Chu-Chung Huang

Treatment of malignant bone tumours by extracorporeally irradiated autograft-prosthetic composite arthroplasty

Autogenous bone graft which has been either autoclaved or irradiated is commonly used in oriental countries as an alternative to allograft. We started to use the technique of extracorporeal irradiation of the resected specimen and reimplantation (ECIR) in 1991. There was, however, a high incidence of fracture of the irradiated bone and loss of articular cartilage. In an attempt to reduce these complications, we combined the irradiated autograft with a conventional arthroplasty. Between 1995 and 1998, 14 patients underwent limb salvage by this method. Seven had an osteosarcoma, two bony metastases, three a chondrosarcoma, one a malignant fibrous histiocytoma, and one a leiomyosarcoma. Ten tumours were located in the proximal femur, two in the proximal humerus, and two in the distal femur. One patient who had a solitary metastasis in the proximal part of the left femur died from lung metastases 13 months after operation. The remaining 13 patients were alive and without evidence of local recurrence or distant metastases at a mean follow-up of 43 months (28 to 72). Postoperative palsy of the sciatic nerve occurred in one patient, but no complications such as wound infection, fracture, or nonunion were seen. All host-irradiated bone junctions healed uneventfully within eight months. Using the Enneking functional evaluation system, the mean postoperative score for all 14 patients was 80% (57 to 93). The use of irradiated autograft prosthesis composites reduces the complications of ECIR and gives good functional results. It may be a good alternative in limb-salvage surgery, especially in countries where it is difficult to obtain allografts.

Complexity of spontaneous BOLD activity in default mode network is correlated with cognitive function in normal male elderly: a multiscale entropy analysis

The nonlinear properties of spontaneous fluctuations in blood oxygen level-dependent (BOLD) signals remain unexplored. We test the hypothesis that complexity of BOLD activity is reduced with aging and is correlated with cognitive performance in the elderly. A total of 99 normal older and 56 younger male subjects were included. Cognitive function was assessed using Cognitive Abilities Screening Instrument and Wechsler Digit Span Task. We employed a complexity measure, multiscale entropy (MSE) analysis, and investigated appropriate parameters for MSE calculation from relatively short BOLD signals. We then compared the complexity of BOLD signals between the younger and older groups, and examined the correlation between cognitive test scores and complexity of BOLD signals in various brain regions. Compared with the younger group, older subjects had the most significant reductions in MSE of BOLD signals in posterior cingulate gyrus and hippocampal cortex. For older subjects, MSE of BOLD signals from default mode network areas, including hippocampal cortex, cingulate cortex, superior and middle frontal gyrus, and middle temporal gyrus, were found to be positively correlated with major cognitive functions, such as attention, orientation, short-term memory, mental manipulation, and language. MSE from subcortical regions, such as amygdala and putamen, were found to be positively correlated with abstract thinking and list-generating fluency, respectively. Our findings confirmed the hypothesis that complexity of BOLD activity was correlated with aging and cognitive performance based on MSE analysis, and may provide insights on how dynamics of spontaneous brain activity relates to aging and cognitive function in specific brain regions.

The influence of the amplitude of low-frequency fluctuations on resting-state functional connectivity.

Studies of brain functional connectivity have provided a better understanding of organization and integration of large-scale brain networks. Functional connectivity using resting-state functional magnetic resonance imaging (fMRI) is typically based upon the correlations of the low-frequency fluctuation of fMRI signals. Reproducible spatial maps in the brain have also been observed using the amplitude of low-frequency fluctuations (ALFF) in resting-state. However, little is known about the influence of the ALFF on the functional connectivity measures. In the present study, we analyzed resting-state fMRI data on 79 healthy old individuals. Spatial independent component analysis and regions of interest (ROIs) based connectivity analysis were performed to obtain measures of functional connectivity. ALFF maps were also calculated. First, voxel-matched inter-subject correlations were computed between back-reconstructed IC and ALFF maps. For all the resting-state networks, there was a consistent correlation between ALFF variability and network strengths (within regions that had high IC strengths). Next, inter-subject variance of correlations across 160 functionally defined ROIs were correlated with the corresponding ALFF variance. The connectivity of several ROIs to other regions were more likely to correlate with its own regional ALFF. These regions were mainly located in the anterior cingulate cortex, medial prefrontal cortex, precuneus, insula, basal ganglia, and thalamus. These associations may suggest a functional significance of functional connectivity modulations. Alternatively, the fluctuation amplitudes may arise from physiological noises, and therefore, need to be controlled when studying resting-state functional connectivity.

