Neuroscience

The production of new neurons in the adult normal cortex in response to the antidepressant, fluoxetine, is reported in a study published online this week in Neuropsychopharmacology.

The research team, which is based at the Institute for Comprehensive Medical Science, Fujita Health University, Aichi, has previously demonstrated that neural progenitor cells exist at the surface of the adult cortex, and, moreover, that ischemia enhances the generation of new inhibitory neurons from these neural progenitor cells. These cells were accordingly named “Layer 1 Inhibitory Neuron Progenitor cells” (L1-INP). However, until now it was not known whether L1-INP-related neurogenesis could be induced in the normal adult cortex.

Tsuyoshi Miyakawa, Koji Ohira, and their colleagues employed fluoxetine, a selective serotonin reuptake inhibitor, and one of the most widely used antidepressants, to stimulate the production of new neurons from L1-INP cells. A large percentage of these newly generated neurons were inhibitory GABAergic interneurons, and their generation coincided with a reduction in apoptotic cell death following ischemia. This finding highlights the potential neuroprotective response induced by this antidepressant drug. It also lends further support to the postulation that induction of adult neurogenesis in cortex is a relevant prevention/treatment option for neurodegenerative diseases and psychiatric disorders.

When initial computed tomography (CT) scans show bleeding within the brain after mild head injury, decisions about repeated CT scans should be based on the patient’s neurological condition, according to a report in the January issue of Neurosurgery, official journal of the Congress of Neurological Surgeons. The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

The study questions the need for routinely obtaining repeated CT scans in patients with mild head trauma. “The available evidence indicates that it is unnecessary to schedule a repeat CT scan after mild head injury when patients are unchanged or improving neurologically,” according to the study by Dr. Saleh Almenawer and colleagues of McMaster University, Hamilton, Ont., Canada.

Are Repeated Scans Necessary after Mild Head Trauma?

In a review of their hospital’s trauma database, the researchers identified 445 adult patients with mild head injury who had evidence of intracranial hemorrhage (ICH)—bleeding within the brain—on an initial CT scan. In many trauma centers, it’s standard practice to schedule a second CT scan within 24 hours after ICH is detected, to make sure that the bleeding has not progressed.

To evaluate the need for routine repeated scans, Dr. Almenawer and colleagues looked at how many patients needed surgery or other additional treatments, and whether the change in treatment was triggered by changes in the patients’ neurological condition or based on the routine CT scan alone. (For patients whose neurological condition worsened, CT was performed immediately.)

Overall, 5.6 percent of the patients required a change in treatment after the second CT scan. Most of these patients underwent surgery (craniectomy) to relieve pressure on the brain. Nearly all patients who underwent further treatment developed neurological changes leading to immediate CT scanning.

Just two patients had a change in treatment based solely on routine repeated CT scans. Both of these patients received a drug (mannitol) to reduce intracranial pressure, rather than surgery

Decisions on CT Scans Can Be Based on Neurological Status

Dr. Almenawer and colleagues extended the same method to patients reported in 15 previous studies of CT scanning after mild head injury. Including the 445 new patients, the analysis included a total of 2,693 patients. Overall, 2.7 percent of patients had a change in management based on neurological changes. In contrast, just 0.6 percent had treatment changes based on CT scans only.

Bleeding within the brain is a potentially life-threatening condition, prompting routine repeated CT scans after even mild head injury. The researchers write, “Although CT scanners are very useful tools, in an era of diminishing resources and a need to justify medical costs, this practice needs to be evaluated.” Each scan also exposes the patient to radiation, contributing to increased cancer risk.

The new study questions the need for routine repeated CT scans, as long as the patient’s neurological condition is improving or stable. “In the absence of supporting data, we question the value of routine follow-up imaging given the associated accumulative increase in cost and risks,” Dr. Almenawer and coauthors conclude.

Neurological examination is the “simple yet important” predictive factor leading to changes in treatment and guiding the need for repeat CT scanning after mild head injury, the researchers add. They emphasize that their findings don’t necessarily apply to patients with more severe head injury.

Older adults with a history of traumatic brain injury (TBI) with loss of consciousness (LOC) have a 2.5- to almost four-fold higher risk of subsequent re-injury later in life, according to research published online Nov. 21 in the Journal of Neurology, Neurosurgery & Psychiatry.

