Multimodal MRI for MRgFUS in essential tremor: post-treatment radiological markers of clinical outcome.

BACKGROUND: MRI-guided focused ultrasound (MRgFUS) thalamotomy is a promising non-invasive treatment option for medication-resistant essential tremor. However, it has been associated with variable efficacy and a relatively high incidence of adverse effects. OBJECTIVES: To assess the evolution of radiological findings after MRgFUS thalamotomy and to evaluate their significance for clinical outcomes. METHODS: Ninety-four patients who underwent MRgFUS between 2012 and 2017 were retrospectively evaluated. Lesion characteristics were assessed on routine MRI sequences, as well as with tractography. Relationships between imaging appearance, extent of white matter tract lesioning (59/94, on a 4-point scale) and clinical outcome were investigated. Recurrence was defined as >33% loss of tremor suppression at 3 months relative to day 7. RESULTS: Acute lesions demonstrated blood products, surrounding oedema and peripheral diffusion restriction. The extent of dentatorubrothalamic tract (DRTT) lesioning was significantly associated with clinical improvement at 1 year (t=4.32, p=0.001). Lesion size decreased over time (180.8±91.5 mm3 at day 1 vs 19.5±19.3 mm3 at 1-year post-treatment). Higher post-treatment oedema (t=3.59, p<0.001) was associated with larger lesions at 3 months. Patients with larger lesions at day 1 demonstrated reduced rates of tremor recurrence (t=2.67, p=0.019); however, lesions over 170 mm3 trended towards greater incidence of adverse effects (sensitivity=0.60, specificity=0.63). Lesion encroachment on the medial lemniscus (Sn=1.00, Sp=0.32) and pyramidal tract (Sn=1.00, Sp=0.12) were also associated with increased adverse effects incidence. CONCLUSION: Lesion size at day 1 predicts symptom recurrence, with fewer recurrences seen with larger lesions. Greater DRTT lesioning is associated with treatment efficacy. These findings may have implications for lesion targeting and extent. TRIAL REGISTRATION NUMBER: NCT02252380.

Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor.

Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive ablative treatment for essential tremor. The size and location of therapeutic lesions producing the optimal clinical benefits while minimizing adverse effects are not known. We examined these relationships in patients with essential tremor undergoing MRgFUS. We studied 66 patients with essential tremor who underwent MRgFUS between 2012 and 2017. We assessed the Clinical Rating Scale for Tremor (CRST) scores at 3 months after the procedure and tracked the adverse effects (sensory, motor, speech, gait, and dysmetria) 1 day (acute) and 3 months after the procedure. Clinical data associated with the postoperative Day 1 lesions were used to correlate the size and location of lesions with tremor benefit and acute adverse effects. Diffusion-weighted imaging was used to assess whether acute adverse effects were related to lesions encroaching on nearby major white matter tracts (medial lemniscus, pyramidal, and dentato-rubro-thalamic). The area of optimal tremor response at 3 months after the procedure was identified at the posterior portion of the ventral intermediate nucleus. Lesions extending beyond the posterior region of the ventral intermediate nucleus and lateral to the lateral thalamic border were associated with increased risk of acute adverse sensory and motor effects, respectively. Acute adverse effects on gait and dysmetria occurred with lesions inferolateral to the thalamus. Lesions inferolateral to the thalamus or medial to the ventral intermediate nucleus were also associated with acute adverse speech effects. Diffusion-weighted imaging revealed that lesions associated with adverse sensory and gait/dysmetria effects compromised the medial lemniscus and dentato-rubro-thalamic tracts, respectively. Lesions associated with adverse motor and speech effects encroached on the pyramidal tract. Lesions larger than 170 mm3 were associated with an increased risk of acute adverse effects. Tremor improvement and acute adverse effects of MRgFUS for essential tremor are highly dependent on the location and size of lesions. These novel findings could refine current MRgFUS treatment planning and targeting, thereby improving clinical outcomes in patients.

