Cerebral Morphology Research Articles

Epicatechin‐mediated modulation of the Nrf2/HO‐1 pathway alleviates senile cerebral ischemic/reperfusion injury

AbstractExcessive reactive oxygen species (ROS) generated during cerebral ischemic reperfusion (CIRI) are crucial for subsequent tissue damage. However, despite the potential benefits of antioxidants reported in clinical applications, few have proven effective in treating CIRI, particularly in the elderly. Epicatechin (EC) is a catechol flavonoid monomer derived from natural tea plants. Multiple phenolic hydroxyl groups give it strong antioxidant properties, which can not only degrade ROS through chemical reactions between hydroxyl and ROS but also enhance the activity of antioxidant enzymes in cells, and it is easy to penetrate the blood–brain barrier. But its antagonistic effect on age‐related CIRI and potential medicinal value are still unknown. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is the most important transcription factor regulating the expression of antioxidant proteins in the body. This study first compared the pathological differences of the Nrf2 system in CIRI between 2‐month‐old and 12‐month‐old Sprague–Dawley (SD) rats. Subsequently, EC was administered to 12‐month‐old rat models of middle cerebral artery occlusion and reperfusion (MCAO/R) and senescent SH‐SY5Y cell models subjected to oxygen glucose deprivation/reoxygenation (OGD/R). EC treatment improved cerebral morphology and function; increased p‐Nrf2, heme oxygenase‐1 (HO‐1), superoxide dismutase (SOD), and glutathione (GSH) expression; reduced infarct volume; and neuronal apoptosis in senescent rats. Moreover, EC enhanced cellular activity and the expression of p‐Nrf2, HO‐1, and quinone oxidoreductase‐1 (NQO‐1) while decreasing ROS and malondialdehyde (MDA) levels and mitigating apoptosis in senescent SH‐SY5Y cells. These effects were reversed upon si‐Nrf2. In sum, we confirm that EC exerts neuroprotective effects by upregulating Nrf2/ARE and reducing oxidative stress, suggesting that EC may be a promising drug for the treatment of senile cerebral apoplexy. This study also provides a scientific basis for the development and selection of new drugs for ischemic stroke in elderly patients.

Spatiotemporal Characteristics of Regional Brain Perfusion Associated with Neuropsychiatric Symptoms in Patients with Alzheimer's Disease.

Current technology for exploring neuroimaging markers and neural circuits of neuropsychiatric symptoms (NPS) in patients with Alzheimer's disease (AD) is expensive and usually invasive, limiting its use in clinical practice. To investigate the cerebral morphology and perfusion characteristics of NPS and identify the spatiotemporal perfusion circuits of NPS sub-symptoms. This nested case-control study included 102 AD patients with NPS and 51 age- and sex-matched AD patients without NPS. Gray matter volume, cerebral blood flow (CBF), and arterial transit time (ATT) were measured and generated using time-encoded 7-delay pseudo-continuous arterial spin labeling (pCASL). Multiple conditional logistic regression analysis was used to identify neuroimaging markers of NPS. The associations between the CBF or ATT of affected brain areas and NPS sub-symptoms were evaluated after adjusting for confounding factors. The neural circuits of sub-symptoms were identified based on spatiotemporal perfusion sequencing. Lower Mini-Mental State Examination scores (p < 0.001), higher Caregiver Burden Inventory scores (p < 0.001), and higher CBF (p = 0.001) and ATT values (p < 0.003) of the right anteroventral thalamic nucleus (ATN) were risk factors for NPS in patients with AD. Six spatiotemporal perfusion circuits were found from 12 sub-symptoms, including the anterior cingulate gyri-temporal pole/subcortical thalamus-cerebellum circuit, insula-limbic-cortex circuit, subcortical thalamus-temporal pole-cortex circuit, subcortical thalamus-cerebellum circuit, frontal cortex-cerebellum-occipital cortex circuit, and subcortical thalamus-hippocampus-dorsal raphe nucleus circuit. Prolonged ATT and increased CBF of the right ATN may be neuroimaging markers for detecting NPS in patients with AD. Time-encoded pCASL could be a reliable technique to explore the neural perfusional circuits of NPS.

