The neural and cognitive basis of expository text comprehension.

As science and technology rapidly progress, it becomes increasingly important to understand how individuals comprehend expository technical texts that explain these advances. This study examined differences in individual readers' technical comprehension performance and differences among texts, using functional brain imaging to measure regional brain activity while students read passages on technical topics and then took a comprehension test. Better comprehension of the technical passages was related to higher activation in regions of the left inferior frontal gyrus, left superior parietal lobe, bilateral dorsolateral prefrontal cortex, and bilateral hippocampus. These areas are associated with the construction of a mental model of the passage and with the integration of new and prior knowledge in memory. Poorer comprehension of the passages was related to greater activation of the ventromedial prefrontal cortex and the precuneus, areas involved in autobiographical and episodic memory retrieval. More comprehensible passages elicited more brain activation associated with establishing links among different types of information in the text and activation associated with establishing conceptual coherence within the text representation. These findings converge with previous behavioral research in their implications for teaching technical learners to become better comprehenders and for improving the structure of instructional texts, to facilitate scientific and technological comprehension.

Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression.

Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016-0.082). In the right BA10, these associations generalized to both infusion arms (p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032-0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.

Overhauser dynamic nuclear polarization (ODNP)-enhanced two-dimensional proton NMR spectroscopy at low magnetic fields.

The majority of low-field Overhauser dynamic nuclear polarization (ODNP) experiments reported so far have been 1D NMR experiments to study molecular dynamics and in particular hydration dynamics. In this work, we demonstrate the application of ODNP-enhanced 2D J-resolved (JRES) spectroscopy to improve spectral resolution beyond the limit imposed by the line broadening introduced by the paramagnetic polarizing agent. Using this approach, we are able to separate the overlapping multiplets of ethyl crotonate into a second dimension and clearly identify each chemical site individually. Crucial to these experiments is interleaved spectral referencing, a method introduced to compensate for temperature-induced field drifts over the course of the NMR acquisition. This method does not require additional hardware such as a field-frequency lock, which is especially challenging when designing compact systems.

End-to-End Distance Probability Distributions of Dilute Poly(ethylene oxide) in Aqueous Solution.

We introduce a powerful, widely applicable approach to characterizing polymer conformational distributions, specifically the end-to-end distance distributions, P(Ree), accessed through double electron-electron resonance (DEER) spectroscopy in conjunction with molecular dynamics (MD) simulations. The technique is demonstrated on one of the most widely used synthetic, disordered, water-soluble polymers: poly(ethylene oxide) (PEO). Despite its widespread importance, no systematic experimental characterization of PEO's Ree conformational landscape exists. The evaluation of P(Ree) is particularly important for short polymers or (bio)polymers with sequence complexities that deviate from simple polymer physics scaling laws valid for long chains. In this study, we characterize the Ree landscape by measuring P(Ree) for low molecular weight (MW: 0.22-2.6 kDa) dilute PEO chains. We use DEER with end-conjugated spin probes to resolve Ree populations from ∼2-9 nm and compare them with full distributions from MD. The P( Ree)'s from DEER and MD show remarkably good agreement, particularly at longer chain lengths where populations in the DEER-unresolvable range (<1.5 nm) are low. Both the P(Ree) and the root-mean-square R̃ee indicate that aqueous PEO is a semiflexible polymer in a good solvent, with the latter scaling linearly with molecular weight up to its persistence length (lp ∼ 0.48 nm), and rapidly transitioning to excluded volume scaling above lp. The R̃ee scaling is quantitatively consistent with that from experimental scattering data on high MW (>10 kDa) PEO and the P(Ree)'s crossover to the theoretical distribution for an excluded volume chain.

The Role of Backbone Polarity on Aggregation and Conduction of Ions in Polymer Electrolytes.

The usual understanding in polymer electrolyte design is that an increase in the polymer dielectric constant results in reduced ion aggregation and therefore increased ionic conductivity. We demonstrate here that in a class of polymers with extensive metal-ligand coordination and tunable dielectric properties, the extent of ionic aggregation is delinked from the ionic conductivity. The polymer systems considered here comprise ether, butadiene, and siloxane backbones with grafted imidazole side-chains, with dissolved Li+, Cu2+, or Zn2+ salts. The nature of ion aggregation is probed using a combination of X-ray scattering, electron paramagnetic resonance (in the case where the metal cation is Cu2+), and polymer field theory-based simulations. Polymers with less polar backbones (butadiene and siloxane) show stronger ion aggregation in X-ray scattering compared to those with the more polar ether backbone. The Tg-normalized ionic conductivities were however unaffected by the extent of aggregation. The results are explained on the basis of simulations which indicate that polymer backbone polarity does impact the microstructure and the extent of ion aggregation but does not impact percolation, leading to similar ionic conductivity regardless of the extent of ion aggregation. The results emphasize the ability to design for low polymer Tg through backbone modulation, separately from controlling ion-polymer interaction dynamics through ligand choice.

