bioRxiv Subject Collection: Neuroscience's Journal

Computational Modelling of Resistance to Hormone-Mediated Remission in Childhood Absence Epilepsy
Childhood absence epilepsy (CAE) often resolves during adolescence, a period marked by hormonal and neurosteroid changes associated with puberty. However, remission does not occur in all individuals. To investigate this clinical heterogeneity, we developed a simplified thalamocortical model with a layered cortical structure, using deep-layer intrinsically bursting (IB) neurons to represent frontal cortex and regular spiking (RS) neurons modelling the parietal cortex. By simulating two cortical configurations, we explored how variations in neuronal composition and frontocortical connectivity influence seizure dynamics and the effectiveness of allopregnanolone (ALLO) in resolving pathological spike-wave discharges (SWDs) associated with CAE. While both models exhibited similar physiological and pathological oscillations, only the parietal-dominant network (with a higher proportion of regular spiking neurons in layer 5) recovered from SWDs under increased frontocortical connectivity following ALLO administration. These findings suggest that neuronal composition critically modulates ALLO-mediated resolution of SWDs, providing a mechanistic link between structural connectivity and clinical outcomes in CAE, and highlighting the potential for personalized treatment strategies based on underlying network architecture.

Ground tilt representation in the rodent cerebral cortex
Information about ground tilt at one's location is indispensable for integrating the body with its surrounding environment. However, how ground-tilt information, together with movement and posture information, is represented in the cerebral cortex remains unclear. To address this issue, we developed a new six-degree-of-freedom platform that can rapidly and precisely impart ground motion to head-fixed mice. Using the Diesel2p large field-of-view two-photon mesoscope, we performed calcium imaging to simultaneously capture activity dynamics across broad cortical areas from the frontal to the parietal cortex while driving the platform through various motion patterns. We found a core area for the ground-tilt information at the parietal cortex, although the tilt-direction neurons were found across the dorsal cortex. Neuronal populations preserved tilt-direction information within a common low-dimensional manifold across three distinct motion conditions, indicating a condition-invariant tilt-code. Furthermore, to investigate shared dynamics across multiple cortical areas, we introduced broadcast-subspace analysis as an extension of communication subspace analysis. This extended framework revealed that tilt information occupied the second principal shared axis, following movement information. These results reveal the core cortical area for processing tilt information, its universal format, and its sharing across the dorsal cortex, thereby providing a framework for cortical information processing that integrates movement, posture, and the environment.

Retention and data exclusion challenges for representative longitudinal neuroimaging in the understanding of addiction
Head motion during resting-state functional magnetic resonance imaging (rsfMRI) poses a major challenge for neuroimaging research, often leading to data quality concerns and participant exclusions, particularly among pediatric and clinical populations. Although necessary for ensuring reliable data, motion-related exclusions may inadvertently bias samples by disproportionately excluding certain sociodemographic groups. Using data from the Adolescent Brain Cognitive Development (ABCD) Study, we employed both frequentist and Bayesian approaches to examine how head motion-related exclusions and participant retention shape sample composition over time. At baseline (ages 9-10), Black, Hispanic, and Asian youth were significantly more likely than White youth to be excluded due to excessive head motion; these disparities were not observed at the two-year follow-up (ages 11-13). In contrast, disparities in retention persisted; Black participants were less likely to return for follow-up, even after accounting for socioeconomic factors and motion. Together, these findings highlight how both motion-related exclusions and differential retention can systematically influence the representativeness of longitudinal neuroimaging samples, with important implications for the generalizability of research in addiction neuroscience.

