Enhancing precision in human neuroscience.

Human neuroscience has always been pushing the boundary of what is measurable. During the last decade, concerns about statistical power and replicability - in science in general, but also specifically in human neuroscience - have fueled an extensive debate. One important insight from this discourse is the need for larger samples, which naturally increases statistical power. An alternative is to increase the precision of measurements, which is the focus of this review. This option is often overlooked, even though statistical power benefits from increasing precision as much as from increasing sample size. Nonetheless, precision has always been at the heart of good scientific practice in human neuroscience, with researchers relying on lab traditions or rules of thumb to ensure sufficient precision for their studies. In this review, we encourage a more systematic approach to precision. We start by introducing measurement precision and its importance for well-powered studies in human neuroscience. Then, determinants for precision in a range of neuroscientific methods (MRI, M/EEG, EDA, Eye-Tracking, and Endocrinology) are elaborated. We end by discussing how a more systematic evaluation of precision and the application of respective insights can lead to an increase in reproducibility in human neuroscience.

A call to leverage a health equity lens to accelerate human neuroscience research.

Investigation of health inequities tend to be examined, in human neurosciences, as biological factors at the level of the individual. In actuality, health inequities arise, due largely in part, to deep-seated structural factors. Structural inequality refers to the systemic disadvantage of one social group compared to others with whom they coexist. The term encompasses policy, law, governance, and culture and relates to race, ethnicity, gender or gender identity, class, sexual orientation, and other domains. These structural inequalities include but are not limited to social segregation, the intergenerational effects of colonialism and the consequent distribution of power and privilege. Principles to address inequities influenced by structural factors are increasingly prevalent in a subfield of the neurosciences, i.e., cultural neurosciences. Cultural neuroscience articulates the bidirectional relationship between biology and environmental contextual factors surrounding research participants. However, the operationalization of these principles may not have the intended spillover effect on the majority of human neurosciences: this limitation is the overarching focus of the present piece. Here, we provide our perspective that these principles are missing and very much needed in all human neuroscience subdisciplines to accelerate our understanding of the human brain. Furthermore, we provide an outline of two key tenets of a health equity lens necessary for achieving research equity in human neurosciences: the social determinants of health (SDoH) framework and how to deal with confounders using counterfactual thinking. We argue that these tenets should be prioritized across future human neuroscience research more generally, and doing so is a pathway to further gain an understanding of contextual background intertwined with the human brain, thus improving the rigor and inclusivity of human neuroscience research.

Changes in brain activity and connectivity as memories age.

The role of the hippocampus during memory consolidation is not fully understood, with human and animal experiments producing conflicting conclusions. In particular, human lesion studies tend to indicate that the hippocampus gradually becomes independent from memory over years, whilst animal studies suggest that this can happen over days. Tallman et al. (this issue) used fMRI to investigate activity and functional connectivity in the brain at four different time points following memory encoding. Their findings include a decrease in functional connectivity between the hippocampus and parahippocampal cortex with memory age, which supports the system consolidation theory, but also argues against the reduced involvement of the hippocampus over time. This study sheds new light on the neurobiology of memory.

Critical Spatial-Temporal Dynamics and Prominent Shape Collapse of Calcium Waves Observed in Human hNT Astrocytes in Vitro.

Networks of neurons are typically studied in the field of Criticality. However, the study of astrocyte networks in the brain has been recently lauded to be of equal importance to that of the neural networks. To date criticality assessments have only been performed on networks astrocytes from healthy rats, and astrocytes from cultured dissociated resections of intractable epilepsy. This work, for the first time, presents studies of the critical dynamics and shape collapse of calcium waves observed in cultures of healthy human astrocyte networks in vitro, derived from the human hNT cell line. In this article, we demonstrate that avalanches of spontaneous calcium waves display strong critical dynamics, including power-laws in both the size and duration distributions. In addition, the temporal profiles of avalanches displayed self-similarity, leading to shape collapse of the temporal profiles. These findings are significant as they suggest that cultured networks of healthy human hNT astrocytes self-organize to a critical point, implying that healthy astrocytic networks operate at a critical point to process and transmit information. Furthermore, this work can serve as a point of reference to which other astrocyte criticality studies can be compared.

Measuring human trace fear conditioning.

