Science 27 June 2008: Vol. 320. no. 5884, p. 1739
Serotonin Modulates Behavioral Reactions to Unfairness
Serotonin (5-HT) has long been implicated in social behavior and impulsivity, but the mechanisms through which it modulates self-control remain unclear. We observed the effects of manipulating 5-HT function on behavior in the ultimatum game, where players must decide whether to accept or reject fair or unfair monetary offers from another player. Participants with depleted 5-HT levels rejected a greater proportion of unfair offers, but not fair offers, without showing changes in mood, fairness judgment, basic reward processing, or response inhibition. Our results suggest that 5-HT plays a critical role in regulating emotion during social decision-making.
Science 27 June 2008: Vol. 320. no. 5884, p. 1712
INFECTIOUS DISEASE: Costs of Meningitis Outbreaks Are Crippling, Too
One illness in a family can exact a huge toll on household income, not only in direct costs but indirect ones as well, including loss of income and property such as cattle and crops.
Science 27 June 2008: Vol. 320. no. 5884, p. 1709
VIROLOGY: 'Biased' Viruses Suggest New Vaccine Strategy for Polio and Other Diseases
Introducing hundreds of seemingly inconsequential mutations into a poliovirus can cripple the virus enough to make it work as a live vaccine in mice, scientists report on page 1784 of this week's issue of Science. The technology might lead to safer polio vaccines and perhaps to so-called live attenuated vaccines against other diseases.
Nature 453, 1192-1194 (26 June 2008)
Behavioural neuroscience: Out of sight, but not out of mind
Flies are cleverer than previously thought. They can remember their original destination even if distracted en route by another landmark. This behaviour depends on a specific group of neurons.
You are walking down a street to meet a friend at the end of it. You are early; so to kill time, you go into a café.
Nature 453, 1244-1247 (26 June 2008)
Analysis of a spatial orientation memory in Drosophila
Flexible goal-driven orientation requires that the position of a target be stored, especially in case the target moves out of sight. The capability to retain, recall and integrate such positional information into guiding behaviour has been summarized under the term spatial working memory. This kind of memory contains specific details of the presence that are not necessarily part of a long-term memory. Neurophysiological studies in primates indicate that sustained activity of neurons encodes the sensory information even though the object is no longer present. Furthermore they suggest that dopamine transmits the respective input to the prefrontal cortex, and simultaneous suppression by GABA spatially restricts this neuronal activity. Here we show that Drosophila melanogaster possesses a similar spatial memory during locomotion. Using a new detour setup, we show that flies can remember the position of an object for several seconds after it has been removed from their environment. In this setup, flies are temporarily lured away from the direction towards their hidden target, yet they are thereafter able to aim for their former target. Furthermore, we find that the GABAergic (stainable with antibodies against GABA) ring neurons of the ellipsoid body in the central brain are necessary and their plasticity is sufficient for a functional spatial orientation memory in flies. We also find that the protein kinase S6KII (ignorant) is required in a distinct subset of ring neurons to display this memory. Conditional expression of S6KII in these neurons only in adults can restore the loss of the orientation memory of the ignorant mutant. The S6KII signalling pathway therefore seems to be acutely required in the ring neurons for spatial orientation memory in flies.
Nature 453, 1248-1252 (26 June 2008)
Hippocampus-independent phase precession in entorhinal grid cells
Theta-phase precession in hippocampal place cells1 is one of the best-studied experimental models of temporal coding in the brain. Theta-phase precession is a change in spike timing in which the place cell fires at progressively earlier phases of the extracellular theta rhythm as the animal crosses the spatially restricted firing field of the neuron. Within individual theta cycles, this phase advance results in a compressed replication of the firing sequence of consecutively activated place cells along the animal's trajectory, at a timescale short enough to enable spike-time-dependent plasticity between neurons in different parts of the sequence. The neuronal circuitry required for phase precession has not yet been established. The fact that phase precession can be seen in hippocampal output stuctures such as the prefrontal cortex suggests either that efferent structures inherit the precession from the hippocampus or that it is generated locally in those structures. Here we show that phase precession is expressed independently of the hippocampus in spatially modulated grid cells in layer II of medial entorhinal cortex, one synapse upstream of the hippocampus. Phase precession is apparent in nearly all principal cells in layer II but only sparsely in layer III. The precession in layer II is not blocked by inactivation of the hippocampus, suggesting that the phase advance is generated in the grid cell network. The results point to possible mechanisms for grid formation and raise the possibility that hippocampal phase precession is inherited from entorhinal cortex.
