Abstract: The use of light (photons) delivered clinically from laser or light-emitting diodes (LED), is referred to as photobiomodulation therapy (PBMt). Increasingly PBMt is accepted particularly in dental practice for pain or pre-emptive anaesthesia. Understanding its mechanism of effectiveness is the key to its increasing acceptance. Of major importance to this is how PBMt affects not only the neurons but also the Schwann cells and fibroblasts of the peripheral nervous system which are unique in morphology and function. The specific roles of the neuronal cells of the dorsal root and trigeminal ganglia, now include consideration of the axon initial segment responsible for the initiation of the action potential and the T junction from which the distal and proximal axons arise which are complex but central to normal function. This cellular complexity, organization and function is discussed leading to a review of the mechanism of effectiveness of PBMt demonstrated by clinical trials in both medicine and dentistry. This review provides evidence of the involvement of the cytoskeleton, mitochondrial organization particularly related to fast and slow axonal flow and mitochondrial membrane potential in response to light in somatosensory neurons and nerves.

Abstract:

Major depressive disorder (MDD) represents a heterogeneous condition lacking reliable neurobiological biomarkers and mechanistic understanding. Time-resolved characterisation of brain dynamics reveals that mental health is associated with a characteristic dynamical regime, exhibiting spontaneous switching between a repertoire of ghost attractor states forming resting-state networks. Analysing resting-state fMRI data from 848 MDD patients and 794 healthy controls across 17 sites in China (REST-meta-MDD) using Leading Eigenvector Dynamics Analysis (LEiDA), we found MDD patients exhibit significantly reduced default mode network (DMN) occupancy (p < 0.001; Hedges' g = −0.51) and increased occipito-parieto-temporal state occupancy (p < 0.001; Hedges' g = 0.42), suggesting compensatory dynamical rebalancing. These findings extend prior observations of disrupted DMN in MDD, aligning with the emerging dynamical systems framework for mental health to advance mechanistic understanding of MDD pathophysiology.

Abstract: Objectives: Addiction disorders remain a major challenge in contemporary psychiatry due to high relapse rates and significant individual and societal burden. Despite advances in addiction neurobiology, current diagnostic frameworks and dominant models offer limited tools for early risk identification and dynamic support of clinical decision-making across the course of treatment. The aim of this narrative review is to introduce the MAC/MAB–RCS model as an integrated conceptual framework for risk stratification and personalized intervention in addiction psychiatry. Methods: The proposed model integrates evidence from four complementary domains: genetic, epigenetic, and stress-axis biomarkers; functional brain network organization; and psychological /psychiatric dimensions relevant to addictive behaviors. These domains are synthesized into a unified conceptual structure designed to capture dynamic regulatory processes underlying addiction vulnerability. Results: At the core of the model lies the Regulatory Control State (RCS), defined as a dynamic construct reflecting an individual’s regulatory capacity via the integration of cognitive control, emotional regulation, and motivational drive modulation. Disruption of the RCS is conceptualized as a shared transdiagnostic mechanism driving craving escalation, compulsive behavior, and relapse vulnerability, independent of substance class or specific addictive behavior. Conclusions: The MAC/MAB–RCS model aligns with the principles of precision psychiatry by offering a pragmatic, clinically oriented translational framework with potential applicability across clinical settings, bridging neurobiological research and clinical practice. The review discusses its relationship to existing models, potential clinical and systemic applications, key limitations, and priorities for future validation studies.

Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder in which gut-brain interactions, enteric alpha-synuclein (αS) pathology, and neuroimmune signals contribute to nigrostriatal degeneration. Alongside the frequent occurrence of early gastrointestinal dysfunction, findings from enteric αS pathology and epidemiological studies support the existence of a gut-first subtype of PD. This article provides an integrated review of current evidence linking gastrointestinal and brain αS pathology, gut barrier dysfunction, inflammation, and microbial imbalance in PD. We discuss how these processes may interact through the microbiota-gut-brain axis to drive neurodegeneration, and explore emerging microbiome-based therapeutic strategies including fecal microbiota transplantation, rifaximin, and probiotic approaches. We also point out future research directions, including improved enteric αS imaging and longitudinal microbiome studies starting before PD diagnosis.

