Behavioral Interventions in Multiple Sclerosis

A Biopsychosocial Perspective

C Heesen; S Köpke; J Kasper; J Poettgen; A Tallner; DC Mohr; SM Gold


Expert Rev Neurother. 2012;12(9):1089-1100. 

In This Article

Biological Mechanisms

As reviewed above, there is emerging evidence that BI may have beneficial effects on clinical outcomes in MS. A growing body of evidence suggests that stress effects as well as the development of neuropsychiatric symptoms in MS (such as depression, fatigue and cognitive impairment) may be associated with biological processes that could directly be relevant for MS pathogenesis or activity. These include inflammatory and neurodegenerative mechanisms as well as disturbances in the bidirectional communication between the brain, the immune system and the endocrine system. Unfortunately, very few studies investigating the potential of BI in MS have included suitable biomarkers so that the biological mechanisms that may mediate the clinical effects remain poorly understood.

A reduced sensitivity of immune cells to glucocorticoids (GCs; 'GC resistance') has been hypothesized as a potential mechanism underlying the stress-relapse link in MS.[77] The importance of intact GC signaling for the endogenous control of autoimmune neuroinflammation was clearly demonstrated in animal studies: conditional knockout of the GC receptor (GR) in T cells[78] to increased severity of experimental autoimmune encephalomyelitis (EAE) in mice. Conversely, overexpression of GRs in thymocytes had a protective effect.[79] In a recent translational study, the authors could demonstrate that a dynamic induction of GC resistance in T cells precedes the onset of EAE and is linked to inflammatory activity and lesion development in EAE as well as patients with MS.[80] Thus, occurrence of GC resistance in the immune system may represent an early permissive step for autoimmune inflammation. Intriguingly, psychological stress has been linked to lower expression of GRs in peripheral blood mononuclear cells in children with asthma[81] and animal experiments indicate that social stress can decrease GC sensitivity in the immune system.[82,83] Therefore, stress may trigger the development of inflammatory lesions[13] and MS relapses[12,82] by 'mimicking' GC resistance that occurs during an inflammatory cascade. If reversal of GC resistance can be achieved by reducing psychological stress and whether or not this may underlie the recently described anti-inflammatory effects of stress management programs in MS,[67] however, remains to be determined.

The high frequency of 'hidden symptoms' of MS such as depression,[17] fatigue[84] and cognitive impairment[85] is likely due to a combination of psychological and biological factors, the latter including mechanisms directly related to MS pathology. What is largely unknown, however, is whether improvements in these symptoms as described for several BI is also linked to normalization of these biological substrates. A few studies are in line with the notion that successful intervention may indeed influence biology. For example, one study indicated that treatment of MS depression (either pharmacologically or with psychotherapy) can reduce IFN-γ production in the immune system.[86] There is also some cross-sectional[87–90] as well as preliminary longitudinal evidence[91] that meditation may positively affect connectivity and regional brain morphology, including hippocampal volumes, at least in healthy subjects. Since decreases in depression and fatigue have been reported in a mindfulness meditation trial in MS[66] and hippocampal atrophy is linked to MS depression and cognitive dysfunction,[92–94] these studies are in line with the possibility that meditation may affect regional atrophy in MS. However, a clinical trial in MS that clearly demonstrates a beneficial effect of a BI such as stress management or meditation on a clinical outcome (e.g., depression) as well as a related biological marker is still lacking.

Exercise seems to be one of the strongest neuroprotective and neuroregenerative interventions. An increase in cell proliferation and cell survival in the dentate gyrus of the hippocampus is one of the most consistently observed effects of exercise treatment in animal studies (for review, see[42]). Exercise-induced hippocampal cell proliferation and cell survival can occur at many stages of development, including young adulthood and in old age. However, the underlying neurobiological mechanisms of this protective effect are poorly understood and may include several pathways.

Our muscles are the biggest organ in the body that can release a number of molecules such as myokines during exercise. A growing body of evidence suggests that these myokines mediate many of the beneficial effects of exercise.[95] In addition, the exercise-induced production of VEGF and IGF1 may mediate angiogenesis and regeneration. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) have been shown to be induced in the CNS by exercise.[96] BDNF is necessary for long-term potentiation, a neural analogue of long-term memory formation, and for the growth and survival of new neurons. BDNF levels in the hippocampus have been directly related to the enhanced learning and memory processes that are observed with exercise in rodents. Even in humans, serum concentrations of BDNF are increased after acute exercise regimens in both young adults and patients with MS.[97] In addition anti-inflammatory processes and regulatory immunity have been shown to be induced through training.[98]