Pioneers of cortical cytoarchitectonics: the forgotten contribution of Herbert Major.

The study of cortical cytoarchitectonics and the histology of the human cerebral cortex was pursued by many investigators in the second half of the nineteenth century, such as Jacob Lockhart Clarke, Theodor Meynert, and Vladimir Betz. Another of these pioneers, whose name has largely been lost to posterity, is considered here: Herbert Coddington Major (1850-1921). Working at the West Riding Asylum in Wakefield, United Kingdom, Major's thesis of 1875 described and illustrated six-layered cortical structure in both non-human primates and man, as well as "giant nerve cells" which corresponded to those cells previously described, but not illustrated, by Betz. Further journal publications by Major in 1876 and 1877 confirmed his finding of six cortical strata. However, Major's work was almost entirely neglected by his contemporaries, including his colleague and sometime pupil at the West Riding Asylum, William Bevan-Lewis (1847-1929), who later (1878) reported the presence of both pentalaminar and hexalaminar cortices. Bevan-Lewis's work was also later credited with the first illustration of Betz cells.

William Aldren Turner (1864-1945).

William Aldren Turner (Fig. 1) was born in Edinburgh, the son of William Turner (1832-1916) who at the time was senior demonstrator in Anatomy at the University, later Professor (1867). His paternal grandmother was Margaret Aldren. He was not related to the American endocrinologist Henry Hubert Turner (1892-1970) who described Turner syndrome (monosomy X) in 1938. Fig. 1 William Aldren Turner (1864-1945).

Herbert Major on the insula: An early depiction of von Economo neurones?

Herbert Major (1850-1921) undertook histopathological studies of human and non-human primate brains at the West Riding Lunatic Asylum in Wakefield, England, during the 1870s. Two of his papers specifically investigated the structure of the island of Reil, or insula, "with the view of ascertaining its exact structure". In addition to describing and illustrating its lamination as six-layered, Major also identified "spindle-shaped" cells in the lower layers of human brains, but not in non-human primates. His written description, including measurements of cell body size, and illustration are suggestive that these were the neurones later described in the frontoinsular and anterior cingulate cortex by Constantin von Economo and Georg N. Koskinas and which were subsequently given the eponym "von Economo neurones". von Economo noted that this special neuronal type had been previously seen by Betz (1881), Hammarberg (1895), and Ramón y Cajal (1899-1904), but he did not mention Major's works. Major also ascribed linguistic functions to the insula. Hence, with respect to both anatomical and physiological features, Major may have pre-empted the findings of later research on this structure.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

The trial of David Ferrier, November 1881: Context, proceedings, and aftermath.

In November 1881, the eminent physiologist and physician David Ferrier was prosecuted under the Cruelty to Animals Act 1876. The prosecution was raised by the Victoria Street Society, formerly known as the Society for the Protection of Animals Liable to Vivisection, through its activist founder, Frances Power Cobbe. This article examines the legislative context prior to Ferrier's trial, the personalities involved in the prosecution, and its course and outcome. The resultant impact, both personal, on Cobbe and Ferrier, and professional, on experimental neurophysiology, is discussed, in particular the foundation of the Association for the Advancement of Medicine by Research (AAMR) and the provision of legal support for medical practitioners subject to litigation.

On the Dependence of the Critical Success Index (CSI) on Prevalence.

The critical success index (CSI) is an established metric used in meteorology to verify the accuracy of weather forecasts. It is defined as the ratio of hits to the sum of hits, false alarms, and misses. Translationally, CSI has gained popularity as a unitary outcome measure in various clinical situations where large numbers of true negatives may influence the interpretation of other, more traditional, outcome measures, such as specificity (Spec) and negative predictive value (NPV), or when unified interpretation of positive predictive value (PPV) and sensitivity (Sens) is needed. The derivation of CSI from measures including PPV has prompted questions as to whether and how CSI values may vary with disease prevalence (P), just as PPV estimates are dependent on P, and hence whether CSI values are generalizable between studies with differing prevalences. As no detailed study of the relation of CSI to prevalence has been undertaken hitherto, the dataset of a previously published test accuracy study of a cognitive screening instrument was interrogated to address this question. Three different methods were used to examine the change in CSI across a range of prevalences, using both the Bayes formula and equations directly relating CSI to Sens, PPV, P, and the test threshold (Q). These approaches showed that, as expected, CSI does vary with prevalence, but the dependence differs according to the method of calculation that is adopted. Bayesian rescaling of both Sens and PPV generates a concave curve, suggesting that CSI will be maximal at a particular prevalence, which may vary according to the particular dataset.

Herbert Coddington Major (1850-1921).

Herbert Coddington Major (Fig. 1) was a late nineteenth century pioneer in neuropathology and comparative neurology. No previous biographical article has been identified, suggesting he is now almost totally, yet unjustifiably, forgotten.

Critical success index or F measure to validate the accuracy of administrative healthcare data identifying epilepsy in deceased adults in Scotland.

