Diffusion Magnetic Resonance Imaging Tractography Guides Investigation of the Zona Incerta: A Novel Target for Deep Brain Stimulation.

BACKGROUND: The zona incerta (ZI) is a subcortical structure primarily investigated in rodents that is implicated in various behaviors, ranging from motor control to survival-associated activities, partly due to its integration in multiple neural circuits. In the current study, we used diffusion magnetic resonance imaging tractography to segment the ZI and gain insight into its connectivity in various circuits in humans. METHODS: We performed probabilistic tractography in 7T diffusion MRI on 178 participants from the Human Connectome Project to validate the ZI's anatomical subdivisions and their respective tracts. K-means clustering segmented the ZI based on each voxel's connectivity profile. We further characterized the connections of each ZI subregion using probabilistic tractography with each subregion as a seed. RESULTS: We identified 2 dominant clusters that delineated the whole ZI into rostral and caudal subregions. The caudal ZI primarily connected with motor regions, while the rostral ZI received a topographic distribution of projections from prefrontal areas, notably the anterior cingulate and medial prefrontal cortices. We generated a probabilistic ZI atlas that was registered to a patient-participant's magnetic resonance imaging scan for placement of stereoencephalographic leads for electrophysiology-guided deep brain stimulation to treat their obsessive-compulsive disorder. Rostral ZI stimulation improved the patient's core symptoms (mean improvement 21%). CONCLUSIONS: We present a tractography-based atlas of the rostral and caudal ZI subregions constructed using high-resolution diffusion magnetic resonance imaging from 178 healthy participants. Our work provides an anatomical foundation to explore the rostral ZI as a novel target for deep brain stimulation to treat refractory obsessive-compulsive disorder and other disorders associated with dysfunctional reward circuitry.

A Twin Study of Altered White Matter Heritability in Youth With Autism Spectrum Disorder.

OBJECTIVE: White matter alterations are frequently reported in autism spectrum disorder (ASD), yet the etiology is currently unknown. The objective of this investigation was to examine, for the first time, the impact of genetic and environmental factors on white matter microstructure in twins with ASD compared to control twins without ASD. METHOD: Diffusion-weighted MRIs were obtained from same-sex twin pairs (6-15 years of age) in which at least 1 twin was diagnosed with ASD or neither twin exhibited a history of neurological or psychiatric disorders. Fractional anisotropy (FA) and mean diffusivity (MD) were examined across different white matter tracts in the brain, and statistical and twin modeling were completed to assess the proportion of variation associated with additive genetic (A) and common/shared (C) or unique (E) environmental factors. We also developed a novel Twin-Pair Difference Score analysis method that produces quantitative estimates of the genetic and environmental contributions to shared covariance between different brain and behavioral traits. RESULTS: Good-quality data were available from 84 twin pairs, 50 ASD pairs (32 concordant for ASD [16 monozygotic; 16 dizygotic], 16 discordant for ASD [3 monozygotic; 13 dizygotic], and 2 pairs in which 1 twin had ASD and the other exhibited some subthreshold symptoms [1 monozygotic; 1 dizygotic]) and 34 control pairs (20 monozygotic; 14 dizygotic). Average FA and MD across the brain, respectively, were primarily genetically mediated in both control twins (A = 0.80, 95% CI [0.57, 1.02]; A = 0.80 [0.55, 1.04]) and twins concordant for having ASD (A = 0.71 [0.33, 1.09]; A = 0.84 [0.32,1.36]). However, there were also significant tract-specific differences between groups. For instance, genetic effects on commissural fibers were primarily associated with differences in general cognitive abilities and perhaps some diagnostic differences for ASD because Twin-Pair Difference-Score analysis indicated that genetic factors may have contributed to ∼40% to 50% of the covariation between IQ scores and FA of the corpus callosum. Conversely, the increased impact of environmental factors on some projection and association fibers were primarily associated with differences in symptom severity in twins with ASD; for example, our analyses suggested that unique environmental factors may have contributed to ∼10% to 20% of the covariation between autism-related symptom severity and FA of the cerebellar peduncles and external capsule. CONCLUSION: White matter alterations in youth with ASD are associated with both genetic contributions and potentially increased vulnerability or responsivity to environmental influences. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as living with a disability. The author list of this paper includes contributors from the location and/or community where the research was conducted and they participated in the data collection, design, analysis, and/or interpretation of the work.

