Picking your brains: what’s going on inside your head?

 Neuroscience has made great gains but the best is yet to come. Jenn and Tony Bot

Welcome to On the Brain, a new Conversation series by people whose job it is to know as much as there is to know about the body’s most complex organ. Here, Professor Geoffrey Donnan, a world-renowned stroke researcher and director of the Florey Neuroscience Institute, summarises major highlights in brain diagnoses and ponders the future of treatments for brain disease. Enjoy.
The past 30 years have seen the most remarkable advances in the study of the brain. And the past ten have seen more advances in our understanding than all the other years combined.
These range from the most fundamental changes within cells right through to how the brain interconnects and functions.

X-ray computed tomography.

Enormous strides were made in brain research during the 19th century and consolidated during the latter half of the 20th century. But then, while our knowledge of brain disease plateaued, significant advances were being made in unravelling our understanding of disease processes in accessible organs such as the heart, liver, kidney and blood.
So much so that exciting new treatments were developed for diseases of these organs.
Meanwhile, progress in neuroscience research remained frustratingly slow as the brain remained in its lofty and boney chamber, isolated, often ravaged by disease and largely untreated.
Up until the mid-1970s, the only way to really access the brain was either during surgical operations or, less fortunately, at autopsy. There were some incredibly crude imaging techniques that offered limited and indirect insight into brain structure – and which were, frankly, dangerous.
The most invasive procedure involved injecting air into the ventricles of the brain via the lumbar spinal region. This took advantage of the continuity of the ventricles with the fluid spaces surrounding the spinal cord.
Interestingly, the technique was an extension of a serendipitous finding by clinicians during the First World War. They found that, when penetrating injuries to the brain allowed air entry to the ventricles, plain X-rays would clearly outline the ventricular contours in sharp relief.
In Melbourne, we had the world expert in research into the interpretation on these images, Dr E Graeme Robertson. This did not diminish the discomfort felt by most patients who were subjected to the procedure: most were left with quite a headache.
Fortunately, the imaging revolution was not far away. During a remarkable decade from the mid-1970s to the mid-1980s, X-ray computed tomography (CT) took us all to another level.
For the first time, neurologists could actually see brain pathologies such as intracerebral haemorrhage – when a blood vessel bursts within the brain – with startling clarity.
The technological advance of computing had allowed a stereotaxic computation of multiple X-ray images accrued by rotating gantry (see below) to be displayed as a simple image.

As if this was not enough, almost overnight, in the 1970s, along came another even more sophisticated technique: magnetic resonance imaging (MRI). Here, scientists had taken advantage of the differing response of atomic structures, particularly protons, to perturbations by radio frequency waves within a magnetic field.
In practice, this meant high-powered computing could generate maps of these protons. Even better, brain blood vessel flow and brain function could be studied.
At about the same time, another technique, Positron Emission Tomography (PET), a nuclear imaging technique, was developed which allowed the distribution of chemical reactions within the brain to be mapped. The sky seemed the limit.
Even the location of human emotions could be mapped to specific locations. If there was ever any doubt the brain ruled the body, this was being dispelled almost weekly as we learned how brain function interpreted the senses and drove motor function.
While these extraordinary advances were occurring in imaging the entire brain and its function, similar developments were occurring in imaging individual cells and their function.

An animation of MRI head scans.

In much the same way astronomers were seeing new objects in space and, as a consequence, determining new theories about the universe, scientists were seeing the inner workings of the cell in wonderful and colourful detail to make similar inferences about its mechanism of action.
These days, critical compounds for cell survival such as calcium can now be imaged as it is pumped in and out of cells. By genetically modifying cells to carry light-sensitive rhodopsin, they may be switched on and off from the distance.
Then groups and systems of cells can be studied so the means by which they interact can be better understood. Suddenly the very working of the brain can be observed at a cellular systems level and scientists have insight into how whole brain components have a functional output.
For example, it should be possible to observe how the brain stem systems work in controlling blood pressure and breathing.