Nature 453, 1253-1257 (26 June 2008)
Rapid strengthening of thalamo-amygdala synapses mediates cue–reward learning
What neural changes underlie individual differences in goal-directed learning? The lateral amygdala (LA) is important for assigning emotional and motivational significance to discrete environmental cues, including those that signal rewarding events. Recognizing that a cue predicts a reward enhances an animal's ability to acquire that reward; however, the cellular and synaptic mechanisms that underlie cue–reward learning are unclear. Here we show that marked changes in both cue-induced neuronal firing and input-specific synaptic strength occur with the successful acquisition of a cue–reward association within a single training session. We performed both in vivo and ex vivo electrophysiological recordings in the LA of rats trained to self-administer sucrose. We observed that reward-learning success increased in proportion to the number of amygdala neurons that responded phasically to a reward-predictive cue. Furthermore, cue–reward learning induced an AMPA (-amino-3-hydroxy-5-methyl-isoxazole propionic acid)-receptor-mediated increase in the strength of thalamic, but not cortical, synapses in the LA that was apparent immediately after the first training session. The level of learning attained by individual subjects was highly correlated with the degree of synaptic strength enhancement. Importantly, intra-LA NMDA (N-methyl-d-aspartate)-receptor blockade impaired reward-learning performance and attenuated the associated increase in synaptic strength. These findings provide evidence of a connection between LA synaptic plasticity and cue–reward learning, potentially representing a key mechanism underlying goal-directed behaviour.
JAMA Vol. 299 No. 24, June 25, 2008
Alcohol Use, Thiamine Deficiency, and Cognitive Impairment
To the Editor: In his Clinical Crossroads article, Dr Brust discussed the patient Mr E, an older, moderate to heavy alcohol drinker experiencing memory difficulty and an apparently unrelated polyneuropathy. Mild cognitive impairment (MCI), early Alzheimer disease (AD), Wernicke-Korsakoff syndrome, and "alcoholic dementia" were considered as possible diagnoses. Appropriate management of the suggested diagnosis of MCI or early AD for this patient included measures to reduce alcohol dependence and to delay progression of the cognitive impairment. However, many epidemiological studies have failed to identify a positive relationship between moderate alcohol intake (usually up to 1 or 2 drinks daily) and risk of dementia, and they have also found such amounts to be protective.
JAMA Vol. 299 No. 24, June 25, 2008
Alcohol Use, Thiamine Deficiency, and Cognitive Impairment
To the Editor: In his consideration of an elderly man with memory loss and neuropathy, Dr Brust discussed Wernicke-Korsakoff syndrome, sometimes known as cerebral beriberi. Brust mentioned the patient's alcohol intake as a possible precipitant. I would like to add 2 points.
First, Brust noted the relatively high prevalence of Wernicke-Korsakoff syndrome in Australia. Flour and bread were not fortified with thiamine in Australia as early as in other countries. An expert committee in Australia had studied the question and concluded that the average Australian diet contained enough thiamine, although it recognized that Australian alcoholics were not consuming enough thiamine.
This principled approach had the unintended effect of providing nutritionists and clinicians with a geographic natural experiment. Autopsies performed in the 1980s showed that the prevalence of Wernicke-Korsakoff syndrome was much higher in Australia than in other countries that enriched their bread.
JAMA Vol. 299 No. 24, June 25, 2008
Alcohol Use, Thiamine Deficiency, and Cognitive Impairment—Reply
In Reply: As noted by Dr Panza and colleagues, the findings of the Italian Longitudinal Study on Aging (ILSA) support the view that mild to moderate alcohol consumption has beneficial effects on cognition in the elderly. Their data do not persuade me, however, that rather than abstinence from alcohol, "a viable alternative option" for Mr. E would be "moderate drinking." As their article notes, studies addressing alcohol's effects on cognition have produced "inconsistent results." In one study, benefit disappeared after adjusting for demographic and socioeconomic factors. One study found the most favorable effects in participants carrying the apolipoprotein E 4 allele, whereas another found the greatest benefit in participants without the apolipoprotein E 4 allele. One found benefit only for wine, whereas another found benefit for wine, beer, or spirits.
JAMA Vol. 299 No. 24, June 25, 2008:2841.
Sleep Apnea Linked to Cardiovascular Risks
Toronto—If viewed through the lens of its most common complaints—loud snoring, disrupted sleep, and excessive daytime sleepiness—obstructive sleep apnea (OSA) may seem to be more of an annoyance rather than a condition with potentially serious health effects. But the condition imposes considerable risks of developing cardiovascular abnormalities because of the repetitive cycles of snoring, airway collapse, and awakening. One reason for this increased risk is that low blood oxygen levels during these cycles induces harmful responses, such as hypertension, in the vasculature.
