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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    ABSTRACT: Huntington's disease (HD) is a genetic, neurodegenerative disorder, which specifically affects striatal neurons of the indirect pathway, resulting in a progressive decline in muscle coordination and loss of emotional and cognitive control. Interestingly, predisposition to pathological gambling and other addictions involves disturbances in the same cortico-striatal circuits that are affected in HD, and display similar disinhibition-related symptoms, including changed sensitivity to punishments and rewards, impulsivity, and inability to consider long-term advantages over short-term rewards. Both HD patients and pathological gamblers also show similar performance deficits on risky decision-making tasks, such as the Iowa Gambling Task (IGT). These similarities suggest that HD patients are a likely risk group for gambling problems. However, such problems have only incidentally been observed in HD patients. In this review, we aim to characterize the risk of pathological gambling in HD, as well as the underlying neurobiological mechanisms. Especially with the current rise of easily accessible Internet gambling opportunities, it is important to understand these risks and provide appropriate patient support accordingly. Based on neuropathological and behavioral findings, we propose that HD patients may not have an increased tendency to seek risks and start gambling, but that they do have an increased chance of developing an addiction once they engage in gambling activities. Therefore, current and future developments of Internet gambling possibilities and related addictions should be regarded with care, especially for vulnerable groups like HD patients.
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