David Qixiang Chen

The challenge of mapping the human connectome based on diffusion tractography

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.

In vivo visualization of cranial nerve pathways in humans using diffusion-based tractography.

OBJECTIVEDiffusion-based tractography has emerged as a powerful technique for 3-dimensional tract reconstruction and imaging of white matter fibers; however, tractography of the cranial nerves has not been well studied. In particular, the feasibility of tractography of the individual cranial nerves has not been previously assessed. METHODS3-Tesla magnetic resonance imaging scans, including anatomic magnetic resonance images and diffusion tensor images, were used for this study. Tractography of the cranial nerves was performed using 3D Slicer software. The reconstructed 3-dimensional tracts were overlaid onto anatomic images for determination of location and course of intracranial fibers. RESULTSDetailed tractography of the cranial nerves was obtained, although not all cranial nerves were imaged with similar anatomic fidelity. Some tracts were imaged in great detail (cranial nerves II, III, and V). Tractography of the optic apparatus allowed tracing from the optic nerve to the occipital lobe, including Meyers loop. Trigeminal tractography allowed visualization of the gasserian ganglion as well as postganglionic fibers. Tractography of cranial nerve III shows the course of the fibers through the midbrain. Lower cranial nerves (cranial nerves IX, XI, and XII) could not be imaged well. CONCLUSIONTractography of the cranial nerves is feasible, although technical improvements are necessary to improve the tract reconstruction of the lower cranial nerves. Detailed assessment of anatomy and the ability of overlaying the tracts onto anatomic magnetic resonance imaging scans is essential, particularly in the posterior fossa, to ensure that the tracts have been reconstructed with anatomic fidelity.

Sensorimotor and Pain Modulation Brain Abnormalities in Trigeminal Neuralgia: A Paroxysmal, Sensory-Triggered Neuropathic Pain

Objective Idiopathic trigeminal neuralgia (TN) is characterized by paroxysms of severe facial pain but without the major sensory loss that commonly accompanies neuropathic pain. Since neurovascular compression of the trigeminal nerve root entry zone does not fully explain the pathogenesis of TN, we determined whether there were brain gray matter abnormalities in a cohort of idiopathic TN patients. We used structural MRI to test the hypothesis that TN is associated with altered gray matter (GM) in brain areas involved in the sensory and affective aspects of pain, pain modulation, and motor function. We further determined the contribution of long-term TN on GM plasticity. Methods Cortical thickness and subcortical GM volume were measured from high-resolution 3T T1-weighted MRI scans in 24 patients with right-sided TN and 24 healthy control participants. Results TN patients had increased GM volume in the sensory thalamus, amygdala, periaqueductal gray, and basal ganglia (putamen, caudate, nucleus accumbens) compared to healthy controls. The patients also had greater cortical thickness in the contralateral primary somatosensory cortex and frontal pole compared to controls. In contrast, patients had thinner cortex in the pregenual anterior cingulate cortex, the insula and the orbitofrontal cortex. No relationship was observed between GM abnormalities and TN pain duration. Conclusions TN is associated with GM abnormalities in areas involved in pain perception, pain modulation and motor function. These findings may reflect increased nociceptive input to the brain, an impaired descending modulation system that does not adequately inhibit pain, and increased motor output to control facial movements to limit pain attacks.

Three-dimensional in vivo modeling of vestibular schwannomas and surrounding cranial nerves with diffusion imaging tractography.

BACKGROUND:Preservation of cranial nerves (CNs) is of paramount concern in the treatment of vestibular schwannomas, particularly in large tumors with thinned and distorted CN fibers. However, imaging of the CN fibers surrounding vestibular schwannomas has been limited with 2-dimensional imaging alone. OBJECTIVE:To assess whether tractography of the CN combined with anatomic magnetic resonance imaging of the tumor can provide superior 3-dimensional (3D) visualization of tumor/CN complexes. METHODS:Magnetic resonance imaging at 3 T, including diffusion tensor imaging and anatomic images, were analyzed in 3 subjects with vestibular schwannomas using 3D Slicer software. The diffusion tensor images were used to track the courses of trigeminal, abducens, facial, and vestibulocochlear nerves. The anatomic images were used to model the 3D volume reconstruction of the tumor. The 2 sets of images were then superimposed through the use of linear registration. RESULTS:Combined 3D tumor modeling and CN tractography can effectively and consistently reconstruct the 3D spatial relationship of CN/tumor complexes and allows superior visualization compared with 2-dimensional imaging. Lateral and superior distortion of the trigeminal nerve was observed in all cases. The position of the facial nerve was primarily anteriorly and inferiorly. The gasserian ganglion and early postganglionic branches could also be visualized. CONCLUSION:Tractography and anatomic imaging were successfully combined to demonstrate the precise location of surrounding CN fibers. This technique can be useful in both neuronavigation and radiosurgical planning. Because knowledge of the course of these fibers is of important clinical interest, implementation of this technique may help decrease injury to CNs during treatment of these lesions.