Kristen Dams-O’Connor, PhD, of the Mount Sinai School of Medicine in New York City, and colleagues conducted a longitudinal, population-based, prospective cohort study enrolling 4,225 people aged >65 years who were dementia-free. The authors sought to determine whether there is a relationship between self-reported TBI with LOC and re-injury, dementia, and mortality later in life.

The researchers found that people who experienced a TBI with LOC before age 25 were 2.54-fold more likely to experience TBI with LOC during follow-up, while those injured after age 55 were 3.79-fold more likely. However, no association between TBI with LOC and dementia or Alzheimer’s disease was noted. Although baseline history of TBI with LOC was not associated with mortality, people who experienced a recent TBI had a 2.12-fold higher risk of mortality.

"This suggests that the risk for negative long-term outcomes (eg, dementia and premature mortality) may decrease with time since injury, such that individuals who survive to older adulthood and do not incur subsequent TBI may be at no greater risk for dementia or mortality than individuals who never sustained a TBI," the authors write. "Overall, the findings reported here underscore the need for effective strategies to prevent injury and re-injury in older adulthood."

A new ray of hope has broken through the clouded outcomes associated with Alzheimer’s disease. A new research report published in January 2013 print issue of The FASEB Journal by scientists from the National Institutes of Health shows that when a molecule called TFP5 is injected into mice with disease that is the equivalent of human Alzheimer’s, symptoms are reversed and memory is restored—without obvious toxic side effects.

"We hope that clinical trial studies in AD patients should yield an extended and a better quality of life as observed in mice upon TFP5 treatment," said Harish C. Pant, Ph.D., a senior researcher involved in the work from the Laboratory of Neurochemistry at the National Institute of Neurological Disorders at Stroke at the National Institutes of Health in Bethesda, MD. "Therefore, we suggest that TFP5 should be an effective therapeutic compound."

To make this discovery, Pant and colleagues used mice with a disease considered the equivalent of Alzheimer’s. One set of these mice were injected with the small molecule TFP5, while the other was injected with saline as placebo. The mice, after a series of intraperitoneal injections of TFP5, displayed a substantial reduction in the various disease symptoms along with restoration of memory loss. In addition, the mice receiving TFP5 injections experienced no weight loss, neurological stress (anxiety) or signs of toxicity. The disease in the placebo mice, however, progressed normally as expected. TFP5 was derived from the regulator of a key brain enzyme, called Cdk5. The over activation of Cdk5 is implicated in the formation of plaques and tangles, the major hallmark of Alzheimer’s disease.

"The next step is to find out if this molecule can have the same effects in people, and if not, to find out which molecule will," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. “Now that we know that we can target the basic molecular defects in Alzheimer’s disease, we can hope for treatments far better – and more specific – than anything we have today.”

Research led by Queen Mary, University of London, has opened up the possibility that drug therapies may one day be able to restore the integrity of the blood-brain barrier, potentially slowing or even reversing the progression of diseases like multiple sclerosis (MS). The study, funded by the Wellcome Trust, is published in Proceedings of the National Academy of Sciences.

The blood-brain barrier (BBB) is a layer of cells, including endothelial cells, which line the blood vessels in the brain and spinal cord. These cells act as a barrier, stopping certain molecules, including immune cells and viruses, passing from the blood stream into the central nervous system (brain and spinal cord).

In a number of neurodegenerative brain diseases, including MS, the BBB is compromised, allowing inappropriate cells to pass into the brain with devastating consequences.

In this study the researchers identified a specific protein – known as Annexin A1 (ANXA1) – as being integral in maintaining the BBB in the brain. The authors initially found that mice bred to lack this protein showed a decrease in integrity of the BBB compared to controls.

Taking this finding, they then investigated the potential role of ANXA1 in conditions which involve progressive breakdown of the BBB, including MS and Parkinson’s disease, by examining post-mortem human brain tissue samples. ANXA1 was present in the cells of samples from individuals who did not have a neurological disease and also in samples from patients who had died with Parkinson’s disease. However, it was not detectable in the endothelial cells in samples from patients who had died with MS.

Crucially, the researchers found that treating in vitro brain endothelial cells with human recombinant ANXA1 restored the key cellular features needed to reinstate the integrity of the BBB. The same was seen with the ANXA1 knockout mice, where administering the protein reversed the permeability of the BBB within 24 hours.

