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1.  Tonic Hyper-Connectivity of Reward Neurocircuitry in Obese Children 
Obesity (Silver Spring, Md.)  2014;22(7):1590-1593.
Objective
Obese children demonstrate less activation in prefrontal regions associated with self-control and inhibition when presented with food cues and advertisements. The current study evaluates the differences between obese and healthy weight children in resting-state functional connectivity to these brain regions.
Design and Methods
Seed regions in bilateral middle frontal gyri were chosen based on previous task-based analysis showing differences between obese and healthy weight children’s responses to food-associated stimuli. Functional connectivity to these seed regions was measured in resting-state scans collected in obese and lean children undergoing fMRI.
Results
Obese children exhibited greater resting-state functional connectivity than healthy weight children between the left middle frontal gyrus and reward-related regions in the left ventromedial prefrontal cortex, as well as the left lateral OFC.
Conclusion
Previously published results demonstrate that obese children exhibit less activity in brain regions associated with self-control when viewing motivationally salient food advertisements. Here we show that obese children also have tonically greater input to these self-control regions from reward neurocircuitry. The greater functional connectivity between reward and self-control regions, in conjunction with weaker activation of self-control neurocircuitry, may render these children more susceptible to food advertisements, placing them at elevated risk for over-feeding and obesity.
doi:10.1002/oby.20741
PMCID: PMC4077951  PMID: 24634397
children; functional magnetic resonance imaging (fMRI); resting-state; impulsivity; orbitofrontal cortex; ventromedial prefrontal cortex
2.  Winning and losing: differences in reward and punishment sensitivity between smokers and nonsmokers 
Brain and Behavior  2014;4(6):915-924.
Background
Smokers show increased brain activation in reward processing regions in response to smoking-related cues, yet few studies have examined secondary rewards not associated with smoking (i.e., money). Inconsistencies exist in the studies that do examine secondary rewards with some studies showing increased brain activation in reward processing brain regions, while others show decreased activation or no difference in activation between smokers and nonsmokers.
Aims
The goal of the current study is to see if smokers process the evaluation and delivery of equally salient real world rewards similarly or differently than nonsmokers.
Methods
The current study employed functional magnetic resonance imaging (fMRI) to examine brain responses in smokers and nonsmokers during the evaluation and delivery of monetary gains and losses.
Results
In comparison to nonsmokers, smokers showed increased activation in the ventromedial prefrontal cortex to the evaluation of anticipated monetary losses and the brain response. Moreover, smokers compared to nonsmokers showed decreased activation in the inferior frontal gyrus to the delivery of expected monetary gains. Brain activations to both the evaluation of anticipated monetary losses and the delivery of expected monetary gains correlated with increased self-reported smoking craving to relieve negative withdrawal symptoms and craving related to positive aspects of smoking, respectively.
Discussion
Together these results indicate that smokers are hyperresponsive to the evaluation of anticipated punishment and hyporesponsive to the delivery of expected rewards. Although further research is needed, this hypersensitivity to punishments coupled with increased craving may negatively impact quit attempts as smokers anticipate the negative withdrawal symptoms associated with quitting.
doi:10.1002/brb3.285
PMCID: PMC4178298  PMID: 25365800
fMRI; punishment sensitivity; reward sensitivity; smoking
3.  Winning and losing: differences in reward and punishment sensitivity between smokers and nonsmokers 
Brain and Behavior  2014;10.1002/brb3.285.
Abstract
Background
Smokers show increased brain activation in reward processing regions in response to smoking‐related cues, yet few studies have examined secondary rewards not associated with smoking (i.e., money). Inconsistencies exist in the studies that do examine secondary rewards with some studies showing increased brain activation in reward processing brain regions, while others show decreased activation or no difference in activation between smokers and nonsmokers.
Aims
The goal of the current study is to see if smokers process the evaluation and delivery of equally salient real world rewards similarly or differently than nonsmokers.
Methods
The current study employed functional magnetic resonance imaging (fMRI) to examine brain responses in smokers and nonsmokers during the evaluation and delivery of monetary gains and losses.
Results
In comparison to nonsmokers, smokers showed increased activation in the ventromedial prefrontal cortex to the evaluation of anticipated monetary losses and the brain response. Moreover, smokers compared to nonsmokers showed decreased activation in the inferior frontal gyrus to the delivery of expected monetary gains. Brain activations to both the evaluation of anticipated monetary losses and the delivery of expected monetary gains correlated with increased self‐reported smoking craving to relieve negative withdrawal symptoms and craving related to positive aspects of smoking, respectively.
