Neuroscience

Injury to the subcortical structures of the inner brain is a major contributor to worsening neurological abnormalities after “awake craniotomy” for brain tumors, reports a study in the February 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.

During a procedure intended to protect critical functional areas in the outer brain (cortex), damage to subcortical areas—which may be detectable on MRI scans—is a major risk factor for persistent neurological deficits. “Our ability to identify and preserve cortical areas of function can still result in significant neurological decline postoperatively as a result of subcortical injury,” write Dr. Victoria T. Trinh and colleagues of The University of Texas MD Anderson Cancer Center, Houston.

Risk Factors for Neurological Deficits after Awake Craniotomy

The researchers analyzed factors associated with worsening neurological function after awake craniotomy for brain tumor surgery. In awake craniotomy, the patient is sedated but conscious so as to be able to communicate with the surgeon during the operation.

The patient is asked to perform visual and verbal tasks while specific areas of the cortex are stimulated, generating a functional map of the brain surface. This helps the surgeon navigate safely to the tumor without damaging the “eloquent cortex”—critical areas of the brain involved in language or movement.

The study included 241 patients who underwent awake craniotomy with functional brain mapping from 2005 through 2010. Of these, 40 patients developed new neurological abnormalities. Dr. Trinh and colleagues examined potential predictive factors—including changes on a type of MRI scan called diffusion-weighted imaging (DWI).

Of the 40 cases with new neurological deficits, 36 developed while the surgeon was operating in the subcortical areas of the brain. These are the inner structures of the brain, located beneath the outer, folded brain cortex. Just one abnormality developed while the surgeon was operating in the cortex only.

MRI Changes May Reflect Subcortical Damage

Neurological abnormalities developing while the surgeon was operating in the subcortex were likely to remain after surgery, and to persist at three months’ follow-up evaluation. Dr. Trinh and coauthors write, “Patients with intraoperative deficits during subcortical dissection were over six times more likely to have persistently worsened neurological function at three-month follow-up.”

In these patients, MRI scans showing more severe changes in the DWI pattern in the subcortex also predicted lasting neurological abnormalities. Of patients who had neurological deficits immediately after surgery and significant DWI changes, 69 percent had persistent deficits three months after surgery.

Patients who had “positive” cortical mapping—that is, in whom eloquent cortex was located during functional mapping—were somewhat more likely to have neurological abnormalities immediately after surgery. However, the risk of lasting abnormalities was not significantly higher compared to patients with negative cortical mapping.

Awake craniotomy with brain stimulation produces a “real-time functional map” of the brain surface that is invaluable to the neurosurgeon in deciding how best to approach the tumor. The new results suggest that, even when the eloquent cortex is not located on cortical mapping, subcortical areas near the tumor can still be injured during surgery. “Subcortical injury is the primary cause of neurological deficits following awake craniotomy procedures,” Dr. Trinh and colleagues write.

The researchers add, “Preserving subcortical areas during tumor resections may reduce the severity of both immediate and late neurological sequelae.” Based on their findings, they believe subcortical mapping techniques may play an important role in avoiding complications after awake craniotomy.

Scientists at the Essex have been working with NASA on a project where they controlled a virtual spacecraft by thought alone.

Using BCI (brain-computer interface) technology, they found that combining the brain power of two people could be more accurate in steering a spacecraft than one person. BCIs convert signals generated from the brain into control commands for various applications, including virtual reality and hands-free control.

Researchers at Essex have already been undertaking extensive projects into using BCI to help people with disabilities to enable spelling, mouse control or to control a wheelchair. The research involves the user carrying our certain mental tasks which the computer then translates into commands to move the wheelchair in different directions.

The University has built-up an international reputation for its BCI research and is expanding its work into the new area of collaborative BCI, where tasks are performed by combining the signals of multiple BCI users.

The £500,000 project with NASA’s Jet Propulsion Lab in Pasadena, California, involved two people together steering a virtual spacecraft to a planet using a unique BCI mouse, developed by scientists at Essex.

Using electroencephalography (EEG), the two users wore a cap with electrodes which picked up different patterns in the brainwaves depending on what they were focusing their attention on a screen – in this case one of the eight directional dots of the cursor. Brain signals representing the users’ chosen direction, as interpreted by the computer, were then merged in real time to produce control commands for steering the spacecraft.

As Professor Riccardo Poli, for the University’s School of Computer Science and Electronic Engineering, explained, the experiment was very intense and involved a lot of concentration. With two people taking part in the test, the results were more accurate as the system could cope if one of the users had a brief lapse in concentration.

Analysis of this collaborative approach showed that two minds could be better than one at producing accurate trajectories. Combining signals also helped reduce the random “noise” that hinders EEG signals, such as heartbeat, breathing, swallowing and muscle activity. “When you average signals from two people’s brains, the noise cancels out a bit,” added Professor Poli.

