Additional Brain Regions Research Articles

RNA editing regulates glutamatergic synapses in the frontal cortex of a molecular subtype of Amyotrophic Lateral Sclerosis

BackgroundAmyotrophic Lateral Sclerosis (ALS) is a highly heterogenous neurodegenerative disorder that primarily affects upper and lower motor neurons, affecting additional cell types and brain regions. Underlying molecular mechanisms are still elusive, in part due to disease heterogeneity. Molecular disease subtyping through integrative analyses including RNA editing profiling is a novel approach for identification of molecular networks involved in pathogenesis.MethodsWe aimed to highlight the role of RNA editing in ALS, focusing on the frontal cortex and the prevalent molecular disease subtype (ALS-Ox), previously determined by transcriptomic profile stratification. We established global RNA editing (editome) and gene expression (transcriptome) profiles in control and ALS-Ox cases, utilizing publicly available RNA-seq data (GSE153960) and an in-house analysis pipeline. Functional annotation and pathway analyses identified molecular processes affected by RNA editing alterations. Pearson correlation analyses assessed RNA editing effects on expression. Similar analyses on additional ALS-Ox and control samples (GSE124439) were performed for verification. Targeted re-sequencing and qRT-PCR analysis targeting CACNA1C, were performed using frontal cortex tissue from ALS and control samples (n = 3 samples/group).ResultsWe identified reduced global RNA editing in the frontal cortex of ALS-Ox cases. Differentially edited transcripts are enriched in synapses, particularly in the glutamatergic synapse pathway. Bioinformatic analyses on additional ALS-Ox and control RNA-seq data verified these findings. We identified increased recoding at the Q621R site in the GRIK2 transcript and determined positive correlations between RNA editing and gene expression alterations in ionotropic receptor subunits GRIA2, GRIA3 and the CACNA1C transcript, which encodes the pore forming subunit of a post-synaptic L-type calcium channel. Experimental data verified RNA editing alterations and editing-expression correlation in CACNA1C, highlighting CACNA1C as a target for further study.ConclusionsWe provide evidence on the involvement of RNA editing in the frontal cortex of an ALS molecular subtype, highlighting a modulatory role mediated though recoding and gene expression regulation on glutamatergic synapse related transcripts. We report RNA editing effects in disease-related transcripts and validated editing alterations in CACNA1C. Our study provides targets for further functional studies that could shed light in underlying disease mechanisms enabling novel therapeutic approaches.

Identifying Novel Proteins for Chronic Pain: Integration of Human Brain Proteomes and Genome-wide Association Data

Numerous genome-wide association studies have identified risk genes for chronic pain, yet the mechanisms by which genetic variants modify susceptibility have remained elusive. We sought to identify key genes modulating chronic pain risk by regulating brain protein expression. We integrated brain proteomic data with the largest genome-wide dataset for multisite chronic pain (N = 387,649) in a proteome-wide association study (PWAS) using discovery and confirmatory proteomic datasets (N = 376 and 152) from the dorsolateral prefrontal cortex. Leveraging summary data-based Mendelian randomization and Bayesian colocalization analysis, we pinpointed potential causal genes, while a transcriptome-wide association study integrating 452 human brain transcriptomes investigated whether cis-effects on protein abundance extended to the transcriptome. Single-cell RNA-sequencing data and single-nucleus transcriptomic data revealed cell-type-specific expression patterns for identified causal genes in the dorsolateral prefrontal cortex and dorsal root ganglia (DRG), complemented by RNA microarray analysis of expression profiles in other pain-related brain regions. Of the 22 genes cis-regulating protein abundance identified by the discovery PWAS, 18 (82%) were deemed causal by summary data-based Mendelian randomization or Bayesian colocalization analysis analyses, with 7 of these 18 genes (39%) replicating in the confirmatory PWAS, including guanosine diphosphate-mannose pyrophosphorylase B, which also associated at the transcriptome level. Several causal genes exhibited selective expression in excitatory and inhibitory neurons, oligodendrocytes, and astrocytes, while most identified genes were expressed across additional pain-related brain regions. This integrative proteogenomic approach identified 18 high-confidence causal genes for chronic pain, regulated by cis-effects on brain protein levels, suggesting promising avenues for treatment research and indicating a contributory role for the DRG. PerspectiveThe current post genome-wide association study analyses identified 18 high-confidence causal genes regulating chronic pain risk via cis-modulation of brain protein abundance, suggesting promising avenues for future chronic pain therapies. Additionally, the significant expression of these genes in the DRG indicated a potential contributory role, warranting further investigation.