Trace fear conditioning is an important research paradigm to model aversive learning in biological or clinical scenarios, where predictors (conditioned stimuli, CS) and aversive outcomes (unconditioned stimuli, US) are separated in time. The optimal measurement of human trace fear conditioning, and in particular of memory retention after consolidation, is currently unclear. We conducted two identical experiments (N1  = 28, N2  = 28) with a 15-s trace interval and a recall test 1 week after acquisition, while recording several psychophysiological observables. In a calibration approach, we explored which learning and memory measures distinguished CS+ and CS- in the first experiment and confirmed the most sensitive measures in the second experiment. We found that in the recall test without reinforcement, only fear-potentiated startle but not skin conductance, pupil size, heart period, or respiration amplitude, differentiated CS+ and CS-. During acquisition without startle probes, skin conductance responses and pupil size responses but not heart period or respiration amplitude differentiated CS+ and CS-. As a side finding, there was no evidence for extinction of fear-potentiated startle over 30 trials without reinforcement. These results may be useful to inform future substantive research using human trace fear conditioning protocols.

Monash DaCRA fPET-fMRI: A dataset for comparison of radiotracer administration for high temporal resolution functional FDG-PET.

BACKGROUND: "Functional" [18F]-fluorodeoxyglucose positron emission tomography (FDG-fPET) is a new approach for measuring glucose uptake in the human brain. The goal of FDG-fPET is to maintain a constant plasma supply of radioactive FDG in order to track, with high temporal resolution, the dynamic uptake of glucose during neuronal activity that occurs in response to a task or at rest. FDG-fPET has most often been applied in simultaneous BOLD-fMRI/FDG-fPET (blood oxygenation level-dependent functional MRI fluorodeoxyglucose functional positron emission tomography) imaging. BOLD-fMRI/FDG-fPET provides the capability to image the 2 primary sources of energetic dynamics in the brain, the cerebrovascular haemodynamic response and cerebral glucose uptake. FINDINGS: In this Data Note, we describe an open access dataset, Monash DaCRA fPET-fMRI, which contrasts 3 radiotracer administration protocols for FDG-fPET: bolus, constant infusion, and hybrid bolus/infusion. Participants (n = 5 in each group) were randomly assigned to each radiotracer administration protocol and underwent simultaneous BOLD-fMRI/FDG-fPET scanning while viewing a flickering checkerboard. The bolus group received the full FDG dose in a standard bolus administration, the infusion group received the full FDG dose as a slow infusion over the duration of the scan, and the bolus-infusion group received 50% of the FDG dose as bolus and 50% as constant infusion. We validate the dataset by contrasting plasma radioactivity, grey matter mean uptake, and task-related activity in the visual cortex. CONCLUSIONS: The Monash DaCRA fPET-fMRI dataset provides significant reuse value for researchers interested in the comparison of signal dynamics in fPET, and its relationship with fMRI task-evoked activity.

Sleep-Aware Adaptive Deep Brain Stimulation Control: Chronic Use at Home With Dual Independent Linear Discriminate Detectors.

Adaptive deep brain stimulation (aDBS) is a promising new technology with increasing use in experimental trials to treat a diverse array of indications such as movement disorders (Parkinson's disease, essential tremor), psychiatric disorders (depression, OCD), chronic pain and epilepsy. In many aDBS trials, a neural biomarker of interest is compared with a predefined threshold and stimulation amplitude is adjusted accordingly. Across indications and implant locations, potential biomarkers are greatly influenced by sleep. Successful chronic embedded adaptive detectors must incorporate a strategy to account for sleep, to avoid unwanted or unexpected algorithm behavior. Here, we show a dual algorithm design with two independent detectors, one used to track sleep state (wake/sleep) and the other used to track parkinsonian motor state (medication-induced fluctuations). Across six hemispheres (four patients) and 47 days, our detector successfully transitioned to sleep mode while patients were sleeping, and resumed motor state tracking when patients were awake. Designing "sleep aware" aDBS algorithms may prove crucial for deployment of clinically effective fully embedded aDBS algorithms.

Protocol for Reducing COVID-19 Transmission Risk in EEG Research.

