Irritability in pre-clinical Huntington's disease

Department of Psychiatry and Psychotherapy, Freiburg Brain Imaging, University Clinic Freiburg, Freiburg, Germany.
Neuropsychologia (Impact Factor: 3.3). 10/2009; 48(2):549-57. DOI: 10.1016/j.neuropsychologia.2009.10.016
Source: PubMed


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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    • "There is also evidence of reduced structural connectivity in frontal regions in a depressed HD group [23] and decreased prefrontal activity related to increased depression scores and reduced cognitive performance in premanifest-HD [16]. Likewise, increased irritability, has been associated with reduced amygdala activity and connectivity between brain regions involved in emotion processing and regulation [24], while apathy levels correlate with reduced structural connectivity in the rectus gyrus [25]. However , despite these findings, neurobiological evidence for neuropsychiatric symptoms in HD is both mixed and limited. "
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    ABSTRACT: Background: Neuropsychiatric symptoms in Huntington's disease (HD) are often evident prior to clinical diagnosis. Apathy is highly correlated with disease progression, while depression and irritability occur at different stages of the disease, both before and after clinical onset. Little is understood about the neural bases of these neuropsychiatric symptoms and to what extent those neural bases are analogous to neuropsychiatric disorders in the general population. Objective: We used Diffusion Tensor Imaging (DTI) to investigate structural connectivity between brain regions and any putative microstructural changes associated with depression, apathy and irritability in HD. Methods: DTI data were collected from 39 premanifest and 45 early-HD participants in the TrackHD study and analysed using whole-brain Tract-Based Spatial Statistics. We used regression analyses to identify white matter tracts whose structural integrity (as measured by fractional anisotropy, FA) was correlated with HADS-depression, PBA-apathy or PBA-irritability scores in gene-carriers and related to cumulative probability to onset (CPO). Results: For those with the highest CPO, we found significant correlations between depression scores and reduced FA in the splenium of the corpus callosum. In contrast, those with lowest CPO demonstrated significant correlations between irritability scores and widespread FA reductions. There was no significant relationship between apathy and FA throughout the whole brain. Conclusions: We demonstrate that white matter changes associated with both depression and irritability in HD occur at different stages of disease progression concomitant with their clinical presentation.
    Journal of Huntington's disease 09/2015; 4(3):239-249. DOI:10.3233/JHD-150160
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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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    • "HD is observed in individuals with more than 39 CAG repeats, and it develops through a triad of complex symptoms. Motor impairment and chorea characterize HD pathology, together with weight loss, deficits in cognitive function and psychiatric symptoms [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. The latter include anxiety and depression [2], [3], [4], [5], [6], [7], [8], altered social behaviors and communication [3], [7], deficits in prepulse inhibition of the acoustic startle response (PPI) [8], and abnormalities in sleep/activity patterns [12], [14], [15], [16]. "
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