Extreme prematurity and intra uterine growth restriction effects in brain network topology at school age

Higher risk for long-term behavioral and emotional sequelae, with attentional problems (with or without hyperactivity) is now becoming one of the hallmarks of extreme premature (EP) birth and birth after pregancy conditions leading to poor intra uterine growth restriction (IUGR) [1,2]. However, little is know so far about the neurostructural basis of these complexe brain functional abnormalities that seem to have their origins in early critical periods of brain development. The development of cortical axonal pathways happens in a series of sequential events. The preterm phase (24-36 post conecptional weeks PCW) is known for being crucial for growth of the thalamocortical fiber bundles as well as for the development of long projectional, commisural and projectional fibers [3]. Is it logical to expect, thus, that being exposed to altered intrauterine environment (altered nutrition) or to extrauterine environment earlier that expected, lead to alterations in the structural organization and, consequently, alter the underlying white matter (WM) structure. Understanding rate and variability of normal brain development, and detect differences from typical development may offer insight into the neurodevelopmental anomalies that can be imaged at later stages. Due to its unique ability to non-invasively visualize and quantify in vivo white matter tracts in the brain, in this study we used diffusion MRI (dMRI) tractography to derive brain graphs [4,5,6]. This relatively simple way of modeling the brain enable us to use graph theory to study topological properties of brain graphs in order to study the effects of EP and IUGR on childrens brain connectivity at age 6 years old.

Improved segmentation of deep brain grey matter structures using magnetization transfer (MT) parameter maps.

Basal ganglia and brain stem nuclei are involved in the pathophysiology of various neurological and neuropsychiatric disorders. Currently available structural T1-weighted (T1w) magnetic resonance images do not provide sufficient contrast for reliable automated segmentation of various subcortical grey matter structures. We use a novel, semi-quantitative magnetization transfer (MT) imaging protocol that overcomes limitations in T1w images, which are mainly due to their sensitivity to the high iron content in subcortical grey matter. We demonstrate improved automated segmentation of putamen, pallidum, pulvinar and substantia nigra using MT images. A comparison with segmentation of high-quality T1w images was performed in 49 healthy subjects. Our results show that MT maps are highly suitable for automated segmentation, and so for multi-subject morphometric studies with a focus on subcortical structures.

Regional and cellular gene expression changes in human Huntington's disease brain.

Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.

Glutamatergic and GABAergic energy metabolism measured in the rat brain by (13) C NMR spectroscopy at 14.1 T.

Energy metabolism supports both inhibitory and excitatory neurotransmission processes. This study investigated the specific contribution of astrocytic metabolism to γ-aminobutyric acid (GABA) synthesis and inhibitory GABAergic neurotransmission that remained to be ilucidated in vivo. Therefore, we measured (13) C incorporation into brain metabolites by dynamic (13) C nuclear magnetic resonance spectroscopy at 14.1 T in rats under α-chloralose anaesthesia during infusion of [1,6-(13) C]glucose. The enhanced sensitivity at 14.1 T allowed to quantify incorporation of (13) C into the three aliphatic carbons of GABA non-invasively. Metabolic fluxes were determined with a mathematical model of brain metabolism comprising glial, glutamatergic and GABAergic compartments. GABA synthesis rate was 0.11 ± 0.01 μmol/g/min. GABA-glutamine cycle was 0.053 ± 0.003 μmol/g/min and accounted for 22 ± 1% of total neurotransmitter cycling between neurons and glia. Cerebral glucose oxidation was 0.47 ± 0.02 μmol/g/min, of which 35 ± 1% and 7 ± 1% was diverted to the glutamatergic and GABAergic tricarboxylic acid cycles, respectively. The remaining fraction of glucose oxidation was in glia, where 12 ± 1% of the TCA cycle flux was dedicated to oxidation of GABA. 16 ± 2% of glutamine synthesis was provided to GABAergic neurons. We conclude that substantial metabolic activity occurs in GABAergic neurons and that glial metabolism supports both glutamatergic and GABAergic neurons in the living rat brain. We performed (13) C NMR spectroscopy in vivo at high magnetic field (14.1 T) upon administration of [1,6-(13) C]glucose. This allowed to measure (13) C incorporation into the three aliphatic carbons of GABA in the rat brain, in addition to those of glutamate, glutamine and aspartate. These data were then modelled to determine fluxes of energy metabolism in GABAergic and glutamatergic neurons and glial cells.

How the visual brain encodes and keeps track of time.

