TRActs Constrained By UnderLying Anatomy Research Articles

Association Between the C4 Binding Protein Level and White Matter Integrity in Major Depressive Disorder.

Objective Considerable evidence suggests that neuroinflammation plays an important role in the pathophysiology of major depressive disorder (MDD). However, the relationship between serum C4 binding protein (C4BP) and white matter (WM) tract integrity in MDD has not been investigated. Methods We obtained diffusion tensor images of 44 patients with MDD and 44 healthy controls and performed TRActs Constrained by UnderLying Anatomy (TRACULA) analysis to assess WM tract integrity. Serum C4-binding protein alpha chain (C4BPA) and C4- binding protein beta chain (C4BPB) levels were measured and in-between group comparisons were obtained. The correlation between serum C4BP levels and WM tract integrity was examined. Results In comparison to healthy controls, both serum C4BPA and C4BPB were higher in MDD. Also, fractional anisotropy (FA) was increased in the left cingulum-angular bundle (CAB) in MDD, but not healthy controls (HCs). A significant correlation was found between serum C4BP and FA levels in the right cingulum-cingulate gyrus bundle (CCG) in MDD. Conclusion This study is the first to investigate the correlation between serum C4BP levels and WM tract integrity in MDD. We identified an increase in WM integrity in the left CAB region in MDD. Furthermore, serum C4BP levels were higher in MDD, and this finding correlated with increased WM integrity in the right CCG region.

Using diffusion MRI data acquired with ultra-high gradient strength to improve tractography in routine-quality data

The development of scanners with ultra-high gradient strength, spearheaded by the Human Connectome Project, has led to dramatic improvements in the spatial, angular, and diffusion resolution that is feasible for in vivo diffusion MRI acquisitions. The improved quality of the data can be exploited to achieve higher accuracy in the inference of both microstructural and macrostructural anatomy. However, such high-quality data can only be acquired on a handful of Connectom MRI scanners worldwide, while remaining prohibitive in clinical settings because of the constraints imposed by hardware and scanning time. In this study, we first update the classical protocols for tractography-based, manual annotation of major white-matter pathways, to adapt them to the much greater volume and variability of the streamlines that can be produced from today's state-of-the-art diffusion MRI data. We then use these protocols to annotate 42 major pathways manually in data from a Connectom scanner. Finally, we show that, when we use these manually annotated pathways as training data for global probabilistic tractography with anatomical neighborhood priors, we can perform highly accurate, automated reconstruction of the same pathways in much lower-quality, more widely available diffusion MRI data. The outcomes of this work include both a new, comprehensive atlas of WM pathways from Connectom data, and an updated version of our tractography toolbox, TRActs Constrained by UnderLying Anatomy (TRACULA), which is trained on data from this atlas. Both the atlas and TRACULA are distributed publicly as part of FreeSurfer. We present the first comprehensive comparison of TRACULA to the more conventional, multi-region-of-interest approach to automated tractography, and the first demonstration of training TRACULA on high-quality, Connectom data to benefit studies that use more modest acquisition protocols.

Asymmetric alterations of white matter integrity in patients with insomnia disorder.

Despite the adverse consequences of insomnia disorder for both individuals and society, the underlying neurobiological processes are poorly understood. The purpose was to further understand the alterations of white matter tracts in patients with insomnia and their association with sleep variables and also to determine if diffusion tensor imaging measures would be a useful disease marker. Twenty-six patients with insomnia and 26 age-matched healthy volunteers underwent diffusion tensor imaging. We employed an automated probabilistic tractography analysis approach using TRActs Constrained by UnderLying Anatomy (TRACULA) to quantify diffusion measures in major white matter tracts. We found significantly increased fractional anisotropy in the right cingulum-angular bundle and uncinate fasciculus in patients group compared to controls. Moreover, the mean diffusivity and radial diffusivity were reduced in the right cingulum-angular bundle in patients group in comparison with controls. We also found significantly increased fractional anisotropy along the bilateral cingulum-angular bundle and right uncinate fasciculus in patients. Also, mean and radial diffusivity were reduced along the right cingulum-angular bundle in patients group compared to controls. There is a significant positive correlation between fractional anisotropy and Epworth Sleepiness Scale scores. Moreover, there are negative correlations between mean, radial and axial diffusivity and total sleep time and sleep efficiency and also positive correlations between mean, radial and axial diffusivity and duration of disease and Pittsburgh Sleep Quality Index scores. This study showed theimportanceof examining whole-tract and waypoint white matter integrity in insomnia disorder. We found asymmetric widespread white matter integrity changes in patients with insomnia.

