Integrating Graphene Oxide-Hydrogels and Electrical Stimulation for Controlled Neurotrophic Factor Encapsulation: A Promising Approach for Efficient Nerve Tissue Regeneration.

Nerve growth factor (NGF) plays a crucial role in cellular growth and neurodifferentiation. To achieve significant neuronal regeneration and repair using in vitro NGF delivery, spatiotemporal control that follows the natural neuronal processes must be developed. Notably, a challenge hindering this is the uncontrolled burst release from the growth factor delivery systems. The rapid depletion of NGF reduces treatment efficacy, leading to poor cellular response. To address this, we developed a highly controllable system using graphene oxygen (GO) and GelMA hydrogels modulated by electrical stimulation. Our system showed superior control over the release kinetics, reducing the burst up 30-fold. We demonstrate that the system is also able to sequester and retain NGF up to 10-times more efficiently than GelMA hydrogels alone. Our controlled release system enabled neurodifferentiation, as revealed by gene expression and immunostaining analysis. The increased retention and reduced burst release from our system show a promising pathway for nerve tissue engineering research toward effective regeneration.

Wired for Success: Probing the Effect of Tissue-Engineered Neural Interface Substrates on Cell Viability.

This study investigates the electrochemical behavior of GelMA-based hydrogels and their interactions with PC12 neural cells under electrical stimulation in the presence of conducting substrates. Focusing on indium tin oxide (ITO), platinum, and gold mylar substrates supporting conductive scaffolds composed of hydrogel, graphene oxide, and gold nanorods, we explored how the substrate materials affect scaffold conductivity and cell viability. We examined the impact of an optimized electrical stimulation protocol on the PC12 cell viability. According to our findings, substrate selection significantly influences conductive hydrogel behavior, affecting cell viability and proliferation as a result. In particular, the ITO substrates were found to provide the best support for cell viability with an average of at least three times higher metabolic activity compared to platinum and gold mylar substrates over a 7 day stimulation period. The study offers new insights into substrate selection as a platform for neural cell stimulation and underscores the critical role of substrate materials in optimizing the efficacy of neural interfaces for biomedical applications. In addition to extending existing work, this study provides a robust platform for future explorations aimed at tailoring the full potential of tissue-engineered neural interfaces.

DRD3 Predicts Cognitive Impairment and Anxiety in Parkinson's Disease: Susceptibility and Protective Effects.

Background: A possible genetic contribution of dopamine D3 receptor (DRD3) to cognitive impairment in Parkinson's disease (PD) has yet to be investigated. Objective: To explore the effects of rs6280 (Ser9Gly) genotype on PD patients' cognitive performance and to clarify possible interactions with psychopathology. Methods: Two hundred and fifty-three consecutive PD patients underwent neurological and neuropsychological evaluations, which included: Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Dementia Rating Scale-2 (DRS-2), and Hospital Anxiety and Depression Scale (HADS). rs6280 polymorphism was genotyped for all PD patients and for 270 ethnically matched healthy volunteers (HC). Non-parametric group comparisons and logistic regressions were used for data analyses. Results: rs6280 genotype did not differ between PD and HC groups. PD patients with rs6280 CC genotype had more impaired cognitive performance (i.e., <1st percentile of demographically adjusted norms) on DRS-2 subscales Initiation/Perseveration and Construction than those with TT genotype. These associations remained statistically significant when other covariates (e.g., demographic features, disease duration, severity of motor symptoms in OFF and ON states, anti-parkinsonian medication, and psychopathology symptoms) were taken into consideration. PD patients with rs6280 TC had less anxiety (i.e., HADS Anxiety≥11) than those with TT (p = 0.012). This association was also independent of other covariates. Conclusions: Study findings suggest that rs6280 CC genotype predisposes to executive dysfunction and visuoconstructional deficits, whereas the heterozygous genotype protects from anxiety in PD. These effects do not appear to be dependent of one another. rs6280 is not a genotypic susceptibility factor for PD.

