Autism First Steps 11-26-01 (Part 3)

AUTISM FIRST STEPS
AUTISM DAILY NEWSLETTER
Monday, November 26, 2001

INDEX:
*   Cerebellum and one of the Leading Researchers Part 2
*   Music, the Brain, and Williams Syndrome
*     Mixing Science and Parenting
*     Florence man to serve on advisory council
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Cerebellum and one of the Leading Researchers Part 2

Nevertheless, it was not this discovery so much as brain imaging that made the cerebellum's expanded role credible. "Imaging was the giant," says Schmahmann, "because with clinical cases people were never quite sure what might be going on elsewhere in the brain. But when functional imaging came in, you could see the cerebellum working....In 1994, when I went to the First International Conference on Functional Mapping of the Human Brain in Paris, a wide range of imaging study slides were presented on nonmotor functions like attention, or working memory, or language, and it was phenomenal how often you could see cerebellar activation on the screen. Once this became apparent, people began to look specifically at the cerebellum's cognitive role." But brain anatomy is tricky, and there was no formal guide explaining which parts of the cerebellum were doing what. So the imaging experts were winging it, using their own words to locate what they saw, and producing descriptions that were often vague or misleading. Therefore, Schmahmann decided to devise an "atlas." Working with investigators in Canada and California, and with several of his own students, he developed a basic model and then mapped the results of 47 published brain-imaging studies onto this model to refine it. That work yielded the first topographic map of the cerebellum's "higher order" functions, a crude guide relating different cerebellar regions to different jobs. "While the approach was fraught with problems," Schmahmann says, "it looks like there is indeed a motor cerebellum and a cognitive cerebellum. When you wiggle your finger, or your foot, or your tongue, different sites in the motor portions of the cerebellum will show the greatest relative activity. Likewise, in the cognitive regions, language tasks tend to activate certain lobules, while other tasks requiring working memory, or attention, or imagined motion most strongly activate other areas." By then a wide range of related theories had emerged. Not all agreed with Schmahmann's theory of modulation, but the points of real difference tended to be small. That seemed reasonable, because it was known that people with severe cerebellar damage could move, think, and function. They just did so less well than if their cerebellums were intact. Therefore, it seemed clear that the cerebellum fine-tuned these functions, coordinating a vast range of activities without departing from its basic role as the sorcerer's apprentice. Meanwhile, as animal and clinical research continued, brain imaging by many scientific teams started to define the cerebellum's role in such acts as identifying objects by touch; exercising conscious thought; generating words; processing music and other sounds; mentally rotating abstract objects; influencing emotions such as sadness, depression, and fear; learning repetitive skills (singing on key or serving tennis balls, for instance); and storing the information needed to exercise those skills. By 1995 some 30 teams in diverse places, from Harvard to New Zealand, were publishing papers on the cerebellum's role. Seeing all this productive effort, Schmahmann decided to compile a book that would report what was happening. So he got the leading investigators in the field to submit articles on chosen subjects. The resulting book, The Cerebellum and Cognition, published in 1997 as a single volume of the International Review of Neurobiology, does not answer all prevailing questions about the cerebellum. But it leaves no doubt about the cerebellum's cognitive role, gives a broad overview of current research, and announces clearly that this field has come of age. Still, one is tempted, like an elder neurologist, to ask, "so what?" We see now that our new learning can help deal with medical matters relating directly to the cerebellum. But the cerebellum is still the sorcerer's apprentice. Is there any reason to suppose that this fresh knowledge can help us to explore major issues like the origin of common psychoses or the nature of human consciousness? While nobody knows, the most likely answer is that it can. To begin with, our new view of the cerebellum shows promise of proving important for psychiatry. Right now we don't know what causes many of the most devastating disorders like schizophrenia, mania, and depression. But they all involve failure to relate to reality. "So," as Schmahmann explains, "if the cerebellum is involved in cognitive and emotional behavior, and if a cerebellar lesion can produce cognitive dysmetria [a mismatch between reality and perceived reality], you are now frankly in the psychiatric realm." Researchers led by Nancy C. Andreasen, A.M. '59, at the University of Iowa have taken this concept and applied it directly to schizophrenia. Their work, dealing with connections linking the cerebellum, the thalamus, and the cerebral cortex, suggests that disturbances in these connections can cause poor mental coordination, which in turn can account for schizophrenia's diverse symptoms. Should this theory prove correct, our new insights into the cerebellum could be putting us on the right track for discovering the cause of humanity's most notorious, severe, and pervasive disorder of the mind. Our growing knowledge could provide insight into other brain mysteries as well. Consider, for instance, the enigma of human consciousness. In the past, certain experts tended to shrug their shoulders and say that consciousness is "distributed" about the brain--that when you get a lot of neurons together, it just "happens." The main problem with this is that the brain is so specialized: different parts of the cerebral cortex do different jobs. And your brain is not like a computer, where impulses travel at the speed of light. Brain messages plod along relatively slowly, typically at about 60 miles an hour; so if one brain site wants to send a complex message to another site, it needs to send a lot of information at one go. That requires a substantial neuron cable. And that would mean, if many areas had to talk back and forth with many other areas to coordinate things in consciousness, your brain would consist of cables and little else. But things do get together in consciousness. We know that. Our conscious minds see a world in which touch, vision, hearing, language, motion, memory, higher thought, attention, speech, and emotion are all included. That suggests that there may be something resembling a "seat of consciousness" within the brain where messages registering in consciousness are sent. Even so, we still need to explain a towering coordination problem. As we all know from experience, the innumerable bits of information getting into consciousness don't just "register" there but seem smoothly coordinated. Our view of the world appears seamless. Vision seems smoothly coordinated with touch and hearing, thought with memory and attention. Likewise, diverse movements seem smoothly coordinated with one another as well as with sensory inputs, attention, and higher thought. Indeed, everything seems coordinated in minute detail with everything else--a major hurdle for theorists trying to figure out how any seat of consciousness could work. Enter the sorcerer's apprentice. If, as now seems likely, the cerebellum is doing most of the brain's fine-tuned coordination, not just for our muscles but for our senses, memories, emotions, thoughts, and attention, then the best place to look for such fine-tuned coordination has been found. This doesn't mean the cerebellum coordinates everything, because other brain centers communicate and coordinate with one another outside the cerebellum. But input from the cerebellum seems key to the sort of consciousness we know. That could be important--because, as we have seen, most processed information from the cerebellum goes first to the thalamus before being sent elsewhere. And, as already noted, the thalamus is mysterious, sizable, centrally located, and well-connected. If anything, "well-connected" is an understatement, because nearly all incoming sensory messages--on everything you see, hear, touch, or taste--go first to the thalamus before being sent elsewhere. In fact, virtually everything needed to establish consciousness as we know it comes to the thalamus--not just new data from sense organs and processed data from the cerebral cortex and emotion centers, but also a vast flood of finely coordinated data received from the cerebellum. Seen this way, our new view of the cerebellum appears to provide a reasonable explanation of why our conscious view of the world is so well coordinated, and also supports evidence suggesting that if a seat of consciousness exists, its probable headquarters is in the thalamus. Of course, one must be careful here. The evidence is circumstantial. We still don't know how consciousness works; and despite the brain's apparent need for a seat of consciousness, nobody has ever proved that such a thing actually exists. Even so, Jeremy Schmahmann and other students of the brain have clearly come a good way down the road to full discovery. Around the turn of the last century, the brain seemed so mysterious that questions about consciousness and thought were relegated to philosophers and religious thinkers. Today, on the eve of the millennium, we have learned volumes about the brain; we have even started to learn the truth about how the brain's complex array of substructures interact; and while we still lack suitable answers to most "big" questions, we may well be approaching a point where such questions can be sensibly considered, and where much or even most of the brain's work is understood. Contributing editor Jonathan Leonard '63 wrote "Dream-Catchers," published in the May-June 1998 issue of Harvard Magazine.
ttp://www.harvard-magazine.com/issues/mj99/sorcerer.html
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RESEARCH
Music, the Brain, and Williams Syndrome

