Cortical Regions Research Articles

Tau-PET in early cortical Alzheimer brain regions in relation to mild behavioral impairment in older adults with either normal cognition or mild cognitive impairment

Mild Behavioral Impairment (MBI) leverages later-life emergent and persistent neuropsychiatric symptoms (NPS) to identify a high-risk group for incident dementia. Phosphorylated tau (p-tau) is a hallmark biological manifestation of Alzheimer disease (AD). We investigated associations between MBI and tau accumulation in early-stage AD cortical regions. In 442 Alzheimer’s Disease Neuroimaging Initiative participants with normal cognition or mild cognitive impairment, MBI status was determined alongside corresponding p-tau and Aβ. Two meta-regions of interest were generated to represent Braak I and III neuropathological stages. Multivariable linear regression modelled the association between MBI as independent variable and tau tracer uptake as dependent variable. Among Aβ positive individuals, MBI was associated with tau uptake in Braak I (β=0.45(0.15), p<.01) and Braak III (β=0.24(0.07), p<.01) regions. In Aβ negative individuals, MBI was not associated with tau in the Braak I region (p=.11) with a negative association in Braak III (p=.01). These findings suggest MBI may be a sequela of neurodegeneration, and can be implemented as a cost-effective framework to help improve screening efficiency for AD.

MRI-Derived AD Signature of Cortical Thinning and Plasma P-Tau217 for Predicting Alzheimer Dementia Among Community-Dwelling Older Adults.

Structural brain MRI and blood-based phosphorylated tau (p-tau) measures are among the least invasive and least expensive Alzheimer's disease (AD) biomarkers to date. The extent to which these biomarkers may outperform one another in predicting future Alzheimer dementia diagnosis is poorly understood, however. This study investigated 2 specific AD biomarkers, i.e., a cortical thickness signature of AD (AD-CT) and plasma p-tau217, for predicting Alzheimer dementia. Data came from community-dwelling older participants of the Religious Orders Study or the Rush Memory and Aging Project. AD-CT was obtained from 3T MRI scans using a magnetization-prepared rapid acquisition gradient echo sequence and by averaging thickness from previously identified cortical regions implicated in AD. Plasma p-tau217 was quantified using an immunoassay developed by Lilly Research Laboratories on the MSD platform. Both MRI scans and blood specimens were collected at the same visits, and subsequent diagnoses of Alzheimer dementia were determined through annual detailed clinical evaluations. Cox proportional hazards models examined the associations of the 2 biomarkers with incident Alzheimer dementia, and prediction accuracy was assessed using c-statistics. A total of 198 older adults, on average 84 years of age, were included. Over a mean follow-up of 4 years, 60 (30%) individuals developed Alzheimer dementia. AD-CT (hazard ratio: 1.71, 95% CI 1.26-2.31) and separately plasma p-tau217 (hazard ratio: 2.57, 95% CI 1.83-3.61) were associated with incident Alzheimer dementia. The c-statistic for prediction accuracy was consistently higher for plasma p-tau217 (between 0.74 and 0.81) than AD-CT (between 0.70 and 0.75) across a range of time horizons. Furthermore, with both biomarkers included in the same model, there was only modest improvement in the c-statistic due to AD-CT. Plasma p-tau217 outperforms an imaging-based cortical thickness signature of AD in predicting future Alzheimer dementia diagnosis. Furthermore, the AD cortical thickness signature adds little to the prediction accuracy above and beyond plasma p-tau217.

Pan-cortical 2-photon mesoscopic imaging and neurobehavioral alignment in awake, behaving mice.

The flow of neural activity across the neocortex during active sensory discrimination is constrained by task-specific cognitive demands, movements, and internal states. During behavior, the brain appears to sample from a broad repertoire of activation motifs. Understanding how these patterns of local and global activity are selected in relation to both spontaneous and task-dependent behavior requires in-depth study of densely sampled activity at single neuron resolution across large regions of cortex. In a significant advance toward this goal, we developed procedures to record mesoscale 2-photon Ca2+ imaging data from two novel in vivo preparations that, between them, allow for simultaneous access to nearly all 0f the mouse dorsal and lateral neocortex. As a proof of principle, we aligned neural activity with both behavioral primitives and high-level motifs to reveal the existence of large populations of neurons that coordinated their activity across cortical areas with spontaneous changes in movement and/or arousal. The methods we detail here facilitate the identification and exploration of widespread, spatially heterogeneous neural ensembles whose activity is related to diverse aspects of behavior.

Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks.

Adolescence is a time of rapid neurodevelopment and the endocannabinoid system is particularly prone to change during this time. Cannabis is a commonly used drug with a particularly high prevalence of use among adolescents. The two predominant phytocannabinoids are Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which affect the endocannabinoid system. It is unknown whether this period of rapid development makes adolescents more or less vulnerable to the effects of cannabis on brain-network connectivity, and whether CBD may attenuate the effects of THC. Using fMRI, we explored the impact of vaporized cannabis (placebo, THC: 8 mg/75 kg, THC + CBD: 8 mg/75 kg THC & 24 mg/75 kg CBD) on resting-state networks in groups of semi-regular cannabis users (usage frequency between 0.5 and 3 days/week), consisting of 22 adolescents (16-17 years) and 24 young adults (26-29 years) matched for cannabis use frequency. Cannabis caused reductions in within-network connectivity in the default mode (F[2,88] = 3.97, P = 0.022, η² = 0.018), executive control (F[2,88] = 18.62, P < 0.001, η² = 0.123), salience (F[2,88] = 12.12, P < 0.001, η² = 0.076), hippocampal (F[2,88] = 14.65, P < 0.001, η² = 0.087), and limbic striatal (F[2,88] = 16.19, P < 0.001, η² = 0.102) networks compared to placebo. Whole-brain analysis showed cannabis significantly disrupted functional connectivity with cortical regions and the executive control, salience, hippocampal, and limbic striatal networks compared to placebo. CBD did not counteract THC's effects and further reduced connectivity both within networks and the whole brain. While age-related differences were observed, there were no interactions between age group and cannabis treatment in any brain network. Overall, these results challenge the assumption that CBD can make cannabis safer, as CBD did not attenuate THC effects (and in some cases potentiated them); furthermore, they show that cannabis causes similar disruption to resting-state connectivity in the adolescent and adult brain.

Structural and functional imaging features of cognitive phenotypes in pediatric multiple sclerosis.

The present study aimed to identify the clinical and MRI features of the distinct cognitive phenotypes in pediatric multiple sclerosis (pedMS). PedMS patients (n = 73) and healthy controls (n = 30) underwent clinical examination and 3.0T MRI. All patients completed neuropsychological testing, and cognitive phenotypes were identified by performing K-means clustering on cognitive scores. MRI metrics included brain T2-hyperintese lesion volume and normalized brain volumes. Within seven cognitively relevant cortical networks, structural disconnectivity (i.e., the mean percentage of streamlines connecting each pair of cortical regions passing through a lesion) and resting-state (RS) functional connectivity (FC) were estimated. Three cognitive phenotypes emerged: Preserved cognition (PC; n = 27, 37%), mild verbal learning and memory/semantic fluency involvement (MVS; n = 28, 38%), and multidomain involvement (MI; n = 18, 25%). Age, sex, and disease duration did not differ among groups. Compared with healthy subjects, PC patients had decreased RS FC within the default mode network (p = 0.045); MVS patients exhibited lower cortical volume and reduced RS FC within the frontoparietal network (all p = 0.045); and MI patients showed decreased volumes in all brain compartments except the hippocampus, and reduced RS FC within the frontoparietal network (all p ≤ 0.045). Compared to PC, MI patients had more severe disability and higher structural disconnectivity within four cortical networks (all p ≤ 0.045). Compared to PC and MVS, MI patients had lower intelligence quotient (all p ≤ 0.005). We identified three cognitive phenotypes in pedMS that demonstrate the existence of a spectrum of impairment. Such phenotypes showed distinct clinical and MRI characteristics that contributed to explain their cognitive profiles.

Whole-brain Mapping of Inputs and Outputs of Specific Orbitofrontal Cortical Neurons in Mice.

