Editorial
On this occasion, our ‘Happy New Year’ greeting carries a health warning, but one that brings some encouragement for those who decided to moderate their New Year's Eve celebrations. On page 36, Andreas Bartsch and colleagues from Würzberg and Aschersleben (Germany), Oxford (UK), Siena (Italy) and Basel (Switzerland) show that 7 weeks sobriety in detoxified alcoholics allows recovery from baseline of reduced brain volume, abnormal metabolism detected by magnetic resonance spectroscopy (cerebellar choline and frontomesial N-acetylaspartate), and impaired cognitive function. In his commentary on this paper, Graeme Mason commends the convergence of several previously disparate lines of investigation on alcohol and the brain, and highlights the motivation that these results provide for helping alcohol-dependent individuals to stay sober (page 8). Clearly, sales of Franconian wines, Gewürtztraminer and Chianti (Oxford has more modest claims to viniculture) are set to fall amongst those who previously considered themselves to ‘have a head for it’. On a related topic, Adolf Pfefferbaum and a team from Stanford University and the Massachusetts Institute of Technology (USA) seek to characterise the neurodegenerative contributions of comorbidity between alcoholism and HIV infection using fibre tractography (page 48): each alone damages the corpus callosum (used here as a surrogate for more distributed brain injury) and, together, the effects are synergistic.
Amongst four papers dealing with neurogenetics, Patrick Chinnery (an Associate Editor of Brain) and colleagues from Newcastle-upon-Tyne, Liverpool, Nottingham, Manchester and London (UK) and Brisbane (Australia) describe 41 cases of neuroferritinopathy resulting from the 460InsA mutation of FTL1, emphasising the presentation with movement disorder (chorea and action specific facial dystonia) and parkinsonism, and the inexorable evolution to severe motor disability and cognitive failure (page 110): confusion with the phenotype of Huntington's disease can be resolved by detecting the low serum ferritin levels seen in all except pre-menopausal female cases. Mathieu Sévin and investigators from Paris and Lyon (France) draw on 13 adult cases, personally observed, and summarise the description of 55 others from the literature, to provide a definitive account of the adult form of Niemann-Pick disease type C (usually due to mutations of NPC1 and resulting in abnormalities of cellular trafficking of endocytosed cholesterol). They identify early visceral, subsequent cortical, and eventual deep brain patterns of clinical evolution (page 120): with the emerging availability of enzymatic therapies for lysosomal storage diseases, early recognition and prevention of the irreversible deep brain lesions seem realistic aims. Markus Ries and investigators from three branches at the National Institutes of Health (Bethesda, USA) assess hearing loss in 109 male cases with Fabry disease (due to mutations of GALA): the high prevalence of deafness correlates directly with evidence for white matter vascular involvement and neuropathy but inversely with residual levels of 
–galactosidase, especially in males (page 143). Thus, restoring levels of –galactosidase may prevent neurological morbidity.
In their review on page 10, Stefano Ramat, John Leigh, David Zee and Lance Optican address one of the most informative aspects of the neurological examination—eye movements—but come at the problem by considering what clinical neurology can teach about normal organisation (focusing on slow and interrupted saccades, and high-frequency and macrosaccadic oscillations), rather than the more usual tactic of seeking to explain clinical signs from the perspective of neurobiological models of normal physiology. Against this background, Sophie Rivaud-Péchoux and colleagues from Paris (France) take forward previous evidence for abnormalities of single saccadic tasks in parkinsonian syndromes to show more sophisticated abnormalities of mixed eye movements dependent upon double dissociations in Parkinson's disease and corticobasal degeneration, in contrast to the abnormal saccades seen in progressive supranuclear palsy (page 256): aside from the contribution to differential diagnosis, these observations exclude the region of the dorsolateral prefrontal cortex—required for reflexive saccades—from involvement in more complex mixed-task eye movements. Philippe Huot, Martin Lévesque and André Parent from Québec (Canada) examine the fate of dopaminergic neurones in the human striatum, found to be increased in experimental models of Parkinson's disease, using the stereological analysis of tyrosine hydroxylase positive (TH+) neurones (page 222). Normally, TH+ interneurones are found throughout the striatum but, nonetheless, clustered in the ventral striatum, and in the putamen more than the caudate. This pattern alters in the context of neurodegeneration: TH+ neurones are much reduced in Parkinson's disease and absent in Huntington's disease but those that do survive show normal morphology—findings that go in the opposite direction from rodent and primate models of dopaminergic denervation of the striatum. Perhaps the explanation lies in the exposure of patients to exogenous L-dopa—an interpretation that informs the debate on the long-term consequences of early exposure to dopamine agonists in parkinsonian disorders. Lynette Tippett and a team from Auckland (New Zealand) and Massachusetts Institute of Technology (USA) compare the distribution of GABAA receptor positive neurones in the striatal striosome and extrastriosomal matrix in the brains of 35 individuals with Huntington's disease (page 206): they correlate affective disorders in life with selective striosomal depletion of these neurones, and those cases tend to be of later onset, less severe and with fewer CAG trinucleotide repeats, thereby implicating strisome-related circuits in mood functioning.
