bioRxiv Subject Collection: Neuroscience's Journal
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Friday, August 16th, 2024
| Time |
Event |
| 1:33a |
Explicitly Nonlinear Connectivity-Matrix Independent Component Analysis in Resting fMRI Data
Independent component analysis (ICA) is a widely used data-driven technique for investigating brain structure and function to extract intrinsic networks. However, the ability of ICA, a linear mixing model, to capture nonlinear relationships is inherently limited. While nonlinear ICA can be used to estimate nonlinear+ linear mixtures, it can be useful to study the degree to which there is nonlinearity above and beyond the widely studied linear resting networks. Here, we propose a way to divide the data into sources exhibiting linear-only or explicitly nonlinear dependencies in resting functional magnetic resonance imaging (fMRI) data. Such an approach can be very informative as it allows us to evaluate the degree to which a given network might be linear, nonlinear, or both linear and nonlinear. Here, we present an enhanced connectivity-domain ICA approach, connectivity-matrix ICA, incorporating normalized mutual information (NMI) after canceling the linear effects to measure explicitly nonlinear (EN) relationships within voxel connectivity. This integration enables the identification of brain spatial maps that exhibit pronounced explicitly nonlinear dependencies while excluding linear relationships. By eliminating linear dependencies and utilizing NMI, we discover highly structured resting networks that conventional functional connectivity methods would typically overlook. The results indicate that several maps show only linear or EN relationships, and the rest of the components display both linear and nonlinear patterns. We categorized these maps as linear-only, EN-only, and linear-EN maps. We also evaluate differences in the identified networks in a schizophrenia dataset. A significant global difference has been discovered between schizophrenia and controls in some linear-EN maps, such as the frontal lobe. Moreover, the temporal lobe and thalamus display linear group differences, while the visual and motor cortex display global differences in nonlinear relationships as their primary driver of these disparities. In sum, our findings emphasize the significance of accounting for explicitly nonlinear dependencies in functional connectivity analysis and demonstrate the effectiveness of the extended cmICA approach in revealing previously unrecognized brain dynamics. | | 1:33a |
Male and female mice respectively form stronger social aversive memories with same and different sex conspecifics
Mice offer a wealth of opportunities for investigating brain circuits regulating multiple behaviors, largely due to their genetic tractability. Social behaviors are of translational relevance, considering both mice and humans are highly social mammals, and disruptions in human social behavior are key symptoms of myriad neuropsychiatric disorders. Stresses related to social experiences are particularly influential in the severity and maintenance of neuropsychiatric disorders like anxiety disorders, and trauma and stressor-related disorders. Yet, induction and study of social stress in mice is disproportionately focused on males, influenced heavily by their natural territorial nature. Conspecific-elicited stress (i.e., defeat), while ethologically relevant, is quite variable and predominantly specific to males, making rigorous and sex-inclusive studies challenging. In pursuit of a controllable, consistent, high throughput, and sex-inclusive paradigm for eliciting social stress, we have discovered intriguing sex-specific social aversions that are dependent upon the sex of both experimental and conspecific mice. Specifically, we trained male and female F1 129S1/SvlmJ x C57BL/6J to associate (via classical conditioning) same or different sex C57BL/6J conspecifics with a mild, aversive stimulus. Upon subsequent testing for social interaction 24 h later, we found that males socially conditioned better to male conspecifics by exhibiting reduced social interaction, whereas females socially conditioned better to male conspecifics. Serum corticosterone levels inversely corresponded to social avoidance after different sex, but not same sex, conditioning, suggesting corticosterone-mediated arousal could influence cross sex interactions. While our paradigm has further optimization ahead, these current findings reveal why past pursuits to develop same sex female social stress paradigms may have met with limited success. Future research should expand investigation of utilizing male mouse conspecifics to instigate social stress across sexes. | | 1:33a |
The effect of microsaccades in the primary visual cortex: a two-phase modulation in the absence of visual stimulation