Widespread Disruptions of White Matter in Familial Multiple Sclerosis: DTI and NODDI Study.

Diffusion tensor imaging (DTI) is a noninvasive, quantitative MRI technique that measures white matter (WM) integrity. Many brain dimensions are heritable, including white matter integrity measured with DTI. Family studies are valuable to provide insights into the interactive effects of non-environmental factors on multiple sclerosis (MS). To examine the contribution of familial factors to the diffusion signals across WM microstructure, we performed DTI and calculated neurite orientation dispersion plus density imaging (NODDI) diffusion parameters in two patient groups comprising familial and sporadic forms of multiple sclerosis and their unaffected relatives. We divided 111 subjects (49 men and 62 women: age range 19–60) into three groups conforming to their MS history. The familial MS group included 30 participants (patients; n = 16, healthy relatives; n = 14). The sporadic group included 41 participants (patients; n = 10, healthy relatives; n = 31). Forty age-matched subjects with no history of MS in their families were defined as the control group. To study white matter integrity, two methods were employed: one for calculating the mean of DTI, FA, and MD parameters on 18 tracts using Tracts Constrained by Underlying Anatomy (TRACULA) and the other for whole brain voxel-based analysis using tract-based spatial statistics (TBSS) on NDI and ODI parameters derived from NODDI and DTI parameters. Voxel-based analysis showed considerable changes in FA, MD, NDI, and ODI in the familial group when compared with the control group, reflecting widespread impairment of white matter in this group. The analysis of 18 tracts with TRACULA revealed increased MD and FA reduction in more tracts (left and right ILF, UNC, and SLFT, forceps major and minor) in familial MS patients vs. the control group. There were no significant differences between the patient groups. We found no consequential changes in healthy relatives of both patient groups in voxel-based and tract analyses. Considering the multifactorial etiology of MS, familial studies are of great importance to clarify the effects of certain predisposing factors on demyelinating brain pathology.

White matter degeneration in diffuse axonal injury and mild traumatic brain injury observed with automatic tractography.

A better understanding of white matter tract damage in patients with diffuse axonal injury (DAI) and mild traumatic brain injury (MTBI) is important to obtain an objective basis for sequelae. The purpose of this study was to clarify the characteristics of white matter tract degeneration in DAI and MTBI using automated tractography. T1-weighted and diffusion tensor imaging (DTI) was performed on seven DAI and seven MTBI patients as well as on nine healthy subjects. Automated probabilistic tractography analysis was performed using FreeSurfer and TRACULA (tracts constrained by underlying anatomy) for the reconstruction of major nerve fibers. We investigated the difference between DTI quantitative values in each white matter nerve fiber between groups and attempted to evaluate the classification accuracy of DAI and MTBI using receiver operator curve analysis. Both DAI and MTBI appeared to exhibit axonal degeneration along the nerve fiber tract in a scattered manner. The mean diffusivity of the ampulla of the corpus callosum was significantly higher in DAI than that in MTBI patients, suggesting axonal degeneration of the corpus callosum in DAI patients. Using mean diffusivity of the right cingulum-angular bundle, DAI and MTBI could be discriminated with an area under the curve of 94%. Both DAI and MTBI exhibited scattered axonal degeneration; however, DAI appeared to exhibit more pronounced axonal degeneration in the ampulla of the corpus callosum than MTBI. Our results suggest that DAI and MTBI can be accurately distinguished using DTI.

Analysis of diffusion tensor parameters in spinocerebellar ataxia type 3 and type 10 patients

IntroductionThere is a dearth of studies of spinocerebellar ataxias (SCAs) and diffusion tensor magnetic resonance imaging (DTI). ObjectiveTo analyze changes observed in DTI parameters and correlate these to clinical findings in SCA3 and SCA10 patients. MethodsSCA3 (n = 19) and SCA10 (n = 18) patients were compared with a similar number of controls and assessed clinically and with the scale for the assessment and rating of ataxia (SARA) before undergoing the same MRI protocol. TRACULA (TRActs Constrained by UnderLying Anatomy) software was used to analyze the DTI metrics FA, AD, RD and MD. ResultsMore white matter fiber tracts with changes in diffusivity were found in SCA3 patients than in SCA10 patients. There was a reduction in AD in altered fiber tracts in SCA3 and a greater increase in RD in SCA10. In the SCA3 patients, FA was reduced in the corticospinal tract (CST) and inferior longitudinal fasciculus (ILF), but this was not observed in the SCA10 patients. SARA score was correlated with DTI findings in SCA3 but not in SCA10. ConclusionChanges were observed in DTI for both SCA3 and SCA10 but were more widespread in SCA3. Our finding of myelin-sheath changes in SCA10 and secondary axonal changes in SCA3 may reflect the more rapid, aggressive clinical course of SCA3.

