Addressing the sources of inter-subject variability in E-field parameters in anodal tDCS stimulation over motor cortical network.

Objetive: .Although transcranial direct current stimulation constitutes a non-invasive neuromodulation technique with promising results in a great variety of applications, its clinical implementation is compromised by the high inter-subject variability reported. This study aims to analyze the inter-subject variability in electric fields (E-fields) over regions of the cortical motor network under two electrode montages: the classical C3Fp2 and an alternative P3F3, which confines more the E-field over this region.Approach.Computational models of the head of 98 healthy subjects were developed to simulate the E-field under both montages. E-field parameters such as magnitude, focality and orientation were calculated over three regions of interest (ROI): M1S1, supplementary motor area (SMA) and preSMA. The role of anatomical characteristics as a source of inter-subject variability on E-field parameters and individualized stimulation intensity were addressed using linear mixed-effect models.Main results.P3F3 showed a more confined E-field distribution over M1S1 than C3Fp2; the latter elicited higher E-fields over supplementary motor areas. Both montages showed high inter-subject variability, especially for the normal component over C3Fp2. Skin, bone and CSF ROI volumes showed a negative association with E-field magnitude irrespective of montage. Grey matter volume and montage were the main sources of variability for focality. The curvature of gyri was found to be significantly associated with the variability of normal E-fields.Significance.Computational modeling proves useful in the assessment of E-field variability. Our simulations predict significant differences in E-field magnitude and focality for C3Fp2 and P3F3. However, anatomical characteristics were also found to be significant sources of E-field variability irrespective of electrode montage. The normal E-field component better captured the individual variability and low rate of responder subjects observed in experimental studies.

Linking inter-subject variability of cerebellar functional connectome to clinical symptoms in major depressive disorder.

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder with remarkable inter-subject variability in clinical manifestations. Neuroimaging changes of the cerebellum have been recently proposed as a way to characterize MDD-related brain disruptions and might further explain various clinical symptoms. However, the cerebellar contributions to MDD clinical heterogeneity remain largely unknown. The analyzed data consisted of 251 MDD patients and 235 matching healthy controls (HC). The inter-subject variability of functional connectomes (IVFC) was estimated via Pearson's correlation analysis between each pair of the cerebellar and cerebral regions based on resting-state functional magnetic resonance imaging (rs-fMRI). A partial least squares (PLS) regression analysis was performed to determine the potential dimension linking the IVFC to clinical symptom measures. The results indicated that similar spatial distribution patterns of the cerebellar IVFC were observed between MDD and HC, but the MDD group exhibited abnormal IVFC alterations in the bilateral Cerebelum_4_5, bilateral Cerebelum_6, Vermis_1_2 and Vermis_8. The PLS model revealed that the IVFC pattern in the left Cerebelum_6 was significantly associated with three HAMD-17 items including the work and activities, psychomotor retardation, and depressed mood. These findings provided new evidence for the cerebellar changes in MDD. Specifically, we found that the altered inter-subject variability measurements correlated with clinical manifestations of this illness. Elucidating this variability could prove helpful for the evaluation of MDD heterogeneity as well as for understanding its pathophysiological mechanism.

Culture shapes spontaneous brain dynamics - Shared versus idiosyncratic neural features among Chinese versus Canadian subjects.

Environmental factors, such as culture, are known to shape individual variation in brain activity including spontaneous activity, but less is known about their population-level effects. Eastern and Western cultures differ strongly in their cultural norms about relationships between individuals. For example, the collectivism, interdependence and tightness of Eastern cultures relative to the individualism, independence and looseness of Western cultures, promote interpersonal connectedness and coordination. Do such cultural contexts therefore influence the group-level variability of their cultural members' spontaneous brain activity? Using novel methods adapted from studies of inter-subject neural synchrony, we compare the group-level variability of resting state EEG dynamics in Chinese and Canadian samples. We observe that Chinese subjects show significantly higher inter-subject correlation and lower inter-subject distance in their EEG power spectra than Canadian subjects, as well as lower variability in theta power and alpha peak frequency. We demonstrate, for the first time, different relationships among subjects' resting state brain dynamics in Chinese and Canadian samples. These results point to more idiosyncratic neural dynamics among Canadian participants, compared with more shared neural features in Chinese participants.

