Structural and functional brain imaging in schizophrenia.

We present an evaluation of the contribution of structural and functional brain imaging to our understanding of schizophrenia. Methodological influences on the validity of the data generated by these new technologies include problems with measurement and clinical and anatomic heterogeneity. These considerations greatly affect the interpretation of the data generated by these technologies. Work in these fields to date, however, has produced strong evidence which suggests that schizophrenia is a disease which involves abnormalities in the structure and function of many brain areas. Structural brain imaging studies of schizophrenia using computed tomography (CT) and magnetic resonance imaging (MRI) are reviewed and their contribution to current theories of the pathogenesis of schizophrenia are discussed. Positron emission tomography (PET) studies of brain metabolic activity and dopamine receptor binding in schizophrenia are summarized and the critical questions raised by these studies are outlined. Future studies in these fields have the potential to yield critical insights into the pathophysiology of schizophrenia; new directions for studies of schizophrenia using these technologies are identified.     

Striatal volume differences between non-human and human primates

Convection-enhanced delivery (CED) has recently entered the clinic and represents a promising new delivery option for targeted gene therapy in Parkinson's disease (PD). The prime stereotactic target for the majority of recent gene therapy clinical trials has been the human putamen. The stereotactic delivery of therapeutic agents into putamen (or other subcortical structures) via CED remains problematic due to the difficulty in knowing what volume of therapeutic agent to deliver. Preclinical studies in non-human primates (NHP) offer a way to model treatment strategies prior to clinical trials. Understanding more accurately the volumetric differences in striatum, especially putamen, between NHP and humans is essential in predicting convective volume parameters in human clinical trials. In this study, magnetic resonance images (MRI) were obtained for volumetric measurements of striatum (putamen and caudate nucleus) and whole brain from 11 PD patients, 13 aged healthy human subjects, as well as 8 parkinsonian and 30 normal NHP. The human brain is 13-18 times larger than the monkey brain. However, this ratio is significantly smaller for striatum (5.7-6.5), caudate nucleus (4.6-6.6) and putamen (4.4-6.6). Size and species of the monkeys used for this comparative study are responsible for differences in ratios for each structure between monkeys and humans. This volumetric ratio may have important implications in the design of clinical therapies for PD and Huntington's disease and should be considered when local therapies such as gene transfer, local protein administration or cellular replacement are translated based on NHP research.     

Evolving Models and Tools for Microglial Studies in the Central Nervous System

Microglia play multiple roles in such processes as brain development, homeostasis, and pathology. Due to their diverse mechanisms of functions, the complex sub-classifications, and the large differences between different species, especially compared with humans, very different or even opposite conclusions can be drawn from studies with different research models. The choice of appropriate research models and the associated tools are thus key ingredients of studies on microglia. Mice are the most commonly used animal models. In this review, we summarize in vitro and in vivo models of mouse and human-derived microglial research models, including microglial cell lines, primary microglia, induced microglia-like cells, transgenic mice, human-mouse chimeric models, and microglial replacement models. We also summarize recent developments in novel single-cell and in vivo imaging technologies. We hope our review can serve as an efficient reference for the future study of microglia.     

Brain imaging technologies: how, what, when and why?

OBJECTIVE: Innovations in physics and computing technology over the past two decades have provided a powerful means of exploring the overall structure and function of the brain using a range of computerised brain imaging technologies (BITs). These technologies offer the means to elucidate the patterns of pathophysiology underlying mental illness. The aim of this paper is to explore the current status and some of the future directions in the application of BITs to psychiatry. METHOD: Brain imaging technologies provide unambiguous measures of brain structure (computerised tomography and magnetic resonance imaging [MRI]) and also index complementary measures of when (electroencephalography, event related potentials, magnetoencephalography) and where (functional MRI, single photon emission computed tomography, positron emission tomography) aspects of brain activity occur. RESULTS: The structural technologies are primarily used to exclude a biological cause in cases of a suspected psychiatric disorder. The functional technologies show considerable potential to delineate subgroups of patients (that may have different treatment outcomes), and evaluate objectively the effects of treatment on the brain as a system. What is seldom emphasised in the literature are the numerous inconsistencies, the lack of specificity of findings and the simplistic interpretation of much of the data. CONCLUSION: Brain imaging technologies show considerable utility, but we are barely scratching the surface of this potential. Simplistic over-interpretation of results can be minimised by: replication of BIT findings, judicious combination of complementary methodologies, use of appropriate activation tasks, analysis with respect to large normative databases, control for performance, examining the data'beyond averaging', delineating clinical subtypes, exploring the severity of symptoms, specificity of findings and effects of treatment in the same patients. The technological innovation of BITs still far outstrips the sophistication of their use; it is essential that the meaning and mechanisms underlying BIT measures are always evaluated with respect to prevailing models of brain function across disciplines.     

