Selected Recent Papers

Here is a short list of some recently published scientific articles from our team. More publications can be found in each specific project page, within the Research menu.

Fundamental research – Molecules & Cells

CDKL5 variants: Improving our understanding of a rare neurologic disorder. Ralph D. Hector, Vera M. Kalscheuer, Friederike Hennig, Helen Leonard, Jenny Downs, Angus Clarke, Tim A. Benke, Judith Armstrong, Mercedes Pineda, Mark E.S. Bailey and Stuart R. Cobb. Neurology Genetics December 2017;

This is a study of all the genetic variants in the CDKL5 gene, in patients with CDKL5 deficiency and in the general population. The study analysed data from recent large-scale studies in which thousands of people in the general population had their DNA and RNA sequenced. The researchers compared the data from these populations with patients with mutations in CDKL5 to gain insights into which parts of the gene (and protein) are important for CDKL5 function, and how best to target genetic therapies.

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Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome. Sophie R. Thomson, Sang S. Seo, Stephanie A. Barnes, Susana R. Louros, Melania Muscas, Owen Dando, Caoimhe Kirby, David J.A. Wyllie, Giles E. Hardingham, Peter C. Kind, Emily K. Osterweil. Neuron. August 2017; Volume 95, Issue 3, p550–563.e5

The Osterweil lab has identified a potential new strategy for treating fragile X syndrome. As excessive protein synthesis is pathological in the fragile X brain, it is thought that over-produced proteins should be downregulated. In their study, they found that one of the most over-produced proteins, muscarinic receptor M4, is something that is potentially protective. By boosting the function of M4 it can correct multiple phenotypes in the fragile X mouse model, including seizures. This suggests that some of the over-produced proteins in the fragile X brain should be enhanced rather than inhibited.

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Stimulated Emission Depletion (STED) Microscopy Reveals Nanoscale Defects in the Developmental Trajectory of Dendritic Spine Morphogenesis in a Mouse Model of Fragile X Syndrome. Wijetunge LS1, Angibaud J, Frick A, Kind PC, Nägerl UV.  J Neurosci. 2014 Apr 30;34(18):6405-12.

Dendritic spines are basic units of neuronal information processing and their structure is closely reflected in their function. Defects in synaptic development are common in neurodevelopmental disorders, making detailed knowledge of age-dependent changes in spine morphology essential for understanding disease mechanisms. However, little is known about the functionally important fine-morphological structures, such as spine necks, due to the limited spatial resolution of conventional light microscopy. Using stimulated emission depletion microscopy (STED), we examined spine morphology at the nanoscale during normal development in mice, and tested the hypothesis that it is impaired in a mouse model of fragile X syndrome (FXS). In contrast to common belief, we find that, in normal development, spine heads become smaller, while their necks become wider and shorter, indicating that synapse compartmentalization decreases substantially with age. In the mouse model of FXS, this developmental trajectory is largely intact, with only subtle differences that are dependent on age and brain region. Together, our findings challenge current dogmas of both normal spine development as well as spine dysgenesis in FXS, highlighting the importance of super-resolution imaging approaches for elucidating structure–function relationships of dendritic spines.

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Link to study summary 

Fundamental research – Circuits & Behaviour

Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome. Antonis Asiminas, Adam D. Jackson, Susana R. Louros, Sally M. Till, Teresa Spano, Owen Dando, Mark F. Bear, Sumantra Chattarji, Giles E. Hardingham, Emily K. Osterweil, David J. A. Wyllie, Emma R. Wood and Peter C. Kind. Science Translational Medicine, May 2019;

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. Pharmacological intervention using the cholesterol-lowering drug lovastatin had therapeutic effect on behavior in patients. Selecting the time of intervention and the therapeutic protocol is critical for maximizing the therapeutic effects. Now, Asiminas et al. tested the effect of temporary early treatment with lovastatin in a rat model of FXS. The authors showed that 5-week treatment initiated before complete development of cognitive abilities rescued cognitive development. The therapeutic effect persisted for more than 3 months after treatment termination. The results suggest that lovastatin treatment initiated early during development might have disease-modifying effect in FXS.

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Clinical research – Diversity & Lived experiences

Mental health on screen: A DSM-5 dissection of portrayals of autism spectrum disorders in film and TV. Anders Nordahl-Hansen, Magnus Tøndevold, Sue Fletcher-Watson. Psychiatry Research August 2017;

The researchers found that representations of autism on screen align unrealistically-perfectly with the diagnostic criteria, making portrayals of autism archetypal, but not representative. This may be contributing to narrow stereotypes about autism, which in turn is expected to impact on the day to day experiences of people on the autism spectrum.

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Links between Autism Spectrum Disorder Diagnostic Status and Family Quality of Life. Andrew G. McKechanie, Vivien J. Moffat, Eve C. Johnstone and Sue Fletcher-Watson. Children 2017; 4:23. doi:10.3390/children4040023

Dr Andrew McKechanie and colleagues have demonstrated that for children who have high levels of autistic traits, those who have been given a formal diagnosis of autism tend to have lower levels of family stress and better family quality of life, than those who have not been given a diagnosis.

