Neuroscience

Adolescent boys with attention deficit hyperactivity disorder (ADHD) are more likely to be shorter and slimmer than their same-age peers, according to a new study published in the Medical Journal of Australia today.

Dr Alison Poulton from the University of Sydney and her coauthors investigated the influence of stimulant medication on the growth and physical development during puberty of adolescent boys with ADHD.

The study found that prolonged treatment for more than three years with stimulant medication was associated with a slower rate of physical development during puberty.

"Our findings suggest that stimulant medication delays the rate of maturation during puberty, including the timing of the peak growth rate, but not the onset of puberty," said Dr Poulton, from Sydney Medical School.

"To maintain an adequate rate of growth during puberty we recommend that boys on ADHD stimulant medication should take the lowest dose that adequately treats their ADHD," said Dr Poulton.

The researchers recruited 65 boys aged between 12 and 16 years who had ADHD and had been on stimulant medication for more than three years. Compared with boys without ADHD, boys aged between 12 and 14 years with ADHD had significantly lower weight and body mass index, and those aged between 14 and 16 years with ADHD had significantly lower height and weight.

There was no difference in pubertal development between boys with and those without ADHD aged between 12 and 14 years, but those aged between 14 and 16 years with ADHD showed significant delay.

The study also found there was a significant inverse relationship between the dose of stimulant medication and the growth rate among boys aged between 14 and 16 years with ADHD.

The authors found that boys who had taken stimulant medication for ADHD for a minimum of three years until 14 years of age showed slower weight gain but comparable height and physical development related to puberty to boys of the same age without ADHD.

However, boys aged between 14 and 16 years with ADHD were significantly behind their peers in height and pubertal development.

Attention Deficit Hyperactivity Disorder (ADHD) is the most common childhood neuropsychiatric disorder. Yet there is currently no tool that will confirm the diagnosis of ADHD. In her thesis entitled “Development of a genotyping system to be applied in Attention Deficit Hyperactivity Disorder and its Pharmacogenetics” (“Desarrollo de un sistema de genotipado para la aplicación en el ‘trastorno por déficit de atención con hiperactividad’ y su farmacogenética”), the researcher Alaitz Molano, a graduate in biochemistry and PhD holder in Pharmacology from the UPV/EHU-University of the Basque Country, presents a tool that could improve not only the diagnosis of but also the therapeutics for this disorder.

The prevalence of ADHD is between 8% and 12% among the infant-adolescent population worldwide, and 50% continue with the symptoms into adult life. Children with ADHD have difficulty paying attention, do not complete the tasks they have been assigned and are frequently distracted. They may also display impulsive behaviour and excessive, inappropriate activity in the context they find themselves in, and experience great difficulty restraining their impulses. “All these symptoms seriously affect the social, academic and working life of the individuals, and impact greatly upon their families and milieu close to them,” says Molano.

In view of the problems existing in diagnosing ADHD patients and deciding about their treatment, this PhD thesis set out to develop and clinically validate a genotyping tool that could help to confirm the diagnosis, to predict how it will evolve, and to select the most suitable pharmacological treatment in each case.

Molano studied how genetic polymorphisms (variations in the DNA sequence between different individuals) are associated with ADHD. “We looked for all the associations that had been described previously in the literature worldwide, and did a clinical study to see whether these polymorphisms also occurred in the Spanish population; the reason is that genetic associations vary a lot between some populations and others.”

About 400 saliva samples of patients with ADHD and a further 400 samples from healthy controls without a history of psychiatric diseases were analysed. And the use of over 250 polymorphisms led to the discovery of 32 polymorphisms associated not only with the diagnosis of ADHD but also with the evolution of the disorder, with the ADHD subtype, the symptomatological severity and the presence of comorbidities.

On the basis of these results, Molano is proposing a DNA chip with these 32 polymorphisms, which could be updated with new polymorphisms, as a tool not only for diagnosing but also for calculating genetic susceptibility to different variables (responding well to drugs, normalisation of symptoms, etc.).

The study has also confirmed the existence of the 3 ADHD subtypes: lack of attention, hyperactivity, and a combination. “It can be seen that on the basis of genetics the children that belong to one subtype or another are different,” explains Molano.

By contrast, no direct associations were found between the polymorphisms analysed and the response to pharmacological treatment (atomoxetine and methylphenidate). Molano believes that this could be due to the fact that “in many cases the data on drugs we had available were not rigorous,” due to the difficulty in collecting data of this kind. Molano will in fact be pursuing her research along this line: “We want to concentrate on the drug response aspect, obtain more, better characterised samples, and monitor the variables in the taking of drugs very closely, whether they were actually being taken or not, etc.”

