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, Stephen M Stahl
Journal of Psychopharmacology, Volume 36, pp 428-438; https://doi.org/10.1177/02698811221087645

Abstract:
Schizophrenia manifests as loss of brain volume in specific areas in a progressive nature and an important question concerns whether long-term treatment with medications contributes to this. The aim of the current PRISMA systematic review was to search for prospective studies involving randomization to treatment. PROSPERO ID: CRD42020197874. The MEDLINE/PUBMED was searched and it returned 2638 articles; 3 were fulfilling the inclusion criteria. A fourth was published later; they included 359 subjects, of whom 86 were healthy controls, while the rest were first-episode patients, with 91 under olanzapine, 93 under haloperidol, 48 under risperidone, 5 under paliperidone, 6 under ziprasidone, and 30 under placebo. Probably one-third of patients were suffering from a psychotic disorder other than schizophrenia. The consideration of their results suggested that there is no significant difference between these medications concerning their effects on brain structure and also in comparison to healthy subjects. There does not seem to be any strong support to the opinion that medications that treat psychosis cause loss of brain volume in patients with schizophrenia. On the contrary, the data might imply the possible presence of a protective effect for D2, 5-HT2, and NE alpha-2 antagonists (previously called SGAs). However, the literature is limited and focused research in large study samples is essential to clarify the issue, since important numerical differences do exist. The possibility of the results and their heterogeneity to be artifacts secondary to a modification of magnetic resonance imaging (MRI) signal by antipsychotics should not be easily rejected until relevant data are available.
Nicholas B. Dadario, Bledi Brahimaj, Jacky Yeung,
Published: 16 August 2021
Frontiers in Neurology, Volume 12; https://doi.org/10.3389/fneur.2021.711646

Abstract:
The surgical management of brain tumors is based on the principle that the extent of resection improves patient outcomes. Traditionally, neurosurgeons have considered that lesions in “non-eloquent” cerebrum can be more aggressively surgically managed compared to lesions in “eloquent” regions with more known functional relevance. Furthermore, advancements in multimodal imaging technologies have improved our ability to extend the rate of resection while minimizing the risk of inducing new neurologic deficits, together referred to as the “onco-functional balance.” However, despite the common utilization of invasive techniques such as cortical mapping to identify eloquent tissue responsible for language and motor functions, glioma patients continue to present post-operatively with poor cognitive morbidity in higher-order functions. Such observations are likely related to the difficulty in interpreting the highly-dimensional information these technologies present to us regarding cognition in addition to our classically poor understanding of the functional and structural neuroanatomy underlying complex higher-order cognitive functions. Furthermore, reduction of the brain into isolated cortical regions without consideration of the complex, interacting brain networks which these regions function within to subserve higher-order cognition inherently prevents our successful navigation of true eloquent and non-eloquent cerebrum. Fortunately, recent large-scale movements in the neuroscience community, such as the Human Connectome Project (HCP), have provided updated neural data detailing the many intricate macroscopic connections between cortical regions which integrate and process the information underlying complex human behavior within a brain “connectome.” Connectomic data can provide us better maps on how to understand convoluted cortical and subcortical relationships between tumor and human cerebrum such that neurosurgeons can begin to make more informed decisions during surgery to maximize the onco-functional balance. However, connectome-based neurosurgery and related applications for neurorehabilitation are relatively nascent and require further work moving forward to optimize our ability to add highly valuable connectomic data to our surgical armamentarium. In this manuscript, we review four concepts with detailed examples which will help us better understand post-operative cognitive outcomes and provide a guide for how to utilize connectomics to reduce cognitive morbidity following cerebral surgery.
Published: 27 March 2021
The publisher has not yet granted permission to display this abstract.
, Chunyan Luo, Wenjing Zhang, Xiyue Yang, Yuan Xiao, , , Qiyong Gong
Published: 22 October 2020
Biomarkers in Neuropsychiatry, Volume 3; https://doi.org/10.1016/j.bionps.2020.100026

The publisher has not yet granted permission to display this abstract.
Yuexiong Yang,
Published: 16 July 2020
Abstract:
Schizophrenia (SCZ) is characterized by abnormal thoughts, behaviors and speech, along with a decreased perception of reality that can included visual or auditory hallucinations, withdrawal of social activity and lack of motivation, etc. Many hypotheses related to the causes of SCZ have been proposed, but the underlying neuropathological mechanism remains unclear. Recent studies have suggested that there is an association between autophagy and SCZ. The strongest evidence for this comes from the expression of ATGs in the BA22 of postmortem samples from SCZ patients, coinciding with some of the brain imaging studies and certain hypotheses about SCZ in interpreting the positive symptoms. Autophagy dysfunction in the hippocampus, especially in the CA2 region, may relate to deficits of social communication and interaction in SCZ patients. mTOR regulation of autophagy is also potentially a piece of strong supporting evidence for the autophagic neuropathogenesis of SCZ. In vitro studies show that antipsychotics often induce autophagy through distinct mechanisms of drug action, but they may all share common features as autophagy inducers and antagonists of dopamine receptors.
, Hans-Jurgen Moeller, Siegfried Kasper, Carol Tamminga, Shigeto Yamawaki, Rene Kahn, Rajiv Tandon, , Afzal Javed
CNS Spectrums, Volume 26, pp 562-586; https://doi.org/10.1017/s1092852920001546

