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.

Prevalence and symptomatology of catatonia in elderly patients referred to a consultation-liaison psychiatry service.

OBJECTIVES: To determine the prevalence and clinical correlations of catatonia in patients aged over 65 years who are referred to a consultation-liaison service within a regional area of Australia. Additionally, to examine if the use of standardised screening tools is likely to change the rate of diagnosis of catatonia within the consultation-liaison service. METHODS: One hundred and eight referrals from general hospital wards were assessed using the Bush-Francis Catatonia Screening Instrument (BFCSI) and associated examination; each consented patient was screened for catatonic symptoms. If two or more signs were present on the BFCSI, then severity was rated using the Bush-Francis Catatonia Rating Scale. These clinical characteristics were compared with their socio-demographic and medical data. RESULTS: Prevalence of catatonia was 5.5%. The most common symptoms appeared to be rigidity, posturing and immobility (67% of cases), and were elicited through routine psychiatric examination. CONCLUSIONS: Routine psychiatric history and examination are likely sufficient to elicit catatonic signs in a consultation-liaison setting. Standardised screening examination may be more suited for conducting research or for use when examining for catatonia in psychiatric inpatient settings.

Affective disorders and functional (non-epileptic) seizures in persons with epilepsy.

OBJECTIVE: This paper aims to describe the prevalence, assessment and management of affective disorders as well as functional (non-epileptic) seizures in people with epilepsy. METHOD: This paper comprises a selective review of the literature of the common affective manifestations of epilepsy. RESULTS: Affective disorders are the most common psychiatric comorbidity seen in people with epilepsy and assessment and management parallels that of the general population. Additionally, people with epilepsy may experience higher rates of mood instability, irritability and euphoria, classified together as a group, interictal dysphoric disorder and resembling an unstable bipolar Type II disorder. Functional seizures present unique challenges in terms of identification of the disorder and a lack of specific management. CONCLUSIONS: Given their high prevalence, it is important to be able to recognise affective disorders in people with epilepsy. Management principles parallel those in the general population with specific caution exercised regarding the potential interactions between antidepressant medications and antiepileptic drugs. Functional seizures are more complex and require a coordinated approach involving neurologists, psychiatrists, general practitioners, nursing and allied health. There is very limited evidence to guide psychological and behavioural interventions for neurotic disorders in epilepsy and much more research is needed.

Shape abnormalities of the caudate nucleus correlate with poorer gait and balance: results from a subset of the LADIS study.

OBJECTIVE: Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in frontostriatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter hyperintensities (WMHs) on magnetic resonance imaging has been found to correlate with poorer performance on measures of gait and balance. This study aimed to determine whether striatal volume and shape changes were correlated with gait dysfunction. METHODS: Magnetic resonance imaging scans and clinical gait/balance data (scores from the Short Physical Performance Battery [SPPB]) were sourced from 66 subjects in the previously published LADIS trial, performed in nondisabled individuals older than age 65 years with WMHs at study entry. Data were obtained at study entry and at 3-year follow-up. Caudate nuclei and putamina were manually traced using a previously published method and volumes calculated. The relationships between volume and physical performance on the SPPB were investigated with shape analysis using the spherical harmonic shape description toolkit. RESULTS: There was no correlation between the severity of WMHs and striatal volumes. Caudate nuclei volume correlated with performance on the SPPB at baseline but not at follow-up, with subsequent shape analysis showing left caudate changes occurred in areas corresponding to inputs of the dorsolateral prefrontal, premotor, and motor cortex. There was no correlation between putamen volumes and performance on the SPPB. CONCLUSION: Disruption in frontostriatal circuits may play a role in mediating poorer physical performance in individuals with WMHs. Striatal volume and shape changes may be suitable biomarkers for functional changes in this population.

The rites of writing papers: steps to successful publishing for psychiatrists.