The avant-garde

When considering the drivers of the tremendous advances in neuroscience in this fairly brief period of time, imaging is an absolute standout. The other two critical components have been the unravelling of cellular biology generally and the revolution that has occurred in the genetics of disease.
Cellular biology involves the study of cellular structure and function in all its facets – how it acts as a minute factory with inputs, outputs and energy sources.

A PET image of the brain.

The third factor associated with this revolution in neuroscience, the genetics of disease, is equally intriguing. The adventure was really launched with the plan to map the human genome in the late 1980s.
It was thought to be such a massive task that it would take more than 20 years. Because of the remarkable advances in technology, not least the harnessing of unexpected increases in computing technology, the genome was cracked in just 13 years, culminating in 2003.
Here in Melbourne we had our own wins with Professor Sam Berkovic and his team of collaborators discovering the first genes responsible for epilepsy.
By tracing the function of these genes, Berkovic and his team were able to establish that the cause of many of the epilepsies involves a disorder of pumps on the surface of cells which keep the ionic concentrations stable within cells.
A failure of these pumps alters the excitability of the cells and allows them to discharge their impulses to neighbouring cells and promote seizures more broadly in the brain.
The next step is to design new medications which might stabilise these cellular pumps.

Gains

So what therapeutic advances have occurred as result of all this frenetic scientific activity? Numerous therapies are now part of the neurologist’s toolkit, whereas in earlier years his or her role was to diagnose and prognosticate with virtually no therapies to offer.
Now a neurologist must be familiar with:

• four categories of intervention to be of proven benefit immediately after the onset of stroke
• seven forms of intervention to prevent recurrent stroke
• four categories of therapy for multiple sclerosis
• new categories of therapies for movement disorders such as Parkinson’s disease and dementias such as Alzheimer’s disease.

Where will it end? My view is that we’re at the beginning of an even more wonderful period of the flowering of the neurosciences.
If I were a young clinician or scientist wondering which area of research to enter there would be no hesitation – the mysteries of our most complex organ and the seat of the soul await.

Celtic Pharma Announces Completion of Enrollment in Dose Tolerance Trial Evaluating XERECEPT® in Pediatric Patients with Primary and Metastatic Brain Tumors

NEW YORK, LONDON and HAMILTON, Bermuda, Oct. 3, 2011 /PRNewswire via COMTEX/ -- Celtic Pharmaceutical Holdings L.P. ("Celtic Pharma") is pleased to announce the completion of enrollment into a maximum dose tolerance study of investigational product Xerecept® (corticorelin acetate) in pediatric patients who were dependent on chronic Decadron (dexamethasone) dosing due to peritumoral brain edema associated with cerebral tumors. In the open label study, 100% of the subjects showed substantive reductions in daily dexamethasone dosing requirements, with approximately 25% of patients able to completely stop steroid dosing.

The study of 15 patients was conducted by Stewart Goldman M.D. at Children's Memorial Hospital in Chicago, IL and Mark Kieran M.D. at Dana-Farber Cancer Institute in Boston, MA. Both investigators commented that the Xerecept® dosing enabled pediatric patients to reduce their dexamethasone requirements even though each patient had at least two previous attempts to reduce the doses of dexamethasone prior to entry into this study. "Both the children and their families noted to me that participation in this trial and the ability to decrease Decadron dosing improved the quality of life for the patients," added Stewart Goldman, M.D.

The daily maximum tolerated dose of Xerecept® in this study was 60g (microgram) per kilogram given in divided doses subcutaneously morning and evening.

"Chronic corticosteroid dosing is not good for anyone," commented Stephen Evans-Freke, Managing General Partner of Celtic Pharma Management L.P., "but the very high doses of dexamethasone needed to control cerebral edema in pediatric brain tumor patients have severely deleterious clinical and quality of life effects on the children. This exciting new pediatric data on Xerecept obliges us to consider a separate pathway to regulatory approval for Xerecept in pediatric patients."

