Science. Vol 320. No 5882, pp 1412 – 1414. June 13, 2008
Neuroimaging: Growing Pains for fMRI
Greg Miller
As the use of functional magnetic resonance imaging has exploded, some researchers say the field could use a dose of rigor. Will new experimental approaches come to the rescue?

Science. Vol 320. No 5882, p 1413. June 13, 2008
NEUROIMAGING: Don't Be Seduced by the Brain
Greg Miller.
The images generated by functional magnetic resonance imaging may have a power to captivate that reaches beyond their power to explain

Science. Vol 320. No. 5882, pp. 1510 – 151213. June 13,  2008
Transfer of Learning After Updating Training Mediated by the Striatum
Erika Dahlin
Process-specific training can improve performance on untrained tasks, but the magnitude of gain is variable and often there is no transfer at all. We demonstrate transfer to a 3-back test of working memory after 5 weeks of training in updating. The transfer effect was based on a joint training-related activity increase for the criterion (letter memory) and transfer tasks in a striatal region that also was recruited pretraining. No transfer was observed to a task that did not engage updating and striatal regions, and age-related striatal changes imposed constraints on transfer. These findings indicate that transfer can occur if the criterion and transfer tasks engage specific overlapping processing components and brain regions

JAMA. Vol 299 No 22, pp 2633-2641. June 11, 2008
Hypericum perforatum (St John's Wort) for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents A Randomized Controlled Trial
Wendy Weber.
Context Stimulant medication can effectively treat 60% to 70% of youth with attention-deficit/hyperactivity disorder (ADHD). Yet many parents seek alternative therapies, and Hypericum perforatum (St John's wort) is 1 of the top 3 botanicals used.
Objective To determine the efficacy and safety of H perforatum for the treatment of ADHD in children.
Design, Setting, and Participants Randomized, double-blind, placebo-controlled trial conducted between March 2005 and August 2006 at Bastyr University, Kenmore, Washington, among a volunteer sample of 54 children aged 6 to 17 years who met Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for ADHD by structured interview.
Intervention:  After a placebo run-in phase of 1 week, participants were randomly assigned to receive 300 mg of H perforatum standardized to 0.3% hypericin (n = 27) or a matched placebo (n = 27) 3 times daily for 8 weeks. Other medications for ADHD were not allowed during the trial.
Main Outcome Measures  Performance on the ADHD Rating Scale–IV (range, 0-54) and Clinical Global Impression Improvement Scale (range, 0-7), and adverse events.
Results One patient in the placebo group withdrew because of an adverse event. No significant difference was found in the change in ADHD Rating Scale–IV scores from baseline to week 8 between the treatment and placebo groups: inattentiveness improved 2.6 points (95% confidence interval [CI], –4.6 to –0.6 points) with H perforatum vs 3.2 points (95% CI, –5.7 to –0.8 points) with placebo (P = .68) and hyperactivity improved 1.8 points (95% CI, –3.7 to 0.1 points) with H perforatum vs 2.0 points (95% CI, –4.1 to 0.1 points) with placebo (P = .89). There was also no significant difference between the 2 groups in the percentage of participants who met criteria for improvement (score 2) on the Clinical Global Impression Improvement Scale (H perforatum, 44.4%; 95% CI, 25.5%-64.7% vs placebo, 51.9%; 95% CI, 31.9%-71.3%; P = .59). No difference between groups was found in the number of participants who experienced adverse effects during the study period (H perforatum, 40.7%; 95% CI, 22.4%-61.2% vs placebo, 44.4%; 95% CI, 25.5%-64.7%; P = .78).
Conclusion  In this study, use of H perforatum for treatment of ADHD over the course of 8 weeks did not improve symptoms

JAMA 2008. Vol 299 No 22 pp 2642-2655. June 11, 2008
Effect of Bright Light and Melatonin on Cognitive and Noncognitive Function in Elderly Residents of Group Care Facilities: A Randomized Controlled Trial
Rixt F.
Context  Cognitive decline, mood, behavioral and sleep disturbances, and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers. Circadian rhythm disturbances have been associated with these symptoms.
Objective  To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: bright light and melatonin.
Design, Setting, and Participants  A long-term, double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands; mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia.
Interventions  Random assignment by facility to long-term daily treatment with whole-day bright (± 1000 lux) or dim (± 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years).
Main Outcome Measures  Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months.
Results  Light attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (–0.5 points; 95% CI, –0.10 to –1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or 9% (treatment x time effect).
Conclusions  Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia. To counteract the adverse effect of melatonin on mood, it is recommended only in combination with light.


