Unraveling Metabolic Changes following Stroke: Insights from a Urinary Metabolomics Analysis.

The neuropathological sequelae of stroke and subsequent recovery are incompletely understood. Here, we investigated the metabolic dynamics following stroke to advance the understanding of the pathophysiological mechanisms orchestrating stroke recovery. Using a nuclear magnetic resonance (NMR)-driven metabolomic profiling approach for urine samples obtained from a clinical group, the objective of this research was to (1) identify novel biomarkers indicative of severity and recovery following stroke, and (2) uncover the biochemical pathways underlying repair and functional recovery after stroke. Urine samples and clinical stroke assessments were collected during the acute (2-11 days) and chronic phases (6 months) of stroke. Using a 700 MHz 1H NMR spectrometer, metabolomic profiles were acquired followed by a combination of univariate and multivariate statistical analyses, along with biological pathway analysis and clinical correlations. The results revealed changes in phenylalanine, tyrosine, tryptophan, purine, and glycerophospholipid biosynthesis and metabolism during stroke recovery. Pseudouridine was associated with a change in post-stroke motor recovery. Thus, NMR-based metabolomics is able to provide novel insights into post-stroke cellular functions and establish a foundational framework for future investigations to develop targeted therapeutic interventions, advance stroke diagnosis and management, and enhance overall quality of life for individuals with stroke.

Activity in the pontine reticular nuclei scales with handgrip force in humans.

The neural pathways that contribute to force production in humans are currently poorly understood, as the relative roles of the corticospinal tract and brainstem pathways, such as the reticulospinal tract (RST), vary substantially across species. Using functional magnetic resonance imaging (fMRI), we aimed to measure activation in the pontine reticular nuclei (PRN) during different submaximal handgrip contractions to determine the potential role of the PRN in force modulation. Thirteen neurologically intact participants (age: 28 ± 6 yr) performed unilateral handgrip contractions at 25%, 50%, 75% of maximum voluntary contraction during brain scans. We quantified the magnitude of PRN activation from the contralateral and ipsilateral sides during each of the three contraction intensities. A repeated-measures ANOVA demonstrated a significant main effect of force (P = 0.012, [Formula: see text] = 0.307) for PRN activation, independent of side (i.e., activation increased with force for both contralateral and ipsilateral nuclei). Further analyses of these data involved calculating the linear slope between the magnitude of activation and handgrip force for each region of interest (ROI) at the individual-level. One-sample t tests on the slopes revealed significant group-level scaling for the PRN bilaterally, but only the ipsilateral PRN remained significant after correcting for multiple comparisons. We show evidence of task-dependent activation in the PRN that was positively related to handgrip force. These data build on a growing body of literature that highlights the RST as a functionally relevant motor pathway for force modulation in humans.NEW & NOTEWORTHY In this study, we used a task-based functional magnetic resonance imaging (fMRI) paradigm to show that activity in the pontine reticular nuclei scales linearly with increasing force during a handgrip task. These findings directly support recently proposed hypotheses that the reticulospinal tract may play an important role in modulating force production in humans.

Females exhibit smaller volumes of brain activation and lower inter-subject variability during motor tasks.

Past work has shown that brain structure and function differ between females and males. Males have larger cortical and sub-cortical volume and surface area (both total and subregional), while females have greater cortical thickness in most brain regions. Functional differences are also reported in the literature, yet to date little work has systematically considered whether patterns of brain activity indexed with functional magnetic resonance imaging (fMRI) differ between females and males. The current study sought to remediate this issue by employing task-based whole brain motor mapping analyses using an openly available dataset. We tested differences in patterns of functional brain activity associated with 12 voluntary movement patterns in females versus males. Results suggest that females exhibited smaller volumes of brain activation across all 12 movement tasks, and lower patterns of variability in 10 of the 12 movements. We also observed that females had greater cortical thickness, which is in alignment with previous analyses of structural differences. Overall, these findings provide a basis for considering biological sex in future fMRI research and provide a foundation of understanding differences in how neurological pathologies present in females vs males.

