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The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate) or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the balance between safety and benefit in consideration of pharmacological cognitive enhancement.

Background The mechanisms of drug-induced visions are poorly understood. Very few serotonergic hallucinogens have been studied in humans in decades, despite widespread use of these drugs and potential relevance of their mechanisms to hallucinations occurring in psychiatric and neurological disorders. Methodology/Principal Findings We investigated the mechanisms of hallucinogen-induced visions by measuring the visual and perceptual effects of the hallucinogenic serotonin 5-HT2AR receptor agonist and monoamine releaser, 3,4-methylenedioxyamphetamine (MDA), in a double-blind placebo-controlled study. We found that MDA increased self-report measures of mystical-type experience and other hallucinogen-like effects, including reported visual alterations. MDA produced a significant increase in closed-eye visions (CEVs), with considerable individual variation. Magnitude of CEVs after MDA was associated with lower performance on measures of contour integration and object recognition. Conclusions/Significance Drug-induced visions may have greater intensity in people with poor sensory or perceptual processing, suggesting common mechanisms with other hallucinatory syndromes. MDA is a potential tool to investigate mystical experiences and visual perception. Trial Registration Clinicaltrials.gov NCT00823407

Background Previous literature suggests that those with reading disability (RD) have more pronounced deficits during semantic processing in reading as compared to listening comprehension. This discrepancy has been supported by recent neuroimaging studies showing abnormal activity in RD during semantic processing in the visual but not in the auditory modality. Whether effective connectivity between brain regions in RD could also show this pattern of discrepancy has not been investigated. Methodology/Principal Findings Children (8- to 14-year-olds) were given a semantic task in the visual and auditory modality that required an association judgment as to whether two sequentially presented words were associated. Effective connectivity was investigated using Dynamic Causal Modeling (DCM) on functional magnetic resonance imaging (fMRI) data. Bayesian Model Selection (BMS) was used separately for each modality to find a winning family of DCM models separately for typically developing (TD) and RD children. BMS yielded the same winning family with modulatory effects on bottom-up connections from the input regions to middle temporal gyrus (MTG) and inferior frontal gyrus(IFG) with inconclusive evidence regarding top-down modulations. Bayesian Model Averaging (BMA) was thus conducted across models in this winning family and compared across groups. The bottom-up effect from the fusiform gyrus (FG) to MTG rather than the top-down effect from IFG to MTG was stronger in TD compared to RD for the visual modality. The stronger bottom-up influence in TD was only evident for related word pairs but not for unrelated pairs. No group differences were noted in the auditory modality. Conclusions/Significance This study revealed a modality-specific deficit for children with RD in bottom-up effective connectivity from orthographic to semantic processing regions. There were no group differences in connectivity from frontal regions, suggesting that the core deficit in RD is not in top-down modulation.

BACKGROUND: An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins. OBJECTIVE: To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159). METHODS AND FINDINGS: Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B(6) and B(12) in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B(12) (0.5 mg/d) and vitamin B(6) (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans. RESULTS: A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63-0.90] in the active treatment group and 1.08% [0.94-1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category. CONCLUSIONS AND SIGNIFICANCE: The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN94410159.

This study aimed to objectivize the quality of smooth pursuit eye movements in a standard laboratory task before and after an Eye Movement Desensitization and Reprocessing (EMDR) session run on seven healthy volunteers. EMDR was applied on autobiographic worries causing moderate distress. The EMDR session was complete in 5 out of the 7 cases; distress measured by SUDS (Subjective Units of Discomfort Scale) decreased to a near zero value. Smooth pursuit eye movements were recorded by an Eyelink II video system before and after EMDR. For the five complete sessions, pursuit eye movement improved after their EMDR session. Notably, the number of saccade intrusions-catch-up saccades (CUS)-decreased and, reciprocally, there was an increase in the smooth components of the pursuit. Such an increase in the smoothness of the pursuit presumably reflects an improvement in the use of visual attention needed to follow the target accurately. Perhaps EMDR reduces distress thereby activating a cholinergic effect known to improve ocular pursuit.

Although genetics is the most significant known determinant of human intelligence, specific gene contributions remain largely unknown. To accelerate understanding in this area, we have taken a new approach by studying the relationship between quantitative gene expression and intelligence in a cohort of 65 patients with Williams Syndrome (WS), a neurodevelopmental disorder caused by a 1.5 Mb deletion on chromosome 7q11.23. We find that variation in the transcript levels of the brain gene STX1A correlates significantly with intelligence in WS patients measured by principal component analysis (PCA) of standardized WAIS-R subtests, r =0.40 (Pearson correlation, Bonferroni corrected p-value =0.007), accounting for 15.6% of the cognitive variation. These results suggest that syntaxin 1A, a neuronal regulator of presynaptic vesicle release, may play a role in WS and be a component of the cellular pathway determining human intelligence. © 2010 Gao et al.

