Search Results (3,112)

Adult neurogenesis, the process of generating new, functional neurons in the mature central nervous system, represents a key mechanism of brain plasticity and a potential source of regeneration. This process occurs primarily within specialised neurogenic niches: the subgranular zone of the hippocampal dentate gyrus (SGZ) and the subependymal zone (SEZ). It is regulated by a complex network of endogenous factors (e.g., hormones, neurotrophins, growth factors) and exogenous factors (environment, stress, diet, physical activity). Impairments in neurogenesis are linked to the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In their course, chronic inflammation, mitochondrial dysfunction, oxidative stress, and the accumulation of pathological proteins (β-amyloid, Tau protein, α-synuclein) create a microenvironment that inhibits the proliferation, differentiation, and survival of new neurons. This results in the exacerbation of cognitive and memory deficits. A review of the literature indicates that modulating neurogenesis through non-pharmacological interventions (e.g., a diet rich in anti-inflammatory compounds, physical exercise) and targeted therapeutic strategies represents a promising, albeit complex, research avenue. The primary challenge remains not only stimulating neuron generation but also ensuring their proper maturation, survival, and functional integration into existing neuronal circuits. A deeper understanding of the molecular and environmental mechanisms regulating adult neurogenesis may open new therapeutic possibilities for slowing the progression of neurodegenerative diseases. Full article

Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by progressive motor and non-motor manifestations, including early gastrointestinal dysfunction. Growing evidence implicates the gut microbiota as an active modulator of host immune tone and neurodegenerative vulnerability, extending beyond descriptive taxonomic associations toward functional and metabolic mechanisms. PD-associated dysbiosis is consistently characterized by altered microbial functional capacity, including reduced short-chain fatty acid (SCFA) production, enrichment of pro-inflammatory metabolic traits, and sustained immune stimulation at the intestinal interface. These shifts promote chronic low-grade inflammation and intestinal barrier perturbations, creating conditions that may facilitate abnormal α-synuclein aggregation within the enteric nervous system. Current management predominantly relies on dopaminergic replacement and related symptomatic strategies, such as levodopa combinations, dopamine agonists, monoamine oxidase-B and catechol-O-methyltransferase (COMT) inhibitors, and device-aided therapies, which alleviate symptoms but do not halt underlying neurodegeneration or modify long-term disease course. These therapeutic limitations have intensified interest in upstream mechanisms that might be amenable to disease-modifying interventions, particularly those arising at the level of the gut microbiota and gut–immune–brain axis. This narrative review integrates clinical, metagenomic, metabolomic, and mechanistic evidence to propose a unified model in which microbiota-driven immune and metabolic perturbations may act as upstream drivers converging on α-synuclein pathology, neuroinflammation, and neurovascular dysfunction. Full article

Background: Aging-related cognitive decline is closely associated with microglial senescence and the resulting chronic neuroinflammation. Emerging evidence identifies the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway as a pivotal innate immune signaling pathway linking DNA damage to cellular senescence and the senescence-associated secretory phenotype (SASP), particularly in microglia. Targeting the formation or selective clearance of senescent cells thus emerges as a promising therapeutic approach to ameliorate cognitive dysfunction. Resveratrol has shown promise in modulating immune response and exerting anti-aging effects. However, the therapeutic potential and underlying mechanisms of resveratrol in mitigating age-associated microglial senescence and cognitive decline are not fully understood. Methods: In the present study, we employed a well-established murine model of accelerated aging induced by chronic intraperitoneal injection of D-galactose (D-gal) to elicit pronounced senescence-associated phenotypes and neuroinflammation. Resveratrol was administered via oral gavage daily for three weeks following D-gal injections. Behavioral assays were conducted to assess cognitive performance. Immunohistochemistry, quantitative PCR, and Western blot analyses were used to evaluate markers of cellular senescence, microglial activation and pro-inflammatory cytokine expression. In addition, in vitro assays in cultured microglia coupled with RNA sequencing were used to investigate the downstream signaling events following resveratrol treatment. Results: Chronic D-gal treatment induced significant cognitive impairment, enhanced microglial activation, elevated pro-inflammatory cytokine levels, and increased markers of cellular senescence in the brain. Resveratrol administration remarkably attenuated these effects, as evidenced by improved memory performance, reduced microglial senescence markers, and suppressed expression of Cxcl-10, Il-1β, and other SASP factors. Mechanistically, unbiased transcriptomic analysis revealed that the cGAS-STING signaling and neuroinflammation pathways were prominently dysregulated with double-stranded DNA-induced cellular senescence, which was effectively normalized by resveratrol in cultured microglia. Interestingly, resveratrol inhibited the translocation of STING from the endoplasmic reticulum to the Golgi apparatus and suppressed phosphorylation of TBK1, thereby blocking downstream STING signaling. Conclusions: These findings demonstrate that resveratrol mitigates microglial senescence and neuroinflammation and preserves cognitive function in D-gal-induced aging mice, at least partly through modulation of the cGAS-STING signaling. Therefore, targeting this pathway may represent a promising therapeutic strategy for age-related neuroinflammatory and cognitive disorders. Full article

