Assessing the causal association between dietary vitamin intake and lymphoma risk: a Mendelian randomisation study.

Observational studies of diet-related vitamins and lymphoma risk results were inconsistent. Our study aimed to estimate the causality between dietary vitamin intake and lymphoma through a Mendelian randomisation (MR) study. We enrolled dietary-related retinol, vitamin C, vitamin E, vitamin B6 and vitamin B12 as exposures of interest, with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) as the outcome. The causal effects were estimated using inverse variance weighting (IVW), MR-Egger regression analysis and weighted median, supplemented by sensitivity analyses. The results revealed that genetically predicted dietary vitamin B12 intake was associated with a reduced HL risk (OR = 0.22, 95% CI 0.05-0.91, p = 0.036). The Q test did not reveal heterogeneity, the MR-Egger test showed no significant intercepts, and the leave-one-out (LOO) analysis did not discover any SNP that affect the results. No causal relationship about dietary vitamin intake on the NHL risk was observed.

Progressive alterations in electrophysiological and epileptic network properties during the development of temporal lobe epilepsy in rats.

OBJECTIVE: Refractory temporal lobe epilepsy (TLE) with recurring seizures causing continuing pathological changes in neural reorganization. There is an incomplete understanding of how spatiotemporal electrophysiological characteristics changes during the development of TLE. Long-term multi-site epilepsy patients' data is hard to obtain. Thus, our study relied on animal models to reveal the changes in electrophysiological and epileptic network characteristics systematically. METHODS: Long-term local field potentials (LFPs) were recorded over a period of 1 to 4 months from 6 pilocarpine-treated TLE rats. We compared variations of seizure onset zone (SOZ), seizure onset pattern (SOP), the latency of seizure onsets, and functional connectivity network from 10-channel LFPs between the early and late stages. Moreover, three machine learning classifiers trained by early-stage data were used to test seizure detection performance in the late stage. RESULTS: Compared to the early stage, the earliest seizure onset was more frequently detected in hippocampus areas in the late stage. The latency of seizure onsets between electrodes became shorter. Low-voltage fast activity (LVFA) was the most common SOP and the proportion of it increased in the late stage. Different brain states were observed during seizures using Granger causality (GC). Moreover, seizure detection classifiers trained by early-stage data were less accurate when tested in late-stage data. SIGNIFICANCE: Neuromodulation especially closed-loop deep brain stimulation (DBS) is effective in the treatment of refractory TLE. Although the frequency or amplitude of the stimulation is generally adjusted in existing closed-loop DBS devices in clinical usage, the adjustment rarely considers the pathological progression of chronic TLE. This suggests that an important factor affecting the therapeutic effect of neuromodulation may have been overlooked. The present study reveals time-varying electrophysiological and epileptic network properties in chronic TLE rats and indicates that classifiers of seizure detection and neuromodulation parameters might be designed to adapt to the current state dynamically with the progression of epilepsy.

Efficacy of different strategies of responsive neurostimulation on seizure control and their association with acute neurophysiological effects in rats.

Responsive neurostimulation (RNS) has shown promising but limited efficacy in the treatment of drug-resistant epilepsy. The clinical utility of RNS is hindered by the incomplete understanding of the mechanism behind its therapeutic effects. Thus, assessing the acute effects of responsive stimulation (AERS) based on intracranial EEG recordings in the temporal lobe epilepsy rat model may provide a better understanding of the potential therapeutic mechanisms underlying the antiepileptic effect of RNS. Furthermore, clarifying the correlation between AERS and seizure severity may help guide the optimization of RNS parameter settings. In this study, RNS with high (130 Hz) and low frequencies (5 Hz) was applied to the subiculum (SUB) and CA1. To quantify the changes induced by RNS, we calculated the AERS during synchronization by Granger causality and analyzed the band power ratio in the classic power band after different stimulations were delivered in the interictal and seizure onset periods, respectively. This demonstrates that only targets combined with an appropriate stimulation frequency could be efficient for seizure control. High-frequency stimulation of CA1 significantly shortened the ongoing seizure duration, which may be causally related to increased synchronization after stimulation. Both high-frequency stimulation of the CA1 and low-frequency stimulation delivered to the SUB reduced seizure frequency, and the reduced seizure risk may correlate with the change in power ratio near the theta band. It indicated that different stimulations may control seizures in diverse manners, perhaps with disparate mechanisms. More focus should be placed on understanding the correlation between seizure severity and synchronization and rhythm around theta bands to simplify the process of parameter optimization.