Tractography-based connectomes are dominated by false-positive connections

Fiber tractography based on non-invasive diffusion imaging is at the heart of connectivity studies of the human brain. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain dataset with ground truth white matter tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. While most state-of-the-art algorithms reconstructed 90% of ground truth bundles to at least some extent, on average they produced four times more invalid than valid bundles. About half of the invalid bundles occurred systematically in the majority of submissions. Our results demonstrate fundamental ambiguities inherent to tract reconstruction methods based on diffusion orientation information, with critical consequences for the approach of diffusion tractography in particular and human connectivity studies in general.

Tractography Delineates Microstructural Changes in the Trigeminal Nerve after Focal Radiosurgery for Trigeminal Neuralgia

Purpose Focal radiosurgery is a common treatment modality for trigeminal neuralgia (TN), a neuropathic facial pain condition. Assessment of treatment effectiveness is primarily clinical, given the paucity of investigational tools to assess trigeminal nerve changes. Since diffusion tensor imaging (DTI) provides information on white matter microstructure, we explored the feasibility of trigeminal nerve tractography and assessment of DTI parameters to study microstructural changes after treatment. We hypothesized that trigeminal tractography provides more information than 2D-MR imaging, allowing detection of unique, focal changes in the target area after radiosurgery. Changes in specific diffusivities may provide insight into the mechanism of action of radiosurgery on the trigeminal nerve. Methods and Materials Five TN patients (4 females, 1 male, average age 67 years) treated with Gamma Knife radiosurgery, 80 Gy/100% isodose line underwent 3Tesla MR trigeminal nerve tractography before and sequentially up to fourteen months after treatment. Fractional anisotropy (FA), radial (RD) and axial (AD) diffusivities were calculated for the radiosurgical target area defined as the region-of-interest. Areas outside target and the contralateral nerve served as controls. Results Trigeminal tractography accurately detected the radiosurgical target. Radiosurgery resulted in 47% drop in FA values at the target with no significant change in FA outside the target, demonstrating highly focal changes after treatment. RD but not AD changed markedly, suggesting that radiosurgery primarily affects myelin. Tractography was more sensitive than conventional gadolinium-enhanced post-treatment MR, since FA changes were detected regardless of trigeminal nerve enhancement. In subjects with long term follow-up, recovery of FA/RD correlated with pain recurrence. Conclusions DTI parameters accurately detect the effects of focal radiosurgery on the trigeminal nerve, serving as an in vivo imaging tool to study TN. This study is a proof of principle for further assessment of DTI parameters to understand the pathophysiology of TN and treatment effects.

Negative childhood experiences alter a prefrontal-insular-motor cortical network in healthy adults: A preliminary multimodal rsfMRI-fMRI-MRS-dMRI study

Research in humans and animals has shown that negative childhood experiences (NCE) can have long‐term effects on the structure and function of the brain. Alterations have been noted in grey and white matter, in the brains resting state, on the glutamatergic system, and on neural and behavioural responses to aversive stimuli. These effects can be linked to psychiatric disorder such as depression and anxiety disorders that are influenced by excessive exposure to early life stressors. The aim of the current study was to investigate the effect of NCEs on these systems. Resting state functional MRI (rsfMRI), aversion task fMRI, glutamate magnetic resonance spectroscopy (MRS), and diffusion magnetic resonance imaging (dMRI) were combined with the Childhood Trauma Questionnaire (CTQ) in healthy subjects to examine the impact of NCEs on the brain. Low CTQ scores, a measure of NCEs, were related to higher resting state glutamate levels and higher resting state entropy in the medial prefrontal cortex (mPFC). CTQ scores, mPFC glutamate and entropy, correlated with neural BOLD responses to the anticipation of aversive stimuli in regions throughout the aversion‐related network, with strong correlations between all measures in the motor cortex and left insula. Structural connectivity strength, measured using mean fractional anisotropy, between the mPFC and left insula correlated to aversion‐related signal changes in the motor cortex. These findings highlight the impact of NCEs on multiple inter‐related brain systems. In particular, they highlight the role of a prefrontal‐insular‐motor cortical network in the processing and responsivity to aversive stimuli and its potential adaptability by NCEs. Hum Brain Mapp 36:4622–4637, 2015.

