Parent Scientists, Children & Informed Consent

On Jan. 17, 2009, Pam Belluck published an article online in the The New York Times with the title "Test Subjects Who Call the Scientist Mom or Dad", in which she describes scientists using their own children in their research. The methods employed were observation of behavior and non-invasive diagnostic techniques, e.g. magnetic resonance imaging (MRI) of brain development and electroencephalography (EEG). In MRI, a scanner maps tiny realignments to high radio-frequency pulses in the spin axes of atomic nuclei inside the body that have been lined up in a strong magnetic field. The measurements are used to reconstruct our body's interior in image slices. With EEG, tiny electrical signals from the nerve cells in the brain are recorded with wire electrodes attached to the surface of the scalp. I conducted such studies as principal investigator. The research is summarized in a chapter of a book entitled "Blindness and Brain Plasticity in Navigation and Object Perception." Some essential findings are described in the posts dated Dec. 31, 2008, and Dec. 9, 2007, on this blog. Both techniques do not pose any known health risks to the participants. I submitted the following comment with the article (comment #9): 

Asking someone to participate in a scientific research study resembles in many ways ancient rites of hospitality. If we are invited to stay with friends, we take it for granted that they shall take good care of us and protect us from harm within their limits.

People who wish to participate in a research study that does not benefit them directly, but furthers scientific knowledge at large, expect to be well informed about the risks that the study may pose. They certainly will expect that the principal investigator is not going to put them knowingly in harms way and that, in case of an accident, everything possible will be done for them within reasonable limits.

Commonly, MRI studies do not pose any risk greater than everyday life for healthy people who do not wear magnetic parts or electronic devices in their bodies. However, the procedure may be quite intimidating, particularly when children are involved. Therefore, it certainly is reassuring for the participants to know that they and/or their children are asked to undergo a procedure that the principal investigator and her/his children have undergone before. Of course, the participants have the right to stop the procedure at any time without any negative consequences and, implicitly, this right extends to the children of principal investigators.

The same rationale applies to EEG and, in principle, to behavior studies. However, while the MRI scanner and the EEG recorder deliver objective results, it is questionable whether parents can be impartial observers of their children's behavior.

Important to all studies with very young children, the question remains to be answered whether the mind of a five-year old has developed sufficiently to understand risk and give informed consent.

Theory of Mind I: Feral Children & Language Development

The human mind is quite robust. We can compensate for the loss of any sense and learn to behave normally. People who cannot see or cannot hear from birth can perfectly graduate with advanced academic degrees, provided they are afforded the necessary help. The brain reorganizes. Cortical regions deprived of dominant sensory input may be recruited in the processing of information of other sensory modalities. Detailed reviews of scientific studies examining the neural basis of such reorganization can be found in the book entitled "Blindness and Brain Plasticity in Navigation and Object Perception."

However, if we are deprived of most social contact in early childhood, our development appears irrevocably impaired. The etiology of only few feral children is documented in depth. Kaspar Hauser is one such case. In Werner Herzog's wonderfully detail-oriented movie "The Enigma of Kaspar Hauser," Bruno S. plays the role of Kaspar so astonishingly real that the movie strikes us as a documentary. This may come as no surprise. Herzog is a brilliant cinematic portrait artist, and Bruno Schleinstein seems predestined for this role, when we learn about his life. Michael Kimmelman published a passionate, yet distanced account on this man in The New York Times on Dec. 24.

Bruno S. possesses the great natural gift to act in one role, that is, as the feral child Kaspar Hauser. In Herzog's epic description of bucolic life in a small town in nineteenth century southern Germany, the story of Kaspar teaches us that we may not be able to attain the language skills necessary to grasp the intricacies of human relations when barred extensively from interacting with others in early childhood. As long as we find sufficient access to language, our mind will develop fine. Social relationships play a fundamental role in this process. The inability to express ourselves in language both constitutes and reflects a disability of thought, hindering the ordinary development of self-awareness. Hence, a meaningful Theory of Mind must consider abstract thought expressed in language and detached from senses as one bearing pillar of our psyche.

Two areas on the left cortical hemisphere are known to play fundamental roles in the processing of language. In an oversimplification, Wernicke's area appears instrumental in the comprehension of speech; Broca's area is crucial for speaking. Functional magnetic resonance imaging studies on the cerebral activation of Braille readers that my colleagues and I carried out (Melzer and others, 2001) suggest that, in addition, regions where visual, auditory, and somatic sensory association areas meet may be engaged in the phonetic and semantic processing of symbolic language. In his book "Language and Mind",Noam Chomsky proposes that language originates from innate roots. A vivid discussion of his ideas with Michel Foucault can be found here. Forkhead box P2 genes, FOXP2 genes for short, have been identified to substantially affect the development of language skills. Recent research provides evidence that these genes may have been expressed already in Neanderthals (Krause and others, 2007). Therefore, hereditary boundaries are set for the nerve cell mechanisms that underlie the development of language. These limitations need to be explored in depth and a valid Theory of Mind must take them into consideration.

Addenda

• A second installment for a Theory of Mind has been posted (02/20/2009).
• FOXP2 genes encode transcription factors. That is, their protein products control the expression of other genes, influencing cascades of developmental events. In a letter to this week's issue of the journal Nature, Konopka and others (2009) report that the product of chimpanzee FOXP2 differs only in two building blocks (amino acids) from that found in humans. Inserting the chimpanzee gene into the DNA of cultured human nerve cells resulted in distinct modifications of the proteins the cells synthesized. The observed differences may be relevant for the development of a speech apparatus (11/11/09).
• In his new book with the title "Through the Language Glass: Why the World Looks Different in Other Languages", Guy Deutscher gives great examples for the fashion in which our language shapes our mind and vice versa? An excerpt of his book can be found in this weeks' New York Times Magazine entitled "Does Your Language Shape How You Think?". The author convincingly demonstrates in astounding examples that language distinctly reflects differences in the perception of space and geographic position in cultures that use an absolute system of reference, that cardinal points (East, West, North, South), as opposed to a relative system, that is body-centric reference (left, right, in front, behind). Lera Boroditsky provides more details in her essay for The Wall Street Journal with the title "Lost in Translation" published online  Jul. 23, 2010. Self-conscience seems to differ accordingly. In a culture using absolute reference, the individual is not surrounded by her/his environment, but situated in it (08/28/10).
• Neanderthals were not that different from us. It is not unreasonable to assume that they were able to speak to each other. The Smithsonian Institution recently unveiled MEanderthal, a face morphing mobile application that may drive this point home (09/03/10)
• You may wish to listen to this interview with Werner Herzog by Tom Ashbrook with the title "Filmmaker Werner Herzog", originally broadcast on National Public Radio's On Point Dec. 11, 2009 (09/06/10).
  
