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Imagination is an adaptive ability that can be directed toward the pursuit of personal goals. Although there is a wealth of research on goals and on imagination, few studies lie at the intersection—little is known about individual differences in goal-directed imagination. In 153 adults, we examined how 28 aspects of goal setting, pursuit, and goal-directed imagination relate to mental health. Higher well-being and lower depressive symptoms were strongly linked (a) to having goals that were more attainable, under control, and expected to bring more joy and (b) to goal-directed imagination that was clearer, more detailed, more positive, and less negative. Importantly, the emotional valence of goal-directed imagination strongly predicted well-being at a 2-month follow-up even after controlling for mental health at baseline. These findings underscore the relevance of goal-directed imagination to well-being and depressive symptoms and highlight potential targets for goal- and imagery-based interventions to improve mental health.

Objective: This study investigated whether previously identified modifiable risk factors for dementia were associated with cognitive change in Māori (indigenous people of New Zealand) and non-Māori octogenarians of LiLACS NZ (Life and Living in Advanced Age; a Cohort Study in New Zealand), a longitudinal study. Method: Multivariable repeated-measure mixed effect regression models were used to assess the association between modifiable risk factors and sociodemographic variables at baseline, and cognitive change over 6 years, with p values of Results: Modifiable factors associated with cognitive change differed between ethnic groups. Depression was a negative factor in Māori only, secondary education in non-Māori was protective, and obesity predicted better cognition over time for Māori. Diabetes was associated with decreased cognition for both Māori and non-Māori. Conclusion: Our results begin to address gaps in the literature and increase understanding of disparities in dementia risk by ethnicity. These findings have implications for evaluating the type and application of culturally appropriate methods to improve cognition.

Huntington’s disease (HD) is caused by a CAG repeat expansion mutation in the gene encoding the huntingtin (Htt) protein, with mutant Htt protein subsequently forming aggregates within the brain. Mutant Htt is a current target for novel therapeutic strategies for HD, however, the lack of translation from preclinical research to disease-modifying treatments highlights the need to improve our understanding of the role of Htt protein in the human brain. This study aims to undertake a high-throughput screen of 12 candidate antibodies against various sequences along the Htt protein to characterize Htt distribution and expression in post-mortem human brain tissue microarrays (TMAs).Immunohistochemistry was performed on middle temporal gyrus TMAs comprising of up to 28 HD and 27 age-matched control cases, using 12 antibodies specific to various sequences along the Htt protein. From this study, six antibodies directed to the Htt N-terminus successfully immunolabelled human brain tissue. The Htt aggregates and Htt protein expression levels for the six successful antibodies were subsequently quantified with high-throughput analysis. Htt aggregates were detected in HD cases using antibodies MAB5374, MW1, and EPR5526, despite no change in overall Htt protein expression compared to control cases, suggesting a redistribution of Htt into aggregates in HD. Significant associations were found between the number of Htt aggregates and both age of disease onset, and CAG repeat length in HD. However, the number of Htt aggregates did not correlate with the degree of striatal degeneration or the degree of cortical neuron loss. Together, these results suggest that longer CAG repeat lengths correlate with Htt aggregation in the HD human brain, and Htt cortical aggregate deposition is associated with the onset of clinical symptoms. This study also reinforces that antibodies MAB5492, MW8, and 2B7 which have been utilized to characterize Htt in animal models of HD are not specific for Htt in human brain tissue, thereby highlighting the need for validated means of Htt detection to support drug development for HD.

Individualised predictive models of cognitive decline require disease-monitoring markers that are repeatable. For wide-spread adoption, such markers also need to be reproducible at different locations. This study assessed the repeatability and reproducibility of MRI markers derived from a dementia protocol.Six participants were scanned at three different sites with a 3T MRI scanner. The protocol employed: T1-weighted (T1w) imaging, resting state functional MRI (rsfMRI), arterial spin labelling (ASL), diffusion-weighted imaging (DWI), T2-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted (T2w) imaging, and susceptibility weighted imaging (SWI). Participants were scanned repeatedly, up to six times over a maximum period of five years. One participant was also scanned a further three times on sequential days on one scanner. Fifteen derived metrics were computed from the seven different modalities.Reproducibility (coefficient of variation; CoV, across sites) was best for T1w derived grey matter, white matter and hippocampal volume (CoV 1.5%), compared to rsfMRI and SWI derived metrics (CoV, 19% and 21%). For a given metric, long-term repeatability (CoV across time) was comparable to reproducibility, with short-term repeatability considerably better.Reproducibility and repeatability were assessed for a suite of markers calculated from a dementia MRI protocol. In general, structural markers were less variable than functional MRI markers. Variability over time on the same scanner was comparable to variability measured across different scanners. Overall, the results support the viability of multi-site longitudinal studies for monitoring cognitive decline.

Fetal Alcohol Spectrum Disorder (FASD) is one of the leading causes of intellectual disability and learning difficulties around the world. Children with FASD often have extremely low adaptive behavior due to the severity of brain impairment, however there is limited understanding as to the important predictors of adaptive behavior. In a study of 39 children with FASD and 29 comparison children, we found that social cognition (specifically recognizing emotions) was the only significant independent predictor of teacher-rated adaptive functioning even after including IQ, executive functioning, and adverse childhood experiences into the model. In this current study, Māori (Indigenous people of Aotearoa New Zealand) were overrepresented; therefore, the research was supported by a strong partnership with Te Wāhanga Hauora Māori (Māori Health Service). Aotearoa New Zealand's colonized history is recognized and findings are discussed with regard to both the psychological literature and a Te Ao Māori worldview.