Diffusivity signatures characterize trigeminal neuralgia associated with multiple sclerosis

Background: Trigeminal neuralgia secondary to multiple sclerosis (MS-TN) is a facial neuropathic pain syndrome similar to classic trigeminal neuralgia (TN). While TN is caused by neurovascular compression of the fifth cranial nerve (CN V), how MS-related demyelination correlates with pain in MS-TN is not understood. Objectives: We aim to examine diffusivities along CN V in MS-TN, TN, and controls in order to reveal differential neuroimaging correlates across groups. Methods: 3T MR diffusion weighted, T1, T2 and FLAIR sequences were acquired for MS-TN, TN, and controls. Multi-tensor tractography was used to delineate CN V across cisternal, root entry zone (REZ), pontine and peri-lesional segments. Diffusion metrics including fractional anisotropy (FA), and radial (RD), axial (AD), and mean diffusivities (MD) were measured from each segment. Results: CN V segments showed distinctive diffusivity patterns. The TN group showed higher FA in the cisternal segment ipsilateral to the side of pain, and lower FA in the ipsilateral REZ segment. The MS-TN group showed lower FA in the ipsilateral peri-lesional segments, suggesting differential microstructural changes along CN V in these conditions. Conclusions: The study demonstrates objective differences in CN V microstrucuture in TN and MS-TN using non-invasive neuroimaging. This represents a significant improvement in the methods currently available to study pain in MS.

Subcallosal Cingulate Connectivity in Anorexia Nervosa Patients Differs From Healthy Controls: A Multi-tensor Tractography Study

BACKGROUND Anorexia nervosa is characterized by extreme low body weight and alterations in affective processing. The subcallosal cingulate regulates affect through wide-spread white matter connections and is implicated in the pathophysiology of anorexia nervosa. OBJECTIVES We examined whether those with treatment refractory anorexia nervosa undergoing deep brain stimulation (DBS) of the subcallosal white matter (SCC) show: (1) altered anatomical SCC connectivity compared to healthy controls, (2) white matter microstructural changes, and (3) microstructural changes associated with clinically-measured affect. METHODS Diffusion magnetic resonance imaging (dMRI) and deterministic multi-tensor tractography were used to compare anatomical connectivity and microstructure in SCC-associated white matter tracts. Eight women with treatment-refractory anorexia nervosa were compared to 8 age- and sex-matched healthy controls. Anorexia nervosa patients also completed affect-related clinical assessments presurgically and 12 months post-surgery. RESULTS (1) Higher (e.g., left parieto-occipital cortices) and lower (e.g., thalamus) connectivity in those with anorexia nervosa compared to controls. (2) Decreases in fractional anisotropy, and alterations in axial and radial diffusivities, in the left fornix crus, anterior limb of the internal capsule (ALIC), right anterior cingulum and left inferior fronto-occipital fasciculus. (3) Correlations between dMRI metrics and clinical assessments, such as low pre-surgical left fornix and right ALIC fractional anisotropy being related to post-DBS improvements in quality-of-life and depressive symptoms, respectively. CONCLUSIONS We identified widely-distributed differences in SCC connectivity in anorexia nervosa patients consistent with heterogenous clinical disruptions, although these results should be considered with caution given the low number of subjects. Future studies should further explore the use of affect-related connectivity and behavioral assessments to assist with DBS target selection and treatment outcome.

Age-Related Changes in Diffusion Tensor Imaging Metrics of Fornix Subregions in Healthy Humans

Objective: White matter diffusivity measures of the fornix change with aging, which likely relates to changes in memory and cognition in older adults. Subregional variations in forniceal diffusivity may exist, given its heterogeneous anatomy and connectivity; however, these have not been closely examined in vivo. We examined diffusivity parameters (fractional anisotropy, FA; radial diffusivity, RD; axial diffusivity, AD) in forniceal subregions of healthy subjects and correlated them with age and hippocampal volume. Methods: Diffusion-weighted imaging and streamline tractography of the fornix were performed on 20 healthy, right-handed females (23-66 years). Six anatomical subregions were defined: midline (body, column, precommissural fornix) or lateral (fimbria, crura, postcommissural fornix). Regression analysis was performed comparing diffusivities against age. Hippocampal and ventricular volumes were also compared. Results: Diffusivity values revealed statistical changes with age in both midline and lateralized subregions. The fornix body and left crus showed age-related alterations in all metrics (FA, RD, AD), whereas only right crus FA was altered. There was no significant change in hippocampal volumes, suggesting that forniceal changes may precede hippocampal age-related changes. Conclusions: Age-related changes in fornix diffusivity measures appear subregion dependent and asymmetrical. Specific subregion diffusivity measures may be a more sensitive aging marker than hippocampal volume change.