• In this interview by Steve Inskeep on National Public Radio's Morning Edition with the title "From Werner Herzog, Three DVDs Worth A Close Look" aired today, Werner Herzog recommends three movies for us to watch (09/16/10):

• This comprehensive review by Kuhl (2010) provides detailed insight into recent findings on early language and brain development, using the latest technology (10/10/2011)

References

• Chomsky N (2006) Language and the Mind. Cambridge Univ Press, Cambridge, UK.
• Deutscher G (2010) Through the Language Glass: Why the World Looks Different in Other Languages. Metropolitan Books, New York, USA.
• Konopka G, Bomar JM, Winden K, Coppola G, Jonsson ZO, Gao F, Peng S, Todd M. Preuss TM, Wohlschlegel JA, Geschwind DH (2009) Human-specific transcriptional regulation of CNS development genes by FOXP2. Nature 462:213-217.
• Krause J, Lalueza-Fox C, Orlando L, Enard W, Green RE, Burbano HA, Hublin J-J, Hänni C, Fortea J, de la Rasilla M, Bertranpetit J, Antonio Rosas A, Pääbo (2007) The Derived FOXP2 Variant of Modern Humans Was Shared with Neandertals. Curr Biol 17:1908-1912.
• Kuhl PK (2010) Brain Mechanisms in Early Language Acquisition. Neuron 67:713-727.
• Melzer P, Morgan VL, Pickens DR, Price RR, Wall RS, Ebner FF (2002) Cortical activation during Braille reading is influenced by early visual experience in subjects with severe visual disability: a correlational fMRI study. Human Brain Mapp 14:186-195.

Related Posts

• Prologue to A Theory of Mind
• A Theory of Mind II: H.M.'s Memory
• A Theory of Mind III: Emotions

The Power of Instruction & The Brain

What is wrong with this tiger's face? Humans strife for harmony in their social relationships as well as in their aesthetic appreciation of artistic expression. In our perception, perfect symmetry reflects absolute harmony. For that reason, we perceive a perfect sphere, that is the shape with greatest symmetry, as most aesthetically pleasing.

When we study this picture (courtesy anonymous), we are struck by the exquisite fur markings of the tiger's face. Black stripes boldly transect a background in mild shades of brown and white. On the cheeks, lines of black dots stand out on a very bright white close to the lips, transforming into light brown toward the nose. Our eye is caught by the side-to-side symmetry of the pattern. On each cheek, we notice four rows of black dots, increasing in number from top to bottom. Visible on occasion, a whisker rises from each dot.

The dot pattern seems entirely symmetrical on first glance. But close inspection tells us that this is not true for this tiger's face. On the animal's left we spot a solemn black dot between the first and the second row at the back. There is no dot at this location on the right side. We discovered a supernumerary whisker! To developmental biologists, this find is as significant as the extra finger or toe physicians observe on rare occasion in humans, a condition known as polydactyly.

The whiskers of a variety of mammals including cats, rodents, rabbits, pinnipeds and manatees are more than just hair. They rather constitute complex organs of touch. Whiskers are sinus hairs. In contrast to the hair of common fur, the follicles of sinus hairs contain large cavities filled with blood surrounding the hair shaft. While perhaps a dozen sensory nerve fibers innervate the hair follicles of common fur, hundreds of nerve fibers innervate the follicles of sinus hairs, ramifying into thousands of endings.

At least four different types of touch receptors have been identified in cat sinus hair follicles (Gottschaldt and Vahle-Hinz, 1981). Merkel cell receptors constitute one common type. They consist of cells on which sensory nerve endings attach and are distributed around and along the hair shaft. When the whisker is bent, the Merkel cells are compressed and the force is transduced into a rapid succession of electrical spikes in the sensory nerve endings. These signals are conducted along the nerve fibers and transmit the touch response via nerve cells in the brain stem, across the mid line to the thalamus in the diencephalon (interbrain) on the opposite side. From there, the signals are relayed into a region of cerebral cortex called primary somatic sensory area.

We may wonder how the somatic sensory system processes the tactile input from the supernumerary whisker. Are supernumerary whiskers inheritable? Does the genetic modification that precipitates the development of an extra whisker result in complementary change in the brain? Is the touch sensation from this whisker transmitted at all? If so, how is the additional sensory input accommodated?

Research in mice provides some answers. As in cats, the whiskers on the mouse's snout are cast in a remarkably conserved pattern. They are arrayed in five distinct rows that Thomas Woolsey and Hendrik Van der Loos (1970) called A to E from dorsal (top) to ventral (bottom). Four whiskers straddle the rows caudally, that is at the back. Woolsey and Van der Loos proposed to number the whiskers in each row in rising order, beginning caudally with 1. Rows A and B are shortest, consisting of only four whiskers, whereas rows C, D and E contain eight whiskers and more.

The snout of a mouse showing the five rows of whiskers (source: Jackson Lab.).

Furthermore and most intriguingly, the two researchers were able to show that cytoarchitectonic units, they called barrels, represent the whiskers on the snout topographically in primary somatic sensory cortex.

Mouse barrelfield (courtesy of H. Van der Loos)

The above picture shows a micrograph of an 80 micrometer-thick section cut tangentially through the left hemisphere of cerebral cortex of an albino mouse. The animal's left side is up (dorsal). The nose (rostral) is right. The section was stained for cell bodies with a blue dye. The barrels are clearly visible as nerve cell-dense rings surrounding cell-sparse centers.

In subsequent work, Woolsey and Van der Loos could demonstrate that the removal of whisker follicles at birth prevented the corresponding barrels from developing (Van der Loos and Woolsey, 1973). This was the first demonstration that the cerebral cortex was organized in structurally modular units and, most importantly, that the development of these structures was dependent on input from the sensory periphery.

After completion of these ground-breaking experiments, Hendrik Van der Loos moved from Johns Hopkins School of Medicine to Lausanne, Switzerland, where he assumed the directorship of the Institute of Anatomy at the medical school of the University of Lausanne. There, he met Josef Dörfl. Josef was going to be the first to knowingly observe a supernumerary whisker. He worked with Hendrik who continued in Switzerland to examine barrels and the factors that influence their development. One day, while they were reconstructing barrel patterns from histologically-stained sections through somatic sensory cortex, they haphazardly discovered a supernumerary barrel in row A. Josef was urged to check this animal's whiskerpads more closely.

