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1.  Scale dependence of structure-function relationship in the emphysematous mouse lung 
The purpose of this study was to determine how the initial distribution of elastase in mouse lungs determines the time course of tissue destruction and how structural heterogeneity at different spatial scales influences lung function. We evaluated lung function and alveolar structure in normal and emphysematous C57BL/6 mice at 2 and 21 days following orotracheal treatment with porcine pancreatic elastase (PPE). Initial distribution of elastase 1 h after treatment was assessed using red fluorescently labeled PPE (f-PPE) by laser scanning confocal microscopy. From measured input impedance of the respiratory system, the global lung compliance, and the variability of regional compliance were obtained. Lungs were fixed and equivalent airspace diameters were measured in four lobes of the right lung and three regions of the left lung. At day 2 and day 21, the mean airspace diameter of each region was significantly enlarged which was accompanied by an increased inter-regional heterogeneity. The deposition of f-PPE on day 0 was much more heterogeneous than the inter-regional diameters at both day 2 and day 21 and, at day 21, this reached statistical significance (p < 0.05). Microscale heterogeneity characterized by the overall variability of airspace diameters correlated significantly better with compliance than macroscale or inter-regional heterogeneity. Furthermore, while the spatial distribution of the inflammatory response does not seem to follow that of the elastase deposition, it correlates with the strongest regional determinant of lung function. These results may help interpret lung function decline in terms of structural deterioration in human patients with emphysema.
PMCID: PMC4428081  PMID: 26029115
heterogeneity; airspace diameter; lung; compliance; inflammation
2.  Characterization of Atypical Language Activation Patterns in Focal Epilepsy 
Annals of neurology  2014;75(1):33-42.
Functional magnetic resonance imaging is sensitive to the variation in language network patterns. Large populations are needed to rigorously assess atypical patterns, which, even in neurological populations, are a minority.
We studied 220 patients with focal epilepsy and 118 healthy volunteers who performed an auditory description decision task. We compared a data-driven hierarchical clustering approach to the commonly used a priori laterality index (LI) threshold (LI < 0.20 as atypical) to classify language patterns within frontal and temporal regions of interest. We explored (n = 128) whether IQ varied with different language activation patterns.
The rate of atypical language among healthy volunteers (2.5%) and patients (24.5%) agreed with previous studies; however, we found 6 patterns of atypical language: a symmetrically bilateral, 2 unilaterally crossed, and 3 right dominant patterns. There was high agreement between classification methods, yet the cluster analysis revealed novel correlations with clinical features. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified an association of handedness with frontal lateralization, early seizure onset with temporal lateralization, and left hemisphere focus with a unilateral right pattern. Intelligence quotient was not significantly different among patterns.
Language dominance is a continuum; however, our results demonstrate meaningful thresholds in classifying laterality. Atypical language patterns are less frequent but more variable than typical language patterns, posing challenges for accurate presurgical planning. Language dominance should be assessed on a regional rather than hemispheric basis, and clinical characteristics should inform evaluation of atypical language dominance. Reorganization of language is not uniformly detrimental to language functioning.
PMCID: PMC4209919  PMID: 24038442
3.  PET of Serotonin 1A Receptors and Cerebral Glucose Metabolism for Temporal Lobectomy 
The objective of this study was to compare 5-hydroxytryptamine receptor 1A (5-HT1A) PET with cerebral metabolic rate of glucose (CMRglc) PET for temporal lobectomy planning.
We estimated 5-HT1A receptor binding preoperatively with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18F-FCWAY) PET and CMRglc measurement with 18F-FDG in regions drawn on coregistered MRI after partial-volume correction in 41 patients who had anterior temporal lobectomy with at least a 1-y follow-up. Surgery was tailored to individual preresection evaluations and intraoperative electrocorticography. Mean regional asymmetry values and the number of regions with asymmetry exceeding 2 SDs in 16 healthy volunteers were compared between seizure-free and non–seizure-free patients. 18F-FCWAY but not 18F-FDG and MRI data were masked for surgical decisions and outcome assessment.
Twenty-six of 41 (63%) patients seizure-free since surgery had significantly different mesial temporal asymmetries, compared with 15 non-seizure-free patients for both 18F-FCWAY (F1,39 = 5.87; P = 0.02) and 18F-FDG PET (F1,38 = 5.79; P = 0.021). The probability of being seizure-free was explained by both 18F-FDG and 18F-FCWAY PET, but not MRI, with a significant additional 18F-FCWAY effect (χ22=9.8796; P = 0.0072) after the probability of being seizure-free was explained by 18F-FDG. Although MRI alone was not predictive, any combination of 2 lateralizing imaging studies was highly predictive of seizure freedom.
Our study provides class III evidence that both 5-HT1A receptor PET and CMRglc PET can contribute to temporal lobectomy planning. Additional studies should explore the potential for temporal lobectomy based on interictal elec-troencephalography and minimally invasive imaging studies.
PMCID: PMC3856554  PMID: 22782314
glucose metabolism; positron emission tomography; serotonin receptors; temporal lobe epilepsy
4.  Thioredoxin-1 Protects against Neutrophilic Inflammation and Emphysema Progression in a Mouse Model of Chronic Obstructive Pulmonary Disease Exacerbation 
PLoS ONE  2013;8(11):e79016.
