Correspondence between white matter hyperintensities and regional grey matter volumes in Alzheimer's disease.

Objective: White matter hyperintensities (WMH) are the most common neuroimaging manifestation of cerebral small vessel disease, and is frequently observed in Alzheimer's disease (AD). This study aimed to investigate the relationship between WMH and cognition and to verify the mediation of grey matter atrophy in this relationship. Methods: The diffusion tensor imaging (DTI) technique analyses white matter fiber tract to assess white matter integrity. Voxel-based morphometry was applied to measure the grey matter volume (GMV). A linear regression model was applied to examine the associations between WMH and GMV, and mediation analyses was performed to determine the mediating role of regional GMV in the effect of WMH on cognitive function. Results: Compared to the HC group, AD group have 8 fiber tract fractional anisotropy (FA) decreased and 16 fiber tract mean diffusivity (MD) increased. Compared to AD without WMH, AD with high WMH had 9 fiber tracts FA decreased and 13 fiber tracts MD increased. High WMH volume was negatively correlated with GMV in the frontal-parietal region. Low WMH volume was also negatively correlated with GMV except for the three regions (right angular gyrus, right superior frontal gyrus and right middle/inferior parietal gyrus), where GMV was positively correlated. Mediation analysis showed that the association between WMH and executive function or episodic memory were mediated by GMV in the frontal-parietal region. Conclusion: Damage to white matter integrity was more severe in AD with WMH. Differential changes in DTI metrics may be caused by progressive myelin and axonal damage. There was a negative correlation between WMH and grey matter atrophy in frontal-parietal regions in a volume-dependent manner. This study indicates the correspondence between WMH volume and GMV in cognition, and GMV being a key modulator between WMH and cognition in AD. This result will contribute to understanding the progression of the disease process and applying targeted therapeutic intervention in the earlier stage to delay neurodegenerative changes in frontal-parietal regions to achieve better treatment outcomes and affordability.

In Vivo visualization of white matter fiber tracts in the brainstem using low flip angle double echo 3D gradient echo imaging at 3T.

BACKGROUND: White matter (WM) fiber tracts in the brainstem communicate with various regions in the cerebrum, cerebellum, and spinal cord. Clinically, small lesions, malformations, or histopathological changes in the brainstem can cause severe neurological disorders. A direct and non-invasive assessment approach could bring valuable information about the intricate anatomical variations of the white matter fiber tracts and nuclei. Although tractography from diffusion tensor imaging has been commonly used to map the WM fiber tracts connectivity, it is difficult to differentiate the complex WM tracts anatomically. Both high field MRI methods and ultrahigh-field MRI methods at 7T and 11.7 T have been used to enhance the contrast of WM fiber tracts. Despite their promising results, it is still challenging to achieve wide clinical adoption at 3T. In this study, we explored a clinically feasible method using a proton density weighted (PDW) 3D gradient echo (GRE) sequence to directly image the WM fiber tracts in the brainstem at 3T in vivo. METHODS: We optimized a 3D high resolution, double echo, short TR, PDW GRE sequence on 5 healthy volunteers using a clinical 3T scanner to visualize the complicated anatomy of WM fiber tracts in the brain stem. Tissue properties including T1, proton density and T2* from in vivo quantitative MRI data were used for simulations to determine the optimal flip angle for the sequence. The visualization of multiple WM fiber tracts in the brainstem was assessed qualitatively and quantitatively using relative contrast and contrast-to-noise ratio (CNR). To improve the CNR, the final images were created by averaging over all echoes from two consecutive scans at the optimal flip angle. The results were compared to anatomical atlases and histology sections to identify the major fiber tracts. All the identified major fiber tracts were labeled on axial, sagittal and coronal slices. RESULTS: The WM fiber tracts were found to have distinct hypointense signal throughout the brainstem and most of the major WM fiber tracts, such as the corticospinal tract, medial lemniscus, medial longitudinal fasciculus, and central tegmental tract, in the brainstem up to and including the thalamus were identified in all subjects. Both qualitative and quantitative evaluations showed that the 3° scan offered the best contrast for WM fiber tracts for a TR of 20 ms. The average over the first two echo times and two consecutive 3° scans gave a CNR of 47.8 ± 6.2 for the pyramidal tracts in particular and CNRs values greater than 6.5 ± 2.4 for the rest of the fiber tracts. CONCLUSIONS: All the major fiber tracts in the brainstem could be visualized. Given the reasonably short scan time of 10 min at 3T, double echo PDW GRE sequence is a very practical approach for clinical adoption.

Mixed reality compared to the traditional ex cathedra format for neuroanatomy learning: the value of a three-dimensional virtual environment to better understand the real world.