Abstract:
This is a report of a joint World Psychiatric Association/International College of Neuropsychopharmacology (WPA/CINP) workgroup concerning the risk/benefit ratio of antipsychotics in the treatment of schizophrenia. It utilized a selective but, within topic, comprehensive review of the literature, taking into consideration all the recently discussed arguments on the matter and avoiding taking sides when the results in the literature were equivocal. The workgroup’s conclusions suggested that antipsychotics are efficacious both during the acute and the maintenance phase, and that the current data do not support the existence of a supersensitivity rebound psychosis. Long-term treated patients have better overall outcome and lower mortality than those not taking antipsychotics. Longer duration of untreated psychosis and relapses are modestly related to worse outcome. Loss of brain volume is evident already at first episode and concerns loss of neuropil volume rather than cell loss. Progression of volume loss probably happens in a subgroup of patients with worse prognosis. In humans, antipsychotic treatment neither causes nor worsens volume loss, while there are some data in favor for a protective effect. Schizophrenia manifests 2 to 3 times higher mortality vs the general population, and treatment with antipsychotics includes a number of dangers, including tardive dyskinesia and metabolic syndrome; however, antipsychotic treatment is related to lower mortality, including cardiovascular mortality. In conclusion, the literature strongly supports the use of antipsychotics both during the acute and the maintenance phase without suggesting that it is wise to discontinue antipsychotics after a certain period of time. Antipsychotic treatment improves long-term outcomes and lowers overall and specific-cause mortality.
, Ricardo Insausti, Peter van Domburg, Benno Küsters, Yoshio Hashizume, Akira Hori
Published: 19 June 2020
The publisher has not yet granted permission to display this abstract.
Published: 11 June 2020
Abstract:
Maternal immune stimulation (MIS) is strongly implicated in the etiology of neuropsychiatric disorders. Magnetic resonance imaging (MRI) studies provide evidence for brain structural abnormalities in rodents following prenatal exposure to MIS. Reported volumetric changes in adult MIS offspring comprise among others larger ventricular volumes, consistent with alterations found in patients with schizophrenia. Linking rodent models of MIS with non-invasive small animal neuroimaging modalities thus represents a powerful tool for the investigation of structural endophenotypes. Traditionally manual segmentation of regions-of-interest, which is laborious and prone to low intra- and inter-rater reliability, was employed for data analysis. Recently automated analysis platforms in rodent disease models are emerging. However, none of these has been found to reliably detect ventricular volume changes in MIS nor directly compared manual and automated data analysis strategies. The present study was thus conducted to establish an automated, structural analysis method focused on lateral ventricle segmentation. It was applied to ex-vivo rat brain MRI scans. Performance was validated for phenotype induction following MIS and preventive treatment data and compared to manual segmentation. In conclusion, we present an automated analysis platform to investigate ventricular volume alterations in rodent models thereby encouraging their preclinical use in the search for new urgently needed treatments.
Na Hu, Huaiqiang Sun, Gui Fu, Wenjing Zhang, Yuan Xiao, Lianqing Zhang, Wenbin Li, Zhe Li, Guoping Huang, Youguo Tan, et al.
European Neuropsychopharmacology, Volume 35, pp 39-48; https://doi.org/10.1016/j.euroneuro.2020.03.020

The publisher has not yet granted permission to display this abstract.
René C. W. Mandl, Hugo G. Schnack, Rachel M. Brouwer,
Published: 19 February 2020
The publisher has not yet granted permission to display this abstract.
Natalya S. Kolomeets,
European Archives of Psychiatry and Clinical Neuroscience, Volume 270, pp 841-850; https://doi.org/10.1007/s00406-020-01108-z

Abstract:
There is increasing evidence to support the notion that oligodendrocyte and myelin abnormalities may contribute to the functional dysconnectivity found in the major psychiatric disorders. The putamen, which is an important hub in the cortico–striato–thalamo–cortical loop, has been implicated in a broad spectrum of psychiatric illnesses and is a central target of their treatments. Previously we reported a reduction in the numerical density of oligodendrocytes and oligodendrocyte clusters in the prefrontal and parietal cortex in schizophrenia. Oligodendrocyte clusters contain oligodendrocyte progenitors and are involved in functionally dependent myelination. We measured the numerical density (Nv) of oligodendrocytes and oligodendrocyte clusters in the putamen in schizophrenia, bipolar disorder (BPD) and major depressive disorder (MDD) as compared to healthy controls (15 cases per group). Optical disector was used to estimate the Nv of oligodendrocytes and oligodendrocyte clusters. A significant reduction in both the Nv of oligodendrocytes (− 34%; p < 0.01) and the Nv of oligodendrocyte clusters (− 41%; p < 0.05) was found in the schizophrenia group as compared to the control group. Sexual dimorphism for both measurements was found only within the control group. The Nv of oligodendrocytes was significantly lower in male schizophrenia cases as compared to the male control cases. However, the Nv of oligodendrocyte clusters was significantly lower in all male clinical cases as compared to the male control group. The data suggest that lowered density of oligodendrocytes and oligodendrocyte clusters may contribute to the altered functional connectivity in the putamen in subjects with schizophrenia.
, Aksel B. Bertelsen, Ida E. Holm, Jens R. Nyengaard, Raben Rosenberg,
Published: 9 November 2019
Brain Research, Volume 1727; https://doi.org/10.1016/j.brainres.2019.146546

The publisher has not yet granted permission to display this abstract.
Jan-Harry Cabungcal, , Rudolf Kraftsik, Michel Cuenod,
Published: 8 March 2019
Schizophrenia Research, Volume 213, pp 96-106; https://doi.org/10.1016/j.schres.2019.02.017

Abstract:
The fast-spiking parvalbumin (PV) interneurons play a critical role in neural circuit activity and dysfunction of these cells has been implicated in the cognitive deficits typically observed in schizophrenia patients. Due to the high metabolic demands of PV neurons, they are particularly susceptible to oxidative stress. Given the extant literature exploring the pathological effects of oxidative stress on PV cells in cortical regions linked to schizophrenia, we decided to investigate whether PV neurons in other select brain regions, including sub-cortical structures, may be differentially affected by redox dysregulation induced oxidative stress during neurodevelopment in mice with a genetically compromised glutathione synthesis (Gclm KO mice). Our analyses revealed a spatio-temporal sequence of PV cell deficit in Gclm KO mice, beginning with the thalamic reticular nucleus at postnatal day (P) 20 followed by a PV neuronal deficit in the amygdala at P40, then in the lateral globus pallidus and the ventral hippocampus Cornu Ammonis 3 region at P90 and finally the anterior cingulate cortex at P180. We suggest that PV neurons in different brain regions are developmentally susceptible to oxidative stress and that anomalies in the neurodevelopmental calendar of metabolic regulation can interfere with neural circuit maturation and functional connectivity contributing to the emergence of developmental psychopathology.
Chunying Jia, Mohammad A. B. S. Akhonda, QunFang Long, Vince D. Calhoun, Shari Waldstein, Tulay Adali
2019 53rd Annual Conference on Information Sciences and Systems (CISS) pp 1-5; https://doi.org/10.1109/ciss.2019.8692878

Abstract:
Fusing datasets from different brain signal modalities improves accuracy in finding biomarkers of neuropsychiatric diseases. Several approaches, such as joint independent component analysis (ICA) and independent vector analysis (IVA), are useful but fall short of exploring multiple associations between different modalities, especially for the case where one underlying component in one modality might have multiple associations with others in another modality. This relationship is possible since one component in a given modality might have associations such as subject covariation with multiple components in another modality. We show that the consecutive independence and correlation transform (C-ICT) model, which successively performs ICA and canonical correlation analysis, is able to discover such multiple associations. C-ICT has been demonstrated to be useful for the fusion of functional magnetic resonance imaging (fMRI) and electroencephalography data but has not been tested for other data combinations. In this study, we apply the C-ICT to fuse fMRI and MRI-based diffusion tensor imaging (DTI) datasets collected from healthy controls and patients with schizophrenia. In addition to independent components that show significant differences between the two groups in the fMRI and DTI datasets separately, we find multiple associations between these components from the two modalities, which provide a unique potential biomarker for schizophrenia.
Zahra Isnaini Mohamed, Shiau Foon Tee, , , Hoi Sen Yong, Abdul Kadir Abu Bakar,
Published: 1 February 2019
Asian Journal of Psychiatry, Volume 40, pp 76-81; https://doi.org/10.1016/j.ajp.2019.02.001

