Transcriptomic and macroscopic architectures of intersubject functional variability in human brain white-matter

Intersubject variability is a fundamental characteristic of brain organizations, and not just “noise”. Although intrinsic functional connectivity (FC) is unique to each individual and varies across brain gray-matter, the underlying mechanisms of intersubject functional variability in white-matter (WM) remain unknown. This study identified WMFC variabilities and determined the genetic basis and macroscale imaging in 45 healthy subjects. The functional localization pattern of intersubject variability across WM is heterogeneous, with most variability observed in the heteromodal cortex. The variabilities of heteromodal regions in expression profiles of genes are related to neuronal cells, involved in synapse-related and glutamic pathways, and associated with psychiatric disorders. In contrast, genes overexpressed in unimodal regions are mostly expressed in glial cells and were related to neurological diseases. Macroscopic variability recapitulates the functional and structural specializations and behavioral phenotypes. Together, our results provide clues to intersubject variabilities of the WMFC with convergent transcriptomic and cellular signatures, which relate to macroscale brain specialization.

Utilizing Inter-Subject Variability to Assess Performance and Brain Activity During Complex Task Learning

With tasks becoming more mentally focused and operators being required to conduct multiple tasks simultaneously, it is important to not only acquire direct measurements from the brain, but also account for changes in performance and brain activity as a function of intersubject variability and task demands. Such methodology is particularly important when evaluating skill acquisition and transfer during training on a complex and ecologically valid task. To evaluate the aforementioned factors, we implemented a search and surveillance task (scanning an assigned area and identifying targets) using a high-fidelity Unmanned Aerial System operator training simulator, acquired brain activity changes via a portable functional near infrared spectroscopy (fNIRS) sensor array, and had novice participants (N = 13) undergo three sessions of easy difficulty followed by two harder difficulty sessions. Behavioral performance results indicated no significant change in scan or target find performance across easy sessions when intersubject variability was not accounted for. However, accounting for intersubject variability indicated that some individuals improved their scan performance, and they deteriorated their target find performance (Attention-focused group), while others deteriorated their scan performance, and they improved their target find performance (Accuracy-focused group). fNIRS results displayed that both groups exhibited a decrease in brain activity across easy sessions within the left dorsolateral prefrontal cortex (LDLPFC) and right anterior medial PFC (RAMPFC), while activity in left anterior medial prefrontal cortex (LAMPFC) increased in the Attention-focused group and decreased in the Accuracy-focused group. In both groups, transitioning to hard sessions resulted in a decrease in performance. The Attention-focused group displayed an increase in brain activity within LDLPFC, RAMPFC and LAMPFC, while the Accuracy-focused group displayed an increase in brain activity within LDLPFC, no change within RAMPFC and a decrease within LAMPFC. These results suggest that the Attention-focused group was able to acquire and transfer the skills needed to efficiently complete the scan task, while remaining engaged in a target find task. Alternatively, the Accuracy-focused group was engaged only on acquiring the skills needed to efficiently complete the target find task. In conclusion, these results suggest that utilizing intersubject variability as relevant information rather than noise improves assessments of skill acquisition and transfer during training on a complex task.

Forward Entrainment: Evidence, Controversies, Constraints, and Mechanisms

We define forward entrainment as that part of the entrainment process that outlasts the entraining stimulus. In this study, we examine conditions under which one may or may not observe forward entrainment. In part 1, we review and evaluate studies that have observed forward entrainment using a variety of psychophysical methods (detection, discrimination and reaction times), different target stimuli (tones, noise, gaps), different entraining sequences (sinusoidal, rectangular or sawtooth waveforms), a variety of physiological measures (MEG, EEG, ECoG, CSD), in different modalities (auditory and visual), across modalities (audiovisual and auditory-motor), and in different species. In part 2, we review those studies that have failed to observe forward entrainment, with emphasis on evaluating the methodological and stimulus design differences that may clarify the contrasting findings across these two classes of studies. In part 3, we describe those experimental conditions under which we ourselves have failed to observe forward entrainment, and provide new data on use of complex envelope patterns as entraining stimuli, show data on intersubject variability, and provide new findings on psychometric functions that characterize the strength of forward entrainment at different SNRs. In part 4 we theorize on potential mechanisms, describe how neurophysiological and psychophysical studies approach the study of entrainment, and caution against drawing direct causal inferences between the two without compelling evidence beyond correlative measures.