OBJECTIVE: Neuroanatomy comprehension is a keystone of understanding intracranial surgeries. Traditionally taught to students during ex cathedra courses, neuroanatomy is described as complex. Mixed reality (MxR) opens new perspectives in the learning process. This study aims to compare MxR-based courses with traditional ex cathedra lectures for neuroanatomy education. METHODS: Two lectures describing the neuroanatomy of the anterior circulation arteries ("Vascular Lecture" [VS]) and important white matter fiber tracts ("White Fibers Lecture" [WF]) were designed and delivered in ex cathedra and MxR-based formats with the same audio content. Ninety-one medical students were randomly assigned to group A (ex cathedra WF/MxR VS) or group B (MxR WF/ex cathedra VS). The MxR content was delivered via MxR goggles. Prior to each lecture, students took a 10-item multiple choice question (MCQ) pretest. After the lectures, students took a 20-item MCQ posttest (75% neuroanatomy, 25% clinical correlation). RESULTS: The pretest scores showed no statistical difference between groups. Median posttest scores increased by 14.3% after using the MxR-based format compared to the ex cathedra format (16.00 [13.0, 18.0] vs 14.0 [11.0, 17.0], respectively, p < 0.01). Regarding the VS, students scored 21.7% better using the MxR format compared to the ex cathedra format (14.0 [12.0, 16.0] vs 11.5 [10.0, 14.0], p < 0.001). Concerning the WF, the median score using MxR was 18.0 (17.0, 19.0), and the median score using the ex cathedra format was 17.0 (16.0, 18.0; p < 0.01). Students showed high motivation to learn neuroanatomy in the future using MxR (74%) rather than ex cathedra format (25%; p < 0.001). Mild discomfort using the MxR goggles was reported by 48.3% of participants. Most participants (95.5%) preferred the MxR-based teaching. CONCLUSIONS: Students acquired a better knowledge of the anatomy of the anterior circulation arteries and white fiber tracts using MxR-based teaching as compared to the standard ex cathedra format. The perception of lecture quality and learning motivation was better using MxR-based teaching despite some mild discomfort. The development of MxR-based solutions is promising to improve neuroanatomy education.

The Subcortical Atlas of the Marmoset ("SAM") monkey based on high-resolution MRI and histology.

A comprehensive three-dimensional digital brain atlas of cortical and subcortical regions based on MRI and histology has a broad array of applications for anatomical, functional, and clinical studies. We first generated a Subcortical Atlas of the Marmoset, called the "SAM," from 251 delineated subcortical regions (e.g., thalamic subregions, etc.) derived from the high-resolution MAP-MRI, T2W, and MTR images ex vivo. We then confirmed the location and borders of these segmented regions in MRI data using matched histological sections with multiple stains obtained from the same specimen. Finally, we estimated and confirmed the atlas-based areal boundaries of subcortical regions by registering this ex vivo atlas template to in vivo T1- or T2W MRI datasets of different age groups (single vs. multisubject population-based marmoset control adults) using a novel pipeline developed within AFNI. Tracing and validating these important deep brain structures in 3D improves neurosurgical planning, anatomical tract tracer injections, navigation of deep brain stimulation probes, fMRI and brain connectivity studies, and our understanding of brain structure-function relationships. This new ex vivo template and atlas are available as volumes in standard NIFTI and GIFTI file formats and are intended for use as a reference standard for marmoset brain research.

White Matter Tract Integrity Is Reduced in Depression and in Individuals With Genetic Liability to Depression.

BACKGROUND: While major depression has been linked to changes in white matter architecture, it remains unclear whether risk factors for depression are directly associated with these alterations. We reexamined white matter fiber tracts in individuals with depressive symptoms and investigated the connection between genetic and environmental risk for depression and structural changes in the brain. METHODS: We included 19,183 participants from the UK Biobank imaging cohort, with depression status and adverse life experience based on questionnaire data and genetic liability for depression quantified by polygenic scores. The integrity of 27 white matter tracts was assessed using mean fractional anisotropy derived from diffusion magnetic resonance imaging. RESULTS: White matter integrity was reduced, particularly in thalamic and intracortical fiber tracts, in individuals with depressive symptoms, independent of current symptom status. In a group of healthy individuals without depression, increasing genetic risk and increasing environmental risk were associated with reduced integrity in relevant fiber tracts, particularly in thalamic radiations. This association was stronger than expected based on statistical dependencies between samples, as confirmed by subsequent in silico simulations and permutation tests. CONCLUSIONS: White matter alterations in thalamic and association tracts are associated with depressive symptoms and genetic risk for depression in unaffected individuals, suggesting an intermediate phenotype at the brain level.

