Remote Corticospinal Tract Degeneration After Cortical Stroke in Rats May Not Preclude Spontaneous Sensorimotor Recovery.

Background. Recovery of motor function after stroke appears to be related to the integrity of axonal connections in the corticospinal tract (CST) and corpus callosum, which may both be affected after cortical stroke. Objective. In the present study, we aimed to elucidate the relationship of changes in measures of the CST and transcallosal tract integrity, with the interhemispheric functional connectivity and sensorimotor performance after experimental cortical stroke. Methods. We conducted in vivo diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and behavior testing in twenty-five male Sprague Dawley rats recovering from unilateral photothrombotic stroke in the sensorimotor cortex. Twenty-three healthy rats served as controls. Results. A reduction in the number of reconstructed fibers, a lower fractional anisotropy, and higher radial diffusivity in the ipsilesional but intact CST, reflected remote white matter degeneration. In contrast, transcallosal tract integrity remained preserved. Functional connectivity between the ipsi- and contralesional forelimb regions of the primary somatosensory cortex significantly reduced at week 8 post-stroke. Comparably, usage of the stroke-affected forelimb was normal at week 28, following significant initial impairment between day 1 and week 8 post-stroke. Conclusions. Our study shows that post-stroke motor recovery is possible despite degeneration in the CST and may be supported by intact neuronal communication between hemispheres.

Imaging Markers for the Characterization of Gray and White Matter Changes from Acute to Chronic Stages after Experimental Traumatic Brain Injury.

Despite clinical symptoms, a large majority of people with mild traumatic brain injury (TBI) have normal computed tomography (CT) and magnetic resonance imaging (MRI) scans. Therefore, present-day neuroimaging tools are insufficient to diagnose or classify low grades of TBI. Advanced neuroimaging techniques, such as diffusion-weighted and functional MRI, may yield novel biomarkers that may aid in the diagnosis of TBI. Therefore, the present study had two aims: first, to characterize the development of MRI-based measures of structural and functional changes in gray and white matter regions from acute to chronic stages after mild and moderate TBI; and second, to identify the imaging markers that can most accurately predict outcome after TBI. To these aims, 52 rats underwent serial functional (resting-state) and structural (T1-, T2-, and diffusion-weighted) MRI before and 1 h, 1 day, 1 week, 1 month and 3-4 months after mild or moderate experimental TBI. All rats underwent behavioral testing. Histology was performed in subgroups of rats at different time points. Early after moderate TBI, axial and radial diffusivities were increased, and fractional anisotropy was reduced in the corpus callosum and bilateral hippocampi, which normalized over time and was paralleled by recovery of sensorimotor function. Correspondingly, histology revealed decreased myelin staining early after TBI, which was not detected at chronic stages. No significant changes in individual outcome measures were detected after mild TBI. However, multivariate analysis showed a significant additive contribution of diffusion parameters in the distinction between control and different grades of TBI-affected brains. Therefore, combining multiple imaging markers may increase the sensitivity for TBI-related pathology.

Distinct structure-function relationships across cortical regions and connectivity scales in the rat brain.

An improved understanding of the structure-function relationship in the brain is necessary to know to what degree structural connectivity underpins abnormal functional connectivity seen in disorders. We integrated high-field resting-state fMRI-based functional connectivity with high-resolution macro-scale diffusion-based and meso-scale neuronal tracer-based structural connectivity, to obtain an accurate depiction of the structure-function relationship in the rat brain. Our main goal was to identify to what extent structural and functional connectivity strengths are correlated, macro- and meso-scopically, across the cortex. Correlation analyses revealed a positive correspondence between functional and macro-scale diffusion-based structural connectivity, but no significant correlation between functional connectivity and meso-scale neuronal tracer-based structural connectivity. Zooming in on individual connections, we found strong functional connectivity in two well-known resting-state networks: the sensorimotor and default mode network. Strong functional connectivity within these networks coincided with strong short-range intrahemispheric structural connectivity, but with weak heterotopic interhemispheric and long-range intrahemispheric structural connectivity. Our study indicates the importance of combining measures of connectivity at distinct hierarchical levels to accurately determine connectivity across networks in the healthy and diseased brain. Although characteristics of the applied techniques may affect where structural and functional networks (dis)agree, distinct structure-function relationships across the brain could also have a biological basis.

Differences in structural and functional networks between young adult and aged rat brains before and after stroke lesion simulations.

