Motor, Cognitive, and Behavioral Impairment in TLR3 and TLR9 Deficient Male Mice: Insights into the Non-Immunological Roles of Toll-Like Receptors.

BACKGROUND: Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to infection or injury. Recent studies have uncovered their intriguing functions as moonlighting proteins involved in various biological processes, including development, learning, and memory. However, the specific functions of individual TLRs are still largely unknown. AIMS: We investigated the effects of TLR3 and TLR9 receptor deficiency on motor, cognitive, and behavioral functions during development using genetically modified male mice of different ages. METHODS: We evaluated the motor coordination, anxiety-like behavior, spatial learning, and working memory of male mice lacking the TLR3 and TLR9 genes at different ages (two, four, six, and eight months) using the rotarod, open field, water maze, and T-maze tests. RESULTS: We observed that the deletion of either TLR3 or TLR9 resulted in impaired motor performance. Furthermore, young TLR3-deficient mice exhibited reduced anxiety-like behavior and spatial learning deficits; however, their working memory was unaffected. In contrast, young TLR9-knockout mice showed hyperactivity and a tendency toward decreased working memory. CONCLUSIONS: These findings provide valuable insights into the broader roles of the TLR system beyond the innate immune response, revealing its involvement in pathways associated with the central nervous system. Importantly, our results establish a strong association between the endosomal receptors TLR3 and TLR9 and the performance of motor, cognitive, and behavioral tasks that change over time. This study contributes to the growing body of research on the multifaceted functions of TLRs and enhances our understanding of their participation in non-immune-related processes.

Effect of Propranolol on Motor Cortex Excitability in Essential Tremor: An Exploratory Study.

Background: Essential tremor, the world's most prevalent movement disorder, lacks a clear understanding of its pathophysiology. Propranolol, a non-specific beta-blocker capable of crossing the blood-brain barrier, is a primary choice for essential tremor treatment. While its tremor-reducing effects are generally attributed to peripheral actions, various uses hint at central adrenergic effects. Nevertheless, propranolol's precise impact on the central nervous system in essential tremor subjects remains unexplored. Methods: In this study, we employed transcranial magnetic stimulation to assess the influence of propranolol on the excitability of the primary motor cortex (M1) in patients with essential tremor, compared to an age- and sex-matched control group. Cortical excitability parameters were measured following placebo and propranolol administration, encompassing resting and active motor thresholds, motor evoked potential characteristics, cortical silent period, and the input/output curve. Results: Distinct effects were observed across the two cortical hemispheres. Essential tremor patients displayed inhibition of the left M1 cortex and heightened excitability in the right M1 cortex four hours after propranolol administration, but not following placebo. Conclusions: These findings suggest potential differential noradrenergic excitatory and inhibitory modulation. However, comprehensive understanding necessitates further investigations, including left-handed participants and more diverse essential tremor subpopulations. This study underscores the need for continued exploration to unravel propranolol's complex effects on motor cortex excitability in essential tremor.

A comprehensive guide to BCI-based stroke neurorehabilitation interventions.

Brain-Computer Interfaces (BCIs) offer the potential to facilitate neurorehabilitation in stroke patients by decoding user intentions from the central nervous system, thereby enabling control over external devices. Despite their promise, the diverse range of intervention parameters and technical challenges in clinical settings have hindered the accumulation of substantial evidence supporting the efficacy and effectiveness of BCIs in stroke rehabilitation. This article introduces a practical guide designed to navigate through these challenges in conducting BCI interventions for stroke rehabilitation. Applicable regardless of infrastructure and study design limitations, this guide acts as a comprehensive reference for executing BCI-based stroke interventions. Furthermore, it encapsulates insights gleaned from administering hundreds of BCI rehabilitation sessions to stroke patients.•Presents a comprehensive methodology for implementing BCI-based upper extremity therapy in stroke patients.•Provides detailed guidance on the number of sessions, trials, as well as the necessary hardware and software for effective intervention.

Methodological approach for assessing motor cortical excitability changes with single-pulse transcranial magnetic stimulation.

