Finally in limited studies it has been suggested

Finally, in limited studies it has been suggested that the presence or absence of any particular comorbid anxiety disorders may alter the pattern and prognosis of bipolar disorder. For instance, Pini et al. (1997) suggested three patterns in association with anxiety and affective disorder: (i) GAD was found to be stronger associated with dysthymia than bipolar or unipolar depression; (ii) panic disorder was found to have a greater tendency to co-occur with bipolar disorder than with dysthymia and possibly than with unipolar depression; (iii) social phobia was less common in bipolar cases. Duffy et al. (2010) suggested a staging model: anxiety disorders appear as an early manifestation of psychopathology in high-risk youth who go on to develop bipolar illness. Perugi et al. (2001) suggested that social phobia most often precedes mania and then resolves, while other comorbid anxiety disorders tend to persist.
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Introduction In neurodegenerative disease, progressive degenerative changes can be detected many years prior to the manifestation of clinical symptoms including cognitive and motor deficits. Such findings indicate that the brain has capacity to compensate for degenerative losses, maintaining normal levels of cognitive and motor function, until such time that neuropathology translates into clinical loss of function. For example, in Huntington\'s disease (HD), a fully penetrant monogenic disorder, individuals far from the onset of overt signs and symptoms demonstrate extensive neuroimaging evidence of subcortical and cortical atrophy. However, such HD expansion mutation carriers perform similarly to healthy controls on a wide variety of motor and cognitive tests and show minimal longitudinal change in performance (Tabrizi et al., 2011; Papoutsi et al., 2014). We can postulate two different mechanisms that might be responsible for this dissociation between progressive structural pathology and minimal measurable phenotypical behavioral change. Inherent cognitive reserve may mitigate against the emergence of measurable phenotypical alterations before a threshold for functional degradation is exceeded. Alternatively, secondary compensatory mechanisms, in which brain pathology leads to EPZ015666 Supplier of neural activity patterns, may emerge in the course of the disease process and could create alternative or modified neural processes to support maintenance of cognitive and motor function at normal levels. However, no universally accepted definition of compensation exists (Barulli and Stern, 2013), and the underlying mechanisms are unknown. Our previous longitudinal multi-site study (Track-HD) showed disease-related reductions in striatal and white matter volume (Tabrizi et al., 2009), and elevated rates of atrophy from the very earliest premanifest stages (Tabrizi et al., 2011, 2012, 2013). Despite this consistent progressive structural loss, high levels of functional performance are maintained in this cohort and there is little evidence of cognitive or motor decline over time (Tabrizi et al., 2009, 2011, 2012, 2013). The current study (Track-On HD) was designed to explore the hypothesis that compensatory brain networks exist to maintain function in the presence of widespread structural damage during the premanifest phase of HD. Recent functional neuroimaging studies indicate augmented task-related brain activity in premanifest HD expansion mutation-carriers compared with healthy control or manifest HD groups, (Georgiou-Karistianis et al., 2013; Gray et al., 2013; Klöppel et al., 2009; Novak et al., 2012; Poudel et al., 2013; Scheller et al., 2013; Wolf et al., 2007; Malejko et al., 2014) providing evidence of increased subcortical (Georgiou-Karistianis et al., 2013; Malejko et al., 2014), and cortical activation in both prefrontal and parietal cortex as well as supplementary motor areas (Klöppel et al., 2009; Scheller et al., 2013). Typically, published studies using such comparisons neither take into account disease-related structural alterations within the groups, nor the variability in performance within each group. Moreover, using group comparison leaves open the possibility that the observed differences in brain activity are not task-related but instead reflect a superimposed effect of neurodegenerative pathology. To overcome these challenges, we developed a measure of neural compensation that takes into account the relationships between behavioral performance and brain activity (or connectivity) seen in healthy individuals, and applied it to functional MRI (fMRI) measures of brain activity in a large cohort of over 100 individuals with premanifest-HD (preHD). We hypothesized that neural compensation could be identified as a positive change in the relationship between performance and brain activation in association with relatively high levels of structural alterations reflecting the impact of the disease processes (‘structural disease load’). Specifically, we hypothesized that for those brain regions showing compensation, higher structural disease load would be associated with tighter relationships between performance and brain activity (Fig. 1 and Eq. (1), Materials and Methods) indicating a need for greater task-associated neural activity to maintain similar levels of performance in individuals with higher structural disease load.