M55. STRUCTURAL CHANGES RELEVANT TO MUSICAL DEFICITS IN SCHIZOPHRENIA

BackgroundMusic is a shared experience in human culture. The ability to perceive, enjoy, and produce music is closely related to a fundamental element of human cognition. We previously reported that patients with schizophrenia have musical disability compared to healthy comparison. Several replications have shown that patients with schizophrenia have low musical ability that correlates with poor cognitive functions and severe psychiatric symptoms. We also reported that thinner cortical thickness in the left temporal, parietal, and inferior frontal regions is associated with lower musical ability in schizophrenia. Next, we sought to investigate diffusion tensor images (DTI) and local gyrification index (LGI) in patients with schizophrenia.MethodsTwenty-two right-handed patients with schizophrenia (12 males and 10 females, mean age = 45.9 years) and 20 right-handed healthy control subjects (13 males and 7 females, mean age = 42.8 years) consented to participate in this study. We measured musical ability, cognitive functions, and clinical assessments using the Montreal Battery for Evaluation of Amusia (MBEA), Brief Assessment of Cognition in Schizophrenia (BACS), and Positive and Negative Syndrome Scale (PANSS), respectively. We employed automatic probabilistic tractography DTI analysis using TRActs Constrained by UnderLying Anatomy (TRACULA) available in the Freesurfer software for the reconstruction of major tract bundles. The LGI was measured by quantifying the gyrification in spherical three-dimensional regions of interest by the Freesurfer.ResultsWhole-tract diffusion characteristics in patients with schizophrenia and controls were significantly different. Fractional anisotropy (FA) was lower for patients with schizophrenia compared to controls in the left superior longitudinal fasciculus - parietal endings (slfp) (p < 0.001), left cingulum - angular bundle (cab) (p < 0.001), and corpus callosum - forceps minor (fminor) (p < 0.001). We found significant correlation between musical abilities and FA alterations in slfp in both controls and patients with schizophrenia. While lower musical ability corresponds to lower FA in slfp of controls (r = -0.572, p = 0.013), it is associated with higher FA in the slfp of patients with schizophrenia (r = 0.515, p = 0.021). We did not reveal any significant correlation of musical ability to LGI in patients with schizophrenia. In controls, the correlation of musical ability to LGI in parahippocampal region after adjusting for age, sex, and years of musical training.DiscussionThis study shows that TRACULA can be used for the detection of decrements in several DTI tracts including the left slfp, left cab, and fminor in patients with schizophrenia. It revealed that while lower musical ability correlates with lower FA values in the left slfp in controls, it is associated with higher FA values in the same region in patients with schizophrenia. This contradictory finding in controls and patients with schizophrenia with regard to white matter pathology may reflect left supramarginal region malfunction resulting in cortical pathology in patients with schizophrenia. The data suggest that patients with schizophrenia may be more susceptible to changes in cortical thickness in the supramarginal region, and white matter alteration in the left slfp. Further study is needed to confirm the results. The characteristics of grey and white matter in the left parietal region which are relevant to musical ability may provide insight into pathological progression in patients with schizophrenia.

White-matter integrity and hearing acuity decline in healthy subjects: Magnetic resonance tractography.

