Progress Report 2009: Roundup
More Important Findings in 2008


by John Timmer

January, 2009

The preceding chapters presented in-depth examinations of six areas of brain research that saw important returns in 2008. However, this year’s promising advancements and discoveries ranged over many other areas of brain science as well. In particular, current research on obsessive-compulsive disorder, pain, autism, fragile X syndrome, sleep, deep brain stimulation, and neuroethics merit brief mention.

Understanding Fear Could Help Treat Obsessive-Compulsive Disorder

People suffering from obsessive-compulsive disorder (OCD) have traditionally had two choices: behavioral therapy for the condition or drugs for the symptoms. Now they may have a third option, in the form of a drug that improves the effectiveness of behavioral therapy.

Behaviors that resemble OCD were described as far back as the 1600s, and the first clinical description of the condition appeared in a French psychiatry text that was published in 1837. People who suffer from OCD frequently experience the recurrence of unwelcome thoughts and repetitive or ritualized behaviors; these generally appear late in childhood. Some experience anxiety or fear that lapses in these behaviors might cause something bad to happen.

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Sabine Wilhelm (right) pantomimes an exposurebased behavioral therapy session with an assistant who is pretending to be a patient with a fear of knives. Similar therapy sessions have shown to be effective in reducing the anxiety associated with OCD. (Sabine Wilhelm, Ph.D. / Massachusetts General Hospital)

OCD affects approximately 2.2 million American adults. Those with OCD also appear to be prone to other anxiety disorders and depression. Like patients with depression, people with OCD can be treated with selective serotonin reuptake inhibitors (SSRIs). Variations in the gene for the serotonin transporter have been shown to be associated with an increased risk of developing OCD.

Research in animals has found that they can learn to overcome fear through a process that involves neurons with receptors for the chemical N-methyl-D-aspartate (NMDA). These findings have suggested that enhanced NMDA signaling may hasten the process of learning to overcome fear and anxiety.

A team of researchers at several New England hospitals decided to test whether our knowledge of animal behavior could be used to improve treatments of human anxiety. The results of their work were published in March 2008 by the American Journal of Psychiatry.1 The researchers recruited patients with OCD and enrolled them in a program of biweekly behavioral therapy sessions. This counseling technique can help patients learn to reduce the anxiety associated with OCD, but its success rate has been low. Half of the patients in the study received a placebo, while the other half received a drug, cycloserine, that increases NMDA receptor activity. Although both populations showed improvement, those who received cycloserine had a larger reduction in OCD symptoms, a difference that persisted for at least a month following treatment. Better still, those receiving the drug saw an improvement in symptoms of depression that often accompany OCD.

This study joins earlier work that described benefits of a combination of cycloserine and therapy in the treatment of other anxiety disorders, including social anxiety and the fear of heights. The researchers call for larger trials of the procedure that will provide a clearer picture of how significant the benefits are. Pursuing these trials should be made easier by the fact that cycloserine was approved for human use more than twenty years ago, as a treatment for tuberculosis.

Zeroing In on Pain with Targeted Drugs

Treatment of pain presents many distinct challenges. Most drugs marketed for limiting the sensation of pain have a number of drawbacks, including addictive properties, reduced effectiveness over time, and side effects. Now the increased understanding of nervous system function is allowing scientists to design drugs targeted to specific types of pain.

Ion channels are the floodgates that regulate the flow of molecules in and out of the body’s cells. Types of ion channels belonging to the transient receptor potential (TRP) family are essential for the sensation of pain. Different members of this family specialize in responding to different types of stimuli, such as cold, heat, and physical strain. Existing chemicals that block pain, from the capsaicin found in chile peppers to the itch-relief drug lidocaine, all work by targeting either TRP proteins or sodium channels.

Migraines can cause debilitating pain, and some sufferers respond poorly to existing painkillers. During the past decade, research has linked migraines to increased blood flow in the brain, a process that is under the control of the nervous system. Nerves in the head produce a protein, calcitonin gene-related peptide (CGRP), that causes blood vessels to dilate, increasing blood flow. Accordingly, drugs that block CGRP function should alleviate migraine symptoms.