Accuracy of an Automated Hearing Aid Fitting Using Real Ear Measures Embedded in a Manufacturer Fitting Software

Background Hearing aid fitting guidelines recommend real ear measures (REM) to verify hearing aid performance. Unfortunately, approximately 70 to 80% of clinicians do not use REM, but instead download manufacturer first-fit. Studies report differences in performance between first-fit and programmed-fit with greatest differences in the higher frequencies. Recently, hearing aid and real ear analyzer (REA) manufacturers allow REA communication with hearing aid software feature to automatically program hearing aids to target. Little research is available reporting the accuracy of this feature. Purpose The aim of the study is to examine whether differences exist at 50, 65, and 80 dB SPL between two ReSound first-fit formulae (Audiogram+ and NAL-NL2) using ReSound AutoREM and Aurical NAL-NL2 Research Design The study design is of repeated measure type. Study Sample The study sample includes 48 ears. Data Collection and Analysis For the two fitting formulae, AutoREM real ear insertion gain (REIG) was measured at 50, 65, and 80 dB SPL and compared with measures from Aurical NAL-NL2. Results Mean AutoREM REIG for ReSound NAL-NL2 was 3 to 8 dB below Aurical NAL-NL2 for 50 dB SPL, within 1 to 3 dB for 65 dB SPL and 1 to 5 dB above for 80 dB SPL. Mean AutoREM REIG for Audiogram + was 1 to 12 dB below Aurical NAL-NL2 for 50 dB SPL, within 2 to 5 dB for 65 dB SPL and 1 to 7 dB above NAL-NL2 for 80 dB SPL. Conclusion Relative to the Aurical NAL-NL2, AutoREM REIG50 for Audiogram + and ReSound NAL-NL2 was lower. Relative to the Aurical NAL-NL2, AutoREM REIG65 for Audiogram + was higher at 1,000 Hz and lower at 4,000 to 6,000 Hz and for ReSound NAL-NL2 it was lower at 500 Hz and 4,000 Hz and higher at 3,000 Hz. Relative to the Aurical NAL-NL2, AutoREM REIG80 for Audiogram + was higher at 500 to 3,000 Hz and 6,000 Hz and ReSound NAL-NL2 was higher at 500 to 6,000 Hz. Because of wide intersubject variability clinicians should continue to use REM as a “check and balance” when using AutoREM.

Intersubject variability in spoken verb production: Effects of hierarchy and transitivity

In two experiments employing the picture-word interference (PWI) paradigm, we explored how a verb’s hierarchy and transitivity influences its retrieval during spoken production. Experiment 1 involved transitive (i.e. object-oriented, e.g. eat) action pictures accompanied by a to-be-ignored distractor word that was either a related coordinate (‘drink’) or troponym (‘devour’), while Experiment 2 employed intransitive (e.g. walk) stimuli. Assuming these relationships operate similarly for verbs and object nouns, we expected to observe faster naming times for troponyms, and slower naming times for coordinates. Conventional group-level analyses of the null average hypothesis revealed no significant effects in either experiment. However, analyses of the global null hypothesis revealed significant interindividual variability for troponym distractors in Experiment 1, with a similar trend in Experiment 2. These results indicate verbs may have a different conceptual-lexical organisation to object nouns in the mental lexicon, less constrained by hierarchical categories, with their processing more influenced by subject-specific variables.

Inferring the heritability of large-scale functional networks with a multivariate ACE modeling approach

Recent evidence suggests that the human functional connectome is stable at different time scales and unique. These characteristics posit the functional connectome not only as an individual marker but also as a powerful discriminatory measure characterized by high intersubject variability. Among distinct sources of intersubject variability, the long-term sources include functional patterns that emerge from genetic factors. Here, we sought to investigate the contribution of additive genetic factors to the variability of functional networks by determining the heritability of the connectivity strength in a multivariate fashion. First, we reproduced and extended the connectome fingerprinting analysis to the identification of twin pairs. Then, we estimated the heritability of functional networks by a multivariate ACE modeling approach with bootstrapping. Twin pairs were identified above chance level using connectome fingerprinting, with monozygotic twin identification accuracy equal to 57.2% on average for whole-brain connectome. Additionally, we found that a visual (0.37), the medial frontal (0.31) and the motor (0.30) functional networks were the most influenced by additive genetic factors. Our findings suggest that genetic factors not only partially determine intersubject variability of the functional connectome, such that twins can be identified using connectome fingerprinting, but also differentially influence connectivity strength in large-scale functional networks.

