Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging.

The human aging brain is characterized by changes in network efficiency that are currently best captured through longitudinal resting-state functional MRI (rs-fMRI). These studies however are challenging due to the long human lifespan. Here we show that the mouse animal model with a much shorter lifespan allows us to follow the functional network organization over most of the animal's adult lifetime. We used a longitudinal study of the functional connectivity of different brain regions with rs-fMRI under anesthesia. Our analysis uncovers network modules similar to those reported in younger mice and in humans (i.e., prefrontal/default mode network (DMN), somatomotor and somatosensory networks). Statistical analysis reveals different patterns of network reorganization during aging. Female mice showed a pattern akin to human aging, with de-differentiation of the connectome, mainly due to increases in connectivity of the prefrontal/DMN cortical networks to other modules. Our male cohorts revealed heterogenous aging patterns with only one group confirming the de- differentiation, while the majority showed an increase in connectivity of the somatomotor cortex to the Nucleus accumbens. In summary, in line with human work, our analysis in mice supports the concept of de-differentiation in the aging mammalian brain and reveals additional trajectories in aging mice networks.

Cerebellar Transcranial Direct Current Stimulation Modulates Anticipatory Postural Adjustments in Healthy Adults.

During forward swinging of the arm, the central nervous system must anticipate the effect of upraising upon the body. Little is known about the cerebellar network that coordinates these anticipatory postural adjustments (APAs). Stimulating different cerebellar regions with transcranial direct current stimulation (tDCS) and with different polarities modulated the APAs. We used surface electromyography (sEMG) to measure muscle activities in a bilateral rapid shoulder flexion task. The onset of APAs was altered after tDCS over the vermis, while the postural stability and the kinematics of arm raising were not affected. To our knowledge, this is the first human cerebellar-tDCS (c-tDCS) study to separate cerebellar involvement in core muscle APAs in bilateral rapid shoulder flexion. These data contribute to our understanding of the cerebellar network supporting APAs in healthy adults. Modulated APAs of the erector spinae by tDCS on the vermis may be related to altered cerebellar brain inhibition (CBI), suggesting the importance of the vermal-cerebral connections in APAs regulation.

Improving Alzheimer's Disease Classification in Brain MRI Images Using a Neural Network Model Enhanced with PCA and SWLDA.

The examination of Alzheimer's disease (AD) using adaptive machine learning algorithms has unveiled promising findings. However, achieving substantial credibility in medical contexts necessitates a combination of notable accuracy, minimal processing time, and universality across diverse populations. Therefore, we have formulated a hybrid methodology in this study to classify AD by employing a brain MRI image dataset. We incorporated an averaging filter during preprocessing in the initial stage to reduce extraneous details. Subsequently, a combined strategy was utilized, involving principal component analysis (PCA) in conjunction with stepwise linear discriminant analysis (SWLDA), followed by an artificial neural network (ANN). SWLDA employs a combination of forward and backward recursion methods to choose a restricted set of features. The forward recursion identifies the most interconnected features based on partial Z-test values. Conversely, the backward recursion method eliminates the least correlated features from the same feature space. After the extraction and selection of features, an optimized artificial neural network (ANN) was utilized to differentiate the various classes of AD. To demonstrate the significance of this hybrid approach, we utilized publicly available brain MRI datasets using a 10-fold cross-validation strategy. The proposed method excelled over existing state-of-the-art systems, attaining weighted average recognition rates of 99.35% and 96.66%, respectively, across all the datasets.

Medication Adherence and Its Associated Factors among Patients with Type 2 Diabetes Mellitus Attending Primary Health Centers of Eastern Province, Saudi Arabia.

Medication adherence by patients with diabetes is critical, as it plays a crucial role in individuals' long-term health and well-being. We evaluated the medication adherence, illness perception, diabetes knowledge, and associated factors among patients with type 2 diabetes mellitus (T2DM) attending primary health centers (PHCs) in the eastern province of the Kingdom of Saudi Arabia (KSA) using a validated Arabic version of a data collection form. In order to identify the variables that are associated with medication adherence, we applied a logistic regression analysis. Furthermore, we performed the Spearman test to find the correlation between medication adherence, illness perception, and diabetes knowledge. Of the 390 studied patients, 21.5% had low medication adherence, and it was significantly associated with gender (adjusted OR (AOR) = 1.89, 95% CI = 1.27-2.73, p = 0.003) and duration of diabetes (AOR = 0.83, 95% CI = 0.67-0.95, p = 0.017). Furthermore, we found a significant positive correlation between medication adherence and illness perception (rho = 0.217, p = 0.007) and knowledge of diabetes and medication adherence (rho = 0.425, p < 0.001). We recommend improving T2DM patients' knowledge about the importance of adherence to their medication regimen in several health education sessions at the PHCs. In addition, we recommend mixed-method medication adherence assessment surveys in different parts of the KSA.

