Image-based analysis and long-term clinical outcomes of deep brain stimulation for Tourette syndrome: a multisite study.

BACKGROUND: Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting. METHODS: We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases. RESULTS: Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi. CONCLUSION: The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities.

Longitudinal changes in cortical thickness in autism and typical development.

The natural history of brain growth in autism spectrum disorders remains unclear. Cross-sectional studies have identified regional abnormalities in brain volume and cortical thickness in autism, although substantial discrepancies have been reported. Preliminary longitudinal studies using two time points and small samples have identified specific regional differences in cortical thickness in the disorder. To clarify age-related trajectories of cortical development, we examined longitudinal changes in cortical thickness within a large mixed cross-sectional and longitudinal sample of autistic subjects and age- and gender-matched typically developing controls. Three hundred and forty-five magnetic resonance imaging scans were examined from 97 males with autism (mean age = 16.8 years; range 3-36 years) and 60 males with typical development (mean age = 18 years; range 4-39 years), with an average interscan interval of 2.6 years. FreeSurfer image analysis software was used to parcellate the cortex into 34 regions of interest per hemisphere and to calculate mean cortical thickness for each region. Longitudinal linear mixed effects models were used to further characterize these findings and identify regions with between-group differences in longitudinal age-related trajectories. Using mean age at time of first scan as a reference (15 years), differences were observed in bilateral inferior frontal gyrus, pars opercularis and pars triangularis, right caudal middle frontal and left rostral middle frontal regions, and left frontal pole. However, group differences in cortical thickness varied by developmental stage, and were influenced by IQ. Differences in age-related trajectories emerged in bilateral parietal and occipital regions (postcentral gyrus, cuneus, lingual gyrus, pericalcarine cortex), left frontal regions (pars opercularis, rostral middle frontal and frontal pole), left supramarginal gyrus, and right transverse temporal gyrus, superior parietal lobule, and paracentral, lateral orbitofrontal, and lateral occipital regions. We suggest that abnormal cortical development in autism spectrum disorders undergoes three distinct phases: accelerated expansion in early childhood, accelerated thinning in later childhood and adolescence, and decelerated thinning in early adulthood. Moreover, cortical thickness abnormalities in autism spectrum disorders are region-specific, vary with age, and may remain dynamic well into adulthood.

A functional network estimation method of resting-state fMRI using a hierarchical Markov random field.

We propose a hierarchical Markov random field model for estimating both group and subject functional networks simultaneously. The model takes into account the within-subject spatial coherence as well as the between-subject consistency of the network label maps. The statistical dependency between group and subject networks acts as a regularization, which helps the network estimation on both layers. We use Gibbs sampling to approximate the posterior density of the network labels and Monte Carlo expectation maximization to estimate the model parameters. We compare our method with two alternative segmentation methods based on K-Means and normalized cuts, using synthetic and real fMRI data. The experimental results show that our proposed model is able to identify both group and subject functional networks with higher accuracy on synthetic data, more robustness, and inter-session consistency on the real data.

Augmented surgical decision-making for glioblastoma: integrating AI tools into education and practice.

Surgical decision-making for glioblastoma poses significant challenges due to its complexity and variability. This study investigates the potential of artificial intelligence (AI) tools in improving "decision-making processes" for glioblastoma surgery. A systematic review of literature identified 10 relevant studies, primarily focused on predicting resectability and surgery-related neurological outcomes. AI tools, especially rooted in radiomics and connectomics, exhibited promise in predicting resection extent through precise tumor segmentation and tumor-network relationships. However, they demonstrated limited effectiveness in predicting postoperative neurological due to dynamic and less quantifiable nature of patient-related factors. Recognizing these challenges, including limited datasets and the interpretability requirement in medical applications, underscores the need for standardization, algorithm optimization, and addressing variability in model performance and then further validation in clinical settings. While AI holds potential, it currently does not possess the capacity to emulate the nuanced decision-making process utilized by experienced neurosurgeons in the comprehensive approach to glioblastoma surgery.