Electroencephalogram (EEG) recordings provide a valuable, noninvasive methofd for measuring human brain activity. This protocol modifies our general protocol for EEG recording (Farrens et al., 2019) for use during the COVID-19 pandemic. It was created with the help of numerous experts, and it specifies a clear set of steps for interacting with research participants, using personal protective equipment (PPE), and disinfecting equipment, all with the goal of reducing the COVID-19 risks for both laboratory personnel and participants. It focuses on the use of EEG in relatively simple research studies of adults who can easily understand and follow instructions, yet can be readily adapted for studies using other types of EEG experiments or other participant populations.

Efficient Coding by Midget and Parasol Ganglion Cells in the Human Retina.

In humans, midget and parasol ganglion cells account for most of the input from the eyes to the brain. Yet, how they encode visual information is unknown. Here, we perform large-scale multi-electrode array recordings from retinas of treatment-naive patients who underwent enucleation surgery for choroidal malignant melanomas. We identify robust differences in the function of midget and parasol ganglion cells, consistent asymmetries between their ON and OFF types (that signal light increments and decrements, respectively) and divergence in the function of human versus non-human primate retinas. Our computational analyses reveal that the receptive fields of human midget and parasol ganglion cells divide naturalistic movies into adjacent spatiotemporal frequency domains with equal stimulus power, while the asymmetric response functions of their ON and OFF types simultaneously maximize stimulus coverage and information transmission and minimize metabolic cost. Thus, midget and parasol ganglion cells in the human retina efficiently encode our visual environment.

Network-Targeted, Multi-site Direct Cortical Stimulation Enhances Working Memory by Modulating Phase Lag of Low-Frequency Oscillations.

Working memory is mediated by the coordinated activation of frontal and parietal cortices occurring in the theta and alpha frequency ranges. Here, we test whether electrically stimulating frontal and parietal regions at the frequency of interaction is effective in modulating working memory. We identify working memory nodes that are functionally connected in theta and alpha frequency bands and intracranially stimulate both nodes simultaneously in participants performing working memory tasks. We find that in-phase stimulation results in improvements in performance compared to sham stimulation. In addition, in-phase stimulation results in decreased phase lag between regions within working memory network, while anti-phase stimulation results in increased phase lag, suggesting that shorter phase lag in oscillatory connectivity may lead to better performance. The results support the idea that phase lag may play a key role in information transmission across brain regions. Thus, brain stimulation strategies to improve cognition may require targeting multiple nodes of brain networks.

High Resolution Human Eye Tracking During Continuous Visual Search.

While several studies have shown human subjects' impressive ability to detect faces in individual images in paced settings (Crouzet et al., 2010), we here report the details of an eye movement dataset in which subjects rapidly and continuously targeted single faces embedded in different scenes at rates approaching six face targets each second (including blinks and eye movement times). In this paper, we describe details of a large publicly available eye movement dataset of this new psychophysical paradigm (Martin et al., 2018). The paradigm produced high-resolution eye-tracking data from an experiment on continuous upright and inverted 3° sized face detection in both background and no-background conditions. The new "Zapping" paradigm allowed large amounts of trials to be completed in a short amount of time. For example, our three studies encompassed a total of 288,000 trials done in 72 separate experiments, and yet only took approximately 40 hours of recording for the three experimental cohorts. Each subject did 4000 trials split into eight blocks of 500 consecutive trials in one of the four different experimental conditions: {upright, inverted} × {scene, no scene}. For each condition, there are several covariates of interest, including: temporal eye positions sampled at 1250 hz, saccades, saccade reaction times, microsaccades, pupil dynamics, target luminances, and global contrasts.

Basic and functional effects of transcranial Electrical Stimulation (tES)-An introduction.

Non-invasive brain stimulation (NIBS) has been gaining increased popularity in human neuroscience research during the last years. Among the emerging NIBS tools is transcranial electrical stimulation (tES), whose main modalities are transcranial direct, and alternating current stimulation (tDCS, tACS). In tES, a small current (usually less than 3mA) is delivered through the scalp. Depending on its shape, density, and duration, the applied current induces acute or long-lasting effects on excitability and activity of cerebral regions, and brain networks. tES is increasingly applied in different domains to (a) explore human brain physiology with regard to plasticity, and brain oscillations, (b) explore the impact of brain physiology on cognitive processes, and (c) treat clinical symptoms in neurological and psychiatric diseases. In this review, we give a broad overview of the main mechanisms and applications of these brain stimulation tools.

Chemical Probes for Visualizing Intact Animal and Human Brain Tissue.