Hippocampal CA1 cell loss in a non-human primate model of transient global ischemia: a pilot study

We exposed adult Rhesus (Macaca mulatta) to a transient global ischemia, which was induced by clipping the innominate and subclavian arteries that originated from the aortic arch. NHP1 received 20-min, while NHP2 and NHP3, were exposed to a 15-min transient global ischemia and were euthanized at day 1 (NHP1), day 5 (NHP2) or day 30 (NHP3) after ischemia, respectively. NHP1 displayed severe paralysis and rigidity, and intermittent convulsions over the next 24 h. Although histological examination of the brain revealed no detectable gross brain damage (i.e., swelling) and only minimal cell loss in the hippocampus, the acute survival time after surgery likely prevented the cerebral ischemia to fully develop and to be morphologically manifested. Nonetheless, the 20-min ischemia might have been too severe and caused a systemic multiple organ collapse that produced the abnormal behavioral symptoms. On the other hand, NHP2 and NHP3 which received 15-min ischemia only exhibited minor hindlimb paralysis. Indeed, by 48 h after ischemia, both animals appeared fully recovered with only fine motor deficits. Immunohistochemical examination revealed that NHP2 and 3, but not NHP1, had a marked neuronal cell loss in the hippocampal region, specifically the cornu Ammonis (CA1) region. The cell loss in these two ischemic NHP hippocampi was further confirmed by direct comparison with a normal Rhesus brain. These findings replicate the brain pathology seen in Japanese macaques exposed to the same ischemia model [T. Tsukada, M. Watanabe, T. Yamashima, Implications of CAD and DNase II in ischemic neuronal necrosis specific for the primate hippocampus, J. Neurochem. 79 (2001) 1196–1206; T. Yamashima, Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates, Prog. Neurobiol. 62 (2000) 273–295; T. Yamashima, Y. Kohda, K. Tsuchiya, T. Ueno, J. Yamashita, T. Yoshioka, E. Kominami, Inhibition of ischemic hippocampal neuronal death in primates with cathepsin B inhibitor CA-074: a novel strategy for neuroprotection based on calpain-cathepsin hypothesis, Eur. J. Neurosci. 10 (1998) 1723–1733; T. Yamashima, T.C. Saido, M. Takita, A. Miyazawa, J. Yamano, A. Miyakawa, H. Nishijyo, J. Yamashita, S. Kawashima, T. Ono, T. Yoshioka, Transient brain ischemia provokes Ca2+, PIP2 and calpain responses prior to delayed neuronal death in monkeys, Eur. J. Neurosci. 8 (1996) 1932–1944; T. Yamashima, A.B. Tonchey, T. Tsukada, T.C. Saido, S. Imajoh-Ohmi, T. Momoi, E. Kominami, Sustained calpain activation associated with lysosomal rupture executes necrosis of the postischemic CA1 neurons in primates, Hippocampus 13 (2003) 791–800]. The present minimally invasive transient global ischemia model using Rhesus shows many histopathological symptoms seen in human patients who experienced global ischemia, and should allow translational validation of experimental therapeutics for ischemic injury. Additional studies are warranted to reveal behavioral deficits associated with this ischemia model.     

Acetylcholinesterase inhibitors may improve myelin integrity.

Recent clinical trials have revealed that cholinergic treatments are efficacious in a wide spectrum of neuropsychiatric disorders that span the entire human lifespan and include disorders without cholinergic deficits. Furthermore, some clinical and epidemiological data suggest that cholinergic treatments have disease modifying/preventive effects. It is proposed that these observations can be usefully understood in a myelin-centered model of the human brain. The model proposes that the human brain's extensive myelination is the central evolutionary change that defines our uniqueness as a species and our unique vulnerability to highly prevalent neuropsychiatric disorders. Within the framework of this model the clinical, biochemical, and epidemiologic data can be reinterpreted to suggest that nonsynaptic effects of cholinergic treatments on the process of myelination and myelin repair contributes to their mechanism of action and especially to their disease modifying/preventive effects. The ability to test the model in human populations with safe and noninvasive imaging technologies makes it possible to undertake novel clinical trial efforts directed at primary prevention of some of the most prevalent and devastating of human disorders.     