International audience; BACKGROUND: Seven genes involved in folate metabolism are located on chromosome 21. Previous studies have shown that folate deficiency may contribute to mental retardation in Down's syndrome (DS). METHODOLOGY: We investigated the effect of oral folate supplementation (daily dose of 1.0+/-0.3 mg/kg) on cognitive functions in DS children, aged from 3 to 30 months. They received 1 mg/kg leucovorin or placebo daily, for 12 months, in a single-centre, randomised, double-blind study. Folinic acid (leucovorin, LV) was preferred to folic acid as its bioavailability is higher. The developmental age (DA) of the patients was assessed on the Brunet-Lezine scale, from baseline to the end of treatment. RESULTS: The intent-to-treat analysis (113 patients) did not show a positive effect of leucovorin treatment. However, it identified important factors influencing treatment effect, such as age, sex, and concomitant treatments, including thyroid treatment in particular. A per protocol analysis was carried out on patients evaluated by the same examiner at the beginning and end of the treatment period. This analysis of 87 patients (43 LV-treated vs. 44 patients on placebo) revealed a positive effect of leucovorin on developmental age (DA). DA was 53.1% the normal value with leucovorin and only 44.1% with placebo (p

Background Numerous neuroimaging studies report abnormal regional brain activity during working memory performance in schizophrenia, but few have examined brain network integration as determined by “functional connectivity” analyses. Methodology/Principal Findings We used independent component analysis (ICA) to identify and characterize dysfunctional spatiotemporal networks in schizophrenia engaged during the different stages (encoding and recognition) of a Sternberg working memory fMRI paradigm. 37 chronic schizophrenia and 54 healthy age/gender-matched participants performed a modified Sternberg Item Recognition fMRI task. Time series images preprocessed with SPM2 were analyzed using ICA. Schizophrenia patients showed relatively less engagement of several distinct “normal” encoding-related working memory networks compared to controls. These encoding networks comprised 1) left posterior parietal-left dorsal/ventrolateral prefrontal cortex, cingulate, basal ganglia, 2) right posterior parietal, right dorsolateral prefrontal cortex and 3) default mode network. In addition, the left fronto-parietal network demonstrated a load-dependent functional response during encoding. Network engagement that differed between groups during recognition comprised the posterior cingulate, cuneus and hippocampus/parahippocampus. As expected, working memory task accuracy differed between groups (p

Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h(2) = .84; composing h(2) = .40; arranging h(2) = .46; improvising h(2) = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (p

Background The goal of this study was to evaluate the effects of L-Dopa medication in Parkinson's disease (PD) on brain activation during the performance of a set-shifting task. Using fMRI, we have previously studied the patterns of activity observed in patients with PD after overnight removal of dopaminergic medication compared with control participants during the performance of different stages of the Wisconsin Card Sorting Task (WCST). The results revealed decreased cortical activity in the PD group compared to controls in the conditions that significantly required striatum, while increased cortical activity was observed when striatum was not involved. However, the effect of dopaminergic medication in PD patients on those patterns of activity has not yet been studied. Methodology/Principal Findings Here, eleven PD patients at early stage of the disease taking L-Dopa medication were recruited and underwent two fMRI sessions while performing the WCST: one session while taking their normal dose of medication and the other following overnight dopaminergic medication withdrawal. We found that L-dopa medication helped restoring a normal pattern of activity when matching and not planning was required, by increasing cortical activity in the premotor cortex. This effect was even stronger in the motor loop, i.e. when the putamen was required for controls, when matching following negative feedback. However, the medication did not change the pattern of activity in conditions relying primarily on a cognitive loop, i.e. when the caudate nucleus was required. Conclusions/Significance These studies provide explanation at the neural level regarding the relatively poor effects of L-Dopa on the cognitive deficits observed in PD.