Impacts of stimulus parameters and configurations on motor cortex direct electrical stimulation using intrinsic optical imaging: a pilot study.

BACKGROUND: Motor cortex stimulation applied as a clinical treatment for neuropathic disorders for decades. With stimulation electrodes placed directly on the cortical surface, this neuromodulation method provides higher spatial resolution than other non-invasive therapies. Yet, the therapeutic effects reported were not in conformity with different syndromes. One of the main issues is that the stimulation parameters are always determined by clinical experience. The lack of understanding about how the stimulation current propagates in the cortex and various stimulation parameters and configurations obstruct the development of this method. METHODS: In this study, we investigated the effect of different stimulation configurations on cortical responses to motor cortical stimulations using intrinsic optical imaging. RESULTS: Our results showed that the cortical activation of electrical stimulation is not only related to the current density but also related to the propagation distance. Besides, stimulation configurations also affect the propagation of the stimulation current. CONCLUSIONS: All these results provide preliminary experimental evidence for parameter and electrode configuration optimizations.

Short report: surgery for implantable brain-computer interface assisted by robotic navigation system.

We present an implantable brain-computer interface surgical case assisted by robotic navigation system in an elderly patient with tetraplegia caused by cervical spinal cord injury. Left primary motor cortex was selected for implantation of microelectrode arrays based on fMRI location of motor imagery. Robotic navigation system was used during this procedure for precise and stable manipulation. A design of bipartite incision was made to reduce the risk of surgery-related infection and facilitate BCI training. At 1-year follow-up, the neural signals were robust, and this patient was able to control three-dimensional movement of a prosthetic limb without any complications.

Vitamin C intake and multiple health outcomes: an umbrella review of systematic reviews and meta-analyses.

The purpose of this article was to assess the existing systematic reviews and meta-analyses for the association between vitamin C intake and multiple health outcomes. A total of 76 meta-analyses (51 papers) of randomised controlled trials and observational studies with 63 unique health outcomes were identified. Dose-response analysis showed that vitamin C intake was associated with reduced risk of all-cause mortality, cardiovascular disease (CVD), oesophageal cancer, gastric cancer, cervical cancer and lung cancer with an increment of 50-100 mg per day. Beneficial associations were also identified for respiratory, neurological, ophthalmologic, musculoskeletal, renal and dental outcomes. Harmful associations were found for breast cancer and kidney stones for vitamin C supplement intake. The benefits of vitamin C intake outweigh the disadvantages for a range of health outcomes. However, the recommendation of vitamin C supplements needs to be cautious. More prospective studies and well-designed randomised controlled trials (RCTs) are needed.

Brain-Machine Interface-Based Rat-Robot Behavior Control.

Brain-machine interface (BMI) provides a bidirectional pathway between the brain and external facilities. The machine-to-brain pathway makes it possible to send artificial information back into the biological brain, interfering neural activities and generating sensations. The idea of the BMI-assisted bio-robotic animal system is accomplished by stimulations on specific sites of the nervous system. With the technology of BMI, animals' locomotion behavior can be precisely controlled as robots, which made the animal turning into bio-robot. In this chapter, we reviewed our lab works focused on rat-robot navigation. The principles of rat-robot system have been briefly described first, including the target brain sites chosen for locomotion control and the design of remote control system. Some methodological advances made by optogenetic technologies for better modulation control have then been introduced. Besides, we also introduced our implementation of "mind-controlled" rat navigation system. Moreover, we have presented our efforts made on combining biological intelligence with artificial intelligence, with developments of automatic control and training system assisted with images or voices inputs. We concluded this chapter by discussing further developments to acquire environmental information as well as promising applications with write-in BMIs.

Determination of glucosamine and its derivatives released from photocrosslinked gelatin hydrogels using HPLC.