OBJECTIVE: To encourage psychiatrists to publish high-quality articles in peer-reviewed journals by demystifying the publishing process. METHODS: This paper will describe the publishing process and outline key factors that ensure that publishing is an achievable goal for psychiatrists. RESULTS: The publishing process can be long and often this is related to delays associated with obtaining reviewers and their comments. Negative reviewer comments often relate to grammatical and typographical errors, an insufficient literature review, failure to adequately discuss limitations and conclusions that are not adequately supported by the results. Authors who systematically respond to their paper's reviewer comments are usually successful in having their papers accepted. Success in publishing is usually determined by a topic that appeals to the readership of a journal, a credible methodology and a paper that is well-written. CONCLUSIONS: Publishing is achievable for all psychiatrists providing they can write a paper that delivers a clear and concise message, are willing to address reviewer comments and that their paper is tailored to the readership of the journal.

A guide to clinical research supervision for psychiatrists: a mentoring approach.

OBJECTIVES: To provide a guide for clinically-based psychiatrist supervisors of research projects for early career researchers. METHODS: This paper will describe a mentoring framework for supervision, for psychiatrist clinical research supervisors and early career researchers. RESULTS: The domains discussed include, across various aspects of a study: the role of the supervisor, project management, and where and when to seek advice. CONCLUSIONS: Supervision of clinical research can be a professionally rewarding experience for psychiatrists, as well as early career researcher supervisees.

How to survive in research: advice for the novice investigator.

OBJECTIVES: This paper, written by the RANZCP Committee for Research, provides an outline for how to survive in research, considering the ingredients likely to contribute to success, the role of supportive structures and the expected challenges. Learning how to survive in research is relevant for both trainees and for Fellows undertaking research at any stage of their career. CONCLUSIONS: Intellectual curiosity, perseverance, frustration tolerance, patience and humility are key for success as a researcher. Selection of the right supervisor is important, as is development and maintenance of a good working supervisor/supervisee relationship. The personal benefits of undertaking research include flexibility in work hours, and improved skills in writing, oral presentations, objectivity, critical thinking, problem solving and project management.

Getting started in research: research questions, supervisors and literature reviews.

OBJECTIVES: Research can seem daunting, especially for trainees and early career researchers. This paper focuses on how to formulate and begin a research project such as the RANZCP Scholarly Project. METHODS: We outline an approach to framing a research question, developing theses and hypotheses, choosing a supervisor and conducting a literature review. CONCLUSIONS: Through systematic planning early career researchers and other clinicians can plan and conduct research suitable for the Scholarly Project or other research activity.

Getting started in research: designing and preparing to conduct a research study.

OBJECTIVE: To discuss common pitfalls and useful tips in designing a quantitative research study, the importance and process of ethical approval, and consideration of funding. CONCLUSIONS: Through careful planning, based on formulation of a research question, early career researchers can design and conduct quantitative research projects within the framework of the Scholarly Project or in their own independent projects.

Getting started in research: systematic reviews and meta-analyses.

OBJECTIVES: Systematic reviews are one of the major building blocks of evidence-based medicine. This overview is an introduction to conducting systematic reviews and meta-analyses. CONCLUSIONS: Systematic reviews and meta-analyses of randomised controlled trials (RCTs) represent the most robust form of design in the hierarchy of research evidence. In addition, primary data do not have to be collected by the researcher him/herself, and there is no need for approval from an ethics committee. Systematic reviews and meta-analyses are not as daunting as they may appear to be, provided the scope is sufficiently narrow and an appropriate supervisor available.

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.

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.

Differential putaminal morphology in Huntington's disease, frontotemporal dementia and Alzheimer's disease.

