Scientists pinpoint brain’s area for numeral recognition

Scientists at the Stanford University School of Medicine have determined the precise anatomical coordinates of a brain “hot spot,” measuring only about one-fifth of an inch across, that is preferentially activated when people view the ordinary numerals we learn early on in elementary school, like “6” or “38.”

Activity in this spot relative to neighboring sites drops off substantially when people are presented with numbers that are spelled out (“one” instead of “1”), homophones (“won” instead of “1”) or “false fonts,” in which a numeral or letter has been altered.

“This is the first-ever study to show the existence of a cluster of nerve cells in the human brain that specializes in processing numerals,” said Josef Parvizi, MD, PhD, associate professor of neurology and neurological sciences and director of Stanford’s Human Intracranial Cognitive Electrophysiology Program. “In this small nerve-cell population, we saw a much bigger response to numerals than to very similar-looking, similar-sounding and similar-meaning symbols.

“It’s a dramatic demonstration of our brain circuitry’s capacity to change in response to education,” he added. “No one is born with the innate ability to recognize numerals.”

The finding pries open the door to further discoveries delineating the flow of math-focused information processing in the brain. It also could have direct clinical ramifications for patients with dyslexia for numbers and with dyscalculia: the inability to process numerical information.

The cluster Parvizi’s group identified consists of perhaps 1 to 2 million nerve cells in the inferior temporal gyrus, a superficial region of the outer cortex on the brain. The inferior temporal gyrus is already generally known to be involved in the processing of visual information.

The new study, published April 17 in the Journal of Neuroscience, builds on an earlier one in which volunteers had been challenged with math questions. “We had accumulated lots of data from that study about what parts of the brain become active when a person is focusing on arithmetic problems, but we were mostly looking elsewhere and hadn’t paid much attention to this area within the inferior temporal gyrus,” said Parvizi, who is senior author of the study.

Not, that is, until fourth-year medical student Jennifer Shum, who also is doing research in Parvizi’s lab, noticed that, among some subjects in the first study, a spot in the inferior temporal gyrus seemed to be substantially activated by math exercises. Charged with verifying that this observation was consistent from one patient to the next, Shum, the study’s lead author, reported that this was indeed the case. So, Parvizi’s team designed a new study to look into it further.

The new study relied on epileptic volunteers who, as a first step toward possible surgery to relieve unremitting seizures that weren’t responding to therapeutic drugs, had a small section of their skulls removed and electrodes applied directly to the brain’s surface. The procedure, which doesn’t destroy any brain tissue or disrupt the brain’s function, had been undertaken so that the patients could be monitored for several days to help attending neurologists find the exact location of their seizures’ origination points. While these patients are bedridden in the hospital for as much as a week of such monitoring, they are fully conscious, in no pain and, frankly, a bit bored.

Over time, Parvizi identified seven epilepsy patients with electrode coverage in or near the inferior temporal gyrus and got these patients’ consent to undergo about an hour’s worth of tests in which they would be shown images presented for very short intervals on a laptop computer screen, while activity in their brain regions covered by electrodes was recorded. Each electrode picked up activity from an area corresponding to about a half-million nerve cells (a drop in the bucket in comparison to the brain’s roughly 100 billion nerve cells).

To make sure that any numeral-responsive brain areas identified were really responding to numerals — and not just generic lines, angles and curves — these tests were carefully calibrated to distinguish brain responses to visual presentations of the classic numerals taught in Western schools, such as 3 or 50, as opposed to squiggly lines, letters of the alphabet, number-denoting words such as “three” or “fifty,” and symbols that in fact were also numerals but — because they were drawn from the Thai, Tibetan and Devanagari languages — were extremely unlikely to be recognized as such by this particular group of volunteers.

In the first test, subjects were shown series of single numerals and letters — along with false fonts, in which the component parts of numerals or letters had been scrambled but defining curves and angles were retained, and the foreign-number symbols just described. A second test, controlling for meaning and sound, included numerals and their spelled-out versions (for instance, “1” and “one,” or “3” and “three”) and other words with the same sound or a similar one (“won” and “tree,” respectively).