Distinct Neural Mechanisms Between Anesthesia Induction and Emergence: A Narrative Review.

Anesthesia induction and emergence are critical periods for perioperative safety in the clinic. Traditionally, the emergence from general anesthesia has been recognized as a simple inverse process of induction resulting from the elimination of general anesthetics from the central nervous system. However, accumulated evidence has indicated that anesthesia induction and emergence are not mirror-image processes because of the occurrence of hysteresis/neural inertia in both animals and humans. An increasing number of studies have highlighted the critical role of orexinergic neurons and their involved circuits in the selective regulation of emergence but not the induction of general anesthesia. Moreover, additional brain regions have also been implicated in distinct neural mechanisms for anesthesia induction and emergence, which extends the concept that anesthetic induction and emergence are not antiparallel processes. Here, we reviewed the current literature and summarized the evidence regarding the differential mechanism of neural modulation in anesthesia induction and emergence, which will facilitate the understanding of the underlying neural mechanism for emergence from general anesthesia.

Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. 445 cross-sectional participants (aged≥50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. We found both tau metrics significantly elevated across increasing disease stages (p<0.0001) and as a function of increasing amyloid burden for participants with preclinical (p<0.0001, p=0.0056) and symptomatic (p=0.010, p=0.0021) AD. An interaction was found between tau burden and tau spatial spread when predicting amyloid burden (p=0.00013). Analyses of slope between tau metrics demonstrated more spread than burden in preclinical AD (β=0.59), but then tau burden elevated relative to spread (β=0.42) once participants had symptomatic AD, when the tau metrics became highly correlated (R=0.83). Tau burden and tau spatial spread are both strong biomarkers for early AD but provide unique information, particularly at the preclinical stage. Tau spatial spread may demonstrate earlier changes than tau burden which could have broad impact in clinical trial design. This research was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, NIH grants P30AG066444, P01AG026276, P01AG003991), Dominantly Inherited Alzheimer Network (DIAN, NIH grants U01AG042791, U19AG03243808, R01AG052550-01A1, R01AG05255003), and the Barnes-Jewish Hospital Foundation Willman Scholar Fund.

Longitudinal brain changes in Parkinson's disease with severe olfactory deficit

IntroductionOlfactory dysfunction and REM sleep behavior disorder (RBD) are associated with distinct cognitive trajectories in the course of Parkinson's disease (PD). The underlying neurobiology for this relationship remains unclear but may involve distinct patterns of neurodegeneration. This study aimed to examine longitudinal cortical atrophy and thinning in early-stage PD with severe olfactory deficit (anosmia) without and with concurrent probable RBD. MethodsLongitudinal MRI data over four years of 134 de novo PD and 49 healthy controls (HC) from the Parkinson Progression Marker Initiative (PPMI) cohort were analyzed using a linear mixed-effects model. Patients were categorized into those with anosmia by the University of Pennsylvania Smell Identification Test (UPSIT) score ≤ 18 (AO+) and those without (UPSIT score > 18, AO-). The AO+ group was further subdivided into AO+ with probable RBD (AO+RBD+) and without (AO+RBD-) for subanalysis. ResultsCompared to subjects without baseline anosmia, the AO+ group exhibited greater longitudinal declines in both volume and thickness in the bilateral parahippocampal gyri and right transverse temporal gyrus. Patients with concurrent anosmia and RBD showed more extensive longitudinal declines in cortical volume and thickness, involving additional brain regions including the bilateral precuneus, left inferior temporal gyrus, right paracentral gyrus, and right precentral gyrus. ConclusionsThe atrophy/thinning patterns in early-stage PD with severe olfactory dysfunction include regions that are critical for cognitive function and could provide a structural basis for previously reported associations between severe olfactory deficit and cognitive decline in PD. Concurrent RBD might enhance the dynamics of cortical changes.