A simple, accurate and validated reverse-phase high-performance liquid chromatography (HPLC)/UV method is developed for the determination of glucosamine hydrochloride (GlcN), N-acetyl-glucosamine (NAG) and N-acryloyl-glucosamine (AGA) released from photocrosslinked gelatin hydrogels. The HPLC separation was achieved on a Shimadzu InertSustain amino column (250 × 4.6 mm, 5 µm particle size) at room temperature using a mobile phase of acetonitrile-phosphate buffer (75:25, v/v, pH 6.0) at a flow rate of 1.0 mL/min and UV detection of 194 nm. The method was validated for specificity, linearity, limit of detection and quantification, accuracy, precision, extraction recovery and solution stability. The calibration curves were with excellent linearity, with correlation coefficients (R(2)) >0.999 for all three drugs. The intra- and inter-day variation was <3.10% and the relative error was between -1.43 and 1.78%. The extraction recovery results ranged from 94.62 to 99.33%, demonstrating the absence of matrix effect. The sample and standard solutions were stable for more than 2 months. The method was successfully used for the analysis of released properties of drugs physically encapsulated and chemically crosslinked in the gelatin hydrogels.

Role of electrophysiological activity and interactions of lateral habenula in the development of depression-like behavior in a chronic restraint stress model.

Closed-loop deep brain stimulation (DBS) system offers a promising approach for treatment-resistant depression, but identifying universally accepted electrophysiological biomarkers for closed-loop DBS systems targeting depression is challenging. There is growing evidence suggesting a strong association between the lateral habenula (LHb) and depression. Here, we took LHb as a key target, utilizing multi-site local field potentials (LFPs) to study the acute and chronic changes in electrophysiology, functional connectivity, and brain network characteristics during the formation of a chronic restraint stress (CRS) model. Furthermore, our model combining the electrophysiological changes of LHb and interactions between LHb and other potential targets of depression can effectively distinguish depressive states, offering a new way for developing effective closed-loop DBS strategies.

GLIM Achieves Best Diagnostic Performance in Non-Cancer Patients with Low BMI: A Hierarchical Bayesian Latent-Class Meta-Analysis.

CONTEXT: Global Leadership Initiative on Malnutrition (GLIM) and Patient-Generated Subjective Global Assessment (PG-SGA) are commonly used nutrition assessment tools, whose performance does not reach a consensus due to different and imperfect reference standards. OBJECTIVE: This study aimed to evaluate and compare the diagnostic accuracy of GLIM and PG-SGA, using a hierarchical Bayesian latent class model, in the absence of a gold standard. DATA SOURCES: A systematic search was undertaken in PubMed, Embase, and Web of Science from inception to October 2022. Diagnostic test studies comparing (1) the GLIM and/or (2) PG-SGA with "semi-gold" standard assessment tools for malnutrition were included. DATA EXTRACTION: Two authors independently extracted data on sensitivity, specificity, and other key characteristics. The methodological quality of each included study was appraised according to the criteria in the Quality Assessment of Diagnostic Accuracy Studies-2. DATA ANALYSIS: A total of 45 studies, comprising 20 876 individuals evaluated for GLIM and 11 575 for PG-SGA, were included. The pooled sensitivity was 0.833 (95% CI 0.744 to 0.896) for GLIM and 0.874 (0.797 to 0.925) for PG-SGA, while the pooled specificity was 0.837 (0.780 to 0.882) for GLIM and 0.778 (0.707 to 0.836) for PG-SGA. GLIM showed slightly better performance than PG-SGA, with a higher diagnostic odds ratio (25.791 vs 24.396). The diagnostic performance of GLIM was most effective in non-cancer patients with an average body mass index (BMI) of <24 kg/m2, followed by non-cancer patients with an average age of ≥60 years. PG-SGA was most powerful in cancer patients with an average age of <60 years, followed by cancer patients with an average BMI of <24 kg/m2. CONCLUSION: Both GLIM and PG-SGA had moderately high diagnostic capabilities. GLIM was most effective in non-cancer patients with a low BMI, while PG-SGA was more applicable in cancer patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration No. CRD42022380409.