Characterization of the Abracl-Expressing Cell Populations in the Embryonic Mammalian Telencephalon.

Abracl (ABRA C-terminal-like protein) is a small, non-typical winged-helix protein that shares similarity with the C-terminal domain of the protein ABRA (Actin-Binding Rho-Activating protein). The role of Abracl in the cell remains elusive, although in cancer cells, it has been implicated in proliferation, migration and actin dynamics. Our previous study showed that Abracl mRNA was expressed in the dividing cells of the subpallial subventricular zone (SVZ), in the developing cortical plate (CP), and in the diencephalic SVZ; however, the molecular identities of the Abracl-expressing cell populations were not defined in that work. In this study, we use double immunofluorescence to characterize the expression of Abracl on sections of embryonic murine (E11.5-E18.5) and feline (E30/31-E33/34) telencephalon; to this end, we use a battery of well-known molecular markers of cycling (Ki67, Ascl1, Dlx2) or post-mitotic (Tubb3, Gad65/67, Lhx6 and Tbr1) cells. Our experiments show that Abracl protein has, compared to the mRNA, a broader expression domain, including, apart from proliferating cells of the subpallial and diencephalic SVZ, post-mitotic cells occupying the subpallial and pallial mantle (including the CP), as well as subpallial-derived migrating interneurons. Interestingly, in late embryonic developmental stages, Abracl was also transiently detected in major telencephalic fiber tracts.

Multimodal anatomical mapping of subcortical regions in marmoset monkeys using high-resolution MRI and matched histology with multiple stains.

Subcortical nuclei and other deep brain structures play essential roles in regulating the central and peripheral nervous systems. However, many of these nuclei and their subregions are challenging to identify and delineate in conventional MRI due to their small size, hidden location, and often subtle contrasts compared to neighboring regions. To address these limitations, we scanned the whole brain of the marmoset monkeys in ex vivo using a clinically feasible diffusion MRI method, called the mean apparent propagator (MAP)-MRI, along with T2W and MTR (T1-like contrast) images acquired at 7 Tesla. Additionally, we registered these multimodal MRI volumes to the high-resolution images of matched whole-brain histology sections with seven different stains obtained from the same brain specimens. At high spatial resolution, the microstructural parameters and fiber orientation distribution functions derived with MAP-MRI can distinguish the subregions of many subcortical and deep brain structures, including fiber tracts of different sizes and orientations. The good correlation with multiple but distinct histological stains from the same brain serves as a thorough validation of the structures identified with MAP-MRI and other MRI parameters. Moreover, the anatomical details of deep brain structures found in the volumes of MAP-MRI parameters are not visible in conventional T1W or T2W images. The high-resolution mapping using novel MRI contrasts, combined and correlated with histology, can elucidate structures that were previously invisible radiologically. Thus, this multimodal approach offers a roadmap toward identifying salient brain areas in vivo in future neuroradiological studies. It also provides a useful anatomical standard reference for the region definition of subcortical targets and the generation of a 3D digital template atlas for the marmoset brain research (Saleem et al., 2023). Additionally, we conducted a cross-species comparison between marmoset and macaque monkeys using results from our previous studies (Saleem et al., 2021). We found that the two species had distinct patterns of iron distribution in subregions of the basal ganglia, red nucleus, and deep cerebellar nuclei, confirmed with T2W MRI and histology.

Differential and correlational tractography as tract-based biomarkers in mild traumatic brain injury: A longitudinal MRI study.

We evaluated the fiber bundles in mild traumatic brain injury (mTBI) patients using differential and correlational tractography in a longitudinal analysis. Diffusion MRI data were acquired in 34 mTBI patients at 7 days (acute stage) and 3 months or longer (chronic stage) after mTBI. Trail Making Test A (TMT-A) and Digital Symbol Substitution Test changes were used to evaluate the cognitive performance. Longitudinal correlational tractography showed decreased anisotropy in the corpus callosum during the chronic mTBI stage. The changes in anisotropy in the corpus callosum were significantly correlated with the changes in TMT-A (false discovery rate [FDR] = 0.000094). Individual longitudinal differential tractography found that anisotropy decreased in the corpus callosum in 30 mTBI patients. Group cross-sectional differential tractography found that anisotropy increased (FDR = 0.02) in white matter in the acute mTBI patients, while no changes occurred in the chronic mTBI patients. Our study confirms the feasibility of using correlational and differential tractography as tract-based monitoring biomarkers to evaluate the disease progress of mTBI, and indicates that normalized quantitative anisotropy could be used as a biomarker to monitor the injury and/or repairs of white matter in individual mTBI patients.

