nervecenter: messages from the brain at rest
TRANSCRIPT
Some of the newest advances in neurol-
ogy will be explored in depth at the
American Neurological Association’s 136th
Annual Meeting, which will be held Sep-
tember 25–28, 2011, in San Diego, Califor-
nia. Advances in brain imaging technology,
genes recently implicated in neurological
disorders, and not-so-simple powers of ob-
servation will be among the exciting discov-
eries presented at the meeting.
Researchers Ask, What Stops a Good Night’s Sleep?Sleep science has found associations between
sleep disorders and numerous other physical
and mental illnesses. Researchers have grow-
ing evidence that a little studied type of sleep
disorder may be one of the earliest manifesta-
tions of Parkinson disease (PD).
Clifford Saper, MD, PhD, Chair of the
Neurology Department at Beth Israel Dea-
coness Medical Center in Boston, Massa-
chusetts, will describe his investigation into
rapid eye movement (REM) sleep behavior
disorder (RBD). In this disorder, the paraly-
sis that should occur during REM sleep is
absent, and patients may act out their violent
dreams. Saper says that RBD, a manifesta-
tion of synucleinopathies, is likely occurring
in most patients with PD. The implication is
that RBD progresses to PD and, further, that
patients with RBD may be a valuable study
group for PD interventional drug studies.
Among those where RBD has been iden-
tified, approximately 33% will have RBD
after 10 years; after 30 years, approximately
80% will have developed PD, he says.
A review of RBD patient histories by
Bradley Boeve, MD, Chair of Behavioral
Neurology at the Mayo Clinic in Roches-
ter, Minnesota, supports that assertion.¹ His
analysis found that, among 27 patients diag-
nosed with RBD, the interval between RBD
and progression to neurological symptoms
for parkinsonism or dementia with Lewy
bodies averaged 25 years. In 1 case, symp-
toms started 50 years after the initial RBD
diagnosis.
Patients with RBD experience recurring
dreams of attacks and home invasions that
require the dreamer to fight. Saper says one
video from a sleep lab shows an older gentle-
man with RBD taking off his shoe and pan-
tomiming hitting an intruder over the head
with it.
Although the gold standard for mak-
ing the diagnosis requires a sleep study with
NERVECENTER
July 2011 A11
July 2011
IMPORTANT DISCOVERIES IN SLEEP AND LANGUAGE RESEARCH FEATURED AT MEETING SYMPOSIA
Slumber and Speech Take Center Stage
at ANA Annual Meeting
Brain activation in people without brain stimulation (top) and with direct cortical brain stimulation (bottom). On these functional MRI scans, orange denotes increased activation following therapy while blue denotes decreased activation following therapy.
Figure 1
Reprinted with permission from J Neurol Neurosurg Psychiatry. 2010;81:1014–1021.
To learn more about the American Neurological
Association’s 136th Annual Meeting and to register for
the meeting, visit: www.aneuroa.org/ana2011
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INFORMATION
video monitoring, most diagnoses are
presumptions based on patient history,
Saper says.
Often a bed partner is the first to
observe the patient’s nighttime distur-
bances. Some patients have hit their
bed partners, but a patient’s tendency
to fall out of bed or trip while sleep
walking have also been clues of the
presence of RBD. “It’s a tricky thing to
study,” says Saper, noting that because
RBD occurs intermittently and sleep
labs tend to inhibit REM sleep, mak-
ing a diagnosis in the laboratory may
require repeated nights of testing.
Work from Saper’s lab may lead to
a better understanding of RBD. “Our
experimental research lab has looked at
brain circuitry in animals. We’ve iden-
tified the area of the brain that, if dam-
aged, causes the disorder.” Saper’s lab is
currently studying the sub-coeruleus region
in people with PD, since that is the key site
inhibited the most during sleep.
Symptoms of RBD can sometimes be
treated with medications such as clonaze-
pam, which reduces the frequency and sever-
ity of the attacks, or melatonin supplements,
says Saper.
Saper will chair the “Neurobiology of
Disease Symposium: The Biological Basis
of Sleep and Circadian Disorders Sympo-
sium,” on Sunday, September 25. He has in-
vited other symposium presenters to discuss
narcolepsy and cataplexy, a familial form of
advanced sleep phase syndrome (FASPS),
and restless legs syndrome (RLS).