An Individualized Tractography Pipeline for the Nucleus Basalis of Meynert Lateral Tract.

Background: At the center of the cortical cholinergic network, the nucleus basalis of Meynert (NBM) is crucial for the cognitive domains most vulnerable in PD. Preclinical evidence has demonstrated the positive impact of NBM deep brain stimulation (DBS) on cognition but early human trials have had mixed results. It is possible that DBS of the lateral NBM efferent white matter fiber bundle may be more effective at improving cognitive-motor function. However, precise tractography modelling is required to identify the optimal target for neurosurgical planning. Individualized tractography approaches have been shown to be highly effective for accurately identifying DBS targets but have yet to be developed for the NBM. Methods: Using structural and diffusion weighted imaging, we developed a tractography pipeline for precise individualized identification of the lateral NBM target tract. Using dice similarity coefficients, the reliability of the tractography outputs was assessed across three cohorts to investigate: 1) whether this manual pipeline is more reliable than an existing automated pipeline currently used in the literature; 2) the inter- and intra-rater reliability of our pipeline in research scans of patients with PD; and 3) the reliability and practicality of this pipeline in clinical scans of DBS patients. Results: The individualized manual pipeline was found to be significantly more reliable than the existing automated pipeline for both the segmentation of the NBM region itself (p<0.001) and the reconstruction of the target lateral tract (p=0.002). There was also no significant difference between the reliability of two different raters in the PD cohort (p=0.25), which showed high inter- (mean Dice coefficient >0.6) and intra-rater (mean Dice coefficient >0.7) reliability across runs. Finally, the pipeline was shown to be highly reliable within the clinical scans (mean Dice coefficient = 0.77). However, accurate reconstruction was only evident in 7/10 tracts. Conclusion: We have developed a reliable tractography pipeline for the identification and analysis of the NBM lateral tract in research and clinical grade imaging of healthy young adult and PD patient scans.

An orexigenic subnetwork within the human hippocampus.

Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing1-4. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone5,6. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

Frequency-dependent diffusion kurtosis imaging in the human brain using an oscillating gradient spin echo sequence and a high-performance head-only gradient.

Measuring the time/frequency dependence of diffusion MRI is a promising approach to distinguish between the effects of different tissue microenvironments, such as membrane restriction, tissue heterogeneity, and compartmental water exchange. In this study, we measure the frequency dependence of diffusivity (D) and kurtosis (K) with oscillating gradient diffusion encoding waveforms and a diffusion kurtosis imaging (DKI) model in human brains using a high-performance, head-only MAGNUS gradient system, with a combination of b-values, oscillating frequencies (f), and echo time that has not been achieved in human studies before. Frequency dependence of diffusivity and kurtosis are observed in both global and local white matter (WM) and gray matter (GM) regions and characterized with a power-law model ∼Λ*fθ. The frequency dependences of diffusivity and kurtosis (including changes between fmin and fmax, Λ, and θ) vary over different WM and GM regions, indicating potential microstructural differences between regions. A trend of decreasing kurtosis over frequency in the short-time limit is successfully captured for in vivo human brains. The effects of gradient nonlinearity (GNL) on frequency-dependent diffusivity and kurtosis measurements are investigated and corrected. Our results show that the GNL has prominent scaling effects on the measured diffusivity values (3.5∼5.5% difference in the global WM and 6∼8% difference in the global cortex) and subsequently affects the corresponding power-law parameters (Λ, θ) while having a marginal influence on the measured kurtosis values (<0.05% difference) and power-law parameters (Λ, θ). This study expands previous OGSE studies and further demonstrates the translatability of frequency-dependent diffusivity and kurtosis measurements to human brains, which may provide new opportunities to probe human brain microstructure in health and disease.

Quantitative MRI reveals widespread, network-specific myelination change during generalized epilepsy progression.