Unique, Shared, and Dominant Brain Activation in Visual Word Form Area and Lateral Occipital Complex during Reading and Picture Naming.

Identifying printed words and pictures concurrently is ubiquitous in daily tasks, and so it is important to consider the extent to which reading words and naming pictures may share a cognitive-neurophysiological functional architecture. Two functional magnetic resonance imaging (fMRI) experiments examined whether reading along the left ventral occipitotemporal region (vOT; often referred to as a visual word form area, VWFA) has activation that is overlapping with referent pictures (i.e., both conditions significant and shared, or with one significantly more dominant) or unique (i.e., one condition significant, the other not), and whether picture naming along the right lateral occipital complex (LOC) has overlapping or unique activation relative to referent words. Experiment 1 used familiar regular and exception words (to force lexical reading) and their corresponding pictures in separate naming blocks, and showed dominant activation for pictures in the LOC, and shared activation in the VWFA for exception words and their corresponding pictures (regular words did not elicit significant VWFA activation). Experiment 2 controlled for visual complexity by superimposing the words and pictures and instructing participants to either name the word or the picture, and showed primarily shared activation in the VWFA and LOC regions for both word reading and picture naming, with some dominant activation for pictures in the LOC. Overall, these results highlight the importance of including exception words to force lexical reading when comparing to picture naming, and the significant shared activation in VWFA and LOC serves to challenge specialized models of reading or picture naming.

High Force Unimanual Handgrip Contractions Increase Ipsilateral Sensorimotor Activation and Functional Connectivity.

Imaging and brain stimulation studies seem to correct the classical understanding of how brain networks, rather than contralateral focal areas, control the generation of unimanual voluntary force. However, the scaling and hemispheric-specificity of network activation remain less understood. Using fMRI, we examined the effects of parametrically increasing right-handgrip force on activation and functional connectivity among the sensorimotor network bilaterally with 25%, 50%, and 75% maximal voluntary contractions (MVC). High force (75% MVC) unimanual handgrip contractions resulted in greater ipsilateral motor activation and functional connectivity with the contralateral hemisphere compared to a low force 25% MVC condition. The ipsilateral motor cortex activation and network strength correlated with relative handgrip force (% MVC). Increases in unimanual handgrip force resulted in greater ipsilateral sensorimotor activation and greater functional connectivity between hemispheres within the sensorimotor network.

Structural connectivity predicts functional activation during lexical and sublexical reading.

A critical question in neuroscience is the extent to which structural connectivity of the brain predicts localization of brain function. Recent research has suggested that anatomical connectivity can predict functional magnetic resonance imaging (fMRI) responses in several cognitive domains, including face, object, scene, and body processing, and development of word recognition skills (Osher et al., 2016; Saygin et al., 2016). However, this technique has not yet been extended to skilled word reading. Thus, we developed a computational model that relates anatomical connectivity (measured using probabilistic tractography) of individual cortical voxels to fMRI responses of the same voxels during lexical and sublexical reading tasks. Our results showed that the model built from structural connectivity was able to accurately predict functional responses of individual subjects based on their structural connectivity alone. This finding was apparent across the cortex, as well as to specific regions of interest associated with reading, language, and spatial attention. Further, we identified the structural connectivity networks associated with different aspects of skilled reading using connectivity analyses, and showed that interconnectivity between left hemisphere language and right hemisphere attentional areas underlies both lexical and sublexical reading. This work has important implications for understanding how structural connectivity contributes to reading and suggests that there is a relationship between skilled reading and neuroanatomical brain connectivity that future research should continue to explore.

Brain Structural Connectivity Predicts Brain Functional Complexity: Diffusion Tensor Imaging Derived Centrality Accounts for Variance in Fractal Properties of Functional Magnetic Resonance Imaging Signal.

