Summoning the courage for philosophising: a new reading of Heidegger's the fundamental concepts of metaphysics

This thesis provides an original reading of Heidegger's 1929-30 lecture course The Fundamental Concepts of Metaphysics. Currently, the notoriety of FCM stems from controversy surrounding its description of human beings as 'world-forming,' and of animals as comparatively 'poor in world.' These propositions are interpreted within the secondary literature as a reinforcement of ontotheological and humanistic metaphysics. However, this standard interpretation misses the more complex and subtle significance of this material in the broader context of the lectures. I argue that Heidegger's 'comparative examination' forms part of a wider metaphysical project of interrogating a contemporary 'delusion,' a metaphysical division drawn between 'life' and 'spirit' engendered by an 'anthropological' worldview which pictures man as a composite of those two elements. Heidegger traces the manifestations of this delusion in Kulturphilosophie and biology, before attempting to recover a more genuinely metaphysical attitude, one founded not on anthropocentric 'worldviews' but on a direct, courageous 'confrontation' with ourselves. Heidegger argues that this confrontation must take its orientation from Greek thought, in which man is interpreted as that part of physis that apprehends physis as a whole. For Heidegger, this notion of the human as a kind of 'meta-physical' being enables us to grasp the coextensive essence of the human and of metaphysics. I argue that Heidegger's position can be extended and enriched if we consider it in conjunction with what he presents in the lecture course as one of its great adversaries; for the German tradition of philosophical anthropology, rather than being a straightforward articulation of the life-spirit divide that Heidegger wishes to eschew, actually harmonises with and deepens Heidegger's reflections in FCM concerning the nature of the human as a meta-physical being

Birth weight and stuttering:Evidence from three birth cohorts

Purpose Previous studies have produced conflicting results with regard to the association between birth weight and developmental stuttering. This study sought to determine whether birth weight was associated with childhood and/or adolescent stuttering in three British birth cohort samples. Methods Logistic regression analyses were carried out on data from the Millenium Cohort Study (MCS), British Cohort Study (BCS70) and National Child Development Study (NCDS), whose initial cohorts comprised over 56,000 individuals. The outcome variables were parent-reported stuttering in childhood or in adolescence; the predictors, based on prior research, were birth weight, sex, multiple birth status, vocabulary score and mother's level of education. Birth weight was analysed both as a categorical variable (low birth weight, <2500 g; normal range; high birth weight, ≥ 4000 g) and as a continuous variable. Separate analyses were carried out to determine the impact of birth weight and the other predictors on stuttering during childhood (age 3, 5 and 7 and MCS, BCS70 and NCDS, respectively) or at age 16, when developmental stuttering is likely to be persistent. Results None of the multivariate analyses revealed an association between birth weight and parent-reported stuttering. Sex was a significant predictor of stuttering in all the analyses, with males 1.6 to 3.6 times more likely than females to stutter. Conclusion Our results suggest that birth weight is not a clinically useful predictor of childhood or persistent stuttering

Genetics and Pathogenesis of Parkinson\u27s Syndrome

Parkinson\u27s disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson\u27s syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson\u27s syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies

Amyotrophic lateral sclerosis and frontotemporal dementia: distinct and overlapping changes in eating behaviour and metabolism.

Metabolic changes incorporating fluctuations in weight, insulin resistance, and cholesterol concentrations have been identified in several neurodegenerative disorders. Whether these changes result from the neurodegenerative process affecting brain regions necessary for metabolic regulation or whether they drive the degenerative process is unknown. Emerging evidence from epidemiological, clinical, pathological, and experimental studies emphasises a range of changes in eating behaviours and metabolism in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS, metabolic changes have been linked to disease progression and prognosis. Furthermore, changes in eating behaviour that affect metabolism have been incorporated into the diagnostic criteria for FTD, which has some clinical and pathological overlap with ALS. Whether the distinct and shared metabolic and eating changes represent a component of the proposed spectrum of the two diseases is an intriguing possibility. Moreover, future research should aim to unravel the complex connections between eating, metabolism, and neurodegeneration in ALS and FTD, and aim to understand the potential for targeting modifiable risk factors in disease development and progression.This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (#1037746 to GH, MK and JH) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021 to OP and JH) and other grants/sources (NHMRC project grant #1003139). We are grateful to the research participants involved with the ForeFront research studies. RA is a Royal Australasian College of Physicians PhD scholar and MND Australia PhD scholar. MI is an ARC Discovery Early Career Researcher Award Fellow (#DE130100463). OP is an NHMRC Career Development Research Fellow (#1022684). GH is a NHMRC Senior Principal Research Fellow (#1079679). L.M.I. is a NHMRC Senior Research Fellow (#1003083).This is the author accepted manuscript. The final version is available from Elsevier at http://dx.doi.org/10.1016/S1474-4422(15)00380-4

Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one- third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although “pure” LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and/or age-related tau astrogliopathy (ARTAG). The pat- terns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions (“synergies”) between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets

Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis

In addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer's disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neuropathology, genetic screening and cognitive profiling of ALS cases. Analyses of more than 1 million synapses using two complimentary high-resolution techniques (electron microscopy and array tomography) revealed a loss of synapses from the prefrontal cortex of ALS patients. Importantly, synapse loss was significantly greater in cognitively impaired cases and was not due to cortical atrophy, nor associated with dementia-associated neuropathology. Interestingly, we found a trend between pTDP-43 pathology and synapse loss in the frontal cortex and discovered pTDP-43 puncta at a subset of synapses in the ALS brains. From these data, we postulate that synapse loss in the prefrontal cortex represents an underlying neurobiological substrate of cognitive decline in ALS

Weak Responses to Auditory Feedback Perturbation during Articulation in Persons Who Stutter: Evidence for Abnormal Auditory-Motor Transformation

Previous empirical observations have led researchers to propose that auditory feedback (the auditory perception of self-produced sounds when speaking) functions abnormally in the speech motor systems of persons who stutter (PWS). Researchers have theorized that an important neural basis of stuttering is the aberrant integration of auditory information into incipient speech motor commands. Because of the circumstantial support for these hypotheses and the differences and contradictions between them, there is a need for carefully designed experiments that directly examine auditory-motor integration during speech production in PWS. In the current study, we used real-time manipulation of auditory feedback to directly investigate whether the speech motor system of PWS utilizes auditory feedback abnormally during articulation and to characterize potential deficits of this auditory-motor integration. Twenty-one PWS and 18 fluent control participants were recruited. Using a short-latency formant-perturbation system, we examined participants’ compensatory responses to unanticipated perturbation of auditory feedback of the first formant frequency during the production of the monophthong [ε]. The PWS showed compensatory responses that were qualitatively similar to the controls’ and had close-to-normal latencies (~150 ms), but the magnitudes of their responses were substantially and significantly smaller than those of the control participants (by 47% on average, p<0.05). Measurements of auditory acuity indicate that the weaker-than-normal compensatory responses in PWS were not attributable to a deficit in low-level auditory processing. These findings are consistent with the hypothesis that stuttering is associated with functional defects in the inverse models responsible for the transformation from the domain of auditory targets and auditory error information into the domain of speech motor commands

Patterns of Amygdala Region Pathology in LATE-NC: Subtypes that Differ with Regard to TDP-43 Histopathology, Genetic Risk Factors, and Comorbid Pathologies

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant agerelated TDP-43 encephalopathy (LATE). The amygdala is afected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age=85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43+processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-β, with neurofbrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer’s disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the “amygdala region” rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confuent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution

Improved detection of RNA foci in C9orf72 amyotrophic lateral sclerosis post-mortem tissue using BaseScope™ shows a lack of association with cognitive dysfunction

Acknowledgements The authors would like to thank: (i) the Medical Research Council Edinburgh Brain Bank (ethics approval from East of Scotland Research Ethics Service, 16/ES/0084)) for supplying all post-mortem brain material and the Scottish Motor Neurone Disease Register (SMNDR)/Care Audit Research and Evaluation for Motor Neurone Disease (CARE-MND) consortium for all clinical and demographic data (ethical approval from Scotland A Research Ethics Committee 10/MRE00/78 and 15/SS/0216); (ii) The Scottish MND Clinical Specialist team for obtaining consent from patients with MND for inclusion in these studies; (iii) MND Scotland and the Sylvia Aitken Charitable Trust for funding CS to help to establish the MND Tissue Bank. The authors would also like to thank Advanced Cell Diagnostics for gifting the C9orf72 probe (BaseScopeTM Probe - BA-GGGGCCn-3zz-st, Cat Code: 704181), prior to it being made commercially available. Funding A.R.M. is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the Medical Research Council and the Motor Neurone Disease Association (MR/R001162/1). He also acknowledges support from the Rowling Scholars scheme, administered by the Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK. The Chandran laboratory is supported by the Euan MacDonald Centre and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.M.G. is funded by a starter grant for clinical lecturers from the Academy of Medical Sciences (AMS: 210JMG 3102 R45620) and C.S. is supported by a Medical Research Council grant (MR/L016400/1).Peer reviewe

Increased representation of the non-dominant hand in pianists demonstrated by measurement of 3D morphology of the central sulcus

Health and self-regulatio