Incidental visual processing of spatiotemporal cues in communicative interactions: An fMRI investigation

Abstract The interpretation of social interactions between people is important in many daily situations. The coordination of the relative body movements between them may provide visual cues that observers use without attention to discriminate such social interactions from the actions of people acting independently of each other. Previous studies highlighted brain regions involved in the visual processing of interacting versus independently acting people, including posterior superior temporal sulcus, and areas of lateral occipitotemporal and parietal cortices. Unlike these previous studies, we focused on the incidental visual processing of social interactions; that is, the processing of the body movements outside the observers’ focus of attention. In the current study, we used functional imaging to measure brain activation while participants were presented with point-light dyads portraying communicative interactions or individual actions. However, their task was to discriminate the brightness of two crosses also on the screen. To investigate brain regions that may process the spatial and temporal relationships between the point-light displays, we either reversed the facing direction of one agent or spatially scrambled the local motion of the points. Incidental processing of communicative interactions elicited activation in right anterior STS only when the two agents were facing each other. Controlling for differences in local motion by subtracting brain activation to scrambled versions of the point-light displays revealed significant activation in parietal cortex for communicative interactions, as well as left amygdala and brain stem/cerebellum. Our results complement previous studies and suggest that additional brain regions may be recruited to incidentally process the spatial and temporal contingencies that distinguish people acting together from people acting individually.

Distinct age-related brain activity patterns in the prefrontal cortex when increasing cognitive load: A functional near-infrared spectroscopy study

Researchers have long observed distinct brain activity patterns in older adults compared with younger adults that correlate with cognitive performance. Mainly, older adults tend to show over-recruitment of bilateral brain regions during lower task loads and improved performance interpreted as compensation, but not observed at higher loads. However, there are discrepancies about whether increases in activity are compensatory and whether older adults can show compensation at higher loads. Our aim was to examine age-related differences in prefrontal cortex (PFC) activity and cognitive performance using functional near-infrared spectroscopy (fNIRS) during single and dual N-back tasks. Twenty-seven young adults (18–27 years) and 31 older adults (64–84 yrs) took part in the study. We used a robust fNIRS data methodology consisting of channel and region of interest analyses. Results showed differences in performance between task load conditions and age-related differences in reaction times but no age-group effects for accuracy. Older adults exhibited more bilateral PFC activation compared with young adults across all tasks and showed increases in brain activity in high compared to low load conditions. Our findings further support previous reports showing that older adults use compensatory recruitment of additional brain regions in PFC to maintain cognitive performance but go against the notion that such compensation is not present at higher cognitive loads. Additionally, our results indicate that fNIRS is a sensitive tool that can characterize adaptive cortical changes in healthy aging.

Me, Myself, and I: Neural Activity for Self versus Other across Development.

