Reduced SMA-M1 connectivity in older than younger adults measured using dual-site TMS.

With advancing age comes a decline in voluntary movement control. Growing evidence suggests that an age-related decline in effective connectivity between the supplementary motor area and primary motor cortex (SMA-M1) might play a role in an age-related decline of bilateral motor control. Dual-site transcranial magnetic stimulation (TMS) can be used to measure SMA-M1 effective connectivity. In the current study, we aimed to (1) replicate previous dual-site TMS research showing reduced SMA-M1 connectivity in older than younger adults and (2) examine whether SMA-M1 connectivity is associated with bilateral motor control in independent samples of younger (n = 30) and older adults (n = 30). SMA-M1 connectivity was measured using dual-site TMS with interstimulus intervals of 6, 7 and 8 ms, and bilateral motor control was measured using the Purdue Pegboard, Four Square Step Test and the Timed Up and Go task. Findings from this study showed that SMA-M1 connectivity was reduced in older than in younger adults, suggesting that the direct excitatory connections between SMA and M1 had reduced efficacy in older than younger adults. Furthermore, greater SMA-M1 connectivity was associated with better bimanual motor control in older adults. Thus, SMA-M1 connectivity in older adults might underpin, in part, the age-related decline in bilateral motor control. These findings contribute to our understanding of age-related declines in motor control and provide a physiological basis for the development of interventions to improve bimanual and bilateral motor control.

Regional structural hypo- and hyperconnectivity of frontal-striatal and frontal-thalamic pathways in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) has been predominantly considered as a frontotemporal cortical disease, with limited direct investigation of frontal-subcortical connections. We aim to characterize the grey and white matter components of frontal-thalamic and frontal-striatal circuits in bvFTD. Twenty-four patients with bvFTD and 24 healthy controls underwent morphological and diffusion imaging. Subcortical structures were manually segmented according to published protocols. Probabilistic pathways were reconstructed separately from the dorsolateral, orbitofrontal and medial prefrontal cortex to the striatum and thalamus. Patients with bvFTD had smaller cortical and subcortical volumes, lower fractional anisotropy, and higher mean diffusivity metrics, which is consistent with disruptions in frontal-striatal-thalamic pathways. Unexpectedly, regional volumes of the striatum and thalamus connected to the medial prefrontal cortex were significantly larger in bvFTD (by 135% in the striatum, p = .032, and 217% in the thalamus, p = .004), despite smaller dorsolateral prefrontal cortex connected regional volumes (by 67% in the striatum, p = .002, and 65% in the thalamus, p = .020), and inconsistent changes in orbitofrontal cortex connected regions. These unanticipated findings may represent compensatory or maladaptive remodeling in bvFTD networks. Comparisons are made to other neuropsychiatric disorders suggesting a common mechanism of changes in frontal-subcortical networks; however, longitudinal studies are necessary to test this hypothesis.

Neuroimaging in psychiatry: an update on neuroimaging in the clinical setting.

OBJECTIVE: We offered guidance on the role of structural and functional neuroimaging modalities for the general psychiatrist and for trainees in the clinical setting. METHODS: We outlined the utility of neuroimaging modalities in the clinical setting, specifically with a view to understanding the pathophysiology of manifestations of disease. RESULTS: Both structural and functional neuroimaging modalities have a clear role in diagnostic evaluation in the spectrum of neurodegenerative disorders. CONCLUSIONS: Whilst the role of neuroimaging in patients with mood, anxiety and psychotic disorders is less clear, structural and functional imaging modalities have utility in the clinical setting in the form of diagnostic refinement and in understanding the pathophysiology of disorders, towards explaining manifestations and planning treatment.

The thalamus as a putative biomarker in neurodegenerative disorders.