Josef was an accomplished anatomist with a keen eye and well versed in examining whiskers. Unlike cats, mice whisk. They move their whiskers rhythmically to palpate objects. Josef was studying the anatomy of the mouse whiskerpad with micro-dissection, identifying the muscles that move the whiskers as well as the sensory and the motor innervation involved (Dörfl, 1982 and 1985). Examining the whiskerpad in question through a surgical microscope, Josef readily identified a supernumerary whisker near the nose at position A5 on the side opposite the cortical hemisphere with the extra barrel. The whisker was located exactly at the position that the extra barrel indicated! In future breeding, mice with supernumerary whiskers would predictably produce offspring with this trait.

This discovery constituted a decisive event laden with consequences. Josef, Hendrik and their colleagues had found an inheritable genetic modification adding a whisker follicle which then instructed the developing brain to add a whisker representation accordingly. Several thousand mice were bred. The effort eventually produced strains with a variety of supernumerary whisker phenotypes. There were mice with twin follicles, mice with fewer whiskers in rows A and B, mice with an extra row of whiskers between rows B and C, and mice with supernumerary whiskers in multiple locations.

In almost all cases, the barrels in somatic sensory cortex matched the whisker pattern. Hendrik's student Egbert Welker and his late wife Karin Van der Saag would spend years, compiling hereditary charts and comparing whisker follicles and follicular innervation with cortical barrel organization. They were instrumental in publishing the research. The effort led to a comprehensive series of publications in renowned scientific journals beginning with two articles in the Journal of Heredity (Van der Loos and others, 1984 and 1986), paving the way for Dr. Welker's thesis.

In the years that followed, Hendrik Van der Loos would end his life during a bout of deep depression and research on the mice with supernumerary whiskers would cease. Their embryos were frozen away, supplanted by vast numbers of genetically engineered mice strains that populate research universities worldwide at present. Nobody checks for supernumerary whiskers anymore.

We know today that the instruction from the whisker follicles for the development of barrels in somatic sensory cortex is crucially dependent on nerve cell activity mediated by the excitatory neurotransmitter glutamate. Genetic knock-out mice lacking glutamate receptors may not develop barrels and their equivalents in thalamus and brainstem, called barreloids and barrelettes, respectively. The neurotransmitter serotonin appears to play a facilitating role in cortex. High levels of serotonin impede proper barrel development in monoamine oxidase A-deficient knock-out mice. Most recently, the metabotropic glutamate receptor subtype mGluR5 has been identified as one pivotal player in the development of barrels, barreloids and barrelettes, affecting all stations of the somatic sensory system (Lu, 2008; Wijetunge and others, 2008). Other research suggests that mGluR5 receptors modulate the development of psychiatric disorders, and new drugs acting specifically at this type of receptor are being tested. I have written about these issues in my posts dated Apr. 1 and Oct.1, 2008.

Despite the advances in elucidating the molecular mechanisms underlying barrel development, the functional significance of these structures is obscure. The sensory inputs from a whisker terminate clustered inside the barrel representing this whisker. In accord, deflection of the whisker evokes the earliest nerve cell responses in the corresponding barrel. The separation of sensory input into discrete domains may, therefore, explain the observed intimate correspondence of functional and morphological whisker representations in somatic sensory cortex of mice. By contrast, cats do not contain barrels in their somatic sensory cortex. Yet, the nerve cells form functional topographic whisker maps as fine-grained as those observed in mice. Hence, barrels seem unnecessary for the separation of sensory input, and their role in the processing of tactile information remains to be elucidated.

On the other end of the whisker-to-barrel pathway, we do not understand to the day what mechanism precisely controls the induction of whisker follicles on the face and which factors determine their number and layout. Would not it be fascinating, if the same set of genes controlled the formation of this pattern in big felines as well as in tiny rodents?

Addenda

• Hendrik Van der Loos already suggested that two independent mechanisms influence the development of the whisker pad: one mechanism that controls whisker follicle formation and another that limits the area of maxillary skin available to follicle formation. Therefore, at least two separate molecular signaling pathways with their own sets of genes control the development of the whisker pattern. Sonic hedgehog and T-box genes may constitute candidates for follicle formation and number, respectively. Wilson and Conlon (2002) published an in-depth review on the role of the t-box family of genes in development and disease (04/22/09).
• In her report for National Public Radio's Health Blog Shots with the title "Touring Memory Lane Inside the Brain" posted online today, Amy Standen describes recent advances in the visualization of cortical cell architecture (Micheva and others, 2010). A demonstration of results is presented in the animated journey along a coronal section through the anterior (nose-ward) mouse barrel cortex below. The movie covers a volume approximately 0.5 mm wide, 12 μm thick and 1.4 mm deep, stretching from the cortical surface (top) to the white matter and the striatum, an underlying subcortical structure (bottom). Nerve cell bodies are labeled green; their processes green and blue. Red labels the contacts between nerve cells known as synapses. The barrels are located above the agglomerations of red synapses at mid-depth (11/18/10).

References

• Dörfl J (1985) The innervation of the mystacial region of the white mouse: A topographical study. J Anat 142: 173-184.
• Dörfl J (1982) The musculature of the mystacial vibrissae of the white mouse. J Anat 135: 147-154.
• Gottschaldt KM, Vahle-Hinz C (1981) Merkel cell receptors: structure and transducer function. Science 214: 183-186.
• Lu H-C (2008) How mGluR5 signaling contributes to the development and plasticity of cortical maps? BSI Forum.
• Micheva KD, Busse B, Weiler NC, O'Rourke N, Smith SJ (2010) Single-Synapse Analysis of a Diverse Synapse Population: Proteomic Imaging Methods and Markers. Neuron 68: 639-653.
• Van der Loos H, Welker E, Dörfl J, Rumo G (1986) Selective breeding for variations in patterns of mystacial vibrissae of mice. Bilaterally symmetrical strains derived from ICR stock. J Hered 77: 66-82.
• Van der Loos H, Dörfl J, Welker E (1984) Variation in pattern of mystacial vibrissae in mice. A quantitative study of ICR stock and several inbred strains.
  J Hered 75: 326-336.
• Van der Loos H, Woolsey TA (1973) Somatosensory cortex: structural alterations following early injury to sense organs. Science 179: 395-398.
• Wijetunge LS, Till SM, Gillingwater TH, Ingham CA, Kind PC (2008) mGluR5 regulates glutamate-dependent development of the mouse somatosensory cortex. J Neurosci 28: 13028-13037.
• Wilson V, Conlon FL (2002) The T-box family. Genome Biol 3: reviews3008.1–reviews3008.7.
• Woolsey TA, Van der Loos H (1970) The structural organization of layer IV in the somatosensory region (SI) of mouse cerebral cortex. The description of a cortical field composed of discrete cytoarchitectonic units. Brain Res 17:205-242