Activity-dependent myelination is a fundamental mode of brain plasticity which significantly influences network function. We recently discovered that absence seizures, which occur in multiple forms of generalized epilepsy, can induce activity-dependent myelination, which in turn promotes further progression of epilepsy. Structural alterations of myelin are likely to be widespread, given that absence seizures arise from an extensive thalamocortical network involving frontoparietal regions of the bilateral hemispheres. However, the temporal course and spatial extent of myelin plasticity is unknown, due to limitations of gold-standard histological methods such as electron microscopy (EM). In this study, we leveraged magnetization transfer and diffusion MRI for estimation of g-ratios across major white matter tracts in a mouse model of generalized epilepsy with progressive absence seizures. EM was performed on the same brains after MRI. After seizure progression, we found increased myelination (decreased g-ratios) throughout the anterior portion (genu-to-body) of the corpus callosum but not in the posterior portion (body-splenium) nor in the fornix or the internal capsule. Curves obtained from averaging g-ratio values at every longitudinal point of the corpus callosum were statistically different with p<0.001. Seizure-associated myelin differences found in the corpus callosum body with MRI were statistically significant (p = 0.0027) and were concordant with EM in the same region (p = 0.01). Notably, these differences were not detected by diffusion tensor imaging. This study reveals widespread myelin structural change that is specific to the absence seizure network. Furthermore, our findings demonstrate the potential utility and importance of MRI-based g-ratio estimation to non-invasively detect myelin plasticity.

Human habit neural circuitry may be perturbed in eating disorders.

Circuit-based mechanisms mediating the development and execution of habitual behaviors involve complex cortical-striatal interactions that have been investigated in animal models and more recently in humans. However, how human brain circuits implicated in habit formation may be perturbed in psychiatric disorders remains unclear. First, we identified the locations of the sensorimotor putamen and associative caudate in the human brain using probabilistic tractography from Human Connectome Project data. We found that multivariate connectivity of the sensorimotor putamen was altered in humans with binge eating disorder and bulimia nervosa and that the degree of alteration correlated with severity of disordered eating behavior. Furthermore, the extent of this circuit aberration correlated with mean diffusivity in the sensorimotor putamen and decreased basal dopamine D2/3 receptor binding potential in the striatum, consistent with previously reported microstructural changes and dopamine signaling mediating habit learning in animal models. Our findings suggest a neural circuit that links habit learning and binge eating behavior in humans, which could, in part, explain the treatment-resistant behavior common to eating disorders and other psychiatric conditions.

Changes in the Cerebello-Thalamo-Cortical Network After Magnetic Resonance-Guided Focused Ultrasound Thalamotomy.

Objective: In recent years, transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) has been established as a potential treatment option for movement disorders, including essential tremor (ET). So far, however, little is known about the impact of tcMRgFUS on structural connectivity. The objective of this study was to detect microstructural changes in tremor- and motor-related white matter tracts in ET patients treated with tcMRgFUS thalamotomy. Methods: Eleven patients diagnosed with ET were enrolled in this tcMRgFUS thalamotomy study. For each patient, 3 Tesla magnetic resonance imaging (3T MRI) including structural and diffusion MRI were acquired and the Clinical Rating Scale for Tremor was assessed before the procedure as well as 1 year after the treatment. Diffusion MRI tractography was performed to identify the cerebello-thalamo-cortical tract (CTCT), the medial lemniscus, and the corticospinal tract in both hemispheres on pre-treatment data. Pre-treatment tractography results were co-registered to post-treatment diffusion data. Diffusion tensor imaging (DTI) metrics, including fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD), were averaged across the tracts in the pre- and post-treatment data. Results: The mean value of tract-specific DTI metrics changed significantly within the thalamic lesion and in the CTCT on the treated side (p < 0.05). Changes of DTI-derived indices within the CTCT correlated well with lesion overlap (FA: r = -0.54, p = 0.04; MD: r = 0.57, p = 0.04); RD: r = 0.67, p = 0.036). Further, a trend was seen for the correlation between changes of DTI-derived indices within the CTCT and clinical improvement (FA: r = 0.58; p = 0.062; MD: r = -0.52, p = 0.64; RD: r = -0.61 p = 0.090). Conclusions: Microstructural changes were detected within the CTCT after tcMRgFUS, and these changes correlated well with lesion-tract overlap. Our results show that diffusion MRI is able to detect the microstructural effects of tcMRgFUS, thereby further elucidating the treatment mechanism, and ultimately to improve targeting prospectively. Impact statement The results of this study demonstrate microstructural changes within the cerebello-thalamo-cortical pathways 1 year after MR-guided focused ultrasound thalamotomy. Even more, microstructural changes within the cerebello-thalamo-cortical pathways correlated significantly with clinical outcome. These findings do not only highly emphasize the need of new targeting strategies for MR-guided focused ultrasound thalamotomy but also help to elucidate the treatment mechanism of it.

