Nature 452, 1 (6 March 2008) | doi:10.1038/452001a; Published online 5 March 2008
No more scavenger hunts
The recent media flap over antidepressants highlights the need for data to be transparent — and for a mandatory database of all clinical trials.
It was not the media's finest hour. When a study was released last week challenging the effectiveness of several popular antidepressant drugs, (I. Kirsch et al. PLoS Med. 5, e45; 2008) some news outlets, particularly in the United Kingdom, responded with headlines blaring 'the drugs don't work' — even though the drugs often do work. Yes, the study showed that the drugs often performed no better than a placebo. But what many of the media missed was that the placebo effect can be remarkably strong in psychological and neurological disorders, especially in mild depression. Doctors scrambled to assure patients that they should not abandon treatment.

Nature 452, 35-36 (6 March 2008) | doi:10.1038/452035a; Published online 5 March 2008
Physiology: Keeping it regular with protons
Muscle coordination is mostly governed by motor programs built into the nervous system. But one program — the defecation cycle in a worm — has a mechanism that avoids nerves completely and uses protons as signals.
For athletes in a race, the crack of the starter's pistol signals an intense burst of physical effort and mental concentration — but at least they don't have to think about coordinating their legs. After the initial impulse from the brain to start running, limb control is mostly unconscious, governed by a motor program in which motor neurons direct muscle fibres to contract in the right sequence.

Nature 452, 38-39 (6 March 2008) | doi:10.1038/452038a; Published online 5 March 2008
Neuroscience: A complex in psychosis
The molecular basis of psychoses such as schizophrenia remains largely mysterious. The interaction between two of the brain receptors involved adds to evidence that will help in the search for explanations.
This is a story that involves three types of receptor in the brain that influence human perception and behaviour (those for the neurotransmitters dopamine, serotonin and glutamate), and the drugs that block or enhance their activity. Such drugs are used by researchers to investigate the causes of psychotic disorders such as schizophrenia, and by clinicians to treat patients.

Nature 452, 93-97 (6 March 2008) | doi:10.1038/nature06612; Received 2 November 2007; Accepted 20 December 2007; Published online 24 February 2008
Identification of a serotonin/glutamate receptor complex implicated in psychosis
The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR–mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR–mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.

Nature 452, E1 (6 March 2008) | doi:10.1038/nature06574; Received 4 September 2007; Accepted 29 November 2007
Arousal by stimulation of deep-brain nuclei
Schiff et al. show that deep-brain stimulation of the unspecific thalamocortical system through certain midline thalamic nuclei produces an alerting effect in a patient in a minimally conscious state. Such nuclei include the central lateral nucleus, paralaminar regions of the median dorsalis, and the posterior–medial aspect of the centromedian/parafascicularis nucleus complex.

Nature 452, 98-102 (6 March 2008) | doi:10.1038/nature06604; Received 24 October 2007; Accepted 21 December 2007; Published online 20 February 2008
Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons
Cytokines affect a variety of cellular functions, including regulation of cell numbers by suppression of programmed cell death. Suppression of apoptosis requires receptor signalling through the activation of Janus kinases and the subsequent regulation of members of the B-cell lymphoma 2 (Bcl-2) family. Here we demonstrate that a Bcl-2-family-related protein, Hax1, is required to suppress apoptosis in lymphocytes and neurons. Suppression requires the interaction of Hax1 with the mitochondrial proteases Parl (presenilin-associated, rhomboid-like) and HtrA2 (high-temperature-regulated A2, also known as Omi). These interactions allow Hax1 to present HtrA2 to Parl, and thereby facilitates the processing of HtrA2 to the active protease localized in the mitochondrial intermembrane space. In mouse lymphocytes, the presence of processed HtrA2 prevents the accumulation of mitochondrial-outer-membrane-associated activated Bax, an event that initiates apoptosis. Together, the results identify a previously unknown sequence of interactions involving a Bcl-2-family-related protein and mitochondrial proteases in the ability to resist the induction of apoptosis when cytokines are limiting.