OBJECTIVE: This review provides a brief account of the clinically relevant functional neuroanatomy of the thalamus, before considering the utility of various modalities utilized to image the thalamus and technical challenges therein, and going on to provide an overview of studies utilizing structural imaging techniques to map thalamic morphology in the spectrum of neurodegenerative disorders. METHODS: A systematic search was conducted for peer-reviewed studies involving structural neuroimaging modalities investigating the morphology (shape and/or size) of the thalamus in the spectrum of neurodegenerative disorders. RESULTS: While the precise role of the thalamus in the healthy brain remains unclear, there is a large body of knowledge accumulating which defines more precisely its functional connectivity within the connectome, and a burgeoning literature implicating its involvement in neurodegenerative disorders. It is proposed that correlation of clinical features with thalamic morphology (as a component of a quantifiable subcortical connectome) will provide a better understanding of neuropsychiatric dysfunction in various neurodegenerative disorders, potentially yielding clinically useful endophenotypes and disease biomarkers. CONCLUSION: Thalamic biomarkers in the neurodegenerative disorders have great potential to provide clinically meaningful knowledge regarding not only disease onset and progression but may yield targets of and perhaps a way of gauging response to future disease-modifying modalities.

The Australian, US, Scandinavian Imaging Exchange (AUSSIE): an innovative, virtually-integrated health research network embedded in health care.

OBJECTIVE: To describe the development, design and function of an innovative international clinical research network for neuroimaging research, based in Australia, within a joint state health service/medical school. This Australian, US, Scandinavian Imaging Exchange (AUSSIE) network focuses upon identifying neuroimaging biomarkers for neuropsychiatric and neurodegenerative disease. METHODS: We describe a case study of the iterative development of the network, identifying characteristic features and methods which may serve as potential models for virtual clinical research networks. This network was established to analyse clinically-derived neuroimaging data relevant to neuropsychiatric and neurodegenerative disease, specifically in relation to subcortical brain structures. RESULTS: The AUSSIE network has harnessed synergies from the individual expertise of the component groups, primarily clinical neuroscience researchers, to analyse a variety of clinical data. CONCLUSION: AUSSIE is an active virtual clinical research network, analogous to a connectome, which is embedded in health care and has produced significant research, advancing our understanding of neuropsychiatric and neurodegenerative disease through the lens of neuroimaging.

Changes in body mass in later life and incident dementia.

BACKGROUND: There is ongoing debate about whether a decline in body mass represents a true risk factor for dementia, whether it is a phenotypic marker of incipient dementia, or perhaps a marker of another process that increases dementia risk. This study was designed to determine if changes in body mass index (BMI) in later life are associated with hazard of incident dementia over a follow-up period of up to eight years. METHODS: Method followed was a prospective cohort study of 4,181 men aged 65-84 years, resident in Perth, Australia. The exposure of interest was change in BMI measured between 1996-1998 and 2001-2004. The outcome was incident dementia, established using the Western Australia Data Linkage System until 2009. We used Cox regression models to establish crude and adjusted hazard of dementia for change in BMI. RESULTS: Compared with men with a stable BMI, those with a decrease in BMI >1 kg/m2 had a higher adjusted hazard of dementia (hazard ratio (HR) = 1.89, 95% CI = 1.32-2.70). The cumulative hazard of dementia over follow-up for changes in BMI was greatest for men with a decrease in BMI >1 kg/m2; this trend was apparent for men in all BMI categories (underweight, normal, overweight, obese). A reverse "J-shaped" association between BMI change and incident dementia was observed, with the lowest dementia rate being for men whose BMI remained stable. CONCLUSIONS: Men who maintained a stable body mass had the lowest incidence of dementia. Further studies are needed to clarify causality and assess feasibility of interventional studies to preserve body mass in aging men.

Does accumulating exposure to illicit drugs bring forward the age at onset in schizophrenia?

