Why Cortical Neurons Cannot Divide,and Why Do They Usually Die in the Attempt?

Cortical neurons are prime examples of terminally differentiated, postmitotic cells. However, under experimental or pathological conditions, they can re‐enter the cell cycle and replicate DNA but are unable to divide, dying by apoptosis or becoming either polyploid or aneuploid. Any cellular state that depends on the action of genes and their products can be reverted or bypassed by spontaneous or induced mutations, yet there are currently no reports of dividing cortical neurons. Thus, it seems unlikely that the remarkably stable postmitotic condition of cortical neurons depends on specific gene functions. This Review summarizes evidence that the postmitotic state of cortical neurons depends on the high stability of its underlying nuclear structure that results from an entropy‐driven process aimed at dissipating the intrinsic structural stress present in chromosomal DNA in such a way that the structural stability of the neuronal nucleus becomes an insurmountable energy barrier for karyokinesis and mitosis. From this perspective, the integral properties of the nuclear higher order structure in neurons provide an explanation not only for why cortical neurons cannot divide but also for why they usually die if they happen to replicate their DNA. © 2016 Wiley Periodicals, Inc.     

Classification and diagnostic criteria for demyelinating diseases of the central nervous system: Where do we stand today?

The diagnosis of multiple sclerosis (MS) and other demyelinating diseases of the central nervous system is challenging, and although the currently available biological and imaging tools offer considerable support to physicians, these tools often fail to provide a simple and final answer at the time of a first event. Thus, sets of diagnostic criteria have been published and tested on patient cohorts, and are now used in clinical trials and in daily clinical practice. These criteria have evolved over time to take into account physicians’ and patients’ needs, along with emerging paraclinical tests. The different presentations of MS have given rise to the use of a common classification system to identify patient profiles and adapt care protocols accordingly. This article reviews the various classifications of the forms and diagnostic criteria of MS and related syndromes, including neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSDs), acute disseminated (demyelinating) encephalomyelitis (ADEM) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Also discussed is their validity in the light of the currently available literature.     

Revisiting the Diagnosis of Schizophrenia: Where have we been and Where are We Going?

Appropriate and reliable classification of mental illness is crucial for advancing the field of psychiatry as agreement on diagnosis has broad implications for treatment of mental disorders and research into the etiopathophysiology of mental disorders. Since schizophrenia was first recognized by Kraepelin (as dementia praecox), there has been much discussion about what does and does not diagnostically constitute the disorder. The importance placed upon different symptoms and course types associated with schizophrenia has been as heterogeneous as the disorder itself. This article focuses upon the classification of schizophrenia over the last 100 years, the current diagnosis of schizophrenia, changes for schizophrenia planned in the upcoming DSM 5, future directions for improving the diagnosis of schizophrenia, and the implications of a new diagnostic paradigm for the illness.     

On the Neuropathology of Schizophrenia and its Dementia: Neurodevelopmental,Neurodegenerative, or Both?

The neuropathology of schizophrenia has begun to emerge following renewed investigation in the past 20 years. However, there remain inconsistencies in the data and their interpretation. In particular, although the brains of schizophrenics have been reported to show an excess of neurodegenerative changes, especially astrocytic gliosis and Alzheimer's disease, it is unclear whether these features are an intrinsic part of the neuropathology of schizophrenia. Nor is it apparent how they relate to the symptoms of dementia which afflict a proportion of schizophrenics. This review focuses upon these questions. Two main conclusions are drawn. Firstly, the neuropathological features of schizophrenia together support a neurodevelopmental pathogenesis wherein the aforementioned degenerative changes are either epiphenomenal, artefactual, or are limited to a subgroup of cases which are otherwise indistinguishable clinically or pathologically. Secondly, the dementia of schizophrenia is not attributable to Alzheimer's disease nor to any other recognized neuropathological substrate.     

Cortical processing of complex sound: a way forward?