Although adults and children differ in self-vs.-other perception, a developmental perspective on this discriminative ability at the brain level is missing. This study examined neural activation for self-vs.-other in a sample of 39 participants spanning four different age groups, from 4-year-olds to adults. Self-related stimuli elicited higher neural activity within two brain regions related to self-referential thinking, empathy, and social cognition processes. Second, stimuli related to 'others' (i.e., unknown peer) elicited activation within nine additional brain regions. These regions are associated with multisensory processing, somatosensory skills, language, complex visual stimuli, self-awareness, empathy, theory of mind, and social recognition. Overall, activation maps were gradually increasing with age. However, patterns of activity were non-linear within the medial cingulate cortex for 'self' stimuli and within the left middle temporal gyrus for 'other' stimuli in 7-10-year-old participants. In both cases, there were no self-vs.-other differences. It suggests a critical period where the perception of self and others are similarly processed. Furthermore, 11-19-year-old participants showed no differences between others and self within the left inferior orbital gyrus, suggesting less distinction between self and others in social learning. Understanding the neural bases of self-vs.-other discrimination during development can offer valuable insights into how social contexts can influence learning processes during development, such as when to introduce peer-to-peer teaching or group learning.

Differential c-Fos Response in Neurocircuits Activated by Repeated Predator Stress in Male and Female C57BL/6J Mice with Stress Sensitive or Resilient Alcohol Intake Phenotypes

Comorbidity of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) worsens the prognosis for each of these individual disorders. The current study aimed to identify neurocircuits potentially involved in regulation of PTSD-AUD comorbidity by mapping expression of c-Fos in male and female C57BL/6J mice following repeated predator stress (PS), modeled by exposure to dirty rat bedding. In experiment 1, the levels of c-Fos in the paraventricular nucleus of the hypothalamus (PVH) and the nucleus accumbens shell were higher after the second PS vs the first PS, indicating a sensitized response to this stressor. Additional brain regions showed varied sex-dependent and independent regulation by the two consecutive PS exposures. In experiment 2, mice that increased voluntary alcohol consumption following four exposures to PS (Sensitive subgroup) showed higher c-Fos induction in the PVH, piriform cortex and ventromedial hypothalamus than mice that decreased consumption following these exposures (Resilient subgroup). In contrast to these brain regions, c-Fos was higher in the anterior olfactory nucleus of Resilient vs Sensitive mice. Taken together, these data demonstrate that repeated PS exposure and voluntary alcohol consumption increase neuronal activity across neurocircuits in which specific components depend on the vulnerability of individual mice to these stressors. Increased PVH activity observed across both experiments suggests this brain area as a potential mediator of PS-induced increases in alcohol consumption. Future investigations of specific neuronal populations within the PVH activated by PS, and manipulation of these specific neuronal populations, could improve our understanding of the mechanisms leading to PTSD-AUD comorbidity.

Is serotonin transporter brain binding associated with the cortisol awakening response? An independent non-replication.

Serotonergic brain signaling is considered critical for an appropriate and dynamic adaptation to stress, seemingly through modulating limbic system functions, such as the hypothalamic-pituitary-adrenal (HPA)-axis. This interplay is of great interest since it holds promise as a target for preventing stress-related brain disorders, e.g., major depression. Our group has previously observed that prefrontal serotonin transporter (5-HTT) binding, imaged with positron emission tomography (PET), is positively associated with the cortisol awakening response (CAR), an index of HPA axis stress hormone dynamics. The aim of this cross-sectional study was to replicate the previous finding in a larger independent group of healthy individuals. Molecular imaging and cortisol data were available for 90 healthy individuals. Prefrontal 5-HTT binding was imaged with [11C]DASB brain PET. Non-displaceable 5-HTT binding potential (BPND) was quantified using the Multilinear Reference Tissue Model 2 (MRTM2) with cerebellum as the reference region. CAR was based on five serial salivary cortisol samples within the first hour upon awakening. The association between CAR and prefrontal 5-HTT BPND was evaluated using a multiple linear regression model adjusted for age and sex. Further, we tested for sex differences in the association. Finally, an exploratory analysis of the association, was performed in 8 additional brain regions. We observed no statistically significant association between 5-HTT binding and CAR corrected for age and sex in the prefrontal cortex (β = -0.28, p = 0.26). We saw no interaction with sex on the association (p = 0.99). We could not confirm a positive association between CAR and prefrontal 5-HTT BPND in this independent dataset. Also, sex differences in the association were not apparent. Our data do not exclude that the serotonin transporter system is involved in the regulation of stress responses in at-risk or manifest depressed states.