Inquérito epidemiológico para residentes do entorno da empresa polo petroquímico de Capuava no município de São Paulo / Epidemiological survey for residents surrounding the Capuava petrochemical hub company in the city of São Paulo

A poluição atmosférica é medida pela quantidade de substâncias poluentes presentes no ar, que o torna impróprio ou nocivo a saúde. Dentre as fontes com elevado potencial poluidor, encontram-se as indústrias petroquímicas, e estudos indicam maior prevalência de hipotireoidismo nas regiões próximas a um polo petroquímico. A partir de denúncias dos moradores da região próxima do Polo Petroquímico de Capuava (PPC), foi instaurada uma Comissão Parlamentar de Inquérito (CPI) pela Câmara Municipal de São Paulo, para investigação, e solicitado a realização de um inquérito epidemiológico. Objetivo: verificar se há maior prevalência de doença tireoidiana nas áreas próximas ao PPC comparando com áreas sem a exposição à emissão de poluentes por esse tipo de fonte fixa. Método: O inquérito epidemiológico foi realizado por sorteio aleatório em duas etapas, sendo cinco áreas trabalhadas com entrevista e levantamento de dados de saúde, exame dos entrevistados que apresentavam três ou mais sintomas e/ou referiram doença tireoidiana, e avaliação médica. Resultados: foram respondidos 3.674 questionários com 879 residentes encaminhados para coleta de exames, onde 654 concluíram todas as etapas passando em consulta médica. Desses, 101 residentes da área de exposição e 65 residentes da área controle receberam diagnóstico de doença tireoidiana. Quando analisada a população total entrevistada, a prevalência da doença tireoidiana foi de 4,6 na área de exposição e 4,4 na área controle. Já considerando apenas a população testada, a prevalência da doença na população foi de 23,7% e 28,5% respectivamente. Em relação a percepção de poluentes, 77% dos residentes da área de exposição referiram pelo menos uma queixa relacionada e emissão de fumaça, odor, poeira, fuligem ou ruído decorrentes das atividades executadas pelo PPC. Conclusão: o estudo demonstrou não haver uma diferença significativa entre as áreas, os resultados mostraram que a probabilidade de desenvolver doença tireoidiana não teve diferença significativa entre as áreas, entretanto, deve ser considerado o grande incômodo referido pela maioria dos entrevistados residentes na área de exposição. Novos estudos devem ser conduzidos nas áreas próximas a polos industriais para levantamento de dados de saúde e qualidade do ar.

A tissue-engineered neural interface with photothermal functionality.

Neural interfaces are well-established as a tool to understand the behaviour of the nervous system via recording and stimulation of living neurons, as well as serving as neural prostheses. Conventional neural interfaces based on metals and carbon-based materials are generally optimised for high conductivity; however, a mechanical mismatch between the interface and the neural environment can significantly reduce long-term neuromodulation efficacy by causing an inflammatory response. This paper presents a soft composite material made of gelatin methacryloyl (GelMA) containing graphene oxide (GO) conjugated with gold nanorods (AuNRs). The soft hydrogel presents stiffness within the neural environment range of modulus below 5 kPa, while the AuNRs, when exposed to light in the near infrared range, provide a photothermal response that can be used to improve the spatial and temporal precision of neuromodulation. These favourable properties can be maintained at safer optical power levels when combined with electrical stimulation. In this paper we provide mechanical and biological characterization of the optical activity of the GO-AuNR composite hydrogel. The optical functionality of the material has been evaluated via photothermal stimulation of explanted rat retinal tissue. The outcomes achieved with this study encourage further investigation into optical and electrical costimulation parameters for a range of biomedical applications.

Reagentless protein-based electrochemical biosensors.