GABA and glutamate levels correlate with MTR and clinical disability: Insights from multiple sclerosis.

Converging areas of research have implicated glutamate and γ-aminobutyric acid (GABA) as key players in neuronal signalling and other central functions. Further research is needed, however, to identify microstructural and behavioral links to regional variability in levels of these neurometabolites, particularly in the presence of demyelinating disease. Thus, we sought to investigate the extent to which regional glutamate and GABA levels are related to a neuroimaging marker of microstructural damage and to motor and cognitive performance. Twenty-one healthy volunteers and 47 people with multiple sclerosis (all right-handed) participated in this study. Motor and cognitive abilities were assessed with standard tests used in the study of multiple sclerosis. Proton magnetic resonance spectroscopy data were acquired from sensorimotor and parietal regions of the brains' left cerebral hemisphere using a MEGA-PRESS sequence. Our analysis protocol for the spectroscopy data was designed to account for confounding factors that could contaminate the measurement of neurometabolite levels due to disease, such as the macromolecule signal, partial volume effects, and relaxation effects. Glutamate levels in both regions of interest were lower in people with multiple sclerosis. In the sensorimotor (though not the parietal) region, GABA concentration was higher in the multiple sclerosis group compared to controls. Lower magnetization transfer ratio within grey and white matter regions from which spectroscopy data were acquired was linked to neurometabolite levels. When adjusting for age, normalized brain volume, MTR, total N-acetylaspartate level, and glutamate level, significant relationships were found between lower sensorimotor GABA level and worse performance on several tests, including one of upper limb motor function. This work highlights important methodological considerations relevant to analysis of spectroscopy data, particularly in the afflicted human brain. These findings support that regional neurotransmitter levels are linked to local microstructural integrity and specific behavioral abilities that can be affected in diseases such as multiple sclerosis.

Abnormal functional connectivity and cortical integrity influence dominant hand motor disability in multiple sclerosis: a multimodal analysis.

Functional reorganization and structural damage occur in the brains of people with multiple sclerosis (MS) throughout the disease course. However, the relationship between resting-state functional connectivity (FC) reorganization in the sensorimotor network and motor disability in MS is not well understood. This study used resting-state fMRI, T1-weighted and T2-weighted, and magnetization transfer (MT) imaging to investigate the relationship between abnormal FC in the sensorimotor network and upper limb motor disability in people with MS, as well as the impact of disease-related structural abnormalities within this network. Specifically, the differences in FC of the left hemisphere hand motor region between MS participants with preserved (n = 17) and impaired (n = 26) right hand function, compared with healthy controls (n = 20) was investigated. Differences in brain atrophy and MT ratio measured at the global and regional levels were also investigated between the three groups. Motor preserved MS participants had stronger FC in structurally intact visual information processing regions relative to motor impaired MS participants. Motor impaired MS participants showed weaker FC in the sensorimotor and somatosensory association cortices and more severe structural damage throughout the brain compared with the other groups. Logistic regression analysis showed that regional MTR predicted motor disability beyond the impact of global atrophy whereas regional grey matter volume did not. More importantly, as the first multimodal analysis combining resting-state fMRI, T1-weighted, T2-weighted and MTR images in MS, we demonstrate how a combination of structural and functional changes may contribute to motor impairment or preservation in MS. Hum Brain Mapp 37:4262-4275, 2016. © 2016 Wiley Periodicals, Inc.

Functional networks in parallel with cortical development associate with executive functions in children.