Learning-related contraction of gray matter in rodent sensorimotor cortex is associated with adaptive myelination.

From observations in rodents, it has been suggested that the cellular basis of learning-dependent changes, detected using structural MRI, may be increased dendritic spine density, alterations in astrocyte volume, and adaptations within intracortical myelin. Myelin plasticity is crucial for neurological function, and active myelination is required for learning and memory. However, the dynamics of myelin plasticity and how it relates to morphometric-based measurements of structural plasticity remains unknown. We used a motor skill learning paradigm in male mice to evaluate experience-dependent brain plasticity by voxel-based morphometry (VBM) in longitudinal MRI, combined with a cross-sectional immunohistochemical investigation. Whole-brain VBM revealed nonlinear decreases in gray matter volume (GMV) juxtaposed to nonlinear increases in white matter volume (WMV) within GM that were best modeled by an asymptotic time course. Using an atlas-based cortical mask, we found nonlinear changes with learning in primary and secondary motor areas and in somatosensory cortex. Analysis of cross-sectional myelin immunoreactivity in forelimb somatosensory cortex confirmed an increase in myelin immunoreactivity followed by a return towards baseline levels. Further investigations using quantitative confocal microscopy confirmed these changes specifically to the length density of myelinated axons. The absence of significant histological changes in cortical thickness suggests that nonlinear morphometric changes are likely due to changes in intracortical myelin for which morphometric WMV in somatosensory cortex significantly correlated with myelin immunoreactivity. Together, these observations indicate a nonlinear increase of intracortical myelin during learning and support the hypothesis that myelin is a component of structural changes observed by VBM during learning.

Incidence of eye complications among sickle cell disease patients in Jeddah, Saudi Arabia: A cross-sectional study.

Introduction: Sickle cell disease (SCD) is a heritable blood disorder resulting in deformed, rigid red blood cells, rendering them more prone to vaso-occlusion. Ocular complications are known to affect multiple organs through the body's vasculature. Here, we evaluated the incidence of eye complications in patients with SCD at King Abdulaziz Medical City in Jeddah, Saudi Arabia. Materials and methods: We used a cross-sectional approach and collected relevant medical data from nine patients with SCD. Ophthalmic assessment included visual acuity and an in-clinic dilated fundus examination. All patients were asked to attend the ophthalmology clinic to undergo optical coherence tomography (OCT) angiography, macular OCT scan, and fundus photography. The results of the imaging tests were interpreted by a certified ophthalmology consultant specializing in retinal diseases. Descriptive analyses of the results were also performed. Results: The mean age of the nine patients was 24.78 ± 10.9 years. All patients were non-hypertensive, one had type 1 diabetes, and another had type 2 diabetes. Five patients had normal visual acuity, two had slight impairments in at least one eye, and two had moderate impairment in at least one eye. One of the nine patients exhibited retinal ischemia in the right eye despite normal macular thickness (visual acuity, OD, 6/30; OS, 6/21). The remaining eight patients showed no ocular abnormalities. Conclusion: Of the nine patients with SCD, five showed no symptoms of ocular complications. One patient showed retinal ischemia in the right eye, despite a normal macular thickness. This study's results suggest routine ophthalmologic examination may not be able to detect or monitor macular or retinal abnormalities unless augmented with detailed imaging techniques.

Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model.

Honey has been used as a traditional remedy for various health benefits. This study investigated the potential of honey against the onset of autoimmune diabetes and its associated secondary complications in type 1 diabetic (T1D) experimental animals. Autoimmune diabetes was induced in Sprague Dawley rats, and at the same time, the rats were treated with honey or metformin. Sandwich ELISAs were used to estimate blood glucose, hemoglobin A1C (HbA1c), total cholesterol, and triglycerides. Histopathological examinations determined the T1D-induced lesions on kidneys, pancreas, cornea, and retina. Treatment of rats with honey during the course of T1D induction showed a significant reduction in fasting-blood-glucose and HbA1c (p < 0.01), and total lipid profile was also improved (p < 0.05). Not only these, but honey also reduced the T1D-induced lesions in the kidney, pancreas, and cornea/retina (p < 0.05). Metformin showed similar effects and was used as a positive control. In conclusion, honey showed therapeutic potential against the onset of autoimmune diabetes, as it reduces blood glucose/HbA1c and improves the lipid profile by reducing the plasma levels of total cholesterol, low-density lipoproteins (LDL), very low-density lipoprotein (VLDL), and triglycerides. Moreover, it also showed protective potential against the development of diabetic nephropathy, pancreatitis, and retinopathy.