Abstract: Background: Fibromyalgia is a chronic disease that predominantly affects women and lasts over several months, causing problems both to individuals and society. While several studies have demonstrated the potential of electroacupuncture (EA) to alleviate fibromyalgia pain in mice, further research is needed to investigate its underlying mechanisms. Programmed cell death ligand-1 (PD-L1)/PD-1 was first identified to be involved in cancer immunotherapy, but its application to pain management has not been yet investigated. Methods: This study aimed to explore the mechanism underlying action of PD-L1 on PD-1 pathway in a mouse model of fibromyalgia. Results: We established such a mouse model using intermittent cold stress (ICS) and confirmed mechanical (D4: 2.02 ± 0.13 g, n = 9) and thermal (D4: 4.28 ± 0.21 s, n = 9) hyperalgesia. We found that EA, intracerebral ventricle (ICV) PD-L1 injection, or transient receptor potential vanilloid 1 (Trpv1) knockout effectively counteracted hyperalgesia. We observed low PD-1 expression in the cerebellum of fibromyalgia mice but increased expression of TRPV1 and pain-related kinases. These phenomena could be further reversed by EA, ICV PD-L1 injection, and Trpv1 knockout. To confirm that these effects were caused by PD-L1 release, we added PD-L1 neutralizing antibodies to the EA and PD-L1 treatment. The analgesic effects and EA and PD-L1 mechanisms were inhibited. Conclusions: Our results elucidate the role of the PD-L1/PD-1 pathway in EA treatment of fibromyalgia and reveal its potential value for fibromyalgia.

Abstract: Stroke has been a topic of extensive research due to its debilitating consequences and high mortality. New findings offer a deeper understanding of specific factors that affect post-stroke recovery and identify therapies that may facilitate this process. One such factor was microglia, neuronal immune cells that are highly reactive to cytokines in the neuroenvironment and can, in turn, affect the inflammatory cascades that originate after stroke, making them ideal candidates for immunomodulation in the brain. Many FDA-approved immunotherapies have been found to target distinct inflammatory signaling molecules and responders, including IL-6 inhibitors, IL-13 inhibitors, IL-12/IL-23 inhibitors, B-cell modulators, Type I interferon inhibitors, CAR T-cell therapy, Calcineurin inhibitors, Complement inhibitors, and JAK-STAT pathway inhibitors. The FDA-approved immunotherapies discussed in this review demonstrate potential in modulating the immune response after stroke by targeting key inflammatory pathways involved in secondary brain injury. Future research should focus on defining optimal therapeutic windows, identifying suitable patient populations, determining the most appropriate timing of therapy, and targeting specific immune mechanisms to balance the attenuation of harmful inflammation with the preservation of reparative processes.

Abstract: Background: Autism spectrum disorder (ASD) affects approximately 1-2% of children worldwide, yet its etiology remains incompletely understood. Emerging evidence suggests that offspring of parents with autoimmune diseases show elevated autism prevalence. Notably, children of parents with psoriasis (OR 1.59), type 1 diabetes (OR 1.49-2.36), and rheumatoid arthritis (OR 1.51) demonstrate particularly strong associations.Hypothesis: I propose that autism is fundamentally an immune-metabolic disorder characterized by TNF-α-mediated mitochondrial dysfunction leading to cerebral energy deficiency. This energy deficit impairs three critical processes: (1) synaptic pruning during neurodevelopment, (2) real-time social cognition including gaze processing and emotion recognition, and (3) protein synthesis of critical synaptic scaffolding molecules. The primary mechanism involves TNF-α pathway dysregulation—through genetic inheritance from parents with autoimmune diseases such as psoriasis, type 1 diabetes, and rheumatoid arthritis, and/or through direct fetal exposure to elevated maternal TNF-α during pregnancy. I further propose that the well-documented "firstborn effect" in autism reflects maternal immune maladaptation during primigravid pregnancies. Additionally, for cases without parental autoimmune history, I propose a speculative secondary mechanism: mitonuclear immune conflict, where paternal immune genes may partially recognize maternal mitochondria as non-self, generating endogenous TNF-α. Implications: This hypothesis unifies disparate observations about autism pathophysiology and suggests that anti-inflammatory interventions targeting the TNF-α pathway may have therapeutic potential, particularly when administered early in neurodevelopment.