Vestibular and visual brain areas in the medial cortex of the human brain.

Self-motion perception involves an interaction between vestibular and visual brain regions. In the lateral brain, it includes the parietoinsular vestibular cortex and the posterior insular cortex. In the medial cortex, the cingulate sulcus visual (CSv) area is known to process visual-vestibular cues. Here, we show that the vestibular-visual network of the medial cortex extends beyond area CSv. We examined brain activations of 36 healthy right-handed participants by functional magnetic resonance imaging (fMRI) during stimulation with caloric vestibular, thermal, or visual motion cues. Consistent with previous research, we found that area CSv responded to both vestibular and visual cues but not to thermal cues. Moreover, the V6 complex and the precuneus motion (PcM) area responded primarily to (laminar-translational) visual motion cues. However, we also observed a region inferior to CSv within the pericallosal sulcus (vicinity of anterior retrosplenial) that primarily responded to vestibular cues. This vestibular pericallosal sulcus (vPCS) region did not respond to either visual or thermal cues. It was also distinct from a more posterior motion-sensitive region in the retrosplenial complex (mRSC) that responded to (radial) visual motion but not to vestibular and thermal cues. Together, our results suggest that the vestibular-visual network in the medial cortex not only includes areas CSv, PcM, and the V6 complex but also two additional brain regions adjacent to the callosum. These two brain regions exhibit similarities in terms of their locations and responses to vestibular and visual cues with self-motion-related brain regions recently described in nonhuman primates.NEW & NOTEWORTHY Self-motion perception involves several vestibular and visual cortical regions. Within the medial cortex, the cingulate sulcus visual (CSv) area, the precuneus motion (PcM) area, and the V6 complex respond selectively to self-motion cues. Here, we show that vestibular information is also processed in the pericallosal sulcus (vPCS), whereas (radial) visual motion information is associated with activation in the retrosplenial cortex (mRSC).

Of dolphins, humans, other long-lived animals and Alzheimer's disease (Commentary on Vacher et al.).

Of dolphins, humans, other long-lived animals and Alzheimer's disease (Commentary on Vacher et al.).

Cocaine and Its Abstinence Condition Modulate Striatal and Hippocampal Wnt Signaling in a Male Rat Model of Drug Self-Administration.

Recent years have provided more and more evidence confirming the important role of Wnt/β-catenin signaling in the pathophysiology of mental illnesses, including cocaine use disorder. High relapse rates, which is a hallmark of drug addiction, prompt the study of changes in Wnt signaling elements (Wnt5a, Wnt7b, and Ctnnb1) in the motivational aspects of cocaine use and early drug-free period (3 days after the last exposure to cocaine). For this purpose, an animal model of intravenous cocaine self-administration and two types of drug-free period (extinction training and abstinence in the home cage) were used. The studies showed that chronic cocaine self-administration mainly disturbs the expression of Wnt5a and Ctnnb1 (the gene encoding β-catenin) in the examined brain structures (striatum and hippocampus), and the examined types of early abstinence are characterized by a different pattern of changes in the expression of these genes. At the same time, in cocaine self-administrated animals, there were no changes in the level of Wnt5a and β-catenin proteins at the tested time points. Moreover, exposure to cocaine induces a significant reduction in the striatal and hippocampal expression of miR-374 and miR-544, which can regulate Wnt5a levels post-transcriptionally. In summary, previous observations from experimenter-administered cocaine have not been fully validated in the cocaine self-administration model. Yoked cocaine administration appears to disrupt Wnt signaling more than cocaine self-administration. The condition of the cocaine-free period, the routes of drug administration, and the motivational aspect of drug administration play an important role in the type of drug-induced molecular changes observed. Furthermore, in-depth research involving additional brain regions is needed to determine the exact role of Wnt signaling in short-term and long-lasting plasticity as well as in the motivational aspects of cocaine use, and thus to assess its potential as a target for new drug therapy for cocaine use disorder.