Magnetic Resonance in Schizophrenia

In vivo magnetic resonance imaging (MRI) of schizophrenic patients permits the direct and noninvasive study of brain biochmeistry, structure, and function. During the last decade, a number of morphological abnormalities have been found in schizophrenic brains on the basis of qualitative and quantitative assessment of MRIs. Changes in ventricular volume, cortical volume, temporal lobe structures, and subcortical regions have been reported. The search for a precise and specific location underlying the pathophysiology of schizophrenia has led to the interpretation of imaging results in the context of interrelated systems of brain function, rather than isolated focal brain abnormalities. Furthermore, an important goal of imaging studies is to describe unusual features of schizophrenic brains that represent abnormalities central to the development of the disorder, including abnormalities that may represent vulnerabilities or risk factors, as well as those that are directly related to psychopathology. Identifying brain pathology that distinguishes schizophrenics' brains has proven difficult because it involves detecting rather subtle changes against a background of extensive normal variation. Application of powerful new magnetic resonance techniques continues to increase our understanding of these subtle changes. The importance of magnetic resonance spectroscopy is derived from the information it provides regarding the chemical content of the tissue being studied. Functional MRI provides a method for the assessment of functional architecture by measuring changes in oxidation and regional blood flow in discrete regions of the brain in response to challenge paradigms. These technologies promise to facilitate both the detection of cortical anomalies as well as provide the methods necessary for the systematic exploration of cortical structure and function needed to examine brain dysfunction from a network perspective.     

Neurostimulation and functional brain imaging

Abstract

Recent advancements in functional neuroimaging have furthered our understanding of the normal and pathological brain. These non-invasive imaging modalities have allowed us to study the human brain in vivo. Concurrently, the revival of neurostimulation in the treatment of pain, movement disorders, and epilepsy has allowed the synergistic combination of these two technologies. Several studies focusing on the use of functional imaging in patients with implanted neurostimulation devices are reviewed. The anticipated roles of these two disciplines are discussed. [Neurol Res 2000; 22: 318–325]     

Multimodal Magnetic Resonance Imaging for Brain Disorders: Advances and Perspectives

Modern brain imaging technologies play essential roles in our understanding of brain information processing and the mechanisms of brain disorders. Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI) can image the anatomy and structure of the brain. In addition, functional MRI (fMRI) can identify active regions, patterns of functional connectivities and functional networks during either tasks that are specifically related to various aspects of brain function or during the resting state. The merging of such structural and functional information obtained from brain imaging may be able to enhance our understanding of how the brain works and how its diseases can occur. In this paper, we will review advances in both methodologies and clinical applications of multimodal MRI technologies, including MRI, DTI, and fMRI. We will also give our perspectives for the future in these fields. The ultimate goal of our study is to find early biomarkers based on multimodal neuroimages and genome datasets for brain disorders. More importantly, future studies should focus on detecting exactly where and how these brain disorders affect the human brain. It would also be also very interesting to identify the genetic basis of the anatomical and functional abnormalities in the brains of people who have neurological and psychiatric disorders. We believe that we can use brain images to obtain effective biomarkers for various brain disorders with the aid of developing computational methods and models.     

Subthalamic Nucleus Deep Brain Stimulation Induces Motor Network BOLD Activation: Use of a High Precision MRI Guided Stereotactic System for Nonhuman Primates

BackgroundFunctional magnetic resonance imaging (fMRI) is a powerful method for identifying in vivo network activation evoked by deep brain stimulation (DBS).ObjectiveIdentify the global neural circuitry effect of subthalamic nucleus (STN) DBS in nonhuman primates (NHP).MethodAn in-house developed MR image-guided stereotactic targeting system delivered a mini-DBS stimulating electrode, and blood oxygenation level-dependent (BOLD) activation during STN DBS in healthy NHP was measured by combining fMRI with a normalized functional activation map and general linear modeling.ResultsSTN DBS significantly increased BOLD activation in the sensorimotor cortex, supplementary motor area, caudate nucleus, pedunculopontine nucleus, cingulate, insular cortex, and cerebellum (FDR < 0.001).ConclusionOur results demonstrate that STN DBS evokes neural network grouping within the motor network and the basal ganglia. Taken together, these data highlight the importance and specificity of neural circuitry activation patterns and functional connectivity.     