Exacerbations of chronic obstructive pulmonary disease (COPD) are characterized by acute enhancement of airway neutrophilic inflammation under oxidative stress and can be involved in emphysema progression. However, pharmacotherapy against the neutrophilic inflammation and emphysema progression associated with exacerbation has not been established. Thioredoxin-1 has anti-oxidative and anti-inflammatory properties and it can ameliorate neutrophilic inflammation through anti-chemotactic effects and prevent cigarette smoke (CS)-induced emphysema. We aimed to determine whether thioredoxin-1 can suppress neutrophilic inflammation and emphysema progression in a mouse model of COPD exacerbation and if so, to reveal the underlying mechanisms.
Mice were exposed to CS and then challenged with polyinosine-polycytidylic acid [poly(I:C)], an agonist for virus-induced innate immunity. Airway neutrophilic inflammation, oxidative stress and lung apoptosis were enhanced in smoke-sensitive C57Bl/6, but not in smoke-resistant NZW mice. Exposure to CS and poly(I:C) challenge accelerated emphysema progression in C57Bl/6 mice. Thioredoxin-1 suppressed neutrophilic inflammation and emphysema progression. Poly(I:C) caused early neutrophilic inflammation through keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor (GM-CSF) release in the lung exposed to CS. Late neutrophilic inflammation was caused by persistent GM-CSF release, which thioredoxin-1 ameliorated. Thioredoxin-1 enhanced pulmonary mRNA expression of MAP kinase phosphatase 1 (MKP-1), and the suppressive effects of thioredoxin-1 on prolonged GM-CSF release and late neutrophilic inflammation disappeared by inhibiting MKP-1.
Using a mouse model of COPD exacerbation, we demonstrated that thioredoxin-1 ameliorated neutrophilic inflammation by suppressing GM-CSF release, which prevented emphysema progression. Our findings deepen understanding of the mechanisms underlying the regulation of neutrophilic inflammation by thioredoxin-1 and indicate that thioredoxin-1 could have potential as a drug to counteract COPD exacerbation.
PMCID: PMC3823967  PMID: 24244404
5.  Cortical mapping and frameless stereotactic navigation in the high-field intraoperative magnetic resonance imaging suite 
Journal of neurosurgery  2009;111(6):1185-1190.
Frameless stereotactic neuronavigation provides tracking of surgical instruments on radiographic images and orients the surgeon to tumor margins at surgery. Bipolar electrical stimulation mapping (ESM) delineates safe limits for resection of brain tumors adjacent to eloquent cortex. These standard techniques could complement the capability of intraoperative MR (iMR) imaging to evaluate for occult residual disease during surgery and promote more complete tumor removal. The use of frameless neuronavigation in the high-field iMR imaging suite requires that a few pieces of standard equipment be replaced by nonferromagnetic instruments. Specific use of ESM in a high-field iMR imaging suite has not been reported in the literature. To study whether frameless neuronavigation and electrical stimulation mapping could be successfully integrated in the high-field iMR imaging suite, the authors employed these modalities in 10 consecutive cases involving patients undergoing conscious craniotomy for primary brain tumors located in or adjacent to eloquent cortices. Equipment included a custom high-field MR imaging–compatible head holder and dynamic reference frame attachment, a standard MR imaging–compatible dynamic reference frame, a standard MR imaging machine with a table top that could be translated to a pedestal outside the 5-gauss line for the operative intervention, and standard neuronavigational and cortical stimulation equipment. Both ESM and frameless stereotactic guidance were performed outside the 5-gauss line. The presence of residual neoplasm was evaluated using iMR imaging; resection was continued until eloquent areas were encountered or iMR imaging confirmed complete removal of any residual tumor. Mapping identified essential language (5 patients), sensory (6), and motor (7) areas. The combined use of frameless stereotactic navigation, ESM, and iMR imaging resulted in complete radiographic resection in 7 cases and resection to an eloquent margin in 3 cases. Postoperative MR imaging confirmed final iMR imaging findings. No patient experienced a permanent new neurological deficit. Familiar techniques such as frameless navigation and ESM can be rapidly, inexpensively, safely, and effectively integrated into the high-field iMR imaging suite.
PMCID: PMC3799986  PMID: 19499978
brain mapping; intraoperative magnetic resonance imaging; brain tumor surgery; stereotactic techniques
6.  Cerebral Blood Flow and fMRI BOLD Auditory Language Activation in Temporal Lobe Epilepsy 
Epilepsia  2012;53(4):631-638.
BOLD fMRI, an important research and clinical tool, depends on relatively greater transient increases in (cerebral blood flow) rCBF than CMRO2 during neural activity. We investigated whether reduced resting rCBF in patients with TLE affects BOLD signal during fMRI language mapping.