The first such drug may be getting close to market. At the 2008 meeting of the American Headache Society, clinicians presented the results of a Phase III clinical trial of the CGRP antagonist MK-0974. This type of drug blocks the binding of CGRP to receptors in order to inhibit blood vessel dilation.2 The drug treated migraine symptoms as effectively as existing therapies, but it produced significantly fewer side effects.

Researchers are also making progress in finding new methods of treating pain from injury and inflammation. They have identified mutations in a specific sodium channel, NaV1.7, that alter people's perception of pain. Loss of the NaV1.7 channel causes indifference to pain, indicating that it is a potential target for painkillers.

Researchers from Merck have determined that a protein in tarantula venom specifically binds NaV1.7 and blocks its function, and they have identified a part of the channel that is essential for this binding.3 Although the tarantula protein is not appropriate for use as a drug, its interaction with NaV1.7 will act as a model for designing targeted pain therapies.

Autism Genetics Reveals Many Causes

The social withdrawal displayed by autistic children was once thought to be the product of poor parenting skills. However, as the incidence of the disorder has risen alongside an increase in scientific research and public awareness, it has become increasingly clear that autism has an underlying biological basis. Evidence now suggests that even sporadic (nonhereditary) cases of autism have a genetic component, and that the diagnosis may encompass a number of distinct underlying disorders. Two studies highlight our new understanding of the origin of these autism spectrum disorders (ASDs).

Studies in twins indicate that genetics play a dominant role as a cause of autism. A 2007 study found that in sporadic cases of autism there is a high frequency of a genetic abnormality called copy number variations (CNVs). CNVs occur when a large segment of the chromosome is either missing or duplicated; they occur quite frequently in humans, often with no symptoms. A 2008 study in the New England Journal of Medicine, performed by the Autism Consortium, found that CNVs are associated with inherited forms of autism as well.4

PR09_CH07_ModelOfAutism_spotlight

Gene mutations can lead to a variety of cellular mishaps that compromise the brain’s ability to form relevant connections in response to experience, leading to autism. The top image shows how experience-based learning occurs in the brain, with an electrical signal traveling down the neuron’s axon, reaching the synapse, releasing chemical messengers known as neurotransmitters that cause special channels to open on the receiving neuron. A cascade of signals then travels to its nucleus, launching a program involving multiple genes that communicates back to the surface, enabling the neuron to strengthen, weaken, create, or destroy synapses or make a different kind of synapse. Some cellular mishaps are described in the bottom image.  (Graham Paterson / Children's Hospital Boston)

The team identified a specific area of human chromosome 16 (16p11.2) that was frequently altered in patients with ASDs. In some cases, the area and the genes it contains were simply absent, but other patients actually had extra copies of 16p11.2. The results suggest that the number of copies of the gene(s) in the area may play a greater role in these cases of autism than the mere presence or absence of that part of the chromosome.

Separately, an international team of researchers studied a panel of families that included autistic children that are the product of marriages between cousins, reasoning that these individuals were likely to carry two copies of an identical region of DNA.5 The study identified six new genes associated with autism and also identified additional areas of the human genome that are deleted in those with autism. One gene, NHE9, was identified in patients with both ASD and epilepsy; the authors found that NHE9 was also damaged in unrelated individuals with autism-like symptoms.

The identified genes perform a variety of functions, including enabling nerve cells to transmit signals and regulating the location and stability of proteins within the nervous system. The diverse gene functions, and the frequent co-occurrence of ASD with other nervous system disorders, led the authors to conclude that autistic symptoms are caused by a variety of underlying disorders. “The genetic architecture of autism resembles that of mental retardation and epilepsy,” they write, “with many syndromes, each individually rare.”

Fragile X Theory Points the Way toward Potential Therapies

Experiments using a mouse model of fragile X syndrome have provided support for a theory regarding the causes of this human genetic disease and point the way toward potential drug interventions.