About Xerecept

Xerecept is a synthetic version of the natural peptide hormone 'corticotrophin releasing factor'. Xerecept is in mid-Phase III development for the treatment of cerebral edema associated with primary and metastatic brain tumors in adults, and has been demonstrated in prior trials to be an effective alternative to the use of chronic, high-dose corticosteroids in this large patient population, while offering a benign side-effect profile even over several years of chronic administration. Recent preclinical studies from leading cancer centers have indicated that Xerecept may also have direct anti-tumor effects, and may be synergistic with Avastin in certain solid tumor indications. Xerecept is expected to have significant patent protection through 2033.

About Celtic Pharmaceutical Holdings L.P.

Celtic Pharmaceutical Holdings L.P. (Celtic Pharma) is a global private equity investment firm focused on the biotechnology and pharmaceutical industries. Celtic Pharma was founded by Stephen Evans-Freke and John Mayo, CBE and is based in Bermuda, with offices in New York and London. Celtic Pharma has acquired and invested in late stage pharmaceutical programs and manages these programs through their development for ultimate sale to established pharmaceutical companies. Celtic Pharma is fully invested at this time. Celtic Pharma's aim has been to bridge the gap between the established pharmaceutical companies' new product pipeline crisis and the biotech industry's capital drought. For further information, please visit Celtic Pharma's website at www.celticpharma.com .

SOURCE Celtic Pharmaceutical Holdings L.P.

Remotely controlling the brain with

Remotely controlling the brain with 

Scientists at the University at Buffalo have received $1.3 million from the National Institute of Mental Health (NIMH) to test how tiny, magnetic particles can be used to remotely control neurons in the brains of mice. If the work is successful, the research team will have given neuroscientists a powerful, new tool: a non-invasive technique for triggering activity deep inside the brain. This kind of remote, neuro-stimulation would help researchers learn more about how the brain's complicated neuronal circuitry controls behavior, leading eventually to better understanding and possibly treatment of ailments that involve the injury or malfunction of specific sets of neurons. Traumatic brain injuries, Parkinson's disease, dystonia and peripheral paralysis all fall into this category.  Research by UB physicist Arne Pralle, (right) shown with his student, will help reveal how the brain's complicated neuronal circuitry controls behavior. "Our early understanding about the brain's functional regions came from patients who showed changes in their behavior after losing a part of their brain to traumatic brain injury or a tumor," said Arnd Pralle, the assistant professor of physics who is leading the new UB study. "The ability to now reversibly turn individual cells off or on and to observe the animal's behavior brings us finally to the level of the actual neurological circuit, which is extremely exciting." The new NIMH funding, which comes from the National Institute of Health's program for Exceptional, Unconventional Research Enabling Knowledge Acceleration (EUREKA), is a testament to the promise of Pralle's work. He and his colleagues have already succeeded in using their remote control technique to open calcium ion channels, activate neurons in cell culture, and even manipulate the behavior of C. elegans, a tiny worm. The approach involves the use of heated, magnetic nanoparticles in conjunction with some clever genetic engineering. Here's how it works in the brain: First, scientists employ harmless viruses to carry a special strand of DNA into the brain. The new genetic material induces specific, targeted cells to build a special ion channel containing a receptor that magnetic nanoparticles will recognize. When the nanoparticles latch onto these ion channels, scientists apply an alternating magnetic field to the brain that causes the particles' magnetization to flip rapidly, generating heat. That heat then stimulates the ion channels to open, depolarizing the neurons and causing them to fire. With the new NIMH funding, Pralle's research team plans to test this method on neurons in the olfactory bulb, which lies in the forward region of the brain and controls how animals perceive odors. Specifically, the scientists will see if they can use the nanoparticles' localized heating to activate specific neurons in the olfactory bulb, causing the mice to "smell" a particular odor even when no actual chemicals are present. As neuroscientists search for better ways to probe the brain, Pralle's method is particularly attractive because magnetic fields are able to penetrate tissues without harming them. Other methods for remotely controlling brain cells are more invasive, including a state-of-the-art technique involving the use of an implanted optical fiber to stimulate light-activated ion channels. Pralle's prior work on magnetic nanoparticles was supported by the UB 2020 Interdisciplinary Research Development Fund, which provides start-up money to projects with the potential to receive larger, external grants. That seed funding enabled Pralle and his collaborators to complete a number of studies, including one in which they attached magnetic nanoparticles to cells near the mouth of C. elegans. When the scientists used their remote technique to heat the nanoparticles, most of the worms began reflexively crawling backward in an attempt to escape the heat when the temperature hit 34 degrees Celsius.