All of our brains are shaped slightly differently. But in almost the identical spot within each study subject’s brain, the investigators observed a significantly larger response to numerals than to similar-shaped stimuli, such as letters or scrambled letters and numerals, or to words that either meant the same as the numerals or sounded like them.

Interestingly, said Parvizi, that numeral-processing nerve-cell cluster is parked within a larger group of neurons that is activated by visual symbols that have lines with angles and curves. “These neuronal populations showed a preference for numerals compared with words that denote or sound like those numerals,” he said. “But in many cases, these sites actually responded strongly to scrambled letters or scrambled numerals. Still, within this larger pool of generic neurons, the ‘visual numeral area’ preferred real numerals to the false fonts and to same-meaning or similar-sounding words.”

It seems, Parvizi said, that “evolution has designed this brain region to detect visual stimuli such as lines intersecting at various angles — the kind of intersections a monkey has to make sense of quickly when swinging from branch to branch in a dense jungle.” The adaptation of one part of this region in service of numeracy is a beautiful intersection of culture and neurobiology, he said.

Having nailed down a specifically numeral-oriented spot in the brain, Parvizi’s lab is looking to use it in tracing the pathways described by the brain’s number-processing circuitry. “Neurons that fire together wire together,” said Shum. “We want to see how this particular area connects with and communicates with other parts of the brain.”

Researchers find out why some stress is good for you

Overworked and stressed out? Look on the bright side. Some stress is good for you.

“You always think about stress as a really bad thing, but it’s not,” said Daniela Kaufer, associate professor of integrative biology at the University of California, Berkeley. “Some amounts of stress are good to push you just to the level of optimal alertness, behavioral and cognitive performance.”

New research by Kaufer and UC Berkeley post-doctoral fellow Elizabeth Kirby has uncovered exactly how acute stress – short-lived, not chronic – primes the brain for improved performance.

In studies on rats, they found that significant, but brief stressful events caused stem cells in their brains to proliferate into new nerve cells that, when mature two weeks later, improved the rats’ mental performance.

“I think intermittent stressful events are probably what keeps the brain more alert, and you perform better when you are alert,” she said.

Kaufer, Kirby and their colleagues in UC Berkeley’s Helen Wills Neuroscience Institute describe their results in a paper published April 16 in the new open access online journal eLife.

The UC Berkeley researchers’ findings, “in general, reinforce the notion that stress hormones help an animal adapt – after all, remembering the place where something stressful happened is beneficial to deal with future situations in the same place,” said Bruce McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University, who was not involved in the study.

Kaufer is especially interested in how both acute and chronic stress affect memory, and since the brain’s hippocampus is critical to memory, she and her colleagues focused on the effects of stress on neural stem cells in the hippocampus of the adult rat brain. Neural stem cells are a sort of generic or progenitor brain cell that, depending on chemical triggers, can mature into neurons, astrocytes or other cells in the brain. The dentate gyrus of the hippocampus is one of only two areas in the brain that generate new brain cells in adults, and is highly sensitive to glucocorticoid stress hormones, Kaufer said.

Much research has demonstrated that chronic stress elevates levels of glucocorticoid stress hormones, which suppresses the production of new neurons in the hippocampus, impairing memory. This is in addition to the effect that chronically elevated levels of stress hormones have on the entire body, such as increasing the risk of chronic obesity, heart disease and depression.

Less is known about the effects of acute stress, Kaufer said, and studies have been conflicting.

To clear up the confusion, Kirby subjected rats to what, to them, is acute but short-lived stress – immobilization in their cages for a few hours. This led to stress hormone (corticosterone) levels as high as those from chronic stress, though for only a few hours. The stress doubled the proliferation of new brain cells in the hippocampus, specifically in the dorsal dentate gyrus.

Kirby discovered that the stressed rats performed better on a memory test two weeks after the stressful event, but not two days after the event. Using special cell labeling techniques, the researchers established that the new nerve cells triggered by the acute stress were the same ones involved in learning new tasks two weeks later.

“In terms of survival, the nerve cell proliferation doesn’t help you immediately after the stress, because it takes time for the cells to become mature, functioning neurons,” Kaufer said. “But in the natural environment, where acute stress happens on a regular basis, it will keep the animal more alert, more attuned to the environment and to what actually is a threat or not a threat.”