Bilateral focused ultrasound medial thalamotomies for trigeminal neuropathic pain: a randomized controlled study.

OBJECTIVE: Medial thalamotomy has been shown to benefit patients with neuropathic pain, but widespread adoption of this procedure has been limited by reporting of clinical outcomes in studies without a control group. This study aimed to minimize confounders associated with medial thalamotomy for treating chronic pain by using modern MRI-guided stereotactic lesioning and a rigorous clinical design. METHODS: This prospective, double-blinded, randomized controlled trial in 10 patients with trigeminal neuropathic pain used sham procedures as controls. Participants underwent assessments by a pain psychologist and pain management clinician, including use of the following measures: the Numeric Pain Rating Scale (NPRS); patient-reported outcome measures; and patient's impression of improvement at baseline, 1 day, 1 week, 1 month, and 3 months postprocedure. Patients in the treated group underwent bilateral focused ultrasound (FUS) medial thalamotomy targeting the central lateral nucleus. Patients in the control group underwent sham procedures with energy output disabled. The primary efficacy outcome measure was between-group differences in pain intensity (using the NPRS) at baseline and at 3 months postprocedure. Adverse events were measured for safety and included MRI analysis. Exploratory measures of connectivity and metabolism were analyzed using diffusion tensor imaging, functional MRI, and PET, respectively. RESULTS: There were no serious complications from the FUS procedures. MRI confirmed bilateral medial thalamic ablations. There was no significant improvement in pain intensity from baseline to 3 months, either for patients undergoing FUS medial thalamotomy or for sham controls; and the between-group change in NPRS score as the primary efficacy outcome measure was not significantly different. Patient-reported outcome assessments demonstrated improvement (i.e., a decrease) only in pain interference with enjoyment of life at 3 months. There was a perception of benefit at 1 week, but only for patients treated with FUS and not for the sham cohort. Advanced neuroimaging showed that these medial thalamic lesions altered structural connectivity with the postcentral gyrus and demonstrated a trend toward hypometabolism in the insula and amygdala. CONCLUSIONS: This randomized controlled trial of bilateral FUS medial thalamotomy did not reduce the intensity of trigeminal neuropathic pain, although it should be noted that the ability to estimate the magnitude of treatment effects is limited by the small cohort.

Regional characterization of longitudinal DT-MRI to study white matter maturation of the early developing brain.

The human brain undergoes rapid and dynamic development early in life. Assessment of brain growth patterns relevant to neurological disorders and disease requires a normative population model of growth and variability in order to evaluate deviation from typical development. In this paper, we focus on maturation of brain white matter as shown in diffusion tensor MRI (DT-MRI), measured by fractional anisotropy (FA), mean diffusivity (MD), as well as axial and radial diffusivities (AD, RD). We present a novel methodology to model temporal changes of white matter diffusion from longitudinal DT-MRI data taken at discrete time points. Our proposed framework combines nonlinear modeling of trajectories of individual subjects, population analysis, and testing for regional differences in growth pattern. We first perform deformable mapping of longitudinal DT-MRI of healthy infants imaged at birth, 1 year, and 2 years of age, into a common unbiased atlas. An existing template of labeled white matter regions is registered to this atlas to define anatomical regions of interest. Diffusivity properties of these regions, presented over time, serve as input to the longitudinal characterization of changes. We use non-linear mixed effect (NLME) modeling where temporal change is described by the Gompertz function. The Gompertz growth function uses intuitive parameters related to delay, rate of change, and expected asymptotic value; all descriptive measures which can answer clinical questions related to quantitative analysis of growth patterns. Results suggest that our proposed framework provides descriptive and quantitative information on growth trajectories that can be interpreted by clinicians using natural language terms that describe growth. Statistical analysis of regional differences between anatomical regions which are known to mature differently demonstrates the potential of the proposed method for quantitative assessment of brain growth and differences thereof. This will eventually lead to a prediction of white matter diffusion properties and associated cognitive development at later stages given imaging data at early stages.