Preoperative serum cortisone levels are associated with cognition in preschool-aged children with tetralogy of Fallot after corrective surgery: new evidence from human populations and mice

BackgroundTetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Children with TOF would be confronted with neurological impairment across their lifetime. Our study aimed to identify the risk factors for cerebral morphology changes and cognition in postoperative preschool-aged children with TOF.MethodsWe used mass spectrometry (MS) technology to assess the levels of serum metabolites, Wechsler preschool and primary scale of intelligence-Fourth edition (WPPSI-IV) index scores to evaluate neurodevelopmental levels and multimodal magnetic resonance imaging (MRI) to detect cortical morphological changes.ResultsMultiple linear regression showed that preoperative levels of serum cortisone were positively correlated with the gyrification index of the left inferior parietal gyrus in children with TOF and negatively related to their lower visual spaces index and nonverbal index. Meanwhile, preoperative SpO2 was negatively correlated with levels of serum cortisone after adjusting for all covariates. Furthermore, after intervening levels of cortisone in chronic hypoxic model mice, total brain volumes were reduced at both postnatal (P) 11.5 and P30 days.ConclusionsOur results suggest that preoperative serum cortisone levels could be used as a biomarker of neurodevelopmental impairment in children with TOF. Our study findings emphasized that preoperative levels of cortisone could influence cerebral development and cognition abilities in children with TOF.

Bridging the Gap between Basic Research and Clinical Practice: The Growing Role of Translational Neurorehabilitation.

Translational neuroscience is intended as a holistic approach in the field of brain disorders, starting from the basic research of cerebral morphology and with the function of implementing it into clinical practice. This concept can be applied to the rehabilitation field to promote promising results that positively influence the patient's quality of life. The last decades have seen great scientific and technological improvements in the field of neurorehabilitation. In this paper, we discuss the main issues related to translational neurorehabilitation, from basic research to current clinical practice, and we also suggest possible future scenarios.

Arterial stiffness and its influence on cerebral morphology and cognitive function.

Recently, arterial stiffness has been associated with cerebral small vessel disease (SVD), brain atrophy and vascular dementia. Arterial stiffness is assessed via pulse wave velocity (PWV) measurement and is strongly dependent on arterial blood pressure. While circadian blood pressure fluctuations are important determinants of end-organ damage, the role of 24-h PWV variability is yet unclear. We here investigated the association between PWV and its circadian changes on brain morphology and cognitive function in community-dwelling individuals. Single-centre, prospective, community-based follow-up study. The study cohort comprised elderly community-based participants of the Austrian Stroke Prevention Family Study which was started in 2006. Patients with any history of cerebrovascular disease or dementia were excluded. The study consists of 84 participants who underwent ambulatory 24-h PWV measurement. White matter hyperintensity volume and brain volume were evaluated by 3-Tesla magnetic resonance imaging (MRI). A subgroup of patients was evaluated for cognitive function using an extensive neuropsychological test battery. PWV was significantly related to reduced total brain volume (p = 0.013), which was independent of blood pressure and blood pressure variability. We found no association between PWV with markers of cerebral SVD or impaired cognitive functioning. Only night-time PWV values were associated with global brain atrophy (p = 0.005). This study shows a relationship of arterial stiffness and reduced total brain volume. Elevations in PWV during night-time are of greater importance than day-time measures.

Effects of recurrent ketamine exposure on brain histopathology in juvenile rats.