They also found that nerve cell proliferation after acute stress was triggered by the release of a protein, fibroblast growth factor 2 (FGF2), by astrocytes — brain cells formerly thought of as support cells, but that now appear to play a more critical role in regulating neurons.

“The FGF2 involvement is interesting, because FGF2 deficiency is associated with depressive-like behaviors in animals and is linked to depression in humans,” McEwen said.

Kaufer noted that exposure to acute, intense stress can sometimes be harmful, leading, for example, to post-traumatic stress disorder. Further research could help to identify the factors that determine whether a response to stress is good or bad.

“I think the ultimate message is an optimistic one,” she concluded. “Stress can be something that makes you better, but it is a question of how much, how long and how you interpret or perceive it.”

Scientists learn what makes nerve cells so strong

How do nerve cells — which can each be up to three feet long in humans — keep from rupturing or falling apart?

Axons, the long, cable-like projections on neurons, are made stronger by a unique modification of the common molecular building block of the cell skeleton. The finding, which may help guide the search for treatments for neurodegenerative diseases, was reported in the April 10 issue of Neuron by researchers at the University of Illinois at Chicago College of Medicine.

Microtubules are long, hollow cylinders that are a component of the cytoskeleton in all cells of the body. They also support transport of molecules within the cell and facilitate growth. They are made up of polymers of a building-block substance called tubulin.

“Except for neurons, cells’ microtubules are in constant dynamic flux — being taking apart and rebuilt,” says Scott Brady, professor and head of anatomy and cell biology at UIC and principal investigator on the study. But only neurons grow so long, he said, and once created they must endure throughout a person’s life, as much as 80 to 100 years. The microtubules of neurons are able to withstand laboratory conditions that cause other cells’ microtubules to break apart.

Brady had been able to show some time ago that the neuron’s stability depended on a modification of tubulin.

“But when we tried to figure out what the modification was, we didn’t have the tools,” he said.

Yuyu Song, a former graduate student in Brady’s lab and the first author of the study, took up the question. “It was like a detective story with many possibilities that had to be ruled out one by one,” she said. Song, who is now a post-doctoral fellow at Howard Hughes Medical Institute at Yale School of Medicine, used a variety of methods to determine the nature of the modification and where it occurs.

She found that tubulin is modified by the chemical bonding of polyamines, positively charged molecules, at sites that might otherwise be chinks where tubulin could be broken down, causing the microtubules to fall apart. She was also able to show that the enzyme transglutaminase was responsible for adding the protective polyamines.

The blocking of a vulnerable site on tubulin would explain the extraordinary stability of neuron microtubules, said Brady. However, convincing others required the “thorough and elegant work” that Song brought to it, he said. “It’s such a radical finding that we needed to show all the key steps along the way.”

The authors also note that increased microtubule stability correlates with decreased neuronal plasticity — and both occur in the process of aging and in some neurodegenerative diseases. Continued research, they say, may help identify novel therapeutic approaches to prevent neurodegeneration or allow regeneration.

New Findings on the Brain’s Immune Cells during Alzheimer’s Disease Progression

The plaque deposits in the brain of Alzheimer’s patients are surrounded by the brain’s own immune cells, the microglia. This was already recognized by Alois Alzheimer more than one hundred years ago. But until today it still remains unclear what role microglia play in Alzheimer’s disease. Do they help to break down the plaque deposit? A study by researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité – Universitätsmedizin Berlin has now shed light on these mysterious microglia during the progression of Alzheimer’s disease.

Dr. Grietje Krabbe of the laboratory of Professor Helmut Kettenmann (MDC) and Dr. Annett Halle of the Neuropathology Department of the Charité headed by Professor Frank Heppner demonstrated that the microglial cells around the deposits do not show the classical activation pattern in mouse models of Alzheimer´s disease. On the contrary, in the course of the Alzheimer’s disease they lose two of their biological functions. Both their ability to remove cell fragments or harmful structures and their directed process motility towards acute lesions are impaired. The impact of the latter loss-of-function needs further investigation. The plaques consist of protein fragments, the beta-amyloid peptides, which in Alzheimer’s disease are deposited in the brain over the course of years. They are believed to be involved in destroying the nerve cells of the affected patients, resulting in an incurable cognitive decline.

