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IntroductionNeurovascular coupling (NVC) is an important mechanism for the regulation of cerebral perfusion during intensive cognitive activity. Thus, it should be examined in terms of its effects on the regulation dynamics of cerebral perfusion and its possible alterations during cognitive impairment. The dynamic dependence of continuous changes in cerebral blood velocity (CBv), which can be measured noninvasively using transcranial Doppler upon fluctuations in arterial blood pressure (ABP) and CO2 tension, using end-tidal CO2 (EtCO2) as a proxy, can be quantified via data-based dynamic modeling to yield insights into two key regulatory mechanisms: the dynamic cerebral autoregulation (dCA) and dynamic vasomotor reactivity (DVR), respectively.MethodsUsing the Laguerre Expansion Technique (LET), this study extracted such models from data in supine resting vs cognitively active conditions (during attention, fluency, and memory tasks from the Addenbrooke’s Cognitive Examination III, ACE-III) to elucidate possible changes in dCA and DVR due to cognitive stimulation of NVC. Healthy volunteers (n = 39) were recruited at the University of Leicester and continuous measurements of CBv, ABP, and EtCO2 were recorded.ResultsModeling analysis of the dynamic ABP-to-CBv and CO2-to-CBv relationships showed significant changes in dCA, but not DVR, under cognitively active conditions compared to resting state.DiscussionInterpretation of these changes through Principal Dynamic Mode (PDM) analysis is discussed in terms of possible associations between stronger NVC stimulation during cognitive tasks and enhanced sympathetic activation.

Abstract We present data from the Heart Rate Variability and Emotion Regulation (HRV-ER) randomized clinical trial testing effects of HRV biofeedback. Younger (N = 121) and older (N = 72) participants completed baseline magnetic resonance imaging (MRI) including T1-weighted, resting and emotion regulation task functional MRI (fMRI), pulsed continuous arterial spin labeling (PCASL), and proton magnetic resonance spectroscopy (1H MRS). During fMRI scans, physiological measures (blood pressure, pulse, respiration, and end-tidal CO2) were continuously acquired. Participants were randomized to either increase heart rate oscillations or decrease heart rate oscillations during daily sessions. After 5 weeks of HRV biofeedback, they repeated the baseline measurements in addition to new measures (ultimatum game fMRI, training mimicking during blood oxygen level dependent (BOLD) and PCASL fMRI). Participants also wore a wristband sensor to estimate sleep time. Psychological assessment comprised three cognitive tests and ten questionnaires related to emotional well-being. A subset (N = 104) provided plasma samples pre- and post-intervention that were assayed for amyloid and tau. Data is publicly available via the OpenNeuro data sharing platform.

ObjectiveHere, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject’s own hippocampal spatiotemporal neural codes for memory.ApproachWe constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task.Main resultsMDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation.SignificanceThese results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

Background: Cerebral flow autoregulation (CFA) is a homeostatic mechanism critical for survival. The autonomic nervous system (ANS) plays a key role in maintaining proper CFA function. More quantitative studies of how the ANS influences CFA are desirable.Objective: To discover and quantify the dynamic effects of cholinergic blockade upon CFA in response to changes of arterial blood pressure and blood CO2 tension in healthy adults.Methods: We analyzed time-series data of spontaneous beat-to-beat mean arterial blood pressure (ABP) and cerebral blood flow velocity in the middle cerebral arteries (CFV), as well as breath-to-breath end-tidal CO2 (CO2), collected in 9 adults before and after cholinergic blockade, in order to obtain subject-specific predictive input-output models of the dynamic effects of changes in ABP and CO2 (inputs) upon CFV (output). These models are defined in convolutional form using “kernel” functions (or, equivalently, Transfer Functions in the frequency domain) that are estimated via the robust method of Laguerre expansions.Results: Cholinergic blockade caused statistically significant changes in the obtained kernel estimates (and the corresponding Transfer Functions) that define the linear dynamics of the ABP-to-CFV and CO2-to-CFV causal relations. The kernel changes due to cholinergic blockade reflect the effects of the cholinergic mechanism and exhibited, in the frequency domain, resonant peaks at 0.22 Hz and 0.06 Hz for the ABP-to-CFV and CO2-to-CFV dynamics, respectively.Conclusion: Quantitative estimates of the dynamics of the cholinergic component in CFA are found as average changes of the ABP-to-CFV and CO2-to-CFV kernels, and corresponding Transfer Functions, before and after cholinergic blockade.

