Keeping you up to date on recent developments in neurology

Nanotools for the neuroscience and brain activity mapping . . . The ambitious and controversial Brain Activity Map (BAM) initiative instituted by a small group of researchers last year, has been steadily gaining momentum. Recently, a proof-of-principle Zebrafish BAM was demonstrated with astounding clarity by a pair of researchers at the Howard Hughes Medical Institute (Chevy Chase, Maryland). Following on the heels of that work, an exhaustive 17-page compendium of current and soon-to-be brain mapping tools was published last week in ACS Nano by a rapidly snowballing list of disciples. The BAM roster has been a carefully manicured player list from the beginning, and the role it has as ship wheel to this diffuse effort should not be underestimated. With the ranks now swelling to 27, each contributor to the paper has, in word or in spirit, contributed notably to the 185 referenced technologies on the paper. What we have here is not a research release, this is a textbook for the new neuroscience, and the journal choice, though not publicly accessible, hints at the desire to draw even more nanoscale researchers into the effort. Media attention has channeled formative criticism to the effort in a way we have not seen before. Those sentiments on the cautionary take at least, might be summarized by likening the BAM scientists to cavemen having just discovered fire. Now sitting in the sand, they appear to be chartering a course to the internal combustion engine as they scribe on the ground with blunt bone instruments . The problem is that having just fleshed out how the brain's wiring, the connectome, might be extracted, the community elites just leapfrogged to the full activity map, or at least one for some of the lesser animals. Among the other wild exotica hinted at in the ACS Nano paper is the DNA barcode proposed by Anthony Zador, from the Cold Spring Harbor Lab. This device would use a genetically modified rabies virus to infiltrate the nervous system, and record every connection in the process, web-crawl style. While Zador is not an author on this or the previous BAM papers, his techniques would not only provide a way to deliver a connectome of a complex brain, they potentially could do it non-destructively. Furthermore, the barcode mechanism would perhaps be the ideal way to propagate the Kording-Church tickertape machinery from cell to cell, bundling topology and activity together. Many of the neurotools mentioned in the ACSNano paper are logical extensions of current technologies, just slightly smaller and a little higher in resolution. Recording cell activity with voltage-sensitive or calcium-imaging dyes, as was done in the Zebrafish map, may or may not be the process used ten years from now. Other ideas, like accessing neurons through fiber optic probes threaded through the vasculature to the capillaries, were re-invigorated, as were new sensors altogether like nanodiamond and nanogold devices.

Study looks at hypertension, genetic risk factor for AD . . . A study by Karen Rodrigue, PhD, of the University of Texas at Dallas, and colleagues suggests that patients with hypertension with at least one genetic risk factor for Alzheimer disease (an apolipoprotein E epsilon4 allele) showed more ß-amyloid (Aß) accumulation than patients with only one risk factor or no risk factors. The study, published in JAMA, included 118 cognitively normal adults ages 47 to 89 years. Participants were classified in the hypertension group (69 participants, average age 74 years) if they had a diagnosis of hypertension or if their blood pressure was higher than 140 mmm Hg systolic/90 mm Hg diastolic. The study participants underwent Aß positron emission tomography and participants were genotyped for apolipoprotein E. “Interestingly, these initial findings suggest that individuals with an APOE Ɛ4 allele may be able to attenuate their likelihood for amyloid accumulation through proper control of blood pressure. However, future studies with larger sample sizes that examine additional factors, such as duration of hypertension treatment, are needed to support these findings. The identification of hypertension as an additional risk factor for amyloid plaque deposition is encouraging as we may be able to prevent, or at least slow, pathological aging in some individuals through lifestyle modification or pharmacological intervention,“ the study concludes.