Neural network changes during aging may contribute to vulnerability and resilience to brain lesions in age-related neurological disorders, such as stroke. However, the relationship between age-related neural network features and stroke outcome is unknown. Therefore, we assessed structural and functional network status in young adult and aged rat brain, and measured the effects of simulated stroke lesions. Eleven rats underwent diffusion-weighted MRI and resting-state functional MRI at young adult age (post-natal day 88) and old age (between post-natal day 760 and 880). Structural and functional brain network features were calculated from graph-based network analysis. We performed three lesion simulations based on the brain injury pattern in frequently applied rodent stroke models, i.e. a small cortical lesion, a subcortical lesion, or a large cortical plus subcortical lesion, for which we computationally removed the involved network regions. Global network characteristics, i.e. integration and segregation, were not significantly different between the two age groups. However, we detected local differences in structural and functional networks between young adult and old rats, mainly reflected by shifts of hub regions. Stroke lesion simulations induced significant global and local network changes, characterized by lower efficiency and shifts of hub regions in structural and functional networks, which was most evident after a large cortical plus subcortical lesion. Functional and structural hub region shifts after lesion simulations differed between young adult and aged rats. Our lesion simulation study demonstrates that age-dependent brain network status affects structural and functional network reorganization after stroke, particularly involving hub shifts, which may influence functional outcome. Computational lesion studies offer a cheap and simple alternative to empirical studies and can complement or guide more complicated experimental studies in animal models and patients.

The power of language: Functional brain network topology of deaf and hearing in relation to sign language experience.

Prolonged auditory sensory deprivation leads to brain reorganization. This is indicated by functional enhancement in remaining sensory systems and known as cross-modal plasticity. In this study we investigated differences in functional brain network topology between deaf and hearing individuals. We also studied altered functional network responses between deaf and hearing individuals with a recording paradigm containing an eyes-closed and eyes-open condition. Electroencephalography activity was recorded in a group of sign language-trained deaf (N = 71) and hearing people (N = 122) living in rural Africa. Functional brain networks were constructed from the functional connectivity between fourteen electrodes distributed over the scalp. Functional connectivity was quantified with the phase lag index based on bandpass filtered epochs of brain signal. We studied the functional connectivity between the auditory, somatosensory and visual cortex and performed whole-brain minimum spanning tree analysis to capture network backbone characteristics. Functional connectivity between different regions involved in sensory information processing tended to be stronger in deaf people during the eyes-closed condition in both the alpha and beta frequency band. Furthermore, we found differences in functional backbone topology between deaf and hearing individuals. The backbone topology altered during transition from the eyes-closed to eyes-open condition irrespective of deafness, but was more pronounced in deaf individuals. The transition of backbone strength was different between individuals with congenital, pre-lingual or post-lingual deafness. Functional backbone characteristics correlated with the experience of sign language. Overall, our study revealed more insights in functional network reorganization caused by auditory deprivation and cross-modal plasticity. It further supports the idea of a brain plasticity potential in deaf and hearing people. The association between network organization and acquired sign language experience reflects the ability of ongoing brain adaptation in people with hearing disabilities.

Statistical power of clinical trials increased while effect size remained stable: an empirical analysis of 136,212 clinical trials between 1975 and 2014.

OBJECTIVES: To study the statistical power of randomized clinical trials and examine developments over time. STUDY DESIGN AND SETTING: We analyzed the statistical power in 136,212 clinical trials between 1975 and 2014 extracted from meta-analyses from the Cochrane database of systematic reviews. We determined study power to detect standardized effect sizes, where power was based on the meta-analyzed effect size. Average power, effect size, and temporal patterns were examined for all meta-analyses and a subset of significant meta-analyses. RESULTS: The number of trials with power ≥80% was low (7%) but increased over time: from 5% in 1975-1979 to 9% in 2010-2014. In significant meta-analyses, the proportion of trials with sufficient power increased from 9% to 15% in these years (median power increased from 16% to 23%). This increase was mainly due to increasing sample sizes, while effect sizes remained stable with a median Cohen's h of 0.09 (interquartile range 0.04-0.22) and a median Cohen's d of 0.20 (0.11-0.40). CONCLUSION: This study demonstrates that sufficient power in clinical trials is still problematic, although the situation is slowly improving. Our data encourage further efforts to increase statistical power in clinical trials to guarantee rigorous and reproducible evidence-based medicine.

Diffusion MRI-based cortical connectome reconstruction: dependency on tractography procedures and neuroanatomical characteristics.

