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Seizure Therapy And White Matter Changes

Seizure Therapy And White Matter Changes

Functional seizures (FS) are a type of functional neurological symptom disorder that mimics epileptic seizures but lacks epileptiform changes on electroencephalography. The neuropathophysiology involves various brain systems, such as sensorimotor, emotion regulation, cognitive control, and multimodal integration. 

Neurobehavioral therapy (NBT) has emerged as a viable treatment for FS, targeting psychopathologies like emotion regulation and stress coping. However, the association between psychotherapeutic treatment response and brain changes in FS patients remains unexplored.

Neurite orientation dispersion and density imaging (NODDI) is a method that assesses the microstructural properties of white matter, providing insights into axon and dendrite density, neurite orientation consistency, and extracellular free water. While studies using diffusion tensor imaging (DTI) in FS have identified abnormalities in various brain regions, NODDI has reported significant correlations between symptom severity and white matter abnormalities in specific tracts.

Between 16 and 83% of FS patients have a history of traumatic brain injury (TBI), suggesting a potential link between brain vulnerabilities and abnormal emotion processing and motor control observed in TBI. This study aims to quantify changes in white matter morphology using NODDI metrics in TBI patients with FS (TBI+FS) after 12 sessions of NBT. 

The investigation also includes a TBI-only group without FS to explore potential differences. Expectations include increased neurite density and orientation consistency, decreased extracellular free water in specific tracts, and correlations with improvements in FS frequency, mental health, quality of life, and postconcussive symptoms in the TBI+FS group. The study hypothesizes that the TBI-only group will not exhibit significant changes in NODDI metrics.

Overview of the Study 

The researchers aimed to prospectively measure alterations in white matter morphology following neurobehavioral therapy (NBT) for functional seizures (FS) using neurite orientation dispersion and density imaging (NODDI). 

The hypothesis posited that individuals with FS would demonstrate white matter plasticity in the uncinate fasciculus, fornix/stria terminalis, cingulum, and corticospinal tract after undergoing NBT. These changes were expected to align with improvements in affective symptoms, postconcussive symptoms, and overall quality of life (QOL).


Forty-two individuals diagnosed with traumatic brain injury (TBI) and functional seizures (TBI+FS) participated in neurobehavioral therapy (NBT) and supplied neuroimaging and behavioral data before and after the intervention.

In parallel, 47 control participants with TBI but without functional seizures (TBI-only) underwent the same assessments but did not undergo NBT. The study compared alterations in neurite density, orientation dispersion (as measured by the orientation dispersion index [ODI]), and extracellular free water (FW) across these two groups.

The study conducted statistical analyses using SPSS Statistics for Mac to examine demographic, behavioral, and region of interest (ROI)-based neuroimaging data. Independent-samples t tests or chi-squared tests assessed between-group differences in demographic characteristics, with a significance threshold of p < 0.05. Repeated-measures t tests evaluated changes in clinical outcomes between the first and second imaging visits for both TBI-only and TBI+FS groups.

Analyses of variance (ANOVAs) were employed to assess differences in neuroimaging outcomes from pre-neurobehavioral therapy (NBT) to the penultimate session, with group and time as factors. Bonferroni-corrected post hoc comparisons were conducted for significant group-by-time interactions (p < 0.05). Similar ANOVA tests were applied to ROI-based Neurite Orientation Dispersion and Density Imaging (NODDI) and diffusion tensor imaging (DTI) data.

Linear mixed effects analyses in AFNI’s 3dLME were utilized for exploratory whole-brain voxelwise analyses, assessing main effects of group and time, and the group-by-time interaction using NODDI and DTI maps. Cluster size thresholds were determined with AFNI’s 3dFWHMx and 3dClustSim to reduce false-positive clusters, with corrected significance (p < 0.05) and uncorrected voxel-level threshold (p < 0.001).

Pearson correlation coefficients were calculated on change scores in ROIs with significant changes, using a false discovery rate (FDR) of 0.05. Post hoc power analyses demonstrated high power for primary NODDI analyses, clinical outcome changes, and correlations between clinical and NODDI outcomes, affirming the study’s statistical robustness.


Significant increases in the orientation dispersion index (ODI) were observed in the left uncinate fasciculus among individuals with traumatic brain injury and functional seizures (TBI+FS) (mean difference = 0.017, p = 0.039). These ODI increases were found to be correlated with improvements in posttraumatic symptoms (r = -0.395, p = 0.013), quality of life (QOL) (r = 0.474, p = 0.002), emotional well-being (r = 0.524, p < 0.001), and energy (r = 0.474, p = 0.002). 

In the TBI-only group, a decrease in ODI (mean difference = -0.008, p = 0.047) and an increase in extracellular free water (FW) (mean difference = 0.011, p = 0.003) were observed in the right cingulum. The FW increases were correlated with heightened psychological problems (r = 0.383, p = 0.013) in this group. For TBI+FS participants undergoing neurobehavioral therapy (NBT), functional seizure frequency decreased by 3.5 seizures per week. Interestingly, none of the observed imaging changes were found to be correlated with the frequency of functional seizures.

Final Thoughts 

The study aimed to evaluate white matter changes after neurobehavioral therapy (NBT) for seizures, expecting alterations in neurite density, orientation dispersion, and extracellular free water in patients with functional seizures (FS). The main findings indicated increased orientation dispersion in the left uncinate fasciculus in traumatic brain injury and FS (TBI+FS) patients post-therapy, correlating with improvements in post-traumatic symptoms, quality of life, and emotional well-being. The untreated TBI-only group showed no corresponding changes, highlighting the importance of the uncinate fasciculus in FS therapy.

The uncinate fasciculus, associated with emotion regulation difficulties in FS, underwent post-treatment reorganization linked to psychological improvements, possibly involving tissue reorganization and dendritic growth impacting emotion regulation and motor control.

In the TBI-only group, spontaneous orientation dispersion decreases in the right cingulum lacked correlation with clinical outcomes, questioning their significance. Significant extracellular free water increase in the right cingulum of TBI-only participants correlated with greater psychological problems, suggesting ongoing disease processes. The absence of such changes in the TBI+FS group hinted at NBT’s potential mitigating effect on neuroinflammation.

Conventional DTI outcomes revealed fractional anisotropy increases in the TBI-only group, possibly indicating glial changes related to ongoing disease processes. Interaction analyses with participant sex uncovered additional findings, such as neurite density decreases in the right cingulum of women with TBI+FS.

Exploratory cluster-level analyses identified hypothesized extracellular free water decreases in TBI+FS patients and unexpected increases in the TBI group in additional clusters. Unexpected fractional anisotropy decreases in the corpus callosum in the TBI+FS group lacked clear explanations or correlations with clinical endpoints.

While no changes in neurite density were observed, orientation dispersion and extracellular free water were sensitive to post-treatment microstructural changes related to clinical outcomes. Notably, no associations were found between these changes and the decrease in weekly seizures, suggesting the need for additional brain imaging techniques to explore the substrates underlying the burden of functional seizures.

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