The Lancet. Vol 371 No 9628, pp 1888. June 7 – 13, 2008
Overcoming barriers to early dementia diagnosis Editorial

The Lancet. Vol 371 No 9628, pp 1955-1969. June 7 – 13, 2008
Induced hypothermia and fever control for prevention and treatment of neurological injuries
Kees H Polderma
Increasing evidence suggests that induction of mild hypothermia (32–35°C) in the first hours after an ischaemic event can prevent or mitigate permanent injuries. This effect has been shown most clearly for postanoxic brain injury, but could also apply to other organs such as the heart and kidneys. Hypothermia has also been used as a treatment for traumatic brain injury, stroke, hepatic encephalopathy, myocardial infarction, and other indications. Hypothermia is a highly promising treatment in neurocritical care; thus, physicians caring for patients with neurological injuries, both in and outside the intensive care unit, are likely to be confronted with questions about temperature management more frequently. This Review discusses the available evidence for use of controlled hypothermia, and also deals with fever control. Besides discussing the evidence, the aim is to provide information to help guide treatments more effectively with regard to timing, depth, duration, and effective management of side-effects. In particular, the rate of rewarming seems to be an important factor in establishing successful use of hypothermia in the treatment of neurological injuries.

Nature. Vol 453 No 7197 p 863. June 12, 2008
Stéphane Palfi, Huntington's disease: Genetics lends a hand
A monkey model of Huntington's disease created by gene transfer is only a work in progress. But as a technological feat it offers great promise for fathoming this devastating condition.

Nature. Vol 453 No 7197, pp 869-878. June 12, 2008
Nikos K. Logothetis What we can do and what we cannot do with fMRI
Functional magnetic resonance imaging (fMRI) is currently the mainstay of neuroimaging in cognitive neuroscience. Advances in scanner technology, image acquisition protocols, experimental design, and analysis methods promise to push forward fMRI from mere cartography to the true study of brain organization. However, fundamental questions concerning the interpretation of fMRI data abound, as the conclusions drawn often ignore the actual limitations of the methodology. Here I give an overview of the current state of fMRI, and draw on neuroimaging and physiological data to present the current understanding of the haemodynamic signals and the constraints they impose on neuroimaging data interpretation.

Nature. Vol 453 No 7197, pp 921-924. June 12, 2008  
Shang-Hsun Yang Towards a transgenic model of Huntington's disease in a non-human primate
Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of human diseases. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10–15 years of the onset of the symptoms. HD is caused by the expansion of cytosine-adenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues, but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities,  between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. A transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies. Moreover, our data suggest that it will be feasible to generate valuable non-human primate models of HD and possibly other human genetic diseases.

Nature. Vol 453 No 7197 pp 925-929. June 12 2008  
Substrate-targeting γ-secretase modulators
Thomas L. Kukar
Selective lowering of A42 levels (the 42-residue isoform of the amyloid- peptide) with small-molecule -secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the -secretase complex, but instead labelled the -amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid- peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP -secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28–36 of amyloid-, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid- act as GSMs, and some GSMs alter the production of cell-derived amyloid- oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in A42 production and inhibition of amyloid- aggregation, which may synergistically reduce amyloid- deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets

