Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson’s disease

Abstract

Cognitive decline is a common feature of Parkinson’s disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson’s disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomised crossover design, 19 people with Parkinson’s disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetisation transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in Parkinson’s disease patients. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalised treatment approaches.

Noradrenergic deficits contribute to apathy in Parkinson’s disease through the precision of expected outcomes

“…Atomoxetine can have mild sedative effects, increasing omission errors and decreasing response accuracy specifically in the context of rapid stimulus presentation (Toschi et al, 2021). However, atomoxetine did not affect basic task performance in the current study or in a stopsignal task, either at the group-average level or in relation to individual differences in locus coeruleus CNR (O'Callaghan et al, 2021). This argues against a simple effect via arousal.…”

Prefrontal cortical connectivity mediates locus coeruleus noradrenergic regulation of inhibitory control in older adults

“…These attentional failures can be common in the stop-signal task and, if not accounted for, bias estimation of the stop process (Band et al, 2003;Matzke et al, 2019;Skippen et al, 2019). Prior to fitting the model, we excluded implausibly fast (< 0.25s) RTs, as well as outliers go RTs exceeding ±2.5 standard deviations from the participant's mean (Matzke, Dolan, Logan, Brown, & Wagenmakers, 2013;O'Callaghan et al, 2021).…”

“…We adopted prior distributions identical to those suggested by the model developers (Heathcote et al, 2018), except for slightly higher prior mean values for μgo-match (1.5s), μgo-mismatch (1.5s) and μstop (1s), to account for slower RT in older age (O'Callaghan et al, 2021). MCMC sampling initially ran with 33 chains (i.e., three times the number of parameters), with thinning of every 10th sample and a 5% probability of migration.…”

“…By exploiting the accumulation of iron-rich neuromelanin, magnetization-transfer (MT) sensitive magnetic resonance imaging sequences can be used to assess the integrity of the locus coeruleus (Liu et al 2019;Ye et al, 2020; but see also Watanabe et al, 2019). Such studies have associated locus coeruleus integrity with diverse cognitive function in health (Liu et al, 2020) and disease Holland, Robbins, & Rowe, 2021;O'Callaghan et al, 2021;Ye et al, 2021).…”

“…Moreover, sub-regions of the locus coeruleus have different projection distributions (Mason & Fibiger, 1979;Loughlin, Foote, Bloom, 1986) with differential associations to cognition, behaviour and pathology. For example, in vivo evidence suggest greater degeneration of the caudal sub-region of the locus coeruleus compared to central and rostral sub-regions in Parkinson's disease (O'Callaghan et al, 2021). Healthy ageing and age-related cognitive decline are more strongly associated with changes in the rostral locus coeruleus (Betts, Cardenas-Blanco, Kanowski, Jessen, & Düzel, 2017;Liu et al, 2020;.…”