Children begin performing similarly to adults on tasks requiring executive functions in late childhood, a transition that is probably due to neuroanatomical fine-tuning processes, including myelination and synaptic pruning. In parallel to such structural changes in neuroanatomical organization, development of functional organization may also be associated with cognitive behaviors in children. We examined 6- to 10-year-old children's cortical thickness, functional organization, and cognitive performance. We used structural magnetic resonance imaging (MRI) to identify areas with cortical thinning, resting-state fMRI to identify functional organization in parallel to cortical development, and working memory/response inhibition tasks to assess executive functioning. We found that neuroanatomical changes in the form of cortical thinning spread over bilateral frontal, parietal, and occipital regions. These regions were engaged in 3 functional networks: sensorimotor and auditory, executive control, and default mode network. Furthermore, we found that working memory and response inhibition only associated with regional functional connectivity, but not topological organization (i.e., local and global efficiency of information transfer) of these functional networks. Interestingly, functional connections associated with "bottom-up" as opposed to "top-down" processing were more clearly related to children's performance on working memory and response inhibition, implying an important role for brain systems involved in late childhood.

Emotional expressions in voice and music: same code, same effect?

Scholars have documented similarities in the way voice and music convey emotions. By using functional magnetic resonance imaging (fMRI) we explored whether these similarities imply overlapping processing substrates. We asked participants to trace changes in either the emotion or pitch of vocalizations and music using a joystick. Compared to music, vocalizations more strongly activated superior and middle temporal cortex, cuneus, and precuneus. However, despite these differences, overlapping rather than differing regions emerged when comparing emotion with pitch tracing for music and vocalizations, respectively. Relative to pitch tracing, emotion tracing activated medial superior frontal and anterior cingulate cortex regardless of stimulus type. Additionally, we observed emotion specific effects in primary and secondary auditory cortex as well as in medial frontal cortex that were comparable for voice and music. Together these results indicate that similar mechanisms support emotional inferences from vocalizations and music and that these mechanisms tap on a general system involved in social cognition.

Birth weight and gestation influence striatal morphology and motor response in normal six-year-old boys.

The relation between fetal growth and attention deficit hyperactivity disorder (ADHD) cuts across the normal range of birth weights suggesting that subtle variations in fetal development may influence brain and cognitive function. We investigated the relation of ADHD-related endophenotypes, such as the striatum morphology, motor response and inhibition, with birth weight and gestational age in healthy children. 157 Six-year-old boys born at term (37 to 41 weeks) within the normal range for birth weight (2500 to 4630 g) underwent magnetic resonance imaging (MRI) and performed the stop signal task. Linear regression was used to examine effects of birth weight, gestational age, and their interaction on striatal volumes and shapes as well as motor response and inhibition. Interactive effects of birth weight and gestational age, even within the normal range, predicted caudate volumes and shapes. Boys with relatively low birth weight and shorter gestation had smaller caudate volumes, reflected by shape contraction in the middle body, and in addition performed worst in motor response, reflected by mean reaction time and its variability. Our results supported the idea that prenatal influences on neurocognitive and brain development are not limited to the extreme range, but occur across the entire population. Variations in brain structure and cognitive endophenotypes associated with childhood ADHD psychopathology are sensitive to subtle prenatal influences, which provides guidance for intervention research to improve mental health of children.

Trigeminal neuralgia diffusivities using Gaussian process classification and merged group tractography.

ABSTRACT: Imaging of trigeminal neuralgia (TN) has demonstrated key diffusion tensor imaging-based diffusivity alterations in the trigeminal nerve; however, imaging has primarily focused on the peripheral nerve segment because of previous limitations in reliably segmenting small fiber bundles across multiple subjects. We used Selective Automated Group Integrated Tractography to study 36 subjects with TN (right-sided pain) and 36 sex-matched controls to examine the trigeminal nerve (fifth cranial nerve [CN V]), pontine decussation (TPT), and thalamocortical fibers (S1). Gaussian process classifiers were trained by scrolling a moving window over CN V, TPT, and S1 tractography centroids. Fractional anisotropy (FA), generalized FA, radial diffusivity, axial diffusivity, and mean diffusivity metrics were evaluated for both groups, analyzing TN vs control groups and affected vs unaffected sides. Classifiers that performed at greater-than-or-equal-to 70% accuracy were included. Gaussian process classifier consistently demonstrated bilateral trigeminal changes, differentiating them from controls with an accuracy of 80%. Affected and unaffected sides could be differentiated from each other with 75% accuracy. Bilateral TPT could be distinguished from controls with at least 85% accuracy. TPT left-right classification achieved 98% accuracy. Bilateral S1 could be differentiated from controls, where the affected S1 radial diffusivity classifier achieved 87% accuracy. This is the first TN study that combines group-wise merged tractography, machine learning classification, and analysis of the complete trigeminal pathways from the peripheral fibers to S1 cortex. This analysis demonstrates that TN is characterized by bilateral abnormalities throughout the trigeminal pathway compared with controls and abnormalities between affected and unaffected sides. This full pathway tractography study of TN demonstrates bilateral changes throughout the trigeminal pathway and changes between affected and unaffected sides.

