Psilocybin modulation of time-varying functional connectivity is associated with plasma psilocin and subjective effects.

BACKGROUND: Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state time-varying functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioral and clinical effects. AIM: Evaluate the association between resting-state time-varying functional connectivity (tvFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after intake of a psychedelic dose of psilocybin in healthy humans. METHODS: Fifteen healthy individuals completed the study. Before and at multiple time points after psilocybin intake, we acquired 10-minute resting-state blood-oxygen-level-dependent functional magnetic resonance imaging scans. Leading Eigenvector Dynamics Analysis (LEiDA) and diametrical clustering were applied to estimate discrete, sequentially active brain states. We evaluated associations between the fractional occurrence of brain states during a scan session and PPL and SDI using linear mixed-effects models. We examined associations between brain state dwell time and PPL and SDI using frailty Cox proportional hazards survival analysis. RESULTS: Fractional occurrences for two brain states characterized by lateral frontoparietal and medial fronto-parietal-cingulate coherence were statistically significantly negatively associated with PPL and SDI. Dwell time for these brain states was negatively associated with SDI and, to a lesser extent, PPL. Conversely, fractional occurrence and dwell time of a fully connected brain state partly associated with motion was positively associated with PPL and SDI. CONCLUSION: Our findings suggest that the acute perceptual psychedelic effects induced by psilocybin may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs. We apply and argue for a modified approach to modeling eigenvectors produced by LEiDA that more fully acknowledges their underlying structure. Together these findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics.

Using connectomics for predictive assessment of brain parcellations.

The organization of the human brain remains elusive, yet is of great importance to the mechanisms of integrative brain function. At the macroscale, its structural and functional interpretation is conventionally assessed at the level of cortical units. However, the definition and validation of such cortical parcellations are problematic due to the absence of a true gold standard. We propose a framework for quantitative evaluation of brain parcellations via statistical prediction of connectomics data. Specifically, we evaluate the extent in which the network representation at the level of cortical units (defined as parcels) accounts for high-resolution brain connectivity. Herein, we assess the pertinence and comparative ranking of ten existing parcellation atlases to account for functional (FC) and structural connectivity (SC) data based on data from the Human Connectome Project (HCP), and compare them to data-driven as well as spatially-homogeneous geometric parcellations including geodesic parcellations with similar size distributions as the atlases. We find substantial discrepancy in parcellation structures that well characterize FC and SC and differences in what well represents an individual's functional connectome when compared against the FC structure that is preserved across individuals. Surprisingly, simple spatial homogenous parcellations generally provide good representations of both FC and SC, but are inferior when their within-parcellation distribution of individual parcel sizes is matched to that of a valid atlas. This suggests that the choice of fine grained and coarse representations used by existing atlases are important. However, we find that resolution is more critical than the exact border location of parcels.

Validation of structural brain connectivity networks: The impact of scanning parameters.

Evaluation of the structural connectivity (SC) of the brain based on tractography has mainly focused on the choice of diffusion model, tractography algorithm, and their respective parameter settings. Here, we systematically validate SC derived from a post mortem monkey brain, while varying key acquisition parameters such as the b-value, gradient angular resolution and image resolution. As gold standard we use the connectivity matrix obtained invasively with histological tracers by Markov et al. (2014). As performance metric, we use cross entropy as a measure that enables comparison of the relative tracer labeled neuron counts to the streamline counts from tractography. We find that high angular resolution and high signal-to-noise ratio are important to estimate SC, and that SC derived from low image resolution (1.03 mm3) are in better agreement with the tracer network, than those derived from high image resolution (0.53 mm3) or at an even lower image resolution (2.03 mm3). In contradiction, sensitivity and specificity analyses suggest that if the angular resolution is sufficient, the balanced compromise in which sensitivity and specificity are identical remains 60-64% regardless of the other scanning parameters. Interestingly, the tracer graph is assumed to be the gold standard but by thresholding, the balanced compromise increases to 70-75%. Hence, by using performance metrics based on binarized tracer graphs, one risks losing important information, changing the performance of SC graphs derived by tractography and their dependence of different scanning parameters.

Rigorous optimisation of multilinear discriminant analysis with Tucker and PARAFAC structures.