Ketamine (KET) is a commonly used anesthetic agent. However, several previous studies reported that KET leads to neuronal damage in neurodevelopmental stages and has neuroprotective effects. The present experimental study aimed to determine the undesirable histopathological effects of KET in the cerebral cortex, striatum, and hippocampus after recurrent KET administration in juvenile rats. After ethical approval was obtained, 32 juvenile male Wistar Albino rats were randomized into four groups: 1 mg/kg serum saline intraperitoneally (i.p.), 5 mg/kg KET i.p., 20 mg/kg KET i.p., and 50 mg/kg KET i.p. KET was administered for three consecutive days at three-h intervals in three doses. Ten days after the last KET dose, the rats were sacrificed. Cerebral hemispheres were fixed. Hematoxylin and eosin stain was used for morphometric analysis. Hippocampi were evaluated by immunohistochemistry with anticleaved caspase-3 antibodies. Statistical analysis was conducted with SPSS 21 software using the ANOVA test and Bonferroni post hoc analysis method. The experimental study findings revealed no difference between the groups' cell counts or sizes in cortical morphometry. No degenerative changes were observed in pyramidal and granular cells in the striatum. Mild gliosis was observed in the 20 mg/kg and 50 mg/kg KET administration groups. Immuno-histo-chemical analysis was conducted to determine apoptosis in the CA1 region of the hippocampus and revealed that caspase-3 positivity increased with the KET dose. However, there was no statistical difference between the groups. While it was lower than the control group in the 5 mg/kg KET group, it was similar to the control group in the 20 mg/kg KET group and higher in the 50 mg/kg KET group (p > 0.05). : Repetitive KET exposure did not significantly affect juvenile cerebral morphology and apoptosis in hippocampal cells.

Baseline cerebral structural morphology predict freezing of gait in early drug-naïve Parkinson’s disease

Freezing of gait (FOG) greatly impacts the daily life of patients with Parkinson’s disease (PD). However, predictors of FOG in early PD are limited. Moreover, recent neuroimaging evidence of cerebral morphological alterations in PD is heterogeneous. We aimed to develop a model that could predict the occurrence of FOG using machine learning, collaborating with clinical, laboratory, and cerebral structural imaging information of early drug-naïve PD and investigate alterations in cerebral morphology in early PD. Data from 73 healthy controls (HCs) and 158 early drug-naïve PD patients at baseline were obtained from the Parkinson’s Progression Markers Initiative cohort. The CIVET pipeline was used to generate structural morphological features with T1-weighted imaging (T1WI). Five machine learning algorithms were calculated to assess the predictive performance of future FOG in early PD during a 5-year follow-up period. We found that models trained with structural morphological features showed fair to good performance (accuracy range, 0.67–0.73). Performance improved when clinical and laboratory data was added (accuracy range, 0.71–0.78). For machine learning algorithms, elastic net-support vector machine models (accuracy range, 0.69–0.78) performed the best. The main features used to predict FOG based on elastic net-support vector machine models were the structural morphological features that were mainly distributed in the left cerebrum. Moreover, the bilateral olfactory cortex (OLF) showed a significantly higher surface area in PD patients than in HCs. Overall, we found that T1WI morphometric markers helped predict future FOG occurrence in patients with early drug-naïve PD at the individual level. The OLF exhibits predominantly cortical expansion in early PD.

Changed cerebral function and morphology serve as neuroimaging evidence for subclinical type 2 diabetic polyneuropathy.

Central and peripheral nervous systems are all involved in type 2 diabetic polyneuropathy mechanisms, but such subclinical changes and associations remain unknown. This study aims to explore subclinical changes of the central and peripheral and unveil their association. A total of 55 type-2 diabetes patients consisting of symptomatic (n = 23), subclinical (n = 12), and no polyneuropathy (n = 20) were enrolled in this study. Cerebral morphology, function, peripheral electrophysiology, and clinical information were collected and assessed using ANOVA and post-hoc analysis. Gaussian random field correction was used for multiple comparison corrections. Pearson/Spearman correlation analysis was used to evaluate the association of the cerebral with the peripheral. When comparing the subclinical group with no polyneuropathy groups, no statistical differences were shown in peripheral evaluations except amplitudes of tibial nerves. At the same time, functional connectivity from the orbitofrontal to bilateral postcentral and middle temporal cortex increased significantly. Gray matter volume of orbitofrontal and its functional connectivity show a transient elevation in the subclinical group compared with the symptomatic group. Besides, gray matter volume in the orbitofrontal cortex negatively correlated with the Neuropathy Symptom Score (r = -0.5871, p < 0.001), Neuropathy Disability Score (r = -0.3682, p = 0.009), and Douleur Neuropathique en 4 questions (r = -0.4403, p = 0.003), and also found correlated positively with bilateral peroneal amplitude (r > 0.4, p < 0.05) and conduction velocities of the right sensory sural nerve(r = 0.3181, p = 0.03). Similarly, functional connectivity from the orbitofrontal to the postcentral cortex was positively associated with cold detection threshold (r = 0.3842, p = 0.03) and negatively associated with Neuropathy Symptom Score (r = -0.3460, p = 0.01). Function and morphology of brain changes in subclinical type 2 diabetic polyneuropathy might serve as an earlier biomarker. Novel insights from subclinical stage to investigate the mechanism of type 2 diabetic polyneuropathy are warranted.

