[ExI] Fwd: [GRG] Building a Search Engine of HM's Brain, Slice by Slice

[Bryan Bishop]

"Search me" takes on new meanings.

---------- Forwarded message ----------
From: L. Stephen Coles, M.D., Ph.D. <scoles at grg.org>
Date: Wed, Dec 23, 2009 at 11:26 PM
Subject: [GRG] Building a Search Engine of HM's Brain, Slice by Slice
To: Gerontology Research Group <grg at lists.ucla.edu>
Cc: "Harry Vinters, M.D." <HVinters at mednet.ucla.edu>


 To Members and Friends of the Los Angeles Gerontology Research Group:

        The brain of an anterograde amnesia patient, Henry Molaison (HM),
has opened the door to a much more
ambitious brain project at UCSD... -- Steve Coles______________

*"Building a Search Engine of the Brain, Slice by Slice"**by*
Benedict Carey
[image: []]
Diego Mariscal/The Brain Observatory, University of California, San Diego

*DISSECTION:* A project with Henry Molaison's brain, shown in a mold of
gelatin, aims to create the first entirely reconstructed, whole-brain atlas
available to anyone.

December 21, 2009; San Diego, CA (*The New York Times*, pp. D1, 6) -- On a
gray Wednesday afternoon here in early December, scientists huddled around
what appeared to be a two-gallon carton of frozen yogurt, its exposed top
swirling with dry-ice fumes.

[image: []]
Diego Mariscal/The Brain Observatory, University of California, San Diego

*LAYERS:* “I feel like the world is watching over my shoulder,” said Jacopo
Annese, who dissected the brain of *Henry Molaison*, known as *HM*.   As the
square container, fixed to a moving platform, inched toward a steel blade
mounted level with its surface, the group held its collective breath. The
blade peeled off the top layer, rolling it up in slow motion like a slice of
pale prosciutto.  “Almost there,” someone said.

        Off came another layer, another, and another. And then there it was:
a pink spot at first, now a smudge, now growing with every slice like
spilled rosé on a cream carpet ­ a human brain. Not just any brain, either,
but the one that had belonged to Henry Molaison, known worldwide as H. M.,
an amnesic who collaborated on hundreds of studies of memory and died last
year at age 82. (Mr. Molaison agreed to donate his brain years ago, in
consultation with a relative.)

        “You can see why everyone’s so nervous,” said Jacopo Annese, an
Assistant Professor of Radiology at the University of California, San
Diego<http://topics.nytimes.com/topics/reference/timestopics/organizations/u/university_of_california/index.html?inline=nyt-org>,
as he delicately removed a slice with an artist’s paintbrush and placed it
in a labeled tray of saline solution. “I feel like the world is watching
over my shoulder.”

        And so it was: thousands logged on to view the procedure via live
Webcast. The dissection marked a culmination, for one thing, of H. M.’s
remarkable life, which was documented by Suzanne Corkin, a memory researcher
at MIT who had worked with Mr. Molaison for the last five decades of his
life.

        But it was also a beginning of something much larger, Dr. Annese and
many other scientists hope. “The advent of brain imaging opened up so much,”
said Sandra Witelson, a neuroscientist with the Michael G. DeGroote School
of Medicine at McMaster University in Canada, who manages a bank of 125
brains, including Albert
Einstein<http://topics.nytimes.com/top/reference/timestopics/people/e/albert_einstein/index.html?inline=nyt-per>’s.
“But I think in all the excitement people have forgotten how important the
anatomical study of brain tissue still is, and this is the sort of project
that could really restart interest in this area.”

         The Brain Observatory at U.C. San
Diego<http://thebrainobservatory.ucsd.edu/>,
set up to accept many donated brains, is an effort to bridge past and
future. Brain dissection is a craft that goes back centuries and has helped
scientists to understand where functions like language processing and vision
are clustered, to compare gray and white matter and cell concentrations
across different populations and to understand the damage done in ailments
like Alzheimer’s
disease<http://www.nytimes.com/info/alzheimers-disease/?inline=nyt-classifier>and
stroke.