Fragile X syndrome is one of the most common inherited forms of mental retardation and results in additional symptoms that include autism spectrum disorder, seizures, and several physical abnormalities. This disorder was first linked to the X chromosome in 1943. In 1969 researchers associated it with a change in the structure of the affected X chromosome. In 1991 scientists identified the molecular basis for this change as the product of a mutation in which a small, repetitive segment of DNA is amplified, resulting in many tandem copies of the repeated sequence. As the number of repeats increases, the production of the protein encoded by the fragile X gene, FMRP, decreases.

FMRP controls the production of many proteins in nerve cells, but evidence has suggested that a key target of FMRP is a receptor for the neurotransmitter glutamate called mGluR5; when FMRP is absent, as in fragile X patients, signaling through mGluR5 is overactive. In a paper published in the final weeks of 2007, researchers tested this directly by genetically reducing mGluR5 in mice.6

Mice with mutations that eliminate the FMRP gene displayed characteristics similar to some of those seen in fragile X patients. When those same mice were missing one of the two copies of the mGluR5 gene, however, the majority of the defects were suppressed. The researchers found that protein expression in nerve cells was restored to normal levels in these mice, and this corresponded with a return to a normal cell structure. Tests of behavior and memory also showed that the reduction of mGluR5 restored the mice to normal. Even changes in body size caused by the loss of FMRP were suppressed by the reduced presence of mGluR5.

Many drugs exist that reduce the activity of mGluR5 receptors, and other such “antagonists” are now under development, although none is approved for therapeutic use in treating fragile X syndrome in humans.

In 2008, Mark Bear, who led the research published in late 2007, and colleagues published a review of fragile X in which they supported the “increasingly strong case” for human clinical trials with mGluR5 antagonists.7 On the strength of this and other animal research, a few small human studies commenced in 2008, for fragile X syndrome and other disorders.8

Building a Unified Theory of Sleep

The function of sleep in humans remains a matter of debate, as does its very existence in other animals. Two reviews in 2008 addressed the sleep cycle across species, and a 2007 study proposed a model of human sleep controlled largely by basic metabolism needs.

On the molecular level, many of the proteins that control the circadian cycle of waking activity and sleep are conserved from flies to humans. However, a 2008 review by Jerome Siegel argued against the widely accepted platitude that “all animals sleep.” Siegel found the notion unverifiable using existing research.9 Only 50 of nearly 16,000 vertebrate species have been tested for the commonly held criteria for sleep.

Indeed, the activity we think of as sleeping appears to vary wildly from species to species. Another 2008 review by Siegel and Ravi Allada looked at the brain patterns of various animals sleeping.10 Sleep studies in terrestrial mammals (including humans) typically measure electrical activity in the brain with an electroencephalogram (EEG). Siegel and Allada's review found an absence of identifiable EEG sleep traits in a diverse set of animals, which suggests that these patterns may not represent an essential feature of sleep for all animals.

Some sleep activities may be unique to certain species. For those molecular aspects of sleep that do seem common from flies to worms to humans, studying insect genetic models may help uncover the basis of sleep in more complex organisms, such as humans.

Other recent research has focused on two potential functions for sleep. The first is its use in fostering the consolidation of learning and memories derived from the waking hours. The second emphasizes its role in allowing the brain to repair the damage caused by its unique metabolic requirements.11

Each of these proposals has experimental support. A role for metabolism is suggested by the fact that smaller animals, which tend to have much higher overall body metabolisms, sleep for significantly longer than larger ones; for example, mice typically sleep for more than half the day, while elephants sleep for as few as four hours daily. Research published in March 2007 by Van Savage and colleagues at the Santa Fe Institute suggests that cell volume and metabolic rate vary depending on the animal’s size, supporting the notion that sleep may be a response to the metabolic needs of the body’s cells.12

In favor of memory consolidation, electrode-based recordings of the brains of sleeping rats have revealed patterns of activity that recapitulate ones observed during their waking activity.