The complexity of brain activity has recently been investigated using the Hurst exponent (H), which describes the extent to which functional magnetic resonance imaging (fMRI) blood oxygen-level dependent (BOLD) activity is simple vs. complex. For example, research has demonstrated that fMRI activity is more complex before than after consumption of alcohol and during task than resting state. The measurement of H in fMRI is a novel method that requires the investigation of additional factors contributing to complexity. Graph theory metrics of centrality can assess how centrally important to the brain network each region is, based on diffusion tensor imaging (DTI) counts of probabilistic white matter (WM) tracts. DTI derived centrality was hypothesized to account for the complexity of functional activity, based on the supposition that more sources of information to integrate should result in more complex activity. FMRI BOLD complexity as measured by H was associated with five brain region centrality measures: degree, eigenvector, PageRank, current flow betweenness, and current flow closeness centrality. Multiple regression analyses demonstrated that eigenvector centrality was the most robust predictor of complexity, whereby greater centrality was associated with increased complexity (lower H). Regions known to be highly connected, including the thalamus and hippocampus, notably were among the highest in centrality and complexity. This research has led to a greater understanding of how brain region characteristics such as DTI centrality relate to the novel Hurst exponent approach for assessing brain activity complexity, and implications for future research that employ these measures are discussed.

Atypical language localization in right temporal lobe epilepsy: An fMRI case report.

We report a 41- year-old, left-handed patient with drug-resistant right temporal lobe epilepsy (TLE). Presurgical fMRI was conducted to examine whether the patient had language functioning in the right hemisphere given that left-handedness is associated with a higher prevalence of right hemisphere dominance for language. The fMRI results revealed bilateral activation in Broca's and Wernicke's areas and activation of eloquent cortex near the region of planned resection in the right temporal lobe. Due to right temporal language-related activation, the patient underwent an awake right-sided temporal lobectomy with intraoperative language mapping. Intraoperative direct cortical stimulation (DCS) was conducted in the regions corresponding to the fMRI activation, and the patient showed language abnormalities, such as paraphasic errors, and speech arrest. The decision was made to abort the planned anterior temporal lobe procedure, and the patient instead underwent a selective amygdalohippocampectomy via the Sylvian fissure at a later date. Post-operatively the patient was seizure-free with no neurological deficits. Taken together, the results support previous findings of right hemisphere language activation in left-handed individuals, and should be considered in cases in which presurgical localization is conducted for left-hand dominant patients undergoing neurosurgical procedures.

How words and space collide: Lexical and sublexical reading are reliant on separable reflexive and voluntary attention regions in hybrid tasks.

Reading ability requires the coordination of many cognitive processes to be effective, including spatial attention. Recent functional magnetic resonance imaging (fMRI) evidence from Ekstrand et al. (2019) suggests that lexical reading is more associated with reflexive attentional orienting regions, whereas sublexical reading is more associated with voluntary attentional orienting regions. The current research sought to further examine the neuroanatomical relationship between reading and attention using a novel experimental design in fMRI. Participants performed four hybrid attentional orienting and reading-aloud tasks, where a reflexive or voluntary spatial cue preceded a lexical or sublexical target. Results indicated that lexical reading resulted in greater activation in the right temporoparietal junction, a reflexive orienting region. Sublexical reading resulted in greater activation in the left inferior frontal gyrus, left fusiform and inferior temporal gyrus, and right superior parietal lobule and intraparietal sulcus (voluntary orienting regions). Further, we found an interaction between reading and attention in the middle occipital gyrus. This study provides the most direct evidence to date that lexical and sublexical reading recruit differential attentional orienting regions during single-word reading in skilled readers. Implications for models of reading and attention, as well as for strategic remediation of their dysfunction, are discussed.

FMRI of shared-stream priming of lexical identification by object semantics along the ventral visual processing stream.

