarkers, together with clinical measures, to monitor disease progression (for further information, see http://ADNI-info.org).

When MRI was first developed for medical imaging, most physicians and investigators focused on brain disorders that could not be easily be diagnosed with X-ray CT scanning. Multiple sclerosis was an obvious example because X-ray CT did not provide sufficient short-tissue contrast to identify lesions in the white matter. So attention was shifted to MRIs, which could readily highlight these areas. The ability of

MRI to identify brain tumors and stroke rapidly became apparent and has been used extensively to characterize many diseases of the brain that have identifiable lesions.

“Improved information concerning the pathogenesis of Alzheimer’s disease now raises the possibility that treatments that modify the rate of neurodegeneration will be available for human testing and clinical trials.”

Until recently, there has been comparatively little interest in using MRI for the study of neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia and Lewy body disease, Parkinson’s disease, amyotropic lateral sclerosi, and other degenerative diseases of the brain. There are several reasons for this: 1) the lack of interest on the part of the MRI community was reflective of the relative lack of interest on the part of the medical community at large; 2) the lack of interest was due to the fact that no treatments were available for neurodegenerative disease, thus, fostering the attitude, “if you can’t treat it, why diagnose it?”; 3) for the most part, neurodegenerative diseases are not characterized by lesions, although various types of lesions, especially in white matter, often occur in these conditions; 4) neurodegenerative diseases do produce brain

30 San Francisco Medicine december 2007

atrophy due to loss of neuronal cell bodies and axons until the disease is very advanced and the atrophy becomes extreme.

Improved information concerning the pathogenesis of Alzheimer’s disease now raises the possibility that treatments that modify the rate of neurodegeneration will be available for human testing and clinical trials.

Validated biomarkers, which have increased statistical power when compared to clinical/ cognitive tests, are needed to detect response to treatments. Thus, in order to assess and compare possible biomarkers, the National Institute of Aging and the pharmaceutical industry, funded the Alzheimer’s Disease Neuroimaging Initiative (ADNI), have set the following goals: Develop improved methods, which will lead to uniform standards for acquiring longitudinal multisite MRI, PET, blood, and CSF biomarker data in patients with Alzheimer’s disease and mild cognitive impairment versus elderly controls; create a generally accessible data repository, which describes longitudinal changes in brain structure and metabolism; in parallel, acquire clinical, cognitive, and biomarker data for validation of imaging surrogates; and determine those methods that provide maximum power to distinguish treatment effects in trials involving Alzheimer’s disease and mild cognitive impairment in patients.

To date, uniform MRI and PET acquisition techniques have been implemented at fifty-five participating ADNI sites, and more than 600 out of 800 subjects have been entered. Subjects with Alzheimer’s disease (n=200), MCI (n=400), and 200 controls will have clinical/cognitive assessments and 1.5 T structural MRI every six months for two to three years; 50 percent of subjects will also have FDG PET scans; Continued on Page 34... www.sfms.org

Neuroscience and the Mind

Neurotechnology Emerging Tools to Treat the Brain and the Nervous System Zack Lynch

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eurotechnology—the tools to treat and understand the brain and nervous system—holds the potential to transform nearly every aspect of our lives and revolutionize our conception of the human mind.

Imagine walking into a doctor’s office where an advanced brain-scanning system can detect cellular-level changes that signal the onset of Alzheimer’s disease, years before any physical or mental symptoms manifest.

An individual’s quality of life could then be extended by decades with a treatment plan personalized to the specific case. Today, brain imaging technologies like this are only just beginning to illuminate the causes of brain-related illnesses.

The annual national economic burden of brain-related disorders has reached more than $1 trillion and is growing alarmingly, due to an aging population. While research into the brain and brain-related illnesses is moving forward more rapidly than any other science today, our understanding of how the brain works still has many gaps, and our ability to repair damage remains limited.

Unmet medical needs exist in almost every area of brain and nervous system disorders, including Alzheimer’s disease, addiction, anxiety, autism, depression, epilepsy, multiple sclerosis, obesity, Parkinson’s disease, pain, sensory disorders, spinal cord injury, stroke, schizophrenia, sleep disorders, and traumatic brain injury.

