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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