Anomalous cerebral morphology of pregnant women with cleft fetuses.

ObjectivePregnancy leads to long-lasting changes in brain structure for healthy women; however, little is known regarding alterations in the cortical features of pregnant women with malformed fetuses. Isolated clefts of the lip and/or palate (ICL/P) are the most common congenital anomaly in the craniofacial region, which is highly gene-associated. We speculated that pregnant women carrying fetuses with ICL/P may have associated risk genes and specific brain changes during pregnancy.MethodsIn this study, we investigated T1-weighted brain magnetic resonance imaging data from 48 pregnant women: 24 women carrying fetuses with ICL/P (ICL/P group) and 24 women carrying normal fetuses (normal controls), then explored intergroup differences in gray matter volume (GMV), cortical thickness (CT) and cortical complexity (gyrification).ResultsCompared with controls, the ICL/P group had decreased total intracranial volume (TIV) than normal controls; besides, they exhibited increased GMV in the left cuneus, decreased GMV in the right superior temporal gyrus; increased CT in the left precuneus and left superior parietal gyrus, decreased CT involving parsopercularis, fusiform, middle temporal in the left hemisphere and supramarginal, precentral gyrus (PreCG) in the right hemisphere; increased gyrification in the left insula and PreCG, the left middle temporal, and the right supratemporal gyrus.ConclusionPregnant women with ICL/P fetuses had brain morphology changes involving language, auditory, vision, and sensory cortex, which may be their special brain changes compared to normal pregnant women. This study may provide clues for the early detection of fetuses with ICL/P, and be vital for preconception and prenatal counseling with non-invasive methods.

Complex housing partially mitigates low dose radiation-induced changes in brain and behavior in rats

In recent years, much effort has been focused on developing new strategies for the prevention and mitigation of adverse radiation effects on healthy tissues and organs, including the brain. The brain is very sensitive to radiation effects, albeit as it is highly plastic. Hence, deleterious radiation effects may be potentially reversible. Because radiation exposure affects dendritic space, reduces the brain's ability to produce new neurons, and alters behavior, mitigation efforts should focus on restoring these parameters. To that effect, environmental enrichment through complex housing (CH) and exercise may provide a plausible avenue for exploration of protection from brain irradiation. CH is a much broader concept than exercise alone, and constitutes exposure of animals to positive physical and social stimulation that is superior to their routine housing and care conditions. We hypothesized that CHs may lessen harmful neuroanatomical and behavioural effects of low dose radiation exposure. We analyzed and compared cerebral morphology in animals exposed to low dose head, bystander (liver), and scatter irradiation on rats housed in either the environmental enrichment condos or standard housing. Enriched condo conditions ameliorated radiation-induced neuroanatomical changes. Moreover, irradiated animals that were kept in enriched CH condos displayed fewer radiation-induced behavioural deficits than those housed in standard conditions. Animal model-based environmental enrichment strategies, such as CH, are excellent surrogate models for occupational and exercise therapy in humans, and consequently have significant translational possibility. Our study may thus serve as a roadmap for the development of new, easy, safe and cost-effective methods to prevent and mitigate low-dose radiation effects on the brain.

Cortisol Regulates Cerebral Mitochondrial Oxidative Phosphorylation and Morphology of the Brain in a Region-Specific Manner in the Ovine Fetus.