Exploring Novel Innovation Strategies to Close a Technology Gap in Neurosurgery: HORAO Crowdsourcing Campaign.

BACKGROUND: Scientific research is typically performed by expert individuals or groups who investigate potential solutions in a sequential manner. Given the current worldwide exponential increase in technical innovations, potential solutions for any new problem might already exist, even though they were developed to solve a different problem. Therefore, in crowdsourcing ideation, a research question is explained to a much larger group of individuals beyond the specialist community to obtain a multitude of diverse, outside-the-box solutions. These are then assessed in parallel by a group of experts for their capacity to solve the new problem. The 2 key problems in brain tumor surgery are the difficulty of discerning the exact border between a tumor and the surrounding brain, and the difficulty of identifying the function of a specific area of the brain. Both problems could be solved by a method that visualizes the highly organized fiber tracts within the brain; the absence of fibers would reveal the tumor, whereas the spatial orientation of the tracts would reveal the area's function. To raise awareness about our challenge of developing a means of intraoperative, real-time, noninvasive identification of fiber tracts and tumor borders to improve neurosurgical oncology, we turned to the crowd with a crowdsourcing ideation challenge. OBJECTIVE: Our objective was to evaluate the feasibility of a crowdsourcing ideation campaign for finding novel solutions to challenges in neuroscience. The purpose of this paper is to introduce our chosen crowdsourcing method and discuss it in the context of the current literature. METHODS: We ran a prize-based crowdsourcing ideation competition called HORAO on the commercial platform HeroX. Prize money previously collected through a crowdfunding campaign was offered as an incentive. Using a multistage approach, an expert jury first selected promising technical solutions based on broad, predefined criteria, coached the respective solvers in the second stage, and finally selected the winners in a conference setting. We performed a postchallenge web-based survey among the solvers crowd to find out about their backgrounds and demographics. RESULTS: Our web-based campaign reached more than 20,000 people (views). We received 45 proposals from 32 individuals and 7 teams, working in 26 countries on 4 continents. The postchallenge survey revealed that most of the submissions came from single solvers or teams working in engineering or the natural sciences, with additional submissions from other nonmedical fields. We engaged in further exchanges with 3 out of the 5 finalists and finally initiated a successful scientific collaboration with the winner of the challenge. CONCLUSIONS: This open innovation competition is the first of its kind in medical technology research. A prize-based crowdsourcing ideation campaign is a promising strategy for raising awareness about a specific problem, finding innovative solutions, and establishing new scientific collaborations beyond strictly disciplinary domains.

Brain recovery of the NAc fibers and prediction of craving changes in person with heroin addiction: A longitudinal study.

BACKGROUND: Progress have been made in brain function recovery after long-term abstinence in person with heroin addiction (PHA). However, less is known about whether the nucleus accumbens (NAc) white matter pathways can recover in PHA by prolonged abstinence. METHODS: Forty-two PHA and Thirty-nine age- and gender- matched healthy controls (HCs) were recruited. Two MRI scans were obtained at baseline (PHA1) and 8-month follow-up (PHA2). We employed tractography atlas-based analysis (TABS) method to investigate fractional anisotropy (FA) changes in NAc fiber tracts (i.e., Insula-NAc, ventral tegmental area (VTA)-NAc, medial prefrontal cortex (MPFC)-NAc) in PHA. A partial least square regression (PLSR) analysis was carried to explore whether FA of NAc fiber tracts can predict longitudinal craving changes. RESULTS: Relative to HCs, lower FA was found in the right Insula-NAc and VTA-NAc fiber tracts in PHA1, and PHA2 showed increased FA values in these tracts compared with PHA1. Furthermore, changes of FA of NAc fiber tracts can predict longitudinal craving changes (r = 0.51). Additionally, craving changes can also be predicted from FA changes in the left Insula-NAc (r = 0.601) and VTA-NAc (r = 0.384) fiber alone. CONCLUSIONS: Results indicated that the right Insula-NAc and VTA-NAc fiber tracts are potential biomarkers for brain recovery. Prediction of craving changes highlighted the utility of structural markers to inform clinical decision-making of treatment for PHA.

5-ALA-guided tumor resection during awake speech mapping in gliomas located in eloquent speech areas: Single-center experience.