Background Depression is a common problem in older adults. The 15-item Geriatric Depression Scale (GDS-15) is a widely used psychometric tool for measuring depression in the elderly, but its psychometric properties have not been yet rigorously investigated. The aim was to evaluate psychometric properties of the GDS-15 and improve precision of the instrument by applying Rasch analysis and deriving conversion tables for transformation of raw scores into interval level data. Methods The data was extracted from the prospective cohort Sydney Memory and Ageing Study of initially not demented individuals aged 70 years and older. The GDS-15 items scores of 212 participants (47.2% males) were analysed using the dichotomous Rasch model. Results Initially poor reliability of the GDS-15, Person Separation Index (PSI) = 0.68, was improved by combining locally dependent items into seven super-items. These modifications improved reliability of the GDS-15 (PSI = 0.78) and resulted in the best Rasch model fit (χ2(28)=37.72, p = =0.104), strict unidimensionality and scale invariance across personal factors such as gender, diagnostic and language background. Limitations Presence of participants with cognitive impairment may be a potential limitation. Conclusions Reliability and psychometric characteristics of the GDS-15 were improved by minor modifications and now satisfy expectations of the unidimensional Rasch model. By using Rasch transformation tables published here psychiatrists, psychologists and researchers can transform GDS raw scores into interval-level data, which improves reliability of the GDS-15 without the need to modify its original response format. These findings increase accuracy of clinical psychometric assessments, leading to more precise diagnosis of depression in the elderly.

Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging (MRI) reflects cerebral perfusion, related to metabolism, and arterial transit time (ATT), related to vascular health. Our aim was to investigate the spatial coefficient of variation (sCoV) of CBF maps as a surrogate for ATT, in volunteers meeting criteria for subjective cognitive decline (SCD), amnestic mild cognitive impairment (MCI) and probable Alzheimer’s dementia (AD). Whole-brain pseudo continuous ASL MRI was performed at 3 T in 122 participants (controls = 20, SCD = 44, MCI = 45 and AD = 13) across three sites in New Zealand. From CBF maps that included all grey matter, sCoV progressively increased across each group with increased cognitive deficit. A similar overall trend was found when examining sCoV solely in the temporal lobe. We conclude that sCoV, a simple to compute imaging metric derived from ASL MRI, is sensitive to varying degrees of cognitive changes and supports the view that vascular health contributes to cognitive decline associated with Alzheimer’s disease.

Objective Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by variable motor and behavioral symptoms attributed to major neuropathology of mainly the basal ganglia and cerebral cortex. The role of the cerebellum, a brain region involved in the coordination of movements, in HD neuropathology has been controversial. This study utilizes postmortem human brain tissue to investigate whether Purkinje cell degeneration in the neocerebellum is present in HD, and how this relates to disease symptom profiles. Methods Unbiased stereological counting methods were used to quantify the total number of Purkinje cells in 15 HD cases and 8 neurologically normal control cases. Based on their predominant symptoms, the HD cases were categorized into 2 groups: "motor" or "mood." Results The results demonstrated a significant 43% loss of Purkinje cells in HD cases with predominantly motor symptoms, and no cell loss in cases showing a major mood phenotype. There was no significant correlation between Purkinje cell loss and striatal neuropathological grade, postmortem delay, CAG repeat in the IT15 gene, or age at death. Interpretation This study shows a compelling relationship between Purkinje cell loss in the HD neocerebellum and the HD motor symptom phenotype, which, together with our previous human brain studies on the same HD cases, provides novel perspectives interrelating and correlating the variable cerebellar, basal ganglia, and neocortical neuropathology with the variability of motor/mood symptom profiles in the human HD brain. ANN NEUROL 2019;85:396-405.

Introduction We assessed the sensitivity and specificity of the Modified Mini–Mental State Examination (3MS) in predicting dementia and cognitive impairment in Māori (indigenous people of New Zealand) and non-Māori octogenarians. Methods A subsample of participants from Life and Living in Advanced Age: a Cohort Study in New Zealand were recruited to determine the 3MS diagnostic accuracy compared with the reference standard. Results Seventy-three participants (44% Māori) completed the 3MS and reference standard assessments. The 3MS demonstrated strong diagnostic accuracy to detect dementia with areas under the curve of 0.87 for Māori and 0.9 for non-Māori. Our cutoffs displayed ethnic variability and are approximately 5 points greater than those commonly applied. Cognitive impairment yielded low accuracy, and discriminatory power was not established. Discussion Cutoffs that are not age or ethnically appropriate may compromise the accuracy of cognitive screens. Consequently, older age and indigeneity increase the risk of mislabeled cognitive status., Highlights • The cutoffs between Māori and non-Māori octogenarians differed. • Dementia versus no dementia had good discriminant validity. • Applying the typical cutoff would likely lead to misclassification of cognitive function.

Visual orienting was studied in a patient (FM) with parietal-occipital damage due to oligodendroglioma and associated surgery, and in eighteen control participants. The ability of FM and control participants to shift attention in response to spatial landmark cues, and in response to cues that recruit endogenous orienting via encoding of cue identity, were assessed. According to the unified model of vision and attention (Lambert, A. et al., Journal of Experimental Psychology: Human PerceptionPerformance, 44, 412-432) FM should find it difficult to orient attention in response to spatial landmarks due to impaired functioning of the dorsal visual stream; but shifting attention in response to cue identity, encoded via the ventral visual stream, should be spared. Consistent with these predictions, FM was unable to shift attention in the landmark cueing task, but shifted attention effectively in response to identity cues; and her visual orienting performance differed reliably from controls. These findings complement our earlier observation of preserved orienting towards landmark cues in a patient with bilateral damage to the ventral visual stream, and add to a growing body of evidence in support of the unified model of vision and attention.