A Phase I Clinical Study Comparing the Tolerance, Immunogenicity, and Pharmacokinetics of Proposed Biosimilar BAT1806 and Reference Tocilizumab in Healthy Chinese Men

Objective: The study aimed to explore the bioequivalence of a proposed biosimilar BAT1806 to its reference products marketed in the EU and US (RoActemra-EU and Actemra-US) among healthy Chinese men. The tolerance, immunogenicity, and pharmacokinetics (PK) of the three drugs were also investigated.Methods: In this randomized, double-blind, single-dose, three-arm, parallel study, a single-dose of 4 mg/kg of the reference products, or the biosimilar was administered to the participants. The participants were followed up for 57 days, and PK, immunogenicity, and tolerance evaluations were completed during this period.Results: The PK parameters were similar in all three groups: BAT1806 (n = 45), RoActemra-EU (n = 42), and Actemra-US (n = 42). The 90% confidence intervals (CIs) for the ratios of Cmax, AUC0–t and AUC0–∞ were 86.90–104.41% for BAT1806 vs. RoActemra-EU, 91.70–106.15% for BAT1806 vs Actemra-US, and 90.04–105.53% for Actemra-US vs RoActemra-EU. For all comparisons, the 90% CIs for the Cmax, AUC0–t, and AUC0–∞ were within the predefined bioequivalence limit of 80.00–125.00%. The intersubject variability ranged from 14.5% to 21.5%, which was considerably low. Among the participants, 19 (42.2%), 10 (23.8%), and 12 (28.6%) from the BAT1806, RoActemra-EU, and Actemra-US groups were, respectively, found to be positive for anti-drug antibodies, while 14 (31.1%), nine (21.4%), and 12 (28.6%) were positive for neutralizing antibodies. Nevertheless, these antibodies did not affect the drug concentrations, and the outcomes in the bioequivalence tests were similar after sensitivity analysis. Treatment-related and treatment-emergent adverse events (TEAEs) were recorded in 27, 34, and 32 participants in the BAT1806, RoActemra-EU, and Actemra-US groups, respectively. The most common treatment-related adverse events observed were a decrease in neutrophil, and white blood cell counts.Conclusion: The PK characteristics of BAT1806 were similar to those of the reference products, RoActemra-EU and Actemra-US. Both BAT1806 and the reference products exhibited low intersubject variability and similar safety profiles.Clinical trial registration number:http://www.chinadrugtrials.org.cn/index.html, CTR20180039; https://clinicaltrials.gov/NCT03606876

Stimulus-evoked phase-locked activity along the human auditory pathway strongly varies across individuals

Phase-locking to the temporal envelope of speech is associated with envelope processing and speech perception. The phase-locked activity of the auditory pathway, across modulation frequencies, is generally assessed at group level and shows a decrease in response magnitude with increasing modulation frequency. With the exception of increased activity around 40 and 80 to 100 Hz. Furthermore, little is known about the phase-locked response patterns to modulation frequencies ≤ 20 Hz, which are modulations predominately present in the speech envelope. In the present study we assess the temporal modulation transfer function (TMTFASSR) of the phase-locked activity of the auditory pathway, from 0.5 to 100 Hz at a high-resolution and by means of auditory steady-state responses. Although the group-averaged TMTFASSR corresponds well with those reported in the literature, the individual TMTFASSR shows a remarkable intersubject variability. This intersubject variability is especially present for ASSRs that originate from the cortex and are evoked with modulation frequencies ≤ 20 Hz. Moreover, we found that these cortical phase-locked activity patterns are robust over time. These results show the importance of the individual TMTFASSR when assessing phase-locked activity to envelope fluctuations, which can potentially be used as a marker for auditory processing.

Individual Differences in Hemodynamic Responses Measured on the Head Due to a Long-Term Stimulation Involving Colored Light Exposure and a Cognitive Task: A SPA-fNIRS Study

When brain activity is measured by neuroimaging, the canonical hemodynamic response (increase in oxygenated hemoglobin ([O2Hb]) and decrease in deoxygenated hemoglobin ([HHb]) is not always seen in every subject. The reason for this intersubject-variability of the responses is still not completely understood. This study is performed with 32 healthy subjects, using the systemic physiology augmented functional near-infrared spectroscopy (SPA-fNIRS) approach. We investigate the intersubject variability of hemodynamic and systemic physiological responses, due to a verbal fluency task (VFT) under colored light exposure (CLE; blue and red). Five and seven different hemodynamic response patterns were detected in the subgroup analysis of the blue and red light exposure, respectively. We also found that arterial oxygen saturation and mean arterial pressure were positively correlated with [O2Hb] at the prefrontal cortex during the CLE-VFT independent of the color of light and classification of the subjects. Our study finds that there is substantial intersubject-variability of cerebral hemodynamic responses, which is partially explained by subject-specific systemic physiological changes induced by the CLE-VFT. This means that both subgroup analyses and the additional assessment of systemic physiology are of crucial importance to achieve a comprehensive understanding of the effects of a CLE-VFT on human subjects.