Neuroanatomical Correlates of Cognitive Tests in Young-onset MCI.

BACKGROUND: Mild Cognitive Impairment (MCI) is a heterogeneous condition characterised by cognitive changes that do not affect everyday functioning and may represent a predementia phase. Research on the neuroanatomical correlates of cognitive tests used to diagnose MCI is heterogeneous and has mainly focused on elderly populations of patients with MCI, usually well above the age of 65. However, the effect of ageing on brain structure is known to be substantial and to affect brain-behaviour associations in older people. We explored the brain correlates of different cognitive tests in a group of young-onset MCI (i.e., with symptoms onset before the age of 65) to minimise the effect of ageing on brain-behaviour associations. METHODS: Patients with a clinical diagnosis of young-onset MCI underwent extensive cognitive assessment and multimodal Magnetic Resonance Imaging (MRI) including high-resolution T1-weighted and Diffusion Tensor Imaging (DTI) sequences. Their scores on cognitive tests were related to measures of grey matter (GM) density and white matter (WM) integrity using, respectively, Voxel Based Morphometry (VBM) and Tract-Based Spatial Statistics (TBSS). RESULTS: 104 young-onset MCI were recruited. VBM and TBSS whole-brain correlational analyses showed that between-subject variability in cognitive performance was significantly associated with regional variability in GM density and WM integrity. While associations between cognitive scores and focal GM density in our young-onset MCI group reflected the well-known lateralization of verbal and visuo-spatial abilities on the left and right hemispheres respectively, the associations between cognitive scores and WM microstructural integrity were widespread and diffusely involved most of the WM tracts in both hemispheres. CONCLUSIONS: We investigated the structural neuroanatomical correlates of cognitive tests in young-onset MCI in order to minimise the effect of ageing on brain-behaviour associations.

Unravelling the impact of frontal lobe impairment for social dysfunction in myotonic dystrophy type 1.

Myotonic dystrophy type 1 is an autosomal dominant multisystemic disorder affecting muscular and extra muscular systems, including the central nervous system. Cerebral involvement in myotonic dystrophy type 1 is associated with subtle cognitive and behavioural disorders, of major impact on socio-professional adaptation. The social dysfunction and its potential relation to frontal lobe neuropsychology remain under-evaluated in this pathology. The neuroanatomical network underpinning that disorder is yet to disentangle. Twenty-eight myotonic dystrophy type 1 adult patients (mean age: 46 years old) and 18 age and sex-matched healthy controls were included in the study. All patients performed an exhaustive neuropsychological assessment with a specific focus on frontal lobe neuropsychology (motivation, social cognition and executive functions). Among them, 18 myotonic dystrophy type 1 patients and 18 healthy controls had a brain MRI with T1 and T2 Flair sequences. Grey matter segmentation, Voxel-based morphometry and cortical thickness estimation were performed with Statistical Parametric Mapping Software SPM12 and Freesurfer software. Furthermore, T2 white matter lesions and subcortical structures were segmented with Automated Volumetry Software. Most patients showed significant impairment in executive frontal functions (auditory working memory, inhibition, contextualization and mental flexibility). Patients showed only minor difficulties in social cognition tests mostly in cognitive Theory of Mind, but with relative sparing of affective Theory of Mind and emotion recognition. Neuroimaging analysis revealed atrophy mostly in the parahippocampal and hippocampal regions and to a lesser extent in basal ganglia, regions involved in social navigation and mental flexibility, respectively. Social cognition scores were correlated with right parahippocampal gyrus atrophy. Social dysfunction in myotonic dystrophy type 1 might be a consequence of cognitive impairment regarding mental flexibility and social contextualization rather than a specific social cognition deficit such as emotion recognition. We suggest that both white matter lesions and grey matter disease could account for this social dysfunction, involving, in particular, the frontal-subcortical network and the hippocampal/arahippocampal regions, brain regions known, respectively, to integrate contextualization and social navigation.

Multiverse to inform neurological research: an example using recovery outcome of neglect.

