White Matter Matters

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BRAIN SCIENCE White Matter Matters Although scientists have long regarded the brain’s white matter as passive infrastructure, new work shows that it actively affects learning and mental illness • • • By R. Douglas Fields

magine if we could peek through the skull entists are now realizing that we have under- KEY CONCEPTS to see what makes one brain smarter than estimated the importance of white matter in ■ White matter, long thought I another. Or to discover whether hidden the proper transfer of information among brain to be passive tissue, active- traits might be driving a person’s schizophrenia regions. New studies show that the extent of ly affects how the brain or dyslexia. A new kind of imaging technique white matter varies in people who have differ- learns and dysfunctions. is helping scientists observe such evidence, and ent mental experiences or who have certain

■ Although gray matter it is revealing a surprise: intelligence, and a dysfunctions. It also changes within one per- (composed of neurons) variety of mental syndromes, may be influenced son’s brain as he or she learns or practices a does the brain’s thinking by tracts within the brain made exclusively of skill such as playing the piano. Even though the and calculating, white white matter. neurons in gray matter execute mental and matter (composed of my- Gray matter, the stuff between your ears physical activities, the functioning of white elin-coated axons) con- your teachers chided you about, is where men- matter may be just as critical to how people trols the signals that neu- tal computation takes place and memories are master mental and social skills, as well as to rons share, coordinating stored. This cortex is the “topsoil” of the brain; why it is hard for old dogs to learn new tricks. how well brain regions it is composed of densely packed neuronal cell work together. bodies—the decision-making parts of nerve More with Mastery ■ A new type of magnetic cells, or neurons. Underneath it, however, is a The myelin that gives white matter its color has resonance technology, bedrock of “white matter” that fills nearly half always posed mysteries. For more than a centu- called diffusion tensor im- of the human brain—a far larger percentage ry scientists looked at neurons through their aging (DTI), has for the than found in the brains of other animals. microscopes and saw long fibers, the axons, first time shown white matter in action, revealing White matter is composed of millions of com- extending from a neuronal cell body to a neigh- its underappreciated role. munications cables, each one containing a long, boring one, like an outstretched, elongated fin- individual wire, or axon, coated with a white, ger. Each axon was found to be coated with a ■ Myelin is only partially fatty substance called myelin. Like the trunk thick crystalline gel. Anatomists surmised that formed at birth and gradu- lines that connect telephones in different parts the fatty covering must insulate axons like rub- ally develops in different regions throughout our of a country, this white cabling connects neu- ber sheathing along a copper wire. Strangely, 20s. The timing of growth rons in one region of the brain with those in however, many axons, especially the smaller fil- and degree of completion other regions. aments, were not coated at all. And even along can affect learning, self- For decades neuroscientists exhibited little insulated fibers, gaps in the insulation appeared control (and why teenag- interest in white matter. They considered the every millimeter or so. The bare spots came to ers may lack it), and men- myelin to be mere insulation and the cables in- be known as nodes of Ranvier, after French tal illnesses such as side it little more than passive passageways. anatomist Louis-Antoine Ranvier, who first schizophrenia, autism and Theories about learning, memory and psychi- described them. even pathological lying. atric disorders centered on molecular action in- Modern investigation has revealed that nerve —The Editors side the neurons and at the famous synapses— impulses race down axons on the order of 100 the tiny contact points between them. But sci- times faster when they are coated with myelin—

SCULPTURE depicts overhead view of brain’s cortex (copper)

SCULPTUREBYMARGIE MCDONALD, PHOTOGRAPHED BYFRANK ROSS and white matter core.