Unlike REM sleep behavior disorder
patients, who thrash or move about during
REM sleep, people with narcolepsy and cata-
plexy experience a temporary paralysis while
falling asleep or when waking up. Jerome Sie-
gel, PhD, Chief of Neurobiology Research at
the David Geffen School of Medicine at the tUniversity of California, Los Angeles, discov-
ered that the loss of hypocretin neurons in
the brains of patients with narcolepsy causes
the condition. Siegel will provide the latest
insights into the neurobiology of narcolepsy
and cataplexy from his research into ways
to identify, manage, and reverse narcolepsy
symptoms in animals and humans.
Louis Ptácek, MD, Professor of Neurol-
ogy at the University of California, San Fran-
cisco (UCSF), identified the genetic basis for
familial advanced sleep phase syndrome, in
collaboration with Ying-Hui Fu, PhD, Profes-
sor of Neurology at UCSF. In this syndrome,
members of affected families have a shorter
circadian cycle than normal, so they want to
go to bed by 8 PM, but are wide awake by
3 AM. In studying families where the syn-
drome was pronounced, Ptácek found
several different mutations that affect
clock genes, a set of genes and their
proteins that interact with each other
in normal 24-hour loop. The family
members studied had a gene muta-
tion that gave them an approximately
23-hour cycle. When Ptácek put the
mutation into mice it also shortened
the animals’ circadian cycle.
David Rye, MD, PhD, Profes-
sor of Neurology at Emory Univer-
sity School of Medicine in Atlanta,
Georgia, co-discovered the first gene
known to be responsible for restless
legs syndrome, along with researchers
at deCODE Genetics, Inc., in Reyk-
javik, Iceland. He will discuss the
neurobiology and genetics of RLS.
The condition causes uncomfortable
sensations in the legs, most often in
the evening, which may make it difficult to
sit still, or to fall asleep. When they finally
fall asleep, patients may have periodic limb
movements during sleep that intermittently
awaken them. The increased prevalence of
both symptoms can be traced to the same
gene.
Neurobiology of Language Gaining InterestBy today’s standards, scientists that studied
neurologic language disorders 20 years ago
had a very narrow set of tools with which to
work. They studied people known to have
focal brain injuries, observing them perform-
ing certain language tasks, and then deduced
the functions of the injured brain areas from
the patients’ performance on the tasks.
Today, the neurobiology of language
is a fast-growing field of study with a tool-
box that includes second and third genera-
tion imaging tools such as high field (3-, 4-,
and 7-Tesla) functional magnetic resonance
imaging (fMRI), diffusion tensor imaging
(DTI), and high density electroencephalog-
raphy (hd-EEG). Researchers in language
labs are also using tools like transcranial
magnetic stimulation (TMS) and transcra-
nial direct current stimulation (TDCS) and
are combining them with other types of im-
aging technology.
“The development of new imaging tech-
NERVECENTER
A12 Volume 70, No. 1
Figure 2
Reprinted with permission from Brain Lang.2010;114:101–114.
Network model for audiovisual language comprehension. This is
used in therapy studies as a baseline for comparison of therapeutic effects.
Special Interest Group Symposia Special Interest Group Symposia (SIGS) will follow each of the major symposia to al-low further discussion on the overed topics. The SIGs, all chaired by Richard Ransohoff,MD, Professor of Molecular Medicine at the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University in Cleveland, Ohio, will focus on cerebrovascular dis-ease, movement disorder, sleep disorders and circadian rhythm, education, behavioralneurology, epilepsy, neuromuscular disease, neuro-opth/neuro-otology, dementia andaging, headache and pain, neuroimmunology, and neuro-oncology.
NERVECENTER
July 2011 A13
nology, PET [positron emission tomogra-
phy] in particular, has allowed noninvasive
ways of measuring regional blood flow and
oxygenation changes in the brain,” according
to Steven Small, MD, PhD, and Chair of the
Department of Neurology at the University
of California, Irvine.
Small believes neurobiol-
ogy of language research will
lead to more precise, physi-
ologically-based treatments
for language disorders. “The
standard of care for aphasia
patients currently involves a
speech pathologist trying to
assess behavior and come up
with a therapy approach based
on the language behavior,” he
says. “What we are proposing
is to use neurobiology to help define the
problem and treat the language disorder.
