Biomechanical Assessment of Liver Integrity: Prospective Evaluation of Mechanical Versus Acoustic MR Elastography.

BACKGROUND: Magnetic resonance elastography (MRE) can quantify tissue biomechanics noninvasively, including pathological hepatic states like metabolic dysfunction-associated steatohepatitis. PURPOSE: To compare the performance of 2D/3D-MRE using the gravitational (GT) transducer concept with the current commercial acoustic (AC) solution utilizing a 2D-MRE approach. Additionally, quality index markers (QIs) were proposed to identify image pixels with sufficient quality for reliably estimating tissue biomechanics. STUDY TYPE: Prospective. POPULATION: One hundred seventy participants with suspected or confirmed liver disease (median age, 57 years [interquartile range (IQR), 46-65]; 66 females), and 11 healthy volunteers (median age, 31 years [IQR, 27-34]; 5 females). FIELD STRENGTH/SEQUENCE: Participants were scanned twice at 1.5 T and 60 Hz vibration frequency: first, using AC-MRE (2D-MRE, spin-echo EPI sequence, 11 seconds breath-hold), and second, using GT-MRE (2D- and 3D-MRE, gradient-echo sequence, 14 seconds breath-hold). ASSESSMENT: Image analysis was performed by four independent radiologists and one biomedical engineer. Additionally, superimposed analytic plane shear waves of known wavelength and attenuation at fixed shear modulus were used to propose pertinent QIs. STATISTICAL TESTS: Spearman's correlation coefficient (r) was applied to assess the correlation between modalities. Interreader reproducibility was evaluated using Bland-Altman bias and reproducibility coefficients. P-values <0.05 were considered statistically significant. RESULTS: Liver stiffness quantified via GT-2D/3D correlated well with AC-2D (r ≥ 0.89 [95% CI: 0.85-0.92]) and histopathological grading (r ≥ 0.84 [95% CI: 0.72-0.91]), demonstrating excellent agreement in Bland-Altman plots and between readers (κ ≥ 0.86 [95% CI: 0.81-0.91]). However, GT-2D showed a bias in overestimating stiffness compared to GT-3D. Proposed QIs enabled the identification of pixels deviating beyond 10% from true stiffness based on a combination of total wave amplitude, temporal sinusoidal nonlinearity, and wave signal-to-noise ratio for GT-3D. CONCLUSION: GT-MRE represents an alternative to AC-MRE for noninvasive liver tissue characterization. Both GT-2D and 3D approaches correlated strongly with the established commercial approach, offering advanced capabilities in abdominal imaging compared to AC-MRE. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Inferring causal connectivity from pairwise recordings and optogenetics.

To understand the neural mechanisms underlying brain function, neuroscientists aim to quantify causal interactions between neurons, for instance by perturbing the activity of neuron A and measuring the effect on neuron B. Recently, manipulating neuron activity using light-sensitive opsins, optogenetics, has increased the specificity of neural perturbation. However, using widefield optogenetic interventions, multiple neurons are usually perturbed, producing a confound-any of the stimulated neurons can have affected the postsynaptic neuron making it challenging to discern which neurons produced the causal effect. Here, we show how such confounds produce large biases in interpretations. We explain how confounding can be reduced by combining instrumental variables (IV) and difference in differences (DiD) techniques from econometrics. Combined, these methods can estimate (causal) effective connectivity by exploiting the weak, approximately random signal resulting from the interaction between stimulation and the absolute refractory period of the neuron. In simulated neural networks, we find that estimates using ideas from IV and DiD outperform naïve techniques suggesting that methods from causal inference can be useful to disentangle neural interactions in the brain.

Neural signatures of natural behavior in socializing macaques.

