Prefrontal activity in Huntington's disease reflects cognitive and neuropsychiatric disturbances: The IMAGE-HD study

Abstract

Functional integrity of prefrontal cortico-striatal circuits underlying executive functioning may be compromised by basal ganglia degeneration during Huntington's disease (HD). This study investigated challenged inhibitory attentional control with a shifting response-set (SRS) task whilst assessing neural response via functional magnetic resonance imaging (fMRI) in 35 healthy controls, 35 matched pre-symptomatic (pre-HD) and 30 symptomatic (symp-HD) participants. A ≥ 70% performance accuracy threshold allowed confident identification of neural activity associated with SRS performance in a sub-set of 33 healthy controls, 32 pre-HD and 20 symp-HD participants. SRS activated dorsolateral prefrontal and dorsal anterior cingulate cortices, premotor, parietal, and basal ganglia regions and deactivated subgenual anterior cingulate cortex. Symp-HD participants showed greater prefrontal functional responses relative to controls and pre-HD, including larger activations and larger deactivations in response to cognitive challenge, consistent with compensatory neural recruitment. We then investigated associations between prefrontal BOLD responses, SRS performance accuracy and neuropsychiatric disturbance in all participants, including those below SRS performance accuracy threshold. We observed that reduced prefrontal responsivity in symp-HD was associated with reduced accuracy in SRS performance, and with increased neuropsychiatric disturbance within domains including executive dysfunction, pathological impulses, disinhibition, and depression. These findings demonstrate prefrontal response during inhibitory attentional control usefully characterises cognitive and neuropsychiatric status in symp-HD. The functional integrity of compensatory prefrontal responses may provide a useful marker for treatments which aim to sustain cognitive function and delay executive and neuropsychiatric disturbance.

Introduction

Progressive neurodegeneration in Huntington's disease (HD) reduces striatal volume in both symptomatic HD (symp-HD) and pre-symptomatic HD (pre-HD) individuals up to 15 years prior to symptom onset (Aylward et al., 2011, Paulsen, 2011, Paulsen et al., 2006). Cognitive and neuropsychiatric disturbances also develop (Julien et al., 2007, Tabrizi et al., 2012), with cognitive deficits in attention, fluency, executive functioning and memory (Paulsen et al., 2008, Stout et al., 2011, Tabrizi et al., 2009) evident during both pre-HD and symp-HD stages. Neuropsychiatric features include irritability, apathy, and depressive, anxiety and affective spectrum disorders, and are often reported as the most debilitating symptoms (Folstein et al., 1983, Julien et al., 2007, Shiwach, 1994). These deficits, which occur independent of motor impairments, can collectively reduce the functional capacity of individuals across a number of domains and thus significantly impact quality of life (Beglinger et al., 2010).

We investigated functional magnetic resonance imaging (fMRI) responses during a “shifting response set” (SRS) paradigm, and their association with independent measures of cognitive and neuropsychiatric function. SRS tasks require the effective integration of executive functioning and inhibitory control, and rely heavily on the integrity of the prefrontal cortex (Allport et al., 1994, Jersild, 1927, Lawrence et al., 1998b). SRS errors within clinical groups, over and above deficits reflecting basic memory and attention, result primarily from perseveration (i.e., difficulty releasing attention from previously relevant) and/or learned irrelevance (i.e., difficulty learning from previously irrelevant) (Owen et al., 1993). Perseverative and learned irrelevance errors are tied to prefrontal dysfunction. For example, patients with neurosurgical prefrontal lesions demonstrate these errors whereas patients with temporal lobectomy, or resection of amygdala or hippocampus, do not (Owen et al., 1991, Robbins, 1996). Prefrontal lesions typically result in disorganised and inappropriate behaviour commonly referred to as “strategy application disorders”, highlighting the importance of prefrontal inhibition of irrelevant or inappropriate response strategies which normally underlies appropriate executive and neuropsychiatric function (Goldstein et al., 1993, Penfield and Evans, 1935, Shallice and Burgess, 1991, Shallice and Burgess, 1993). SRS may be a particularly relevant neuroimaging challenge in HD for two reasons. Firstly, perseverative SRS errors are evident in HD (Lawrence et al., 1996, Lawrence et al., 1998a). Secondly, DLPFC activity underlying executive functioning is integrated with striatal activity, a primary region of neurodegeneration in HD (Alexander and Crutcher, 1990, Bonelli and Cummings, 2007, Lawrence et al., 1998b).

Specifically, we therefore applied fMRI to ascertain, for the first time, how prefrontal SRS responses differ across pre-HD, symp-HD and controls in participants who could accurately perform the task. Moreover, we sought to determine how prefrontal activity evoked during SRS related to cognitive and neuropsychiatric function across participants within each group irrespective of task accuracy. We hypothesised that accurate SRS performance (≥ 70% accuracy threshold) would significantly activate DLPFC, dorsal anterior cingulate cortex (ACC) and striatal regions across all groups, with greater responses in pre-HD and symp-HD. Moreover, across all symp-HD participants, failure to recruit DLPFC activity would be associated with cognitive (SRS performance accuracy) and neuropsychiatric function.