Posts tagged Tourette syndrome

A chemical in the brain plays a vital role in controlling the involuntary movements and vocal tics associated with Tourette Syndrome (TS), a new study has shown.

The research by psychologists at The University of Nottingham, published in the latest edition of the journal Current Biology, could offer a potential new target for the development of more effective treatments to suppress these unwanted symptoms.

The study, led by PhD student Amelia Draper under the supervision of Professor Stephen Jackson, found that higher levels of a neurochemical called GABA in a part of the brain known as the supplementary motor area (SMA) helps to dampen down hyperactivity in the cortical areas that produce movement.

By reducing this hyperactivity, only the strongest signals would get through and produce a movement.

Greater control

Amelia said: “This result is significant because new brain stimulation techniques can be used to increase or decrease GABA in targeted areas of the cortex. It may be possible that such techniques to adjust the levels of GABA in the SMA could help young people with TS gain greater control over their tics.”

Tourette Syndrome is a developmental disorder associated with these involuntary and repetitive vocal and movement tics. Although the exact cause of TS is unknown, research has shown that people with TS have alterations in their brain ‘circuitry’  that are involved in producing and controlling motor functions.

Both the primary motor cortex (M1) and the supplementary motor area (SMA) are thought to be hyperactive in the brains of those with TS, causing the tics which can be both embarrassing and disruptive, especially for children who often find it difficult to concentrate at school.

Tics can be partially controlled by many people with TS but this often takes enormous mental energy and can leave them exhausted towards the end of the day and can often make their tics more frequent and excessive when they ‘relax’. The majority of people diagnosed with TS in childhood manage to gain control over their tics gradually until they have only mild symptoms by early adulthood but this is often too late for some people who have had their education and social friendships disrupted.

Greater detail

The scientists used a technique called magnetic resonance spectroscopy (MRS) in a 7 Tesla Magnetic Resonance Imaging (MRI) scanner to measure the concentration of certain chemicals in the brain known as neurotransmitters which offer an indication of brain activity.

The chemicals were measured in the M1, the SMA and an area involved in visual processing (V1) which was used as a control (comparison) site. They tested a group of young people with TS and a matched group of typical young people with no known disorders.

They discovered that the people with TS had higher concentrations of GABA, which inhibits neuronal activity, in the SMA.

They used other neuroscience techniques to explore the result in greater detail, finding that having more GABA in the SMA meant that the people with Tourette Syndrome had less activity in the SMA when asked to perform a simple motor task, in this case tapping their finger, which they were able to measure using functional MRI.

Using another technique called transcranial magnetic stimulation (TMS) in which a magnetic field is passed over the brain to stimulate neuron activity, they found that those with the most GABA dampen down the brain activity in the M1 when preparing to make a movement. In contrast, the typically developing group increased their activity during movement preparation.

Paradoxical finding

Finally, they considered how GABA was related to brain structure, specifically the white matter fibre bundles that connect the two hemispheres of the brain, a structure called the corpus callosum. They discovered that those with the highest levels of GABA also had the most connecting fibres, leading them to conclude that the more connecting fibres there are then the more excitatory signals are being produced leading to the need for even more GABA to calm this excess hyperactivity.

The results could lead the way to more targeted approaches to controlling tics. New brain techniques such as transcranial direct-current stimulation (tdcs), a form of neurostimulation which uses constant, low level electrical current delivered directly to the brain via electrodes, has already been shown to be successful in increasing or decreasing GABA in targeted areas of the cortex.

Professor Stephen Jackson added: “This finding is paradoxical because prior to our finding, most scientists working on this topic would have thought that GABA levels in TS would be reduced and not increased as we show. This is because a distinction should be made between brain changes that are causes of the disorder (e.g., reduced GABA cells in some key brain areas) and secondary consequences of the disorder (e.g., increased release of GABA in key brain areas) that act to reduce the effects of the disorder.”

New tdcs devices, similar to commercially-available TENS machines, could potentially be produced to be used by young people with TS to ‘train’ their brains to help them gain control over their tics, offering the benefit that they could be relatively cheap and could be used in the home while performing other tasks such as watching television.

(Source: nottingham.ac.uk)

An international research consortium led by investigators at Massachusetts General Hospital (MGH) and the University of Chicago has answered several questions about the genetic background of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS), providing the first direct confirmation that both are highly heritable and also revealing major differences between the underlying genetic makeup of the disorders. Their report is being published in the October issue of the open-access journal PLOS Genetics.