Our understanding of the neurobiology of primate behavior largely derives from artificial tasks in highly-controlled laboratory settings, overlooking most natural behaviors primate brains evolved to produce1. In particular, how primates navigate the multidimensional social relationships that structure daily life and shape survival and reproductive success remains largely unexplored at the single neuron level. Here, we combine ethological analysis with new wireless recording technologies to uncover neural signatures of natural behavior in unrestrained, socially interacting pairs of rhesus macaques within a larger colony. Population decoding of single neuron activity in prefrontal and temporal cortex unveiled robust encoding of 24 species-typical behaviors, which was strongly modulated by the presence and identity of surrounding monkeys. Male-female partners demonstrated near-perfect reciprocity in grooming, a key behavioral mechanism supporting friendships and alliances, and neural activity maintained a running account of these social investments. When confronted with an aggressive intruder, behavioral and neural population responses reflected empathy and were buffered by the presence of a partner. Surprisingly, neural signatures in prefrontal and temporal cortex were largely indistinguishable and irreducible to visual and motor contingencies. By employing an ethological approach to the study of primate neurobiology, we reveal a highly-distributed neurophysiological record of social dynamics, a potential computational foundation supporting communal life in primate societies, including our own.

Neural spiking for causal inference and learning.

When a neuron is driven beyond its threshold, it spikes. The fact that it does not communicate its continuous membrane potential is usually seen as a computational liability. Here we show that this spiking mechanism allows neurons to produce an unbiased estimate of their causal influence, and a way of approximating gradient descent-based learning. Importantly, neither activity of upstream neurons, which act as confounders, nor downstream non-linearities bias the results. We show how spiking enables neurons to solve causal estimation problems and that local plasticity can approximate gradient descent using spike discontinuity learning.

The study of plasticity has always been about gradients.

The experimental study of learning and plasticity has always been driven by an implicit question: how can physiological changes be adaptive and improve performance? For example, in Hebbian plasticity only synapses from presynaptic neurons that were active are changed, avoiding useless changes. Similarly, in dopamine-gated learning synapse changes depend on reward or lack thereof and do not change when everything is predictable. Within machine learning we can make the question of which changes are adaptive concrete: performance improves when changes correlate with the gradient of an objective function quantifying performance. This result is general for any system that improves through small changes. As such, physiology has always implicitly been seeking mechanisms that allow the brain to approximate gradients. Coming from this perspective we review the existing literature on plasticity-related mechanisms, and we show how these mechanisms relate to gradient estimation. We argue that gradients are a unifying idea to explain the many facets of neuronal plasticity.

Do Biological Constraints Impair Dendritic Computation?

Computations on the dendritic trees of neurons have important constraints. Voltage dependent conductances in dendrites are not similar to arbitrary direct-current generation, they are the basis for dendritic nonlinearities and they do not allow converting positive currents into negative currents. While it has been speculated that the dendritic tree of a neuron can be seen as a multi-layer neural network and it has been shown that such an architecture could be computationally strong, we do not know if that computational strength is preserved under these biological constraints. Here we simulate models of dendritic computation with and without these constraints. We find that dendritic model performance on interesting machine learning tasks is not hurt by these constraints but may benefit from them. Our results suggest that single real dendritic trees may be able to learn a surprisingly broad range of tasks.

On PDE Characterization of Smooth Hierarchical Functions Computed by Neural Networks.

Neural networks are versatile tools for computation, having the ability to approximate a broad range of functions. An important problem in the theory of deep neural networks is expressivity; that is, we want to understand the functions that are computable by a given network. We study real, infinitely differentiable (smooth) hierarchical functions implemented by feedforward neural networks via composing simpler functions in two cases: (1) each constituent function of the composition has fewer inputs than the resulting function and (2) constituent functions are in the more specific yet prevalent form of a nonlinear univariate function (e.g., tanh) applied to a linear multivariate function. We establish that in each of these regimes, there exist nontrivial algebraic partial differential equations (PDEs) that are satisfied by the computed functions. These PDEs are purely in terms of the partial derivatives and are dependent only on the topology of the network. Conversely, we conjecture that such PDE constraints, once accompanied by appropriate nonsingularity conditions and perhaps certain inequalities involving partial derivatives, guarantee that the smooth function under consideration can be represented by the network. The conjecture is verified in numerous examples, including the case of tree architectures, which are of neuroscientific interest. Our approach is a step toward formulating an algebraic description of functional spaces associated with specific neural networks, and may provide useful new tools for constructing neural networks.