The organization of the cortical auditory system remains controversial. In particular, the extent to which there is regional specialization in the cortical processing of complex sound is unclear. Here, we ask whether we are currently asking the right questions of auditory cortex, or using the appropriate techniques to do so. A key factor that will promote such understanding in the future will be increasing dialogue between workers using electrophysiological recording methods to assess the response properties of single neurons and those using imaging techniques to map regional organization. In the future, further insights will be obtained by efforts to test hypotheses developed on the basis of one approach by the use of the other. Imaging can tell the neurophysiologists where to look, and work on single neurons can constrain network models based on imaging. There is a crucial need for better understanding of the anatomy of the auditory cortex in different species and for comparative studies that will underpin both approaches.     

Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees?

Although amyloid-beta-containing senile plaques and phospho-tau containing neurofibrillary tangles are hallmark lesions of Alzheimer disease (AD), neither is specific for AD, nor even a marker of AD. Rather, they are empirical lesions that require close correlation with age and clinical signs for optimal interpretation. In essence, these lesions represent the effect rather than the cause of disease. In this review, we discuss diagnostic criteria for AD, the relationship between pathology, pathogenesis and multiple treatment approaches that have so far been disappointing, including those that presume to address pathological lesions. An acceptance that lesion-based therapies do not address etiology or rate-limiting pathogenic factors is probably necessary for the best chance of significant advances that have thus far been elusive.     

Subtypes of Parkinson’s Disease: What Do They Tell Us About Disease Progression?

Parkinson’s disease is a widely heterogeneous disorder with a broad list of motor and nonmotor manifestations. Identifying subtypes of Parkinson’s disease is one of the top clinical and research priorities. This review aims to summarize the most valid conventional and recent subtyping solutions that have been introduced so far and to update our current knowledge with recent discoveries on the association between subtypes and disease progression. We also discuss the challenges of subtyping in the context of Parkinson’s disease, stability of the subtypes over time, and potential clinical implications. Sophisticated evidence show that there are distinct subtypes of Parkinson’s disease with diverging trends of progression. A more holistic view of subtyping to merge traditional motor features with key nonmotor manifestations is a promising approach to identify subgroups with different prognosis. Subtyping could improve further by adding continuing to add data from imaging, CSF, and genetic biomarkers.     

Cortical spreading depression and migraine: new insights from imaging?

The possibility that spreading depression (SD) of cortical activity, a phenomenon observed in all vertebrates, causes the aura of migraine remains an open question in spite of nearly half a century of investigation. SD is also thought to be associated with the progressive neuronal injury observed during cerebral ischaemia. Thus, the ability to detect and investigate SD in humans might prove clinically significant. Animal studies of cortical spreading depression (CSD) have benefited greatly from the advent of relatively non-invasive imaging techniques. The use of these new imaging techniques for clinical studies will accelerate progress in this area of neurobiology.     

Radial Microcolumnar Cortical Architecture: Maturational Arrest or Cortical Dysplasia?

The fetal neocortical plate, from initiation of radial migration at 5 weeks' gestation until midgestation, exhibits radial microcolumnar architecture. Horizontal histologic layering or lamination becomes superimposed in the second half of gestation, although residua of the columnar pattern persist postnatally, particularly where the cortex bends: at the crowns of gyri and in the depths of sulci. Columnar architecture of the cortical plate in the first half of gestation mostly results from radial migration of neuroblasts, but the Cajal-Retzius neurons and GABAergic neuroblasts from tangential migration regulate a transition to horizontal lamination of the mature cortex. In children and adults, prominent columnar architecture is a feature of many focal cortical dysplasias and is now recognized as a distinctive pattern of focal cortical dysplasias in the new International League Against Epilepsy classification. It also occurs, however, in many genetic syndromes and chromosomopathic conditions, including 22q12 deletions (DiGeorge syndrome), in several primary cerebral malformations, in the contralateral cingulate gyrus in hemimegalencephaly, in cortical tubers of tuberous sclerosis, in the margins of porencephalic cysts resulting from prenatal infarcts, and in some inborn metabolic defects such as methylmalonic acidemia. Synaptophysin demonstrates both radial and horizontal lamination of synaptic layers. Persistent fetal cortical architecture is potentially epileptogenic. We conclude that columnar architecture is a maturational arrest in histogenesis of the neocortical plate and becomes a component of cortical dysplasia in the perinatal period. An initially physiological process thus becomes pathologic by virtue of advancing age, but traces of it persist in normal mature brains. It also occurs in many genetic and inborn metabolic diseases and after acquired ischemic insults of the fetal brain.     