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Fundamental Research & Fragile X Syndrome

On Sep. 23, 2008, National Public Radio's Morning Edition aired a report on progress in research on Fragile X syndrome or FXS for short. You may listen to the podcast here. In FXS, the gene Fmr1 is not expressed in nerve cells. This gene encodes a messenger RNA-binding repressor protein known as fragile X mental retardation protein, or FMRP for short. The protein hinders the translation of the genetic code into protein in protein synthesis. Recent studies in the laboratory of Mark Bear, director of the Picower Institute at M.I.T., suggest that a specific type of receptor for the excitatory neurotransmitter glutamate plays a crucial role in the synthesis of FMRP. Neurotransmitters are molecules that convey information from one nerve cell to another across the synaptic cleft. The synapse constitutes the contact between the nerve cells. Glutamate and its receptors are instrumental in the strengthening of synapses. 

Mark Bear is fundamentally interested in the development of the cerebral cortex. As I summarized in my post dated Aug. 14, 2008, the strengthening of glutamatergic synapses is understood today as the basic mechanism underlying brain plasticity, learning and memory. The stabilization of synapses profoundly affects cortical development. Perturbation of synaptic growth and pruning is suspected to be involved in the development of mental disorders like autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), and manic depression.

I met Mark and his family for the first time when I was visiting Wolf Singer's laboratory at the Max-Planck-Institute for Brain Research where Mark was staying as a postdoctoral fellow. The Max-Planck Society funds 80 research establishments covering a broad range of topics from art, law and anthropology to biology, medicine, chemistry, material sciences and physics. The MPI for Brain Research comprised three laboratories at the time. The facilities were located in a cluster of brick-tiled buildings on the opposite bank of the Main in Frankfurt.

Mark proudly drove a very used green BMW 2000Ti and lived with wife and daughter in a small apartment in the western suburb of Schwanheim across the river from a huge chemical plant. Frankfurt's air quality was not as good as today. The river's water was pitch black. A subsidiary of the conglomerate Hoechst AG, Messer Griesheim, was still in full operation. On rainy days the air smelled like in Philadelphia when you pass the refineries.

I remember vividly one occasion on which Mark tried hard with little success to convince his Frankfurter colleagues of the refined taste of the All-American soul food: peanut butter-and-jelly sandwiches. His wife had prepared plates piled high with more than enough for everybody. Not unlike Frankfurt's Aeppelwoi, peanut butter-and-jelly sandwiches are an acquired taste. Only those who have raised children on them will fully appreciate the profound usefulness and true satisfaction they deliver.

By contrast, Mark's work with Wolf Singer and colleagues was a convincing success. The team showed with elegant experiments published in the journals Nature (Bear and Singer, 1986) and Science (Kleinschmidt and others, 1987) and Nature that glutamate and the neuromodulators acetyl choline and norepinephrine play fundamental roles in the plasticity of domains of ocular dominance in visual cortex during postnatal development. The discovery of ocular dominance plasticity had won D.H. Hubel and T.N. Wiesel the Nobel Prize half a dozen years earlier (Hubel and Wiesel, 1998).

After his return to the U.S., Mark continued to investigate the role of glutamate in the organization of nerve cell circuits in cerebral cortex. In a long series of studies, he and his colleagues examined long-term potentiation (LTP) and long-term depression (LTD) as mechanisms for cortical plasticity. The elucidation of the underlying molecular mechanisms led to the G-protein-coupled metabotropic glutamate receptor mGluR5. By contrast to ionotropic receptors that regulate ion fluxes across cellular membranes important to electrical nerve cell signaling, metabotropic receptors regulate cell protein activity and homeostasis. The mGluR5-receptor appears to play a major role in FXS and autism. I have written about this in my post dated April 1, 2008. Designing antagonists against the receptor's actions promises a treatment. Mark points out in his interview with NPR that he was not planning on finding a cure for mental disorders. Things came together serendipitously. It was only with the support and encouragement of the Fragile X Research Foundation (FRAXA) that the work on a potential treatment began.

The National Institutes of Health (NIH) provide most funding for biomedical research in the U.S. Measured in inflation-adjusted dollars, the NIH have seen their budget erode in the past 8 years. By contrast, the number of applications for research grants has doubled. As consequence according to the NIH online report, the success rate of competitive grant applications diminished from 32 percent in fiscal year (FY) 2000 to 21 percent in FY 2007. The NIH were able to award about 41 percent of the total cost to new investigator-initiated applications (R01). These are proposals for projects that scientists submit based on their most recent findings. They advance the most innovative ideas and are most likely to lead to new discoveries. The success rate of R01 applications decreased to 19 percent in FY 2007 from 26 percent in FY 2000. The mounting budgetary constraints inevitably result in increasingly conservative funding decisions. Under these circumstances, it is not surprising that Mark Bear and his colleagues sought funding outside government for their novel ideas.