Distributed sub-systems of the brain's semantic network have been shown to process semantics associated with visual features of objects (e.g., shape, colour) in the ventral visual processing stream, whereas semantics associated with actions are processed in the dorsal stream. Orthographic lexical processing has also been shown to occur in the ventral stream. Past research from our lab (Neudorf et al., 2019) has demonstrated a temporal (i.e., reaction time) priming advantage for object primes over action primes in the lexical decision task consistent with ventral shared-stream processing of visual feature object semantics and orthographic lexical identification, whereby object primes produced larger priming effects than action primes. The current experiment explored this paradigm using functional magnetic resonance imaging (fMRI) and identified the potential loci of shared-stream processing to regions in the ventral stream just anterior to colour sensitive visual area V4 cortex in the left fusiform gyrus and anterior to lexical and shape sensitive regions in the left fusiform gyrus, as well as in cerebellar lobule VI. Action priming showed more activation than object priming in dorsal stream motion related regions of the right parietal occipital junction, right superior occipital gyrus, and bilateral visual area V3. The fMRI activation observed in this experiment supports the theory that spatially shared-stream activation occurs in the ventral stream during object (but not action) priming of lexical identification, which is consistent with our earlier behavioural research showing that these processes are also temporally shared.

Where words and space collide: The overlapping neural activation of lexical and sublexical reading with voluntary and reflexive spatial attention.

Recent research has shown a relationship between reading and attention, however the neuroanatomical overlap of these two processes has remained relatively unexplored. Therefore, we sought to investigate the overlapping neural mechanisms of spatial attention and reading using functional magnetic resonance imaging. Participants performed two attentional orienting tasks (reflexive and voluntary), and two overt word-reading tasks (lexical and sublexical). We hypothesized that there would be greater unique activation overlap of reflexive attention with lexical reading, and of voluntary attention with sublexical reading. Results indicated that lexical reading had greater overlapping activation in reflexive orienting areas compared to sublexical reading, suggesting that lexical reading may employ more automatic attentional mechanisms. In contrast, sublexical reading had greater overlapping activation with voluntary attention areas compared to lexical reading, suggesting that phonetic decoding may rely more heavily on voluntary attention. This research broadens our understanding of the neural overlap that underlies the relationship between reading and spatial attention.

The Effect of Tumor Neovasculature on Functional Magnetic Resonance Imaging Blood Oxygen Level-Dependent Activation.

BACKGROUND: We report the case of a 40-year-old patient with a large, World Health Organization grade III oligodendroglioma in the left parietal lobe. CASE DESCRIPTION: Presurgical planning included functional magnetic resonance imaging (fMRI) localization of language, motor, and somatosensory processing. fMRI results for motor and somatosensory tasks revealed activation in perilesional regions near the surgical resection as well as deactivation in the tumor for the sensory task, suggesting decreased autoregulation in the region owing to the glioma. fMRI results showed left-hemisphere dominance for language and activation in perilesional regions for all 3 speech tasks (i.e., word reading, picture naming, and semantic questions). In addition, the results demonstrated that the high vascularity of the lesion altered the blood oxygen level-dependent function, resulting in false-positive and false-negative activation in the semantic questions and leg/foot rubbing task, respectively. Intraoperative direct cortical stimulation was conducted in the regions corresponding to fMRI activation while the patient performed motor, sensory, and language tasks and showed no loss of function. Follow-up fMRI revealed that there was no longer activation in the tumor or in perilesional regions, presumably owing to the resection of the vascularized tumor. CONCLUSIONS: This case highlights the importance of presurgical fMRI to inform the neurosurgical approach and emphasizes the need for careful interpretation of fMRI data, especially in cases of malignant glioma, which can decrease autoregulation in surrounding regions, affecting fMRI blood oxygen level-dependent signal.

Immersive and interactive virtual reality to improve learning and retention of neuroanatomy in medical students: a randomized controlled study.

