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The mechanism of action of deep brain stimulation (DBS) to the basal ganglia for Parkinson’s disease remains unclear. Studies have shown that DBS decreases pathological beta hypersynchrony between the basal ganglia and motor cortex. However, little is known about DBS’s effects on long range corticocortical synchronization. Here, we use machine learning combined with graph theory to compare resting-state cortical connectivity between the off and on-stimulation states and to healthy controls. We found that turning DBS on increased high beta and gamma band synchrony (26 to 50 Hz) in a cortical circuit spanning the motor, occipitoparietal, middle temporal, and prefrontal cortices. The synchrony in this network was greater in DBS on relative to both DBS off and controls, with no significant difference between DBS off and controls. Turning DBS on also increased network efficiency and strength and subnetwork modularity relative to both DBS off and controls in the beta and gamma band. Thus, unlike DBS’s subcortical normalization of pathological basal ganglia activity, it introduces greater synchrony relative to healthy controls in cortical circuitry that includes both motor and non-motor systems. This increased high beta/gamma synchronization may reflect compensatory mechanisms related to DBS’s clinical benefits, as well as undesirable non-motor side effects.

Prior neuroimaging studies have reported white matter network underconnectivity as a potential mechanism for autism spectrum disorder (ASD). In this study, we examined the structural connectome of children with ASD using edge density imaging (EDI), and then applied machine-learning algorithms to identify children with ASD based on tract-based connectivity metrics. Boys aged 8–12 years were included: 14 with ASD and 33 typically developing children. The edge density (ED) maps were computed from probabilistic streamline tractography applied to high angular resolution diffusion imaging. Tract-based spatial statistics was used for voxel-wise comparison and coregistration of ED maps in addition to conventional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Tract-based average DTI/connectome metrics were calculated and used as input for different machine-learning models: naïve Bayes, random forest, support vector machines (SVMs), and neural networks. For these models, cross-validation was performed with stratified random sampling ( × 1,000 permutations). The average accuracy among validation samples was calculated. In voxel-wise analysis, the body and splenium of corpus callosum, bilateral superior and posterior corona radiata, and left superior longitudinal fasciculus showed significantly lower ED in children with ASD; whereas, we could not find significant difference in FA, MD, and RD maps between the two study groups. Overall, machine-learning models using tract-based ED metrics had better performance in identification of children with ASD compared with those using FA, MD, and RD. The EDI-based random forest models had greater average accuracy (75.3%), specificity (97.0%), and positive predictive value (81.5%), whereas EDI-based polynomial SVM had greater sensitivity (51.4%) and negative predictive values (77.7%). In conclusion, we found reduced density of connectome edges in the posterior white matter tracts of children with ASD, and demonstrated the feasibility of connectome-based machine-learning algorithms in identification of children with ASD.

We report white matter changes after mild traumatic brain injury and their relationship with self-reported and cognitive symptoms., Neuroimaging biomarkers that can detect white matter (WM) pathology after mild traumatic brain injury (mTBI) and predict long-term outcome are needed to improve care and develop therapies. We used diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to investigate WM microstructure cross-sectionally and longitudinally after mTBI and correlate these with neuropsychological performance. Cross-sectionally, early decreases of fractional anisotropy and increases of mean diffusivity corresponded to WM regions with elevated free water fraction on NODDI. This elevated free water was more extensive in the patient subgroup reporting more early postconcussive symptoms. The longer-term longitudinal WM changes consisted of declining neurite density on NODDI, suggesting axonal degeneration from diffuse axonal injury for which NODDI is more sensitive than DTI. Therefore, NODDI is a more sensitive and specific biomarker than DTI for WM microstructural changes due to mTBI that merits further study for mTBI diagnosis, prognosis, and treatment monitoring.