Background: The onset and progression of dementia can result in changes in the subjective experience of self, impacting on psychological health. Objective: We aimed to explore the extent to which people with mild-to-moderate dementia experience discontinuity in the subjective experience of self, and the factors associated with this experience for people with dementia and their family caregivers. Methods: We used data from the baseline assessment of the IDEAL cohort. Discontinuity in the subjective experience of self was assessed by asking participants about their agreement with the statement ‘I feel I am the same person that I have always been’. Participants were divided into those who did and did not experience discontinuity, and the two groups were compared in terms of demographic and disease-related characteristics, psychological well-being, measures of ‘living well’, and caregiver stress. Results: Responses to the continuity question were available for 1,465 participants with dementia, of whom 312 (21%) reported experiencing discontinuity. The discontinuity group experienced significantly poorer psychological well-being and had significantly lower scores on measures of ‘living well’. There was no clear association with demographic or disease-related characteristics, but some indication of increased caregiver stress. Conclusion: A significant proportion of people with mild-to-moderate dementia describe experiencing discontinuity in the subjective sense of self, and this is associated with poorer psychological health and reduced ability to ‘live well’ with the condition. Sensitively asking individuals with dementia about the subjective experience of self may offer a simple means of identifying individuals who are at increased risk of poor well-being.

Both short and long-term video-game play may result in superior performance on visual and attentional tasks. To further these findings, we compared the performance of experienced male video-game players (VGPs) and non-VGPs on a Simon-task. Experienced-VGPs began playing before the age of 10, had a minimum of 8 years of experience and a minimum play time of over 20 h per week over the past 6 months. Our results reveal a significantly reduced Simon-effect in experienced-VGPs relative to non-VGPs. However, this was true only for the right-responses, which typically show a greater Simon-effect than left-responses. In addition, experienced-VGPs demonstrated significantly quicker reaction times and more balanced left-versus-right-hand performance than non-VGPs. Our results suggest that experienced-VGPs can resolve response-selection conflicts more rapidly for right-responses than non-VGPs, and this may in part be underpinned by improved bimanual motor control.

Introduction: To estimate the cognitive-load of self-reported physical and cognitive activities by New Zealand’s (NZ) indigenous population (Māori) and non‑Māori from the Life and Living in Advanced Age‑Cohort Study New Zealand (LiLACS NZ). Methods: Three-round panel Delphi exercise in NZ involving six panellists across an expert rater group and a peer-rater agroup of Māori and non‑Māori respectively, via web-based and face‑to‑face discussion. Results: In Round i (pre-Delphi exercise) the investigator group, gathered and categorised data from LiLACS NZ and developed a 9-point Likert-scale to rate the cognitive-load. Round ii panellists each rated the cognitive‑load of each activity. If a priori specified criteria were not met, then round iii involved a face‑to‑face meeting to discuss and re-rate activities on which consensus was lacking. Conclusions: Māori reached consensus in round ii while non‑Māori did so in round iii. Panellists provided a formal consensus-based cognitive-load rating for 181 activities separately for Māori and non‑Māori. Keywords: three to five keywords: Delphi Technique, physical activity, ageing, cognitive activity

Reduced specificity of autobiographical memory has been well established in depression, but whether this overgenerality extends to future thinking has not been the focus of a meta-analysis. Following a preregistered protocol, we searched six electronic databases, Google Scholar, and personal libraries and contacted authors in the field for studies matching search terms related to depression, future thinking, and specificity. We reduced an initial 7,332 results to 46 included studies, with 89 effect sizes and 4,813 total participants. Random-effects meta-analytic modeling revealed a small but robust correlation between reduced future specificity and higher levels of depression ( r = −.13, p < .001). Of the 11 moderator variables examined, the most striking effects were related to the emotional valence of future thinking ( p < .001) and the sex of participants ( p = .025). Namely, depression was linked to reduced specificity for positive (but not negative or neutral) future thinking, and the relationship was stronger in samples with a higher proportion of males. This meta-analysis contributes to our understanding of how prospection is altered in depression and dysphoria and, by revealing areas where current evidence is inconclusive, highlights key avenues for future research.

Task-related functional connectivity (fc-MRI) indexes the interaction of brain regions during cognitive tasks. Two general classes of methods exist to investigate fc-MRI: the most widely-used method calculates temporal correlations between voxels/regions within subjects, and then determines if within-subject correlations are reliable across subjects (ws-fcMRI); the other calculates the average (BOLD) signal within voxels/regions and then performs correlations across subjects (as-fcMRI). That is, while both methods rely on correlational techniques, the level at which correlations are calculated is fundamentally different. While conceptually distinct, it is not known how well these two methods of fc-MRI analyses converge on the same findings. The current study addresses this question across a number of analyses. First, using default-mode network regions as seeds, we show that as-fcMRI does not strongly predict ws-fcMRI during episodic simulation tasks. Next, we show that the relationship between as-fcMRI and ws-fcMRI is contingent on whether correlations are calculated between regions from the same functional network (default mode or dorsal attention networks) or between regions from different functional networks. Lastly, we compare seed partial least squares (PLS) - a well-established as-fcMRI method - with a novel version of seed PLS that combines the multivariate approach of PLS analyses and within-subject correlations. The results showed that while many regions exhibited congruent as-fcMRI and ws-fcMRI effects, in some regions the two analyses produced effects in opposite directions. Results are discussed in relation to the Simpson's Paradox, a phenomenon in which across-subject correlations are reversed within individuals present in a sample. Overall, our results suggest that the findings of as-fcMRI do not always map onto those from ws-fcMRI. We end by discussing the advantages associated with using ws-fcMRI to assess the task-related interactions between brain regions.