        Yet there is no single standard for cutting up a brain. Some
researchers slice from the crown of the head down, parallel to the plane
that runs through the nose and ears; others cut the organ into several
chunks, and proceed to section areas of interest. No method is perfect, and
any cutting can make it difficult, if not impossible, to reconstruct
circuits that connect cells in disparate areas of the brain and somehow
create a thinking, feeling mind.

        To create as complete a picture as possible, Dr. Annese cuts very
thin slices ­ *70 microns each*, paper-thin ­ from the whole brain, roughly
parallel with the plane of the forehead, moving from front to back. Perhaps
the best-known pioneer of such whole-brain sectioning is Dr. Paul Ivan
Yakovlev, who built a collection of slices from hundreds of brains now kept
at a facility in Washington.

        But Dr. Annese has something Dr. Yakovlev did not: advanced computer
technology that tracks and digitally reproduces each slice. An entire brain
produces some 2,500 slices, and the amount of information in each one, once
microscopic detail is added, will fill about a* terabyte of computer storage
*. Computers at UCSD are now fitting all those pieces together for Mr.
Molaison’s brain, to create what Dr. Annese calls a “*Google- Earthlike
search engine*,” the first entirely reconstructed, whole-brain atlas
available to anyone who wants to log on.

        “We’re going to get the kind of resolution, all the way down to the
level of single cells, that we have not had widely available before,” said
Donna Simmons, a Visiting Scholar at the Brain Architecture Center at
the University
of Southern California<http://topics.nytimes.com/top/reference/timestopics/organizations/u/university_of_southern_california/index.html?inline=nyt-org>.
The thin whole-brain slicing “will allow much better opportunities to study
the connection between cells, the circuits themselves, which we have so much
more to learn about.”

        Experts estimate that there are about 50 brain banks in the world,
many with organs from medical patients with neurological or psychiatric
problems, and some with a stock donated by people without disorders.
“Ideally, anyone with the technology could do the same with their own
specimens,” Dr. Corkin said.

        The technical challenges, however, are not trivial. To prepare a
brain for dissection, Dr. Annese first freezes it in a formaldehyde and
sucrose solution, to about -40 degrees Celsius. The freezing in the case of
HM was *done over four hours, a few degrees at a time:* the brain, like most
things, becomes more brittle when frozen. It can crack.

        *Mr. Molaison lost his ability to form new memories after an
operation that removed a slug-size chunk of tissue from deep in each
hemisphere of his brain,* making it more delicate than most.

        “A crack would have been a disaster,” Dr. Annese said. It did not
happen.

        With the help of David Malmberg, a mechanical engineer at UCSD who
had designed equipment for use in the Antarctic, the laboratory fashioned a
metal collar to keep the suspended brain at just the right temperature. A
few degrees too cold and the blade would chatter instead of cutting cleanly;
too warm, and the blade wants to dip into the tissue. Mr. Malmberg held the
temperature steady by pumping ethanol through the collars continually, at
minus 40 degrees. He suspended the hoses using surfboard leashes picked up
days before the dissection.

        After the slicing and storing, a process that took some* 53 hours*,
Dr. Annese’s laboratory will soon begin the equally painstaking process of
mounting each slice in a glass slide. The lab will stain slides at regular
intervals, to illustrate the features of the reconstructed organ. And it
plans to provide slides for study. Outside researchers can request samples
and use their own methods to stain and analyze the composition of specific
high-interest areas.

        “For the work I do, looking at which genes are preferentially
expressed in different areas of the brain, this will be an enormous
resource,” Dr. Simmons said.

        If all goes as planned, and the Brain Observatory catalogs a diverse
collection of normal and abnormal brains ­ and if, crucially, other
laboratories apply similar techniques to their own collections ­ brain
scientists will have data that will keep them busy for generations. In her
own work, Dr. Witelson has found interesting anatomical differences between
male and female brains; and, in Einstein’s brain, *a parietal lobe, where
spatial perception is centered, that was 15 percent larger than average.
*
        “With more of this kind of data,” Dr. Witelson said, “we'll be able
to look at all sorts of comparisons, for example, comparing the brain of
people who are superb at math with those who are not so good.”