High-resolution Overhauser dynamic nuclear polarization enhanced proton NMR spectroscopy at low magnetic fields.

Dynamic nuclear polarization (DNP) has gained large interest due to its ability to increase signal intensities in nuclear magnetic resonance (NMR) experiments by several orders of magnitude. Currently, DNP is typically used to enhance high-field, solid-state NMR experiments. However, the method is also capable of dramatically increasing the observed signal intensities in solution-state NMR spectroscopy. In this work, we demonstrate the application of Overhauser dynamic nuclear polarization (ODNP) spectroscopy at an NMR frequency of 14.5 MHz (0.35 T) to observe DNP-enhanced high-resolution NMR spectra of small molecules in solutions. Using a compact hybrid magnet with integrated shim coils to improve the magnetic field homogeneity we are able to routinely obtain proton linewidths of less than 4 Hz and enhancement factors >30. The excellent field resolution allows us to perform chemical-shift resolved ODNP experiments on ethyl crotonate to observe proton J-coupling. Furthermore, recording high-resolution ODNP-enhanced NMR spectra of ethylene glycol allows us to characterize the microwave induced sample heating in-situ, by measuring the separation of the OH and CH2 proton peaks.

Reduced White Matter Integrity and Deficits in Neuropsychological Functioning in Adults With Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is currently viewed as a disorder of cortical systems connectivity, with a heavy emphasis being on the structural integrity of white matter tracts. However, the majority of the literature to date has focused on children with ASD. Understanding the integrity of white matter tracts in adults may help reveal the nature of ASD pathology in adulthood and the potential contributors to cognitive impairment. This study examined white matter water diffusion using diffusion tensor imaging in relation to neuropsychological measures of cognition in a sample of 45 adults with ASD compared to 20 age, gender, and full-scale-IQ-matched healthy volunteers. Tract-based spatial statistics were used to assess differences in diffusion along white matter tracts between groups using permutation testing. The following neuropsychological measures of cognition were assessed: processing speed, attention vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. Results indicated that fractional anisotropy (FA) was significantly reduced in adults with ASD in the anterior thalamic radiation (P = 0.022) and the right cingulum (P = 0.008). All neuropsychological measures were worse in the ASD group, but none of the measures significantly correlated with reduced FA in either tract in the adults with ASD or in the healthy volunteers. Together, this indicates that the tracts that are the most impacted in autism may not be (at least directly) responsible for the behavioral deficits in ASD. Autism Res 2020, 13: 702-714. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: White matter tracts are the data cables in the brain that efficiently transfer information, and damage to these tracts could be the cause for the abnormal behaviors that are associated with autism. We found that two long-range tracts (the anterior thalamic radiation and the cingulum) were both impaired in autism but were not directly related to the impairments in behavior. This suggests that the abnormal tracts and behavior are the effects of another underlying mechanism.

White matter structure in schizophrenia and autism: Abnormal diffusion across the brain in schizophrenia.

BACKGROUND: Schizophrenia and autism share many behavioral and neurological similarities, including altered white matter tract structure. However, because schizophrenia and autism are rarely compared directly, it is difficult to establish whether white matter abnormalities are disorder-specific or are common across these disorders that share some symptomatology. METHODS: In the current study, we compared white matter water diffusion using tensor imaging in 25 adults with autism, 15 adults with schizophrenia, all with IQ scores above 88, and 19 neurotypical adults. RESULTS: Although the three groups evinced no statistically significant differences in measures of fractional anisotropy (FA), the schizophrenia group showed significantly greater mean diffusivity (MD; Cohen's d > 0.77), due to greater radial diffusivity (RD; Cohen's d > 0.92), compared to both the autism and control groups. This effect was evident across the brain rather than specific to a particular tract. CONCLUSIONS: The greater MD and RD in schizophrenia appears to be diagnosis-specific. The altered diffusion may reflect subtle abnormalities in myelination, which could be a potential mechanism underlying the widespread behavioral deficits associated with schizophrenia.

Converging measures of neural change at the microstructural, informational, and cortical network levels in the hippocampus during the learning of the structure of organic compounds.

