The Imprint of Psychogenic Non-Epileptic Seizures on the Brain: A New Model and Imaging Biomarker
Abstract
Background: Psychogenic non-epileptic seizures (PNES) are defined by the occurrence of episodes that resemble epileptic seizures (ES) but do not show the characteristic electroencephalogram (EEG) manifestations of real epileptic seizures. Up to 20% of the patients who have initially been diagnosed with epilepsy ultimately receive the diagnosis of PNES, making this disorder as common as multiple sclerosis or Parkinson’s disease. The misdiagnosis of PNES as ES is not only costly because drug therapy against ES does not prevent PNES but also potentially harmful to the patients because of the side effects of the ES treatment. PNES are thought to be mediated by overwhelming psychological stress, but it is currently unknown why stress manifests itself in this peculiar way in some individuals. Hypothesis: The overall goal of this application is to investigate potential mechanisms for PNES. This will be accomplished by identifying the characteristic signature of this mechanism in task-free functional magnetic resonance imaging (fMRI) data of PNES patients and by demonstrating a relationship between PNES severity and the expression of this signature. This mechanism assumes that PNES are caused by an overshooting recruitment of brain regions normally involved in emotion control but also in additional brain regions that facilitate PNES by abnormally interacting with them (facilitating brain regions). Repeated or prolonged stress or traumatic experiences will further reinforce the overshooting and ultimately generate a characteristic, intermittent overshooting imprint that can be detected in the individual’s task-free fMRI activity even in the absence of subjective stress. On the behavioral level, the reinforced overshooting allows for individual aspects of abnormal emotion processing, e.g., anxiety, to become apparent even in situations of mild stress. Ultimately, it also facilitates the uncontrolled recruitment of those facilitating brain regions that are usually not involved in emotion processing but that are required to generate the individual’s typical PNES in moderate to high stress situations. The few fMRI studies that have been conducted in PNES patients so far found supporting evidence for overshooting in form of increased functional connectivity in brain regions involved in emotion processing even when the patients were lying relaxed in the MRI doing nothing. However, the transient imprint of each individual’s pathologic network that is the hallmark of the proposed PNES mechanism and reflects best its severity and the individual clinical features will be missed with the analysis methods that are used in these traditional so-called resting state fMRI analyses. A new dynamic analysis approach that combines the so-called sliding windows dynamic analysis with a new network analysis based on a combination of graph analysis and hierarchical cluster analysis will be used in this project to identify the characteristic imprint or resting state fMRI signature of the hypothesized overshooting mechanism. Specific Aim 1: PNES is associated with phases of overshooting recruitment between regions involved in emotion processing whose configuration reflects aspects of the individual’s pathological emotion processing and PNES semiology. The purpose of this aim is to support the new mechanism and to demonstrate that the new dynamic approach is capable to capture the hypothesized overshooting signature in regions involved in emotion control and PNES facilitating regions at the group level and in individual subjects. (A) The total duration during which the overshooting signature can be observed is longer in PNES than in controls and is positively correlated with the psychiatric comorbidity and seizure frequency. (B) The network configurations observed during these phases are compatible with abnormal emotion processing and reflect the clinical symptoms of the PNES. Specific Aim 2: PNES is characterized by increased statio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710336
Entities
People
- Susanne G Mueller
Organizations
- Northern California Institute for Research and Education
- United States Army