Addenda

• First federal funds for research dry up. Now nonprofit private support evaporates. Read here (12/21/08).
• Brain plasticity and memory share similar underlying molecular mechanisms. Recent studies have provided evidence that the brain-specific protein-phosphorylating enzyme protein kinase Mzeta (PKMzeta) is necessary to sustain LTP (Sacktor, 2008). Such enzymes commonly upregulate the activity of other enzymes. An increase in enzyme activity resulted in the doubling of postsynaptic glutamatergic ionotropic AMPA receptors, augmenting synaptic transmission in rodents. Inhibiting PKMzeta disrupts long-term memory (Serrano and others, 2008). Benedict Carey published an article entitled "Brain Researchers Open Doors to Editing Memory" in The New York Times on this research and its potential implications for future medical treatments today (04/05/08).
• According to Lauran Neergaard's report for Associated Press with the title "Experiment Takes Aim at Genetic Learning Disorder" published online in The New York Times today, the first clinical trials to treat FXS in adults with mGluR5 antagonists are underway at five medical centers (02/01/10).
• According to Gardiner Harris' report with the title "Promise Seen in Drug for Retardation Syndrome" for the New York Times dated Apr. 29, 2010, Novartis completed its first double blind study using its mGluR5 drug on adults with FXS with encouraging results. Details of the study were not disclosed (05/01/10).
• In her report with the title "Special Report: new drugs, fresh hope for autism patients" published online on Reuters today, Julie Steenhuysen informs us how the search for new drugs to treat FXS and ASD has been shaping up. The article's focus is on the use of derivatives of the established psychoactive compound baclofen. Seaside Therapeutics Inc., co-founded by Mark Bear, is testing arbaclofen (STX209) in clinical trials. The compound acts as an agonist of the inhibitory neurotransmitter gamma-aminobutyric acid, or GABA for short. Baclofen binds to G-protein-coupled metabotropic GABA_B-receptors and has traditionally been used to relieve skeletal muscle spasms. In contrast to the compounds acting on mGluR5-receptors discussed in the post, this drug modulates the effects of glutamate indirectly (Fejgin and others, 2009). Considering that more than 100 genes have been identified to play a role in autism, Dr. Edwin Cook's claim in Julie Steenhuysen's report that “many of the genes related to autism are right in the same pathway that has been implicated and worked out in Fragile X” does not come as a surprise (05/31/2012).
• Two studies of note have been published online in Science Translational Medicine yesterday. Henderson and others (2012) showed in a fragile X mouse model, that The GABA_B-receptor agonist arbaclofen alleviated known biochemical (basal protein synthesis), molecular (AMPA-receptor internalization), and cellular (dendritic spine density) manifestations of the disorder. In addition, Barry-Kravis and others (2012) report first encouraging results for arbaclofen in phase II clinical trials. The drug seems to improve social function (09/20/2012).

References

• Bear MF, Singer W (1986) Modulation of visual cortical plasticity by acetylcholine and noradrenaline. Nature 320: 172-176.
• Berry-Kravis EM, Hessl D, Rathmell B, Zarevics P, Cherubini M, Walton-Bowen K, Mu Y, Nguyen DV, Gonzalez-Heydrich J, Wang PP, Carpenter RL, Bear MF, Hagerman RF (2012) Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial. Sci. Transl. Med. 4, 152ra127.
• Fejgin K, Erik Pålsson E, Wass C, Finnerty N, Lowry J, Klame D (2009) Prefrontal GABA_B Receptor Activation Attenuates Phencyclidine-Induced Impairments of Prepulse Inhibition: Involvement of Nitric Oxide. Neuropsychopharmacol 34: 1673–1684.
• Henderson C, Wijetunge L, Kinoshita MN, Shumway M, Hammond RS, Postma FR, Brynczka C, Rush R, Thomas A, Paylor R, Warren ST, Vanderklish PW, Kind PC, Carpenter RL, Bear MF, Healy AM (2012) Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABA_B Receptors with Arbaclofen. Sci. Transl. Med. 4, 152ra128.
• Hubel DH, Wiesel TN (1998) Early Exploration of the Visual Cortex. Neuron 20: 401-412.
• Kleinschmidt A, Bear MF, Singer W (1987) Blockade of "NMDA" receptors disrupts experience-dependent plasticity of kitten striate cortex. Science 238: 355-358.
• Sacktor TC (2008) PKMzeta, LTP maintenance, and the dynamic molecular biology of memory storage. Prog Brain Res 169: 27-40.
• Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J, Alberini C, Kelley AE, Maren S, Rudy JW, Yin JC, Sacktor TC, Fenton AA (2008) PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories. PLoS Biol 6:2698-2706.
  

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Limits of Brain & Mind

While I was pedaling across a beautiful college campus the other day, the above inscription caught my eye. It adorns a magnificently restored building. The statement gave me pause. I am a anatomist. The human brain weighs roughly 1,350 g and fits snug into a half-gallon pale. I looked down into my bicycle helmet. The brain does not take much room. Yet, this clump of nondescript soft tissue allows us to produce statements that bold.

The interactions between the nerve cells in the brain define who we are. Networks of nerve cells control our behavior and permit us to muse about the world around us, ponder the limits of the sky and make dreams come true. We are even able to comprehend happenings in places too distant for us to travel. We can imagine the universe. Our mind is indeed wider than the sky.

Alas, the brain is vulnerable, the mind is fragile. Injury to the brain alters the mind. Both are inseparably complementary. Rhymes formed up in my mind. I put them down in a poem with magic ink. Take six minutes and watch the words unfold in the viewer below.

Addendum

• "The brain is wider than the sky..." is the opening to a poem by Emily Dickinson who lived in the 19^th century. She was no neuro-anatomist. Her poem is more beautiful than mine.

Cortical Development & Schizophrenia

In its Health Guide section of June 13, 2008, The New York Times published a comprehensive article entitled "Schizophrenia and the Brain" (the article has been found irretrievable on Jan. 29, 2011, but the animations can be found in the NIMH Science Update of Oct. 30, 2008, with the title "Brain's Wiring Stunted, Lopsided in Childhood Onset Schizophrenia"). The article includes a series of fascinating time lapse movies showing the maturation of cerebral cortex from early childhood (4 years of age) to young adulthood (21 years of age). The normal developmental profile was compared to that of people with early-childhood schizophrenia, the symptoms of which can manifest themselves as early as 8 years of age. A commentator explains the changes in the movies and an accompanying interview with P.M. Thompson, a principal investigator of this research, provides further perspective on the findings. The intriguing dynamics of cortical maturation shown in the time-lapse movies give pause to the close observer and evoke the desire for more information.

The human cerebrum consists of gray and white matter in roughly equal proportions. The gray matter comprises deep structures as well as the cerebral cortex containing the nerve cells and nerve cell processes that connect these cells locally. The cerebral white matter underlying the cortex is composed of the nerve cell processes known as axons that connect the cortical cells with distant regions in the same hemisphere, the other hemisphere, the deep gray matter structures and the spinal cord. It also contains the axons of ascending projections that terminate in the cerebral cortex. The axons are wrapped in sheeths of a fatty substance known as myelin. The myelination gives the white matter the color of cream.

