Neural Compensation in Huntington's Disease: Teaching Mental Disorders New Tricks?

The brain's ability to maintain function in the presence of an incipiby linear effects at the level of regional activity and functional coupling, ent or ongoing detrimental neural condition is well-recognized (Grady, 2008). In neurodegenerative diseases, such neural mechanisms may be able to counteract progressive pathology, at least until theminimumcapacity which is needed until cognitive and sensorimotor performance falls below a critical threshold. Such mechanisms have been often referred to as “compensatory” and may involve neural activity increases in brain regions normally recruited during a task, reconfiguration of functional coupling or recruitment of alternative neural pathways. In neuropsychiatric diseases, identifying neural mechanisms as “compensatory” – and not just as aberrant patterns of brain function – is of outstanding relevance. If neuroimaging should be used as a technique for identifying, validating and implementing biological markers, then any measurable deviation of brain activity will need to be classified not only as “abnormal” but also with respect to its functional consequences, i.e. whether they may be detrimental or beneficial for thought and behavior. If compensatory mechanisms are at play then in an interventional trial designed to delay the onset or progression of a disease, a specific intervention may not want to disrupt neural compensation. In such a case, promoting compensation is one of the primary goals. Huntington's disease (HD) in many ways is a neuropsychiatric “model disease” (Ross and Tabrizi, 2011). The availability of genetic testing allows an identification of persons who carry the HTT-gene mutation but who will remain presymptomatic for several decades (preHD). In these individuals functional magnetic resonance imaging (MRI) has been shown to be sensitive to neural dysfunction in situations where atrophy can be hardly detected by standard structural neuroimaging. Klöppel and colleagues for the first time explicitly investigate potential compensatory mechanisms in preHD (Klöppel et al., 2015). The essential advance for future research is that compensation was not addressed post-hoc or discussed among other plausible explanations. The authors employ a specific statistical model which takes into account task performance, structural disease load and neural activity. The assumption is that higher structural disease burden is accompanied