A step for precise medicine: genetic patterns indicate efficacy of oxytocin on autistic social behaivours

Watanabe, T., Otowa, T., Abe, O., Kuwabara, H., Aoki, Y., Natsubori, T., et al. (2016). Oxytocin receptor gene variations predict neural and behavioral response to oxytocin in autism. Social Cognitive and Affective Neuroscience, nsw150. http://doi.org/10.1093/scan/nsw150

 

Oxytocin and its receptor (OXTR) are known to be deeply associated with autism spectrum disorder (ASD), a prevalent neurodevelopmental disorder with impaired social communication and interactions as its core symptoms. A line of genetics studies have identified associations between ASD and more than a dozen single-nucleotide polymorphisms (SNPs) in OXTR, and clinical trials have shown a possibility that administration of oxytocin could behaviorally and neurally mitigate its social symptoms.

However, despite these biologically and clinically crucial relationships, the neurobiological functionality of OXTR SNPs in ASD is poorly understood, and hence, the crucial OXTR SNPs determining oxytocin efficacy in ASD are also unknown.

Here, to address this issue, we have applied a newly-developed machine-learning-based algorithm to newly-obtained genetic information of ASD participants, whose sample size was determined based on a power analysis a priori.

We have found that specific OXTR SNPs have functionally dissociable influences on behavioral and neural responses to oxytocin in ASD. In particular, ASD risk alleles in the two most prominent OXTR SNPs (rs53576 and rs2254298) were suggested to have opposite neurobiological effects on oxytocin-related neural systems in ASD. Furthermore, we have demonstrated that allelic information in such specific SNP sets enables accurate prediction of behavioral, neural, and neurochemical responses to oxytocin for each individual with ASD.

These results provide novel biological understandings of functionality of OXTR SNPs in ASD, and the current analysis approach is widely applicable to future investigations on gene-endophenotype relationships.

Anatomical imbalance in autistic brains

Watanabe, T., & Rees, G. (2016). Anatomical imbalance between cortical networks in autism. Scientific Reports, 6, 31114. http://doi.org/10.1038/srep31114. 

 

 

Core symptoms of autism spectrum disorder (ASD) consist of socio-communicational deficits and repetitive, restricted behaviours. Although the neuroanatomy underlying these two symptoms has been studied, the biological mechanisms that allow these two seemingly irrelevant behavioural characteristics to coexist in a single developmental disorder remains unclear.

In this study using open anatomical neuroimaging data of high-functioning males with ASD and age-/sex-/IQ-matched controls, we found that atypical balance of grey matter volumes (GMV) between three large-scale cortical brain networks can be a key biological mechanism underlying such integration and segregation of these distinct symptoms of ASD.

We identified age-related atypical increases in relative GMVs of the regions constituting auditory and visual networks, and an age-associated aberrant decrease in relative GMV of fronto-parietal network (FPN) regions in ASD children. In addition, the atypically enlarged relative GMV of the auditory network in ASD adults was associated with the severity of their socio-communicational deficits, and that of visual network was correlated with cognitive inflexibility. Moreover, the atypical decrease in relative GMV of FPN was related to both of the two core symptoms.

These observations suggest that disproportionate undergrowth of FPN may be a common anatomical basis for the two dissociable and seemingly heterogeneous core symptoms of ASD, and relative overgrowth of the two different sensory networks may selectively underlie the different autistic symptoms.

 

 

Age-related changes in rich-club structure in neurotypical and autistic brain networks

Watanabe T, Rees G. Age-associated changes in rich-club organisation in autistic and neurotypical human brains. Sci Rep. 2015;5:16152. doi:10.1038/srep16152.

 

Macroscopic structural networks in the human brain have a rich-club architecture comprising both highly inter-connected central regions and sparsely connected peripheral regions. Recent studies show that disruption of this functionally efficient organisation is associated with several psychiatric disorders.

However, despite increasing attention to this network property, whether age-associated changes in rich-club organisation occur during human adolescence remains unclear.

Here, analysing a publicly shared diffusion tensor imaging dataset, we found that, during adolescence, brains of typically developing (TD) individuals showed increases in rich-club organisation and inferred network functionality, whereas individuals with autism spectrum disorders (ASD) did not. These differences between TD and ASD groups were statistically significant for both structural and functional properties. Moreover, this typical age-related changes in rich-club organisation were characterised by progressive involvement of the right anterior insula. In contrast, in ASD individuals, did not show typical increases in grey matter volume, and this relative anatomical immaturity was correlated with the severity of ASD social symptoms.