Dr. Thompson and his colleagues measured the density of cortical gray matter repeatedly in the same people with nuclear resonance imaging in two-year intervals. The changes across the samples are projected in false colors and time lapse on virtual reconstructions of cerebral cortex. The studies providing the data for normal development have been described in detail by Gogtay and others (2004) and for early-onset schizophrenia by Gogtay (2008) and Thompson and others (2001). Some of the cited studies can be accessed for free, others need a subscription.
Dr. Thompson and his colleagues attribute the diminutions in gray matter density to enhanced myelination in the white matter and/or the loss of nerve cells, nerve cell processes known as neuropil and nerve cell contacts known as synapses in the gray matter. Myelination of axons accelerates nerve cell signal conduction at increased efficiency and is believed to continue into advanced age. The loss of synapses in the cerebral cortex may result from the pruning of neural networks in which used nerve cell connections are spared whereas idle connections are eliminated.

Based on his observations on animal behavior in the 1940s, the psychologist Donald O. Hebb was the first to suggest that the strengthening of synapses that are activated together may provide a neural mechanism for learning and memory. In the 1960s and 1970s, the Nobel Prize-laureates T. Wiesel, D. Hubel and their colleagues observed that the arbors of the endings of inputs to visual cortex from the eyes overlap at first, but separate into distinct, eye-specific domains during brain maturation (LeVail and others, 1980). As an important affirmation of the validity of Hebb's hypothesis, the development of the ocular dominance domains was plastic and depended on active input. When input from one eye was deprived, most endings of the idled input were pruned, whereas the endings of the functional, active input remained extended, claiming the cortical territory of the deprived eye. During a critical period the effect could be reversed when the inputs from the intact eye were deprived and the hitherto deprived inputs were reactivated. The experiments demonstrated elegantly that the development of connections between nerve cells can be highly dynamic and particularly sensitive to sensory stimulation during a critical period. 

In the 1980s, Hebb's hypothesis was validated on the cellular level with the discovery that repeated stimulation of the input of particular types of cortical nerve cells strengthened their response to stimulation. The effect is known as long-term potentiation or LTP for short. Subsequently, researchers identified the molecular mechanism for LTP. A particular type of receptor for the excitatory neurotransmitter glutamate plays a key role. Glutamatergic synapses are the most abundant in cerebral cortex. The receptor involved in LTP is known as N-methyl-D-aspartic acid receptor or NMDA-receptor for short. The receptor channels positively charged ions through the nerve cell membrane, increasing the the postsynaptic excitatory potential or EPSP for short. This voltage initiates electric spiking known as action potentials in the nerve cell's axon. The action potentials travel along the axon to the nerve cell endings and trigger the release of neurotransmitter into the cleft of the next synapse. NMDA-receptors can enhance synaptic transmission and thereby strengthen synapses because the opening of the ion channels is voltage dependent and multiple receptor activation facilitates the opening of disproportionately more channels. It is widely accepted today that via this mechanism Hebb's rule applies to the experience-dependent strengthening of glutamatergic synapses, and synaptic stabilization and loss are understood as basic mechanisms for the refinement of cortical nerve cell circuitry. 

In support of this concept, nerve cell connections between and within the cortical hemispheres have been shown to develop in steps of exuberance and elimination (for review see Innocenti, 1995). In harmony, P.R. Huttenlocher was the first to report a waxing and waning of nerve cell contact density in the maturing human cerebral cortex (see Huttenlocher and others, 1982-83). The exact time course appeared to differ among cortical areas. In accord, local peaks of energy metabolism were observed (Chugani and others, 1987). Eventually, comprehensive synaptic counts in the cortex of non-human primates affirmed the initial increase and the subsequent decrease in the number of synapses as fundamental steps in the maturation of cerebral cortex (Rakic and others, 1994).

In the time-lapse movies shown in The New York Times, Dr. Thompson and his colleagues use measurements of gray matter density to track the maturation of cerebral cortex. Gray matter density may indeed be closely associated with synaptic density. W.T. Greenough and colleagues showed that exposure to an enriched environment and the ensuing enhanced sensory stimulation increases myelination, cortical synaptic density and, notably, cortical thickness in rats (for review see Markham and Greenough, 2004).  In separate studies, Thompson and colleagues could establish that cortical gray matter density tightly correlates with cortical thickness (Sowell and others, 2004). The thickness varies regionally between 1.5 and 5.5 mm and diminished by as much as 0.3 mm in a year during development. In accord, the time-lapse movies on normal development show that the gray matter density in cerebral cortex diminishes on both hemispheres with advancing age. The diminution progresses in waves originating in the parietal lobes and sweeping toward the frontal lobes.

Exuberance of synapses in human cortex commonly peaks before the age of 4 years and the range of the time-lapse movies may not cover the synaptic build up. However, taking the findings reviewed above into consideration, it is reasonable to suggest that the reductions in gray matter density reflect synaptic elimination following exuberance and the dynamic in the movies may be accurately labeled as cortical maturation. By contrast, the changes in gray matter density visible in the time-lapse movie shown for childhood-onset schizophrenia are more complex. The color scale of maturation seems inverse. Despite the bright colors, the changes seem subtle. Thompson and others (2001) report that they observed more rapid and, in some areas, greater than normal decreases in gray matter density on both cortical hemispheres, suggesting a loss of synapses in addition to the normal pruning of underutilized connections.

The most striking diminutions of gray matter density were found in the parietal lobes. Large swaths of parietal cortex receive multi-modal sensory input. The information from multiple senses is integrated here. In humans, parietal areas process language. In my studies on cortical responses to Braille reading, distinct foci of activation were found in posterior parietal cortex near the borders of regions that predominantly receive visual, auditory or somatic sensory input (Melzer and others, 2001). Information that establishes our  identity may be processed in parietal cortex. In order to be able to interpret the gray matter density decrease in early-childhood schizophrenia more rigorously, it is essential to disambiguate the causes for the diminution and perhaps establish a relationship with synapse formation.

In my own research on developmental plasticity in mice, I observed considerable thinning of somatic sensory cortex in addition to cytoarchitectonic alterations after the deprivation of tactile input by neonatal whisker follicle removal (Melzer and others, 1993). The cortical layer that shrank the most normally receives the densest tactile input and synapses are lost when the input is disrupted. The cortex was not fully developed at the time of follicle removal. It takes the entire first week after birth for somatic sensory cortex to mature to a degree that the structural alterations visibly manifest themselves. Mouse somatic sensory cortex is considered fully mature three weeks after birth. That is, the effects of the deprivation of input take about the third of time for postnatal maturation to become obvious. In analogy, the cause for the gray matter loss observed in schizophrenia most likely affects cortical development well in advance of the manifestation of the loss.