Rationale: Deep brain stimulation (DBS) of the hippocampus is proposed for enhancement of memory impaired by injury or disease. Many pre-clinical DBS paradigms can be addressed in epilepsy patients undergoing intracranial monitoring for seizure localization, since they already have electrodes implanted in brain areas of interest. Even though epilepsy is usually not a memory disorder targeted by DBS, the studies can nevertheless model other memory-impacting disorders, such as Traumatic Brain Injury (TBI). Methods: Human patients undergoing Phase II invasive monitoring for intractable epilepsy were implanted with depth electrodes capable of recording neurophysiological signals. Subjects performed a delayed-match-to-sample (DMS) memory task while hippocampal ensembles from CA1 and CA3 cell layers were recorded to estimate a multi-input, multi-output (MIMO) model of CA3-to-CA1 neural encoding and a memory decoding model (MDM) to decode memory information from CA3 and CA1 neuronal signals. After model estimation, subjects again performed the DMS task while either MIMO-based or MDM-based patterned stimulation was delivered to CA1 electrode sites during the encoding phase of the DMS trials. Each subject was sorted (post hoc) by prior experience of repeated and/or mild-to-moderate brain injury (RMBI), TBI, or no history (control) and scored for percentage successful delayed recognition (DR) recall on stimulated vs. non-stimulated DMS trials. The subject’s medical history was unknown to the experimenters until after individual subject memory retention results were scored. Results: When examined compared to control subjects, both TBI and RMBI subjects showed increased memory retention in response to both MIMO and MDM-based hippocampal stimulation. Furthermore, effects of stimulation were also greater in subjects who were evaluated as having pre-existing mild-to-moderate memory impairment. Conclusion: These results show that hippocampal stimulation for memory facilitation was more beneficial for subjects who had previously suffered a brain injury (other than epilepsy), compared to control (epilepsy) subjects who had not suffered a brain injury. This study demonstrates that the epilepsy/intracranial recording model can be extended to test the ability of DBS to restore memory function in subjects who previously suffered a brain injury other than epilepsy, and support further investigation into the beneficial effect of DBS in TBI patients.

Background: Recent studies have utilized data-based dynamic modeling to establish strong association between dysregulation of cerebral perfusion and Mild Cognitive Impairment (MCI), expressed in terms of impaired CO2 dynamic vasomotor reactivity in the cerebral vasculature. This raises the question of whether this is due to dysregulation of central mechanisms (baroreflex and chemoreflex) or mechanisms of cortical tissue oxygenation (CTO) in MCI patients. We seek to answer this question using data-based input-output predictive dynamic models.Objective: To use subject-specific data-based multivariate input-output dynamic models to quantify the effects of systemic hemodynamic and blood CO2 changes upon CTO and to examine possible differences in CTO regulation in MCI patients versus age-matched controls, after the dynamic effects of central regulatory mechanisms have been accounted for by using cerebral flow measurements as another input.Methods: The employed model-based approach utilized the general dynamic modeling methodology of Laguerre expansions of kernels to analyze spontaneous time-series data in order to quantify the dynamic effects upon CTO (an index of relative capillary hemoglobin saturation distribution measured via near-infrared spectroscopy) of contemporaneous changes in end-tidal CO2 (proxy for arterial CO2), arterial blood pressure and cerebral blood flow velocity in the middle cerebral arteries (measured via transcranial Doppler). Model-based indices (physio-markers) were computed for these distinct dynamic relationships.Results: The obtained model-based indices revealed significant statistical differences of CO2 dynamic vasomotor reactivity in cortical tissue, combined with “perfusivity” that quantifies the dynamic relationship between flow velocity in cerebral arteries and CTO in MCI patients versus age-matched controls (p = 0.006). Significant difference between MCI patients and age-matched controls was also found in the respective model-prediction accuracy (p = 0.0001). Combination of these model-based indices via the Fisher Discriminant achieved even smaller p-value (p = 5 × 10–5) when comparing MCI patients with controls. The differences in dynamics of CTO in MCI patients are in lower frequencies (

There are currently intensified efforts by the scientific community world-wide to analyze the dynamics of the Covid-19 pandemic in order to predict key epidemiological effects and assist the proper planning for its clinical management, as well as guide sociopolitical decision-making regarding proper mitigation measures. Most efforts follow variants of the established SIR methodological framework that divides a population into “Susceptible”, “Infectious” and “Recovered/Removed” fractions and defines their dynamic inter-relationships with first-order differential equations. Goal: This paper proposes a novel approach based on data-guided detection and concatenation of infection waves - each of them described by a Riccati equation with adaptively estimated parameters. Methods: This approach was applied to Covid-19 daily time-series data of US confirmed cases, resulting in the decomposition of the epidemic time-course into five “Riccati modules” representing major infection waves to date (June 18th). Results: Four waves have passed the time-point of peak infection rate, with the fifth expected to peak on July 20th. The obtained parameter estimates indicate gradual reduction of infectivity rate, although the latest wave is expected to be the largest. Conclusions: This analysis suggests that, if no new waves of infection emerge, the Covid-19 epidemic will be controlled in the US (