Background: Chronic cocaine exposure is increasingly associated with persistent brain alterations, yet it remains unclear whether these changes reflect reversible neuroadaptation, accelerated brain ageing, or a degeneration-like trajectory in a vulnerable subgroup. This Perspective proposes a neuroprogressive vulnerability framework—referred to as cocaine-specific encephalopathy/cerebropathy only in a heuristic sense—to organise heterogeneous evidence without implying a distinct neurodegenerative disease entity. Methods: We conducted a structured, critical synthesis of peer-reviewed human and preclinical literature (PubMed, Scopus, Web of Science; inception to December 2025), integrating neuroimaging (MRI/DTI/fMRI/PET/SPECT), neuropathology/post-mortem findings, neurochemical and molecular mechanisms, and neuropsychological outcomes, with explicit attention to confounders (polysubstance use, psychiatric and medical comorbidity, HIV, vascular risk, abstinence duration). Results: Convergent evidence supports a multi-hit vulnerability model in which chronic stimulant exposure may weaken neural resilience through dopaminergic dysregulation, oxidative stress, mitochondrial dysfunction, neuroinflammatory signalling, and putative α-synuclein–related mechanisms. Human imaging studies consistently implicate fronto–striato–limbic circuits and suggest possible cerebellar involvement, but findings are heterogeneous and often cross-sectional; direct evidence of progressive neuronal loss or disease-defining proteinopathies attributable to cocaine remains limited. Conclusions: Rather than asserting cocaine-induced classic neurodegeneration, we outline an exploratory framework in which chronic cocaine exposure may increase susceptibility to neuroprogressive impairment in a subset of biologically vulnerable individuals. Longitudinal multimodal studies combining advanced imaging, biomarkers, and phenotypic stratification are needed to clarify causality, temporal progression, and reversibility with sustained abstinence. Full article

Background: Non-invasive brain stimulation (NIBS) is increasingly used as an adjunctive option in late-life depression (≥60 years), a condition frequently complicated by multimorbidity and incomplete response to standard treatments. Comparative real-world evidence between repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS), particularly including functional outcomes, remains limited. Methods: We conducted a retrospective, naturalistic comparative study of 104 depressed inpatients (≥60 years), either unipolar or bipolar, treated with rTMS (n = 48) or tDCS (n = 56) as part of routine care. Depression severity was assessed with the 21-item Hamilton Depression Rating Scale (HDRS21) at baseline, 2 weeks, and 1 month; response was defined as ≥50% HDRS21 score reduction and remission as HDRS21 < 7 at 1 month. Global Assessment of Functioning (GAF) was assessed at admission and discharge (baseline and 1 month). Longitudinal changes were examined using covariate-adjusted mixed-effects models; categorical outcomes were compared using χ² tests. Propensity score matching was applied as an additional approach to reduce confounding due to the observational design. Results: At 1 month, response and remission rates were significantly higher in the rTMS group than in the tDCS group (87.5% vs. 55.4%, p < 0.001; 62.5% vs. 41.1%, p = 0.047, respectively). rTMS showed greater HDRS21 score reductions at 2 weeks and 1 month (Time × Treatment, p < 0.001). GAF scores significantly improved over time in both groups (Time effect, p < 0.001) without between-technique differences (Time × Treatment, p = 0.56), and GAF scores did not differ by response/remission status. Conclusions: In this cohort of inpatients aged ≥ 60 years with depressive episodes, rTMS was associated with greater short-term reductions in HDRS21 scores compared with tDCS, whereas both modalities showed comparable improvements in GAF from admission to discharge. Full article