Side by side, these two proposals appear to be inconsistent. If large animals spend most of their day awake, then their complex brains should require more time to consolidate memories. Also, the ratio of brain to body size varies dramatically across species, which means that for different animals the brain may be responsible for different percentages of the overall body.

The theory published by Savage relates body mass and metabolism to both time spent asleep and the proportion of time spent in REM sleep, a normal stage of sleep that appears important to memory and other waking functions. The researchers’ model accurately predicts both of these aspects, using as input the weight and metabolic rates of ninety-six species of mammals that differ in body size by as much as a factor of a million.

The authors conclude that “sleep is a special state of the brain that is devoted primarily to the critical activities of repair and reorganization.” At the moment, their theory cannot distinguish between the relative importance of these activities, but they suggest that future biological studies based on their model might provide insight.

Deep Brain Stimulation Therapy Matures with New Targets

In deep brain stimulation (DBS) electrodes implanted in the brain deliver electrical pulses to patients suffering from movement disorders such as Parkinson's disease (PD). The technique has proved highly effective, so much so that the procedure is covered by Medicare. “Whether deep brain stimulation can dramatically help patients with Parkinson’s disease and other movement disorders is no longer questioned,” wrote Jerrold Vitek of the Cleveland Clinic in a recent review of the field.13 The frontiers of DBS have now moved on to other maladies, such as clinical depression and Tourette’s syndrome.

Vitek notes that the means by which DBS leads to long-term changes in brain activity are not well understood. Nevertheless, the ability to inhibit neural activity suggests that DBS may be an effective treatment for other disorders in which a specific region of the brain has been implicated as being aberrantly active.

Pilot studies are beginning to apply DBS to cases of depression in which other, more traditional forms of therapy have failed. In a 2008 study involving twenty severely depressed patients, 35 percent had a reduction of symptoms a month after DBS was started. By six months after surgery, more than half of the patients had responded to treatment, with seven showing a complete remission of their depression.14

DBS has also been used as an experimental therapy for a small number of patients with Tourette’s syndrome, a neuropsychiatric disorder characterized by motor and vocal tics. The pathology of Tourette’s syndrome—which in severe cases can cause debilitating obsessive-compulsive and self-injurious behaviors—is still debated, but since 1999 DBS has been applied successfully in multiple brain areas in patients who did not respond to other forms of therapy.

A 2008 study of eighteen patients with severe Tourette’s found that several months after the surgery, every patient’s symptoms had decreased, with no adverse side effects. This study targeted a specific region in the brain’s thalamus, known as the centromedian-parafascicular and ventralis oralis complex, and researchers recommended the procedure as “a useful and safe treatment for severe” Tourette’s.15 However, not all patients responded equally well, and future research will need to investigate the factors that might make a person more or less responsive to the therapy.

Neuroethics: Exploring Expectations of Future Medical Technology

Scientists concerned with neuroethics seek, among other things, to gauge the moral and legal ramifications of current neuroscience research in terms of possible future developments and applications, especially regarding fears and uncertainties of the public. Recently, the use of functional magnetic resonance imaging (fMRI) as lie detector, political compass, emotion monitor, and all-around mind reader has captured much media attention, incensing some scientists who worry about misapplication of the technology but signifying to others promising new areas of research. In particular, research in 2008 raised questions about whether fMRI might predict a person’s decisive action before the conscious decision to act is even made.

Functional MRI uses MRI equipment to non-invasively monitor changes in blood flow within the brain, which provides a measure of neural activity. Neural researchers have used it to identify brain areas involved in normal mental processes, and they have used differences in fMRI signals to identify those with mental disorders.

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Activity in certain brain regions (shown as dark gray spots) can predict the outcome of a participant’s decision up to seven seconds before it is consciously made. At top, a three-dimensional structure depicts a computer-analyzed pattern of activity from one informative brain region. The graph features information from computer-based pattern classifiers that have been trained to recognize predictive activity.  (John-Dylan Haynes, Ph.D.)