UAB lab research yields a possible tool for fighting brain tumors

The Birmingham News/Tamika MooreGrad student Avinash Honasoge works with human glioma cells in Harald Sontheimer's lab at UAB's Comprehensive Cancer Center. Sontheimer, left, whose brain cancer research is getting international attention, has about 15 people working in his lab and annual funding between $800,000 and $1 million.

Harald Sontheimer is a basic scientist.
He revels in all that stuff we don't understand very well -- molecular genetics of human glioma cancer cells, organic chemistry, sophisticated experiments with specially bred lab mice, laboratory chats about micromolar concentrations and competitive inhibitors.
But something very strange has now hit Sontheimer's ivory tower.
Brain cancer patients -- and brain cancer doctors -- are calling him up. They have heard about his experiments with mice, and want to know if they will work in human brain tumors.
You see, over 13 years of research Sontheimer, his post-docs and grad students have done something remarkable. Through steadily posing, and then answering, basic science questions, they have found an existing human drug that has the power to shrink glioma tumors in lab mice.
Formal studies haven't started with human patients who have glioblastoma multiforme -- the deadliest and most common form of malignant brain cancer. But based on animal results, some doctors around the world are already giving the drug to their patients as an "off-label" treatment.
Last month, Sontheimer's research made a splash at the EuroGlia 2011 meeting in Prague, attended by 1,000 glial cell clinicians and scientists.
"People loved the story," said Sontheimer, a neurobiologist and senior scientist in the University of Alabama at Birmingham's Comprehensive Cancer Center. "It created a kind of excitement. ... The potential of the drug to alter the disease progression is significant."
Room to grow
It all started in 1998 with a basic question: How do human glioma cancer cells differ from the brain's normal glial cells, which provide support and protection for the brain's neurons?
One role of glia is taking up glutamate, a neurotransmitter used in the brain. But surprisingly, the Sontheimer group found, glioma cells were releasing glutamate. Massive amounts of it.
It had been learned in the 1970s that production of lots of glutamate in the brain was a major reason that brain cells die during human strokes. High levels are toxic to neurons.
Though no one had ever posed the question, glutamate production by glioma cells made sense, Sontheimer said. Unlike all other cancers, glioma cells grow in a fully enclosed space -- the brain cavity. How did the growing tumor make room for itself?
In lab experiments, Sontheimer's group put human glioma tumor cells into the brain cavities of specially bred lab mice. There they grew and killed off surrounding brain, just like human disease.
By 2005, Sontheimer's group had found that if they added a pharmacological agent that inhibited glutamate production, the glioma cells did not kill surrounding mouse brain.
"Glutamate," Sontheimer said, "is the killer, the killer molecule."
Serendipity
How is glutamate produced? Sontheimer's group found that a transporter protein in the glial cell membrane works like a tiny revolving door. It grabs a molecule of the amino acid cysteine from outside and shuffles it inside. At the same time, the "revolving door" kicks out a molecule of glutamate.
Sontheimer's group began to search for a drug to clog that revolving door and slow the release of glutamate. But potentially useful chemicals faced a huge drawback. To win possible approval as human drugs, they faced long and expensive clinical trials to test for safety.
In a stroke of fortune, graduate student Zucheng Ye in 2001 found a possible shortcut. He found a leukemia cell research paper that said an existing human drug called sulfasalazine appeared to inhibit cysteine uptake. Could it be that sulfasalazine -- already approved for use in Crohn's disease, and known to be safe for humans -- was blocking the transporter protein that produced glutamate in glioma cells?
The answer was yes. In lab experiments, the drug blocked the uptake of cysteine and the release of glutamate.
So what would happen when the experiment was moved up to animals, mice that had human glioma cells planted in their brains?
Sontheimer's lab found that without the drug, the mice begin to get seizures, an early hallmark of glioma, in two to three weeks. The mice then grow worse as the glioma cells kill the brain.
But with a dose of sulfasalazine, seizures were suppressed for several hours. When the mice got two doses a day, the tumor volume shrank as much as 80 percent.
This was startling-- a new, possibly useful drug that was "available now, and one month's supply costs $10," Sontheimer said.
And so the phone is ringing, even though Sontheimer is not a physician and knows that mouse studies often don't translate well to people.
Doctors call. And patients call, including one with Crohn's disease who had a glioblastoma removed 10 years ago. "It never came back," she told Sontheimer.
Some early human data is now being reviewed for a possible clinical trial of sulfasalazine in glioma patients.
It's a dramatic leap from a slow and steady asking of basic science questions in a UAB lab, which Sontheimer calls incremental progress "from A to B, B to C, C to D."
"It's pretty much 100 percent our contribution," he said of the glutamate research, "and it's been going on for 13 years."