Abstract: The vaginal microbiome plays a crucial role in protecting its host from bacterial, viral, and fungal pathogens and serves as a first line of immune system defense for the lower reproductive tract. The composition of the microbiome is relatively understudied despite its integral role in women’s reproductive health. Maintenance of the correct abundances of bacteria can help prevent many different infections. Additionally, the microbiota also serve to initiate and support the immune system of a newborn in the case of vaginal birth. The introduction of these organisms can mediate many interactions in the developing brain and nervous system of the infant (Günther, V. et al. 2022). Similarly, research on biological causes of sexual orientation is a new field that severely lacks extensive research. There are a few theories related to the development of homosexuality that have been backed by research. Synthesizing what we know from previous research on these two fields, we aim to bridge the gap between these two areas of study by postulating a relationship between the composition of the female vaginal microbiome during pregnancy and the fraternal birth order effect leading to male homosexuality. We propose that during pregnancy, changes in the maternal vaginal microbiome result in a change in the vaginal microbiome that makes them more susceptible to the development of anti-NLGN4Y antibodies responsible for the immune attack on the Y-linked NLGN4Y protein responsible for male brain development (Bogaert, A. et al. 2017), specifically in the anterior hypothalamus. We propose that mothers who have already given birth to males are especially susceptible to this antibody development, providing a possible explanation for the Fraternal Birth Order effect.

Abstract: IQSEC2 (IQ motif and SEC7 domain-containing protein 2) is a rare X-linked genetic disorder associated with intellectual disability, epilepsy, and synaptic dysfunction. No targeted pharmacological treatments are currently available. IQSEC2 functions as a guanine nucleotide exchange factor (GEF) regulating ADP-ribosylation factors (ARFs), particularly ARF6, a key regulator of synaptic vesicle trafficking and neuronal signaling. In this study, we performed in silico molecular docking to evaluate the binding potential of two natural compounds, Polydatin and Amentoflavone, against ARF isoforms (ARF1–ARF6), IQSEC2, IQSEC1, and Ras-related Rab/Ras GTPases. Polydatin demonstrated strong binding affinity to ARF6 (−9.1 kcal/mol) and favorable interactions with IQSEC2 (−7.6 kcal/mol) and IQSEC1 (−7.6 kcal/mol). Amentoflavone exhibited even stronger binding to multiple ARFs and IQSEC proteins, with particularly high affinity for ARF3 (−9.7 kcal/mol) and IQSEC2 (−9.5 kcal/mol). Polydatin also showed significant interactions with Rab and Ras family proteins, including Rab-4A, Rab-5A, Rab-6B, Rab-18, Rab-31, and HRas (−9.6 to −10.5 kcal/mol), suggesting network-level modulation.These findings indicate that both Polydatin and Amentoflavone are computationally plausible probes for experimental studies on IQSEC2 dysfunction, with potential to modulate the IQSEC2–ARF6 axis and associated GTPase signaling. These results remain predictive and require in vitro and in vivo validation, but they provide a strong rationale for prioritizing these natural compounds in IQSEC2-related research. Future studies should include cell-based ARF6/IQSEC2 assays.