Investigation into the mechanisms and functions of the brain will lead to vastly improved understanding of brain disease and injuries, human cognition and behavior, and will give us an unprecedented ability to treat and heal those in need.

Emerging neurotech companies developing drugs, medical devices, or diagnostics www.sfms.org

for the brain and nervous system face more difficult investment requirements, research and development challenges, and regulatory milestones than other health care sectors.

This additional complexity results in higher costs and longer time to market for many neurotech treatments. For example, it costs nearly $100 million more and takes two years longer to bring a neuropharmaceutical treatment to market than to market the average drug.

In an effort to improve national coordination and accelerate neurotech innovation, the Neurotechnology Industry Organization is spearheading the National Neurotechnology Initiative (NNTI). The NNTI calls for establishing a National Neurotechnology Coordinating Office within the Department of Health and Human Services to help agencies plan joint and complementary research strategies and to serve as the unified voice of federal neurotechnology efforts. The new initiative also seeks to create an advisory panel of experts from industry, academic institutions, and nonprofit organizations to inform the new office on issues including research and development priorities; technology transfer; commercial applications; and ethical, legal, and social issues.

Under this proposal, the National Institutes of Health would receive funds to coordinate research and move that research out of government labs and into young, innovative companies developing the next generation of neurotech treatments. The FDA would be able to hire neurosciencerelated staff and develop workshops to create more robust neurotech standards to ensure the increased timeliness and safety of the neurotechnology review process.

Like previous successful models of

coordinated federal investment initiatives, including the Human Genome Project and the National Nanotechnology Initiative, the National Neurotechnology Initiative will lead to a cascade of investment, discovery, applications, and benefits that can only be imagined today. At the same time, a federal research effort can help ensure the responsible development of neurotechnology by establishing ethical guidelines and policy for research, development, and applications.

Today the United States leads the world in neurotechnology R&D, but the United Kingdom, China, Sweden, Japan, and Germany are all developing their own centers of neurotechnology excellence. The global expansion of knowledge in this new scientific arena is good for the United States and good for humanity. It is important that the progressive traditions of American science and technology, especially our longstanding focus on the legal and ethical implications of new scientific discoveries, carry special weight as this new science matures.

Neurotechnology applications have the potential to transform highly specialized areas of medicine and will also affect the everyday lives of Americans.

Zack Lynch is Executive Director of the Neurotechnology Industry Organization (NIO), the trade association representing companies involved in neuroscience (drugs, devices, and diagnostics), brain research centers, and advocacy groups. For more information, visit the NIO’s website at www.neurotechindustry. org.

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hospital news Chinese

Joseph Woo, MD

The Fall Biathlon, pitting medical staff against hospital staff in basketball and softball, proved to be exciting and fun for all attendees.

The basketball team was captained by Shu-Wing Chan, who led an able squad including Sam Kao, Ed Chan, Arthur Chin, Ken Tai, Dong Lin, Irwin Chow, Gifford Leoung, Clifford Chew, and Vincent Wong. While the medical staff team excelled at the boards, shooting failed them as they fell to the youthful hospital squad.

The softball team played well but lost 9 to 8 in the final inning. Captained and anchored by James Yan, there were some surprisingly athletic performances by Fred Lui, Ken Tai, and medical student Vincent Lam. Thanks to hospital administration and our Executive Committee for hosting such a successful picnic.

Also, Chinese Dragon Boaters also put in an admirable performance again this year as they came in third in a tough division. Physician participants were Vernon Fong and Arthur Chin.

The golf fund-raiser at the Olympic Club was again a huge success. On a beautiful Columbus Day, this annual tournament raised more than half a million dollars for the hospital.

Thanks to our cochairs, Board Member Rose Pak and San Francisco City Manager Ed Lee—and most of all, to the participants and donors.