BACKGROUND: We propose rigorously optimised supervised feature extraction methods for multilinear data based on Multilinear Discriminant Analysis (MDA) and demonstrate their usage on Electroencephalography (EEG) and simulated data. While existing MDA methods use heuristic optimisation procedures based on an ambiguous Tucker structure, we propose a rigorous approach via optimisation on the cross-product of Stiefel manifolds. We also introduce MDA methods with the PARAFAC structure. We compare the proposed approaches to existing MDA methods and unsupervised multilinear decompositions. RESULTS: We find that manifold optimisation substantially improves MDA objective functions relative to existing methods and on simulated data in general improve classification performance. However, we find similar classification performance when applied to the electroencephalography data. Furthermore, supervised approaches substantially outperform unsupervised mulitilinear methods whereas methods with the PARAFAC structure perform similarly to those with Tucker structures. Notably, despite applying the MDA procedures to raw Brain-Computer Interface data, their performances are on par with results employing ample pre-processing and they extract discriminatory patterns similar to the brain activity known to be elicited in the investigated EEG paradigms. CONCLUSION: The proposed usage of manifold optimisation constitutes the first rigorous and monotonous optimisation approach for MDA methods and allows for MDA with the PARAFAC structure. Our results show that MDA methods applied to raw EEG data can extract discriminatory patterns when compared to traditional unsupervised multilinear feature extraction approaches, whereas the proposed PARAFAC structured MDA models provide meaningful patterns of activity.

Predictive assessment of models for dynamic functional connectivity.

In neuroimaging, it has become evident that models of dynamic functional connectivity (dFC), which characterize how intrinsic brain organization changes over time, can provide a more detailed representation of brain function than traditional static analyses. Many dFC models in the literature represent functional brain networks as a meta-stable process with a discrete number of states; however, there is a lack of consensus on how to perform model selection and learn the number of states, as well as a lack of understanding of how different modeling assumptions influence the estimated state dynamics. To address these issues, we consider a predictive likelihood approach to model assessment, where models are evaluated based on their predictive performance on held-out test data. Examining several prominent models of dFC (in their probabilistic formulations) we demonstrate our framework on synthetic data, and apply it on two real-world examples: a face recognition EEG experiment and resting-state fMRI. Our results evidence that both EEG and fMRI are better characterized using dynamic modeling approaches than by their static counterparts, but we also demonstrate that one must be cautious when interpreting dFC because parameter settings and modeling assumptions, such as window lengths and emission models, can have a large impact on the estimated states and consequently on the interpretation of the brain dynamics.

The missing link: Predicting connectomes from noisy and partially observed tract tracing data.

Our understanding of the wiring map of the brain, known as the connectome, has increased greatly in the last decade, mostly due to technological advancements in neuroimaging techniques and improvements in computational tools to interpret the vast amount of available data. Despite this, with the exception of the C. elegans roundworm, no definitive connectome has been established for any species. In order to obtain this, tracer studies are particularly appealing, as these have proven highly reliable. The downside of tract tracing is that it is costly to perform, and can only be applied ex vivo. In this paper, we suggest that instead of probing all possible connections, hitherto unknown connections may be predicted from the data that is already available. Our approach uses a 'latent space model' that embeds the connectivity in an abstract physical space. Regions that are close in the latent space have a high chance of being connected, while regions far apart are most likely disconnected in the connectome. After learning the latent embedding from the connections that we did observe, the latent space allows us to predict connections that have not been probed previously. We apply the methodology to two connectivity data sets of the macaque, where we demonstrate that the latent space model is successful in predicting unobserved connectivity, outperforming two baselines and an alternative model in nearly all cases. Furthermore, we show how the latent spatial embedding may be used to integrate multimodal observations (i.e. anterograde and retrograde tracers) for the mouse neocortex. Finally, our probabilistic approach enables us to make explicit which connections are easy to predict and which prove difficult, allowing for informed follow-up studies.

Correction: The missing link: Predicting connectomes from noisy and partially observed tract tracing data.

[This corrects the article DOI: 10.1371/journal.pcbi.1005374.].

Quantifying functional connectivity in multi-subject fMRI data using component models.