In adults, glucocorticoids are stress hormones that act, partly, through actions on mitochondrial oxidative phosphorylation (OXPHOS) to increase energy availability. Before birth, glucocorticoids are primarily maturational signals that prepare the fetus for new postnatal challenges. However, the role of the normal prepartum glucocorticoid rise in preparing mitochondria for the increased postnatal energy demands remains largely unknown. This study examined the effect of physiological increases in the fetal cortisol concentration on cerebral mitochondrial OXPHOS capacity near term (~130 days gestation, term ~145 days gestation). Fetal sheep were infused with saline or cortisol for 5 days at ~0.8 of gestation before the mitochondrial content, respiratory rates, abundance of the electron transfer system proteins and OXPHOS efficiency were measured in their cortex and cerebellum. Cerebral morphology was assessed by immunohistochemistry and stereology. Cortisol treatment increased the mitochondrial content, while decreasing Complex I-linked respiration in the cerebellum. There was no effect on the cortical mitochondrial OXPHOS capacity. Cortisol infusion had regional effects on cerebral morphology, with increased myelination in the cerebrum. The findings demonstrate the importance of cortisol in regulating the cerebral mitochondrial OXPHOS capacity prenatally and have implications for infants born preterm or after glucocorticoid overexposure due to pregnancy complications or clinical treatment.

Cerebral aneurysms at major arterial bifurcations are associated with the arterial branch forming a smaller angle with the parent artery

Currently, the relationship of bifurcation morphology and aneurysm presence at the major cerebral bifurcations is not clear. This study was to investigate cerebral arterial bifurcation morphology and accompanied hemodynamic stresses associated with cerebral aneurysm presence at major cerebral arterial bifurcations. Cerebral angiographic data of major cerebral artery bifurcations of 554 anterior cerebral arteries, 582 internal carotid arteries, 793 middle cerebral arteries and 195 basilar arteries were used for measurement of arterial diameter, lateral and bifurcation angles and aneurysm deviation. Hemodynamic stresses were analyzed using computational fluid dynamic simulation. Significantly (P < 0.001) more aneurysms deviated toward the smaller branch and the smaller lateral angle than towards the larger branch and larger lateral angle at all four major bifurcations. At the flow direct impinging center, the total pressure was the greatest while the dynamic pressure, wall shear stress (WSS), vorticity and strain rate were the least. Peak 1 and Peak 2 were located on the branch forming a smaller and larger angle with the parent artery, respectively. The dynamic pressure (175.4 ± 18.6 vs. 89.9 ± 7.6 Pa), WSS (28.9 ± 7.4 vs. 15.7 ± 5.3 Pa), vorticity (9874.6 ± 973.4 vs. 7237.8 ± 372.7 1/S), strain rate (9873.1 ± 625.6 vs. 7648.3 ± 472.5 1/S) and distance (1.9 ± 0.8 vs. 1.3 ± 0.3 mm) between the peak site and direct flow impinging center were significantly greater at Peak 1 than at Peak 2 (P < 0.05 or P < 0.01). Moreover, aneurysms deviation and Peak 1 were always on the same side. In conclusion, the branch forming a smaller angle with the parent artery is associated with abnormally enhanced hemodynamic stresses to initiate an aneurysm at the bifurcation apex.

Short Juvenile Stress Has No Long-Lasting Effects on Anxiety-Like Behavior, Object Recognition Memory, or Gross Brain Morphology but Affects Dendritic Spines in the Hippocampus in Male Rats

Purpose: During the juvenile stage, such areas as the hippocampus and corpus callosum (CC) are still immature and sensitive to stress exposure. The present study investigated whether two different types of stressors in the juvenile stage of life have a long-lasting impact on behavior and biological outcomes in adult rats. Methods: Male juvenile rats were exposed to restraint or predator stress on postnatal day 25 (P25) for 3 days. Thirty-two days later (P60-74), behavioral and biological analyses were conducted. The behavioral analysis included measures of anxiety-like behavior and recognition memory. The biological analysis investigated gross cerebral morphology, based on volume analysis of the CC and hippocampus, perirhinal cortex thickness, and dendritic spine density. Results: Neither restraint stress nor predator stress affected anxiety-like behavior or object recognition memory in adulthood. Body weight and adrenal gland weight were unaffected by both types of stress. Overall, volumetric measures of the CC and hippocampus were not significant, with no changes in perirhinal cortex thickness. Spine density in the medial prefrontal cortex also was unaffected, but a decrease in dendritic spine density was found in the hippocampus in response to restraint stress and an increase to predator stress. Conclusion: Short-term and daily restraint and predator stress during the juvenile stage had no long-lasting effects on anxiety-like behavior, object memory, volume of the CC or hippocampus, or perirhinal cortex thickness, but a decrease in dendritic spine density was found in the hippocampus. These findings suggest that different types of stressors have different impacts on microstructures in the brain without affecting behavior or the gross morphology of stress-sensitive brain areas.