The association between hearing acuity and white-matter (WM) microstructure integrity was evaluated in a normal healthy population with a variety of hearing acuity using an automated tractography technique known as TRACULA (TRActs Constrained by UnderLying Anatomy) in order to investigate whether hearing acuity decline is correlated with brain structural connectivity. Forty healthy controls were recruited to this study, which used a Siemens 3T Trio with a standard eight-channel head coil. Hearing acuity was assessed using pure-tone air conduction audiometry (Amplivox 2160, with Audiocups to eliminate noise and allow accurate pure-tone audiometry). Handedness and anxiety and depression were assessed for all participants in this study using the Edinburgh Handedness Inventory and the Hospital Anxiety and Depression Scale, respectively. This study showed a significant reduction in WM volume of the left cingulum angular bundle (CAB; t = 2.32, p = 0.02) in the mild to moderate hearing-loss group (238 ± 223 mm2) compared to the group with normal hearing (105  ± 121 mm2). The WM integrity of the left CAB was found to be significantly different (t = 2.06, p = 0.04) in the mild to moderate hearing-loss group (0.18 ± 0.06 mm2/s) compared to the group with normal hearing (0.22 ± 0.05 mm2/s). The WM integrity of the left anterior thalamic radiation (ATR) was found to be significantly different (t = 2.58, p = 0.014) in the mild to moderate hearing-loss group (0.33 ± 0.05 mm2/s) compared to the group with normal hearing (0.37 ± 0.03 mm2/s). A significant negative correlation was found between age and the WM integrity of the right ATR (r = -0.33, p = 0.038), and between hearing acuity and the WM integrity of the right ATR (r = -0.38, p = 0.013) and left CAB (r = -0.36, p = 0.019). Discussion and conclusion: An important finding in this study is that brain structural connectivity changes in the left hemisphere seem to be associated with age-related hearing loss found mainly in the ATR and CAB tracts.

Whole-exome sequencing identifies variants associated with structural MRI markers in patients with bipolar disorders

Bipolar disorder (BD) is one of the most heritable psychiatric disorders. A growing number of whole-exome sequencing (WES) studies for BD has been performed, however, no research has examined the association between single nucleotide variants (SNVs) from WES and structural magnetic resonance imaging (MRI) data. We sequenced whole-exomes in 53 patients with BD and 82 healthy control participants at an initial discovery stage and investigated the impacts of SNVs in risk genes from WES analysis on the cortical gray-matter thickness and integrity of white matter tracts and in the following stage. Cortical thickness and white matter integrity were investigated using the FreeSurfer and TRACULA (Tracts Constrained by UnderLying Anatomy). We identified 122 BD-related genes including KMT2C, AHNAK, CDH23, DCHS1, FRAS1, MACF1 and RYR3 and observed 27 recurrent copy number alteration regions including gain on 8p23.1 and loss on 15q11.1 - q11.2. Among them, single nucleotide polymorphism (SNP) rs4639425 in KMT2C gene, which regulates histone H3 lysine 4 (H3K4) methylation involved in chromatin remodeling, was associated with widespread alterations of white matter integrity including the cingulum, uncinate fasciculus, cortico-spinal tract, and superior longitudinal fasciculus. The small sample size of patients with BD in the genome data may cause our study to be underpowered when searching for putative rare mutations. This study first combined a WES approach and neuroimaging findings in psychiatric disorders. We postulate the rs4639425 may be associated with BD-related microstructural changes of white matter tracts.

The detection of white matter alterations in obsessive-compulsive disorder revealed by TRActs Constrained by UnderLying Anatomy (TRACULA).

PurposeIn recent years, a large number of studies have investigated obsessive–compulsive disorder (OCD) using diffusion-weighted images (DWIs) and have reported microstructural abnormalities in various regions, mainly the corpus callosum and cingulum. In the present study, we aimed to detect microstructural changes in the white matter using whole-brain tractography.Patients and methodsWe obtained MRI data from 25 adult non-medicated OCD patients and 27 healthy controls. DWI data from MRI scans were analyzed by the automated probabilistic tractography method referred to as TRActs Constrained by UnderLying Anatomy (TRACULA). We investigated diffusivity parameters: fractional anisotropy, radial diffusivity (RD), axial diffusivity, and mean diffusivity in 18 major white matter tracts and examined indices to know which measurements in which fibers can predict the diagnosis of OCD.ResultsCompared to healthy controls, OCD patients had significantly increased RD in the forceps major and a reduction of RD in the right cingulum angular (infracallosal) bundle. There was no correlation between these values and the clinical features.ConclusionWe found RD alterations in the forceps major and the right cingulum angular (infracallosal) bundle, which might be associated with myelination changes in the temporal and occipital regions in OCD. Our results suggest that the pathogenesis of OCD may include abonormality of myelination status in not only the fronto-striato-thalamic circuit but also the posterior and temporal regions.

