bioRxiv Science⌕ Search

Biology subjects

Linden, D. E. J.

Publications and source records attributed to Linden, D. E. J..

12 recordsLinked to original sources

Searchlight Optimization Using Representational Similarity Analysis for Subject-Level Voxel Selection in Emotional State Decoding

Identifying informative voxels is a critical, yet challenging step in functional magnetic resonance imaging (fMRI), particularly for multivariate analyses involving multiple related conditions. Existing approaches often rely on predefined regions of interest (ROIs) or activation-based criteria, which may be insufficient for capturing fine-grained representational differences. This challenge becomes particularly relevant in experimental settings and interventions such as neurofeedback training, where voxels are not only measured as neural responses but also used as targets for intervention based on their previously observed activity patterns. In this study, we propose a subject-level searchlight optimization framework that integrates voxel-wise general linear model (GLM)-based univariate analysis with representational similarity analysis (RSA)-based multivariate refinement to identify voxels that are both task-relevant and condition-sensitive. To enhance practical applicability, the framework further incorporates a data-driven hyperparameter tuning step based on Bayesian optimization, enabling efficient identification of high-performing configurations from small pilot datasets, with consistent performance when applied to larger samples. The proposed framework was evaluated using an emotion imagery fMRI dataset with four affective conditions. Results demonstrate that the multivariate refinement improves alignment between empirical and target representational structures compared with univariate selection alone. Compared with a classifier-based voxel selection approach, the RSA-based approach better preserves the representational geometry of emotional states while maintaining discriminative capacity. These findings highlight the effectiveness, efficiency, and robustness of the proposed RSA framework, providing a practical solution for identifying condition-sensitive voxels and supporting more precise multivariate investigation of affective brain states in multi-condition fMRI studies.

neuroscience↗

Revisiting Alpha Resting State Dynamics Underlying Hallucinatory Vulnerability: Insights from Hidden Semi-Markov Modeling

Resting state (RS) brain activity is inherently non-stationary. Hidden Semi-Markov Models (HsMM) can characterize the continuous RS data as a sequence of recurring and distinct brain states along with their spatio-temporal dynamics. Recent explorations suggest that EEG brain state dynamics in the alpha frequency link to auditory hallucination proneness (HP) in non-clinical individuals. The present study aims to replicate these findings to elucidate robust neural correlates of hallucinatory vulnerability. Specifically, we aimed to investigate the reproducibility of HsMM states across different data sets and within-data set variants as well as the replicability of the association between alpha brain state dynamics and HP. We found that most brain states are reproducible in different data sets, confirming that the HsMM characterized robust and generalizable EEG RS dynamics. Brain state topographies and temporal dynamics of different within-data set variants showed substantial similarities and were robust against reduced data length and number of electrodes. However, the association with HP was not directly reproducible across data sets. These results indicate that the sensitivity of brain state dynamics to capture individual variability in HP may depend on the data recording characteristics and individual variability in RS cognition, such as mind wandering. We suggest that the order in which eyes-open and eyes-closed RS data are acquired directly influences an individuals attentional state and generation of spontaneous thoughts, and thereby might mediate the link to hallucinatory vulnerability.

neuroscience↗

Hallucination proneness alters sensory feedback processing in self-voice production

BackgroundSensory suppression occurs when hearing ones self-generated voice, as opposed to passively listening to ones own voice. Quality changes of sensory feedback to the self-generated voice can increase attentional control. These changes affect the self-other voice distinction and might lead to hearing non-existent voices in the absence of an external source (i.e., auditory verbal hallucinations (AVH)). However, it is unclear how changes in sensory feedback processing and attention allocation interact and how this interaction might relate to hallucination proneness (HP). Study DesignParticipants varying in HP self-generated and passively listened to their voice that varied in emotional quality and certainty of recognition -- 100% neutral, 60-40% neutral-angry, 50-50% neutral-angry, 40-60% neutral-angry, 100% angry, during EEG recordings. Study ResultsThe N1 auditory evoked potential was more suppressed for the self-generated than externally generated voices. Increased HP was associated with (i) an increased N1 response to the self-compared to externally generated voices, (ii) a reduced N1 response for angry compared to neutral voices, and (iii) a reduced N2 response to unexpected voice quality in sensory feedback (60-40% neutral-angry) compared to neutral voices. ConclusionsThe current study highlights an association between increased HP and systematic changes of the emotional quality and certainty in sensory feedback processing (N1) and attentional control (N2) in self-voice production in a non-clinical population. Considering that voice hearers also display these changes, these findings support the continuum hypothesis. However, additional research is needed to validate this conclusion.

