Characterization of the spontaneous EEG activity in the Alzheimer's disease continuum: from local activation to network organization

La presente Tesis Doctoral se presenta como un compendio de cuatro publicaciones indexadas en el Journal Citation Reports. El objetivo de estas publicaciones es la caracterización de los cambios neuronales subyacentes en las diferentes etapas de la enfermedad de Alzheimer (EA) y su etapa prodrómica, el deterioro cognitivo leve (DCL), siguiendo tres niveles de análisis: activación local, interacción entre pares de sensores, y organización de red. Los principales cambios encontrados a medida que progresa la enfermedad son: (i) una lentificación, y una pérdida de complejidad e irregularidad de la actividad EEG espontánea; (ii) una disminución significativa de la conectividad en bandas altas de frecuencia y un aumento en las bandas bajas; y (iii) una pérdida en la integración y la segregación de las redes neuronales. Estos hallazgos han proporcionado información adicional sobre las alteraciones cerebrales de la EA en sus diferentes etapas, útiles para comprender mejor sus mecanismos fisiopatológicos.Departamento de Teoría de la Señal y Comunicaciones e Ingeniería TelemáticaDoctorado en Tecnologías de la Información y las Telecomunicacione

Any-way and Sparse Analyses for Multimodal Fusion and Imaging Genomics

This dissertation aims to develop new algorithms that leverage sparsity and mutual information across data modalities built upon the independent component analysis (ICA) framework to improve the performance of current ICA-based multimodal fusion approaches. These algorithms are further applied to both simulated data and real neuroimaging and genomic data to examine their performance. The identified neuroimaging and genomic patterns can help better delineate the pathology of mental disorders or brain development. To alleviate the signal-background separation difficulties in infomax-decomposed sources for genomic data, we propose a sparse infomax by enhancing a robust sparsity measure, the Hoyer index. Hoyer index is scale-invariant and well suited for ICA frameworks since the scale of decomposed sources is arbitrary. Simulation results demonstrate that sparse infomax increases the component detection accuracy for situations where the source signal-to-background (SBR) ratio is low, particularly for single nucleotide polymorphism (SNP) data. The proposed sparse infomax is further extended into two data modalities as a sparse parallel ICA for applications to imaging genomics in order to investigate the associations between brain imaging and genomics. Simulation results show that sparse parallel ICA outperforms parallel ICA with improved accuracy for structural magnetic resonance imaging (sMRI)-SNP association detection and component spatial map recovery, as well as with enhanced sparsity for sMRI and SNP components under noisy cases. Applying the proposed sparse parallel ICA to fuse the whole-brain sMRI and whole-genome SNP data of 24985 participants in the UK biobank, we identify three stable and replicable sMRI-SNP pairs. The identified sMRI components highlight frontal, parietal, and temporal regions and associate with multiple cognitive measures (with different association strengths in different age groups for the temporal component). Top SNPs in the identified SNP factor are enriched in inflammatory disease and inflammatory response pathways, which also regulate gene expression, isoform percentage, transcription expression, or methylation level in the frontal region, and the regulation effects are significantly enriched. Applying the proposed sparse parallel ICA to imaging genomics in attention-deficit/hyperactivity disorder (ADHD), we identify and replicate one SNP component related to gray matter volume (GMV) alterations in superior and middle frontal gyri underlying working memory deficit in adults and adolescents with ADHD. The association is more significant in ADHD families than controls and stronger in adults and older adolescents than younger ones. The identified SNP component highlights SNPs in long non-coding RNAs (lncRNAs) in chromosome 5 and in several protein-coding genes that are involved in ADHD, such as MEF2C, CADM2, and CADPS2. Top SNPs are enriched in human brain neuron cells and regulate gene expression, isoform percentage, transcription expression, or methylation level in the frontal region. Moreover, to increase the flexibility and robustness in mining multimodal data, we propose aNy-way ICA, which optimizes the entire correlation structure of linked components across any number of modalities via the Gaussian independent vector analysis and simultaneously optimizes independence via separate (parallel) ICAs. Simulation results demonstrate that aNy-way ICA recover sources and loadings, as well as the true covariance patterns with improved accuracy compared to existing multimodal fusion approaches, especially under noisy conditions. Applying the proposed aNy-way ICA to integrate structural MRI, fractal n-back, and emotion identification task functional MRIs collected in the Philadelphia Neurodevelopmental Cohort (PNC), we identify and replicate one linked GMV-threat-2-back component, and the threat and 2-back components are related to intelligence quotient (IQ) score in both discovery and replication samples. Lastly, we extend the proposed aNy-way ICA with a reference constraint to enable prior-guided multimodal fusion. Simulation results show that aNy-way ICA with reference recovers the designed linkages between reference and modalities, cross-modality correlations, as well as loading and component matrices with improved accuracy compared to multi-site canonical correlation analysis with reference (MCCAR)+joint ICA under noisy conditions. Applying aNy-way ICA with reference to supervise structural MRI, fractal n-back, and emotion identification task functional MRIs fusion in PNC with IQ as the reference, we identify and replicate one IQ-related GMV-threat-2-back component, and this component is significantly correlated across modalities in both discovery and replication samples.Ph.D