The orbitofrontal cortex (ORB), a region crucial for stimulus-reward association, decision-making, and flexible behaviors, extensively connects with other brain areas. However, brain-wide inputs to projection-defined ORB neurons and the distribution of inhibitory neurons postsynaptic to neurons in specific ORB subregions remain poorly characterized. Here we mapped the inputs of five types of projection-specific ORB neurons and ORB outputs to two types of inhibitory neurons. We found that different projection-defined ORB neurons received inputs from similar cortical and thalamic regions, albeit with quantitative variations, particularly in somatomotor areas and medial groups of the dorsal thalamus. By counting parvalbumin (PV) or somatostatin (SST) interneurons innervated by neurons in specific ORB subregions, we found a higher fraction of PV neurons in sensory cortices and a higher fraction of SST neurons in subcortical regions targeted by medial ORB neurons. These results provide insights into understanding and investigating the function of specific ORB neurons.

Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms

BackgroundSocial affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with “profound” autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known.MethodsBecause ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions.ResultsAt the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences.LimitationsLarger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes.ConclusionsBy embryogenesis, the biological bases of two subtypes of ASD social and brain development—profound autism and mild autism—are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler’s social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.

Kinematic descriptors of arm reaching movement are sensitive to hemisphere-specific immediate neuromodulatory effects of transcranial direct current stimulation post stroke

Transcranial direct current stimulation (tDCS) exerts beneficial effects on motor recovery after stroke, presumably by enhancement of adaptive neural plasticity. However, patients with extensive damage may experience null or deleterious effects with the predominant application mode of anodal (excitatory) stimulation of the damaged hemisphere. In such cases, excitatory stimulation of the non-damaged hemisphere might be considered. Here we asked whether tDCS exerts a measurable effect on movement quality of the hemiparetic upper limb, following just a single treatment session. Such effect may inform on the hemisphere that should be excited. Using a single-blinded crossover experimental design, stroke patients and healthy control subjects were assessed before and after anodal, cathodal and sham tDCS, each provided during a single session of reaching training (repeated point-to-point hand movement on an electronic tablet). Group comparisons of endpoint kinematics at baseline—number of peaks in the speed profile (NoP; smoothness), hand-path deviations from the straight line (SLD; accuracy) and movement time (MT; speed)—disclosed greater NoP, larger SLD and longer MT in the stroke group. NoP and MT revealed an advantage for anodal compared to sham stimulation of the lesioned hemisphere. NoP and MT improvements under anodal stimulation of the non-lesioned hemisphere correlated positively with the severity of hemiparesis. Damage to specific cortical regions and white-matter tracts was associated with lower kinematic gains from tDCS. The study shows that simple descriptors of movement kinematics of the hemiparetic upper limb are sensitive enough to demonstrate gain from neuromodulation by tDCS, following just a single session of reaching training. Moreover, the results show that tDCS-related gain is affected by the severity of baseline motor impairment, and by lesion topography.

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.

RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity-regulated by RNA binding proteins-in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders.

Canine Electroencephalography Electrode Positioning Using a Neuronavigation System

Background: Studies in people suggest that surface electroencephalography (EEG) electrode positions vary across participants and that the consistency of these positions is electrode-, region-, and examiner-dependent. The aim was to investigate the variability in EEG electrode positions to their underlying cortical regions (CRs) in dogs using a neuronavigation system and evaluate the use of said system in electrode positioning, via a cadaver study with 22 dogs. CT scans and MRI were performed for each dog. These were uploaded onto a neuronavigation system where the desired CRs were annotated. The electrode positions were marked on the heads, which were positioned using only a previously established guide and anatomical landmarks. Using the neuronavigation system, alignment or deviations from the desired CRs were noted. Fifty-three percent of all the marked electrode positions showed an alignment with the desired CRs. Thirty-three percent showed no alignment, and fourteen percent showed partial alignment. Three percent deviated to different cortical lobes. Placement via the neuronavigation system enabled reliable and replicable electrode positioning and CR alignment. The standard for EEG electrode placement in dogs is subjected to a high variance. A neuronavigation system can aid in more precise electrode placements. Specific gyri cannot accurately be evaluated on EEG without imaging-controlled electrode placement.