In the search for the mechanisms underlying the gray matter loss, the time-lapse movies on the development of cortical gray matter density provide invaluable information. They allow us to begin the search in the cortical areas with the greatest loss. The movies represent group results. In order to select the best suited areas, it would be helpful to examine whether some cases in the sample contribute substantially more to the mapped averages of gray matter density loss than the rest of the sample and whether those cases share common factors in their medical histories.

References

• Chugani HT, Phelps ME, Mazziotta JC.
  
  
  Positron emission tomography study of human brain functional development.
  Ann Neurol. 1987 Oct;22(4):487-97.
• Gogtay N.
  
  
  Cortical brain development in schizophrenia: insights from neuroimaging studies in childhood-onset schizophrenia.
  Schizophr Bull. 2008 Jan;34(1):30-6.
  
• Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF 3rd, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM.
  
  
  Dynamic mapping of human cortical development during childhood through early adulthood.
  Proc Natl Acad Sci U S A. 2004 May 25;101(21):8174-9.
  
• Huttenlocher PR, De Courten C, Garey LJ, van der Loos H.
  
  
  Synaptic development in human cerebral cortex.
  Int J Neurol. 1982-1983;16-17:144-54.
  
• Innocenti GM.
  
  
  Exuberant development of connections, and its possible permissive role in cortical evolution.
  Trends Neurosci. 1995 Sep;18(9):397-402.
  
• LeVay S, Wiesel TN, Hubel DH.
  
  
  The development of ocular dominance columns in normal and visually deprived monkeys.
  J Comp Neurol. 1980 May 1;191(1):1-51.
  
• Markham JA, Greenough WT.
  
  
  Experience-driven brain plasticity: beyond the synapse.
  Neuron Glia Biol. 2004 Nov;1(4):351-363.
• Melzer P, Crane AM, Smith CB.
  
  
  Mouse barrel cortex functionally compensates for deprivation produced by neonatal lesion of whisker follicles.
  Eur J Neurosci. 1993 Dec 1;5(12):1638-52.
• Melzer P, Morgan VL, Pickens DR, Price RR, Wall RS, Ebner FF.
  
  
  Cortical activation during Braille reading is influenced by early visual experience in subjects with severe visual disability: a correlational fMRI study.
  Hum Brain Mapp. 2001 Nov;14(3):186-95.
• Rakic P, Bourgeois JP, Goldman-Rakic PS.
  
  
  Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness.
  Prog Brain Res. 1994;102:227-43.
  
• Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW.
  
  
  Longitudinal mapping of cortical thickness and brain growth in normal children.
  J Neurosci. 2004 Sep 22;24(38):8223-31.
• Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J, Nicolson R, Toga AW, Rapoport JL.
  
  
  Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia.
  Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11650-5.

Autism & Genes, Revisited

In a post earlier this year, I summarized the findings of a comprehensive study published in the magazine Science in which the authors screened for faulty genes in people with schizophrenia. Numerous genes with small defects were identified. Some are known to play a role in the growth and stabilization of connections between nerve cells during brain development. The genes were damaged around birth. Schizophrenia's symptoms are narrowly defined compared with autism. Autism is a spectrum disorder with a wide range of behaviors. That is why, the illness is known as Autism Spectrum Disorder, or ASD for short. I suggested that the genes involved in autism may even be more numerous than those implicated in schizophrenia and that the underlying molecular mechanisms may be more diverse.

In a research study published in this week's issue of Science (Vol. 321:218-223), Morrow and others screened for inherited faulty genes in 104 families comprising 115 males and 24 females with ASD. The families were recruited from an ethnic group that allows cousin-to-cousin marriages. Family trees could be reconstructed for 393 members. Maggie Fox reported on the study in an article published on Reuters on July 10, 2008. The researchers concentrated their effort on damaged homozygous autosomal recessive genes. That is, these genes were unrelated to sex and their defects came to bear only when they were inherited in identical pairs. The identified genes differed considerably, involving 1-2 specific chromosomal loci per family. Notably, several families showed large genetic deletions. In one autistic boy suffering from seizures, the largest deletion was situated on chromosome 3q and comprised gene c3orf58 and the beginning of gene NHE9. Smaller deletions were found on chromosome 4q near genes PCDH10 and on chromosome 2q near genes CNTN3, RNF8 and SCN7A. The authors could provide evidence with studies in animal tissue cultures that this type of damage affects the expression of genes that are commonly activated by the electrical activity of nerve cells and are instrumental in the development of nerve cell networks. The products of these genes play crucial roles in the establishment and maintenance of the contacts that nerve cells use to transmit information, i.e. the synapses.

The number of synapses in our cerebral cortex continues to increase after birth and reaches a peak at about 3 years of age. Then, their number gradually declines. Synapses that are used to transmit information between nerve cells are known to stabilize. Synapses that remain underutilized are pruned. The brain is particularly plastic and sensitive to environmental stimuli during this critical period of synaptic exuberance and elimination. Experience-dependent nerve cell activity determines which synapses stay and which go. The behavioral symptoms of autism manifest themselves at that time and experts in special education strive to develop methods for their early detection and intervention.

Fifty years ago, Nicholas Hobbs and Susan Gray pioneered the early detection of behavioral abnormalities with non-interfering observational methods at Peabody College. The assessors examined the social interactions of the children and their care givers unnoticed through one-way mirrors. This type of research continues at the Susan Gray School to the day. My son was a student there. The Director at the time was convinced that an environment rich in sensory experience benefits the mental development of any child and is of special importance to children with learning differences. The curriculum was structured accordingly. In harmony with this concept, the findings of the genetic study discussed above suggest that exposure to enriched environments may be instrumental in the effort to compensate for the deficits caused by inherited genetic deletions in children with ASD.