Multiple sclerosis (MS) is a highly disabling chronic autoimmune disease of the central nervous system with neuroinflammatory and neurodegenerative alterations found in the white and grey matter of the brain. The pathogenesis of MS is complex and not fully understood. Mitochondrial dysfunctions are suspected to play an important role. The visual system is often affected in MS. Optic neuritis is a frequent symptom, but also the retina itself, including retinal synapses appear compromised in MS independent from demyelination of the optic nerve. A previous study demonstrated synapse-specific alterations of mitochondria in photoreceptor synapses in the Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS at day 9 after injection, an early time point in pre-clinical EAE. In the present study, we analysed even earlier stages of pre-clinical EAE for possible alterations of synaptic mitochondria. For this purpose, we performed qualitative and quantitative immunolabelling analyses of the mitochondrial cristae organising protein MIC60 at retinal synapses and functional analyses by measuring synaptic mitochondrial membrane potential (during rest and depolarisation-induced exocytosis) and visually guided behaviour (optometry analyses). At day 3 after injection, morphological and functional data were indistinguishable between MOG/CFA-injected EAE mice and CFA-injected control mice. But already on day 5 after injection, we observed a decreased expression of the mitochondrial MIC60 protein at synaptic mitochondria, a decreased synaptic mitochondrial membrane potential at rest, an enhanced drop of mitochondrial membrane potential during stimulated exocytosis and a decreased visual performance of the respective EAE mice. These data argue that synaptic pathology in the EAE retina begins as early as day 5 after injection. Our data propose that dysfunctions of mitochondria play an important role already at the very early stages of synaptic pathology in EAE. Full article

Neuroinflammation mediated by reactive microglia, the immune cells of the brain, contributes to numerous neuropathologies. Damage-associated molecular patterns (DAMPs), released from stressed or damaged cells, are implicated in neuroinflammation. Succinate, a tricarboxylic acid cycle intermediate, can accumulate intracellularly and be released into the extracellular space where it may function as a DAMP-like molecule. However, its specific roles in central nervous system (CNS) neuroimmune responses, particularly when acting extracellularly, remain largely unexplored. This study utilizes cell membrane-impermeable disodium succinate to model extracellular action and cell-permeable diethyl succinate to assess the intracellular activity of this metabolite in cell culture models. We demonstrate that extracellular disodium succinate significantly reduces the secretion of pro-inflammatory cytokines tumor necrosis factor-α (TNF) and interleukin (IL)-6, and lowers neurotoxic and phagocytic activities of immune-stimulated BV-2 murine microglia. It also rescues lipopolysaccharide (LPS)-induced decreases in mitochondrial respiration in human peripheral blood mononuclear cells (PBMCs) used as microglia models, which correlates with its actions on phagocytosis. In contrast, while intracellular diethyl succinate reduces TNF and IL-6 secretion, it does not reduce BV-2 microglia toxicity towards murine NSC-34 neuronal cells, indicating location-dependent effects. These results support extracellular succinate as a novel CNS DAMP with a predominantly anti-inflammatory action on microglia. Full article

