Anatomical Deficits Research Articles

Clinical and Hematological profile of Paediatric Patients with Cleft Lip and Palate in a Tertiary Care Hospital of Haryana, India

Introduction: Cleft lip and/ or cleft palate are the most common visible craniofacial anomalies. These patients often have feeding difficulties and recurrent infections leading to an altered immune system which can be assessed by the variations in hematological parameters. We intended to assess the clinical profile and the hematological parameters in patients with cleft lip and palate. Methods: This is a three-year cross-sectional study conducted at SGT Medical College, Gurugram, Haryana, India from January 2017 to December 2019 involving assessment of patients with cleft lip and palate who visited the paediatric unit for complete evaluation before surgery. Syndromic children or those with associated deformities were excluded .A total of 115 patients were enrolled in the study and the following information was recorded: Age, Gender and type of cleft (Cleft lip and alveolus, cleft lip, alveolus and palate, and isolated cleft palate). Hematological parameters including hemoglobin, total leukocyte count, differential leukocyte count, absolute eosinophil count, and red cell indices were evaluated and compared amongst the anatomical subtypes. Results: A total of 115 patients were included in the study, of which 66 (57.4%) were males and 49 (42.6%) were females. 57 (49.6%) had a cleft lip, alveolus, and palate, 36 (31.3%) had a cleft lip and alveolus and 22 (19.1%) had cleft palate only. Anaemia was present in 71.1% of cases. 83.4% cases of cleft lip and alveolus while81.8% of isolated cleft palate were anaemic. Microcytic hypochromic anaemia was present in 63.4% of cases while 36.6% had normocytic normochromic anaemia. The total leukocyte count was elevated in 60 children (52.2%) which was highest in cleft lip and alveolus (66%). Absolute neutrophil count was significantly high in the lip and alveolus groups.(13.9%) Absolute lymphocyte count was highest in lip and alveolus (30.56%). Absolute monocyte count and the absolute eosinophil count was low in the majority of cases. Conclusions: A large number of children with cleft lip and/ or palate are not exclusively breastfed due to anatomical deficits. They need supplemental iron to meet the demands. A standard policy to provide auxillary iron by health care professionals should be made at the first visit to the health centre because nutritional anaemia negatively affects the physical and cognitive development of a child. It also unnecessarily prolongs the date for optimum and safe surgery.

A schizophrenia risk factor induces marked anatomical deficits at GABAergic-dopaminergic synapses in the rat ventral tegmental area: Essential evidence for new targeted therapies.

To develop new therapies for schizophrenia, evidence accumulated over decades highlights the essential need to investigate the GABAergic synapses that presynaptically influence midbrain dopaminergic neurons. Since current technology restricts these studies to animals, and evidence accumulated in recent decades indicates a developmental origin of schizophrenia, we investigated synaptic changes in male rat offspring exposed to maternal immune activation (MIA), a schizophrenia risk factor. Using a novel combination of lentiviruses, peroxidase-immunogold double labeling, three-dimensional serial section transmission electron microscopy and stereology, we observed clear anatomical alterations in synaptic inputs on dopaminergic neurons in the midbrain posterior ventral tegmental area (pVTA). These changes relate directly to a characteristic feature of schizophrenia: increased dopamine release. In 3-month-old and 14-month-old MIA rats, we found a marked decrease in the volume of presynaptic GABAergic terminals from the rostromedial tegmental nucleus (RMTg) and in the length of the synapses they made, when innervating pVTA dopaminergic neurons. In MIA rats in the long-term, we also discovered a decrease in the volume of the postsynaptic density (PSD) and in the maximum thickness of the PSD at the same synapses. These marked deficits were evident in conventional GABA-dopamine synapses and in synaptic triads that we discovered involving asymmetric synapses that innervated RMTg GABAergic presynaptic terminals, which in turn innervated pVTA dopaminergic neurons. In triads, the PSD thickness of asymmetric synapses was significantly decreased in MIA rats in the long-term cohort. The extensive anatomical deficits provide a potential basis for new therapies targeted at synaptic inputs on midbrain pVTA dopaminergic neurons, in contrast to current striatum-targeted antipsychotic drugs.