OBJECTIVE: Direct neuronal loss or deafferentation of the putamen, a critical hub in corticostriatal circuits, may result in diverse and distinct cognitive and motoric dysfunction in neurodegenerative disease. Differential putaminal morphology, as a quantitative measure of corticostriatal integrity, may thus be evident in Huntington's disease (HD), Alzheimer's disease (AD) and frontotemporal dementia (FTD), diseases with differential clinical dysfunction. METHODS: HD (n = 17), FTD (n = 33) and AD (n = 13) patients were diagnosed according to international consensus criteria and, with healthy controls (n = 17), were scanned on the same MRI scanner. Patients underwent brief cognitive testing using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG). Ten MRI scans from this dataset were manually segmented as a training set for the Adaboost algorithm, which automatically segmented all remaining scans for the putamen, yielding the following subset of the data: 9 left and 12 right putamen segmentations for AD; 25 left and 26 right putamina for FTD; 16 left and 15 right putamina for HD; 12 left and 12 right putamina for controls. Shape analysis was performed at each point on the surface of each structure using a multiple regression controlling for age and sex to compare radial distance across diagnostic groups. RESULTS: Age, but not sex and intracranial volume (ICV), were significantly different in the segmentation subgroups by diagnosis. The AD group showed significantly poorer performance on cognitive testing than FTD. Mean putaminal volumes were HD < FTD < AD ≤ controls, controlling for age and ICV. The greatest putaminal shape deflation was evident in HD, followed by FTD, in regions corresponding to the interconnections to motoric cortex. CONCLUSIONS: Differential patterns of putaminal atrophy in HD, FTD and AD, with relevance to corticostriatal circuits, suggest the putamen may be a suitable clinical biomarker in neurodegenerative disease.

Frontotemporal dementia as a frontostriatal disorder: neostriatal morphology as a biomarker and structural basis for an endophenotype.

OBJECTIVE: This article reviews the evidence for a re-conceptualisation of a subtype of frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), as a frontostriatal disorder, working towards an endophenotype. METHOD: We provide an overview of the role of frontostriatal circuits relevant to FTLD and FTD, as a subset of larger-scale distributed brain networks. We discuss the role of a strategic structure in these circuits, the neostriatum. Then we review the relationship of the clinical features of FTLD to frontostriatal circuits, correlating this with neuropsychological and neuropathological data. CONCLUSION: The unique structure and linkages of the neostriatum make it an ideal structure for in vivo neuroimaging to understand the neuroanatomical basis of FTD. We develop a frontostriatal endophenotypic model for FTD as a platform for further investigation.

Morphometric analysis of subcortical structures in progressive supranuclear palsy: In vivo evidence of neostriatal and mesencephalic atrophy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by gait and postural disturbance, gaze palsy, apathy, decreased verbal fluency and dysexecutive symptoms, with some of these clinical features potentially having origins in degeneration of frontostriatal circuits and the mesencephalon. This hypothesis was investigated by manual segmentation of the caudate and putamen on MRI scans, using previously published protocols, in 15 subjects with PSP and 15 healthy age-matched controls. Midbrain atrophy was assessed by measurement of mid-sagittal area of the midbrain and pons. Shape analysis of the caudate and putamen was performed using spherical harmonics (SPHARM-PDM, University of North Carolina). The sagittal pons area/midbrain area ratio (P/M ratio) was significantly higher in the PSP group, consistent with previous findings. Significantly smaller striatal volumes were found in the PSP group - putamina were 10% smaller and caudate volumes were 17% smaller than in controls after controlling for age and intracranial volume. Shape analysis revealed significant shape deflation in PSP in the striatum, compared to controls; with regionally significant change relevant to frontostriatal and corticostriatal circuits in the caudate. Thus, in a clinically diagnosed and biomarker-confirmed cohort with early PSP, we demonstrate that neostriatal volume and shape are significantly reduced in vivo. The findings suggest a neostriatal and mesencephalic structural basis for the clinical features of PSP leading to frontostriatal and mesocortical-striatal circuit disruption.

Comparison of consultation-liaison psychiatry services for inner-city, district or regional general hospitals using a common tool: Does one size fit all?