www.SciAm.com SCIENTIFIC AMERICAN 55 © 2008 SCIENTIFIC AMERICAN, INC. and that myelin is laid on axons somewhat like “know” whether 10 or 100 layers of insulation electrical tape, wrapped up to 150 times be- Myelin is laid are required to create the proper thickness on tween every node. The substance is manufac- axons of different diameters. But recently biol- tured in sheets by two types of glial cells. These down until age ogist Klaus-Armin Nave of the Max Planck In- cells are not neurons, but they are prevalent in 25 or so, one stitute for Experimental Medicine in Göttingen, the brain and nervous system [see “The Other Germany, discovered that Schwann cells detect Half of the Brain,” by R. Douglas Fields; Sci- reason teenagers a protein called neuregulin that coats axons, entific American, April 2004]. An octopus- do not have and if the amount of this protein is augmented shaped glial cell called an oligodendrocyte does or inhibited, the Schwann cell will wrap more the wrapping. Electrical signals, unable to leak adult decision- or fewer sheets of myelin around the axon. In- out through the sheath, jump swiftly down the making abilities. terestingly, many people who suffer bipolar dis- axon from node to node. In nerves outside the order or schizophrenia have a defect in the gene brain and spinal cord, a sausage-shaped glial that regulates production of this protein. cell called a Schwann cell forms myelin. The wrapping occurs at different ages. My- Without myelin, the signal leaks and dissi- elin is prevalent only in a few brain regions at pates. For maximum conduction velocity, the birth, expands in spurts and is not fully laid un- insulation thickness must be strictly propor- til age 25 or 30 in certain places. Myelination tional to the diameter of the fiber inside. The generally proceeds in a wave from the back of optimal ratio of bare axon diameter divided by the cerebral cortex (shirt collar) to its front the total fiber diameter (including the myelin) is (forehead) as we grow into adulthood. The 0.6. We have no idea how oligodendrocytes frontal lobes are the last places where myelina-

[BASICS] WHAT IS WHITE MATTER?

White matter ﬁlls nearly half the brain. It consists of millions of cables (white) that connect individual neurons (gray matter) in different brain regions, like trunk lines connecting telephones across a country.

White matter

Gray matter Cortex

Cingulum Corpus callosum Cingulum

Corpus callosum )

Axon tractography

Myelin cingulum (

Neuron CardiffUniversity

Corpus callosum, a mass of white matter );DEREK JONES cables, connects the brain’s left and

right hemispheres. On either side, the illustration cables extend up and outward toward the cortex, creating a structure called the cin- Each cable leads from a neuron in gulum. A new form of imaging, DTI tractog- one region to a neuron elsewhere. A cable is raphy, can chart the actual cable pathways. an axon insulated with milky-white myelin. JENCHRISTIANSEN (

56 SCIENTIFIC AMERICAN Marc h 20 0 8 © 2008 SCIENTIFIC AMERICAN, INC. CONVENTIONAL MRI machine (top) can roughly depict white matter (bottom left, white areas). But a new MRI process called DTI shows structure in greater detail (bottom right); red and yellow indicate more highly organized white matter. tion occurs. These regions are responsible for higher-level reasoning, planning and judg- ment—skills that only come with experience. Researchers have speculated that skimpy forebrain myelin is one reason that teenagers do not have adult decision-making abilities. Such ob- servations suggest that myelin is important to intelligence. Presumably the brain does not ﬁnish wrapping human axons until early adulthood be- Forehead cause, throughout that time, axons continue to grow, gain new branches and trim others in response to experience. Once axons are myelin- ) ated, the changes they can undergo become more limited. Still, for a long time a question re- mained: Is myelin formation totally pro-

black-and-whitescan grammed, or do our life experiences alter the ( degree of wrapping and thus how well we learn? Does myelin actually build cognitive ability, or is cognition simply limited in regions where it has not yet formed? Piano virtuoso Fredrik Ullén decided to ﬁnd out. Ullén also happens to be an associate pro- fessor at the Stockholm Brain Institute in Swe- UlsterMedical and Surgical Specialists den. In 2005 he and his colleagues used a new Back brain-scanning technology called diffusion tensor imaging (DTI) to investigate the brains of He also found that the more hours a day a );JOE GALLIVAN professional pianists. DTI is done with the same musician had practiced over time, the stronger