Therapeutic options in female stress urinary incontinence

Stress urinary incontinence in female patients is characterised by loss of urine without the need to urinate. Causes are manifold and require a good knowledge of the pelvic floor structures and the functionality of the bladder's occlusion system. Before any treatment can be initiated, differentiated diagnostic investigation must uncover the causes in order to be able to show incontinent women the ideal therapeutic options. In addition to conservative treatment strategies, there are several surgical alternatives available that can be used depending on the functional and/or anatomical deficit. Surgical correction produces good results, although a minor rate of possible complications must be accepted.

Alloplastic Facial Implants

AbstractAs the face ages, there is thinning of the epidermis, volume loss and rearrangement of the soft tissues, and malabsorption of the skeletal framework. It is essential to have a thorough understanding of the aging process for successful facial augmentation and rejuvenation. Alloplastic implants can be used to provide a long-lasting solution for augmentation of skeletal deficiencies, restoration of facial irregularities, and rejuvenation of the face. In this study, we describe the ideal implant characteristics along with the advantages and disadvantages of various implant materials. We also present techniques in nasal and premaxillary augmentation, midface augmentation, mandibular augmentation, and lip augmentation. Additionally, computer-aided design and manufacturing as well as bioprinting are emerging technologies with growing applications in facial plastic and reconstructive surgery. We discuss their role in the creation of patient-specific custom implants. The overall goal of facial rejuvenation is to address multiple aspects of the facial aging process including deficiencies in the skin, soft tissues, and skeletal framework. The use of alloplastic implants alone or synergistically with additional surgical procedures can restore a wide range of anatomical deficits that occur with age.

Load Transfer during Magnetic Mucoperiosteal Distraction in Newborns with Complete Unilateral and Bilateral Orofacial Clefts: A Three-Dimensional Finite Element Analysis

The primary correction of congenital complete unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP) is challenging due to inherent lack of palatal tissue and small extent of the palatal shelves at birth. The tissue deficiency affects the nasal mucosa, maxillary bone and palatal mucosa. This condition has driven the evolution of several surgical and non-surgical techniques for mitigating the inherent problem of anatomical deficits. These techniques share the common principle of altering the neighboring tissues around the defect area in order to form a functional seal between the oral and nasal cavity. However, there is currently no option for rectifying the tissue deficiency itself. Investigations have repeatedly shown that despite the structural tissue deficiency of the cleft, craniofacial growth proceeds normal if the clefts remain untreated, but the cleft remains wide. Conversely, craniofacial growth is reduced after surgical repair and the related alteration of the tissues. Therefore, numerous attempts have been made to change the surgical technique and timing so as to reduce the effects of surgical repairs on craniofacial growth, but they have been only minimally effective so far. We have determined whether the intrinsic structural soft and hard tissue deficiency can be ameliorated before surgical repair using the principles of periosteal distraction by means of magnetic traction. Two three-dimensional maxillary finite element models, with cleft patterns of UCLP and BCLP, respectively, were created from computed tomography slice data using dedicated image analysis software. A virtual dental magnet was positioned on either side of the cleft at the mucoperiosteal borders, and an incremental magnetic attraction force of up to 5 N was applied to simulate periosteal distraction. The stresses and strains in the periosteal tissue induced by the magnet were calculated using finite element analysis. For a 1 N attraction force the maximum strains did not exceed 1500 µstrain suggesting that adaptive remodeling will not take place for attraction forces lower than 1 N. At 5 N the regions subject to remodeling differed between the UCLP and BCLP models. Stresses and strains at the periosteum of the palatal shelf ridges in the absence of compressive forces at the alveolar borders were greater in the UCLP model than the BCLP model. The findings suggest that in newborns with UCLP and BCLP, periosteal distraction by means of a magnetic 5 N attraction force can promote the generation of soft and hard tissues along the cleft edges and rectify the tissue deficiency associated with the malformation.

