Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations

Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal Charcot- Marie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination.     

X‐linked Charcot‐Marie‐Tooth type 1: stroke‐like presentation of a novel GJB1 mutation

X‐linked Charcot‐Marie‐Tooth type 1 (CMTX1) is the second most common type of CMT and is caused by mutations in the Gap‐Junction Beta‐1 gene (GJB1), encoding connexin 32 which is expressed in Schwann cells as well as in oligodendrocytes. More than 400 GJB1 mutations have been described to date. Many mutation‐carrier males have subclinical central nervous system (CNS) involvement, a few show mild CNS clinical signs, whereas only rarely overt though transient CNS dysfunction occurs. We report a 29‐year‐old man with CMTX1 who, at 16 years, showed short‐lived CNS symptoms with transitory white matter abnormalities on cerebral magnetic resonance imaging (MRI) as first clinical presentation of a novel GJB1 mutation (p.Gln99_His100insGln). He had three consecutive episodes of right hemiparesis, together with sensory loss in the paretic limbs and expressive aphasia, all lasting a few hours, over a 2‐day period, with concurrent white matter hyperintensity on MRI. These “stroke‐like” episodes occurred just after arriving at sea level, after travelling from home at 700 m of altitude. Only a few years later did symptoms of peripheral neuropathy appear. In conclusion, CMTX1 should be included in the differential diagnosis of diseases characterized by transient CNS symptoms and white matter abnormalities on MRI.     

Cortical and subcortical white matter abnormalities in adults with remitted first‐episode mania revealed by Tract‐Based Spatial Statistics

Chan W‐Y, Yang G‐L, Chia M‐Y, Woon P‐S, Lee J, Keefe R, Sitoh Y‐Y, Nowinski WL, Sim K. Cortical and subcortical white matter abnormalities in adults with remitted first‐episode mania revealed by Tract‐Based Spatial Statistics.
Bipolar Disord 2010: 12: 383–389. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Abnormalities of brain white matter have been noted in structural magnetic resonance imaging and diffusion tensor imaging (DTI) studies of bipolar disorder, but there are fewer investigations specifically examining white matter integrity early in the course of illness. In this study, we employed DTI to elucidate white matter changes in adult patients with remitted first‐episode mania and hypothesized that first‐episode mania was associated with decreased fractional anisotropy in cortical (frontal) and subcortical (thalamus, striatum) white matter as well as white matter tracts (cingulum, corpus callosum). Methods: Diffusion tensor images were acquired from 16 patients with remitted first‐episode mania and 16 healthy controls matched for age, gender, handedness, and years of education. Fractional anisotropy and radial and axial diffusivities were analyzed using Tract‐Based Spatial Statistics. Results: Patients had lower fractional anisotropy and higher radial diffusivity in the left anterior frontal white matter, right posterior thalamic radiation, left cingulum, and bilateral sagittal striatum. In addition, increased radial diffusivity was found in the left corpus callosum. Conclusion: Our findings highlighted that white matter abnormalities were present by the time of remission of first‐episode mania. The widespread occurrence of these white matter abnormalities both in first‐episode mania and chronic bipolar disorder suggested that disruption of white matter cortical‐subcortical networks as well as projection, associative, and commissural tracts is a hallmark of the illness.     

Diffusion tensor imaging abnormalities in focal cortical dysplasia

PURPOSE: Focal cortical dysplasia (FCD) is one of the most common underlying pathologic substrates in patients with medically intractable epilepsy. While magnetic resonance imaging (MRI) evidence of FCD is an important predictor of good surgical outcome, conventional MRI is not sensitive enough to detect all lesions. Previous reports of diffusion tensor imaging (DTI) abnormalities in FCD suggest the potential of DTI in the detection of FCD. The purpose of this study was to study subcortical white matter underlying small lesions of FCD using DTI. METHODS: Five patients with medically intractable epilepsy and FCD were investigated. Diffusion tensor imaging images were acquired (20 contiguous 3 mm thick axial slices) with maps of fractional anisotropy (FA), trace apparent diffusion coefficient (trace/3 ADC), and principal eigenvalues (ADC parallel and ADC perpendicular to white matter tracts) being calculated for each slice. Region of interest analysis was used to compare subcortical white matter ipsilateral and contralateral to the lesion. RESULTS: Three subjects with FCD associated with underlying white matter hyperintensities on T2 weighted MRI were observed to have increased trace/3 ADC, reduced fractional anisotropy and increased perpendicular water diffusivity which was greater than the relative increase in the parallel diffusivity. No DTI abnormalities were identified in two patients with FCD without white matter hyperintensities on conventional T2-weighted MRI. CONCLUSIONS: While DTI abnormalities in FCD with obvious white matter involvement are consistent with micro-structural degradation of the underlying subcortical white matter, DTI changes were not identified in FCD lesions with normal appearing white matter.     