Functional magnetic resonance imaging (fMRI) is increasingly used to characterize functional connectivity between brain regions. Given the vast number of between-voxel interactions in high-dimensional fMRI data, it is an ongoing challenge to detect stable and generalizable functional connectivity in the brain among groups of subjects. Component models can be used to define subspace representations of functional connectivity that are more interpretable. It is, however, unclear which component model provides the optimal representation of functional networks for multi-subject fMRI datasets. A flexible cross-validation approach that assesses the ability of the models to predict voxel-wise covariance in new data, using three different measures of generalization was proposed. This framework is used to compare a range of component models with varying degrees of flexibility in their representation of functional connectivity, evaluated on both simulated and experimental resting-state fMRI data. It was demonstrated that highly flexible subject-specific component subspaces, as well as very constrained average models, are poor predictors of whole-brain functional connectivity, whereas the best-generalizing models account for subject variability within a common spatial subspace. Within this set of models, spatial Independent Component Analysis (sICA) on concatenated data provides more interpretable brain patterns, whereas a consistent-covariance model that accounts for subject-specific network scaling (PARAFAC2) provides greater stability in functional connectivity relationships between components and their spatial representations. The proposed evaluation framework is a promising quantitative approach to evaluating component models, and reveals important differences between subspace models in terms of predictability, robustness, characterization of subject variability, and interpretability of the model parameters. Hum Brain Mapp 38:882-899, 2017. © 2016 Wiley Periodicals, Inc.

Infinite von Mises-Fisher Mixture Modeling of Whole Brain fMRI Data.

Cluster analysis of functional magnetic resonance imaging (fMRI) data is often performed using gaussian mixture models, but when the time series are standardized such that the data reside on a hypersphere, this modeling assumption is questionable. The consequences of ignoring the underlying spherical manifold are rarely analyzed, in part due to the computational challenges imposed by directional statistics. In this letter, we discuss a Bayesian von Mises-Fisher (vMF) mixture model for data on the unit hypersphere and present an efficient inference procedure based on collapsed Markov chain Monte Carlo sampling. Comparing the vMF and gaussian mixture models on synthetic data, we demonstrate that the vMF model has a slight advantage inferring the true underlying clustering when compared to gaussian-based models on data generated from both a mixture of vMFs and a mixture of gaussians subsequently normalized. Thus, when performing model selection, the two models are not in agreement. Analyzing multisubject whole brain resting-state fMRI data from healthy adult subjects, we find that the vMF mixture model is considerably more reliable than the gaussian mixture model when comparing solutions across models trained on different groups of subjects, and again we find that the two models disagree on the optimal number of components. The analysis indicates that the fMRI data support more than a thousand clusters, and we confirm this is not a result of overfitting by demonstrating better prediction on data from held-out subjects. Our results highlight the utility of using directional statistics to model standardized fMRI data and demonstrate that whole brain segmentation of fMRI data requires a very large number of functional units in order to adequately account for the discernible statistical patterns in the data.

The Functional Segregation and Integration Model: Mixture Model Representations of Consistent and Variable Group-Level Connectivity in fMRI.

The brain consists of specialized cortical regions that exchange information between each other, reflecting a combination of segregated (local) and integrated (distributed) processes that define brain function. Functional magnetic resonance imaging (fMRI) is widely used to characterize these functional relationships, although it is an ongoing challenge to develop robust, interpretable models for high-dimensional fMRI data. Gaussian mixture models (GMMs) are a powerful tool for parcellating the brain, based on the similarity of voxel time series. However, conventional GMMs have limited parametric flexibility: they only estimate segregated structure and do not model interregional functional connectivity, nor do they account for network variability across voxels or between subjects. To address these issues, this letter develops the functional segregation and integration model (FSIM). This extension of the GMM framework simultaneously estimates spatial clustering and the most consistent group functional connectivity structure. It also explicitly models network variability, based on voxel- and subject-specific network scaling profiles. We compared the FSIM to standard GMM in a predictive cross-validation framework and examined the importance of different model parameters, using both simulated and experimental resting-state data. The reliability of parcellations is not significantly altered by flexibility of the FSIM, whereas voxel- and subject-specific network scaling profiles significantly improve the ability to predict functional connectivity in independent test data. Moreover, the FSIM provides a set of interpretable parameters to characterize both consistent and variable aspects functional connectivity structure. As an example of its utility, we use subject-specific network profiles to identify brain regions where network expression predicts subject age in the experimental data. Thus, the FSIM is effective at summarizing functional connectivity structure in group-level fMRI, with applications in modeling the relationships between network variability and behavioral/demographic variables.

The Danish 22q11 research initiative.