Intranasal delivery of BDNF rescues memory deficits in AD11 mice and reduces brain microgliosis

A decrease in brain-derived neurotrophic factor (BDNF), a neurotrophin essential for synaptic function, plasticity and neuronal survival, is evident early in the progression of Alzheimer’s disease (AD), being apparent in subjects with mild cognitive impairment or mild AD, and both proBDNF and mature BDNF levels are positively correlated with cognitive measures. BDNF delivery is, therefore, considered of great interest as a potentially useful therapeutic strategy to contrast AD. Invasive BDNF administration has indeed been recently used in animal models of AD with promising results in rescuing memory deficits, synaptic density and cell loss. Here, we tested whether non-invasive intranasal administration of different BDNF concentrations after the onset of cognitive and anatomical deficits (6 months of age) could rescue neuropathological and memory deficits in AD11 mice, a model of NGF deprivation-induced neurodegeneration. In addition to AD hallmarks, we investigated BDNF effects on microglia presence in the brain of AD11 mice, since alterations in microglia activation have been associated with ageing-related cognitive decline and with the progression of neurodegenerative diseases, including AD. We found that intranasal delivery of 42 pmol BDNF (1 μM), but not PBS, was sufficient to completely rescue performance of AD11 mice both in the object recognition test and in the object context test. No further improvement was obtained with 420 pmol (10 μM) BDNF dose. The strong improvement in memory performance in BDNF-treated mice was not accompanied by an amelioration of AD-like pathology, Aβ burden, tau hyperphosphorylation and cholinergic deficit, but there was a dramatic decrease of CD11b immunoreactive brain microglia. These results reinforce the potential therapeutic uses of BDNF in AD and the non-invasive intranasal route as an effective delivery strategy of BDNF to the brain. They also strengthen the connection between neuroinflammation and neurodegenerative dementia and suggest microglia as a possible mediator of BDNF therapeutic actions in the brain.

Atrophic Corpus Callosum Associated with Altered Functional Asymmetry in Major Depressive Disorder.

PurposeImpairments in intra- and inter-hemispheric information transfer circuits have been reported in patients with major depressive disorder (MDD). However, the specific anomalous connection (intra- and/or inter-hemispheric) and hemisphere (left and/or right) in which this connection plays a more dominant role in the pathogenic mechanism underlying MDD are still poorly understood.Patients and MethodsStructural magnetic resonance imaging and resting-state functional magnetic resonance imaging were performed in 33 patients with MDD and 33 healthy controls. The intra- and inter-hemispheric functional connectivity (FC) strength in the default mode network areas and volume of the callosal subregions were computed using independent samples t-tests. The partial correlations between the volumes and FCs were also computed.ResultsThe patients with MDD had smaller volumes in the genu of the corpus callosum than the controls. The intrahemispheric FCs of the bilateral posterior cingulate gyrus, left precuneus, left medial superior frontal gyrus, left medial orbitofrontal gyrus, left angular gyrus and left middle temporal gyrus, and interhemispheric FCs of the bilateral posterior cingulate gyrus in the patients with MDD were lower than those in the controls. Moreover, the intrahemispheric FCs of the precuneus and interhemispheric FCs of middle frontal gyrus, orbital middle frontal gyrus, and anterior cingulate gyrus in the patients with MDD showed right-lateralized asymmetry, which were opposite from the asymmetry patterns observed in the controls. The functional asymmetry of the anterior cingulate gyrus was correlated with the volume of the genu of the corpus callosum and disease duration.ConclusionThese findings provide robust evidence that intra- and inter-hemispheric disconnections are involved in MDD, and that functional disruptions in the left hemisphere may be more relevant to the pathophysiology of MDD. Furthermore, imbalanced interhemispheric exchanges may contribute to the anatomical deficits in the corpus callosum in patients with MDD.