Rare disorder offers insight into the genetic basis of cognition
By Brendan A. Maher

Gloria Lenhoff is a 46-year-old lyric soprano singer who has performed with such diverse groups as the San Diego Master Chorale and members of Aerosmith. She can sing nearly 2,500 songs in more than 25 languages, reportedly in a perfect accent. She even has perfect pitch.
But the rest of her world is not perfect. Gloria is affected by a rare genetic disorder called Williams syndrome. With an IQ of about 55, Gloria literally cannot subtract three from five or make change for a dollar. But what she and others with her affliction share is music. Innately connected, they often have an astute grasp of music's technical aspects-the beat, rhythm, tone, and timbre. Identified more than 40 years ago, Williams syndrome results from non-homologous recombination during gametogenesis that deletes about 20 genes on one copy of chromosome 7.1 Characteristics of Williams syndrome include pixie-like features-upturned nose, small chin, protrusive ears-as well as stunted growth, heart problems, poor visuospatial cognition, sensitivity to loud noises, a gregarious personality, and an average IQ of about 60. Many of these individuals have difficulty with the simplest of mental and physical tasks, but some abilities, especially verbal skills, appear to be spared. Classified by some as a nonverbal learning disability, this syndrome allows speech and language aptitude that far exceeds their other cognitive functions. A Williams-afflicted person, for example, couldn't scribble more than a few lines to depict an elephant but could describe one in expressive, almost lyrical detail. "It has long gray ears, fan ears, ears that can blow in the wind. It has a long trunk that can pick up grass or pick up hay," said a patient in an experiment conducted by Ursula Bellugi, director, Laboratory for Cognitive Neuroscience at the Salk Institute for Biological Studies.1
©Ursula Bellugi, the Salk Institute