OBJECTIVE: Whilst cannabis has been associated with an earlier age at onset in schizophrenia, the impact of amphetamine and/or cocaine plus cannabis consumption on age at onset remains unclear. The present study was designed to test the hypothesis that consumption of amphetamine and/or cocaine in addition to cannabis would lead to an earlier age at onset of schizophrenia than that seen for cannabis consumption alone. A secondary objective was to determine what kind of effect additional substance use exerted (e.g. additive, multiplicative). METHOD: Patients with a diagnosis of schizophrenia were recruited from consecutive admissions to the inpatient and outpatient services of a large psychiatric hospital in Perth, Australia and 167 participants were assessed using the Diagnostic Interview for Psychosis, which included detailed inquiry into illicit drug use in the 12 months prior to the onset of psychiatric symptoms. Participants were categorized into four groups: no illicit substance use (n = 65), cannabis use (n = 68), cannabis plus amphetamine use (n = 25), and cocaine plus cannabis/cocaine plus cannabis plus amphetamine use (n = 9). Analysis of variance was performed to detect trends, and linear regression used to analyze the consumption of each additional substance as a predictor of age at onset. RESULTS: We observed a linear trend for mean age at onset: 23.34 (SD = 6.91) years for no illicit substance use, 22.51 (SD = 5.27) years for cannabis use, 20.84 (SD = 3.48) years for cannabis plus amphetamine use, and 19.56 (SD = 3.54) years for cocaine plus cannabis/cocaine plus cannabis plus amphetamine use; the variation in the means between groups was statistically significant: F(1,163) = 5.66, p = 0.008, Cohen's d = 0.38. For the consumption of each additional substance, age at onset was earlier by 1.2 years: R (2) = 0.034, F(1,165) = 5.72, p = 0.018. CONCLUSIONS: Whilst preliminary, these findings suggest that additional consumption of each substance predicted an earlier age at onset by approximately 1 additional year.

Clusters according to patient need in a long-stay inpatient population with schizophrenia: does executive dysfunction underpin needs-directed care?

PURPOSE: To identify the external validators of patient clusters according to need in a long-stay inpatient population with schizophrenia. METHODS: We recruited without exclusion 112 in-patients with chronic schizophrenia in a long-stay rehabilitation facility of a major psychiatric hospital in Perth, Western Australia. Case managers completed a number of measures for participants, including The Camberwell Assessment of Need-Short Appraisal Schedule, which evaluates health and social needs. Latent class analysis according to patient need was performed to identify clusters within the cohort. One way analysis of variance was used to identify the external validators of these clusters, using variables obtained from the additional study measures (Social Behaviour Schedule, Global Assessment of Function, Basic Everyday Living Skills, Behaviour Rating Inventory of Executive Function-Adult version). RESULTS: Three distinct needs-based clusters with different external profiles were identified. A "low unmet needs" group (n = 50) with relatively intact executive function, with the least problematic behaviour and most independent functioning; a "high unmet need (drug abstinent)" group (n = 43) with greatest executive dysfunction, most problematic behaviour and least independent function; a "high unmet need (drug using)" group (n = 19), with less severe executive dysfunction, and intermediate relative to the other groups on measures of social behaviour and independent functioning. CONCLUSIONS: The clinical heterogeneity we have identified, which may well be explained by executive dysfunction, suggests further exploration of appropriate assessment and streams of care for those in the rehabilitation setting is warranted.

Structural and microstructural thalamocortical network disruption in sporadic behavioural variant frontotemporal dementia.

BACKGROUND: Using multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD). METHOD: Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity. RESULTS: Bilateral anterior-dorsal thalamic atrophy, reduction in mean diffusivity of thalamic projections, and frontotemporal cortical thinning, were the main features predicting bvFTD group membership. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes. CONCLUSIONS: Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.

Brief screening for executive dysfunction in schizophrenia in a rehabilitation hospital.

Few tools assessing neurocognitive dysfunction in schizophrenia are able to measure integrated executive functions in the context of the problem-solving demands of a patient's everyday world. The authors evaluated the BRIEF-A (Behavior Rating Inventory of Executive Function-Adult version) Informant Report in 112 inpatients with chronic schizophrenia in a rehabilitation hospital. Factor analysis yielded a three-factor solution (Emotional Regulation, Problem-Solving, Orderliness). The BRIEF-A is psychometrically robust in this population and, in the absence of patient participation, provides an estimate of executive functions in a population that may otherwise be beyond the reach of formal neurocognitive testing.

Structural and functional neuroimaging changes associated with cognitive impairment and dementia in Parkinson's disease.