However, just why the microglial cells, which cluster around the deposits, are inactivated or lose their functionality is still not fully understood. The researchers concluded that this process occurs at a very early stage of disease development and is likely triggered by the beta-amyloid. This is confirmed by the fact that the loss-of-function of the microglial cells in the mice could be reversed by beta-amyloid antibodies thereby decreasing the beta-amyloid burden. According to the researchers, the potential to restore microglial function by directed manipulation should be pursued and exploited to develop treatments for Alzheimer’s disease.

'Strikingly similar' brains of man and fly may aid mental health research

A new study by scientists at King’s College London’s Institute of Psychiatry and the University of Arizona (UA) published in Science reveals the deep similarities in how the brain regulates behaviour in arthropods (such as flies and crabs) and vertebrates (such as fish, mice and humans).

The findings shed new light on the evolution of the brain and behaviour and may aid understanding of disease mechanisms underlying mental health problems.

Based on their own findings and available literature, Dr Frank Hirth (King’s) and Dr Nicholas Strausfeld (UA) compared the development and function of the central brain regions in arthropods (the ‘central complex’) and vertebrates (the ‘basal ganglia’).

Research suggests that both brain structures derive from embryonic stem cells at the base of the developing forebrain and that, despite the major differences between species, their respective constitutions and specifications derive from similar genetic programmes.

The authors describe that nerve cells in the central complex and the basal ganglia become inter-connected and communicate with each other in similar ways, facilitating the regulation of adaptive behaviours. In other words, the response of a fly or a mouse to internal stimuli such as hunger or sleep, and external stimuli such as light/dark or temperature, are regulated by similar neural mechanisms.

Dr Hirth from the Department of Neuroscience at King’s Institute of Psychiatry says: “Flies, crabs, mice, humans: all experience hunger, need sleep and have a preference for a comfortable temperature so we speculated there must be a similar mechanism regulating these behaviours. We were amazed to find just how deep the similarities go, despite the differences in size and appearance of these species and their brains.”

Dr Strausfeld, a Regents Professor in the UA’s Department of Neuroscience and the Director of the UA’s Center for Insect Science, says: “When you compare the two structures, you find that they are very similar in terms of how they’re organized. Their development is orchestrated by a whole suite of genes that are homologous between flies and mice, and the behavioral deficits resulting from disturbances in the two systems are remarkably similar as well.”

In humans, dysfunction of the basal ganglia can cause severe mental health problems ranging from autism, schizophrenia and psychosis, to neurodegeneration - as seen in Parkinson’s disease, motor neurone disease and dementia - as well as sleep disturbances, attention deficits and memory impairment. Similarly, when parts of the central complex are affected in fruit flies, they display similar impairments.

Dr Hirth (King’s) adds: “The deep similarities we see between how our brains and those of insects regulate behaviour suggest a common evolutionary origin. It means that prototype brain circuits, essential for behavioural choice, originated very early and have been maintained across animal species throughout evolutionary time. As surprising as it may seem, from insects’ dysfunctional brains, we can learn a great deal about how human brain disorders come about.”

The findings suggest that arthropod and vertebrate brain circuitries derive from a common ancestor already possessing a complex neural structure mediating the selection and maintenance of behavioural actions.

Although no fossil remains of the common ancestor exist, trace fossils, in the form of tracks criss-crossing the seafloor hundreds of millions of years ago, reveal purposeful changes in direction.

Dr Strausfeld (UA) says: “If you compare these tracks to the tracks left behind by a foraging fly larva on an agar plate or the tunnels made by a leaf-mining insect, they’re very similar. They all suggest that the animal chose to perform various different actions, and action selection is precisely what the central complex and the basal ganglia do.”

The trace fossils may thus support the early existence of brains complex enough to allow for action selection and a shared ancestry of neural structures between invertebrates and vertebrates.

How ‘free will’ is implemented in the brain and is it possible to intervene in the process?

Researchers have been able to identify the precise moment when a network of nerve cells (neurons) in the brain creates the signal to perform an action, before a person is even aware of deciding to take that action. Now they are building on this work to make initial attempts to interfere with consciously made decisions by decoding the pattern of brain activity in real time before an action is taken.