EP200: Noonan syndrome associated with focal occipital alopecia in a patient with RAF1 variant: A case report and literature review

Noonan syndrome (NS) is a heterogenous condition characterized by distinctive craniofacial features, cardiac defects, and neurodevelopmental changes and is caused by variants in one of seven genes coding for proteins within the Ras-MAPK pathway. Pathogenic variants in RAF1 account for approximately 3-17% of cases and are associated with a high prevalence of severe hypertrophic cardiomyopathy (HCM) and pulmonary hypertension (PHTN). Cerebrovascular and Chiari I malformations, although rare, have also been described in individuals with RAF-1 NS. To our knowledge, the presence of congenital occipital alopecia in an individual with NS has not been previously reported. We report a patient with a de novo pathogenic heterozygous RAF1 gene sequence variant, c.770C>T (p.Ser257Leu), with atypical scalp findings. Our proband was a 4-week-old female dichorionic, diamniotic twin born at 35 weeks 2 days gestation to nonconsanguineous parents. At birth, her length was 45.7 cm (14th centile), weight was 2656 g (69th centile), and head circumference was 34.5 cm (97th centile). The mother was 38 at the time of birth. There was no history of maternal or gestational diabetes. Prenatal ultrasound was concerning for cystic hygroma. The immediate neonatal course was complicated by acute respiratory failure, left ventricular outflow tract obstruction with concern for coarctation on echocardiogram, poor feeding, and failed newborn hearing screen which prompted transfer to a tertiary NICU for further management. At the time of consultation, the following problems had been identified: bilateral cataracts, significant redundant posterior neck folds that showed fatty soft tissue neck mass without a cystic component, and hypertrophic cardiomyopathy with elevated pulmonary arterial pressures. Physical exam was notable for relative macrocephaly with turricephaly, lowset, posteriorly rotated ears, redundant posterior neck folds, and a focal, 1cm circular area of alopecia at the midline occipital region. These findings were concerning for a RASopathy. Imaging of her superficial midline scalp defect with brain MRI showed a suspected atretic encephalocele, but CT did not reveal any occipital bony defects. After re-evaluation, it was confirmed that there was no intracranial connection or bony defect at the area of the congenital alopecia nor at the level of the suboccipital skin thickening/redundancy. Chromosomal microarray was nondiagnostic and thus exome sequence analysis was preformed which detected the pathogenic RAF1 variant. The diagnosis of RAF1 NS accounts for nearly all of the physical changes seen in our patient, particularly the severe degree of PHTN and HCM, with the exception of her occipital alopecia. Since our initial consultation, the patient continues to grow along NS-specific curve, has persistent mild bilateral hearing loss, and has had interval placement of gastric tube secondary to oral feeding difficulties. There has been mild improvement in cardiac function, septal hypertrophy, and PHTN. She remains seizure-free. This report expands the phenotype of RAF1 Noonan syndrome to include congenital focal alopecia. We recommend that NS should be added to the differential when this same scalp finding is present. Although the presence of this physical finding in our patient was not definitively associated with any underlying structural CNS or bony changes, this case highlights the importance of investigating with detailed cranial and spinal imaging to better characterize cerebral morphology and guide genetic testing in suspected RASopathy cases. Additional cases with this finding are needed to better understand potential associations.