neuroscience↗

Oxysterol-liver X receptor signaling mediates CYFIP1 regulation of cortical neurogenesis

Dysregulation in neural progenitor proliferation and neuronal differentiation has been increasingly recognised as a common pathology in neural cells harboring genetic risks to neuropsychiatric and neurodevelopmental disorders, yet the underlying molecular mechanisms remains largely unknown. Deletions and duplications of the 15q11.2 region containing the CYFIP1 gene have been associated with autism and schizophrenia. Using patient-derived iPSCs carrying 15q11.2 deletion and genetically manipulated hESCs with CYFIP1 gain- and loss-of-function (GoF and LoF), we show that 15q11.2 deletion and CYFIP1-LoF leads to premature neuronal differentiation while CYFIP1-GoF favours neural progenitor maintenance. We identified cholesterol biosynthesis and metabolism as a biological process disturbed by CYFIP1 dosage change, leading to altered neuro-oxysterol profiles. 24S,25-epoxycholesterol, which was decreased in CYFIP1-GoF and increased in CYFIP1-LoF and 15q11.2del neural cells, can mimic the 15q11.2del and CYFIP1-LoF phenotype by promoting cortical neuronal differentiation and restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of the brain expressed isoform of the liver X receptor LXRb while compound deletion of LXRb in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR mediated oxysterol regulation of neurogenesis as a novel pathological mechanism in neural cells carrying 15q11.2CNV and provides a potential target for therapeutic strategies for genetic disorders associated with this risk locus.

neuroscience↗

EEG resting state alpha dynamics predict individual proneness to auditory hallucinations

IntroductionAuditory verbal hallucinations (AVH) are a transdiagnostic phenomenon but also occur in the general population. The disposition to experience AVH is considered a continuous expression from non-clinical to clinical hallucination proneness (HP). Currently, little is known about the neurophysiology of the non-clinical HP part of the continuum. AVH might result from a heightened sensitivity to sensory inputs and a decreased ability to differentiate between externally and internally generated input. Resting state (RS) alpha band activity is associated with perceptual sensitivity, attentional shifts, and cognitive control. Accordingly, spontaneous alpha fluctuations might present as a HP correlate. To investigate the time-varying dynamics of alpha band activity, we deployed a novel method for brain state allocation. MethodsWe recorded RS electroencephalography (EEG) data from 33 individuals with varying levels of HP but without clinically relevant hallucinations and used a Hidden Semi-Markov Model (HsMM) to identify five recurrent alpha states with unique temporal dynamics and topographies. The states mean duration and occupancy were analyzed as a function of HP. The sources of each state were reconstructed to identify the most active brain areas and their correspondence with known resting state networks. ResultsOccupancy and mean duration of a state corresponding to sensorimotor, auditory, and default-mode network (DMN) areas significantly predicted auditory and auditory-verbal HP, but not general HP. The temporal dynamics of all other states did not relate to HP. ConclusionAlpha brain state sources align with prior results on the role of the alpha in the DMN. The temporal dynamics of alpha might reflect individual differences for attentional biases to internally generated sensory events and altered auditory perceptual sensitivity. Thus, changes in the temporal brain state dynamics of RS alpha oscillations could present as a neural marker of increased vulnerability to auditory hallucinatory experiences.

neuroscience↗

Using rare genetic mutations to revisit structural brain asymmetry

Asymmetry between the left and right brain is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variant studies, which typically exert small effects on brain phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We quantitatively dissected the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior mapping highlights the consequences of genetically controlled brain lateralization on human-defining cognitive traits.

neuroscience↗

Converging pathways found in copy number variation syndromes with high schizophrenia risk

Schizophrenia genetics is complex, and the contribution of common and rare variants are not fully understood. Several specific copy number variations (CNVs) confer increased risk for schizophrenia, and the study of their effects is central to molecular models of mental illness. However, these CNVs - microdeletions or -duplications - are spread across the genome and differ in the number of genes affected and classes of coded proteins. This suggests that, in order to fully understand the contribution of these genetic variants to mental illness, we need to look beyond the deleted or duplicated genes, to their interaction partners and involved molecular pathways. In this study, we developed machine-readable interactive pathways to enable analysis of downstream effects of genes within CNV loci and identify common pathways between CNVs with high schizophrenia risk using the WikiPathways database, and schizophrenia risk gene collections from GWAS studies and a gene-disease association database. For CNVs that are pathogenic for schizophrenia, we found overlapping pathways, including BDNF signaling, cytoskeleton, cell-cell connections, inflammation and MAPK3 signaling. Common schizophrenia risk genes identified by different studies are found in all CNV pathways but not enriched. Our findings suggest that specific pathways - such as BDNF signaling - may be critical contributors to schizophrenia risk conferred by rare CNVs, and common risk variants may operate through distinct mechanisms. Our approach also highlights the importance of not only investigating deleted or duplicated genes within pathogenic CNV loci, but also study their direct interaction partners, which may explain pleiotropic effects of CNVs on schizophrenia risk.

systems biology↗

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome.

