Future Neurology[JOURNAL]
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105 papers
From singing to speaking: facilitating recovery from nonfluent aphasia.
Schlaug G, Norton A, Marchina S … +2 more , Zipse L, Wan CY
Future Neurol · 2010 Sep · PMID 21088709 · Full text
It has been reported for more than 100 years that patients with severe nonfluent aphasia are better at singing lyrics than they are at speaking the same words. This observation led to the development of melodic intonatio...
It has been reported for more than 100 years that patients with severe nonfluent aphasia are better at singing lyrics than they are at speaking the same words. This observation led to the development of melodic intonation therapy (MIT). However, the efficacy of this therapy has yet to be substantiated in a randomized controlled trial. Furthermore, its underlying neural mechanisms remain unclear. The two unique components of MIT are the intonation of words and simple phrases using a melodic contour that follows the prosody of speech and the rhythmic tapping of the left hand that accompanies the production of each syllable and serves as a catalyst for fluency. Research has shown that both components are capable of engaging fronto-temporal regions in the right hemisphere, thereby making MIT particularly well suited for patients with large left hemisphere lesions who also suffer from nonfluent aphasia. Recovery from aphasia can happen in two ways: either through the recruitment of perilesional brain regions in the affected hemisphere, with variable recruitment of right-hemispheric regions if the lesion is small, or through the recruitment of homologous language and speech-motor regions in the unaffected hemisphere if the lesion of the affected hemisphere is extensive. Treatment-associated neural changes in patients undergoing MIT indicate that the unique engagement of right-hemispheric structures (e.g., the superior temporal lobe, primary sensorimotor, premotor and inferior frontal gyrus regions) and changes in the connections across these brain regions may be responsible for its therapeutic effect.
The clinical implications of mouse models of enhanced anxiety.
Sartori SB, Landgraf R, Singewald N
Future Neurol · 2011 Jul · PMID 21901080 · Full text
Mice are increasingly overtaking the rat model organism in important aspects of anxiety research, including drug development. However, translating the results obtained in mouse studies into information that can be applie...
Mice are increasingly overtaking the rat model organism in important aspects of anxiety research, including drug development. However, translating the results obtained in mouse studies into information that can be applied in clinics remains challenging. One reason may be that most of the studies so far have used animals displaying 'normal' anxiety rather than 'psychopathological' animal models with abnormal (elevated) anxiety, which more closely reflect core features and sensitivities to therapeutic interventions of human anxiety disorders, and which would, thus, narrow the translational gap. Here, we discuss manipulations aimed at persistently enhancing anxiety-related behavior in the laboratory mouse using phenotypic selection, genetic techniques and/or environmental manipulations. It is hoped that such models with enhanced construct validity will provide improved ways of studying the neurobiology and treatment of pathological anxiety. Examples of findings from mouse models of enhanced anxiety-related behavior will be discussed, as well as their relation to findings in anxiety disorder patients regarding neuroanatomy, neurobiology, genetic involvement and epigenetic modifications. Finally, we highlight novel targets for potential anxiolytic pharmacotherapeutics that have been established with the help of research involving mice. Since the use of psychopathological mouse models is only just beginning to increase, it is still unclear as to the extent to which such approaches will enhance the success rate of drug development in translating identified therapeutic targets into clinical trials and, thus, helping to introduce the next anxiolytic class of drugs.
Modeling neurological diseases using patient-derived induced pluripotent stem cells.
Juopperi TA, Song H, Ming GL
Future Neurol · 2011 May · PMID 21731471 · Full text
Reprogramming of somatic cells to an embryonic-like state has dramatically changed the landscape of stem cell research. Although still in its formative stages, the field of induced pluripotent stem cells (iPSCs) has the...
Reprogramming of somatic cells to an embryonic-like state has dramatically changed the landscape of stem cell research. Although still in its formative stages, the field of induced pluripotent stem cells (iPSCs) has the potential to advance the study of neurodegenerative and neurodevelopmental disorders at the molecular and cellular levels. The iPSC technology could be employed to establish in vitro experimental model systems for the identification of molecular lesions and to aid in the discovery of therapeutic targets and effective compounds. The derivation of patient-specific iPSCs has also opened up the possibility of generating disease-relevant cells for toxicity screening and for cellular therapy. In this article, we review the recent progress in the use of disease-specific iPSCs for in vitro and in vivo modeling of neurological diseases.
Fetal neurosurgery: current state of the art.