Discussion
Together these results indicate that smokers are hyperresponsive to the evaluation of anticipated punishment and hyporesponsive to the delivery of expected rewards. Although further research is needed, this hypersensitivity to punishments coupled with increased craving may negatively impact quit attempts as smokers anticipate the negative withdrawal symptoms associated with quitting.
doi:10.1002/brb3.285
PMCID: PMC4178298  PMID: 25365800
fMRI; punishment sensitivity; reward sensitivity; smoking
4.  A comparison of functional brain changes associated with surgical versus behavioral weight loss 
Obesity (Silver Spring, Md.)  2013;22(2):337-343.
Objective
Few studies have examined brain changes in response to effective weight loss; none have compared different methods of weight-loss intervention. We compared functional brain changes associated with a behavioral weight loss intervention to those associated with bariatric surgery.
Methods
15 obese participants were recruited prior to adjustable gastric banding surgery and 16 obese participants were recruited prior to a behavioral diet intervention. Groups were matched for demographics and amount of weight lost. fMRI scans (visual food motivation paradigm while hungry and following a meal) were conducted before, and 12 weeks after surgery/behavioral intervention.
Results
When compared to bariatric patients in the pre-meal analyses, behavioral dieters showed increased activation to food images in right medial PFC and left precuneus following weight loss. When compared to behavioral dieters, bariatric patients showed increased activation in in bilateral temporal cortex following the weight loss.
Conclusions
Behavioral dieters showed increased responses to food cues in medial PFC – a region associated with valuation and processing of self-referent information – when compared to bariatric patients. Bariatric patients showed increased responses to food cues in brain regions associated with higher level perception—when compared to behavioral dieters. The method of weight loss determines unique changes in brain function.
doi:10.1002/oby.20630
PMCID: PMC3946492  PMID: 24115765
functional MRI; bariatric surgery; neuroscience; weight loss; neuroimaging
5.  Effects of aging on blood brain barrier and matrix metalloproteases following controlled cortical impact in mice 
Experimental neurology  2011;234(1):50-61.
Aging alters the ability of the brain to respond to injury. One of the major differences between the adult and aged brain is that comparable injuries lead to greater blood brain barrier disruption in the aged brain. The goals of these studies were to quantify the effects of age on BBB permeability using high field strength MRI T1 mapping and to determine whether activation of matrix metalloproteases, their inhibitors, or expression of blood brain barrier structural proteins, occludin, zonnula occludins-1 (ZO-1) and claudin-5 were altered following injury to the aged C57/Bl6 mouse brain. T1 mapping studies revealed greater blood brain barrier permeability in the aged (21–15 months old) brain than in the adult (4–6 months old) following controlled cortical impact. The increased blood brain barrier permeability in the pericontusional region was confirmed with IgG immunohistochemistry. MMP-9 activity was increased following controlled cortical impact in the aged brain, and this was accompanied by increased MMP-9 gene expression. MMP-2 activity was higher in the uninjured aged brain than in the adult brain. Occludin and ZO-1 mRNA levels were unchanged following injury in either age group, but claudin-5 mRNA levels were lower in the aged than the adult brain following injury. These results demonstrate quantitative increases in blood brain barrier permeability in the aged brain following injury that are accompanied by increased MMP-9 activation and decreased blood brain barrier repair responses.
doi:10.1016/j.expneurol.2011.12.016
PMCID: PMC4042317  PMID: 22201549
Controlled cortical impact; Traumatic brain injury; Aging; T1 mapping; Blood brain barrier; MMP-9; MMP-2; Occludin; ZO-1; Claudin-5
6.  Motor and premotor cortices in subcortical stroke: proton magnetic resonance spectroscopy measures and arm motor impairment 
Background
Although functional imaging and neurophysiological approaches reveal alterations in motor and premotor areas after stroke, insights into neurobiological events underlying these alterations are limited in human studies.
Objective
We tested whether cerebral metabolites related to neuronal and glial compartments are altered in the hand representation in bilateral motor and premotor areas and correlated with distal and proximal arm motor impairment in hemiparetic persons.
Methods
In twenty participants at >6 months post-onset of a subcortical ischemic stroke and sixteen age and sex-matched healthy controls, the concentrations of N-acetylaspartate and myoinositol were quantified by proton magnetic resonance spectroscopy (1H-MRS). Regions of interest, identified by functional MRI, included primary (M1), dorsal premotor (PMd), and supplementary (SMA) motor areas. Relationships between metabolite concentrations and distal (hand) and proximal (shoulder/elbow) motor impairment using Fugl-Meyer Upper Extremity (FMUE) subscores were explored.