The New England Journal of Medicine. Vol 358 No 24, pp 2619-2628. June 12, 2008
Case 18-2008 — A 68-Year-Old Man with Headache and Visual Changes after Liver Transplantation
Margaret Seton
A 68-year-old man was admitted to the hospital because of headache and loss of vision in the right eye. Orthotopic allogeneic liver transplantation had been performed 3 1/2 months earlier because of liver failure due to hepatitis C virus (HCV) infection. Perioperative medications included rabbit antithymocyte globulin, vancomycin, fluconazole, and piperacillin–tazobactam. Tacrolimus, azathioprine, furosemide, spironolactone, and a short course of corticosteroids were administered postoperatively. The immediate postoperative course was complicated by coagulopathy, intraperitoneal thrombi, and worsening renal function, with ascites and peripheral edema. The patient was discharged 2 weeks after transplantation

The New England Journal of Medicine. Vol 358 No 24, pp 2645-2647. June 12, 2008
Rituximab in Relapsing–Remitting Multiple Sclerosis
To the Editor: Hauser et al. (Feb. 14 issue) report positive results of a phase 2 trial of rituximab in relapsing–remitting multiple sclerosis. I wish to draw attention to the Food and Drug Administration (FDA) public health advisory concerning rituximab. This advisory was recently updated after the reported deaths from progressive multifocal leukoencephalopathy of two patients who were treated with rituximab for systemic lupus erythematosus. Keeping pace with the use of more potent and specific immunosuppressant agents, the incidence of opportunistic infections such as progressive multifocal leukoencephalopathy seems to be increasing. In clinical trials of natalizumab for the treatment of . .

The New England Journal of Medicine. Vol 358 No 24, pp 2647-2648. June 12, 2008
Lumbar Spinal Stenosis
To the Editor: As Katz and Harris (Feb. 21 issue) note, electromyography is not routinely necessary in the diagnostic workup of spinal stenosis. However, a complete electrodiagnostic examination (i.e., nerve-conduction studies and electromyography) can often be quite helpful in differentiating symptoms related to spinal stenosis from those due to a peripheral neuropathy. In general, a patient with clinically significant spinal stenosis will have electromyographic evidence of multilevel lumbosacral radiculopathies with essentially normal nerve-conduction studies, whereas a patient with clinically significant peripheral neuropathy will have just the opposite findings (i.e., abnormal nerve-conduction studies and normal electromyography). Even when both disorders are…

BMJ. Vol 336 No 7657, p 1320. June 14, 2008
Treating migraine in the emergency department
Corticosteroids do not relieve acute pain but do reduce recurrence
Randolph W Evans
In the accompanying systematic review, Colman and colleagues assess the effectiveness of parenteral corticosteroids for treating acute severe migraine and preventing recurrence.In Western Europe and the United States, about 12% of adults experience migraine each year, and 63% of these people have one to four migraines a month. Most people have nausea and moderate to severe pain, which results in severe impairment or requires bed rest, and one third have vomiting. If untreated, these headaches last for four to 72 hours, with a median duration of 24 hours.
In the US, only 56% of affected patients have received a medical diagnosis of migraine and instead believe that they have sinus, tension, or stress headache. About half of these people use over the counter drugs,3 which are effective in up to 59% of cases. But even with seven different types of triptans and various ways of giving them, 25% of . .

BMJ. Vol 336 No 7657, p 1359-1361 June 14, 2008
Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence
Ian Colman
Objective To examine the effectiveness of parenteral corticosteroids for the relief of acute severe migraine headache and prevention of recurrent headaches.
Design Meta-analysis.
Data sources Electronic databases (Cochrane Central Register of Controlled Trials, Medline, Embase, LILACS, and CINAHL), conference proceedings, clinical practice guidelines, contacts with industry, and correspondence with authors.
Selection criteria Randomised controlled trials in which corticosteroids (alone or combined with standard abortive therapy) were compared with placebo or any other standard treatment for acute migraine in adults.
Review methods Two reviewers independently assessed relevance, inclusion, and study quality. Weighted mean differences and relative risks were calculated and are reported with 95% confidence intervals.
Results From 666 potentially relevant abstracts, seven studies met the inclusion criteria. All included trials used standard abortive therapy and subsequently compared single dose parenteral dexamethasone with placebo, examining pain relief and recurrence of headache within 72 hours. Dexamethasone and placebo provided similar acute pain reduction (weighted mean difference 0.37, 95% confidence interval –0.20 to 0.94). Dexamethasone was, however, more effective than placebo in reducing recurrence rates (relative risk 0.74, 95% confidence interval 0.60 to 0.90). Side effect profiles between dexamethasone and placebo groups were similar.
Conclusion When added to standard abortive therapy for migraine headache, single dose parenteral dexamethasone is associated with a 26% relative reduction in headache recurrence (number needed to treat=9) within 72 hours.