The critical role of the hippocampus in human learning has been illuminated by neuroimaging studies that increasingly improve the detail with which hippocampal function is understood. However, the hippocampal information developed with different types of imaging technologies is seldom integrated within a single investigation of the neural changes that occur during learning. Here, we show three different ways in which a small hippocampal region changes as the structures and names of a set of organic compounds are being learned, reflecting changes at the microstructural, informational, and cortical network levels. The microstructural changes are sensed using measures of water diffusivity. The informational changes are assessed using machine learning of the neural representations of organic compounds as they are encoded in the fMRI-measured activation levels of a set of hippocampal voxels. The changes in cortical networks are measured in terms of the functional connectivity between hippocampus and parietal regions. The co-location of these three hippocampal changes reflects that structure's involvement in learning at all three levels of explanation, consistent with the multiple ways in which learning brings about neural change.

Tau-Cofactor Complexes as Building Blocks of Tau Fibrils.

The aggregation of the human tau protein into neurofibrillary tangles is directly diagnostic of many neurodegenerative conditions termed tauopathies. The species, factors and events that are responsible for the initiation and propagation of tau aggregation are not clearly established, even in a simplified and artificial in vitro system. This motivates the mechanistic study of in vitro aggregation of recombinant tau from soluble to fibrillar forms, for which polyanionic cofactors are the most commonly used external inducer. In this study, we performed biophysical characterizations to unravel the mechanisms by which cofactors induce fibrillization. We first reinforce the idea that cofactors are the limiting factor to generate ThT-active tau fibrils, and establish that they act as templating reactant that trigger tau conformational rearrangement. We show that heparin has superior potency for recruiting monomeric tau into aggregation-competent species compared to any constituent intermediate or aggregate "seeds." We show that tau and cofactors form intermediate complexes whose evolution toward ThT-active fibrils is tightly regulated by tau-cofactor interactions. Remarkably, it is possible to find mild cofactors that complex with tau without forming ThT-active species, except when an external catalyst (e.g., a seed) is provided to overcome the energy barrier. In a cellular context, we propose the idea that tau could associate with cofactors to form a metastable complex that remains "inert" and reversible, until encountering a relevant seed that can trigger an irreversible transition to ß-sheet containing species.

Cofactors are essential constituents of stable and seeding-active tau fibrils.

Amyloid fibrils are cross-ß-rich aggregates that are exceptionally stable forms of protein assembly. Accumulation of tau amyloid fibrils is involved in many neurodegenerative diseases, including Alzheimer's disease (AD). Heparin-induced aggregates have been widely used and assumed to be a good tau amyloid fibril model for most biophysical studies. Here we show that mature fibrils made of 4R tau variants, prepared with heparin or RNA, spontaneously depolymerize and release monomers when their cofactors are removed. We demonstrate that the cross-ß-sheet assembly formed in vitro with polyanion addition is unstable at room temperature. We furthermore demonstrate high seeding capacity with transgenic AD mouse brain-extracted tau fibrils in vitro that, however, is exhausted after one generation, while supplementation with RNA cofactors resulted in sustained seeding over multiple generations. We suggest that tau fibrils formed in brains are supported by unknown cofactors and inhere higher-quality packing, as reflected in a more distinct conformational arrangement in the mouse fibril-seeded, compared with heparin-induced, tau fibrils. Our study suggests that the role of cofactors in tauopathies is a worthy focus of future studies, as they may be viable targets for diagnosis and therapeutics.

Surface chemical heterogeneity modulates silica surface hydration.

An in-depth knowledge of the interaction of water with amorphous silica is critical to fundamental studies of interfacial hydration water, as well as to industrial processes such as catalysis, nanofabrication, and chromatography. Silica has a tunable surface comprising hydrophilic silanol groups and moderately hydrophobic siloxane groups that can be interchanged through thermal and chemical treatments. Despite extensive studies of silica surfaces, the influence of surface hydrophilicity and chemical topology on the molecular properties of interfacial water is not well understood. In this work, we controllably altered the surface silanol density, and measured surface water diffusivity using Overhauser dynamic nuclear polarization (ODNP) and complementary silica-silica interaction forces across water using a surface forces apparatus (SFA). The results show that increased silanol density generally leads to slower water diffusivity and stronger silica-silica repulsion at short aqueous separations (less than ∼4 nm). Both techniques show sharp changes in hydration properties at intermediate silanol densities (2.0-2.9 nm-2). Molecular dynamics simulations of model silica-water interfaces corroborate the increase in water diffusivity with silanol density, and furthermore show that even on a smooth and crystalline surface at a fixed silanol density, adjusting the spatial distribution of silanols results in a range of surface water diffusivities spanning ∼10%. We speculate that a critical silanol cluster size or connectivity parameter could explain the sharp transition in our results, and can modulate wettability, colloidal interactions, and surface reactions, and thus is a phenomenon worth further investigation on silica and chemically heterogeneous surfaces.