We used [15O] water PET to measure rCBF, and 3T EPI BOLD fMRI with an auditory description decision task in 33 patients with temporal lobe epilepsy (16 men; age 33.6±10.6 years; epilepsy onset 14.8±10.6 years; mean duration 18.8±13.2 years; 23 left focus, 10 right focus). Anatomical regions drawn on structural MRI, based on the Wake Forest PickAtlas, included Wernicke’s area (WA), inferior frontal gyrus (IFG), middle frontal gyrus (MFG), and hippocampus (HC)]. Laterality indices (LI), and Asymmetry Indices (AI), were calculated on co-registered fMRI and PET.
Key findings
Twelve patients had mesial temporal sclerosis (7 left), two a tumor or malformation of cortical development (both left), one a right temporal cyst and 18 normal MRI (14 left). Decreasing relative left WA CBF correlated with decreased left IFG voxel activation and decreasing left IFG LI. However, CBF WA AI was not related to left WA voxel activation itself or WA LI. There was a weak positive correlation between absolute CBF and fMRI activation in left IFG, right IFG, and left WA. Patients with normal and abnormal MRI did not differ in fMRI activation or rCBF AI.
Reduced WA rCBF is associated with reduced fMRI activation in IFG but not WA itself, suggesting distributed network effects, but not impairment of underlying BOLD response. Hypoperfusion in TLE does not affect fMRI clinical value.
PMCID: PMC3319237  PMID: 22332720
PET; CBF; fMRI; TLE; language; BOLD
7.  Serotonin 1A Receptors, Depression, and Memory in Temporal Lobe Epilepsy 
Epilepsia  2011;53(1):129-133.
Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous PET studies have shown reduced mesial temporal 5HT1A receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A receptor binding binding measured with 18FCWAY positron emission tomography (PET) in a cross sectional study.
We studied 40 patients (24 male; mean age 34.5 ±10.7) with TLE. Seizure diagnosis and focus localization were based on ictal Video-Electoencephalographic recording. Patients had neuropsychological testing with Weschler Adult Intelligence Score III (WAIS III) and Weschler Memory Score III (WMS III) on stable AED regimens at least 24 hours since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with [18F]FCWAY, a fluorinated derivative of WAY100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected [18F]FCWAY volume of distribution (V/f1).
Key Findings
Hippocampal V/f1 was significantly lower ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 versus 95.4 ± 28.4; p<.001). We found a significant relation between both left hippocampal FCWAY V/f1 (r= 0.41; p < 0.02) and left hippocampal volume (r=0.36; p < 0.03) and delayed auditory memory score. On multiple regression there was a significant effect of the interaction of left hippocampal FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal FCWAY V/f1 but not focus laterality retained significance.
Mean BDI was 8.3 ±7.0. There was a significant inverse relation between BDI and FCWAY V/f1 ipsilateral to the patient’s epileptic focus (r= 0.38 p<0.02) There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory.
Our study suggests that reduced left hippocampal 5-HT1A receptor binding may play a role in memory impairment in patients with TLE.
PMCID: PMC3253243  PMID: 22050514
Serotonin Receptors; Temporal Lobe Epilepsy; Memory; Depression; PET Scanning
9.  Neonatal Diagnosis and Treatment of Menkes Disease 
The New England journal of medicine  2008;358(6):605-614.
Menkes disease is a fatal neurodegenerative disorder of infancy caused by diverse mutations in a copper-transport gene, ATP7A. Early treatment with copper injections may prevent death and illness, but presymptomatic detection is hindered by the inadequate sensitivity and specificity of diagnostic tests. Exploiting the deficiency of a copper enzyme, dopamine-β-hydroxylase, we prospectively evaluated the diagnostic usefulness of plasma neurochemical levels, assessed the clinical effect of early detection, and investigated the molecular bases for treatment outcomes.
Between May 1997 and July 2005, we measured plasma dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol in 81 infants at risk. In 12 newborns who met the eligibility criteria and began copper-replacement therapy within 22 days after birth, we tracked survival and neurodevelopment longitudinally for 1.5 to 8 years. We characterized ATP7A mutations using yeast complementation, reverse-transcriptase–polymerase-chain-reaction analysis, and immunohistochemical analysis.
Of 81 infants at risk, 46 had abnormal neurochemical findings indicating low dopamine-β-hydroxylase activity. On the basis of longitudinal follow-up, patients were classified as affected or unaffected by Menkes disease, and the neurochemical profiles were shown to have high sensitivity and specificity for detecting disease. Among 12 newborns with positive screening tests who were treated early with copper, survival at a median follow-up of 4.6 years was 92%, as compared with 13% at a median follow-up of 1.8 years for a historical control group of 15 late-diagnosis and late-treatment patients. Two of the 12 patients had normal neurodevelopment and brain myelination; 1 of these patients had a mutation that complemented a Saccharomyces cerevisiae copper-transport mutation, indicating partial ATPase activity, and the other had a mutation that allowed some correct ATP7A splicing.
Neonatal diagnosis of Menkes disease by plasma neurochemical measurements and early treatment with copper may improve clinical outcomes. Affected newborns who have mutations that do not completely abrogate ATP7A function may be especially responsive to early copper treatment.