The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice.

To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D1 and D2 receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [11C]Raclopride and [11C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BP ND ), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BP ND for D2 receptors over time, whereas no significant change was found for D1 receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [11C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D2 receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D1 were found, which may be attributed to altered [11C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.

Increase of vesicular glutamate transporter 2 co-expression in the deep cerebellar nuclei related to skilled reach learning.

Motor learning induces plasticity in multiple brain regions involving the cerebellum as a crucial player. Synaptic plasticity in the excitatory collaterals to the cerebellar output, the deep cerebellar nuclei (DCN), have recently been shown to be an important part of motor learning. These synapses are composed of climbing fiber (CF) and mossy fiber synapses, with the former conveying unconditioned and the latter conditioned responses in classical conditioning paradigms. The CF synapse on to the cerebellar cortex and the DCN express vesicular transporter 2 (vGluT2), whereas mossy fibers express vGluT1 and /or vGluT2 in their terminals. However, the underlying regulatory mechanism of vGluT expression in the DCN remains unknown. Here we confirm the increase of vGluT2 in a specific part of the DCN during the acquisition of a skilled reaching task in mice. Furthermore, our findings show that this is due to an increase in co-expression of vGluT2 in vGluT1 presynapses instead of the formation of new vGluT2 synapses. Our data indicate that remodeling of synapses - in contrast to synaptogenesis - also plays an important role in motor learning and may explain the presence of both vGluT's in some mossy fiber synapses.

Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.

Physical exercise keeps the brain connected by increasing white matter integrity in healthy controls.

ABSTRACT: Physical exercise leads to structural changes in the brain. However, it is unclear whether the initiation or continuous practice of physical exercise causes this effect and whether brain connectivity benefits from exercise. We examined the effect of 6 months of exercise on the brain in participants who exercise regularly (n = 25) and in matched healthy controls (n = 20). Diffusion tensor imaging brain scans were obtained from both groups. Our findings demonstrate that regular physical exercise significantly increases the integrity of white matter fiber tracts, especially those related to frontal function. This implies that exercise improves brain connectivity in healthy individuals, which has important implications for understanding the effect of fitness programs on the brains of healthy subjects.

Antidiabetic efficacy of a honey-royal jelly mixture: Biochemical study in rats.

OBJECTIVES: The current tools for the management of diabetes mellitus (DM) do not prevent its development or complications, so investigations into promising new treatments, for example, honey-royal jelly (H-RJ) mixtures, are needed. This study was conducted to evaluate the effect of royal jelly on DM by measuring the biochemical parameters (fasting blood glucose and glycated hemoglobin [HbA1c]) accompanying streptozotocin (i.p. 75 mg/kg once)-induced type 1 DM (T1DM) in rats. Other objectives were to evaluate the effects of H-RJ on lipid parameters. METHODS: Ten healthy control male Sprague-Dawley rats (120-150 g) were compared to untreated T1DM (n = 10), metformin-treated T1DM (n = 10), and H-RJ-treated T1DM rats (n = 10) on plasma and whole-blood glycemic control indices (fasting blood glucose, HbA1c %, insulin, and insulin resistance) and plasma lipid profile (triglycerides [TGs] and total, low-density lipoprotein -, high-density lipoprotein -, and very low-density lipoprotein [VLDL]-cholesterol). Diabetes was induced by a single intraperitoneal injection of streptozotocin (SZT) at 75 mg/kg body weight (BW). The T1DM-H-RJ rat group received daily RJ (100 mg/kg BW). Parametric data are presented as mean ± SD and were analyzed for comparison using one-way ANOVA in SPSS software. RESULTS: H-RJ normalized glycemic control indices, but its effect on lipid parameters was variable. H-RJ and metformin had comparable effects. The H-RJ treatment caused a significant reduction in plasma VLDL-C content in comparison to the control treatment and metformin. The limitation of this study is that it was restricted to T1DM and did not involve type 2 DM. In addition, the study was limited to male Sprague-Dawley rats, with no females. CONCLUSION: The H-RJ mixture is a promising antidiabetic alternative medicine. It effectively reduces VLDL-C and TG in diabetic rats.

Medical benefits of camel's milk: A comprehensive review.