        “You could take someone like Wayne
Gretzky<http://topics.nytimes.com/top/reference/timestopics/people/g/wayne_gretzky/index.html?inline=nyt-per>,
for example,” she added, “who could know not only where the puck was but
where it was going to be ­ who was apparently seeing a fourth dimension,
time ­ and see whether he had any special anatomical features.” (For the
time being, Mr. Gretzky is still using his brain.)

        So it is that Mr. Molaison, who kicked off the modern study of
memory by cooperating in studies in the middle of the 20th century, may help
inaugurate a new era in the 21st century. That is, as soon as Dr. Annese and
his lab team finish sorting the slices they have collected.

        “It’s very exciting work to talk about,” Dr. Annese said. “But to
see it being done, it’s like watching the grass grow.”
*__________________________________*
*"Dissection Begins on Famous Brain"**by *
Benedict Carey

December 2, 2009; San Diego, CA (*NY Times*) -- The man who could not
remember has left scientists a gift that will provide insights for
generations to come: his brain, now being dissected and digitally mapped in
exquisite detail.

        The man, Henry Molaison ­ known during his lifetime only as H.M., to
protect his privacy ­ lost the ability to form new memories after a brain
operation in 1953, and over the next half century he became the most studied
patient in brain science.

        He consented years ago to donate his brain for study, and last
February Dr. Jacopo Annese, an assistant professor of radiology at the
University
of California, San
Diego<http://topics.nytimes.com/topics/reference/timestopics/organizations/u/university_of_california/index.html?inline=nyt-org>,
traveled across the country and flew back with the brain seated next to him
on Jet Blue.

        Just after noon on Wednesday, on the first anniversary of Mr.
Molaison’s death at 82 from pulmonary complications, Dr. Annese and fellow
neuroscientists began painstakingly slicing their field’s most famous organ.
The two-day process will produce about 2,500 tissue samples for analysis.

        A computer recording each sample will produce a searchable Google
Earth-like map of the brain with which scientists expect to clarify the
mystery of how and where memories are created ­ and how they are retrieved.

        “Ah ha ha!” Dr. Annese said, as he watched a computer-guided blade
scrape the first shaving of gray matter from Mr. Molaison’s frozen brain.
“One down, 2,499 more to go.”

        Dr. Annese carefully dropped the shaving into fluid. The procedure
is being shown live on-line: thebrainobservatory.ucsd.edu/hm_live.php.

        “It’s just amazing that this one patient ­ this one person ­ would
contribute so much historically to the early study of
memory<http://health.nytimes.com/health/guides/test/mental-status-tests/overview.html?inline=nyt-classifier>,”
said Dr. Susumu Tonegawa, a Professor of Neuroscience at the Picower
Institute for Learning and Memory at
M.I.T.<http://topics.nytimes.com/top/reference/timestopics/organizations/m/massachusetts_institute_of_technology/index.html?inline=nyt-org>“And
now his brain will be available” for future study.

        Good fortune and very bad luck conspired to make Mr. Molaison one of
science’s most valuable resources and most productive collaborators. Growing
up in and around Hartford, he began to suffer
seizures<http://health.nytimes.com/health/guides/symptoms/seizures/overview.html?inline=nyt-classifier>as
a boy. The seizures grew worse after he was knocked to the ground by a
bicycle rider, and by the time he was 26 they were so severe he consented to
an experimental brain operation to relieve them.

        His doctor, the prominent brain surgeon William Beecher Scoville,
suctioned out two slug-sized slivers of tissue, one from each side of the
brain. The operation controlled the seizures, but it soon became clear that
the patient could not form new memories.

        “He loved to converse, for example, but within 15 minutes he would
tell you the same story three times, with same words and intonation, without
remembering that he'd just told it,” said Suzanne Corkin, a neuroscientist
at the Massachusetts Institute of Technology who studied and followed Mr.
Molaison in the last five decades of his life.