The Lancet Vol: 371 Issue: 9630, June 21 - 27 2008 pp: 2059-2060
Laquinimod, a new oral drug for multiple sclerosis
Relapsing-remitting multiple sclerosis is an inflammatory demyelinating disease of the CNS that is presumed to have an autoimmune cause. In most patients, the disease is chronic and progresses over decades. Early stages are heralded by relapses of neurological dysfunction within the CNS associated with transient gadolinium-enhancing lesions on T1-weighted MRI that usually leave chronic non-enhancing T1 and T2 lesions in their wake. MRI measures of disease activity have been widely adopted to screen for effectiveness of new therapies in phase I and II clinical trials, although they do not serve as the sole determinant of efficacy in phase III trials.
The Lancet Vol: 371 Issue: 9630, June 21 - 27 2008 pp: 2085-2092
Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
Background
A 24-week phase II trial has shown that 0·3 mg of laquinimod given daily to patients with relapsing-remitting multiple sclerosis was well tolerated and reduced the formation of active lesions. We assessed the effect of oral daily 0·3 and 0·6 mg laquinimod on MRI-monitored disease activity in a 36-week double-blind, placebo-controlled phase IIb study.
Methods
The study was done in 51 centres in nine countries. Inclusion criteria were one or more relapses in the year before entry and at least one gadolinium enhancing (GdE) lesion on screening MRI. Of 720 patients screened, 306 eligible patients were enrolled. Patients, aged 18–50 years, were randomly assigned to placebo (n=102), laquinimod 0·3 mg a day (n=98), or 0·6 mg a day (n=106). Brain MRI scans and clinical assessments were done at week −4, baseline, and monthly from week 12 to week 36. The primary outcome was the cumulative number of GdE lesions at weeks 24, 28, 32, and 36. The principal analysis of the primary endpoint was done on the intention-to-treat cohort. This study is registered with ClinicalTrials.gov , number NCT00349193 .
Findings
Compared with placebo, treatment with laquinimod 0·6 mg per day showed a 40·4% reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans (simple means 4·2 [SD 9·2] vs 2·6 [5·3], p=0·0048); treatment with 0·3 mg per day showed no significant effects (3·9 [5·5] vs placebo, p=0·6740). Both doses of laquinimod were well tolerated, with some transient and dose-dependent increases in liver enzymes. A case of Budd-Chiari syndrome—ie, a thrombotic venous outflow obstruction of the liver—occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0·6 mg laquinimod. Anticoagulant treatment resulted in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation.
Interpretation
In patients with relapsing-remitting multiple sclerosis, 0·6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated.
The Lancet Vol: 371 Issue: 9630, June 21 - 27 2008 pp: 2120-2133
Spinal muscular atrophy
Spinal muscular atrophy is an autosomal recessive neurodegenerative disease characterised by degeneration of spinal cord motor neurons, atrophy of skeletal muscles, and generalised weakness. It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation. Although no medical treatment is available, investigations have elucidated possible mechanisms underlying the molecular pathogenesis of the disease. Treatment strategies have been developed to use the unique genomic structure of the SMN1 gene region. Several candidate treatment agents have been identified and are in various stages of development. These and other advances in medical technology have changed the standard of care for patients with spinal muscular atrophy. In this Seminar, we provide a comprehensive review that integrates clinical manifestations, molecular pathogenesis, diagnostic strategy, therapeutic development, and evidence from clinical trials.
The Lancet Vol: 371 Issue: 9630, June 21 - 27 2008 pp: 2144
Seizures, hyponatraemia, and “poison”
In May, 2007, a 63-year-old woman vomited, collapsed, had a seizure, and lost consciousness. She was intubated at home before being brought to our hospital by ambulance.
Blood pressure, temperature, and respiratory rate were normal; the arterial oxygen saturation was 98%, and the blood glucose concentration was 10 mmol/L. The patient was not dehydrated; the central venous pressure was equivalent to 9 cm water. CT of the brain showed nothing abnormal. Blood tests showed severe hyponatraemia (100 mmol/L), hypokalaemia (2·9 mmol/L), and severe hypochloraemia (64 mmol/L). Concentrations of creatine kinase and lactate were high, consistent with the recent seizure.
NEJM Volume 358:2849-2850 June 26, 2008 Number 26
Early Coenzyme Q10 Supplementation in Primary Coenzyme Q10 Deficiency
Primary coenzyme Q10 deficiency is considered to be the only treatable mitochondrial disorder, since patients have a response to oral coenzyme Q10 supplementation. The disease usually manifests with nephropathy and encephalomyopathy. It has been shown that oral coenzyme Q10 may stop the progression of encephalopathy, but no benefit from this therapy has been noted with respect to the evolution of renal disease associated with this deficiency.