Dr Egle Solito, from Barts and The London School of Medicine and Dentistry, part of Queen Mary, who co-ordinated the study said: “Our findings suggest this protein plays a key role in maintaining a functioning BBB and, more importantly, has the potential to rescue defects in the BBB. We now need to carry on our research to see how much this molecule may be exploited for therapeutic uses in conditions such as MS, or as a biomarker to help in early diagnosis.”

Depression in a group of Medicare recipients ages 65 years and older appears to be associated with prevalent mild cognitive impairment and an increased risk of dementia, according to a report published Online First by Archives of Neurology, a JAMA Network publication.

Depressive symptoms occur in 3 percent to 63 percent of patients with mild cognitive impairment (MCI) and some studies have shown an increased dementia risk in individuals with a history of depression. The mechanisms behind the association between depression and cognitive decline have not been made clear and different mechanisms have been proposed, according to the study background.

Edo Richard, M.D., Ph.D., of the University of Amsterdam, the Netherlands, and colleagues evaluated the association of late-life depression with MCI and dementia in a group of 2,160 community-dwelling Medicare recipients.

“We found that depression was related to a higher risk of prevalent MCI and dementia, incident dementia, and progression from prevalent MCI to dementia, but not to incident MCI,” the authors note.

Baseline depression was associated with prevalent MCI (odds ratio [OR], 1.4) and dementia (OR, 2.2), while baseline depression was associated with an increased risk of incident dementia (hazard ratio [HR], 1.7) but not with incident MCI (HR, 0.9). Patients with MCI and coexisting depression at baseline also had a higher risk of progression to dementia (HR, 2.0), especially vascular dementia (HR, 4.3), but not Alzheimer disease (HR, 1.9), according to the study results.

“Our finding that depression was associated cross sectionally with both MCI and dementia and longitudinally only with dementia suggests that depression develops with the transition from normal cognition to dementia,” the authors conclude.

(Image: U.S. Dept. of Energy Office of Science)

The amount of time and money needed to sequence genomes continued to fall this year, perhaps to no one’s surprise. But while the field seemed to be finally approaching the heralded $1,000 human genome, the implications of reaching that milestone are not clear. Without expert analysis, the result of sequencing a human genome is just a large file of letters. You still need to manipulate and understand what those letters mean. Different companies announced services to help, from initial processing and storage of data to interpretation of the genetic data into medical meaning.

As human genomics garnered more attention from the medical community, the technology attracted new business opportunities. In April, the company behind the most widely used DNA sequencer, Illumina, fought off a hostile bid from pharmaceutical giant Roche. Just seven months later, Illumina tried to take over Complete Genomics, a company with technology well suited to medical genomics but which has never achieved financial success. That offer followed what seemed to be an all-but-assured purchased of Complete Genomics by China’s BGI. Illumina and BGI continue to fight over Complete Genomics.

Still, the medical community is only at the cusp of its understanding of how genome sequences can be used to help patients. Two branches of medicine that seem to be at the forefront of bringing on board DNA technology are reproductive medicine and cancer. Early in the summer, scientists at the University of Washington in Seattle reported a technique for determining the genome sequence of a fetus by analyzing DNA in the mother’s blood and from the father. Illumina’s CEO Jay Flatley said that prenatal diagnostics will be a major focus for the company, which has been expanding its business from sequencer manufacturing to broad DNA analysis service. In September, Illumina purchased BlueGnome, a chromosome-focused diagnostic company whose technology can detect abnormal numbers of chromosomes in IVF embryos. DNA analysis could also help prior to conception, according to a start-up called GenePeeks. That company announced it would offer predictive genome analysis for sperm bank clients to help guide them away from risky donor matches.  

Cancer patients and their doctors were also early adopters of medical genome science this year. Cancer is a disease of the genome: genetic mutations lead to abnormal cellular proliferation and behavior. Each person’s tumor and even different cells within a single tumor can have a unique profile of mutations, which makes finding the right drug to treat each patient difficult. Cambridge, Massachusetts-based  Foundation Medicine offered a sequencing service that searches for mutations that can be addressed with drugs in a patient’s tumor. Another Cambridge company, H3 Biomedicine, is using public databases of tumor sequences to find new drug targets specific to certain patient populations. 

