Recent relevant contributions
- Linking inhibition from molecular to systems and cognitive levels in neurodevelopmental disorders in the autism spectrum
This contribution was awarded the FLAD Life Sciences Prize for Clinical and Translational Research – 2016 (in a nationwide competition). International awards related to this achievement were are obtained as follows: 2014 Top 3 (Finalist) of Investigator Awards (out of ~1250 submitted papers) at the World Molecular Imaging Conference, Seoul, Korea and ISMRM (International Society for Magnetic Resonance in Medicine) certificate of Honor (top 10, in out of 1000 submissions).
In a series of studies of a genetically defined cohort in the autism spectrum disorder (ASD), as well as idiopathic ASD, we employed multimodal imaging and spectroscopy measures to investigate GABA type A (GABAA) receptor binding, using [(11)C]-flumazenil PET, and GABA concentration, using magnetic resonance spectroscopy (MRS). We found that abnormalities in the GABA system in NF1 involve both GABA concentration and GABAA receptor density suggestive of neurodevelopmental synaptopathy with both pre- and postsynaptic involvement.
We tested whether a mechanistic link can be established between synaptic inhibitory dysfunction, systems level changes in oscillatory synchrony and regulation of behavioral inhibition; which motivates our strategic plan to identify therapeutic targets related to abnormal modulation of inhibition in Neurofibromatosis Type 1 (NF1) and ASD in general. Here have been addressing all these aspects, in a series of papers ranging from preclinical studies in rodents (Gonçalves et al., Molecular Autism) to human clinical studies. We found that lower GABA levels occur in NF1 patients with the most deleterious mutations and are associated with most impaired phenotypes (Brain, 2013, Cortex, 2015, Neurology, 2016). We also found that GABA levels are anticorrelated with GABA-A receptor levels in the frontal eye fields (FEF) which are involved in saccadic inhibitory control, and provide a model region to link behavioral and physiological inhibition.
- Studying different forms of brain plasticity in the adult brain
We published a series of studies addressing visual brain plasticity, such as an fMRI study to assess how the brain adapts to the visual dysphotopsia caused by the new visual environment imposed by multifocal intraocular lenses (published in Opthalmology, the leading journal of basic and clinical research in Ophthalmology.)
This contribution won the European Clinical Research Awards 2016 of the ESCRS Society. This competition involved more than 108 applications from 26 countries. It was also awarded one the PT Pfizer Award for Clinical Research, 2016. The PhD project that originated this research was also awarded D. Manuel de Mello prize 2014. This study shows, for the first time, the association between patient reported subjective difficulties, fMRI outcomes, independently of optical parameters and psychophysical performance. We found a neural basis for the neuroadaptation process to the change in visual experience imposed by multifocal intraocular lenses.
We also published an article in a top Journal in the field, Neuroimage (D’ Almeida et al, 2013) showing how the brain structurally reorganizes due to genetically determined subclinical loss of peripheral visual function in Leber Hereditary Neuropathy. A subsequent study by Mateus et al (Brain Struct. and Function, 2016) demonstrated that a retinal trigger at the level of the retinal ganglion cell causes such reorganization at the level of the extrastriate cortex. We showed for the first time evidence for functional visual remapping in a peripheral visual disorder, Retinitis Pigmentosa, a genetic disorder characterized by tubular vision. The peripheral silent zone gradually remaps to central representations, as a function of disease duration (Ferreira, Neuroimage Clinical, 2016).
- Mapping the impulsive Brain
A series of studies were published concerning the neural basis of obsessive compulsive disorder (Banca et al, Brain. 2015, Neuropsychopharmacology, 2015) and genetically determined impulsive behavior in Neurofibromatosis (Ribeiro et al, Cortex, 2015). In the 1st we identified an imbalance in circuitry underlying habitual and goal-directed action control, as a fundamental mechanism underlying compulsivity in obsessive-compulsive disorder (OCD). Our results using causality analysis inform new models of symptom generation in OCD. In the 2nd study, diffusion-drift models to provide evidence for impaired decision-making in OCD, with a differential influence of high and low uncertainty contexts on evidence accumulation (decision threshold) and on the quality of evidence gathered (drift rates). In the final multimodal study, we found an abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1. We recently published work on impairment of multiples impulsivity domains (reactive, proactive and cognitive) in Parkinson´s Disease.
- Neural correlates of perceptual decision-making: models of neural integration and the binding problem
We conducted a series of studies on the neural correlates of perceptual decision-making. In a first study (Castelhano, et al (2014). Human Brain Mapping (Journal Cover), we performed simultaneous EEG/fMRI using an ambiguous perception paradigm requiring holistic integration. We showed that topographically distinct gamma-band modulations underlie sensory processing and perceptual decision mechanisms. This is also directly relevant to autism research. We published a series of studies on holistic perceptual integration in autism and related disorders (Bernardino, et al, J. of Cognitive Neuroscience, 2014, Castelhano et al, J. of Cognitive Neuroscience 2015).
Finally we used perceptual paradigms requiring interhemispheric integration to critically test the binding by synchrony hypothesis (Costa, J. of Cognitive Neuroscience, 2017), which was also recently pursued in an Electrocortigraphy paper (Castelhano et al, 2017). Our recent work demonstrated a pivotal role of hMT+ in long-range interhemispheric perceptual integration (Duarte et al, Human Brain Mapping, 2017).
- Achievements in Biomarker discovery, patents and clinical trials
We achieved a novel molecular imaging World Patent (Abrunhosa et al.) based on a novel way to produce Ga68 based radiotracers, for applications in neuroendocrinology and oncology, based on the Cyclotron. Bernardes et al. have a European patent on statistical classifiers applied to optical coherence data as biomarkers for central neurodegenerative disorders. We have to additional patents on new methods to measure arterial input functions in PET, and a novel visual function test for glaucoma using low cost hardware. We published several articles on biomarker testing and validation in MR (Duarte et al Hum Brain Mapp. 2014, 2016; Duarte et al, J. of Cerebral Blood Flow and Metabolism. 2016) and PET data (Oliveira et al., J Neural Eng. 2015, Eur J Nucl Med Mol Imaging, 2017).
We developed non-invasive brain-computer interfaces (EEG-BCI) and fMRI based Neurofeedback, tested in Clinical Trials focusing on disorders such as autism (Amaral et al, 2017, J. of Neurosci. Methods, Sousa et al J Neural Eng. 2017, PlosOne 2016, Banca et al, J Neural Eng. 2015).
Investigator Initiated Clinical trials with medical devices, radiopharmaceuticals and drugs: we have been involved in 3 European H2020 projects (RADICAL- 1 diagnostic imaging trial, BRAINTRAIN – 2 interventional trials, EU-AIMS- 2 trials, and STIPED – 4 trials). Concerning BRAINTRAIN, in this project with partners from the UK, Israel, Germany and The Netherlands we have been in charge for developing 2 medical device approaches in autism (EEG based BCI and fMRI based Neurofeedback). We have already completed these trials. We were also involved in a partnership with a company, Thales with which we have developed serious games for autism. A business model is now being developed for spinning-off. We also developed gaming technologies interfaced with biosensors to improve cognitive function in realistic settings. This work won the international ICVR 2015 award, for developing virtual reality applications for Medicine. We were also finalist in the international BCI award competition and won the second Prize of the Frauenhofer Portugal award. We also developed an EcoKitchen gaming interface which won a prize at the EuroHuntington EHDN meeting.