Cortical Areas Research Articles

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.

Brain representations of motion and position in the double-drift illusion

In the ‘double-drift’ illusion, local motion within a window moving in the periphery of the visual field alters the window’s perceived path. The illusion is strong even when the eyes track a target whose motion matches the window so that the stimulus remains stable on the retina. This implies that the illusion involves the integration of retinal signals with non-retinal eye-movement signals. To identify where in the brain this integration occurs, we measured BOLD fMRI responses in visual cortex while subjects experienced the double-drift illusion. We then used a combination of univariate and multivariate decoding analyses to identify (1) which brain areas were sensitive to the illusion and (2) whether these brain areas contained information about the illusory stimulus trajectory. We identified a number of cortical areas that responded more strongly during the illusion than a control condition that was matched for low-level stimulus properties. Only in area hMT+ was it possible to decode the illusory trajectory. We additionally performed a number of important controls that rule out possible low-level confounds. Concurrent eye tracking confirmed that subjects accurately tracked the moving target; we were unable to decode the illusion trajectory using eye position measurements recorded during fMRI scanning, ruling out explanations based on differences in oculomotor behavior. Our results provide evidence for a perceptual representation in human visual cortex that incorporates extraretinal information.

Acetyl-L-carnitine Improves Depressive-like Behaviors Through Nitric Oxide Modulation in the Cuprizone Intoxication Mouse Model of Multiple Sclerosis

Background: Demyelination and inflammation are the most common pathobiological manifestations contributing to depression in multiple sclerosis (MS). Objectives: The current study aimed to evaluate the effects of acetyl-L-carnitine (ALC) in attenuating depressive-like symptoms in the cuprizone intoxication mouse model. Methods: C57BL/6 mice were categorized into three groups (n = 6 each) as follows: The control animals (CTL), the cuprizone-intoxicated mice (CPZ), and the group that received cuprizone and acetyl-L-carnitine (CPZ+ALC). Depressive-like behaviors were evaluated by the forced swim test (FST) and the tail suspension test (TST). The prefrontal cortex (PFC) and corpus callosum (CC) areas were assessed in terms of histopathology, biochemistry, and gene expression. Results: Following oral gavage of ALC, the immobility time, which represents the despairing time, significantly decreased compared to the CPZ group. Histopathological evaluation showed that remyelination in the CC increased significantly in animals receiving ALC compared to the CPZ mice. Acetyl-L-carnitine considerably decreased the nitric oxide (NO) level in the PFC of the brain in the demyelinated mice compared to the CPZ group. The qRT-PCR results revealed that ALC significantly increased neuronal nitric oxide synthase (nNOS) expression but decreased inducible nitric oxide synthase (iNOS) gene expression compared to the CPZ group. Conclusions: ALC attenuated depressive-like behaviors in the cuprizone demyelination mouse model of MS. These neuroprotective effects of ALC may be exerted by facilitating the remyelination process and modulating the NO level in the PFC.

Altered morphometric similarity networks in insomnia disorder.

Previous studies on structural covariance network (SCN) suggested that patients with insomnia disorder (ID) show abnormal structural connectivity, primarily affecting the somatomotor network (SMN) and default mode network (DMN). However, evaluating a single structural index in SCN can only reveal direct covariance relationship between two brain regions, failing to uncover synergistic changes in multiple structural features. To cover this research gap, the present study utilized novel morphometric similarity networks (MSN) to examine the morphometric similarity between cortical areas in terms of multiple sMRI parameters measured at each area. With seven T1-weighted imaging morphometric features from the Desikan-Killiany atlas, individual MSN was constructed for patients with ID (N = 87) and healthy control groups (HCs, N = 84). Two-sample t-test revealed differences in MSN between patients with ID and HCs. Correlation analyses examined associations between MSNs and sleep quality, insomnia symptom severity, and depressive symptoms severity in patients with ID. The right paracentral lobule (PCL) exhibited decreased morphometric similarity in patients with ID compared to HCs, mainly manifested by its de-differentiation (meaning loss of distinctiveness) with the SMN, DMN, and ventral attention network (VAN), as well as its decoupling with the visual network (VN). Greater PCL-based de-differentiation correlated with less severe insomnia and fewer depressive symptoms in the patients group. Additionally, patients with less depressive symptoms showed greater PCL de-differentiation from the SMN. As an important pilot step in revealing the underlying morphometric similarity alterations in insomnia disorder, the present study identified the right PCL as a hub region that is de-differentiated with other high-order networks. Our study also revealed that MSN has an important potential to capture clinical significance related to insomnia disorder.

