bioRxiv Subject Collection: Neuroscience's Journal

Carrier-frequency specific omission-related neural activity in ordered sound sequences are independent of omissions-predictability
Regularities in our surroundings lead to predictions about upcoming events. Previous research has shown, that omitted sounds during otherwise regular tone sequences elicit frequency-specific neural activity related to the upcoming but omitted tone. We tested whether this neural response is depending on the unpredictability of the omission. Therefore we recorded MEG data while participants listened to ordered or random tone sequences with omissions occurring either ordered or randomly. Using multivariate pattern analysis shows that the frequency-specific neural pattern during omission within ordered tone sequences occurs independent of the regularity of the omissions suggesting that the auditory predictions based on sensory experiences are not immediately updated by violations of those expectations.

Mapping patterns of thought onto brain activity during movie-watching
Movie watching is a central aspect of our lives and an important paradigm for understanding the brain mechanisms behind cognition as it occurs in daily life. Contemporary cognitive neuroscience has made important strides in understanding how brain activity emerges during movies and determining how the dynamics of brain regions during movies can be mapped across individuals. However, we currently lack an understanding of how patterns of ongoing thoughts map onto the brain signals that occur when we watch a film, partly because methods of sampling experience disrupt the dynamics of brain activity and the experience of movie watching. Our study established a novel method for mapping thought patterns onto the brain activity that occur at different moments of a film, which does not disrupt the time course of brain activity or the movie-watching experience. We found that in moments when experience sampling highlighted engagement with multi-sensory features of the film, or highlighted thought with episodic features, regions of sensory cortex were more active and subsequent memory for events in the movie is better. These results highlight the critical role that sensory systems play in the multi-modal experience of movie-watching and place important constraints on the contribution of systems in association cortex, like the default network.

Computational basis of hierarchical and counterfactual information processing
Cognitive theories attribute humans' unparalleled capacity in solving complex multistage decision problems to distinctive hierarchical and counterfactual reasoning strategies. Here, we used a combination of human psychophysics and behaviorally-constrained neural network modeling to understand the computational basis of these cognitive strategies. We first developed a multi-stage decision-making task that humans solve using a combination of hierarchical and counterfactual processing. We then used a series of hypothesis-driven behavioral experiments to systematically dissect the potential computational constraints that underlie these strategies. One experiment revealed that humans have limited capacity for parallel processing. Another indicated that counterfactuals do not fully compensate for this limitation because of working memory limits. A third experiment revealed that the degree to which humans use counterfactuals depends on the fidelity of their working memory. Next, we asked whether the strategies humans adopt are computationally rational; i.e., optimal under these constraints. To do so, we analyzed the behavior of a battery of task-optimized recurrent neural networks (RNNs) that were subjected to one or more of these constraints. Remarkably, only RNNs that were subjected to all these constraints behaved similarly to humans. Further analysis of the RNNs revealed that what cognitive theories posit as distinctive strategies such as hierarchical and counterfactual are subdivisions in a continuum of computationally rational solutions that includes optimal, counterfactual, postdictive, and hierarchical.

Building compositional tasks with shared neural subspaces
Cognition is remarkably flexible; we are able to rapidly learn and perform many different tasks. Theoretical modeling has shown artificial neural networks trained to perform multiple tasks will re-use representations and computational components across tasks. By composing tasks from these sub-components, an agent can flexibly switch between tasks and rapidly learn new tasks. Yet, whether such compositionality is found in the brain is unknown. Here, we show the same subspaces of neural activity represent task-relevant information across multiple tasks, with each task compositionally combining these subspaces in a task-specific manner. We trained monkeys to switch between three compositionally related tasks. Neural recordings found task-relevant information about stimulus features and motor actions were represented in subspaces of neural activity that were shared across tasks. When monkeys performed a task, neural representations in the relevant shared sensory subspace were transformed to the relevant shared motor subspace. Subspaces were flexibly engaged as monkeys discovered the task in effect; their internal belief about the current task predicted the strength of representations in task-relevant subspaces. In sum, our findings suggest that the brain can flexibly perform multiple tasks by compositionally combining task-relevant neural representations across tasks.