OBJECTIVE: Multiverse analysis provides an ideal tool for understanding how inherent, yet ultimately arbitrary methodological choices impact the conclusions of individual studies. With this investigation, we aimed to demonstrate the utility of multiverse analysis for evaluating generalisability and identifying potential sources of bias within studies employing neurological populations. METHODS: Multiverse analysis was used to evaluate the robustness of the relationship between post-stroke visuospatial neglect and poor long-term recovery outcome within a sample of 1113 (age = 72.5, 45.1% female) stroke survivors. A total of 25,600 t-test comparisons were run across 400 different patient groups defined using various combinations of valid inclusion criteria based on lesion location, stroke type, assessment time, neglect impairment definition, and scoring criteria across 16 standardised outcome measures. RESULTS: Overall, 33.9% of conducted comparisons yielded significant results. 99.9% of these significant results fell below the null specification curve, indicating a highly robust relationship between neglect and poor recovery outcome. However, the strength of this effect was not constant across all comparison groups. Comparisons which included < 100 participants, pre-selected patients based on lesion type, or failed to account for allocentric neglect impairment were found to yield average effect sizes which differed substantially. Similarly, average effect sizes differed across various outcome measures with the strongest average effect in comparisons involving an activities of daily living measure and the weakest in comparisons employing a depression subscale. CONCLUSIONS: This investigation demonstrates the utility of multiverse analysis techniques for evaluating effect robustness and identifying potential sources of bias within neurological research.

Dissociated motor learning and de-adaptation in patients with functional gait disorders.

Walking onto a stationary platform that had been previously experienced as moving generates a locomotor after-effect-the so-called 'broken escalator' phenomenon. The motor responses that occur during locomotor after-effects have been mapped theoretically using a hierarchal Bayesian model of brain function that takes into account current sensory information that is weighted according to prior contextually-relevant experiences; these in turn inform automatic motor responses. Here, we use the broken escalator phenomenon to explore motor learning in patients with functional gait disorders and probe whether abnormal postural mechanisms override ascending sensory information and conscious intention, leading to maladaptive and disabling gait abnormalities. Fourteen patients with functional gait disorders and 17 healthy control subjects walked onto a stationary sled ('Before' condition, five trials), then onto a moving sled ('Moving' condition, 10 trials) and then again onto the stationary sled ('After' condition, five trials). Subjects were warned of the change in conditions. Kinematic gait measures (trunk displacement, step timing, gait velocity), EMG responses, and subjective measures of state anxiety/instability were recorded per trial. Patients had slower gait velocities in the Before trials (P < 0.05) but were able to increase this to accommodate the moving sled, with similar learning curves to control subjects (P = 0.87). Although trunk and gait velocity locomotor after-effects were present in both groups, there was a persistence of the locomotor after-effect only in patients (P < 0.05). We observed an increase in gait velocity during After trials towards normal values in the patient group. Instability and state anxiety were greater in patients than controls (P < 0.05) only during explicit phases (Before/After) of the task. Mean 'final' gait termination EMG activity (right gastrocnemius) was greater in the patient group than controls. Despite a dysfunctional locomotor system, patients show normal adaptive learning. The process of de-adaptation, however, is prolonged in patients indicating a tendency to perpetuate learned motor programmes. The trend to normalization of gait velocity following a period of implicit motor learning has implications for gait rehabilitation potential in patients with functional gait disorders and related disorders (e.g. fear of falling).

An International Curriculum and Behavioural Neurology / Un currículo internacional para neuropsiquiatría y neurología conductual

Abstract With major advances in neuroscience in the last three decades, there is an emphasis on understanding disturbances in thought, behaviour and emotion in terms of their neuroscientific underpinnings. While psychiatry and neurology, both of which deal with brain diseases, have a historical standing as distinct disciplines, there has been an increasing need to have a combined neuropsychiatric approach to deal with many conditions and disorders. Additionally, there is a body of disorders and conditions that warrants the skills sets and knowledge bases of both disciplines. This is the territory covered by the subspecialty of Neuropsychiatry from a 'mental' health perspective and Behavioural Neurology from a 'brain' health perspective. This paper elaborates the neuropsychiatric approach to dealing with brain diseases, but also argues for the delineation of a neuropsychiatric territory. In the process, it describes a curriculum for the training of a neuropsychiatrist or a behavioural neurologist who is competent in providing a unified approach to the diagnosis and management of this set of conditions and disorders. The paper describes in some detail the objectives of training in neuropsychiatry and the key competencies that should be achieved in such higher training after a foundational training in psychiatry and neurology. While aiming for an internationally relevant training program, the paper acknowledges the local and regional differences in training expertise and requirements. It provides a common framework of training for both Neuropsychiatry and Behavioural Neurology, while accepting the differences in skills and emphasis that basic training in psychiatry or neurology will bring to the subspecialty training. The future of Neuropsychiatry (or Behavioural Neurology) as a discipline will be influenced by the successful adoption of such a unified training curriculum.

