Disruption of response inhibition circuits in prodromal Huntington disease

Abstract

Cognitive changes in the prodromal phase of Huntington disease (prHD) are found in multiple domains, yet their neural bases are not well understood. One component process that supports cognition is inhibitory control. In the present fMRI study, we examined brain circuits involved in response inhibition in 65 prHD participants and 36 gene-negative (NEG) controls using the stop signal task (SST). PrHD participants were subdivided into three groups (LOW, MEDIUM, HIGH) based on their CAG-Age Product (CAP) score, an index of genetic exposure and a proxy for expected time to diagnosis. Poorer response inhibition (stop signal duration) correlated with CAP scores. When response inhibition was successful, activation of the classic frontal inhibitory-network was normal in prHD, yet stepwise reductions in activation with proximity to diagnosis were found in the posterior ventral attention network (inferior parietal and temporal cortices). Failures in response inhibition in prHD were related to changes in inhibition centers (supplementary motor area (SMA)/anterior cingulate and inferior frontal cortex/insula) and ventral attention networks, where activation decreased with proximity to diagnosis. The LOW group showed evidence of early compensatory activation (hyperactivation) of right-hemisphere inhibition and attention reorienting centers, despite an absence of cortical atrophy or deficits on tests of executive functioning. Moreover, greater activation for failed than successful inhibitions in an ipsilateral motor-control network was found in the control group, whereas such differences were markedly attenuated in all prHD groups. The results were not related to changes in cortical volume and thickness, which did not differ among the groups. However, greater hypoactivation of classic right-hemisphere inhibition centers [inferior frontal gyrus (IFG)/insula, SMA/anterior cingulate cortex (ACC)] during inhibition failures correlated with greater globus pallidus atrophy. These results are the first to demonstrate that response inhibition in prHD is associated with altered functioning in brain networks that govern inhibition, attention, and motor control.

Functional brain changes underlying irritability in premanifest Huntington's disease

“…Atrophy of the ACC has been documented at the early manifest and even premanifest stage [Hobbs et al, 2011]. Functional abnormalities of the ACC in preHD have been related to cognitive deficits, that is, response inhibition [Rao et al, 2014]. Functional abnormalities of the ACC in preHD have been related to cognitive deficits, that is, response inhibition [Rao et al, 2014].…”

Large-scale brain network abnormalities in Huntington's disease revealed by structural covariance

“…Specifically, working memory is among the first cognitive domains to be affected and dysfunctions are characterized by reduced connectivity in frontostriatal and frontoparietal networks in mHD [Wolf et al, 2008a[Wolf et al, , 2008b, as well as by volume loss in anterior cingulate cortex, parietal lobe, and striatum [Rosas et al, 2008;Tabrizi et al, 2009]. Also, deficits in executive functions, including motor control [Biglan et al, 2009;Kl€ oppel et al, 2009a], cognitive flexibility [Hanes et al, 1995;O'Rourke et al, 2011;Paulsen et al, 1995], and inhibitory control mechanisms [Georgiou- Karistianis et al, 2007Kl€ oppel et al, 2008;Rao et al, 2014], have been confirmed for both pre-HD and mHD and are possibly the result of striatal atrophy, as well as of volume loss in prefrontal regions [Lawrence, 1998;Rosas et al, 2003]. Moreover, impairments in striatum, amygdala, pallidum, and insula [Henley et al, 2012;Thieben et al, 2002], all considered to be part of the limbic loop [Douaud et al, 2006], may account for the deficits in emotion recognition that are observed in pre-HD and mHD [Gray et al, 1997;Henley et al, 2012;Hennenlotter et al, 2004;Milders et al, 2003;Sprengelmeyer et al, 1996Sprengelmeyer et al, , 2006.…”

The BACHD Rat Model of Huntington Disease Shows Signs of Fronto-Striatal Dysfunction in Two Operant Conditioning Tests of Short-Term Memory

“…Evaluating the BACHD rats’ performance in such tests might also help to determine if the impairment in the delayed alternation test truly concerned a failure to inhibit erroneous responses, as opposed to a failure to realize that the initiated responses would be erroneous. Interestingly, changes in neuronal signaling have been found in HD patients during performance of tests where they had to inhibit ongoing motor responses [47]. In addition, HD patients [48], HD mouse models [49] and BACHD rats [50] have all been found to show impaired performance in other tests of response inhibition.…”