For love of neuroscience: The Neuromatch movement.

In this meeting report, I applaud the Neuromatch community, which runs virtual summer schools and conferences in response to the pandemic. Its members love science, aim to advance our understanding of the brain, and work extremely hard to include everyone.

Might a Single Neuron Solve Interesting Machine Learning Problems Through Successive Computations on Its Dendritic Tree?

Physiological experiments have highlighted how the dendrites of biological neurons can nonlinearly process distributed synaptic inputs. However, it is unclear how aspects of a dendritic tree, such as its branched morphology or its repetition of presynaptic inputs, determine neural computation beyond this apparent nonlinearity. Here we use a simple model where the dendrite is implemented as a sequence of thresholded linear units. We manipulate the architecture of this model to investigate the impacts of binary branching constraints and repetition of synaptic inputs on neural computation. We find that models with such manipulations can perform well on machine learning tasks, such as Fashion MNIST or Extended MNIST. We find that model performance on these tasks is limited by binary tree branching and dendritic asymmetry and is improved by the repetition of synaptic inputs to different dendritic branches. These computational experiments further neuroscience theory on how different dendritic properties might determine neural computation of clearly defined tasks.

Towards Democratizing and Automating Online Conferences: Lessons from the Neuromatch Conferences.

Legacy conferences are costly and time consuming, and exclude scientists lacking various resources or abilities. During the 2020 pandemic, we created an online conference platform, Neuromatch Conferences (NMC), aimed at developing technological and cultural changes to make conferences more democratic, scalable, and accessible. We discuss the lessons we learned.

Quantifying the role of neurons for behavior is a mediation question.

Many systems neuroscientists want to understand neurons in terms of mediation; we want to understand how neurons are involved in the causal chain from stimulus to behavior. Unfortunately, most tools are inappropriate for that while our language takes mediation for granted. Here we discuss the contrast between our conceptual drive toward mediation and the difficulty of obtaining meaningful evidence.

On Functions Computed on Trees.

Any function can be constructed using a hierarchy of simpler functions through compositions. Such a hierarchy can be characterized by a binary rooted tree. Each node of this tree is associated with a function that takes as inputs two numbers from its children and produces one output. Since thinking about functions in terms of computation graphs is becoming popular, we may want to know which functions can be implemented on a given tree. Here, we describe a set of necessary constraints in the form of a system of nonlinear partial differential equations that must be satisfied. Moreover, we prove that these conditions are sufficient in contexts of analytic and bit-valued functions. In the latter case, we explicitly enumerate discrete functions and observe that there are relatively few. Our point of view allows us to compare different neural network architectures in regard to their function spaces. Our work connects the structure of computation graphs with the functions they can implement and has potential applications to neuroscience and computer science.

Quantifying How Staining Methods Bias Measurements of Neuron Morphologies.

The process through which neurons are labeled is a key methodological choice in measuring neuron morphology. However, little is known about how this choice may bias measurements. To quantify this bias we compare the extracted morphology of neurons collected from the same rodent species, experimental condition, gender distribution, age distribution, brain region and putative cell type, but obtained with 19 distinct staining methods. We found strong biases on measured features of morphology. These were largest in features related to the coverage of the dendritic tree (e.g., the total dendritic tree length). Understanding measurement biases is crucial for interpreting morphological data.

Policies or knowledge: priors differ between a perceptual and sensorimotor task.

If the brain abstractly represents probability distributions as knowledge, then the modality of a decision, e.g., movement vs. perception, should not matter. If, on the other hand, learned representations are policies, they may be specific to the task where learning takes place. Here, we test this by asking whether a learned spatial prior generalizes from a sensorimotor estimation task to a two-alternative-forced choice (2-Afc) perceptual comparison task. A model and simulation-based analysis revealed that while participants learn prior distribution in the sensorimotor estimation task, measured priors are consistently broader than sensorimotor priors in the 2-Afc task. That the prior does not fully generalize suggests that sensorimotor priors are more like policies than knowledge. In disagreement with standard Bayesian thought, the modality of the decision has a strong influence on the implied prior distributions. NEW & NOTEWORTHY We do not know whether the brain represents abstract and generalizable knowledge or task-specific policies that map internal states to actions. We find that learning in a sensorimotor task does not generalize strongly to a perceptual task, suggesting that humans learned policies and did not truly acquire knowledge. Priors differ across tasks, thus casting doubt on the central tenet of many Bayesian models, that the brain's representation of the world is built on generalizable knowledge.