This study seeks a better understanding of possible pathophysiological mechanisms associated with cognitive impairment and dementia in Parkinson's disease using structural and functional MRI. We investigated resting-state functional connectivity of important subdivisions of the caudate nucleus, putamen and thalamus, and also how the morphology of these structures are impacted in the disorder. We found cognitively unimpaired Parkinson's disease subjects (n = 33), compared to controls (n = 26), display increased functional connectivity of the dorsal caudate, anterior putamen and mediodorsal thalamic subdivisions with areas across the frontal lobe, as well as reduced functional connectivity of the dorsal caudate with posterior cortical and cerebellar regions. Compared to cognitively unimpaired subjects, those with mild cognitive impairment (n = 22) demonstrated reduced functional connectivity of the mediodorsal thalamus with the paracingulate cortex, while also demonstrating increased functional connectivity of the mediodorsal thalamus with the posterior cingulate cortex, compared to subjects with dementia (n = 17). Extensive volumetric and surface-based deflation was found in subjects with dementia compared to cognitively unimpaired Parkinson's disease participants and controls. Our research suggests that structures within basal ganglia-thalamocortical circuits are implicated in cognitive impairment and dementia in Parkinson's disease, with cognitive impairment and dementia associated with a breakdown in functional connectivity of the mediodorsal thalamus with para- and posterior cingulate regions of the brain respectively.

Morphometric in vivo evidence of thalamic atrophy correlated with cognitive and motor dysfunction in Huntington's disease: The IMAGE-HD study.

In Huntington's disease (HD), neurodegeneration causes progressive atrophy to the striatum, cortical areas, and white matter tracts - components of corticostriatal circuitry. Such processes may affect the thalamus, a key circuit node. We investigated whether differences in dorsal thalamic morphology were detectable in HD, and whether thalamic atrophy was associated with neurocognitive, neuropsychiatric and motor dysfunction. Magnetic resonance imaging scans and clinical outcome measures were obtained from 34 presymptomatic HD (pre-HD), 29 early symptomatic HD (symp-HD), and 26 healthy control individuals who participated in the IMAGE-HD study. Manual region of interest (ROI) segmentation was conducted to measure dorsal thalamic volume, and thalamic ROI underwent shape analysis using the spherical harmonic point distribution method. The symp-HD group had significant thalamic volumetric reduction and global shape deflation, indicative of atrophy, compared to pre-HD and control groups. Thalamic atrophy significantly predicted neurocognitive and motor dysfunction within the symp-HD group only. Thalamic morphology differentiates symp-HD from pre-HD and healthy individuals. Thalamic changes may be one of the structural bases (endomorphotypes), of the endophenotypic neurocognitive and motor manifestations of disease. Future research should continue to investigate the thalamus as a potential in vivo biomarker of disease progression in HD.

Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington's disease: A nine-month pilot study.

BACKGROUND: Hypothalamic pathology is a well-documented feature of Huntington's disease (HD) and is believed to contribute to circadian rhythm and habitual sleep disturbances. Currently, no therapies exist to combat hypothalamic changes, nor circadian rhythm and habitual sleep disturbances in HD. OBJECTIVE: To evaluate the effects of multidisciplinary rehabilitation on hypothalamic volume, brain-derived neurotrophic factor (BDNF), circadian rhythm and habitual sleep in individuals with preclinical HD. METHODS: Eighteen individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group), which included exercise, cognitive and dual task training and social events, and were compared to a community sample of eleven individuals with premanifest HD receiving no intervention (control group). Hypothalamic volume, serum BDNF, salivary cortisol and melatonin concentrations, subjective sleep quality, daytime somnolence, habitual sleep-wake patterns, stress and anxiety and depression symptomatology were evaluated. RESULTS: Hypothalamus grey matter volume loss was significantly attenuated in the intervention group compared to the control group after controlling for age, gender, Unified Huntington's Disease Rating Scale-Total Motor Score and number of cytosine-adenine-guanine repeats. Serum BDNF levels were maintained in the intervention group, but decreased in the control group following the study period. Both groups exhibited decreases in cortisol and melatonin concentrations. No changes were observed in sleep or mood outcomes. CONCLUSIONS: This exploratory study provides evidence that multidisciplinary rehabilitation can reduce hypothalamic volume loss and maintain peripheral BDNF levels in individuals with preclinical HD but may not impact on circadian rhythm. Larger, randomised controlled trials are required to confirm these findings.

Apathy predicts more severe parkinsonism in Alzheimer's disease.