Multiple diffusivities define white matter degeneration in amnestic mild cognitive impairment and Alzheimer's disease

Different diffusivity measurements in diffusion-tensor imaging (DTI) could be helpful for detecting the distinct mechanisms of white matter degeneration in Alzheimer's disease (AD). However, few studies have explored the changes of white matter in amnestic mild cognitive impairment (aMCI) and AD by whole-brain voxel-wise analyses of all diffusivity indices. The association between grey matter atrophy and white matter damage measured by distinct diffusivities is still uncertain. Structural magnetic resonance imaging and DTI with four diffusivity indices, comprising fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, were performed in 30 normal controls, 26 mild AD patients, and 40 aMCI patients with isolated memory impairment. T1 voxel-based morphometry and DTI tract-based spatial statistics were applied to compare the grey and white matter changes in the 3 groups. In contrast to the lack of significant white matter change presenting in aMCI patients, extended white matter degeneration over entire cerebral networks was exhibited in mild AD patients. Both axonal degradation and demyelination contributed to the white matter degeneration in AD; nevertheless, demyelination essentially involved the frontal portion of cerebral networks. Axonal degradation and demyelination over the temporal region were associated with the contiguous grey matter atrophy. However, only the severity of demyelination over the frontal region was correlated with the degree of atrophy over adjacent frontal grey matter. Our results suggest that different mechanisms of white matter damage demonstrate discrete regional distribution in AD. Demyelination may independently correlate with contiguous grey matter over the frontal region.     

Test–retest reliability and minimal detectable change of corticospinal tract integrity in chronic stroke

Diffusion tensor imaging (DTI) can be used to index white matter integrity of the corticospinal tract (CST) after stroke; however, the psychometric properties of DTI‐based measures of white matter integrity are unknown. The purpose of this study was to examine test–retest reliability as determined by intraclass correlation coefficients (ICC) and calculate minimal detectable change (MDC) of DTI‐based measures of CST integrity using three different approaches: a Cerebral Peduncle approach, a Probabilistic Tract approach, and a Tract Template approach. Eighteen participants with chronic stroke underwent DTI on the same magnetic resonance imaging scanner 4 days apart. For the Cerebral Peduncle approach, a researcher hand drew masks at the cerebral peduncle. For the Probabilistic Tract approach, tractography was seeded in motor areas of the cortex to the cerebral peduncle. For the Tract Template approach, a standard CST template was transformed into native space. For all approaches, the researcher performing analyses was blind to participant number and day of data collection. All three approaches had good to excellent test–retest reliability for fractional anisotropy (FA; ICCs >0.786). Mean diffusivity, axial diffusivity, and radial diffusivity were less reliable than FA. The ICC values were highest and MDC values were the smallest for the most automated approach (Tract Template), followed by the combined manual/automated approach (Probabilistic Tract) then the manual approach (Cerebral Peduncle). The results of this study may have implications for how DTI‐based measures of CST integrity are used to define impairment, predict outcomes, and interpret change after stroke.     

Spinal charcot‐marie‐tooth disease: A reappraisal

Introduction: Distal hereditary motor neuropathy (dHMN) is characterized by isolated distal muscle atrophy without sensory deficit. Nevertheless, clinical sensory loss has been reported despite preserved sensory nerve conduction in a few patients, thus differentiating these cases from the classical type 2 Charcot‐Marie‐Tooth disease (CMT2). Methods: We report 4 patients who presented with clinical sensory and motor neuropathy and normal peripheral sensory nerve conduction studies and were investigated with complete electrophysiological studies, including somatosensory evoked potentials (SEP). Results: These patients had a clinical presentation of classical CMT with isolated axonal motor neuropathy suggestive of dHMN. Interestingly, tibial nerve SEPs showed abnormalities suggestive of proximal involvement of dorsal roots that may explain the clinical somatosensory disturbances. Conclusions: These cases support the concept of spinal CMT that should be recognized as an intermediate form between dHMN and CMT2. SEP recording was helpful in defining a more precise phenotype of spinal CMT. Muscle Nerve 46: 603–607, 2012     

