The relationship between disease-specific psychosocial stressors and depressive symptoms in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disease involving motor abnormalities, cognitive decline, and psychological difficulties. Depression is among the most common psychological difficulties in HD. People with HD encounter numerous stressors related to their diagnosis and the impact of HD on their daily lives. Understanding the relationship between HD-specific psychosocial stressors and depression symptoms is critical for optimising treatment and developing a holistic, disease-specific model of depression in HD. METHODS: Fifty-seven adults with the HD gene expansion (33 pre-symptomatic, 24 symptomatic) completed a self-report depression questionnaire and rated how much stress they experienced in relation to 20 psychosocial challenges commonly associated with HD. We examined associations between depression symptoms and each stressor individually, and after clustering using principal components analysis. RESULTS: Depression symptoms were significantly associated with most of the psychosocial stressors assessed. Clustering with principal components analysis revealed that higher depression scores had significant independent associations with greater stress related to the future implications of HD (ß = .44, p = .001) and sleep and psychological difficulties (ß = .28, p = .005), but not with stress related to functional limitations (ß = .11, p = .33) or interpersonal issues caused by HD (ß = .15, p = .21). CONCLUSIONS: Stressful experiences associated with HD constitute an important risk factor for depression in HD. Our findings support the use of more psychologically informed models of depression in HD and necessitate further research on tailored psychosocial interventions for HD patients with depression.

A pilot evaluation of an 8-week mindfulness-based stress reduction program for people with pre-symptomatic Huntington's disease.

People with Huntington's disease (HD) face difficult emotional and practical challenges throughout their illness, including in the pre-symptomatic stage. There are, however, extremely limited psychosocial interventions adapted to or researched for HD. We adapted and piloted an 8-week mindfulness-based stress reduction (MBSR) program in people with pre-symptomatic HD to determine if the program (i) was feasible and acceptable to participants, (ii) resulted in increased mindfulness understanding and skills, and (iii) led to improved psychological adjustment. Quantitative measures of mindfulness, emotion regulation, mood, and quality of life were administered pre and post the MBSR program and at 3-month follow-up. Measures of mindfulness practice and session clarity were administered weekly. Qualitative participant feedback was collected with a post-program interview conducted by independent clinicians. Seven participants completed the 8-week course. The program's feasibility and acceptability was supported by excellent retention and participation rates and acceptable rates of home practice completion. In addition, qualitative feedback indicated participant satisfaction with the program structure and content. Two core mindfulness skills (observing and non-judgment) showed significant improvement from pre- to post-assessment. Participant qualitative feedback indicated increased confidence and capacity to use mindfulness techniques, particularly in emotionally challenging situations. Participant questionnaire data showed good psychological adjustment at baseline, which did not change after treatment. Psychological benefits of the program identified in qualitative data included fewer ruminations about HD, reduced isolation and stigma, and being seen by others as calmer. These findings justify expansion of the program to determine its efficacy in a larger, controlled study.

Subjective sleep problems in Huntington's disease: A pilot investigation of the relationship to brain structure, neurocognitive, and neuropsychiatric function.

Subjective reports of sleep disturbance are a common feature of Huntington's disease (HD); however, there is limited research investigating the relationship between sleep problems with changes in brain and behaviour. This study aimed to investigate whether subjective reports of sleep problems in HD are associated with brain volume, neurocognitive decline, and neuropsychiatric symptoms. This retrospective pilot study used brain volume, neurocognitive and neuropsychiatric data from premanifest (pre-HD) and symptomatic HD (symp-HD). Subjective sleep problem was measured using the sleep item of the Beck's Depression Inventory-II (BDI-II). Pre-HD individuals reporting sleep problems had significantly poorer neuropsychiatric outcomes compared to those not reporting sleep problems. In the symp-HD group, those with sleep problems had significantly accelerated thalamic degeneration and poorer neuropsychiatric outcomes compared to those without sleep problems. There was no relationship between subjective sleep problems and neurocognitive measures. These findings suggest an association between subjective sleep disturbance, neuropathology, and development of neuropsychiatric symptoms in HD. Further studies using quantitative EEG-based monitoring of sleep in HD and changes in the brain and behaviour will be necessary to establish the causal nature of this relationship.

