Jordan Grafman - US grants

We examined the relationship of preinjury intelligence, brain tissue volume loss, lesion location, demographic variables and a number of genetic markers to long-term cognitive decline in a group of Vietnam veterans with predominantly penetrating head injury (PHI) suffered more than thirty years ago. Using linear and stepwise regression procedures, we found that those with PHI demonstrated a greater degree of cognitive decline overall during the years following injury compared to a control group of uninjured Vietnam veterans. This became increasingly significant later in life. We also found that preinjury intelligence was the most consistent predictor of cognitive outcome across all phases of potential recovery and decline after such injuries. Laterality of lesion was not a factor. Finally, we found evidence for an association between level of cognitive decline following penetrating head injury and the possession of certain genetic markers that have been linked with brain injury and neurodegeneration. Thus exacerbated decline does occur in Vietnam veterans with PHI, is apparently unrelated to dementia and is determined by multiple factors (most notably preinjury intelligence). Post-traumatic stress disorder (PTSD) is an often debilitating mental illness that is characterized by recurrent distressing memories of traumatic events. PTSD is associated with hypoactivity in the ventromedial prefrontal cortex (vmPFC), hyperactivity in the amygdala and reduced volume in the hippocampus, but it is unknown whether these neuroimaging findings reflect the underlying cause or a secondary effect of the disorder. To investigate the causal contribution of specific brain areas to PTSD symptoms, we studied a unique sample of Vietnam War veterans who suffered brain injury and emotionally traumatic events. We found a substantially reduced occurrence of PTSD among those individuals with damage to one of two regions of the brain: the vmPFC and an anterior temporal area that included the amygdala. These results suggest that the vmPFC and amygdala are critically involved in the pathogenesis of PTSD.

The Section focuses its research on the functions of the human prefrontal cortex and cognitive neuroplasticity. We continue to refine a model developed in the Section that specifies some of the characteristics of the prefrontal cortex's underlying cognitive architecture and representational knowledge. We have determined that ease of access to knowledge stored in the prefrontal cortex is determined by the category and familiarity of that knowledge. In addition, failure to selectively retrieve such knowledge leads to impaired plan development and/or execution. Activating knowledge stored in prefrontal cortex allows that knowledge to manage information that has to be kept temporarily active. Social and non-social knowledge may be distinctively stored in the prefrontal cortex. Access to such knowledge helps modulate more primitive behaviors such as aggression. In an effort to better understand some aspects of cognitive neuroplasticity, we have examined the learning rate of patients recovering from brain damage and with deficits on the task of interest and compared their performance to matched controls. There is some indication that patients can show new learning in deficit areas but it is not clear that if new learning is without a cost to preserved cognitive functions. The section also utilizes positron emission tomography (PET), functional magnetic resonance imaging (fMRI), Direct Current Polarization (DCp) and transcranial magnetic stimulation (rTMS) to map planning processes, representational knowledge, reasoning processes, social cognition, reward systems, number processing and calculation to brain. For example, we have determined with fMRI the importance of the anterior prefrontal cortex for multitasking, task-switching, and adaptive behavior. We have used rTMS to facilitate the speed of analogical reasoning in healthy normal control subjects possibly providing a framework to use rTMS to aid rehabilitation of brain-injured patients. The Section utilizes data from normal control studies, patient studies, functional neuroimaging, and rTMS to provide convergent evidence about the functions of the human prefrontal cortex and cognitive neuroplasticity.

Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined. We examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations. We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination. Our judgment that this mutation results in a heterogeneous clinical presentation has been confirmed in an international in press study of a much large sampling of patients.[unreadable] [unreadable] Many patients with FTD come to our evaluations still driving. To evaluate driving competency and the relationship between neuropsychiatric symptoms and driving behavior in frontotemporal dementia (FTD) patients, we studied 15 patients with a diagnosis of FTD and 15 healthy controls using a driving simulation task. The FTD patients received more speeding tickets, ran more stop signs and were involved in more off-road crashes and collisions than the controls. The patients' overall average speed was significantly higher. Driving performance was correlated with agitated behavior. Based on this finding that behavioral changes characteristic of FTD patients have an impact on their driving skills leading to inappropriate driving behavior, we now caution that all patients with a diagnosis of FTD should cease driving.[unreadable] [unreadable] Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype. We attempted to determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U. We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings. FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X). We conclude that neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis.