Transcranial Magnetic Stimulation (TMS) serves as a crucial tool in evaluating motor cortex excitability by applying short magnetic pulses to the skull, inducing neuron depolarization in the cerebral cortex through electromagnetic induction. This technique leads to the activation of specific skeletal muscles recorded as Motor-Evoked Potentials (MEPs) through electromyography. Although various methodologies assess cortical excitability with TMS, measuring MEP amplitudes offers a straightforward approach, especially when comparing excitability states pre- and post-interventions designed to alter cortical excitability. Despite TMS's widespread use, the absence of a standardized procedure for such measurements in existing literature hinders the comparison of results across different studies. This paper proposes a standardized procedure for assessing changes in motor cortical excitability using single-pulse TMS pre- and post-intervention. The recommended approach utilizes an intensity equating to half of the MEP's maximum amplitude, thereby ensuring equal likelihood of amplitude increase or decrease, providing a consistent basis for future studies and facilitating meaningful comparisons of results.•A method for assessing changes in motor cortical excitability using single-pulse TMS before and after a specified intervention.•We recommend using an intensity equal to half of the MEP's maximum amplitude during evaluations to objectively assess motor cortical excitability changes post-intervention.

Remote Assessment of Parkinson's Disease Patients Amidst the COVID-19 Lockdown in Mexico.

The COVID-19 pandemic introduced unprecedented challenges in managing patients with Parkinson's disease (PD) due to disruptions in healthcare services and the need for social distancing. Understanding the effects of COVID-19 on PD symptoms is crucial for optimizing patient care. We conducted a comprehensive analysis of the data obtained during the period of COVID-19 lockdown, comparing it with analogous timeframes in 2018 and 2019. Our objective was to examine the influence of this unique circumstance on both motor and non-motor symptoms in patients with PD. Telemedicine was employed to assess symptoms using the Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Our findings revealed a notable worsening of symptoms, evidenced by a significant increase in the total MDS-UPDRS score. Specifically, there was an increase in Part III scores, reflecting changes in motor function. However, no differences were observed in Parts I or II, which pertain to non-motor symptoms. Additionally, patient satisfaction and the feasibility of telemedicine consultations were high, highlighting the efficacy of this alternative approach during the pandemic. The COVID-19 pandemic had a discernible impact on PD symptoms, with a significant worsening of motor symptoms observed during the lockdown period. Telemedicine was a valuable tool for remote assessment and follow-up, ensuring continuity of care for individuals with PD in the face of pandemic-related challenges.

A case report: Upper limb recovery from stroke related to SARS-CoV-2 infection during an intervention with a brain-computer interface.

COVID-19 may increase the risk of acute ischemic stroke that can cause a loss of upper limb function, even in patients with low risk factors. However, only individual cases have been reported assessing different degrees of hospitalization outcomes. Therefore, outpatient recovery profiles during rehabilitation interventions are needed to better understand neuroplasticity mechanisms required for upper limb motor recovery. Here, we report the progression of physiological and clinical outcomes during upper limb rehabilitation of a 41-year-old patient, without any stroke risk factors, which presented a stroke on the same day as being diagnosed with COVID-19. The patient, who presented hemiparesis with incomplete motor recovery after conventional treatment, participated in a clinical trial consisting of an experimental brain-computer interface (BCI) therapy focused on upper limb rehabilitation during the chronic stage of stroke. Clinical and physiological features were measured throughout the intervention, including the Fugl-Meyer Assessment for the Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), the Modified Ashworth Scale (MAS), corticospinal excitability using transcranial magnetic stimulation, cortical activity with electroencephalography, and upper limb strength. After the intervention, the patient gained 8 points and 24 points of FMA-UE and ARAT, respectively, along with a reduction of one point of MAS. In addition, grip and pinch strength doubled. Corticospinal excitability of the affected hemisphere increased while it decreased in the unaffected hemisphere. Moreover, cortical activity became more pronounced in the affected hemisphere during movement intention of the paralyzed hand. Recovery was higher compared to that reported in other BCI interventions in stroke and was due to a reengagement of the primary motor cortex of the affected hemisphere during hand motor control. This suggests that patients with stroke related to COVID-19 may benefit from a BCI intervention and highlights the possibility of a significant recovery in these patients, even in the chronic stage of stroke.

Automatic selection and feature extraction of motor-evoked potentials by transcranial magnetic stimulation in stroke patients.