fMRI Shows My Bullshit Detector Going Ape Shit Over iPhone Lust

Not really my insula freaking out

The fMRI scan above shows my brain* reading a truly horrific NY Times Op-Ed piece. The piece, written by a man named Martin Lindstrom, who calls himself a “fan of the consumer” (meaning what? he blows on us?), is called You Love Your iPhone. Literally. Literally. Lindstrom claims to see actual love for iPhones declared by the insulas of the 16 people in a scan study he performed. Several people have already spankingly revealed this claim’s bare-assed absurdity, most notably academic researchers Russ Poldrack and Tal Yarkoni, who declare, respectively, that the piece is complete crap that (returning to fan theme) blows it big time. It came to my attention via a spirited take-down by the ever-watchful Neurocritic — a sort of master class in bullshit detection about fMRI studies that claim to see Specific Emotion X rooted in Area Y of the brain.
As Poldrack, Yarkoni, and Neurocritic note, Lindstrom’s big fail is that he claims to spot clear sign of a very specific emotion — not just love, but iPhone love — in an area that shows up active in about a third of all fMRI studies [PDF]. This is the insula. These insula studies include quite a few that find the insula fire up when people feel disgust; one is one of my favorite fMRI titles ever, “Both of Us Disgusted in My Insula.”
And it’s not just love and disgust that can stir your insula. As Neurocritic describes (quoting him- or herself, which really fires up my insula, in a good way):

[The insula]’s a pretty large area. Besides being crowned the “seat of emotional reactions” (whatever that means), portions of the insula have been associated with interoceptive awareness, visceral sensation, pain, autonomic control, and taste, among other things… a lot of other things. Do a search of the BrainMap database using just two of the many insular foci reported by the Caltech researchers [Hsu et al., 2008] and you’ll see activations related to action execution, speech, attention, language, explicit memory, working memory, and audition.

It’s a shame the Times ran such a thing on their Op-Ed page, which remains one of  the most prominent platforms in all of print media. It’s significant, methinks, that it did NOT run in the Times science section; would never have passed muster there. You Love Your iPhone. Literally. Really?
Among Lindstrom’s books is one called Buyology. Seriously. I’m not buying it. Not literally. Not no way, no how.
If you want something good to read, hit those three blogs I linked to above: Neurocritic; Russ Poldrack; and Tarkoni’s [citation needed]. They’re all splendid.
*Not really my brain. It is, however, an insula firing up.
Image from University of Cambridge Center for Speech and Language.