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Attitudes of the autism community to early autism research. Fletcher-Watson S, Apicella F, Auyeung B, Beranova S, Bonnet-Brilhault F, Canal-Bedia R, Charman T, Chericoni N, Conceição IC, Davies K, Farroni T, Gomot M, Jones E, Kaale A, Kapica K, Kawa R, Kylliäinen A, Larsen K, Lefort-Besnard J, Malvy J, Manso de Dios S, Markovska-Simoska S, Millo I, Miranda N, Pasco G, Pisula E, Raleva M, Rogé B, Salomone E, Schjolberg S, Tomalski P, Vicente AM, Yirmiya N. Autism 2017; 21(1):61-74.

Dr Sue Fletcher-Watson led a large-scale international project to examine how the autism community views early autism research.  Over 2000 people were surveyed for the research, from across 11 European countries. Although generally favourably disposed, concerns were raised about certain aspects of early autism research, highlighting the importance of seeking community input into future research design.

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Endocrine Dysfunction in Female FMR1 Premutation Carriers: Characteristics and Association with Ill Health. Sonya Campbell, Sarah E. A. Eley, Andrew G. McKechanie and Andrew C. Stanfield. Genes 2016; 7: 101. doi:10.3390/genes7110101

Dr Sonya Campbell and colleagues examined the health of a group of women who carry the fragile X premutation and found that those with signs of endocrine disorders (such as thyroid disease or reproductive difficulties) were at greater risk of developing other health problems.  Although only a small study, this suggests that women with the premutation should be actively screened for endocrine disorders as a risk marker for other health problems.

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Clinical research – Behaviour & Cognition

Preterm birth is associated with atypical social orienting in infancy detected using eye tracking. Emma J. Telford, Sue Fletcher-Watson, Karri Gillespie-Smith, Rozalia Patak, Sarah Sparrow, Ian C. Murray,Anne O’Hare, James P. Boardman. 

Researchers at the Jennifer Brown Research Laboratory, in partnership with the Patrick Wild Centre, have recently published work exploring how babies born too soon and too small develop and learn. The project found widespread evidence, across a range of different types of experiments, of unusual attention to social information in the babies who had been born premature. In a nutshell, these infants seemed to find socially important information, like people’s faces, less interesting than other babies who had been born around their due date. The group is now going to follow up these same babies to see if early signs of unusual social interest relate to later things like how children play and interact with others.

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Evaluation of a screening instrument for autism spectrum disorders in prisoners. Robinson L, Spencer MD, Thomson LD, Stanfield AC, Owens DG, Hall J, Johnstone EC. PLoS One. 2012; 7(5):e36078.

There have been concerns that individuals with autism spectrum disorders (ASD) are over-represented but not recognised in prison populations. A screening tool for ASD in prisons was therefore developed and tested in 2458 prisoners in Scotland.  The tool was found to be a measure of autistic traits in this population but did not perform sufficiently accurately to recommend its routine use.

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Social cognition, the male brain and the autism spectrum. Hall J, Philip RC, Marwick K, Whalley HC, Romaniuk L, McIntosh AM, Santos I, Sprengelmeyer R, Johnstone EC, Stanfield AC, Young AW, Lawrie SM. PLoS One. 2012; 7(12):e49033.

This study aimed to test the idea that autism spectrum disorders (ASD) represent an extreme form of a thinking style usually associated with men.  Using functional magnetic resonance imaging, brain function during a social task was compared between men and women; these results were then compared to those found using the same task in a group of people with ASD.  Similar differences were found when men were compared to women as were seen when people with ASD were compared to those without the condition.  These results are supportive of the idea that ASD is at least in part associated with an extreme form of male thinking.

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Synaptic scaffold evolution generated components of vertebrate cognitive complexity. Nithianantharajah, ., Komiyama, NH, McKechanie, A, Johnstone, M, Blackwood, DH, St Clair, D, Emes, RD, Lagemaat, LNvd, Saksida, L, Bussey, T & Grant, SGN. Nature Neuroscience. 2013; 16(1):16-24. 

This paper addresses how intelligence in humans first evolved from a genetic event 550 million years ago.  Using computerised touchscreen tests on both mice and humans, the team analysed genes which are required for various cognitive processes, including flexibility in thinking and how this may have contributed to the development of mental illness in humans.

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Clinical research – Of minds and brains

A systematic review and meta-analysis of the fMRI investigation of autism spectrum disorders.  Philip RC, Dauvermann MR, Whalley HC, Baynham K, Lawrie SM and Stanfield AC Neurosci Biobehav Rev. 2012; 36(2): 901-42

Recent years have seen a rapid increase in the investigation of autism spectrum disorders through the use of functional magnetic resonance imaging (fMRI). This study reviewed and combined the existing literature on fMRI in ASD. A disturbance to the function of social brain regions was among the most well replicated finding but it may be that  a lack of preference for social stimuli as opposed to a primary dysfunction of these regions is responsible. There was also evidence for a lack of effective integration of distributed functional brain regions and disruptions in the subtle modulation of brain function in relation to changing task demands. Limitations of the literature to date include the use of small sample sizes and the restriction of investigation to primarily high functioning males with autism.