F179. NEURAL CORRELATES IN MUSICAL DEFICITS IN SCHIZOPHRENIA

BackgroundSeveral studies have shown that patients with schizophrenia have low musical ability that correlates with poor cognitive functions and severe negative symptoms. Recently, using surface-based analysis, we reported that thinner cortical thickness in the left temporal, parietal, and inferior frontal regions is associated with lower musical ability in schizophrenia. Interestingly, thicker cortical thickness in the left supramarginal region correlates with lower musical ability in controls. Musical deficits such as congenital amusia was shown to contribute to white and grey matter pathophysiology in schizophrenia. We, therefore, sought to investigate diffusion tensor images (DTI) of patients with schizophrenia using an automated probabilistic tractography algorithm.MethodsTwenty-two right-handed patients with schizophrenia (12 males and 10 females, mean age = 45.9 years) and 20 right-handed healthy control subjects (13 males and 7 females, mean age = 42.8 years) consented to participate in this study. We measured musical ability, cognitive functions, and clinical assessments using the Montreal Battery for Evaluation of Amusia (MBEA), Brief Assessment of Cognition in Schizophrenia (BACS), and Positive and Negative Syndrome Scale (PANSS), respectively. We employed automatic probabilistic tractography DTI analysis using TRActs Constrained by UnderLying Anatomy (TRACULA) available in the Freesurfer software for the reconstruction of major tract bundles.ResultsWhole-tract diffusion characteristics in patients with schizophrenia and controls were significantly different. Fractional anisotropy (FA) was lower for patients with schizophrenia compared to controls in the left superior longitudinal fasciculus - parietal endings (slfp) (p < 0.001), left cingulum - angular bundle (cab) (p < 0.001), and corpus callosum - forceps minor (fminor) (p < 0.001). We found significant correlation between musical abilities and FA alterations in slfp in both controls and patients with schizophrenia. While lower musical ability corresponds to lower FA in slfp of controls (r = -0.572, p = 0.013), it is associated with higher FA in the slfp of patients with schizophrenia (r = 0.515, p = 0.021).DiscussionThis study shows that TRACULA can be used for the detection of decrements in several DTI tracts including the left slfp, left cab, and fminor in patients with schizophrenia. It revealed that while lower musical ability correlates with lower FA values in the left slfp in controls, it is associated with higher FA values in the same region in patients with schizophrenia. This contradictory finding in controls and patients with schizophrenia with regard to white matter pathology may reflect left supramarginal region malfunction resulting in cortical pathology in patients with schizophrenia. The data suggest that patients with schizophrenia may be more susceptible to changes in cortical thickness in the supramarginal region, and white matter alteration in the left slfp. Further study is needed to confirm the results. The characteristics of grey and white matter in the left parietal region which are relevant to musical ability may provide insight into pathological progression in patients with schizophrenia.

Complex spatial and temporally defined myelin and axonal degeneration in Huntington disease.

Although much prior work has focused on the basal ganglia and cortical pathology that defines Huntington's disease (HD), recent studies have also begun to characterize cerebral white matter damage (Rosas et al., 2006; Dumas et al., 2012; Poudel et al., 2014). In this study, we investigated differences in the large fascicular bundles of the cerebral white matter of gene-positive HD carriers, including pre-manifest individuals and early symptomatic patients, using recently developed diffusion tractography procedures. We examined eighteen major fiber bundles in 37 patients with early HD (average age 55.2 ± 11.5, 14 male, 23 female), 31 gene-positive, motor negative pre-symptomatic HD (PHD) (average age 48.1 ± 11.5, 13 male, 18 female), and 38 healthy age-matched controls (average age 55.7 ± 8.6, 14 male, 24 female), using the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. We calculated the mean fractional anisotropy (FA) and the mean radial (RD) and axial diffusivities (AD) for each fiber bundle. We also evaluated the relationships between diffusion measures, cognition and regional cortical thinning. We found that early changes in RD of select tracts in PHD subjects were associated with impaired performance on neuropsychological tests, suggesting that early changes in myelin might underlie early cognitive dysfunction. Finally, we found that increases in AD of select tracts were associated with regionally select cortical thinning of areas known to atrophy in HD, including the sensorimotor, supramarginal and fusiform gyrus, suggesting that AD may be reflecting pyramidal cell degeneration in HD. Together, these results suggest that white matter microstructural changes in HD reflect a complex, clinically relevant and dynamic process.

Freezing of gait in Parkinson's disease: gray and white matter abnormalities.