The creation of reagentless protein-based biosensors that are capable of monitoring molecular analytes directly in bodily fluids could revolutionize our understanding of biology and personalized health monitoring. The limited number of molecular sensors that are currently available in the market depends on the specific enzymatic or chemical reactivity of their target analytes and therefore are not applicable to many relevant biomarkers. Aiming to overcome this limited molecular sensing generality, a new class of reagentless protein-based electrochemical sensors has been introduced for the direct measurements of biomarkers in unprocessed biological fluids. This mini-review will discuss the most recent cutting-edge discoveries for the development of electroanalytical modular biosensors, where all the sensors' components are integrated into a self-sufficient sensor allowing hence its autonomous functionality.

The impact of electrical stimulation protocols on neuronal cell survival and proliferation using cell-laden GelMA/graphene oxide hydrogels.

The development of electroactive cell-laden hydrogels (bioscaffolds) has gained interest in neural tissue engineering research due to their inherent electrical properties that can induce the regulation of cell behaviour. Hydrogels combined with electrically conducting materials can respond to external applied electric fields, where these stimuli can promote electro-responsive cell growth and proliferation. A successful neural interface for electrical stimulation should present the desired stable electrical properties, such as high conductivity, low impedance, increased charge storage capacity and similar mechanical properties related to a target neural tissue. We report how different electrical stimulation protocols can impact neuronal cells' survival and proliferation when using cell-laden GelMA/GO hydrogels. The rat pheochromocytoma cell line, PC12s encapsulated into hydrogels showed an increased proliferation behaviour with increasing current amplitudes applied. Furthermore, the presence of GO in GelMA hydrogels enhanced the metabolic activity and DNA content of PC12s compared with GelMA alone. Similarly, hydrogels provided survival of encapsulated cells at higher current amplitudes when compared to cells seeded onto ITO flat surfaces, which expressed significant cell death at a current amplitude of 2.50 mA. Our findings provide new rational choices for electroactive hydrogels and electrical stimulation with broad potential applications in neural tissue engineering research.

Striatum expresses region-specific plasticity consistent with distinct memory abilities.

The striatum mediates two learning modalities: goal-directed behavior in dorsomedial (DMS) and habits in dorsolateral (DLS) striata. The synaptic bases of these learnings are still elusive. Indeed, while ample research has described DLS plasticity, little remains known about DMS plasticity and its involvement in procedural learning. Here, we find symmetric and asymmetric anti-Hebbian spike-timing-dependent plasticity (STDP) in DMS and DLS, respectively, with opposite plasticity dominance upon increasing corticostriatal activity. During motor-skill learning, plasticity is engaged in DMS and striatonigral DLS neurons only during early learning stages, whereas striatopallidal DLS neurons are mobilized only during late phases. With a mathematical modeling approach, we find that symmetric anti-Hebbian STDP favors memory flexibility, while asymmetric anti-Hebbian STDP favors memory maintenance, consistent with memory processes at play in procedural learning.

An Iterative and Collaborative End-to-End Methodology Applied to Digital Mental Health.

Artificial intelligence (AI) algorithms together with advances in data storage have recently made it possible to better characterize, predict, prevent, and treat a range of psychiatric illnesses. Amid the rapidly growing number of biological devices and the exponential accumulation of data in the mental health sector, the upcoming years are facing a need to homogenize research and development processes in academia as well as in the private sector and to centralize data into federalizing platforms. This has become even more important in light of the current global pandemic. Here, we propose an end-to-end methodology that optimizes and homogenizes digital research processes. Each step of the process is elaborated from project conception to knowledge extraction, with a focus on data analysis. The methodology is based on iterative processes, thus allowing an adaptation to the rate at which digital technologies evolve. The methodology also advocates for interdisciplinary (from mathematics to psychology) and intersectoral (from academia to the industry) collaborations to merge the gap between fundamental and applied research. We also pinpoint the ethical challenges and technical and human biases (from data recorded to the end user) associated with digital mental health. In conclusion, our work provides guidelines for upcoming digital mental health studies, which will accompany the translation of fundamental mental health research to digital technologies.

Intracellular Properties of Deep-Layer Pyramidal Neurons in Frontal Eye Field of Macaque Monkeys.