Peripheral Nerve Focused Ultrasound Lesioning-Visualization and Assessment Using Diffusion Weighted Imaging.

Objectives: Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive targeted tissue ablation technique that can be applied to the nervous system. Diffusion weighted imaging (DWI) can visualize and evaluate nervous system microstructure. Tractography algorithms can reconstruct fiber bundles which can be used for treatment navigation and diffusion tensor imaging (DTI) metrics permit the quantitative assessment of nerve microstructure in vivo. There is a need for imaging tools to aid in the visualization and quantitative assessment of treatment-related nerve changes in MRgFUS. We present a method of peripheral nerve tract reconstruction and use DTI metrics to evaluate the MRgFUS treatment effect. Materials and Methods: MRgFUS was applied bilaterally to the sciatic nerves in 6 piglets (12 nerves total). T1-weighted and diffusion images were acquired before and after treatment. Tensor-based and constrained spherical deconvolution (CSD) tractography algorithms were used to reconstruct the nerves. DTI metrics of fractional anisotropy (FA), and mean (MD), axial (AD), and radial diffusivities (RD) were measured to assess acute (<1-2 h) treatment effects. Temperature was measured in vivo via MR thermometry. Histological data was collected for lesion assessment. Results: The sciatic nerves were successfully reconstructed in all subjects. Tract disruption was observed after treatment using both CSD and tensor models. DTI metrics in the targeted nerve segments showed significantly decreased FA and increased MD, AD, and RD. Transducer output power was positively correlated with lesion volume and temperature and negatively correlated with MD, AD, and RD. No correlations were observed between FA and other measured parameters. Conclusions: DWI and tractography are effective tools for visualizing peripheral nerve segments for targeting in non-invasive surgical methods and for assessing the microstructural changes that occur following MRgFUS treatment.

Multi-manifold diffeomorphic metric mapping for aligning cortical hemispheric surfaces.

Cortical surface-based analysis has been widely used in anatomical and functional studies because it is geometrically appropriate for the cortex. One of the main challenges in the cortical surface-based analysis is to optimize the alignment of the cortical hemispheric surfaces across individuals. In this paper, we introduce a multi-manifold large deformation diffeomorphic metric mapping (MM-LDDMM) algorithm that allows simultaneously carrying the cortical hemispheric surface and its sulcal curves from one to the other through a flow of diffeomorphisms. We present an algorithm based on recent derivation of a law of momentum conservation for the geodesics of diffeomorphic flow. Once a template is fixed, the space of initial momentum becomes an appropriate space for studying shape via geodesic flow since the flow at any point on curves and surfaces along the geodesic is completely determined by the momentum at the origin. We solve for trajectories (geodesics) of the kinetic energy by computing its variation with respect to the initial momentum and by applying a gradient descent scheme. The MM-LDDMM algorithm optimizes the initial momenta encoding the anatomical variation of each individual relative to a common coordinate system in a linear space, which provides a natural scheme for shape deformation average and template (or atlas) generation. We applied the MM-LDDMM algorithm for constructing the templates for the cortical surface and 14 sulcal curves of each hemisphere using a group of 40 subjects. The estimated template shape reflects regions which are highly variable across these subjects. Compared with existing single-manifold LDDMM algorithms, such as the LDDMM-curve mapping and the LDDMM-surface mapping, the MM-LDDMM mapping provides better results in terms of surface to surface distances in five predefined regions.