BACKGROUND: Methods to undertake diagnostic accuracy studies of administrative epilepsy data are challenged by lack of a way to reliably rank case-ascertainment algorithms in order of their accuracy. This is because it is difficult to know how to prioritise positive predictive value (PPV) and sensitivity (Sens). Large numbers of true negative (TN) instances frequently found in epilepsy studies make it difficult to discriminate algorithm accuracy on the basis of negative predictive value (NPV) and specificity (Spec) as these become inflated (usually >90%). This study demonstrates the complementary value of using weather forecasting or machine learning metrics critical success index (CSI) or F measure, respectively, as unitary metrics combining PPV and sensitivity. We reanalyse data published in a diagnostic accuracy study of administrative epilepsy mortality data in Scotland. METHOD: CSI was calculated as 1/[(1/PPV) + (1/Sens) - 1]. F measure was calculated as 2.PPV.Sens/(PPV + Sens). CSI and F values range from 0 to 1, interpreted as 0 = inaccurate prediction and 1 = perfect accuracy. The published algorithms were reanalysed using these and their accuracy re-ranked according to CSI in order to allow comparison to the original rankings. RESULTS: CSI scores were conservative (range 0.02-0.826), always less than or equal to the lower of the corresponding PPV (range 39-100%) and sensitivity (range 2-93%). F values were less conservative (range 0.039-0.905), sometimes higher than either PPV or sensitivity, but were always higher than CSI. Low CSI and F values occurred when there was a large difference between PPV and sensitivity, e.g. CSI was 0.02 and F was 0.039 in an instance when PPV was 100% and sensitivity was 2%. Algorithms with both high PPV and sensitivity performed best in terms of CSI and F measure, e.g. CSI was 0.826 and F was 0.905 in an instance when PPV was 90% and sensitivity was 91%. CONCLUSION: CSI or F measure can combine PPV and sensitivity values into a convenient single metric that is easier to interpret and rank in terms of diagnostic accuracy than trying to rank diagnostic accuracy according to the two measures themselves. CSI or F prioritise instances where both PPV and sensitivity are high over instances where there are large differences between PPV and sensitivity (even if one of these is very high), allowing diagnostic accuracy thresholds based on combined PPV and sensitivity to be determined. Therefore, CSI or F measures may be helpful complementary metrics to report alongside PPV and sensitivity in diagnostic accuracy studies of administrative epilepsy data.

The West Riding Lunatic Asylum Medical Reports: the precursor of Brain?

First published in 1878, Brain: A Journal of Neurology is generally considered to be the world's first neuroscientific journal. However, this claim might be challenged since the West Riding Lunatic Asylum Medical Reports, another journal with significant neuroscientific content, was published between 1871 and 1876. Some have suggested this journal was the precursor of Brain, since it shared similar subject matter as well as editorial and authorial contributors, including James Crichton-Browne, David Ferrier and John Hughlings Jackson. To address this question, this article examines the origins, aims, structure and contents of, and some of the contributors and contributions to, the West Riding Lunatic Asylum Medical Reports and compares these elements to the first six volumes of Brain (1878-9 to 1883-4). Although the two journals did overlap in terms of some shared neuroscientific interests, Brain evidently had a broader scope and a more international authorship. Nevertheless, this analysis suggests that, through the agency of Crichton-Browne, Ferrier and Hughlings Jackson, it is appropriate to regard the West Riding Lunatic Asylum Medical Reports as not only the antecedent but also the precursor of Brain.

A month in the country: The sesquicentenary of David Ferrier's classical cerebral localisation researches of 1873.

The experimental studies of David Ferrier (1843-1928), establishing many of the principles of cerebral localisation which still underpin neurological reasoning in clinical practice, were first reported 150 years ago. This paper briefly reviews Ferrier's experimental work, first undertaken in the laboratory at the West Riding Lunatic Asylum in Wakefield, West Yorkshire and his resulting publications of 1873, as well as some contemporaneous responses to his findings. These not only established 'motor centres' pertinent to physiology and the signs of cerebral disease but also, from the outset, had ramifications for Ferrier's understanding of higher mental functions. That linguistic, mnemonic and perceptual cognitive functions might be related to localised areas within the brain received its most emphatic initial impetus from Ferrier's work.

Using Critical Success Index or Gilbert Skill Score as composite measures of positive predictive value and sensitivity in diagnostic accuracy studies: Weather forecasting informing epilepsy research.

The Critical Success Index (CSI) and Gilbert Skill score (GS) are verification measures that are commonly used to check the accuracy of weather forecasting. In this article, we propose that they can also be used to simplify the joint interpretation of positive predictive value (PPV) and sensitivity estimates across diagnostic accuracy studies of epilepsy data. This is because CSI and GS each provide a single measure that takes the weather forecasting equivalent of PPV and sensitivity into account. We have re-analysed data from our recent systematic review of diagnostic accuracy studies of administrative epilepsy data using CSI and GS. We summarise the results and benefits of this approach.

Melatonin protects against cadmium-induced oxidative stress via mitochondrial STAT3 signaling in human prostate stromal cells.

Melatonin protects against Cadmium (Cd)-induced toxicity, a ubiquitous environmental toxicant that causes adverse health effects by increasing reactive oxygen species (ROS) production and mitochondrial dysfunction. However, the underlying mechanism remains unclear. Here, we demonstrate that Cd exposure reduces the levels of mitochondrially-localized signal transducer and activator of transcription 3 (mitoSTAT3) using human prostate stromal cells and mouse embryonic fibroblasts. Melatonin enhances mitoSTAT3 abundance following Cd exposure, which is required to attenuate ROS damage, mitochondrial dysfunction, and cell death caused by Cd exposure. Moreover, melatonin increases mitochondrial levels of GRIM-19, an electron transport chain component that mediates STAT3 import into mitochondria, which are downregulated by Cd. In vivo, melatonin reverses the reduced size of mouse prostate tissue and levels of mitoSTAT3 and GRIM-19 induced by Cd exposure. Together, these data suggest that melatonin regulates mitoSTAT3 function to prevent Cd-induced cytotoxicity and could preserve mitochondrial function during Cd-induced stress.