Organization of corticocortical and thalamocortical top-down inputs in the primary visual cortex.

Unified visual perception requires integration of bottom-up and top-down inputs in the primary visual cortex (V1), yet the organization of top-down inputs in V1 remains unclear. Here, we used optogenetics-assisted circuit mapping to identify how multiple top-down inputs from higher-order cortical and thalamic areas engage V1 excitatory and inhibitory neurons. Top-down inputs overlap in superficial layers yet segregate in deep layers. Inputs from the medial secondary visual cortex (V2M) and anterior cingulate cortex (ACA) converge on L6 Pyrs, whereas ventrolateral orbitofrontal cortex (ORBvl) and lateral posterior thalamic nucleus (LP) inputs are processed in parallel in Pyr-type-specific subnetworks (Pyr←ORBvl and Pyr←LP) and drive mutual inhibition between them via local interneurons. Our study deepens understanding of the top-down modulation mechanisms of visual processing and establishes that V2M and ACA inputs in L6 employ integrated processing distinct from the parallel processing of LP and ORBvl inputs in L5.

Higher surface folding of the human premotor cortex is associated with better long-term learning capability

The capacity to learn enabled the human species to adapt to various challenging environmental conditions and pass important achievements on to the next generation. A growing body of research suggests links between neocortical folding properties and numerous aspects of human behavior, but their impact on enhanced human learning capacity remains unexplored. Here we leverage three training cohorts to demonstrate that higher levels of premotor cortical folding reliably predict individual long-term learning gains in a challenging new motor task, above and beyond initial performance differences. Individual folding-related predisposition to motor learning was found to be independent of cortical thickness and intracortical microstructure, but dependent on larger cortical surface area in premotor regions. We further show that learning-relevant features of cortical folding occurred in close spatial proximity to practice-induced structural brain plasticity. Our results suggest a link between neocortical surface folding and human behavioral adaptability.

Multimodal imaging and electrophysiological study in the differential diagnosis of rest tremor

IntroductionDistinguishing tremor-dominant Parkinson's disease (tPD) from essential tremor with rest tremor (rET) can be challenging and often requires dopamine imaging. This study aimed to differentiate between these two diseases through a machine learning (ML) approach based on rest tremor (RT) electrophysiological features and structural MRI data.MethodsWe enrolled 72 patients including 40 tPD patients and 32 rET patients, and 45 control subjects (HC). RT electrophysiological features (frequency, amplitude, and phase) were calculated using surface electromyography (sEMG). Several MRI morphometric variables (cortical thickness, surface area, cortical/subcortical volumes, roughness, and mean curvature) were extracted using Freesurfer. ML models based on a tree-based classification algorithm termed XGBoost using MRI and/or electrophysiological data were tested in distinguishing tPD from rET patients.ResultsBoth structural MRI and sEMG data showed acceptable performance in distinguishing the two patient groups. Models based on electrophysiological data performed slightly better than those based on MRI data only (mean AUC: 0.92 and 0.87, respectively; p = 0.0071). The top-performing model used a combination of sEMG features (amplitude and phase) and MRI data (cortical volumes, surface area, and mean curvature), reaching AUC: 0.97 ± 0.03 and outperforming models using separately either MRI (p = 0.0001) or EMG data (p = 0.0231). In the best model, the most important feature was the RT phase.ConclusionMachine learning models combining electrophysiological and MRI data showed great potential in distinguishing between tPD and rET patients and may serve as biomarkers to support clinicians in the differential diagnosis of rest tremor syndromes in the absence of expensive and invasive diagnostic procedures such as dopamine imaging.