ARX regulates interneuron subtype differentiation and migration
Mutations in the aristaless-related homeobox (ARX) gene are associated with a spectrum of neurodevelopmental disorders with neurologic phenotypes including epilepsy, intellectual disabilities and autism spectrum disorders, with or without structural malformations. Some features of these disorders have been linked to abnormal cortical interneuron (IN) development and function. Currently, more than 50 subtypes of cortical INs have been identified thanks to the single cell transcriptomics. The existence of these many IN subtypes, with differing functions, raise the likelihood that distinct phenotypic dysfunction be associated with specific IN subtype defects. Despite the functional significance of each IN subtype, the molecular mechanisms underlying their development remain incompletely understood. To further extend our understanding of IN subtype development and to evaluate the implications of subtype defects, different types of Arx mutation models were investigated: conditional loss of function mutations of Arx (Arx cKO) driven by three IN-specific Cre lines (Gad2Cre, Nkx2.1Cre, and SstCre) and a poly-alanine tract expansion mutation (Arx(GCG)7). Single cell as well as total transcriptomic analysis, along with ARX chromatin immunoprecipitation sequencing (ChIP-seq), reveal that ARX regulates transcription of cortical IN development- and migration-associated genes. Our data obtained in embryonic and perinatal stage indicate that the relatively early loss of ARX in the progenitor cells or immature INs leads to IN subtype changes and migration defects, whereas its loss in postmitotic INs did not. On the other hand, the poly-alanine tract expansion mutation results in IN migration defects without affecting IN subtype development during embryonic stages, although postnatal reduction of certain subtypes of INs were detected. Our data provide new insights into how different mutations in the same gene can result in a spectrum of clinical phenotypes.

Electrophysiological responses to syntactic and 'morphological' structures: evidence from Mandarin Chinese
What are syntactic relations, and how does our brain infer them from a string of text characters? In the EEG study reported here we aimed to investigate these questions by contrasting syntactically separable compounds (zao4...fan3 -> 'rebel') and non-separable compounds (chi2yi2 -> 'hesitate') in Mandarin Chinese. Because both kinds of compounds have non-compositional meanings, their syntactic differences provide an elegant means for dissociating syntactic from semantic relations. Because non-separable compounds fit the traditional criteria for 'wordhood', this contrast also provides a means for asking whether syntactic and morphological relations are inferred in qualitatively different ways. We found that, relative to non-separable compounds, syntactically separable compounds elicited a left anterior negativity (LAN) effect between 275-400ms. Even though readers were always presented with the compounds in their unseparated form, our results suggest that the potentially separable compound forms drive the inference of a more complex set of underlying syntactic relations. In a companion manipulation in the same participants, we observed a qualitatively similar LAN effect when comparing non-separable compound nouns with simplex nouns. This finding raises doubts for the existence of a clear-cut distinction between 'syntax' and 'morphology', at least in processing.

Exploring distinct and joint contributions of the Locus Coeruleus and the Substantia Nigra/Ventral Tegmental Area complex to reward and valence processing using high-resolution fMRI
Dopaminergic neurons in the substantia nigra and the ventral tegmental area (SN/VTA) are classically viewed as key mediators in reward processing, while noradrenergic cells in the locus coeruleus (LC) are thought to modulate (negative) saliency processing. However, this conventional distinction is being revised by more recent research in animals. To explore the respective contributions of both the LC and SN/VTA in reward and valence processing in humans, we assessed fMRI data during stimulus encoding and response phase of a rewarded emotion-discrimination task (n=38). Participants responded significantly faster to reward-predicting and negative valence stimuli compared to their non-salient counterparts. LC activity was overall higher during trials involving reward prospect, and in particular for reward trials featuring positive valence, demonstrating an additive effect of reward and positive valence in LC. Moreover, LC activity was differentially increased for negative compared to positive valence in the response phase, indexing its role in invigorating responses to negative events. The SN/VTA showed increased activity in the response phase of reward trials (neutral valence) and negative valence trials (no-reward), which aligns with coding relative saliency of these events in their respective contexts. LC modulations were accompanied by covariations in occipital cortex, suggesting noradrenergic contributions to visual prioritization of salient events. The findings underscore the sensitivity of both LC and SN/VTA to reward prospects and negative valence, challenging the dominant view of SN/VTA's involvement in merely positive events and emphasizing their essential role in action invigoration above and beyond mere stimulus encoding. The intricate roles of the DA and NA system in reward and emotional valence processing in humans warrant further exploration and validation, given the limitations inherent to neuroimaging of deep brain structures.