Background: Achieving maximal functionally safe resection of gliomas located within the eloquent speech areas is challenging, and there is a lack of literature on the combined use of 5-aminolevulinic acid (5-ALA) guidance and awake craniotomy. Objective: The aim of this study was to describe our experience with the simultaneous use of 5-ALA fluorescence and awake speech mapping in patients with left frontal gliomas located within the vicinity of eloquent speech areas. Materials and methods: A prospectively collected database of patients was reviewed. 5-ALA was administered at a dose of 20 mg/kg 2 h prior to operation, and an operating microscope in BLUE400 mode was used to visualize fluorescence. All patients underwent surgery using the "asleep-awake-asleep" protocol with monopolar and bipolar electrical stimulation to identify the proximity of eloquent cortex and white matter tracts and to guide safe limits of resection along with fluorescence guidance. Speech function was assessed by a trained neuropsychologist before, during, and after surgery. Results: In 28 patients operated with cortical mapping and 5-ALA guidance (12 Grade 4, 6 Grade 3, and 10 Grade 2 gliomas), Broca's area was identified in 23 cases and Wernicke's area was identified in 5 cases. Fluorescence was present in 14 cases. Six tumors had residual fluorescence due to the positive speech mapping in the tumor bed. Transient aphasia developed in 14 patients, and permanent aphasia developed in 4 patients. In 6 patients operated with cortical and subcortical speech mapping and 5-ALA guidance (4 Grade 4, 1 Grade 3, and 1 Grade 2 gliomas), cortical speech areas were mapped in 5 patients and subcortical tracts were encountered in all cases. In all cases, resection was stopped despite the presence of residual fluorescence due to speech mapping findings. Transient aphasia developed in 6 patients and permanent aphasia developed in 4 patients. In patients with Grade 2-3 gliomas, targeted biopsy of focal fluorescence areas led to upgrading the grade and thus more accurate diagnosis. Conclusion: 5-ALA guidance during awake speech mapping is useful in augmenting the extent of resection for infiltrative high-grade gliomas and identifying foci of anaplasia in non-enhancing gliomas, while maintaining safe limits of functional resection based on speech mapping. Positive 5-ALA fluorescence in diffuse Grade 2 gliomas may be predictive of a more aggressive disease course.

Microsurgical Anatomy of the Cerebellar Interpeduncular Entry Zones.

OBJECTIVE: The cerebellar interpeduncular region, particularly the middle cerebellar peduncle (MCP) and interpeduncular sulcus (IPS) are significant surgical relevance areas due to the high prevalence of vascular and tumoral pathologies, such as cavernomas, arteriovenous malformations, and gliomas. We defined safer access areas of the MCP and the IPS, according to the surface anatomy, involved vessels, and fiber tracts of the cerebellar interpeduncular region. METHODS: Fifteen formalin-fixed and silicone-injected cadaveric heads and 23 human brainstems with attached cerebellums prepared with the Klingler's technique were bilaterally dissected to study the vascular and intrinsic anatomy. RESULTS: Surface anatomy: The mean length of the IPS was 12.73 mm (standard deviation [SD],2.15 mm), and the average measured angle formed by the IPS and the lateral mesencephalic sulcus was 144.53°. The mean distance from the uppermost point of the IPS to cranial nerve IV was 2.63 mm (SD, 2.84 mm). Vascular anatomy: The perforating branches of the superior cerebellar peduncle, IPS, and MCP originated predominantly from the caudal trunk of the superior cerebellar artery. The inferior third of the superior cerebellar peduncle and IPS was the third most pierced by perforating arteries, and for the MCP, was its superior third. Crossing vessels: The branches of the pontotrigeminal vein and the caudal trunk of the superior cerebellar artery crossed the IPS mostly. The superior third of the IPS was the most crossed by arteries and veins. CONCLUSIONS: The middle thirds of the IPS and MCP as entry zones might be safer than their superior and inferior thirds due to fewer perforating branches, arterial trunks, and veins crossing the sulcus as fewer eloquent tracts.

Sensitivity of Diffusion MRI to White Matter Pathology: Influence of Diffusion Protocol, Magnetic Field Strength, and Processing Pipeline in Systemic Lupus Erythematosus.