Results
N-acetylaspartate was lower in M1 (p=0.04) and SMA (p=0.004) and myo-inositol was higher in M1 (p=0.003) and PMd (p=0.03) in the injured (ipsilesional) hemisphere after stroke compared to the left hemisphere in controls. N-acetylaspartate in ipsilesional M1 was positively correlated with hand FMUE subscores (p=0.04). Significant positive correlations were also found between N-acetylaspartate in ipsilesional M1, PMd, and SMA and in contralesional M1 and shoulder/elbow FMUE subscores (p=0.02, 0.01, 0.02 and 0.02 respectively).
Conclusions
Our preliminary results demonstrated that 1H-MRS is a sensitive method to quantify relevant neuronal changes in spared motor cortex after stroke, and consequently increase our knowledge of the factors leading from these changes to arm motor impairment.
doi:10.1177/1545968312469835
PMCID: PMC3943339  PMID: 23300210
subcortical stroke; motor and premotor cortices; proton magnetic resonance spectroscopy; distal and proximal arm motor impairment
7.  Stroke after Carotid Stenting and Endarterectomy in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) 
Circulation  2012;126(25):3054-3061.
Background
Stroke occurs more commonly after carotid artery stenting than carotid endarterectomy. Details regarding stroke type, severity, and characteristics have not been previously reported. We describe the strokes occurring in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
Methods and Results
CREST is a randomized, open-allocation, controlled trial with blinded endpoint adjudication. Stroke was a component of the primary composite outcome. Patients who received their assigned treatment within 30 days of randomization are included. Stroke was adjudicated by a panel of board-certified vascular neurologists with secondary central review of clinically-obtained brain images. Stroke type, laterality, timing, and outcome are reported. A periprocedural stroke occurred among 81 of the 2502 patients randomized and among 69 of the 2272 in this analysis. Strokes were predominantly minor (81%, n=56), ischemic (90%, n=62), in the anterior circulation (94%, n=65), and ipsilateral to the treated artery (88%, n=61). There were seven hemorrhages, occurring 3-21 days post-procedure, and five were fatal. Major stroke occurred in 13 (0·6%) of the 2272 patients. The estimated four-year mortality after stroke was 21·1% compared to 11·6% for those without stroke. The adjusted risk of death at four years was higher after periprocedural stroke (HR = 2·78, CI95 1·63-4·76).
Conclusions
Stroke, particularly severe stroke, was uncommon after carotid intervention in CREST, but stroke was associated with significant morbidity and was independently associated with a near threefold increased future mortality. The delayed timing of major and hemorrhagic stroke after revascularization suggests that these strokes may be preventable.
doi:10.1161/CIRCULATIONAHA.112.120030
PMCID: PMC3638912  PMID: 23159552
stroke; carotid stenosis; endarterectomy; stents; randomized controlled trial; prevention
8.  Neurochemical Analysis of Primary Motor Cortex in Chronic Low Back Pain 
Brain sciences  2012;2(3):319-331.
The involvement of the primary motor cortex (M1) in chronic low back pain (LBP) is a relatively new concept. Decreased M1 excitability and an analgesic effect after M1 stimulation have been recently reported. However, the neurochemical changes underlying these functional M1 changes are unknown. The current study investigated whether neurochemicals specific to neurons and glial cells in both right and left M1 are altered. N-Acetylaspartate (NAA) and myo-inositol (mI) were measured with proton magnetic resonance spectroscopy in 19 subjects with chronic LBP and 14 healthy controls. We also examined correlations among neurochemicals within and between M1 and relationships between neurochemical concentrations and clinical features of pain. Right M1 NAA was lower in subjects with LBP compared to controls (p = 0.008). Left M1 NAA and mI were not significantly different between LBP and control groups. Correlations between neurochemical concentrations across M1s were different between groups (p = 0.008). There were no significant correlations between M1 neurochemicals and pain characteristics. These findings provide preliminary evidence of neuronal depression and altered neuronalglial interactions across M1 in chronic LBP.
doi:10.3390/brainsci2030319
PMCID: PMC3678773  PMID: 23766894
chronic low back pain; primary motor cortex; magnetic resonance spectroscopy; N-acetylaspartate; myo-inositol
9.  Neuronal–glial alterations in non-primary motor areas in chronic subcortical stroke 
Brain research  2012;1463:75-84.