Multi-band multi-shot diffusion MRI reconstruction with joint usage of structured low-rank constraints and explicit phase mapping.

PURPOSE: To develop a joint reconstruction method for multi-band multi-shot diffusion MRI. THEORY AND METHODS: Multi-band multi-shot EPI acquisition is an effective approach for high-resolution diffusion MRI, but requires specific algorithms to correct the inter-shot phase variations. The phase correction can be done by first estimating the explicit phase map and then feeding it into the k-space signal formulation model. Alternatively, the phase information can be used indirectly as structured low-rank constraints in k-space. The 2 methods differ in reconstruction accuracy and efficiency. We aim to combine the 2 different approaches for improved image quality and reconstruction efficiency simultaneously, termed "joint usage of structured low-rank constraints and explicit phase mapping" (JULEP). The proposed JULEP reconstruction is tested on both single-band and multi-band, multi-shot diffusion data, with different resolutions and b values. The results of JULEP are compared with conventional methods with explicit phase mapping (i.e., multiplexed sensitivity-encoding [MUSE]) and structured low-rank constraints (i.e., MUSSELS), and another joint reconstruction method (i.e., network estimated artifacts for tempered reconstruction [NEATR]). RESULTS: JULEP improves the quality of the navigator and subsequently facilitates the reconstruction of final diffusion images. Compared with all 3 other methods (MUSE, MUSSELS, and NEATR), JULEP mitigates residual structural bias and improves temporal SNRs in the final diffusion image, particularly at high multi-band factors. Compared with MUSSELS, JULEP also improves computational efficiency. CONCLUSION: The proposed JULEP method significantly improves the image quality and reconstruction efficiency of multi-band multi-shot diffusion MRI, which can promote a broader application of high-resolution diffusion MRI.

Augmented Reality for Retrosigmoid Craniotomy Planning.

While medical imaging data have traditionally been viewed on two-dimensional (2D) displays, augmented reality (AR) allows physicians to project the medical imaging data on patient's bodies to locate important anatomy. We present a surgical AR application to plan the retrosigmoid craniotomy, a standard approach to access the posterior fossa and the internal auditory canal. As a simple and accurate alternative to surface landmarks and conventional surgical navigation systems, our AR application augments the surgeon's vision to guide the optimal location of cortical bone removal. In this work, two surgeons performed a retrosigmoid approach 14 times on eight cadaver heads. In each case, the surgeon manually aligned a computed tomography (CT)-derived virtual rendering of the sigmoid sinus on the real cadaveric heads using a see-through AR display, allowing the surgeon to plan and perform the craniotomy accordingly. Postprocedure CT scans were acquired to assess the accuracy of the retrosigmoid craniotomies with respect to their intended location relative to the dural sinuses. The two surgeons had a mean margin of d avg = 0.6 ± 4.7 mm and d avg = 3.7 ± 2.3 mm between the osteotomy border and the dural sinuses over all their cases, respectively, and only positive margins for 12 of the 14 cases. The intended surgical approach to the internal auditory canal was successfully achieved in all cases using the proposed method, and the relatively small and consistent margins suggest that our system has the potential to be a valuable tool to facilitate planning a variety of similar skull-base procedures.

Aberrant impulse control circuitry in obesity.

The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in impulsive eaters with obesity. Initially, we analyzed publicly available, high-resolution, normative imaging data to localize where vmPFC structural connections converged within the NAc. These structural connections were found to converge ventromedially in the presumed NAc shell subregion. We then analyzed multimodal clinical and imaging data to test the a priori hypothesis that the vmPFC-NAc shell circuit is linked to obesity in a sample of female participants that regularly engaged in impulsive eating (i.e., binge eating). Functionally, vmPFC-NAc shell resting-state connectivity was inversely related to body mass index (BMI) and decreased in the obese state. Structurally, vmPFC-NAc shell structural connectivity and vmPFC thickness were inversely correlated with BMI; obese binge-prone participants exhibited decreased vmPFC-NAc structural connectivity and vmPFC thickness. Finally, to examine a causal link to binge eating, we directly probed this circuit in one binge-prone obese female using NAc deep brain stimulation in a first-in-human trial. Direct stimulation of the NAc shell subregion guided by local behaviorally relevant electrophysiology was associated with a decrease in number of weekly episodes of uncontrolled eating and decreased BMI. This study unraveled vmPFC-NAc shell circuit aberrations in obesity that can be modulated to restore control over eating behavior in obesity.