Objective Numerous studies have focused on striatal neurodegeneration in Huntington disease (HD). In comparison, the globus pallidus (GP), a main striatal output nucleus, has received less focus in HD research. This study characterizes the pattern of neurodegeneration in 3 subdivisions of the human GP, and its relation to clinical symptomatology. Methods Stereology was used to measure regional atrophy, neuronal loss, and soma neuronal atrophy in 3 components of the GP-the external segment (GPe), internal segment (GPi), and ventral pallidum (VP)-in 8 HD cases compared with 7 matched control cases. The findings in the HD patients were compared with HD striatal neuropathological grade, and symptom scores of motor impairment, chorea, cognition, and mood. Results Relative to controls, in the HD patients the GPe showed a 54% overall volume decline, 60% neuron loss, and 34% reduced soma volume. Similarly, the VP was reduced in volume by 31%, with 48% neuron loss and 64% reduced soma volume. In contrast, the GPi was less affected, with a 38% reduction in overall volume only. The extent of GP neurodegeneration correlated with increasing striatal neuropathological grade. Decreasing GPe and VP volumes were associated with poorer cognition and increasing motor impairments, but not chorea. In contrast, decreasing GPi volumes were associated with decreasing levels of irritability. Interpretation The HD gene mutation produces variable degrees of GP segment degeneration, highlighting the differential vulnerability of striato-GP target projections. The relationship established between clinical symptom scores and pallidal degeneration provides a novel contribution to understanding the clinicopathological associations in HD. Ann Neurol 2016;80:185-201.

Introduction: Community knowledge and stroke awareness is crucial for primary prevention of stroke and timely access to stroke treatments including acute reperfusion therapies. We conducted a national telephone survey to quantify the level of community stroke awareness. Methods: A random sample of 400 adults in New Zealand (NZ), stratified by the 4 main ethnic groups, was surveyed. Eligible participants answered stroke awareness questions using both unprompted (open-ended) and prompted questions (using a list). Proportional odds logistic regression models were used to identify factors associated with stroke awareness. Results: Only 1.5% of participants named stroke as a major cause of death. The stroke signs and symptoms most frequently identified from a list were sudden speech difficulty (94%) and sudden 1-sided weakness (92%). Without prompting, 78% of participants correctly identified at least 1 risk factor, 62% identified at least 2, and 35% identified 3 or more. When prompted with the list, scores increased 10-fold compared with unprompted responses. Ethnic disparities were observed, with Pacific peoples having the lowest level of awareness among the 4 ethnic groups. Higher education level, higher income, and personal experience of stroke were predictive of greater awareness (P ≤ .05). Conclusions: Stroke was not recognized as a major cause of death. Although identification of stroke risk factors was high with prompting, awareness was low without prompting, particularly among those with lower education and income. Nationwide, culturally tailored public awareness campaigns are necessary to improve knowledge of stroke risk factors, recognition of stroke in the community and appropriate actions to take in cases of suspected stroke.

