Mouse Models of Osteoarthritis: A Summary of Models and Outcomes Assessment

Osteoarthritis (OA) is a multidimensional health problem and a common chronic disease. It has a substantial impact onpatient quality of life and is a common cause of pain and mobility issues in older adults. The functional limitations, lack of curative treatments, and cost to society all demonstrate the need for translational and clinical research. The use of OA models in mice is important for achieving a better understanding of the disease. Models with clinical relevance are needed to achieve 2 main goals: to assess the impact of the OA disease (pain and function) and to study the efficacy of potential treatments. However, few OA models include practical strategies for functional assessment of the mice. OA signs in mice incorporate complex interrelations between pain and dysfunction. The current review provides a comprehensive compilation of mousemodels of OA and animal evaluations that include static and dynamic clinical assessment of the mice, merging evaluationof pain and function by using automatic and noninvasive techniques. These new techniques allow simultaneous recordingof spontaneous activity from thousands of home cages and also monitor environment conditions. Technologies such as videographyand computational approaches can also be used to improve pain assessment in rodents but these new tools must first be validated experimentally. An example of a new tool is the digital ventilated cage, which is an automated home-cage monitor that records spontaneous activity in the cages.

Globally Aging Cortical Spontaneous Activity Revealed by Multiple Metrics and Frequency Bands Using Resting-State Functional MRI

Most existing aging studies using functional MRI (fMRI) are based on cross-sectional data but misinterpreted their findings (i.e., age-related differences) as longitudinal outcomes (i.e., aging-related changes). To delineate aging-related changes the of human cerebral cortex, we employed the resting-state fMRI (rsfMRI) data from 24 healthy elders in the PREVENT-AD cohort, obtaining five longitudinal scans per subject. Cortical spontaneous activity is measured globally with three rsfMRI metrics including its amplitude, homogeneity, and homotopy at three different frequency bands (slow-5: 0.02–0.03 Hz, slow-4: 0.03–0.08 Hz, and slow-3 band: 0.08–0.22 Hz). General additive mixed models revealed a universal pattern of the aging-related changes for the global cortical spontaneous activity, indicating increases of these rsfMRI metrics during aging. This aging pattern follows specific frequency and spatial profiles where higher slow bands show more non-linear curves and the amplitude exhibits more extensive and significant aging-related changes than the connectivity. These findings provide strong evidence that cortical spontaneous activity is aging globally, inspiring its clinical utility as neuroimaging markers for neruodegeneration disorders.

Sequential propagation and routing of activity in a cortical network

Single spikes can trigger repeatable sequences of spikes in cortical networks. The mechanisms that support reliable propagation from such small events and their functional consequences for network computations remain unclear. We investigated the conditions in which single spikes trigger reliable and temporally precise sequences in a network model constrained by experimental measurements from turtle cortex. We examined the roles of connectivity, synaptic strength, and spontaneous activity in the generation of sequences. Sparse but strong connections support sequence propagation, while dense but weak connections modulate propagation reliability. Unsupervised clustering reveals that sequences can be decomposed into sub-sequences corresponding to divergent branches of strongly connected neurons. The sparse backbone of strong connections defines few failure points where activity can be selectively gated, enabling the controlled routing of activity. These results reveal how repeatable sequences of activity can be triggered, sustained, and controlled, with significant implications for cortical computations.

Changes in the spatiotemporal pattern of spontaneous activity across a cortical column after noise trauma

In the auditory modality, noise trauma has often been used to investigate cortical plasticity as it causes cochlear hearing loss. One limitation of these past studies, however, is that the effects of noise trauma have been mostly documented at the granular layer, which is the main cortical recipient of thalamic inputs. Importantly, the cortex is composed of six different layers each having its own pattern of connectivity and specific role in sensory processing. The present study aims at investigating the effects of acute and chronic noise trauma on the laminar pattern of spontaneous activity in primary auditory cortex of the anesthetized guinea pig. We show that spontaneous activity is dramatically altered across cortical layers after acute and chronic noise-induced hearing loss. First, spontaneous activity was globally enhanced across cortical layers, both in terms of firing rate and amplitude of spike-triggered average of local field potentials. Second, current source density on (spontaneous) spike-triggered average of local field potentials indicates that current sinks develop in the supra- and infragranular layers. These latter results suggest that supragranular layers become a major input recipient and that the propagation of spontaneous activity over a cortical column is greatly enhanced after acute and chronic noise-induced hearing loss. We discuss the possible mechanisms and functional implications of these changes.

Elucidating the Effects of a Cryptomeria fortunei Forest Environment on Overall Health Based on Open Field Testing of Mice

In order to elucidate the impact of fortunei forest environment on overall health, the effect of the Cryptomeria fortunei forest environment on mice was examined. Using an OFT (Open Field Test), the behavior of mice in fortunei forest and in an indoor environment (used as a control) was analyzed, while minor changes in climate, oxygen, and suspended particulate matter were observed and recorded simultaneously. The results indicated that the two environments were significantly different in regard to relative humidity, wind speed, and the oxygen content of air, while there were no significant differences in temperature. Importantly, spontaneous activity behavioral indicators in mice were significantly different. Mice in the Cryptomeria fortunei environment (LS group) spent less time in the corners and near walls in comparison to mice in the indoor environment (CK group). Compared with indoor control mice, for the mice exposed to forest environments total distance traveled, central grid distance, frequency of movement through the central grid, frequency of standing, and body mass significantly increased; The number of fecal grains significantly decreased. The spontaneous activity behavioral indicators changed over time stages. In the early stages there were no differences, but after accumulation of environmental effects in the late stages, significant differences were evident. The above results showed that the Cryptomeria fortunei forest environment increased excitability and cognitive ability of mice, was able to effectively alleviate anxiety, and was able to emotionally relax and improve the appetite of the mice.