Saadai P, Runyon T, Farmer DL
Future Neurol · 2011 Mar · PMID 21709818 · Full text
Congenital CNS abnormalities have been targets for prenatal intervention since the founding of fetal surgery 30 years ago, but with historically variable results. Open fetal neurosurgery for myelomenigocele has demonstra...
Congenital CNS abnormalities have been targets for prenatal intervention since the founding of fetal surgery 30 years ago, but with historically variable results. Open fetal neurosurgery for myelomenigocele has demonstrated the most promising results of any CNS malformation. Improvements in the understanding of congenital diseases and in fetal surgical techniques have reopened the door to applying fetal surgery to other congenital CNS abnormalities. Advances in gene therapy, bioengineering and neonatal neuroprotection will aid in the future expansion of fetal neurosurgery to other CNS disorders.
What can post-mortem studies tell us about the pathoetiology of suicide?
Pandey GN, Dwivedi Y
Future Neurol · 2010 Sep · PMID 21436961 · Full text
Suicide is a major public health concern; however, its neurobiology is unclear. Post-mortem brain tissue obtained from suicide victims and normal controls offers a useful method for studying the neurobiology of suicide....
Suicide is a major public health concern; however, its neurobiology is unclear. Post-mortem brain tissue obtained from suicide victims and normal controls offers a useful method for studying the neurobiology of suicide. Despite several limitations, these studies have offered important leads in the neurobiology of suicide. In this article, we discuss some important findings resulting from these studies, focusing on serotonergic mechanisms, signal transduction systems, neuroendocrine studies and immune function abnormalities in suicide. These studies suggest that abnormalities of certain receptor subtypes, components of signaling systems such as protein kinase C and protein kinase A, transcription factors such as cyclic AMP response element-binding protein and neurotrophins may play an important role in the pathophysiology of suicide. These studies also suggest abnormalities of hypothalamic-pituitary-adrenal axis system components, feedback mechanisms and cytokines, which are chemical mediators of the immune functions. Post-mortem brain tissue offers an opportunity for future studies, such as genetic and epigenetic studies.
Recent trends in rehabilitation interventions for visual neglect and anosognosia for hemiplegia following right hemisphere stroke.
Kortte KB, Hillis AE
Future Neurol · 2011 Jan · PMID 21339836 · Full text
This article highlights the most recent findings regarding the rehabilitation interventions for the syndromes of visual neglect and anosognosia for hemiplegia that occur following right hemisphere stroke. We review paper...
This article highlights the most recent findings regarding the rehabilitation interventions for the syndromes of visual neglect and anosognosia for hemiplegia that occur following right hemisphere stroke. We review papers published in the past 4 years pertaining to therapeutic approaches for these two syndromes in order to identify the trends in the development of effective interventions. Overall, it appears well recognized that visual neglect syndromes and awareness syndromes frequently co-occur and both include complex, multifaceted impairments leading to significant difficulties in daily life functioning following stroke. Thus, the interventions for these syndromes must be multifaceted in order to address the complex interplay of cognitive-behavioral-emotional components. There appears to be a trend for using combination therapeutic interventions that address these components.
Neural pathways for language in autism: the potential for music-based treatments.
Wan CY, Schlaug G
Future Neurol · 2010 Nov · PMID 21197137 · Full text
Language deficits represent the core diagnostic characteristics of autism, and some of these individuals never develop functional speech. The language deficits in autism may be due to structural and functional abnormalit...
Language deficits represent the core diagnostic characteristics of autism, and some of these individuals never develop functional speech. The language deficits in autism may be due to structural and functional abnormalities in certain language regions (e.g., frontal and temporal), or due to altered connectivity between these brain regions. In particular, a number of anatomical pathways that connect auditory and motor brain regions (e.g., the arcuate fasciculus, the uncinate fasciculus and the extreme capsule) may be altered in individuals with autism. These pathways may also provide targets for experimental treatments to facilitate communication skills in autism. We propose that music-based interventions (e.g., auditory-motor mapping training) would take advantage of the musical strengths of these children, and are likely to engage, and possibly strengthen, the connections between frontal and temporal regions bilaterally. Such treatments have important clinical potential in facilitating expressive language in nonverbal children with autism.
Insights into synaptic function from mouse models of human cognitive disorders.
Banko JL, Trotter J, Weeber EJ
Future Neurol · 2011 Jan · PMID 25083141 · Full text
Modern approaches to the investigation of the molecular mechanisms underlying human cognitive disease often include multidisciplinary examination of animal models engineered with specific mutations that spatially and tem...