Diachronic unity is the belief that, despite changes, we are the same person across the lifespan. We propose that diachronic unity is supported by the experience of remembering the self over time during episodic recall (i.e., phenomenological continuity). However, we also predict that diachronic unity is also possible when episodic memory is impaired, as long as the ability to construct life narratives from semantic memory (i.e., semantic continuity) is intact. To examine this prediction, we investigated diachronic unity in Alzheimer's Disease (AD) and amnestic mild cognitive impairment (aMCI), two conditions characterised by disrupted phenomenological continuity. If semantic continuity is also altered in these conditions, there should be an associated deterioration in diachronic unity. Participants with AD, aMCI, and healthy controls (HC) completed a self-persistence interview measuring diachronic unity (beliefs about self-persistence, explanations for stability/change). Semantic continuity was assessed with a life-story interview measuring autobiographical reasoning (self-event connections), and coherence (temporal/thematic/causal) of narratives. Our results highlight a complex relationship between semantic continuity and diachronic unity and revealed a divergence between two aspects of diachronic unity: AD/aMCI groups did not differ from HC in continuity beliefs, but AD explanations for self-persistence were less sophisticated. Semantic continuity was most impaired in AD: their narratives had fewer self-event connections (vs. HCs) and lower temporal/thematic coherence (vs. HC/aMCI), while both AD/aMCI groups had lower causal coherence. Paradoxically AD participants who scored higher on measures of beliefs in the persistence of the core self, provided less sophisticated explanations for their self-persistence and were less able to explore persistence in their life narratives. These findings support the importance of semantic continuity to diachronic unity, but suggest a more nuanced and multifaceted relationship than originally proposed in our model. In AD, diminished life narratives that retain features of cultural life scripts are sufficient for strong subjective beliefs of self-persistence, but not for sophisticated explanations about persistence. Better semantic continuity, with the ability to weave high-quality life narratives, may scaffold the capacity to understand and explain one's diachronic unity, but this produces less surety about self-persistence.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterised by extensive neuronal loss in the striatum and cerebral cortex, and a triad of clinical symptoms affecting motor, cognitive/behavioural and mood functioning. The mutation causing HD is an expansion of a CAG tract in exon 1 of the HTT gene. This chapter provides a multifaceted overview of the clinical complexity of HD. We explore recent directions in molecular genetics including the identification of loci that are genetic modifiers of HD that could potentially reveal therapeutic targets beyond the HTT gene transcript and protein. The variability of clinical symptomatology in HD is considered alongside recent findings of variability in cellular and neurochemical changes in the striatum and cerebral cortex in human brain. We review evidence from structural neuroimaging methods of progressive changes of striatum, cerebral cortex and white matter in pre-symptomatic and symptomatic HD, with a particular focus on the potential identification of neuroimaging biomarkers that could be used to test promising disease-specific and modifying treatments. Finally we provide an overview of completed clinical trials in HD and future therapeutic developments.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by extensive neuronal loss in the striatum and cerebral cortex, and a triad of clinical symptoms affecting motor, cognitive/behavioural and mood functioning. The mutation causing HD is an expansion of a CAG tract in exon 1 of the HTT gene. This chapter provides a multifaceted overview of the clinical complexity of HD. We explore recent directions in molecular genetics including the identification of loci that are genetic modifiers of HD that could potentially reveal therapeutic targets beyond the HTT gene transcript and protein. The variability of clinical symptomatology in HD is considered alongside recent findings of variability in cellular and neurochemical changes in the striatum and cerebral cortex in human brain. We review evidence from structural neuroimaging methods of progressive changes of striatum, cerebral cortex and white matter in pre-symptomatic and symptomatic HD, with a particular focus on the potential identification of neuroimaging biomarkers that could be used to test promising disease-specific and modifying treatments. Finally we provide an overview of completed clinical trials in HD and future therapeutic developments.

This chapter focuses on the involvement of the cerebral cortex in Huntington disease, with special emphasis on the link between cortical pathology and variable clinical manifestations. Huntington disease is an autosomal-dominant neurodegenerative disorder characterized by involuntary movements and cognitive and psychiatric disturbances. The disease is caused by an expansion of polyglutamine repeats in the N-terminal domain of the huntingtin protein from a genetic mutation in the HTT gene on human chromosome 4. The major pathosis occurs in the brain with profound degeneration in the forebrain regions, namely the striatum and the cerebral cortex. Despite the single gene etiology, there is major variability in the neuropathology, as well as major heterogeneity in the symptom profiles. Recent in vivo imaging and pathological studies have shown that cortical degeneration is related to variable symptomatology. Here, we summarize the recent progress on how cortical degeneration contributes to symptom heterogeneity in Huntington disease.

Twenty-two experienced action video-game players (AVGPs) and 18 non-VGPs were tested on a pen-and-paper line bisection task that was untimed. Typically, right-handers bisect lines 2 % to the left of true centre, a bias thought to reflect the dominance of the right-hemisphere for visuospatial attention. Expertise may affect this bias, with expert musicians showing no bias in line bisection performance. Our results show that experienced-AVGPs also bisect lines with no bias with their right hand and a significantly reduced bias with their left hand compared to non-AVGPs. Bisections by experienced-AVGPs were also more precise than those of non-AVGPs. These findings show the cognitive proficiencies of experienced-AVGPs can generalize beyond computer based tasks, which resemble their training environment.

Objective: The cellular basis of variable symptoms in Huntington disease (HD) is unclear. One important possibility is that degeneration of the interneurons in the cerebral cortex, which play a critical role in modulating cortical output to the basal ganglia, might play a significant role in the development of variable symptomatology in HD. This study aimed to examine whether symptom variability in HD is specifically associated with variable degeneration of cortical interneurons. Methods: We undertook a double-blind study using stereological cell counting methods to quantify the 3 major types of gamma-aminobutyric acidergic interneurons (calbindin-D28k, calretinin, parvalbumin) in 13 HD cases of variable motor/mood symptomatology and 15 matched control cases in the primary motor and anterior cingulate cortices. Results: In the primary motor cortex, there was a significant loss (57% reduction) of only calbindin interneurons (p=0.022) in HD cases dominated by motor symptoms, but no significant interneuron loss in cases with a dominant mood phenotype. In contrast, the anterior cingulate cortex showed a major significant loss in all 3 interneuron populations, with 71% loss of calbindin (p=0.001), 60% loss of calretinin (p=0.001), and 80% loss of parvalbumin interneurons (p=0.005) in HD cases with major mood disorder, and no interneuron loss was observed in cases with major motor dysfunction. Interpretation: These findings suggest that region-specific degeneration of cortical interneurons is a key component in understanding the neural basis of symptom heterogeneity in HD.

Huntington's disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntington's disease cases and 15 controls. The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntington's disease cases. The results also show that neuronal loss in the primary sensory and secondary visual cortices relate to Huntington's disease motor symptom profiles, and neuronal loss across the associational cortices in the frontal, parietal and temporal lobes is related to both Huntington's disease motor and to mood symptom profiles. This finding considerably extends a previous study (Thu et al., Brain, 2010; 133:1094-1110) which showed that neuronal loss in the primary motor cortex was related specifically to the motor symptom profiles while neuronal loss in the anterior cingulate cortex was related specifically to mood symptom profiles. The extent of cortical cell loss in the current study was generally related to the striatal neuropathological grade, but not to CAG repeat length on the HTT gene. Overall our findings show that Huntington's disease is characterized by a heterogeneous pattern of neuronal cell loss across the entire cerebrum which varies with symptom profile.