Freezing of gait (FOG) is a disabling disorder that often affects Parkinson's disease (PD) patients in advanced stages of the disease. To study structural gray matter (GM) and white matter (WM) changes in PD patients with and without FOG, twenty-one PD patients with FOG (PD-FOG), 16 PD patients without FOG (PD-nFOG) and 19 healthy subjects (HS) underwent a standardized MRI protocol. For the gray matter evaluation, cortical volume (CV), cortical thickness (CTh), and surface area (SA) were analyzed using the FreeSurfer pipeline. For the white matter evaluation, DTI images were analyzed using tracts constrained by underlying anatomy (TRACULA) toolbox in FreeSurfer. PD-FOG patients exhibited lower CTh than HS in the mesial surface of both cerebral hemispheres, including the superior frontal gyrus, paracentral lobule, posterior cingulate cortex, precuneus and pericalcarine cortex, and in the right dorsolateral prefrontal cortex. Moreover, significant WM changes were observed in PD-FOG patients in comparison with HS in the superior longitudinal fasciculus, uncinate fasciculus, cingulum cingulate gyrus and inferior longitudinal fasciculus (prevalently in the right hemisphere) and in the frontal radiations of the corpus callosum. DTI abnormalities in specific WM bundles correlated significantly with cognitive measures. The damage of multiple cortical areas involved in high-level gait control together with WM disruption between motor, cognitive and limbic structures may represent the anatomical correlate of FOG.

Age- and sex-related effects in children with mild traumatic brain injury on diffusion magnetic resonance imaging properties: A comparison of voxelwise and tractography methods.

Although there are several techniques to analyze diffusion-weighted imaging, any technique must be sufficiently sensitive to detect clinical abnormalities. This is especially critical in disorders like mild traumatic brain injury (mTBI), where pathology is likely to be subtle. mTBI represents a major public health concern, especially for youth under 15 years of age. However, the developmental period from birth to 18 years is also a time of tremendous brain changes. Therefore, it is important to establish the degree of age- and sex-related differences. Participants were children aged 8-15 years with mTBI or mild orthopedic injuries. Imaging was obtained within 10 days of injury. We performed tract-based spatial statistics (TBSS), deterministic tractography using Automated Fiber Quantification (AFQ), and probabilistic tractography using TRACULA (TRActs Constrained by UnderLying Anatomy) to evaluate whether any method provided improved sensitivity at identifying group, developmental, and/or sex-related differences. Although there were no group differences from any of the three analyses, many of the tracts, but not all, revealed increases of fractional anisotropy and decreases of axial, radial, and mean diffusivity with age. TBSS analyses resulted in age-related changes across all white matter tracts. AFQ and TRACULA revealed age-related changes within the corpus callosum, cingulum cingulate, corticospinal tract, inferior and superior longitudinal fasciculus, and uncinate fasciculus. The results are in many ways consistent across all three methods. However, results from the tractography methods provided improved sensitivity and better tract-specific results for identifying developmental and sex-related differences within the brain.

TESC gene-regulating genetic variant (rs7294919) affects hippocampal subfield volumes and parahippocampal cingulum white matter integrity in major depressive disorder

Two recent genome-wide association studies have suggested that rs7294919 is associated with changes in hippocampal volume. rs7294919 regulates the transcriptional products of the TESC gene, which is involved in neuronal proliferation and differentiation. We investigated the interactive effect of rs7294919 and major depressive disorder (MDD) on the volume of the hippocampal subfields and the integrity of the parahippocampal cingulum (PHC). We also investigated the correlation of these structural changes with the DNA methylation status of rs7294919. A total of 105 patients with MDD and 85 healthy control subjects underwent T1-weighted structural magnetic resonance imaging and diffusion tensor imaging. The rs7294919 was genotyped and its DNA methylation status was assessed in all the participants. We analyzed the hippocampal subfield volumes and PHC integrity using FreeSurfer and the Tracts Constrained by Underlying Anatomy (TRACULA) respectively. Significant interactive effects of rs7294919 and MDD were observed in the volumes of the dentate gyrus and CA4. The patients with MDD had increased methylation in two of the three CpG loci of rs7294919, and the methylation of CpG3 was significantly correlated with right PHC integrity in the MDD group. Our results provide neurobiological evidence for the association of rs7294919 with brain structural changes in MDD.