Professor Gabriel Kreiman will tell the British Neuroscience Association Festival of Neuroscience (BNA2013) today (Tuesday): “This could be useful to help elucidate the mechanistic basis by which neuronal circuits orchestrate ‘free’ will.”

Normally it is difficult to research the activity of neurons in the brain because it involves implanting electrodes – an invasive procedure that would not be ethical to do simply for scientific curiosity alone. However, Prof Kreiman, who is an associate professor at the Harvard Medical School, Boston, USA, together with neurosurgeon Itzhak Fried from University of California at Los Angeles (UCLA), had a rare opportunity to record the activity of over 1,000 neurons in two areas of the brain, the frontal and temporal lobes, when patients with epilepsy had had electrodes implanted to try to identify the source of their seizures.

“These patients have epilepsy that does not respond to drug treatment; Itzhak Fried implanted their brains with very thin electrodes (microwires) of about 40 micrometres in diameter in order to localise the focus of a seizure onset for a potential surgical procedure to alleviate the seizures. The microwires capture the extracellular electrical activity of neurons. Patients stay in the hospital for about a week. During this time, we have a unique opportunity to interrogate the activity of neurons and neural ensembles in the human brain at high spatial and temporal resolution,” explains Prof Kreiman.

The researchers asked the patients to move their index finger to click a computer mouse and to report when they made that decision. “Based on the activity of small groups of neurons, we could predict this decision several hundreds of milliseconds and, in some cases, seconds before the action. In a variant of the main experiment, the patients were allowed to choose whether to use their left hand or right hand and we showed that we could also predict this decision.”

The researchers found that an increasing number of neurons in two specific brain regions started to become active before the person was aware of their decision to move their finger. The two regions were the supplementary motor area, which is thought to be the area for preparing to perform motor actions, and the anterior cingulate cortex, which has a number of roles including the signalling processes associated with reward.

Prof Kreiman believes that these results provide initial steps to elucidate the mechanism for the emergence of conscious will in humans. “The activity of multiple neurons in extremely simple neural circuits precedes volition – in this case the decision to make a simple movement – until a threshold is crossed and the action is taken,” he will say.

Knowing when this threshold will be reached could enable researchers to see whether it is possible to interfere and maybe change the decision before any action is taken. “We are now making initial attempts to interfere with volition by decoding the neural responses in real time and asking whether there is a ‘point of no return’ in the hierarchical chain of command from unconscious decisions to volition to action,” says Prof Kreiman.

How these findings fit into the concept of “free will” is more complicated. “The concept of free will has been debated for millennia. Ultimately, current scientific understanding strongly suggests that ‘will’ has to be orchestrated by neurons in our brains (as opposed to magic or religious beliefs or other notions). We have provided initial steps to try to disentangle which neurons are involved, to show where and how ‘will’ or ‘volition’ could be implemented in the brain.

“Our work does not say that life is predetermined, that we can predict the future and that we can, for instance, determine what you are going to eat for lunch two weeks from now, or who you are going to marry.

“We are saying that volition (like other aspects of consciousness) is a brain phenomenon that is instantiated by physical hardware, i.e. neurons.  We are making claims about volition for very simple tasks, such as moving an index finger or choosing which hand to use, over scales of hundreds of milliseconds to seconds. Nothing more. Nothing less.

“Ultimately, our actions depend on multiple variables, several of which are external (for instance, it rains, hence, I will take my umbrella) and cannot be decoded or predicted from neurons. However, our volitional decision of whether to take the red umbrella or the blue one today – ultimately perhaps the real core of free will – is dictated by neurons,” Prof Kreiman will conclude.

Legal high Benzo Fury may be dangerous due to stimulant and hallucinogenic effects

The ‘legal high’ known as Benzo Fury may have stimulant as well as hallucinogenic effects according to new research presented at the British Neuroscience Association Festival of Neuroscience today (Tuesday 9 April 2013).

In a poster presentation at the meeting, Dr Jolanta Opacka-Juffry and Dr Colin Davidson reported that one of the main ingredients of Benzo Fury (also known as 5-APB) acts on brain tissue like both a stimulant and a hallucinogen – a combination of properties that is often found in illegal drugs and which can make them dangerous to users. The researchers believe this information should be disseminated to let potential users know the possible dangers of the drug.