Molano hopes that this tool will reach the clinics: “The project was funded by Progenika Biopharma and the pharmaceutical company JUSTE SAFQ, but we also have another 10 collaborating clinics belonging to public and private centres in Spain, and it’s tricky getting them all to agree on matters like patents, marketing, etc. But our idea is that it should eventually be marketed and be welcomed.”

Scientists at the University of Birmingham have devised a unique screening instrument that provides a ‘one-stop’ brain function profile of patients who have suffered stroke or other neurological damage.

The Birmingham Cognitive Screen (BCoS) can offer a visual snapshot of the cognitive abilities and deficits of an individual which can then be used to guide clinical decision making.

Following brain damage, including stroke, head injury, carbon monoxide poisoning and degenerative change, people can experience a range of cognitive problems as well as difficulty with physical movement. Cognitive problems strongly influence a patient’s ability to recover but patients are not routinely screened to detect them.

The first test of its kind, BCoS has been designed by a team of brain experts co-ordinated by Research Fellow Dr Wai-Ling Bickerton (also a chartered psychologist and occupational therapist) at the University of Birmingham in collaboration with Professors Glyn Humphreys and Jane Riddoch at Oxford University and Dana Samson at Louvain University.

Comprising a user-friendly manual, a test book, a CD containing Auditory Attention Test stimuli, a supply of examiner and examinee booklets and a zip-up pouch of test objects, the test takes 45-60 minutes and is carried out by trained health professionals and covers a range of cognitive abilities, including attention, executive function, spatial awareness, speech and language processing, action planning and control, memory, and number processing.

‘Through research outcomes supported by the Stroke Association, BCoS has already been used to successfully assess more than 1,000 stroke survivors in the West Midlands,’ explains Dr Bickerton. ‘BcoS has been validated against “standard” neuropsychological tests and assessed against measures of cognition and activities of everyday living for patients in the chronic stage.

‘The test has been designed to be highly inclusive and, as such, is an optimal tool for most stroke survivors regardless of the cognitive effects of stroke,’ she says. ‘It is also applicable to individuals with brain injury or dementia. 

A Queen’s University study is giving new insight into how the neurons in our brains control our limbs. The research might one day help with the design of more functional artificial limbs.

“We’ve taken a step closer to understanding how our arms and legs work and how we move our bodies,” says neuroscience researcher Tim Lillicrap, who worked with neuroscience professor Stephen Scott on the study.

The researchers used a novel network model, coupled with a computer biophysics model of a limb, to explain some of the prominent patterns of neural activity seen in the brain during movements.

The findings refine previous notions of how neurons in the primary motor cortex fire and drive muscles. The primary motor cortex is the region of the brain that sends the largest number of connections to the spinal cord.

When moving an arm or a leg, nerve impulses are sent along nerve fibres to control the movement of limbs. Different movements require different patterns of nerve impulses — the relationship between these neural patterns and the resulting movements is poorly understood.

The study demonstrates that the patterns of activity are related to specific details of limb physics — for example, the patterns of neural activity are tuned (or optimized) for muscle architecture and limb geometry.

Dr. Lillicrap, who did the study as part of his PhD thesis at Queen’s and is now a post-doctoral fellow at Oxford University in England, says better understanding of how the brain controls limbs will help develop artificial limbs in the future.

Approximately half a million individuals suffer strokes in the US each year, and about one in five develops some form of post-stroke aphasia, the partial or total loss of the ability to communicate. By comparing different types of aphasia, investigators have been able to gain new insights into the normal cognitive processes underlying language, as well as the potential response to interventions. Their findings are published alongside papers on hemispatial neglect and related disorders in the January, 2013 issue of Behavioural Neurology.

The January issue of Behavioural Neurology, edited by the journal’s co-Editor in Chief, Argye E. Hillis, MD, of the Departments of Neurology, Physical Medicine and Rehabilitation, and Department of Cognitive Science, Johns Hopkins University, Baltimore, Maryland, features papers on two topics that have traditionally captured the interest of behavioral neurologists – aphasia and hemispatial neglect.

The first section on aphasia includes a number of papers that compare post-stroke aphasia with primary progressive aphasia (PPA), in which the predominant deficit is language (with or without apraxia).

Andreia V. Faria, MD, Department of Radiology, Johns Hopkins University School of Medicine, and colleagues from Johns Hopkins and University College, London, report patterns of dysgraphia (spelling impairment) in participants with primary progressive aphasia, and compare these patterns to those in participants with dysgraphia following stroke. They also report the areas of focal atrophy associated with the most common pattern of dysgraphia in PPA and suggest this can not only provide a better understanding of the neural substrates of spelling, but may also provide clues to more effective treatment approaches.