A Cre-driver rat model for anatomical and functional analysis of glucagon (Gcg)-expressing cells in the brain and periphery

ObjectiveThe glucagon gene (Gcg) encodes preproglucagon, which is cleaved to form glucagon-like peptide 1 (GLP1) and other mature signaling molecules implicated in metabolic functions. To date there are no transgenic rat models available for precise manipulation of GLP1-expressing cells in the brain and periphery. MethodsTo visualize and manipulate Gcg-expressing cells in rats, CRISPR/Cas9 was used to express iCre under control of the Gcg promoter. Gcg-Cre rats were bred with tdTomato reporter rats to tag Gcg-expressing cells. Cre-dependent AAVs and RNAscope in situ hybridization were used to evaluate the specificity of iCre expression by GLP1 neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt), and by intestinal and pancreatic secretory cells. Food intake was assessed in heterozygous (Het) Gcg-Cre rats after chemogenetic stimulation of cNTS GLP1 neurons expressing an excitatory DREADD. ResultsWhile genotype has minimal effect on body weight or composition in chow-fed Gcg-Cre rats, homozygous (Homo) rats have lower plasma glucose levels. In neonatal and adult Gcg-Cre/tdTom rats, reporter-labeled cells are present in the cNTS and IRt, and in additional brain regions (e.g., basolateral amygdala, piriform cortex) that lack detectable Gcg mRNA in adults but display transient developmental or persistently low Gcg expression. Compared to wildtype (WT) rats, hindbrain Gcg mRNA and GLP1 protein in brain and plasma are markedly reduced in Homo Gcg-Cre rats. Chemogenetic stimulation of cNTS GLP1 neurons reduced overnight chow intake in males but not females, the effect in males was blocked by antagonism of central GLP1 receptors, and hypophagia was enhanced when combined with a subthreshold dose of cholecystokinin-8 to stimulate gastrointestinal vagal afferents. ConclusionsGcg-Cre rats are a novel and valuable experimental tool for analyzing the development, anatomy, and function of Gcg-expressing cells in the brain and periphery. In addition, Homo Gcg-Cre rats are a unique model for assessing the role of Gcg-encoded proteins in glucose homeostasis and energy metabolism.

Serotonin receptor expression in hippocampus and temporal cortex of temporal lobe epilepsy patients by postictal generalized electroencephalographic suppression duration.

Prolonged postictal generalized electroencephalographic suppression (PGES) is a potential biomarker for sudden unexpected death in epilepsy (SUDEP), which may be associated with dysfunctional autonomic responses and serotonin signaling. To better understand molecular mechanisms, PGES duration was correlated to 5HT1A and 5HT2A receptor protein expression and RNAseq from resected hippocampus and temporal cortex of temporal lobe epilepsy patients with seizures recorded in preoperative evaluation. Analyses included 36 cases (age=14-64 years, age at epilepsy onset=0-51 years, epilepsy duration=2-53 years, PGES duration=0-93 s), with 13 cases in all hippocampal analyses. 5HT1A and 5HT2A protein was evaluated by Western blot and histologically in hippocampus (n= 16) and temporal cortex (n= 9). We correlated PGES duration to our previous RNAseq dataset for serotonin receptor expression and signaling pathways, as well as weighted gene correlation network analysis (WGCNA) to identify correlated gene clusters. In hippocampus, 5HT2A protein by Western blot positively correlated with PGES duration (p= .0024, R2 = .52), but 5HT1A did not (p= .87, R2 = .0020). In temporal cortex, 5HT1A and 5HT2A had lower expression and did not correlate with PGES duration. Histologically, PGES duration did not correlate with 5HT1A or 5HT2A expression in hippocampal CA4, dentate gyrus, or temporal cortex. RNAseq identified two serotonin receptors with expression that correlated with PGES duration in an exploratory analysis: HTR3B negatively correlated (p= .043, R2 = .26) and HTR4 positively correlated (p= .049, R2 = .25). WGCNA identified four modules correlated with PGES duration, including positive correlation with synaptic transcripts (p= .040, Pearson correlation r=.52), particularly potassium channels (KCNA4, KCNC4, KCNH1, KCNIP4, KCNJ3, KCNJ6, KCNK1). No modules were associated with serotonin receptor signaling. Higher hippocampal 5HT2A receptor protein and potassium channel transcripts may reflect underlying mechanisms contributing to or resulting from prolonged PGES. Future studies with larger cohorts should assess functional analyses and additional brain regions to elucidate mechanisms underlying PGES and SUDEP risk.