G1899, an American ginseng extract, alleviates neuroinflammation and cognitive impairment in models of Alzheimer's disease
Background: Alzheimer's disease (AD) is characterized by amyloid {beta} (A{beta}) accumulation, tau pathology, and chronic neuroinflammation, yet current therapeutic strategies provide only limited efficacy. Natural compounds with pleiotropic actions have emerged as potential adjunctive interventions. This study evaluated G1899, a standardized American ginseng (Panax quinquefolius) extract, for its effects on neuroinflammation, A{beta} clearance, and cognitive function. Methods: Neuronal cultures were exposed to glutamate or A{beta} oligomers (A{beta}o) and pre-treated with G1899 to assess cell viability and excitotoxicity. Primary murine microglia were analyzed for validating expression levels of TMEM119, CD68, NLRP3 inflammasome, IL-1{beta}, Caspase-1, and STAT3 phosphorylation. Behavioral testing was performed in scopolamine-injected mice with short term G1899 treatment and in 5xFAD transgenic mice following long-term G1899 administration at multiple doses. Amyloid burden, microglial recruitment, and plaque morphology were quantified by immunohistochemistry and high-resolution imaging. Human induced microglia (iMG) were examined for neuroinflammatory responses following A{beta}o exposure with or without G1899 treatment. Results: G1899 significantly improved neuronal viability and reduced glutamate- and A{beta}o-induced toxicity. In microglia, G1899 upregulated TMEM119 and CD68, while suppressing NLRP3 inflammasome formation, proinflammatory cytokine expression, and STAT3 phosphorylation. G1899 rescued scopolamine-induced memory deficits and, in 5xFAD mice, reduced hippocampal and cortical A{beta} burden, alleviated neuroinflammatory markers, and improved both spatial/fear learning and memory, with the most consistent efficacy observed at 300 mg/kg. Imaging revealed enhanced microglial recruitment to plaques and facilitated fragmentation of A{beta} deposits. In iMG, G1899 elevated homeostatic and phagocytic markers while attenuating A{beta}o-induced NLRP3/STAT3-mediated neuroinflammatory signaling pathway. Conclusions: G1899 confers multimodal neuroprotection by preserving neuronal survival, modulating microglial activity, and facilitating A{beta} clearance. These findings highlight its potential as a safe and clinically translatable botanical intervention for AD.

Disruption of the developmental factor Otp in the adult forebrain reveals its diverse physiological functions
Orthopedia (Otp) transcription factor is a critical determinant in the development of the neuroendocrine hypothalamus, and its embryonic deletion results in lethality. Although Otp expression is maintained throughout life, its physiological function in adulthood is not well understood. Here, we generated a forebrain-specific, tamoxifen-inducible, conditional knockout mouse model to investigate the roles of Otp beyond development. Conditional deletion of Otp in two-month-old mice resulted in impaired stress responses, characterized by increased depressive-like behavior and elevated stress-induced cortisol levels. It also led to various metabolic changes, including reduced thyroid hormone levels and body temperature, a higher percentage of fat mass, and diminished responsiveness to ghrelin without affecting food intake, energy expenditure, or body weight. This composite metabolic phenotype was associated with reduced hypothalamic neuropeptides TRH, CRH, AgRP, and NPY expression. Our findings highlight the role of Otp in adult physiological functions as a key neuroendocrine integrator of adaptive stress response and energy balance.

Nociceptors use multiple neurotransmitters to drive pain
Nociceptors are excitatory neurons that express a range of neuropeptides and have the essential role of detecting noxious mechanical, thermal and chemical stimuli. Ablating these neurons profoundly reduces responses to pain. Here we investigated how nociceptive information is transmitted by developing genetic approaches to suppress glutamate transmission and neuropeptide signaling, individually and in combination. Remarkably, many pain responses persisted in mice where either nociceptor glutamate or neuropeptide signaling was blocked. By contrast, mice lacking both glutamate and neuropeptide transmission in nociceptors displayed profound pain insensitivity closely matching the effects of cell ablation. Together our results establish a role for neuropeptides as bone fide pain transmitters and demonstrate redundancy in nociceptor signaling, resolving long-standing questions about how pain is communicated to the brain.

Adaptive Eye Movement Behavior for Actions in Younger and Older Adults
Humans typically combine eye and head movements to visually track and interact with moving objects. If the object's trajectory can be predicted, humans can shift gaze to the anticipated object's future location. For instance, when hitting a moving ball, people predictively look at the ball's bouncing location, allowing them to overcome sensorimotor delays that would otherwise limit visual information uptake from that position. Such delays become pronounced with healthy aging, which might drive a behavioral shift towards stronger reliance on predictive gaze allocation to future positions of interest during visuomotor tasks. To investigate this, we examined gaze and hand movements of older and younger adults who played an iPad-based version of the game 'Pong' against an automated opponent. Participants moved a paddle of two different sizes with their finger to intercept a ball moving in two speeds and bouncing off the side walls. We hypothesized that aging would lead to earlier gaze shifts to positions of interest, such as to the final wall bounce location before the ball moved toward the participants' paddle, and to their own paddle around the moment of interception. As expected, both age groups intercepted fewer balls when using smaller paddles. Contrary to our hypothesis, older participants looked later than younger adults to the final wall bounce. However, they shifted their gaze earlier to their own paddle before interception, especially at the beginning of the experiment. This suggests that aging enhances predictive gaze shifts related to the immediate action. While gaze allocation patterns largely overlap between older and younger adults, aging specifically leads to adaptive eye movements just before interacting with the environment.