Although many details remain unknown, several positive statements can be made about the laminar distribution of primate frontal eye field (FEF) neurons with different physiological properties. Most certainly, pyramidal neurons in the deep layer of FEF that project to the brainstem carry movement and fixation signals but clear evidence also support that at least some deep-layer pyramidal neurons projecting to the superior colliculus carry visual responses. Thus, deep-layer neurons in FEF are functionally heterogeneous. Despite the useful functional distinctions between neuronal responses in vivo, the underlying existence of distinct cell types remain uncertain, mostly due to methodological limitations of extracellular recordings in awake behaving primates. To substantiate the functionally defined cell types encountered in the deep layer of FEF, we measured the biophysical properties of pyramidal neurons recorded intracellularly in brain slices issued from macaque monkey biopsies. Here, we found that biophysical properties recorded in vitro permit us to distinguish two main subtypes of regular-spiking neurons, with, respectively, low-resistance and low excitability vs. high-resistance and strong excitability. These results provide useful constraints for cognitive models of visual attention and saccade production by indicating that at least two distinct populations of deep-layer neurons exist.

Evaluation of Multivariable Modeling Methods for Monitoring the Health of Guyed Towers in Overhead Power Lines.

This article proposes a methodology for monitoring the structural stability of each tower of an electric power transmission line through sensor measurements which estimates the different situations that may indicate the need for intervention to prevent the structure collapsing. The extended Kalman filter was adopted to predict the failures, considering sensor fusion techniques such as the displacements of the upper central position of the tower above certain limits. The load of the stay cables is calculated from the natural frequencies, which are determined by the accelerometers connected to the cables. The average value of these forces, which must be higher than a normal limit, were calculated to predict a failure. All guyed towers of a power transmission line thousands of kilometers long will be individually monitored considering the methodology described in this study, which makes this article one of the first relevant research studies in this area. Typically, guyed towers must often be manually inspected to ensure that the stay cables have acceptable pretension to prevent a lack of stability in the transmission line towers.

Enhanced Electroactivity, Mechanical Properties, and Printability through the Addition of Graphene Oxide to Photo-Cross-linkable Gelatin Methacryloyl Hydrogel.

The human tissues most sensitive to electrical activity such as neural and muscle tissues are relatively soft, and yet traditional conductive materials used to interface with them are typically stiffer by many orders of magnitude. Overcoming this mismatch, by creating both very soft and electroactive materials, is a major challenge in bioelectronics and biomaterials science. One strategy is to imbue soft materials, such as hydrogels, with electroactive properties by adding small amounts of highly conductive nanomaterials. However, electroactive hydrogels reported to date have required relatively large volume fractions (>1%) of added nanomaterial, have shown only modest electroactivity, and have not been processable via additive manufacturing to create 3D architectures. Here, we describe the development and characterization of improved biocompatible photo-cross-linkable soft hybrid electroactive hydrogels based on gelatin methacryloyol (GelMA) and large area graphene oxide (GO) flakes, which resolve each of these three limitations. The addition of very small amounts (less than a 0.07% volume fraction) of GO to a 5% w/v GelMA hydrogel resulted in a dramatic (∼35-fold) decrease in the impedance at 1 Hz compared with GelMA alone. The GelMA/GO coated indium tin oxide (ITO) electrode also showed a considerable reduction in the impedance at 1 kHz (down to 170 Ω compared with 340 Ω for the GelMA-coated ITO), while charge injection capacity increased more than 6-fold. We attribute this enhanced electroactivity to the increased electroactive surface area contributed by the GO. Despite this dramatic change in electroactivity, the GelMA/GO composite hydrogels' mechanical properties were only moderately affected. Mechanical properties increased by ∼2-fold, and therefore, the hydrogels' desired softness of <4 kPa was retained. Also, we demonstrate how light attenuation through the gel can be used to create a stiffness gradient with the exposed surface of the gel having an elastic modulus of <1.5 kPa. GO addition also enhanced the rheological properties of the GelMA composites, thus facilitating 3D extrusion printing. GelMA/GO enhanced filament formation as well as improved printability and the shape fidelity/integrity of 3D printed structures compared with GelMA alone. Additionally, the GelMA/GO 3D printed structures presented a higher electroactive behavior than nonprinted samples containing the same GelMA/GO amount, which can be attributed to the higher electroactive surface area of 3D printed structures. These findings provide new rational choices of electroactive hydrogel (EAH) compositions with broad potential applications in bioelectronics, tissue engineering, and drug delivery.