Genetic medicines also got a boost with the first Western approval of gene therapy in November. Amsterdam-based Uniqure will begin selling its virus-mediated gene correction for a rare metabolic disorder sometime next year. The announcement could be good news for other companies trying to develop gene therapies as well as other groups developing molecular medicines, such as gene-silencing RNAi treatments that continue to move through clinical trials.

Although still untested in patients, another genetic manipulation is proving to be a powerful tool for neuroscientists. With optogenetics, scientists can manipulate neuron activity with flashes of light, and this year a group demonstrated for the first time that primate behavior could be controlled with the technique. Lab animal studies this year suggest optogenetics might one day help patients with blindness caused by retinal degeneration.

The melding of mind and machine was also big this year. Scientists in Winston-Salem, North Carolina, demonstrated that a brain implant could replace some cognitive function in primates, which could one day help people with brain damage. On the flip side, two research groups published the first accounts of quadriplegic people using brain implants to control robotic limbs. The implants recorded the participants’ intentions to move, which were translated by a computer into instructions for a robotic arm. The idea is that one day people with severe paralysis or amputations could use such neural prosthetics at home to help with the tasks of daily life.

Brain electronics were also implanted into Alzheimer’s patients this year in an attempt to slow a disease that has so far evaded pharmaceutical treatment.  The urgency for treatment is growing, but the community still doesn’t know what sets into motion the cascade of molecular events that robs people of their memory and thinking skills. With better diagnostic tools and the discovery that there are warnings decades before symptoms, scientists are turning to treating patients with a genetic predisposition for the disease before they start having symptoms. Perhaps this will be the key to treatments in future years.

Unless you have been deaf and blind to the world over the past decade, you know that functional magnetic resonance brain imaging (fMRI) can look inside the skull of volunteers lying still inside the claustrophobic, coffinlike confines of a loud, banging magnetic scanner. The technique relies on a fortuitous property of the blood supply to reveal regional activity. Active synapses and neurons consume power and therefore need more oxygen, which is delivered by the hemoglobin molecules inside the circulating red blood cells. When these molecules give off their oxygen to the surrounding tissue, they not only change color—from arterial red to venous blue—but also turn slightly magnetic.

(Image: Todd Davidson/Stock Illustration Source)

Activity in neural tissue causes an increase in the volume and flow of fresh blood. This change in the blood supply, called the hemodynamic signal, is tracked by sending radio waves into the skull and carefully listening to their return echoes. FMRI does not directly measure synaptic and neuronal activity, which occurs over the course of milliseconds; instead it uses a relatively sluggish proxy—changes in the blood supply—that rises and falls in seconds. The spatial resolution of fMRI is currently limited to a volume element (voxel) the size of a pea, encompassing about one million nerve cells.

Neuroscientists routinely exploit fMRI to infer what volunteers are seeing, imagining or intending to do. It is really a primitive form of mind reading. Now a team has taken that reading to a new, startling level.

A number of groups have deduced the identity of pictures viewed by volunteers while lying in the magnet scanner from the slew of map­like representations found in primary, secondary and higher-order visual cortical regions underneath the bump on the back of the head.

Jack L. Gallant of the University of California, Berkeley, is the acknowledged master of these techniques, which proceed in two stages. First, a volunteer looks at a couple of thousand images while lying in a magnet. The response of a few hundred voxels in the visual cortex to each image is carefully registered. These data are then used to train an algorithm to predict the magnitude of the fMRI response for each voxel. Second, this procedure is inverted. That is, for a given magnitude of hemodynamic response, a probabilistic technique called Bayesian decoding infers the most likely image that gave rise to the observed response in that particular volunteer (human brains differ substantially, so it is difficult to use one brain to predict the responses of another).

The best of these techniques exploit preexisting, or prior, knowledge about pictures that could have been seen before. The number of mathematically possible images is vast, but the types of actual scenes that are encountered in a world populated by people, animals, trees, buildings and other objects encompass a tiny fraction of all possible images. Appropriately enough, the images that we usually encounter are called natural images. Using a database of six million natural images, Gallant’s group showed in 2009 how brain responses of volunteers to photographs they had not previously encountered could be reconstructed.

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