A novel approach with “skeletonised MTR” measures tract‐specific microstructural changes in early primary‐progressive MS

We combined tract‐based spatial statistics (TBSS) and magnetization transfer (MT) imaging to assess white matter (WM) tract‐specific short‐term changes in early primary‐progressive multiple sclerosis (PPMS) and their relationships with clinical progression. Twenty‐one PPMS patients within 5 years from onset underwent MT and diffusion tensor imaging (DTI) at baseline and after 12 months. Patients' disability was assessed. DTI data were processed to compute fractional anisotropy (FA) and to generate a common WM “skeleton,” which represents the tracts that are “common” to all subjects using TBSS. The MT ratio (MTR) was computed from MT data and co‐registered with the DTI. The skeletonization procedure derived for FA was applied to each subject's MTR image to obtain a “skeletonised” MTR map for every subject. Permutation tests were used to assess (i) changes in FA, principal diffusivities, and MTR over the follow‐up, and (ii) associations between changes in imaging parameters and changes in disability. Patients showed significant decreases in MTR over one year in the corpus callosum (CC), bilateral corticospinal tract (CST), thalamic radiations, and superior and inferior longitudinal fasciculi. These changes were located both within lesions and the normal‐appearing WM. No significant longitudinal change in skeletonised FA was found, but radial diffusivity (RD) significantly increased in several regions, including the CST bilaterally and the right inferior longitudinal fasciculus. MTR decreases, RD increases, and axial diffusivity decreases in the CC and CST correlated with a deterioration in the upper limb function. We detected tract‐specific multimodal imaging changes that reflect the accrual of microstructural damage and possibly contribute to clinical impairment in PPMS. We propose a novel methodology that can be extended to other diseases to map cross‐subject and tract‐specific changes in MTR. Hum Brain Mapp 35:723–733, 2014. © 2013 Wiley Periodicals, Inc.     

Altered white matter connectivity in never‐medicated patients with schizophrenia

Numerous diffusion tensor imaging (DTI) studies have implicated white matter brain tissue abnormalities in schizophrenia. However, the vast majority of these studies included patient populations that use antipsychotic medication. Previous research showed that medication intake can affect brain morphology and the question therefore arises to what extent the reported white matter aberrations can be attributed to the disease rather than to the use of medication. In this study we included 16 medication‐naïve patients with schizophrenia and compared them to 23 healthy controls to exclude antipsychotic medication use as a confounding factor. For each subject DTI scans and magnetization transfer imaging (MTI) scans were acquired. A new tract‐based analysis was used that combines fractional anisoptropy (FA), mean diffusivity (MD) and magnetization transfer ratio (MTR) to examine group differences in 12 major white matter fiber bundles. Significant group differences in combined FA, MD, MTR values were found for the right uncinate fasciculus and the left arcuate fasciculus. Additional analysis revealed that the largest part of both tracts showed an increase in MTR in combination with an increase in MD for patients with schizophrenia. We interpret these group‐related differences as disease‐related axonal or glial aberrations that cannot be attributed to antipsychotic medication use. Hum Brain Mapp 34:2353–2365, 2013. © 2012 Wiley Periodicals, Inc.     

White matter abnormalities in HIV-1 infection: a diffusion tensor imaging study

Diffuse white matter pallor is the most frequent neuropathological feature of HIV-1 infection and has been found to be particularly prominent in the advanced stages of the disease. The purpose of this study was to determine whether subtle white matter abnormalities can be detected in medically stable, ambulatory HIV-1 patients, in vivo, using diffusion tensor imaging (DTI). DTI is a magnetic resonance imaging (MRI) technique that is uniquely suited for the study of subtle white matter abnormalities. DTI was performed in six HIV-1 patients and nine controls. The two groups were similar in age. Abnormal fractional anisotropy was found in the white matter of the frontal lobes and internal capsules of the HIV-1 patients, in the absence of group differences in mean diffusivity, computed proton density, and computed T2. DTI may be more sensitive than conventional MRI methods for detecting subtle white matter disruptions in HIV-1 disease.     