BMJ  2008;336:461 (1 March), doi:10.1136/bmj.39500.434086.1F
Long term outcome of stroke Stroke is a chronic disease with acute events
Bruins et al and the accompanying editorial on stroke care make a compelling case for reviewing conventional policy approaches to stroke, which often show a dysequilibrium towards the (very important) front end of stroke, and a relative agnosia for (equally important) aftercare. Although it is clearly very important that all should have access to stroke unit care (and thrombolysis for those for whom it is indicated), most patients will still have residual disability after both of these interventions and will be more prone to further strokes than the rest of the population. Comprehensive national audits of stroke care show alarming levels of neglect in terms of chronic disease management and seem to indicate a collective nihilism about the potential for altering function and wellbeing after the early treatment of stroke, despite evidence of the effectiveness of continuing therapy and support at long intervals after stroke.

BMJ  2008;336:466 (1 March), doi:10.1136/bmj.39503.656852.DB (published 26 February 2008)
Meta-analysis shows difference between antidepressants and placebo is only significant in severe depression
New generation antidepressants achieve almost no benefit compared with placebo in mild to moderate depression, with slightly more benefit in severe depression but only because of less response to placebo, a meta-analysis of clinical trial data has shown.
Researchers analysed all available data from clinical trials submitted to the US Food and Drug Administration for the licensing of four selective serotonin or serotonin-noradrenaline reuptake inhibitors—fluoxetine (Prozac), venlafaxine (Efexor), nefazodone (Serzone), and paroxetine (Seroxat, Paxil).
They analysed the degree to which people improved in relation to the initial severity of the depression in people randomised to drug or placebo.
Results showed almost no difference between the effects of drug treatment and placebo at moderate levels of initial depression, rising to a relatively small difference in patients with severe depression.

BMJ  2008;336:466-467 (1 March), doi:10.1136/bmj.39503.343993.DB
Downward trend in dementia linked to better education and personal wealth, US study says
"Cognitive decline" is declining among Americans older than 70, a study of 11 000 elderly US residents carried out at the University of Michigan Medical School has found (Alzheimer’s and Dementia 2008 http://alzheimersanddementia.org/webfiles/images/journals/jalz/JALZ_731.pdf).
Cognitive decline includes significant memory loss, dementia, and Alzheimer’s disease among people older than 70.
The study showed that higher education and higher net financial worth protected against cognitive impairment.
The authors used data from the health and retirement study, a nationally representative, population based longitudinal study of US adults. They compared two groups of people aged 70 and older—7406 in the 1993 cohort and 7104 in the 2002 cohort. The authors used a 35 point cognitive scale or proxy assessments of memory and judgment to determine cognitive impairment.
Cognitive impairment "consistent with dementia" declined from 12.2% of the 1993 cohort to 8.7% of the 2002 cohort—a decrease of almost 30%, the authors report.

JAMA. 2008;299(9):1046-1054.
CLINICIAN'S CORNER
A 74-Year-Old Man With Memory Loss and Neuropathy Who Enjoys Alcoholic Beverages
Adverse effects of alcohol on the peripheral and central nervous system can be direct (ie, neurotoxicity) or indirect (eg, nutritional deficiency). Using the case of Mr E, an older, moderate to heavy drinker experiencing memory difficulty, the diagnostic considerations, which include mild cognitive impairment, early Alzheimer dementia, Wernicke-Korsakoff syndrome, and "alcoholic dementia," are discussed. These disorders are not mutually exclusive, and in a patient with either mild cognitive impairment or dementia, the contributory role of alcohol can be difficult to determine. In fact, epidemiological studies suggest that mild to moderate intake of alcohol actually reduces the risk of developing mild cognitive impairment or dementia, including Alzheimer dementia. Appropriate management includes measures to reduce alcohol dependence (eg, behavioral or pharmacological therapy) and to delay progression of the cognitive impairment (eg, engaging in healthy behaviors such as cognitive leisure activities).