Validity and Reliability of Inertial Measurement Unit (IMU)-Derived 3D Joint Kinematics in Persons Wearing Transtibial Prosthesis.

BACKGROUND: A validity and reliability assessment of inertial measurement unit (IMU)-derived joint angular kinematics during walking is a necessary step for motion analysis in the lower extremity prosthesis user population. This study aimed to assess the accuracy and reliability of an inertial measurement unit (IMU) system compared to an optical motion capture (OMC) system in transtibial prosthesis (TTP) users. METHODS: Thirty TTP users were recruited and underwent simultaneous motion capture from IMU and OMC systems during walking. Reliability and validity were assessed using intra- and inter-subject variability with standard deviation (S.D.), average S.D., and intraclass correlation coefficient (ICC). RESULTS: The intra-subject S.D. for all rotations of the lower limb joints were less than 1° for both systems. The IMU system had a lower mean S.D. (o), as seen in inter-subject variability. The ICC revealed good to excellent agreement between the two systems for all sagittal kinematic parameters. CONCLUSION: All joint angular kinematic comparisons supported the IMU system's results as comparable to OMC. The IMU was capable of precise sagittal plane motion data and demonstrated validity and reliability to OMC. These findings evidence that when compared to OMC, an IMU system may serve well in evaluating the gait of lower limb prosthesis users.

Inter-subject variability of pleasant pain relief using a data-driven approach in healthy volunteers.

Background: The offset of a painful and unpleasant sensation can elicit pleasure. This phenomenon, namely pleasant pain relief (PPR), is attracting growing interest in research. While the cold pressor test (CPT) has been frequently used to study the inhibition of pain by the administration of another painful stimulation (inhibitory conditioned pain modulation; ICPM), a preliminary study from our research team has shown that CPT can also elicit a robust and long-lasting PPR. However, its effects on pain relief and inhibition vary greatly between subjects. Although substantial research has been carried out on inter-individual variability in the case of ICPM, the same cannot be said of PPR. Therefore, the current study sought to identify clusters of healthy volunteers with similar dynamic pain responses during the CPT, using a data-driven approach, and to investigate the inter-subject variability for PPR and ICPM. Methods: One hundred and twenty-two healthy volunteers were recruited. A sequential ICPM paradigm was carried out with CPT (water at 10°C) and a Peltier Thermode to evaluate pain intensity and unpleasantness. Moreover, PPR was measured for four minutes at CPT offset. Statistical analyses were performed using group-based trajectory modelling. Results: Four trajectories (groups) were identified for CPT pain intensity and unpleasantness ratings with varying levels of tonic pain and pain sensitization (e.g., temporal summation). PPR scores were correlated with both pain ratings trajectories (p < 0.001). On the other hand, no differences were found between groups regarding ICPM efficacy (percentage pain inhibition). Discussion: This study has provided a first step into the investigation of PPR and ICPM interindividual variability. Using a data-driven approach, it was shown that PPR at CPT offset differs between clusters of participants identified based on dynamic pain intensity and unpleasantness responses from CPT. Thus, it was brought to light that both the levels of tonic pain and pain sensitization underlie individual differences in PPR. The lack of correlation between CPT pain trajectories and ICPM efficacy may be explained by the hypotheses that eliciting ICPM requires only a certain threshold of stimulation which doesn't need to be noxious. In the future, studies on the inter-subject variability of PPR in large samples of chronic pain patients are warranted.

Inter-Individual Variability in tDCS Effects: A Narrative Review on the Contribution of Stable, Variable, and Contextual Factors.

Due to its safety, portability, and cheapness, transcranial direct current stimulation (tDCS) use largely increased in research and clinical settings. Despite tDCS's wide application, previous works pointed out inconsistent and low replicable results, sometimes leading to extreme conclusions about tDCS's ineffectiveness in modulating behavioral performance across cognitive domains. Traditionally, this variability has been linked to significant differences in the stimulation protocols across studies, including stimulation parameters, target regions, and electrodes montage. Here, we reviewed and discussed evidence of heterogeneity emerging at the intra-study level, namely inter-individual differences that may influence the response to tDCS within each study. This source of variability has been largely neglected by literature, being results mainly analyzed at the group level. Previous research, however, highlighted that only a half-or less-of studies' participants could be classified as responders, being affected by tDCS in the expected direction. Stable and variable inter-individual differences, such as morphological and genetic features vs. hormonal/exogenous substance consumption, partially account for this heterogeneity. Moreover, variability comes from experiments' contextual elements, such as participants' engagement/baseline capacity and individual task difficulty. We concluded that increasing knowledge on inter-dividual differences rather than undermining tDCS effectiveness could enhance protocols' efficiency and reproducibility.