Time is embedded in any sensory experience: the movements of a dance, the rhythm of a piece of music, the words of a speaker are all examples of temporally structured sensory events. In humans, if and how visual cortices perform temporal processing remains unclear. Here we show that both primary visual cortex (V1) and extrastriate area V5/MT are causally involved in encoding and keeping time in memory and that this involvement is independent from low-level visual processing. Most importantly we demonstrate that V1 and V5/MT come into play simultaneously and seem to be functionally linked during interval encoding, whereas they operate serially (V1 followed by V5/MT) and seem to be independent while maintaining temporal information in working memory. These data help to refine our knowledge of the functional properties of human visual cortex, highlighting the contribution and the temporal dynamics of V1 and V5/MT in the processing of the temporal aspects of visual information.

Restricted transgene expression in the brain with cell-type specific neuronal promoters.

Tissue-targeted expression is of major interest for studying the contribution of cellular subpopulations to neurodegenerative diseases. However, in vivo methods to investigate this issue are limited. Here, we report an analysis of the cell specificity of expression of fluorescent reporter genes driven by six neuronal promoters, with the ubiquitous phosphoglycerate kinase 1 (PGK) promoter used as a reference. Quantitative analysis of AcGFPnuc expression in the striatum and hippocampus of rodents showed that all lentiviral vectors (LV) exhibited a neuronal tropism; however, there was substantial diversity of transcriptional activity and cell-type specificity of expression. The promoters with the highest activity were those of the 67 kDa glutamic acid decarboxylase (GAD67), homeobox Dlx5/6, glutamate receptor 1 (GluR1), and preprotachykinin 1 (Tac1) genes. Neuron-specific enolase (NSE) and dopaminergic receptor 1 (Drd1a) promoters showed weak activity, but the integration of an amplification system into the LV overcame this limitation. In the striatum, the expression profiles of Tac1 and Drd1a were not limited to the striatonigral pathway, whereas in the hippocampus, Drd1a and Dlx5/6 showed the expected restricted pattern of expression. Regulation of the Dlx5/6 promoter was observed in a disease condition, whereas Tac1 activity was unaffected. These vectors provide safe tools that are more selective than others available, for the administration of therapeutic molecules in the central nervous system (CNS). Nevertheless, additional characterization of regulatory elements in neuronal promoters is still required.

Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease.

Machado-Joseph disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado-Joseph disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado-Joseph disease. For this purpose, we inhibited calpain activity in mouse models of Machado-Joseph disease by overexpressing the endogenous calpain-inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado-Joseph disease.

Brain injury program to ensure greater access to community-based services, July 2006

More than 2,200 Iowans each year experience a traumatic brain injury that requires hospitalization. Of those, more than 750 will experience long-term disability as a result. According to a 2000 CDC report, there are an estimated 50,000 such individuals living in Iowa – a number similar to the population of Ames.

Brain injury program to ensure greater access to community-based services, July 2006

More than 2,200 Iowans each year experience a traumatic brain injury that requires hospitalization. Of those, more than 750 will experience long-term disability as a result. According to a 2000 CDC report, there are an estimated 50,000 such individuals living in Iowa – a number similar to the population of Ames.

Brain Injuries In Iowa, September 2001

Under Iowa law, hospitals treating persons with a brain or spinal cord injury which results in a hospital admission, patient transfer, or death must report that injury to the Central Registry for Brain and Spinal Cord Injuries of the Iowa Department of Public Health.

Coming into Focus A Needs Assessment and State Plan for Iowans with Brain Injury, November 1998

Coming Into Focus presents a needs assessment related to Iowans with brain injury, and a state action plan to improve Iowa’s ability to meet those needs. Support for this project came from a grant from the Office of Maternal and Child Health to the Iowa Department of Public Health, Iowa’s lead agency for brain injury. The report is a description of the needs of people with brain injuries in Iowa, the status of services to meet those needs and a plan for improving Iowa’s system of supports. Brain injury can result from a skull fracture or penetration of the brain, a disease process such as tumor or infection, or a closed head injury, such as shaken baby syndrome. Traumatic brain injury is a leading cause of death and disability in children and young adults (Fick, 1997). In the United States there are as many as 2 million brain injuries per year, with 300,000 severe enough to require hospitalization. Some 50,000 lives are lost every year to TBI. Eighty to 90 thousand people have moderate to acute brain injuries that result in disabling conditions which can last a lifetime. These conditions can include physical impairments, memory defects, limited concentration, communication deficits, emotional problems and deficits in social abilities. In addition to the personal pain and challenges to survivors and their families, the financial cost of brain injuries is enormous. With traumatic brain injuries, it is estimated that in 1995 Iowa hospitals charged some $38 million for acute care for injured persons. National estimates offer a lifetime cost of $4 million for one person with brain injury (Schootman and Harlan, 1997). With this estimate, new injuries in 1995 could eventually cost over $7 billion dollars. Dramatic improvements in medicine, and the development of emergency response systems, means that more people sustaining brain injuries are being saved. How can we insure that supports are available to this emerging population? We have called the report Coming into Focus, because, despite the prevalence and the personal and financial costs to society, brain injury is poorly understood. The Iowa Department of Public Health, the Iowa Advisory Council on Head Injuries State Plan Task Force, the Brain Injury Association of Iowa and the Iowa University Affiliated Program have worked together to begin answering this question. A great deal of good information already existed. This project brought this information together, gathered new information where it was needed, and carried out a process for identifying what needs to be done in Iowa, and what the priorities will be.