Although dystonia represents a major source of motor disability in Huntington's disease (HD), its pathophysiology remains unknown. Because recent animal studies indicate that loss of parvalbuminergic (PARV+) striatal interneurons can cause dystonia, we investigated if loss of PARV+ striatal interneurons occurs during human HD progression, and thus might contribute to dystonia in HD. We used immunolabeling to detect PARV+ interneurons in fixed sections, and corrected for disease-related striatal atrophy by expressing PARV+ interneuron counts in ratio to interneurons co-containing somatostatin and neuropeptide Y (whose numbers are unaffected in HD). At all symptomatic HD grades, PARV+ interneurons were reduced to less than 26% of normal abundance in rostral caudate. In putamen rostral to the level of globus pallidus, loss of PARV+ interneurons was more gradual, not dropping off to less than 20% of control until grade 2. Loss of PARV+ interneurons was even more gradual in motor putamen at globus pallidus levels, with no loss at grade 1, and steady grade-wise decline thereafter. A large decrease in striatal PARV+ interneurons, thus, occurs in HD with advancing disease grade, with regional variation in the loss per grade. Given the findings of animal studies and the grade-wise loss of PARV+ striatal interneurons in motor striatum in parallel with the grade-wise appearance and worsening of dystonia, our results raise the possibility that loss of PARV+ striatal interneurons is a contributor to dystonia in HD.

Accurately recognizing the emotional states of others is crucial for successful social interactions and social relationships. Individuals with Parkinson's disease (PD) have shown deficits in emotional recognition abilities although findings have been inconsistent. This study examined recognition of emotions from prosody and from facial emotional expressions with three levels of subtlety, in 30 individuals with PD (without dementia) and 30 control participants. The PD group were impaired on the prosody task, with no differential impairments in specific emotions. PD participants were also impaired at recognizing facial expressions of emotion, with a significant association between how well they could recognize emotions in the two modalities, even after controlling for disease severity. When recognizing facial expressions, the PD group had no difficulty identifying prototypical Ekman and Friesen (1976) emotional faces, but were poorer than controls at recognizing the moderate and difficult levels of subtle expressions. They were differentially impaired at recognizing moderately subtle expressions of disgust and sad expressions at the difficult level. Notably, however, they were impaired at recognizing happy expressions at both levels of subtlety. Furthermore how well PD participants identified happy expressions conveyed by either face or voice was strongly related to accuracy in the other modality. This suggests dysfunction of overlapping components of the circuitry processing happy expressions in PD. This study demonstrates the usefulness of including subtle expressions of emotion, likely to be encountered in everyday life, when assessing recognition of facial expressions.

Age-related changes in neuroplasticity may be central to the cognitive decline associated with healthy ageing. Modulated Long-Term Potentiation (LTP) and Long-Term Depression (LTD) have been repeatedly demonstrated in aged rodents, however the translation to human research has been limited by a scarcity of non-invasive methods for doing so. We have previously demonstrated that, following a block of high frequency presentations of a visual stimulus (referred to as a "visual tetanus"), there is a LTP-like enhancement of the N1b component of the visually evoked potential (VEP) to subsequent low frequency presentations of the same stimulus. The aims of the current study were, firstly, to use this electroencephalography (EEG) paradigm to assess age group differences in neocortical plasticity in humans, and secondly, to expand on the visual LTP paradigm by examining plasticity in another component of the VEP; the P2a. While a young participant group (N=29, age range=19-35) demonstrated the expected LTP-like enhancement of the N1b immediately following the visual tetanus, an older participant group (N=19, age range=68-91) did not. However, both age groups demonstrated a positive shift of the P2a component after repeated presentations of low frequency baseline blocks, which is hypothesized to be an LTD-like shift in the VEP. These results support the rodent literature indicating an age-related shift in threshold for LTP, but a relative preservation of the threshold for LTD. This study not only provides valuable insight into healthy age-related alterations in neocortical plasticity, but is also the first to identify an LTD-like modulation of the VEP in humans.

Background Huntington's disease (HD) is characterised by variable symptoms and neuropathology of the basal ganglia and cortex. Previously, we have shown that the pattern of pyramidal cell loss in 8 different cortical regions correlates with the phenotypic variability in HD. In the primary motor and anterior cingulate cortices, the pattern of interneuron degeneration correlates with pyramidal cell death and variable HD symptom profiles. Objectives This study aimed to examine the pattern of interneuron degeneration in 3 further regions of the HD cortex (primary sensory, superior frontal, superior parietal cortices) to determine whether HD neuropathogenesis was characterised by a general fundamental pattern of cortical interneuron loss, and explore the relationship between cortical interneuron loss with previously determined pyramidal cell loss and clinical heterogeneity. Methods Stereological counting was used to quantify 3 sub-populations of calcium-binding protein containing interneurons in 3 cortical human brain regions of 14 HD and 13 control cases as used in our previous studies (Nana et al., 2014; Kim et al., 2014). The HD cases were grouped according to their predominant symptom profile (“motor”, “mood”, “mixed”). Results The present results demonstrated a heterogeneous loss of interneurons across the 3 cortical regions which, when compared with our previous studies, mirrored the pattern of pyramidal cell loss in the same cortical areas. Most interestingly, the pattern of neuronal loss in these regions correlated with the variable HD symptom profiles. Conclusion The overall findings in our present and previous cortical studies establish a clear correlative pattern of variable cortical neuronal degeneration in HD pathogenesis, which mirrors the heterogeneity of HD symptom phenotypes.