There are many ways to acquire and process diffusion MRI (dMRI) data for group studies, but it is unknown which maximizes the sensitivity to white matter (WM) pathology. Inspired by this question, we analyzed data acquired for diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) at 3T (3T-DTI and 3T-DKI) and DTI at 7T in patients with systemic lupus erythematosus (SLE) and healthy controls (HC). Parameter estimates in 72 WM tracts were obtained using TractSeg. The impact on the sensitivity to WM pathology was evaluated for the diffusion protocol, the magnetic field strength, and the processing pipeline. Sensitivity was quantified in terms of Cohen's d for group comparison. Results showed that the choice of diffusion protocol had the largest impact on the effect size. The effect size in fractional anisotropy (FA) across all WM tracts was 0.26 higher when derived by DTI than by DKI and 0.20 higher in 3T compared with 7T. The difference due to the diffusion protocol was larger than the difference due to magnetic field strength for the majority of diffusion parameters. In contrast, the difference between including or excluding different processing steps was near negligible, except for the correction of distortions from eddy currents and motion which had a clearly positive impact. For example, effect sizes increased on average by 0.07 by including motion and eddy correction for FA derived from 3T-DTI. Effect sizes were slightly reduced by the incorporation of denoising and Gibbs-ringing removal (on average by 0.011 and 0.005, respectively). Smoothing prior to diffusion model fitting generally reduced effect sizes. In summary, 3T-DTI in combination with eddy current and motion correction yielded the highest sensitivity to WM pathology in patients with SLE. However, our results also indicated that the 3T-DKI and 7T-DTI protocols used here may be adjusted to increase effect sizes.

nTMS-derived DTI-based motor fiber tracking in radiotherapy treatment planning of high-grade gliomas for avoidance of motor structures.

BACKGROUND: Management of high-grade gliomas (HGGs) close to motor areas is challenging due to the risk of treatment-related morbidity. Thus, for resection, functional mapping of the corticospinal tract (CST) with navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI)-based fiber tracking (DTI-FTTMS) is increasingly used. This study investigated the application of DTI-FTTMS in adjuvant radiation therapy (RT) planning of HGGs for CST avoidance. METHODS: The preoperative DTI-FTTMS-based CST reconstructions of 35 patients harboring HGGs were incorporated into the RT planning system and merged with planning imaging. The CST was delineated as the planning risk volume (PRV-FTTMS). Intensity-modulated RT (IMRT) plans were optimized to preserve PRV-FTTMS. Segments within the planning target volume (PTV) were not spared (overlap). RESULTS: With plan optimization, mean dose (Dmean) of PRV-FTTMS can be reduced by 17.1% on average (range 0.1-37.9%), thus from 25.5 Gy to 21.2 Gy (p < 0.001). For PRV-FTTMS segments beyond the PTV dose, reduction is possible by 26.8% (range 0.1-43.9%, Dmean 17.4 Gy vs. 12.5 Gy, p < 0.001). Considering only portions within the 50% isodose level, Dmean is decreased by 46.7% from 38.6 Gy to 20.5 Gy (range 19.1-62.8%, p < 0.001). PTV coverage was not affected: V95% and V90% were 96.4 ± 3.1% and 98.0 ± 3.9% vs. 96.1 ± 3.5% (p = 0.34) and 98.3 ± 2.9% (p = 0.58). Dose constraints for organs at risk (OARs) were all met. CONCLUSION: This study demonstrates that DTI-FTTMS can be utilized in the RT planning of HGGs for CST sparing. However, the degree of dose reduction depends on the overlap with the PTV. The functional benefit needs to be investigated in future prospective clinical trials.

Differential Tractography and Correlation Tractography Findings on Patients With Mild Traumatic Brain Injury: A Pilot Study.

Differential tractography and correlation tractography are new tractography modalities to study neuronal changes in brain diseases, but their performances in detecting neuronal injuries are yet to be investigated in patients with mild traumatic brain injury (mTBI). Here we investigated the white matter injury in mTBI patients using differential and correlation tractography. The diffusion MRI was acquired at 33 mTBI patients and 31 health controls. 7 of the mTBI patients had one-year follow-up scans, and differential tractography was used to evaluate injured fiber bundles on these 7 patients. All subjects were evaluated using digital symbol substitution test (DSST) and trail making test A (TMT-A), and the correlation tractography was performed to explore the exact pathways related to the cognitive performance. Our results showed that differential tractography revealed neuronal changes in the corpus callosum in all 7 follow-up mTBI patients with FDR between 0.007 and 0.17. Further, the correlation tractography showed that the splenium of the corpus callosum, combined with the right superior longitudinal fasciculus and right cingulum, were correlated with DSST (FDR = 0.001669) in the acute mTBI patients. The cognitive impairment findings in the acute stage and the longitudinal findings in the corpus callosum in the chronic stage of mTBI patients suggest that differential tractography and correlation tractography are valuable tools in the diagnostic and prognostic evaluation of neuronal injuries in mTBI patients.

Mapping Motor Pathways in Parkinson's Disease Patients with Subthalamic Deep Brain Stimulator: A Diffusion MRI Tractography Study.