Complex negative emotions induced by electrical stimulation of the human hypothalamus.

BACKGROUND: Stimulation of the ventromedial hypothalamic region in animals has been reported to cause attack behavior labeled as sham-rage without offering information about the internal affective state of the animal being stimulated. OBJECTIVE: To examine the causal effect of electrical stimulation near the ventromedial region of the human hypothalamus on the human subjective experience and map the electrophysiological connectivity of the hypothalamus with other brain regions. METHODS: We examined a patient (Subject S20_150) with intracranial electrodes implanted across 170 brain regions, including the hypothalamus. We combined direct electrical stimulation with tractography, cortico-cortical evoked potentials (CCEP), and functional connectivity using resting state intracranial electroencephalography (EEG). RESULTS: Recordings in the hypothalamus did not reveal any epileptic abnormalities. Electrical stimulations near the ventromedial hypothalamus induced profound shame, sadness, and fear but not rage or anger. When repeated single-pulse stimulations were delivered to the hypothalamus, significant responses were evoked in the amygdala, hippocampus, ventromedial-prefrontal and orbitofrontal cortices, anterior cingulate, as well as ventral-anterior and dorsal-posterior insula. The time to first peak of these evoked responses varied and earliest propagations correlated best with the measures of resting-state EEG connectivity and structural connectivity. CONCLUSION: This patient's case offers details about the affective state induced by the stimulation of the human hypothalamus and provides causal evidence relevant to current theories of emotion. The complexity of affective state induced by the stimulation of the hypothalamus and the profile of hypothalamic electrophysiological connectivity suggest that the hypothalamus and its connected structures ought to be seen as causally important for human affective experience.

Distortion-Free Diffusion Imaging Using Self-Navigated Cartesian Echo-Planar Time Resolved Acquisition and Joint Magnitude and Phase Constrained Reconstruction.

Echo-planar time resolved imaging (EPTI) is an effective approach for acquiring high-quality distortion-free images with a multi-shot EPI (ms-EPI) readout. As with traditional ms-EPI acquisitions, inter-shot phase variations present a main challenge when incorporating EPTI into a diffusion-prepared pulse sequence. The aim of this study is to develop a self-navigated Cartesian EPTI-based (scEPTI) acquisition together with a magnitude and phase constrained reconstruction for distortion-free diffusion imaging. A self-navigated Cartesian EPTI-based diffusion-prepared pulse sequence is designed. The different phase components in EPTI diffusion signal are analyzed and an approach to synthesize a fully phase-matched navigator for the inter-shot phase correction is demonstrated. Lastly, EPTI contains richer magnitude and phase information than conventional ms-EPI, such as the magnitude and phase correlations along the temporal dimension. The potential of these magnitude and phase correlations to enhance the reconstruction is explored. The reconstruction results with and without phase matching and with and without phase or magnitude constraints are compared. Compared with reconstruction without phase matching, the proposed phase matching method can improve the accuracy of inter-shot phase correction and reduce signal corruption in the final diffusion images. Magnitude constraints further improve image quality by suppressing the background noise and thereby increasing SNR, while phase constraints can mitigate possible image blurring from adding magnitude constraints. The high-quality distortion-free diffusion images and simultaneous diffusion-relaxometry imaging capacity provided by the proposed EPTI design represent a highly valuable tool for both clinical and neuroscientific assessments of tissue microstructure.

Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue.

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin's nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method's sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.