BACKGROUND: Tinnitus is a frequent condition with high morbidity and impairment in quality of life. The pathophysiology is still incompletely understood. Electromagnetic fields are discussed to be involved in the multi-factorial pathogenesis of tinnitus, but data proofing this relationship are very limited. Potential health hazards of electromagnetic fields (EMF) have been under discussion for long. Especially, individuals claiming themselves to be electromagnetic hypersensitive suffer from a variety of unspecific symptoms, which they attribute to EMF-exposure. The aim of the study was to elucidate the relationship between EMF-exposure, electromagnetic hypersensitivity and tinnitus using a case-control design. METHODOLOGY: Tinnitus occurrence and tinnitus severity were assessed by questionnaires in 89 electromagnetic hypersensitive patients and 107 controls matched for age-, gender, living surroundings and workplace. Using a logistic regression approach, potential risk factors for the development of tinnitus were evaluated. FINDINGS: Tinnitus was significantly more frequent in the electromagnetic hypersensitive group (50.72% vs. 17.5%) whereas tinnitus duration and severity did not differ between groups. Electromagnetic hypersensitivity and tinnitus were independent risk factors for sleep disturbances. However, measures of individual EMF-exposure like e.g. cell phone use did not show any association with tinnitus. CONCLUSIONS: Our data indicate that tinnitus is associated with subjective electromagnetic hypersensitivity. An individual vulnerability probably due to an over activated cortical distress network seems to be responsible for, both, electromagnetic hypersensitivity and tinnitus. Hence, therapeutic efforts should focus on treatment strategies (e.g. cognitive behavioral therapy) aiming at normalizing this dysfunctional distress network.

International audience; Background: A major question in understanding the functional organization of the brain is to delineate the functional divisions of the prefrontal cortex. Of particular importance to the cognitive capacities that are uniquely human is the fronto-polar cortex (Brodmann's area 10), which is disproportionally larger in humans relative to the rest of the brain than it is in the ape's brain. The specific function of this brain region remains poorly understood, but recent neuroimaging studies have proposed that it may hold goals in mind while exploring and processing secondary goals.Principal Findings:Here we show that the extent of damage to the fronto-polar cortex predicts impairment in themanagement of multiple goals. This result reveals that the integrity of the fronto-polar cortex is necessary to perform tasksthat require subjects to maintain a primary goal in mind while processing secondary goals, an ability which is crucial forcomplex human cognitive abilities.Conclusion/Significance:These results provide important new insights concerning the cerebral basis of complex humancognition such as planning and multitasking.

Chronic use of cocaine is associated with impairment in response inhibition but it is an open question whether and to which degree findings from chronic users generalize to the upcoming type of recreational users. This study compared the ability to inhibit and execute behavioral responses in adult recreational users and in a cocaine-free-matched sample controlled for age, race, gender distribution, level of intelligence, and alcohol consumption. Response inhibition and response execution were measured by a stop-signal paradigm. Results show that users and non users are comparable in terms of response execution but users need significantly more time to inhibit responses to stop-signals than non users. Interestingly, the magnitude of the inhibitory deficit was positively correlated with the individuals lifetime cocaine exposure suggesting that the magnitude of the impairment is proportional to the degree of cocaine consumed.

Pathways linking the thalamus and cortex mediate our daily shifts from states of attention to quiet rest, or sleep, yet little is known about their architecture in high-order neural systems associated with cognition, emotion and action. We provide novel evidence for neurochemical and synaptic specificity of two complementary circuits linking one such system, the prefrontal cortex with the ventral anterior thalamic nucleus in primates. One circuit originated from the neurochemical group of parvalbumin-positive thalamic neurons and projected focally through large terminals to the middle cortical layers, resembling ‘drivers’ in sensory pathways. Parvalbumin thalamic neurons, in turn, were innervated by small ‘modulatory’ type cortical terminals, forming asymmetric (presumed excitatory) synapses at thalamic sites enriched with the specialized metabotropic glutamate receptors. A second circuit had a complementary organization: it originated from the neurochemical group of calbindin-positive thalamic neurons and terminated through small ‘modulatory’ terminals over long distances in the superficial prefrontal layers. Calbindin thalamic neurons, in turn, were innervated by prefrontal axons through small and large terminals that formed asymmetric synapses preferentially at sites with ionotropic glutamate receptors, consistent with a driving pathway. The largely parallel thalamo-cortical pathways terminated among distinct and laminar-specific neurochemical classes of inhibitory neurons that differ markedly in inhibitory control. The balance of activation of these parallel circuits that link a high-order association cortex with the thalamus may allow shifts to different states of consciousness, in processes that are disrupted in psychiatric diseases.