Whether functional changes of the non-primary motor areas, e.g., dorsal premotor (PMd) and supplementary motor (SMA) areas, after stroke, reflect reorganization phenomena or recruitment of a pre-existing motor network remains to be clarified. We hypothesized that cellular changes in these areas would be consistent with their involvement in post-stroke reorganization. Specifically, we expected that neuronal and glial compartments would be altered in radiologically normal-appearing, i.e., spared, PMd and SMA in patients with arm paresis. Twenty survivors of a single ischemic subcortical stroke and 16 age-matched healthy controls were included. At more than six months after stroke, metabolites related to neuronal and glial compartments: N-acetylaspartate, myo-inositol, and glutamate/glutamine, were quantified by proton magnetic resonance spectroscopy in PMd and SMA in both injured (ipsilesional) and un-injured (contralesional) hemispheres. Correlations between metabolites were also calculated. Finally, relationships between metabolite concentrations and arm motor impairment (total and proximal Fugl-Meyer Upper Extremity, FMUE, scores) were analyzed. Compared to controls, stroke survivors showed significantly higher ipsilesional PMd myo-inositol and lower SMA N-acetylaspartate. Significantly lower metabolite correlations were found between ipsilesional and contralesional SMA. Ipsilesional N-acetylaspartate was significantly related to proximal FMUE scores. This study provides evidence of abnormalities in metabolites, specific to neuronal and glial compartments, across spared non-primary motor areas. Ipsilesional alterations were related to proximal arm motor impairment. Our results suggest the involvement of these areas in post-stroke reorganization.
doi:10.1016/j.brainres.2012.04.052
PMCID: PMC3626290  PMID: 22575560
1H-MRS; Neuronal and glial compartments; Non-primary motor areas; Subcortical stroke
10.  The Histopathologic Associates of Neurometabolite Abnormalities in Fatal Neuropsychiatric Systemic Lupus Erythematosus 
Arthritis and rheumatism  2010;62(7):2055-2063.
Objective
The present study determined the histopathologic basis of altered brain neurometabolites in neuropsychiatric systemic lupus erythematosus (NPSLE).
Methods
Brain neurometabolite concentrations in 20 voxels of brain were determined pre-mortem by magnetic resonance spectroscopy (MRS) in 7 individuals with NPSLE. Absolute neurometabolite concentrations for N-acetylaspartate (NAA), choline, Cre, and lactate were measured. After death, histopathologic changes were determined at brain autopsy, and matched to neurometabolites voxel by voxel.
Results
Absolute concentrations of NAA (Controls: 12.2±0.8 mM, NPSLE: 9.15±1.78 mM; p<0.01) and Cre (Controls: 6.90±0.60mM, NPSLE: 6.43±0.16 mM; p<0. 0.003) were significantly reduced, and levels choline (Controls: 1.92±0.32mM, NPSLE: 2.51±0.42 mM; p<0.04) were significantly elevated. Widespread heterogeneous histological changes in brain were present, including microinfarcts, microhemorrhages, bland angiopathy thrombotic angiopathy with platelet and fibrin thrombi, neuronal necrosis in various states of resolution, reduced numbers of axons and neurons, vacuole and space formation among the fibers, reduced numbers of oligodendrocytes, reactive microglia and astrocytes, lipid-laden macrophages, and cyst formation. Neurometabolite abnormalities were closely associated with underlying brain histopathologic changes: 1) elevated choline was independently associated with gliosis, vasculopathy, and edema (multivariate model: r = 0.75, p = 0.004); 2) reduced Cre with reduced neuronal-axonal density and gliosis (multivariate model: r = 0.72, p = 0.002); 3) reduced NAA with reduced neuronal-axonal density (0multivariate model: r = 0.66, p = 0.001), and 4) lactate with necrosis, microhemorrhages, and edema (multivariate model: r = 0.996, p = 0.0001).
Conclusions
Altered neurometabolites by MRS are a grave prognostic sign indicating serious underlying histologic brain injury.
doi:10.1002/art.27458
PMCID: PMC3612546  PMID: 20309864
Neuropsychiatric Lupus Erythematosus; Magnetic Resonance Spectroscopy; NPSLE; Pathology
11.  Magnetic Resonance Imaging And Brain Histopathology In Neuropsychiatric Systemic Lupus Erythematosus 
Objective
Magnetic resonance imaging (MRI) often demonstrates brain lesions in neuropsychiatric systemic lupus erythematosus (NPSL). The present study compared post-mortem histopathology with pre-mortem MRI in NPSL.
Methods
200 subjects with NPSLE were studied prospectively with MRI over a 10-year period during which 22 subjects died. In 14 subjects, a brain autopsy with histopathology that permitted direct comparison with pre mortem MRI was successfully obtained. Surface anatomy was used to determine the approximate location of individual lesions.