New test developed to gauge severity of concussions . . . Neurologists at Mayo Clinic in Arizona have taken a promising step toward identifying a test that helps support the diagnosis of concussion. Their research has shown that autonomic reflex testing, which measures involuntary changes in heart rate and blood pressure, consistently appear to demonstrate significant changes in those with concussion. They presented the findings at the American Academy of Neurology (Minneapolis) annual meeting in San Diego. Right now doctors rely primarily on self-reporting of symptoms to make a diagnosis of concussion. In addition, other than the absence of symptoms, there is no reliable test to determine when an athlete's brain has fully recovered from concussion. Doctors know from brain imaging research studies, that there is a lag between when the patient reports that their symptoms have resolved and the time when the brain has actually healed. Therefore, a rapid, reliable, cost-effective tool is needed to identify full brain recovery from concussion. “This has the potential to change the way we approach concussion patients,“ says David Dodick, MD, a neurologist and director of the Mayo Clinic Concussion Program. “One of the challenges of treating someone with a concussion is to reliably make a diagnosis: to know when the brain is injured and to know when the brain is actually recovered. Autonomic nervous system dysfunction has long been recognized as a possible complication of people with severe traumatic brain injury but has rarely been associated with people with concussions or milder forms of brain injury,“ adds co-author Brent Goodman, MD, a Mayo neurologist and autonomic expert. The autonomic nervous system acts as an involuntary control system for functions such as heart rate, blood pressure, digestion, respiratory rate and perspiration. In the study, Mayo Clinic doctors monitored 21 consecutive patients after concussion, and all experienced significant abnormalities in heart rate and blood pressure during autonomic testing. The physicians conclude that these abnormalities are tied to the concussion.

Anti-nausea drug destroys brain tumor cells . . . New research from the University of Adelaide in Australia has shown for the first time that the growth of brain tumors can be halted by a drug currently being used to help patients recover from the side effects of chemotherapy. The discovery has been made during a study looking at the relationship between brain tumors and a peptide associated with inflammation in the brain, called “substance P“. Substance P is commonly released throughout the body by the nervous system, and contributes to tissue swelling following injury. In the brain, levels of substance P greatly increase after traumatic brain injury and stroke. “Researchers have known for some time that levels of substance P are also greatly increased in different tumor types around the body,“ said Elizabeth Harford-Wright, PhD, a postdoctoral fellow in the University's Adelaide Centre for Neuroscience Research. “We wanted to know if these elevated levels of the peptide were also present in brain tumor cells, and if so, whether or not they were affecting tumor growth. Importantly, we wanted to see if we could stop tumor growth by blocking substance P.“ In laboratory studies, Harford-Wright found that levels of substance P were greatly increased in brain tumor tissue. Knowing that substance P binds to a receptor called NK1, Harford-Wright used an antagonist drug called Emend® to stop substance P binding to the receptor. Emend® is already used in cancer clinics to help patients with chemotherapy-induced nausea. The results were startling. “We were successful in blocking substance P from binding to the NK1 receptor, which resulted in a reduction in brain tumor growth – and it also caused cell death in the tumor cells,“ said Harford-Wright. “So preventing the actions of substance P from carrying out its role in brain tumors actually halted the growth of brain cancer.

Sleep study examines adolescent brain transition to mature thinking . . . A new study conducted by monitoring the brain waves of sleeping adolescents has found that remarkable changes occur in the brain as it prunes away neuronal connections and makes the major transition from childhood to adulthood. “We've provided the first long-term, longitudinal description of developmental changes that take place in the brains of youngsters as they sleep,“ said Irwin Feinberg, professor emeritus of psychiatry and behavioral sciences and director of the UC Davis Sleep Laboratory. “Our outcome confirms that the brain goes through a remarkable amount of reorganization during puberty that is necessary for complex thinking.“ The research, published in the American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, also confirms that electroencephalogram, or EEG, is a powerful tool for tracking brain changes during different phases of life, and that it could potentially be used to help diagnose age-related mental illnesses. It is the final component in a three-part series of studies carried out over 10 years and involving more than 3,500 all-night EEG recordings. The data provide an overall picture of the brain's electrical behavior during the first two decades of life. Feinberg explained that scientists have generally assumed that a vast number of synapses are needed early in life to recover from injury and adapt to changing environments. These multiple connections, however, impair the efficient problem solving and logical thinking required later in life. His study is the first to show how this shift can be detected by measuring the brain's electrical activity in the same children over the course of time. Two earlier studies by Feinberg and his colleagues showed that EEG fluctuations during the deepest (delta or slow wave) phase of sleep, when the brain is most recuperative, consistently declined for 9- to 18-year-olds. The most rapid decline occurred between the ages of 12 and 16-1/2. This led the team to conclude that the streamlining of brain activity – or “neuronal pruning“ – required for adult cognition occurs together with the timing of reproductive maturity. Questions remained, though, about electrical activity patterns in the brains of younger children. For the current study, Feinberg and his research team monitored 28 healthy, sleeping children between the ages of 6 and 10 for two nights every six months. The new findings show that synaptic density in the cerebral cortex reaches its peak at age 8 and then begins a slow decline. The recent findings also confirm that the period of greatest and most accelerated decline occurs between the ages of 12 and 16-1/2 years, at which point the drop markedly slows.

— Compiled by Robert Kimball, MDD