Balancing Parts: Integrating Uncertainty/Ambiguity into Anatomy Education

Tolerance of Uncertainty/Ambiguity (ToU/A) is a construct describing individuals’ responses to ambiguous stimuli. ToA is recognised as impacting healthcare outcomes, however, little is known about whether education may impact students’ ToA, and if so, how we can develop pedagogy to improve students’ ToU/A. Framework analysis of longitudinal qualitative data, collected via online discussions and semi‐structured interviews from 207 undergraduate medical students across three semesters of anatomy, identified anatomy pedagogy which either fostered or hindered students’ ToU/A. Anatomy curricula which integrates opportunities for students to distribute responsibility for knowledge (i.e. working in teams) and/or provide anonymity for those conveying knowledge (i.e. online anonymous discussion forums) appear to foster students’ ToU/A, while didactic educator approaches (suggesting that knowledge is finite and knowable) appear to hinder students’ ToU/A. Thematic analysis across time‐points suggest that active learning approaches can be effective stimuli for students’ ToU/A development. Active learning approaches within our study balanced communication of anatomy discipline knowledge with clinical applications, so that the context of knowledge became the stimulus of uncertainty. Exemplar anatomy curricula fostering ToU/A include “choose your own adventure” chest pain team‐based learning, where students elect which patient information they receive and in which order, engaging anatomical knowledge through the “adventure”. Another approach is using short clinical case scenarios wherein more than one underlying anatomical deficit may explain symptoms described in the scenario. Despite evidence that students develop ToA/U in their cognition and behaviour (e.g. through acknowledgement of the clinical importance of ToU/ToA, and perseverance when faced with ambiguous/unknown knowledge), student talk in this study suggests that emotionally, students remain negative about ToU/A (e.g. feeling overwhelmed, fearing errors). Together our data and examples illustrate that foundational science knowledge education can be balanced with effective student development of ToU/A, but student feedback may remain negative; an important consideration in evaluating effective curricula. Future work will focus on whether students’ negative emotions change with time and clinical exposure.Support or Funding InformationResearch supported by Monash Education Academy, Faculty of Medicine, Nursing and Health Sciences (Monash University) and a Medical Education Travel Fellowship

Breathing retraining in sleep apnoea: a review of approaches and potential mechanisms.

Anatomically based treatments for obstructive sleep apnoea (OSA) may not completely resolve OSA. This has led to interest in exploring ways of addressing physiological risk factors. This review examines the literature for research reporting on the effects of various types of breathing training and breathing activities on sleep apnoea. It also reviews and discusses proposed therapeutic mechanisms. A search of electronic databases was performed using the search terms related to various breathing therapies or to activities requiring high levels of breath control such as singing and the playing of musical instruments and sleep apnoea. A total of 14 suitable studies were reviewed. A diverse variety of breathing retraining approaches are reported to improve sleep apnoea, e.g., Buteyko method, inspiratory resistance training, and diaphragmatic breathing. There is also a reduced incidence of sleep apnoea with intensive and regular participation in activities that require high levels of breath control, e.g., singing and playing wind instruments. Improvements in sleep-disordered breathing are thought to be related to improvements in (1) muscle tone of the upper airway; (2) respiratory muscle strength; (3) neuroplasticity of breathing control; (4) oxygen levels; (5) hyperventilation/dysfunctional breathing; and (6) autonomic nervous system, metabolic, and inflammatory status. Breathing retraining and regular practice of breath control activities such as singing and playing wind instruments are potentially helpful for sleep apnoea, particularly for individuals with minimal anatomical deficit and daytime breathing dysfunction. Research is needed to elucidate mechanisms, to inform patient selection, and to refine clinical protocols.