Past appendectomy may be related to early cognitive dysfunction in Parkinson's disease.

INTRODUCTION: The vermiform appendix is a potential site of initiation of Parkinson's disease (PD) pathology. We hypothesized that the appendectomy earlier in life may alter the clinical expression of PD. OBJECTIVE: To explore the effects of appendectomy prior to onset of PD motor symptoms on patients' symptoms, in particular on cognitive dysfunction. METHODS: Two hundred and sixty-two consecutive PD patients were asked about past history of appendectomy and underwent an evaluation, which included the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Schwab & England Independence Scale (S&E), Dementia Rating Scale-2 (DRS-2), Apathy Evaluation Scale, Hospital Anxiety and Depression Scale, and Brief Smell Identification Test. Motor symptoms were evaluated in OFF and ON states. Non-parametric group comparisons and logistic regressions were used for data analyses. RESULTS: Thirty-one patients (11.8%) had history of appendectomy prior to PD onset. These patients had more severe motor symptoms (UPDRS-III and H&Y) and lower functional independence (S&E) in ON and had higher frequency of cognitive dysfunction (DRS-2 Initiation/Perseveration, Conceptualization, and Memory subscales) (p < 0.05). The association between history of appendectomy and cognitive dysfunction was evident only in patients with late onset PD (≥ 55 years) and with disease duration ≤ 5 years. History of appendectomy remained statistically associated with impairment on DRS-2 Conceptualization and Memory subscales, when demographic and clinical variables were considered. CONCLUSION: History of appendectomy appears to alter the clinical expression of late onset PD, with early cognitive impairment, more severe motor symptoms in ON, and poorer functional independence under anti-parkinsonian medication.

Spontaneous Intracranial Hypotension Followed by Intracranial Hypertension.

INTRODUCTION: Spontaneous intracranial hypotension is a secondary cause of headache caused by suspected cerebrospinal fluid leaks. It is associated with vascular changes that may predispose to superficial siderosis. When treated with an epidural blood patch, rebound intracranial hypertension may ensue. CASE REPORT: A 55-year-old man presented with orthostatic headaches responsive to rest and hydration. Brain magnetic resonance revealed subdural collections, consistent with intracranial hypotension. Three weeks later, the patient experienced sudden severe holocranial headache and spontaneous subarachnoid hemorrhage was found. This resulted in rebound intracranial hypertension with bilateral papilledema and sixth-nerve palsy, which completely resolved with acetazolamide. DISCUSSION: Spontaneous intracranial hypotension may predispose to subarachnoid hemorrhage through vascular compensatory changes. Blood in subarachnoid space may seal the hidden cerebrospinal fluid leak or trigger an inflammatory reaction, leading to rebound intracranial hypertension, a well-known epidural blood patch complication.

Sensor Positioning Influences the Accuracy of Knee Rom Data of an E-Rehabilitation System: A Preliminary Study with Healthy Subjects.