Randomization and resilience of brain functional networks as systems-level endophenotypes of schizophrenia

Significance Using network analysis of resting-state functional MRI data, we demonstrate that significant randomization of global network metrics, and greater resilience to targeted attack on network hubs, was replicably demonstrable in Chinese patients with schizophrenia, and was also demonstrated for the first time in their nonpsychotic first-degree relatives. These results support the hypothesis that functional networks are abnormally randomized and resilient in schizophrenia and indicate that network randomization/resilience may be an endophenotype, or marker of familial risk, for schizophrenia. We suggest that the greater randomization of the brain network endophenotype of schizophrenia may confer advantages in terms of greater resilience to pathological attack that may explain the selection and persistence of risk genes for schizophrenia in the general population. Schizophrenia is increasingly conceived as a disorder of brain network organization or dysconnectivity syndrome. Functional MRI (fMRI) networks in schizophrenia have been characterized by abnormally random topology. We tested the hypothesis that network randomization is an endophenotype of schizophrenia and therefore evident also in nonpsychotic relatives of patients. Head movement-corrected, resting-state fMRI data were acquired from 25 patients with schizophrenia, 25 first-degree relatives of patients, and 29 healthy volunteers. Graphs were used to model functional connectivity as a set of edges between regional nodes. We estimated the topological efficiency, clustering, degree distribution, resilience, and connection distance (in millimeters) of each functional network. The schizophrenic group demonstrated significant randomization of global network metrics (reduced clustering, greater efficiency), a shift in the degree distribution to a more homogeneous form (fewer hubs), a shift in the distance distribution (proportionally more long-distance edges), and greater resilience to targeted attack on network hubs. The networks of the relatives also demonstrated abnormal randomization and resilience compared with healthy volunteers, but they were typically less topologically abnormal than the patients’ networks and did not have abnormal connection distances. We conclude that schizophrenia is associated with replicable and convergent evidence for functional network randomization, and a similar topological profile was evident also in nonpsychotic relatives, suggesting that this is a systems-level endophenotype or marker of familial risk. We speculate that the greater resilience of brain networks may confer some fitness advantages on nonpsychotic relatives that could explain persistence of this endophenotype in the population.

Altered gray matter volume in the frontal pain modulation network in patients with cluster headache

&NA; Reduced gray matter volume was found in frontal pain‐modulation areas in patients with cluster headache, suggesting the involvement of insufficient pain‐modulating capacity in this disorder. &NA; Previous functional imaging studies in episodic cluster headache (CH) patients revealed altered brain metabolism concentrated on the central descending pain control system. However, it remains unclear whether changes in brain metabolism during the “in bout” period are due to structural changes and whether these structural changes vary between the “in bout” and “out of bout” periods. To quantify brain structural changes in CH patients, the regional gray matter volume (GMV) was compared among 49 episodic CH patients during the “in bout” period and 49 age‐ and sex‐matched controls. Twelve patients were rescanned during the “out of bout” period to evaluate the changes, if any, between these 2 periods. Compared with healthy controls, CH patients showed significant “in bout” GMV reductions in the bilateral middle frontal, left superior, and medial frontal gyri. Compared to “out of bout” scans, the “in bout” scans revealed significant GMV increases in the left anterior cingulate, insula, and fusiform gyrus. Additionally, compared to healthy controls, the “out of bout” scans revealed a trend of GMV reduction in the left middle frontal gyrus. These affected regions primarily belong to frontal pain modulation areas, and thus these GMV changes may reflect insufficient pain‐modulating capacity in the frontal areas of CH patients.