A complementary approach for neocortical cytoarchitecture inspection with cellular resolution imaging at whole brain scale

Cytoarchitecture, the organization of cells within organs and tissues, serves as a crucial anatomical foundation for the delineation of various regions. It enables the segmentation of the cortex into distinct areas with unique structural and functional characteristics. While traditional 2D atlases have focused on cytoarchitectonic mapping of cortical regions through individual sections, the intricate cortical gyri and sulci demands a 3D perspective for unambiguous interpretation. In this study, we employed fluorescent micro-optical sectioning tomography to acquire architectural datasets of the entire macaque brain at a resolution of 0.65 μm × 0.65 μm × 3 μm. With these volumetric data, the cortical laminar textures were remarkably presented in appropriate view planes. Additionally, we established a stereo coordinate system to represent the cytoarchitectonic information as surface-based tomograms. Utilizing these cytoarchitectonic features, we were able to three-dimensionally parcel the macaque cortex into multiple regions exhibiting contrasting architectural patterns. The whole-brain analysis was also conducted on mice that clearly revealed the presence of barrel cortex and reflected biological reasonability of this method. Leveraging these high-resolution continuous datasets, our method offers a robust tool for exploring the organizational logic and pathological mechanisms of the brain’s 3D anatomical structure.

Vestibular Function is Associated with Prefrontal and Sensorimotor Cortical Gray Matter Volumes in a Cross-Sectional Study of Healthy, Older Adults

Background The vestibular system is associated with alterations in the structure and function of the central nervous system. Yet, whether age-related vestibular loss is related to volume loss in the cerebral cortical areas that have been reported to receive vestibular input remains unknown. In this cross-sectional study of 117 healthy, older adults from the Baltimore Longitudinal Study of Aging, we examine the relationships between age-related vestibular functions and the gray matter volumes of the prefrontal cortex and its subregions and of the sensorimotor cortex—regions known to process vestibular information. Methods T1-weighted MRI scans were automatically segmented using MRICloud. Log-linear multiple regression was used to investigate the relationships between average regional volume and vestibular function, adjusting for age, sex, and intracranial volume. Permutation testing was used for hypothesis testing, and bootstrapping was used to estimate confidence intervals. Results We found that age-related changes in vestibular end-organ function are associated with differentially altered gray matter volumes in the prefrontal and sensorimotor cortices, with many findings persisting when considering left (or right) side only. Concomitant with age-related, global brain atrophy, lower canal and utricular function were associated with additional volume atrophy of the prefrontal cortex and middle frontal gyrus, respectively. Lower saccular and utricular function were associated with the preservation of the volumes of the sensorimotor cortex and the pole of the superior frontal gyrus, respectively, against age-related, global brain atrophy. Canal and utricular function were not associated with the volumes of the sensorimotor cortex, and saccular function was not associated with the relative volumes of the prefrontal cortex. Conclusion Together, these findings of relative volume preservation or additional atrophy suggest that vestibular function may play a role in the resilience to or magnification of global age effects on cerebral cortical structure.

The relationship between coffee-related factors and cortical and hippocampal structure: a triangulation of evidence approach and Mendelian randomization research

ObjectiveExisting studies have reported sustained changes in the cortical structure of rats due to coffee-related factors, which are speculated to occur in the human body. However, there is a lack of research on this topic. Additionally, previous observational studies have found the impact of diseases on cortical structure and the potential therapeutic effects of coffee on these diseases. Our aim was to study the causal effects of coffee-related factors on the human brain using SNPs (single nucleotide polymorphisms). We will connect these discovered causal effects to the impact of diseases on the brain. Through triangulating evidence, we will reveal the potential active areas of coffee in preventing diseases.MethodsWe utilized GWAS data from multiple cohorts and their databases, selecting instrumental variables for genetic prediction of coffee intake and plasma levels of caffeine and its direct metabolites. We applied these instrumental variables to individual data on cortical thickness and surface area, as well as hippocampal volume, from the ENIGMA and CHARGE consortium for Mendelian randomization analysis (MR). Triangular evidence was obtained by integrating existing evidence through a specified retrieval strategy, calculating the overlap between coffee's effects on brain regions and disease-related brain regions to identify potential regions of action.ResultsThe MR analysis yielded 93 positive results for 9 exposures, among which theobromine, a metabolite in the caffeine pathway, was found to be associated with increased hippocampal volume. For cortical structure, theobromine in the caffeine pathway was associated with a decrease in total surface area, while theobromine and caffeine in the pathway were associated with an increase in total thickness. The overlap rate of triangular evidence showed no difference in both overall and subgroup analyses, indicating a high overlap between the effects of coffee on brain regions and disease.ConclusionsFrom predicted outcomes from causal effects, coffee intake-related factors may have lasting effects on cortical structure. Additionally, theobromine and theophylline have the greatest impact on certain brain gyri, rather than caffeine. Triangulation evidence indicates that disease and coffee intake-related factors act on the same cortical regions, suggesting the presence of potential shared or antagonistic pathways.