Conformation-based assay of tau protein aggregation.

Amyloid fiber-forming proteins are predominantly intrinsically disordered proteins (IDPs). The protein tau, present mostly in neurons, is no exception. There is a significant interest in the study of tau protein aggregation mechanisms, given the direct correlation between the deposit of ß-sheet structured neurofibrillary tangles made of tau and pathology in several neurodegenerative diseases, including Alzheimer's disease. Among the core unresolved questions is the nature of the initial step triggering aggregation, with increasing attention placed on the question whether a conformational change of the IDPs plays a key role in the early stages of aggregation. Specifically, there is growing evidence that a shift in the conformation ensemble of tau is involved in its aggregation pathway, and might even dictate structural and pathological properties of mature fibers. Yet, because IDPs lack a well-defined 3D structure and continuously exchange between different conformers, it has been technically challenging to characterize their structural changes on-pathway to aggregation. Here, we make a case that double spin labeling of the ß-sheet stacking region of tau combined with pulsed double electron-electron resonance spectroscopy is a powerful method to assay conformational changes occurring during the course of tau aggregation, by probing intramolecular distances around aggregation-prone domains. We specifically demonstrate the potential of this approach by presenting recent results on conformation rearrangement of the ß-sheet stacking segment VQIINK (known as PHF6*) of tau. We highlight a canonical shift of the conformation ensemble, on-pathway and occurring at the earliest stage of aggregation, toward an opening of PHF6*. We expect this method to be applicable to other critical segments of tau and other IDPs.

Water Dynamics from the Surface to the Interior of a Supramolecular Nanostructure.

Water within and surrounding the structure of a biological system adopts context-specific dynamics that mediate virtually all of the events involved in the inner workings of a cell. These events range from protein folding and molecular recognition to the formation of hierarchical structures. Water dynamics are mediated by the chemistry and geometry of interfaces where water and biomolecules meet. Here we investigate experimentally and computationally the translational dynamics of vicinal water molecules within the volume of a supramolecular peptide nanofiber measuring 6.7 nm in diameter. Using Overhauser dynamic nuclear polarization relaxometry, we show that drastic differences exist in water motion within a distance of about one nanometer from the surface, with rapid diffusion in the hydrophobic interior and immobilized water on the nanofiber surface. These results demonstrate that water associated with materials designed at the nanoscale is not simply a solvent, but rather an integral part of their structure and potential functions.

Alterations of functional connectivity and intrinsic activity within the cingulate cortex of suicidal ideators.

The 'default mode network' (DMN), a collection of brain regions including the posterior cingulate cortex (PCC), shows reliable inter-regional functional connectivity at rest. It has been implicated in rumination and other negative affective states, but its role in suicidal ideation is not well understood. We employed seed based functional connectivity methods to analyze resting state fMRI data in 34 suicidal ideators and 40 healthy control participants. Whole-brain connectivity with dorsal PCC or ventral PCC was broadly intact between the two groups, but while the control participants showed greater coupling between the dorsal anterior cingulate cortex (dACC) and dorsal PCC, compared to the dACC and ventral PCC, this difference was reversed in the ideators. Furthermore, ongoing low frequency BOLD signal in these three regions (dorsal, ventral PCC, dACC) was reduced in the ideators. The structural integrity of the cingulum bundle, as measured using diffusion tensor imaging (DTI), also explained variation in the functional connectivity measures but did not abolish the group differences. Together, these findings provide evidence of abnormalities in the DMN underlying the tendency towards suicidal ideation.

Structural and functional neuroplasticity in human learning of spatial routes.

Recent findings with both animals and humans suggest that decreases in microscopic movements of water in the hippocampus reflect short-term neuroplasticity resulting from learning. Here we examine whether such neuroplastic structural changes concurrently alter the functional connectivity between hippocampus and other regions involved in learning. We collected both diffusion-weighted images and fMRI data before and after humans performed a 45min spatial route-learning task. Relative to a control group with equal practice time, there was decreased diffusivity in the posterior-dorsal dentate gyrus of the left hippocampus in the route-learning group accompanied by increased synchronization of fMRI-measured BOLD signal between this region and cortical areas, and by changes in behavioral performance. These concurrent changes characterize the multidimensionality of neuroplasticity as it enables human spatial learning.