OBJECTIVES: Parkinsonian signs are frequent in Alzheimer disease (AD) and are associated with a faster cognitive decline, worse quality of life, and early nursing home admission. Cross-sectional studies in AD reported a significant association between parkinsonism and apathy. The aim of this study was to assess the chronological association between apathy and parkinsonism in AD. DESIGN: Longitudinal study of a consecutive series of patients with AD. SETTING: Dementia clinic from a tertiary clinical center. PARTICIPANTS: One hundred sixty-nine patients meeting diagnostic criteria for AD. INTERVENTION: A consecutive series of 169 patients with probable AD were assessed for the presence of parkinsonism, cognitive deficits, apathy, and depression with the Unified Parkinson's Disease Rating Scale and a comprehensive neuropsychiatry assessment. One hundred thirty-six (80%) of the patients had a follow-up assessment between 1 and 4 years after the baseline evaluation. MEASUREMENTS: Scores on apathy, parkinsonism, and depression scales at follow-up were the main outcome measures. RESULTS: Patients with apathy at baseline or those who developed apathy during follow-up had a significant increase in parkinsonism at follow-up when compared with patients with no apathy at both assessments. The association between apathy and increasing parkinsonism was unrelated to age, gender, the severity of cognitive deficits, the presence of depression, or use of psychotropic medications. On the other hand, neither the presence of parkinsonism nor depression at baseline was significantly associated with more severe apathy at follow-up. CONCLUSION: Apathy may be an early manifestation of a more aggressive AD phenotype characterized by loss of motivation, increasing parkinsonism, a faster cognitive and functional decline, and more severe depression.

Neuroimaging correlates of apathy and depression in Alzheimer's disease.

A consecutive series of 79 patients with probable Alzheimer's disease were assessed with a structured psychiatric evaluation, and diagnoses of apathy and depression were made using standardized criteria. Three-dimensional MRI scans were obtained from all patients, and images were segmented into gray matter, white matter, and CSF. White matter hyperintensities were edited on segmented images, and lobar assignments (frontal, temporal, parietal, and occipital) were made based on Talairach coordinates. Patients with apathy showed a significantly larger volume of frontal white matter hyperintensities than patients without apathy. Patients with depression had a significantly larger volume of right parietal white matter hyperintensities than patients without depression. However, neither apathy nor depression was significantly associated with lobar gray or white matter atrophy. Frontal and right parietal white matter hyperintensities are the strongest brain structural correlates of apathy and depression in Alzheimer's disease.

Reviewing the preclinical curriculum in a Problem Based Learning driven medical program: challenges and strategies.

This article was migrated. The article was marked as recommended. In order for medical curricula to remain progressive and contemporary, continuous review is critical to ensure that the learners are directed to achieve the intended goals and become workforce ready. We developed a framework for continuous curriculum review at the School of Medicine Fremantle (The University of Notre Dame Australia), taking the key aspects of a curriculum review process into consideration. In planning and implementing the review process we identified several challenges, including management of metadata, work load on staff members, and evaluation. These challenges were addressed successfully by applying necessary strategies using limited resources. The framework we have developed provides a guide to key stakeholders who are involved in medical curriculum review and development.

Increased functional connectivity of thalamic subdivisions in patients with Parkinson's disease.

Parkinson's disease (PD) affects 2-3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n = 32) compared to Controls (n = 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.

Depression in Alzheimer's disease: phenomenology, clinical correlates and treatment.

Depression is one of the most frequent comorbid psychiatric disorders in Alzheimer's disease and other dementias, and is associated with worse quality of life, greater disability in activities of daily living, a faster cognitive decline, a high rate of nursing home placement, relatively higher mortality, and a higher frequency of depression and burden in caregivers. Depression in Alzheimer's disease is markedly under-diagnosed, and most patients with depression are either not treated or are on subclinical doses of antidepressants. This is related to the lack of validated diagnostic criteria and specific instruments to assess depression in dementia. Apathy and pathological affect-crying are the main differential diagnoses of depression in Alzheimer's disease. Left untreated, major depression in Alzheimer's disease may last for about 12 months. Recent randomized controlled trials demonstrated the efficacy of sertraline and moclobemide to treat depression in Alzheimer's disease. Other psychoactive compounds may be useful as well, but careful consideration must be given to potentially serious side-effects.