Visual training after central retinal loss limits structural white matter degradation: an MRI study

BackgroundMacular degeneration of the eye is a common cause of blindness and affects 8% of the worldwide human population. In adult cats with bilateral lesions of the central retina, we explored the possibility that motion perception training can limit the associated degradation of the visual system. We evaluated how visual training affects behavioral performance and white matter structure. Recently, we proposed (Kozak et al. in Transl Vis Sci Technol 10:9, 2021) a new motion-acuity test for low vision patients, enabling full visual field functional assessment through simultaneous perception of shape and motion. Here, we integrated this test as the last step of a 10-week motion-perception training.ResultsCats were divided into three groups: retinal-lesioned only and two trained groups, retinal-lesioned trained and control trained. The behavioral data revealed that trained cats with retinal lesions were superior in motion tasks, even when the difficulty relied only on acuity. 7 T-MRI scanning was done before and after lesioning at 5 different timepoints, followed by Fixel-Based and Fractional Anisotropy Analysis. In cats with retinal lesions, training resulted in a more localized and reduced percentage decrease in Fixel-Based Analysis metrics in the dLGN, caudate nucleus and hippocampus compared to untrained cats. In motion-sensitive area V5/PMLS, the significant decreases in fiber density were equally strong in retinal-lesioned untrained and trained cats, up to 40% in both groups. The only cortical area with Fractional Anisotropy values not affected by central retinal loss was area V5/PMLS. In other visual ROIs, the Fractional Anisotropy values increased over time in the untrained retinal lesioned group, whereas they decreased in the retinal lesioned trained group and remained at a similar level as in trained controls.ConclusionsOverall, our MRI results showed a stabilizing effect of motion training applied soon after central retinal loss induction on white matter structure. We propose that introducing early motion-acuity training for low vision patients, aimed at the intact and active retinal peripheries, may facilitate brain plasticity processes toward better vision.

#2717 Fermentable and viscous dietary fiber types improve cortical bone in a rat model of chronic kidney disease-mineral and bone disorder

Abstract Background and Aims Renal osteodystrophy is highly prevalent among people with chronic kidney disease (CKD). We recently showed that inulin, a prebiotic fermentable dietary fiber, improved cortical bone parameters in rats with moderate-to-severe CKD. Our objective was to evaluate if this effect was unique to the prebiotic fibers or if other fiber properties, such as viscosity, could be beneficial to bone in a rat model of CKD-mineral and bone disorder (CKD-MBD). Method 22-week-old Cy/+ male rats (50% kidney function compared to normal; CKD hereafter) were randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (−fermentability, −viscosity), 2) Inulin (+fermentability, −viscosity), 3) Psyllium husk (−fermentability, +viscosity), or 4) Pectin (+ fermentability, +viscosity). These diets were formulated with a semi-purified, casein-based background diet with 0.7% calcium and 0.7% phosphorus. Treatments lasted 10 weeks, and rats were euthanized at 32 weeks of age (kidney failure; ∼15% of normal). Micro-computed tomography (μCT) at 12-μm resolution was performed on the proximal tibia. Serum creatinine, plasma phosphorus, and plasma calcium were analyzed using colorimetric assays. One-way ANOVA was used to test the effect of dietary fiber types on outcome measures. Results At 32 weeks of age, serum creatinine was lower in the inulin, psyllium, and pectin-treated CKD rats (<0.04). Plasma calcium concentrations were similar between treatments, but phosphorus was lower in the psyllium and pectin-treated CKD rats (p < 0.02). Bone cortical area was higher in the inulin and psyllium-treated CKD rats compared to cellulose-treated rats (p < 0.007). Cortical thickness was higher in the inulin, psyllium, and pectin-treated CKD rats compared to cellulose-treated rats (p < 0.02). There was less cortical porosity in the inulin, psyllium, and pectin-treated rats (p < 0.02). Fermentable or viscous fibers did not impact trabecular bone volume, thickness, spacing, and number (p < 0.05). Plasma phosphorus was negatively associated with cortical area (r = −0.56; p < 0.0001) and cortical thickness (r = −0.75; p < 0.0001), and positively associated with cortical porosity (r = 0.74; p < 0.0001). Conclusion Fermentable and viscous fibers improved cortical bone but had no effect on trabecular bone. This effect may be, at least in part, due to the fiber's ability to lower plasma phosphorus and likely parathyroid hormone.