Specialization of anterior and posterior hippocampal functional connectivity differs in autism.

Structural and functional differences in the hippocampus have been related to the episodic memory and social impairments observed in autism spectrum disorder (ASD). In neurotypical individuals, hippocampal-cortical functional connectivity systematically varies between anterior and posterior hippocampus, with changes observed during typical development. It remains unknown whether this specialization of anterior-posterior hippocampal connectivity is disrupted in ASD, and whether age-related differences in this specialization exist in ASD. We examined connectivity of the anterior and posterior hippocampus in an ASD (N = 139) and non-autistic comparison group (N = 133) aged 5-21 using resting-state functional magnetic resonance imaging (MRI) data from the Healthy Brain Network (HBN). Consistent with previous results, we observed lower connectivity between the whole hippocampus and medial prefrontal cortex in ASD. Moreover, preferential connectivity of the posterior relative to the anterior hippocampus for memory-sensitive regions in posterior parietal cortex was reduced in ASD, demonstrating a weaker anterior-posterior specialization of hippocampal-cortical connectivity. Finally, connectivity between the posterior hippocampus and precuneus negatively correlated with age in the ASD group but remained stable in the comparison group, suggesting an altered developmental specialization. Together, these differences in hippocampal-cortical connectivity may help us understand the neurobiological basis of the memory and social impairments found in ASD.

Motor network dynamic resting state fMRI connectivity of neurotypical children in regions affected by cerebral palsy

BackgroundNormative childhood motor network resting-state fMRI effective connectivity is undefined, yet necessary for translatable dynamic resting-state-network-informed evaluation in pediatric cerebral palsy.MethodsCross-spectral dynamic causal modeling of resting-state-fMRI was investigated in 50 neurotypically developing 5- to 13-year-old children. Fully connected six-node network models per hemisphere included primary motor cortex, striatum, subthalamic nucleus, globus pallidus internus, thalamus, and contralateral cerebellum. Parametric Empirical Bayes with exhaustive Bayesian model reduction and Bayesian modeling averaging informed the model; Purdue Pegboard Test scores of hand motor behavior were the covariate at the group level to determine the effective-connectivity-functional behavior relationship.ResultsAlthough both hemispheres exhibited similar effective connectivity of motor cortico-basal ganglia-cerebellar networks, magnitudes were slightly greater on the right, except for left-sided connections of the striatum which were more numerous and of opposite polarity. Inter-nodal motor network effective connectivity remained consistent and robust across subjects. Age had a greater impact on connections to the contralateral cerebellum, bilaterally. Motor behavior, however, affected different connections in each hemisphere, exerting a more prominent effect on the left modulatory connections to the subthalamic nucleus, contralateral cerebellum, primary motor cortex, and thalamus.DiscussionThis study revealed a consistent pattern of directed resting-state effective connectivity in healthy children aged 5–13 years within the motor network, encompassing cortical, subcortical, and cerebellar regions, correlated with motor skill proficiency. Both hemispheres exhibited similar effective connectivity within motor cortico-basal ganglia-cerebellar networks reflecting inter-nodal signal direction predicted by other modalities, mainly differing from task-dependent studies due to network differences at rest. Notably, age-related changes were more pronounced in connections to the contralateral cerebellum. Conversely, motor behavior distinctly impacted connections in each hemisphere, emphasizing its role in modulating left sided connections to the subthalamic nucleus, contralateral cerebellum, primary motor cortex, and thalamus. Motor network effective connectivity was correlated with motor behavior, validating its physiological significance. This study is the first to evaluate a normative effective connectivity model for the pediatric motor network using resting-state functional MRI correlating with behavior and serves as a foundation for identifying abnormal findings and optimizing targeted interventions like deep brain stimulation, potentially influencing future therapeutic approaches for children with movement disorders.