BACKGROUND: Neurodevelopmental brain disorders such as schizophrenia, autism and attention deficit hyperactivity disorder are complex disorders with heterogeneous etiologies. Schizophrenia and autism are difficult to treat and often cause major individual suffering largely owing to our limited understanding of the disease biology. Thus our understanding of the biological pathogenesis needs to be substantiated to enable development of more targeted treatment options with improved efficacy. Insights into the pre-morbid disease dynamics, the morbid condition and the underlying biological disease mechanisms may come from studies of subjects with homogenous etiologies. Breakthroughs in psychiatric genetics have shown that several genetic anomalies predispose for neurodevelopmental brain disorders. We have established a Danish research initiative to study the common microdeletion at chromosome 22q11.2, which is one of the genetic anomalies that confer high risk of schizophrenia, autism and attention deficit hyperactivity disorder. METHODS/DESIGN: The study applies a "cause-to-outcome" strategy to identify pre-morbid pathogenesis and underlying biological disease mechanisms of psychosis and secondarily the morbid condition of autism and attention deficit hyperactivity disorder. We use a population based epidemiological design to inform on disease prevalence, environmental risk factors and familial disposition for mental health disorders and a case control study design to map the functional effects across behavioral and neurophysiological traits of the 22q11 deletion in a recruited sample of Danish individuals. DISCUSSION: Identification of predictive pre-morbid clinical, cognitive, functional and structural brain alterations in 22q11 deletion carriers may alter current clinical practice from symptomatic therapy of manifest mental illness into early intervention strategies, which may also be applicable to at risk subjects without known etiology. Hopefully new insights into the biological disease mechanisms, which are mandatory for novel drug developments, can improve the outcome of the pharmacological interventions in psychiatry.

Self-disorder and brain processing of proprioception in schizophrenia spectrum patients: a re-analysis.

BACKGROUND: Anomalies of self-awareness (self-disorders, SDs) are theorized to be basic to schizophrenia psychopathology. We have previously observed dysfunction of brain processing of proprioception in schizophrenia spectrum disorders (SZS). We hypothesized that SDs could be associated with abnormalities of early contralateral proprioceptive evoked oscillatory brain activity. METHODS: We investigated the association between proprioceptive evoked potential components and SDs in a re-analysis of data from a subsample (n = 12) of SZS patients who had previously been observed with deviant proprioceptive evoked potentials and interviewed with the Examination of Anomalous Self-Experience (EASE) scale. RESULTS: Higher EASE scores (i.e. increased SD) were associated with lower peak parietal gamma frequencies and higher peak beta amplitudes over frontal and parietal electrodes in the left hemisphere following right-hand proprioceptive stimulation. CONCLUSION: Disorders of self-awareness may be associated with dysfunction of early phases of somatosensory processing. The findings are potentially relevant to our understanding of the pathophysiology of schizophrenia, but further studies are needed.

Non-parametric Bayesian graph models reveal community structure in resting state fMRI.

Modeling of resting state functional magnetic resonance imaging (rs-fMRI) data using network models is of increasing interest. It is often desirable to group nodes into clusters to interpret the communication patterns between nodes. In this study we consider three different nonparametric Bayesian models for node clustering in complex networks. In particular, we test their ability to predict unseen data and their ability to reproduce clustering across datasets. The three generative models considered are the Infinite Relational Model (IRM), Bayesian Community Detection (BCD), and the Infinite Diagonal Model (IDM). The models define probabilities of generating links within and between clusters and the difference between the models lies in the restrictions they impose upon the between-cluster link probabilities. IRM is the most flexible model with no restrictions on the probabilities of links between clusters. BCD restricts the between-cluster link probabilities to be strictly lower than within-cluster link probabilities to conform to the community structure typically seen in social networks. IDM only models a single between-cluster link probability, which can be interpreted as a background noise probability. These probabilistic models are compared against three other approaches for node clustering, namely Infomap, Louvain modularity, and hierarchical clustering. Using 3 different datasets comprising healthy volunteers' rs-fMRI we found that the BCD model was in general the most predictive and reproducible model. This suggests that rs-fMRI data exhibits community structure and furthermore points to the significance of modeling heterogeneous between-cluster link probabilities.

Archetypal analysis of diverse Pseudomonas aeruginosa transcriptomes reveals adaptation in cystic fibrosis airways.