Sex differences in brain-behavior relationships in the first two years of life
Background: Evidence for sex differences in cognition in childhood is established, but less is known about the underlying neural mechanisms for these differences. Recent findings suggest the existence of brain-behavior relationship heterogeneities during infancy; however, it remains unclear whether sex underlies these heterogeneities during this critical period when sex-related behavioral differences arise. Methods: A sample of 316 infants was included with resting-state functional magnetic resonance imaging scans at neonate (3 weeks), 1, and 2 years of age. We used multiple linear regression to test interactions between sex and resting-state functional connectivity on behavioral scores of working memory, inhibitory self-control, intelligence, and anxiety collected at 4 years of age. Results: We found six age-specific, intra-hemispheric connections showing significant and robust sex differences in functional connectivity-behavior relationships. All connections are either with the prefrontal cortex or the temporal pole, which has direct anatomical pathways to the prefrontal cortex. Sex differences in functional connectivity only emerge when associated with behavior, and not in functional connectivity alone. Furthermore, at neonate and 2 years of age, these age-specific connections displayed greater connectivity in males and lower connectivity in females in association with better behavioral scores. Conclusions: Taken together, we critically capture robust and conserved brain mechanisms that are distinct to sex and are defined by their relationship to behavioral outcomes. Our results establish brain-behavior mechanisms as an important feature in the search for sex differences during development.

Functionally distinct subdomains of dopamine in the hippocampus
Numerous studies have identified dopamine signaling in the hippocampus as necessary for certain types of learning and memory. Since dopamine in the striatum is strongly tied to rewards, dopamine in the hippocampus is thought to reinforce reward learning. Despite the critical influence of dopamine on hippocampal function, little is known about dopamine release in the hippocampus or the specific ways dopamine can influence hippocampal function. Based on the functional complexity of hippocampal circuitry, we hypothesized the existence of multiple dopamine signaling domains. Using optical dopamine sensors, two-photon imaging, and head-fixed behaviors, we identified two functionally and spatially distinct dopamine domains in the hippocampus. The "superficial" domain (cell somata and apical dendrites) showed reward-related dopamine transients early in Pavlovian conditioning but were replaced by "deep" domain transients (basal dendritic layer) with experience. These two domains also play distinct roles in a hippocampal-dependent, goal-directed virtual reality task where mice use exploratory licks to discover the location of a hidden reward zone. Here, positive dopamine ramps appeared in the superficial domain as mice approached the reward zone, similar to those seen in the striatum. At the same time, the deep domain showed strong reward-related transients. These results reveal small-scale, anatomically segregated, dopamine domains in the hippocampus. Furthermore dopamine domain activity had temporal-specificity for different phases of behavior. Finally, the subcellular scale of dopamine domains suggests specialized postsynaptic pathways for processing and integrating functionally distinct dopaminergic influences.

Cycling reduces the entropy of neuronal activity in the human adult cortex
Electroencephalogram (EEG) data is often analyzed from a Brain Complexity (BC) perspective, having successfully been applied to study the brain in both health and disease. In this study, we employed recurrence entropy to quantify BC associated with the neurophysiology of movement by comparing BC in both resting state and cycling movement. We measured EEG in 24 healthy adults, and placed the electrodes on occipital, parietal, temporal and frontal sites, on both the right and left sides. EEG measurements were performed for cycling and resting states and for eyes closed and open. We then computed recurrence entropy for the acquired EEG series. Our results show that open eyes show larger entropy compared to closed eyes; the entropy is also larger for resting state, compared to cycling state for all analyzed brain regions. The decrease in neuronal complexity measured by the recurrence entropy could explain the neural mechanisms involved in how the cycling movements suppress the freezing of gate in patients with Parkinsons disease due to the constant sensory feedback caused by cycling that is associated with entropy reduction.

