Article

Irritability in pre-clinical Huntington's disease

Department of Psychiatry and Psychotherapy, Freiburg Brain Imaging, University Clinic Freiburg, Freiburg, Germany.
Neuropsychologia (Impact Factor: 3.45). 10/2009; 48(2):549-57. DOI: 10.1016/j.neuropsychologia.2009.10.016
Source: PubMed

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.

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    • "Depressive symptoms have been related to increased activity in the ventromedial prefrontal cortex (Unschuld et al., 2012). Irritability is associated with orbitofrontal circuit dysfunction, which leads to decreased control over emotional responses in the amygdala (Klöppel et al., 2010). Other, less commonly observed psychiatric symptoms and disorders in HD are anxiety, obsessive-compulsive disorder, mania, schizophrenia-like psychotic symptoms, such as paranoia, hallucinations , and delusions (Caine and Shoulson, 1983; Folstein and Folstein, 1983; Craufurd et al., 2001; Kirkwood et al., 2001; van Duijn et al., 2007). "
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