Editorial
One consequence of the intense interest in neuroscience shown by contemporary society is to challenge the strictly neurocentric formulation on how the brain works in health and disease. Once, it was an organ that could be understood by appreciating neuronal activities, scaled up through systems that sense and respond to the internal and external environments. The gathering of higher order behaviours such as emotion and associative memory within this reductionist framework is no longer palatable to those who view social interactions and cultural factors as crucial in shaping the development of the nervous system and in orchestrating its effects on behaviour of the individual and of groups. Thus, ‘neurodeterminism’ bumps up against the analyses of social science and it challenges the assumed ownership of the brain by those trained in neuroscience. Social factors influence the organization of ‘brain and behaviour’, and ‘a vocabulary of genes, neurones and reinforcers’ is no longer a sufficient basis for understanding the nervous system. This debate is argued in ‘Explaining Emotion in the Brain’ where Ralph Adolphs reviews ‘Emotion explained’ by Edmund T. Rolls (page 2517) Professor Adolphs, now at the California Institute of Technology, was formerly in the Department of Neurology and Neuroscience at the University of Iowa where, with colleagues, he systematically used the examples of clinical neurology to understand patterns of human behaviour with an emphasis on decision-making, reward, sadness, fear and disgust, and the emotional valence of vision and music, alone and in the broader cultural context. On this topic, we publish a paper by Virginia Sturm and colleagues from the Universities of California at Berkeley and San Francisco (USA) on the failure of individuals with fronto-temporal dementia to register emotional events that require self-recognition but in a social setting, using embarrassment induced by startle as the index (page 2508); whilst noting the surprise of an acoustic stimulus by appropriate physiological responses, cases show reduced self-consciousness indicating a role for the medial prefrontal cortex in emotions that relate to the individual, and explaining some of the social difficulties these patients may encounter. Nicholas Danziger, Kenneth Prkachin, and Jean-Claude Willer from the Pitié-Salpétrière, Paris (France) and the University of British Columbia (Canada) consider how individuals with congenital insensitivity to pain perceive discomfort in other people: whilst showing appropriate semantic responses and recognizing facial gestures registering pain, those who do not feel it themselves badly under-rate the painful experiences of others especially when emotional cues are lacking (page 2494).Amongst 11 papers in the present issue having a neurogenetics flavour (several relating to Creutzfeldt–Jakob disease, see later), we publish an analysis by Kathrin Lasek and colleagues from Lübeck, Rostock and Hamburg (Germany) of regional grey matter degeneration in spinocerebellar ataxia 17 (SCA17): motor deficits correlate with atrophy of the cerebellum and basal ganglia; whereas psychiatric features predict loss of grey matter in the frontal and temporal lobes, the cuneus, cingulum and, especially, nucleus accumbens (page 2341). But how do these neurones die? On page 2353, Kenji Sakai and investigators from Universities in Kanazawa, Niigita and Tokyo (Japan) use a mouse model of dentatorubropallidoluysian atrophy (DRPLA) to take forward the suggestion that regional differences in intranuclear mutant protein accumulation, resulting from variable repeat sizes, determine neuronal loss: DRPLA transgenic mice with 129 polyglutamine repeats show significant atrophy of the perikarya and dendrites, whose spines are decreased in number and appear stubby; inter-microtubular spacing is disrupted in atrophic axons sampled in the pyramid and corpus callosum; and synaptic structures are also partially disrupted. Hence, the polyglutamine pathogenesis is critical to cell loss and it shapes the clinical phenotype in this particular model of spinocerebellar degeneration.
Three papers describe the role of transforming growth factor-ß (TGF-ß) in infections of the brain, and in tumour formation. Ursula Malipiero and colleagues from Zurich and Geneva (Switzerland), Munich (Germany) and Lund (Sweden) show that the complex behaviour of leucocytes recruited to sites of bacterial infection is differentially affected by deletion in mice of the TGF-ß type 2 receptor gene (page 2404); leucocyte recruitment is enhanced and bacterial clearance improves whereas necrotizing vasculitis does not occur, the benefits involving a mechanism that limits the normal loss of L-selectin expression on polymorphonuclear leucocytes in response to TGF-ß. Günter Eisele and investigators from Tübingen (Germany) characterize the differential expression of NKG2D receptors on human glioma cells: compared with normal brain cells up-regulation occurs in response to local TGF-ß expression but with subsequent cleavage by metalloproteinases (page 2416); the activity of natural killer cells in regulating tumour immunity may therefore be compromised by an autocrine loop that increases TGF-ß, and perturbs metalloproteinase-dependent shedding of the NKG2D receptor on which immune surveillance normally depends. The same group, under the authorship of Ghazaleh Tabatabai, build on previous evidence for TGF-ß tropism to gliomas of adult haematopoietic stem and progenitor cells to show that hypoxia-inducible factor-1
, interacting with TGF-ß, also increases cell migration by an effect on the chemokine CXCL12 under conditions of radiation or hypoxic stress; here is a potential strategy for increasing the recruitment of stem cells carrying an anti-tumour payload to sites of tumour formation (page 2426).