Evidence for the role of the dorsal ventral lateral posterior thalamic nucleus connectivity in deep brain stimulation for Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) can manifest as debilitating, medically-refractory tics for which deep brain stimulation (DBS) of the centromedian-parafascicular complex (CM) can provide effective treatment. However, patients have reported benefit with activation of contacts dorsal to the CM and likely in the ventro-lateral thalamus (VL). At our institution, a case of a robust and durable response in a GTS patient required stimulation in the CM and more dorsally. We explore the structural connectivity of thalamic subregions associated with GTS using diffusion MRI tractography. Diffusion weighted images from 40 healthy Human Connectome Project (HCP) subjects and our GTS patient were analyzed. The VL posterior nucleus (VLp) and the CM were used as seeds for whole-brain probabilistic tractography. Leads were localized via linear registration of pre-/post-operative imaging and cross-referenced with the DBS Intrinsic Template Atlas. Tractography revealed high streamline probability from the CM and VLp to the superior frontal gyrus, rostral middle frontal gyrus, brainstem, and ventral diencephalon. Given reported variable responses to DBS along the thalamus, we segmented the VLp based on its connectivity profile. Ventral and dorsal subdivisions emerged, with streamline probability patterns differing between the dorsal VLp and CM. The CM, the most reported DBS target for GTS, and the dorsal VLp have different but seemingly complimentary connectivity profiles as evidenced by our patient who, at 1-year post-operatively, had significant therapeutic benefit. Stimulation of both regions may better target reward and motor circuits, resulting in enhanced symptom control for GTS.

Case Report on Deep Brain Stimulation Rescue After Suboptimal MR-Guided Focused Ultrasound Thalamotomy for Essential Tremor: A Tractography-Based Investigation.

Essential tremor (ET) is the most prevalent movement disorder in adults, and can often be medically refractory, requiring surgical intervention. MRI-guided focused ultrasound (MRgFUS) is a less invasive procedure that uses ultrasonic waves to induce lesions in the ventralis intermedius nucleus (VIM) to treat refractory ET. As with all procedures for treating ET, optimal targeting during MRgFUS is essential for efficacy and durability. Various studies have reported cases of tremor recurrence following MRgFUS and long-term outcome data is limited to 3-4 years. We present a tractography-based investigation on a case of DBS rescue for medically refractory ET that was treated with MRgFUS that was interrupted due to the development of dysarthria during the procedure. After initial improvement, her hand tremor started to recur within 6 months after treatment, and bilateral DBS was performed targeting the VIM 24 months after MRgFUS. DBS induced long-term tremor control with monopolar stimulation. Diffusion MRI tractography was used to reconstruct the dentatorubrothalamic (DRTT) and corticothalmic (CTT) tracts being modulated by the procedures to understand the variability in efficacy between MRgFUS and DBS in treating ET in our patient. By comparing the MRgFUS lesion and DBS volume of activated tissue (VAT), we found that the MRgFUS lesion was located ventromedially to the VAT, and was less than 10% of the size of the VAT. While the lesion encompassed the same proportion of DRTT streamlines, it encompassed fewer CTT streamlines than the VAT. Our findings indicate the need for further investigation of targeting the CTT when using neuromodulatory procedures to treat refractory ET for more permanent tremor relief.

Application of holographic augmented reality for external approaches to the frontal sinus.

BACKGROUND: External approaches to the frontal sinus such as osteoplastic flaps are challenging because they require blind entry into the sinus, posing risks of injury to the brain or orbit. Intraoperative computed tomography (CT)-based navigation is the current standard for planning the approach, but still necessitates blind entry into the sinus. The aim of this work was to describe a novel technique for external approaches to the frontal sinus using a holographic augmented reality (AR) application. METHODS: Our team developed an AR system to create a 3-dimensional (3D) hologram of key anatomical structures, based on CT scans images. Using Magic Leap AR goggles for visualization, the frontal sinus hologram was aligned to the surface anatomy in 6 fresh cadaveric heads' anatomic boundaries, and the boundaries of the frontal sinus were demarcated based on the margins of the fused image. Trephinations and osteoplastic flap approaches were performed. The specimens were re-scanned to assess the accuracy of the osteotomy with respect to the actual frontal sinus perimeter. RESULTS: Registration and surgery were completed successfully in all specimens. Registration required an average of 2 minutes. The postprocedure CT showed a mean difference of 1.4 ± 4.1 mm between the contour of the osteotomy and the contour of the frontal sinus. One surgical complication (posterior table perforation) occurred (16%). CONCLUSION: We describe proof of concept of a novel technique utilizing AR to enhance external approaches to the frontal sinus. Holographic AR-enhanced surgical navigation holds promise for enhanced visualization of target structures during surgical approaches to the sinuses.

Oscillating diffusion-encoding with a high gradient-amplitude and high slew-rate head-only gradient for human brain imaging.