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high early mortality and long-term disability. Prognostic assessment relies mainly on neurological grading scales, which may incompletely capture the systemic metabolic response to acute brain injury. Non-thyroidal illness syndrome (NTIS), particularly low triiodothyronine syndrome (LT3S), is common in critical illness, but its prognostic relevance in aSAH remains unclear. Objectives: To evaluate the prognostic impact of early thyroid hormone alterations on 30-day mortality and early clinical outcomes including delayed cerebral ischemia (DCI) in patients with aSAH, with particular emphasis on the magnitude of triiodothyronine (T3) deficiency. Methods: We conducted a retrospective single-center observational cohort study of 157 consecutive adult patients admitted with confirmed aSAH between 2014 and 2025. Serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) were measured within 72 h of admission. Hormone values were normalized to contemporaneous reference intervals to generate continuous reference-adjusted metrics (FT3_level, TSH_level). Associations with 30-day in-hospital mortality were analyzed using logistic regression and Cox proportional hazards models adjusted for admission variables including age, sex, APACHE II score, World Federation of Neurosurgical Societies grade, Fisher grade, and treatment modality. Results: Binary LT3S classification was frequent but not independently associated with 30-day mortality. In contrast, lower FT3_level values were significantly associated with increased mortality and shorter survival time. In logistic regression analyses, each 0.1 increase in FT3_level was associated with an 18% lower odds of death (adjusted OR 0.82, 95% CI 0.69–0.97). This association persisted after adjustment for established clinical severity measures and was concordant with time-to-event analyses. FT3_level was not correlated with TSH_level, consistent with NTIS. Endovascular coiling was associated with more pronounced peripheral fT3 deficiency (p < 0.05) but was not independently associated with mortality. FT3_level was not independently associated with early neurological status or functional outcome at hospital discharge. Conclusions: Lower FT3_level values were independently associated with higher 30-day mortality, indicating that early peripheral T3 reduction reflects clinically relevant metabolic vulnerability in aSAH. Full article

Background/Objectives: This study investigates the effects of multi-sensory stimulation on brain functional connectivity in patients with disorders of consciousness (DOC). DOC patients experience prolonged loss of consciousness due to brain injury, posing significant challenges for rehabilitation. Methods: In the study, visual, olfactory, and visual–olfactory (V-O) combined stimulation were applied to DOC patients while their EEG signals were recorded. A brain functional network was constructed based on the conditional Granger causality (CGC) method to analyze its topological characteristics. Results: The results revealed that the strength of brain functional connectivity in Minimally Conscious State (MCS) patients was significantly higher than that in Vegetative State (VS) patients, indicating a strong correlation between the intensity of synergistic activity in brain functional connectivity and the level of consciousness. Furthermore, V-O combined stimulation significantly enhanced brain functional connectivity compared to single-modality stimulation. The selection of different stimulation also differentially affected brain functional connectivity, with olfactory stimulation exhibiting high pleasure, arousal, and dominance (Self-Assessment Manikin) values demonstrating unique advantages in reducing individual variability and improving global efficiency. Conclusions: The study provides a theoretical foundation for the application of multi-sensory stimulation in the rehabilitation of DOC patients. V-O stimulation not only enhances information transmission in brain regions corresponding to visual and olfactory processing under single-modality stimulation but also increases the intensity of information transfer to other brain regions; this may serve as a reference for understanding the effects of multi-sensory stimulation on brain networks. Full article

Background/Objectives: This study aimed to describe temporal trends in deep brain stimulation (DBS) use for Parkinson’s disease (PD), essential tremor (ET), and dystonia; characterize patient age and sex distribution and comorbidity; assess postoperative complications and in-hospital mortality (IHM) after implantation and explantation; and explore sex-specific differences in utilization and outcomes. Methods: We conducted a retrospective nationwide population-based study using the Spanish National Hospital Discharge Database (RAE-CMBD) from 2002 to 2019. All hospital admissions with DBS implantation or explantation/revision and a diagnosis of PD, ET, or dystonia were identified. Sociodemographic variables, the Charlson Comorbidity Index (CCI), length of hospital stay (LOHS), postoperative complications, and IHM were analyzed across three calendar periods and stratified by diagnosis and sex. Results: A total of 4883 admissions for DBS electrode implantations and 497 admissions for DBS explantation/revision were recorded. PD accounted for 82.6% of implantations, followed by ET (11.2%) and dystonia (6.3%). DBS activity increased significantly over time, while median LOHS declined from 12 to 6 days for implantations and from 13 to 5 days for explantations. Overall IHM after implantation was 0.27%, decreasing to 0.05% in 2014–2019; IHM after explantation was 0.6%. Most hospitalizations had low comorbidity (CCI = 0 in 87.8%), although comorbidity increased over time. Men represented approximately 60% of procedures in PD and ET. Women with PD underwent DBS at older ages, despite similar LOHS and IHM. Postoperative complications were recorded in 14.6% of implantations, mainly hardware-related issues (5–6%) and infections (1–2%), whereas infections (33%) and mechanical problems (27%) predominated among explantations. Conclusions: DBS use in Spain has expanded substantially, with shorter hospital stays and very low in-hospital mortality. Sex-related differences in utilization are increasing, and hardware complications and infections remain the most frequent conditions associated with explantation. As complications were identified only during the same hospitalization as the DBS procedure, late post-discharge events are not captured and could be underestimated; patient-level risks cannot be derived. Full article