Dr Opacka-Juffry, who is a principal lecturer in neuroscience and director of the health sciences research centre at the University of Roehampton, and Dr Davidson, senior lecturer in neuropharmacology and expert in drugs of addiction at St George’s, University of London, studied the effect of 5-APB samples from the brains of rats. In particular, they looked at the effect it had on serotonin receptors, which are affected by hallucinogenic drugs, and on a protein called the dopamine transporter (DAT), which pumps a neurotransmitter, dopamine, back in to nerve cells, terminating its activity, and which is involved in addiction. They compared the effects of 5-APB with those caused by cocaine and amphetamine.

“We have found that 5-APB behaves a little like amphetamine – that is, like a stimulant with addictive potential – and a bit like a hallucinogen, acting via serotonin receptors. This kind of mixed properties can be found in some illegal ‘designer’ drugs,” the presenting author, Dr Opacka-Juffry said.

“This finding is significant because it demonstrates that some ‘legal highs’ may have addictive properties, which are unlikely to be well-known amongst the users of these drugs. In addition, its effects on the serotonin receptors – known as 5-HT2A receptors – would suggest that it may lead to high blood pressure by causing constriction of the blood vessels, which would make the drug more dangerous. It is possible that the reason these drugs are so popular is because they are seen as safer than their illegal counterparts. It is important to challenge these assumptions.”

The researchers also found that 5-APB caused “reverse transport of dopamine”.

Dr Davidson said: “In theory, drugs which cause reverse transport could cause damage to the dopamine nerve cells. Other drugs such as amphetamines can also cause reverse transport, where dopamine is displaced from the nerve rather than mopped up by the dopamine transporter.”

Dr Opacka-Juffry said: “It is in the combination of these stimulant and hallucinogenic properties that the greatest danger lies. Pure hallucinogens are not addictive as such because they do not cause an increase in dopamine release, unlike amphetamine or cocaine. They are attractive to many people who enjoy the ‘mind altering’ properties of hallucinogens. But Benzo Fury with its mixed properties is a trap as its repetitive use for the hallucinogenic effects could lead to dependence, which the user may not expect.”

Further work needs to be carried out to find out more. “Rat data are quite informative as the brain addiction pathway is similar in rodents and humans. Long-term effects should be tested in rodents to investigate the potential toxic effects on the nervous system and the cardiovascular system, in addition to its liability for abuse due to addiction. We also need to collate data from human users. Taken together we can determine how dangerous this drug is,” she said.

Benzo Fury is currently one of the most popular legal highs in the UK and is also sold in the USA. It appears to be fairly easy to buy via the internet, at music festivals and clubs, and its street price is around £10 a pill or £25 for three. “However, tragedies such as the death of 19-year-old Alex Heriot at a music festival in June 2012 after taking Benzo Fury demonstrate the importance of making as much information available as possible about the potential adverse effects of these ‘highs’ as quickly as possible,” said Dr Opacka-Juffry.

Drs Opacka-Juffry and Davidson report that the approach they used to study Benzo Fury could be applied to other drugs as well, so that as new legal high drugs emerge, they can be tested quickly against the “gold standard” drugs such as cocaine and amphetamines to establish their relative danger.

Dr Davidson said: ”Over the last few years 40 or more new legal highs have appeared each year. Given the speed with which legal highs are developed and reach the market, it is important to be able to respond quickly to assess their potential dangers, and disseminate this information accordingly.”

Remarkable Success In Patients With Major Depression

For the first time, physicians from the Bonn University Hospital have stimulated patients’ medial forebrain bundles.

Researchers from the Bonn University Hospital implanted pacemaker electrodes into the medial forebrain bundle in the brains of patients suffering from major depression with amazing results: In six out of seven patients, symptoms improved both considerably and rapidly. The method of Deep Brain Stimulation had already been tested on various structures within the brain, but with clearly lesser effect. The results of this new study have now been published in the renowned international journal “Biological Psychiatry.”