BackgroundAlthough acute neurologic impairment might be transient, other long-term effects can be observed with mild traumatic brain injury. However, when pediatric patients with mild traumatic brain injury present for medical care, conventional imaging with CT and MR imaging often does not reveal abnormalities.ObjectiveTo determine whether edge density imaging can separate pediatric mild traumatic brain injury from typically developing controls.Materials and methodsSubjects were recruited as part of the "Therapeutic Resources for Attention Improvement using Neuroimaging in Traumatic Brain Injury" (TRAIN-TBI) study. We included 24 adolescents (χ=14.1years of age, σ=1.6years, range 10-16years), 14 with mild traumatic brain injury (TBI) and 10 typically developing controls. Neurocognitive assessments included the pediatric version of the California Verbal Learning Test (CVLT) and the Attention Network Task (ANT). Diffusion MR imaging was acquired on a 3-tesla (T) scanner. Edge density images were computed utilizing fiber tractography. Principal component analysis (PCA) and support vector machines (SVM) were used in an exploratory analysis to separate mild TBI and control groups. The diagnostic accuracy of edge density imaging, neurocognitive tests, and fractional anisotropy (FA) from diffusion tensor imaging (DTI) was computed with two-sample t-tests and receiver operating characteristic (ROC) metrics.ResultsSupport vector machine-principal component analysis of edge density imaging maps identified three white matter regions distinguishing pediatric mild TBI from controls. The bilateral tapetum, sagittal stratum, and callosal splenium identified mild TBI subjects with sensitivity of 79% and specificity of 100%. Accuracy from the area under the ROC curve (AUC) was 94%. Neurocognitive testing provided an AUC of 61% (CVLT) and 71% (ANT). Fractional anisotropy yielded an AUC of 48%.ConclusionIn this proof-of-concept study, we show that edge density imaging is a new form of connectome mapping that provides better diagnostic delineation between pediatric mild TBI and healthy controls than DTI or neurocognitive assessments of memory or attention.

Pharmacological treatment of major depressive disorder (MDD) typically involves a lengthy trial and error process to identify an effective intervention. This lengthy period prolongs suffering and worsens all-cause mortality, including from suicide, and is typically longer in late-life depression (LLD). Our group has recently demonstrated that during an open-label venlafaxine (serotonin-norepinephrine reuptake inhibitor) trial, significant changes in functional resting state connectivity occurred following a single dose of treatment, which persisted until the end of the trial. In this work, we propose an analysis framework to translate these perturbations in functional networks into predictors of clinical remission. Participants with LLD (N = 49) completed 12-weeks of treatment with venlafaxine and underwent functional magnetic resonance imaging (fMRI) at baseline and a day following a single dose of venlafaxine. Data was collected at rest as well as during an emotion reactivity task and an emotion regulation task. Remission was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) ≤10 for two weeks. We computed eigenvector centrality (whole brain connectivity) and activation during the emotion regulation and emotion reactivity tasks. We employed principal components analysis, Tikhonov-regularized logistic classification, and least angle regression feature selection to predict remission by the end of the 12-week trial. We utilized ten-fold cross-validation and Receiver Operator Curves (ROC) curve analysis. To determine task-region pairs that significantly contributed to the algorithm's ability to predict remission, we used permutation testing. Using the fMRI data at both baseline and after the first dose of treatment yielded a sensitivity of 72% and a specificity of 68% (AUC = 0.77), a 15% increase in accuracy over baseline MADRS. In general, the accuracy at baseline was further improved by using the change in activation following a single dose. Activation of the frontal cortex, hippocampus, parahippocampus, caudate, thalamus, medial temporal cortex, middle cingulate, and visual cortex predicted treatment remission. Acute, dynamic trajectories of functional imaging metrics in response to a pharmacological intervention are a valuable tool for predicting treatment response in late-life depression and elucidating the mechanism of pharmacological therapies in the context of the brain's functional architecture., Highlights • Neural activation changes after a single dose of antidepressants have been observed. • Patients with late-life depression were treated with an antidepressant for 12 weeks. • Neuroimaging data was recorded pre-treatment and after a single dose. • Pre-treatment neuroimaging predicted remission at the end of the trial. • Neuroimaging after a single dose improved prediction and may guide treatment.

The “sensory processing disorder” (SPD) refers to brain's inability to organize sensory input for appropriate use. In this study, we determined the diffusion tensor imaging (DTI) microstructural and connectivity correlates of SPD, and apply machine learning algorithms for identification of children with SPD based on DTI/tractography metrics. A total of 44 children with SPD and 41 typically developing children (TDC) were prospectively recruited and scanned. In addition to fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD), we applied probabilistic tractography to generate edge density (ED) and track density (TD) from DTI maps. For identification of children with SPD, accurate classification rates from a combination of DTI microstructural (FA, MD, AD, and RD), connectivity (TD) and connectomic (ED) metrics with different machine learning algorithms – including naïve Bayes, random forest, support vector machine, and neural networks – were determined. In voxel-wise analysis, children with SPD had lower FA, ED, and TD but higher MD and RD compared to TDC – predominantly in posterior white matter tracts including posterior corona radiata, posterior thalamic radiation, and posterior body and splenium of corpus callosum. In stepwise penalized logistic regression, the only independent variable distinguishing children with SPD from TDC was the average TD in the splenium (p