PMCID: PMC3477514  PMID: 18256395
10.  Longitudinal Study of Spatially Heterogeneous Emphysema Progression in Current Smokers with Chronic Obstructive Pulmonary Disease 
PLoS ONE  2012;7(9):e44993.
Cigarette smoke is the main risk factor for emphysema, which is a key pathology in chronic obstructive pulmonary disease (COPD). Low attenuation areas (LAA) in computed tomography (CT) images reflect emphysema, and the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D. This property of LAA clusters can be explained by model simulation, where mechanical force breaks alveolar walls causing local heterogeneous lung tissue destruction. However, a longitudinal CT study has not investigated whether continuous smoking causes the spatially heterogeneous progression of emphysema.
We measured annual changes in ratios of LAA (LAA%), D and numbers of LAA clusters (LAN) in CT images acquired at intervals of ≥3 years from 22 current and 31 former smokers with COPD to assess emphysema progression. We constructed model simulations using CT images to morphologically interpret changes in current smokers.
D was decreased in current and former smokers, whereas LAA% and LAN were increased only in current smokers. The annual changes in LAA%, D, and LAN were greater in current, than in former smokers (1.03 vs. 0.37%, p = 0.008; −0.045 vs. −0.01, p = 0.004; 13.9 vs. 1.1, p = 0.007, respectively). When LAA% increased in model simulations, the coalescence of neighboring LAA clusters decreased D, but the combination of changes in D and LAN in current smokers could not be explained by the homogeneous emphysema progression model despite cluster coalescence. Conversely, a model in which LAAs heterogeneously increased and LAA clusters merged somewhat in relatively advanced emphysematous regions could reflect actual changes.
Susceptibility to parenchymal destruction induced by continuous smoking is not uniform over the lung, but might be higher in local regions of relatively advanced emphysema. These could result in the spatially heterogeneous progression of emphysema in current smokers.
PMCID: PMC3445600  PMID: 23028728
11.  An Open Label Trial of Donepezil for Enhancement of Rapid Eye Movement Sleep in Young Children with Autism Spectrum Disorders 
Rapid eye movement (REM) sleep is greatest in the developing brain, is driven by acetylcholine, and may represent a protected time for neuroplasticity. Recently published data from our lab observed that children with autism spent significantly less time in this state during a single night recording than did typically developing children and those with developmental delay without autism. The objective of this study was to determine whether or not donepezil can increase the REM % in children with diagnosed autism spectrum disorder (ASD) found to have REM % values of at least two standard deviations below expected for age.
Five subjects found to have an ASD (ages 2.5–6.9 years) and demonstrated deficits in REM sleep compared with within-lab controls were enrolled in a dose finding study of donepezil. Each subject was examined by polysomnography for REM sleep augmentation after drug administration.
REM sleep as a percentage of Total Sleep Time was increased significantly and REM latency was decreased significantly after drug administration in all subjects. No other observed sleep parameter was changed significantly.
Donepezil can increase the amount of time that children with an ASD spend in the REM sleep state. A double-blind, placebo-controlled trial is needed to assess the association between REM sleep augmentation and learning, cognition, and behavior in such children.
PMCID: PMC3157749  PMID: 21851192
12.  Relationship between Periodontitis-Related Antibody and Frequent Exacerbations in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2012;7(7):e40570.
To identify patients with chronic obstructive pulmonary disease (COPD) who are susceptible to frequent exacerbations is important. Although periodontitis aggravated by poor oral hygiene might increase the risk of lower respiratory tract infection, the relationship between periodontitis and COPD exacerbations remains unknown. This prospective cohort study investigates the relationship between periodontitis-related antibody and exacerbation frequency over a one-year period.
We assessed an IgG antibody titer against Porphyromonas gingivalis, which is a major pathogen of periodontitis, and then prospectively followed up 93 individuals over one year to detect exacerbations.
The numbers of exacerbations and the rate of individuals with frequent exacerbations (at least two per year) were significantly lower in patients with higher IgG titer than those with normal IgG titer (0.8 vs. 1.2 per year, p  = 0.045 and 14.3 vs. 38.6%, p  = 0.009, respectively). Multivariate logistic regression analysis showed that being normal-IgG titer for periodontitis-related antibody significantly increased the risk of frequent exacerbations (relative risk, 5.27, 95% confidence interval, 1.30–25.7; p  = 0.019) after adjusting for other possible confounders, such as a history of exacerbations in the past year, disease severity, COPD medication and smoking status.
Normal-IgG titer for periodontitis-related antibody can be an independent predictor of frequent exacerbations. Measuring periodontitis-related antibody titers might be useful to identify patients with susceptibility to frequent exacerbations so that an aggressive prevention strategy can be designed.
PMCID: PMC3394734  PMID: 22792372
13.  Emphysema distribution and annual changes in pulmonary function in male patients with chronic obstructive pulmonary disease 
Respiratory Research  2012;13(1):31.
The progression of chronic obstructive pulmonary disease (COPD) considerably varies among patients. Those with emphysema identified by quantitative computed tomography (CT) are associated with the rapid progression assessed by forced expiratory volume in one second (FEV1). However, whether the rate of the decline in lung function is independently affected by the regional distribution or the severity of emphysema in the whole lung is unclear.