Abstract:
Transcription factor 4 (TCF4) gene plays an important role in nervous system development and it always associated with the risk of schizophrenia. Since miRNAs regulate targetgenes by binding to 3'UTRs of target mRNAs, the functional variants located in 3'UTR of TCF4 are highly suggested to affect the gene expressions in schizophrenia. To test the hypothesis regarding the effects of the variants located in 3'UTR of TCF4, we conducted an in silico analysis to identify the functional variants and their predicted functions. In this study, we sequenced the 3'UTR of TCF4 in 13 multiplex schizophrenia families and 14 control families. We found two functional variants carried by three unrelated patients. We determined that the C allele of rs1272363 and the TC insert of rs373174214 might suppress post- transcriptional expression. Secondly, we cloned the region that flanked these two variants into a dual luciferase reporter system and compared the luciferase activities between the pmirGLO-TCF4 (control), pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263. Both pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263 caused lower reporter gene activities, as compared to the control. However, only the C allele of rs1272363 reduced the luciferase activity significantly (p = 0.0231). Our results suggested that rs1273263 is a potential regulator of TCF4 expression, and might be associated with schizophrenia.
Published: 24 January 2019
The Neuroscientist, Volume 25, pp 528-547; https://doi.org/10.1177/1073858418824072

Abstract:
Hippocampal abnormalities have been heavily implicated in the pathophysiology of schizophrenia. The dentate gyrus of the hippocampus was shown to manifest an immature molecular profile in schizophrenia subjects, as well as in various animal models of the disorder. In this position paper, we advance a hypothesis that this immature molecular profile is accompanied by an identifiable immature morphology of the dentate gyrus granule cell layer. We adduce evidence for arrested maturation of the dentate gyrus in the human schizophrenia-affected brain, as well as multiple rodent models of the disease. Implications of this neurohistopathological signature for current theory regarding the development of schizophrenia are discussed.
Roar Fosse, Andrew Moskowitz, Ciaran Shannon, Ciaran Mulholland
Published: 19 November 2018
The publisher has not yet granted permission to display this abstract.
, Linda Chang, Hao Huang
Published: 3 April 2018
NeuroImage, Volume 185, pp 865-880; https://doi.org/10.1016/j.neuroimage.2018.04.003

Abstract:
The baby brain is constantly changing due to its active neurodevelopment, and research into the baby brain is one of the frontiers in neuroscience. To help guide neuroscientists and clinicians in their investigation of this frontier, maps of the baby brain, which contain a priori knowledge about neurodevelopment and anatomy, are essential. “Brain atlas” in this review refers to a 3D-brain image with a set of reference labels, such as a parcellation map, as the anatomical reference that guides the mapping of the brain. Recent advancements in scanners, sequences, and motion control methodologies enable the creation of various types of high-resolution baby brain atlases. What is becoming clear is that one atlas is not sufficient to characterize the existing knowledge about the anatomical variations, disease-related anatomical alterations, and the variations in time-dependent changes. In this review, the types and roles of the human baby brain MRI atlases that are currently available are described and discussed, and future directions in the field of developmental neuroscience and its clinical applications are proposed. The potential use of disease-based atlases to characterize clinically relevant information, such as clinical labels, in addition to conventional anatomical labels, is also discussed.
Arash Aghamohammadi-Sereshki, Yushan Huang, Fraser Olsen,
Published: 1 April 2018
NeuroImage, Volume 170, pp 151-163; https://doi.org/10.1016/j.neuroimage.2017.03.016

Abstract:
The amygdala (AG) is an almond-shaped heterogeneous structure located in the medial temporal lobe. The majority of previous structural Magnetic Resonance Imaging (MRI) volumetric methods for AG measurement have so far only been able to examine this region as a whole. In order to understand the role of the AG in different neuropsychiatric disorders, it is necessary to understand the functional role of its subnuclei. The main goal of the present study was to develop a reliable volumetric method to delineate major AG subnuclei groups using ultra-high resolution high field MRI. 38 healthy volunteers (15 males and 23 females, 21-60 years of age) without any history of medical or neuropsychiatric disorders were recruited for this study. Structural MRI datasets were acquired at 4.7 T Varian Inova MRI system using a fast spin echo (FSE) sequence. The AG was manually segmented into its five major anatomical subdivisions: lateral (La), basal (B), accessory basal (AB) nuclei, and cortical (Co) and centromedial (CeM) groups. Inter-(intra-) rater reliability of our novel volumetric method was assessed using intra-class correlation coefficient (ICC) and Dice's Kappa. Our results suggest that reliable measurements of the AG subnuclei can be obtained by image analysts with experience in AG anatomy. We provided a step-by-step segmentation protocol and reported absolute and relative volumes for the AG subnuclei. Our results showed that the basolateral (BLA) complex occupies seventy-eight percent of the total AG volume, while CeM and Co groups occupy twenty-two percent of the total AG volume. Finally, we observed no hemispheric effects and no gender differences in the total AG volume and the volumes of its subnuclei. Future applications of this method will help to understand the selective vulnerability of the AG subnuclei in neurological and psychiatric disorders.
Published: 1 November 2017
Biochemical Pharmacology, Volume 143, pp 10-24; https://doi.org/10.1016/j.bcp.2017.05.009

Abstract:
In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a single diagnostic entity; the needs for in depth clinical phenotyping to leverage the findings of schizophrenia genetics and advance the understanding of the disease biology; the symptom domains that are the major sources of disability in order to improve functional outcomes beyond current treatment options. In spite of the progress achieved during the last century the task ahead is still daunting and will require the efforts of scientists and clinicians through inclusive public-private partnerships and consortia to create the scientific basis for new therapeutic approaches to schizophrenia.
, Vasilios Thomaidis, Panos Prassopoulos, Aliki Fiska
Published: 31 August 2017
Surgical and Radiologic Anatomy, Volume 40, pp 145-157; https://doi.org/10.1007/s00276-017-1915-y

The publisher has not yet granted permission to display this abstract.
Mireia Forns-Nadal, , Federico Sem, Anna Mané, , Dani Guinart,
Psychiatry Research: Neuroimaging, Volume 263, pp 57-60; https://doi.org/10.1016/j.pscychresns.2017.03.007

Abstract:
Nucleus accumbens has been reported as a key structure in the neurobiology of schizophrenia. Studies analyzing structural abnormalities have shown conflicting results, possibly related to confounding factors. We investigated the nucleus accumbens volume using manual delimitation in first-episode psychosis (FEP) controlling for age, cannabis use and medication. Thirty-one FEP subjects who were naive or minimally exposed to antipsychotics and a control group were MRI scanned and clinically assessed from baseline to 6 months of follow-up. FEP showed increased relative and total accumbens volumes. Clinical correlations with negative symptoms, duration of untreated psychosis and cannabis use were not significant.
Comment
Published: 13 March 2017
Frontiers in Neuroscience, Volume 11; https://doi.org/10.3389/fnins.2017.00117

