Interaction between spatial perception and temporal perception enables preservation of cause-effect relationship: Visual psychophysics and neuronal dynamics.

INTRODUCTION: Visual perception of moving objects is integral to our day-to-day life, integrating visual spatial and temporal perception. Most research studies have focused on finding the brain regions activated during motion perception. However, an empirically validated general mathematical model is required to understand the modulation of the motion perception. Here, we develop a mathematical formulation of the modulation of the perception of a moving object due to a change in speed, under the formulation of the invariance of causality. METHODS: We formulated the perception of a moving object as the coordinate transformation from a retinotopic space onto perceptual space and derived a quantitative relationship between spatiotemporal coordinates. To validate our model, we undertook the analysis of two experiments: (i) the perceived length of the moving arc, and (ii) the perceived time while observing moving stimuli. We performed a magnetic resonance imaging (MRI) tractography investigation of subjects to demarcate the anatomical correlation of the modulation of the perception of moving objects. RESULTS: Our theoretical model shows that the interaction between visual-spatial and temporal perception, during the perception of moving object is described by coupled linear equations; and experimental observations validate our model. We observed that cerebral area V5 may be an anatomical correlate for this interaction. The physiological basis of interaction is shown by a Lotka-Volterra system delineating interplay between acetylcholine and dopamine neurotransmitters, whose concentrations vary periodically with the orthogonal phase shift between them, occurring at the axodendritic synapse of complex cells at area V5. CONCLUSION: Under the invariance of causality in the representation of events in retinotopic space and perceptual space, the speed modulates the perception of a moving object. This modulation may be due to variations of the tuning properties of complex cells at area V5 due to the dynamic interaction between acetylcholine and dopamine. Our analysis is the first significant study, to our knowledge, that establishes a mathematical linkage between motion perception and causality invariance.

Empirically validated theoretical analysis of visual-spatial perception under change of nervous system arousal.

Introduction: Visual-spatial perception is a process for extracting the spatial relationship between objects in the environment. The changes in visual-spatial perception due to factors such as the activity of the sympathetic nervous system (hyperactivation) or parasympathetic nervous system (hypoactivation) can affect the internal representation of the external visual-spatial world. We formulated a quantitative model of the modulation of visual-perceptual space under action by hyperactivation or hypoactivation-inducing neuromodulating agents. We showed a Hill equation based relationship between neuromodulator agent concentration and alteration of visual-spatial perception utilizing the metric tensor to quantify the visual space. Methods: We computed the dynamics of the psilocybin (hyperactivation-inducing agent) and chlorpromazine (hypoactivation-inducing agent) in brain tissue. Then, we validated our quantitative model by analyzing the findings of different independent behavioral studies where subjects were assessed for alterations in visual-spatial perception under the action of psilocybin and under chlorpromazine. To validate the neuronal correlates, we simulated the effect of the neuromodulating agent on the computational model of the grid-cell network, and also performed diffusion MRI-based tractography to find the neural tracts between the cortical areas involved: V2 and the entorhinal cortex. Results: We applied our computational model to an experiment (where perceptual alterations were measured under psilocybin) and found that for n (Hill-coefficient) = 14.8 and k = 1.39, the theoretical prediction followed experimental observations very well (χ2 test robustly satisfied, p > 0.99). We predicted the outcome of another psilocybin-based experiment using these values (n = 14.8 and k = 1.39), whereby our prediction and experimental outcomes were well corroborated. Furthermore, we found that also under hypoactivation (chlorpromazine), the modulation of the visual-spatial perception follows our model. Moreover, we found neural tracts between the area V2 and entorhinal cortex, thus providing a possible brain network responsible for encoding visual-spatial perception. Thence, we simulated the altered grid-cell network activity, which was also found to follow the Hill equation. Conclusion: We developed a computational model of visuospatial perceptual alterations under altered neural sympathetic/parasympathetic tone. We validated our model using analysis of behavioral studies, neuroimaging assessment, and neurocomputational evaluation. Our quantitative approach may be probed as a potential behavioral screening and monitoring methodology in neuropsychology to analyze perceptual misjudgment and mishaps by highly stressed workers.

A mechanistic analysis of spontaneous cancer remission phenomenon: identification of genomic basis and effector biomolecules for therapeutic applicability.