Functional connectivity magnetic resonance imaging classification of autism.

Group differences in resting state functional magnetic resonance imaging connectivity between individuals with autism and typically developing controls have been widely replicated for a small number of discrete brain regions, yet the whole-brain distribution of connectivity abnormalities in autism is not well characterized. It is also unclear whether functional connectivity is sufficiently robust to be used as a diagnostic or prognostic metric in individual patients with autism. We obtained pairwise functional connectivity measurements from a lattice of 7266 regions of interest covering the entire grey matter (26.4 million connections) in a well-characterized set of 40 male adolescents and young adults with autism and 40 age-, sex- and IQ-matched typically developing subjects. A single resting state blood oxygen level-dependent scan of 8 min was used for the classification in each subject. A leave-one-out classifier successfully distinguished autism from control subjects with 83% sensitivity and 75% specificity for a total accuracy of 79% (P = 1.1 × 10(-7)). In subjects <20 years of age, the classifier performed at 89% accuracy (P = 5.4 × 10(-7)). In a replication dataset consisting of 21 individuals from six families with both affected and unaffected siblings, the classifier performed at 71% accuracy (91% accuracy for subjects <20 years of age). Classification scores in subjects with autism were significantly correlated with the Social Responsiveness Scale (P = 0.05), verbal IQ (P = 0.02) and the Autism Diagnostic Observation Schedule-Generic's combined social and communication subscores (P = 0.05). An analysis of informative connections demonstrated that region of interest pairs with strongest correlation values were most abnormal in autism. Negatively correlated region of interest pairs showed higher correlation in autism (less anticorrelation), possibly representing weaker inhibitory connections, particularly for long connections (Euclidean distance >10 cm). Brain regions showing greatest differences included regions of the default mode network, superior parietal lobule, fusiform gyrus and anterior insula. Overall, classification accuracy was better for younger subjects, with differences between autism and control subjects diminishing after 19 years of age. Classification scores of unaffected siblings of individuals with autism were more similar to those of the control subjects than to those of the subjects with autism. These findings indicate feasibility of a functional connectivity magnetic resonance imaging diagnostic assay for autism.

Microstructural connectivity of the arcuate fasciculus in adolescents with high-functioning autism.

The arcuate fasciculus is a white matter fiber bundle of great importance in language. In this study, diffusion tensor imaging (DTI) was used to infer white matter integrity in the arcuate fasciculi of a group of subjects with high-functioning autism and a control group matched for age, handedness, IQ, and head size. The arcuate fasciculus for each subject was automatically extracted from the imaging data using a new volumetric DTI segmentation algorithm. The results showed a significant increase in mean diffusivity (MD) in the autism group, due mostly to an increase in the radial diffusivity (RD). A test of the lateralization of DTI measurements showed that both MD and fractional anisotropy (FA) were less lateralized in the autism group. These results suggest that white matter microstructure in the arcuate fasciculus is affected in autism and that the language specialization apparent in the left arcuate of healthy subjects is not as evident in autism, which may be related to poorer language functioning.

The geometric median on Riemannian manifolds with application to robust atlas estimation.

One of the primary goals of computational anatomy is the statistical analysis of anatomical variability in large populations of images. The study of anatomical shape is inherently related to the construction of transformations of the underlying coordinate space, which map one anatomy to another. It is now well established that representing the geometry of shapes or images in Euclidian spaces undermines our ability to represent natural variability in populations. In our previous work we have extended classical statistical analysis techniques, such as averaging, principal components analysis, and regression, to Riemannian manifolds, which are more appropriate representations for describing anatomical variability. In this paper we extend the notion of robust estimation, a well established and powerful tool in traditional statistical analysis of Euclidian data, to manifold-valued representations of anatomical variability. In particular, we extend the geometric median, a classic robust estimator of centrality for data in Euclidean spaces. We formulate the geometric median of data on a Riemannian manifold as the minimizer of the sum of geodesic distances to the data points. We prove existence and uniqueness of the geometric median on manifolds with non-positive sectional curvature and give sufficient conditions for uniqueness on positively curved manifolds. Generalizing the Weiszfeld procedure for finding the geometric median of Euclidean data, we present an algorithm for computing the geometric median on an arbitrary manifold. We show that this algorithm converges to the unique solution when it exists. In this paper we exemplify the robustness of the estimation technique by applying the procedure to various manifolds commonly used in the analysis of medical images. Using this approach, we also present a robust brain atlas estimation technique based on the geometric median in the space of deformable images.