A Self-Adaptive Dual-ILRO Clock-Recovery Technique for Two-Tone Battery-Free Crystal-Free Neural-Recording SoC.

Wireless implantable devices are widely used in medical treatment, which should meet clinical constraints such as longevity, miniaturization, and reliable communication. Wireless power transfer (WPT) can eliminate the battery to reduce system size and prolong device life, while it's challenging to generate a reliable clock without a crystal. In this work, we propose a self-adaptive dual-injection-locked-ring-oscillator (dual-ILRO) clock-recovery technique based on two-tone WPT and integrate it into a battery-free neural-recording SoC. The 2[Formula: see text]-order inter-modulation (IM2) component of the two WPT tones is extracted as a low-frequency reference for battery-free SoC, and the proposed self-adaptive dual-ILRO technique extends the lock range to ensure an anti-interference PVT-robust clock generation. The neural-recording SoC includes a low-noise signal acquisition unit, a power management unit, and a backscatter circuit to perform neural signal recording, wireless power harvesting, and neural data transmission. Benefiting from the 6.4 µW low power of the clock recovery circuit, the overall SoC power is cut down to 49.8 µW. In addition, the proposed clock-recovery technique enables both signal acquisition and uplink communication to perform as well as that synchronized by an ideal clock, i.e., an effective number of 9.6 bits and a bit error rate (BER) less than 4.8 × 10-7 in chip measurement. The SoC takes a die area of 2.05 mm 2, and an animal test is conducted in a Sprague-Dawley rat to validate the wireless neural-recording performance, compared to a crystal-synchronized commercial chip.

Miniaturized Implantable Fluorescence Probes Integrated with Metal-Organic Frameworks for Deep Brain Dopamine Sensing.

Continuously monitoring neurotransmitter dynamics can offer profound insights into neural mechanisms and the etiology of neurological diseases. Here, we present a miniaturized implantable fluorescence probe integrated with metal-organic frameworks (MOFs) for deep brain dopamine sensing. The probe is assembled from physically thinned light-emitting diodes (LEDs) and phototransistors, along with functional surface coatings, resulting in a total thickness of 120 µm. A fluorescent MOF that specifically binds dopamine is introduced, enabling a highly sensitive dopamine measurement with a detection limit of 79.9 nM. A compact wireless circuit weighing only 0.85 g is also developed and interfaced with the probe, which was later applied to continuously monitor real-time dopamine levels during deep brain stimulation in rats, providing critical information on neurotransmitter dynamics. Cytotoxicity tests and immunofluorescence analysis further suggest a favorable biocompatibility of the probe for implantable applications. This work presents fundamental principles and techniques for integrating fluorescent MOFs and flexible electronics for brain-computer interfaces and may provide more customized platforms for applications in neuroscience, disease tracing, and smart diagnostics.

Restoration of coherent reach-grasp-pull movement via sequential intraneural peripheral nerve stimulation in rats.

Objective.Peripheral nerve stimulation (PNS) has been demonstrated as an effective way to selectively activate muscles and to produce fine hand movements. However, sequential multi-joint upper limb movements, which are critical for paralysis rehabilitation, has not been tested with PNS. Here, we aimed to restore multiple upper limb joint movements through an intraneural interface with a single electrode, achieving coherent reach-grasp-pull movement tasks through sequential stimulation.Approach.A transverse intrafascicular multichannel electrode was implanted under the axilla of the rat's upper limb, traversing the musculocutaneous, radial, median, and ulnar nerves. Intramuscular electrodes were implanted into the biceps brachii (BB), triceps brachii (TB), flexor carpi radialis (FCR), and extensor carpi radialis (ECR) muscles to record electromyographic (EMG) activity and video recordings were used to capture the kinematics of elbow, wrist, and digit joints. Charge-balanced biphasic pulses were applied to different channels to recruit distinct upper limb muscles, with concurrent recording of EMG signals and joint kinematics to assess the efficacy of the stimulation. Finally, a sequential stimulation protocol was employed by generating coordinated pulses in different channels.Main results.BB, TB, FCR and ECR muscles were selectively activated and various upper limb movements, including elbow flexion, elbow extension, wrist flexion, wrist extension, digit flexion, and digit extension, were reliably generated. The modulation effects of stimulation parameters, including pulse width, amplitude, and frequency, on induced joint movements were investigated and reach-grasp-pull movement was elicited by sequential stimulation.Significance.Our results demonstrated the feasibility of sequential intraneural stimulation for functional multi-joint movement restoration, providing a new approach for clinical rehabilitation in paralyzed patients.