Based on the well-documented studies, numerous tumors episodically regress permanently without treatment. Knowing the host tissue-initiated causative factors would offer considerable translational applicability, as a permanent regression process may be therapeutically replicated on patients. For this, we developed a systems biological formulation of the regression process with experimental verification and identified the relevant candidate biomolecules for therapeutic utility. We devised a cellular kinetics-based quantitative model of tumor extinction in terms of the temporal behavior of three main tumor-lysis entities: DNA blockade factor, cytotoxic T-lymphocyte and interleukin-2. As a case study, we analyzed the time-wise biopsy and microarrays of spontaneously regressing melanoma and fibrosarcoma tumors in mammalian/human hosts. We analyzed the differentially expressed genes (DEGs), signaling pathways, and bioinformatics framework of regression. Additionally, prospective biomolecules that could cause complete tumor regression were investigated. The tumor regression process follows a first-order cellular dynamics with a small negative bias, as verified by experimental fibrosarcoma regression; the bias is necessary to eliminate the residual tumor. We identified 176 upregulated and 116 downregulated DEGs, and enrichment analysis showed that the most significant were downregulated cell-division genes: TOP2A-KIF20A-KIF23-CDK1-CCNB1. Moreover, Topoisomerase-IIA inhibition might actuate spontaneous regression, with collateral confirmation provided from survival and genomic analysis of melanoma patients. Candidate molecules such as Dexrazoxane/Mitoxantrone, with interleukin-2 and antitumor lymphocytes, may potentially replicate permanent tumor regression process of melanoma. To conclude, episodic permanent tumor regression is a unique biological reversal process of malignant progression, and signaling pathway understanding, with candidate biomolecules, may plausibly therapeutically replicate the regression process on tumors clinically. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03515-0.

Neuroprotective Drug Discovery From Phytochemicals and Metabolites for CNS Viral Infection: A Systems Biology Approach With Clinical and Imaging Validation.

Background: Recent studies have reported that pulmo-neurotropic viruses can cause systemic invasion leading to acute respiratory failure and neuroinfection. The tetracycline class of secondary metabolites of microorganisms is effective against several migrating neurotropic viral disorders, as Japanese-Encephalitis (JE), Severe-Acute-Respiratory-Syndrome Coronavirus-2 (SARS-COV2), Human-Immunodeficiency-Virus (HIV), and Simian-Immunodeficiency-Virus (SIV). Another microbial secondary metabolite, cephalosporin, can be used for anti-viral combination therapy. However, a substantial public health debacle is viral resistance to such antibiotics, and, thus, one needs to explore the antiviral efficiency of other secondary metabolites, as phytochemicals. Hence, here, we investigate phytochemicals like podophyllotoxin, chlorogenic acid, naringenin, and quercetin for therapeutic efficiency in neurotropic viral infections. Methods: To investigate the possibility of the afferent neural pathway of migrating virus in man, MRI scanning was performed on human subjects, whereby the connections between cranial nerves and the brain-stem/limbic-region were assessed by fiber-tractography. Moreover, human clinical-trial assessment (n = 140, p = 0.028) was done for formulating a quantitative model of antiviral pharmacological intervention. Furthermore, docking studies were performed to identify the binding affinity of phytochemicals toward antiviral targets as (i) host receptor [Angiotensin-converting Enzyme-2], (ii) main protease of SARS-COV2 virus (iii) NS3-Helicase/Nucleoside triphosphatase of Japanese-encephalitis-virus, and the affinities were compared to standard tetracycline and cephalosporin antibiotics. Then, network pharmacology analysis was utilized to identify the possible mechanism of action of those phytochemicals. Results: Human MRI-tractography analysis showed fiber connectivity, as: (a) Path-1: From the olfactory nerve to the limbic region (2) Path-2: From the peripheral glossopharyngeal nerve and vagus nerves to the midbrain-respiratory-center. Docking studies revealed comparable binding affinity of phytochemicals, tetracycline, and cephalosporin antibiotics toward both (a) virus receptors, (b) host cell receptors where virus-receptor binds. The phytochemicals effectively countered the cytokine storm-induced neuroinflammation, a critical pathogenic pathway. We also found that a systems-biology-based double-hit mathematical bi-exponential model accounts for patient survival-curve under antiviral treatment, thus furnishing a quantitative-clinical framework of secondary metabolite action on virus and host cells. Conclusion: Due to the current viral resistance to antibiotics, we identified novel phytochemicals that can have clinical therapeutic application to neurotropic virus infection. Based on human MRI scanning and clinical-trial analysis, we demarcated the anatomical pathway and systems-biology-based quantitative formulation of the mechanism of antiviral action.