Automated tractography in patients with temporal lobe epilepsy using TRActs Constrained by UnderLying Anatomy (TRACULA)

PurposeA detailed understanding of white matter tract alterations in patients with temporal lobe epilepsy (TLE) is important as it may provide useful information for likely side of seizure onset, cognitive impairment and postoperative prognosis. However, most diffusion-tensor imaging (DTI) studies have relied on manual reconstruction of tract bundles, despite the recent development of automated techniques. In the present study, we used an automated white matter tractography analysis approach to quantify temporal lobe white matter tract alterations in TLE and determine the relationships between tract alterations, the extent of hippocampal atrophy and the chronicity and severity of the disorder.MethodsWe acquired preoperative T1-weighted and DTI data in 64 patients with well-characterized TLE, with imaging and histopathological evidence of hippocampal sclerosis. Identical acquisitions were collected for 44 age- and sex-matched healthy controls. We employed automatic probabilistic tractography DTI analysis using TRActs Constrained by UnderLying Anatomy (TRACULA) available in context of Freesurfer software for the reconstruction of major temporal lobe tract bundles. We determined the factors influencing probabilistic tract reconstruction and investigated alterations of DTI scalar metrics along white matter tracts with respect to hippocampal volume, which was automatically estimated using Freesurfer's morphometric pipelines. We also explored the relationships between white matter tract alterations and duration of epilepsy, age of onset of epilepsy and seizure burden (defined as a function of seizure frequency and duration of epilepsy).ResultsWhole-tract diffusion characteristics of patients with TLE differed according to side of epilepsy and were significantly different between patients and controls. Waypoint comparisons along each tract revealed that patients had significantly altered tissue characteristics of the ipsilateral inferior-longitudinal, uncinate fasciculus, superior longitudinal fasciculus and cingulum relative to controls. Changes were more widespread (ipsilaterally and contralaterally) in patients with left TLE while patients with right TLE showed changes that remained spatially confined in ipsilateral tract regions. We found no relationship between DTI alterations and volume of the epileptogenic hippocampus. DTI alterations of anterior ipsilateral uncinate and inferior-longitudinal fasciculus correlated with duration of epilepsy (over and above effects of age) and age at onset of epilepsy. Seizure burden correlated with tissue characteristics of the uncinate fasciculus.ConclusionThis study shows that TRACULA permits the detection of alterations of DTI tract scalar metrics in patients with TLE. It also provides the opportunity to explore relationships with structural volume measurements and clinical variables along white matter tracts. Our data suggests that the anterior temporal lobe portions of the uncinate and inferior-longitudinal fasciculus may be particularly vulnerable to pathological alterations in patients with TLE. These alterations are unrelated to the extent of hippocampal atrophy (and therefore potentially mediated by independent mechanisms) but influenced by chronicity and severity of the disorder.

Neuroanatomical Mechanism of Cerebellar Mutism After Stroke.

Cerebellar mutism (CM) is a rare neurological condition characterized by lack of speech due to cerebellar lesions. CM is often reported in children. We describe a rare case of CM after spontaneous cerebellar hemorrhage. The patient showed mutism, irritability, decreased spontaneous movements and oropharyngeal apraxia. Diffusion tensor imaging revealed significant volume reduction of medial frontal projection fibers from the corpus callosum. In Tracts Constrained by UnderLying Anatomy (TRACULA) analysis, forceps major and minor and bilateral cingulum-angular bundles were not visualized. Cerebello-frontal pathway reconstructed from the FMRIB Software Library showed continuity of fibers, with decreased number of fibers on qualitative analysis. These results suggest that cerebello-frontal disconnection may be a neuroanatomical mechanism of CM. Damage of brain network between occipital lobe, cingulate and cerebellum caused by hemorrhage may also have role in the mechanism of CM in our case.

Preserved white matter microstructure in young patients with anorexia nervosa?