We review recent investigations regarding the relationship between selective neurodegeneration in the human brain and the variability in symptom profiles in Huntington's disease. Huntington's disease is a genetic neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the Huntingtin gene on chromosome 4, encoding a protein called huntingtin. The huntingtin protein is expressed ubiquitously in somatic tissue, however, the major pathology affects the brain with profound degeneration in the striatum and the cerebral cortex. Despite the disease being caused by a single gene, there is a major variability in the neuropathology, as well as major heterogeneity in the symptom profiles observed in Huntington's disease patients. The symptoms may vary throughout the disease course and present as varying degrees of movement disorder, cognitive decline, and mood and behavioral changes. To determine whether there is an anatomical basis underlying symptom variation, recent studies on the post-mortem human brain have shown a relationship between the variable degeneration in the forebrain and the variable symptom profile. In this review, we will summarize the progress relating cell loss in the striatum and cerebral cortex to symptom profile in Huntington's disease.

Numerous studies have focused on striatal neurodegeneration in Huntington disease (HD). In comparison, the globus pallidus (GP), a main striatal output nucleus, has received less focus in HD research. This study characterizes the pattern of neurodegeneration in 3 subdivisions of the human GP, and its relation to clinical symptomatology.Stereology was used to measure regional atrophy, neuronal loss, and soma neuronal atrophy in 3 components of the GP-the external segment (GPe), internal segment (GPi), and ventral pallidum (VP)-in 8 HD cases compared with 7 matched control cases. The findings in the HD patients were compared with HD striatal neuropathological grade, and symptom scores of motor impairment, chorea, cognition, and mood.Relative to controls, in the HD patients the GPe showed a 54% overall volume decline, 60% neuron loss, and 34% reduced soma volume. Similarly, the VP was reduced in volume by 31%, with 48% neuron loss and 64% reduced soma volume. In contrast, the GPi was less affected, with a 38% reduction in overall volume only. The extent of GP neurodegeneration correlated with increasing striatal neuropathological grade. Decreasing GPe and VP volumes were associated with poorer cognition and increasing motor impairments, but not chorea. In contrast, decreasing GPi volumes were associated with decreasing levels of irritability.The HD gene mutation produces variable degrees of GP segment degeneration, highlighting the differential vulnerability of striato-GP target projections. The relationship established between clinical symptom scores and pallidal degeneration provides a novel contribution to understanding the clinicopathological associations in HD. Ann Neurol 2016;80:185-201.

Previous neuroimaging research has shown that the cerebellum is often activated during autobiographical memory (AM) retrieval. However, the reliability of that activation, its localization within the cerebellum, and its relationship to other areas of the AM network remains unknown. The current study used Activation Likelihood Estimation meta-analysis (ALE) as well as resting-state and task-related functional connectivity analyses to better characterize cerebellar activation in relation to AM. The ALE meta-analysis was run on 32 neuroimaging studies of AM retrieval. The results revealed a cluster of reliable AM-related activity within the Crus I lobule of the right posterior cerebellum. Using the peak ALE coordinate within Crus I as a seed region, both task-related and resting state functional connectivity analyses were run on fMRI data from 38 healthy participants. To determine the specificity of connectivity patterns to Crus I, we also included a cerebellar seed region in right Lobule VI previously identified in an ALE meta-analysis as associated with working memory. Resting-state functional connectivity analyses indicated that Crus I was intrinsically connected with other areas of the AM network as well as surrounding and contralateral cerebellar regions. In contrast, the Lobule VI seed was functionally connected with cerebral and cerebellar regions typically associated with working memory. The task-related connectivity analyses revealed a similar pattern, where the Crus I seed exhibited significant connectivity with key nodes of the AM network while the Lobule IV seed did not. During a semantic control task, both Crus I and Lobule VI showed significant correlations with a network of regions that was largely distinct from the AM network. Together these results indicate that right Crus I lobule is reliably engaged during AM retrieval and is functionally connected to the AM network both during rest, and more importantly, during AM retrieval.

there is debate about the extent of overlap between music and language processing in the brain and whether these processes are functionally independent in expert musicians. A language comprehension task and a visuospatial search task were administered to 36 expert musicians and 36 matched nonmusicians in conditions of silence and piano music played correctly and incorrectly. Musicians performed more poorly on the language comprehension task in the presence of background music compared to silence, but there was no effect of background music on the musicians' performance on the visuospatial task. In contrast, the performance of nonmusicians was not affected by music on either task. The findings challenge the view that music and language are functionally independent in expert musicians, and instead suggest that when musicians process music they recruit a network that overlaps with the network used in language processing. Additionally, musicians outperformed nonmusicians on both tasks, reflecting either a general cognitive advantage in musicians or enhancement of more specific cognitive abilities such as processing speed or executive functioning.