Legal but immoral: attitudes toward non-invasive brain stimulation for cognitive enhancement
Cognitive enhancement involves using substances or technologies to improve mental performance in healthy individuals. While methods such as caffeine are widely accepted, others, including prescription stimulants and non-invasive brain stimulation (tDCS), evoke ethical concern. This study examined how university students evaluate three forms of cognitive enhancement (natural, pharmacological, brain stimulation) across five moral domains: academic fairness, free will, naturalness, self-identity, and safety. We also tested how evaluations were shaped by framing (preservation vs. enhancement) and priming (self-affecting vs. non-self-affecting). A total of 449 students completed an online experiment with a 2 by 2 by 3 mixed design, rating enhancement acceptability after reading intervention-specific scenarios. Natural enhancers were judged most positively, followed by brain stimulation and then pharmacological agents. Importantly, although brain stimulation is legal and marketed as non-invasive, it was evaluated more like pharmacological enhancement than natural methods, indicating that legality does not equate to moral acceptability. Framing effects showed that participants were more accepting of enhancement when it was described as preserving ability rather than augmenting it beyond baseline. Priming participants to consider how others use might affect their own outcomes reduced moral acceptability, particularly for pharmacological and brain stimulation methods in the domain of academic fairness. Overall, public attitudes toward enhancement appeared shaped less by legality or objective safety than by intuitive moral reasoning. These findings highlight the importance of adopting pluralistic, context-sensitive approaches to policy and regulation, as student judgments reflect concerns about fairness, authenticity, and competition in academic life.

Inter-individual variability of neurotransmitter receptor and transporter density in the human brain
Neurotransmitter receptors guide the propagation of signals between brain regions. Mapping receptor distributions in the brain is therefore necessary for understanding how neurotransmitter systems mediate the link between brain structure and function. Normative receptor density can be estimated using group averages from Positron Emission Tomography (PET) imaging. However, the generalizability and reliability of group-average receptor maps depends on the inter-individual variability of receptor density, which is currently unknown. Here we collect group standard deviation brain maps of PET-estimated protein abundance for 12 different neurotransmitter receptors and transporters across 7 neurotransmitter systems, including dopamine, serotonin, acetylcholine, glutamate, GABA, cannabinoid, and opioid. We illustrate how cortical and subcortical inter-individual variability of receptor and transporter density varies across brain regions and across neurotransmitter systems. We complement inter-individual variability with inter-regional variability, and show that receptors that vary more across brain regions than across individuals also demonstrate greater out-of-sample spatial consistency. Altogether, this work quantifies how receptor systems vary in healthy individuals, and provides a means of assessing the generalizability of PET-derived receptor density quantification.

Distinct contributions of hippocampal pathways in learning regularities and exceptions revealed by functional footprints
Fundamental aspects of learning are theorized to be supported by hippocampal pathways: monosynaptic pathway (MSP) extracts regularities whereas trisynaptic pathway (TSP) rapidly encodes exceptional items. Yet, the empirical evidence for the dynamic involvement of MSP and TSP in learning remains elusive. We leveraged diffusion-weighted imaging to estimate the end points of MSP- and TSP-related white matter structures (i.e., footprints) within hippocampal subfields and entorhinal cortex. We then measured the activation of pathway-specific footprints with functional magnetic resonance imaging while participants learned novel concepts defined by regularities and exceptions. The functional footprint method revealed links between MSP-related footprint activation and regularity encoding early in learning, and TSP-related footprint activation and exception encoding late in learning. These findings provide novel evidence that learning concept regularities and exceptions is distinctly supported by hippocampal pathways. Pathway footprint approach provides insights into the functional dynamics of the human hippocampus, translating theoretical and computational work into empirically testable questions in humans.

The anterior cingulate cortex drives lateralized age-dependent modulation of claustrum circuits
The anterior cingulate cortex (ACC) sends top-down inputs to the claustrum during sensory, motor, and cognitive processing. This ACC input is thought to drive the activation of claustrum neurons which in turn project back to the cortex to help orchestrate cortical networks during demanding cognitive states such as attention. However, the circuit mechanisms underlying ACC-claustrum signaling are not fully understood. Using in vivo single neuron recordings in mice, we show that ACC neuron activation drives a lateralized modulation of claustrum excitability that changes as a function of postnatal age. In adulthood, ACC activation evoked feed-forward inhibition of ipsilateral excitatory claustrum neurons and activation of contralateral excitatory claustrum neurons. Chemogenetic manipulation in adult mice revealed that ipsilateral claustrum inhibition by the ACC was due to feed-forward activation of claustrum parvalbumin inhibitory neurons. However, in neonatal mice, which lack mature parvalbumin interneurons, ACC inputs evoked claustrum excitation. In juvenile mice, the developmental switch from ACC-evoked claustrum excitation to inhibition occurred in parallel with the maturation of claustrum parvalbumin interneurons, thus corroborating the chemogenetic findings. Therefore, this work provides a novel mechanism of cortical control over claustrum activity that is refined during early postnatal life.