Resumen Los grandes avances en las neurociencias en las últimas 3 décadas han hecho hincapié en la comprensión de las perturbaciones en el pensamiento, el comportamiento y las emociones. Mientras que la psiquiatría y la neurología se ocupan de enfermedades del cerebro, recientemente ha habido una creciente necesidad de tener un enfoque neuropsiquiátrico combinado para tratar muchos trastornos. Además, hay múltiples condiciones en las que confluyen habilidades y bases de conocimiento de ambas disciplinas. Este es el territorio cubierto por la subespecialidad de Neuropsiquiatría desde una perspectiva de salud «mental¼ y la Neurología Conductual desde una perspectiva de salud «cerebral¼. Este artículo elabora el enfoque neuropsiquiátrico para tratar las enfermedades cerebrales, pero también discute los límites del territorio neuropsiquiátrico. En este proceso, se describe un currículo para la formación de un neuropsiquiatra o un neurólogo conductual competente para proveer un abordaje integral en términos diagnósticos y terapéuticos. El documento describe con cierto detalle los objetivos de la formación en neuropsiquiatría y las competencias clave que se debe alcanzar en dicha formación superior, después de una formación inicial en psiquiatría y neurología. Al mismo tiempo que aspira a un programa de formación internacionalmente pertinente, el documento reconoce las diferencias locales y regionales en materia de conocimientos y requisitos de formación. Proporciona un marco común de formación tanto para la Neuropsiquiatría como para la Neurología Conductual, aceptando las diferencias en habilidades y el énfasis que la formación básica en psiquiatría o neurología traerá a la formación de la subespecialidad. El futuro de la Neuropsiquiatría (o Neurología Conductual) como disciplina estará influido por la instauración exitosa de un currículo de capacitación unificado.

An International Curriculum for Neuropsychiatry and Behavioural Neurology.

With major advances in neuroscience in the last three decades, there is an emphasis on understanding disturbances in thought, behaviour and emotion in terms of their neuroscientific underpinnings. While psychiatry and neurology, both of which deal with brain diseases, have a historical standing as distinct disciplines, there has been an increasing need to have a combined neuropsychiatric approach to deal with many conditions and disorders. Additionally, there is a body of disorders and conditions that warrants the skills sets and knowledge bases of both disciplines. This is the territory covered by the subspecialty of Neuropsychiatry from a 'mental' health perspective and Behavioural Neurology from a 'brain' health perspective. This paper elaborates the neuropsychiatric approach to dealing with brain diseases, but also argues for the delineation of a neuropsychiatric territory. In the process, it describes a curriculum for the training of a neuropsychiatrist or a behavioural neurologist who is competent in providing a unified approach to the diagnosis and management of this set of conditions and disorders. The paper describes in some detail the objectives of training in neuropsychiatry and the key competencies that should be achieved in such higher training after a foundational training in psychiatry and neurology. While aiming for an internationally relevant training program, the paper acknowledges the local and regional differences in training expertise and requirements. It provides a common framework of training for both Neuropsychiatry and Behavioural Neurology, while accepting the differences in skills and emphasis that basic training in psychiatry or neurology will bring to the subspecialty training. The future of Neuropsychiatry (or Behavioural Neurology) as a discipline will be influenced by the successful adoption of such a unified training curriculum.

Mouse models of frontotemporal dementia: A comparison of phenotypes with clinical symptomatology.

Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients.

Neuroeconomic dissociation of semantic dementia and behavioural variant frontotemporal dementia.

Many neuropsychiatric disorders are marked by abnormal behaviour and decision-making, but prevailing diagnostic criteria for such behaviours are typically qualitative and often ambiguous. Behavioural variant frontotemporal dementia and semantic variant primary progressive aphasia (also called semantic dementia) are two clinical variants of frontotemporal dementia with overlapping but distinct anatomical substrates known to cause profound changes in decision-making. We investigated whether abnormal decision-making in these syndromes could be more precisely characterized in terms of dissociable abnormalities in patients' subjective evaluations of valence (positive versus negative outcome) and of time (present versus future outcome). We presented 28 patients with behavioural variant frontotemporal dementia, 14 patients with semantic variant primary progressive aphasia, 25 patients with Alzheimer's disease (as disease controls), and 61 healthy older control subjects with experimental tasks assaying loss aversion and delay discounting. In general linear models controlling for age, gender, education and Mini-Mental State Examination score, patients with behavioural variant frontotemporal dementia were less averse to losses than control subjects (P < 0.001), while patients with semantic variant primary progressive aphasia discounted delayed rewards more steeply than controls (P = 0.019). There was no relationship between loss aversion and delay discounting across the sample, nor in any of the subgroups. These findings suggest that abnormal behaviours in neurodegenerative disease may result from the disruption of either of two dissociable neural processes for evaluating the outcomes of action. More broadly, these findings suggest a role for computational methods to supplement traditional qualitative characterizations in the differential diagnosis of neuropsychiatric disorders.