In the last decade, there has been an emergent interest, supported by various experimental and epidemiological studies, for health benefits of camel milk, in preventing various pathologic conditions, ranging from cancer to diabetes. However, the precise mechanisms by which camel milk induce these health benefits remain to be investigated. Various reports have shown that consumption of camel milk by diabetes patients on a daily basis reduces blood sugar and glycosylated hemoglobin (HbA1C) levels and also reduces insulin requirements. Despite that these findings provide scientific evidences of anti-diabetic activities of camel milk, research is yet to be initiated with assurance for patients of diabetes and other metabolic disorders. This review summarizes the medicinal values of bioactive constituents of camel milk and reviews camel milk findings from the most significant preclinical studies in diabetes.

Knowledge and awareness of plantar fasciitis in the Saudi population.

OBJECTIVE: To evaluate and assess the knowledge and awareness level of lay people about plantar fasciitis (PF). METHODS: The cross-sectional study was conducted at a shopping mall in Riyadh, Saudi Arabia, from May to July 2017, and comprised random individuals busy shopping in the area. Data was collected through a self-administered questionnaire. , and was analysed using SPSS 22. . RESULTS: Of the 176 subjects, 101(57.4%) were females and 75(42.6%) were males. The age range was 18-55 years, and 153(87%) belonged to urban population. Overall, 60(34%) subjects had never heard of plantar fasciitis. Also, 148(84%) subjects thought that specialised medical shoes can be used as possible treatment for plantar fasciitis (p<0.001).Females had significantly higher knowledge regarding plantar fasciitis than males (p=0.009). CONCLUSIONS: Over 30% subjects did not have any knowledge about plantar fasciitis.

Quantitative organization of the excitatory synapses of the primate cerebellar nuclei: further evidence for a specialized architecture underlying the primate cerebellum.

The cerebellar intrinsic connectivity is of remarkable regularity with a similar build repeated many times over. However, several modifications of this basic circuitry occur that can provide important clues to evolutionary adaptations. We have observed differences in the wiring of the cerebellar output structures (the deep cerebellar nuclei, DCN) with higher dendritic length density in the phylogenetically newer DCN. In rats, we showed that an increase in wiring is associated with an increase in the presynaptic vesicular glutamate transporter 1 (vGluT1). In this study, we have extended our analysis to the rhesus monkey and can show similarities and differences between the two species. The similarities confirm a higher density in vGluT1+ boutons in the lateral (LN/dentate) and posterior interpositus nucleus compared to the phylogenetically older DCN. In general, we also observe a lower density of vGluT1 and 2+ boutons in the monkey, which however, yields a similar number of excitatory boutons per neuron in both species. The only exception is the vGlut1+ boutons in the macaque LN/dentate, which showed a significantly lower number of vGluT1+ boutons per neuron. We also detected a higher percentage of co-labelled vGluT1 and 2 boutons in the macaque than we found in the rat. In summary, these results confirm that the hyposcalled dendrites of the monkey LN/dentate also show a lower number of vGluT1+ boutons per neuron. These results provide further support of our model relating the dendritic morphology of the LN/dentate neurons to the morphology of the specially enlarged LN/dentate nucleus in primates.

Quality assurance of Cyberknife robotic stereotactic radiosurgery using an angularly independent silicon detector.

PURPOSE: The aim of this work was to evaluate the use of an angularly independent silicon detector (edgeless diodes) developed for dosimetry in megavoltage radiotherapy for Cyberknife in a phantom and for patient quality assurance (QA). METHOD: The characterization of the edgeless diodes has been performed on Cyberknife with fixed and IRIS collimators. The edgeless diode probes were tested in terms of basic QA parameters such as measurements of tissue-phantom ratio (TPR), output factor and off-axis ratio. The measurements were performed in both water and water-equivalent phantoms. In addition, three patient-specific plans have been delivered to a lung phantom with and without motion and dose measurements have been performed to verify the ability of the diodes to work as patient-specific QA devices. The data obtained by the edgeless diodes have been compared to PTW 60016, SN edge, PinPoint ionization chamber, Gafchromic EBT3 film, and treatment planning system (TPS). RESULTS: The TPR measurement performed by the edgeless diodes show agreement within 2.2% with data obtained with PTW 60016 diode for all the field sizes. Output factor agrees within 2.6% with that measured by SN EDGE diodes corrected for their field size dependence. The beam profiles' measurements of edgeless diodes match SN EDGE diodes with a measured full width half maximum (FWHM) within 2.3% and penumbra widths within 0.148 mm. Patient-specific QA measurements demonstrate an agreement within 4.72% in comparison with TPS. CONCLUSION: The edgeless diodes have been proved to be an excellent candidate for machine and patient QA for Cyberknife reproducing commercial dosimetry device measurements without need of angular dependence corrections. However, further investigation is required to evaluate the effect of their dose rate dependence on complex brain cancer dose verification.