Active cancellation - A means to zero dead-time pulse EPR.

The necessary resonator employed in pulse electron paramagnetic resonance (EPR) rings after the excitation pulse and creates a finite detector dead-time that ultimately prevents the detection of signal from fast relaxing spin systems, hindering the application of pulse EPR to room temperature measurements of interesting chemical or biological systems. We employ a recently available high bandwidth arbitrary waveform generator (AWG) to produce a cancellation pulse that precisely destructively interferes with the resonant cavity ring-down. We find that we can faithfully detect EPR signal at all times immediately after, as well as during, the excitation pulse. This is a proof of concept study showcasing the capability of AWG pulses to precisely cancel out the resonator ring-down, and allow for the detection of EPR signal during the pulse itself, as well as the dead-time of the resonator. However, the applicability of this approach to conventional EPR experiments is not immediate, as it hinges on either (1) the availability of low-noise microwave sources and amplifiers to produce the necessary power for pulse EPR experiment or (2) the availability of very high conversion factor micro coil resonators that allow for pulse EPR experiments at modest microwave power.

Aberrant functioning of the theory-of-mind network in children and adolescents with autism.

BACKGROUND: Theory-of-mind (ToM), the ability to infer people's thoughts and feelings, is a pivotal skill in effective social interactions. Individuals with autism spectrum disorders (ASD) have been found to have altered ToM skills, which significantly impacts the quality of their social interactions. Neuroimaging studies have reported altered activation of the ToM cortical network, especially in adults with autism, yet little is known about the brain responses underlying ToM in younger individuals with ASD. This functional magnetic resonance imaging (fMRI) study investigated the neural mechanisms underlying ToM in high-functioning children and adolescents with ASD and matched typically developing (TD) peers. METHODS: fMRI data were acquired from 13 participants with ASD and 13 TD control participants while they watched animations involving two "interacting" geometrical shapes. RESULTS: Participants with ASD showed significantly reduced activation, relative to TD controls, in regions considered part of the ToM network, the mirror network, and the cerebellum. Functional connectivity analyses revealed underconnectivity between frontal and posterior regions during task performance in the ASD participants. CONCLUSIONS: Overall, the findings of this study reveal disruptions in the brain circuitry underlying ToM in ASD at multiple levels, including decreased activation and decreased functional connectivity.

Identifying autism from neural representations of social interactions: neurocognitive markers of autism.

Autism is a psychiatric/neurological condition in which alterations in social interaction (among other symptoms) are diagnosed by behavioral psychiatric methods. The main goal of this study was to determine how the neural representations and meanings of social concepts (such as to insult) are altered in autism. A second goal was to determine whether these alterations can serve as neurocognitive markers of autism. The approach is based on previous advances in fMRI analysis methods that permit (a) the identification of a concept, such as the thought of a physical object, from its fMRI pattern, and (b) the ability to assess the semantic content of a concept from its fMRI pattern. These factor analysis and machine learning methods were applied to the fMRI activation patterns of 17 adults with high-functioning autism and matched controls, scanned while thinking about 16 social interactions. One prominent neural representation factor that emerged (manifested mainly in posterior midline regions) was related to self-representation, but this factor was present only for the control participants, and was near-absent in the autism group. Moreover, machine learning algorithms classified individuals as autistic or control with 97% accuracy from their fMRI neurocognitive markers. The findings suggest that psychiatric alterations of thought can begin to be biologically understood by assessing the form and content of the altered thought's underlying brain activation patterns.

Modulation of cortical activity during comprehension of familiar and unfamiliar text topics in speed reading and speed listening.

Brain activation associated with normal and speeded comprehension of expository texts on familiar and unfamiliar topics was investigated in reading and listening. The goal was to determine how brain activation and the comprehension processes it reflects are modulated by comprehension speed and topic familiarity. Passages on more familiar topics differentially activated a set of areas in the anterior temporal lobe and medial frontal gyrus, areas often associated with text-level integration processes, which we interpret to reflect integration of previous knowledge with the passage content. Passages presented at the faster presentation resulted in more activation of a network of frontal areas associated with strategic and working-memory processes (as well as visual or auditory sensory-related regions), which we interpret to reflect maintenance of local coherence among briefly available passage segments. The implications of this research is that the brain system for text comprehension adapts to varying perceptual and knowledge conditions.