Acquired olfactory loss alters functional connectivity and morphology

Removing function from a developed and functional sensory system is known to alter both cerebral morphology and functional connections. To date, a majority of studies assessing sensory-dependent plasticity have focused on effects from either early onset or long-term sensory loss and little is known how the recent sensory loss affects the human brain. With the aim of determining how recent sensory loss affects cerebral morphology and functional connectivity, we assessed differences between individuals with acquired olfactory loss (duration 7–36 months) and matched healthy controls in their grey matter volume, using multivariate pattern analyses, and functional connectivity, using dynamic connectivity analyses, within and from the olfactory cortex. Our results demonstrate that acquired olfactory loss is associated with altered grey matter volume in, among others, posterior piriform cortex, a core olfactory processing area, as well as the inferior frontal gyrus and angular gyrus. In addition, compared to controls, individuals with acquired anosmia displayed significantly stronger dynamic functional connectivity from the posterior piriform cortex to, among others, the angular gyrus, a known multisensory integration area. When assessing differences in dynamic functional connectivity from the angular gyrus, individuals with acquired anosmia had stronger connectivity from the angular gyrus to areas primary responsible for basic visual processing. These results demonstrate that recently acquired sensory loss is associated with both changed cerebral morphology within core olfactory areas and increase dynamic functional connectivity from olfactory cortex to cerebral areas processing multisensory integration.

Development of cerebral mitochondrial respiratory function is impaired by thyroid hormone deficiency before birth in a region-specific manner.

Thyroid hormones regulate adult metabolism partly through actions on mitochondrial oxidative phosphorylation (OXPHOS). They also affect neurological development of the brain, but their role in cerebral OXPHOS before birth remains largely unknown, despite the increase in cerebral energy demand during the neonatal period. Thus, this study examined prepartum development of cerebral OXPHOS in hypothyroid fetal sheep. Using respirometry, Complex I (CI), Complex II (CII), and combined CI&CII OXPHOS capacity were measured in the fetal cerebellum and cortex at 128 and 142days of gestational age (dGA) after surgical thyroidectomy or sham operation at 105dGA (term ~145dGA). Mitochondrial electron transfer system (ETS) complexes, mRNA transcripts related to mitochondrial biogenesis and ATP production, and mitochondrial density were quantified using molecular techniques. Cerebral morphology was assessed by immunohistochemistry and stereology. In the cortex, hypothyroidism reduced CI-linked respiration and CI abundance at 128dGA and 142dGA, respectively, and caused upregulation of PGC1α (regulator of mitochondrial biogenesis) and thyroid hormone receptor β at 128dGA and 142dGA, respectively. In contrast, in the cerebellum, hypothyroidism reduced CI&II- and CII-linked respiration at 128dGA, with no significant effect on the ETS complexes. In addition, cerebellar glucocorticoid hormone receptor and adenine nucleotide translocase (ANT1) were downregulated at 128dGA and 142dGA, respectively. These alterations in mitochondrial function were accompanied by reduced myelination. The findings demonstrate the importance of thyroid hormones in the prepartum maturation of cerebral mitochondria and have implications for the etiology and treatment of the neurodevelopmental abnormalities associated with human prematurity and congenital hypothyroidism.

Multiparametric and multilevel characterization of morphological alterations in patients with transient ischemic attack.

Transient ischemic attack (TIA), an important risk factor for stroke, is associated with widespread disruptions of functional brain architecture. However, TIA‐related structural alterations are not well established. By analyzing structural MRI data from 50 TIA patients versus 40 healthy controls (HCs), here we systematically investigated TIA‐related morphological alterations in multiple cortical surface‐based indices (cortical thickness [CT], fractal dimension [FD], gyrification index [GI], and sulcal depth [SD]) at multiple levels (local topography, interregional connectivity and whole‐brain network topology). For the observed alterations, their associations with clinical risk factors and abilities as diagnostic and prognostic biomarkers were further examined. We found that compared with the HCs, the TIA patients showed widespread morphological alterations and the alterations depended on choices of morphological index and analytical level. Specifically, the patients exhibited: (a) regional CT decreases in the transverse temporal gyrus and lateral sulcus; (b) impaired FD‐ and GI‐based connectivity mainly involving visual, somatomotor and ventral attention networks and interhemispheric connections; and (c) altered GI‐based whole‐brain network efficiency and decreased FD‐based nodal centrality in the middle frontal gyrus. Moreover, the impaired morphological connectivity showed high sensitivities and specificities for distinguishing the patients from HCs. Altogether, these findings demonstrate the emergence of morphological index‐dependent and analytical level‐specific alterations in TIA, which provide novel insights into neurobiological mechanisms underlying TIA and may serve as potential biomarkers to help diagnosis of the disease. Meanwhile, our findings highlight the necessity of using multiparametric and multilevel approaches for a complete mapping of cerebral morphology in health and disease.