The Role of Diffusion Tensor Imaging in Detecting Microstructural Changes in Prodromal Alzheimer's Disease

The MRI technique diffusion tensor imaging (DTI) is reviewed along with microstructural changes associated with prodromal Alzheimer's disease (AD) as a potential biomarker for clinical applications. The prodromal stage of AD is characterized by mild cognitive impairment (MCI), representing a transitional state between normal aging and AD. Microstructural abnormalities on DTI are promising in vivo biomarkers of gray and white matter changes associated with the progression of AD pathology. Elevated mean diffusivity and decreased fractional anisotropy are consistently found in prodromal AD, and even in cognitively normal elderly who progress to MCI. However, quality of parameter maps may be affected by artifacts of motion, susceptibility, and eddy current‐induced distortions. The DTI maps are typically analyzed by region‐of‐interest or voxel‐based analytic techniques such as tract‐based spatial statistics. DTI‐based index of diffusivity is complementary to macrostructural gray matter changes in the hippocampus in detecting prodromal AD. Breakdown of structural connectivity measured with DTI may impact cognitive performance during early AD. Furthermore, assessment of hippocampal connections may help in understanding the cerebral organization and remodeling associated with treatment response.     

Diffusion Tensor Tractography in Hypothyroidism and its Correlation with Memory Function

Diffusion tensor tractography (DTT) was performed to determine the microstructural changes in the white matter fibre tracts of hypothyroid patients compared to controls and to correlate these changes with memory dysfunction scores. DTT and Postgraduate Institute Memory Scale test were performed in eight hypothyroid patients and eight healthy controls. Diffusion tensor imaging (DTI) measures [fractional anisotropy (FA) and mean diffusivity (MD)] from all of the major cerebral tracts were calculated and a comparison was made between the patient group and controls. Pearson's correlation was performed between Memory Dysfunction score and DTI measures. Significant changes in DTI measures were observed in various white matter fibre tracts in hypothyroid patients compared to controls. In hypothyroid patients, an inverse correlation of Memory Dysfunction score with FA was observed in the right and left inferior fronto‐occipital fasciculus, whereas a positive correlation with MD was observed in the right anterior thalamic radiation among all white matter tracts. These findings suggest that microstructural changes in white matter fibres may contribute to the underlying dysfunction in memory in hypothyroid patients.     

Age‐related decline in task switching is linked to both global and tract‐specific changes in white matter microstructure

Task‐switching performance relies on a broadly distributed frontoparietal network and declines in older adults. In this study, they investigated whether this age‐related decline in task switching performance was mediated by variability in global or regional white matter microstructural health. Seventy cognitively intact adults (43–87 years) completed a cued‐trials task switching paradigm. Microstructural white matter measures were derived using diffusion tensor imaging (DTI) analyses on the diffusion‐weighted imaging (DWI) sequence. Task switching performance decreased with increasing age and radial diffusivity (RaD), a measure of white matter microstructure that is sensitive to myelin structure. RaD mediated the relationship between age and task switching performance. However, the relationship between RaD and task switching performance remained significant when controlling for age and was stronger in the presence of cardiovascular risk factors. Variability in error and RT mixing cost were associated with RaD in global white matter and in frontoparietal white matter tracts, respectively. These findings suggest that age‐related increase in mixing cost may result from both global and tract‐specific disruption of cerebral white matter linked to the increased incidence of cardiovascular risks in older adults. Hum Brain Mapp 38:1588–1603, 2017. © 2016 Wiley Periodicals, Inc.     

White matter abnormalities in gene‐positive myoclonus‐dystonia

Myoclonus‐dystonia is an autosomal dominantly inherited movement disorder clinically characterized by myoclonic jerks and dystonic movements of the upper body. Functional imaging and structural gray matter imaging studies in M‐D suggest defective sensorimotor integration and an association between putaminal volume and severity of dystonia, possibly because of neuronal plasticity. As we expect changes in the connections between the cortical and subcortical regions, we performed a combination of white matter voxel‐based morphometry (wVBM) and diffusion tensor imaging (DTI) to detect macro‐ and microstructural white matter changes, respectively, in DYT‐11 mutations carriers (M‐D). Sixteen clinically affected DYT‐11 mutation carriers and 18 control subjects were scanned with 3‐Tesla MRI to compare white matter volume, fractional anisotropy, and mean diffusivity between groups. In DYT11 mutation carriers, increased white matter volume and FA and decreased mean diffusivity werefound in the subthalamic area of the brain stem, including the red nucleus. Furthermore, decreased mean diffusivity was found in the subgyral cortical sensorimotor areas. The white matter changes found in the subthalamic area of the brain stem, connecting the cerebellum with the thalamus, are compatible with the hypothesis that abnormal function in M‐D involves a network that includes the cerebellum, brain stem, and basal ganglia. Whether these changes are causative or an effect of M‐D requires further study. © 2012 Movement Disorder Society     