Abstract:
A commentary onMicrostructure, length, and connection of limbic tracts in normal human brain developmentby Yu, Q., Peng, Y., Mishra, V., Ouyang, A., Li, H., Zhang, H., et al. (2014). Front. Aging Neurosci. 6:228. doi: 10.3389/fnagi.2014.00228 Limbic tracts are affected in various neurological and psychiatric diseases/disorders (Bogerts et al., 1985; Modell et al., 1989; Braak and Braak, 1991; Tamminga et al., 1992; Becker et al., 2001; Amaral et al., 2008; Sheth et al., 2013; Gottlich et al., 2014; Posner et al., 2014). The onset of the abnormality is of particular interest since many psychiatric disorders are known to have genetic backgrounds that might result in a specific phenotype of the brain anatomy (endophenotype) before the onset of the symptoms (Menzies et al., 2008; Hajek et al., 2009; Fornito et al., 2013; Nery et al., 2013; Dixson et al., 2014; Scognamiglio and Houenou, 2014; Zannas et al., 2014; Chakravarty et al., 2015; Ordóñez et al., 2016). There is the potential that such endophenotypes could be detected even in very early developmental stages, therefore, quantification of the developmental status of the limbic fibers might be useful for identifying groups at high-risk for developing psychiatric disorders in the future. However, little is known about the normal developmental trajectories of these fiber tracts from a neonatal age to young adulthood, which is essential for the evaluation of a pathological deviation from normal brain development (Oishi et al., 2013). MRI scans are particularly challenging in subjects less than 4 years of age without sedation (Oishi et al., 2012), and therefore, establishing the normal developmental trajectory of this age-range will be an important asset for research communities(Oishi et al., 2011; Akazawa et al., 2015; Chang et al., 2016). Yu and his colleagues aimed to identify the normal developmental characteristics of the limbic fibers (Yu et al., 2014). They used diffusion tensor imaging (DTI) to characterize the microscopic, anatomical features of the live human brain from the neonatal period to 25 years of age, based on cross-sectional observation of 65 healthy individuals. Diffusion property, length, and anatomical connections of the three limbic tracts were evaluated: The cingulate gyrus part of the cingulum (cgc); the hippocampal part of the cingulum (cgh); and the fornix. The tracts-of-interest (TOI) approach was applied to accurately identify the white matter tracts and has been used to evaluate the microscopic status of the developing brain. Tractography was also used to measure the length of the limbic tracts, as well as to evaluate the connectivity of the anatomical structures that are related to the default mode network (DMN), which is defined by resting-state fMRI. In adult brains, the limbic fibers are known to connect the DMN-related structures. However, the role of these limbic fibers in connecting DMN structures has been unclear in early development. There were three major findings. First, the developmental curve of four DTI-derived measures were mostly logarithmic, with rapid changes until 2 years of age, followed by slow changes that went on until 25 years of age. The important contribution to science here is that these results were compared with and without free water elimination (FWE) (Pasternak et al., 2009), which was introduced to eliminate the partial volume artifact that is caused by the inclusion of cerebrospinal fluid (CSF) into each pixel, which results in falsely high diffusivity of such pixels. There was a concern about whether to apply the FEW to brains under development, since it could potentially eliminate the effect of physiological changes of the brain related to development by eliminating the intercellular water content that is prominent in early development. The authors first demonstrated that contamination of the CSF is the major source of free water that is eliminated by the FWE algorithm. Importantly, the application of the FWE did not change the pattern of the developmental curves of the limbic fibers, which means that both values, with and without FWE, are legitimate for the evaluation of brain development, as long as the method for evaluation is consistent. Second, the authors demonstrated that the length of the cgc, normalized by the anterior-to-posterior length of the brain, increased with age, but the normalized length of the cgh and the fornix were unchanged. This means that the development of the cgc is disproportionally rapid during this age-range, but the development of the cgh and the fornix is proportional. Third, the anatomical connections of DMN-related structures were similar in both neonates and young adults, which means that the functional and anatomical connectivity of the DMN is already established in the early postnatal period. This suggested the importance of the DMN in the basic brain functions that are already needed at birth. The simultaneous evaluation of the DTI-derived measures—length and connectivity of the limbic fibers from early to late development—provide an important foundation with which to assess the types and onset of abnormalities in brain development related to various neurological or psychiatric disorders. Indeed, during the two years since publication, the results of this paper were referenced to interpret DTI findings of traumatic brain injury (TBI) and major depressive disorder (MDD); the left-side dominancy in the effect of TBI was interpreted in relation to the leftward asymmetry observed in normal development (Ewing-Cobbs et al., 2016), and disrupted functional connectivity in MDD was interpreted in the context of chronological patterns in white matter maturation (Sacchet et al., 2016). Several limitations should be noted. The limited number of participants might introduce a selection bias. The limbic pathways investigated were limited; the uncinate fasciculus, stria terminalis, and the mammillothalamic fasciculus were not included. The parameters investigated from diffusion MRI were limited to those derived from the tensor model; parameters acquired through advanced models, such as diffusion spectrum imaging or high-angular resolution diffusion imaging, remain to be investigated. For the evaluation of intra-individual variation, a longitudinal design would be needed (Baltes, 1968). To overcome these general and well-recognized limitations, several longitudinal studies have been launched since the publication of this paper, including the Developing Human Connectome Project, Baby Connectome Project, Lifespan Human Connectome Project, and the Adolescent Brain Cognitive Development (ABCD) study. These projects adopted state-of-the-art scanners and scan protocols. Among them, the ABCD study is the largest study, and involves approximately 10,000 children, who will be followed for 9–10 years. These studies are expected to overcome the limitations of previous cross-sectional studies. KO contributed to all aspects of the work, including conception and writing, and is accountable for all aspects of this commentary. The author is supported by NIH grant R01HD065955 and an inHealth Pilot Project grant from the Johns Hopkins Individualized Health Initiative. 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K., Ernst, T., Anderson, L., Buchthal, S., et al. (2011). Multi-contrast human neonatal brain atlas: application to normal neonate development analysis. Neuroimage 56, 8–20. doi: 10.1016/j.neuroimage.2011.01.051 PubMed Abstract | CrossRef Full Text | Google Scholar Ordóñez, A. E., Luscher, Z. I., and Gogtay, N. (2016). Neuroimaging findings from childhood onset schizophrenia patients and their non-psychotic siblings. Schizophr. Res. 173, 124–131. doi: 10.1016/j.schres.2015.03.003 PubMed Abstract | CrossRef Full Text | Google Scholar Pasternak, O., Sochen, N., Gur, Y., Intrator, N., and Assaf, Y. (2009). Free water elimination and mapping from diffusion MRI. Magn. Reson. Med. 62, 717–730. doi: 10.1002/mrm.22055 PubMed Abstract | CrossRef Full Text | Google Scholar Posner, J., Marsh, R., Maia, T. V., Peterson, B. S., Gruber, A., and Simpson, H. B. (2014). Reduced functional connectivity within the limbic cortico-striato-thalamo-cortical loop in unmedicated adults with obsessive-compulsive disorder. Hum. Brain Mapp. 35, 2852–2860. doi: 10.1002/hbm.22371 PubMed Abstract | CrossRef Full Text | Google Scholar Sacchet, M. D., Ho, T. C., Connolly, C. G., Tymofiyeva, O., Lewinn, K. Z., Han, L. K., et al. (2016). Large-scale hypoconnectivity between resting-state functional networks in unmedicated adolescent major depressive disorder. Neuropsychopharmacology 41, 2951–2960. doi: 10.1038/npp.2016.76 PubMed Abstract | CrossRef Full Text | Google Scholar Scognamiglio, C., and Houenou, J. (2014). A meta-analysis of fMRI studies in healthy relatives of patients with schizophrenia. Aust. N. Z. J. Psychiatry 48, 907–916. doi: 10.1177/0004867414540753 PubMed Abstract | CrossRef Full Text | Google Scholar Sheth, S. A., Neal, J., Tangherlini, F., Mian, M. K., Gentil, A., Cosgrove, G. R., et al. (2013). Limbic system surgery for treatment-refractory obsessive-compulsive disorder: a prospective long-term follow-up of 64 patients. J. Neurosurg. 118, 491–497. doi: 10.3171/2012.11.JNS12389 PubMed Abstract | CrossRef Full Text | Google Scholar Tamminga, C. A., Thaker, G. K., Buchanan, R., Kirkpatrick, B., Alphs, L. D., Chase, T. N., et al. (1992). Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch. Gen. Psychiatry 49, 522–530. doi: 10.1001/archpsyc.1992.01820070016003 PubMed Abstract | CrossRef Full Text | Google Scholar Yu, Q., Peng, Y., Mishra, V., Ouyang, A., Li, H., Zhang, H., et al. (2014). Microstructure, length, and connection of limbic tracts in normal human brain development. Front. Aging Neurosci. 6:228. doi: 10.3389/fnagi.2014.00228 PubMed Abstract | CrossRef Full Text | Google Scholar Zannas, A. S., Mcquoid, D. R., Payne, M. E., Macfall, J. R., Ashley-Koch, A., Steffens, D. C., et al. (2014). Association of gene variants of the renin-angiotensin system with accelerated hippocampal volume loss and cognitive decline in old age. Am. J. Psychiatry 171, 1214–1221. doi: 10.1176/appi.ajp.2014.13111543 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: default mode network, development, diffusion tensor imaging, limbic tracts, free water elimination, neonate, resting-state fMRI, tractography Citation: Oishi K (2017) Commentary: Microstructure, length, and connection of limbic tracts in normal human brain development. Front. Neurosci. 11:117. doi: 10.3389/fnins.2017.00117 Received: 15 February 2016; Accepted: 24 February 2017; Published: 13 March 2017. Edited by: Reviewed by: Copyright © 2017 Oishi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Kenichi Oishi, [email protected]
, Rebecca Schennach, Tania Lincoln, ,
Published: 1 January 2017
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Y Zhang, V S Catts, D Sheedy, T McCrossin, J J Kril,
Published: 13 December 2016
Translational Psychiatry, Volume 6; https://doi.org/10.1038/tp.2016.238