Inhibitory Control in Aging: The Compensation-Related Utilization of Neural Circuits Hypothesis.

As one of the core executive functions, inhibitory control plays an important role in human life. Inhibitory control refers to the ability to suppress task irrelevant information both internally and externally. Modern cognitive neuroscience has extensively investigated the neural basis of inhibitory control, less is known about the inhibitory control mechanisms in aging. Growing interests in cognitive declines of aging have given raise to the compensation-related utilization of neural circuits hypothesis (CRUNCH). In this review, we survey both behavioral, functional, and structural changes relevant to inhibitory control in aging. In line with CRUNCH, we found that older adults engage additional brain regions than younger adults when performing the same cognitive task, to compensate for declining brain structures and functions. Moreover, we propose CRUNCH could well take functional inhibitory deficits in older adults into account. Finally, we provide three sensible future research directions.

Dorsal-Ventral Visual Pathways and Object Characteristics: Beamformer Source Analysis of EEG

In performing a gaming task, mental rotation (MR) is one of the important aspects of visuospatial processing. MR involves dorsal-ventral pathways of the brain. Visual objects/models used in computer-games play a crucial role in gaming experience of the users. The visuospatial characteristics of the objects used in the computer-game influence the engagement of dorsal-ventral visual pathways. The current study investigates how the objects’ visuospatial characteristics (i.e., angular disparity and dimensionality) in an MR-based computer-game influence the cortical activities in dorsal-ventral visual pathways. Both the factors have two levels, angular disparity: convex angle (CA) vs. reflex angle (RA) and dimensionality: 2D vs. 3D. Sixty healthy adults, aged, 18–29 years (M = 21.6) were recruited for the study and randomly assigned to four gaming conditions i.e., 15 participants in each group. The multichannel electroencephalogram (EEG) data were recorded from 60 healthy adults while playing the game. The source reconstruction was done for ∼3000 sources inside the brain using the Dynamic Imaging of Coherent Sources (DICS) beamforming method for θ1(4–5.75), θ2(5.75–7.5), α1(7.5–9), α2(9–11), α3(11–13), β1(13–17.25), β2(17.25–21.5) Hz frequency sub-bands. The reconstructed neuronal sources were segmented into 68 functionally parcellated brain regions, and the percentage of active sources for each region was computed. Further, the differences across the 68 regions among the four gaming conditions were evaluated using the percentage of active sources. The differences in activation for the dorsal-ventral pathways and some additional brain regions were observed among the four groups. The game with 2D objects and CA showed higher activation than that with 3D objects and RA, respectively. The dorsal pathway was found to be more active in contrast to the ventral pathway. The findings suggest that angular disparity and dimensionality in MR influence the engagement of dorsal-ventral visual pathways in such a way that angular disparity has a greater impact on cortical activation across this region than dimensionality. Also, higher activation for CA as compared to RA irrespective of dimensionality reflects the complexity of spatial information processing under CA. Similarly, greater activation was seen for 2D objects than 3D, indicating difficulty in information processing due to deficient visual features.