Addenda

• On Mar. 16, 2009, Donald G. McNeil Jr. reports in The New York Times on an unusually high occurrence of ASD among Somali children in Minnesota. Somali culture permits marriages among cousins. Taking the findings of the study discussed above into consideration, the most likely cause for this cluster is a genetic predisposition (03/17/09).
• Today, National Public Radio's Morning Edition broadcast a segment about the utility of a nation-wide register for families affected by ASD. You may wish to check out the interactive autism network site here (04/08/09). 
• Two recent studies using genome-wide analysis across large numbers of participants identified more variants of genes associated with ASD. The studies were published online back-to-back in the journal Nature on Apr. 29, 2009. In the first study, Wang and others (2009) compared the DNA of children diagnosed with ASD and their families (3101 participants from 780 families) with that of 1204 adults with ASD and that of 6491 unaffected volunteers. The authors found 6 single nucleotide polymorphisms in genes CDH9 and CDH10 to be most tightly associated with ASD. Genes of this type encode nerve cell adhesion molecules that guide the growth of connections between nerve cells during brain development. In the second study, Glessner and others (2009) compared variations in the copy number (CNVs) of DNA segments in DNA from 859 children with ASD and 1409 children without ASD. The authors affirmed the identified gene candidates using DNA from 1336 other cases with ASD and 1110 volunteers without ASD. The authors detected CNVs associated with ASD in cell adhesion-related genes NRXN1, CNTN4, NLGN1 and ASTN2. In addition, CNVs were detected in and near genes, whose products are involved in the metabolism of ubiquitin. It is important to note that the methods used in both studies permit us to identify genetic modifications only for the whole sample. They may not be present in each case of ASD. Furthermore, the candidate genes were implicated only by association. Causalities between the genetic modifications and autistic behavior remain to be established (05/15/09).
• A genome-wide association study enrolling more than one thousand families with children diagnosed with ASD uncovered a single nucleotide polymorphism (SNP) statistically significantly associated with ASD on chromosome 5p15 between genes SEMA5A, involved in the growth of nerve cell connections, and TAS2R1, playing a role in gustation (Weiss and others, 2009). The expression of the former proved reduced in ASD (11/30/09).
• Researchers at the University of Washington recently published evidence in support of the contention that early behavioral intervention may ameliorate autism (Dawson and others, 2009). A novel play-at-home therapy called Early Start Denver Model, or ESDM for short, showed promising results after only 24 months. The 20 hour/week program is designed for toddlers diagnosed with autism as young as 18 months of age. Participants scored ten points higher in IQ tests than peers in conventional programs with enhanced scores in listening and understanding as well as motor and self-care skills (11/30/09).
  
• In a genome-wide analysis of rare genetic copy number variants (CNVs) in 996 people of European descent with ASD compared to 1,287 controls, Pinto and others (2010) identified genes SHANK2, SYNGAP1 and DLGAP2, in addition to previously implicated genes NRXN1, NLGN3, NLGN4X and SHANK3, as high-probability candidates playing a role in autism. The results of the study were published online yesterday in the journal Nature. The products of these genes are involved in the establishment and maintenance of nerve cell connections. Genes influencing the formation of excitatory nerve cell connections using the neurotransmitter glutamate are of particular interest because of their fundamental role in brain plasticity. Notably, SHANK2 regulates metabotropic glutamate receptors, and SYNGAP1 is engaged in AMPA receptor trafficking (06/10/10).
• Oller and others (2010) developed a method that allows us to record and analyze the utterances of children as young as ten months of age for speech modifications related to ASD. The LENA Foundation supports the method. Emma Ashburn summarizes the research in her post entitled "Screening speech may aid autism diagnosis: study" on Reuters yesterday. The method may help behavioral intervention experts in their assessment. Modified speech evident early during development suggests that nerve cell connections in Wernicke's area of the cerebral cortex may be the first to be affected in ASD (07/20/10).
• O'Roak and other (2012) sequenced the exomes, that is the DNA regions that code for the protein product of genes, of children with sporadic autism as well as of their parents and unaffected siblings. Sixhundredseventyseven exomes of 209 families were examined. Eighty percent of the discovered gene mutations were of paternal origin, increasing with age. Roughly 40 percent of the new protein-altering mutations were associated with a molecular signaling pathway regulating gene transcription through beta-catenin/chromatin remodeling. Recurrent mutations were found in genes CHD8 and NTNG1. The product of CHD8 is a protein involved in chromatin remodeling. This finding points at a specific molecular mechanism that may explain impaired transcription of the genetic code, representing the most disruptive genetic modification identified in this study according to the authors. NTNG1's product Netrin-G1 is a protein that serves as cue in nerve cell axon guidance and has been associated with schizophrenia. In addition, mutation screening identified genes GRIN2B, LAMC3 and SCN1A. GRIN2B encodes a subunit protein of N-methyl-D-aspartate (NMDA) receptors for the excitatory neurotransmitter glutamate. NMDA receptors are voltage-gated calcium channels playing an instrumental role in the plasticity of nerve cell connections, memory and learning and have been implicated in schizophrenia. LAMC3's product represents a laminin in the extracellular protein matrix of brain tissue that affects cell adhesion and may guide nerve cell connections. SCN1A codes for a subunit protein of voltage-gated nerve cell sodium channels the malfunction of which is instrumental in migraine and epilepsy. In a companion study, Neale and others (2012) using genetic models identified mutations of genes CHD8 and KATNAL2 as the greatest risk for autism. The latter encodes a protein involved in the organization of microtubule arrays in cells. As interesting as these candidates for a genetic basis of the disorder may seem, it remains difficult to conceive how proteins with such fundamental and ubiquitous influences on brain development that have also been associated with other developmental mental disorders like schizophrenia can cause a spectrum disorder with the diverse behavioral symptoms of autism (04/09/2012).

References

• Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A, Varley J (2009) Randomized, Controlled Trial of an Intervention for Toddlers With Autism: The Early Start Denver Model. Pediatrics doi:10.1542/peds.2009-0958.
• Glessner JT, 58 others (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459: 569-573.
• Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science 321:218-223.
• Oller DK, Niyogi P, Gray S, Richards JA, Gilkerson J, Xu D, Yapanel U, and Warren SF (2010) Automated vocal analysis of naturalistic recordings from children with autism, language delay, and typical development. Proc Natl Acad Sci doi: 10.1073/pnas.1003882107
• Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, Lin C-F, Stevens C, Wang L-S, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature doi:10.1038/nature11011.
• O'Roak, BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature doi:10.1038/nature10989.
• Pinto D, 176 others (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature: doi:10.1038/nature09146.
  
• Wang K, 55 others (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459:528-533.
• Weiss LA, Arking DE, Gene Discovery Project of Johns Hopkins & the Autism Consortium, Daly MJ, Chakravarti A (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802-808.

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