The dissociation between language and spatial cognition in Williams syndrome is evident in this contrast between the drawing and verbal description of an elephant by an 18-year-old with Williams syndrome.
To some, perhaps the most striking distinction is the extraordinary connection that these people have with music. All exhibit a strong affinity for music, and while their attention span for many tasks is fleeting, they will spend hours listening to or making music. Research is scarce, but some evidence shows a high incidence of perfect pitch, and an uncanny sense of rhythm among this group.2,3 One boy with Williams syndrome was taught to tap a complicated 7/4-time rhythm with one hand while keeping 4/4-time with the other.4 Some researchers will not use the word "savant," but all admit that a connection with music exists, and that it and the other anomalies in this syndrome might help to further knowledge about disease and how the brain develops and works.

Lessons from the Heart

Genetic discoveries of Williams syndrome began at the heart. "We were interested-still are interested-in obstructive vascular disease," says Mark T. Keating, Howard Hughes Medical Institute investigator and professor of cell biology at Harvard Medical School. One such disease, supravalvular aortic stenosis (SVAS), exists in many Williams syndrome patients but also occurs in otherwise healthy patients. For the latter, this genetic disorder results from a defective copy of the ELN gene that encodes for elastin, a substance that comprises about half of the dry weight of arteries. While conducting linkage analysis and fluorescence in situ hybridization (FISH), Keating, then at the University of Utah, and his team traced Williams syndrome to a de novo deletion of ELN on Chromosome 7. They discovered that the responsible microdeletion at 7q11.23, unseen without FISH, included about 2 million base pairs that were flanked by highly duplicative chromosome regions.1
Using FISH to identify the deletion region has reigned as a diagnostic tool for Williams syndrome, although work done by Stephen Scherer at Toronto's Hospital for Sick Children department of genetics and genomic biology, recently uncovered a 1.5 million-base pair inversion of the deletion area that occurs in roughly 5 percent of Williams patients.5 Scherer says, "There's this fallacy that you have to have the deletion to have the disease," which can cause health insurance problems. In 30 percent of these cases, the parents were found to have the inversion without the clinical manifestations of Williams. This inversion increases the likelihood of unequal crossing over and may be a mechanistic explanation for the Williams deletion. Genes in the usual deletion region include the Drosophila homologue, frizzled (FZD3), syntaxin 1A (STX1A), replication factor C2 (RFC2), the gene encoding for LIM-kinase 1 (LIMK1). Rare partial deletions, smaller than the typical 2MB standard, exist, and the varying degrees of Williams syndrome characteristics they produce offer important insight in connecting cognitive function and genetics. Individuals with a deletion that included only ELN and LIMK1 had the heart problems and the impaired visuospatial constructive cognition associated with Williams syndrome, but no other symptoms. It's believed, says Keating, that LIMK1's role in cytoskeletal control and actin formation is responsible for developmental deficiencies in the posterior parietal cortex. Though work from a UK lab refutes this evidence,1 examining those rare cases of partial deletions and the traits they produce can lead to previously unconsidered gene-brain connections. "For instance," says Colleen A. Morris, professor of pediatrics, University of Nevada School of Medicine and clinical collaborator with Keating, "most children with Williams syndrome have anxiety, but anxiety is also common in the general population. Might there be a gene within the Williams deleted region that is important in the general population in terms of anxiety?" It's a story that will continue to unfold as new technology becomes available. Eric Green, director, NIH Intramural Sequencing Center, presented six previously unreported genes in the deletion area at the American Society of Human Genetics meeting in October. His lab has been studying the deleted region in humans and 11 other non-human vertebrates. "In primates," Green says, "this is a very complicated region with these large duplicated blocks. In lower vertebrates it's not so complicated and it's not duplicated." The evolutionary implications of this have incited Green to study this gene dense region on chromosome seven, "in everything from chimpanzees on down to pufferfish."