Comparison of Adductor Canal Block and Femoral Nerve Block for Early Ambulation After Primary Total Knee Arthroplasty: A Randomized Controlled Trial.

Purpose: The purpose of this study was to assess the efficacy of adductor canal block (ACB) as compared to femoral nerve block (FNB) in ambulation distance, opioid consumption, and physical therapy participation on postoperative days (PODs) 1 and 2 after total knee arthroplasty (TKA). We hypothesized ACB would have increased the ambulation distance and decreased the opioid consumption in comparison to FNB.Methods: All elective TKAs at a single institution, age 18 and older, without existing neurologic or anatomic deficit in the operative limb, were considered. Participants were randomized 1:1 to receive either an ACB (AC group) or a FNB (FN group), in addition to standard care. Visual analog pain scores (VAS) and oral morphine equivalents (OMEs) were recorded preoperatively, in post-anesthesia care unit (PACU), and on PODs 1 and 2. Postoperative ambulation distance was recorded on PODs 1 and 2. Patient satisfaction with analgesia and physical therapist-rated participation in therapy sessions was obtained as well. Results: From 2014 to 2015, 84 participants were recruited: 41 in FN, and 43 in AC. On POD 1, mean ambulation distances in AC and FN were 70.2 and 48.5 ft, respectively (p = 0.045). On POD 2, mean ambulation distances in AC and FN were 129.0 and 106.4 ft, respectively (p = 0.225). VAS, OME, satisfaction, and physical therapy participation were not significantly different.Conclusions: Ambulation after TKA is superior with ACB on the first POD, but there is no difference in VAS scores, OME, patient satisfaction, or ambulation on POD 2.

Two stage mandible reconstruction with PEEK implant tissue spacer and autologous iliac crest bone following ameloblastoma resection

Introduction Ameloblastoma is a locally aggressive benign odontogenic tumour with increased risk of recurrence. Depending on histological subtype, management usually consists of wide surgical resection of the tumour. This will result in an anatomical deficit which can be a surgical challenge to restore.

Functional and anatomical deficits in visceral nociception with age: a mechanism of silent appendicitis in the elderly?

The ability to sense visceral pain during appendicitis is diminished with age leading to delay in seeking health care and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined visceral nociception in aged mouse and human tissue. Inflamed and noninflamed appendixes were collected from consenting patients undergoing surgery for the treatment of appendicitis or bowel cancer. Supernatants were generated by incubating samples in buffer and used to stimulate multiunit activity in intestinal preparations, or single-unit activity from teased fibres in colonic preparations, of young and old mice. Changes in afferent innervation with age were determined by measuring the density of calcitonin gene-related peptide-positive afferent fibres and by counting dorsal root ganglia back-labelled by injection of tracer dye into the wall of the colon. Finally, the effect of age on nociceptor function was studied in mouse and human colon. Afferent responses to appendicitis supernatants were greatly impaired in old mice. Further investigation revealed this was due to a marked reduction in the afferent innervation of the bowel and a substantial impairment in the ability of the remaining afferent fibres to transduce noxious stimuli. Translational studies in human tissue demonstrated a significant reduction in the multiunit but not the single-unit colonic mesenteric nerve response to capsaicin with age, indicative of a loss of nociceptor innervation. Our data demonstrate that anatomical and functional deficits in nociception occur with age, underpinning the atypical or silent presentation of appendicitis in the elderly.