DESCRIPTION (provided by applicant): The proposed application, entitled Precursors and Prognosis of Traumatic Brain Injury in Young to Middle Aged Adults seeks to determine whether single or repeated traumatic brain injuries (TBI) increase risk for later life decline in cognition mood, behavior and daily function. This project leverages already available health, lifestyle, biomarker, genetic, cognitive and neuroimaging data and combines it with proposed acquisition of new TBI data recommended as Common Data Elements (CDE) by the National Institute of Neurological Disorders and Stroke (NINDS). This study marks an initial effort to systematically collect specific NINDS CDE on TBI in a community-based sample. Further, while the concept of developing risk profile scores originated within the Framingham Heart Study and have been widely used, risk profile scores have not been utilized for documenting activities that can lead to impact exposures and TBIs in order to characterize whether those exposures lead to later life consequences. The proposed study will obtain detailed histories of military service, sports participation, and employment to retrospectively assess exposure to impacts, and will also determine prevalence of diagnosed TBI in the Framingham Heart Study Generation 3 (Gen 3; n=4095) and its smaller multi-ethnic Omni Generation 2 (n=410; Omni Gen 2) cohorts. We will then relate these risk factors to available and new computerized measures of cognition to determine whether history of impact exposures and/or diagnosed TBI is associated with cognitive impairment and accelerated decline. We will also examine whether history of impact exposures and/or diagnosed TBI is associated with smaller brain volumes and compromised white matter integrity, particularly in the regions of the brain linked to memory and executive function. Further we will address the question of whether these risk factors are associated with changes in mood, behavior and daily functioning. Finally, we will seek to identify metabolic and inflammatory biomarkers associated with history of impact exposures and/or diagnosed TBI and whether specific genetic markers modify the relationship between TBI and chronic health outcomes. Our focus on the potential long-term consequences of engaging in activities that can lead to impact exposures and TBIs in the general population has significant implications for public health.

? DESCRIPTION (provided by applicant): Funds are requested for a 3-channel transcranial magnetic stimulation (TMS) system with simultaneous whole-head 64-channel electroencephalography (EEG) instrument. The fully integrated instrument system includes a magnetic resonance imaging (MRI) guided frameless stereotactic navigator, coupled with three powerful stimulators and small but efficient cooled TMS coils that allow spatiotemporally precise injection of current into up to 3 brain areas. Multi- channel TMS is of key value because even simple stimuli and tasks involve networks that engage multiple distinct brain regions (nodes). Thus, in order to probe and modulate network properties of the human brain, single-channel TMS systems (one stimulator, one coil) that target one node of a network are often not sufficient. Multi-channel arrangements (multiple stimulators, each with one coil) can modulate multiple nodes - even different nodes into different directions - and therefore offer much greater control over networks, permitting development of novel diagnostic and therapeutic brain stimulation/modulation regimens. The temporal relations between the three stimulation targets can be adjusted to achieve different types of effects. For example, network state and functional organization can be probed by delivering the TMS pulses in rapid millisecond-level biologically inspired sequences. With paired-pulse TMS techniques, each of the targeted cortical areas can be switched ON or OFF for a short time (~tens of milliseconds). Further, repetitive TMS of multiple sites can be used to change the functional connectivity between them using Hebbian principles, which can be experimentally and therapeutically valuable. All of the above TMS techniques can be used for non-invasive validation of models based on neuroimaging (fMRI/PET/EEG/MEG) data. To understand how brain functions change as a result of TMS we will use simultaneous TMS+EEG and/or TMS+fMRI. These techniques are also used to probe cortical excitability, functional state, and interregional connectivity. The instrument system thus allows noninvasive network-level modulation of the human brain, as is necessary to test for causal roles of brain regions and networks in healthy individuals. These methods could be ultimately used to induce plastic changes to steer networks away from pathological states associated with neurological and psychiatric disorders. The instrument components are selected to allow multi-channel MRI- guided TMS and simultaneous TMS+EEG and TMS+fMRI in an integrated instrument system. The instrument will be situated at the Rehabilitation Institute of Chicago (RIC), a leading neurological rehabilitation and research hospital worldwide. The instrument will support a large number of NIH funded large-scale grants (N=26) and PIs (N=20) from several Chicago area institutions (RIC, Northwestern University, and University of Illinois at Chicago) and is likely to become a widely used research resource in the Midwestern US. The Advisory Committee has hands-on expertise in building and managing multi-channel TMS/imaging instruments and the RIC institutional support is strong.