Professor Poli said an exciting development for BCI research in the future relates to joint decision making, where a physiological signal, like pressing a button, and brain activity can be combined to give a superior result. “It is like measuring someone’s gut feeling,” added Professor Poli.

Researchers have overcome a major challenge to treating brain diseases by engineering an experimental molecular therapy that crosses the blood-brain barrier to reverse neurological lysosomal storage disease in mice.

Posted online in PNAS Early Edition on Feb. 4, the study was led by scientists at Cincinnati Children’s Hospital Medical Center.

“This study provides a non-invasive procedure that targets the blood-brain barrier and delivers large-molecule therapeutic agents to treat neurological lysosomal storage disorders,” said Dao Pan, PhD, principal investigator on the study and researcher in the Cancer and Blood Diseases Institute at Cincinnati Children’s. “Our findings will allow the development of drugs that can be tested for other brain diseases like Parkinson’s and Alzheimer’s.”

The scientists assembled the large molecular agents by merging part of a fatty protein called apolipoprotein E (apoE) with a therapeutic lysosomal enzyme called a-L-idurondase (IDUA). Naming the agents IDUAe1 and IDUAe2, researchers used them initially to treat laboratory cultured human cells of the disease mucopolysaccharidosis type I (MPS I). They also tested the agents on mouse models of MPS I.

MPS I is one of the most common lysosomal storage diseases to affect the central nervous system, which in severe form can become Hurler syndrome. In humans, patients can suffer from hydrocephalus, learning delays and other cognitive deficits. If not treated, many patients die by age 10.

Lysosomes are part of a cell’s internal machinery, serving as a waste disposal system that helps rid cells of debris to retain normal function. In lysosomal storage diseases like MPS I, enzymes needed to dissolve debris are missing, allowing debris to build up in cells until they malfunction.

In MPS I, cells lack the IDUA enzyme, allowing abnormal accumulation of a group of large molecules called glycosaminoglycans in the brain and other organs. Researchers in the current study used the new therapeutic procedure to deliver IDUA to brain cells. But first they had to successfully engineer the therapy to carry IDUA through the blood-brain barrier to diseased brain cells.

The blood-brain barrier is a physiological blockade that alters the permeability of tiny blood vessels called capillaries in the brain. Its purpose is to protect the brain by preventing certain drugs, pathogens and other foreign substances from entering brain tissues. The barrier has also been a persistent roadblock to treating brain disease with drugs.

The scientists experimented with a set of derivative components of the fatty protein apoE, which binds to fat receptors on endothelial cells that form the inside surface of capillaries in the blood-brain barrier. They discovered that tagging some of the apoE components to the IDUA enzyme allowed the modified protein to attach to endothelial cells and cross through the cells to reach brain tissues.

Researchers injected experimental IDUAe1 into the tail veins of MPS I mouse models. The tests showed that – unlike currently available un-modified enzyme treatments – the modified enzyme penetrated the blood-brain barrier and entered brain neurons and astrocytes in a dose-dependent manner.

The researchers also reported that brain cells in the treated mice exhibited normalized levels of the glycosaminoglycans and the lysosomal enzyme beta-hexosaminidase. With continued treatment through hematopoietic stem cell gene therapy, normalized levels persisted until the end of a five-month observation period, researchers said.

The scientists are continuing their preclinical studies to further verify the use of the experimental IDUA-based agents for treating MPS I, cautioning that results in laboratory mice may face additional challenges when translating to clinical application in humans. Researchers are also testing whether the large-molecule therapeutic procedure used in the current study can be leveraged to develop other neurotherapeutic agents that cross the blood-brain barrier.

A research team in Israel has devised a novel approach to identifying the molecular basis for designing a drug that might one day decrease the risk diabetes patients face of developing Alzheimer’s disease. The team will present its work at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.

A recent study suggests that people who suffer from type 2 diabetes face twice the risk of developing Alzheimer’s disease later in life compared to those who do not have diabetes. The link these diseases share relates to the formation of two types of peptide deposits that aggregate, or clump together. Peptides are chains of amino acids; longer chains form proteins. One type of peptide, called amyloid beta, is found in Alzheimer plaques in neurons of the brain. The other type, amylin, is found in the pancreas and the brain. Two years ago, researchers found both molecules in the pancreas of diabetic patients, and in both diseases their presence has been linked to the progression of the disease state.

To explore the hypothesis that interactions between the two molecules might play a critical role in the self-assembly of peptides that leads to protein aggregation, Yifat Miller, assistant professor from Ben-Gurion University of the Negev, Beer-Sheva, Israel, characterized the way the two protein molecules interact with each other through an examination of their structure. It was the first analysis of its kind.

"By identifying the specific ‘hot regions’ of these peptides that strongly interact with each other, our study may provide insight into the link between type 2 diabetes and Alzheimer’s disease," Miller says. "We believe that preventing these interactions by developing a drug will decrease the risk that type 2 diabetes patients face of developing Alzheimer’s disease later life."