Relationship Between Sleep Quality and Mood: Ecological Momentary Assessment Study.

BACKGROUND: Sleep disturbances play an important role in everyday affect and vice versa. However, the causal day-to-day interaction between sleep and mood has not been thoroughly explored, partly because of the lack of daily assessment data. Mobile phones enable us to collect ecological momentary assessment data on a daily basis in a noninvasive manner. OBJECTIVE: This study aimed to investigate the relationship between self-reported daily mood and sleep quality. METHODS: A total of 208 adult participants were recruited to report mood and sleep patterns daily via their mobile phones for 6 consecutive weeks. Participants were recruited in 4 roughly equal groups: depressed and anxious, depressed only, anxious only, and controls. The effect of daily mood on sleep quality and vice versa were assessed using mixed effects models and propensity score matching. RESULTS: All methods showed a significant effect of sleep quality on mood and vice versa. However, within individuals, the effect of sleep quality on next-day mood was much larger than the effect of previous-day mood on sleep quality. We did not find these effects to be confounded by the participants' past mood and sleep quality or other variables such as stress, physical activity, and weather conditions. CONCLUSIONS: We found that daily sleep quality and mood are related, with the effect of sleep quality on mood being significantly larger than the reverse. Correcting for participant fixed effects dramatically affected results. Causal analysis suggests that environmental factors included in the study and sleep and mood history do not mediate the relationship.

The development of Bayesian integration in sensorimotor estimation.

Examining development is important in addressing questions about whether Bayesian principles are hard coded in the brain. If the brain is inherently Bayesian, then behavior should show the signatures of Bayesian computation from an early stage in life. Children should integrate probabilistic information from prior and likelihood distributions to reach decisions and should be as statistically efficient as adults, when individual reliabilities are taken into account. To test this idea, we examined the integration of prior and likelihood information in a simple position-estimation task comparing children ages 6-11 years and adults. Some combination of prior and likelihood was present in the youngest sample tested (6-8 years old), and in most participants a Bayesian model fit the data better than simple baseline models. However, younger subjects tended to have parameters further from the optimal values, and all groups showed considerable biases. Our findings support some level of Bayesian integration in all age groups, with evidence that children use probabilistic quantities less efficiently than adults do during sensorimotor estimation.

Although optimal models are useful, optimality claims are not that common.

Rahnev & Denison (R&D) argue that human behavior is often described as "optimal," despite many previous findings of suboptimality. We address how the literature handles these concepts and discuss our own findings on suboptimality. Although we agree that the field should embrace the "systematic weirdness of human behavior" (sect. 6, para. 1), this does not detract from the value of the Bayesian approach.

Could a Neuroscientist Understand a Microprocessor?

There is a popular belief in neuroscience that we are primarily data limited, and that producing large, multimodal, and complex datasets will, with the help of advanced data analysis algorithms, lead to fundamental insights into the way the brain processes information. These datasets do not yet exist, and if they did we would have no way of evaluating whether or not the algorithmically-generated insights were sufficient or even correct. To address this, here we take a classical microprocessor as a model organism, and use our ability to perform arbitrary experiments on it to see if popular data analysis methods from neuroscience can elucidate the way it processes information. Microprocessors are among those artificial information processing systems that are both complex and that we understand at all levels, from the overall logical flow, via logical gates, to the dynamics of transistors. We show that the approaches reveal interesting structure in the data but do not meaningfully describe the hierarchy of information processing in the microprocessor. This suggests current analytic approaches in neuroscience may fall short of producing meaningful understanding of neural systems, regardless of the amount of data. Additionally, we argue for scientists using complex non-linear dynamical systems with known ground truth, such as the microprocessor as a validation platform for time-series and structure discovery methods.