The role of cortical structural variance in deep learning-based prediction of fetal brain age

BackgroundDeep-learning-based brain age estimation using magnetic resonance imaging data has been proposed to identify abnormalities in brain development and the risk of adverse developmental outcomes in the fetal brain. Although saliency and attention activation maps have been used to understand the contribution of different brain regions in determining brain age, there has been no attempt to explain the influence of shape-related cortical structural features on the variance of predicted fetal brain age.MethodsWe examined the association between the predicted brain age difference (PAD: predicted brain age–chronological age) from our convolution neural networks-based model and global and regional cortical structural measures, such as cortical volume, surface area, curvature, gyrification index, and folding depth, using regression analysis.ResultsOur results showed that global brain volume and surface area were positively correlated with PAD. Additionally, higher cortical surface curvature and folding depth led to a significant increase in PAD in specific regions, including the perisylvian areas, where dramatic agerelated changes in folding structures were observed in the late second trimester. Furthermore, PAD decreased with disorganized sulcal area patterns, suggesting that the interrelated arrangement and areal patterning of the sulcal folds also significantly affected the prediction of fetal brain age.ConclusionThese results allow us to better understand the variance in deep learning-based fetal brain age and provide insight into the mechanism of the fetal brain age prediction model.

#1716 IgA nephropathy: our center's experience

Abstract Background and Aims IgA Nephropathy (IgAN) is the most common primary glomerulopathy worldwide. In the last years, significant advances have been made in understanding its pathophysiology and developing newer promising treatments. The accuracy of the International Risk-Prediction Tool in IgAN (IRP-IgAN) was already validated. Herein, we retrospectively analysed the relation of this risk score and the kidney outcomes. Method We performed a single center retrospective observational cross-sectional study of patients with histological diagnosis of IgAN between 2015 and 2023 in Centro Hospitalar de Setúbal, aiming to describe the demography, clinical presentation, histological characteristics, treatment and follow up of our cohort. The International Risk-Prediction Tool in IgAN was applied for patient stratification. Results Twenty-eight patients were diagnosed with IgAN in this eight-year period. Mean age was 46 years-old (SD ±12.2) and 71.4% were male. The majority were Caucasian (n = 26) with only two patients of Asian e African descent, respectively. The mean calculated Charlson Comorbidity Index was 1.43 (SD ±1.5). Eighteen patients (64.3%) had known arterial hypertension, diabetes was seen only in 2 patients, obesity in 4 patients, and hepatitis B in 2 patients. No cardiovascular disease or cancer was documented. On presentation, 71.4% (n = 20) had hypertension, 14.3% (n = 4) presented with rapidly progressive renal insufficiency, and 14.3% (n = 4) presented with nephrotic syndrome. Two patients (7.1%) required dialysis on presentation. Also, the mean glomerular filtration rate (GFR) was 55.3 ml/min (SD ±31.9) and mean proteinuria level (protein-to-creatinine ratio) was 2.42g/g (SD ±2.41). Most patients had hematuria (82.1%), C3 consumption was seen in only one patient while 10 patients had isolated higher levels of IgA. Mean time between the first symptoms or documented clinical features and dedicated Nephrology consultation was 2.9 years (SD ±3.78). Regarding the histological data and considering de MEST-C score, 71.4% had mesangial hypercellularity in more than 50% of the glomerulus (M1), 25% had endocapillary hypercellularity (E1), 17% had segmental glomerulosclerosis of at least one glomerulus (S1), 7% had interstitial fibrosis or cortical atrophy in 25-50% of the cortical area (T1) and 11% in more than 50% (T2), 17.9% had crescents in less than 25% of the glomerulus (C1) and 2.6% in more than 25% (C2). Fibrinoid necrosis was noticed in 7.1% of the patients. The presence of IgA in the mesangium on IF was universal and 18 patients (64.3%) had C3 co-stain. Approximately half of the patients (46.4%) were already on angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) by the time of clinical presentation and nearly all (92.9%) by the time the diagnosis was established. SGTL-2 inhibitors were started in 42.9% of the patients. Eight patients (28.6%) started immunosuppression therapy, within a mean time from histological diagnosis of 0.7 years (SD ±1.03). Of those, all of them were on corticosteroids, one patient was additionally under oral cyclophosphamide and another one under mofetil mycophenolate. According to the IRP-IgAN, patients were stratified in low (35.7%), intermediate (10%) and high risk (8%) of kidney disease progression (GFR decline >50%) or ESKD. In a mean time of 0.53 (SD ±0.34) years of follow-up after diagnosis, 8 patients (28.6%) required renal replacement therapy, with 7 choosing hemodialysis and 1 peritoneal dialysis. Six patients lost follow-up. Three patients died a mean time of 1.2 years after diagnosis, one from immunosuppression-related adverse events. We also found an association between higher risk group and progression to ESKD (p < 0.001). Conclusion The IRP-IgAN tool is a useful tool for prediction of kidney disease progression and the need for renal replacement therapy. The supportive care in IgAN even with antiproteinuric approach could be insufficient for patients with high and intermediate risk. The risk progression to ESKD is indeed heterogeneous, and close follow-up of these patients should be guaranteed.