Group analysis of DTI fiber tract statistics with application to neurodevelopment.

Diffusion tensor imaging (DTI) provides a unique source of information about the underlying tissue structure of brain white matter in vivo including both the geometry of major fiber bundles as well as quantitative information about tissue properties represented by derived tensor measures. This paper presents a method for statistical comparison of fiber bundle diffusion properties between populations of diffusion tensor images. Unbiased diffeomorphic atlas building is used to compute a normalized coordinate system for populations of diffusion images. The diffeomorphic transformations between each subject and the atlas provide spatial normalization for the comparison of tract statistics. Diffusion properties, such as fractional anisotropy (FA) and tensor norm, along fiber tracts are modeled as multivariate functions of arc length. Hypothesis testing is performed non-parametrically using permutation testing based on the Hotelling T(2) statistic. The linear discriminant embedded in the T(2) metric provides an intuitive, localized interpretation of detected differences. The proposed methodology was tested on two clinical studies of neurodevelopment. In a study of 1 and 2 year old subjects, a significant increase in FA and a correlated decrease in Frobenius norm was found in several tracts. Significant differences in neonates were found in the splenium tract between controls and subjects with isolated mild ventriculomegaly (MVM) demonstrating the potential of this method for clinical studies.

Surface-Based Spatial Pyramid Matching of Cortical Regions for Analysis of Cognitive Performance.

We propose a method to analyze the relationship between the shape of functional regions of the cortex and cognitive measures, such as reading ability and vocabulary knowledge. Functional regions on the cortical surface can vary not only in size and shape but also in topology and position relative to neighboring regions. Standard diffeomorphism-based shape analysis tools do not work well here because diffeomorphisms are unable to capture these topological differences, which include region splitting and merging across subjects. State-of-the-art cortical surface shape analyses compute derived regional properties (scalars), such as regional volume, cortical thickness, curvature, and gyrification index. However, these methods cannot compare the full extent of topological or shape differences in cortical regions. We propose icosahedral spatial pyramid matching (ISPM) of region borders computed on the surface of a sphere to capture this variation in regional topology, position, and shape. We then analyze how this variation corresponds to measures of cognitive performance. We compare our method to other approaches and find that it is indeed informative to consider aspects of shape beyond the standard approaches. Analysis is performed using a subset of 27 test/retest subjects from the Human Connectome Project in order to understand both the effectiveness and reproducibility of this method.

Revisiting Abnormalities in Brain Network Architecture Underlying Autism Using Topology-Inspired Statistical Inference.

A large body of evidence relates autism with abnormal structural and functional brain connectivity. Structural covariance magnetic resonance imaging (scMRI) is a technique that maps brain regions with covarying gray matter densities across subjects. It provides a way to probe the anatomical structure underlying intrinsic connectivity networks (ICNs) through analysis of gray matter signal covariance. In this article, we apply topological data analysis in conjunction with scMRI to explore network-specific differences in the gray matter structure in subjects with autism versus age-, gender-, and IQ-matched controls. Specifically, we investigate topological differences in gray matter structure captured by structural correlation graphs derived from three ICNs strongly implicated in autism, namely the salience network, default mode network, and executive control network. By combining topological data analysis with statistical inference, our results provide evidence of statistically significant network-specific structural abnormalities in autism.

Complex Economic Behavior Patterns Are Constructed from Finite, Genetically Controlled Modules of Behavior.