E-rehabilitation is the term used to define medical rehabilitation programs that are implemented at home with the use of information and communication technologies. The aim was to test whether sensor position and the sitting position of the patient influence the accuracy of knee range of movement (ROM) data displayed by the BPMpathway e-rehabilitation system. A preliminary study was conducted in a laboratory setting with healthy adults. Knee ROM data was measured with the BPMpathway e-rehabilitation system and simultaneously with a BIOPAC twin-axis digital goniometer. The main outcome was the root mean squared error (RMSE). A 20% increase or reduction in sitting height led to a RMSE increase. A ventral shift of the BPMpathway sensor by 45° and 90° caused significant measurement errors. A vertical shift was associated with a diminution of the measurement errors. The lowest RMSE (2.4°) was achieved when the sensor was placed below the knee. The knee ROM data measured by the BPMpathway system is comparable to the data of the concurrent system, provided the instructions of the manufacturer are respected concerning the sitting position of the subject for knee exercises, and disregarding the same instructions for sensor positioning, by placing the sensor directly below the knee.

Concurrent Thalamostriatal and Corticostriatal Spike-Timing-Dependent Plasticity and Heterosynaptic Interactions Shape Striatal Plasticity Map.

The striatum integrates inputs from the cortex and thalamus, which display concomitant or sequential activity. The striatum assists in forming memory, with acquisition of the behavioral repertoire being associated with corticostriatal (CS) plasticity. The literature has mainly focused on that CS plasticity, and little remains known about thalamostriatal (TS) plasticity rules or CS and TS plasticity interactions. We undertook here the study of these plasticity rules. We found bidirectional Hebbian and anti-Hebbian spike-timing-dependent plasticity (STDP) at the thalamic and cortical inputs, respectively, which were driving concurrent changes at the striatal synapses. Moreover, TS- and CS-STDP induced heterosynaptic plasticity. We developed a calcium-based mathematical model of the coupled TS and CS plasticity, and simulations predict complex changes in the CS and TS plasticity maps depending on the precise cortex-thalamus-striatum engram. These predictions were experimentally validated using triplet-based STDP stimulations, which revealed the significant remodeling of the CS-STDP map upon TS activity, which is notably the induction of the LTD areas in the CS-STDP for specific timing regimes. TS-STDP exerts a greater influence on CS plasticity than CS-STDP on TS plasticity. These findings highlight the major impact of precise timing in cortical and thalamic activity for the memory engram of striatal synapses.

Unveiling the relationship between central parkinsonian pain and motor symptoms in Parkinson's disease.

BACKGROUND: Pain in Parkinson's disease (PD) is a common and heterogeneous non-motor symptom. Although the characteristics and predictors of pain in general and of central pain in particular are still largely unknown. METHODS: A semi-structured interview, the Brief Pain Inventory and the Pain Disability Index were used to identify and characterize pain in a consecutive series of 292 PD patients. Unified PD Rating Scale-III, Hoehn & Yahr, Schwab and England Independence Scale and Freezing of Gait Questionnaire were applied to assess motor symptoms and functional independence in off and on conditions. Hospital Anxiety and Depression Scale and Questionnaire of Impulsive-Compulsive Control Disorders were used to screen for anxiety, depression and impulse control disorders. RESULTS: Two hundred and twelve patients (73%) reported pain, which was classified as: musculoskeletal (63%), dystonia-related (27%), central parkinsonian (22%) and/or radicular or neuropathic (9%). Patients with pain had more comorbidities and more severe motor symptoms. Patients with central parkinsonian pain were significantly younger, had earlier disease onset, fewer comorbidities, greater non-axial motor symptom severity in on, more pain-related disability and more relief of pain with antiparkinsonian medication than patients with non-central parkinsonian pain. CONCLUSIONS: PD patients with central parkinsonian pain have some distinctive demographic and clinical features, including lower levodopa responsiveness of motor appendicular/limb symptoms to levodopa, associated with greater responsiveness of pain symptoms to these same medications. These findings suggest the need for a more integrated approach to motor and non-motor symptoms in these patients' clinical care. SIGNIFICANCE: In a consecutive series of 292 patients with PD, almost three quarters of patients with PD reported pain. The study results revealed that pain was related to more severe motor symptoms, anxiety symptoms and comorbidities. Among patients with pain, those with central parkinsonian subtype had distinct demographic and clinical features, including lower levodopa responsiveness for non-axial motor symptoms and greater responsiveness of pain to antiparkinsonian treatment.