Transcranial magnetic stimulation (TMS) allows the assessment of stroke patients' cortical excitability and corticospinal tract integrity, which provide information regarding motor function recovery. However, the extraction of features from motor-evoked potentials (MEP) elicited by TMS, such as amplitude and latency, is performed manually, increasing variability due to observer-dependent subjectivity. Therefore, an automatic methodology could improve MEP analysis, especially in stroke, which increases the difficulty of manual MEP measurements due to brain lesions. A methodology based on time-frequency features of stroke patients' MEPs that allows to automatically select and extract MEP amplitude and latency is proposed. The method was validated using manual measurements, performed by three experts, computed from patients' affected and unaffected hemispheres. Results showed a coincidence of 58.3 to 80% between automatic and manual MEP selection. There were no significant differences between the amplitudes and latencies computed by two of the experts with those obtained with the automatic method, for most comparisons. The median relative error of amplitudes and latencies computed by the automatic method was 5% and 23%, respectively. Therefore, the proposed method has the potential to reduce processing time and improve the computation of MEP features, by eliminating observer-dependent variability due to the subjectivity of manual measurements.

Simple and portable low frequency lock-in amplifier designed for photoacoustic measurements and its application to thermal effusivity determination in liquids.

The lock-in amplifier is a very useful instrument for observing very small signals under adverse signal-to-noise conditions. In this work, we describe a simple and portable lock-in amplifier designed to be used in photoacoustic measurements. The device was used to measure the thermal effusivity of eight different liquid samples (distilled water, glycerol, acetone, ethanol, 2-propanol, chloroform, hexane, and methanol), as well as the effusivity of acetone in aqueous solution at distinct concentrations, giving good results. The instrument has a bandwidth of 10 Hz-10 kHz and a sensitivity of 1 µV.

Depletion of Hypocretin/Orexin Neurons Increases Cell Proliferation in the Adult Subventricular Zone.

BACKGROUND & OBJECTIVE: Adult neurogenesis, a specific form of brain plasticity in mammals that occurs in the subventricular zone, is subject to complex regulation. Hypocretin/orexin neurons are implicated in the regulation of sleep and arousal states, among other functions. Here we report for the first time the presence of orexinergic projections within the adult rat subventricular zone. Post-mortem retrograde tracing combined with immunofluorescence indicated orexinergic projections toward the subventricular zone. To establish the relationship between the depletion of orexin neurons and the number of proliferating cells in the subventricular zone, we labeled mitotic cells. Histological analysis revealed proliferating cells to be in close contact with orexinergic fibers. Neurotoxinlesioning of orexin neurons in the lateral hypothalamus significantly activated precursor cell proliferation in the subventricular zone. Furthermore, cell proliferation in both normal and lesioned animals failed to reveal newly born orexin neurons in the lateral hypothalamus. CONCLUSION: Based on these findings, we suggest that the adult subventricular zone is affected by orexinergic signaling, the functional implication of which must be further elucidated.

Interaction and cytotoxic effects of hydrophobized chitosan nanoparticles on MDA-MB-231, HeLa and Arpe-19 cell lines.

In this work, we investigate the effect of chitosan hydrophobization on the internalization and cytotoxic effect of chitosan-based nanoparticles (NPs) on breast cancer cells (MDA-MB-231), cervical cancer cells (HeLa) and noncancer cells (Arpe-19). We also analyzed the interaction of NPs with a phospholipid (DPPC) membrane model at the airwater interface. An alkylation procedure to insert 8 carbon chains along the chitosan macromolecule with final 10 and 30 % substitution degrees was used. Nuclear magnetic resonance (NMR) and infrared spectroscopes (IR) were used to evaluate the success and extent of the hydrophobization procedure. Size, shape, and charge of NPs were evaluated by dynamic light scattering (DLS), atomic force microscope (AFM), and zeta potential, respectively. The effect of hydrophobicity on NPs was the reduction of the NPs average size, the formation of slightly elongated structures and the enhancing of the interaction of NPs with a DPPC monolayer at the air-water interface. By using fluorescence images on fluorescein-chitosan NPs, we observed a higher internalization of hydrophobic chitosan NPs in cancer cells in comparison with a low internalization of these NPs in normal cells. Even when non modified chitosan NPs were highly internalized in all cell lines, hydrophobized chitosan NPs showed a significantly higher cytotoxic effect on cancer cells in comparison with a lower effect showed by non-modified chitosan NPs on these cells. The cytotoxic effect on the normal cell line used was low for native chitosan NPs and negligible for hydrophobized chitosan NPs.