Self-Fulfilling Prophecies Through Withdrawal of Care: Do They Exist in Traumatic Brain Injury, Too?

Objective

We examined factors associated with withdrawal of care (WOC) in moderate-severe traumatic brain injury (msTBI) patients, and how WOC may affect short-term mortality and receipt of neurosurgery. Variability in msTBI-related outcome prognostication by clinicians from different specialties was also assessed.

Methods

Rates of WOC, factors associated with WOC, and the relation between WOC and in-hospital case-fatality rate (CFR) and neurosurgery were determined in 232 prospectively enrolled msTBI patients in the ongoing OPTIMISM Study at a level-1 trauma center. In a concomitant web-based survey with clinical vignettes, outcome prognostication comfort, treatment aggressiveness, and WOC recommendations were examined among 106 respondents from neurology, neurocritical care, neurosurgery, trauma and anesthesia/critical care.

Results

The average age of the study sample was 53 years, with a median Glasgow Coma Scale of 6. The in-hospital CFR was 36 and 68 % of patients had WOC. Factors independently associated with WOC were advanced age, pupillary reactivity, lower intensive care unit-length-of-stay, pre- and in-hospital cardiac arrest, herniation, intracranial pressure crisis, and pre-existing endocrine disease. Inclusion of WOC in our multivariable regression model predicting in-hospital CFRs negated all other variables. Survey results suggested that in younger patients, some clinicians prognosticated overly pessimistically based upon data available at the time of presentation.

Conclusion

In our msTBI cohort, WOC was the most important predictor of in-hospital mortality. We identified several important independent predictors of WOC. Large within-center variability in msTBI outcome prognostication with varying levels of possible clinical nihilism exists, which may form the basis of self-fulfilling prophecies.     

Chronic Traumatic Encephalopathy: Where Are We and Where Are We Going?

Chronic traumatic encephalopathy (CTE, previously called punch drunk and dementia pugilistica) has a rich history in the medical literature in association with boxing, but has only recently been recognized with other contact sports, such as football and ice hockey, as well as with military blast injuries. CTE is thought to be a neurodegenerative disease associated with repeated concussive and subconcussive blows to the head. There is characteristic gross and microscopic pathology found in the brain, including frontal and temporal atrophy, axonal degeneration, and hyperphosphorylated tau and TAR DNA-binding protein 43 pathology. Clinically, there are characteristic progressive deficits in cognition (memory, executive dysfunction), behavior (explosivity, aggression), mood (depression, suicidality), and motor function (parkinsonism), which correlate with the anatomic distribution of brain pathology. While CTE shares clinical and neuropathological traits with other neurodegenerative diseases, the clinical syndrome and the neuropathology as a whole are distinct from other neurodegenerative diseases. Here we review the CTE literature to date. We also draw on the literature from mild traumatic brain injury and other neurodegenerative dementias, particularly when these studies provide guidance for future CTE research. We conclude by suggesting seven essential areas for future CTE research.     

Anemia and stroke: Where do we stand?