Contextual Cues and Transition Statistics Drive Expression of Competing Motor Memories
Learning multiple motor skills without interference and expressing the correct one in a changing environment is a fundamental challenge. Contextual cues are known to help separate these memories, but how they interact during retrieval is not well understood. We investigated how the stability, recency, and transitional statistics of learning environments influence this process. Across six visuomotor adaptation experiments, participants learned opposing rotations (Tasks A and B) tagged with distinct contextual cues under different schedules (blocked or interleaved) and were tested in stable or dynamic environments. We found that while contextual cues can successfully separate memories, expression is systematically biased by learned transition statistics: towards more stable memories after imbalanced training, and towards more recent memories when stabilities are matched. Critically, when the stable statistics of training mismatched the volatile statistics of testing, cue-based retrieval collapsed, and behavior was dominated by these stability or recency biases. Conversely, learning in a high-entropy, interleaved environment enabled precise, cue-appropriate expression regardless of the testing schedule. These results demonstrate that memory retrieval is not cue-driven but arises from an arbitration process between cues and transition priors. Our findings reveal that memory retrieval involves weighting sensory information against latent priors derived from the history of context transitions. This work provides a unifying theoretical framework for understanding adaptive memory expression, positing that the brain leverages the learned statistical structure of the environment to infer which memory to recall, thereby balancing cue-driven selection with the stability and predictability of past experience. This principle offers a unifying explanation for interference, spontaneous recovery, and the benefits of variable practice, providing a more holistic model of adaptive motor behavior.

Immediate early genes act in the medial hypothalamus to promote adaptation to social defeat
Territorial animals must moderate their social aggression and avoidance behaviors in a manner that maximizes their access to resources and fitness. The ventrolateral division of the ventromedial hypothalamic nucleus (VMHvl) has been shown to control both social aggression and avoidance in mice, and emerging data show that neural plasticity within VMHvl can drive the experience-dependent adaptation of these behaviors. Here, we investigated the contribution of immediate early gene (IEG) function in supporting this plasticity. In initial experiments, we found that downregulation of the IEG cFos in VMHvl did not significantly moderate the long-term increase in social avoidance seen following an experience of social defeat. However, local knockout of the IEG master regulator Serum Response Factor (SRF, Srf) was able to blunt the impact of social defeat on social avoidance and prevented the effect of social defeat on local optogenetic-evoked social avoidance behavior, demonstrating a critical role for subcortical IEG activity in social defeat-induced behavioral plasticity. To test whether NMDA receptor dependent plasticity might be involved in this effect, we locally infused the NMDA receptor antagonist MK-801 into VMHvl and assessed the impact of social defeat. Unexpectedly, MK-801 treatment led to an increase in social defeat-induced avoidance, pointing to the existence of opposing IEG and NMDA receptor-dependent adaptive mechanisms in medial hypothalamus. These findings suggest that multiple neural plasticity mechanisms are likely to be at play in the hypothalamic nuclei supporting innate behavior adaptation and show how IEG blockade can be used as a genetic tool to systematically map neural plasticity in the brain.