Our eyes are never still. Even when we attempt to fixate, the visual gaze is never motionless, as we continuously perform miniature oculomotor movements termed as fixational eye movements. The fastest eye movements during the fixation epochs are termed microsaccades (MSs), that are leading to continual motion of the visual input, affecting mainly neurons in the fovea. Yet our vision appears to be stable. To explain this gap, previous studies suggested the existence of an extra-retinal input (ERI) into the visual cortex that can account for the motion and produce visual stability. Here, we investigated the existence of an ERI to V1 fovea in behaving monkeys while they performed spontaneous MSs, during fixation. We used voltage-sensitive dye imaging (VSDI) to measure and characterize at high spatio-temporal resolution the influence of MSs on neural population activity, in the foveal region of the primary visual cortex (V1). In the absence of a visual stimulus, MSs induced a two-phase response modulation: an early suppression transient followed by an enhancement transient. A correlation analysis revealed an increase in neural synchronization around ~100 ms after MS onset. Next, we investigated the MS effects in the presence of a small visual stimulus, and found that this modulation was different from the non-stimulated condition yet both modulations co-existed in the fovea. Finally, the VSD response to an external motion of the fixation point could not explain the MS modulation. These results support an ERI that may be involved in visual stabilization already at the level of V1. | | 8:35a |
Working memory processing boosts the retrieval of existing long-term memory representations
Understanding the interaction between short-term and long-term memory systems is essential for advancing our knowledge of human memory and learning. The current study examines whether processing in working memory, specifically attentional prioritization (Experiments 1 and 2) and testing (Experiment 2), can enhance the retrieval of recently encoded long-term memories. Eighty-six participants completed a three-phase task across two experiments. In the first phase, they learned object-location associations. In the second phase, using a retro-cue paradigm, these pairs reappeared with either informative (Experiments 1 and 2) or uninformative (Experiment 2) cues for a subsequent match-no-match test. In the final retrieval phase, participants recalled the locations associated with each object. Behavioral performance and electroencephalogram data recorded during this final retrieval phase of Experiment 1 revealed that attentional prioritization improved long-term memory retrieval. Experiment 2 indicated that prioritization and testing jointly enhance retrieval. These findings suggest that working memory does not only serve as a temporary store but has the capacity to actively strengthen long-term memory representations. | | 8:35a |
Whole-brain dynamics of articulatory, acoustic and semantic speech representations
Speech production is a complex process that traverses several representations, from the meaning of spoken words (semantic), through the movement of articulatory muscles (articulatory) and, finally, to the produced audio waveform (acoustic). In our study, we aimed to identify how these different representations of speech are spatially and temporally distributed throughout the depth of the brain. By considering multiple representations from the same exact data, we can limit potential con-founders to better understand the different aspects of speech production and acquire crucial complementary information for speech brain-computer interfaces (BCIs). Intracranial speech production data was collected of 15 participants, recorded from 1647 electrode contacts, while they overtly spoke 100 unique words. The electrodes were distributed across the entire brain, including sulci and subcortical areas. We found a bilateral spatial distribution for all three representations, although there was a stronger tuning in the left hemisphere with a more widespread and temporally dynamic distribution than in the right hemisphere. The articulatory and acoustic representations share a similar spatial distribution surrounding the Sylvian fissure, while the semantic representation appears to be widely distributed across the brain in a mostly distinct network. These results highlight the distributed nature of the speech production process and the potential of non-motor representations for speech BCIs. | | 8:35a |
Microglia morphology in the developing primate amygdala and effects of early life stress
A unique pool of immature glutamatergic neurons in the primate amygdala, known as the paralaminar nucleus (PL), are maturing between infancy and adolescence. The PL is a potential substrate for the steep growth curve of amygdala volume during this developmental period. A microglial component is also embedded among the PL neurons, and likely supports local neuronal maturation and emerging synaptogenesis. Microglia may alter neuronal growth following environmental perturbations such as stress. Using multiple measures, we first found that microglia in the infant primate PL had relatively large somas, and a small arbor size. In contrast, microglia in the adolescent PL had a smaller soma, and a larger dendritic arbor. We then examined microglial morphology in the PL after a novel maternal separation protocol, to examine the effects of early life stress. After maternal separation, the microglia had increased soma size, arbor size and complexity. Surprisingly, strong effects were seen not only in the infant PL, but also in the adolescent PL from subjects who had experienced the separation many years earlier. We conclude that under maternal-rearing conditions, PL microglia morphology tracks PL neuronal growth, progressing to a more mature phenotype by adolescence. Maternal separation has long-lasting effects on microglia, altering their normal developmental trajectory, and resulting in a hyper-ramified phenotype that persists for years. We speculate that these changes have consequences for neuronal development in young primates. | | 9:48a |