"Both TS and OCD appear to have a genetic architecture of many different genes – perhaps hundreds in each person – acting in concert to cause disease,” says Jeremiah Scharf, MD, PhD, of the Psychiatric and Neurodevelopmental Genetics Unit in the MGH Departments of Psychiatry and Neurology, senior corresponding author of the report. “By directly comparing and contrasting both disorders, we found that OCD heritability appears to be concentrated in particular chromosomes – particularly chromosome 15 – while TS heritability is spread across many different chromosomes.”

An anxiety disorder characterized by obsessions and compulsions that disrupt the lives of patients, OCD is the fourth most common psychiatric illness. TS is a chronic disorder characterized by motor and vocal tics that usually begins in childhood and is often accompanied by conditions like OCD or attention-deficit hyperactivity disorder. Both conditions have been considered to be heritable, since they are known to often recur in close relatives of affected individuals, but identifying specific genes that confer risk has been challenging.

Two reports published last year in the journal Molecular Psychiatry (1, 2), with leadership from Scharf and several co-authors of the current study, described genome-wide association studies (GWAS) of thousands of affected individuals and controls. While those studies identified several gene variants that appeared to increase the risk of each disorder, none of the associations were strong enough to meet the strict standards of genome-wide significance. Since the GWAS approach is designed to identify relatively common gene variants and it has been proposed that OCD and TS might be influenced by a number of rare variants, the research team adopted a different method. Called genome-wide complex trait analysis (GCTA), the approach allows simultaneous comparision of genetic variation across the entire genome, rather than the GWAS method of testing sites one at a time, as well as estimating the proportion of disease heritability caused by rare and common variants.

"Trying to find a single causative gene for diseases with a complex genetic background is like looking for the proverbial needle in a haystack,” says Lea Davis, PhD, of the section of Genetic Medicine at the University of Chicago, co-corresponding author of the PLOS Genetics report. “With this approach, we aren’t looking for individual genes. By examining the properties of all genes that could contribute to TS or OCD at once, we’re actually testing the whole haystack and asking where we’re more likely to find the needles.”

Using GCTA, the researchers analyzed the same genetic datasets screened in the Molecular Psychiatry reports – almost 1,500 individuals affected with OCD compared with more than 5,500 controls, and nearly TS 1,500 patients compared with more than 5,200 controls. To minimize variations that might result from slight difference in experimental techniques, all genotyping was done by collaborators at the Broad Institute of Harvard and MIT, who generated the data at the same time using the same equipment. Davis was able to analyze the resulting data on a chromosome-by-chromosome basis, along with the frequency of the identified variants and the function of variants associated with each condition.

The results found that the degree of heritability for both disorders captured by GWAS variants is actually quite close to what previously was predicted based on studies of families impacted by the disorders. “This is a crucial point for genetic researchers, as there has been a lot of controversy in human genetics about what is called ‘missing heritability’,” explains Scharf. “For many diseases, definitive genome-wide significant variants account for only a minute fraction of overall heritability, raising questions about the validity of the approach. Our findings demonstrate that the vast majority of genetic susceptibility to TS and OCD can be discovered using GWAS methods. In fact, the degree of heritability captured by GWAS variants is higher for TS and OCD than for any other complex trait studied to date.”

Nancy Cox, PhD, section chief of Genetic Medicine at the University of Chicago and co-senior author of the PLOS Genetics report, adds, “Despite the fact that we confirm there is shared genetic liability between these two disorders, we also show there are notable differences in the types of genetic variants that contribute to risk. TS appears to derive about 20 percent of genetic susceptibility from rare variants, while OCD appears to derive all of its susceptibility from variants that are quite common, which is something that has not been seen before.”

In terms of the potential impact of the risk-associated variants, about half the risk for both disorders appears to be accounted for by variants already known to influence the expression of genes in the brain. Further investigation of those findings could lead to identification of the affected genes and how the expression changes contribute to the development of TS and OCD. Additional studies in even larger patient populations, some of which are in the planning stages, could identify the biologic pathways disrupted in the disorder, potentially leading to new therapeutic approaches.

(Source: medicalxpress.com)

16 August 2012

Ten out of 11 patients with severe Tourette’s Syndrome have reported improvement after receiving deep brain stimulation surgery, according to University of New South Wales research published in the American Journal of Psychiatry. 

Tourette’s Syndrome is a neurological disorder characterised by repetitive involuntary movements and vocalisations called tics and can also include behavioural difficulties. 