BACKGROUND: Spatial 3-dimensional understanding of the brain is essential to learning neuroanatomy, and 3-dimensional learning techniques have been proposed as tools to enhance neuroanatomy training. The aim of this study was to examine the impact of immersive virtual-reality neuroanatomy training and compare it to traditional paper-based methods. METHODS: In this randomized controlled study, participants consisted of first- or second-year medical students from the University of Saskatchewan recruited via email and posters displayed throughout the medical school. Participants were randomly assigned to the virtual-reality group or the paper-based group and studied the spatial relations between neural structures for 12 minutes after performing a neuroanatomy baseline test, with both test and control questions. A postintervention test was administered immediately after the study period and 5-9 days later. Satisfaction measures were obtained. RESULTS: Of the 66 participants randomly assigned to the study groups, 64 were included in the final analysis, 31 in the virtual-reality group and 33 in the paper-based group. The 2 groups performed comparably on the baseline questions and showed significant performance improvement on the test questions following study. There were no significant differences between groups for the control questions, the postintervention test questions or the 7-day postintervention test questions. Satisfaction survey results indicated that neurophobia was decreased. INTERPRETATION: Results from this study provide evidence that training in neuroanatomy in an immersive and interactive virtual-reality environment may be an effective neuroanatomy learning tool that warrants further study. They also suggest that integration of virtual-reality into neuroanatomy training may improve knowledge retention, increase study motivation and decrease neurophobia.

More than a feeling: The bidirectional convergence of semantic visual object and somatosensory processing.

Prevalent theories of semantic processing assert that the sensorimotor system plays a functional role in the semantic processing of manipulable objects. While motor execution has been shown to impact object processing, involvement of the somatosensory system has remained relatively unexplored. Therefore, we developed two novel priming paradigms. In Experiment 1, participants received a vibratory hand prime (on half the trials) prior to viewing a picture of either an object interacted primarily with the hand (e.g., a cup) or the foot (e.g., a soccer ball) and reported how they would interact with it. In Experiment 2, the same objects became the prime and participants were required to identify whether the vibratory stimulation occurred to their hand or foot. In both experiments, somatosensory priming effects arose for the hand objects, while foot objects showed no priming benefits. These results suggest that object semantic knowledge bidirectionally converges with the somatosensory system.

Reorganized neural activation in motor cortex following subdural fluid collection: an fMRI and DTI study.

We report a patient with a cavernous malformation involving the right lentiform nucleus. Pre-surgical planning included fMRI localization of language, motor, and sensory processing, and DTI of white matter tracts. fMRI results revealed no activation near the planned resection zone. However, post-surgery the patient developed a subdural fluid collection, which applied pressure to the primary motor cortex (M1). Follow-up scans revealed that motor activation had shifted due to pressure, and then shifted to a new location after the fluid collection subsided. This case report suggests that long-term neural reorganization can occur in response to short term compression in the cortex.

Presurgical language mapping in epilepsy: Using fMRI of reading to identify functional reorganization in a patient with long-standing temporal lobe epilepsy.

We report a 55-year-old, right-handed patient with intractable left temporal lobe epilepsy, who previously had a partial left temporal lobectomy. The patient could talk during seizures, suggesting that he might have language dominance in the right hemisphere. Presurgical fMRI localization of language processing including reading of exception and regular words, pseudohomophones, and dual meaning words confirmed the clinical hypothesis of right language dominance, with only small amounts of activation near the planned surgical resection and, thus, minimal eloquent cortex to avoid during surgery. Postoperatively, the patient was rendered seizure-free without speech deficits.

Pre-Surgical Integration of fMRI and DTI of the Sensorimotor System in Transcortical Resection of a High-Grade Insular Astrocytoma.

Herein we report on a patient with a WHO Grade III astrocytoma in the right insular region in close proximity to the internal capsule who underwent a right frontotemporal craniotomy. Total gross resection of insular gliomas remains surgically challenging based on the possibility of damage to the corticospinal tracts. However, maximizing the extent of resection has been shown to decrease future adverse outcomes. Thus, the goal of such surgeries should focus on maximizing extent of resection while minimizing possible adverse outcomes. In this case, pre-surgical planning included integration of functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), to localize motor and sensory pathways. Novel fMRI tasks were individually developed for the patient to maximize both somatosensory and motor activation simultaneously in areas in close proximity to the tumor. Information obtained was used to optimize resection trajectory and extent, facilitating gross total resection of the astrocytoma. Across all three motor-sensory tasks administered, fMRI revealed an area of interest just superior and lateral to the astrocytoma. Further, DTI analyses showed displacement of the corona radiata around the superior dorsal surface of the astrocytoma, extending in the direction of the activation found using fMRI. Taking into account these results, a transcortical superior temporal gyrus surgical approach was chosen in order to avoid the area of interest identified by fMRI and DTI. Total gross resection was achieved and minor post-surgical motor and sensory deficits were temporary. This case highlights the utility of comprehensive pre-surgical planning, including fMRI and DTI, to maximize surgical outcomes on a case-by-case basis.