Abstract: Precise quantification of fine motor behavior is essential for understanding neural circuit function and evaluating therapeutic interventions in neurological disorders. While markerless pose estimation frameworks such as DeepLabCut (DLC) have transformed behavioral phenotyping, the choice of convolutional neural network (CNN) backbone significantly impacts tracking performance, particularly for tasks involving small distal joints and partial occlusions. in this paper, we present the first systematic comparison of nine CNN architectures implemented in DLC for lateral-view analysis of fine reaching movements in the Montoya Staircase test, a gold standard assay for skilled forelimb co-ordination in rodent models of stroke and neurodegenerative disease. Using a dataset of videos representing both control and M1-lesioned conditions, we rigorously evaluated models across six critical dimensions: spatial accuracy (RMSE, PCK@5px), mean average precision (mAP), occlusion robustness, inference speed and GPU memory usage. Our results reveal that multi-scale DLCRNet architectures substantially outperformed classical backbones, with DLCRNet_ms5 achieving the highest overall accuracy and DLCRNet_stride16_ms5 providing the best trade-off between precision and computational efficiency. These findings provide critical methodological guidance for neuroscience la-boratories and highlight the importance of architecture selection for rigorous quantification of fine motor behavior in preclinical research.

Abstract: Spinal cord regeneration requires a transformative strategy capable of rewriting inhibitory genetic programs while orchestrating real-time electrical communication with regenerating neural tissues. Recent advancements in precision CRISPR genome editing effectively silence or activate crucial molecular gatekeepers such as PTEN, SOCS3, and various epigenetic repressors, thereby reactivating dormant intrinsic regenerative pathways and enabling robust axonal growth. Concurrently, cutting-edge bioelectronic technologies utilizing piezoelectric, triboelectric, and magnetoelectric scaffolds have emerged, adeptly harnessing the body's inherent biomechanical energy. These innovative materials convert subtle physiological micromotions into finely tuned electrical stimuli, precisely guiding neuronal regeneration without external power sources, addressing limitations associated with traditional implants such as infection risks and mechanical incompatibility.Integrating these genetic modifications with bioelectric innovations creates a potent synergy. Genome-level reprogramming amplifies neuronal responsiveness to bioelectrical signals, markedly enhancing axonal regeneration. Simultaneously, autonomous electrical stimulation sustains and stabilizes cellular, metabolic, and synaptic improvements induced by genomic interventions, forming a closed-loop, self-sustaining therapeutic platform. This advanced system significantly transcends conventional transient recovery approaches, moving toward durable, personalized outcomes. Such convergence of advanced genetic engineering and intelligent biomaterial design represents a groundbreaking shift in regenerative neurology.Despite promising preclinical outcomes, significant translational challenges remain. Critical hurdles include ensuring precise delivery of CRISPR tools, mitigating off-target genomic effects, enhancing biocompatibility and scaffold stability, and navigating rigorous regulatory pathways. Addressing these challenges necessitates integrating next-generation gene-editing technologies, comprehensive genomic surveillance, advanced biomaterial sciences, and meticulous preclinical evaluations. Future directions in spinal cord injury research encompass multiplex genome editing, AI-driven scaffold optimization via digital twins, and tailored immune-evasive biomaterials. Collectively, this innovative approach has the potential to redefine regenerative medicine's boundaries, offering unprecedented hope for sustained, personalized recovery and dramatically improving quality of life for individuals affected by spinal cord injuries.