We followed up 131 male patients with COPD for a median of 3.7 years. We measured wall area percent (WA%) in right apical segmental bronchus, total lung volume, percent low attenuation volume (LAV%), and the standard deviation (SD) of LAV% values from CT images of 10 isovolumetric partitions (SD-LAV) as an index of cranial-caudal emphysema heterogeneity. Annual changes in FEV1 were then determined using a random coefficient model and relative contribution of baseline clinical parameters, pulmonary function, and CT indexes including LAV%, SD-LAV, and WA% to annual changes in FEV1 were examined.
The mean (SD) annual change in FEV1 was −44.4 (10.8) mL. Multivariate random coefficient model showed that higher baseline FEV1, higher LAV%, current smoking, and lower SD-LAV independently contributed to an excessive decline in FEV1, whereas ratio of residual volume to total lung capacity, ratio of diffusing capacity to alveolar ventilation, and WA% did not, after adjusting for age, height, weight, and ratio of CT-measured total lung volume to physiologically-measured total lung capacity.
A more homogeneous distribution of emphysema contributed to an accelerated decline in FEV1 independently of baseline pulmonary function, whole-lung emphysema severity, and smoking status. In addition to whole-lung analysis of emphysema, CT assessment of the cranial-caudal distribution of emphysema might be useful for predicting rapid, progressive disease and for developing a targeted strategy with which to prevent disease progression.
PMCID: PMC3478996  PMID: 22512922
Chronic obstructive pulmonary diseases; COPD; CT; Emphysema; Lung function; Heterogeneity
14.  Molecular correlates of epilepsy in early diagnosed and treated Menkes disease 
Epilepsy is a major feature of Menkes disease, an X-linked recessive infantile neurodegenerative disorder caused by mutations in ATP7A, which produces a copper-transporting ATPase. Three prior surveys indicated clinical seizures and electroencephalographic (EEG) abnormalities in a combined 27 of 29 (93%) symptomatic Menkes disease patients diagnosed at 2 months of age or older. To assess the influence of earlier, presymptomatic diagnosis and treatment on seizure semiology and brain electrical activity, we evaluated 71 EEGs in 24 Menkes disease patients who were diagnosed and treated with copper injections in early infancy (≤6 weeks of age), and whose ATP7A mutations we determined. Clinical seizures were observed in only 12.5% (3/24) of these patients, although 46% (11/24) had at least one abnormal EEG tracing, including 50% of patients with large deletions in ATP7A, 50% of those with small deletions, 60% of those with nonsense mutations, and 57% of those with canonical splice junction mutations. In contrast, five patients with mutations shown to retain partial function, either via some correct RNA splicing or residual copper transport capacity, had neither clinical seizures nor EEG abnormalities. Our findings suggest that early diagnosis and treatment improve brain electrical activity and decrease seizure occurrence in classical Menkes disease irrespective of the precise molecular defect. Subjects with ATP7A mutations that retain some function seem particularly well protected by early intervention against the possibility of epilepsy.
PMCID: PMC3113468  PMID: 20652413
15.  REM Sleep Percentage in Children with Autism Compared to Children with Developmental Delay and Typical Development 
To compare objective polysomnographic parameters between three cohorts: children with autism, with typical development, and with developmental delay without autism.
Overnight polysomnographic recordings were scored for sleep architecture according to American Academy of Sleep Medicine criteria by a board certified sleep medicine specialist blind to diagnosis for studies collected between July 2006, September 2009.
Subjects evaluated pediatric ward in Clinical Center of the National Institutes of Health.
First 60 consecutive children with autism, 15 with typical development, and 13 with developmental delay matched for non-verbal IQ to the autism group. Ranging in age from 2 to 13, selected without regard to the presence or absence of sleep problem behavior.
Main Outcome Measure
Total Sleep Time (TST), latencies to non-REM sleep and REM and percentages of total sleep time for stages 1, 2, slow wave sleep (SWS) and REM.
There were no differences between typical v developmental delay groups. Autism v typical revealed shorter TST (p = .004), greater SWS percentage (p=.001), and much smaller REM percentage, 14.5 v 22.6 (p<.001). Autism v developmental delay revealed shorter TST (p=.001), greater stage 1 percentage (p= <.001), greater SWS percentage (p = <.001) and much less REM percentage, 14.5 v 25 (p= <.001).
A relative deficiency of REM may indicate an abnormality in neural organization in young children with autism that is not directly associated or related to inherent intellectual disability but may serve as a window into understanding core neurotransmitter abnormalities unique to this disorder.
PMCID: PMC3111973  PMID: 21041596
16.  Examination of useful items for the assessment of fall risk in the community-dwelling elderly Japanese population 
The aim of this study was to select useful items for assessing fall risk in healthy elderly Japanese individuals.
A total of 965 healthy elderly Japanese subjects aged ≥60 years (349 males 70.4 ± 7.1 years, 616 females 69.9 ± 7.1 years) participated in this study. Of these, 16.6% had suffered from a previous fall. We assumed five fall risk factors: symptoms of falling, physical function, disease and physical symptoms, environment, and behavior and character. Eighty-six items were selected to represent these factors. To confirm the component items for each risk factor, we performed factor analysis (principle factor solution and varimax rotation). The high-fall risk response rate was also calculated for each item, and significant differences in this rate were examined between groups of those who had and not had experienced a fall.