A massive but reversible reduction of cortical thickness and subcortical gray matter (GM) volumes in Anorexia Nervosa (AN) has been recently reported. However, the literature on alterations in white matter (WM) volume and microstructure changes in both acutely underweight AN (acAN) and after recovery (recAN) is sparse and results are inconclusive. Here, T1-weighted and diffusion-weighted MRI data in a sizable sample of young and medication-free acAN (n = 35), recAN (n = 32), and age-matched female healthy controls (HC, n = 62) were obtained. For analysis, a well-validated global probabilistic tractography reconstruction algorithm including rigorous motion correction implemented in FreeSurfer: TRACULA (TRActs Constrained by UnderLying Anatomy) were used. Additionally, a clustering algorithm and a multivariate pattern classification technique to WM metrics to predict group membership were applied. No group differences in either WM volume or WM microstructure were detected with standard analysis procedures either in acAN or recAN relative to HC after controlling for the number of performed statistical tests. These findings were not affected by age, IQ, or psychiatric symptoms. While cluster analysis was unsuccessful at discriminating between groups, multivariate pattern classification showed some ability to separate acAN from HC (but not recAN from HC). However, these results were not compatible with a straightforward hypothesis of impaired WM microstructure. The current findings suggest that WM integrity is largely preserved in non-chronic AN. This finding stands in contrast to findings in GM, but may help to explain the relatively intact cognitive performance of young patients with AN and provide the basis for the fast recovery of GM structures. Hum Brain Mapp 37:4069-4083, 2016. © 2016 Wiley Periodicals, Inc.

Tract-based analysis of white matter degeneration in Alzheimer’s disease

Although much prior work has focused on the known cortical pathology that defines Alzheimer’s disease (AD) histologically, recent work has additionally demonstrated substantial damage to the cerebral white matter in this condition. While there is large evidence of diffuse damage to the white matter in AD, it is unclear whether specific white matter tracts exhibit a more accelerated pattern of damage and whether the damage is associated with the classical neurodegenerative changes of AD. In this study, we investigated microstructural differences in the large fascicular bundles of the cerebral white matter of individuals with AD and mild cognitive impairment (MCI), using recently developed automated diffusion tractography procedures in the Alzheimer’s disease Neuroimaging Initiative (ADNI) dataset. Eighteen major fiber bundles in a total of 36 individuals with AD, 81 MCI and 60 control participants were examined with the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. For each fiber bundle, the mean fractional anisotropy (FA), and mean, radial and axial diffusivities were calculated. Individuals with AD had increased diffusivities in both left and right cingulum-angular bundles compared to control participants (p<0.001). Individuals with MCI also had increased axial and mean diffusivities and increased FA in both cingulum-angular bundles compared to control participants (p<0.05) and decreased radial diffusivity compared to individuals with AD (p<0.05). We additionally examined how white matter deterioration relates to hippocampal volume, a traditional imaging measure of AD pathology, and found the strongest negative correlations in AD patients between hippocampal volume and the diffusivities of the cingulum-angular and cingulum-cingulate gyrus bundles and of the corticospinal tracts (p<0.05). However, statistically controlling for hippocampal volume did not remove all group differences in white matter measures, suggesting a unique contribution of white matter damage to AD unexplained by this disease biomarker. These results suggest that (1) AD-associated deterioration of white matter fibers is greatest in tracts known to be connected to areas of pathology in AD and (2) lower white matter tract integrity is more diffusely associated with lower hippocampal volume indicating that the pathology in the white matter follows to some degree the neurodegenerative staging and progression of this condition.

Tractography reveals diffuse white matter abnormalities in Myotonic Dystrophy Type 1

Cerebral involvement in Myotonic Dystrophy Type 1 (DM1) is well-established but not well characterized. This study applied new Diffusion Tensor Imaging (DTI) tractography to characterize white matter disturbance in adults with DM1. Forty-five participants with DM1 and 44 control participants had MRIs on a Siemens 3T TIM Trio scanner. Data were processed with TRActs Constrained by UnderLying Anatomy (TRACULA) and 7 tracts were evaluated. Bilateral disturbances in white matter integrity were seen in all tracts in participants with DM1 compared to controls. There were no right–left hemisphere differences. The resulting DTI metrics were correlated with cognitive functioning, particularly working memory and processing speed. Motor speed was not significantly correlated with white matter microstructural integrity and, thus, was not the core explanation for the working memory and processing speed findings. White matter integrity was correlated with important clinical variables including the muscular impairment rating scale (MIRS). CTG repeat length was moderately associated with white matter status in corticospinal tract and cingulum. Sleepiness (Epworth Sleepiness Scale) was moderately associated with white matter status in the superior longitudinal fasciculus and cingulum. Overall, the results add to an emerging literature showing widespread white matter disturbances in both early-onset and adult-onset DM1. Results suggest that further investigation of white matter pathology is warranted in DM1 and that non-invasive measures such as DTI have a potentially important clinical value in characterizing the status of individuals with DM1.