At the upcoming Christmas party to be held at the Grand Hyatt this December 7, an amateur dancing competition pits medical staff, hospital staff, and IPA against one another. The doctors will be represented by our veteran, Raymond Fay, and relative newcomer Mai-Sie Chan. Currently they are both taking lessons, and, in the format of “Dancing with the Stars,” we expect Ray and Mai-Sie to waltz their way to a win.

Based on the number of events we’ve had this year, perhaps we should invest in a portable defibrillator … or maybe a ping-pong table instead.

CPMC

Damian Augustyn, MD

The CPMC Department of Pediatrics held its Second Annual Frontiers in Pediatric Hospitalist Medicine Conference October 25–26, 2007. Approximately seventy-five pediatricians from around the nation attended the two-day conference, which took place at the Sir Francis Drake Hotel. The program focused on a variety of clinical subjects including child abuse, pediatric neuroimaging, childhood obesity, and pediatric orthopaedics. Planning is underway for the 2008 conference. Stay tuned for more details.

California Pacific Medical Center is part of the San Francisco Hep B Free Campaign recently launched by the San Francisco Department of Public Health. This major collaborative brings together city government, private health care, and nonprofit community organizations to help stop the spread of hepatitis B during a two-year campaign to screen all Asian and Pacific Islander residents for hepatitis B virus (HBV) infection.

The campaign puts San Francisco at the forefront of America in fighting chronic hepatitis and is the largest health care campaign in the nation to target Asians and Pacific Islanders.

As part of the SF Hep B Free collaborative, California Pacific Medical Center is offering free, confidential hepatitis B screening at our St. Luke’s and California campuses, as well as at other sites in San Francisco including churches, community organizations, and health fairs. For a list of testing dates, visit www.cpmc.org/hepb for California Pacific testing sites or www.sfhepbfree. org for testing dates and sites offered by everyone in the collaborative. All individuals tested are notified of their results via mail. For individuals who do not have hepatitis B and are not immune, California Pacific will provide free vaccination.

CPMC is firmly committed to preventing transmission of hepatitis B by providing free screening and vaccination, and by offering access to hepatitis B specialists to keep current and future generations of San Franciscans healthy.

32 San Francisco Medicine december 2007

Kaiser

Robert Mithun, MD

For several decades, the driving thrust in mental health treatment has focused on medication therapies and short-term, face-to-face interactions. This phenomenon was the result of several factors affecting the field of mental health, including exhaustive neuroscientific research into brain activity and the effects of medications on dozens of psychiatric diagnoses.

Another factor included the attempt to legitimize a specialty within medicine that had been viewed as less scientific than other areas. What resulted from this “medicalization” of mental health was a disconnect between treating the brain and treating the person.

Those currently practicing in mental health are witnessing a trend toward moving back to a more behavioral, psychological paradigm, one that acknowledges the importance of neuroscience and medication but that also treats the entire person. The shift has begun to swing toward a more humanistic and integrated approach to treating those afflicted with a variety of mental illnesses and conditions. Medications are indeed important to many treatments, but without the behavioral component, such vital aspects as compliance and motivation can be neglected and ignored on the part of the patient and the provider.

As an example of the integration between science and behavioral therapies at Kaiser Permanente San Francisco, depression and anxiety disorders are managed by asking patients to attend cognitive-behavior therapy groups as their primary treatment. Medications are only used under circumstances when there is specific evidence that they are indicated.

Neuroscience has given us many useful tools to explore the intricate workings of the brain. In conjunction with psychology, the study of the brain can yield manifold benefits to psychiatric patients and, by extension, to their families.

www.sfms.org

hospital news Saint Francis

Wade Aubrey, MD

Saint Francis is pleased to announce the appointment of Clyde Ikeda, MD, Plastic and Reconstructive Surgeon, to the post of Medical Director of the Bothin Burn Center. Dr. Ikeda has been involved with the Bothin Burn Center for a number of years, having graduated from his residency in plastic and reconstructive surgery here at Saint Francis in 1986. Dr. Ikeda is an Associate Clinical Professor of Plastic Surgery at UCSF and Adjunct Clinical Associate Professor in the Department of Surgery at Stanford.