Aberrant Brain Spontaneous Activity and Synchronization in Type 2 Diabetes Mellitus Subjects Without Mild Cognitive Impairment

Objective: We aimed to explore whether the percent amplitude of fluctuation (PerAF) measurement could provide supplementary information for amplitude of low-frequency fluctuation (ALFF) about spontaneous activity alteration in type 2 diabetes mellitus (T2DM) subjects without mild cognitive impairment (MCI). Then we further evaluated the synchronization through the method of functional connectivity (FC) to better demonstrate brain changes in a more comprehensive manner in T2DM.Methods: Thirty T2DM subjects without MCI and thirty well-matched healthy subjects were recruited in this study. Subjects’ clinical data, neuropsychological test results, and resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired. Voxel-based group difference comparisons between PerAF and ALFF were conducted. Then, seed-based FC between the recognized brain regions based on PerAF and ALFF and the rest of the whole brain was performed.Results: Compared with healthy group, T2DM group had significantly decreased PerAF in the bilateral middle occipital gyrus and the right calcarine, increased ALFF in the right orbital inferior frontal gyrus and decreased ALFF in the right calcarine. Seed-based FC analysis showed that the right middle occipital gyrus of T2DM subjects exhibited significantly decreased FC with the right caudate nucleus and right putamen. According to the partial correlation analyses, hemoglobin A1c (HbA1c) and immediate memory scores on the auditory verbal learning test (AVLT) were negatively correlated in the T2DM group. However, we found that total cholesterol was positively correlated with symbol digit test (SDT) scores.Conclusion: PerAF and ALFF may have different sensitivities in detecting the abnormal spontaneous brain activity in T2DM subjects. We suggest PerAF values may add supplementary information and indicate additional potential neuronal spontaneous activity in T2DM subjects without MCI, which may provide new insights into the neuroimaging mechanisms underlying early diabetes-associated cognitive decline.

Tightly coupled inhibitory and excitatory functional networks in the developing primary visual cortex

Intracortical inhibition plays a critical role in shaping activity patterns in the mature cortex. However, little is known about the structure of inhibition in early development prior to the onset of sensory experience, a time when spontaneous activity exhibits long-range correlations predictive of mature functional networks. Here, using calcium imaging of GABAergic neurons in the ferret visual cortex, we show that spontaneous activity in inhibitory neurons is already highly organized into distributed modular networks before visual experience. Inhibitory neurons exhibit spatially modular activity with long-range correlations and precise local organization that is in quantitative agreement with excitatory networks. Furthermore, excitatory and inhibitory networks are strongly co-aligned at both millimeter and cellular scales. These results demonstrate a remarkable degree of organization in inhibitory networks early in the developing cortex, providing support for computational models of self-organizing networks and suggesting a mechanism for the emergence of distributed functional networks during development.

When is needle examination of thenar muscle necessary in the evaluation of mild and moderate carpal tunnel syndrome?

Objectives: This study aims to evaluate the predictors of standard nerve conduction study (NCS) parameters in determining the presence of axonal loss by means of spontaneous activity in patients with mild and moderate carpal tunnel syndrome (CTS). Patients and methods: Between May 2015 and April 2018, a total of 118 patients (11 males, 107 females; mean age: 52.3±10.6 years; range, 27 to 79 years) who underwent electrophysiological studies and were diagnosed with CTS were included. Demographic data of the patients including age, sex, and symptom duration were recorded. Electrodiagnostic studies were performed in all patients. All the needle electromyography (EMG) findings were recorded, but only the presence or absence of spontaneous EMG activities was used as the indicator of axonal injury. Results: In 37 (31.4%) of the patients, spontaneous activity was detected at the thenar muscle needle EMG. No spontaneous activity was observed in any of 43 (36.4%) patients with normal distal motor latency (DML). There were significant differences in DMLs, compound muscle action potential (CMAP) amplitudes, sensory nerve action potentials amplitudes, and sensory nerve conduction velocities between the groups with and without spontaneous activity (p<0.05). The multiple logistic regression analysis revealed that DML was a significant independent risk variable in determining presence of spontaneous activity. The most optimal cut-off value for median DML was calculated as 4.9 ms. If the median DML was >4.9 ms, the relative risk of finding spontaneous activity on thenar muscle needle EMG was 13.5 (95% CI: 3.6-51.2). Conclusion: Distal motor latency is the main parameter for predicting the presence of spontaneous activity in mild and moderate CTS patients with normal CMAP. Performing needle EMG of the thenar muscle in CTS patients with a DML of >4.9 ms may be beneficial to detect axonal degeneration in early stages.