Prolonged stress can shrink the brain

Prolonged stress can shrink the brain (Thinkstock photos/Getty Images)

Suffering from stress for long periods of time can shrink the brain and even lead to dementia, researchers have claimed.

Chemicals released by the body during prolonged stress are toxic to brain tissue, they found.

Types of stress linked to the condition include that suffered by those in loveless marriages, dead end jobs and post traumatic situations.

The research suggests chemicals - called corticosteroids - can kill off brain cells if concentrations remain high over long periods.

Corticosteroids help the body in 'fight or flight' situations - suppressing the immune system and increasing the amount of sugar in the bloodstream.

The hippocampus, a part of the brain involved in the formation of memories, is particularly susceptible - which leads doctors to believe stress may lead to dementia.

"The sample size is too small to draw conclusions but the implication is that stress had affected the hippocampus," the Daily Mail quoted T Byram Karasu, professor of psychiatry at the Albert Einstein College of Medicine in New York, as saying.

Cost of brain disorders 'doubles'

The cost of treating brain disorders, such as depression, insomnia, Parkinson's and stroke, has more than doubled in just six years, according to a study.
Researchers warn of a financial "ticking timebomb" across Europe, with one in three people in 2010 suffering a brain disorder or caring for somebody with one, a figure that is on the rise.
In the UK, 9.7 million people are thought to have a brain disorder, at a cost of more than 134 billion euro (around £116 billion) a year. Overall, almost 800 billion euro (£689 billion) is now spent across Europe every year on dealing with these disorders.
Experts examined 30 countries and 19 groups of disorders, including anxiety disorders, addictions, brain tumours, childhood and adolescent developmental disorders, dementia, eating disorders, epilepsy, migraine, multiple sclerosis, Parkinson's, sleep disorders, stroke and traumatic brain injury.
Mood disorders, such as depression and bipolar, are thought to be the most costly group, at more than 113 billion euro (£97 billion) each year, with 33.3 million sufferers. Dementia is a close second at just over 105 billion euro (£90 billion), with more than 88 billion euro (£76 billion) of that coming from costs such as social care.
The number of people suffering brain disorders is expected to rise as people live longer.
"We have to emphasise that the burden of disorder of the brain will likely increase further, simply due to the continuing life expectancy in Europe," the experts said. "Because of the ageing European population, degenerative disorders are particularly destined to become more common, such as dementia, Parkinson's disease and stroke, but anxiety and mood disorders are also very prevalent at high age."
The team, writing in the journal European Neuropsychopharmacology, said dealing with brain disorders represents "the number one economic challenge for European healthcare now and in the future".
They call for more investment in science and teaching, including time spent on brain disorders in medical schools. And they warn their figures are "very conservative" and almost certainly an underestimate.
The experts came from universities and hospitals across Europe.

Has our brain reached full capacity?

ISLAMABAD: Scientists have claimed that the human brain may have reached its full capacity and can't get cleverer.
A team at Cambridge University, led by Professor Simon Laughlin, says this is because the people are unable to provide the amount of extra energy and oxygen needed to become more intelligent.
The scientists have based their findings after analysing the structure of the brain and worked out how much energy its cells use up.
Professor Simon Laughlin was quoted by the British media as saying, "We have demonstrated that brains must consume energy to function and that these requirements are sufficiently demanding to limit our performance and determine design.
Far-reaching powers of deduction demand a lot of energy because for the brain to search out new relationships it must constantly correlate information from different sources. Such energy demands mean there is a limit to the information we can process."
The scientists say that the wiring inside the brain would need vast amounts of extra energy to become more efficient. As it's impossible for humans to provide this, they can't become any smarter.
In their research, the team measured the efficiency with which different parts of the brain communicated with each other and found impulses travelled fastest in smarter people and slower in those who were less intelligent.
"High integration of brain networks seems to be associated with high IQ. You pay a price for intelligence. Becoming smarter means improving connections between different brain areas but this runs into tight limits on energy, along with space for the wiring," Ed Bullmore, team member said.