Human physiology is among the most complex systems in nature, characterized by intricate structural and functional networks and rich temporal dynamics. Electrophysiological signals produced by different tissues/organs reflect physiological activity, and are inherently non-stationary, non-linear, and noisy. This work focuses on fractal analysis, a framework that captures the self-similar and scale-free properties of electrophysiological signals, which is considered to act as an output of complex physiological structures that generate complex processes. Central to this approach is the principle of ‘decomplexification’, whereby aging and disease are associated with a loss of physiological complexity. We discuss key algorithms, particularly Higuchi’s fractal dimension, which is often combined with other nonlinear measures and machine-learning models for real-time analysis of electrophysiological signals. Evidence shows that fractal metrics enable the early detection and monitoring of neurological and psychiatric disorders, outperforming traditional spectral measures. In movement disorders and mood disorders, fractal and nonlinear features show high diagnostic accuracy. Beyond diagnostics, we discuss therapeutic applications, including the prediction of responsiveness to non-invasive brain stimulation. Here, we envisage the evolution of one fractal or nonlinear measure use, to several measures applied, then use it as a feature for machine learning, and then realize that a whole cluster of biomarkers must be used to reflect the state of autonomic profile, which then can be used for ontology-based application profiles that can be machine-actionable. In addition, we discuss the fractal and fractional description of transport processes, which offer innovative improvement for a much more accurate description of physiological reality as a prerequisite for further modeling: for example, this is needed for digital twins to support the clinical translation of fractal analysis for personalized medicine. In essence, if one is trying to mathematically describe or quantify structures or processes in human physiology, fractal and fractional are the supreme and adequate approach to accurately model that reality. Full article

Background: We previously established that striatal, but not cortical, dopaminergic activation stimulates movement, indicating that the crucial and original site of dopaminergic stimulation of motor function is the striatum, not the motor cortex. In the present study, we have further investigated the potential effects of the cortical and striatal dopaminergic activity on cortical pyramidal neuron physiology. Methods and Results: First, under a constant fluorescence imaging condition, we established that DA innervation and D1R and D2R expression were very low in the cerebral cortex but very high in the striatum. Second, we performed cellular neurophysiological experiments on layer 2/3 pyramidal neurons in the primary motor cortex (M1) in tyrosine hydroxylase gene knockout (TH-KO) DA-depleted mice that have hyperfunctional DA receptors. Using brain slice–whole-cell patch-clamping techniques, we found that M1 layer 2/3 pyramidal neurons had lower input resistance, stronger inward rectification, more negative RMP, and fired fewer spikes in DA-depleted TH-KO mice than in DA-intact WT mice; M1 layer 2/3 pyramidal neurons also had a diminished synaptic release function with reduced frequencies for spontaneous and miniature excitatory synaptic currents in TH-KO mice compared to WT mice. Third, we also found that when TH-KO mice were treated with L-dopa before brain slice preparation, these neurophysiological deficits of M1 layer 2/3 pyramidal neurons were reversed, but 30 min incubation of cortical brain slices with 10–20 μM DA produced no detectable effect in M1 layer 2/3 pyramidal neurons in TH-KO mice and WT mice. Fourth, Golgi staining showed that cortical pyramidal neuron morphology was indistinguishable between WT mice and TH-KO mice. Conclusions: Our results indicate that DA loss in the striatum, not in the cortex, indirectly reduces cortical pyramidal neuron membrane excitability and weakens synaptic function. Our data also indicate that (1) the normal direct effects of the cortical DA system on cortical pyramidal neurons are weak, (2) the striatal DA system is the dominant DA system in the brain, and (3) striatal DA activity can indirectly increase cortical neuron activity (spike firing and synaptic activity) and thus critically contribute to brain function. Additionally, our data suggest that in DA depletion rodent PD models, DA loss-induced effects on cortical pyramidal neurons and other neurons are functional rather than structural, such that DA replenishment restores motor function almost instantaneously. These findings provide important insights into how the brain’s dopaminergic system controls our motor and cognitive functions and indicate that the striatum is the main therapeutic target of dopaminergic drugs. Full article