Whole Brain Network Dynamics of Epileptic Seizures at Single Cell Resolution

Epileptic seizures are characterised by abnormal brain dynamics at multiple scales, engaging single neurons, neuronal ensembles and coarse brain regions. Key to understanding the cause of such emergent population dynamics, is capturing the collective behaviour of neuronal activity at multiple brain scales. In this thesis I make use of the larval zebrafish to capture single cell neuronal activity across the whole brain during epileptic seizures. Firstly, I make use of statistical physics methods to quantify the collective behaviour of single neuron dynamics during epileptic seizures. Here, I demonstrate a population mechanism through which single neuron dynamics organise into seizures: brain dynamics deviate from a phase transition. Secondly, I make use of single neuron network models to identify the synaptic mechanisms that actually cause this shift to occur. Here, I show that the density of neuronal connections in the network is key for driving generalised seizure dynamics. Interestingly, such changes also disrupt network response properties and flexible dynamics in brain networks, thus linking microscale neuronal changes with emergent brain dysfunction during seizures. Thirdly, I make use of non-linear causal inference methods to study the nature of the underlying neuronal interactions that enable seizures to occur. Here I show that seizures are driven by high synchrony but also by highly non-linear interactions between neurons. Interestingly, these non-linear signatures are filtered out at the macroscale, and therefore may represent a neuronal signature that could be used for microscale interventional strategies. This thesis demonstrates the utility of studying multi-scale dynamics in the larval zebrafish, to link neuronal activity at the microscale with emergent properties during seizures

C-Trend parameters and possibilities of federated learning

Abstract. In this observational study, federated learning, a cutting-edge approach to machine learning, was applied to one of the parameters provided by C-Trend Technology developed by Cerenion Oy. The aim was to compare the performance of federated learning to that of conventional machine learning. Additionally, the potential of federated learning for resolving the privacy concerns that prevent machine learning from realizing its full potential in the medical field was explored. Federated learning was applied to burst-suppression ratio’s machine learning and it was compared to the conventional machine learning of burst-suppression ratio calculated on the same dataset. A suitable aggregation method was developed and used in the updating of the global model. The performance metrics were compared and a descriptive analysis including box plots and histograms was conducted. As anticipated, towards the end of the training, federated learning’s performance was able to approach that of conventional machine learning. The strategy can be regarded to be valid because the performance metric values remained below the set test criterion levels. With this strategy, we will potentially be able to make use of data that would normally be kept confidential and, as we gain access to more data, eventually develop machine learning models that perform better. Federated learning has some great advantages and utilizing it in the context of qEEGs’ machine learning could potentially lead to models, which reach better performance by receiving data from multiple institutions without the difficulties of privacy restrictions. Some possible future directions include an implementation on heterogeneous data and on larger data volume.C-Trend-teknologian parametrit ja federoidun oppimisen mahdollisuudet. Tiivistelmä. Tässä havainnointitutkimuksessa federoitua oppimista, koneoppimisen huippuluokan lähestymistapaa, sovellettiin yhteen Cerenion Oy:n kehittämään C-Trend-teknologian tarjoamaan parametriin. Tavoitteena oli verrata federoidun oppimisen suorituskykyä perinteisen koneoppimisen suorituskykyyn. Lisäksi tutkittiin federoidun oppimisen mahdollisuuksia ratkaista yksityisyyden suojaan liittyviä rajoitteita, jotka estävät koneoppimista hyödyntämästä täyttä potentiaaliaan lääketieteen alalla. Federoitua oppimista sovellettiin purskevaimentumasuhteen koneoppimiseen ja sitä verrattiin purskevaimentumasuhteen laskemiseen, johon käytettiin perinteistä koneoppimista. Kummankin laskentaan käytettiin samaa dataa. Sopiva aggregointimenetelmä kehitettiin, jota käytettiin globaalin mallin päivittämisessä. Suorituskykymittareiden tuloksia verrattiin keskenään ja tehtiin kuvaileva analyysi, johon sisältyi laatikkokuvioita ja histogrammeja. Odotetusti opetuksen loppupuolella federoidun oppimisen suorituskyky pystyi lähestymään perinteisen koneoppimisen suorituskykyä. Menetelmää voidaan pitää pätevänä, koska suorituskykymittarin arvot pysyivät alle asetettujen testikriteerien tasojen. Tämän menetelmän avulla voimme ehkä hyödyntää dataa, joka normaalisti pidettäisiin salassa, ja kun saamme lisää dataa käyttöömme, voimme lopulta kehittää koneoppimismalleja, jotka saavuttavat paremman suorituskyvyn. Federoidulla oppimisella on joitakin suuria etuja, ja sen hyödyntäminen qEEG:n koneoppimisen yhteydessä voisi mahdollisesti johtaa malleihin, jotka saavuttavat paremman suorituskyvyn saamalla tietoja useista eri lähteistä ilman yksityisyyden suojaan liittyviä rajoituksia. Joitakin mahdollisia tulevia suuntauksia ovat muun muassa heterogeenisen datan ja suurempien tietomäärien käyttö

Fluctuations of attention network activation during the resting state reflect fluctuations in subjective attentional state.

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