Quantitative evaluation of LDDMM, FreeSurfer, and CARET for cortical surface mapping.

Cortical surface mapping has been widely used to compensate for individual variability of cortical shape and topology in anatomical and functional studies. While many surface mapping methods were proposed based on landmarks, curves, spherical or native cortical coordinates, few studies have extensively and quantitatively evaluated surface mapping methods across different methodologies. In this study we compared five cortical surface mapping algorithms, including large deformation diffeomorphic metric mapping (LDDMM) for curves (LDDMM-curve), for surfaces (LDDMM-surface), multi-manifold LDDMM (MM-LDDMM), FreeSurfer, and CARET, using 40 MRI scans and 10 simulated datasets. We computed curve variation errors and surface alignment consistency for assessing the mapping accuracy of local cortical features (e.g., gyral/sulcal curves and sulcal regions) and the curvature correlation for measuring the mapping accuracy in terms of overall cortical shape. In addition, the simulated datasets facilitated the investigation of mapping error distribution over the cortical surface when the MM-LDDMM, FreeSurfer, and CARET mapping algorithms were applied. Our results revealed that the LDDMM-curve, MM-LDDMM, and CARET approaches best aligned the local curve features with their own curves. The MM-LDDMM approach was also found to be the best in aligning the local regions and cortical folding patterns (e.g., curvature) as compared to the other mapping approaches. The simulation experiment showed that the MM-LDDMM mapping yielded less local and global deformation errors than the CARET and FreeSurfer mappings.

Combined analyses of thalamic volume, shape and white matter integrity in first-episode schizophrenia.

The thalamus has been considered to be integral to the pathophysiology of schizophrenia. To determine whether its anatomical abnormalities may be associated with cognitive deficits in the onset of schizophrenia, we assessed thalamic volume, shape, white matter integrity, and their correlations with cognition in patients with first-episode schizophrenia. T1-weighted magnetic resonance and diffusion tensor (DT) images were collected in 49 healthy comparison controls (CON) and 32 patients with FES (FES). Large deformation diffeomorphic metric mapping (LDDMM) algorithms were used to delineate and assess the thalamic shape from MRI scans. The thalamic white matter integrity was quantified by fractional anisotropy (FA) and mean diffusivity (MD) averaged over the thalamus using DTI. Our analysis revealed that FES did not differ from CON in FA and MD but did differ markedly from them in the thalamic volume and shape. Patients with FES also performed poorly in spatial working memory and executive tasks. The correlation study found that regional thalamic shapes highly correlate with the two cognitive scores in the entire sample and healthy comparison controls but not in patients with FES even though no correlation was found between the thalamic volumes with the two cognitive scores in any group. Left thalamic FA was correlated with spatial working memory deficits in FES. Our findings suggest that thalamic volume and shape abnormalities are evident at the onset of FES prior to thalamic abnormal white matter integrity. Altered microstructural white matter integrity assessed using DTI may not be apparent in FES but may be observed as the disease progresses. Cognitive deficits related to spatial working memory and executive functioning in FES were observed in the context of loss of their normal relationship with the thalamic shapes, that is, regionally-specific thalamic shape compression is associated with poor performance in executive functioning and spatial working memory.

Acute ex vivo changes in brain white matter diffusion tensor metrics.