Abstract Computational neuroscience is a field that traces its origins to the efforts of Hodgkin and Huxley, who pioneered quantitative analysis of electrical activity in the nervous system. While also continuing as an independent field, computational neuroscience has combined with computational systems biology, and neural multiscale modeling arose as one offshoot. This consolidation has added electrical, graphical, dynamical system, learning theory, artificial intelligence and neural network viewpoints with the microscale of cellular biology (neuronal and glial), mesoscales of vascular, immunological and neuronal networks, on up to macroscales of cognition and behavior. The complexity of linkages that produces pathophysiology in neurological, neurosurgical and psychiatric disease will require multiscale modeling to provide understanding that exceeds what is possible with statistical analysis or highly simplified models: how to bring together pharmacotherapeutics with neurostimulation, how to personalize therapies, how to combine novel therapies with neurorehabilitation, how to interlace periodic diagnostic updates with frequent reevaluation of therapy, how to understand a physical disease that manifests as a disease of the mind. Multiscale modeling will also help to extend the usefulness of animal models of human diseases in neuroscience, where the disconnects between clinical and animal phenomenology are particularly pronounced. Here we cover areas of particular interest for clinical application of these new modeling neurotechnologies, including epilepsy, traumatic brain injury, ischemic disease, neurorehabilitation, drug addiction, schizophrenia and neurostimulation.

Abstract Objective To compare the novel model‐based hemodynamic physiomarker of Dynamic Vasomotor Reactivity (DVR) with biomarkers based on Diffusion Tensor Imaging (DTI) and some widely used neurocognitive scores in terms of their ability to delineate patients with amnestic Mild Cognitive Impairment (MCI) from age‐matched cognitively normal controls. Materials & Methods The model‐based DVR and MRI‐based DTI markers were obtained from 36 patients with amnestic MCI and 16 age‐matched controls without cognitive impairment, for whom widely used neurocognitive scores were available. These markers and scores were subsequently compared in terms of statistical delineation between patients and controls. Results It was found that statistically significant delineation between MCI patients and controls was comparable for DVR or DTI markers (p

Parameters describing dynamic cerebral autoregulation (DCA) have limited reproducibility. In an international, multi-center study, we evaluated the influence of multiple analytical methods on the reproducibility of DCA. Fourteen participating centers analyzed repeated measurements from 75 healthy subjects, consisting of 5 min of spontaneous fluctuations in blood pressure and cerebral blood flow velocity signals, based on their usual methods of analysis. DCA methods were grouped into three broad categories, depending on output types: (1) transfer function analysis (TFA); (2) autoregulation index (ARI); and (3) correlation coefficient. Only TFA gain in the low frequency (LF) band showed good reproducibility in approximately half of the estimates of gain, defined as an intraclass correlation coefficient (ICC) of >0.6. None of the other DCA metrics had good reproducibility. For TFA-like and ARI-like methods, ICCs were lower than values obtained with surrogate data (p < 0.05). For TFA-like methods, ICCs were lower for the very LF band (gain 0.38 ± 0.057, phase 0.17 ± 0.13) than for LF band (gain 0.59 ± 0.078, phase 0.39 ± 0.11, p ≤ 0.001 for both gain and phase). For ARI-like methods, the mean ICC was 0.30 ± 0.12 and for the correlation methods 0.24 ± 0.23. Based on comparisons with ICC estimates obtained from surrogate data, we conclude that physiological variability or non-stationarity is likely to be the main reason for the poor reproducibility of DCA parameters.

Compartmental and data-based modeling of cerebral hemodynamics are alternative approaches that utilize distinct model forms and have been employed in the quantitative study of cerebral hemodynamics. This paper examines the relation between a compartmental equivalent circuit and a data-based input-output model of dynamic cerebral autoregulation (DCA) and dynamic CO2-vasomotor reactivity (DVR). The compartmental model is constructed as an equivalent circuit utilizing putative first principles and previously proposed hypothesis-based models. The linear input-output dynamics of this compartmental model are compared with the data-based estimates of the DCA-DVR process. This comparative study indicates that there are some qualitative similarities between the two-input compartmental model and experimental results.