Modern approaches to the investigation of the molecular mechanisms underlying human cognitive disease often include multidisciplinary examination of animal models engineered with specific mutations that spatially and temporally restrict expression of a gene of interest. This approach not only makes possible the development of animal models that demonstrate phenotypic similarities to their respective human disorders, but has also allowed for significant progress towards understanding the processes that mediate synaptic function and memory formation in the nondiseased state. Examples of successful mouse models where genetic manipulation of the mouse resulted in recapitulation of the symptomatology of the human disorder and was used to significantly expand our understanding of the molecular mechanisms underlying normal synaptic plasticity and memory formation are discussed in this article. These studies have broadened our knowledge of several signal transduction cascades that function throughout life to mediate synaptic physiology. Defining these events is key for developing therapies to address disorders of cognitive ability.
Inter-relationships among behavioral markers, genes, brain and treatment in dyslexia and dysgraphia.
Berninger V, Richards T
Future Neurol · 2010 Jul · PMID 20953351 · Full text
Cross-country, longitudinal twin studies provide strong evidence for both the biological and environmental basis of dyslexia, and the stability of genetic influences on reading and spelling, even when skills improve in r...
Cross-country, longitudinal twin studies provide strong evidence for both the biological and environmental basis of dyslexia, and the stability of genetic influences on reading and spelling, even when skills improve in response to instruction. Although DNA studies aimed at identifying gene candidates in dyslexia and related phenotypes (behavioral expression of underlying genotypes); and imaging studies of brain differences between individuals with and without dyslexia and the brain's response to instructional treatment are increasing, this review illustrates, with the findings of one multidisciplinary research center, an emerging trend to investigate the inter-relationships among genetic, brain and instructional treatment findings in the same sample, which are interpreted in reference to a working-memory architecture, for dyslexia (impaired decoding and spelling) and/or dysgraphia (impaired handwriting). General principles for diagnosis and treatment, based on research with children who failed to respond to the regular instructional program, are summarized for children meeting research criteria for having or being at risk for dyslexia or dysgraphia. Research documenting earlier emerging specific oral language impairment during preschool years associated with reading and writing disabilities during school years is also reviewed. Recent seminal advances and projected future trends are discussed for linking brain endophenotypes and gene candidates, identifying transchromosomal interactions, and exploring epigenetics (chemic al modifications of gene expression in response to developmental or environmental changes). Rather than providing final answers, this review highlights past, current and emerging issues in dyslexia research and practice.
Estimating and disclosing the risk of developing Alzheimer's disease: challenges, controversies and future directions.
Roberts JS, Tersegno SM
Future Neurol · 2010 Jul · PMID 20856693 · Full text
With Alzheimer's disease increasing in prevalence and public awareness, more people are becoming interested in learning their chances of developing this condition. Disclosing Alzheimer's disease risk has been discouraged...
With Alzheimer's disease increasing in prevalence and public awareness, more people are becoming interested in learning their chances of developing this condition. Disclosing Alzheimer's disease risk has been discouraged because of the limited predictive value of available tests, lack of prevention and treatment options, and concerns regarding potential psychological and social harms. However, challenges to this status quo include the availability of direct-to-consumer health risk information (e.g., genetic susceptibility tests), as well as a growing literature suggesting that people seeking risk information for Alzheimer's disease through formal education and counseling protocols generally find it useful and do not experience adverse effects. This paper reviews current and potential methods of risk assessment for Alzheimer's disease, discusses the process and impact of disclosing risk to interested patients and consumers, and considers the practical and ethical challenges in this emerging area. Anticipated future directions are addressed.
Insights into neurogenesis and aging: potential therapy for degenerative disease?
Marr RA, Thomas RM, Peterson DA
Future Neurol · 2010 Jul · PMID 20806052 · Full text
Neurogenesis is the process by which new neural cells are generated from a small population of multipotent stem cells in the adult CNS. This natural generation of new cells is limited in its regenerative capabilities and...
Neurogenesis is the process by which new neural cells are generated from a small population of multipotent stem cells in the adult CNS. This natural generation of new cells is limited in its regenerative capabilities and also declines with age. The use of stem cells in the treatment of neurodegenerative disease may hold great potential; however, the age-related incidence of many CNS diseases coincides with reduced neurogenesis. This review concisely summarizes current knowledge related to adult neurogenesis and its alteration with aging and examines the feasibility of using stem cell and gene therapies to combat diseases of the CNS with advancing age.
Amyloid precursor protein and tau transgenic models of Alzheimer's disease: insights from the past and directions for the future.
Sahara N, Lewis J
Future Neurol · 2010 May · PMID 20730022 · Full text
During the last 20 years, our understanding of the mechanisms underlying Alzheimer's disease (AD) has considerably improved, in part owing to both in vitro and in vivo model systems. Studies in mice expressing both human...
