Default-mode network changes in preclinical Huntington's disease
Highlights
► We examine the functional connectivity of the default-mode network in preclinical HD. ► The data suggest within- and between-network connectivity changes in preHD. ► Functional connectivity measures were related to cognitive performance. ► Network connectivity changes in preHD may reflect compensatory neural mechanisms.
Introduction
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by an extended trinucleotide repeat in the HTT gene on chromosome 4 (Ross and Tabrizi, 2011). The neuropathological hallmark of the disease is progressive neuronal degeneration, preferentially within regions of the striatum (Vonsattel et al., 1985). Clinically, the disease is characterised by progressive motor dysfunction, psychiatric symptoms and cognitive deficits. Much effort at present focuses on identifying therapeutic targets and developing treatments that could delay the onset of the disease or slow down or stop the progression of the disease once it manifests (see e.g. Bohanna et al., 2008, Kloppel et al., 2009b, Paulsen, 2009). In this context, the development of objective measures to reliably assess the biology of HD independent of clinical signs is crucial since such measures may serve as surrogate endpoints in future clinical trials (Weir et al., 2011).
Imaging brain structure and metabolism has been successfully used to assess neural markers of the disease, revealing differences in preHD compared to healthy control individuals (Aylward, 2007, Feigin et al., 2007, Gomez-Anson et al., 2009, Harris et al., 1999, Lawrence et al., 1998, Paulsen et al., 2006, Pavese et al., 2010, Rosas et al., 2005, Tabrizi et al., 2009, Wolf et al., 2007). Furthermore, functional magnetic resonance imaging (fMRI) in preHD revealed widespread functional changes of the brain while performing cognitive or affective tasks (Hennenlotter et al., 2004, Kloppel et al., 2009b, 2011; Reading et al., 2004, Wolf et al., 2007, Zimbelman et al., 2007). Importantly, brain function may change in the absence of significant structural or behavioural changes in preHD (Wolf et al., 2007, Zimbelman et al., 2007) suggesting that fMRI is a powerful method for detecting early neural dysfunction prior to brain atrophy (Bohanna et al., 2008, Kloppel et al., 2009b, Paulsen, 2009).
FMRI findings in preHD have been reported for task-based conditions, where brain physiology is assessed in experimentally controlled states of functional activation relative to a predefined control condition or baseline. In contrast, the role of brain regions which are deactivated with task-related processing demand has been less studied. In the last decade, the so-called “default-mode network” (DMN) of brain function attracted interest. The DMN consists of inter- and intraindividually stable brain regions; their activation increases during resting periods and is attenuated or “deactivated” with active processing demand (Broyd et al., 2008, Buckner et al., 2008, Meindl et al., 2010, Raichle et al., 2001). The DMN typically includes cortical midline regions such as the anterior medial prefrontal cortex, the anterior and posterior cingulate cortices, the precuneus and bilateral inferior parietal regions (Broyd et al., 2008, Buckner et al., 2008). Numerous neuroimaging studies have suggested a role of the DMN in monitoring of the external environment, in autobiographical memory, in decision making, and in supporting prospective thoughts (Broyd et al., 2008, Buckner et al., 2008, Gusnard and Raichle, 2001, Gusnard et al., 2001, Raichle et al., 2001). Importantly, the integrity of the DMN probably is relevant for the allocation of attentional resources needed for higher cognitive processes such as episodic memory, working memory or executive function (Sambataro et al., 2008, Sambataro et al., 2010, Wolf et al., 2009). Recent evidence suggests that the DMN is segregated into at least two spatiotemporally distinct subsystems (Damoiseaux et al., 2006, Uddin et al., 2009) which differentially modulate their corresponding “task-positive” networks, i.e. networks showing increasing activation when processing demands increase. These different DMN subsystems may have specific roles in their interaction with “task-positive” networks. For instance, it has been shown that the posterior cingulate cortex (PCC) region of the DMN interacts with a motor-related neural system, whereas an anterior medial prefrontal region node is coupled to a network subserving attention (Andrews-Hanna et al., 2010, Uddin et al., 2008). The well-described functional architecture of the DMN, its inter- and intraindividual reliability (Meindl et al., 2010) and its relevance for cognitive change have made the DMN an attractive and promising target for biomarker development within a wide range of neuropsychiatric disorders and related at-risk populations (Delaveau et al., 2011, Hafkemeijer et al., 2012, van Eimeren et al., 2009). However, DMN function has so far not been examined in preHD.
In this study, we investigated DMN function in preHD individuals and explored the relationship between neural network changes, cognition and clinical markers of the disease. We used blood-oxygen level dependent fMRI during an attention task (Posner, 2008, Sturm and Willmes, 2001) together with a group independent component analysis for fMRI data (Calhoun et al., 2001, Calhoun et al., 2004, Esposito et al., 2006, Sambataro et al., 2008) to estimate the functional connectivity of two distinct DMN subsystems (Damoiseaux et al., 2006, Uddin et al., 2009). In addition, we investigated the functional coupling between the two DMN subsystems by means of a constrained maximal lag correlation (Jafri et al., 2008). We predicted functional connectivity changes within and between DMN subsystems in preHD compared to controls. We also predicted an association between DMN changes in preHD and their performance during the attention task.
Section snippets
Participants
We analysed data from 18 right-handed (Oldfield, 1971) preHD participants with a genetically confirmed CAG repeat expansion (≥ 39 CAG repeats, range 39–48) in the huntingtin gene, as reported previously (Wolf et al., in press). Participants were included as preHD if the diagnostic confidence score on the motor Unified Huntington's Disease Rating Scale (UHDRS, Huntington-Study-Group, 1996) was ≤ 2. PreHD individuals with a history of another neurological disorder, a history of head trauma or
Clinical data and behavioural results
Ratings on the UHDRS motor scale confirmed that preHD participants were presymptomatic with low motor scores. BDI scores were higher in preHD than in controls, whereas HAMD-scores were similar in preHD and controls (Table 1). Performance during the alertness task was similar in preHD and controls (Table 2).
FMRI results
Twenty independent components were estimated, consisting of individual spatially independent maps and time-courses. In controls and preHD, two components of interest were identified using a
Discussion
The present study demonstrates that preclinical HD is associated with functional connectivity changes of two distinct DMN subsystems relative to controls. PreHD individuals differed from controls in two ways: 1) within the DMN subsystems they had lower functional connectivity in the PCC, the amPFC and the left IPL; and 2) the functional network connectivity between the two DMN subsystems was greater in preHD than in controls. These findings suggest that in preHD task-related deactivating neural
Acknowledgments
This study was supported by a grant from the CHDI/High Q foundation, a non-profit organisation dedicated to increase the understanding of Huntington's disease and to facilitate the development of new treatment strategies for this illness (http://www.highqfoundation.org/). This study also received support from the European Huntington's Disease Network (EHDN, http://www.euro-hd.net/html/network). We are grateful to Jürn Wolf and Johanna Fischer for their assistance with data collection. The
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