Safety of Transcranial Direct Current Stimulation of Frontal, Parietal, and Cerebellar Regions in Fasting Healthy Adults.

(1) Background: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation modality that has been investigated in a large number of studies in terms of it is effects on brain function, safety of use, and future implications. The principal aim of this study was to investigate the safety of 1.5-mA tDCS of three brain areas, that is, frontal, partial, and cerebellar cortices, in fasting healthy individuals during the month of Ramadan. (2) Methods: In a single-blinded, sham-controlled study, we assessed the safety of a 20-min tDCS current (1.5 mA, 35 cm²) over the right frontal, parietal, and cerebellar cortex areas after 8 h of fasting in healthy right-handed adult subjects using a standard safety questionnaire. (3) Results: A total of 49 subjects completed the tDCS sessions and safety questionnaire. None of the sessions were stopped due to pain or discomfort during stimulation. Moreover, no subject experienced serious adverse events such as seizures or loss of consciousness. (4) Conclusions: There was no significant difference in the frequency or type of side effects between active and sham stimulation sessions. The tDCS protocol applied in this study was found to be safe in fasting healthy adults.

In vivo Diffusion Tensor Imaging, Diffusion Kurtosis Imaging, and Tractography of a Sciatic Nerve Injury Model in Rat at 9.4T.

Peripheral nerve injuries result in severe loss of sensory and motor functions in the afflicted limb. There is a lack of standardised models to non-invasively study degeneration, regeneration, and normalisation of neuronal microstructure in peripheral nerves. This study aimed to develop a non-invasive evaluation of peripheral nerve injuries, using diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and tractography on a rat model of sciatic nerve injury. 10 female Sprague Dawley rats were exposed to sciatic nerve neurotmesis and studied using a 9.4 T magnet, by performing DTI and DKI of the sciatic nerve before and 4 weeks after injury. The distal nerve stump showed a decrease in fractional anisotropy (FA), mean kurtosis (MK), axonal water fraction (AWF), and radial and axonal kurtosis (RK, AK) after injury. The proximal stump showed a significant decrease in axial diffusivity (AD) and increase of MK and AK as compared with the uninjured nerve. Both mean diffusivity (MD) and radial diffusivity (RD) increased in the distal stump after injury. Tractography visualised the sciatic nerve and the site of injury, as well as local variations of the diffusion parameters following injury. In summary, the described method detects changes both proximal and distal to the nerve injury.

Brain Training Games Enhance Cognitive Function in Healthy Subjects.

BACKGROUND Brain training games (BTG) are believed to play a major role in improving cognitive functions. The current study evaluated if BTG showed positive impact on attention and memory functions compared with baseline visit in healthy subjects. MATERIAL AND METHODS The study was carried out from October 2015 until April 2016 in the Department of Physiology, College of Medicine, King Saud University and in King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia. We enrolled 51 normal healthy subjects to use a computerized cognitive training game (Lumosity) for exercises that target a range of cognitive functions, including attention, processing speed, visual memory, and executive functions for about 15 min per day, at least 7 days per week, for 3 weeks. The control (n=21) group did not perform the training. Both groups took the CANTAB test before and 3 weeks after training for various cognitive functions (flexibility, memory, attention, speed, and problem solving). Serum samples were used to study the brain-derived growth factor (BDNF) and apolipoprotein (Apo) E (APOE) levels. RESULTS A significant improvement in Lumosity performance index was observed in the active group compared to the control group by the end of training (p-value 0.001). After the training, a statistically significant difference in most of the CANTAB measures, such as attention-switching task (AST), mean correct latency, AST switching cost, AST mean correct latency (congruent), AST mean correct latency (incongruent), AST mean correct latency (blocks 3 and 5) [non-switching blocks], AST mean correct latency (block 7) [switching block], and MOT mean correct latency (all P=0.000). However, in the control group, significant improvements were not observed. A positive correlation between pattern recognition memory (PRM) and APOE was found and people who had higher ApoE levels had faster response. CONCLUSIONS An improvement in different cognitive domains was noted, including attention and motor speed. However, this study warrants further research to determine the long-term effect on other cognitive functions and in different groups (e.g., elderly vs. adults).