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Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13444-13449. Epub 2016 Nov 7.

Stress-induced brain activity, brain atrophy, and clinical disability in multiple sclerosis.

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Berlin Center for Advanced Neuroimaging, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;
Bernstein Center for Computational Neuroscience Berlin, Charité-Universitätsmedizin Berlin, 10115 Berlin, Germany.
Cluster of Excellence NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, 13125 Berlin, Germany.
Berlin Center for Advanced Neuroimaging, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany.


Prospective clinical studies support a link between psychological stress and multiple sclerosis (MS) disease severity, and peripheral stress systems are frequently dysregulated in MS patients. However, the exact link between neurobiological stress systems and MS symptoms is unknown. To evaluate the link between neural stress responses and disease parameters, we used an arterial-spin-labeling functional MRI stress paradigm in 36 MS patients and 21 healthy controls. Specifically, we measured brain activity during a mental arithmetic paradigm with performance-adaptive task frequency and performance feedback and related this activity to disease parameters. Across all participants, stress increased heart rate, perceived stress, and neural activity in the visual, cerebellar and insular cortex areas compared with a resting condition. None of these responses was related to cognitive load (task frequency). Consistently, although performance and cognitive load were lower in patients than in controls, stress responses did not differ between groups. Insula activity elevated during stress compared with rest was negatively linked to impairment of pyramidal and cerebral functions in patients. Cerebellar activation was related negatively to gray matter (GM) atrophy (i.e., positively to GM volume) in patients. Interestingly, this link was also observed in overlapping areas in controls. Cognitive load did not contribute to these associations. The results show that our task induced psychological stress independent of cognitive load. Moreover, stress-induced brain activity reflects clinical disability in MS. Finally, the link between stress-induced activity and GM volume in patients and controls in overlapping areas suggests that this link cannot be caused by the disease alone.


brain atrophy; clinical disability; functional magnetic resonance imaging; multiple sclerosis; psychological stress

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