OBJECTIVE: Consultation-liaison psychiatry (CLP) services vary in terms of structure, function and responsiveness. It is not known whether evaluation measurements can be meaningfully compared across different CLP services to assess value and efficiency. The aim was to develop and test a common tool for measuring process and outcome measures in CLP. METHODS: A data collection tool was developed using the literature and consultation with CLP clinicians. The tool was used to prospectively gather referral data, response times, health utilisation data and functional outcomes for individuals referred over seven months to three different CLP teams, servicing inner city, district and regional areas. RESULTS: The structure, staffing, liaison attachments and scope of practice varied between the services. The regional CLP service attended seven hospitals and had the highest referral rate and largest inpatient population pool. The three services received referrals for similar reasons and made similar diagnoses. Multimodal management was the norm, and CLP facilitated follow-up arrangements upon discharge. Only the district CLP service saw all emergency referrals within an hour. Age and need for an interpreter did not affect response times. CONCLUSION: Despite local differences in geography, CLP roles, hospital and community mental health service pathways and patient populations, the CLP data collection tool was applicable across sites. Staff resourcing and referral demand are key determinants of CLP response times.

Striatal Atrophy in the Behavioural Variant of Frontotemporal Dementia: Correlation with Diagnosis, Negative Symptoms and Disease Severity.

INTRODUCTION: Behavioural variant frontotemporal dementia (bvFTD) is associated with changes in dorsal striatal parts of the basal ganglia (caudate nucleus and putamen), related to dysfunction in the cortico-striato-thalamic circuits which help mediate executive and motor functions. We aimed to determine whether the size and shape of striatal structures correlated with diagnosis of bvFTD, and measures of clinical severity, behaviour and cognition. MATERIALS AND METHODS: Magnetic resonance imaging scans from 28 patients with bvFTD and 26 healthy controls were manually traced using image analysis software (ITK-SNAP). The resulting 3-D objects underwent volumetric analysis and shape analysis, through spherical harmonic description with point distribution models (SPHARM-PDM). Correlations with size and shape were sought with clinical measures in the bvTFD group, including Frontal Behavioural Inventory, Clinical Dementia Rating for bvFTD, Color Word Interference, Hayling part B and Brixton tests, and Trail-Making Test. RESULTS: Caudate nuclei and putamina were significantly smaller in the bvFTD group compared to controls (left caudate 16% smaller, partial eta squared 0.173, p=0.003; right caudate 11% smaller, partial eta squared 0.103, p=0.023; left putamen 18% smaller, partial eta squared 0.179, p=0.002; right putamen 12% smaller, partial eta squared 0.081, p=0.045), with global shape deflation in the caudate bilaterally but no localised shape change in putamen. In the bvFTD group, shape deflations on the left, corresponding to afferent connections from dorsolateral prefrontal mediofrontal/anterior cingulate and orbitofrontal cortex, correlated with worsening disease severity. Global shape deflation in the putamen correlated with Frontal Behavioural Inventory scores-higher scoring on negative symptoms was associated with the left putamen, while positive symptoms were associated with the right. Other cognitive tests had poor completion rates. CONCLUSION: Behavioural symptoms and severity of bvFTD are correlated with abnormalities in striatal size and shape. This adds to the promise of imaging the striatum as a biomarker in this disease.

Saccadic eye movement characteristics in adult Niemann-Pick Type C disease: relationships with disease severity and brain structural measures.

Niemann-Pick Type C disease (NPC) is a rare genetic disorder of lipid metabolism. A parameter related to horizontal saccadic peak velocity was one of the primary outcome measures in the clinical trial assessing miglustat as a treatment for NPC. Neuropathology is widespread in NPC, however, and could be expected to affect other saccadic parameters. We compared horizontal saccadic velocity, latency, gain, antisaccade error percentage and self-paced saccade generation in 9 adult NPC patients to data from 10 age-matched controls. These saccadic measures were correlated with appropriate MRI-derived brain structural measures (e.g., dorsolateral prefrontal cortex, frontal eye fields, supplemental eye fields, parietal eye fields, pons, midbrain and cerebellar vermis) and with measures of disease severity and duration. The best discriminators between groups were reflexive saccade gain and the two volitional saccade measures. Gain was also the strongest correlate with disease severity and duration. Most of the saccadic measures showed strongly significant correlations with neurophysiologically appropriate brain regions. While our patient sample is small, the apparent specificity of these relationships suggests that as new diagnostic methods and treatments become available for NPC, a broader range of saccadic measures may be useful tools for the assessment of disease progression and treatment efficacy.