Matthew A. Lambon Ralph, FRSLT (hons), FBPsS, and colleagues from the School of Psychological Sciences, University of Manchester, UK; the Department of Psychology, University of York, UK; and the Stroke and Dementia Research Centre, St George’s University of London, UK, use a novel approach to explore nonverbal semantic processing to demonstrate the qualitative differences between semantic aphasia and semantic dementia. Their conclusions provide further support for the proposal that semantic cognition is underpinned by two principle components: semantic representations and regulatory control processes which regulate and shape activation within the semantic system.

Cynthia K. Thompson, PhD, and colleagues from the Department of Communication Sciences and Disorders, Department of Neurology, Cognitive Neurology and Alzheimer’s Disease Center, and Department of Psychiatry and Behavioral Sciences at Northwestern University, Evanston, Illinois, evaluate the distinct patterns of morphological and syntactic errors in the variants of PPA, and compare them with patterns of errors in post-stroke aphasia.

Other papers compare treatment results of spelling in one individual with logopenic variant PPA (lvPPA) with an individual with post-stroke dysgraphia, and results of a new method of assessment of verbal and nonverbal memory in PPA. The issue is completed by three Clinical Notes including a fascinating case of an unusual form of lvPPA that degenerated into jargon aphasia, a case of nonfluent agrammatic variant PPA due to Pick disease with (what is argued to be) concomitant incidental Alzheimer’s disease pathology, and a case of successful treatment of PPA.

“Together, these papers illustrate how investigating PPA and post-stroke aphasia can yield complementary insights about brain-behavior relationships as well as about potential response to interventions and the normal cognitive processes underlying language,” says Dr Hillis.

Hemispatial neglect is characterized by reduced awareness of stimuli on one side of space. It occurs only after relatively focal (or at least asymmetric) brain damage, most commonly stroke, but is occasionally observed in other syndromes. In this second group of seven papers, Jonathan T. Kleinman, MD, of Johns Hopkins University School of Medicine, and Stanford University School of Medicine, Stanford, California, and colleagues from Johns Hopkins University School of Medicine, report an investigation of perseveration versus hemispatial neglect, and the lesion sites associated with each in acute stroke. The issue also includes an important paper by Junichi Ishizaki, PhD, and co-workers at the Department of Geriatric Behavioral Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan, of impaired visual-spatial attention in Alzheimer’s disease, which shows how a symmetric neurodegenerative disease results in impaired shifting of visual spatial attention, but not hemispatial neglect.

“Hemispatial neglect remains one of the most remarkable syndromes investigated by behavioral neurologists,” comments Dr Hillis. “These novel studies of neglect and related disorders provide new insights into brain-behavior relationships on the basis of detailed analysis of patient performance – and in many cases, their lesion sites.“

Genetics researchers have identified 25 additional copy number variations (CNVs)—missing or duplicated stretches of DNA—that occur in some patients with autism. These CNVs, say the researchers, are “high impact”: although individually rare, each has a strong effect in raising an individual’s risk for autism.

“Many of these gene variants may serve as valuable predictive markers,” said the study’s corresponding author, Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia. “If so, they may become part of a clinical test that will help evaluate whether a child has an autism spectrum disorder.”

Hakonarson collaborated with scientists from the University of Utah and the biotechnology company Lineagen, Inc., in the study, published in the journal PLOS ONE.

The current study builds on and extends previous gene research by Hakonarson and other scientists on autism spectrum disorders (ASDs), a group of childhood neurodevelopmental disorders that cause impairments in verbal communication, social interaction and behavior. Estimated by the CDC to affect as many as one in 88 U.S. children, ASDs are known from family studies to be strongly influenced by genetics.

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A micrograph of a killer T cell, a white blood cell that destroys germs or cancers, but that can sometimes attack the body’s own normal cells.

Misguided killer T cells may be the missing link in sustained tissue damage in the brains and spines of people with multiple sclerosis, findings from the University of Washington reveal. Cytoxic T cells, also known as CD8+ T cells, are white blood cells that normally are in the body’s arsenal to fight disease.

Multiple sclerosis is characterized by inflamed lesions that damage the insulation surrounding nerve fibers and destroy the axons, electrical impulse conductors that look like long, branching projections. Affected nerves fail to transmit signals effectively.

Intriguingly, the UW study, published this week in Nature Immunology, also raises the possibility that misdirected killer T cells might at other times act protectively and not add to lesion formation. Instead they might retaliate against the cells that tried to make them mistake the wrappings around nerve endings as dangerous.