Abstract:
Cortical grey matter volume deficits and neuro-inflammation exist in patients with schizophrenia, although it is not clear whether elevated cytokines contribute to the cortical volume reduction. We quantified cortical and regional brain volumes in fixed postmortem brains from people with schizophrenia and matched controls using stereology. Interleukin (IL)-6, IL-1β, IL-8 and SERPINA3 messenger RNAs (mRNAs) were quantified in the contralateral fresh frozen orbitofrontal cortex. We found a small, but significant reduction in cortical grey matter (1.3%; F(1,85)=4.478, P=0.037) and superior frontal gyrus (6.5%; F(1,80)=5.700, P=0.019) volumes in individuals with schizophrenia compared with controls. Significantly reduced cortical grey matter (9.2%; F(1,24)=8.272, P=0.008) and superior frontal gyrus (13.9%; F(1,20)=5.374, P=0.031) volumes were found in cases with schizophrenia and ‘high inflammation’ status relative to schizophrenia cases with ‘low inflammation’ status in the prefrontal cortex. The expression of inflammatory mRNAs in the orbitofrontal cortex was significantly correlated with those in dorsolateral prefrontal cortex (all r>0.417, all P<0.022), except for IL-8. Moreover, average daily and lifetime antipsychotic intake negatively correlated with cortical grey matter and superior frontal gyrus volumes (all r<−0.362, all P<0.05). The results suggest that the reduction in cortical grey matter volume in people with schizophrenia is exaggerated in those who have high expression of inflammatory cytokines. Further, antipsychotic medication intake does not appear to ameliorate the reduction in brain volume.
, Rebecca Schennach, Tania Lincoln, Annette Schaub, Alkomiet Hasan
Published: 2 November 2016
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Eerika Flinkkilä, , Mauri Marttunen,
Published: 17 August 2016
Psychopathology, Volume 49, pp 317-333; https://doi.org/10.1159/000448054

Abstract:
Background: The objective of this descriptive review is to summarize the current scientific evidence on the effect of prenatal exposure to maternal infection and immune response on the offspring's risk for mental disorders (schizophrenia spectrum disorders, autism spectrum disorders, attention-deficit hyperactivity disorder, anorexia nervosa, and mood disorders). Sampling and Methods: Studies were searched from PubMed and Ovid MEDLINE (R) databases with the following keywords: ‘prenatal exposure delayed effects' and ‘infection', and ‘inflammation' and ‘mental disorders'. A comprehensive manual search, including a search from the reference list of included articles, was also performed. Results: Prenatal exposure to maternal influenza appears to increase the offspring's risk for schizophrenia spectrum disorders, although studies are not fully consistent. Prenatal exposure to maternal fever and elevated cytokine levels seems to be related to the elevated risk for autism spectrum disorders in the offspring. No replicated findings of an association between prenatal infectious exposure and other mental disorders exist. Conclusions: Evidence for the effect of prenatal exposure to maternal infection on risk for mental disorders exists for several different infections, suggesting that common factors occurring in infections (e.g. elevated cytokine levels and fever), rather than the infectious agent itself, might be the underlying factor in increasing the risk for mental disorders. Additionally, it is likely that genetic liability to these disorders operates in conjunction with the exposure. Therefore, genetically sensitive study designs are needed in future studies.
, David G. Amaral, Elizabeth A. Buffalo, , Neal Cohen, , , Stephan Heckers, Richard G. M. Morris, Edvard I. Moser, et al.
Published: 11 July 2016
Hippocampus, Volume 26, pp 1238-1249; https://doi.org/10.1002/hipo.22616