Sequence action representations contextualize during rapid skill learning
Activities of daily living rely on our ability to acquire new motor skills composed of precise action sequences. Early learning of a new sequential skill is characterized by steep performance improvements that develop predominantly during rest intervals interspersed with practice, a form of rapid consolidation. Here, we ask if the millisecond level neural representation of an action performed at different locations within a skill sequence contextually differentiates or remains stable as learning evolves. Optimization of machine learning decoders to classify sequence-embedded finger movements from MEG activity reached approximately 94% accuracy. The representation manifolds of the same action performed in different sequence contexts progressively differentiated during rest periods of early learning, predicting skill gains. We conclude that sequence action representations contextually differentiate during early skill learning, an issue relevant to brain-computer interface applications in neurorehabilitation. | | 5:47p |
Circulating extracellular microRNAs in the blood promote sociability in mice
Extracellular vesicles (EVs) are cell-derived membrane vesicles that circulate throughout the body. Accordingly, circulating EVs and their associated molecules, such as RNAs and proteins, are regarded as promising sources of molecular biomarkers for various disorders. Cell culture-derived EVs have also drawn substantial attention as possible delivery tools for therapeutic molecules. Nevertheless, the biological impact of circulating EVs on in vivo physiology and pathology remains elusive. Here we report that systemic exposure to blood circulating EVs from wild-type (WT) mice attenuates sociability deficits in Rag1-/- mice. Intravenously injected WT mouse blood EVs reach the brain and restore postsynaptic inhibitory signals in the Rag1-/- medial prefrontal cortex (PFC) pyramidal neurons. Mechanistically, WT EV-associated microRNAs, miR-23a-3p and miR-103-3p, reduce PKC{varepsilon} expression, increasing postsynaptic GABAA receptors in the mPFC pyramidal neurons. Our findings reveal a sociability-promoting effect of blood circulating EVs and associated miRNAs with therapeutic potential for sociability deficits. | | 7:47p |
Gray matter correlates of childhood maltreatment in the context of major depression: searching for replicability in a multi-cohort brain-wide association study of 3225 adults
Background: Childhood maltreatment has been associated with gray matter alterations, particularly within limbic and prefrontal regions. However, findings are heterogeneous, potentially due to differing methodologies and sample characteristics. Here, we investigate the cross-cohort replicability of gray matter correlates of childhood maltreatment across large clinical and non-clinical adult samples using harmonized assessment, preprocessing and analysis pipelines. Methods: Three independent adult cohorts comprising a total of N=3225 individuals (healthy control [HC]: n=1898 and participants with major depressive disorder [MDD]: n=1327) underwent structural MRI and maltreatment assessment via the Childhood Trauma Questionnaire (CTQ). Associations between childhood maltreatment and voxel-based gray matter volume (GMV) were tested on a wholebrain level in two steps: 1) pooling all three cohorts together to harvest maximum statistical power (applying a voxel-wise FWE-corrected threshold of pFWE<.05) and 2) investigating the replicability of effects by assessing cross-cohort spatial overlap of significant voxels at two liberal uncorrected thresholds (punc<.001 and punc<.01). Twelve statistical models were tested, that varied in maltreatment operationalizations, subsamples and covariates. Results: Pooling cohorts yielded no significant maltreatment-GMV associations when controlling for lifetime MDD diagnosis. Dropping MDD diagnosis as a covariate yielded significant negative effects of maltreatment within widespread clusters across temporal regions, a fusiform-lingual-parahippocampal complex, the thalamus and the orbitofrontal cortex (k=4970, pFWE<.05). Including only HC subsamples, small clusters emerged either when using the CTQ sum score (k=99, pFWE<.05, orbitofrontal) or when investigating severe forms of maltreatment in HCs (k=132, pFWE<.05, cerebellum). The largest effect size when pooling all three cohorts was partial R2=.022. Replicability analyses using a liberal uncorrected thresholding at punc<.001 yielded maltreatment-GMV associations within all single cohorts and across all statistical models. However, these associations were effectively non-replicable across cohorts, which was largely consistent across statistical models. Even extending the significance threshold to a liberal threshold of punc<.01 yielded only marginal replicability across cohorts. Conclusions: Gray matter correlates of childhood maltreatment, measured with the CTQ, are non-replicable across large cohorts when adequately controlling for depression diagnosis, even when employing harmonized study protocols, lenient statistical thresholds and exploring various maltreatment operationalizations and subgroups. Previous findings may have been inflated by inadequate control for confounding diagnosis effects or due to publication bias. Our findings underscore the importance of a paradigm shift towards investigating the replicability of neuroimaging findings. | | 7:47p |