#2781 Renal cortical necrosis—a rare cause of acute kidney injury

Abstract Background and Aims Renal cortical necrosis (RCN) is a rare and catastrophic cause of acute kidney injury (AKI). It is characterized by ischemic destruction of all the elements of renal cortex due to marked reduction in renal arterial perfusion of renal cortex due to vascular spasm and microvascular injury. It can be patchy or diffuse depending upon the cause and extent of hypoperfusion. Snake bite is rare cause of RCN. Incidence of RCN following snake bite has been reported to be as high as in 25% of the bitten patients to <1%. Lack or delay in receiving anti snake venom (ASV) has been observed to be a contributing factor in development of RCN following snake bite. Method A 45-year-old female had an unknown bite on foot while returning to home at twilight. She had intense pain at site of bite with slight ooze of blood. Overnight she had vomiting and pain abdomen. Subsequently she developed progressive fall in urine output and dyspnoea. After about 36 hours of bite at the time of admission in hospital she had anuria, prolonged whole blood clotting time, tachypnoea, hypoxemia and required oxygen (O2) to maintain normal O2 saturation. She was given two doses of polyvalent ASV 6 hours apart which corrected her coagulation defect. Investigations showed: haemoglobin—9 gm/dl, total leucocyte count—18700/mcl, platelet—1.15 lakh/mcl, blood urea—88 mg/dl and serum creatinine—10.5 mg/dl. She was managed with haemodialysis and supportive care. Even after 3 weeks of onset of AKI, she had anuria so a kidney biopsy was done. Results kidney biopsy on light microscopy examination showed 9 glomeruli; 8 revealing global tuft necrosis along with necrosis of adjacent tubules and vasculature and necrotic process affected around 60% of sampled cortical area consistent with cortical necrosis (Fig. 1). She was continued with haemodialysis support and urine output and pre-dialysis serum creatinine were monitored. Her urine output after 3 months of onset of AKI is around one litre per day but her pre-dialysis serum creatinine stays in the range of 9-10 mg/dl and so she continues to receive biweekly haemodialysis. Conclusion In our index case, there was delay in getting ASV which may have contributed to development of RCN. So, early treatment of snake bite is important to prevent this catastrophic complication.