BACKGROUND: Hypochondriasis is prevalent in primary care, but the diagnosis is hampered by its stigmatizing label and lack of valid diagnostic criteria. Recently, new empirically established criteria for Health anxiety were introduced. Little is known about Health anxiety's impact on longitudinal outcome, and this study aimed to examine impact on self-rated health and health care costs. METHODOLOGY/PRINCIPAL FINDINGS: 1785 consecutive primary care patients aged 18-65 consulting their family physicians (FPs) for a new illness were followed-up for two years. A stratified subsample of 701 patients was assessed by the Schedules for Clinical Assessment in Neuropsychiatry interview. Patients with mild (N = 21) and severe Health anxiety (N = 81) and Hypochondriasis according to the DSM-IV (N = 59) were compared with a comparison group of patients who had a well-defined medical condition according to their FPs and a low score on the screening questionnaire (N = 968). Self-rated health was measured by questionnaire at index and at three, 12, and 24 months, and health care use was extracted from patient registers. Compared with the 968 patients with well-defined medical conditions, the 81 severe Health anxiety patients and the 59 DSM-IV Hypochondriasis patients continued during follow-up to manifest significantly more Health anxiety (Whiteley-7 scale). They also continued to have significantly worse self-rated functioning related to physical and mental health (component scores of the SF-36). The severe Health anxiety patients used about 41-78% more health care per year in total, both during the 3 years preceding inclusion and during follow-up, whereas the DSM-IV Hypochondriasis patients did not have statistically significantly higher total use. A poor outcome of Health anxiety was not explained by comorbid depression, anxiety disorder or well-defined medical condition. Patients with mild Health anxiety did not have a worse outcome on physical health and incurred significantly less health care costs than the group of patients with a well-defined medical condition. CONCLUSIONS/SIGNIFICANCE: Severe Health anxiety was found to be a disturbing and persistent condition. It is costly for the health care system and must be taken seriously, i.e. diagnosed and treated. This study supports the validity of recently introduced new criteria for Health anxiety.

Background Social-environmental influences can affect animal cognition and health. Also, human socio-economic status is a covariate factor connecting psychometric test-performance (a measure of cognitive ability), educational achievement, lifetime health, and survival. The complimentary hypothesis, that mechanisms in physiology can explain some covariance between the same traits, is disputed. Possible mechanisms involve metabolic biology affecting integrity and stability of physiological systems during development and ageing. Knowledge of these relationships is incomplete, and underlying processes are challenging to reveal in people. Model animals, however, can provide insights into connections between metabolic biology and physiological stability that may aid efforts to reduce human health and longevity disparities. Results We document a positive correlation between a measure of associative learning performance and the metabolic stress resilience of honeybees. This relationship is independent of social factors, and may provide basic insights into how central nervous system (CNS) function and metabolic biology can be associated. Controlling for social environment, age, and learning motivation in each bee, we establish that learning in Pavlovian conditioning to an odour is positively correlated with individual survival time in hyperoxia. Hyperoxia induces oxidative metabolic damage, and provides a measure of metabolic stress resistance that is often related to overall lifespan in laboratory animals. The positive relationship between Pavlovian learning ability and stress resilience in the bee is not equally established in other model organisms so far, and contrasts with a genetic cost of improved associative learning found in Drosophila melanogaster. Conclusions Similarities in the performances of different animals need not reflect common functional principles. A correlation of honeybee Pavlovian learning and metabolic stress resilience, thereby, is not evidence of a shared biology that will give insight about systems integrity in people. Yet, the means to resolve difficult research questions often come from findings in distant areas of science while the model systems that turn out to be valuable are sometimes the least predictable. Our results add to recent findings indicating that honeybees can become instrumental to understanding how metabolic biology influences life outcomes.

BACKGROUND: To understand the genetics of schizophrenia, a hunt for so-called intermediate phenotypes or endophenotypes is ongoing. Visual masking has been proposed to be such an endophenotype. However, no systematic study has been conducted yet to prove this claim. Here, we present the first study showing that masking meets the most important criteria for an endophenotype. METHODOLOGY/PRINCIPAL FINDINGS: We tested 62 schizophrenic patients, 39 non-affected first-degree relatives, and 38 healthy controls in the shine-through masking paradigm and, in addition, in the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST). Most importantly, masking performance of relatives was significantly in between the one of patients and controls in the shine-through paradigm. Moreover, deficits were stable throughout one year. Using receiver operating characteristics (ROC) methods, we show that the shine-through paradigm distinguishes with high sensitivity and specificity between schizophrenic patients, first-order relatives and healthy controls. CONCLUSIONS/SIGNIFICANCE: The shine-through paradigm is a potential endophenotype.