Disentangling Genuine Semantic Stroop Effects in Reading from Contingency Effects: On the Need for Two Neutral Baselines.

The automaticity of reading is often explored through the Stroop effect, whereby color-naming is affected by color words. Color associates (e.g., "sky") also produce a Stroop effect, suggesting that automatic reading occurs through to the level of semantics, even when reading sub-lexically (e.g., the pseudohomophone "skigh"). However, several previous experiments have confounded congruency with contingency learning, whereby faster responding occurs for more frequent stimuli. Contingency effects reflect a higher frequency-pairing of the word with a font color in the congruent condition than in the incongruent condition due to the limited set of congruent pairings. To determine the extent to which the Stroop effect can be attributed to contingency learning of font colors paired with lexical (word-level) and sub-lexical (phonetically decoded) letter strings, as well as assess facilitation and interference relative to contingency effects, we developed two neutral baselines: each one matched on pair-frequency for congruent and incongruent color words. In Experiments 1 and 3, color words (e.g., "blue") and their pseudohomophones (e.g., "bloo") produced significant facilitation and interference relative to neutral baselines, regardless of whether the onset (i.e., first phoneme) was matched to the color words. Color associates (e.g., "ocean") and their pseudohomophones (e.g., "oshin"), however, showed no significant facilitation or interference relative to onset matched neutral baselines (Experiment 2). When onsets were unmatched, color associate words produced consistent facilitation on RT (e.g., "ocean" vs. "dozen"), but pseudohomophones (e.g., "oshin" vs. "duhzen") failed to produce facilitation or interference. Our findings suggest that the Stroop effects for color and associated stimuli are sensitive to the type of neutral baseline used, as well as stimulus type (word vs. pseudohomophone). In general, contingency learning plays a large role when repeating congruent items more than incongruent items, but appropriate pair-frequency matched neutral baselines allow for the assessment of genuine facilitation and interference. Using such baselines, we found reading processes proceed to a semantic level for familiar words, but not pseudohomophones (i.e., phonetic decoding). Such assessment is critical for separating the effects of genuine congruency from contingency during automatic word reading in the Stroop task, and when used with color associates, isolates the semantic contribution.

Attentional Network Differences Between Migraineurs and Non-migraine Controls: fMRI Evidence.

Migraine is a headache disorder characterized by sensitivity to light and sound. Recent research has revealed abnormal visual-spatial attention in migraineurs in between headache attacks. Here, we ask whether these attentional abnormalities can be attributed to specific regions of the known attentional network to help characterize the abnormalities in migraine. Specifically, the ventral frontoparietal network of attention is involved with assessing the behavioural relevance of unattended stimuli. Given the decreased suppression of unattended stimuli reported in migraineurs, we hypothesized that migraineurs would have abnormal processing in the ventral portion of the frontoparietal network of attention. To address this, we used functional magnetic resonance imaging to assess the attentional control networks during visual spatial-orienting tasks in migraineurs (N = 16) as compared to non-migraine controls (N = 16). We employed two visual orienting paradigms with target discrimination tasks: (1) voluntary orienting to central arrow cues, and (2) reflexive orienting to peripheral flash cues. While both groups showed activation in the key areas of attentional processing networks, migraineurs showed less activation than non-migraine controls in a key area of the ventral frontoparietal network of attention, the right temporal parietal junction (rTPJ), during both voluntary and reflexive visual spatial orienting. Given the role of rTPJ is to assess the visual environment for behaviorally relevant sensory stimuli outside the focus of attention and signal other attentional areas to reorient attention to behaviorally salient stimuli, our findings fit with previous research showing that migraineurs lack suppression of unattended events and have heightened orienting to sudden onset stimuli in peripheral locations.