A fixel-based analysis of micro- and macro-structural changes to white matter following adult traumatic brain injury.

Diffusion tensor imaging is often used to assess white matter (WM) changes following traumatic brain injury (TBI), but is limited in voxels that contain multiple fibre tracts. Fixel-based analysis (FBA) addresses this limitation by using a novel method of analysing high angular resolution diffusion-weighted imaging (HARDI) data. FBA examines three aspects of each fibre tract within a voxel: tissue micro-structure (fibre density [FD]), tissue macro-structure (fibre-bundle cross section [FC]) and a combined measure of both (FD and fibre-bundle cross section [FDC]). This study used FBA to identify the location and extent of micro- and macro-structural changes in WM following TBI. A large TBI sample (Nmild = 133, Nmoderate-severe = 29) and control group (healthy and orthopaedic; N = 107) underwent magnetic resonance imaging with HARDI and completed reaction time tasks approximately 7 months after their injury (range: 98-338 days). The TBI group showed micro-structural differences (lower FD) in the corpus callosum and forceps minor, compared to controls. Subgroup analyses revealed that the mild TBI group did not differ from controls on any fixel metric, but the moderate to severe TBI group had significantly lower FD, FC and FDC in multiple WM tracts, including the corpus callosum, cerebral peduncle, internal and external capsule. The moderate to severe TBI group also had significantly slower reaction times than controls, but the mild TBI group did not. Reaction time was not related to fixel findings. Thus, the WM damage caused by moderate to severe TBI manifested as fewer axons and a reduction in the cross-sectional area of key WM tracts.

Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

Prospective memory impairment in patients with white matter lesions.

OBJECTIVE: A vast majority of the episodic memory literature in white matter lesions (WML) had focused on "retrospective memory (RM)", little was known about prospective memory (PM) in WML patients. The aim of our study was to investigate the effect of WML patients on event-based prospective memory (EBPM) and time-based prospective memory (TBPM). In addition, our study attempted to understand the possible mechanisms of PM damage in WML patients. METHODS: A total of 42 WML patients and 40 age and education level matched healthy controls were included. EBPM (an action whenever particular words were presented) and TBPM (an action at certain times) were performed to test the involvement of PM in WML. The extent of WML within cholinergic pathways were assessed using the cholinergic pathways hyperintensities scale (CHIPS). RESULTS: A significant difference was found in the performance of Montreal Cognitive Assessment (MOCA) (21.8 ± 3.9 vs. 26.6 ± 1.7, p < 0.05) and TBPM (2.88 ± 1.21 vs. 4.27 ± 0.78, p < 0.05), but not Mini-Mental State Examination (MMSE) (26.9 ± 2.8 vs. 27.3 ± 1.2, p > 0.05) and EBPM (3.62 ± 1.25 vs.4.47 ± 1.11, p > 0.05) in WML patients compared with the healthy controls. Moreover, TBPM and MOCA scores were negatively correlated with CHIPS scores. CONCLUSIONS: WML patients were impaired in TBPM but not in EBPM, supporting that EBPM and TBPM have different neural mechanisms. Our results demonstrated that WML are involved in the TBPM probably by affecting the central cholinergic pathway.

Anodal Transcranial Direct Current Stimulation Provokes Neuroplasticity in Repetitive Mild Traumatic Brain Injury in Rats.

Repetitive mild traumatic brain injury (rmTBI) provokes behavioral and cognitive changes. But the study about electrophysiologic findings and managements of rmTBI is limited. In this study, we investigate the effects of anodal transcranial direct current stimulation (tDCS) on rmTBI. Thirty-one Sprague Dawley rats were divided into the following groups: sham, rmTBI, and rmTBI treated by tDCS. Animals received closed head mTBI three consecutive times a day. Anodal tDCS was applied to the left motor cortex. We evaluated the motor-evoked potential (MEP) and the somatosensory-evoked potential (SEP). T2-weighted magnetic resonance imaging was performed 12 days after rmTBI. After rmTBI, the latency of MEP was prolonged and the amplitude in the right hind limb was reduced in the rmTBI group. The latency of SEP was delayed and the amplitude was decreased after rmTBI in the rmTBI group. In the tDCS group, the amplitude in both hind limbs was increased after tDCS in comparison with the values before rmTBI. Anodal tDCS after rmTBI seems to be a useful tool for promoting transient motor recovery through increasing the synchronicity of cortical firing, and it induces early recovery of consciousness. It can contribute to management of concussion in humans if further study is performed.

Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014.

This study elucidates the genotypic and phenotypic spectrum and histopathological findings related to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Japan. For this single-center retrospective observational study, we enrolled 215 patients who were clinically suspected of having CADASIL and were examined at Kumamoto University from 1997 to 2014, and we diagnosed CADASIL in 70 patients. We found 19 different NOTCH3 mutations in the patients, with the NOTCH3 Arg133Cys mutation being found most frequently. We also found the Arg75Pro mutation, a cysteine-sparing NOTCH3 mutation. CADASIL patients with this Arg75Pro mutation were frequently found throughout Japan, and fewer patients with the Arg75Pro mutation showed MRI hyperintensity in the anterior temporal pole compared with patients with other NOTCH3 mutations. Significantly more CADASIL patients with the NOTCH3 Arg133Cys mutation had hyperintensity in the external capsule compared with CADASIL patients with the other mutations not including the NOTCH3 Arg75Pro mutation. We also showed postmortem pathological findings of the first Japanese CADASIL case with the NOTCH3 Arg133Cys mutation, and histopathological findings of fresh frozen skin biopsy specimens of CADASIL patients. In conclusions, the spectrum of NOTCH3 mutations in Japanese CADASIL patients may be partially explained by founder effects. Genotype-phenotype correlations may exist in CADASIL, which should be considered so as to make an accurate diagnosis of CADASIL in each population. Fresh frozen skin biopsy specimens may aid detection of Notch3 deposits on vascular walls for an improved diagnosis of CADASIL.

Anatomically related gray and white matter alterations in the brains of functional dyspepsia patients.

BACKGROUND: Previous studies summarized altered brain functional patterns in functional dyspepsia (FD) patients, but how the brain structural patterns are related to FD remains largely unclear. The objective of this study was to determine the brain structural characteristics in FD patients. METHODS: Optimized voxel-based morphometry and tract-based spatial statistics were employed to investigate the changes in gray matter (GM) and white matter (WM) respectively in 34 FD patients with postprandial distress syndrome and 33 healthy controls based on T1-weighted and diffusion-weighted imaging. The Pearson's correlation evaluated the link among GM alterations, WM abnormalities, and clinical variables in FD patients. The optimal brain structural parameters for identifying FD were explored using the receiver operating characteristic curve. KEY RESULTS: Compared to controls, FD patients exhibited a decrease in GM density (GMD) in the right posterior insula/temporal superior cortex (marked as pINS), right inferior frontal cortex (IFC), and left middle cingulate cortex, and an increase in fractional anisotropy (FA) in the posterior limb of the internal capsule, posterior thalamic radiation, and external capsule (EC). Interestingly, the GMD in the pINS was significantly associated with GMD in the IFC and FA in the EC. Moreover, the EC adjacent to the pINS provided the best performance for distinguishing FD patients from controls. CONCLUSIONS & INFERENCES: Our results showed pINS-related structural abnormalities in FD patients, indicating that GM and WM parameters were not affected independently. These findings would lay the foundation for probing an efficient target in the brain for treating FD.