Useful items were selected using the following criteria: (1) items showing a significant difference in high fall risk response rate between faller and non-faller groups were selected as useful items; (2) items showing low factor loading (<0.4) for any factor were deleted as inappropriate items; (3) the top two items showing a greater amount of the difference in high fall risk response rate among the representative items for each factor. A total of 50 items were selected from each fall risk factor (symptoms of falling, 3 items; physical function, 22 items; disease and physical symptom, 13 items; environment, 4 items; behavior and character, 8 items).
Based on our results, the selected items can comprehensively assess the fall risk of a healthy elderly Japanese population. In addition, the assessment items for physical function comprised items of different levels of difficulty, and these are able to gradually and comprehensively assess physical function.
PMCID: PMC2854334  PMID: 20013325
Community-dwelling elderly; Factor analysis; Item analysis; Prevention fall; Risk factors
17.  Contributions to singing ability by the posterior portion of the superior temporal gyrus of the non-language-dominant hemisphere: First evidence from subdural cortical stimulation, Wada testing, and fMRI 
Although the substrates that mediate singing abilities in the human brain are not well understood, invasive brain mapping techniques used for clinical decision making such as intracranial electrocortical testing and Wada testing offer a rare opportunity to examine music-related function in a select group of subjects, affording exceptional spatial and temporal specificity.
We studied eight patients with medically refractory epilepsy undergoing indwelling subdural electrode seizure focus localization. All patients underwent Wada testing for language lateralization. Functional assessment of language and music tasks was done by electrode grid cortical stimulation. One patient was also tested non-invasively with functional MRI. Functional organization of singing ability compared to language ability was determined based on four regions-ofinterest: left and right inferior frontal gyrus (IFG), and left and right posterior superior temporal gyrus (pSTG).
In some subjects, electrical stimulation of dominant pSTG can interfere with speech and not singing, whereas stimulation of non-dominant pSTG area can interfere with singing and not speech. Stimulation of the dominant IFG tends to interfere with both musical and language expression, while non-dominant IFG stimulation was often observed to cause no interference with either task; and finally, that stimulation of areas adjacent to but not within non-dominant pSTG typically does not affect either ability. FMRI mappings of one subject revealed similar music/language dissociation with respect to activation asymmetry within the regions-of-interest.
Despite inherent limitations with respect to strictly research objectives, invasive clinical techniques offer a rare opportunity to probe musical and language cognitive processes of the brain in a select group of patients.
PMCID: PMC2821975  PMID: 19570530
singing laterality; cortical stimulation; fMRI; Wada test; music ability
18.  Temporal Lobectomy: Resection Volume, Neuropsychological Effects and Seizure Outcome 
Epilepsy & behavior : E&B  2009;16(2):311-314.
To evaluate relations among resection volume, seizure outcome, and cognitive morbidity after temporal lobectomy for intractable epilepsy.
Thirty patients with mesial temporal sclerosis were evaluated with pre- and postoperative WAIS III, WMS III, and 3D coronal SPGR magnetic resonance imaging (MRI). Preoperative whole brain volumes were calculated with Statistical Parametric Mapping (SPM). Resection volume was calculated by manual tracing. Systat was used for statistical analysis.
All resections included the temporal tip, at least 1 cm of the superior temporal gyrus and 3 cm to 5 cm of the middle and inferior temporal gyri. Left were significantly smaller than right temporal resections. Seizure free patients had significantly larger resections. Immediate verbal memory was significantly worse in patients after left temporal lobectomy. Surgical outcome and resection volume did not affect postoperative neuropsychological results.
Dominant temporal lobe resections are associated with immediate verbal memory deficits. Larger resection volume was associated with improved seizure control but not worse cognitive outcome.
PMCID: PMC2785019  PMID: 19703792
Epilepsy; Cognition; Neuropsychology; Temporal Lobe; Resection; Mesiotemporal Sclerosis
19.  Temporal Lobe Epilepsy, Depression, and Hippocampal Volume 
Epilepsia  2008;50(5):1067-1071.
To evaluate the relationship between hippocampal volume loss, depression, and epilepsy.
There is a significantly increased incidence of depression and suicide in patients with epilepsy. Both epilepsy and depression are associated with reduced hippocampal volumes, but it is uncertain whether patients with both conditions have greater atrophy than those with epilepsy alone. Previous studies used depression measures strongly weighted to current state, and did not necessarily assess the influence of chronic major depressive disorder (“trait”), which could have a greater impact on hippocampal volume.
Fifty-five epilepsy patients with complex partial seizures (CPS) confirmed by EEG had 3D-SPGR MRI scans for hippocampal volumetric analysis. Depression screening was performed with Beck Depression Inventory (BDI, 51 patients) and with the structured clinical inventory for DSM-IV (SCID, 34 patients). For the BDI, a score above 10 was considered mild to moderate, above 20 moderate to severe, and above 30 severe depression. MRI and clinical analysis were performed blinded to other data. Statistical analysis was performed with Systat (Point Richmond CA) using Student’s t-test and analysis of variance.