During the last 20 years, our understanding of the mechanisms underlying Alzheimer's disease (AD) has considerably improved, in part owing to both in vitro and in vivo model systems. Studies in mice expressing both human amyloid precursor protein and human tau have provided clear evidence that amyloid-beta and tau interact in the pathogenesis of AD. Moreover, amyloid-beta toxicity has been shown to be tau-dependent since reducing tau levels prevents behavioral deficits and sudden death in amyloid precursor protein transgenic mice. As tau pathology preferentially develops in specific sites and spreads in a predictable manner across the brain, understanding the mechanism underlying tau dysfunction should be a focus in AD mouse modeling. A defined effort must be made to develop therapies that directly address the impact of tau dysfunction in the pathogenesis of AD. Finally, early diagnosis of AD is essential and this must be made possible by identification of early biomarkers, behavioral changes or use of novel imaging techniques.
Neurobiology of dysregulated motivational systems in drug addiction.
Edwards S, Koob GF
Future Neurol · 2010 May · PMID 20563312 · Full text
The progression from recreational drug use to drug addiction impacts multiple neurobiological processes and can be conceptualized as a transition from positive to negative reinforcement mechanisms driving both drug-takin...
The progression from recreational drug use to drug addiction impacts multiple neurobiological processes and can be conceptualized as a transition from positive to negative reinforcement mechanisms driving both drug-taking and drug-seeking behaviors. Neurobiological mechanisms for negative reinforcement, defined as drug taking that alleviates a negative emotional state, involve changes in the brain reward system and recruitment of brain stress (or antireward) systems within forebrain structures, including the extended amygdala. These systems are hypothesized to be dysregulated by excessive drug intake and to contribute to allostatic changes in reinforcement mechanisms associated with addiction. Points of intersection between positive and negative motivational circuitry may further drive the compulsivity of drug addiction but also provide a rich neurobiological substrate for therapeutic intervention.
Microglia in ischemic brain injury.
Weinstein JR, Koerner IP, Möller T
Future Neurol · 2010 Mar · PMID 20401171 · Full text
Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked c...
Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene-expression profile and phenotype of a variety of endogenous CNS cell types (astrocytes, neurons and microglia), as well as an influx of leukocytic cells (neutrophils, macrophages and T-cells) from the periphery. Many molecules and conditions can trigger a transformation of surveying microglia to microglia of an alerted or reactive state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. In particular, we focus on the role of specific molecular signaling systems, such as hypoxia inducible factor-1 and Toll-like receptor-4, in regulating the microglial response in this setting. We then review histological and novel radiological data that confirm a key role for microglial activation in the setting of ischemic stroke in humans. We also discuss recent progress in the pharmacologic and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in pre-emptively targeting microglial activation in order to reduce stroke severity.
Promoting neurological recovery of function via metaplasticity.
Cho KK, Bear MF
Future Neurol · 2010 Jan · PMID 20209094 · Full text
The modification of synapses by neural activity has been proposed to be the substrate for experience-dependent brain development, learning, and recovery of visual function after brain injury. The effectiveness or 'streng...
The modification of synapses by neural activity has been proposed to be the substrate for experience-dependent brain development, learning, and recovery of visual function after brain injury. The effectiveness or 'strength' of synaptic transmission can be persistently modified in response to defined patterns of pre- and post-synaptic activity. Well-studied examples of this type of synaptic plasticity are long-term potentiation and long-term depression. Can we exploit the current understanding of these mechanisms in order to strengthen brain connections that may have been weakened or impaired by sensory deprivation, disease or injury? Theoretically motivated research in the visual cortex has suggested ways to promote synaptic potentiation. The theoretical concept is that the type and extent of synaptic plasticity caused by patterns of activity depend critically on the recent prior history of synaptic or cellular activity. Studies in visual cortex strongly support this concept, and have suggested a mechanism for 'metaplasticity' - the plasticity of synaptic plasticity - based on activity-dependent modification of NMDA-receptor structure and function. The knowledge gained by these studies suggests ways in which recovery of function can be promoted.
Sex-specific responses to stroke.
Turtzo LC, McCullough LD
Future Neurol · 2010 Jan · PMID 20190872 · Full text
Stroke is a sexually dimorphic disease, with differences between males and females observed both clinically and in the laboratory. While males have a higher incidence of stroke throughout much of the lifespan, aged femal...