MRI mean diffusivity detects widespread brain degeneration in multiple sclerosis

We investigated the magnetic resonance imaging (MRI) findings of 32 multiple sclerosis (MS) patients using voxel-based morphometry (VBM) and voxel-based analysis of white matter fluid-attenuated inversion recovery image (FLAIR) high-intensity lesions and diffusion tensor imaging (DTI). Compared with 18 healthy controls, MS patients showed gray matter volume reduction in the thalamus, hypothalamus, caudate, limbic lobe, and frontal lobe. A marked volume reduction of white matter was evident along the ventriculus lateralis and corpus callosum. FLAIR high-intensity lesions were observed beside the ventriculus lateralis. DTI revealed reduced fractional anisotropy areas similar to those of the FLAIR high-intensity lesions. Changes in the volume of increased mean diffusivity (MD) were the most widespread and extended to normal-appearing white matter (p<0.001). Multiple regression analysis revealed that MD values were significantly correlated with both disease duration (r=0.381, p=0.032) and expanded disability status scale scores (EDSS) (r=0.393, p=0.026). This study demonstrated that combined voxel-based analysis for volumetry, FLAIR high-intensity lesions, and DTI could reveal widespread brain abnormalities in MS patients. Furthermore, DTI, especially MD, showed far more widespread brain degeneration than other MRI parameters, and was significantly correlated with both severity and disease duration.     

Altered corticomotor‐cerebellar integrity in young ataxia telangiectasia patients

Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia‐telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion‐weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7‐22 years; mean, 12 years) and 11 typically developing age‐matched participants (age range, 8‐23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel‐based morphometry, whereas tract‐based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral‐postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P < 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P < 0.05). Cerebellum‐localized gray matter changes are seen in young ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early‐stage white matter motor pathway degeneration within young patients. © 2014 International Parkinson and Movement Disorder Society     

Clinical spectrum of AIFM1‐associated disease in an Irish family,from mild neuropathy to severe cerebellar ataxia with colour blindness

Mutations in apoptosis‐inducing factor mitochondrion‐associated‐1 (AIFM1) cause X‐linked peripheral neuropathy (Cowchock syndrome, CMT4X); however, more recently a cerebellar presentation has been described. We describe a large Irish family with seven affected males. They presented with a variable age of onset, 18 months to 39 years of age. All developed variably present sensorineural deafness, peripheral neuropathy, cerebellar ataxia, and pyramidal involvement. In addition, three had colour vision deficiency. Scale for the assessment and rating of ataxia ranged 2 to 23/40, while Charcot‐Marie‐Tooth neuropathy score 2 varied between 7 and 13/36. All individuals had normal cognitive assessment. Neurophysiology demonstrated length‐dependent large‐fibre sensorimotor axonal neuropathy, with particular involvement of superficial radial sensory responses. Brain imaging, performed in four, revealed varying extent of cerebellar atrophy, and white matter changes in one. Optical coherence tomography was abnormal in one, who had unrelated eye pathology. Four obligate female carriers were assessed clinically, two of them neurophysiologically; all were unaffected. Whole genome sequencing demonstrated a previously reported hemizygous AIFM1 mutation. Analysis for mutations in other genes associated with colour deficiency was negative. AIFM1‐associated phenotype in this family demonstrated significant variability. To our knowledge, this is the first report of AIFM1‐associated colour blindness. Superficial radial nerve was particularly affected neurophysiologically, which could represent a phenotypic marker towards this specific genetic diagnosis.     