Transcranial Neuromodulation Array With Imaging Aperture for Simultaneous Multifocus Stimulation in Nonhuman Primates.

Even simple behaviors arise from the simultaneous activation of multiple regions in the brain. Thus, the ability to simultaneously stimulate multiple regions within a brain circuit should allow for better modulation of function. However, performing simultaneous multifocus ultrasound neuromodulation introduces challenges to transducer design. Using 3-D Fullwave simulations, we have designed an ultrasound neuromodulation array for nonhuman primates that: 1) can simultaneously focus on multiple targets and 2) include an imaging aperture for additional functional imaging. This design is based on a spherical array, with 128 15-mm elements distributed in a spherical helix pattern. It is shown that clustering the elements tightly around the 65-mm imaging aperture located at the top of the array improves targeting at shallow depths, near the skull surface. Spherical arrays have good focusing capabilities through the skull at the center of the array, but focusing on off-center locations is more challenging due to the natural geometric configuration and the angle of incidence with the skull. In order to mitigate this, the 64 elements closest to the aperture were rotated toward and focusing on a shallow target, and the 64 elements farthest from the aperture were rotated toward and focusing on a deeper target. Data illustrated that this array produced focusing on the somatosensory cortex with a gain of 4.38 and to the thalamus with a gain of 3.82. To improve upon this, the array placement was optimized based on phase aberration simulations, allowing for the elements with the largest impact on the gain at each focal point to be found. This optimization resulted in an array design that can focus on the somatosensory cortex with a gain of 5.19 and the thalamus with a gain of 4.45. Simulations were also performed to evaluate the ability of the array to focus on 28 additional brain regions, showing that off-center target regions can be stimulated, but those closer to the skull will require corrective steps to deliver the same amount of energy to those locations. This simulation and design process can be adapted to an individual monkey or human skull morphologies and specific target locations within individuals by using orientable 3-D printing of the transducer case and by electronic phase aberration correction.

Lesion-symptom mapping with NIHSS sub-scores in ischemic stroke patients

BackgroundLesion-symptom mapping (LSM) is a statistical technique to investigate the population-specific relationship between structural integrity and post-stroke clinical outcome. In clinical practice, patients are commonly evaluated using the National Institutes...

CRISPR Generated SIX6 and POU4F2 Reporters Allow Identification of Brain and Optic Transcriptional Differences in Human PSC-Derived Organoids.

Human pluripotent stem cells (PSCs) represent a powerful tool to investigate human eye development and disease. When grown in 3D, they can self-assemble into laminar organized retinas; however, variation in the size, shape and composition of individual organoids exists. Neither the microenvironment nor the timing of critical growth factors driving retinogenesis are fully understood. To explore early retinal development, we developed a SIX6-GFP reporter that enabled the systematic optimization of conditions that promote optic vesicle formation. We demonstrated that early hypoxic growth conditions enhanced SIX6 expression and promoted eye formation. SIX6 expression was further enhanced by sequential inhibition of Wnt and activation of sonic hedgehog signaling. SIX6 + optic vesicles showed RNA expression profiles that were consistent with a retinal identity; however, ventral diencephalic markers were also present. To demonstrate that optic vesicles lead to bona fide “retina-like” structures we generated a SIX6-GFP/POU4F2-tdTomato dual reporter line that labeled the entire developing retina and retinal ganglion cells, respectively. Additional brain regions, including the hypothalamus and midbrain-hindbrain (MBHB) territories were identified by harvesting SIX6 + /POU4F2- and SIX6- organoids, respectively. Using RNAseq to study transcriptional profiles we demonstrated that SIX6-GFP and POU4F2-tdTomato reporters provided a reliable readout for developing human retina, hypothalamus, and midbrain/hindbrain organoids.