#1918 L-NAME accelerates the progression of diabetic kidney disease in mice

Abstract Background and Aims Diabetic kidney disease (DKD) represents one of the major causes of end stage kidney disease worldwide. Despite DN having such a high incidence, mouse models of DN rarely mimic all aspects of the human disease, besides showing very slow progression and sometimes maintenance issues. For this reason, in this project we aimed to develop an accelerated, reproducible and accessible mouse model of DN. Method For our experiments we chose 9-week-old female and male of the leptin receptor knock-out (BKS.Cg-Dock7m +/+ Leprdb/J) mice as type 2 diabetes model. As these mice are still not prone to develop severe kidney injury despite their diabetic condition, we administered the eNOS inhibitor L-NAME for 6 weeks, in order to suppress nitric oxide production and therefore to aggravate kidney damage. Mice were divided in three groups: one vehicle control group, one receiving 40/mg/kg/day of L-NAME and one receiving 80/mg/kg/day of L-NAME dissolved in drinking water. Blood pressure and glomerular filtration rate (GFR) were measured at different time points, together with glycemia and albuminuria. Weight and water intake were also monitored throughout the study. At the end of the experiment, animals were killed and blood and organs collected for further analysis. Results Mice treated with 80 mg/kg/day of L-NAME showed an average increase of 10 mmHg in systolic blood pressure, with a peak of 30 mmHg increase at week 4 of treatment. On the other hand, 40 mg/kg/day of L-NAME did show any effect on blood pressure. Despite the different effect on blood pressure, three weeks of L-NAME administration caused a significant reduction in GFR at both doses, with 5% reduction for the 40 mg-group and 23% for the 80 mg-group. For the 80 mg-group we observed an even further GFR decline after 5 weeks of treatment, with a 28% reduction. No change in GFR was observed in the controls. This decrease in GFR was accompanied by a 10-fold increase in urinary albumin for both experimental groups already after 3 weeks of treatment, which after 4 weeks slightly declined but remained significantly higher than the controls (p < 0.0001). At a histological level, PAS staining of kidney sections revealed that in particular mice treated with 80 mg of L-NAME have enlarged Bowman capsule and glomerular tuft area, besides a reduced glomerular capillary density, coinciding with mesangial expansion. We also stained for overall collagen deposition with picrosirius red staining in order to detect possible fibrosis formation. We then observed that 80 mg of L-NAME accelerates interstitial fibrosis in the cortical area of the kidney, which also overlapped with an increased deposition of collagen I. This increase in collage I was also detected in kidney cortex of mice treated with 40 mg of L-NAME, although their overall collagen deposition and therefore fibrotic tissue did not differ from the control group. The medullar region of kidneys was also analyzed, but none of the two experimental groups revealed significant differences in terms overall collagen or collagen I deposition. Unlike mesangial expansion and fibrosis, L-NAME did not influence microphages infiltration, as revealed by CD68 staining in kidney sections. This suggests that L-NAME treatment does not accelerate kidney damage by triggering or accelerating inflammatory processes. This was also confirmed by qPCR analysis of kidney tissue, where the expression pro-inflammatory markers, such as IL1β, TNFα and MCP-1, did not change in the experimental groups. Conclusion Our results show that L-NAME considerably accelerates the progression of DKD in diabetic mice, with GFR declining and progressive albuminuria already after 3 weeks. Such disfunction is confirmed at 6 weeks by histological analysis, where mesangial expansion and fibrosis were detected. This model can be used to assess the therapeutic potential of novel interventions aimed to slow down DKD.

Perceptual Learning of Fine Contrast Discrimination Under Non-roving, Roving-Without-Flanker, and Roving-with-Flanker Conditions and its Relation to Neuronal Activity in Macaque V1

AbstractPerceptual learning refers to an improvement in perceptual abilities with training. Neural signatures of visual perceptual learning have been demonstrated mostly in mid- and high-level cortical areas, while changes in early sensory cortex were often more limited. We recorded continuously from multiple neuronal clusters in area V1 while macaque monkeys learned a fine contrast categorization task. Monkeys performed the contrast discrimination task initially when a constant-contrast sample stimulus was followed by a test stimulus of variable contrast, whereby they had to indicate whether the test was of lower or higher contrast than the sample. This was followed by sessions where we employed stimulus roving; i.e. the contrast of the sample stimulus varied from trial to trial. Finally, we trained animals, under ‘stimulus roving-with-flanker’ conditions, where the test stimuli to be discriminated were flanked by ‘flanking stimuli’. Perceptual discrimination abilities improved under non-roving conditions and under roving-with-flanker conditions as training progressed. Neuronal discrimination abilities improved with training mostly under non-roving conditions, but the effect was modest and limited to the most difficult contrast. Choice probabilities, quantifying how well neural activity is correlated with choice, equally increased with training during non-roving, but not during either of the roving conditions (with and without flankers). Noise correlations changed with training in both monkeys, but the changes were not consistent between monkeys. In one monkey, noise correlations decreased with training for non-roving and both roving conditions. In the other monkey, noise correlations changed for some conditions, but lacked a systematic pattern. Thus, while perceptual learning occurred under non-roving and roving-with-flanker conditions, the changes in neural activity in V1 were overall modest and were essentially absent under the different roving conditions.