Complex ethological behaviors could be constructed from finite modules that are reproducible functional units of behavior. Here, we test this idea for foraging and develop methods to dissect rich behavior patterns in mice. We uncover discrete modules of foraging behavior reproducible across different strains and ages, as well as nonmodular behavioral sequences. Modules differ in terms of form, expression frequency, and expression timing and are expressed in a probabilistically determined order. Modules shape economic patterns of feeding, exposure, activity, and perseveration responses. The modular architecture of foraging changes developmentally, and different developmental, genetic, and parental effects are found to shape the expression of specific modules. Dissecting modules from complex patterns is powerful for phenotype analysis. We discover that both parental alleles of the imprinted Prader-Willi syndrome gene Magel2 are functional in mice but regulate different modules. Our study found that complex economic patterns are built from finite, genetically controlled modules.

Autism Classification Using Topological Features and Deep Learning: A Cautionary Tale.

The identification of autistic individuals using resting state functional connectivity networks can provide an objective diagnostic method for autism spectrum disorder (ASD). The present state-of-the-art machine learning model using deep learning has a classification accuracy of 70.2% on the ABIDE (Autism Brain Imaging Data Exchange) data set. In this paper, we explore the utility of topological features in the classification of ASD versus typically developing control subjects. These topological features have been shown to provide a complementary source of discriminative information in applications such as 2D object classification and social network analysis. We evaluate the performance of three different representations of topological features - persistence diagrams, persistence images, and persistence landscapes - for autism classification using neural networks, support vector machines and random forests. We also propose a hybrid approach of augmenting topological features with functional correlations, which typically outperforms the models that use functional correlations alone. With this approach, even with a simple 3-layer neural network, we are able to achieve a classification accuracy of 69.2% on the ABIDE data set. However, our experiments also show that the improvement due to topological features is not always statistically significant. Therefore, we offer a cautionary tale to the practitioners regarding the limited discriminative power of topological features derived from fMRI data for the classification of autism.

Realizing the potential of positron emission tomography with 18F-fluorodeoxyglucose to improve the treatment of Alzheimer's disease.

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG-PET) thus far rarely has been used to advance the development of new treatments for Alzheimer's disease (AD). Now that FDG-PET with standard acquisition protocols for dementia is widely available, change in cerebral glucose metabolism is a feasible outcome variable for clinical drug trials. Individual analysis of FDG-PET results also might prove valuable. FDG-PET can detect metabolic changes very early in the course of AD and identify subjects for earlier treatment. FDG-PET reliably distinguishes AD from frontotemporal dementia so that only those most likely to benefit are enrolled in trials. Finally, objectively identifying phenotypic variations of AD with FDG-PET might have pathogenic and prognostic implications that can be used for personalized treatment approaches. The judicious use of FDG-PET is needed to accelerate the evaluation of promising new drugs and more rationally target treatments for dementing diseases.

Nonparametric Aggregation of Geodesic Trends for Longitudinal Data Analysis.

We propose a technique for analyzing longitudinal imaging data that models individual changes with diffeomorphic geodesic regression and aggregates these geodesics into a nonparametric group average trend. Our model is specifically tailored to the unbalanced and sparse characteristics of longitudinal imaging studies. That is, each individual has few data points measured over a short period of time, while the study population as a whole spans a wide age range. We use geodesic regression to estimate individual trends, which is an appropriate model for capturing shape changes over a short time window, as is typically found within an individual. Geodesics are also adept at handling the low sample sizes found within individuals, and can model the change between as few as two timepoints. However, geodesics are limited for modeling longer-term trends, where constant velocity may not be appropriate. Therefore, we develop a novel nonparametric regression to aggregate individual trends into an average group trend. We demonstrate the power of our method to capture non-geodesic group trends on hippocampal volume (real-valued data) and diffeomorphic registration of full 3D MRI from the longitudinal OASIS data.

Riemannian Regression and Classification Models of Brain Networks Applied to Autism.