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, Achim Hochlehnert, Philipp Arthur Thomann, Katharina Maria Kubera, Knut Schnell
Published: 8 July 2016
Abstract:
Schizophrenia spectrum disorders result in enormous individual suffering and financial burden on patients and on society. In Germany, there are about 1,000,000 individuals suffering from schizophrenia (SZ) or schizoaffective disorder (SAD), a combination of psychotic and affective symptoms. Given the heterogeneous nature of these syndromes, one may assume that there is a difference in treatment costs among patients with paranoid SZ and SAD. However, the current the national system of cost accounting in psychiatry and psychosomatics in Germany assesses all schizophrenia spectrum disorders within one category. The study comprised a retrospective audit of data from 118 patients diagnosed with paranoid SZ (F20.0) and 71 patients with SAD (F25). We used the mean total costs as well as partial cost, i.e., mean costs for medication products, mean personal costs and mean infrastructure costs from each patient for the statistical analysis. We tested for differences in the four variables between SZ and SAD patients using ANCOVA and confirmed the results with bootstrapping. SAD patients had a longer duration of stay than patients with SZ (p = .02). Mean total costs were significantly higher for SAD patients (p = .023). Further, we found a significant difference in mean personnel costs (p = .02) between patients with SZ and SAD. However, we found no significant differences in mean pharmaceutical costs (p = .12) but a marginal difference of mean infrastructure costs (p = .05) between SZ and SAD. We found neither a common decrease of costs over time nor a differential decrease in SZ and SAD. We found evidence for a difference of case related costs of inpatient treatments for paranoid SZ and SAD. The differences in mean total costs seem to be primarily related to the mean personnel costs in patients with paranoid SZ and SAD rather than mean pharmaceutical costs, possibly due to higher personnel effort and infrastructure.
, Julia K. Garami, , Jan Golembieski, Szabolcs Keri, , Dorota Frydecka
Reviews in the Neurosciences, Volume 27, pp 435-448; https://doi.org/10.1515/revneuro-2015-0060

Abstract:
Introduction:Schizophrenia is a severe mental disorder with multiple psychopathological domains being affected. Several lines of evidence indicate that cognitive impairment serves as the key component of schizophrenia psychopathology. Although there have been a multitude of cognitive studies in schizophrenia, there are many conflicting results. We reasoned that this could be due to individual differences among the patients (i.e. variation in the severity of positive vs. negative symptoms), different task designs, and/or the administration of different antipsychotics.Methods:We thus review existing data concentrating on these dimensions, specifically in relation to dopamine function. We focus on most commonly used cognitive domains: learning, working memory, and attention.Results:We found that the type of cognitive domain under investigation, medication state and type, and severity of positive and negative symptoms can explain the conflicting results in the literature.Conclusions:This review points to future studies investigating individual differences among schizophrenia patients in order to reveal the exact relationship between cognitive function, clinical features, and antipsychotic treatment.
, Jingshan Chen, , Ming Ren, Peixiong Yuan, Qingjun Tian, Audrey Bebensee, Grace Y. Zhang, Jing Du, Paul Glineburg, et al.
Published: 9 February 2016
Molecular Psychiatry, Volume 21, pp 1517-1526; https://doi.org/10.1038/mp.2015.219

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Xiaofan Zhang, Qi Li, Naikei Wong, Min Zhang, Wei Wang, Bitao Bu,
Published: 1 July 2015
Brain Research Bulletin, Volume 116, pp 16-24; https://doi.org/10.1016/j.brainresbull.2015.05.003

Abstract:
Experimental animals provide valuable opportunities to establish aetiological mechanisms and test new treatments for neurodevelopmental psychiatric conditions. However, it is increasingly appreciated that inter-strain differences cannot be neglected in the experimental design. In addition, the importance of including females in preclinical - but also clinical - research is now recognised. Here, we compared behaviour and prefrontal protein differences in male and female C57BL/6N and 129X1/SvJ mice as both are commonly used experimental rodents. Relative to 129X1/SvJ mice, both sexes of C57BL/6N mice had weaker sensorimotor gating, measured in the prepulse inhibition (PPI) of startle paradigm, and were more sensitive to amphetamine challenge in the open field. The pattern of protein expression in the prefrontal cortex of C57BL6N mice was also clearly distinct from 129X1/SvJ mice. Proteins differentially expressed were those associated with oxidative metabolism, receptor protein signalling, cell communication and signal transduction and energy pathways. We suggest that the C57BL/6N mouse may usefully proxy features of the neurodevelopmental disorders and could have application in pre-translational screening of new therapeutic approaches. The 129X1/SvJ strain in contrast, might be better suited to experimental studies of causal risk factors expected to lower PPI and increase amphetamine sensitivity.
Published: 7 May 2015
BMC Psychiatry, Volume 15, pp 1-15; https://doi.org/10.1186/s12888-015-0482-1

Abstract:
With the dramatic rise in mental disorders and mental illnesses, psychiatry has become one of the fastest growing clinical medical disciplines. This has led to a rise in the number of scientific research papers being published in this field. We selected research papers in ten psychiatric journals that were published during 1983 to 2012. These ten journals were those with the top Impact Factor (IF) as indicated by the Science Citation Index Expanded (SCI-Expanded). We utilized information visualization software (CiteSpace) to conduct co-citation and Hierarchal clustering analysis to map knowledge domains to determine the evolution and the foci of research in this field. In the evolution of the field of psychiatry, there were four stages identified. The result of hierarchal clustering analysis revealed that the research foci in the psychiatric field were primarily studies of child and adolescent psychiatry, diagnostic and classification criteria, brain imaging and molecular genetics. The results provide information about the evolution and the foci of the research in the field of psychiatry. This information can help researchers determine the direction of the research in the field of psychiatry; Moreover, this research provides reasonable suggestions to guide research in psychiatry field and provide scientific evidence to aid in the effective prevention and treatment of mental disorders.
, , T G Schulze, A Hasan, M M Brzózka, B Malchow, W G Honer,
Published: 31 March 2015
Molecular Psychiatry, Volume 20, pp 671-676; https://doi.org/10.1038/mp.2015.35