Structural deficits in the emotion circuit and cerebellum are associated with depression, anxiety and cognitive dysfunction in methadone maintenance patients: A voxel-based morphometric study

Heroin users on methadone maintenance treatment (MMT) have elevated rates of co-morbid depression and are associated with have higher relapse rates for substance abuse. Structural abnormalities in MMT patients have been reported, but their impact on clinical performance is unknown. We investigated differences in gray matter volume (GMV) between 27 MMT patients and 23 healthy controls with voxel-based morphometry, and we correlated findings in the patients with Beck Depression Inventory scores, Beck Anxiety Inventory scores, and diminished cognitive functioning. MMT patients exhibited higher emotional deficits than healthy subjects. There was significantly smaller GMV in multiple cortices, especially in the left inferior frontal gyrus and left cerebellar vermis in the MMT group. The smaller GMV in the pre-frontal cortices, left sub-callosal cingulate gyrus, left post-central gyrus, left insula, and right cerebellar declive correlated with higher depression scores. The smaller GMV in the pre-frontal cortices, left sub-callosal cingulate gyrus, and left postcentral gyrus also correlated with higher anxiety scores, while smaller GMV in the cerebellum and bilateral insula was associated with impaired performance on tests of executive function. These results reveal that MMT patients have low GMV in brain regions that are hypothesized to influence cognition and emotion, and the GMV findings might be involved comorbid disorders in the MMT group.

The APOE ɛ4 allele affects complexity and functional connectivity of resting brain activity in healthy adults

The apolipoprotein E (APOE) gene is associated with structural and functional brain changes. We have used multiscale entropy (MSE) analysis to detect changes in the complexity of resting blood oxygen level‐dependent (BOLD) signals associated with aging and cognitive function. In this study, we further hypothesized that the APOE genotype may affect the complexity of spontaneous BOLD activity in younger and older adults, and such altered complexity may be associated with certain changes in functional connectivity. We conducted a resting‐state functional magnetic resonance imaging experiment in a cohort of 100 younger adults (aged 20–39 years; mean 27.2 ± 4.3 years; male/female: 53/47) and 112 older adults (aged 60–79 years; mean 68.4 ± 6.5 years; male/female: 54/58), and applied voxelwise MSE analysis to assess the main effect of APOE genotype on resting‐state BOLD complexity and connectivity. Although the main effect of APOE genotype on BOLD complexity was not observed in younger group, we observed that older APOE ɛ4 allele carriers had significant reductions in BOLD complexity in precuneus and posterior cingulate regions, relative to noncarriers. We also observed that reduced BOLD complexity in precuneus and posterior cingulate regions was associated with increased functional connectivity to the superior and inferior frontal gyrus in the older group. These results support the compensatory recruitment hypothesis in older APOE ɛ4 carriers, and confer the impact of the APOE genotype on the temporal dynamics of brain activity in older adults. Hum Brain Mapp 35:3238–3248, 2014.

White matter abnormalities correlating with memory and depression in heroin users under methadone maintenance treatment.

Methadone maintenance treatment (MMT) has elevated rates of co-morbid memory deficit and depression that are associated with higher relapse rates for substance abuse. White matter (WM) disruption in MMT patients have been reported but their impact on these co-morbidities is unknown. This study aimed to investigate changes in WM integrity of MMT subjects using diffusion tensor image (DTI), and their relationship with history of heroin and methadone use in treated opiate-dependent individuals. The association between WM integrity changes from direct group comparisons and the severity of memory deficit and depression was also investigated. Differences in WM integrity between 35 MMT patients and 23 healthy controls were evaluated using DTI with tract-based spatial statistical analysis. Differences in DTI indices correlated with diminished memory function, Beck Depression Inventory, duration of heroin use and MMT, and dose of heroin and methadone administration. Changes in WM integrity were found in several WM regions, including the temporal and frontal lobes, pons, cerebellum, and cingulum bundles. The duration of MMT was associated with declining DTI indices in the superior longitudinal fasciculus and para-hippocampus. MMT patients had more memory and emotional deficits than healthy subjects. Worse scores in both depression and memory functions were associated with altered WM integrity in the superior longitudinal fasciculus, para-hippocampus, and middle cerebellar peduncle in MMT. Patients on MMT also had significant WM differences in the reward circuit and in depression- and memory-associated regions. Correlations among decreased DTI indices, disease severity, and accumulation effects of methadone suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities in MMT.