Dissociating endogenous and exogenous delta activity during natural speech comprehension
Decoding human speech requires the brain to segment the incoming acoustic signal into meaningful linguistic units, ranging from syllables and words to phrases. Integrating these linguistic constituents into a coherent percept sets the root of compositional meaning and hence understanding. One important cue for segmentation in natural speech are prosodic cues, such as pauses, but their interplay with higher-level linguistic processing is still unknown. Here we dissociate the neural tracking of prosodic pauses from the segmentation of multi-word chunks using magnetoencephalography (MEG). We find that manipulating the regularity of pauses disrupts slow speech-brain tracking bilaterally in auditory areas (below 2 Hz) and in turn increases left-lateralized coherence of higher frequency auditory activity at speech onsets (around 25 - 45 Hz). Critically, we also find that multi-word chunks - defined as short, coherent bundles of inter-word dependencies - are processed through the rhythmic fluctuations of low frequency activity (below 2 Hz) bilaterally and independently of prosodic cues. Importantly, low-frequency alignment at chunk onsets increases the accuracy of an encoding model in bilateral auditory and frontal areas, while controlling for the effect of acoustics. Our findings provide novel insights into the neural basis of speech perception, demonstrating that both acoustic features (prosodic cues) and abstract processing at the multi-word timescale are underpinned independently by low-frequency electrophysiological brain activity.

Multiplexing of temporal and spatial information in the lateral entorhinal cortex
Episodic memory involves the processing of spatial and temporal aspects of personal experiences. The lateral entorhinal cortex (LEC) plays an essential role in subserving memory. However, the specific mechanism by which LEC integrates spatial and temporal information remains elusive. Here, we recorded LEC neurons while rats performed foraging and shuttling behaviors on one-dimensional, linear or circular tracks. Unlike open-field foraging tasks, many LEC cells displayed spatial firing fields in these tasks and demonstrated selectivity for traveling directions. Furthermore, some LEC neurons displayed changes in the firing rates of their spatial rate maps during a session, a phenomenon referred to as rate remapping. Importantly, this temporal modulation was consistent across sessions, even when the spatial environment was altered. Notably, the strength of temporal modulation was found to be greater in LEC compared to other brain regions, such as the medial entorhinal cortex (MEC), CA1, and CA3. Thus, the spatial rate mapping observed in LEC neurons may serve as a coding mechanism for temporal context, allowing for flexible multiplexing of spatial and temporal information.

Ensemble learning and ground-truth validation of synaptic connectivity inferred from spike trains
Probing the architecture of neuronal circuits and the principles that underlie their functional organization remains an important challenge of modern neurosciences. This holds true, in particular, for the inference of neuronal connectivity from large-scale extracellular recordings. Despite the popularity of this approach and a number of elaborate methods to reconstruct networks, the degree to which synaptic connections can be reconstructed from spike-train recordings alone remains controversial. Here, we provide a framework to probe and compare connectivity inference algorithms, using a combination of synthetic and empirical ground-truth data sets, obtained from simulations and parallel single-cell patch-clamp and high-density microelectrode array (HD-MEA) recordings in vitro. We find that reconstruction performance critically depends on the regularity of the recorded spontaneous activity, i.e., their dynamical regime, the type of connectivity, and the amount of available spike train data. We find gross differences between different algorithms, and many algorithms have difficulties in detecting inhibitory connections. We therefore introduce an ensemble artificial neural network (eANN) to improve connectivity inference. We train the eANN on the validated outputs of six established inference algorithms, and show how it improves network reconstruction accuracy and robustness. Overall, the eANN was robust across different dynamical regimes, with shorter recording time, and ameliorated the identification of synaptic connections, in particular inhibitory ones. Results indicated that the eANN also improved the topological characterization of neuronal networks. The presented methodology contributes to advancing the performance of inference algorithms and facilitates our understanding of how neuronal activity relates to synaptic connectivity.

Brain white matter pathways of resilience to chronic back pain: a multisite validation
Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have shown that brain characteristics can serve as robust predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over six- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ~ 0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.