The Language of Music

Anecdotal evidence of an intimate connection with music, a great memory for songs, and the kind of auditory finesse that can discern the differences between vacuum cleaner brands, has followed Williams people for some time, but little evidence has been published. Neuropsychologist Audrey Don, now at the children's therapy unit at Good Samaritan Hospital in Seattle, was one of the first to explore the relationship. "Cognitively, kids with Williams syndrome are better with verbal skills. Their word knowledge and use of words is better than their nonverbal type of thinking," she says.
She administered a simple musical test of tones and beats to people with Williams syndrome and a control group matched for vocabulary level. She found that musical ability matches verbal ability and was higher than the Williams' children overall cognitive abilities.2 Their parents, providing further survey information, reported an extremely strong and emotional connection with music. A lullaby tape, says Don, made one infant cry. When the child was older, she was asked why she wept; the child said the songs were too sad. An impromptu study conducted at the Williams Syndrome Music and Arts Camp in Massachusetts' Berkshire Mountains gave another inkling into this particular peak of Williams cognition. The experimenters asked eight children to imitate clapped rhythms. They performed as well as normal, musically trained students who were matched to their mental age of five to seven years.3 But, the professional musicians that coded the responses qualified the mistakes of Williams subjects as "wrong in an interesting way."3 They often missed the exact sequences, but creatively kept within the realm of the time signature, much like a jazz musician will jam. The Williams subjects were three times as likely as controls to offer what the researchers called "creative completion" to the test rhythm when giving an incorrect response. Howard M. Lenhoff, professor emeritus, School of Biological Science, University of California, Irvine, recently completed a study linking Williams syndrome to a higher incidence of absolute or perfect pitch, a condition that normally occurs in one out of 10,000 people in Western populations; these people often study music from a very early age. In numerous trials, five musically trained Williams subjects, including Lenhoff's daughter, Gloria, displayed near-ceiling levels of absolute pitch.2 Of the subjects, which represent about 1/1000 of the Williams population, four could read music and name notes, a rare ability in Williams people. Gloria, says Lenhoff, was the only one unable to read music and had to be taught, but she still performed within the acceptable range of absolute pitch. Lenhoff chose a nonrandom sample of subjects because of their ability to name notes. While criticized for choosing outliers, he says, "If you look for the average, you'll find the average." The age at which these participants began to study music raises other questions. It's commonly accepted that to develop perfect pitch, one has to study music before age six, yet all of the subjects, save one, started after this critical period. Lenhoff predicts that this period is extended in those with the syndrome. "The open window gets jammed," he says, "It's open in extended years, and I think into adulthood." Lenhoff and others hypothesize that this open window may be critical for language acquisition in early years, but in normal populations it often fades with disuse-somewhat less often, incidentally, in populations that speak tonal languages such as Mandarin or Vietnamese.2
Back to the Brain
The cognitive strengths and weaknesses of these people have given support to the existence of multiple intelligences,3 and a number of neurological studies are beginning to uncover the connections between function and brain. Comparative magnetic resonance imaging (MRI) studies between Williams and Down patients uncovered a different profile of development. While the frontal cortex of all these individuals is smaller than that of a normal person, those with Williams syndrome have a volume proportionate with the rest of the brain, while in Down syndrome it is reduced. In both the neocerebellum, believed to be the most recently evolved part of the brain, and Heschl's gyrus, an area within the primary auditory cortex, size is even comparable to that of normal subjects.1
The neocerebellum, originally thought to be involved in movement, has many anatomical connections with the frontal cortex, says Paul P. Wang, assistant professor of pediatrics in child development and neurology at Children's Seashore House, University of Pennsylvania Children's Hospital. "I think we're not ready to make any earth-shattering conclusions, but it gives us some clues as to what these areas of the brain may be important for," says Wang, who is involved in studies on phonological working memory-a kind of short-term memory for sounds. Whether innately gifted in music or not, Williams people display a unique set of cognitive and physical symptoms that could further aid in other research areas, from cardiovascular disease to the very root of how genetics translate into ability. Yet, studies of the connection between music and Williams syndrome offer a creative outlet and method to reach out to this population. "For these kids the emotional engagement really pulls them. Music encourages something of normalcy and fulfillment," says Don. Morris speaks of counseling families to use music to instruct and for its calming effect. Though she worries that some parents might be disappointed if their child is not quite the musical prodigy, she speculates about what could be learned. "[Music] is one of the things that's found in all cultures and in all forms. So I think that it's a basic human characteristic. If there is a genetic component to that, then that is absolutely fascinating." Brendan A. Maher can be contacted at bmaher@the-scientist.com.
References
1. U. Bellugi et al., "Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome," Trends in Neuroscience, 22[5]: 197-207, 1999.
2. H.M. Lenhoff et al., "Absolute pitch in Williams syndrome," Music Perception, 18[4]:491-503, 2001.
3. D.J. Levitin et al., "Musical abilities in individuals with Williams syndrome," Music Perception, 15[4]:357-89, 1998.
4. H.M. Lenhoff et al., "Williams syndrome and the brain," Scientific American, 277[6]: 68-73, 1997.
5. L.R. Osborne et al., "A 1.5 million-base pair inversion polymorphism in families with Williams-Buren syndrome," Nature Genetics, 29[3]:321-5, November 2001.
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Mixing Science and Parenting