colorscan kind of magnetic resonance imaging machines the DTI signals were in these white matter found in hospitals but involves a different type tracts; the axons were more heavily myelinated of magnetic ﬁeld and different algorithms to or tightly packed. Of course, the axons could create the many brain-image slices that are as- simply have expanded, requiring more myelin sembled into a three-dimensional picture. The to maintain the optimal 0.6 ratio. Without per- [THE AUTHOR] slices display the vectors (mathematically de- forming an autopsy, the question remains open. ﬁned as tensors) of water that diffuses in tissue. The discovery is important, however, because it In gray matter the DTI signals are low because shows that when learning a complex skill, no- );ZEPHYR/ PHOTO RESEARCHERS, INC. ( water diffuses symmetrically. But water diffus- ticeable changes occur in white matter—a brain

machine es asymmetrically along bundles of axons; this structure that contains no neuronal cell bodies ( irregular pattern illuminates white matter, ex- or synapses, only axons and glia. Studies on an- posing the major highways of information that imals, in which brains can be physically exam- HEALTHCARE ﬂow among brain regions. The more tightly ined, show myelin can change in response to packed and heavily coated with myelin the ﬁ- mental experience and a creature’s developmen-

);PHILIPS R. Douglas Fields is chief of the bers are, the stronger the DTI signal. tal environment. Recently neurobiologist Wil- Nervous System Development and Fields Ullén found that in professional pianists, cer- liam T. Greenough of the University of Illinois Plasticity Section at the National tain white matter regions are more highly devel- at Urbana-Champaign confirmed that rats Institute of Child Health and Human oped than in nonmusicians. These regions con- raised in “enriched” environments (with access Development. He has written sev- nect parts of the cerebral cortex that are crucial to abundant toys and social interaction) had eral articles for Scientific American, most recently in the August 2007 to coordinated movement of the fingers with ar- more myelinated fibers in the corpus callosum— issue on how sharks zero in on prey eas involving other cognitive processes that op- the hefty bundle of axons that connects the by sensing extremely weak electri-

COURTESYOF R. DOUGLAS FIELDS ( erate when making music. brain’s two hemispheres. cal ﬁelds emitted by ﬁsh.

www.SciAm.com SCIENTIFIC AMERICAN 57 © 2008 SCIENTIFIC AMERICAN, INC. KNOWN DISEASES These results seem to jibe with DTI studies platinum electrodes, we can impose patterns of performed by neuroscientist Vincent J. Schmit- impulses on them. We found that these impuls- Faulty or missing myelin horst of Cincinnati Children’s Hospital, which es can regulate specific genes in neurons. One in the central nervous system can cause several debilitating compared white matter in children ages five to of the genes causes production of a sticky pro- diseases, including: 18. A higher development of white matter struc- tein called L1-CAM that is crucial for pasting ture, Schmithorst found, correlates directly with the first layer of membrane around an axon as MULTIPLE SCLEROSIS higher IQ. Other reports reveal that children myelin begins to form. (degeneration of central who suffer severe neglect have up to 17 percent We also found that glia can “listen in” on im- nervous system) less white matter in the corpus callosum. pulses shooting through axons and that the

trafﬁc heard alters the degree of myelination; a ) CEREBRAL PALSY Stimulating Change type of glial cell called an astrocyte releases a

(severely impaired illustration Such findings strongly suggest that experience chemical factor when it senses increased im- ( muscle control) influences myelin formation and that the result- pulse traffic. This chemical code stimulates oli- ing myelin supports learning and improvement godendrocytes to form more myelin. Children ALEXANDER DISEASE MedicalArts

of skills. But to be fully convinced of that con- who succumb to Alexander disease, a fatal NIH (destruction of central clusion, investigators need a plausible explana- childhood disorder causing mental retardation nervous system) tion of how abundant myelin can enhance cog- and abnormal myelin, have a mutation of an as- nition, as well as some direct evidence that trocyte gene.

defects can impair mental abilities. Logic, too, helps to explain how white mat- );ALAN HOOFRING My lab has uncovered several ways in which ter can inﬂuence cognitive ability. It might seem

an individual’s experiences can inﬂuence myelin that, by analogy to the Internet, all information micrograph formation. In the brain, neurons ﬁre electrical in the brain should be transmitted as quickly as impulses down axons; by growing neurons possible. That would mean all axons should be

from fetal mice in culture dishes equipped with equally myelinated. But for neurons, faster is VARSHASHUKLA (