Targeted Optical Neural Stimulation: A New Era for Personalized Medicine.

Targeted optical neural stimulation comprises infrared neural stimulation and optogenetics, which affect the nervous system through induced thermal transients and activation of light-sensitive proteins, respectively. The main advantage of this pair of optical tools is high functional selectivity, which conventional electrical stimulation lacks. Over the past 15 years, the mechanism, safety, and feasibility of optical stimulation techniques have undergone continuous investigation and development. When combined with other methods like optical imaging and high-field functional magnetic resonance imaging, the translation of optical stimulation to clinical practice adds high value. We review the theoretical foundations and current state of optical stimulation, with a particular focus on infrared neural stimulation as a potential bridge linking optical stimulation to personalized medicine.

Infrared neural stimulation in human cerebral cortex.

BACKGROUND: Modulation of brain circuits by electrical stimulation has led to exciting and powerful therapies for diseases such as Parkinson's. Because human brain organization is based in mesoscale (millimeter-scale) functional nodes, having a method that can selectively target such nodes could enable more precise, functionally specific stimulation therapies. Infrared Neural Stimulation (INS) is an emerging stimulation technology that stimulates neural tissue via delivery of tiny heat pulses. In nonhuman primates, this optical method provides focal intensity-dependent stimulation of the brain without tissue damage. However, whether INS application to the human central nervous system (CNS) is similarly effective is unknown. OBJECTIVE: To examine the effectiveness of INS on human cerebral cortex in intraoperative setting and to evaluate INS damage threshholds. METHODS: Five epileptic subjects undergoing standard lobectomy for epilepsy consented to this study. Cortical response to INS was assessed by intrinsic signal optical imaging (OI, a method that detects changes in tissue reflectance due to neuronal activity). A custom integrated INS and OI system was developed specifically for short-duration INS and OI acquisition during surgical procedures. Single pulse trains of INS with intensities from 0.2 to 0.8 J/cm2 were delivered to the somatosensory cortex and responses were recorded via optical imaging. Following tissue resection, histological analysis was conducted to evaluate damage threshholds. RESULTS: As assessed by OI, and similar to results in monkeys, INS induced responses in human cortex were highly focal (millimeter sized) and led to relative suppression of nearby cortical sites. Intensity dependence was observed at both stimulated and functionally connected sites. Histological analysis of INS-stimulated human cortical tissue provided damage threshold estimates. CONCLUSION: This is the first study demonstrating application of INS to human CNS and shows feasibility for stimulating single cortical nodes and associated sites and provided INS damage threshold estimates for cortical tissue. Our results suggest that INS is a promising tool for stimulation of functionally selective mesoscale circuits in the human brain, and may lead to advances in the future of precision medicine.

Representation and decoding of bilateral arm motor imagery using unilateral cerebral LFP signals.

Introduction: In the field of upper limb brain computer interfaces (BCIs), the research focusing on bilateral decoding mostly based on the neural signals from two cerebral hemispheres. In addition, most studies used spikes for decoding. Here we examined the representation and decoding of different laterality and regions arm motor imagery in unilateral motor cortex based on local field potentials (LFPs). Methods: The LFP signals were recorded from a 96-channel Utah microelectrode array implanted in the left primary motor cortex of a paralyzed participant. There were 7 kinds of tasks: rest, left, right and bilateral elbow and wrist flexion. We performed time-frequency analysis on the LFP signals and analyzed the representation and decoding of different tasks using the power and energy of different frequency bands. Results: The frequency range of <8 Hz and >38 Hz showed power enhancement, whereas 8-38 Hz showed power suppression in spectrograms while performing motor imagery. There were significant differences in average energy between tasks. What's more, the movement region and laterality were represented in two dimensions by demixed principal component analysis. The 135-300 Hz band signal had the highest decoding accuracy among all frequency bands and the contralateral and bilateral signals had more similar single-channel power activation patterns and larger signal correlation than contralateral and ipsilateral signals, bilateral and ipsilateral signals. Discussion: The results showed that unilateral LFP signals had different representations for bilateral motor imagery on the average energy of the full array and single-channel power levels, and different tasks could be decoded. These proved the feasibility of multilateral BCI based on the unilateral LFP signal to broaden the application of BCI technology. Clinical trial registration: https://www.chictr.org.cn/showproj.aspx?proj=130829, identifier ChiCTR2100050705.