Diffusion MRI (dMRI)-based tractography offers unique abilities to map whole-brain structural connections in human and animal brains. However, dMRI-based tractography indirectly measures white matter tracts, with suboptimal accuracy and reliability. Recently, sophisticated methods including constrained spherical deconvolution (CSD) and global tractography have been developed to improve tract reconstructions through modeling of more complex fiber orientations. Our study aimed to determine the accuracy of connectome reconstruction for three dMRI-based tractography approaches: diffusion tensor (DT)-based, CSD-based and global tractography. Therefore, we validated whole brain structural connectome reconstructions based on ten ultrahigh-resolution dMRI rat brain scans and 106 cortical regions, from which varying tractography parameters were compared against standardized neuronal tracer data. All tested tractography methods generated considerable numbers of false positive and false negative connections. There was a parameter range trade-off between sensitivity: 0.06-0.63 interhemispherically and 0.22-0.86 intrahemispherically; and specificity: 0.99-0.60 interhemispherically and 0.99-0.23 intrahemispherically. Furthermore, performance of all tractography methods decreased with increasing spatial distance between connected regions. Similar patterns and trade-offs were found, when we applied spherical deconvolution informed filtering of tractograms, streamline thresholding and group-based average network thresholding. Despite the potential of CSD-based and global tractography to handle complex fiber orientations at voxel level, reconstruction accuracy, especially for long-distance connections, remains a challenge. Hence, connectome reconstruction benefits from varying parameter settings and combination of tractography methods to account for anatomical variation of neuronal pathways.

White matter abnormalities at a regional and voxel level in focal and generalized epilepsy: A systematic review and meta-analysis.

OBJECTIVE: Since the introduction of diffusion tensor imaging, white matter abnormalities in epilepsy have been studied extensively. However, the affected areas reported, the extent of abnormalities and the association with relevant clinical parameters are highly variable. We aimed to obtain a more consistent estimate of white matter abnormalities and their association with clinical parameters in different epilepsy types. METHODS: We systematically searched for differences in white matter fractional anisotropy and mean diffusivity, at regional and voxel level, between people with epilepsy and healthy controls. Meta-analyses were used to quantify the directionality and extent of these differences. Correlations between white matter differences and age of epilepsy onset, duration of epilepsy and sex were assessed with meta-regressions. RESULTS: Forty-two studies, with 1027 people with epilepsy and 1122 controls, were included with regional data. Sixteen voxel-based studies were also included. People with temporal or frontal lobe epilepsy had significantly decreased fractional anisotropy (Δ -0.021, 95% confidence interval -0.026 to -0.016) and increased mean diffusivity (Δ0.026 × 10-3 mm2/s, 0.012 to 0.039) in the commissural, association and projection white matter fibers. White matter was much less affected in generalized epilepsy. White matter changes in people with focal epilepsy correlated with age at onset, epilepsy duration and sex. SIGNIFICANCE: This study provides a better estimation of white matter changes in different epilepsies. Effects are particularly found in people with focal epilepsy. Correlations with the duration of focal epilepsy support the hypothesis that these changes are, at least partly, a consequence of seizures and may warrant early surgery. Future studies need to guarantee adequate group sizes, as white matter differences in epilepsy are small.

The association of alcohol intake with γ-glutamyl transferase (GGT) levels: evidence for correlated genetic effects.

BACKGROUND: Blood levels of gamma-glutamyl transferase (GGT) are used as a marker for (heavy) alcohol use. The role of GGT in the anti-oxidant defense mechanism that is part of normal metabolism supposes a causal effect of alcohol intake on GGT. However, there is variability in the response of GGT to alcohol use, which may result from genetic differences between individuals. This study aimed to determine whether the epidemiological association between alcohol intake and GGT at the population level is necessarily a causal one or may also reflect effects of genetic pleiotropy (genes influencing multiple traits). METHODS: Data on alcohol intake (grams alcohol/day) and GGT, originating from twins, their siblings and parents (N=6465) were analyzed with structural equation models. Bivariate genetic models tested whether genetic and environmental factors influencing alcohol intake and GGT correlated significantly. Significant genetic and environmental correlations are consistent with a causal model. If only the genetic correlation is significant, this is evidence for genetic pleiotropy. RESULTS: Phenotypic correlations between alcohol intake and GGT were significant in men (r=.17) and women (r=.09). The genetic factors underlying alcohol intake correlated significantly with those for GGT, whereas the environmental factors were weakly correlated (explaining 4-7% vs. 1-2% of the variance in GGT respectively). CONCLUSIONS: In this healthy population sample, the epidemiological association of alcohol intake with GGT is at least partly explained by genetic pleiotropy. Future longitudinal twin studies should determine whether a causal mechanism underlying this association might be confined to heavy drinking populations.