After months of deep sadness, a first smile appears on a patient’s face. For many years, she had suffered from major depression and tried to end her life several times. She had spent the past years mostly in a passive state on her couch; even watching TV was too much effort for her. Now this young woman has found her joie de vivre again, enjoys laughing and traveling. She and an additional six patients with treatment resistant depression participated in a study involving a novel method for addressing major depression at the Bonn University Hospital.

Considerable amelioration of depression within days

Prof. Dr. Volker Arnd Coenen, neurosurgeon at the Department of Neurosurgery (Klinik und Poliklinik für Neurochirurgie), implanted electrodes into the medial forebrain bundles in the brains of subjects suffering from major depression with the electrodes being connected to a brain pacemaker. The nerve cells were then stimulated by means of a weak electrical current, a method called Deep Brain Stimulation. In a matter of days, in six out of seven patients, symptoms such as anxiety, despondence, listlessness and joylessness had improved considerably. “Such sensational success both in terms of the strength of the effects, as well as the speed of the response has so far not been achieved with any other method,” says Prof. Dr. Thomas E. Schläpfer from the Bonn University Hospital Department of Psychiatry und Psychotherapy (Bonner Uniklinik für Psychiatrie und Psychotherapie).

Central part of the reward circuit

The medial forebrain bundle is a bundle of nerve fibers running from the deep-seated limbic system to the prefrontal cortex. In a certain place, the bundle is particularly narrow because the individual nerve fibers lie close together. “This is exactly the location in which we can have maximum effect using a minimum of current,” explains Prof. Coenen, who is now the new head of the Freiburg University Hospital’s Department of Stereotactic and Functional Neurosurgery (Abteilung Stereotaktische und Funktionelle Neurochirurgie am Universitätsklinikum Freiburg). The medial forebrain bundle is a central part of a euphoria circuit belonging to the brain’s reward system. What kind of effect stimulation exactly has on nerve cells is not yet known. But it obviously changes metabolic activity in the different brain centers.

Success clearly increased over that of earlier studies

The researchers have already shown in several studies that deep brain stimulation shows an amazing and–given the severity of the symptoms– unexpected degree of amelioration of symptoms in major depression. In those studies, however, the physicians had not implanted the electrodes into the medial forebrain bundle but instead into the nucleus accumbens, another part of the brain’s reward system. This had resulted in clear and sustainable improvements in about 50 percent of subjects. “But in this new study, our results were even much better,” says Prof. Schläpfer. A clear improvement in complaints was found in 85 percent of patients, instead of the earlier 50 percent. In addition, stimulation was performed with lower current levels, and the effects showed within a few days, instead of after weeks.

Method’s long-term success proven

“Obviously, we have now come closer to a critical structure within the brain that is responsible for major depression,” says the psychiatrist from the Bonn University Hospital. Another cause for optimism among the group of physicians is that, since the study’s completion, an eighth patient has also been treated successfully. The patients have been observed for a period of up to 18 month after the intervention. Prof. Schläpfer reports, “The anti-depressive effect of deep brain stimulation within the medial forebrain bundle has not decreased during this period.” This clearly indicates that the effects are not temporary. This method gives those who suffer from major depression reason to hope. However, it will take quite a bit of time for the new procedure to become part of standard therapy.

Brain cell signal network genes linked to schizophrenia risk in families

New genetic factors that predispose to schizophrenia have been uncovered in five families with several affected relatives. The psychiatric disorder can disrupt thinking, feeling, and acting, and blur the border between reality and imagination.

Dr. Debby W. Tsuang, professor of psychiatry and behavioral sciences, and Dr. Marshall S. Horwitz, professor of pathology, both at the University of Washington in Seattle, led the multi-institutional study. Tsuang is also a staff physician at the Puget Sound Veterans Administration Health Care System.

The results are published in the April 3 online edition of the JAMA Psychiatry.

Loss of brain nerve cell integrity occurs in schizophrenia, but scientists have not worked out the details of when and how this happens. In all five families in the present study, the researchers found rare variants in genes tied to the networking of certain signal receptors on nerve cells distributed throughout the brain. These N-methyl-D-aspartate, or NMDA, receptors are widespread molecular control towers in the brain. They regulate the release of chemical messages that influence the strength of brain cell connections and the ongoing remodeling of the networks.