There was a significant interaction between depression detected on SCID, side of focus, and left hippocampal volume. Patients with a diagnosis of depression and a right temporal seizure focus had significantly lower left hippocampal volume. A similar trend for an effect of depression on right hippocampal volume in patients with a right temporal focus did not reach statistical significance.
Our results suggest that patients with right temporal lobe epilepsy and depression have hippocampal atrophy that cannot be explained by epilepsy alone.
PMCID: PMC2692336  PMID: 19054394
Epilepsy; Temporal lobe; Depression; Comorbidity; Hippocampus; SCID; BDI
20.  Relationship between peripheral airway function and patient-reported outcomes in COPD: a cross-sectional study 
Health status, dyspnea and psychological status are important clinical outcomes in chronic obstructive pulmonary disease (COPD). However, forced expiratory volume in one second (FEV1) measured by spirometry, the standard measurement of airflow limitation, has only a weak relationship with these outcomes in COPD. Recently, in addition to spirometry, impulse oscillometry (IOS) measuring lung resistance (R) and reactance (X) is increasingly being used to assess pulmonary functional impairment.
We aimed to identify relationships between IOS measurements and patient-reported outcomes in 65 outpatients with stable COPD. We performed pulmonary function testing, IOS, high-resolution computed tomography (CT), and assessment of health status using the St. George's Respiratory Questionnaire (SGRQ), dyspnea using the Medical Research Council (MRC) scale and psychological status using the Hospital Anxiety and Depression Scale (HADS). We then investigated the relationships between these parameters. For the IOS measurements, we used lung resistance at 5 and 20 Hz (R5 and R20, respectively) and reactance at 5 Hz (X5). Because R5 and R20 are regarded as reflecting total and proximal airway resistance, respectively, the fall in resistance from R5 to R20 (R5-R20) was used as a surrogate for the resistance of peripheral airways. X5 was also considered to represent peripheral airway abnormalities.
R5-R20 and X5 were significantly correlated with the SGRQ and the MRC. These correlation coefficients were greater than when using other objective measurements of pulmonary function, R20 on the IOS and CT instead of R5-R20 and X5. Multiple regression analyses showed that R5-R20 or X5 most significantly accounted for the SGRQ and MRC scores.
IOS measurements, especially indices of peripheral airway function, are significantly correlated with health status and dyspnea in patients with COPD. Therefore, in addition to its simplicity and non-invasiveness, IOS may be a useful clinical tool not only for detecting pulmonary functional impairment, but also to some extent at least estimating the patient's quality of daily life and well-being.
PMCID: PMC2841100  PMID: 20205936
21.  18F-FCWAY and 18F-FDG PET in MRI Negative Temporal Lobe Epilepsy 
Epilepsia  2008;50(2):234-239.
Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) shows widespread hypometabolism even in temporal lobe epilepsy (TLE) patients with mesial temporal foci. 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) PET may show more specific 5-HT1A receptor binding reduction in seizure initiation than propagation regions. 18FCWAY PET might be valuable for detecting epileptic foci, and distinguishing mesial from lateral temporal foci in MRI negative TLE patients.
We performed 18F-FCWAY-PET and 18F-FDG-PET in 12 MRI negative TLE patients who had had either surgery or subdural electrode recording, and 15 healthy volunteers. After partial volume correction for brain atrophy, free fraction-corrected volume of distribution (V/f1) measurement and asymmetry indices (AIs) were computed. We compared 18F-FCWAY-PET and 18F-FDG-PET results with scalp video electroencephalography (EEG), invasive EEG and surgical outcome.
Mean 18F-FCWAY V/f1, compared with normal controls, was decreased significantly in fusiform gyrus, hippocampus and parahippocampus ipsilateral to epileptic foci, and AIs significantly greater in hippocampus, parahippocampus, fusiform gyrus, amygdala and inferior temporal regions. Eleven patients had clearly lateralized epileptogenic zones. Nine had congruent, and two non-lateralized, 18F-FCWAY PET. One patient with bitemporal seizure onset had non-lateralized 18F-FCWAY-PET. 18FFDG-PET showed congruent hypometabolism in 7/11 EEG-lateralized patients, bilateral hypometabolic regions in one, contralateral hypometabolism in one, as well as lateralized hypometabolism in the patient with bitemporal subdural seizure onset. Patients with mesial temporal foci tended to have lower superior and mid temporal 18F-FCWAY V/f1 binding AI than those with lateral or diffuse foci.
18F-FCWAY-PET can detect reduced binding in patients with normal MRI, and may be more accurate than 18F-FDG-PET.
PMCID: PMC2642908  PMID: 18801033
Epilepsy; Positron Emission Tomography; Serotonin Receptors; Temporal Lobe; Glucose Metabolism
22.  Involvement of Insula and Cingulate Cortices in Control and Suppression of Natural Urges 
Cerebral Cortex (New York, NY)  2008;19(1):218-223.