Brain transcriptomic signatures for mood disorders and suicide phenotypes: an anterior insula and subgenual ACC network postmortem study
Maintaining a balanced mood state is necessary for human well-being and survival. Several brain changes, including reduced anatomical integrity identified in imaging studies and molecular measures of transcriptomic changes identified in postmortem brain RNA-sequencing (RNA-Seq) studies, have been found in major depressive disorder (MDD) and bipolar disorder (BD) (here referred to as mood disorders). Although the human anterior insula (Ant-Ins) and subgenual anterior cingulate (sgACC) are involved in the regulation of mood/affect, and feeling states, studies dissecting the molecular neurobiological mechanisms of mood (dys)functions have not consistently targeted this critical brain network. Here, we studied the postmortem Ant-Ins and sgACC and applied whole-tissue RNA-seq measures of differentially expressed genes (DEGs) in mood disorders versus (vs.) psychiatrically unaffected controls (controls). We identified DEGs associated with mood disorder-related diagnostic phenotypes by combining gene co-expression, differential gene expression, and pathway-enrichment analyses. Using factor analysis of the postmortem phenotypic variables to determine relevant sources of population variances, we identified downregulation/under expression of inflammatory and protein synthesis-related genes associated with psychiatric morbidity (i.e., all co-occurring mental disorders and suicide outcomes/death by suicide) in Ant-Ins, in contrasts to upregulation of synaptic membrane and ion channel-related genes with increased psychiatric morbidity in sgACC. We further identified a preponderance of downregulated metabolic, protein synthesis, inflammatory, and synaptic membrane DEGs associated with suicide outcomes in relation to a factor representing longevity in the Ant-Ins and sgACC network. Our findings revealed a critical brain network molecular repertoire for mood disorder phenotypes, including suicide outcomes and longevity. This work provides a framework for studying directionally defined (downregulated vs. upregulated) molecular mechanisms for mood disorder phenotypic complexity and disease outcomes. | | 7:47p |
Dopaminergic modulation of behavioral and electrocortical markers of interpersonal performance monitoring in Parkinson's Disease: insights from multivariate and univariate analyses
Effective interpersonal interaction necessitates constant monitoring and adaptation to others' actions, a process known as interpersonal performance monitoring, which is influenced by the dopaminergic system and marked by specific electrocortical signatures. To explore the connection between deficits in interpersonal performance monitoring and altered neural markers, we assessed patients with Parkinson's Disease (PD) performing coordination tasks with a virtual partner (VP) under two conditions: on dopaminergic medication (PD ON) and after withdrawal (PD OFF). In Interactive trials, which required adaptation to the VP's actions, PD OFF performance was impaired compared to PD ON. EEG analysis revealed in PD OFF increased midfrontal Delta-Theta activity during Interactive trials. Higher Delta-Theta synchronization was associated with improved performance, suggesting compensatory mechanisms. Multivariate EEG analysis distinguished Interactive from Cued trials, especially in PD OFF. Our findings highlight dopamine's role in modulating electrocortical markers of interpersonal performance monitor, with significant implications for understanding and treating PD. | | 7:47p |
Imaging high-frequency voltage dynamics in multiple neuron classes of behaving mammals
Fluorescent genetically encoded voltage indicators report transmembrane potentials of targeted cell-types. However, voltage-imaging instrumentation has lacked the sensitivity to track spontaneous or evoked high-frequency voltage oscillations in neural populations. Here we describe two complementary TEMPO voltage-sensing technologies that capture neural oscillations up to ~100 Hz. Fiber-optic TEMPO achieves ~10-fold greater sensitivity than prior photometry systems, allows hour-long recordings, and monitors two neuron-classes per fiber-optic probe in freely moving mice. With it, we uncovered cross-frequency-coupled theta- and gamma-range oscillations and characterized excitatory-inhibitory neural dynamics during hippocampal ripples and visual cortical processing. The TEMPO mesoscope images voltage activity in two cell-classes across a ~8-mm-wide field-of-view in head-fixed animals. In awake mice, it revealed sensory-evoked excitatory-inhibitory neural interactions and traveling gamma and 3-7 Hz waves in the visual cortex, and previously unreported propagation directions for hippocampal theta and beta waves. These technologies have widespread applications probing diverse oscillations and neuron-type interactions in healthy and diseased brains. |
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