The effects of electromagnetic fields on living organs have been explored with the use of both biological experimentation and computer simulations. In this paper we will examine the effects of the repeated electromagnetic field stimulation (REMFS) on cell cultures, mouse models, and computer simulations for diagnostic purposes. In our biological experiments we used 50 MHz and 64 MHz since this is approved in MRI systems. REMFS upregulated pathways that control the aging process such as proteostasis. REMFS delayed and reversed cellular senescence in mouse and human cell cultures. More recently we determined that REMFS decreases toxic protein beta amyloid levels, which is the cause of Alzheimer's disease (AD), in human neuronal cultures. The mechanism of these effects is the reactivation of the heat shock factor 1 (HSF1). HSF1 activation is a quantum effect of the EMF-oscillations on the water that surrounds a long non-coding RNA, allowing it to then bind and activate the HSF1. We also performed electromagnetic (EM) computer simulations of virtual prototypes of bone cancer, femur fracture, and diabetic foot ulcers utilizing different frequencies and power applications to build an accurate differential diagnosis. These applications indicate the feasibility of subsequent practical models for diagnosing and treating human diseases.
Abstract The single pellet reaching task is commonly used in rodents to assess the acquisition of fine motor skill and recovery of function following nervous system injury. Although this task is useful for gauging skilled forelimb use in rodents, the process of training animals is labor intensive and variable across studies and labs. To address these limitations, we developed a single pellet reaching paradigm for training and testing group housed mice within their home cage. Mice enter a training compartment attached to the outside of the cage and retrieve millet seeds presented on a motorized pedestal that can be individually positioned to present seeds to either forelimb. To identify optimal training parameters, we compared task participation and success rates between groups of animals that were presented seeds at two different heights (floor vs mouth height) and at different intervals (fixed-time vs trial-based). The mouth height/fixed interval presentation style was most effective at promoting reaching behavior as all mice reached for seeds within 5 d. Using this paradigm, we assessed stroke-induced deficits in home-cage reaching. Following three weeks of baseline training, reaching success rate was ∼40%, with most trials performed during the dark cycle. A forelimb motor cortex stroke significantly decreased interaction with presented seeds within the first 2 d and impaired reaching success rates for the first 7 d. Our data demonstrate that group-housed mice can be efficiently trained on a single pellet reaching task in the home cage and that this assay is sensitive to stroke induced motor impairments.
In human upper-limb stroke, initial level of functional impairment or corticospinal tract injury can accurately predict the degree of poststroke recovery, independent of rehabilitation practices. This proportional recovery rule implies that current rehabilitation practices may play little or no role in brain repair, with recovery largely a result of spontaneous biological recovery processes.The present study sought to determine if similar biomarkers predict recovery of poststroke function in rats, indicating that an endogenous biological recovery process might be preserved across mammalian species.Using a cohort of 593 male Sprague-Dawley rats, we predicted poststroke change in pellet retrieval in the Montoya staircase-reaching task based on initial impairment alone. Stratification of the sample into "fitters" and "nonfitters" of the proportional recovery rule using hierarchical cluster analysis allowed identification of distinguishing characteristics of these subgroups.Approximately 30% of subjects were identified as fitters of the rule. These rats showed recovery in proportion to their initial level of impairment of 66% (95% CI = 62%-70%). This interval overlaps with those of multiple human clinical trials. A number of variables, including less severe infarct volumes and initial poststroke impairments distinguished fitters of the rule from nonfitters.These findings suggest that proportional recovery is a cross-species phenomenon that can be used to uncover biological mechanisms contributing to stroke recovery.
Evidence supports early rehabilitation after stroke to limit disability. However, stroke survivors are typically sedentary and experience significant cardiovascular and muscular deconditioning. Despite growing consensus that preclinical and clinical stroke recovery research should be aligned, there have been few attempts to incorporate cardiovascular and skeletal muscle deconditioning into animal models of stroke. Here, we demonstrate in rats that a hindlimb sensorimotor cortex stroke results in both cardiovascular and skeletal muscle deconditioning and impairments in gait akin to those observed in humans. To reduce poststroke behavioral, cardiovascular, and skeletal muscle perturbations, we then used a combinatorial intervention consisting of aerobic and resistance exercise in conjunction with administration of resveratrol (RESV), a drug with exercise mimetic properties. A combination of aerobic and resistance exercise mitigated decreases in cardiovascular fitness and attenuated skeletal muscle abnormalities. RESV, beginning 24 hours poststroke, reduced acute hindlimb impairments, improved recovery in hindlimb function, increased vascular density in the perilesional cortex, and attenuated skeletal muscle fiber changes. Early RESV treatment and aerobic and resistance exercise independently provided poststroke benefits, at a time when individuals are rapidly becoming deconditioned as a result of inactivity. Although no additive effects were observed in these experiments, this approach represents a promising strategy to reduce poststroke behavioral impairments and minimize deconditioning. As such, this treatment regime has potential for enabling patients to engage in more intensive rehabilitation at an earlier time following stroke when mechanisms of neuroplasticity are most prevalent.