[HOW IT WORKS] MYELIN FORMATION

Neuron Long axons insulated with myelin Node of carry signals between neurons Ranvier faster than unmyelinated axons. Oligodendrocyte cells manufacture the fatty membrane and wrap the axon with 10 to 150 layers. Differ- ent factors can stimulate the myelination process; often astrocyte cells “listen in” on the signals Oligodendrocyte traveling along axons and relay Astrocyte chemical messages to the oligodendrocytes. Below, a microscope shows axons in red being wrapped.

Oligodendrocyte

Axon

Myelin sheath Axon

58 SCIENTIFIC AMERICAN Marc h 20 0 8 © 2008 SCIENTIFIC AMERICAN, INC. not always better. Information must travel enor- cluded that far from being mistakes, the nodes SUSPECTED mous distances between brain centers. Each act as intricate, bioelectric repeaters—relay sta- ILLNESSES center carries out its particular function and tions that generate, regulate and rapidly propa- sends the output to another region for the next gate electrical signals along an axon. By study- Abnormal myelin formation is suspected of contributing to several step of analysis. For complex learning, such as ing owls’ excellent hearing, neurobiologists mental illnesses, including: learning the piano, information must be shut- have shown that during myelination the oligo- tled back and forth among many regions; infor- dendrocytes insert more nodes than are optimal SCHIZOPHRENIA mation ﬂowing over different distances must ar- for fast signaling along certain axons to slow (delusions, hallucinations) rive simultaneously at one place at a certain signals traveling along them. time. For such precision to occur, delays are Clearly, the speed of impulse transmission is AUTISM necessary. If all axons transmitted information a vital aspect of brain function. We know that (impaired communication at the maximum rate, signals from distant neu- memory and learning occur when certain neu- and emotional detachment) )

inset rons would always arrive later than signals from ronal circuits connect more strongly. It seems neighboring neurons. An impulse typically likely that myelin affects this strength, by ad- BIPOLAR DISORDER takes 30 milliseconds to travel from one cere- justing conduction velocity so that volleys of (periods of mania alternating bral hemisphere to the other through myelinat- electrical impulses arrive at the same neuron si- with periods of depression) ed axons in the corpus callosum, compared multaneously from multiple axons. When this

ANDJEN CHRISTIANSEN ( with 150 to 300 milliseconds through unmy- convergence occurs, the individual voltage blips DYSLEXIA (spelling, reading or more elinated axons. None of the corpus callosum’s pile up, increasing the strength of the signal, thus general language disorder)

MedicalArts axons are myelinated at birth, and by adult- making a stronger connection among the neu-

NIH hood 30 percent remain that way. The variation rons involved. Much more research must be done helps to coordinate transmission speeds. to explore this theory, but there is no doubt that Perhaps just as crucial are the nodes of Ran- myelin responds to the environment and partic-

ALANHOOFRING vier. In the past few years scientists have con- ipates in learning skills.

Learning and Mental Illness MYELIN FORMATION With this new perspective, it is not hard to imagine how faulty transmission could lead to mental challenges. After decades of searching Node of Ranvier acts like gray matter for the causes of mental disabilities, a repeater, quickly relaying impulses along an axon. neuroscientists now have circumstantial evi- The impulse is strength- dence suggesting that white matter plays a role. ened and volleyed from Dyslexia, for example, results from disrupted node to node as a voltage spike, initiated timing of information transmission in circuits when channels in the required for reading; brain imaging has node open up, flooding the node with sodium revealed reduced white matter in these tracts, ions. Potassium which could cause such disruption. The white channels concentrated matter abnormalities are thought to reflect at the juxtaparanode then open to sling- both defects in myelination and developmental shot the impulse abnormalities in neurons affecting these white down the axon to the next node. matter connections. Tone deafness results from defects in higher- Node of Ranvier Channel level processing in the cerebral cortex where Myelin sounds are analyzed; psychologist Kristi L. responds to Paranode Hyde of McGill University has found that white (purple) matter is reduced in a specific fiber bundle in the Sodium ion the environment right forebrain of tone-deaf individuals. Fur- thermore, recent research by Leslie K. Jacobsen and participates Juxtaparanode Potassium (blue) channels of Yale University indicates that exposure to to- in learning, bacco smoke during late fetal development or Axon adolescence, when this bundle is undergoing in part by Myelin sheath myelination, disrupts the white matter. The strengthening Signal impulse structure, as seen by DTI, correlates directly with performance on auditory tests. Nicotine is neuronal known to affect receptors on oligodendrocytes connections.