Scientists Qingyong Ji and Luca Castelli performed the research with Joan Goverman, UW professor and chair of immunology. Goverman is noted for her work on the cells involved in autoimmune disorders of the central nervous system and on laboratory models of multiple sclerosis.

Multiple sclerosis generally first appears between ages 20 to 40. It is believed to stem from corruption of the body’s normal defense against pathogens, so that it now attacks itself. For reasons not yet known, the immune system, which wards off cancer and infection, is provoked to vandalize the myelin sheath around nerve cells. The myelin sheath resembles the coating on an electrical wire. When it frays, nerve impulses are impaired.

Depending on which nerves are harmed, vision problems, an inability to walk, or other debilitating symptoms may arise. Sometimes the lesions heal partially or temporarily, leading to a see-saw of remissions and flare ups. In other cases, nerve damage is unrelenting.

The myelin sheaths on nerve cell projections are fashioned by support cells called oligodendrocytes. Newborn’s brains contain just a few sections with myelinated nerve cells. An adult’s brains cells are not fully myelinated until age 25 to 30.

For T cells to recognize proteins from a pathogen, a myelin sheath or any source, other cells must break the desired proteins into small pieces, called peptides, and then present the peptides in a specific molecular package to the T cells. Scientists had previously determined which cells present pieces of a myelin protein to a type of T cell involved in the pathology of multiple sclerosis called a CD4+ T cell. Before the current study, no cells had yet been found that present myelin protein to CD8+ T cells.

Scientists strongly suspect that CD8+ T cells, whose job is to kill other cells, play an important role in the myelin-damage of multiple sclerosis. In experimental autoimmune encephalitis, which is a mouse model of multiple sclerosis in humans, CD4+ T cells have a significant part in the inflammatory response. However, scientists observed that, in acute and chronic multiple sclerosis lesions, CD8+T cells actually outnumber CD4+ T cells and their numbers correlate with the extent of damage to nerve cell projections. Other studies suggest the opposite: that CD8+ T cells may tone down the myelin attack.

The differing observations pointed to a conflicting role for CD8+ T cells in exacerbating or ameliorating episodes of multiple sclerosis. Still, how CD8+ T cells actually contributed to regulating the autoimmune response in the central nervous system, for better or worse, was poorly understood.

TIP dendritic cells, stained to show their physical features.

Goverman and her team showed for the first time that naive CD8+ T cells were activated and turned into myelin-recognizing cells by special cells called Tip-dendritic cells. These cells are derived from a type of inflammatory white blood cell that accumulates in the brain and the spinal cord during experimental autoimmune encephalitis originally mediated by CD4+ T cells. The membrane folds and protrusions of mature dendritic cells often look like branched tentacles or cupped petals well-suited to probing the surroundings.

The researchers proposed that the Tip dendritic cells can not only engulf myelin debris or dead oligodendrocytes and then present myelin peptides to CD4+ T cells, they also have the unusual ability to load a myelin peptide onto a specific type of molecule that also presents it to CD8+ T cells. In this way, the Tip dendritic cells can spread the immune response from CD4+ T cells to CD8+ T cells. This presentation enables CD8+ T cells to recognize myelin protein segments from oligodendrocytes, the cells that form the myelin sheath. The phenomenon establishes a second-wave of autoimmune reactivity in which the CD8+ T cells respond to the presence of oligodendrocytes by splitting them open and spilling their contents.

“Our findings are consistent,” the researchers said, “with the critical role of dendritic cells in promoting inflammation in autoimmune diseases of the central nervous system.” They mentioned that mature dendritic cells might possibly wait in the blood vessels of normal brain tissue to activate T-cells that have infiltrated the blood/brain barrier.

The oligodendrocytes, under the inflammatory situation of experimental autoimmune encephalitis, also present peptides that elicit an immune response from CD8+ T cells. Under healthy conditions, oligodendrocytes wouldn’t do this.

The researchers proposed that myelin-specific CD8+ T cells might play a role in the ongoing destruction of nerve-cell endings in “slow burning” multiple sclerosis lesions. A drop in inflammation accompanied by an increased degeneration of axons (electrical impulse-conducting structures) coincides with multiple sclerosis leaving the relapsing-remitting stage of disease and entering a more progressive state.

Medical scientists are studying the roles of a variety of immune cells in multiple sclerosis in the hopes of discovering pathways that could be therapeutic targets to prevent or control the disease, or to find ways to harness the body’s own protective mechanisms. This could lead to highly specific treatments that might avoid the unpleasant or dangerous side effects of generalized immunosuppressants like corticosteroids or methotrexate.