This changes the nature of therapy from
education to neural repair, and brings it into
the scope of neurology. Further, we can use
functional brain imaging to predict how pa-
tients will respond on different therapies.”
He is organizing the Monday, September
26, “Fundamental Neurobiology of Lan-
guage and Clinical Implications Sympo-
sium,” with co-chair David Fink, MD, Rob-
ert Brear Professor and Chair of Neurology at
the University of Michigan Medical School in
Ann Arbor. Symposium speakers will discuss
how neuroscientists are using neurophysiol-
ogy to treat aphasia after stroke, anatomy to
better understand degenerative diseases that
interfere with language, and brain imaging to
characterize atypical language development.
Small will discuss computational network
models used in measuring neurobiological
changes and present experimental data that
suggest the mirror neuron system (the pari-
etal-frontal circuit characterized in monkeys)
that explains the mirrored response to hand,
mouth, and foot actions observed in primates
is also present in humans. He’ll review the
evidence on the role of the mirror neuron
system in action and interventional studies
that use action observation and imitation as a
rehabilitative approach for patients with mo-
tor impairment of the upper limb and apha-
sia following stroke.
Using a computational model of lan-
guage comprehension across brain regions,
Small’s lab has found that neural networks
used in speech comprehension and process-
ing extend to areas not previously associ-
ated with language, and that the underlying
mechanism probably includes action simula-
tion via the mirror neuron system.
Following this theory, Small’s team has
launched experimental studies that involve
electrical stimulation of the frontal lobe to
bring about language improvement. Another
study observed how the neural circuit in-
volved in language is stimulated when people
observe other people talking. This suggests
that mirror neuron activity supports imita-
tion and other cognitive functions. “Imi-
tation of actions starts in the visual system
and connects to other parts of the brain, ulti-
mately leading to a motor action,” Small says.
“When you observe actions, the visual system
feeds information to the superior temporal
sulcus, focus and on to the inferior parietal
lobe and inferior frontal regions.”
Getting a better understanding of the
mechanisms involved in language process-
ing will help neurologists develop better in-
formed treatments, says Small.
Other speakers at the symposium will
include Bradley Schlaggar, MD, PhD, A.
Ernest and Jane G. Stein Associate Professor
of Developmental Neurology at Washington
University School of Medicine in St. Louis,
Missouri, who is using resting state function-
al connectivity MRI (rs-fcMRI)
to study reading development
and the development of cogni-
tion in patients with Tourette
syndrome (TS). (See “Mes-
sages From the Brain at Rest”
sidebar for more on rs-fcMRI
research.)
Maria Luisa Gorno-Tempi-
ni, MD, PhD, Associate Profes-
sor of Neurology at the Univer-
sity of California, San Francisco,
will discuss how clinical and neuroimaging
findings, genetics, and other markers can
guide in vivo diagnosis of primary progressive
aphasia (PPA). Gorno-Tempini has theorized
that deficits in language processing in PPA
are caused by functional imbalances between
ventral and dorsal networks.
Daniel Llano, MD, PhD, Assistant Pro-
fessor of Physiology at the University of Il-
linois, Urbana–Champaign, will discuss the
role of the thalamus in language and recent
findings on the interactions between the
thalamus and cortex and how they may relate
to language.
This research represents some of the se-
rious work in brain physiology involving
animal models, human volunteers, imaging
tools, and computational analysis, says Small.
Researchers have been studying the neurobi-
Other Symposia of Note Karen Furie, MD, Director of the Stroke Service at the Massachusetts General Hospital in Boston, will chair a symposium on “Managing Cerebrovascular Abnormalities: TheNeurologist’s Perspective” on Sunday, September 25. This symposium will explore thelatest therapeutic advances and risks associated with procedures for treating asymp-tomatic cerebrovascular lesions. “The Neurobiology of Neuro-Oncology,” chaired by David Gutmann, MD, PhD, Don-ald O. Schnuck Family Professor of Neurology and Codirector of the Neuro-OncologyProgram in the Washington University/A// lvin J. Siteman Cancer Center at WashingtonUniversity in St. Louis, on Tuesday,TT September 27, will focus on advances in brain tumorswith an emphasis on the intersection of developmental neurobiology and neoplasia.
What we are proposing is to use neu-robiology to help define the problem and treat the language disorder. This changes the nature of therapy from
education to neural repair, and bringsit into the scope of neurology.