Comparison of the selective aromatase inhibitor formestane with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer.

A total of 409 postmenopausal patients with advanced metastatic breast cancer were randomized to receive either formestane (Lentaron) 250 mg every 2 weeks by intramuscular injection, or tamoxifen 30 mg/day orally. Treatment continued until tumor progression. The groups were well matched for pretreatment characteristics including age, performance status, hormone receptor status (patients with known negative receptor status of their primary tumor were excluded), site and extent of metastases, disease-free interval, and previous primary and adjuvant therapy. Patients were assessed for antitumor efficacy at 3-monthly intervals using UICC criteria. Of the 348 patients evaluable for response, 33% had an objective response to formestane (14 complete and 43 partial responses), while 37% had an objective response to tamoxifen (10 complete and 54 partial responses). Median duration of response was 15 months for formestane and 20 months for tamoxifen; survival was 35 and 38 months respectively. There were no statistically significant differences between the treatments for all these variables, but time to disease progression and time to treatment failure significantly favoured tamoxifen. Systemic tolerability was excellent for both treatments. Local side effects due to intramuscular injection of formestane were mild and transient. In this comparative trial of first-line therapy for advanced breast cancer, formestane gave results comparable to tamoxifen for both efficacy and tolerability. We conclude that formestane is an effective and well tolerated addition to the therapeutic options available for the treatment of postmenopausal women with advanced breast cancer.

Influence of chemotherapy on hormone receptor concentration in a xenotransplanted endometrial cancer.

There is growing evidence that chemotherapy may influence the hormone receptor capacity in human carcinomas. The consideration of this assumption may be of importance for the therapeutic management of tumors with metastatic spread which underwent previous adjuvant chemotherapy. Therefore we investigated the influence of six different kinds of chemotherapy on the hormone receptor concentration and the percentage of receptor positive cells in xenotransplanted endometrial cancer. Our results can be summarized as follows: (1) We find neither a significant decrease in hormone receptor capacity after chemotherapeutic treatment (biochemical determination), nor do we see a decrease in the percentage of ER/PR pos. cells (immunohistochemistry). (2) On the other hand, there is no increase in hormone receptor concentration inducible by chemotherapy and no increase in ER/PR pos. cells immunohistochemically.

[Hormone receptor contents and tumor growth in a series of transplantable human breast carcinoma during and after radiotherapy]. / Hormonrezeptorgehalt und Wachstumsverhalten eines in Serie transplantierten menschlichen Mammakarzinoms unter und nach radiologischer Therapie.

The influence of radiotherapy on tumor growth and hormone receptor concentration (estrogen-, progesteron-receptor) in xenotransplanted human breast cancer is observed. Tumor growth significantly is delayed under therapy during the first 35 days after radiation. Renewed growth follows after that time. After the first days of treatment the ER and PR concentration decreases considerably and finally reaches 40% respectively 30% of the pretreatment level for a period of approximately 35 days after the end of radiotherapy. In general radiation therapy seems to affect the PR stronger than the ER. After this period ER and PR levels increase again with the regrowing tumor. The results point out that radiotherapy reduces the concentration of ER and PR in human breast cancer. Therefore the assay of steroid receptors in human breast cancer after radiation therapy is useful in predicting hormone dependency and prognosis only when receptor concentrations are positive.

1,1,2-triphenylbut-1-enes: relationship between structure, estradiol receptor affinity, and mammary tumor inhibiting properties.

1,1,2-Triphenylbut-1-enes, which are substituted with acetoxy groups on one, two, or three aromatic rings in the para and/or meta positions, were synthesized. The identity of the occurring E and Z isomers were established by 1H NMR spectroscopy. A study on structure-activity relationships was carried out with regard to estradiol receptor affinity and to inhibiting effects on the growth of a postmenopausal human mammary carcinoma implanted in nude mice. The para-substituted compounds generally exhibited a higher receptor affinity and a better antitumor activity than the corresponding meta-substituted ones. The E isomers were superior to the respective Z isomers in those two properties. The tumor-inhibiting effect of the mono- and disubstituted compounds was better than that of the trisubstituted ones. Except for the trisubstituted compounds, they all show a good correlation between estradiol receptor affinity and antitumor activity. One of the compounds was also tested on the 9,10-dimethylbenz[a]-anthracene-induced, hormone-dependent mammary carcinoma of the Sprague-Dawley rat, and the results corresponded to those obtained in the xenograft tumor.