PURPOSE: Diffusion magnetic resonance imaging and tractography has an important role in the visualization of brain white matter and assessment of tissue microstructure. There is a lack of correspondence between diffusion metrics of live tissue, ex vivo tissue, and histological findings. The objective of this study is to elucidate this connection by determining the specific diffusion alterations between live and ex vivo brain tissue. This may have an important role in the incorporation of diffusion imaging in ex vivo studies as a complement to histological sectioning as well as investigations of novel neurosurgical techniques. METHODS: This study presents a method of high angular resolution diffusion imaging and tractography of intact and non-fixed ex vivo piglet brains. Most studies involving ex vivo brain specimens have been formalin-fixed or excised from their original biological environment, processes both of which are known to affect diffusion parameters. Thus, non-fixed ex vivo tissue is used. A region-of-interest based analysis of diffusion tensor metrics are compared to in vivo subjects in a selection of major white matter bundles in order to assess the translatability of ex vivo diffusion measurements. RESULTS: Tractography was successfully achieved in both in vivo and ex vivo groups. No significant differences were found in tract connectivity, average streamline length, or apparent fiber density. Significantly decreased diffusivity (mean, axial, and radial; p<0.0005) in the non-fixed ex vivo group and unaltered fractional anisotropy (p>0.059) between groups were observed. CONCLUSION: This study validates the extrapolation of non-fixed fractional anisotropy measurements to live tissue and the potential use of ex vivo tissue for methodological development.

Acute MR-Guided High-Intensity Focused Ultrasound Lesion Assessment Using Diffusion-Weighted Imaging and Histological Analysis.

Objectives: The application of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of neurological conditions has been of increasing interest. Conventional MR imaging can provide structural information about the effect of MRgFUS, where differences in ablated tissue can be seen, but it lacks information about the status of the cellular environment or neural microstructure. We investigate in vivo acute changes in water diffusion and white matter tracts in the brain of a piglet model after MRgFUS treatment using diffusion-weighted imaging (DWI) with histological verification of treatment-related changes. Methods: MRgFUS was used to treat the anterior body of the fornix in four piglets. T1 and diffusion-weighted images were collected before and after treatment. Mean diffusion-weighted imaging (MDWI) images were generated to measure lesion volumes via signal intensity thresholds. Histological data were collected for volume comparison and assessment of treatment effect. DWI metric maps of fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were generated for quantitative assessment. Fornix-related fiber tracts were generated before and after treatment for qualitative assessment. Results: The volume of treated tissue measured via MDWI did not differ significantly from histological measurements, and both were significantly larger than the treatment cell volume. Diffusion metrics in the treatment region were significantly decreased following MRgFUS treatment, with the peak change seen at the lesion core and decreasing radially. Histological analysis confirmed an area of coagulative necrosis in the targeted region with sharp demarcation zone with surrounding brain. Tractography from the lesion core and the fornix revealed fiber disruptions following treatment. Conclusions: Diffusion maps and fiber tractography are an effective method for assessing lesion volumes and microstructural changes in vivo following MRgFUS treatment. This study demonstrates that DWI has the potential to advance MRgFUS by providing convenient in vivo microstructural lesion and fiber tractography assessment after treatment.

Prediction of Laterality in Temporal Lobe Epilepsy Using White Matter Diffusion Metrics.

BACKGROUND: Diagnostic methods of the epileptogenic area continue to be a challenge in epilepsy surgery research. We hypothesized that temporal lobe epilepsy (TLE) will result in white matter changes that can be detected using diffusion tensor imaging. Measurement of white matter diffusivity will therefore be useful for presurgical assessment. METHODS: Twelve patients with TLE who had undergone temporal lobectomy and amygdalohippocampectomy were included. In 6 patients, magnetic resonance imaging (MRI) showed evidence of mesial temporal sclerosis (m-TLE), whereas the 6 remaining MRI studies were informed without any abnormality (nl-TLE). All had excellent outcomes from surgery. Patients were compared with 12 age- and sex-matched controls. Five pairs of white matter fiber tracts were traced, and fiber tract fractional anisotropy and mean diffusivity were calculated. RESULTS: There were several alterations in diffusion parameters in white matter tracts, both ipsilateral and on the contralateral side, these alterations were more pronounced in the hemisphere ipsilateral to the epileptogenic focus. m-TLE patients had more alterations on ipsilateral side than nl-TLE patients, but similar alterations on contralateral side and bilateral fornix. The discriminant function analysis successfully lateralized all the patients with left TLE, 83.3% of the patients with right TLE, and all nl-TLE. CONCLUSIONS: Our results suggest that there are alterations in diffusion parameters in white matter tracts both in m-TLE and nl-TLE patients. Diffusion tensor imaging could be a useful presurgical tool to help establish the laterality of TLE, including patients with "normal" MRI. Further studies with a larger number of patients would be necessary to confirm these results.