I would like to take this opportunity to thank his predecessor, James Macho, MD, for his outstanding dedication over the last few years and his leadership.

It is with great sadness that I inform my colleagues of the passing of our professional colleague John G. Ward, MD. Dr. Ward passed away at his home in Hillsborough on October 7. Dr. Ward joined our Medical Staff in September 1946. He graduated from the University of Manitoba Medical School in 1943 and was a medical officer of the Royal Canadian Army Medical Corps. Dr. Ward was a charter member of the American Academy of Family Physicians since 1972. Over his sixty-plus year career at Saint Francis, he served two terms on the Board of Trustees, several terms on the Medical Staff Executive Committee, and participated on numerous departmental committees. Dr. Ward is survived by his devoted wife of sixty-four years, Margaret Ward, his daughter Valerie Sherer, and son Richard Ward, MD. Our condolences to the entire Ward family.

On a happier note, Saint Francis is pleased to welcome the BaySpring Medical group to the hospital’s campus. The physicians relocated to 1199 Bush Street MOB in July, and on November 1 they hosted an open house for physician colleagues and hospital staff. We applaud their successful implementation of an outpatient electronic medical records system. www.sfms.org

St. Mary’s

St. Luke’s

Richard Podolin, MD

Jerome Franz, MD

Despite the uncertainties about the future of acute care at St. Luke’s, our people continue to provide high levels of service to this community.

The Joint Commission and IMQ showed up early one morning in October to give us three days of review. We achieved full accreditation with very complimentary statements about our ability to maintain a strong organization in the face of much change. I am especially proud of our medical staff leaders, who were prepared to answer all of the many detailed questions. They embody the spirit of our hospital.

On a lighter note, the St. Luke’s Auxiliary put on its annual Musée de Nöel at the Sheraton Palace on October 24 with silent and live auctions and a fashion show sponsored by Tommy Bahama and Cartier. This year’s event honored Ed Kersh, who almost single-handedly established the superb cardiovascular service at St. Luke’s and has devoted his entire practice to our community. His suite of offices at 1580 Valencia is a gallery for local artists.

The proceeds from the Musée go to the planned upgrade of the emergency department, which served more than 28,000 patients last year.

If acute care closes as planned, the ED will remain as a freestanding emergency room, the details of which have not yet been worked out. By the time this goes to press, you will have read much more about this process in the daily media.

As St. Mary’s Medical Center’s (SMMC) 150th anniversary year draws to a close, we want to highlight two important new services introduced this year.

This fall, SMMC opened the Plastic, Reconstructive, and Orthopedic Surgery (PROS) Center. At the PROS Center, a team of orthopedic and plastic surgeons can treat patients with complex extremity trauma due to injury or disease. Working collaboratively, surgeons are able to perform even the most complex reconstructive procedures more efficiently, improving outcomes and offering patients quicker recovery times and fewer procedures.

SMMC invested in a new 64-slice CT scanner this year in an effort to prevent heart attacks in people at moderate risk. The new scanner captures high-resolution, 3-D images of the heart, coronary arteries, and the surrounding chest cavity. Traditional tests are useful in detecting major blockages of more than 70 percent, but a majority of heart attacks are caused by soft plaque blockages of less than 50 percent. This minimally invasive procedure can detect blockages and narrowing in coronary arteries that the traditional tests may miss. This new diagnostic tool allows SMMC to provide improved early warning to patients.

On the neurological front, practice guidelines for acute stroke, status epilepticus, and brain hemorrhage have been updated by section chief Dr. Donald Kitt and implemented into the CareConnect medical records system under the leadership of Dr. John Umekubo. St. Mary’s Emergency Department has full-time coverage for neurological and neurosurgical emergencies.