Functional connectivity from resting-state functional MRI (rsfMRI) is typically represented as a symmetric positive definite (SPD) matrix. Analysis methods that exploit the Riemannian geometry of SPD matrices appropriately adhere to the positive definite constraint, unlike Euclidean methods. Recently proposed approaches for rsfMRI analysis have achieved high accuracy on public datasets, but are computationally intensive and difficult to interpret. In this paper, we show that we can get comparable results using connectivity matrices under the log-Euclidean and affine-invariant Riemannian metrics with relatively simple and interpretable models. On ABIDE Preprocessed dataset, our methods classify autism versus control subjects with 71.1% accuracy. We also show that Riemannian methods beat baseline in regressing connectome features to subject autism severity scores.

Interactive visualization of volumetric white matter connectivity in DT-MRI using a parallel-hardware Hamilton-Jacobi solver.

In this paper we present a method to compute and visualize volumetric white matter connectivity in diffusion tensor magnetic resonance imaging (DT-MRI) using a Hamilton-Jacobi (H-J) solver on the GPU (Graphics Processing Unit). Paths through the volume are assigned costs that are lower if they are consistent with the preferred diffusion directions. The proposed method finds a set of voxels in the DTI volume that contain paths between two regions whose costs are within a threshold of the optimal path. The result is a volumetric optimal path analysis, which is driven by clinical and scientific questions relating to the connectivity between various known anatomical regions of the brain. To solve the minimal path problem quickly, we introduce a novel numerical algorithm for solving H-J equations, which we call the Fast Iterative Method (FIM). This algorithm is well-adapted to parallel architectures, and we present a GPU-based implementation, which runs roughly 50-100 times faster than traditional CPU-based solvers for anisotropic H-J equations. The proposed system allows users to freely change the endpoints of interesting pathways and to visualize the optimal volumetric path between them at an interactive rate. We demonstrate the proposed method on some synthetic and real DT-MRI datasets and compare the performance with existing methods.

Efficient Parallel Transport in the Group of Diffeomorphisms via Reduction to the Lie Algebra.

This paper presents an efficient, numerically stable algorithm for parallel transport of tangent vectors in the group of diffeomorphisms. Previous approaches to parallel transport in large deformation diffeomorphic metric mapping (LDDMM) of images represent a momenta field, the dual of a tangent vector to the diffeomorphism group, as a scalar field times the image gradient. This "scalar momenta" constraint couples tangent vectors with the images being deformed and leads to computationally costly horizontal lifts in parallel transport. This paper uses the vector momenta formulation of LDDMM, which decouples the diffeomorphisms from the structures being transformed, e.g., images, point sets, etc. This decoupling leads to parallel transport expressed as a linear ODE in the Lie algebra. Solving this ODE directly is numerically stable and significantly faster than other LDDMM parallel transport methods. Results on 2D synthetic data and 3D brain MRI demonstrate that our algorithm is fast and conserves the inner products of the transported tangent vectors.

Revisiting Abnormalities in Brain Network Architecture Underlying Autism Using Topology-Inspired Statistical Inference.

A large body of evidence relates autism with abnormal structural and functional brain connectivity. Structural covariance MRI (scMRI) is a technique that maps brain regions with covarying gray matter density across subjects. It provides a way to probe the anatomical structures underlying intrinsic connectivity networks (ICNs) through the analysis of the gray matter signal covariance. In this paper, we apply topological data analysis in conjunction with scMRI to explore network-specific differences in the gray matter structure in subjects with autism versus age-, gender- and IQ-matched controls. Specifically, we investigate topological differences in gray matter structures captured by structural covariance networks (SCNs) derived from three ICNs strongly implicated in autism, namely, the salience network (SN), the default mode network (DMN) and the executive control network (ECN). By combining topological data analysis with statistical inference, our results provide evidence of statistically significant network-specific structural abnormalities in autism, from SCNs derived from SN and ECN. These differences in brain architecture are consistent with direct structural analysis using scMRI (Zielinski et al. 2012).