Tractography-based targeting of the ventral intermediate nucleus: accuracy and clinical utility in MRgFUS thalamotomy.

OBJECTIVE: Tractography-based targeting of the thalamic ventral intermediate nucleus (T-VIM) is a novel method conferring patient-specific selection of VIM coordinates for tremor surgery; however, its accuracy and clinical utility in magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy compared to conventional indirect targeting has not been specifically addressed. This retrospective study sought to compare the treatment locations and potential adverse effect profiles of T-VIM with indirect targeting in a large cohort of MRgFUS thalamotomy patients. METHODS: T-VIM was performed using diffusion tractography outlining the pyramidal and medial lemniscus tracts in 43 MRgFUS thalamotomy patients. T-VIM coordinates were compared with the indirect treatment coordinates used in the procedure. Thalamotomy lesions were delineated on postoperative T1-weighted images and displaced ("translated") by the anteroposterior and mediolateral difference between T-VIM and treatment coordinates. Both translated and actual lesions were normalized to standard space and subsequently overlaid with areas previously reported to be associated with an increased risk of motor and sensory adverse effects when lesioned during MRgFUS thalamotomy. RESULTS: T-VIM coordinates were 2.18 mm anterior and 1.82 mm medial to the "final" indirect treatment coordinates. Translated lesions lay more squarely within the boundaries of the VIM compared to nontranslated lesions and showed significantly less overlap with areas associated with sensory adverse effects. Translated lesions overlapped less with areas associated with motor adverse effects; however, this difference was not significant. CONCLUSIONS: T-VIM leads to the selection of more anterior and medial coordinates than the conventional indirect methods. Lesions moved toward these anteromedial coordinates avoid areas associated with an increased risk of motor and sensory adverse effects, suggesting that T-VIM may improve clinical outcomes.

Author Correction: The challenge of mapping the human connectome based on diffusion tractography.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Early postsurgical diffusivity metrics for prognostication of long-term pain relief after Gamma Knife radiosurgery for trigeminal neuralgia.

OBJECTIVE: Gamma Knife radiosurgery (GKRS) is an important treatment modality for trigeminal neuralgia (TN). Current longitudinal assessment after GKRS relies primarily on clinical diagnostic measures, which are highly limited in the prediction of long-term clinical benefit. An objective, noninvasive, predictive tool would be of great utility to advance the clinical management of patients. Using diffusion tensor imaging (DTI), the authors' aim was to determine whether early (6 months post-GKRS) target diffusivity metrics can be used to prognosticate long-term pain relief in patients with TN. METHODS: Thirty-seven patients with TN treated with GKRS underwent 3T MRI scans at 6 months posttreatment. Diffusivity metrics of fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity were extracted bilaterally from the radiosurgical target of the affected trigeminal nerve and its contralateral, unaffected nerve. Early (6 months post-GKRS) diffusivity metrics were compared with long-term clinical outcome. Patients were identified as long-term responders if they achieved at least 75% reduction in preoperative pain for 12 months or longer following GKRS. RESULTS: Trigeminal nerve diffusivity at 6 months post-GKRS was predictive of long-term clinical effectiveness, where long-term responders (n = 19) showed significantly lower fractional anisotropy at the radiosurgical target of their affected nerve compared to their contralateral, unaffected nerve and to nonresponders. Radial diffusivity and mean diffusivity, correlates of myelin alterations and inflammation, were also significantly higher in the affected nerve of long-term responders compared to their unaffected nerve. Nonresponders (n = 18) did not exhibit any characteristic diffusivity changes after GKRS. CONCLUSIONS: The authors demonstrate that early postsurgical target diffusivity metrics have a translational, clinical value and permit prediction of long-term pain relief in patients with TN treated with GKRS. Importantly, an association was found between the footprint of radiation and clinical effectiveness, where a sufficient level of microstructural change at the radiosurgical target is necessary for long-lasting pain relief. DTI can provide prognostic information that supplements clinical measures, and thus may better guide the postoperative assessment and clinical decision-making for patients with TN.