Parametric subtracted post‐ictal diffusion tensor imaging for guiding direct neurostimulation therapy

Parametric subtracted post‐ictal diffusion tensor imaging (pspiDTI) is a novel imaging technique developed at our center to visualize transient, patient‐specific, ictal‐associated water diffusion abnormalities in hippocampal‐associated axonal tissue. PspiDTI can elucidate putative connectivity patterns, tracing ictal propagation following a partial‐onset seizure without generalization secondarily. PspiDTI compares two DTI volumes acquired during the early post‐ictal period (<4 hr), and baseline inter‐ictal interval (>24 hr post‐seizure). This technique performs a voxel‐wise parametric test to identify statistically significant transient ictal‐associated changes in water diffusivity involving white matter (WM). Our technique was applied to six patients with refractory partial‐onset epilepsy who were candidates for direct cortical responsive neurostimulation (RNS) therapy. Global and region‐specific fractional anisotropy decreases, relative to baseline, were detected in all patients with a 17.01% (p < .01) relative mean decrement, while trace increases were found in 6/6 (100%) patients with a 13.30% (p < .01) relative global mean increment. Changes in diffusivity were anatomically compared with transient hyper‐perfusion as detected by subtracted ictal SPECT co‐registered to MRI (SISCOM). In 5/6 (83.33%) patients, alterations in WM diffusivity were detected adjacent to the SISCOM signal localized predominantly in gray matter. In 4/6 patients, post‐implant RNS electrocorticography revealed early ictal propagation between implanted RNS depth leads guided by pspiDTI, hence validating concordant abnormal diffusivity regions detected by our technique. PspiDTI can complement the conventional pre‐surgical evaluation to provide additional crucial information regarding WM ictal‐propagation pathways between predominantly gray matter ictal‐onset zones. When incorporated into a multi‐modality pre‐surgical workflow, pspiDTI can aid in defining critical nodes between ictogenic regions. This information can be used to strategically implant a limited set of two RNS depth leads for maximizing the extent to which direct cortical RNS can modulate a potentially extensive epileptogenic network.     

Heritability of white matter microstructure in late middle age: A twin study of tract‐based fractional anisotropy and absolute diffusivity indices

There is evidence that differences among individuals in white matter microstructure, as measured with diffusion tensor imaging (DTI), are under genetic control. However, little is known about the relative contribution of genetic and environmental effects on different diffusivity indices among late middle‐aged adults. Here, we examined the magnitude of genetic influences for fractional anisotropy (FA), and mean (MD), axial (AD), and radial (RD) diffusivities in male twins aged 56–66 years old. Using an atlas‐based registration approach to delineate individual white matter tracts, we investigated mean DTI‐based indices within the corpus callosum, 12 bilateral tracts and all these regions of interest combined. All four diffusivity indices had high heritability at the global level (72%–80%). The magnitude of genetic effects in individual tracts varied from 0% to 82% for FA, 0% to 81% for MD, 8% to 77% for AD, and 0% to 80% for RD with most of the tracts showing significant heritability estimates. Despite the narrow age range of this community‐based sample, age was correlated with all four diffusivity indices at the global level. In sum, all diffusion indices proved to have substantial heritability for most of the tracts and the heritability estimates were similar in magnitude for different diffusivity measures. Future studies could aim to discover the particular set of genes that underlie the significant heritability of white matter microstructure. Hum Brain Mapp 38:2026–2036, 2017. © 2017 Wiley Periodicals, Inc.     

Mapping the order and pattern of brain structural MRI changes using change‐point analysis in premanifest Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that progressively affects motor, cognitive, and emotional functions. Structural MRI studies have demonstrated brain atrophy beginning many years prior to clinical onset (“premanifest” period), but the order and pattern of brain structural changes have not been fully characterized. In this study, we investigated brain regional volumes and diffusion tensor imaging (DTI) measurements in premanifest HD, and we aim to determine (1) the extent of MRI changes in a large number of structures across the brain by atlas‐based analysis, and (2) the initiation points of structural MRI changes in these brain regions. We adopted a novel multivariate linear regression model to detect the inflection points at which the MRI changes begin (namely, “change‐points”), with respect to the CAG‐age product (CAP, an indicator of extent of exposure to the effects of CAG repeat expansion). We used approximately 300 T1‐weighted and DTI data from premanifest HD and control subjects in the PREDICT‐HD study, with atlas‐based whole brain segmentation and change‐point analysis. The results indicated a distinct topology of structural MRI changes: the change‐points of the volumetric measurements suggested a central‐to‐peripheral pattern of atrophy from the striatum to the deep white matter; and the change points of DTI measurements indicated the earliest changes in mean diffusivity in the deep white matter and posterior white matter. While interpretation needs to be cautious given the cross‐sectional nature of the data, these findings suggest a spatial and temporal pattern of spread of structural changes within the HD brain. Hum Brain Mapp 38:5035–5050, 2017. © 2017 Wiley Periodicals, Inc.