Abstract: Neural oscillations are fundamental to the integration of sensory, affective, and cognitive processes that contribute to pain perception. Transcranial alternating current stimulation (tACS) provides a valuable tool for investigating and modulating these oscillatory dynamics. In this review, we examine the effects of tACS on pain perception and pain-related oscillations in both healthy participants and individuals with chronic pain, highlighting methodological variability and mechanistic uncertainties that may contribute to mixed findings. We identified 14 studies, including 9 studies of experimental pain in healthy individuals and 5 of clinical pain disorders, comparing tACS to sham. Somatosensory alpha was the most frequently targeted oscillatory feature. Results varied considerably. Several studies reported reductions in pain, increases in alpha power, or changes in sensorimotor and prefrontal connectivity, but others showed no meaningful neural or behavioral effects. Out of the 14 studies, 6 demonstrated analgesic benefits and 2 showed improvements only under specific conditions or within subgroups, for a total of 8/14 studies with positive findings. Possible sources of heterogeneity include variation in stimulation duration, electrode montage, frequency alignment with individual rhythms, contextual state, and anatomical and neurophysiological differences across individuals. Pre-registered studies with sufficient power are needed to replicate effects within the most promising intervention protocols to establish a foundation in the field. We also recommend inclusion of brain imaging or electrophysiological recordings to verify whether stimulation effectively modulates the targeted neural oscillations. Finally, recent methodological advances, including phase-specific tACS, amplitude-modulated tACS, and individualized electric-field modeling, offer new opportunities to enhance mechanistic precision and clinical applicability. We argue that by integrating these approaches, future research can move beyond fixed, one-size-fits-all protocols, toward personalized, state-dependent, closed-loop tACS approaches. Exploring these frontiers will transform tACS from an exploratory tool into a reliable intervention for pain.

Abstract: The human connectome displays nontrivial large-scale organization despite being assembled through decentralized, local biological processes. Most generative models reproduce selected connectomic features by invoking global optimization principles, predefined wiring targets or developmental templates. This leaves unresolved which properties of the connectome are genuine consequences of local interactions and which require additional mechanisms operating beyond local scales. We introduce a simulation framework conceptually aligned with recent theoretical results showing that global coherence can arise from local compatibility alone. Networks are generated exclusively through local constraints: nodes interact within bounded spatial neighborhoods, edge formation is probabilistic and local, and incompatible configurations are suppressed without reference to any global objective, target topology, or long-range coordination. Ensembles of simulated networks are compared with empirically reported human connectome descriptors using quantitative statistics and qualitative structural criteria. Several mesoscopic properties, including high clustering, modular organization, motif enrichment and short-range wiring bias, emerge robustly under local interaction rules and compatibility. In contrast, other features such as absolute connectivity scale, rich-club organization and long-range hub-to-hub coupling, systematically diverge from empirical values. Unlike optimization-based or template-driven models, our framework does not aim to reproduce the full connectome. Instead, it identifies which properties are structurally implied by locality and which remain underdetermined, providing a complementary explanatory perspective. Our results support a principled classification of connectome properties according to their dependence on local compatibility constraints, clarifying the explanatory scope and limits of decentralized network formation, and suggesting several directions for further work.

Abstract: Frontotemporal lobar degeneration (FTD) is a proteinopathy that induces neuroinflammation and neurodegeneration; Alzheimer´s disease (AD) is characterized by Abeta-42 deposits, microglia overactivation, astroglial alterations and p-Tau accumulation. Identification of neuroinflammatory mediators as predictors of cognitive cognition have gained attention. We compared several biomarkers in plasma as predictors of cognitive impairment between AD and FTD patients (Nfl, p-Tau217, TDP-43 and CX3CR1 and soluble fractalkine levels) by ELISA (pg/ml) and age-matched controls (without cognitive impairment) or HIV-1 seropositive patients. To our knowledge, this is the first study showing that increased plasma CX3CR1 and soluble fractalkine predict cognitive impairment specifically in FTD. In addition, high plasma p-Tau 271 levels correlate with sFK levels and their mini mental scores in FTD. Thus, fractalkine and TDP-43 are exclusive biomarkers of cognitive impairment in FTD. However, Nfl, GFAP and p-Tau271 levels did not differ between AD or FTD patients. Anatomically, we observed hippocampal involution as well as Tau deposits in human FTD postmortem brains. On the other hand, neuroinflammation contributes to dementia; and chemokines as HIV-1 co-receptors facilitate spread of HIV-1 infection inducing apoptosis in the brain. On the other hand, chemokines promote neuronal survival and regulate neuron-glia interactions. Fractalkine is a delta chemokine (also termed CX3CL1), that binds to its CX3CR1 chemokine receptor, that as a membrane-isoform can be released as a soluble form by damaged neurons. We confirmed that fractalkine prevents LPS (an inflammation inductor)-induced apoptosis by decreasing caspase-3 activation in cortical neurons at 7 DIV LPS exposure. Thus, fractalkine may play a dual role: it is associated with cognitive impairment in both FTD and AD, yet it also exerts neuroprotective effects by reducing LPS-induced neuronal apoptosis at 7 DIV.