Multivariate pattern classification of brain white matter connectivity predicts classic trigeminal neuralgia.

Trigeminal neuralgia (TN) is a severe form of chronic facial neuropathic pain. Increasing interest in the neuroimaging of pain has highlighted changes in the root entry zone in TN, but also group-level central nervous system gray and white matter (WM) abnormalities. Group differences in neuroimaging data are frequently evaluated with univariate statistics; however, this approach is limited because it is based on single, or clusters of, voxels. By contrast, multivariate pattern analyses consider all the model's neuroanatomical features to capture a specific distributed spatial pattern. This approach has potential use as a prediction tool at the individual level. We hypothesized that a multivariate pattern classification method can distinguish specific patterns of abnormal WM connectivity of classic TN from healthy controls (HCs). Diffusion-weighted scans in 23 right-sided TN and matched controls were processed to extract whole-brain interregional streamlines. We used a linear support vector machine algorithm to differentiate interregional normalized streamline count between TN and HC. This algorithm successfully differentiated between TN and HC with an accuracy of 88%. The structural pattern emphasized WM connectivity of regions that subserve sensory, affective, and cognitive dimensions of pain, including the insula, precuneus, inferior and superior parietal lobules, and inferior and medial orbital frontal gyri. Normalized streamline counts were associated with longer pain duration and WM metric abnormality between the connections. This study demonstrates that machine-learning algorithms can detect characteristic patterns of structural alterations in TN and highlights the role of structural brain imaging for identification of neuroanatomical features associated with neuropathic pain disorders.

Affective Circuitry Alterations in Patients with Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a severe chronic neuropathic facial pain disorder. Affect-related behavioral and structural brain changes have been noted across chronic pain disorders, but have not been well-studied in TN. We examined the potential impact of TN (37 patients: 23 with right-sided TN, 14 with left-sided TN), compared to age- and sex-matched healthy controls, on three major white matter tracts responsible for carrying affect-related signals-i.e., cingulum, fornix, and medial forebrain bundle. Diffusion magnetic resonance imaging (dMRI), deterministic multi-tensor tractography for tract modeling, and a model-driven region-of-interest approach was used. We also used volumetric gray matter analysis on key targets of these pathways (i.e., hippocampus, cingulate cortex subregions, nucleus accumbens, and ventral diencephalon). Hypotheses included: (1) successful modeling of tracts; (2) altered white matter microstructure of the cingulum and medial forebrain bundle (via changes in dMRI metrics such as fractional anisotropy, and mean, axial, and radial diffusivities) compared to controls; (3) no alterations in the control region of the fornix; (4) corresponding decreases in gray matter volumes. Results showed (1) all 325 tracts were successfully modeled, although 11 were partially complete; (2) The cingulum and medial forebrain bundle (MFB) were altered in those with TN, with dMRI metric changes in the middle (p = 0.001) and posterior cingulum (p < 0.0001), and the MFB near the ventral tegmental area (MFB-VTA) (p = 0.001). The posterior cingulum and MFB-VTA also showed unilateral differences between right- and left-sided TN patients; (3) No differences were noted at any fornix subdivision; (4) decreased volumes were noted for the hippocampus, posterior cingulate, nucleus accumbens, and ventral diencephalon. Together, these results support the notion of selectively altered affective circuits in patients with TN, which may be related to the experience of negative affect and the increased comorbidity of mood and anxiety disorders in this population.