Novel imaging tools for investigating the role of immune signalling in the brain

The importance of neuro-immune interactions in both physiological and pathophysiological states cannot be overstated. As our appreciation for the neuroimmune nature of the brain and spinal cord grows, so does our need to extend the spatial and temporal resolution of our molecular analysis techniques. Current imaging technologies applied to investigate the actions of the neuroimmune system in both health and disease states have been adapted from the fields of immunology and neuroscience. While these classical techniques have provided immense insight into the function of the CNS, they are however, inherently limited. Thus, the development of innovative methods which overcome these limitations are crucial for imaging and quantifying acute and chronic neuroimmune responses. Therefore, this review aims to convey emerging novel and complementary imaging technologies in a form accessible to medical scientists engaging in neuroimmune research.     

Neurostimulation and functional brain imaging

Recent advancements in functional neuroimaging have furthered our understanding of the normal and pathological brain. These non-invasive imaging modalities have allowed us to study the human brain in vivo. Concurrently, the revival of neurostimulation in the treatment of pain, movement disorders, and epilepsy has allowed the synergistic combination of these two technologies. Several studies focusing on the use of functional imaging in patients with implanted neurostimulation devices are reviewed. The anticipated roles of these two disciplines are discussed.     

How useful is magnetic resonance imaging in predicting severity and outcome in traumatic brain injury?

Major advances have been made in the ever-expanding field of magnetic resonance imaging and related technologies, such as magnetic resonance spectroscopy, haemodynamic and functional imaging. Although these magnetic resonance modalities are of great research interest, it is still questionable as to how useful these investigations are in the clinical setting. All of these modalities strive to define a few variables that might dominate the heterogeneous but common aetiopathology of traumatic brain injury. Recent studies have found that the use of various magnetic resonance imaging techniques at early and delayed time points can provide useful information with regard to the severity and clinical outcome of patients following traumatic brain injury. These new observations offer opportunities for improved clinical management in such patients.     

Focal and global brain measurements in siblings of patients with schizophrenia

Background: It remains unclear whether structural brain abnormalities in schizophrenia are caused by genetic and/or disease-related factors. Structural brain abnormalities have been found in nonpsychotic first-degree relatives of patients with schizophrenia, but results are inconclusive. This large magnetic resonance imaging study examined brain structures in patients with schizophrenia, their nonpsychotic siblings, and healthy control subjects using global and focal brain measurements. Methods: From 155 patients with schizophrenia, their 186 nonpsychotic siblings, and 122 healthy controls (including 25 sibling pairs), whole-brain scans were obtained. Segmentations of total brain, gray matter (GM), and white matter of the cerebrum, lateral and third ventricle, and cerebellum volumes were obtained. For each subject, measures of cortical thickness and GM density maps were estimated. Group differences in volumes, cortical thickness, and GM density were analyzed using Structural Equation Modeling, hence controlling for familial dependency of the data. Results: Patients with schizophrenia, but not their nonpsychotic siblings, showed volumetric differences, cortical thinning, and reduced GM density as compared with control subjects. Conclusions: This study did not reveal structural brain abnormalities in nonpsychotic siblings of patients with schizophrenia compared with healthy control subjects using multiple imaging methods. Therefore, the structural brain abnormalities observed in patients with schizophrenia are for the largest part explained by disease-related factors.     

Age-related predictors of institutionalization: results of the German study on ageing, cognition and dementia in primary care patients (AgeCoDe)

Background

In the last decades, many community-based studies have addressed predictors of nursing home placement (NHP) among the elderly. So far, predictors have not been analyzed separately for different age groups.

Methods

For a German GP-sample of 3,208 subjects aged 75?years and older, socio-demographic, clinical, and psychometric parameters were requested every 1.5?years over three waves. Logistic regression models determined predictors of NHP for total sample and for two different age groups. A CART analysis identified factors discriminating best between institutionalized and non-institutionalized individuals.

Results

Of the overall sample, 4.7% of the sample (n?=?150) was institutionalized during the study period. Baseline characteristics associated with a higher risk of NHP for the total sample were age, living without spouse, cognitive and functional impairment and depression. In the CART analysis, age was the major discriminator at the first level (at age 81). In subgroup regression analyses, for the younger elderly (age 75?C81) being single as well as cognitive and functional impairment increased the risk of NHP; in the advanced elderly (age 82+) being widowed and subjective memory impairment were significant predictors for NHP, and cognitive and functional impairment became non-significant as predictors of NHP.