These results provide evidence that rich-club architecture is one of the bases of functionally efficient brain networks underpinning complex cognitive functions in adult human brains. Furthermore, our findings suggest that immature rich-club organisation might be associated with some neurodevelopmental disorders.

A brief video about long term oxytocin's effects on social interaction disorders in autism

A brief video for our recent work in Brain. Thanks to this, I learnt lots about how to use Final Cut Pro…

https://www.youtube.com/watch?v=keyJntfbMpc

 

Six-week oxytocin seems to work for autistic social symptom

Watanabe T, Kuroda M, Kuwabara H, Aoki Y, Iwashiro N, Tatsunobu N, Takao H, Nippashi Y, Kawakubo Y, Kunimatsu A, Kasai K, Yamasue H (2015) Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism. Brain:awv249.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder but is not given established medical treatment. Despite previous literatures showing temporal positive effects of single-dose administration of oxytocin in experimental settings, until now, it is still controversial whether such potentially beneficial reactions can yield clinically therapeutic effects after long-term intervention, which is currently impeding further development of medications for the developmental disorder.

Here, we performed a randomised, double-blind, placebo-controlled, crossover trial, and found that six-week continual administration of oxytocin significantly reduced the clinically evaluated core symptoms specifically in the social domain. Critically, this clinical improvement was associated with increases in brain activity and functional connectivity in medial prefrontal cortex. Furthermore, using the same psychological task as in our recent single-dose oxytocin trial, we showed that the long and continual administration did not magnify the effect sizes seen in the single-dose intervention, which might have made it difficult for previous trials to detect significant effects of long-term administration of this neuropeptide.

The current study, to our best of knowledge, provides the first direct clinical and biological evidence for therapeutic effects of long-term oxytocin administration; in addition, this research also indicates that we still need to seek the optimal dosing regimen to maximize such effects of continual oxytocin interventions. We believe that this study provides major observations that will stimulate and guide the future development of novel medical treatments for ASD.

[New Paper] Cortico-basal-ganglia network for response inhibition

Watanabe, T., Hanajima, R., Shirota, Y., Tsutsumi, R., Shimizu, T., Hayashi, T., et al. (2015). Effects of rTMS of Pre-Supplementary Motor Area on Fronto Basal Ganglia Network Activity during Stop-Signal Task. The Journal of Neuroscience: 35(12), 4813–4823. 

Response inhibition is one of the key cognitive functions that enable humans to realise their own intentions, and is considered to be supported by fronto-basal-ganglia network. However, causal relationship inside the network has remained unclear.

Here, combining relatively long-lasting types of repetitive transcranial magnetic stimulation (rTMS) with functional magnetic resonance imaging (fMRI), we revealed causal effects of presupplementary motor area (PreSMA) on the network. Using well-established stop-signal task, we found that excitatory and inhibitory rTMS over PreSMA induced significant activity changes in a neural pathway consisting of PreSMA, striatum (STR) and globus pallidus pars interna (GPi). Furthermore, this effect on PreSMA–STR–GPi network activity was highly predictive of behavioral modulations. Interestingly, such causal effects were not seen in right inferior prefrontal cortex or subthalamic nucleus, both of which have been considered to mainly constitute neural mechanisms for response inhibition.

The work will not only demonstrate a causal relationship from PreSMA to basal ganglia during response inhibition, but also add direct evidence for the notion that the fronto-basal-ganglia network for response inhibition comprises multiple top-down regulation pathways in humans. 

[New Paper] Energy landscape during bistable perception

Watanabe, T., Masuda, N., Megumi, F., Kanai, R., & Rees, G. (2014). Energy landscape and dynamics of brain activity during human bistable perception. Nature Communications, 5, 4765. doi:10.1038/ncomms5765

Bistable visual perception is a key paradigm for probing human and animal brainfunctions, and several studies have now shown an intriguing link between the dynamics of bistable perception and the grey matter volume in particular areas of cortex. However, the mechanisms that might link such anatomical features of the brain to subjective experience remained unclear. In this study, we established just such a link by characterising the energy landscapes of brain activity during bistable perception.

During bistable visual perception, we found that human brain activity patterns transited between three spatially distributed energy states. For each participant, this energy landscape predicted both the behavioural dynamics of their perceptual reports and the structural characteristics of focal cortical regions. These findings suggest that the dynamics of brain activity determined by the features of the energy landscape link individual differences in brain anatomy and subjective visual experience.