These receptors respond to glutamate, one of the most common nerve-signaling chemicals in the brain, and they are also found on brain circuits that manage dopamine release. Dopamine is a nerve signal associated with reward-seeking, movement and emotions. Deficits in glutamate and dopamine function have both been implicated in schizophrenia but most of the medications that have been developed to treat schizophrenia have targeted dopamine receptors.

Tsuang and her groups’ discovery of gene variations that disturb N-methyl-D-aspartate receptor networking functions supports the hypothesis that decreased NMDA receptor-mediated nerve-signal transmissions contributes to some cases of schizophrenia.

Tsuang pointed out that several hallucinogenic drugs, such as ketamine and phencyclidine (PCP, or angel dust), block N-methyl-D-aspartate receptors and can produce symptoms similar to schizophrenia. These are the strongest evidence implicating these receptors in schizophrenia. The drugs sometimes induce psychosis and terrifying sensory detachment. Reports of such effects in recreational drug users fingered faulty NMDA receptor networks as suspects in schizophrenia.

In all five of their study families, Tsuang’s team detected rare protein-altering variants in one of three genes involved with the N-methyl-D-aspartate receptor network. One of the genes, GRM5, is directly linked with glutamate signaling. In the other two genes, the links are indirect and connected through other proteins synthesized in brain cells. One of these proteins, PPEF2, appears to affect the levels of certain brain nerve-cell signaling mediators, and the other altered protein, LRP1B, may compete with a normal protein for a binding spot on a subunit of the NMDA receptor.

These discoveries provide additional clues to the molecular disarray that might occur in the brain nerve cells of some patients with schizophrenia, and suggest new targets for therapy for certain patients. In a disease occurring in about 1 percent of the population, the picture of how and why schizophrenia arises in all these people is far from complete.

“Disorders like schizophrenia are likely to have many underlying causes,” Tsuang noted. She added that it might eventually make sense to divide schizophrenia into categories based, for example, on which biochemical pathways in the brain are disrupted. Treatments might be developed to correct the exact malfunctioning mechanisms underlying various forms of the disease.

Tsuang gave an example: Agents that stimulate N-methyl-D-aspartate receptor-mediated nerve-signal transmissions include glycine-site blockers and glycine-transport inhibitors have shown some encouraging results in pre-clinical drug trials, but mostly in adjunctive treatment in addition to standard antipsychotic therapy.

“But perhaps the data we have generated will help pharmaceutical companies target specific subunits of the NMDA receptors and pathways,” Tsuang said. She added, however, that effective treatments may lag by many years after these kinds of discoveries. Someday it may make sense to initiate such treatments in people at high genetic risk when early symptoms, such as apathy and lack of motivation, appear, and before brain dysfunction is severe.

Also, possessing the newly discovered gene mutations does not always mean that a person will become schizophrenic. In the recent family study, three of the five families had relatives with the protein-altering variants who did not have schizophrenia.

“This isn’t surprising,” Tsuang observed, “Given that schizophrenia is such a complex disorder, we would expect that not everyone who carries the variants would develop the disease.” In the future, researchers will be seeking what triggers the gene variants into causing problems, other mutations within affected individuals’ genetic profile that might promote or protect against disease, as well as non-genetic factors in the onset of the illness in genetically susceptible people.

The researchers also utilized a strategy and selected more distant relatives of affected individuals for genetic sequencing. Distant kin share, a smaller proportion of genes compared to closely related family members. For example,siblings typically on the average share about 50 percent of their genes whereas cousins on the average share 12.5 percent of their genes. The researhers also hypothesized that the causative mutation within each family would be the same variant.

This strategy helped the researchers decrease the number of genetic variants that were detected by sequencing and thereby concentrate only on the remaining strongest candidates. The researchers also filtered their results against the many publicly available sequencing databases. This allowed them to pick out genetic variants not seen in individuals without psychiatric illness.

According to Tsuang, the research team was excited by recent advances in technology enabled them to uncover unknown, rare genetic variants not previously found in large populations without psychiatric condition. The ability to rapidly sequence only those portions of the genome that code for proteins made this experiment possible.

The next step for the researchers will be to screen for the newly discovered genetic variants in a large sample of unrelated cases of schizophrenia compared to controls. They want to determine if the variants are statistically associated with the disease.