In 2008, John-Dylan Haynes and colleagues at the Max Planck Institute for Human Cognitive and Brain Sciences measured the brain activity of subjects as they were asked to press a button with their left or right hand. The subjects were free to choose a hand at any time, but were instructed to remember the exact moment when they were conscious of making the decision. By identifying the relevant traces of brain activity and using a computer to recognize those signals in subsequent subjects, the researchers were able to accurately predict which hand a subject would use to press the button seven seconds before the subject recorded making the decision. In some cases, brain activity (particularly in the frontal and parietal lobes) predicted the move a full ten seconds ahead of the conscious thought.16

Common sense suggests that people choose between possible actions by their own conscious volition, but Haynes’s study appears to suggest otherwise. The authors write that the delay between the telltale neural activity and the reported choice “presumably reflects the operation of a network of high-level control areas that begin to prepare an upcoming decision long before it enters awareness.”

The length of the delay suggests that the results cannot be explained away as a miscalculation on the part of the subject as to when he made the decision, a criticism levied at earlier work in this field. The authors refrain from discussing the moral ramifications of their findings; neither do they mention the potential for clinical or commercial applications.

Notes

1. Wilhelm S, Buhlmann U, Tolin DF, Meunier SA, Pearlson GD, Reese HE, Cannistraro P, Jenike MA, and Rauch SL. Augmentation of behavioral therapy with d-cycloserine for obsessive-compulsive disorder. American Journal of Psychiatry 2008 165(3):335–341.

2. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Koppen H, and Winner P. Acute antimigraine efficacy and tolerability of the novel oral CGRP receptor antagonist MK-0974: A phase III clinical trial versus placebo and zolmitriptan. Presented at American Headache Society Annual Scientific Meeting, June 2008, https://www.americanheadachesociety.org/assets/50th_abstracts.pdf (accessed October 22, 2008).

3. Schmalhofer W, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, and Priest BT. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Molecular Pharmacology Fast Forward 2008 74(5):1476–1484.

4. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, and Daly MJ, for the Autism Consortium. Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 2008 358(7):667–675.

5. 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, and Walsh CA. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008 321(5886):218–223.

6. Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, and Bear MF. Correction of fragile X syndrome in mice. Neuron 2007 56(6):955–962.

7. Bear MF, Dölen G, Osterweil E, and Nagarajan N. Fragile X: Translation in action. Neuropsychopharmacology 2008 33(1):84–87.

8. Hamilton J. Drugs hint at potential reversal of autism. National Public Radio Morning Edition, September 23, 2008.

9. Siegel JM. Do all animals sleep? Trends in Neurosciences 2008 31(4):208–213.

10. Allada R and Siegel JM. Unearthing the phylogenetic roots of sleep. Current Biology 2008 18(15):R670–R679.

11. Savage VM and Best GB. A quantitative, theoretical framework for understanding mammalian sleep. Proceedings of the National Academy of Sciences USA 2007 104(3):1051–1056.

12. Savage VM, Allen AP, Brown JH, Gillooly JF, Herman AB, Woodruff WH, and West GB. Scaling of number, size, and metabolic rate of cells with body size in mammals. Proceedings of the National Academy of Sciences USA 2007 104(11):4718–4723.

13. Vitek J. Deep brain stimulation: How does it work? Cleveland Clinic Journal of Medicine 2008 75:S59–S65.

14. Lozanoa AM, Maybergb HS, Giacobbeb P, Hamania C, Craddock RC, and Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatmentresistant depression. Biological Psychiatry 2008 64(6):461–467.

15. Servello D, Porta M, Sassi M, Brambilla A, and Robertson MM. Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment: The surgery and stimulation. Journal of Neurology, Neurosurgery, and Psychiatry 2008 79:136–142.

16. Soon CS, Brass M, Heinze H, and Haynes J. Unconscious determinants of free decisions in the human brain. Nature Neuroscience 2008 11:543–545.