Exposure to microcystin-LR promotes astrocyte proliferation both in vitro and in vivo via Hippo signaling pathway

Microcystins (MCs) are toxic to the central nervous system of mammals. However, the direct toxicity of MCs on mammalian brain cells and the involved molecular mechanisms are not fully elucidated. Here, we incubated primary astrocytes, the major glial cell-type in the brain, with 0-12.5μM concentrations of MC-LR for 48h, and the impairment was evaluated. We found that MC-LR caused significant increases in the cell viability at the range of 0.05-1μM concentrations with the highest density at 0.1μM concentration. Treatment with 0.1μM MC-LR induced YAP nuclear translocation and decreased the ratio of p-YAP to YAP. It also decreased mRNA levels of the upstream regulator (AMOT), and enhanced expressions of YAP interacted genes (Egfr, Tead1, and Ctgf) in primary astrocytes. Overexpression of AMOT significantly attenuated the increase of MC-LR-induced astrocyte proliferation and the expression of YAP downstream genes. These results indicate that Hippo signaling contributed to MC-LR-caused astrocyte proliferation. Further, reactive astrogliosis was observed in the mice brain after MC-LR exposure to environmentally relevant concentrations (20 or 100μg/L) through drinking water for 16 weeks. Pathological observations revealed that 100μg/L MC-LR exposure caused neuronal damages with characteristics of shrunken or vacuolation in the region of the cerebral cortex, striatum and cerebellum. These results were accompanied with increased oxidative stress and inflammatory response. Our data reveal the potential astrocytic mechanisms in MC-induced neurotoxicity and raise an alarm for neurodegenerative disease risk following daily exposure to MC-LR.

Cortical networks relating to arousal are differentially coupled to neural activity and hemodynamics.

Even in the absence of specific sensory input or a behavioral task, the brain produces structured patterns of activity. This organized activity is modulated by changes in arousal. Here, we use wide-field voltage imaging to establish how arousal relates to cortical network voltage and hemodynamic activity in spontaneously behaving head-fixed male and female mice expressing the voltage-sensitive fluorescent FRET sensor Butterfly 1.2. We find that global voltage and hemodynamic signals are both positively correlated with changes in arousal with a maximum correlation of 0.5 and 0.25 respectively at a time lag of 0 seconds. We next show that arousal influences distinct cortical regions for both voltage and hemodynamic signals. These include a broad positive correlation across most sensory-motor cortices extending posteriorly to the primary visual cortex observed in both signals. In contrast, activity in prefrontal cortex is positively correlated to changes in arousal for the voltage signal while it is a slight net negative correlation observed in the hemodynamic signal. Additionally, we show that coherence between voltage and hemodynamic signals relative to arousal is strongest for slow frequencies below 0.15 Hz and is near zero for frequencies greater than 1Hz. We finally show that coupling patterns are dependent on the behavioral state of the animal with correlations being driven by periods of increased orofacial movement. Our results indicate that while hemodynamic signals show strong relations to behavior and arousal, these relations are distinct from those observed by voltage activity.Significance Statement We leverage wide-field voltage imaging to examine the relation between cortical changes in membrane potential dynamics and hemodynamics. These two signals are then examined with respect to changes in arousal, as measured by pupil diameter, in awake head fixed mice. Our results show similarities as well as important differences in the correlation of arousal with neuronal population activity dynamics and the hemodynamic signal. Further, the spatial activity correlation maps with arousal depended differentially on the behavioral state of the animal in a frequency dependent manner. Our results indicate that the modulation of brain networks by arousal is dynamically regulated, and only partly overlap between functional networks determined from hemodynamic or voltage activity.

Striatal Blood Flow Changes by Middle Cerebral Artery Occlusion and Its Effect on Neurological Deficits in Mice.