Abstract:
One hundred years after its conceptual definition as 'Dementia Praecox' by Emil Kraepelin, schizophrenia is still a serious psychiatric illness that affects young adults and leads to disability in at least half of patients. The key treatment issue is partial or non-response, especially of negative symptoms. The illness is also associated with different degrees of cognitive dysfunction, particularly in verbal and working memory; the resulting functional impairment may lead to unemployment and an inability to maintain stable relationships. Patients' cognitive dysfunction led Kraepelin to the assumption that schizophrenia is a form of juvenile dementia caused by a degenerative process of the human brain. Postmortem studies and a plethora of imaging studies do not support the notion of a degenerative process, but such a process is supported by the recently published, largest genome-wide association study on schizophrenia. More than a 100 hits were described, converging on pathways that have a significant role in dopamine metabolism in immune modulation, calcium signalling and synaptic plasticity. This review suggests that research should focus on animal models based on risk genes like transcription factor 4 and study the effects of exposure to environmental stressors relevant for schizophrenia. The use of relevant end points like pre-pulse inhibition or cognitive dysfunction will allow us to gain an understanding of the molecular pathways in schizophrenia and consequently result in improved treatment options, especially for the disabling aspects of this illness.
, Barbara Jean Knowlton, Jessica Rachel Cohen, , , Vindia Gisela Fernandez, Robert Franklin Asarnow
Published: 22 December 2014
Schizophrenia Research, Volume 161, pp 345-350; https://doi.org/10.1016/j.schres.2014.12.006

Abstract:
Patients with childhood onset schizophrenia (COS) display widespread gray matter (GM) structural brain abnormalities. Healthy siblings of COS patients share some of these structural abnormalities, suggesting that GM abnormalities are endophenotypes for schizophrenia. Another possible endophenotype for schizophrenia that has been relatively unexplored is corticostriatal dysfunction. The corticostriatal system plays an important role in skill learning. Our previous studies have demonstrated corticostriatal dysfunction in COS siblings with a profound skill learning deficit and abnormal pattern of brain activation during skill learning. This study investigated whether structural abnormalities measured using volumetric brain morphometry (VBM) were present in siblings of COS patients and whether these were related to deficits in cognitive skill learning. Results revealed smaller GM volume in COS siblings relative to controls in a number of regions, including occipital, parietal, and subcortical regions including the striatum, and greater GM volume relative to controls in several subcortical regions. Volume in the right superior frontal gyrus and cerebellum were related to performance differences between groups on the weather prediction task, a measure of cognitive skill learning. Our results support the idea that corticostriatal and cerebellar impairment in unaffected siblings of COS patients are behaviorally relevant and may reflect genetic risk for schizophrenia.
Thomas J. Whitford, Sun Woo Lee, Jungsu S. Oh, , Peter Savadjiev, Jorge L. Alvarado, Carl-Fredrik Westin, Margaret Niznikiewicz, Paul G. Nestor, Robert W. McCarley, et al.
Published: 17 June 2014
NeuroImage: Clinical, Volume 5, pp 93-99; https://doi.org/10.1016/j.nicl.2014.06.003

Abstract:
The cingulum bundle (CB) connects gray matter structures of the limbic system and as such has been implicated in the etiology of schizophrenia. There is growing evidence to suggest that the CB is actually comprised of a conglomeration of discrete sub-connections. The present study aimed to use Diffusion Tensor tractography to subdivide the CB into its constituent sub-connections, and to investigate the structural integrity of these sub-connections in patients with schizophrenia and matched healthy controls. Diffusion Tensor Imaging scans were acquired from 24 patients diagnosed with chronic schizophrenia and 26 matched healthy controls. Deterministic tractography was used in conjunction with FreeSurfer-based regions-of-interest to subdivide the CB into 5 sub-connections (I1 to I5). The patients with schizophrenia exhibited subnormal levels of FA in two cingulum sub-connections, specifically the fibers connecting the rostral and caudal anterior cingulate gyrus (I1) and the fibers connecting the isthmus of the cingulate with the parahippocampal cortex (I4). Furthermore, while FA in the I1 sub-connection was correlated with the severity of patients' positive symptoms (specifically hallucinations and delusions), FA in the I4 sub-connection was correlated with the severity of patients' negative symptoms (specifically affective flattening and anhedonia/asociality). These results support the notion that the CB is a conglomeration of structurally interconnected yet functionally distinct sub-connections, of which only a subset are abnormal in patients with schizophrenia. Furthermore, while acknowledging the fact that the present study only investigated the CB, these results suggest that the positive and negative symptoms of schizophrenia may have distinct neurobiological underpinnings.
, , , Hans Van Bokhoven, Karin Kamphuis-Van Ulzen, Akira Hori
Published: 19 April 2014
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Sara J. M. Arnold, , Tejas A. Gopal, Anil P. Reddy, Haekyung Jeon-Slaughter, Carolyn B. Sacco, Alan N. Francis, Neeraj Tandon, Anup S. Bidesi, Bradley Witte, et al.
Schizophrenia Bulletin, Volume 41, pp 233-249; https://doi.org/10.1093/schbul/sbu009

Abstract:
This study examined hippocampal volume as a putative biomarker for psychotic illness in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) psychosis sample, contrasting manual tracing and semiautomated (FreeSurfer) region-of-interest outcomes. The study sample ( n = 596) included probands with schizophrenia (SZ, n = 71), schizoaffective disorder (SAD, n = 70), and psychotic bipolar I disorder (BDP, n = 86); their first-degree relatives (SZ-Rel, n = 74; SAD-Rel, n = 62; BDP-Rel, n = 88); and healthy controls (HC, n = 145). Hippocampal volumes were derived from 3Tesla T1-weighted MPRAGE images using manual tracing/3DSlicer3.6.3 and semiautomated parcellation/FreeSurfer5.1,64bit. Volumetric outcomes from both methodologies were contrasted in HC and probands and relatives across the 3 diagnoses, using mixed-effect regression models (SAS9.3 Proc MIXED); Pearson correlations between manual tracing and FreeSurfer outcomes were computed. SZ ( P = .0007–.02) and SAD ( P = .003–.14) had lower hippocampal volumes compared with HC, whereas BDP showed normal volumes bilaterally ( P = .18–.55). All relative groups had hippocampal volumes not different from controls ( P = .12–.97) and higher than those observed in probands ( P = .003–.09), except for FreeSurfer measures in bipolar probands vs relatives ( P = .64–.99). Outcomes from manual tracing and FreeSurfer showed direct, moderate to strong, correlations ( r = .51–.73, P< .05). These findings from a large psychosis sample support decreased hippocampal volume as a putative biomarker for schizophrenia and schizoaffective disorder, but not for psychotic bipolar I disorder, and may reflect a cumulative effect of divergent primary disease processes and/or lifetime medication use. Manual tracing and semiautomated parcellation regional volumetric approaches may provide useful outcomes for defining measurable biomarkers underlying severe mental illness.
John Read, Roar Fosse, Andrew Moskowitz, Bruce Perry
Published: 1 February 2014
Neuropsychiatry, Volume 4, pp 65-79; https://doi.org/10.2217/npy.13.89