BACKGROUND: Analysis of global gene expression by DNA microarrays is widely used in experimental molecular biology. However, the complexity of such high-dimensional data sets makes it difficult to fully understand the underlying biological features present in the data.The aim of this study is to introduce a method for DNA microarray analysis that provides an intuitive interpretation of data through dimension reduction and pattern recognition. We present the first "Archetypal Analysis" of global gene expression. The analysis is based on microarray data from five integrated studies of Pseudomonas aeruginosa isolated from the airways of cystic fibrosis patients. RESULTS: Our analysis clustered samples into distinct groups with comprehensible characteristics since the archetypes representing the individual groups are closely related to samples present in the data set. Significant changes in gene expression between different groups identified adaptive changes of the bacteria residing in the cystic fibrosis lung. The analysis suggests a similar gene expression pattern between isolates with a high mutation rate (hypermutators) despite accumulation of different mutations for these isolates. This suggests positive selection in the cystic fibrosis lung environment, and changes in gene expression for these isolates are therefore most likely related to adaptation of the bacteria. CONCLUSIONS: Archetypal analysis succeeded in identifying adaptive changes of P. aeruginosa. The combination of clustering and matrix factorization made it possible to reveal minor similarities among different groups of data, which other analytical methods failed to identify. We suggest that this analysis could be used to supplement current methods used to analyze DNA microarray data.

Bayesian community detection.

Many networks of scientific interest naturally decompose into clusters or communities with comparatively fewer external than internal links; however, current Bayesian models of network communities do not exert this intuitive notion of communities. We formulate a nonparametric Bayesian model for community detection consistent with an intuitive definition of communities and present a Markov chain Monte Carlo procedure for inferring the community structure. A Matlab toolbox with the proposed inference procedure is available for download. On synthetic and real networks, our model detects communities consistent with ground truth, and on real networks, it outperforms existing approaches in predicting missing links. This suggests that community structure is an important structural property of networks that should be explicitly modeled.

Combining electro- and magnetoencephalography data using directional archetypal analysis.

Metastable microstates in electro- and magnetoencephalographic (EEG and MEG) measurements are usually determined using modified k-means accounting for polarity invariant states. However, hard state assignment approaches assume that the brain traverses microstates in a discrete rather than continuous fashion. We present multimodal, multisubject directional archetypal analysis as a scale and polarity invariant extension to archetypal analysis using a loss function based on the Watson distribution. With this method, EEG/MEG microstates are modeled using subject- and modality-specific archetypes that are representative, distinct topographic maps between which the brain continuously traverses. Archetypes are specified as convex combinations of unit norm input data based on a shared generator matrix, thus assuming that the timing of neural responses to stimuli is consistent across subjects and modalities. The input data is reconstructed as convex combinations of archetypes using a subject- and modality-specific continuous archetypal mixing matrix. We showcase the model on synthetic data and an openly available face perception event-related potential data set with concurrently recorded EEG and MEG. In synthetic and unimodal experiments, we compare our model to conventional Euclidean multisubject archetypal analysis. We also contrast our model to a directional clustering model with discrete state assignments to highlight the advantages of modeling state trajectories rather than hard assignments. We find that our approach successfully models scale and polarity invariant data, such as microstates, accounting for intersubject and intermodal variability. The model is readily extendable to other modalities ensuring component correspondence while elucidating spatiotemporal signal variability.

Uncovering Cortical Units of Processing From Multi-Layered Connectomes.

Modern diffusion and functional magnetic resonance imaging (dMRI/fMRI) provide non-invasive high-resolution images from which multi-layered networks of whole-brain structural and functional connectivity can be derived. Unfortunately, the lack of observed correspondence between the connectivity profiles of the two modalities challenges the understanding of the relationship between the functional and structural connectome. Rather than focusing on correspondence at the level of connections we presently investigate correspondence in terms of modular organization according to shared canonical processing units. We use a stochastic block-model (SBM) as a data-driven approach for clustering high-resolution multi-layer whole-brain connectivity networks and use prediction to quantify the extent to which a given clustering accounts for the connectome within a modality. The employed SBM assumes a single underlying parcellation exists across modalities whilst permitting each modality to possess an independent connectivity structure between parcels thereby imposing concurrent functional and structural units but different structural and functional connectivity profiles. We contrast the joint processing units to their modality specific counterparts and find that even though data-driven structural and functional parcellations exhibit substantial differences, attributed to modality specific biases, the joint model is able to achieve a consensus representation that well accounts for both the functional and structural connectome providing improved representations of functional connectivity compared to using functional data alone. This implies that a representation persists in the consensus model that is shared by the individual modalities. We find additional support for this viewpoint when the anatomical correspondence between modalities is removed from the joint modeling. The resultant drop in predictive performance is in general substantial, confirming that the anatomical correspondence of processing units is indeed present between the two modalities. Our findings illustrate how multi-modal integration admits consensus representations well-characterizing each individual modality despite their biases and points to the importance of multi-layered connectomes as providing supplementary information regarding the brain's canonical processing units.