Many patients spending time on an intensive care unit develop a subacute neuropathy. The nature is not altogether clear; but on page 2461 Werner Z'Graggen and investigators from the Institute of Neurology and St Thomas's Hospital, London (UK) characterize the electrophysiological deficits in 10 patients with critical illness neuropathy as membrane hyperpolarization resulting from metabolic abnormalities, especially hypokalaemia and raised bicarbonate with base excess attributable to respiratory acidosis, and hypoperfusion. As a rule, critical illness recovers if the patient survives, and presumably the nerve fibres regenerate. An old subject revisited by Mihai Moldovan, Jesper Sørensen and Christian Krarup from Copenhagen (Denmark) tests the fastest rates of recovery for motor and sensory fibres after crush injury or section of the cat tibial nerve (page 2471); using meticulous methods of assessment, elite axonal sensory and motor athletes come in equal first, recording similar conduction velocities and rates of regeneration although, as a team, sensory axons may just breach the tape ahead of motor fibres.
In From the Archives for July, we discussed a paper from 1934 by James Purdon Martin and Dr ‘Barney’ Alcock, then ‘happily living and in his 98th year’: sadly, Dr Alcock died on July 3, 2006. Brain does not, as a rule, offer thematic issues, although we aim to group articles on similar topics and to move the contents effortlessly across the spectrum of clinical disorders featured each month. Occasionally, by chance, several papers on a related subject are simultaneously ready for publication. In October, we anticipate printing eight articles, in various categories, on music and the brain; in November, we will devote the issue to papers on Alzheimer's and related disorders, in celebration of the centenary of the original description of Auguste D on November 3, 1906; and, here, we publish six papers that deal with the spongiform encephalopathies. Clare Trevitt and John Collinge from the MRC Prion Unit, London, review past efforts to devise rational therapies for these disorders, and they provide a comprehensive catalogue of what has been tried and what might now be tested as knowledge on the nature and pathogenesis of the spongiform encephalopathies increases (page 2241). Simon Mead from the same Unit, and with colleagues from the Institute of Neurology and Kings College Hospital, London, brings up to date genotype–phenotype correlations in 86 individuals from a family—the largest, by a distance—with an inherited octapeptide repeat insertion in the prion protein gene from South-east England; they include an autopsy report from 1901, predating by two decades the original single-authored reports of Hans Gerhard Creutzfeldt (1885–1964) and Alfons Maria Jakob (1884–1931) in 1920 and 1921, respectively (page 2297; and see cover). Ignazio Cali and colleagues from Case Western Reserve University, Cleveland, and the University of Maryland, Baltimore (USA), and the University of Bologna (Italy) revisit the classification of Creutzfeldt–Jakob disease (page 2266); Steven Collins writes on behalf of investigators in EUROCJD from Melbourne (Australia), Rotterdam (Netherlands), Rome (Italy), Madrid (Spain), Vienna (Austria), Zurich (Switzerland), Göttingen and Munich (Germany), Ottawa (Canada), Bratislava (Slovakia), Paris, (France) and Edinburgh (UK) to describe the diagnostic sensitivity of laboratory investigations across the spectrum of 2451 pathologically proven cases of Creutzfeldt–Jakob disease (page 2278); and Anna Krasnianski and colleagues from Göttingen and Munich (Germany) and Edinburgh (UK) provide a phenotypic description of the MV2 subtype of sporadic Creutzfeldt–Jakob disease (page 2288). These three papers are discussed in the scientific commentary by Mark Head and James Ironside who clarify the debate on molecular classification of PrPSc isoforms that accumulate in the brain of individuals with Creutzfeldt–Jakob disease.
The story of Creutzfeldt–Jakob disease includes detailed reports of conditions in which the clinical fate and crude pathological descriptions were all too apparent but the nature of the disorder remained obscure. Gradually, the nature of these degenerative diseases was illuminated, and conditions considered to be vascular disorders, or utterly mysterious, when first described gradually came to be recognized within the group of transmissible spongiform encephalopathies. Starting in 1940, Brain has charted many evolutions in understanding these conditions. In From the Archives, we review: (i) A form of familial presenile dementia with spastic paralysis (including the pathological examination of a case). (By Worster-Drought C, Greenfield JG and McMenemey WH. Brain 1940: 63; 237–54); (ii) A form of familial presenile dementia with spastic paralysis. (By Worster-Drought C, Greenfield JG and McMenemey WH. Brain 1944: 67; 37–43); (iii) Subacute spongiform encephalopathy—a subacute form of encephalopathy attributable to vascular dysfunction (spongiform cerebral atrophy). (By Nevin S, McMenemey WH, Behrman S and Jones DP. Brain 1960: 83; 521–64); (iv) Creutzfeldt–Jakob disease. The neuropathology of a transmission experiment. (By Elisabeth Beck, Daniel PM, Matthews WB, Stevens DL, Alpers MP, Asher DM, Gajdusek DC and Gibbs CJ Jr. Brain 1969: 92; 699–716); (v) Subacute spongiform encephalopathy (Creutzfeldt–Jakob disease). The nature and progression of spongiform change. (By Masters CL and Richardson EP Jr. Brain 1978: 101; 333–44); and (vi) Creutzfeldt–Jakob disease virus isolations from the Gerstmann–Sträussler syndrome with an analysis of the various forms of amyloid plaque deposition in the virus-induced spongiform encephalopathies. (By Masters CL, Carleton Gajdusek D and Gibbs CJ Jr. Brain 1981: 104; 559–88).
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