INTRODUCTION: This study assessed the safety of postoperative diffusion tensor imaging (DTI) with on-state deep brain stimulation (DBS) and the feasibility of reconstruction of the white matter tracts in the vicinity of the stimulation site of the subthalamic nucleus (STN). The association between the impact of DBS on the nigrostriatal pathway (NSP) and the treatment effect on motor symptoms in Parkinson's disease (PD) was then evaluated. METHODS: Thirty-one PD patients implanted with STN-DBS (mean age: 66 years; 25 male) were scanned on a 1.5-T magnetic resonance imaging (MRI) scanner using the DTI sequence with DBS on. Twenty-three of them were scanned a second time with DBS off. The NSP, dentato-rubro-thalamic tract (DRTT), and hyperdirect pathway (HDP) were generated using both deterministic and probabilistic tractography methods. The DBS-on-state and off-state tractography results were validated and compared. Afterward, the relationships between the characteristics of the reconstructed white matter tracts and the clinical assessment of PD symptoms and the DBS effect were further examined. RESULTS: No adverse events related to DTI were identified in either the DBS-on-state or off-state. Overall, the NSP was best reconstructed, followed by the DRTT and HDP, using the probabilistic tractography method. The connection probability of the left NSP was significantly lower than that of the right side (p < 0.05), and a negative correlation (r = -0.39, p = 0.042) was identified between the preoperative symptom severity in the medication-on state and the connection probability of the left NSP in the DBS-on-state images. Furthermore, the distance from the estimated left-side volume of tissue activated (VTA) by STN-DBS to the ipsilateral NSP was significantly shorter in the DBS-responsive group compared to the DBS-non-responsive group (p = 0.046). CONCLUSIONS: DTI scanning is safe and delineation of white matter pathway is feasible for PD patients implanted with the DBS device. Postoperative DTI is a useful technique to strengthen our current understanding of the therapeutic effect of DBS for PD and has the potential to refine target selection strategies for brain stimulation.

For some more seriously affected Parkinson's disease (PD) patients, drugs are no longer effective in treating their symptoms. An alternate treatment is to use deep brain stimulation (DBS), a commonly used neurosurgical therapy for PD patients. For those DBS treatments targeting the subthalamic nucleus (STN), the electrical stimulation used may impact nearby white matter tracts and alter the effectiveness of the DBS treatment. The nigrostriatal pathway (NSP), dentato-rubro-thalamic tract, and hyperdirect pathway are three white matter tracts near the STN. They are all relevant to motor symptoms in PD. This study examined whether imaging these tracts using magnetic resonance imaging (MRI) is safe and feasible in the presence of DBS leads. The relationships between the fiber-tracking characteristics and distance to the DBS leads were then evaluated. For this purpose, 31 PD patients with stimulation-on were scanned on a 1.5 T MRI scanner using a diffusion tensor imaging sequence. A total of 23 subjects underwent another scan using the same sequence with stimulation-off. No adverse events related to diffusion tensor imaging were found. Among the white matter tracts near the STN, the NSP was best delineated, followed by the dentato-rubro-thalamic tract and the hyperdirect pathway. The connection probability of the left NSP was significantly lower than that of the right side as were the subject's motor symptoms. The closer the distance between the NSP and the stimulation location, the better the DBS outcome. These findings indicate that imaging white matter tracts with DBS on is safe and useful in mapping DBS outcomes.

Bridging the callosal gap in gait: corpus callosum white matter integrity's role in lower limb coordination.

Bilateral coordination of the lower extremities is an essential component of mobility. The corpus callosum bridges the two hemispheres of the brain and is integral for the coordination of such complex movements. The aim of this project was to assess structural integrity of the transcallosal sensorimotor fiber tracts and identify their associations with gait coordination using novel methods of ecologically valid mobility assessments in persons with multiple sclerosis and age-/gender-matched neurotypical adults. Neurotypical adults (n = 29) and persons with multiple sclerosis (n = 27) underwent gait and diffusion tensor imaging assessments; the lower limb coordination via Phase Coordination Index, and radial diffusivity, an indirect marker of myelination, were applied as the primary outcome measures. Persons with multiple sclerosis possessed poorer transcallosal white matter microstructural integrity of sensorimotor fiber tracts compared to the neurotypical adults. Further, persons with multiple sclerosis demonstrated significantly poorer bilateral coordination of the lower limbs during over-ground walking in comparison to an age and gender-matched neurotypical cohort. Finally, bilateral coordination of the lower limbs was significantly associated with white matter microstructural integrity of the dorsal premotor and primary motor fiber bundles in persons with multiple sclerosis, but not in neurotypical adults. This analysis revealed that persons with multiple sclerosis exhibit poorer transcallosal microstructural integrity than neurotypical peers. Furthermore, these structural deficits were correlated to poorer consistency and accuracy of gait in those with multiple sclerosis. Together, these results, emphasize the importance of transcallosal communication for gait coordination in those with multiple sclerosis.