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.

#2027 Activation of histone deacetylase-1 in fibroblasts and pericytes induces renal interstitial fibrosis after ischemia-reperfusion injury

Abstract Background and Aims Following an acute kidney ischemic event the chromatin remodelling enzyme, histone deacetylase-1 (HDAC1), is activated in many cell types of the kidney including fibroblasts and pericytes. During kidney injury, the fibroblasts/pericytes differentiate into the myofibroblasts and produce extracellular matrix that can lead to a permanent decline in kidney function. Pharmacological inhibition of HDACs can attenuate ischemia-reperfusion-injury (IRI) mediated interstitial fibrosis. The hypothesis of this study was that fibroblast/pericyte HDAC1 activation promotes myofibroblast differentiation and interstitial fibrosis. Method Tamoxifen inducible, fibroblast/pericyte HDAC1 knockout (KO) mice (HDAC1Fl/Fl; Col1a2-CreEr) and littermate controls (HDAC1Fl/Fl) were used. Male and female mice were given tamoxifen by ip at 8-10 weeks of age and IRI or sham surgery completed after a 2-week tamoxifen washout period. A mild, 18 min, bilateral, warm IRI model was used, and samples collected over 4 weeks. Glomerular filtration rate (GFR) was assessed using transdermal FITC-Sinistrin clearance. In vitro experiments with kidney fibroblast cells (NRK49F) overexpressing empty vector or HDAC1 were used for RNA-sequencing to determine the HDAC1-dependent myofibroblast transcriptome. Results We confirmed that HDAC1 was knockdown in myofibroblast cells from KO mice with co-localization of HDAC1 and PDGFRβ or α-smooth muscle actin in the kidneys of IRI mice. Twenty-four hours post-surgery, all IRI mice exhibited 2-3 times increase in serum creatinine and a ∼50% reduction in GFR compared to sham mice (control IRI = 513 ± 129 μl /min/100 g body mass, control sham = 1010 ± 218, n = 4-5, p = 0.02; KO IRI = 529 ± 116, KO sham = 1187 ± 59 μl/min/100 g body mass, n = 4-5, p = 0.004). Subsequent GFR measurements over the next 4 weeks showed a gradual recovery of renal function of IRI mice starting at week 2 and fully restored to sham values by week 4. However, the male control IRI mice had significant focal interstitial fibrosis 2- and 4-weeks post injury (4-week data: sham = 0.3 ± 0.09 % of cortical area, IRI = 1.2 ± 0.2%, n = 6/group, p = 0.0011) but this was attenuated in the KO male IRI mice (sham = 0.4 ± 0.07% n = 4, IRI = 0.5 ± 0.1%, n = 7, p = 0.93). The female mice, regardless of genotype, had very little kidney damage or interstitial fibrosis at 4 weeks. Transcriptomes of NRK49F cells overexpressing HDAC1 had an upregulation of 55 genes related to pro-inflammatory cytokines and tumour necrosis factor signalling and downregulation of 367 genes related to cell junctions, cytoskeleton proteins, and cell adhesion compared to the empty vector control cells. Fibroblast proliferation rates were not statistically different among the groups, suggesting HDAC1 does not affect myofibroblast proliferation but rather pro-inflammatory gene expression. Conclusion In male mice, fibroblast/pericyte activation of HDAC1 leads to the production of pro-inflammatory cytokines that we predict will lead to immune cell infiltration and crosstalk that leads to the excessive production of interstitial fibrosis following IRI.