The physiology of control and suppression of natural urges is not well understood. We used [15O]H2O positron-emission tomography imaging to identify neural circuits involved in suppression of spontaneous blinking as a model of normal urges. Suppression of blinking was associated with prominent activation of bilateral insular-claustrum regions, right more than left; activation was also found in bilateral anterior cingulate cortex (ACC), supplementary motor areas, and the face area of the primary motor cortex bilaterally. These results suggest a central role for the insula possibly together with ACC in suppression of blinking.
PMCID: PMC2638741  PMID: 18469316
blinking; insula; PET; suppression; urges; visceral homunculus
23.  Effect of exacerbations on health status in subjects with chronic obstructive pulmonary disease 
Acute exacerbations may cause deteriorations in the health status of subjects with chronic obstructive pulmonary disease (COPD). The present study prospectively evaluated the effects of such exacerbations on the health status and pulmonary function of subjects with COPD over a 6-month period, and examined whether those subjects showed a steeper decline in their health status versus those subjects without exacerbations.
A total of 156 subjects with COPD (mean age 71.4 ± 6.3 years) were included in the analysis. At baseline and after 6 months, their pulmonary function and health status were evaluated using the Chronic Respiratory Disease Questionnaire (CRQ) and the St. George's Respiratory Questionnaire (SGRQ). An acute exacerbation was defined as a worsening of respiratory symptoms requiring the administration of systemic corticosteroids or antibiotics, or both.
Forty-eight subjects experienced one or more exacerbations during the 6-month study period, and showed a statistically and clinically significant decline in Symptom scores on the SGRQ, whereas subjects without exacerbations did not show a clinically significant decline. Logistic multiple regression analyses confirmed that the exacerbations significantly influenced the Fatigue and Mastery domains of the CRQ, and the Symptoms in the SGRQ. Twelve subjects with frequent exacerbations demonstrated a more apparent decline in health status.
Although pulmonary function did not significantly decline during the 6-month period, acute exacerbations were responsible for a decline in health status. To minimize deteriorations in health status, one must prevent recurrent acute exacerbations and reduce the exacerbation frequencies in COPD subjects.
PMCID: PMC2723082  PMID: 19624834
24.  Relationships between physical activity, ADL capability and fall risk in community-dwelling Japanese elderly population 
The purpose of this study was to clarify the relationships among fall risk, physical activity habits, and ADL capability in a community-dwelling Japanese elderly population.
The subjects were 1,407 Japanese aged 65 or older (604 males, 803 females). Fall risk was evaluated using the Falling Assessment Chart of Suzuki et al. (2003). Physical activity habits such as the frequency of leaving the house, the use of transportation, the frequency of physical exercise, and interests were evaluated. ADL capability was evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence.
Approximately 25% of the subjects had a high fall risk (score of 5 or more). Fall risk increased with age and ADL capability decreased with age. The group with a low fall risk (score<5) had a significantly higher ADL capability than the group with a high fall risk (score≥5). From results of two-way ANCOVA (gender×physical activity habits) with age as the covariate, the fall risk of people who regularly go on leaving the house, exercise, and have interests tended to be low. Further more, the relationships between the scores and physical activity habits were examined by two-way ANCOVA with age and ADL capability as the covariates. There were significant differences in the frequency of leaving the house, and elderly persons who leaved regularly the house, had a low fall risk.
This study showed that fall risk is closely related to ADL capability, and that the frequency of leaving the house is very important for reducing fall risk.
PMCID: PMC2723624  PMID: 21432078
fall risk; ADL; physical activity; frequency of leaving the house; Falling Assessment Chart
25.  Agreement in depression determination among four self-rating depression scales applied to Japanese community-dwelling elderly 
In this study, we examined the characteristics of depression determination using four representative self-rating depression scales (Geriatric Depression Scale, GDS; Self-rating Depression Scale, SDS; Center for Epidermiologic Studies Depression Scale, CES-D; and Carroll Rating Scale, CRS) applied to Japanese community-dwelling elderly.
Subjects were 563 community-dwelling independent elderly living in twelve prefectures (330 males, 68,9±6.3 yr; 233 females, 68.1±5.8 yr).
Depression rates determined using SDS (45.8%) and CES-D (68.6%) were higher than those determined using GDS (5.7%) and CRS (14.7%). Although correlations of depression scale scores among the four scales were significant and comparable (r: 0.61 (GDS vs. SDS, p<0.01) to 0.78 (SDS vs. CES-D, p<0.01)), the agreement in depression determination varied among scales (kappa coefficients: 0.05 (GDS vs. CES-D, p>0.05) to 0.46 (SDS vs. CES-D, p<0.01)).
Similarities in depression determination were found between GDS and CRS, and between CES-D and SDS. Depression rates determined on the basis of cut-off point for each scale were higher for CES-D and SDS than for GDS and CRS. Depression determination using a four-point rating scale may overestimate a slightly depressive symptom, compared with that using a two-point scale.
PMCID: PMC2723289  PMID: 21432377
Geriatric Depression Scale (GDS); Self-Rating Depression Scale (SDS); Center for Epidemiologic Studies Depression Scale (CES-D); Carroll Rating Scale (CRS)

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