Anemia seems to have a clear relationship with cerebrovascular events (CVEs), as there is a direct connection between central nervous system, blood supply, and tissue oxygen delivery. Anemia is considered a hyperkinetic state which disturbs endothelial adhesion molecule genes that may lead to thrombus formation. Furthermore, blood flow augmentation and turbulence may result in the migration of this thrombus, thus producing artery‐to‐artery embolism. It is for this reason that anemia is characterized as “the fifth cardiovascular risk factor.” Anemia is consistently present in patients with acute stroke, ranging from 15% to 29%, while the mortality rate was significantly higher in patients suffering from anemia at the time of admission. Different types of anemia (sickle cell disease, beta thalassemia, iron deficiency anemia [IDA]) have been associated with increased cardiovascular and CVE risk. The relation between hemoglobin level and stroke would require further investigation. Unfortunately, treatment of anemia in cardiovascular and cerebrovascular disease still lacks clear targets and specific therapy has not developed. However, packed red blood cell transfusion is generally reserved for therapy in patients with CVEs. What is more, treatment of IDA prevents thrombosis and the occurrence of stroke; although iron levels should be checked, chronic administration favors thrombosis. Regarding erythropoietin (EPO), as there is lack of studies in anemic stroke patients, it would be desirable to utilize both neuroprotective and hematopoietic properties of EPO in anemic stroke patients. This review aims to clarify the poorly investigated and defined issues concerning the relation of anemia and CVEs.     

The Small Specific Effects of Antidepressants in Clinical Trials: What Do They Mean to Psychiatrists?

Although antidepressants continue to be a mainstay for clinicians who treat people suffering from depressive disorders, there have recently been articles published in both the scientific literature and the popular press that have raised questions about the utility of this class of medications. This paper briefly examines recent meta-analyses that have reported small drug versus placebo differences in randomized controlled trials and, from the perspective of a prescribing psychiatrist, discusses the clinical significance of these findings. It is concluded that antidepressants do have relatively modest effects (as compared with placebo) in contemporary randomized controlled trials, and that the contribution of placebo-expectancy factors to individual outcomes is often underestimated. Nevertheless, it is also concluded that the modest benefits of antidepressants in grouped datasets obscure large, specific, and very meaningful therapeutic effects for 10% to 20% of those treated with antidepressants.     

The Role of Habits in Anorexia Nervosa: Where We Are and Where to Go From Here?

Purpose of Review

The persistent maladaptive eating behavior characteristic of anorexia nervosa (AN) can be understood as a learned habit. This review describes the cognitive neuroscience background and the existing data from research in AN.

Recent Findings

Behavior is habitual after it is frequently repeated and becomes nearly automatic, relatively insensitive to outcome, and mediated by dorsal frontostriatal neural systems. There is evidence for such behavior in AN, in which restrictive intake has been related to dorsal frontostriatal systems. Other neural and neurocognitive data provide mixed findings, some of which suggest disturbances in habit systems in AN.

Summary

There are compelling behavioral and neural data to suggest that habit systems may underlie the persistence of AN. The habit model needs further research, via more direct behavioral hypothesis testing and probes of the development of habitual behavior. Investigation of the habit-centered model of AN may open avenues for the development of novel treatments.

     

Mitochondrial Targeted Therapies: Where Do We Stand in Mental Disorders?

The neurobiology of psychiatric disorders is still unclear, although changes in multiple neuronal systems, specifically the dopaminergic, glutamatergic, and gamma-aminobutyric acidergic systems as well as abnormalities in synaptic plasticity and neural connectivity, are currently suggested to underlie their pathophysiology. A growing body of evidence suggests multifaceted mitochondrial dysfunction in mental disorders, which is in line with their role in neuronal activity, growth, development, and plasticity. In this review, we describe the main endeavors toward development of treatments that will enhance mitochondrial function and their transition into clinical use in congenital mitochondrial diseases and chronic disorders such as types 1 and 2 diabetes, cardiovascular disorders, and cancer. In addition, we discuss the relevance of mitochondrial targeted treatments to mental disorders and their potential to become a novel therapeutic strategy that will improve the efficiency of the current treatments.