Highlights from the Journal of Huntington’s Disease

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By: Govinda Poudel, PhD and Nellie Georgiou-Karistianis, PhD on behalf of the IMAGE-HD study team

Neuropsychiatric disturbances in HD can appear before clinical diagnosis, and usually become worse with disease progression. The most commonly reported neuropsychiatric symptoms are obsessions and compulsions, irritability, apathy, depression, and anxiety. These symptoms contribute to reduced brain function, disability, and impaired quality of life.

Measurement of brain activity using functional magnetic resonance imaging (fMRI) is an important tool to investigate altered brain activity, and offers avenues for new discoveries. In particular, fMRI can be used to investigate whether any functional disruptions in brain circuits are associated with the development and severity of neuropsychiatric disturbances in HD.

Figure: Association between fMRI activity in the right DLPF and SCOPI OCD scores in Pre-HD far from onset, close to onset, and healthy controls.
Figure: Association between fMRI activity in the right DLPF and SCOPI OCD scores in Pre-HD far from onset, close to onset, and healthy controls.

We aimed to investigate whether functional brain responses during the performance of a working memory task were associated with neuropsychiatric disturbances during the presymptomatic stages of HD. We used fMRI and neuropsychiatric data acquired from the IMAGE-HD study, and focused our analysis on 35 presymptomatic HD gene carriers (18 far from onset, 17 close to onset) and 32 healthy controls. Data from a battery of neuropsychiatric tests included measures of obsessions, compulsions, and pathological impulse (SCOPI); the frontal systems dysfunction (FrSBE); and anxiety and depression (BDI and HADS). fMRI activity was measured during an N-BACK working memory task with baseline (0-BACK) and two load levels (1- and 2-BACK). Participants who performed below 70% accuracy on the low-load (1-BACK only) task were excluded to ensure that all included participants had understood task instructions and had been sufficiently motivated to perform the task. Given the important role of frontal cortical areas in working memory function, and their known association in several neuropsychiatric disorders, we used the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) as brain targets for further investigations of the interplay between the neuropsychiatric disturbance in pre-HD and the fMRI response during working memory. We performed partial correlations between average fMRI activity in each brain region of interest, and scores on each neuropsychiatric inventory (including subscales), controlling for age, gender, and accuracy.

We found that in individuals close to predicted HD onset, increased symptoms of obsessions and compulsions are associated with decreased neural activity during working memory in the right DLPFC and ACC (see Figure.) Increased symptoms of depression and anxiety, in particular, are associated with reduced neural activity during 2-BACK working memory load.

While these findings are correlational in nature, they nevertheless support the association between the development of neuropsychiatric symptoms and impaired brain function during cognitive tasks in HD. The association between neuropsychiatric function and brain activity is more readily detectable during higher (and more challenging) working memory loads, and becomes more pronounced as individuals approach onset of clinical symptoms of HD. Fresh insights into such brain mechanisms may open up new avenues for biomarker and treatment options for neuropsychiatric impairments in HD. Importantly, more research is needed to identify whether neuropsychiatric symptoms accelerate progression to symptomatic HD.

Original Article: Poudel GR, Shannon D, Domínguez D FJ, Stout JC, Churchyard A, Chua P, Egan GF, and Georgiou-Karistianis N. Functional brain correlates of neuropsychiatric symptoms in presymptomatic Huntington’s disease: The IMAGE-HD study. J Huntingtons Dis. 2015 Dec 27;4(4):325-32. doi: 10.3233/JHD-150154

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