And St. Mary’s continues its commitment to didactic and case-based teaching of neurological disorders for its Internal Medicine Residency Training program. The teaching cycle covers the major disorders and includes a clinically based approach.

december 2007 San Francisco Medicine 33

hospital news UCSF

Veterans

Ronald Miller, MD

A new survey by University HealthSystem Consortium (UHC) ranks UCSF Medical Center as one of the nation’s top ten academic medical centers in overall quality. The survey examined a variety of factors, including safety, effectiveness, equity of providing care, efficiency, and patient-centered care. The UHC report recognized the Medical Center for making significant improvements and rising steadily in overall rankings. UCSF was rated first in serving a diverse patient population in gender, race, and socioeconomic status, and eighth in offering patient-centered care.

The UCSF Brain Tumor Research Center has initiated a Phase II clinical trial of the investigational vaccine vitespan for treating glioma.

The vaccine is derived from the patient’s own tumor and is designed to program the body’s immune system to target cancer cells of that individual. In an earlier Phase I trial, UCSF researchers found the vaccine was effective in stimulating the patient’s immune system in all twelve patients who were treated. The Phase II trial is expected to enroll about thirty patients.

Andrew Parsa, MD, PhD, assistant professor neurological surgery, is principal investigator.

UCSF Medical Center has begun offering its fertility services in Marin County through an agreement with Marin Reproductive Medical Associates in Greenbrae, whose practice is now incorporated into UCSF services. The satellite clinic, which opened in late October, includes IVF, other fertility services, and counseling on reproductive options for patients who have been diagnosed with cancer. According to Marcelle I. Cedars, MD, director of the UCSF Center for Reproductive Health, new patients from the North Bay will add to the already rapidly growing fertility practice at UCSF and will help UCSF reach the numbers of patients and reproductive cycles needed to conduct statistically significant research.

Diana Nicoll, MD, PhD, MPA

Traumatic brain injury (TBI) is said to be one of the signature injuries of the conflict in Iraq, and it accounts for a larger proportion of troop casualties than it has in previous wars. Advances in body armor and Kevlar helmets have reduced the number of fatal gunshot wounds but leave limbs vulnerable to improvised explosive devices, land mines, and mortar attack. About 25 percent of the soldiers injured return home with a traumatic brain injury, many without external head injury. Symptoms include memory loss, personality changes, and difficulty with common tasks of everyday life.

San Francisco V.A. Medical Center scientists are actively involved in various research projects related to traumatic brain injuries, including projects focused on earlier diagnosis and treatment; new therapies; the identification of compounds that could be given immediately after injury is sustained, possibly preventing a TBI; and the development of compounds to prevent inflammation, a major cause of brain damage as a result of traumatic brain injury. Grant Gauger, SFVAMC’s Chief of Neurosurgery Service, is currently investigating blunt trauma of the human brain. According to Gauger, mild traumatic brain injury, or concussion, is frequently followed by a clinical syndrome that is associated with serious disability, despite the absence of significant abnormalities on conventional radiologic imaging.

Previous studies of concussion subjects using 1.5 Tesla magnetic resonance imaging have revealed evidence of widespread metabolic changes. In order to clarify the extent and significance of such changes, his research project studies concussion subjects using a higher-resolution 4 Tesla MRI system, with repeat testing at six months after injury. This research is anticipated to lead to improved understanding of postconcussion syndrome, with early application to important decisions in the assessment and treatment of injured military personnel.

34 San Francisco Medicine december 2007

Neurodegenerative Diseases Continued from Page 30... ninety-six subjects will have annual PIB scans for amyloid, and 25 percent of subjects (who do not also have PET) will have 3T MRI at each time interval. All scans are rapidly and electronically transferred to the Laboratory of Neuroimaging at UCLA and will be available for image processing.

All clinical data is collected at UCSD. Blood, urine, and CSF samples for biomarker analysis are sent to the University of Pennsylvania and stored for later analysis. All ADNI data will be accessible to all qualified scientists through the Internet. To date, more than 300 subjects have been enrolled in ADNI. Beyond ADNI, there is considerable interest in early detection of Alzheimer’s disease, distinguishing early Alzheimer’s disease from normal aging by using improved MRI techniques. We have enrolled 150 nondemented elderly subjects with memory complaints or impairments in a study aimed at predicting cognitive decline. Our results show that atrophy of the entorhinal cortex and reduced cerebral blood flow in the posterior cingulate predict cognitive decline. Recently we found that reduced fractional anisotrophy of the cingulum, measured with diffusion tensor imaging, distinguishes mild cognition impairment from Alzheimer’s disease.