Decreased resting‐state brain activity complexity in schizophrenia characterized by both increased regularity and randomness

Schizophrenia is characterized by heterogeneous pathophysiology. Using multiscale entropy (MSE) analysis, which enables capturing complex dynamics of time series, we characterized MSE patterns of blood‐oxygen‐level‐dependent (BOLD) signals across different time scales and determined whether BOLD activity in patients with schizophrenia exhibits increased complexity (increased entropy in all time scales), decreased complexity toward regularity (decreased entropy in all time scales), or decreased complexity toward uncorrelated randomness (high entropy in short time scales followed by decayed entropy as the time scale increases). We recruited 105 patients with schizophrenia with an age of onset between 18 and 35 years and 210 age‐ and sex‐matched healthy volunteers. Results showed that MSE of BOLD signals in patients with schizophrenia exhibited two routes of decreased BOLD complexity toward either regular or random patterns. Reduced BOLD complexity toward regular patterns was observed in the cerebellum and temporal, middle, and superior frontal regions, and reduced BOLD complexity toward randomness was observed extensively in the inferior frontal, occipital, and postcentral cortices as well as in the insula and middle cingulum. Furthermore, we determined that the two types of complexity change were associated differently with psychopathology; specifically, the regular type of BOLD complexity change was associated with positive symptoms of schizophrenia, whereas the randomness type of BOLD complexity was associated with negative symptoms of the illness. These results collectively suggested that resting‐state dynamics in schizophrenia exhibit two routes of pathologic change toward regular or random patterns, which contribute to the differences in syndrome domains of psychosis in patients with schizophrenia. Hum Brain Mapp 36:2174–2186, 2015.

Longitudinal Brain White Matter Alterations in Minimal Hepatic Encephalopathy before and after Liver Transplantation

Cerebral edema is the common pathogenic mechanism for cognitive impairment in minimal hepatic encephalopathy. Whether complete reversibility of brain edema, cognitive deficits, and their associated imaging can be achieved after liver transplantation remains an open question. To characterize white matter integrity before and after liver transplantation in patients with minimal hepatic encephalopathy, multiple diffusivity indices acquired via diffusion tensor imaging was applied. Twenty-eight patients and thirty age- and sex-matched healthy volunteers were included. Multiple diffusivity indices were obtained from diffusion tensor images, including mean diffusivity, fractional anisotropy, axial diffusivity and radial diffusivity. The assessment was repeated 6–12 month after transplantation. Differences in white matter integrity between groups, as well as longitudinal changes, were evaluated using tract-based spatial statistical analysis. Correlation analyses were performed to identify first scan before transplantation and interval changes among the neuropsychiatric tests, clinical laboratory tests, and diffusion tensor imaging indices. After transplantation, decreased water diffusivity without fractional anisotropy change indicating reversible cerebral edema was found in the left anterior cingulate, claustrum, postcentral gyrus, and right corpus callosum. However, a progressive decrease in fractional anisotropy and an increase in radial diffusivity suggesting demyelination were noted in temporal lobe. Improved pre-transplantation albumin levels and interval changes were associated with better recoveries of diffusion tensor imaging indices. Improvements in interval diffusion tensor imaging indices in the right postcentral gyrus were correlated with visuospatial function score correction. In conclusion, longitudinal voxel-wise analysis of multiple diffusion tensor imaging indices demonstrated different white matter changes in minimal hepatic encephalopathy patients. Transplantation improved extracellular cerebral edema and the results of associated cognition tests. However, white matter demyelination may advance in temporal lobe.