Neuroimaging biomarkers show promise for improving precision diagnosis and prognosis after mild traumatic brain injury (mTBI), but none has yet been adopted in routine clinical practice. Biophysical modeling of multishell diffusion MRI, using the neurite orientation dispersion and density imaging (NODDI) framework, may improve upon conventional diffusion tensor imaging (DTI) in revealing subtle patterns of underlying white matter microstructural pathology, such as diffuse axonal injury (DAI) and neuroinflammation, that are important for detecting mTBI and determining patient outcome. With a cross-sectional and longitudinal design, we assessed structural MRI, DTI and NODDI in 40 mTBI patients at 2 weeks and 6 months after injury and 14 matched control participants with orthopedic trauma but not suffering from mTBI at 2 weeks. Self-reported and performance-based cognitive measures assessing postconcussive symptoms, memory, executive functions and processing speed were investigated in post-acute and chronic phase after injury for the mTBI subjects. Machine learning analysis was used to identify mTBI patients with the best neuropsychological improvement over time and relate this outcome to DTI and NODDI biomarkers. In the cross-sectional comparison with the trauma control group at 2 weeks post-injury, mTBI patients showed decreased fractional anisotropy (FA) and increased mean diffusivity (MD) on DTI mainly in anterior tracts that corresponded to white matter regions of elevated free water fraction (FISO) on NODDI, signifying vasogenic edema. Patients showed decreases from 2 weeks to 6 months in white matter neurite density on NODDI, predominantly in posterior tracts. No significant longitudinal changes in DTI metrics were observed. The machine learning analysis divided the mTBI patients into two groups based on their recovery. Voxel-wise group comparison revealed associations between white matter orientation dispersion index (ODI) and FISO with degree and trajectory of improvement within the mTBI group. In conclusion, white matter FA and MD alterations early after mTBI might reflect vasogenic edema, as shown by elevated free water on NODDI. Longer-term declines in neurite density on NODDI suggest progressive axonal degeneration due to DAI, especially in tracts known to be integral to the structural connectome. Overall, these results show that the NODDI parameters appear to be more sensitive to longitudinal changes than DTI metrics. Thus, NODDI merits further study in larger cohorts for mTBI diagnosis, prognosis and treatment monitoring.

Recent research has demonstrated the use of the structural connectome as a powerful tool to characterize the network architecture of the brain and potentially generate biomarkers for neurologic and psychiatric disorders. In particular, the anatomic embedding of the edges of the cerebral graph have been postulated to elucidate the relative importance of white matter tracts to the overall network connectivity, explaining the varying effects of localized white matter pathology on cognition and behavior. Here, we demonstrate the use of a linear diffusion model to quantify the impact of these perturbations on brain connectivity. We show that the eigenmodes governing the dynamics of this model are strongly conserved between healthy subjects regardless of cortical and sub-cortical parcellations, but show significant, interpretable deviations in improperly developed brains. More specifically, we investigated the effect of agenesis of the corpus callosum (AgCC), one of the most common brain malformations to identify differences in the effect of virtual corpus callosotomies and the neurodevelopmental disorder itself. These findings, including the strong correspondence between regions of highest importance from graph eigenmodes of network diffusion and nexus regions of white matter from edge density imaging, show converging evidence toward understanding the relationship between white matter anatomy and the structural connectome., Author summary While the structural connectome of the brain has emerged as a powerful tool towards understanding the progression of neurologic and psychiatric disorders, links between the anatomy of connections within the brain and the effects of localized white matter pathology on cognition are still an active area of investigation. Here, we propose the use of the diffusion process towards understanding perturbations of brain connectivity. We find that while the dynamics of this process are strongly conserved in healthy subjects, they display significant, interpretable deviations in agenesis of the corpus callosum, one of the most common brain malformations. These findings, including the strong similarity between regions identified to be crucial towards diffusion and nexus regions of white matter from edge density imaging, show converging evidence towards understanding the relationship between white matter anatomy and the structural connectome.