Irritability in pre-clinical Huntington's disease

Abstract

Irritability, together with depression and anxiety, form three salient clinical features of pre-symptomatic Huntington's disease (HD). To date, the understanding of irritability in HD suffers from a paucity of experimental data and is largely based on questionnaires or clinical anecdotes. Factor analysis suggests that irritability is related to impulsivity and aggression and is likely to engage the same neuronal circuits as these behaviours, including areas such as medial orbitofrontal cortex (OFC) and amygdala. 16 pre-symptomatic gene carriers (PSCs) and 15 of their companions were asked to indicate the larger of two squares consecutively shown on a screen while undergoing functional magnetic resonance imaging (fMRI). Despite correct identification of the larger square, participants were often told that they or their partner had given the wrong answer. Size differences were subtle to make negative feedback credible but detectable. Although task performance, baseline irritability, and reported task-induced irritation were the same for both groups, fMRI revealed distinct neuronal processing in those who will later develop HD. In controls but not PSCs, task-induced irritation correlated positively with amygdala activation and negatively with OFC activation. Repetitive negative feedback induced greater amygdala activations in controls than PSCs. In addition, the inverse functional coupling between amygdala and OFC was significantly weaker in PSCs compared to controls. Our results argue that normal emotion processing circuits are disrupted in PSCs via attenuated modulation of emotional status by external or internal indicators. At later stages, this dysfunction may increase the risk for developing recognised, HD-associated, psychiatric symptoms such as irritability.

Fig. 1

Overview of task. Subjects had to identify the larger of two squares shown sequentially. This was followed by feedback on the correctness of the answer of the first and second player. A separate screen indicated if the round was won (when both players answered correctly) or lost. Timing intervals between screens were randomised (jittered) where indicated.

Fig. 2

Left: The graph displays the changing percentage of positive feedback in the last three trials for each run given that a subject's true answer was always correct. Right: Bilaterally the amygdala showed significantly greater activations in controls compared to PSCs when subjects were repeatedly given feedback that they had chosen the wrong square.

Fig. 3

Areas showing a stronger negative correlation between right amygdala activity (white circle) in the control group compared to PSCs. The seed region in the amygdala is enlarged for visualisation purposes. The plots on the left display the strength and direction of coupling. Bars report the strength of correlation in arbitrary units (a.u.) with 90% confidence intervals. Imaging results are overlaid on the mean brain from all subjects in MNI space at a threshold, for visualisation purposes only, of p < 0.01 (uncorrected).

Fig. 4

Areas showing an interaction between groups in the subject-specific rating of task-induced negative emotions. Whereas controls show increased activations in amygdala with increasing levels of reported negative emotions, such correlations are absent in the PSC group. Graphs show the correlation of rating with activation at the voxel marked by cross hairs in controls (green triangle) and PSC (red diamonds). Results are displayed at a threshold of p < 0.01 (uncorrected). a.u.: arbitrary units. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Fig. 5

Effect of identity of the second player. The top left panel depicts areas where controls show increased activations when the second player is a human partner compared to a computer. The lower left panel indicates that this effect is weaker in PSCs, resulting in a positive interaction in both areas. The two right panels depict the signal change in both areas when partner and computer conditions are compared (co-ordinates are in MNI space). In both areas, PSCs have reduced activations when the second player is a companion. Error bars indicate 90% confidence intervals. Results are displayed at a level of p < 0.01 (uncorrected) for visualisation purposes. dACC: dorsal anterior cingulate cortex; dmPFC: dorso-medial prefrontal cortex; a.u.: arbitrary units.