Acanthamoeba castellanii, an opportunistic free-living amoeba, causes severe infections including Acanthamoeba keratitis. This exploratory study evaluated whether three non-steroidal anti-inflammatory drugs (NSAIDs)—acetylsalicylic acid, ibuprofen, and diclofenac (100 µM)—modulate pathogenicity-related processes in A. castellanii and explored the involvement of a gp63-like protein during encystment and adhesion. Trophozoites were continuously exposed to each drug and analyzed for adhesion, migration on host-derived discontinuous brain micropatterns, encystment efficiency, and parasite-induced cytoskeletal remodeling in MDCK epithelial cells. In silico docking was performed to assess potential drug–protein interactions. Drug exposure reduced adhesion with maximal inhibition at 60 min. After 1 h, migration decreased by 49%, 64%, and 38%, and encystment was reduced by 50%, 85%, and up to 90%, respectively, in cultures treated with acetylsalicylic acid, ibuprofen, and diclofenac. Co-incubation with untreated trophozoites lowered actin fluorescence to approximately 50%, whereas drug-treated co-cultures preserved fluorescence near control levels. Colocalization analysis showed increased spatial overlap between gp63-like protein and F-actin in cysts (~40%) and migrating trophozoites (~20%) compared with non-stimulated forms (~3.8%). Collectively, these findings suggest that NSAID-sensitive pathways influence host interaction, migration, and encystment in A. castellanii and allow for the proposal of gp63-like protein as a putative molecular component of the NSAIDs sensitive pathways. Full article

Alzheimer’s disease (AD) is a serious medical challenge, representing an incurable and insidious disease. Current treatments can slow AD progression but cannot cure it. Promising new methods for AD therapy are essential for addressing the growing number of people with dementia, especially after the COVID-19 pandemic. The review highlights pioneering approaches to AD treatment based on innovative methods for the stimulation of brain drainage and clearance, in which the meningeal lymphatic vessels (MLVs) play a key role. Clinically promising noninvasive technologies using photobiomodulation for the effective clearance of metabolites, including amyloid beta (Aβ), and for the improvement of cognitive impairment during AD progression are discussed. An interesting part of the review is its analysis of innovative methods of improving the efficacy of anti-Aβ immunotherapy by stimulating MLV growth. The review is also focused on lifestyle, including sleep and physical exercises, discussing their support for the efficient lymphatic removal of waste products from the brain. Overall, the review provides an important, informative platform to excite the interest of a wide range of readers in the development of promising and clinically significant strategies for the treatment of AD, based on new strategies for the stimulation of brain drainage and clearance. Full article

Major depressive disorder (MDD) is one of the most prevalent mental illnesses and, despite the availability of multiple treatment options, remains difficult to treat for a substantial proportion of patients. Repetitive transcranial magnetic stimulation (rTMS) is an important therapeutic approach for depression, modulating brain activity through targeted magnetic pulses in a non-invasive manner. This review examined scientific evidence from clinical trials, large-scale analyses, and laboratory investigations regarding the effectiveness and safety of rTMS, as well as its role within contemporary therapeutic strategies for depression. In addition to conventional rTMS, the review addresses theta-burst stimulation (TBS), deep TMS, and various approaches aimed at enhancing treatment efficacy or accelerating clinical response, while also discussing the practical utility of different stimulation devices. rTMS applied to specific regions of the prefrontal cortex has demonstrated significant antidepressant effects, and intermittent theta-burst stimulation (iTBS) appears to achieve comparable outcomes within a shorter time frame. Research further indicates that rTMS is associated with neurobiological changes in brain connectivity, modulation of neurotransmitter systems, and the promotion of neuroplasticity. Across studies, rTMS is generally considered safe, with reported adverse effects being mild and transient. However, further research is needed to optimize stimulation protocols, clarify medium and long-term effects, individualize treatment approaches, and determine the durability of therapeutic benefits. Full article