Frontolimbic, Frontoparietal, and Default Mode Involvement in Functional Dysconnectivity in Psychotic Bipolar Disorder

BackgroundFunctional abnormalities, mostly involving functionally specialized subsystems, have been associated with disorders of emotion regulation such as bipolar disorder (BD). Understanding how independent functional subsystems integrate globally and how they relate with anatomical cortical and subcortical networks is key to understanding how the human brain’s architecture constrains functional interactions and underpins abnormalities of mood and emotion, particularly in BD. MethodsResting-state functional magnetic resonance time series were averaged to obtain individual functional connectivity matrices (using AFNI software); individual structural connectivity matrices were derived using deterministic non-tensor-based tractography (using ExploreDTI, version 4.8.6), weighted by streamline count and fractional anisotropy. Structural and functional nodes were defined using a subject-specific cortico-subcortical mapping (using Desikan-Killiany Atlas, FreeSurfer, version 5.3). Whole-brain connectivity alongside a permutation-based statistical approach and structure–function coupling were employed to investigate topological variance in individuals with predominantly euthymic BD relative to psychiatrically healthy control subjects. ResultsPatients with BD (n = 41) exhibited decreased (synchronous) connectivity in a subnetwork encompassing frontolimbic and posterior-occipital functional connections (T > 3, p = .048), alongside increased (antisynchronous) connectivity within a frontotemporal subnetwork (T > 3, p = .014); all relative to control subjects (n = 56). Preserved whole-brain functional connectivity and comparable structure-function coupling among whole-brain and edge-class connections were observed in patients with BD relative to control subjects. ConclusionsThis study presents a functional map of BD dysconnectivity that differentially involves communication within nodes belonging to functionally specialized subsystems—default mode, frontoparietal, and frontolimbic systems; these changes do not extend to be detected globally and may be necessary to maintain a remitted clinical state of BD. Preserved structure–function coupling in BD despite evidence of regional anatomical and functional deficits suggests a dynamic interplay between structural and functional subnetworks.

Progress in cardiovascular biomaterials.

In 1986, the European Society of Biomaterials Consensus Conference gave a simplified definition of biomaterials as “a non-viable material used in a medical device intended to interact with biological systems”. This seems to be more appropriate when we look into the versatility of applications of biomaterials in the health sector, especially in cardiovascular practice. This field has expanded exponentially in every direction, with multifunctional capability. Heart valves have undergone an evolution in biomaterials and design. Patches and conduits have been developed to correct anatomical deficits, and solutions have been found for narrowing or ballooning of the arteries. Research is ongoing to find replacements for every part of this system by creating replicas made of various materials. To investigate problems pertaining to the cardiovascular system, catheters have undergone an astounding leap in material optimization. In these three sectors, the trends, successes, and failures are worth discussing. This review mainly focuses on the types of biomaterial used for making cardiovascular devices and their advantages and limitations.

Long-Term Fine Motor Capability on the Staircase Test Correlates with the Absolute Number, but Not the Density, of DARPP-Positive Neurons in the Caudate-Putamen.

Measurement of long-term functional and anatomical outcomes in the same animal is considered a powerful strategy for correlating structure with function. In a neonatal animal model of hypoxic-ischemic brain injury that is relevant to cerebral palsy, long-term functional deficits on the staircase test and long-term anatomical deficits in the absolute number of medium-spiny projection neurons in the caudate-putamen were reported in different animals due to logistical constraints. Here, we investigated if these functional and anatomical measures were correlated when measured in the same animals. The medium-spiny projection neurons were investigated because (1) they comprise the vast majority (>97%) of all neurons in the caudate-putamen and (2) motor deficits observed during staircase testing are likely to involve these striatal medium-spiny projection neurons through their connections. We found that long-term skilled forepaw capability on the staircase test was correlated with the absolute number of DARPP-32-positive medium-spiny projection neurons in the caudate-putamen. Specifically, deficits in skilled forepaw ability for the number of sugar pellets eaten and retrieved, and for the maximum staircase level reached, were significantly correlated with a lower absolute neuronal number. We also found that skilled forepaw ability on the staircase test was not correlated with the neuronal density (i.e., number per unit volume) of DARPP-32-positive medium-spiny projection neurons. Since neuronal density is an indirect measure of neuronal survival that is used in the literature, and absolute neuronal number is a direct measure, the results also highlight the scientific value of measuring absolute neuronal number. Anat Rec, 302:2040-2048, 2019. © 2019 American Association for Anatomy.