Cortical-layer EEG-fMRI at 7T: experimental setup and analysis pipeline to elucidate generating mechanisms of alpha oscillations
Alpha band (8-13Hz) electroencephalography (EEG) oscillations play a key role in cognition, but their generating mechanisms are still poorly understood. Most studies investigating laminar origins of alpha oscillations have been conducted on animals using invasive intracranial recordings. To relate these findings to human alpha generation, non-invasive techniques need to be developed. Layer functional Magnetic Resonance Imaging (fMRI) at ultra-high field (UHF, 7T) allows for the interrogation of brain responses across cortical depths and combined with simultaneous EEG, provides the opportunity to gain new insight into human alpha generation mechanisms. This work establishes a framework to study the generating mechanisms of electrophysiological signals non-invasively in humans using simultaneous EEG layer-fMRI. Data were acquired on 10 participants during an eyes closed/eyes open paradigm. We showed that in 9/10 participants the quality of EEG and Blood Oxygenation Level Dependent (BOLD) fMRI data were sufficient to observe a significant negative correlation between EEG alpha power and the BOLD signal in visual cortex grey matter to the eyes open/eyes closed task. "Deveining" was performed to overcome the increase in BOLD signal toward the pial surface due to draining veins, and the effects of each of the steps in the deveining analysis on the cortical depth profiles of the negative alpha-BOLD correlations studied. The largest effect was dependent on the exclusion of voxels in the tissue immediately surrounding veins. Following deveining, the cortical depth profiles showed the negative alpha-BOLD correlations were significantly weaker in the middle depths compared with deep and superficial depths. When a boxcar rather than EEG alpha power was used to model the task, this depth-dependence was not seen, suggesting this was specific to spontaneous alpha-power modulations. In conclusion, we have established a method to non-invasively interrogate the origins of electrophysiological signals. Our alpha-BOLD depth profiles suggest the alpha signal to an eyes open-closed task is generated in superficial and deep layers suggesting top-down processes.

A molecular atlas of cell-type specific signatures in the parkinsonian striatum.
The progressive degeneration of dopaminergic projections to the striatum is a key disease mechanism in Parkinson's disease (PD). To define the cellular landscape in the parkinsonian striatum, we mapped the cell-type specific transcriptional landscape in early and progressive PD mouse models and in human PD stages. Our analyses revealed substantial transcriptomic changes across both neuronal and glial populations, with astrocytes and oligodendrocytes exhibiting distinct disease-associated gene expression profiles. Notably, progressive dopamine depletion uncovered differential neuronal vulnerability, identifying eccentric striatal projection neurons (SPNs) and Chst9-expressing direct-pathway SPNs as among the most resilient subtypes in both species. This cross-species resource establishes a comprehensive framework for investigating cell-state dynamics in the parkinsonian striatum and uncovers selectively vulnerable and resistant cell types that can inspire new therapeutic strategies.

Teneurin-4 switches between self-recognition and canonical Latrophilin binding to direct neuronal migration
Cortical migration is a complex process in which neurons migrate along radial glial cells (RGC) to form functional layers. Teneurins (Ten1-4) play a role by interacting with Latrophilins (Lphn/ADGRL1-3). Teneurins are also known as cell adhesion molecules, but how homophilic and heterophilic Teneurin interactions are integrated is unknown. Here, single-particle-cryo-EM data of Ten2 shows that canonical Latrophilin-binding is sterically incompatible with Ten2-dimerisation, making these interactions exclusive. We engineered surface mutations that specifically disrupt Ten2-Ten2 or Ten2-Latrophilin interactions. These are transferrable to Ten4, suggesting conserved binding mechanisms. Proteomics, in-vivo-gene-editing and super-resolution-microscopy show that Ten4 is expressed along RGC fibres and that migrating neurons switch from low-to-high Ten4-expression. Ten4 expression is highest in the cortical plate where Ten4-Ten4 interactions reduce RGC-attachment. In the intermediate zone, Ten4-Latrophilin interactions are required to promote neuron-RGC association. The results show how Ten4 orchestrates cortical migration by exclusive structural mechanisms, underpinning the integration of distinct migration programmes.

Information, Movement and Adaptation in Human Vision
Our eyes are never still. Even when fixating, they exhibit small, jittery motions. While it has long been argued that these fixational eye movements (FEMs) aid the acquisition of visual information, a complete theoretical description of their impact on the information available in the early visual system has been lacking. Here we build FEMs into a minimal theoretical model of the early visual response, including the critical process of adaptation (a fading response to a fixed image). We establish the effect of FEMs on the mutual information between a visual stimulus and this response. Our approach identifies the key dimensionless parameters that characterise the effect of fixational eye movements, and reveals the regimes in which this effect can be beneficial, detrimental or negligible. Taking parameter values appropriate for human vision, we show that the spatio-temporal couplings induced by fixational eye movements can explain the qualitative features of the human contrast sensitivity function as well as classic experiments on temporal integration. To our knowledge, the consideration of fixational eye movements in this latter context is novel, and our results suggest the need for future experiments to determine the mechanisms by which spatial and temporal responses are coupled in the human visual system.