Abstract: Decision-making relies on coordinated neural dynamics that integrate sensory evidence with top-down control. In this EEG study, we examined sensor (scalp) -level theta and alpha-band oscillations, as well as fronto-parietal network connectivity, during a tactile spatial discrimination task. Blindfolded participants judged the lateral offset of the central dot of a three-dot array delivered to the right index finger while EEG was recorded. Time–frequency analyses revealed that both theta and alpha power were greater for correct than incorrect decision trials during pre-stimulus and post-stimulus intervals, suggesting enhanced preparatory and mnemonic engagement during accurate decisions. Directional connectivity assessed using block (multivariate) Granger causality demonstrated significantly stronger frontal to parietal influence in the theta band during both pre- and post-stimulus periods for correct decisions, supporting the role for long-range theta communication for top-down control in guiding tactile judgment. These findings highlight theta-band fronto-parietal communication as a key mechanism supporting successful tactile decision-making.

Abstract: Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early‐onset epileptic encephalopathy and metabolic brain dysfunction, yet its devel-opmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal–postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed WGCNA built on biweight midcor-relation placed SLC13A5 in a large module. The module eigengene tracked brain mat-uration (Spearman ρ = 0.802, P = 8.62×10⁻⁶) and closely matched SLC13A5 abundance (ρ = 0.884, P = 2.73×10⁻⁶), with a significant partial association after adjusting for developmental rank (ρ = 0.672, P = 6.17×10⁻⁴). Functional enrichment converged on oxidative phos-phorylation and mitochondria. A force-directed subnetwork of the top intramodular members (|bicor| > 0.6) positioned SLC13A5 adjacent to a densely connected nucleus including CYP46A1, ITM2B, NRGN, GABRD, FBXO2, CHCHD10, CYSTM1, and MFSD4A. Conclusions: Together, these results define a developmentally tuned, mito-chondria-centered program that co-varies with SLC13A5 in the human brain across the lifespan. It may provide insights to interrogate age-dependent phenotypes and therapeutic avenues for disorders involving citrate metabolism.

Abstract:

(1) Background: Electroencephalography (EEG) is widely used to monitor the depth of anesthesia; however, conventional Fourier-based analyses are limited in their ability to characterize non-stationary anesthetic-induced EEG dynamics. In this study, we investigated the utility of singular spectrum analysis (SSA) combined with the Hilbert transform for extracting physiologically meaningful EEG features during sevoflurane general anesthesia. (2) Methods: Frontal EEG data from ten patients undergoing sevoflurane anesthesia were analyzed from the maintenance phase through emergence. Using SSA, short EEG segments were decomposed into six intrinsic mode functions (IMFs) without pre-specified basis functions or frequency bands. Hilbert spectral analysis was applied to each IMF to obtain instantaneous frequency and amplitude characteristics. (3) Results: The SSA-based decomposition clearly captured phase-dependent EEG changes, including α spindle activity during maintenance and increasing high-frequency components preceding emergence. Multiple linear regression models incorporating IMF center frequencies and total power demonstrated strong correlations with the bispectral index (BIS), achieving high predictive accuracy (R² = 0.88, MAE < 4). Compared with conventional spectral approaches, SSA provided superior temporal resolution and stable feature extraction for non-stationary EEG signals. (4) Conclusions: These findings indicate that SSA combined with Hilbert analysis is a robust framework for quantitative EEG analysis during general anesthesia and may enhance real-time, individualized assessments of anesthetic depth.