Conclusions

Predictors of NHP may differ in old age groups. The fact that many predictors show inconsistent results as predictors of NHP in the international literature may be attributed to the lack of differentiation in age groups.     

Three‐dimensional distribution of tyrosine hydroxylase,vasopressin and oxytocin neurones in the transparent postnatal mouse brain

Over the years, advances in immunohistochemistry techniques have been a critical step in detecting and mapping neuromodulatory substances in the central nervous system. The better quality and specificity of primary antibodies, new staining procedures and the spectacular development of imaging technologies have allowed such progress. Very recently, new methods permitting tissue transparency have been successfully used on brain tissues. In the present study, we combined whole‐mount immunostaining for tyrosine hydroxylase (TH), oxytocin (OXT) and arginine vasopressin (AVP), with the iDISCO+ clearing method, light‐sheet microscopy and semi‐automated counting of three‐dimensionally‐labelled neurones to obtain a (3D) distribution of these neuronal populations in a 5‐day postnatal (P5) mouse brain. Segmentation procedure and 3D reconstruction allowed us, with high resolution, to map TH staining of the various catecholaminergic cell groups and their ascending and descending fibre pathways. We show that TH pathways are present in the whole P5 mouse brain, similar to that observed in the adult rat brain. We also provide new information on the postnatal distribution of OXT and AVP immunoreactive cells in the mouse hypothalamus, and show that, compared to AVP neurones, OXT neurones in the supraoptic (SON) and paraventricular (PVN) nuclei are not yet mature in the early postnatal period. 3D semi‐automatic quantitative analysis of the PVN reveals that OXT cell bodies are more numerous than AVP neurones, although their immunoreactive soma have a volume half smaller. More AVP nerve fibres compared to OXT were observed in the PVN and the retrochiasmatic area. In conclusion, the results of the present study demonstrate the utility and the potency of imaging large brain tissues with clearing procedures coupled to novel 3D imaging technologies to study, localise and quantify neurotransmitter substances involved in brain and neuroendocrine functions.     

Rodent models of ischemic stroke lack translational relevance… are baboon models the answer?

Abstract

Rodent models of ischemic stroke are associated with many issues and limitations, which greatly diminish the translational potential of these studies. Recent studies demonstrate that significant differences exist between rodent and human ischemic stroke. These differences include the physical characteristics of the stroke, as well as changes in the subsequent inflammatory and molecular pathways following the acute ischemic insult. Non-human primate (NHP) models of ischemic stroke, however, are much more similar to humans. In addition to evident anatomical similarities, the physiological responses that NHPs experience during ischemic stroke are much more applicable to the human condition and thus make it an attractive model for future research. The baboon ischemic stroke model, in particular, has been studied extensively in comparison to other NHP models. Here we discuss the major shortcomings associated with rodent ischemic stroke models and provide a comparative overview of baboon ischemic stroke models. Studies have shown that baboons, although more difficult to obtain and handle, are more representative of ischemic events in humans and may have greater translational potential that can offset these deficiencies. There remain critical issues within these baboon stroke studies that need to be addressed in future investigations. The most critical issue revolves around the size and the variability of baboon ischemic stroke. Compared to rodent models, however, issues such as these can be addressed in future studies. Importantly, baboon models avoid many drawbacks associated with rodent models including vascular variability and inconsistent inflammatory responses – issues that are inherent to the species and cannot be avoided.     

An approach to studying the neural correlates of reserve

The goal of this paper is to review my current understanding of the concepts of cognitive reserve (CR), brain reserve and brain maintenance, and to describe our group’s approach to using imaging to study their neural basis. I present a working model for utilizing data regarding brain integrity, clinical status, cognitive activation and CR proxies to develop analyses that can explore the neural basis of cognitive reserve and brain maintenance. The basic model assumes that the effect of brain changes on cognition is mediated by task-related activation. We treat CR as a moderator to understand how task-related activation might vary as a function of CR, or how CR might operate independently of these differences in task-related activation. My hope is that this presentation will spark discussion across groups that study these concepts, allowing us to come to some common agreement on definitions, methodology and approaches.