Deep brain stimulation is a therapeutic technique that involves placing electrodes at specific sites in the brain to deliver continuous stimulation from an implanted generator.

Study leader, UNSW Scientia Professor Perminder Sachdev, says deep brain stimulation may have an important role in treating Tourette’s Syndrome in its most severe form. He says tics are generally treated with medications that work well in about 50 to 70 per cent of cases. Drugs, however, can have side effects in some patients. 

Eleven patients, eight of them in their late thirties with severe Tourette’s Syndrome, underwent deep brain stimulation at St Andrew’s Hospital in Brisbane - under the care of neurologist Professor Peter Silburn and neurosurgeon Associate Professor Terry Coyne - as part of the study. They were followed up initially one month after surgery and then around a year after the procedure.

Ten out of the 11 patients involved in the joint UNSW Medicine and Asia-Pacific Centre for Neuromodulation study reported immediate improvement in tic severity soon after the treatment, with an overall 48 per cent reduction in monitor tics and a 57 per cent reduction in phonic tics at final follow-up. Associated psychiatric symptoms also improved.

“Because deep brain stimulation involves brain surgery, it has some risks, even though these are low. It is therefore only likely to be used in individuals who are significantly affected by their tics,” Scientia Professor Sachdev says.

“Our study demonstrates that when suitably selected, patients can benefit greatly from deep brain stimulation.”

Source: University of New South Wales

The first genome-wide searches for the genes responsible for Tourette syndrome and obsessive-compulsive disorder have uncovered a few clues to the underpinnings of both disorders.

Tourette syndrome is a neurological disorder characterized by muscle and vocal tics such as eye blinking, throat clearing and uttering taboo words or phrases. Tourette’s often co-occurs with obsessive-compulsive disorder (OCD), a mental illness marked by repetitive behaviors and anxiety-producing intrusive thoughts.

Neither Tourette syndrome nor OCD are simple enough to be traced to a single gene, but two new studies detailed today (Aug. 14) in the journal Molecular Psychiatry find several locations on the human chromosome that may contribute to the conditions.

A DNA molecule.
CREDIT: Giovanni Cancemi | Shutterstock

"Both disorders clearly have a complex underlying genetic architecture, and these two studies lay the foundation for understanding the underlying genetic etiology of Tourette syndrome and OCD," said Jeremiah Scharf, a neurologist at Massachusetts General Hospital in Boston, who worked on both projects. 

Genetics of Tourette Syndrome

In the Tourette syndrome study, Scharf and his colleagues compared the genomes of more than 1,200 people with the disorder with the genomes of nearly 5,000 healthy individuals. They conducted what’s called a genome-wide association study, scanning hundreds of thousands of genetic variants from across the genomes to see if any were more common in the people with the disorder.

They found that no single genetic signal was significantly different between the two genomes, meaning that the researchers could not rule out random chance as the reason for any given difference. But among the top genetic variations, the researchers found an unusually high number that influence levels of gene expression in the frontal lobe of the brain — a region important in both Tourette syndrome and OCD, Scharf said.

One intriguing gene that varied the most between Tourette- and non-Tourette genomes was called COL27A1, a gene that encodes a collagen protein found in cartilage. The same gene is also active in the cerebellum, a brain region important for motor control during development. More research will be necessary to find what link, if any, COL27A1 has to Tourette syndrome, Scharf said.

The architecture of OCD

In a separate study, the scientists carried out the same analysis on healthy genomes as well as about 1,500 people with obsessive-compulsive disorder. Again, no one gene rose to the top as a definitive OCD gene, but the results revealed a good candidate near a gene called BTBD3, which is involved in multiple cellular functions. BTBD3 is very active in the brain during childhood and adolescent development, when OCD often first appears. It’s also related to a gene called BTBD9, which has been linked to Tourette syndrome in the past.

This first genome-wide pass is bound to turn up some false positives, Scharf said, so researchers will now need to home in on the intriguing genes in larger samples of people. They are also merging the two studies to look for genetic linkages that might explain why Tourette syndrome and OCD so frequently co-occur.

"The important thing this study does is that it really brings Tourette syndrome and OCD into the company of a number of other psychiatric diseases, which people have studied using genome-wide association," Scharf said, citing autism, schizophrenia and bipolar disorder as examples. “Now that we have these data for Tourette syndrome and OCD, we can work with investigators who are studying those other diseases to try to see what we can learn about what variants are shared between different neurodevelopment disorders.”

Source: Live Science