Early life adversity drives sex-dependent changes in 5-mC DNA methylation of parvalbumin cells in the prefrontal cortex in rats
Early life adversity (ELA) can result in increased risk for developing affective disorders, such as anxiety or depression, later in life, with women showing increased risk. Interactions between an organism's genes and their environment play key roles in producing, as well as mitigating, later life neuropathology. Our current understanding of the underlying epigenomic drivers of ELA associated anxiety and depression are limited, and this stems in part from the complexity of underlying biochemical processes associated with how early experiences shapes later life behavior. Epigenetic alterations, or experience-driven modifications to DNA, can be leveraged to understand the interplay between genes and the environment. The present study characterized DNA methylation patterning, assessed via evaluation of 5-methylcytosine (5-mC), following ELA in a Sprague Dawley rat model of ELA induced by early caregiver deprivation. This study utilized maternal separation to investigate sex- and age-specific outcomes of ELA on epigenetic patterning in parvalbumin (PV)-containing interneurons in the prefrontal cortex (PFC), a subpopulation of inhibitory neurons which are associated with ELA and affective dysfunction. While global analysis of 5-mC methylation and CpG site specific pyrosequencing of the PV promoter, Pvalb, showed no obvious effects of ELA, when analyses were restricted to assessing 5-mC intensity in colocalized PV cells, there were significant sex and age dependent effects. We found that ELA leads sex-specific changes in PV cell counts, and that cell counts can be predicted by 5-mC intensity, with males and females showing distinct patterns of methylation and PV outcomes. ELA also produced sex-specific effects in corticosterone reactivity, with juvenile females showing a blunted stress hormone response compared to controls. Overall, ELA led to a sex-specific developmental shift in PV profile, which is comparable to profiles that are seen at a later developmental timepoint, and this shift may be mediated in part by epigenomic alterations driven by altered DNA methylation.

The Circadian Neuropeptide PDF has Sexually Dimorphic Effects on Activity Rhythms
The circadian system regulates the timing of multiple molecular, physiological, metabolic, and behavioral phenomena. In Drosophila as in other species, most of the research on how the timekeeping system in the brain controls timing of behavioral outputs has been conducted in males, or sex was not included as a biological variable. The main circadian pacemaker neurons in Drosophila release the neuropeptide Pigment Dispersing Factor (PDF), which functions as a key synchronizing factor in the network with complex effects on other clock neurons. Lack of Pdf or its receptor, PdfR, results in most flies displaying arrhythmicity in activity-rest cycles under constant conditions. However, our results show that female circadian rhythms are less affected by mutations in both Pdf and PdfR. Crispr-Cas9 mutagenesis of Pdf specifically in the ventral lateral neurons (LNvs) also has a greater effect on male rhythms. We tested the influence of the M-cells over the circadian network and show that speeding up the molecular clock specifically in the M-cells leads to sexually dimorphic phenotypes, with a more pronounced effect on male rhythmic behavior. Our results suggest that the female circadian system is more resilient to manipulations of the PDF pathway and that circadian timekeeping is more distributed across the clock neuron network in females.

Characteristics of vicarious touch reports in a general population
Vicarious sensory perception occurs when one feels touch or pain while observing others experiencing these sensations. Here we examined vicarious sensory perception in a large sample of undergraduate students (N = 422) using videos from the Validated Touch-Video Database, which depict various tactile interactions and have been independently rated for hedonic qualities, arousal levels, and perceived threat. A substantial 83% of participants reported sensations such as touch, tingling, pressure when observing the touch videos, with 53% of participants reporting pain when observing painful touch. Reported sensations often mirrored the location of touch seen in the videos. Women were more inclined to report vicarious touch than men, and did so in more trials on average. There was also a modest but significant correlation between stronger vicarious touch experiences and higher emotional empathy scores. The frequency and intensity of reported sensations strongly correlated with the rated arousal of the videos, with painful videos being most arousing and eliciting the most frequent and intense responses. The valence of the reported sensations aligned with the assigned valence ratings of the touch videos. Pleasant videos typically induced sensations like ticklishness, tingling, or warmth, whereas painful videos elicited feelings of pain, pressure, or coldness. Similar sensations were reported, though less frequently, for videos depicting touch on non-human objects. Our criteria, consistent with prior research, suggested a high prevalence of potential mirror-touch (6%) and mirror-pain (20%) synaesthesia in our sample. Mirror-touch synaesthetes primarily described exteroceptive sensations like touch and pressure, contrasting with non-synaesthetes who more often reported tingling sensations. Overall, this study contributes to a deeper understanding of vicarious sensory perception in the general population with implications for understanding mirror-sensory synaesthesia and empathy.