www.SciAm.com SCIENTIFIC AMERICAN 59 © 2008 SCIENTIFIC AMERICAN, INC. [DEVELOPMENT] that regulate the cells’ development. Exposure to environmental factors during crucial periods THE BRAIN MATURES of myelination can have lifelong consequences. Schizophrenia is now understood to be a de- Few axons are covered with myelin at birth. More are velopmental disorder that involves abnormal insulated over time, from the Back connectivity. The evidence is multifold. Doctors

back of the cerebral cortex to the whitematter have always wondered why schizophrenia typi- front. The sequence here, by Paul Relatively more cally develops during adolescence—but recall Thompson of the University of that this is the primary age when the forebrain California, Los Angeles, depicts is being myelinated. The neurons there have the pruning of neurons and the largely been established, but the myelin is chang- relative increase in myelin. Basic ing, making it suspect. In addition, nearly 20 functional areas such as vision studies in recent years have concluded that (back) are completed before age Forehead white matter is abnormal (possessing fewer oli- 4, followed by language and, last, godendrocytes than it should) in several regions self-control (forehead). Relativelymore mattergray Age 4 of the schizophrenic brain. And when gene chips—tiny diagnostic devices that can survey optimal communication among brain regions, thousands of genes at a time—recently became To reach which is also fundamental to proper cognition, available, researchers were startled to discover depends on the white matter bedrock connect- that many of the mutated genes linked to schizo- world-class ing the regions. In 2007 Gabriel Corfas, a neu- phrenia were involved in myelin formation. status in certain rologist at Children’s Hospital Boston, showed White matter abnormalities have also been that experimental disruption of genes in oligo- found in people affected by ADHD, bipolar dis- intellectual dendrocytes—not in neurons—of mice causes order, language disorders, autism, cognitive de- or athletic striking behavioral changes that mimic schizo- cline in aging and Alzheimer’s disease and even phrenia. And the behavioral effects involve one in individuals afﬂicted with pathological lying. skills, an of the same genes, neuregulin, found to be ab- Of course, underdeveloped or withered my- individual must normal in biopsies of schizophrenic brains. elin could be a result of poor signaling among The chicken-and-egg question of whether neurons, not necessarily a cause. After all, cog- start young. changes in myelin alter neurons or whether nitive function does depend on neuronal com- changing neuronal patterns alter myelin will be munication across synapses in the cortex’s gray settled the same way such dilemmas always are: matter, where most psychoactive drugs act. Yet with the acknowledgment that there is a close interdependence between the two mechanisms. Myelinating glia can respond to changes in PROFESSIONAL PIANISTS have axon diameter, but they also regulate that diam- more highly developed white matter in certain eter. And they can determine whether or not a regions than nonmusicians given axon survives. In multiple sclerosis, for do, suggesting it affects example, axons and neurons can die after my- learning. Furthermore, it is elin is lost as a result of the disease. more extensive in pianists who begin regular practice Remodeling Old Age before age 11 than in those Whatever the mechanism, as our brain matures who start during their teens from childhood to adulthood the precision of or later, indicating that connections among regions improves. How well critical periods exist for the connections are made may dictate how well superior skill acquisition. we can learn certain skills at certain ages. Indeed, Ullén’s studies of accomplished pianists revealed an additional ﬁnding: white matter was more highly developed throughout the brains of individuals who had taken up the in- strument at an earlier age. In people who

learned after adolescence, white matter develop- ettyImages G ment was increased only in the forebrain—the region that was still undergoing myelination.