JAMA. 2008;299(9):1008.
Neuronal Map
A new map of mouse neuronal proteins constructed by researchers at the University of California, San Diego, School of Medicine may help investigators discover how neurites in the brain develop and function (Pertz OC et al. Proc Natl Acad Sci U S A. 10.1073/pnas.0706545105 [published online ahead of print February 1, 2008]).
Neurons regenerate by sending out long, thin neurites that differentiate into axons or dendrites. The researchers developed a microporous filter technology that can isolate and purify these long membrane extensions, which bud from neuronal bodies, or somata. They then used quantitative mass spectrometry, computational software, and bioinformatics to match neurite proteins to their cellular functions and to construct a blueprint of how the proteins work together to facilitate neurite formation. They mapped 4855 proteins in neurites and somata, revealing distinct types of signaling proteins in each.

The Lancet Volume 371, Issue 9614, 1 March 2008-7 March 2008, Page 698
Music in stroke rehabilitation
Around a third of people who survive after stroke remain reliant on others for their care. For both patients and their families, rehabilitation services are crucial to reduce disability and dependency after stroke.
Stroke rehabilitation has been criticised for not being rooted in science. However, over the past 10 years an evidence base for rehabilitation has been building and interest in stroke recovery is being revitalised. New potential therapies are under investigation and include the use of virtual reality to simulate real-life learning and robotic devices to increase the amount and intensity of limb exercise.
Last week, the publication of a single-blind randomised trial on listening to music after middle-cerebral-artery stroke raised another intriguing possibility for rehabilitation. In a 60 patient trial, Finnish investigators found that patients who listened to self-selected music daily during the first 2 months after stroke had better cognitive recovery and mood when compared with those who listened to audio books or those with no listening materials. Patients' verbal memory and focused attention improved significantly more in the music group than in the language or control group when measured 3 and 6 months post-stroke.

The Lancet Volume 371, Issue 9614, 1 March 2008-7 March 2008, Pages 715-716
The neuroscience of art
Jonah Lehrer, Proust Was A Neuroscientist, Houghton Mifflin (2007) ISBN 0-618-62010-9 Pp 242. US$24·00. The premise of this entertaining book can be simply put: that the work of certain groundbreaking artists anticipated later scientific discoveries. Thus Walt Whitman was before his time when he passionately insisted in his poetry that the mind-body dualism was false, while the broken shapes of Paul Cézanne's paintings were subsequently shown to be an exact representation of how the eye first perceives reality, before the brain interprets it. The mixed reception granted to such works of art in their day was due not only to the demands they made on aesthetic taste but also to the fact that, consciously or not, they represented other truths with which the public was unfamiliar.

NEJM Volume 358:1009-1017  March 6, 2008  Number 10
A Parkinsonian Syndrome in Methcathinone Users and the Role of Manganese
Background A distinctive extrapyramidal syndrome has been observed in intravenous methcathinone (ephedrone) users in Eastern Europe and Russia.
Methods We studied 23 adults in Latvia who had extrapyramidal symptoms and who had injected methcathinone for a mean (±SD) of 6.7±5.1 years. The methcathinone was manufactured under home conditions by potassium permanganate oxidation of ephedrine or pseudoephedrine. All patients were positive for hepatitis C virus, and 20 were also positive for the human immunodeficiency virus (HIV).
Results The patients reported that the onset of their first neurologic symptoms (gait disturbance in 20 and hypophonia in 3) occurred after a mean of 5.8±4.5 years of methcathinone use. At the time of neurologic evaluation, all 23 patients had gait disturbance and difficulty walking backward; 11 patients were falling daily, and 1 of these patients used a wheelchair. Twenty-one patients had hypophonic speech in addition to gait disturbance, and one of these patients was mute. No patient reported decline in cognitive function. T1-weighted magnetic resonance imaging (MRI) showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all 10 active methcathinone users. Among the 13 former users (2 to 6 years had passed since the last use), lesser degrees of change in the MRI signal were noted. Whole-blood manganese levels (normal level, <209 nmol per liter) averaged 831 nmol per liter (range, 201 to 2102) in the active methcathinone users and 346 nmol per liter (range, 114 to 727) in former users. The neurologic deficits did not resolve after patients discontinued methcathinone use.
Conclusions Our observation of a distinctive extrapyramidal syndrome, changes in the MRI signal in the basal ganglia, and elevated blood manganese levels in methcathinone users suggests that manganese in the methcathinone solution causes a persistent neurologic disorder.