Disentangling cortical functional connectivity strength and topography reveals divergent roles of genes and environment.

The human brain varies across individuals in its morphology, function, and cognitive capacities. Variability is particularly high in phylogenetically modern regions associated with higher order cognitive abilities, but its relationship to the layout and strength of functional networks is poorly understood. In this study we disentangled the variability of two key aspects of functional connectivity: strength and topography. We then compared the genetic and environmental influences on these two features. Genetic contribution is heterogeneously distributed across the cortex and differs for strength and topography. In heteromodal areas genes predominantly affect the topography of networks, while their connectivity strength is shaped primarily by random environmental influence such as learning. We identified peak areas of genetic control of topography overlapping with parts of the processing stream from primary areas to network hubs in the default mode network, suggesting the coordination of spatial configurations across those processing pathways. These findings provide a detailed map of the diverse contribution of heritability and individual experience to the strength and topography of functional brain architecture.

Safety and pharmacokinetics of a new biosimilar trastuzumab (HL02): a Phase I bioequivalence study in healthy Chinese men.

OBJECTIVES: The study aimed to explore the bioequivalence of a proposed biosimilar HL02 vs. its reference products (US-trastuzumab) among healthy Chinese men. METHODS: In this study, nine healthy male subjects received single ascending doses of trastuzumab biosimilar (HL02, 2-8 mg/kg), and then a randomized, double-blind, two-arm, parallel study was conducted to investigate the PK similarity of HL02 (6 mg/kg) with that of US-trastuzumab as a reference drug. RESULTS: PK properties exhibited by HL02 (N = 55) were similar to those of US-trastuzumab (N = 52). The comparison of biosimilarity with US-trastuzumab showed that the 90% confidence intervals (CIs) of the ratios for Cmax, AUC0-t, and AUC0-∞ were within 80-125%. Nineteen subjects were positive for ADA and negative for NAb in both HL02 and US-trastuzumab groups. In total, 81.67% of subjects in HL02 and 78.95% in US-trastuzumab groups showed treatment-related mild or moderate adverse events, mild elevation of transaminase level being the most common adverse events (AE) recorded. CONCLUSIONS: The PK characteristics and immunogenicity exhibited by HL02 were similar to that of the reference product, US-trastuzumab. The safety profiles were similar in both the treatment groups with mild-moderate adverse effects.

Slow Resting State Fluctuations Enhance Neuronal and Behavioral Responses to Looming Sounds.

We investigate both experimentally and using a computational model how the power of the electroencephalogram (EEG) recorded in human subjects tracks the presentation of sounds with acoustic intensities that increase exponentially (looming) or remain constant (flat). We focus on the link between this EEG tracking response, behavioral reaction times and the time scale of fluctuations in the resting state, which show considerable inter-subject variability. Looming sounds are shown to generally elicit a sustained power increase in the alpha and beta frequency bands. In contrast, flat sounds only elicit a transient upsurge at frequencies ranging from 7 to 45 Hz. Likewise, reaction times (RTs) in an audio-tactile task at different latencies from sound onset also present significant differences between sound types. RTs decrease with increasing looming intensities, i.e. as the sense of urgency increases, but remain constant with stationary flat intensities. We define the reaction time variation or "gain" during looming sound presentation, and show that higher RT gains are associated with stronger correlations between EEG power responses and sound intensity. Higher RT gain further entails higher relative power differences between loom and flat in the alpha and beta bands. The full-width-at-half-maximum of the autocorrelation function of the eyes-closed resting state EEG also increases with RT gain. The effects are topographically located over the central and frontal electrodes. A computational model reveals that the increase in stimulus-response correlation in subjects with slower resting state fluctuations is expected when EEG power fluctuations at each electrode and in a given band are viewed as simple coupled low-pass filtered noise processes jointly driven by the sound intensity. The model assumes that the strength of stimulus-power coupling is proportional to RT gain in different coupling scenarios, suggesting a mechanism by which slower resting state fluctuations enhance EEG response and shorten reaction times.