This ﬁnding suggests that the insulating of INTIST. CLAIR

Age 8 Age 12 Age 16 Age 20

nerve fibers in part determines age limits for mental exercise into a person’s 60s, 70s and 80s learning new skills—windows of opportunity, helps to delay the onset of Alzheimer’s. And or critical periods, when certain learning can how does a person’s wisdom increase over the occur or at least can occur readily. Learn a for- decades? Answers are still forthcoming. Re- eign language after puberty, and you are des- searchers have not yet looked for myelin chang- tined to speak it with an accent; learn the lan- es in older animals. Other experiments suggest guage as a child, and you will speak it like a na- myelination continues into our mid-50s but on tive. The difference occurs because the brain a much subtler level. circuits that detect speech rewire according to Certainly white matter is key to types of the sounds we hear only as a child. We literally learning that require prolonged practice and lose the connections that would allow us to repetition, as well as extensive integration hear sounds unique to foreign languages. In among greatly separated regions of the cerebral evolutionary terms, the brain has no reason to cortex. Children whose brains are still myelinat- retain connections to detect sounds that it has ing widely find it much easier to acquire new never heard after years of childhood. Critical skills than their grandparents do. For a range of periods are also one of the main reasons adults intellectual and athletic abilities, if an individ- do not recover as well from brain injuries as ual wants to reach world-class level he or she children do. must start young. You built the brain you have ➥ MORE TO Specialists have identified specific protein today by interacting with the environment while EXPLORE molecules in myelin that stop axons from you were growing up and your neural connec- sprouting and forming new connections. Mar- tions were still myelinating. You can adapt Myelination: An Overlooked Mechanism of Synaptic Plasticity? tin E. Schwab, a brain researcher at the Univer- those abilities in many ways, but neither you nor R. Douglas Fields in Neuroscientist, sity of Zurich, revealed the first of several my- I will become a world-class pianist, chess player Vol. 11, No. 5, pages 528–531; 2005. elin proteins that cause young sprouts from ax- or tennis pro unless we began our training when ons to wither instantly on contact. When this we were children. Extensive Piano Practicing Has protein, which he named Nogo (now referred to Of course, old geezers can still learn, but Regionally Specific Effects on White Matter Development. as Nogo-A), is neutralized, animals with a spi- they are engaged in a different kind of learning Sara L. Bengtsson et al. in Nature nal cord injury can repair their damaged con- involving the synapses directly. And yet inten- Neuroscience, Vol. 8, No. 9, pages nections and recover sensation and movement. sive training causes neurons to fire, so the po- 1148–1150; September 2005. Recently Stephen M. Strittmatter of Yale found tential exists for that firing to stimulate myelin- Astrocytes Promote Myelination ) that the critical period for wiring the brains of ation. Perhaps someday, when we fully under- in Response to Electrical Impulses. animals through experience could be reopened stand when and why white matter forms, we T. Ishibashi et al. in Neuron, Vol. 49, by blocking signals from Nogo. When the pro- can devise treatments to change it, even as it No. 6, pages 823–832; March 16, 2006. graymatter scans

( tein is disrupted in old mice, the critters can re- grows old. To deliver on that speculation, we wire connections for vision. would need to ﬁnd the signal that tells an oligo- How to Grow a Super Athlete. C.L.A. U. If myelination is largely ﬁnished in a person’s dendrocyte to myelinate one axon and not an- D. Coyle in Play Magazine, (New York Times Sports) March 4, 2007. 20s, however, does that contradict recent claims other one nearby. That discovery, buried deep Available at www.nytimes.com/ that the brain remains plastic throughout mid- underneath the gray matter, awaits unearthing 2007/03/04/sports/playmagazine/

PAULTHOMPSON dle and old age? For example, studies show that by future explorers. ■ 04play-talent.html