Increased frontal gray matter volume in individuals with prodromal psychosis.

BackgroundBrain anatomical deficits associated with cognitive dysfunction have been reported in patients with schizophrenia. However, it remains unknown whether such anatomical deficits exist in individuals with prodromal psychosis. The present study is designed to investigate anatomical deficits in prodromal individuals and their associations with clinical/cognitive features.MethodsSeventy‐four prodromal individuals and seventy‐six healthy controls were scanned using structural magnetic resonance imaging. Support vector machines were applied to test whether anatomical deficits might be used to discriminate prodromal individuals from healthy controls.ResultsProdromal individuals showed significantly increased gray matter volume (GMV) in the right inferior frontal gyrus (IFG) and right rectus gyrus relative to healthy controls. No correlations were observed between increased GMV and clinical/cognitive characteristics. The combination of increased GMV in the right rectus gyrus and right IFG showed a sensitivity of 74.32%, a specificity of 67.11%, and an accuracy of 70.67% in differentiating prodromal individuals from healthy controls.ConclusionOur results provide evidence of increased frontal GMV in prodromal individuals. A combination of GMV values in the two frontal brain areas may serve as potential markers to discriminate prodromal individuals from healthy controls. The results thus highlight the importance of the frontal regions in the pathophysiology of psychosis.

Abstract WP348: Astrocyte Reaction After Ischemic Stroke in Nonhuman Primate

In the mammalian central nervous system, gliogenesis and neurogenesis constitutively occurs in the subventricular zone (SVZ) and the hippocampus albeit on a much lower scale in comparison to the other organs. In response to stroke and presumably as an endogenous mechanism of brain self repair, the neural precursors located in the SVZ and the hippocampus are induced to proliferate and migrate towards stroke-damaged tissue. This innate neural reaction in adult brain may represent a mechanism of neuroplasticity and structural remodeling that leads to functional recovery. The rodent animal model of ischemic stroke (IS) showed a clear and pronounced neurogenesis and gliogenesis. However, to date little is known about this innate response in human and nonhuman primates to IS. We have developed a nonhuman primate model of IS with well-defined anatomical infarct lesions and motor behavioral deficit. After a small craniotomy, the dura was opened and with microsurgical technique and the M3 segment of the middle cerebral artery was occluded for 90 minutes followed by reperfusion. Animals with IS showed significant (p<0.005) motor deficit in right hand. To label endogenous neural precursors undergoing cell proliferation in vivo we injected all animals with the S-phase marker 5-bromo-2-deoxyuridine (BrdU). Postmortem analysis demonstrated significant increase of GFAP+ astrocytes (P<0.0001) in the infarct area. These astrocytes exhibited unique re-organization around the infarct zone and expressed various types of morphologies and phenotypes. Less than 1% incorporated BrdU. Sixty-five % of astrocytes with elongated processes oriented toward the IS co-expressed vimentin while tissue from control animals expressed no vimentin. Approximately 35% of astrocytes co-expressed Sox-2, while control animals showed about 4% in the same area of the cortex. Both vimentin and Sox-2 are markers for neural stem cells. These data suggests that astrocytes may be more heterogeneous than previously thought and may undertake various roles in response to IS. A subpopulation of astrocytes may be reprogrammed to an early developmental stage under IS conditions to promote tissue repair and homeostasis.