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density, and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

neuroscience↗

Analysis of diffusion tensor imaging data from UK Biobank confirms dosage effect of 15q11.2 copy-number variation on white matter and shows association with cognition

BackgroundCopy-number variations at the 15q11.2 BP1-BP2 locus are present in 0.5 to 1.0% of the population, and the deletion is associated with a range of neurodevelopmental disorders. Previously, we showed a reciprocal effect of 15q11.2 copy-number variation on fractional anisotropy, with widespread increases in deletion carriers. We aim to replicate and expand these findings, using a larger sample of participants (n=30,930), higher resolution imaging, and examining the implications for cognitive performance. MethodsDiffusion tensor imaging measures from participants with no neurological/psychiatric diagnoses were obtained from the UK Biobank database. We compared 15q11.2 BP1-BP2 deletion (n=103) and duplication (n=119) carriers to a large cohort of control individuals with no neuropsychiatric copy-number variants (n=29,870). Additionally, we assessed how changes in white matter mediated the association between carrier status and cognitive performance. ResultsDeletion carriers showed increases in fractional anisotropy in the internal capsule and cingulum, and decreases in the posterior thalamic radiation, compared to both duplication carriers and controls (who had intermediate values). Deletion carriers had lower scores across cognitive tasks compared to controls, which were mildly influenced by white matter alterations. Reduced fractional anisotropy in the posterior thalamic radiation partially contributed to worse cognitive performance in deletion carriers. ConclusionsThis study, together with our previous findings, provides convergent evidence for a dosage-dependent effect of 15q11.2 BP1-BP2 on white matter microstructure. Additionally, changes in white matter were found to partially mediate cognitive ability in deletion carriers, providing a link between white matter changes in 15q11.2 BP1-BP2 carriers and cognitive function.

neuroscience↗

The Effect of MR Image Quality on Structural and Functional Brain Connectivity: The Maastricht Study

In large population-based cohort studies, magnetic resonance imaging (MRI) is often used to study the structure and function of the brain. Advanced MRI techniques such as diffusion-tensor (dMRI) or resting-state functional MRI (rs-fMRI) can be used to study connections between distinct brain regions. However, brain connectivity measures are likely affected by biases introduced during MRI data acquisition and/or processing.\n\nWe identified three sources that may lead to bias, i.e. signal-to-noise ratio (SNR), head motion, and spatial mismatch between MRI-based anatomy and a brain atlas. After quantifying these sources, we determined the associations between the image quality metrics and brain connectivity measures derived from dMRI and rs-fMRI in 5,110 participants of the population-based Maastricht Study.\n\nMore head motion and low SNR were negatively associated with structural and functional brain connectivity, respectively, and these metrics substantially affected (>10%) associations of brain connectivity with age, sex and body mass index (BMI), whereas associations with diabetes status, educational level, history of cardiovascular disease, and white matter hyperintensities were less or not affected. In addition, age, sex, and BMI were associated with head motion, SNR, and atlas mismatch (all p < 0.001). Based on our results, we strongly advise that, in large population-based cohort neuroimaging studies, statistical analyses on structural and functional brain connectivity should adjust for potentially confounding effects of image quality.\n\nHighlightsO_LILow MR image quality compromises brain connectivity measures\nC_LIO_LIMR image quality is negatively associated with age, body mass index, and male sex\nC_LIO_LIStatistical analyses in large neuroimaging studies should account for image quality\nC_LI

neuroscience↗

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.

neuroscience↗

Cyfip1 haploinsufficiency is associated with white matter changes, myelin thinning, reduction of mature oligodendrocytes and behavioural inflexibility

The biological basis of the increased risk for psychiatric disorders due to the pathogenic 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion at this locus. Using a novel rat model, we have recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval to reveal alterations in white matter microstructure. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutants that were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with a reduction in the number of mature oligodendrocytes. Finally, we demonstrated functional effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.

neuroscience↗