Therapeutic effects of glatiramer acetate and grafted CD115⁺ monocytes in a mouse model of Alzheimer's disease.

Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer's disease resulted in retained cognition (Morris water maze test), decreased amyloid-ß plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow-derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115(+) monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1ΔE9 Alzheimer's disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate-buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6-8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001-0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-ß protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-ß; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-ß plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-ß, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-ß1-42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-ß phagocytosis, and the amyloid-ß-degrading enzyme MMP9 (P < 0.0001-0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer's models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-ß as well as regulation of brain inflammation.

Autism: reduced connectivity between cortical areas involved in face expression, theory of mind, and the sense of self.

Whole-brain voxel-based unbiased resting state functional connectivity was analysed in 418 subjects with autism and 509 matched typically developing individuals. We identified a key system in the middle temporal gyrus/superior temporal sulcus region that has reduced cortical functional connectivity (and increased with the medial thalamus), which is implicated in face expression processing involved in social behaviour. This system has reduced functional connectivity with the ventromedial prefrontal cortex, which is implicated in emotion and social communication. The middle temporal gyrus system is also implicated in theory of mind processing. We also identified in autism a second key system in the precuneus/superior parietal lobule region with reduced functional connectivity, which is implicated in spatial functions including of oneself, and of the spatial environment. It is proposed that these two types of functionality, face expression-related, and of one's self and the environment, are important components of the computations involved in theory of mind, whether of oneself or of others, and that reduced connectivity within and between these regions may make a major contribution to the symptoms of autism.

Post-stroke fatigue: a deficit in corticomotor excitability?

The pathophysiology of post-stroke fatigue is poorly understood although it is thought to be a consequence of central nervous system pathophysiology. In this study we investigate the relationship between corticomotor excitability and self-reported non-exercise related fatigue in chronic stroke population. Seventy first-time non-depressed stroke survivors (60.36 ± 12.4 years, 20 females, 56.81 ± 63 months post-stroke) with minimal motor and cognitive impairment were included in the cross-sectional observational study. Fatigue was measured using two validated questionnaires: Fatigue Severity Scale 7 and Neurological Fatigue Index - Stroke. Perception of effort was measured using a 0-10 numerical rating scale in an isometric biceps hold-task and was used as a secondary measure of fatigue. Neurophysiological measures of corticomotor excitability were performed using transcranial magnetic stimulation. Corticospinal excitability was quantified using resting and active motor thresholds and stimulus-response curves of the first dorsal interosseous muscle. Intracortical M1 excitability was measured using paired pulse paradigms: short and long interval intracortical inhibition in the same hand muscle as above. Excitability of cortical and subcortical inputs that drive M1 output was measured in the biceps muscle using a modified twitch interpolation technique to provide an index of central activation failure. Stepwise regression was performed to determine the explanatory variables that significantly accounted for variance in the fatigue and perception scores. Resting motor threshold (R = 0.384; 95% confidence interval = 0.071; P = 0.036) accounted for 14.7% (R(2)) of the variation in Fatigue Severity Scale 7. Central activation failure (R = 0.416; 95% confidence interval = -1.618; P = 0.003) accounted for 17.3% (R(2)) of the variation in perceived effort score. Thus chronic stroke survivors with high fatigue exhibit high motor thresholds and those who perceive high effort have low excitability of inputs that drive motor cortex output. We suggest that low excitability of both corticospinal output and its facilitatory synaptic inputs from cortical and sub-cortical sites contribute to high levels of fatigue after stroke.

Neuropsychiatry: where are we and where do we go from here?

INTRODUCTION: Neuropsychiatry has generally been regarded as a hybrid discipline that lies in the borderland between the disciplines of psychiatry and neurology. There is much debate on its current and future identity and status as a discipline. MATERIALS AND METHODS: Taking a historical perspective, the future of neuropsychiatry is placed within the context of recent developments in clinical neuroscience. RESULTS: The authors argue that with the maturation of the discipline, it must define its own identity that is not dependent entirely upon the parent disciplines. The requirements for this are the claiming of neuropsychiatric territory, a strong training agenda, an emphasis on treatments that are uniquely neuropsychiatric, and a bold embrace of new developments in clinical neuroscience. CONCLUSION: The exponential growth in neuroscientific knowledge places neuropsychiatry in an excellent position to carve out a strong identity. It is imperative that the leaders of the discipline seize the moment.