Increased Frontal Gray Matter Volume in Individuals with Ultra-High Risk for Psychosis

Background: Anatomical brain deficits have been reported in patients with schizophrenia. However, whether anatomical brain deficits exist in individuals with ultra-high risk (UHR) for psychosis remains unknown. The present study is designed to investigate structural changes in UHR individuals and their associations with clinical/cognitive features. Methods: Seventy-four UHR individuals and seventy-six healthy controls were scanned using structural MRI. Receiver operating characteristic curves and support vector machines were applied to test whether abnormal brain regions may be used to discriminate UHR individuals from healthy controls. Findings: UHR individuals showed significantly increased gray matter volume (GMV) in the right inferior frontal gyrus (IFG) and the right rectal gyrus relative to the healthy controls. No significant correlations were observed between abnormal GMV and clinical characteristics. ROC analyses showed that the under curve area of the GMV values in the right rectal gyrus was 0·717 with sensitivity and that specificity values were 66·22% and 72·37%.The combination of increased GMV in the right rectal gyrus and right IFG showed a sensitivity of 74·32%, a specificity of 67·11%, and an accuracy of 70·67% in differentiating UHR individuals from healthy controls. Interpretation: Our results provide evidence of increased frontal GMV in UHR individuals. The GMV values in the right rectal gyrus might serve as potential biomarkers to discriminate UHR individuals from controls at an individual level. Moreover, the combination of GMV in the two frontal brain areas may be a potential image marker to differentiate UHR from healthy controls. The results thus highlight the importance of the frontal regions in the pathophysiology of psychosis. Funding Statement: The National Key National Key R&D Program of China (2016YFC1307100 and 2016YFC1306900) and the National Natural Science Foundation of China ((Grant Nos. 81571310, 81630033, 81771447, 81622018, and 81471363) Declaration of Interests: We declare that none of the authors holds any actual or potential conflict of interest for this study Ethics Approval Statement: The Ethics Committee of the Second Xiangya Hospital of Central South University approved this study. After a complete explanation, all participants submitted their written informed consent.

Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice.

The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers.SIGNIFICANCE STATEMENT The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the 16p11.2 chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the 16p11.2del mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult 16p11.2del mice. These data provide a strong rationale for therapeutic approaches to this disorder.

Bidirectional Causal Connectivity in the Cortico-Limbic-Cerebellar Circuit Related to Structural Alterations in First-Episode, Drug-Naive Somatization Disorder.

Background: Anatomical and functional deficits in the cortico-limbic-cerebellar circuit are involved in the neurobiology of somatization disorder (SD). The present study was performed to examine causal connectivity of the cortico-limbic-cerebellar circuit related to structural deficits in first-episode, drug-naive patients with SD at rest.Methods: A total of 25 first-episode, drug-naive patients with SD and 28 healthy controls underwent structural and resting-state functional magnetic resonance imaging. Voxel-based morphometry and Granger causality analysis (GCA) were used to analyze the data.Results: Results showed that patients with SD exhibited decreased gray matter volume (GMV) in the right cerebellum Crus I, and increased GMV in the left anterior cingulate cortex (ACC), right middle frontal gyrus (MFG), and left angular gyrus. Causal connectivity of the cortico-limbic-cerebellar circuit was partly affected by structural alterations in the patients. Patients with SD showed bidirectional cortico-limbic connectivity abnormalities and bidirectional cortico-cerebellar and limbic-cerebellar connectivity abnormalities. The mean GMV of the right MFG was negatively correlated with the scores of the somatization subscale of the symptom checklist-90 and persistent error response of the Wisconsin Card Sorting Test (WCST) in the patients. A negative correlation was observed between increased driving connectivity from the right MFG to the right fusiform gyrus/cerebellum IV, V and the scores of the Eysenck Personality Questionnaire extraversion subscale. The mean GMV of the left ACC was negatively correlated with the WCST number of errors and persistent error response. Negative correlation was found between the causal effect from the left ACC to the right middle temporal gyrus and the scores of WCST number of categories achieved.Conclusions: Our findings show the partial effects of structural alterations on the cortico-limbic-cerebellar circuit in first-episode, drug-naive patients with SD. Correlations are observed between anatomical alterations or causal effects and clinical variables in patients with SD, and bear clinical significance. The present study emphasizes the importance of the cortico-limbic-cerebellar circuit in the neurobiology of SD.