Reaction time (ms) for controls and patients with Parkinson’s disease (PD) in the externally-triggered condition in potential shock (PS) and no potential shock (NPS) trials.

<p>Reaction time (ms) for controls and patients with Parkinson’s disease (PD) in the externally-triggered condition in potential shock (PS) and no potential shock (NPS) trials.</p

Motivational Modulation of Self-Initiated and Externally Triggered Movement Speed Induced by Threat of Shock: Experimental Evidence for Paradoxical Kinesis in Parkinson’s Disease

<div><p>Background</p><p>Paradoxical kinesis has been observed in bradykinetic people with Parkinson’s disease. Paradoxical kinesis occurs in situations where an individual is strongly motivated or influenced by relevant external cues. Our aim was to induce paradoxical kinesis in the laboratory. We tested whether the motivation of avoiding a mild electric shock was sufficient to induce paradoxical kinesis in externally-triggered and self-initiated conditions in people with Parkinson’s disease tested on medication and in age-matched controls.</p><p>Methods</p><p>Participants completed a shock avoidance behavioural paradigm in which half of the trials could result in a mild electric shock if the participant did not move fast enough. Half of the trials of each type were self-initiated and half were externally-triggered. The criterion for avoiding shock was a maximum movement time, adjusted according to each participant’s performance on previous trials using a staircase tracking procedure.</p><p>Results</p><p>On trials with threat of shock, both patients with Parkinson’s disease and controls had faster movement times compared to no potential shock trials, in both self-initiated and externally-triggered conditions. The magnitude of improvement of movement time from no potential shock to potential shock trials was positively correlated with anxiety ratings.</p><p>Conclusions</p><p>When motivated to avoid mild electric shock, patients with Parkinson’s disease, similar to healthy controls, showed significant speeding of movement execution. This was observed in both self-initiated and externally-triggered versions of the task. Nevertheless, in the ET condition the improvement of reaction times induced by motivation to avoid shocks was greater for the PD patients than controls, highlighting the value of external cues for movement initiation in PD patients. The magnitude of improvement from the no potential shock to the potential shock trials was associated with the threat-induced anxiety. This demonstration of paradoxical kinesis in the laboratory under both self-initiated and externally-triggered conditions has implications for motivational and attentional enhancement of movement speed in Parkinson’s disease.</p></div

The Shock Avoidance Behavioural paradigm with self-initiated (A) and externally-triggered (B) conditions.

<p>The Shock Avoidance Behavioural paradigm with self-initiated (A) and externally-triggered (B) conditions.</p

Demographic data and scores on tests of cognition, executive function and mood scales for controls and patients with Parkinson’s disease (PD).

<p>MDS UPDRS = Movement Disorder’s Society Unified Parkinson’s Disease rating Scale; EHI = Edinburgh Handedness Inventory; BDI = Beck Depression Inventory; MMSE = Mini Mental State Examination; NART IQ = National Adult Reading Test Intelligence Quotient.</p><p>The data are means (±SEM).</p

Movement time (ms) for controls and patients with Parkinson’s disease (PD) in self-initiated (SI) and externally-triggered (ET) conditions for the potential shock (PS) and no potential shock (NPS) trials.

<p>Movement time (ms) for controls and patients with Parkinson’s disease (PD) in self-initiated (SI) and externally-triggered (ET) conditions for the potential shock (PS) and no potential shock (NPS) trials.</p

Reaction time (ms) for controls and patients with Parkinson’s disease (PD) in the externally-triggered condition in potential shock (PS) and no potential shock (NPS) trials.

<p>Reaction time (ms) for controls and patients with Parkinson’s disease (PD) in the externally-triggered condition in potential shock (PS) and no potential shock (NPS) trials.</p

Assumptions and Properties of Limiting Pathway Models for Analysis of Epistasis in Complex Traits

<p>For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by standard methods using correlations between relatives. This difference has been called the "missing heritability''. One explanation is that heritability estimates from family (including twin) studies are biased upwards. Zuk et al. revisited overestimation of narrow sense heritability from twin studies as a result of confounding with non-additive genetic variance. They propose a limiting pathway (LP) model that generates significant epistatic variation and its simple parametrization provides a convenient way to explore implications of epistasis. They conclude that overestimation of narrow sense heritability from family data ('phantom heritability') may explain an important proportion of missing heritability. We show that for highly heritable quantitative traits large phantom heritability estimates from twin studies are possible only if a large contribution of common environment is assumed. The LP model is underpinned by strong assumptions that are unlikely to hold, including that all contributing pathways have the same mean and variance and are uncorrelated. Here, we relax the assumptions that underlie the LP model to be more biologically plausible. Together with theoretical, empirical, and pragmatic arguments we conclude that in outbred populations the contribution of additive genetic variance is likely to be much more important than the contribution of non-additive variance.</p>