Newly developed tissue clearing techniques can be used to render intact tissues transparent. When combined with fluorescent labeling technologies and optical sectioning microscopy, this allows visualization of fine structure in three dimensions. Gene-transfection techniques have proved very useful in visualizing cellular structures in animal models, but they are not applicable to human brain tissue. Here, we discuss the characteristics of an ideal chemical fluorescent probe for use in brain and other cleared tissues, and offer a comprehensive overview of currently available chemical probes. We describe their working principles and compare their performance with the goal of simplifying probe selection for neuropathologists and stimulating probe development by chemists. We propose several approaches for the development of innovative chemical labeling methods which, when combined with tissue clearing, have the potential to revolutionize how we study the structure and function of the human brain.

Influence of White and Gray Matter Connections on Endogenous Human Cortical Oscillations.

Brain oscillations reflect changes in electrical potentials summated across neuronal populations. Low- and high-frequency rhythms have different modulation patterns. Slower rhythms are spatially broad, while faster rhythms are more local. From this observation, we hypothesized that low- and high-frequency oscillations reflect white- and gray-matter communications, respectively, and synchronization between low-frequency phase with high-frequency amplitude represents a mechanism enabling distributed brain-networks to coordinate local processing. Testing this common understanding, we selectively disrupted white or gray matter connections to human cortex while recording surface field potentials. Counter to our original hypotheses, we found that cortex consists of independent oscillatory-units (IOUs) that maintain their own complex endogenous rhythm structure. IOUs are differentially modulated by white and gray matter connections. White-matter connections maintain topographical anatomic heterogeneity (i.e., separable processing in cortical space) and gray-matter connections segregate cortical synchronization patterns (i.e., separable temporal processing through phase-power coupling). Modulation of distinct oscillatory modules enables the functional diversity necessary for complex processing in the human brain.

Preliminary evidence for human globus pallidus pars interna neurons signaling reward and sensory stimuli.

The globus pallidus pars interna (GPi) is a component of the basal ganglia, a network of subcortical nuclei that process motor, associative, and limbic information. While non-human primate studies have suggested a role for the GPi in non-motor functions, there have been no single-unit studies of non-motor electrophysiological behavior of human GPi neurons. We therefore sought to extend these findings by collecting single-unit recordings from awake patients during functional stereotactic neurosurgery targeting the GPi for deep brain stimulation. To assess cellular responses to non-motor information, patients performed a reward task where virtual money could be won, lost, or neither, depending on their performance while cellular activity was monitored. Changes in the firing rates of isolated GPi neurons after the presentation of reward-related stimuli were compared between different reward contingencies (win, loss, null). We observed neurons that modulated their firing rate significantly to the presentation of reward-related stimuli. We furthermore found neurons that responded to visual-stimuli more broadly. This is the first single-unit evidence of human GPi neurons carrying non-motor information. These results are broadly consistent with previous findings in the animal literature and suggest non-motor information may be represented in the single-unit activity of human GPi neurons.

Fascicular Topography of the Human Median Nerve for Neuroprosthetic Surgery.

One of the most sought-after applications of neuroengineering is the communication between the arm and an artificial prosthetic device for the replacement of an amputated hand or the treatment of peripheral nerve injuries. For that, an electrode is placed around or inside the median nerve to serve as interface for recording and stimulation of nerve signals coming from the fascicles that innervate the muscles responsible for hand movements. Due to the lack of a standard procedure, the electrode implantation by the surgeon is strongly based on intuition, which may result in poor performance of the neuroprosthesis because of the suboptimal location of the neural interface. To provide morphological data that can aid the neuroprosthetic surgeon with this procedure, we investigated the fascicular topography of the human median nerve along the forearm and upper arm. We first performed a description of the fascicular content and branching patterns along the length of the arm. Next we built a 3D reconstruction of the median nerve so we could analyze the fascicle morphological features in relation to the arm level. Finally, we characterized the motor content of the median nerve fascicles in the upper arm. Collectively, these results indicate that fascicular organization occurs in a short segment distal to the epicondyles and remains unaltered until the muscular branches leave the main trunk. Based on our results, overall recommendations based on electrode type and implant location can be drawn to help and aid the neuroprosthetic procedure. Invasive interfaces would be more convenient for the upper arm and the most proximal third of the forearm. Epineural electrodes seem to be most suitable for the forearm segment after fascicles have been divided from the main trunk.