The Center for Imaging of Neurodegenerative Diseases at the V.A. Medical Center/UCSF is also focused on developing and using advanced MRI techniques to image changes in the brain in other forms of dementia, Parkinson’s disease, epilepsy, depression, posttraumatic stress disorder, traumatic brain injury, and other brain disorders.

The Center has more than seventy employees and more than twenty-five separate funded grants totaling more than $15 million per year, and it is staffed by Norbert Schuff, PhD, Professor of Radiology; Dieter Meyerhoff, PhD, Professor of Radiology; Kenneth Laxer, MD, Director of the CPMC Epilepsy Center; and Susanne Mueller, MD, Assistant Professor of Radiology.

Michael W. Weiner, MD, Professor of Radiology, Medicine, Psychiatry, and Neurology is the Director of the Center for Imaging of Neurodegenerative Diseases at the V.A. Medical Center, UCSF School of Medicine.

www.sfms.org

In Memoriam Nancy Thomson, MD Allen B. Wheelis, MD

Robert N. Shaffer, MD

Allen B. Wheelis, MD, died June 14, 2007, in a San Francisco hospital following back surgery. He was 91.

He was a noted Bay Area psychoanalyst and author of fourteen books (published between 1959 and 2006) that drew heavily from his experiences both as a doctor and also as a man hobbled by neuroses stemming from childhood traumas. They were often dark and difficult to read, but they were told with such honesty that they ultimately affirmed and even celebrated the resiliency of the human spirit.

Dr. Wheelis was born on October 23, 1915, in Marion, Louisiana, and grew up in San Antonio, Texas, in crushing poverty with a domineering and sometimes cruel father. His mother was so intensely needy she bordered on obsessive. His father contracted tuberculosis when Allen was five, became bedridden, and died when his son was nine. At that point, he became the focal point of his mother’s life. This emotional dependence, which he explored in his 1992 book The Life and Death of My Mother, deepened when his older sister departed for college. He left home to attend Louisiana State University and the University of Texas in Austin, where he graduated in 1937. He did graduate work in economics and was the artistic director of the Little Theater in Austin before starting medical school at the College of Physicians and Surgeons at Columbia University.

He graduated in 1943 and served in the U.S. Navy as a medical officer in the South Pacific until 1946.

He then studied at the Menninger School of Psychiatry, then in Topeka, Kansas, as a resident. He next worked at the Austen Riggs Center in Stockbridge, Massachusetts. After undergoing further training at the New York Psychoanalytic Institute, he moved to San Francisco in 1954, where he remained in private practice until his death.

Dr. Wheelis had tried to write a novel as a young man but gave up in frustration. He returned to writing later in life and proved quite skilled at it, authoring—in addition to his fourteen books—several pieces for Commentary, the New Yorker, and various professional journals. His first book, The Quest for Identity, was published in 1959. A story that appeared in his nonfiction book The Illusionless Man: Fantasies and Meditations on Disillusionment (1966) was the basis of John Korty’s film The Crazy Quilt.

After forty-five years of helping others understand their psyches and the traumas that shaped them, Dr. Wheelis examined his own in The Listener: A Psychoanalyst Examines His Life (1999), a memoir written with unflinching insight. His last book, The Way We Are, was published in August 2006.

Dr. Wheelis is survived by his wife, Ilse K. Wheelis of San Francisco; his children, Mark Wheelis of Davis, Victoria Jenkins of Seattle, and Joan Wheelis of Cambridge, Massachusetts; seven grandchildren, and a great-granddaughter.

Robert N. Shaffer, MD, one of the world’s leading glaucoma specialists, passed away on July 13, 2007, at the age of 95.