Neurologists are often castigated for indulging in hagiography. This issue of Brain exposes that weakness. In the first of two book essays, Humphrey Rang uses ‘The chemical languages of the nervous system’ by Josef Donnerer and Fred Lembeck, and ‘The war of the soups and the sparks’ by Elliott Valenstein to tell the story of how the contest between physiologists and pharmacologists on how nerve cells communicate was resolved in the favour of those who espoused the doctrine of chemical transmission (page 299). The heroes are Otto Loewi (1873–1961), Henry Dale (1875–1968), Wilhelm Feldberg (1900–1993), and the one who was somewhat forgotten—Walter B Cannon (1871–1945). As professor emeritus of pharmacology in the University of London, and himself a distinguished scientist who built on the work of these investigators, Professor Rang supplements the first-hand accounts of events and of each other provided by these four pioneers, two of whom received the Nobel prize for their work. Humphrey Rang tells how summary arrest by the Nazis elicited a main concern from Loewi and Feldberg that each would be killed before their latest experiments could be completed and published; and Loewi persuaded his guard to provide paper and pencil, so that the work might be written and mailed to ‘Die Naturwissenchaften’ (by the guard). At much the same time, the leading exponent of neurosurgery in the 20th century, Harvey Cushing (1869–1939), was resurrecting the status of this surgical discipline. As Samuel Greenblatt makes clear in his essay, based on the new biography of Cushing (Harvey Cushing. A life in Surgery, by Michael Bliss 2005, supplementing that written sixty years ago by John Fulton, Harvey Cushing: a biography. Blackwell and CC Thomas 1946), neurosurgery was then at its nadir given the awful mortality and morbidity of neurosurgical procedures in the early 1900s (page 303). British heroes of neurosurgery—Sir Wiliam Macewen (1848–1924) and Sir Victor Horsley (1857–1916)—are badged by Dr Greenblatt, himself a distinguished neurosurgeon and medical historian, as eccentric and not well disposed to research. Cushing understood that the problem to be solved was peri-operative raised intracranial pressure. Gradually, and partly through the influence of Theodor Kocher (1841–1917) and others in Europe, Cushing introduced techniques that, by 1910, had reduced his own operative mortality to 6%. Thereafter, Cushing established neurosurgery at the Brigham Hospital in Boston, was founding president of the Society of Neurosurgeons, and also made important contributions to medical history. The Life of Sir William Osler (Oxford at the Clarendon Press, 1925) was awarded the 1926 Pulitzer Prize for biography. Modestly, given the intensity of their personal relationship, the name ‘Cushing’ does not appear. And in the terrible passage describing the death of Osler's only child, Edward Revere, we read: "... they did not even hear the scream of the first shell, which dropped in their very midst and wounded or killed eight out of the twenty. .. To the officer who first leaned over him, Revere's first word was: ‘This will take me home’ .. a Blighty one – hopefully spoken by the wounded of whatever rank. .. Late that night an operation was undertaken: and a blood transfusion from one of his own less seriously wounded men brought in at the same time. All in vain; he died before sunrise on [August] the 30th [1917]". By a quirk of fate, Cushing was that anonymous officer, and it was a comfort to Sir William and Lady Osler that their great friend had administered to Revere as he lay dying in France.
On page 288, Ian McDonald summarises the neurological contributions of another hero of 20th century neurology—Sir Gordon Holmes (1876–1965)—who also saw at first hand and exploited the opportunity of studying injuries in soldiers during and after the Great War, so as better to understand brain function. This ‘occasional paper’ is based on the 11th Gordon Holmes lecture sponsored by the Guarantors of Brain. As with Cushing, Holmes understood and experienced the foundations of modern neurological medicine in the German tradition, and projected his own vision into the 20th century combining the insights of the anatomist with those of an astute clinician who thought physiologically, and earned the respect of many whose expertise was confined to one only of these disciplines. Not uncritical of Holmes's views on the psychological aspects of military life and clinical neurology, Professor McDonald—through his own contacts with neurologists who were themselves directly influenced by Holmes—established continuity, through the oral tradition, with the founders of modern clinical neuroscience. Sadly, as many of our readers will know, Ian McDonald died on December 13th 2006, soon after correcting the proofs of this, his last paper. Although Holmes studied every aspect of the cerebellum, and knew a great deal about the neurology of sensation, he did not consider that sensory disorders are ever a feature of cerebellar disease. On page 276. Domenico Restuccia and investigators from Udine and Rome (Italy), test the cerebellar influence on the processing of incoming somatosensory stimuli: they first establish that electrical finger stimulation normally elicits a parieto-occipital event related response and then show that this is altered in the context of cerebellar lesions, indicating that cerebellar processing is involved in pre-attentive detection of cortical somatosensory inputs. In From the Archives, Jan van Gijn reviews Holmes's contributions to neurology and the cerebellum: Symptomatology of cerebellar tumours; a study of forty cases. By T Grainger Stewart and Gordon Holmes. Brain 1904; 27: 522–591; The symptoms of acute cerebellar injuries due to gunshot injuries. By Gordon Holmes. Brain 1917; 40: 461–535; and The cerebellum of man. By Gordon Holmes. Brain 1939; 62: 1–30.
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