Stroke is a sexually dimorphic disease, with differences between males and females observed both clinically and in the laboratory. While males have a higher incidence of stroke throughout much of the lifespan, aged females have a higher burden of stroke. Sex differences in stroke result from a combination of factors, including elements intrinsic to the sex chromosomes as well as the effects of sex hormone exposure throughout the lifespan. Research investigating the sexual dimorphism of stroke is only in the beginning stages, but early findings suggest that different cell death pathways are activated in males and females after ischemic stroke. A greater understanding of the mechanisms underlying sex differences in stroke will lead to more appropriate treatment strategies for patients of both sexes.
Development of histone deacetylase inhibitors as therapeutics for neurological disease.
Gottesfeld JM, Pandolfo M
Future Neurol · 2009 Nov · PMID 20177429 · Full text
Postsynthetic modifications of histone and other chromosomal proteins by reversible acetylation and/or methylation regulate many aspects of chromatin dynamics, such as transcription, replication and DNA repair. Aberrant...
Postsynthetic modifications of histone and other chromosomal proteins by reversible acetylation and/or methylation regulate many aspects of chromatin dynamics, such as transcription, replication and DNA repair. Aberrant modification states are associated with several neurological and neuromotor diseases. Thus, small molecules that inhibit or activate the enzymes responsible for these chromatin modifications have received considerable attention as potential human therapeutics. This paper summarizes the current state of development of histone deacetylase inhibitors in a variety of neurological diseases.
Dopamine transporter trafficking: rapid response on demand.
Chen R, Furman CA, Gnegy ME
Future Neurol · 2010 Jan · PMID 20174452 · Full text
The dopamine transporter (DAT) is a primary determinant of the concentration of dopamine in the synapse and is involved in a number of psychiatric and neurological diseases. The transporter actively takes up its physiolo...
The dopamine transporter (DAT) is a primary determinant of the concentration of dopamine in the synapse and is involved in a number of psychiatric and neurological diseases. The transporter actively takes up its physiological substrate, dopamine, when it is on the surface of the plasmalemmal membrane, but the concentration of DAT in the membrane is highly regulated by substrate. Substrates initially, and very rapidly, recruit more DAT into the membrane for greater function, but continued presence of substrate downregulates the activity of DAT and even membrane DAT content. This biphasic regulation is orchestrated by numerous signal transduction mechanisms, including a palette of protein kinases. Understanding the mechanisms of rapid regulation of DAT could provide new therapeutic strategies to improve transporter function and modulate responses to its more notorious substrates, amphetamine and methamphetamine.
Evidence for RNA-mediated toxicity in the fragile X-associated tremor/ataxia syndrome.
Galloway JN, Nelson DL
Future Neurol · 2009 Nov · PMID 20161676 · Full text
Fragile X premutation carriers are at risk for developing a late-onset, progressive neurodegenerative disorder termed fragile X-associated tremor/ataxia syndrome (FXTAS). A growing body of evidence suggests the character...
Fragile X premutation carriers are at risk for developing a late-onset, progressive neurodegenerative disorder termed fragile X-associated tremor/ataxia syndrome (FXTAS). A growing body of evidence suggests the characteristic excess CGG repeat containing FMR1 mRNA observed in premutation carriers is pathogenic and leads to clinical features of FXTAS. The current model suggests premutation mRNA transcripts can induce the formation of intranuclear inclusions by the sequestration of RNA-binding proteins and other proteins. The sequestered proteins are prevented from performing their normal functions, which is thought to lead to the neuropathology-observed FXTAS. This paper discusses the existing evidence that microsatellite expansions at the level of RNA play a role in the disease pathogenesis of FXTAS and some of the approaches that may uncover downstream effects of expanded riboCGG expression.
Predicting dementia: role of dementia risk indices.
Barnes DE, Yaffe K
Future Neurol · 2009 Sep · PMID 20161571 · Full text
There are currently more than 5 million people in the USA living with Alzheimer's disease and other forms of dementia, and prevalence is expected to triple over the next 40 years. As new strategies for prevention and tre...
There are currently more than 5 million people in the USA living with Alzheimer's disease and other forms of dementia, and prevalence is expected to triple over the next 40 years. As new strategies for prevention and treatment are developed, it will be critically important to be able to identify older adults who do not currently have dementia but have a high risk of developing symptoms within a few years so that they can be targeted for monitoring, prevention and early treatment. In other fields, prognostic models and risk indices are often used to identify high-risk individuals (e.g., Framingham Heart Index and Breast Cancer Risk Assessment Tool). The objective of this paper is to describe the development of Dementia Risk Indices and to discuss the potential for these tools to be incorporated into clinical and research settings for the identification of individuals with a high risk of dementia.
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