Automatic measure and normalization of spinal cord cross-sectional area using the pontomedullary junction.

Spinal cord cross-sectional area (CSA) is a relevant biomarker to assess spinal cord atrophy in neurodegenerative diseases. However, the considerable inter-subject variability among healthy participants currently limits its usage. Previous studies explored factors contributing to the variability, yet the normalization models required manual intervention and used vertebral levels as a reference, which is an imprecise prediction of the spinal levels. In this study we implemented a method to measure CSA automatically from a spatial reference based on the central nervous system (the pontomedullary junction, PMJ), we investigated factors to explain variability, and developed normalization strategies on a large cohort (N = 804). Following automatic spinal cord segmentation, vertebral labeling and PMJ labeling, the spinal cord CSA was computed on T1w MRI scans from the UK Biobank database. The CSA was computed using two methods. For the first method, the CSA was computed at the level of the C2-C3 intervertebral disc. For the second method, the CSA was computed at 64 mm caudally from the PMJ, this distance corresponding to the average distance between the PMJ and the C2-C3 disc across all participants. The effect of various demographic and anatomical factors was explored, and a stepwise regression found significant predictors; the coefficients of the best fit model were used to normalize CSA. CSA measured at C2-C3 disc and using the PMJ differed significantly (paired t-test, p-value = 0.0002). The best normalization model included thalamus, brain volume, sex and the interaction between brain volume and sex. The coefficient of variation went down for PMJ CSA from 10.09 (without normalization) to 8.59%, a reduction of 14.85%. For CSA at C2-C3, it went down from 9.96 to 8.42%, a reduction of 15.13 %. This study introduces an end-to-end automatic pipeline to measure and normalize cord CSA from a neurological reference. This approach requires further validation to assess atrophy in longitudinal studies. The inter-subject variability of CSA can be partly accounted for by demographics and anatomical factors.

An empirical evaluation of functional alignment using inter-subject decoding.

Inter-individual variability in the functional organization of the brain presents a major obstacle to identifying generalizable neural coding principles. Functional alignment-a class of methods that matches subjects' neural signals based on their functional similarity-is a promising strategy for addressing this variability. To date, however, a range of functional alignment methods have been proposed and their relative performance is still unclear. In this work, we benchmark five functional alignment methods for inter-subject decoding on four publicly available datasets. Specifically, we consider three existing methods: piecewise Procrustes, searchlight Procrustes, and piecewise Optimal Transport. We also introduce and benchmark two new extensions of functional alignment methods: piecewise Shared Response Modelling (SRM), and intra-subject alignment. We find that functional alignment generally improves inter-subject decoding accuracy though the best performing method depends on the research context. Specifically, SRM and Optimal Transport perform well at both the region-of-interest level of analysis as well as at the whole-brain scale when aggregated through a piecewise scheme. We also benchmark the computational efficiency of each of the surveyed methods, providing insight into their usability and scalability. Taking inter-subject decoding accuracy as a quantification of inter-subject similarity, our results support the use of functional alignment to improve inter-subject comparisons in the face of variable structure-function organization. We provide open implementations of all methods used.

A Biosimilarity Study Between QX001S and Ustekinumab in Healthy Chinese Male Subjects.

Objective: To evaluate the tolerance, variability, and pharmacokinetics (PK) of QX001S, a biosimilar for ustekinumab, in healthy Chinese men. Methods: One hundred and seventy-eight healthy men were recruited in this randomized, double-blind, single-dose, two-arm, parallel study, and received 45 mg of QX001S or ustekinumab in a single subcutaneous injection. PK, immunogenicity, and tolerance were evaluated in all participants for a period of 113°days. Results: The similarity between the two drugs was determined by comparing the baseline characteristics for each drug. The PK parameters were similar in the two groups: QX001S (n = 89) and ustekinumab (n = 88). The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of QX001S to the reference (ustekinumab) for the maximum observable serum concentration (C max ), area under the curve (AUC) from zero to the final quantifiable concentration (AUC0-t), and AUC from zero to infinity (AUC0-∞) were 100.90-118.68%, 98.71-115.26%, and 98.49-115.81%, respectively, which were within the predefined bioequivalence limit of 80.00-125.00%. High inter-subject variability (ranging from 32.0 to 33.5%) was observed. A total of 17 participants (19.1%) in the QX001S group and 36 (40.9%) in the ustekinumab group developed anti-drug antibodies (ADA) after administration. Nevertheless, the ADA did not affect the outcomes of the bioequivalence tests. Adverse reactions were recorded in 38 individuals injected with QX001S and 37 injected with ustekinumab. The most common adverse reactions were upper respiratory infection and elevated alanine aminotransferase. Conclusions: Our study ratified pharmacokinetic biosimilarity between QX001 S and ustekinumab, with high variability between subjects.