PURPOSE: We investigate the importance of high gradient-amplitude and high slew-rate on oscillating gradient spin echo (OGSE) diffusion imaging for human brain imaging and evaluate human brain imaging with OGSE on the MAGNUS head-gradient insert (200 mT/m amplitude and 500 T/m/s slew rate). METHODS: Simulations with cosine-modulated and trapezoidal-cosine OGSE at various gradient amplitudes and slew rates were performed. Six healthy subjects were imaged with the MAGNUS gradient at 3T with OGSE at frequencies up to 100 Hz and b = 450 s/mm2 . Comparisons were made against standard pulsed gradient spin echo (PGSE) diffusion in vivo and in an isotropic diffusion phantom. RESULTS: Simulations show that to achieve high frequency and b-value simultaneously for OGSE, high gradient amplitude, high slew rates, and high peripheral nerve stimulation limits are required. A strong linear trend for increased diffusivity (mean: 8-19%, radial: 9-27%, parallel: 8-15%) was observed in normal white matter with OGSE (20 Hz to 100 Hz) as compared to PGSE. Linear fitting to frequency provided excellent correlation, and using a short-range disorder model provided radial long-term diffusivities of D∞,MD = 911 ± 72 µm2 /s, D∞,PD = 1519 ± 164 µm2 /s, and D∞,RD = 640 ± 111 µm2 /s and correlation lengths of lc,MD = 0.802 ± 0.156 µm, lc,PD = 0.837 ± 0.172 µm, and lc,RD = 0.780 ± 0.174 µm. Diffusivity changes with OGSE frequency were negligible in the phantom, as expected. CONCLUSION: The high gradient amplitude, high slew rate, and high peripheral nerve stimulation thresholds of the MAGNUS head-gradient enables OGSE acquisition for in vivo human brain imaging.

High-gradient diffusion MRI reveals distinct estimates of axon diameter index within different white matter tracts in the in vivo human brain.

Axon diameter and density are important microstructural metrics that offer valuable insight into the structural organization of white matter throughout the human brain. We report the systematic acquisition and analysis of a comprehensive diffusion MRI data set acquired with 300 mT/m maximum gradient strength in a cohort of 20 healthy human subjects that yields distinct and consistent patterns of axon diameter index in white matter tracts of arbitrary orientation. We use a straightforward, previously validated approach to estimating indices of axon diameter and volume fraction that involves interpolating the diffusion signal perpendicular to the principal fiber orientation and fitting a three-compartment model of intra-axonal, extra-axonal and free water diffusion. The resultant maps confirm the presence of larger diameter indices in the body of corpus callosum compared to the genu and splenium, as previously reported, and show larger axon diameter index in the corticospinal tracts compared to adjacent white matter tracts such as the cingulum. An anterior-to-posterior gradient in axon diameter index is also observed, with smaller diameter indices in the frontal lobes and larger diameter indices in the parieto-occipital white matter. These observations are consistent with known trends from prior histologic studies in humans and non-human primates. Rather than serving as fully quantitative measures of axon diameter and density, our results may be considered as axon diameter- and volume fraction-weighted images that appear to be modulated by the underlying microstructure and may capture broad trends in axonal size and packing density, acknowledging that the precise origin of such modulation requires further investigation that will be facilitated by the availability of high gradient strengths for in vivo human imaging.

Multimodal image registration and connectivity analysis for integration of connectomic data from microscopy to MRI.

3D histology, slice-based connectivity atlases, and diffusion MRI are common techniques to map brain wiring. While there are many modality-specific tools to process these data, there is a lack of integration across modalities. We develop an automated resource that combines histologically cleared volumes with connectivity atlases and MRI, enabling the analysis of histological features across multiple fiber tracts and networks, and their correlation with in-vivo biomarkers. We apply our pipeline in a murine stroke model, demonstrating not only strong correspondence between MRI abnormalities and CLARITY-tissue staining, but also uncovering acute cellular effects in areas connected to the ischemic core. We provide improved maps of connectivity by quantifying projection terminals from CLARITY viral injections, and integrate diffusion MRI with CLARITY viral tracing to compare connectivity maps across scales. Finally, we demonstrate tract-level histological changes of stroke through this multimodal integration. This resource can propel investigations of network alterations underlying neurological disorders.