—Steven Small
NERVECENTER
A14 Volume 70, No. 1
ology of language for more than a century,
but the physiology of language has emerged
as a formal area of study because of the de-
velopment of brain imaging during the past
10 years.
The newly established Society for the
Neurobiology of Language grew out of 2
neurobiology of language conferences of-
fered in 2009 and 2010 that drew research-
ers from North and South America, Europe,
and Asia. About 75% of the society’s mem-
bership is studying the basic neurobiology of
language, and 25% are studying disruptions
in language. “For people studying the physi-
ology of human language, it is an impor-
tant development in the history of science,”
Small says.
He predicts continued rapid advances in
the field. “In the future, clinical researchers
will be taking data from fMRI, gene profiles,
and DTI profiles and loading them into a
computer model to determine treatment out-
comes,” he says.
Reference1. Claassen DO, Josephs KAKK , Ahlskog JE, Silber
MH, Tippmann-Peikert M, Boeve BF.FF REM
sleep behavior disorder preceding other as-
pects of synucleinopathies by up to half a cen-
tury. Neurology. 2010;75:494–499.
KATHLYN STONE
DOI: 10.1002/ana.22504
Messages From the Brain at Rest
Brain imaging, when used in language research or diagno-sis, is typically task-based and done in response to a stimulus. Data obtained from these images are critical for understand-ing how the brain processes information when doing tasks. However, task-based imaging is difficult—if not impossible—to perform on infants, toddlers, or people in clinical states that lessen their cognitive abilities, making them unable to perform a given task very well.
For these populations, resting state functional connectiv-ity MRI (rs-fcMRI) may be the answer, according to Bradley Schlaggar, MD, PhD, A. Ernest and Jane G. Stein Associate Professor of Developmental Neurology at Washington Univer-sity School of Medicine in St. Louis, Missouri. He uses rs-fcMRIto study cognitive and language development in both typi-cally developing populations and atypically developing pop-ulations, such as patients with TS. The imaging technology also lends itself to work in patients with autism, aphasia, and gross dementia conditions, he says. Patients can be asleep or anesthetized. With rs-fcMRI there are no task demands other than to hold still in the scanner.
Rs-fcMRI imaging should be thought of as complementary to, not duplicative of or instead of, task-based imaging. “One very important thing that’s been learned from the technology is that, for example, the motor cortex and motor thalamus, brain regions that work together during motor tasks, show spontaneous correlated activity at rest, too,” says Schlaggar. “It’s a fundamental insight and reflects an organization that ’we would expect to glean from task data.”
In Septemeber 2010, Schlaggar and colleagues reported in Science a strategy to use rs-fcMRI and a multivariate pat-tern analysis method to characterize the development of the brain’s functional network architecture.1 They showed that this strategy allows investigators to extract much more informa-tion than what is lurking beneath the surface in a standard, clinical MRI, says Schlaggar. The method allowed them to use information from hundreds of functional connections simulta-
neously to generate a maturation index that could be applied to an individual.
“It’s like a growth curve that allows us to look across hun-dreds of brain regions. There’s enough information in even a ’brief scan to make a determination of where an individual sits on the maturation curve,” says Schlaggar. “Often, in a clinical seizure disorder, a standard MRI shows normality. We contend that there is enough information in a 5-minute rs-fcMRI scan to go beyond the typical clinical MRI and may be useful for management.”
With rs-fcMRI, one might be able to see if there is some-thing wrong within the temporal lobe that is causing the sei-zures, even in the absence of a structural lesion, based on the rs-fcMRI relationships, he says.
The first published study on rs-fcMRI was in 1995 by Bharat Biswal and colleagues, but the research stayed relatively dor-mant until about a decade ago when the field recognized the value rs-fcMRI could have in the study of cognition and lan-guage, including in patient populations. “Since then, it has captured the interest of the field globally,” Schlaggar says. “People always said the brain was a network. Now people are actually studying the brain as a network with network tools.”
Reference1. Dosenbach NU, Nardos B, Cohen AL, et al. Prediction of individual
brain maturity using fMRI. Science. 2010;329:1358–1361.
DOI: 10.1002/ana.22505
People always said thebrain was a network.
Now people are actuallystudying the brain as anetwork with network
tools. —Bradley Schlaggar
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