Abstract:
Evidence that childhood adversities are risk factors for psychosis has accumulated rapidly. Research into the mechanisms underlying these relationships has focused, productively, on psychological processes, including cognition, attachment and dissociation. In 2001, the traumagenic neurodevelopmental model sought to integrate biological and psychological research by highlighting the similarities between the structural and functional abnormalities in the brains of abused children and adults diagnosed with 'schizophrenia'. No review of relevant literature has subsequently been published. The aim of this paper, therefore, is to summarize the literature on biological mechanisms underlying the relationship between childhood trauma and psychosis published since 2001. A comprehensive search for relevant papers was undertaken via Medline, PubMed and psycINFO. In total, 125 papers were identified, with a range of methodologies, and provided both indirect support for and direct confirmation of the traumagenic neurodevelopmental model. Integrating our growing understanding of the biological sequelae of early adversity with our knowledge of the psychological processes linking early adversity to psychosis is valuable both theoretically and clinically
, Rakhee Krishna, , Abeer M. Eissa, Doaa H. Hewedi
Published: 21 January 2014
Cognitive Neuropsychiatry, Volume 19, pp 381-398; https://doi.org/10.1080/13546805.2013.877385

Abstract:
Psychosis and hallucinations occur in 20-30% of patients with Parkinson's disease (PD). In the current study, we investigate cognitive functions in relation to the occurrence of psychosis in PD patients. We tested three groups of subjects - PD with psychosis, PD without psychosis and healthy controls - on working memory, learning and transitive inference tasks, which are known to assess prefrontal, basal ganglia and hippocampal functions. In the working memory task, results show that patients with and without psychosis were more impaired than the healthy control group. In the transitive inference task, we did not find any difference among the groups in the learning phase performance. Importantly, PD patients with psychosis were more impaired than both PD patients without psychosis and controls at transitive inference. We also found that the severity of psychotic symptoms in PD patients [as measured by the Unified Parkinson Disease Rating Scale Thought Disorder (UPDRS TD) item] is directly associated with the severity of cognitive impairment [as measured by the mini-mental status exam (MMSE)], sleep disturbance [as measured by the Scales for Outcome in Parkinson Disease (SCOPA) sleep scale] and transitive inference (although the latter did not reach significance). Although hypothetical, our data may suggest that the hippocampus is a neural substrate underlying the occurrence of psychosis, sleep disturbance and cognitive impairment in PD patients.
J.R. Glausier,
Published: 22 October 2013
Neuroscience, Volume 251, pp 90-107; https://doi.org/10.1016/j.neuroscience.2012.04.044

Abstract:
Schizophrenia is a neurodevelopmental disorder whose clinical features include impairments in perception, cognition and motivation. These impairments reflect alterations in neuronal circuitry within and across multiple brain regions that are due, at least in part, to deficits in dendritic spines, the site of most excitatory synaptic connections. Dendritic spine alterations have been identified in multiple brain regions in schizophrenia, but are best characterized in layer 3 of the neocortex, where pyramidal cell spine density is lower. These spine deficits appear to arise during development, and thus are likely the result of disturbances in the molecular mechanisms that underlie spine formation, pruning, and/or maintenance. Each of these mechanisms may provide insight into novel therapeutic targets for preventing or repairing the alterations in neural circuitry that mediate the debilitating symptoms of schizophrenia.
Marc T. Pisansky, Robert J. Wickham, Jianjun Su, Stephanie Fretham, Li-Lian Yuan, Mu Sun, Jonathan C. Gewirtz,
Published: 3 June 2013
Hippocampus, Volume 23, pp 952-962; https://doi.org/10.1002/hipo.22151

Abstract:
Iron deficiency (ID) during early life causes long‐lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early‐life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus‐specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT‐1). Our second model used a classic rat dietary‐based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT‐1 knockout model displayed reduced long‐term potentiation (LTP) and elevated paired‐pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 43, pp 96-107; https://doi.org/10.1016/j.pnpbp.2012.11.014

Abstract:
Schizotypal personality disorder is the prototypical schizophrenia-spectrum condition, sharing similar phenomenological, cognitive, genetic, physiological, neurochemical, neuroanatomical and neurofunctional abnormalities with schizophrenia. Investigations into SPD circumvent many confounds inherent to schizophrenia such as medication and institutionalization. Hence, SPD offers a unique vantage point from which to study schizophrenia-spectrum conditions. We systematically reviewed the neuroimaging literature in SPD to establish: (1) whether there are concordant findings in SPD and schizophrenia, possibly reflective of core pathology between the two conditions and (2) whether there are discordant findings in SPD and schizophrenia, possibly reflecting protective factors in the former. The findings are synthesized across structural and functional neuroimaging domains. A total of 54 studies were identified. Medial temporal lobe structures seem to be compromised in both SPD and schizophrenia. In schizophrenia prefrontal structures are further compromised, whereas in SPD these seem to be larger-than-normal, possibly reflecting a compensatory mechanism. Additional pathology is discussed, including evidence of aberrant subcortical dopaminergic functioning. SPD is a schizophrenia-spectrum condition that shares pathology with schizophrenia, but is distinct in showing unique neural findings. Future studies are needed to confirm and localize regions of common and disparate pathology between SPD and schizophrenia.
Published: 1 February 2013
Nagoya journal of medical science, Volume 75, pp 11-28

Abstract:
Studies that seek to determine the etiology of schizophrenia through pathological images and morphological abnormalities of the brain have been conducted since the era of E. Kraepelin, and pioneers in neuropathology such as A. Alzheimer have also eagerly pursued such studies. However, there have been no disease-specific findings, and there was a brief era in which it was said that "schizophrenia is the graveyard of neuropathologists." However, since the 1980s, neuroimaging studies with CT and MRI etc., have been used in many reports of cases of schizophrenia with abnormal brain morphology, thus generating renewed interest in developments within brain tissue and leading to new neuropathological studies. There are now many reports in which, in addition to morphological observations, cell distribution and the like are image-processed and statistically processed through computers. Due to methodological problems in making progress in the field of cerebral pathology, we have not yet been able to observe disease-specific findings, although there are several findings with high certainty. However, the neurodevelopmental hypothesis has been supported as being able to reasonably explain the accumulated findings of previous studies. At the same time, results of recent molecular-biological studies have revealed the risk genes for this disease, and because many of those genes are associated with functions related to nerve differentiation, development, and plasticity, there is growing interest in their correlations with cerebral pathology. We are now on the verge of uncovering the etiology of this disease by integrating cerebral neuroimaging, molecular genetics, and cerebral neuropathology. In that sense, neuropathological studies of this disease from new viewpoints have become essential.
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