Sleep Deprivation Primes Synaptic Vulnerability Without Inducing Oxidative Damage: A Mechanistic Reappraisal
The question of whether sleep deprivation is inherently lethal has remained unresolved due to the inability to separate pure sleep loss from experimental stress. Historical studies dating back over a century have consistently reported that prolonged wakefulness leads to death, but these findings have been confounded by the stressful nature of the experimental interventions used to maintain wakefulness. Recent work has suggested that sleep deprivation-induced lethality may result from accumulation of reactive oxygen species (ROS) in the intestines, providing a potential molecular explanation for these long-standing observations. Here we address whether lethality stems from sleep loss itself or experimental stress using stress-controlled sleep deprivation in Drosophila and stress paradigms in both flies and mice. Using real-time feedback-controlled sleep deprivation in Drosophila -- which only stimulates animals when they attempt to sleep -- we found no lethality or intestinal ROS accumulation even after 240 hours of continuous wakefulness. In contrast, both physical perturbation and psychological challenges rapidly induced intestinal ROS accumulation independent of sleep loss, in flies and mice. Transcriptomic analysis revealed entirely distinct molecular signatures between sleep deprivation and oxidative stress, demonstrating these represent fundamentally different biological challenges. However, while sleep deprivation alone caused no lethality or intestinal oxidative stress, it increased susceptibility to traumatic brain injury through enhanced synaptic strength. Sleep-deprived flies showed increased mortality when subjected to violent physical challenges, an effect that correlated with synaptic excitability rather than sleep duration, and was rescued by restorative recovery sleep or prevented in mutants lacking synaptic potentiation mechanisms. Our findings demonstrate that experimental stress, not sleep loss, drives the oxidative damage and lethality historically attributed to sleep deprivation. Sleep deprivation, however, creates conditional vulnerability by transforming the brain into a hyperexcitable state susceptible to trauma, rather than causing cumulative damage.

Periodic and aperiodic contributions to EEG delta power are translatable and complementary Angelman syndrome biomarkers
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of maternal UBE3A expression. With promising AS therapies now in clinical trials, there is a pressing need for reliable and translatable biomarkers. Elevated EEG delta power is a hallmark of AS and a promising biomarker, but traditional measures conflate delta oscillations with broadband spectral shifts, limiting interpretability and utility. We dissociated periodic and aperiodic contributions to delta power using spectral parameterization in children with AS and Ube3a mutant mice. In both species, elevated delta power reflected a combination of increased periodic delta oscillations and elevated aperiodic slope and offset. These features were linked to different behavioral domains and followed divergent developmental trajectories, suggesting distinct underlying mechanisms. Together, our findings establish aperiodic changes as a novel translatable EEG biomarker for AS and support the complementary use of periodic and aperiodic features in preclinical and clinical research.

Facial Micro-Movements as a Proxy of Increasingly Erratic Heart Rate Variability While Experiencing Pressure Pain
The sensation of pain varies from person to person. These patterns of individual variations are difficult to capture using coarse subjective self-reports. However, they are important when prescribing therapies and tailoring them to the person 's own sensations. Pain can be experienced differently by the same person, and fluctuate differently depending on the context, yet most analyses treat the problem under a one-size-fits-all model. In this work, we introduce a series of assays to objectively assess pressure pain across tasks with different motoric and cognitive demands, in relation to resting state. In a cohort of healthy individuals, we examine pain-free vs. pain states at rest, during drawing with heavy cognitive demands, during pointing to a visual target, and during a grooved peg task like inserting a grooved key in a matching grooved keyhole. We recorded face videos, electrocardiographic signals and adopt a standardized data type called the micro-movement spikes (MMS) to characterize the biorhythmic activities of the face micro-expressions and of the micro-fluctuations in the heart 's inter beat interval timings. Using the MMS peaks, we find that the continuous Gamma family of probability distribution functions best fit the frequency histograms of both the Face and the heart data. Further, we find that the Gamma shape and scale parameters in both signals span a scaling power law whereby as the noise-to-signal ratio (Gamma scale parameter) increases, so does the randomness of the stochastic process (the Gamma shape decreases towards the memoryless exponential range). We find that as the heart IBI turns more erratic (noisier and more random) the facial ophthalmic region increases the noise and randomness too, with higher linear correlation for tasks requiring haptic feedback (R2 0.84) than for tasks requiring higher cognitive and memory loads (R2 0.77). Increases in transfer entropy shows that recent past activity (~167ms back) of the heart IBI and Face combined lower the uncertainty in the prediction of the present ophthalmic-Face activity, suggesting that this Face region may serve as a proxy of an increasingly dysregulated heart. These results bear implications for the detection and monitoring of pressure pain and heart dysregulated states.