Hypomania and saccadic changes in Parkinson's disease: influence of D2 and D3 dopaminergic signalling

Abstract

In order to understand the influence of two dopaminergic signalling pathways, TaqIA rs1800497 (influencing striatal D2 receptor density) and Ser9Gly rs6280 (influencing the striatal D3 dopamine-binding affinity), on saccade generation and psychiatric comorbidities in Parkinson's disease, this study aimed to investigate the association of saccadic performance in hypomanic or impulsive behaviour in parkinsonian patients; besides we questioned whether variants of D2 (A1+/A1-) and D3 (B1+/B1-) receptor polymorphism influence saccadic parameters differently, and if clinical parameters or brain connectivity changes modulate this association in the nigro-caudatal and nigro-collicular tract. Initially, patients and controls were compared regarding saccadic performance and differed in the parameter duration in memory-guided saccades (MGS) and visually guided saccades (VGS) trials (p < 0.0001) and in the MGS trial (p < 0.03). We were able to find associations between hypomanic behaviour (HPS) and saccade parameters (duration, latency, gain and amplitude) for both conditions [MGS (p = 0.036); VGS (p = 0.033)], but not for impulsive behaviour. For the A1 variant duration was significantly associated with HPS [VGS (p = 0.024); MGS (p = 0.033)]. In patients with the B1 variant, HPS scores were more consistently associated with duration [VGS (p = 0.005); MGS (p = 0.015), latency [VGS (p = 0.022)]] and amplitude [MGS (p = 0.006); VGS (p = 0.005)]. The mediation analysis only revealed a significant indirect effect for amplitude in the MGS modality for the variable UPDRS-ON (p < 0.05). All other clinical scales and brain connectivity parameters were not associated with behavioural traits. Collectively, our findings stress the role of striatal D2 and D3 signalling mechanisms in saccade generation and suggest that saccadic performance is associated with the clinical psychiatric state in Parkinson's disease.

Keywords: Clinical genetics; Oculomotor system; Parkinson's disease.

Fig. 1. Saccade characteristics in Parkinson’s disease.

a The exemplary raw gaze positions of one control and three patients are shown. Gaze during reflexive trials is always presented in red, gaze during memory trials is shown in blue. Each dot represents a single eye position measurement. Data are presented in visual angle space (degrees), centred around central fixation at coordinates (0,0). Visual targets were presented at a distance of 10° from the centre in either the vertical or horizontal direction. b Data from one control (left) and patient 3 (right) are presented in more detail with saccade latencies (in ms) during reflexive (red) and memory (blue) trials; additionally scheduled for patient 3 are velocity profiles (deg/s over ms) during each trial type. While patients show large differences in precision and the overall eye movement pattern, gaze during memory trials (blue) appears to more often land in between target and central fixation spot than during reflexive trials (red) (a). Similarly, latencies show slight differences between memory and reflexive trials in patient 3 (b). More prominently, saccadic velocity profiles show saccades with lower peak velocity in memory trials (blue) than in reflexive trials (red), indicating saccades more often stopping short during the memory task.

Fig. 2. Vertical and horizontal traces.

Vertical and horizontal eye position traces (in degree of visual angle) are plotted over time in steps of 10 ms for a healthy control (a) and a patient (b). In each time series, the respective trial's trigger to initiate a saccade to the previously shown target location (i.e., turning off of the fixation point) is indicated per trial as a coloured vertical line, coloured, according to each trial's stimulus condition, in red (reflexive) or blue (memory).

Fig. 3. Experimental design of the MGS and VGS.

a Each experimental run consisted of a sequence of blocks of memory-guided saccade task trials (MGS) and visually guided (VGS) saccade task trials. After a fixation phase (shown as central cross in Fig. 3a), the saccade target (red dot) was presented alongside the fixation target. Saccade targets were placed at one of four possible locations (Fig. 3a inset) with a distance of 10° from central fixation. Participants were asked to saccade to the target only after the offset of the fixation cross. In VGS trials, this offset occurred right away, that is, saccades were allowed right after onset of the saccade target. In MGS trials, the fixation target stayed visible for a variable delay (jitter delay) after offset of the saccade target. That is, patients had to memorise the target's location, and only after a delay, they were allowed to initiate the saccade to that location. Each trial lasted around 1.5 s. Thirty MGS and 30 VGS trials were presented per run. b Blocks of MGS- and VGS trials were presented in a randomised sequence, summing up to a total of 240 trials and about 6 min of testing time.