The Effects of Individual Differences, Non-Stationarity, and the Importance of Data Partitioning Decisions for Training and Testing of EEG Cross-Participant Models.

EEG-based deep learning models have trended toward models that are designed to perform classification on any individual (cross-participant models). However, because EEG varies across participants due to non-stationarity and individual differences, certain guidelines must be followed for partitioning data into training, validation, and testing sets, in order for cross-participant models to avoid overestimation of model accuracy. Despite this necessity, the majority of EEG-based cross-participant models have not adopted such guidelines. Furthermore, some data repositories may unwittingly contribute to the problem by providing partitioned test and non-test datasets for reasons such as competition support. In this study, we demonstrate how improper dataset partitioning and the resulting improper training, validation, and testing of a cross-participant model leads to overestimated model accuracy. We demonstrate this mathematically, and empirically, using five publicly available datasets. To build the cross-participant models for these datasets, we replicate published results and demonstrate how the model accuracies are significantly reduced when proper EEG cross-participant model guidelines are followed. Our empirical results show that by not following these guidelines, error rates of cross-participant models can be underestimated between 35% and 3900%. This misrepresentation of model performance for the general population potentially slows scientific progress toward truly high-performing classification models.

Normalization of Spinal Cord Total Cross-Sectional and Gray Matter Areas as Quantified With Radially Sampled Averaged Magnetization Inversion Recovery Acquisitions.

Background: MR imaging of the spinal cord (SC) gray matter (GM) at the cervical and lumbar enlargements' level may be particularly informative in lower motor neuron disorders, e. g., spinal muscular atrophy, but also in other neurodegenerative or autoimmune diseases affecting the SC. Radially sampled averaged magnetization inversion recovery acquisition (rAMIRA) is a novel approach to perform SC imaging in clinical settings with favorable contrast and is well-suited for SC GM quantitation. However, before applying rAMIRA in clinical studies, it is important to understand (i) the sources of inter-subject variability of total SC cross-sectional areas (TCA) and GM area (GMA) measurements in healthy subjects and (ii) their relation to age and sex to facilitate the detection of pathology-associated changes. In this study, we aimed to develop normalization strategies for rAMIRA-derived SC metrics using skull and spine-based metrics to reduce anatomical variability. Methods: Sixty-one healthy subjects (age range 11-93 years, 37.7% women) were investigated with axial two-dimensional rAMIRA imaging at 3T MRI. Cervical and thoracic levels including the level of the cervical (C4/C5) and lumbar enlargements (Tmax) were examined. SC T2-weighted sagittal images and high-resolution 3D whole-brain T1-weighted images were acquired. TCA and GMAs were quantified. Anatomical variables with associations of |r| > 0.30 in univariate association with SC areas, and age and sex were used to construct normalization models using backward selection with TCAC4/C5 as outcome. The effect of the normalization was assessed by % relative standard deviation (RSD) reductions. Results: Mean inter-individual variability and the SD of the SC area metrics were considerable: TCAC4/5: 8.1%/9.0; TCATmax: 8.9%/6.5; GMAC4/C5: 8.6%/2.2; GMATmax: 12.2%/3.8. Normalization based on sex, brain WM volume, and spinal canal area resulted in RSD reductions of 23.7% for TCAs and 12.0% for GM areas at C4/C5. Normalizations based on the area of spinal canal alone resulted in RSD reductions of 10.2% for TCAs and 9.6% for GM areas at C4/C5, respectively. Discussion: Anatomic inter-individual variability of SC areas is substantial. This study identified effective normalization models for inter-subject variability reduction in TCA and SC GMA in healthy subjects based on rAMIRA imaging.