C-C chemokine receptor type 5 (CCR5) antagonists may improve both acute stroke outcome and long-term recovery. Despite their evaluation in ongoing clinical trials, gaps remain in the evidence supporting their use.With a panel of patients with lived experiences of stroke, we performed a systematic review of animal models of stroke that administered a CCR5 antagonist and assessed infarct size or behavioral outcomes. MEDLINE, Web of Science, and Embase were searched. Article screening and data extraction were completed in duplicate. We pooled outcomes using random effects meta-analyses. We assessed risk of bias using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool and alignment with the Stroke Treatment Academic Industry Roundtable (STAIR) and Stroke Recovery and Rehabilitation Roundtable (SRRR) recommendations.Five studies representing 10 experiments were included. CCR5 antagonists reduced infarct volume (standard mean difference −1.02; 95% confidence interval −1.58 to −0.46) when compared to stroke-only controls. Varied timing of CCR5 administration (pre- or post-stroke induction) produced similar benefit. CCR5 antagonists significantly improved 11 of 16 behavioral outcomes reported. High risk of bias was present in all studies and critical knowledge gaps in the preclinical evidence were identified using STAIR/SRRR.CCR5 antagonists demonstrate promise; however, rigorously designed preclinical studies that better align with STAIR/SRRR recommendations and downstream clinical trials are warranted.Prospective Register of Systematic Reviews (PROSPERO CRD42023393438)
Lesion size and location affect the magnitude of impairment and recovery following stroke, but the precise relationship between these variables and functional outcome is unknown. Herein, we systematically varied the size of strokes in motor cortex and surrounding regions to assess effects on impairment and recovery of function. Female Sprague Dawley rats (N = 64) were evaluated for skilled reaching, spontaneous limb use, and limb placement over a 7 week period after stroke. Exploration and reaching were also tested in a free ranging, more naturalistic, environment. MRI voxel-based analysis of injury volume and its likelihood of including the caudal forelimb area (CFA), rostral forelimb area (RFA), hindlimb (HL) cortex (based on intracranial microstimulation), or their bordering regions were related to both impairment and recovery. Severity of impairment on each task was best predicted by injury in unique regions: impaired reaching, by damage in voxels encompassing CFA/RFA; hindlimb placement, by damage in HL; and spontaneous forelimb use, by damage in CFA. An entirely different set of voxels predicted recovery of function: damage lateral to RFA reduced recovery of reaching, damage medial to HL reduced recovery of hindlimb placing, and damage lateral to CFA reduced recovery of spontaneous limb use. Precise lesion location is an important, but heretofore relatively neglected, prognostic factor in both preclinical and clinical stroke studies, especially those using region-specific therapies, such as transcranial magnetic stimulation. SIGNIFICANCE STATEMENT By estimating lesion location relative to cortical motor representations, we established the relationship between individualized lesion location, and functional impairment and recovery in reaching/grasping, spontaneous limb use, and hindlimb placement during walking. We confirmed that stroke results in impairments to specific motor domains linked to the damaged cortical subregion and that damage encroaching on adjacent regions reduces the ability to recover from initial lesion-induced impairments. Each motor domain encompasses unique brain regions that are most associated with recovery and likely represent targets where beneficial reorganization is taking place. Future clinical trials should use individualized therapies (e.g., transcranial magnetic stimulation, intracerebral stem/progenitor cells) that consider precise lesion location and the specific functional impairments of each subject since these variables can markedly affect therapeutic efficacy.
A coordinated pattern of multi-muscle activation is essential to produce efficient reaching trajectories. Disruption of these coordinated activation patterns, termed synergies, is evident following stroke and results in reaching deficits; however, preclinical investigation of this phenomenon has been largely ignored. Furthermore, traditional outcome measures of post-stroke performance seldom distinguish between impairment restitution and compensatory movement strategies. We sought to address this by using kinematic analysis to characterize reaching movements and kinematic synergies of rats performing the Montoya staircase task, before and after ischemic stroke. Synergy was defined as the simultaneous movement of the wrist and other proximal forelimb joints (i.e. shoulder, elbow) during reaching. Following stroke, rats exhibited less individuation between joints, moving the affected limb more as a unit. Moreover, abnormal flexor synergy characterized by concurrent elbow flexion, shoulder adduction, and external rotation was evident. These abnormalities ultimately led to inefficient and unstable reaching trajectories, and decreased reaching performance (pellets retrieved). The observed reaching abnormalities in this preclinical stroke model are similar to those classically observed in humans. This highlights the potential of kinematic analysis to better align preclinical and clinical outcome measures, which is essential for developing future rehabilitation strategies following stroke.