Short predictable stress promotes resistance to anxiety behavior and increases dendritic spines in prefrontal cortex and hippocampus

PurposeSome stress paradigms have shown protective effects of stress, suggesting increased resilience. Here we investigated whether a short predictable psychological stress, continuous or discontinuous, has a protective or negative long-lasting effect on behavior and cerebral morphology, and if there is difference when stress is experienced at different phases of neurodevelopment, namely in juvenile, adolescent, and adult rats. MethodsMale and female rats were stressed on an elevated open platform at different ages (P23, P40, P75), and behavior was assessed later around 90 days of age. Behavioral analysis included measures of anxiety-like behavior, motor activity, and contextual memory. We also investigated the cerebral morphology by using dendritic spine analysis in pyramidal cells, in medial prefrontal cortex (Cg3), orbital prefrontal (AID) and hippocampal region CA1 as well as granule cells in the dentate gyrus (DG) of the hippocampus. ResultsOur results showed that short predictable psychological stress, continuous or discontinuous for 12 days, altered emotional behavior and neuronal morphology. Both behavioral and morphological results were sexually dimorphic and suggest a habituation and protective effect, as seen in the decrease of the anxiety-like behavior in the elevated plus maze (EPM), and an increase in excitatory synapse number, which is inferred from an increase of dendritic spines in the hippocampus and prefrontal cortex. ConclusionWe conclude that the response to short predictable psychological stress induces a protective/positive effect in both sexes and at different developmental ages.

Changes in Cortical Thickness Are Associated With Cognitive Ability in Postoperative School-Aged Children With Tetralogy of Fallot.

In children with tetralogy of Fallot (TOF), there is a risk of brain injury even if intracardiac deformities are corrected. This population follow-up study aimed to identify the correlation between cerebral morphology changes and cognition in postoperative school-aged children with TOF. Resting-state functional magnetic resonance imaging (rs-fMRI) and the Wechsler Intelligence Scale for Children–Chinese revised edition (WISC-CR) were used to assess the difference between children with TOF and healthy children (HCs). Multiple linear regression showed that the TOF group had a lower verbal intelligence quotient (VIQ, 95.000 ± 13.433, p = 0.001) than the HC group and that VIQ had significant positive correlations with the cortical thickness of both the left precuneus (p < 0.05) and the right caudal middle frontal gyrus (p < 0.05) after adjustment for preoperative SpO2, preoperative systolic blood pressure (SBP), preoperative diastolic blood pressure (DBP) and time of aortic override (AO). Our results suggested that brain injury induced by TOF would exert lasting effects on cortical and cognitive development at least to school age. This study provides direct evidence of the relationship between cortical thickness and VIQ and of the need for strengthened verbal training in school-aged TOF patients after corrective surgery.

Morphological changes in secondary, but not primary, sensory cortex in individuals with life-long olfactory sensory deprivation

Individuals with congenital sensory deprivation usually demonstrate altered brain morphology in areas associated with early processing of the absent sense. Here, we aimed to establish whether this also applies to individuals born without a sense of smell (congenital anosmia) by comparing cerebral morphology between 33 individuals with isolated congenital anosmia and matched controls. We detected no morphological alterations in the primary olfactory (piriform) cortex. However, individuals with anosmia demonstrated gray matter volume atrophy in bilateral olfactory sulci, explained by decreased cortical area, curvature, and sulcus depth. They further demonstrated increased gray matter volume and cortical thickness in the medial orbital gyri; regions closely associated with olfactory processing, sensory integration, and value-coding. Our results suggest that a lifelong absence of sensory input does not necessarily lead to morphological alterations in primary sensory cortex and extend previous findings with divergent morphological alterations in bilateral orbitofrontal cortex, indicating influences of different developmental processes.