Increases in cell proliferation in the hippocampus have been robustly demonstrated in animal models of neurodegenerative diseases like Huntington's disease (HD). However, in the subventricular zone, animal models of HD have demonstrated no change in cell proliferation compared to wild types, while in humans there is a distinct increase in cell proliferation in HD cases. Interestingly, there have been no reports on cell proliferation in the human subgranular zone (SGZ) of the hippocampus in HD, despite numerous transgenic mouse models of HD showing decreased proliferation in the SGZ. Furthermore, HD can be divided into those with mainly mood and mainly motor symptomatology. We hypothesized that HD cases with mainly mood symptomatology would show a greater change in hippocampal proliferation, which has previously been implicated in mood disorders such as depression. Therefore, in the current study we examined and compared proliferation in the SGZ in normal vs. HD, HD mood, and HD motor affected cases. However, our results revealed no significant differences in SGZ proliferation between normal and HD cases, and no differences when divided into groups based on mood and motor symptomatology. Our results were confirmed using a range of cell-cycle protein markers and, overall, were comparable with previous studies of the human hippocampus, where very little proliferation was detected in the adult SGZ. These results demonstrate that in humans the SGZ is far less proliferative than the SVZ, and suggests that hippocampal plasticity in humans does not primarily involve cell proliferation.

The form of the structural asymmetries across the cerebral hemispheres, that support well-established functional asymmetries, are not well understood. Although, many previous studies have investigated structural differences in areas associated with strong functional asymmetries, such as language processes, regions of the brain with less well established functional laterality have received less attention. The current study aims to address this by exploring global white matter asymmetries of the healthy human brain using diffusion tensor imaging (DTI) and tractography. DTI was conducted on twenty-nine healthy right-handed males, and pathways from the four major lobes were reconstructed using probabilistic tractography. Mean FA, parallel and perpendicular diffusion values were calculated and compared across hemispheres for each pathway generated. Significant asymmetries in the parietal (rightward asymmetry) and occipital (leftward asymmetry) pathways were found in FA measures. However, asymmetric patterns in parallel and/or perpendicular diffusion were observed in all four lobes, even in pathways with symmetrical FA. For instance, significant rightward asymmetry in parallel diffusion was found in the parietal and frontal lobes, whereas significant leftward asymmetry was found in the temporal and occipital lobes. We suggest that these different patterns of diffusion asymmetry reflect differences in microanatomy that support the known patterns of differential functional asymmetry. The different directions of anatomical asymmetry support the notion that there may be a number of different lateralising influences operating in the brain.

Huntington's disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntington's disease correlates with the variable compartmental pattern of GABAA receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntington's disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntington's disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntington's disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntington's disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntington's disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate cortex.

In transgenic mouse models of Huntington disease (HD) environmental enrichment significantly delays disease onset. A questionnaire-based survey of 154 adults with diagnosed HD (mean 4.2 years postdiagnosis) and a known IT15 CAG repeat length, explored whether premorbid lifestyle may relate to age-at-onset (AO). Participants were drawn from HD outpatient clinics in Australia and New Zealand. Premorbid physical, intellectual, and passive activity levels were used to generate scores in the categories of leisure, nonleisure (education, occupation and domestic duties) and total lifestyle. AO was associated with increased CAG repeat length as expected (r = -0.72, P < 0.001), but also with a lifestyle that included higher levels of passive activity (r = -0.38, P < 0.001). Multiple linear regression modeling showed lifestyle passivity to be a variable independent of CAG repeat length in predicting AO (R(2) = 0.54, b = -0.22, P = 0.005). Comparison of the mean AO across tertiles of lifestyle passivity scores showed onset 4.6 years (95% CI = 1.3-7.9) later in the least compared with the most passive tertile. CAG repeat length was also shown to predict lifestyle passivity (R(2) = 0.12, b = 1.08, P < 0.0005). Neither intellectual nor physical activity showed significant relationships to AO or CAG repeat length in this cohort. Our study leads to two conclusions: that a passive lifestyle may be a preclinical expression of HD, and that it actually contributes to the earlier onset of symptoms. Overcoming the tendency to be passive may substantially delay onset of HD. (c) 2010 Movement Disorder Society.

Multiple Sclerosis (MS) is one of the most common chronic diseases of the central nervous system, and in New Zealand an estimated 4000 people are currently affected. This study was conducted to examine executive functioning, memory and general ability in a community-based sample of 95 participants with MS. The sample included those with relapsing-remitting, secondary progressive, chronic progressive and benign MS with an average duration of illness of 11.8 years. Only 9% of the participants showed no indication of cognitive impairment with most exhibiting mild executive dysfunction across the range of shifting, inhibition, fluency and working memory categories. As this became more widespread, all other measures of cognitive ability and memory also showed evidence of deterioration, but in some, this may have been due to slowed information processing. Overall, there was a high degree of variability in the levels of performance and there was no 'typical' pattern of deficits associated with MS. Thus, a proportion of those living with MS may have to cope with noticeable and unpredictable cognitive decline in addition to their physical disabilities.

Attention in neurologically intact adults normally errs towards the left side of space, as documented in studies involving tasks of visual attention (i.e., line bisection). The aim of this study was to further investigate lateralisation of attention in musicians and non-musicians. Reaction times and accuracy were recorded to stimuli presented to the left and right of a vertical line in 20 right-handed musicians and 20 matched non-musician controls. While both groups performed more accurately to left-sided stimuli, performance by the musician group was significantly more accurate than the non-musician group for the right-sided stimuli. Musicians also had faster reaction times overall. Consistent with previous research, the results indicate a more balanced attentional capacity in musicians, as well as enhanced visuomotor ability, and are interpreted with reference to extended musical training.