Selective vulnerability of Rich Club brain regions is an organizational principle of structural connectivity loss in Huntington's disease.

Huntington's disease can be predicted many years before symptom onset, and thus makes an ideal model for studying the earliest mechanisms of neurodegeneration. Diffuse patterns of structural connectivity loss occur in the basal ganglia and cortex early in the disease. However, the organizational principles that underlie these changes are unclear. By understanding such principles we can gain insight into the link between the cellular pathology caused by mutant huntingtin and its downstream effect at the macroscopic level. The 'rich club' is a pattern of organization established in healthy human brains, where specific hub 'rich club' brain regions are more highly connected to each other than other brain regions. We hypothesized that selective loss of rich club connectivity might represent an organizing principle underlying the distributed pattern of structural connectivity loss seen in Huntington's disease. To test this hypothesis we performed diffusion tractography and graph theoretical analysis in a pseudo-longitudinal study of 50 premanifest and 38 manifest Huntington's disease participants compared with 47 healthy controls. Consistent with our hypothesis we found that structural connectivity loss selectively affected rich club brain regions in premanifest and manifest Huntington's disease participants compared with controls. We found progressive network changes across controls, premanifest Huntington's disease and manifest Huntington's disease characterized by increased network segregation in the premanifest stage and loss of network integration in manifest disease. These regional and whole brain network differences were highly correlated with cognitive and motor deficits suggesting they have pathophysiological relevance. We also observed greater reductions in the connectivity of brain regions that have higher network traffic and lower clustering of neighbouring regions. This provides a potential mechanism that results in a characteristic pattern of structural connectivity loss targeting highly connected brain regions with high network traffic and low clustering of neighbouring regions. Our findings highlight the role of the rich club as a substrate for the structural connectivity loss seen in Huntington's disease and have broader implications for understanding the connection between molecular and systems level pathology in neurodegenerative disease.

Volumetric analysis of the hypothalamus in Huntington Disease using 3T MRI: the IMAGE-HD Study.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Non-motor symptoms and signs such as psychiatric disturbances, sleep problems and metabolic dysfunction are part of the disease manifestation. These aspects may relate to changes in the hypothalamus, an area of the brain involved in the regulation of emotion, sleep and metabolism. Neuropathological and imaging studies using both voxel-based morphometry (VBM) of magnetic resonance imaging (MRI) as well as positron emission tomography (PET) have demonstrated pathological changes in the hypothalamic region during early stages in symptomatic HD. In this investigation, we aimed to establish a robust method for measurements of the hypothalamic volume in MRI in order to determine whether the hypothalamic dysfunction in HD is associated with the volume of this region. Using T1-weighted imaging, we describe a reproducible delineation procedure to estimate the hypothalamic volume which was based on the same landmarks used in histologically processed postmortem hypothalamic tissue. Participants included 36 prodromal HD (pre-HD), 33 symptomatic HD (symp-HD) and 33 control participants who underwent MRI scanning at baseline and 18 months follow-up as part of the IMAGE-HD study. We found no evidence of cross-sectional or longitudinal changes between groups in hypothalamic volume. Our results suggest that hypothalamic pathology in HD is not associated with volume changes.

Evidence for sex differences in the loudness dependence of the auditory evoked potential in humans.

OBJECTIVE: The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a marker of the serotonin system, although studies directly examining the relationship between acute changes in serotonin and the LDAEP have been inconsistent. Given the reported sex dichotomy in serotonin neurotransmission, this study examined if there are sex differences in the LDAEP. METHODS: Data from 65 healthy participants from four independent studies were pooled, and their N1/P2 slopes were quantified. RESULTS: Mean N1/P2 slopes for female participants were higher than those for male participants (p < 0.0001). CONCLUSION: These findings suggest that the LDAEP is modulated by sex potentially because of differences in serotonergic neurotransmission, and these differences may account for some of the inconsistent findings linking serotonin function and LDAEP.