Abstract: Damage to the chorda tympani (CT) nerve through trauma or experimental nerve axotomy results in the degeneration of anterior taste buds and taste loss. Our previous work demonstrated that Il1r signaling is required for taste bud regeneration and the recovery of taste function. However, the effects of experimental axotomy on immune responses in the absence of Il1r signaling remain unclear. To test this, we performed unilateral CT sectioning in Il1r KO or wild-type mice as previously described. We found that CD45+ immune cells, CD68+ and CD206+ M2-like macrophages are significantly increased near anterior taste buds at day two post-injury in wild-type but not Il1r KO mice. By day 5, these macrophage responses were slightly elevated in wild-type mice but remained at baseline levels in KO mice, indicating that immune responses to injury were suppressed rather than delayed in the absence of Il1r signaling. However, taste buds degenerated at similar time points in both strains. These results suggest that delayed taste bud degeneration in Il1r KO mice is not the primary reason for later functional deficits, though suppressed immune response may have other consequences in the injured peripheral taste system.

Abstract: (1) Background: We developed a novel technology that regulates human locomotion using transcutaneous electrical spinal cord stimulation to activate spinal locomotor networks and posterior root stimulation to activate leg flexor and extensor motor pools during swing and stance phases, respectively. This technology effectively restores walking in post-stroke individuals while forward propulsion in the stance phase and foot dorsiflexion in the swing phase are insufficient. In this study the effectiveness of regulating the stance and swing phases while walking healthy volunteers on the treadmill with transcutaneous electrical stimulation of the posterior roots, leg muscles, and their combined effects has been examined. (2) Methods: We analyzed the kinematic characteristics of stepping movements in healthy participants with spinal stimulation of the posterior roots and flexor/extensor leg muscles. (3) Results: Our findings clearly show that posterior root stimulation at T12 combined with the tibialis anterior muscle stimulation during the swing phase effectively regulates foot dorsiflexion, whereas posterior root stimulation at L2 combined with the hamstrings and medial gastrocnemius stimulation during the stance phase effectively regulates forward propulsion. (4) Conclusions: Combined stimulation in the stance and swing phases within same gait cycle resulted in the most coordinated stepping, and effective control of forward propulsion and foot dorsiflexion.

Abstract:

Background: There is a critical need for effective therapeutics for Alzheimer’s disease. However, the majority of previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, a personalized, precision medicine approach, with increased data set size to include the potential contributors to cognitive decline for each patient, and treatment of the identified potential contributors, has emerged as a potentially more effective strategy. Recent proof-of-concept trials have provided clinical data that support this approach. Objective: To determine whether a precision medicine approach to Alzheimer’s disease at the mild cognitive impairment or early dementia stage is effective in a randomized controlled clinical trial. Methods: Seventy-three patients with mild cognitive impairment or early dementia, with Montreal Cognitive Assessment (MoCA) scores of 18 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, immune dysfunction, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Genetic and epigenetic evaluations were included, as well as Alzheimer’s-associated biomarkers. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Participants were randomly assigned to either a personalized, precision medicine protocol or standard of care treatment. Cognition and clinical symptoms were assessed at 0, 3, 6, and 9 months. Results: Relative to the standard of care protocol, statistically significant incremental effects of the precision medicine protocol were observed for broad neurocognitive functioning, composite memory (verbal plus visual), executive function, processing speed, cognitive symptom severity, and Alzheimer’s disease symptom severity. Furthermore, overall health was enhanced, with improvements in blood pressure, body mass index, glycemic index, lipid profiles, and methylation status. The treatment effect size for overall cognitive function was calculated to be greater than previously published clinical trials, seven times the effect size of the lecanemab trial and four times the effect size of the donanemab trial. Conclusion: A personalized, precision medicine approach represents an effective treatment for patients with mild cognitive impairment or early-stage dementia due to Alzheimer’s disease. In most cases, this treatment leads to cognitive improvement rather than simply retarding decline, and it does so without significant negative side effects such as brain edema, microhemorrhage, or atrophy.