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Dissociation of Brain Activation in Autism and Schizotypal Personality Disorder During Social Judgments. Andrew C. Stanfield, Ruth C. M. Philip, Heather Whalley, Liana Romaniuk, Jeremy Hall, Eve C. Johnstone, Stephen M. Lawrie. Schizophrenia Bulletin. June 2017; sbx083,

The researchers set out to examine brain activity during social judgements in people with autism spectrum disorders (ASD) and compared it to a group with a schizophrenia spectrum disorder (called a schizotypal personality disorder (SPD)).  Interestingly, they found that the group with ASD tended to show lower levels of brain activation when making social judgements, whereas those with SPD tended to show increased brain activation.  This means that although the difficulties may look similar between the conditions they actually arise from different underlying mechanisms.

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Longitudinal gray matter change in young people who are at enhanced risk of schizophrenia due to intellectual impairment. Moorhead TW, Stanfield AC, McKechanie AG, Dauvermann MR, Johnstone EC, Lawrie SM, Cunningham Owens DG. Biol Psychiatry. 2013; 73(10):985-92.

This study used magnetic resonance imaging to determine the changes to brain structure which occurred over 6 years in people with intellectual impairment who later went on to develop psychotic symptoms.  A region of the brain called the medial temporal lobe was found to reduce in size more in those people with psychotic symptoms than in those without such symptoms.  This region has been previously associated with schizophrenia in non-intellectually impaired people suggesting that the mechanism of development of the condition is the same regardless of intellectual level.

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A Genome Wide Survey Supports the Involvement of Large Copy Number Variants in Schizophrenia With and Without Intellectual Disability. Derks EM, Ayub M, Chambert K, Del Favero J, Johnstone M, MacGregor S, Maclean A, McKechanie AG, McRae AF, Moran JL, Pickard BS, Purcell S, Sklar P, StCLair DM, Wray NR, Visscher PM, Blackwood DHR. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2013; 162(8) :847–854.

This paper compares the genetic makeup of individuals with intellectual disability with and without schizophrenia.  The principal finding of the study was that in individuals with an intellectual disability and schizophrenia, there was an increased rate (9 out of 64 subjects) of large genetic changes in a region of the genome that has previously been described as being associated with schizophrenia. This genetic change was present at a much higher rate than in people with schizophrenia alone.  A possible explanation for this, which is discussed in the paper, is that the intellectual disability and the schizophrenia seen in these subjects are actually part of one condition, rather than being entirely separate conditions which happen to co-occur.

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Clinical research – Clinical trials & Interventions

Facilitating individuals and families affected by fragile X syndrome to participate in medication trials. Eley SEA, McKechanie AG, Campbell S, Stanfield AC. J Intellect Disabil Res. 2020

More than 300 people (peoiple with fragile X syndrome, parentsand carer of people with fragile X syndrome) took part in the study. They discussed the barriers to clinical trials participations, and the facilitators that could promote participation. Many of the barriers identified could be addressed efficiently thanks to simple adjustements.

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Determinants of adult functional outcome in adolescents receiving special educational assistance. McGeown HR, Johnstone EC, McKirdy J, Owens DC, Stanfield AC. J Intellect Disabil Res. 2013; 57(8):766-773

The predictive role of intellectual ability, autistic traits and challenging behaviour were considered in relation to the 6 year outcome of 58 people receiving special education assistance as adolescents.  The most important predictor of poor outcome was found to be the presence of challenging behaviour then the degree of intellectual impairment.  The presence of autistic traits in itself did not predict outcome.  Interventions to reduce challenging behaviour in adolescence may lead to better function in adult life.

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Psychopharmacology in children with intellectual disability and autism — a cross-sectional analysis (2010). Perumal N, Balan N, Stanfield A. International Journal of Intellectual Disabilities. 2013; 59(1):11-19.

There is a large body of research showing that there is a much higher prevalence of psychiatric disorders in children and adolescents with intellectual disability (ID) than in those without. Emerson and Hatton (2007) found that the risk for a mental health problem for children with intellectual disability (ID) was higher but these children are also more likely to live in poverty, have a reduced social network and have more difficult family circumstances which are factors known to increase risk of developing mental health problems. The current research aims to identify any association between prescription of psychotropic medication and bio-psycho-social factors. A cross sectional analysis of prescribing patterns in children open to the Child and Adolescent Intellectual Disability and Autism service from February 2010 to June 2010 was carried out. Information was collected from all 149 cases open to this team during this period. Prescription of psychotropic medication is associated with biological factors, such as age, diagnosis, degree of intellectual disability; behavioural factors such as self-injury, causing injury to others; and social factors like deprivation and unemployment. Prescription of psychotropic medication in children and adolescents with intellectual disability in specialist medical services is high, with anti-attention deficit hyperactivity disorder (ADHD) medication being the most prescribed medication, followed by antipsychotics. The rates of prescription were associated with a combination of biological, behavioural and social factors.

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