A 4.43 TΩ ZIN 0.0128 mm2 Cascaded Instrumentation Amplifier with Input-biased Pseudo Resistor for Implantable Brain Machine Interfaces.

A cascaded instrumentation amplifier (CaIA) with input-biased pseudo resistors (IBPR) is presented for implantable brain machine interfaces (BMI). The gain distribution of two-stage cascaded amplifiers, instead of a single-stage amplifier, helps to achieve an input impedance of 4.43TΩ at 100Hz, and maintain the small active area (0.0128 mm2). The input-biased pseudo resistors contribute to a much lower high-pass corner (fHP=0.00011Hz) compared with the conventional structure, the input-referred noise is only 3.836µVrms integrated from 0.5Hz to 10kHz with 0.98µW power consumption.Clinical Relevance- This establishes an area-efficient amplifier design with ultra-high input impedance (4.43TΩ at 100Hz) and hyper-low high-pass corner frequency (fHP=0.00011Hz), which is suitable for long-term monitoring of neural activities (including slow oscillations) in implantable brain-machine interfaces.

A Wireless Headstage System Based on Neural-Recording Chip Featuring 315 nW Kickback-Reduction SAR ADC.

Wireless neural-recording instruments eliminate the bulky cables in multi-channel signal transmission, while the system size should be reduced to mitigate the impact on freely-moving animals. As the battery usually dominates the system size, the neural-recording chip should be low power to minimize the battery in long-termly monitoring. In general, a neural-recording chip consists of an analog front end (AFE) and an 8 bit -10 bit analog-to-digital converter (ADC), while it's challenging to design an ADC with an 8 -10 effective number of bits (ENOB) and sub- µ W power consumption due to the kickback noise. In this work, we propose a kickback-reduction technique for a successive-approximation-register (SAR) ADC based on neural-recording chip. Fabricated in 65 nm CMOS process, the proposed technique reduce the ADC power to 315 nW, resulting in an 8-channel neural-recording chip with 249 µW in total. Measured results show that the chip achieves an ADC ENOB of 9.73 bits, as well as an AFE gain of 43.3 dB and input-referred noise (IRN) of 9.68 µVrms in a bandwidth of 0.9 Hz -7.2 kHz. Combined with a BLE chip and a PCB antenna, the chip is implemented into a 2.6 g wireless headstage system (w/o battery), and an in-vivo demonstration is conducted on a male Sprague-Dawley rat with Parkinson's disease. The headstage system transfers the in-vivo neural signals to a commodity smartphone through BLE, and the miniature size induces little impact on freely-moving activities.

Neuronal representation of bimanual arm motor imagery in the motor cortex of a tetraplegia human, a pilot study.

Introduction: How the human brain coordinates bimanual movements is not well-established. Methods: Here, we recorded neural signals from a paralyzed individual's left motor cortex during both unimanual and bimanual motor imagery tasks and quantified the representational interaction between arms by analyzing the tuning parameters of each neuron. Results: We found a similar proportion of neurons preferring each arm during unimanual movements, however, when switching to bimanual movements, the proportion of contralateral preference increased to 71.8%, indicating contralateral lateralization. We also observed a decorrelation process for each arm's representation across the unimanual and bimanual tasks. We further confined that these changes in bilateral relationships are mainly caused by the alteration of tuning parameters, such as the increased bilateral preferred direction (PD) shifts and the significant suppression in bilateral modulation depths (MDs), especially the ipsilateral side. Discussion: These results contribute to the knowledge of bimanual coordination and thus the design of cutting-edge bimanual brain-computer interfaces.