Iowa Plan for Brain Injury, 2007-2010

Traumatic Brain Injury (TBI) impacts the lives of thousands of Iowans every year. TBI has been described as the “Silent Epidemic” because so often the scars are not visible to others. The affects of brain injury are cognitive, emotional, social, and can result in physical disability. In addition to the overwhelming challenges individuals with brain injury experience, families also face many difficulties in dealing with their loved one’s injury, and in navigating a service delivery system that can be confusing and frustrating. In 1998, the Iowa Department of Public Health (IDPH) conducted a comprehensive statewide needs assessment of brain injury in Iowa. This assessment led to the development of the first Iowa Plan for Brain Injury, “Coming Into Focus.” An updated state plan, the Iowa Plan for Brain Injuries 2002 – 2005, was developed, which reported on progress of the previous state plan, and outlined gaps in service delivery in Iowa. Four areas of focus were identified by the State Plan for Brain Injuries Task Force that included: 1) Expanding the Iowa Brain Injury Resource Network (IBIRN); 2) Promoting a Legislative and Policy Agenda, While Increasing Legislative Strength; 3) Enhancing Data Collection; and, 4) Increasing Funding. The IDPH utilized “Coming Into Focus” as the framework for an application to the federal TBI State Grant Program, which has resulted in more than $900,000 for plan implementation. Iowa continues to receive grant dollars through the TBI State Grant Program, which focuses on increasing capacity to serve Iowans with brain injury and their families. Highlighting the success of this grant project, in 2007 the IDPH received the federal TBI Program’s “Impacting Systems Change” Award. The Iowa Brain Injury Resource Network (IBIRN) is the product of nine years of TBI State Grant Program funding. The IBIRN was developed to ensure that Iowans got the information and support they needed after a loved one sustained a TBI. It consists of a hospital and service provider pre-discharge information and service linkage process, a resource facilitation program, a peer-to-peer volunteer support network, and a service provider training and technical assistance program. Currently over 90 public and private partners work with the IDPH and the Brain Injury Association of Iowa (BIA-IA) to administer the IBIRN system and ensure that families have a relevant and reliable location to turn for information and support. Further success was accomplished in 2006 when the Iowa legislature created the Brain Injury Services Program within the IDPH. This program consists of four components focusing on increasing access to services and improving the effectiveness of services available to individuals with TBI and their families, including: 1) HCBS Brain Injury Waiver-Eligible Component; 2) Cost Share Component; 3) Neuro-Resource Facilitation; and, 4) Enhanced Training. The Iowa legislature appropriated $2.4 million to the Brain Injury Services Program in state fiscal year (SFY) 2007, and increased that amount to $3.9 million in SFY 2008. The Cost Share Component models the HCBS Brain Injury Waiver menu of services but is available for Iowans who do not qualify functionally or financially for the Waiver. In addition, the Neuro-Resource Facilitation program links individuals with brain injury and their families to needed supports and services. The Iowa Plan for Brain Injury highlights the continued need for serving individuals with brain injury and their families. Additionally, the Plan outlines the paths of prevention and services, which will expand the current system and direct efforts into the future.

Iowa Plan for Brain Injury: Executive Summary, 2007-2010

Traumatic Brain Injury (TBI) impacts the lives of thousands of Iowans every year. TBI has been described as the “Silent Epidemic” because so often the scars are not visible to others. The affects of brain injury are cognitive, emotional, and social and can result in physical disability. In addition to the overwhelming challenges individuals with brain injury experience, families also face many difficulties in dealing with their loved one’s injury and in navigating a service delivery system that can be confusing and frustrating.

Traumatic Brain Injury in Iowa: An Analysis of Core Surveillance Data 2006-2008, July 15, 2011

Termed the “silent epidemic”, traumatic brain injury is the most debilitating outcome of injury characterized by the irreversibility of its damages, long-term effects on quality of life, and healthcare costs. The latest data available from the Centers for Disease Control and Prevention (CDC) estimate that nationally 50,000 people with traumatic brain injury (TBI) die each year; three times as many are hospitalized and more than twenty times as many are released from emergency room departments (ED) (CDC, 2008)1. The purpose of this report is to describe the epidemiology of TBI in Iowa to help guide policy and programming. TBI is a result of an external force which transfers energy to the brain. Stroke is caused by a disruption of blood flow in the brain that leads to brain injury. Though stroke is recognized as the 3rd leading cause of death nationally2, and is an injury that affects the brain it does not meet the definition a traumatic brain injury and is not included in this report.