Results
Pre mortem MRI findings in fatal NPSLE were small focal white matter lesions (100%), cortical atrophy (64%), ventricular dilation (57%), cerebral edema (50%), diffuse white matter abnormalities (43%), focal atrophy (36%), cerebral infarction (29%), acute leukoencephalopathy (25%), intracranial hemorrhage (21%), and calcifications (7%). Microscopic findings in fatal NPSLE included global ischemic changes (57%), parenchymal edema (50%), microhemorrhages (43%), glial hyperplasia (43%), diffuse neuronal/axonal loss (36%), resolved cerebral infarction (33%), microthomboemboli (29%), blood vessel remodeling (29%), acute cerebral infarction (14%), acute macrohemorrhages (14%), and resolved intracranial hemorrhages (7%). Cortical atrophy and ventricular dilation seen by MRI predicted brain mass at autopsy (r = -0.72, p = 0.01, and r = -0.77, p =0.01, respectively). Cerebral autopsy findings, including infarction, cerebral edema, intracranial hemorrhage, calcifications, cysts, and focal atrophy were also predicted accurately by pre mortem MRI.
Conclusion
Brain lesions in NPSLE detected by MRI accurately represent serious underlying cerebrovascular and parenchymal brain injury on pathology.
doi:10.1016/j.semarthrit.2009.08.005
PMCID: PMC3586567  PMID: 19880162
SLE; Neuropsychiatric; Magnetic Resonance; NPSLE; MRI; Autopsy
12.  Insulin is Differentially Related to Cognitive Decline and Atrophy in Alzheimer’s Disease and Aging 
Biochimica et Biophysica Acta  2011;1822(3):333-339.
We assessed the relationship of insulin resistance with cognitive decline and brain atrophy over two years in early Alzheimer’s disease (AD, n=48) and nondemented controls (n=61). Intravenous glucose tolerance tests were conducted at baseline to determine insulin area-under-the-curve (AUC). A standard battery of cognitive tasks and MRI were conducted at baseline and 2-year follow-up. In nondemented controls, higher baseline insulin AUC was associated with 2-year decline in global cognitive performance (beta=−0.36, p=0.005). In early AD, however, higher insulin AUC was associated with less decline in global cognitive performance (beta=0.26, p=0.06), slower global brain atrophy (beta=0.40, p=0.01) and less regional atrophy in the bilateral hippocampi and cingulate cortices. While insulin resistance is associated with cognitive decline in nondemented aging, higher peripheral insulin may have AD-specific benefits or insulin signaling may be affected by systemic physiologic changes associated with AD.
doi:10.1016/j.bbadis.2011.06.011
PMCID: PMC3264795  PMID: 21745566
13.  The Neuroanatomy of Genetic Subtype Differences in Prader-Willi Syndrome 
American Journal of Medical Genetics  2012;159B(2):243-253.
Objective
Despite behavioral differences between genetic subtypes of Prader-Willi syndrome, no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of Prader-Willi syndrome (PWS) [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)].
Methods
Fifteen individuals with PWS due to a typical deletion ((DEL) Type I; n=5, Type II; n=10), 8 with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume between groups, covarying for age, sex, and body mass index (BMI).
Results
Overall, compared to HWC, PWS individuals had lower gray matter volumes that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower white matter volumes in the brain stem, cerebellum, medial temporal and frontal cortex. Compared to UPD, the DEL subtypes had lower gray matter volume primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and white matter volumes in the orbitofrontal and limbic cortices compared to HWC.
Conclusions
These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes.
doi:10.1002/ajmg.b.32022
PMCID: PMC3296480  PMID: 22241551
chromosome 15q; hyperphagia; obesity; voxel-based morphometry; MRI
14.  C9ORF72 Repeat Expansion in Australian and Spanish Frontotemporal Dementia Patients 
PLoS ONE  2013;8(2):e56899.
A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in ‘non-expansion’ patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5–17% of patients (21–41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine ‘expansion-positive’ patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an ‘intermediate’ allele with a mean size of only ∼65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of ‘non-expansion’ FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as ∼65 repeats may be sufficient to cause disease.
doi:10.1371/journal.pone.0056899
PMCID: PMC3577667  PMID: 23437264
15.  Frontotemporal dementia–amyotrophic lateral sclerosis syndrome locus on chromosome 16p12.1–q12.2: genetic, clinical and neuropathological analysis 
Acta Neuropathologica  2013;125(4):523-533.
Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1–16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1–16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1–q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1078-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-013-1078-9
PMCID: PMC3611035  PMID: 23338750
Frontotemporal dementia; Amyotrophic lateral sclerosis; Motor neuron disease; Corticobasal degeneration; Tau; TDP-43
16.  Branding and a child’s brain: an fMRI study of neural responses to logos 
Branding and advertising have a powerful effect on both familiarity and preference for products, yet no neuroimaging studies have examined neural response to logos in children. Food advertising is particularly pervasive and effective in manipulating choices in children. The purpose of this study was to examine how healthy children’s brains respond to common food and other logos. A pilot validation study was first conducted with 32 children to select the most culturally familiar logos, and to match food and non-food logos on valence and intensity. A new sample of 17 healthy weight children were then scanned using functional magnetic resonance imaging. Food logos compared to baseline were associated with increased activation in orbitofrontal cortex and inferior prefrontal cortex. Compared to non-food logos, food logos elicited increased activation in posterior cingulate cortex. Results confirmed that food logos activate some brain regions in children known to be associated with motivation. This marks the first study in children to examine brain responses to culturally familiar logos. Considering the pervasiveness of advertising, research should further investigate how children respond at the neural level to marketing.
doi:10.1093/scan/nss109
PMCID: PMC3871732  PMID: 22997054
children; brands; fMRI; prefrontal cortex; neuromarketing; food logos
17.  Altered neurochemical profile after traumatic brain injury: 1H-MRS biomarkers of pathological mechanisms 
Specific neurochemicals measured with proton magnetic resonance spectroscopy (1H-MRS) may serve as biomarkers of pathological mechanism in the brain. We used high field in vivo 1H-MRS to measure a detailed neurochemical profile after experimental traumatic brain injury (TBI) in rats. We characterized neurochemical changes in the contused cortex and the normal-appearing perilesional hippocampus over a time course from 1 hour to 2 weeks after injury. We found significant changes in 19 out of 20 neurochemicals in the cortex, and 9 out of 20 neurochemicals in the hippocampus. These changes provide evidence of altered cellular metabolic status after TBI, with specific compounds proposed to reflect edema, excitotoxicity, neuronal and glial integrity, mitochondrial status and bioenergetics, oxidative stress, inflammation, and cell membrane disruption. Our results support the utility of 1H-MRS for monitoring cellular mechanisms of TBI pathology in animal models, and the potential of this approach for preclinical evaluation of novel therapies.
doi:10.1038/jcbfm.2012.114
PMCID: PMC3519407  PMID: 22892723
animal models; brain trauma; cell death mechanisms; MR spectroscopy; neurochemistry
18.  Importance of Reward and Prefrontal Circuitry in Hunger and Satiety: Prader-Willi Syndrome vs. Simple Obesity 
Background
The majority of research on obesity has focused primarily on clinical features (eating behavior, adiposity measures), or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions which are associated with appetite-regulatory hormones are also involved in the development and maintenance of obesity. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic obesity. Simple (non-PWS) obesity (OB) represents an obesity control state.
Objective
This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (i.e., hypothalamus, amygdala) and prefrontal regions associated with cognitive control [i.e., dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC)] after eating.
Design and Participants
Fourteen individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls (HWC) viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC, and DLPFC.
Results
Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in hypothalamus and hippocampus, in response to food (vs. non-food) images pre-meal. Post-meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared to OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control.
Conclusion
In PWS compared with obesity per se, results suggest hyperactivations in subcortical reward circuitry and hypoactivations in cortical inhibitory regions after eating, which provides evidence of neural substrates associated with variable abnormal food motivation phenotypes in PWS and simple obesity.
doi:10.1038/ijo.2011.204
PMCID: PMC3270121  PMID: 22024642
obesity; DLPFC; inhibition; motivation; fMRI; Prader-Willi syndrome
19.  Neurochemical Analysis of Primary Motor Cortex in Chronic Low Back Pain 
Brain Sciences  2012;2(3):319-331.
The involvement of the primary motor cortex (M1) in chronic low back pain (LBP) is a relatively new concept. Decreased M1 excitability and an analgesic effect after M1 stimulation have been recently reported. However, the neurochemical changes underlying these functional M1 changes are unknown. The current study investigated whether neurochemicals specific to neurons and glial cells in both right and left M1 are altered. N-Acetylaspartate (NAA) and myo-inositol (mI) were measured with proton magnetic resonance spectroscopy in 19 subjects with chronic LBP and 14 healthy controls. We also examined correlations among neurochemicals within and between M1 and relationships between neurochemical concentrations and clinical features of pain. Right M1 NAA was lower in subjects with LBP compared to controls (p = 0.008). Left M1 NAA and mI were not significantly different between LBP and control groups. Correlations between neurochemical concentrations across M1s were different between groups (p = 0.008). There were no significant correlations between M1 neurochemicals and pain characteristics. These findings provide preliminary evidence of neuronal depression and altered neuronal-glial interactions across M1 in chronic LBP.
doi:10.3390/brainsci2030319
PMCID: PMC3678773  PMID: 23766894
chronic low back pain; primary motor cortex; magnetic resonance spectroscopy; N-acetylaspartate; myo-inositol
20.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
21.  Alternate Day Fasting Impacts the Brain Insulin Signaling Pathway of Young Adult Male C57BL/6 Mice 
Journal of neurochemistry  2011;117(1):154-163.
