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Anxiety in multiple sclerosis: Psychoneurobiological mechanisms, clinical importance, and relation to other stress-related neuropsychiatric syndromes

Subject Area Biological Psychiatry
Clinical Neurology; Neurosurgery and Neuroradiology
Human Cognitive and Systems Neuroscience
Term from 2016 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 320333215
 
Final Report Year 2024

Final Report Abstract

Multiple Sclerosis (MS) is a CNS disease linked to altered neuro-immunological stress processing and stress-related syndromes such as depression and anxiety – psychopathological factors also shown to be capable of proactively modulating neurologic symptoms. Despite this potential effect, however, their neural foundations have only been investigated scarcely in MS. Consequently, we conducted two research projects aiming at investigating neural processes of psychological stress and depression (Project I) and anxiety (Project II) to facilitate a better understanding of the role of these psychobiological factors in MS. In Project I, we studied neural stress processing by employing a mental arithmetic functional MRI (fMRI) task comprising evaluative performance feedback in 16 persons with MS (PwMS) and depression, 26 PwMS without depression and 28 healthy persons (HPs) in a first experiment. In a second, we used an fMRI emotion regulation task (a key deficit of depressed patients according to its prominent cognitive model) to study alterations in emotion processing in MS depression. The first experiment showed that neural stress processing is differently linked to T cell stress hormone sensitivity in PwMS and HPs and that the extent of this deviation is linked to key neurological MS severity measures. The second showed that MS depression is characterized by impaired emotion regulation in amygdala and prefrontal cortex (PFC) – hallmarks of idiopathic depression – and that this impairment is amplified by lesions in amygdala - PFC tracts in PwMS with but not without depression. In Project II, we investigated neurobehavioral processes of two mechanisms known to contribute crucially to anxiety in persons without MS in 18 PwMS with anxiety, 36 PwMS without anxiety and 29 HP by employing an fMRI fear generalization (Experiment I) and fear extinction (Experiment II) paradigm. In these Pavlovian conditioning tasks, fear was elicited by applying mild electrical shocks whose intensity was determined by the participants themselves in a calibration session. Regarding fear generalization, the results show that PwMS with (vs. without) anxiety overgeneralize fear on a behavioral level, and that these differences are reflected by altered activity of brain regions contributing to neural fear and safety signaling. Further, a machine learning algorithm trained to associate neural responses to stimuli of varying shock risk (i.e., fearintensity) to participants’ behavioral risk ratings exclusively based on HP’s data was highly accurate in predicting the rated risk in PwMS with and without anxiety when presented with their neural fear response signals. Regarding fear extinction, PwMS with (vs. without) anxiety showed a neural processing deficit in that ventromedial prefrontal cortex, a region known to signal safety, signaled lower safety during previously but not currently fear associated stimuli. Finally, impaired fear processing was linked to a structural hyperconnectivity of primarily prefrontal areas in MS. Together, the findings obtained substantially deepen insights into the neural foundations of stress, depression and anxiety in MS, strongly emphasize the importance of psychobiological processes for MS, and advocate studying them with a systems biology approach.

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