BMJ. Vol 336 No 7657, p 1351-1354 June 14, 2008
Prolonged conservative care versus early surgery in patients with sciatica from lumbar disc herniation: cost utility analysis alongside a randomised controlled trial
Wilbert B van den Hout.
Objective To determine whether the faster recovery after early surgery for sciatica compared with prolonged conservative care is attained at reasonable costs.
Design Cost utility analysis alongside a randomised controlled trial.
Setting Nine Dutch hospitals.
Participants 283 patients with sciatica for 6-12 weeks, caused by lumbar disc herniation.
Interventions Six months of prolonged conservative care compared with early surgery.
Main outcome measures Quality adjusted life years (QALYs) at one year and societal costs, estimated from patient reported utilities (UK and US EuroQol, SF-6D, and visual analogue scale) and diaries on costs (healthcare, patient’s costs, and productivity).
Results Compared with prolonged conservative care, early surgery provided faster recovery, with a gain in QALYs according to the UK EuroQol of 0.044 (95% confidence interval 0.005 to 0.083), the US EuroQol of 0.032 (0.005 to 0.059), the SF-6D of 0.024 (0.003 to 0.046), and the visual analogue scale of 0.032 (–0.003 to 0.066). From the healthcare perspective, early surgery resulted in higher costs (difference €1819 (£1449; $2832), 95% confidence interval € 842 to € 2790), with a cost utility ratio per QALY of €41 000 (€14 000 to €430 000). From the societal perspective, savings on productivity costs led to a negligible total difference in cost (€–12, €–4029 to €4006).
Conclusions Faster recovery from sciatica makes early surgery likely to be cost effective compared with prolonged conservative care. The estimated difference in healthcare costs was acceptable and was compensated for by the difference in absenteeism from work. For a willingness to pay of € 40 000 or more per QALY, early surgery need not be withheld for economic reasons

BMJ. Vol 336 No 7657, p 1355-1358 June 14, 2008
Prolonged conservative care versus early surgery in patients with sciatica caused by lumbar disc herniation: two year results of a randomised controlled trial
Wilco C Peul
Objectives To evaluate the effects of early lumbar disc surgery compared with prolonged conservative care for patients with sciatica over two years of follow-up.
Design Randomised controlled trial.
Setting Nine Dutch hospitals.
Participants 283 patients with 6-12 weeks of sciatica.
Interventions Early surgery or an intended six months of continued conservative treatment, with delayed surgery if needed.
Main outcome measures Scores from Roland disability questionnaire for sciatica, visual analogue scale for leg pain, and Likert self rating scale of global perceived recovery.
Results Of the 141 patients assigned to undergo early surgery, 125 (89%) underwent microdiscectomy. Of the 142 patients assigned to conservative treatment, 62 (44%) eventually required surgery, seven doing so in the second year of follow-up. There was no significant overall difference between treatment arms in disability scores during the first two years (P=0.25). Improvement in leg pain was faster for patients randomised to early surgery, with a significant difference between "areas under the curves" over two years (P=0.05). This short term benefit of early surgery was no longer significant by six months and continued to narrow between six months and 24 months. Patient satisfaction decreased slightly between one and two years for both groups.
At two years 20% of all patients reported an unsatisfactory outcome.
Conclusions Early surgery achieved more rapid relief of sciatica than conservative care, but outcomes were similar by one year and these did not change during the second year.