EEGs Vary Less Between Lab and Home Locations Than They Do Between People.

Given the rapid development of light weight EEG devices which we have witnessed the past decade, it is reasonable to ask to which extent neuroscience could now be taken outside the lab. In this study, we have designed an EEG paradigm well suited for deployment "in the wild." The paradigm is tested in repeated recordings on 20 subjects, on eight different occasions (4 in the laboratory, 4 in the subject's own home). By calculating the inter subject, intra subject and inter location variance, we find that the inter location variation for this paradigm is considerably less than the inter subject variation. We believe the paradigm is representative of a large group of other relevant paradigms. This means that given the positive results in this study, we find that if a research paradigm would benefit from being performed in less controlled environments, we expect limited problems in doing so.

A randomized phase-I pharmacokinetic trial comparing the potential biosimilar tocilizumab (QX003S) with the reference product (Actemra®) in Chinese healthy subjects.

PURPOSE: QX003S is a biosimilar candidate for the reference tocilizumab, Actemra®. We investigated the tolerance, variability, and pharmacokinetics (PK) of QX003S biosimilar in healthy Chinese male subjects. DESIGN: A randomised, double-blind, two-arm, parallel study was performed to examine the bioequivalence of QX003S (8 mg/kg) with that of Actemra® as a reference drug. RESULTS: QX003S (N = 40) and Actemra® (N = 40) groups exhibited similar PK properties. The inter-subject variability ranged from 14.95% to 18.78%. The 90% confidence intervals of the ratios for Cmax, AUC0-t andAUC0-∞ in both groups were within the range of 80-125%. After administration, the number of subjects who tested positive for anti-drug antibodies (ADA) in the QX003S group and Actemra® groups was 6 (14.3%) and 14 (34.1%), respectively. Adverse reactions occurred in 100% and 97.6% subjects in the QX003S and Actemra® groups, respectively. The most common adverse reactions were decrease in fibrinogen level and neutrophil and leukocyte counts. CONCLUSION: The PK characteristics and immunogenicity exhibited by QX003S were similar to that of the reference product, Actemra®. The safety profile was similar in the two treatment groups with mild-moderate adverse effects.Trial RegistrationThe trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html#CTR20190002)Key pointsThis was the first clinical report of a new proposed tocilizumab biosimilar, QX003S.This phase-I randomized, controlled study compared pharmacokinetics, variability,immunogenicity, and safety of QX003S vs. the approved tocilizumab product (Actemra@).The results demonstrate bioequivalence between BAT1806 and the reference products (Actemra@), as well as comparable immunogenicity, safety and tolerability profiles.

Light Through the Fog: Using Precision fMRI Data to Disentangle the Neural Substrates of Cognitive Control.

Cognitive control, the ability to engage in goal-related behavior, is linked to frontal, parietal, and cingulate brain regions. However, the underlying function(s) of these regions is still in question, with ongoing discussions about their specificity and/or multifunctionality. These brain regions are also among the most variable across individuals, which may confound multi-functionality with inter-individual heterogeneity. Precision fMRI-extended data acquisition from single individuals-allows for reliable individualized mapping of brain organization. We review examples of recent studies that use precision fMRI to surmount inter-individual variability in functional neuroanatomy. These studies provide evidence of interleaved specialized and multifunctional regions in the frontal cortex. We discuss the potential for these techniques to address outstanding controversies on the neural underpinnings of cognitive control.

Safety and pharmacokinetics of a biosimilar of denosumab (KN012): Phase 1 and bioequivalence study in healthy Chinese subjects.

BACKGROUND: KN012 is a proposed biosimilar candidate for the reference drug denosumab, with the brand name Prolia®. This study explored the tolerance, variability, and pharmacokinetics (PK) of denosumab and its biosimilar in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: A randomized, double-blind, parallel, two-arm study was performed to analyze the bioequivalence of denosumab biosimilar (60 mg) compared with denosumab. RESULTS: The PK properties of denosumab biosimilar were similar to those of denosumab. When denosumab biosimilar was compared to denosumab, the geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ were 98.74%, 102.54%, and 102.18%, respectively, and the 90% confidence interval was observed to be within 80-125%. The inter-subject variability ranged from 31.4% to 34.6%. Five subjects in the denosumab biosimilar group and one subject in the denosumab group were positive for anti-drug antibodies (ADAs) and negative for neutralizing antibodies (NAbs). Adverse reactions were observed in 100% (52 subjects) and 94.0% (47 subjects) of the subjects in the denosumab biosimilar and denosumab groups, respectively. Reductions in the blood calcium and phosphate levels were the most common adverse reactions. CONCLUSION: The PK characteristics were comparable for the denosumab biosimilar and denosumab groups. Their safety profiles were also similar. TRIAL REGISTRATION: : The trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html #CTR20181231).