Changes in the visual areas of the cerebral cortex in children with left-sided anisometropic amblyopia according to structural MRI and resting-state fMRI

Thanks to the development of structural and functional magnetic resonance imaging (MRI) methods, in recent decades there has been a lot of research aimed at elucidating brain abnormalities caused by amblyopia. In the cases of this prevalent visual disorder, the anomalies causing decreased visual acuity and other visual disabilities cannot be determined by standard ophthalmologic examination. Since there are several types of this disorder that are fundamentally different in etiology, it is natural to suggest the presence of different types of corresponding brain abnormalities. In this regard, before obtaining a general picture of the pathogenesis of amblyopia, studies conducted on groups of specially selected similar patients are very important. This paper presents the results of a study of school-age children with left-sided anisometropic amblyopia. In the patients investigated, MRI data revealed interhemispheric differences in the thickness of the lateral occipital cortex, and resting-state fMRI revealed interhemispheric differences in the local coherence of the hemodynamic signal within 17 Brodmann area and in the functional connectivity between 17 and 18+19 Brodmann areas. The data obtained contribute to the creation of a general MRI database on the pathophysiology of amblyopia, help clarify some controversial issues and indicate the advisability of using resting-state fMRI in ophthalmology.

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.

The Role of Cerebellum and Basal Ganglia Functional Connectivity in Altered Voluntary Movement Execution in Essential Tremor.

Substantial evidence highlights the role of the cerebellum in the pathophysiology of tremor in essential tremor (ET), although its potential involvement in altered movement execution in this condition remains unclear. This study aims to explore potential correlations between the cerebellum and basal ganglia functional connectivity and voluntary movement execution abnormalities in ET, objectively assessed with kinematic techniques. A total of 20 patients diagnosed with ET and 18 healthy subjects were enrolled in this study. Tremor and repetitive finger tapping were recorded using an optoelectronic kinematic system. All participants underwent comprehensive 3T-MRI examinations, including 3D-T1 and blood-oxygen-level dependent (BOLD) sequences during resting state. Morphometric analysis was conducted on the 3D-T1 images, while a seed-based analysis was performed to investigate the resting-state functional connectivity (rsFC) of dorsal and ventral portions of the dentate nucleus and the external and internal segments of the globus pallidus. Finally, potential correlations between rsFC alterations in patients and clinical as well as kinematic scores were assessed. Finger tapping movements were slower in ET than in healthy subjects. Compared to healthy subjects, patients with ET exhibited altered FC of both dentate and globus pallidus with cerebellar, basal ganglia, and cortical areas. Interestingly, both dentate and pallidal FC exhibited positive correlations with movement velocity in patients, differently from that we observed in healthy subjects, indicating the higher the FC, the faster the finger tapping. The findings of this study indicate the possible role of both cerebellum and basal ganglia in the pathophysiology of altered voluntary movement execution in patients with ET.

Sensory integration for neuroprostheses: from functional benefits to neural correlates.

In the field of sensory neuroprostheses, one ultimate goal is for individuals to perceive artificial somatosensory information and use the prosthesis with high complexity that resembles an intact system. To this end, research has shown that stimulation-elicited somatosensory information improves prosthesis perception and task performance. While studies strive to achieve sensory integration, a crucial phenomenon that entails naturalistic interaction with the environment, this topic has not been commensurately reviewed. Therefore, here we present a perspective for understanding sensory integration in neuroprostheses. First, we review the engineering aspects and functional outcomes in sensory neuroprosthesis studies. In this context, we summarize studies that have suggested sensory integration. We focus on how they have used stimulation-elicited percepts to maximize and improve the reliability of somatosensory information. Next, we review studies that have suggested multisensory integration. These works have demonstrated that congruent and simultaneous multisensory inputs provided cognitive benefits such that an individual experiences a greater sense of authority over prosthesis movements (i.e., agency) and perceives the prosthesis as part of their own (i.e., ownership). Thereafter, we present the theoretical and neuroscience framework of sensory integration. We investigate how behavioral models and neural recordings have been applied in the context of sensory integration. Sensory integration models developed from intact-limb individuals have led the way to sensory neuroprosthesis studies to demonstrate multisensory integration. Neural recordings have been used to show how multisensory inputs are processed across cortical areas. Lastly, we discuss some ongoing research and challenges in achieving and understanding sensory integration in sensory neuroprostheses. Resolving these challenges would help to develop future strategies to improve the sensory feedback of a neuroprosthetic system.