Attenuation of beta and gamma oscillations in schizophrenia spectrum patients following hand posture perturbation.

Several electroencephalographic (EEG) studies in schizophrenia report that the patients have reduced evoked gamma activity following visual and auditory stimulation. Somatosensory gamma activity has not previously been examined. It has been suggested that a dysfunction basic to schizophrenia spectrum traits would involve proprioceptive information processing and this has recently been supported by the finding of diminished latency of early proprioceptive evoked potentials in a sample of chronic schizophrenia patients. The proprioceptive stimulus used previously, and presently, consisted of an abrupt increase of weight on a hand-held load. Eighteen first-time admitted schizophrenia spectrum patients and 18 healthy matched comparison subjects were included. Proprioceptive evoked potentials were recorded as 64-channels EEG for 120 trials in two runs differing in sequence. Contra-lateral evoked beta (latency 90 ms, frequency 21 Hz) and gamma (latency 70 ms, frequency 32 Hz) oscillations were attenuated in the patient group. The healthy comparison subjects had increased gamma amplitude in the left hemisphere in the regular sequence, a phenomenon not seen in the patients. The deviant findings were unexpectedly more circumscribed in the schizophrenia than in the schizotypal personality disorder (SPD) patients. Future studies should include several concurrent psychophysiological measures.

The Bayesian Cut.

An important task in the analysis of graphs is separating nodes into densely connected groups with little interaction between each other. Prominent methods here include flow based graph cutting procedures as well as statistical network modeling approaches. However, adequately accounting for this, the so-called community structure, in complex networks remains a major challenge. We present a novel generic Bayesian probabilistic model for graph cutting in which we derive an analytical solution to the marginalization of nuisance parameters under constraints enforcing community structure. As a part of the solution a large scale approximation for integrals involving multiple incomplete gamma functions is derived. Our multiple cluster solution presents a generic tool for Bayesian inference on Poisson weighted graphs across different domains. Applied on three real world social networks as well as three image segmentation problems our approach shows on par or better performance to existing spectral graph cutting and community detection methods, while learning the underlying parameter space. The developed procedure provides a principled statistical framework for graph cutting and the Bayesian Cut source code provided enables easy adoption of the procedure as an alternative to existing graph cutting methods.

Machine Learning-Based Adherence Detection of Type 2 Diabetes Patients on Once-Daily Basal Insulin Injections.

BACKGROUND: Lack of treatment adherence can lead to life-threatening health complications for people with type 2 diabetes (T2D). Recent improvements and availability in continuous glucose monitoring (CGM) technology have enabled various possibilities to monitor diabetes treatment. Detection of missed once-daily basal insulin injections can be used to provide feedback to patients, thus improving their diabetes management. In this study, we explore how machine learning (ML) based on CGM data can be used for detecting adherence to once-daily basal insulin injections. METHODS: In-silico CGM data were generated to simulate a cohort of T2D patients on once-daily insulin injection (Tresiba®). Deep learning methods within ML based on automatic feature extraction including convolutional neural networks were explored and compared with simple feature-engineered ML classification models for adherence detection. It was further investigated whether fused expert-dependent and automatically learned features could improve performance, resulting in a comparison of six different detection models. Adherence was detected throughout each day with an increasing amount of CGM data available. RESULTS: The adherence detection accuracy improved as more CGM data became available on the day of classification. The three classification models based on expert-engineered features obtained mean accuracies of 78.6%, 78.2%, and 78.3%. The classification model based purely on learned features obtained a mean accuracy of 79.7%. The two classification models fusing expert-engineered and learned features obtained mean accuracies of 79.7% and 79.8%. All the mentioned results were obtained 16 hours after time of injection. CONCLUSION: The results suggest that adherence detection based on CGM data is feasible. Even though our study based on in-silico data indicates only slightly improved performance of more complex models, the question remains whether advanced models would outperform the simple in a real-world setting. Thus, future studies on adherence monitoring using real CGM data are relevant.