Dietary restriction (DR) has recognized health benefits that may extend to brain. We examined how DR affects bioenergetics-relevant enzymes and signaling pathways in the brains of C57BL/6 mice. Five month-old male mice were placed in ad libitum (AL) or one of two repeated fasting and refeeding (RFR) groups, an alternate day (intermittent fed; IF) or alternate day plus antioxidants (blueberry, pomegranate, and green tea extracts) (IF+AO) fed group. During the 24 hour fast blood glucose levels initially fell but stabilized within 6 hours of starting the fast, thus avoiding frank hypoglycemia. DR in general appeared to enhance insulin sensitivity. After six weeks brain AKT and GSK3β phosphorylation were lower in the RFR mice, suggesting RFR reduced brain insulin signaling pathway activity. Pathways that mediate mitochondrial biogenesis were not activated; AMPK phosphorylation, SIRT1 phosphorylation, PGC1a levels, and COX4 levels did not change. ATP levels also did not decline, which suggests the RFR protocols did not directly impact brain bioenergetics. Antioxidant supplementation did not affect the brain parameters we evaluated. Our data indicate in young adult male C57BL/6 mice, RFR primarily affects brain energy metabolism by reducing brain insulin signaling, which potentially results indirectly as a consequence of reduced peripheral insulin production.
doi:10.1111/j.1471-4159.2011.07184.x
PMCID: PMC3055925  PMID: 21244426
antioxidants; brain; caloric restriction; dietary restriction; insulin; mitochondrial biogenesis
22.  Primary Motor Cortex in Stroke A Functional MRI-Guided Proton MR Spectroscopic Study 
Background and Purpose
Our goal was to investigate whether certain metabolites, specific to neurons, glial cells, or the neuronal-glial neurotransmission system, in primary motor cortices (M1), are altered and correlated with clinical motor severity in chronic stroke.
Methods
Fourteen survivors of a single ischemic stroke located outside the M1 and 14 age-matched healthy control subjects were included. At >6 months after stroke, N-acetylaspartate, myo-inositol, and glutamate/glutamine were measured using proton magnetic resonance spectroscopic imaging (in-plane resolution=5×5 mm2) in radiologically normal-appearing gray matter of the hand representation area, identified by functional MRI, in each M1. Metabolite concentrations and analyses of metabolite correlations within M1 were determined. Relationships between metabolite concentrations and arm motor impairment were also evaluated.
Results
The stroke survivors showed lower N-acetylaspartate and higher myo-inositol across ipsilesional and contral-esional M1 compared with control subjects. Significant correlations between N-acetylaspartate and glutamate/glutamine were found in either M1. Ipsilesional N-acetylaspartate and glutamate/glutamine were positively correlated with arm motor impairment and contralesional N-acetylaspartate with time after stroke.
Conclusions
Our preliminary data demonstrated significant alterations of neuronal-glial interactions in spared M1 with the ipsilesional alterations related to stroke severity and contralesional alterations to stroke duration. Thus, MR spectroscopy might be a sensitive method to quantify relevant metabolite changes after stroke and consequently increase our knowledge of the factors leading from these changes in spared motor cortex to motor impairment after stroke.
doi:10.1161/STROKEAHA.110.601047
PMCID: PMC3266712  PMID: 21330627
1H-MRS; motor impairment; plasticity; primary motor cortex; stroke; plasticity
23.  Safety of Stenting and Endarterectomy by Symptomatic Status in the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) 
Background and Purpose
The safety of carotid artery stenting (CAS) and carotid endarterectomy (CEA) has varied by symptomatic status in previous trials. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) data were analyzed to determine safety in symptomatic and asymptomatic patients.
Methods
CREST is a randomized trial comparing safety and efficacy of CAS versus CEA in patients with high-grade carotid stenoses. Patients were defined as symptomatic if they had relevant symptoms within 180 days of randomization. The primary endpoint was stroke, myocardial infarction, or death within the periprocedural period or ipsilateral stroke up to 4 years.