For more than 40 years, Howard M. Lenhoff studied the enzyme kinetics of the freshwater hydra. An accomplished enzymologist, Lenhoff's strict adherence to the "grind and find" tactics of his field earned him an impressive publication record on the nitty-gritty molecular mechanics of this model organism. But two years ago, at age 70, Lenhoff switched research gears to study cognitive neuroscience. The reason: Lenhoff's daughter, Gloria, suffers from Williams syndrome.
Gloria was born in 1955. Says Lenhoff, "It was pretty obvious when Gloria was an infant that she was handicapped mentally and physically." For 34 years, her parents grieved, believing that an oxygen deficiency at birth had caused her problems. They didn't learn the truth until years later. Her condition was identified by cardiologists in the late 1950s and early 1960s, but Gloria wasn't diagnosed with Williams syndrome until 1989. As Lenhoff learned more about the disorder, he attended gatherings of researchers and physicians who were investigating various aspects of Williams. "I harassed them year after year," he says, "asking that they investigate the many anecdotal reports of musical talent made by parents and teachers. Finally, one said, 'Why don't you do it?'" Having taken an early retirement from the University of California, Irvine, Lenhoff used the time to convince the National Science Foundation to award him a small, high-risk grant for the study. The results of this study were published this past summer.1 Still, the parent in him presides. Even though Gloria is living safely in a Methodist-run community for handicapped people, Lenhoff and his wife worry about her future. They recently moved to Oxford, Miss., to be near her. Says dad: "We just want to make sure that everything is all right for her before we die." -Brendan A. Maher .M. Lenhoff et al., "Absolute pitch in Williams syndrome," Music Perception, 18[4]:491-503, 2001.
http://www.the-scientist.com/yr2001/nov/research_011126.html
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Florence man to serve on advisory council

By Bernie Delinski, Staff Writer
November 24, 2001
FLORENCE - Jane Chase has never told her son he can't do something.Throughout his 23 years, J. Paul Chase has listened to his mother's confidence in him and taken it into action.The Florence resident's list of accomplishments includes serving on the National Council on Disability's Youth Advisory Council, receiving recognition through Alabama's Circle of Friends Award by the Autism Society of Alabama and having an exhibit of his life displayed in the tunnel connecting the Alabama Capitol and Statehouse in Montgomery.Now, the impressive list is growing again with an announcement by U.S. Secretary of Labor Elaine L. Chao that Chase is among 15 members of the national Youth Advisory Council to the Presidential Task Force on Employment of Adults with Disabilities.Chase said he believes he will be able to provide valuable input into the council. After all, he is autistic.Jane Chase does not expect her son to be intimidated by serving on the council since the Youth Advisory Council he already is on often requires him to fly to Washington, D.C., for meetings."I was selected because of my prior work with other agencies," J. Paul Chase said.He said it is an important council. "We work with the labor secretary identifying barriers for people going to work who have disabilities," he said.J. Paul Chase works part time at Blockbuster Video in Florence. He had been attending the University of North Alabama but is taking a break this semester."I can't keep up with everything, he's got so much business going," Jane Chase said.She said the advisory council on employment of adults with disabilities hasn't convened, but she and her son have been to Washington several times for other Youth Advisory meetings.She added that many people have misconceptions about autism, and her son quickly changes those by example. "He does some major things," she said. "I don't think it's slowed him down."He has lots of grit and determination. We just never did tell him he couldn't do something."J. Paul Chase doesn't want sympathy, saying he doesn't understand why someone would feel sorry for him, considering he is a normal person.He hopes working on the council will help other people get jobs despite misconceptions about any disabilities they may have.That is the attitude his parents have instilled into him."I've learned from him more than he has from me," Jane Chase said. "People with disabilities are no different than anyone else."Bernie Delinski can be reached at bernie.delinski@timesdaily.com or 740-5739.
http://www.timesdaily.com/news/stories/11207newsstories.html
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