We attempted to record the regional cerebral blood flow (CBF) simultaneously at various regions of the cerebral cortex and the striatum during middle cerebral artery (MCA) occlusion and to evaluate neurological deficits and infarct formation. In male C57BL/6J mice, CBF was recorded in three regions including the ipsilateral cerebral cortex and the striatum with laser Doppler flowmeters, and the origin of MCA was occluded with a monofilament suture for 15-90 min. After 48 h, neurological deficits were evaluated, and infarct was examined by triphenyltetrazolium chloride (TTC) staining. CBF decrease in the striatum was approximately two-thirds of the MCA-dominant region of the cortex during MCA occlusion. The characteristic CBF fluctuation because of spontaneously occurred spreading depolarization observed throughout the cortex was not found in the striatum. Ischemic foci with slight lower staining to TTC were found in the ipsilateral striatum in MCA-occluded mice for longer than 30 min (n = 54). Twenty-nine among 64 MCA-occluded mice exhibited neurological deficits even in the absence of apparent infarct with minimum staining to TTC in the cortex, and the severity of neurological deficits was not correlated with the size of the cortical infarct. Neurological deficits might be associated with the ischemic striatum rather than with cortical infarction.

Network-targeted transcranial direct current stimulation of the hypothalamus appetite-control network: a feasibility study.

The hypothalamus is the key regulator for energy homeostasis and is functionally connected to striatal and cortical regions vital for the inhibitory control of appetite. Hence, the ability to non-invasively modulate the hypothalamus network could open new ways for the treatment of metabolic diseases. Here, we tested a novel method for network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in the control of appetite. Based on the resting-state functional connectivity map of the hypothalamus, a 12-channel net-tDCS protocol was generated (Neuroelectrics Starstim system), which included anodal, cathodal and sham stimulation. Ten participants with overweight or obesity were enrolled in a sham-controlled, crossover study. During stimulation or sham control, participants completed a stop-signal task to measure inhibitory control. Overall, stimulation was well tolerated. Anodal net-tDCS resulted in faster stop signal reaction time (SSRT) compared to sham (p = 0.039) and cathodal net-tDCS (p = 0.042). Baseline functional connectivity of the target network correlated with SSRT after anodal compared to sham stimulation (p = 0.016). These preliminary data indicate that modulating hypothalamus functional network connectivity via net-tDCS may result in improved inhibitory control. Further studies need to evaluate the effects on eating behavior and metabolism.

Linking cognitive integrity to working memory dynamics in the aging human brain.

Aging is accompanied by a decline of working memory, an important cognitive capacity that involves stimulus-selective neural activity that persists after stimulus presentation. Here, we unraveled working memory dynamics in older human adults (male and female) including those diagnosed with mild cognitive impairment (MCI) using a combination of behavioral modeling, neuropsychological assessment, and magnetoencephalographic (MEG) recordings of brain activity. Younger adults (male and female) were studied with behavioral modeling only. Participants performed a visuo-spatial delayed match-to-sample task under systematic manipulation of the delay and distance between sample and test stimuli. Their behavior (match/non-match decisions) was fit with a computational model permitting the dissociation of noise in the internal operations underlying the working memory performance from a strategic decision threshold. Task accuracy decreased with delay duration and sample/test proximity. When sample/test distances were small, older adults committed more false alarms than younger adults. The computational model explained the participants' behavior well. The model parameters reflecting internal noise (not decision threshold) correlated with the precision of stimulus-selective cortical activity measured with MEG during the delay interval. The model uncovered an increase specifically in working memory noise in older compared to younger participants. Furthermore, in the MCI group, but not in the older healthy controls, internal noise correlated with the participants' clinically assessed cognitive integrity. Our results are consistent with the idea that the stability of working memory contents deteriorates in aging, in a manner that is specifically linked to the overall cognitive integrity of individuals diagnosed with MCI.Significance statement Several cognitive functions decline during aging, and this process is aggravated in MCI - a condition constituting a primary risk factor for developing dementia. One function susceptible to age-related cognitive decline is working memory: the ability to maintain information online for the flexible control of behavior, which entails persistent stimulus-selective neural activity in different regions of the cerebral cortex. We used computational modeling of behavioral and neural recordings to show that the stability of working memory contents is reduced in older human subjects and predicts overall cognitive decline in MCI patients. Our findings provide new mechanistic insight into cognitive aging and MCI and highlight working memory stability as an objective marker of the mechanisms underlying cognitive impairment.