Each time he met a new acquaintance, each time he visited the corner store,
each time he strolled around the block, it was as if for the first time.

        Before H.M., scientists thought that memory was widely distributed
throughout the brain, not dependent on any one area. But by testing Mr.
Molaison, researchers in Montreal and Hartford soon established that the
areas that were removed ­ in the medial temporal lobe, about an inch deep in
the brain level with the ear ­ are critical to forming new memories. One
organ, the* hippocampus*, is especially crucial and is now the object of
intense study.

        In a series of studies, Mr. Molaison soon altered forever the
understanding of learning by demonstrating that a part of his memory was
fully intact. A 1962 paper by Dr. Brenda Milner of the Montreal Neurological
Institute described a landmark study in which she had Mr. Molaison try to
trace a line between two five-point stars, one inside the other.

        Each time he tried the experiment, it seemed to him an entirely new
experience. Yet he gradually became more proficient ­ showing that there are
at least two systems in the brain for memory, one for events and facts and
another for implicit or motor learning, for things like playing a guitar or
riding a bicycle.

        In the new brain-mapping project here, set to catalog many donated
brains, scientists will have the ability to study areas of Mr. Molaison’s
brain at a level of detail that imaging cannot reveal, to solve lingering
mysteries about the man and the brain.

        Mr. Molaison stunned researchers several times, for instance, by
demonstrating that he could hold onto some new memories. He could reproduce
exactly the floor map of his house on Crescent Drive in East Hartford, where
he lived for years after his operation with his parents.

        These and other scattered surprises suggest that Mr. Molaison’s
brain, deprived of its central memory hub, recruited other nearby areas to
try to compensate, scientists say. Now researchers can begin to study these
poorly understood areas more closely. One region, called the parahippocampal
cortex, appears to support “familiarity” memory, the sensation that we have
seen or heard something before, though we cannot place it.

        “We've learned a lot about memory, we’re getting close to the fire,
and H.M.’s brain will really help us clarify the division of labor in this
area for making memories,” said Dr. Lila Davachi, a neuroscientist at New
York University<http://topics.nytimes.com/top/reference/timestopics/organizations/n/new_york_university/index.html?inline=nyt-org>.


        The dissection, a novel whole-brain technique, is part of a project
known as the Brain Observatory and the culmination of a year of frantic
preparation. Dr. Corkin arranged for Mr. Molaison’s brain to be preserved
and imaged; up until Sunday the laboratory was tweaking its equipment,
buying surfboard leashes at the last minute to support some of its freezing
hoses.

        “We hope that this project as it grows will catalyze cooperation
across many disciplines” to study disorders like
amnesia<http://health.nytimes.com/health/guides/symptoms/memory-loss/overview.html?inline=nyt-classifier>,
tremors, and dementias, Dr. Annese said. “But we wanted to kick it off with
the most famous brain of them all.”

_____________________________
At 06:22 PM 12/22/2009, you wrote:

Dr. George Martin,

    Thanks for this article.  Note that the preservation was with
formaldehyde ("To prepare a brain for dissection, Dr. Annese first freezes
it in a formaldehyde and sucrose solution, to about -40 degrees Celsius.")
which would make a problem for analyzing gene expression.  Maybe, if we
would combine freezing with vitrification and then slicing like they did in
the study of Henry Molaison's brain, we could do even better.  That would be
the Rolls Royce version!

-- Stan

*From:* gmmartin at u.washington.edu
*Sent:* Tuesday, December 22, 2009 8:32 PM
*To:* Stanley_Primmer at hotmail.com
*Subject:* NYTimes.com: Building a Search Engine of the Brain, Slice by
Slice

Message from sender:

        Would they try this out for three or four of our Supercentarians
(two males & two females)? Costs? -- George Martin

 L. Stephen Coles, M.D., Ph.D., Co-Founder
Los Angeles Gerontology Research Group
*URL:* http://www.grg.org
*E-mail:* *scoles at grg.org
**E-mail: **scoles at ucla.edu*

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-- 
- Bryan
http://heybryan.org/
1 512 203 0507
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