Results
For 1321 symptomatic and 1181 asymptomatic patients, the periprocedural aggregate of stroke, myocardial infarction, and death did not differ between CAS and CEA (5.2% versus 4.5%; hazard ratio, 1.18; 95% CI, 0.82 to 1.68; P=0.38). The stroke and death rate was higher for CAS versus CEA (4.4% versus 2.3%; hazard ratio, 1.90; 95% CI, 1.21 to 2.98; P=0.005). For symptomatic patients, the periprocedural stroke and death rates were 6.0%±0.9% for CAS and 3.2%±0.7% for CEA (hazard ratio, 1.89; 95% CI, 1.11 to 3.21; P=0.02). For asymptomatic patients, the stroke and death rates were 2.5%±0.6% for CAS and 1.4%±0.5% for CEA (hazard ratio, 1.88; 95% CI, 0.79 to 4.42; P=0.15). Rates were lower for those aged <80 years.
Conclusions
There were no significant differences between CAS versus CEA by symptomatic status for the primary CREST endpoint. Periprocedural stroke and death rates were significantly lower for CEA in symptomatic patients. However, for both CAS and CEA stroke and death rates were below or comparable to those of previous randomized trials and were within the complication thresholds suggested in current guidelines for both symptomatic and asymptomatic patients.
doi:10.1161/STROKEAHA.110.610212
PMCID: PMC3125963  PMID: 21307169
carotid endarterectomy; cerebral infarct; cerebrovascular disease; clinical trials; myocardial infarction; stenting; surgery/endarterectomy
24.  Cutaneous stimulation of the digits and lips evokes responses with different adaptation patterns in primary somatosensory cortex 
NeuroImage  2010;52(4):1477-1486.
Neuromagnetic evoked fields were recorded to compare the adaptation of the primary somatosensory cortex (SI) response to tactile stimuli delivered to the glabrous skin at the fingertips of the first three digits (condition 1) and between midline upper and lower lips (condition 2). The stimulation paradigm allowed to characterize the response adaptation in the presence of functional integration of tactile stimuli from adjacent skin areas in each condition. At each stimulation site, cutaneous stimuli (50 ms duration) were delivered in three runs, using trains of 6 pulses with regular stimulus onset asynchrony (SOA). The pulses were separated by SOAs of 500 ms, 250 ms or 125 ms in each run, respectively, while the inter-train interval was fixed (5 s) across runs. The evoked activity in SI (contralateral to the stimulated hand, and bilaterally for lips stimulation) was characterized from the best-fit dipoles of the response component peaking around 70 ms for the hand stimulation, and 8 ms earlier (on average) for the lips stimulation. The SOA-dependent long-term adaptation effects were assessed from the change in the amplitude of the responses to the first stimulus in each train. The short-term adaptation was characterized by the lifetime of an exponentially saturating model function fitted to the set of suppression ratios of the second relative to the first SI response in each train. Our results indicate: 1) the presence of a rate-dependent long-term adaptation effect induced only by the tactile stimulation of the digits; and 2) shorter recovery lifetimes for the digits compared with the lips stimulation.
doi:10.1016/j.neuroimage.2010.05.062
PMCID: PMC2910220  PMID: 20561996
magnetoencephalography; somatosensory evoked fields
25.  Diagnostic Utility of Cerebral White Matter Integrity in Early Alzheimer's Disease 
We compared white matter integrity with brain atrophy in healthy controls and participants with very mild dementia (Clinical Dementia Rating 0 vs. 0.5) from the Brain Aging Project, a longitudinal study of aging and memory at the University of Kansas Medical Center. Structural magnetic resonance imaging and diffusion tensor imaging (DTI) including fractional anisotropy and mean diffusivity were performed on 27 patients with very mild dementia (Clinical Dementia Rating = 0.5) of the Alzheimer's type (DAT), and 32 cognitively normal subjects. Patient groups were compared across 6 volumetric measures and 14 DTI regions of interest. Very mildly demented patients showed expected disease-related patterns of brain atrophy with reductions in whole-brain and hippocampal volumes most prominent. DTI indices of white matter integrity were mixed. Right parahippocampus showed significant but small disease-related reductions in fractional anisotropy. Right parahippocampus and left internal capsule showed greater mean diffusivity in early DAT compared with controls. A series of discriminant analyses demonstrated that gray matter atrophy was a significantly better predictor of dementia status than were DTI indices. Brain atrophy was most strongly related to very mild DAT. Modest disease-related white matter anomalies were present in temporal cortex, and deep white matter had limited discriminatory diagnostic power, probably because of the very mild stage of disease in these participants.
doi:10.3109/00207454.2010.494788
PMCID: PMC3108435  PMID: 20615058
Alzheimer's disease; brain atrophy; diffusion tensor imaging (DTI); white matter disease

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