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects.

OBJECTIVE: This study was conducted to explore the tolerance, variability, pharmacokinetics (PK), and pharmacodynamics (PD) of denosumab biosimilar (QL1206) in healthy Chinese subjects. METHODS: This is a randomized, double-blind, two-arm, parallel study performed to examine the bioequivalence of denosumab biosimilar, QL1206, with that of Xgeva® (Denosumab) as a reference drug. A single dose of 120 mg/kg of the denosumab biosimilar or Xgeva® was administered to the subjects, who were followed up for 134 days. RESULTS: Similar PK properties as those of Xgeva® were exhibited by QL1206. When compared to QL1206 with Xgeva®, the 90% confidence intervals of the ratios for Cmax, AUC0-t, and AUC0-∞ were observed to be within 80-125%. The inter-subject variability (inter-CV) ranged from 29% to 39.5%. Six and three subjects in the QL1206 and Xgeva® groups were found to be positive for the ADA and negative for the NAb, respectively. The CTX1 concentration-time profiles appeared similar (about 80% decrease from 48 hours to134 days) between the QL1206 and Xgeva® groups. Adverse events (AEs) were observed in 92.6% and 93.4% of subjects in the QL1206 and Xgeva® groups, respectively. Reduction in blood calcium level was found to be the most common AE recorded, with an incidence of 72.8% versus 72.4% in the QL1206 and Xgeva® groups, respectively. CONCLUSION: Similar PK and PD characteristics were exhibited by QL1206 as compared to those of Xgeva®. The inter-CV was slightly large. The safety profiles of denosumab biosimilars and Xgeva® were found to be similar.

Prediction of Human Inhibition Brain Function with Inter-Subject and Intra-Subject Variability.

The stop signal task has been used to quantify the human inhibitory control. The inter-subject and intra-subject variability was investigated under the inhibition of human response with a realistic environmental scenario. In present study, we used a battleground scenario where a sniper-scope picture was the background, a target picture was a go signal, and a nontarget picture was a stop signal. The task instructions were to respond on the target image and inhibit the response if a nontarget image appeared. This scenario produced a threatening situation and endorsed the evaluation of how subject's response inhibition manifests in a real situation. In this study, 32 channels of electroencephalography (EEG) signals were collected from 20 participants during successful stop (response inhibition) and failed stop (response) trials. These EEG signals were used to predict two possible outcomes: successful stop or failed stop. The inter-subject variability (between-subjects) and intra-subject variability (within-subjects) affect the performance of participants in the classification system. The EEG signals of successful stop versus failed stop trials were classified using quadratic discriminant analysis (QDA) and linear discriminant analysis (LDA) (i.e., parametric) and K-nearest neighbor classifier (KNNC) and Parzen density-based (PARZEN) (i.e., nonparametric) under inter- and intra-subject variability. The EEG activities were found to increase during response inhibition in the frontal cortex (F3 and F4), presupplementary motor area (C3 and C4), parietal lobe (P3 and P4), and occipital (O1 and O2) lobe. Therefore, power spectral density (PSD) of EEG signals (1-50Hz) in F3, F4, C3, C4, P3, P4, O1, and O2 electrodes were measured in successful stop and failed stop trials. The PSD of the EEG signals was used as the feature input for the classifiers. Our proposed method shows an intra-subject classification accuracy of 97.61% for subject 15 with QDA classifier in C3 (left motor cortex) and an overall inter-subject classification accuracy of 71.66% ± 9.81% with the KNNC classifier in F3 (left frontal lobe). These results display how inter-subject and intra-subject variability affects the performance of the classification system. These findings can be used effectively to improve the psychopathology of attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), schizophrenia, and suicidality.