Topographic Evolution of Anterior Cerebral Artery Infarction and Its Impact on Motor Impairment.

INTRODUCTION: Motor deficit is common following anterior cerebral artery (ACA) stroke. This study aimed to determine the impact on the motor outcome, given the location of descending corticofugal fiber tracts (from the primary motor cortex [M1], dorsal and ventral premotor area [PMdv], and supplementary motor area [SMA]) and the regional variations in collateral support of the ACA territory. METHODS: Patients with ACA vessel occlusion were included. Disruption to corticofugal fibers was inferred by overlap of tracts with a lesion on computed tomography perfusion at the onset and on magnetic resonance imaging (MRI) poststroke. The motor outcome was defined by dichotomized and combined National Institute of Health Stroke Scale (NIHSS) sub-scores for the arm and leg. Multivariate hierarchical partitioning was used to analyze the proportional contribution of the corticofugal fibers to the motor outcome. RESULTS: Forty-seven patients with a median age of 77.5 (interquartile range 68.0-84.5) years were studied. At the stroke onset, 96% of patients showed evidence of motor deficit on the NIHSS, and the proportional contribution of the corticofugal fibers to motor deficit was M1-33%, SMA-33%, and PMdv-33%. By day 7, motor deficit was present in <50% of patients and contribution of M1 fiber tracts to the motor deficit was reduced (M1-10.2%, SMA-61.0%, PMdv-28.8%). We confirmed our findings using publicly available high-resolution templates created from Human Connectome Project data. This also showed a reduction in involvement of M1 fiber tracts on initial perfusion imaging (33%) compared to MRI at a median time of 7 days poststroke (11%). CONCLUSION: Improvements in the motor outcome seen in ACA stroke may be due to the relative sparing of M1 fiber tracts from infarction. This may occur as a consequence of the posterior location of M1 fiber tracts and the evolving topography of ACA stroke due to the compensatory capacity of leptomeningeal anastomoses.

Three-Dimensional Quantitative Analysis of the Brainstem Safe Entry Zones Based on Internal Structures.

OBJECTIVE: Brainstem safe entry zones (EZs) are gates to access the intrinsic pathology of the brainstem. We performed a quantitative analysis of the intrinsic surgical corridor limits of the most commonly used EZs and illustrated these through an inside perspective using 2-dimensional photographs, 3-dimensional photographs, and interactive 3-dimensional model reconstructions. METHODS: A total of 26 human brainstems (52 sides) with the cerebellum attached were prepared using the Klingler method and dissected. The safe working areas and distances for each EZ were defined according to the eloquent fiber tracts and nuclei. RESULTS: The largest safe distance corresponded to the depth for the lateral mesencephalic sulcus (4.8 mm), supratrigeminal (10 mm), epitrigeminal (13.2 mm), peritrigeminal (13.3 mm), lateral transpeduncular (22.3 mm), and infracollicular (4.6 mm); the rostrocaudal axis for the perioculomotor (11.7 mm), suprafacial (12.6 mm), and transolivary (12.8 mm); and the mediolateral axis for the supracollicular (9.1 mm) and infracollicular (7 mm) EZs. The safe working areas were 46.7 mm2 for the perioculomotor, 21.3 mm2 for the supracollicular, 14.8 mm2 for the infracollicular, 33.1 mm2 for the supratrigeminal, 34.3 mm2 for the suprafacial, 21.9 mm2 for the infrafacial, and 51.7 mm2 for the transolivary EZs. CONCLUSIONS: The largest safe distance in most EZs corresponded to the depth, followed by the rostrocaudal axis and, finally, the mediolateral axis. The transolivary had the largest safe working area of all EZs. The supracollicular EZ had the largest safe area to access the midbrain tectum and the suprafacial EZ for the floor of the fourth ventricle.

High-resolution virtual brain modeling personalizes deep brain stimulation for treatment-resistant depression: Spatiotemporal response characteristics following stimulation of neural fiber pathways.

Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient, with an average response rate of ∼50%. The engagement of specific fiber tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here we provide a computational framework that can explore each individual's brain response characteristics elicited by selective stimulation of fiber tracts. We use a novel personalized in-silico approach, the Virtual Big Brain, which makes use of high-resolution virtual brain models at a mm-scale and explicitly reconstructs more than 100,000 fiber tracts for each individual. Each fiber tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient, even though validation against empirical patient data reveals some limitations (i.e., the need for individual parameter adjustment, and differential accuracy across stimulation locations). This study provides evidence for the capacity of personalized high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalized optimization of brain stimulation.