He was born January 18, 1912, in Meadville, Pennsylvania, and received his MD from Stanford University in 1939. He was deferred from the military in WWII because of an earlier knee injury. He completed his residency at Stanford Lane Hospital while the campus was still in San Francisco. Among his professors were Dr. Hans Barkan and his brother, Dr. Otto Barkan, from whom Dr. Shaffer learned gonioscopy. He then went to UCSF and, under Professor Frederick Cordes, established the first glaucoma clinic there.

He married his childhood sweetheart, Virginia, and they moved to San Francisco in 1948, where he established what became the leading glaucoma practice west of the Mississippi, at 490 Post St. He had a twentyfive-year affiliation with the American Board of Ophthalmology, where he served as director. He also became widely known for his landmark book, coauthored with Dr. Bernard Becker, Diagnosis and Therapy of the Glaucomas, first published in 1961. This important reference book has been revised and published many times since and is still a primary source for doctors treating glaucoma.

Dr. Shaffer’s proudest accomplishment, in both his view and that of his wife, was the establishment of the annual Shaffer Fellowship, whereby Dr. Shaffer and his wife “adopted” promising young physicians for a year of personal training in the diagnosis and treatment of glaucoma. More than thirty Shaffer Fellows received this training, and many went on to prominent roles in the medical profession. Shaffer fellows remember fondly their year with the couple and the important lessons they learned as they were taught to respect and listen to their patients, to treat the whole patient and not just the glaucoma.

With his two partners, Dr. H. Dunbar Hoskins, Jr., and Dr. John Hetherington, Dr. Shaffer founded the Glaucoma Research Foundation in 1978, with the mission of preventing vision loss from glaucoma by investing in innovative research, education, and support with the ultimate goal of finding a cure. Thomas M. Brunner is the President and CEO of the foundations at this time.

Dr. Shaffer is survived by Virginia, his wife of sixty-eight years, and two sons. John and his wife Susan live in Santa Fe, New Mexico; Stuart lives in San Diego and daughter-in-law Kim resides in Grass Valley, California.

His son, William, predeceased him.

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december 2007 San Francisco Medicine 35

Dental Open Enrollment Effective Date: January 1, 2008!

It’s Open Enrollment time for the San Francisco Medical Society sponsored Group Dental program. This plan is designed to help you, your family and your employees minimize the out-of-pocket expense of regular dental care.

New for 2008! Rollover Benefit: This new feature allows for the unused portion of the maximum benefit amount from one year to roll over and be used in the following calendar year.

This program helps you maximize your out-of-pocket savings by using network dentists, but also allows you to use any dentist you like and receive lower benefits. Following are many valuable benefits that can save you money: • Annual Benefits of $2,000 per person for dental care, using network providers ($1,500 if you use non-network providers).

• During Open Enrollment only, members may join as an individual or as a group with your employees.

• Low calendar year deductible of $50 per person, ($100 per calendar year maximum for families).

• Pay no deductible on oral exams, x-rays and routine cleanings.

Remember, the open enrollment period is available once per year. To be eligible for coverage applications must be received during the special open enrollment period that ends on December 31, 2007.

Call a Client Service Representative at (800) 842-3761 for more information, a brochure and an application. Or e-mail CMACounty.Insurance@marsh.com.

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Underwritten by:

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DentalGuard is underwritten by The Guardian Life Insurance Company of America, New York, NY. Group Contract #G-271907

© 2007 Seabury & Smith Insurance Program Management • CA Insurance License #0633005

777 South Figueroa Street, Los Angeles, CA 90017 • (800) 842-3761 • CMACounty.Insurance@marsh.com• www.MarshAffinity.com • 10/07

Marsh is part of the family of MMC companies, including Kroll, Guy Carpenter, Mercer Human Resource Consulting (including Mercer Health & Benefits, Mercer HR Services, Mercer Investment Consulting, and Mercer Global Investments), and Mercer specialty consulting businesses (including Mercer Management Consulting, Mercer Oliver Wyman, Mercer Delta Organizational Consulting, NERA Economic Consulting, and Lippincott Mercer).