Lessons learned from clinical trials investigating minor depressive BGJ398 molecular weight disorder One can use randomized clinical trials in minor depressive disorder as a case study to emphasize some of the challenges faced in trial design and possibly some solutions to these challenges. Minor depressive disorder is an area where there is no consensus about its conceptualization or definition. Some individuals Inhibitors,research,lifescience,medical believe that minor

depression is merely a segue into major depressive disorder, while others consider minor depression an entity in itself.15-17 Some individuals worry that investigating minor depression trivializes the core concept of major depressive disorder, while others consider Inhibitors,research,lifescience,medical it an important part of the spectrum of depressive syndromes.18 Even among those who believe that minor depression is a valid concept that requires rigorous investigation, there is considerable debate about what the definition of minor depression is or should be.19 Furthermore, there is little empirical evidence to support any of the currently employed definitions. Many of the older clinical trials investigating minor depression actually grouped patients into cohorts that contained individuals with major depressive disorder described as being mild in severity. Some of these trials did not differentiate between major depressive disorder

and Inhibitors,research,lifescience,medical a diagnosis of minor depression, but merely stated that those with lower Hamilton Depression Rating Scale (HAMD) scores should be considered as having minor depression. Other trials combined patients with major depression of a milder form with Research Inhibitors,research,lifescience,medical Diagnostic Criteria (RDC) patients with minor depression. Older trials employed either tricyclic antidepressant medications or antipsychotic medications. It is not surprising, based on the side-effect profiles of these agents and the weighting of the HAMD towards somatic concerns, that it was difficult to differentiate an active treatment response from a placebo response. A second Inhibitors,research,lifescience,medical challenge that studies of

minor depression emphasize is the use of rating scales that were developed at another time and for another diagnostic entity to assess minor depression. All of the older studies used the HAMD 17 as a primary outcome measure:20 As discussed above, this rating scale, developed to assess inpatients with endogenous depression, is heavily Vasopressin Receptor weighted toward somatic and/or vegetative factors. This makes the HAMD a ver>’ coarse instrument to use for individuals with milder forms of depression or minor depression, since neither somatic nor vegetative symptoms are highly prominent in such patients. Furthermore, these less highly prominent symptoms tend to be transient in presentation and thus may vary greatly from week to week on a rating scale. This emphasizes the importance of carefully ensuring that the methods of assessment fit the most relevant signs of the syndrome being studied.

The exceptions to this observation have a tendency to include the exclusively UPUC set UPUC∩SAc∩MCc where Xc denotes the absolute complement. On the other hand, the majority of combinatorial sets is significantly enriched for essential reactions (Figure 5c). More importantly, more than half of the combinatorial sets exhibit a clear separation of essential from conditional lethal and non-essential classes. Comparing Figure 5a and Figure 5c reveals that the sequence of combinatorial sets in the

sorted non-essential enrichment resembles the essential sequence in reverse order (e.g., the Inhibitors,research,lifescience,medical exclusive UPUC set being visually absent for high essential reaction enrichment). This observation provides evidence for a strong negative association between these two essentiality

classes in the context of the UPUC, SA and MC categories. Figure 5 Enrichment of combinatorial reaction category sets for essentiality classes. Combinatorial Inhibitors,research,lifescience,medical sets sorted on the basis of (a) non-essential, (b) conditional lethal and (c) essential class enrichment. Venn diagrams [34] on the abscissa indicate each of the … Unfortunately, no clear separation of conditional lethal from non-essential and essential reactions is achieved by this combinatorial approach (Figure 5b). These results indicate that UPUC, SA and MC, albeit good Inhibitors,research,lifescience,medical essentiality predictors, do not provide the means for a topological characterization of medium-dependent Inhibitors,research,lifescience,medical essentiality. 2.3. Distribution of Essentiality Classes Across Three-Node Subgraphs In the following we will now quantify whether the established topological categories or the three-node subgraphs contain more information about medium-dependent essential reactions. Figure 6 shows the statistical over-

and under-representation of the three established topological categories (Figure 6a) and the three essentiality classes (Figure 6b) across all possible three-node subgraphs of the reaction-centric metabolic network (Figure 3). The striking result is that the three established topological categories display very similar subgraph associations, while the three essentiality classes show strong differences in their Inhibitors,research,lifescience,medical subgraph associations. Counter-intuitively, subgraphs thus perform better in distinguishing essentiality classes than in distinguishing secondly the established topological categories discussed above. Figure 6 Enrichment on three-node subgraphs. The statistical over- and under-representation of (a) reaction categories and (b) essentiality classes on all occurring three-node subgraphs (two motifs have been omitted as they were not detected in any effective network). … Conditional lethal reactions have a fundamentally check details different “footprint” when mapped onto subgraphs. The most important building block is the bidirectional V-in (i.e., the V-in with one of the links being bi-directional). Non-essential reactions, on the other hand, are suppressed in chains, but elevated in V-in and V-out subgraphs.

Narcolepsy has thus often been associated with psychiatric disturbance, but surveys have produced contradictory results. Schizophrenia has been found at rates ranging from 0% to 14% and depression at rates ranging from 5% to 30 %.9,21-23 Krishnan et al,23 for example, showed that two thirds of narcoleptic patients had psychiatric disorders according to Diagnostic and Statistical Manual of PS-341 molecular weight Mental

Health, Third Edition (DSM-III) criteria, including adjustment disorder, major depressive episode, alcohol dependence, and personality disorder. However, those studies were made in small samples,22,23 with no control group,21-23 Inhibitors,research,lifescience,medical often based on case notes and in patients taking amphetamines, which were, until recently, the mainstay of treatment for narcolepsy. Inhibitors,research,lifescience,medical The well-documented side effects of amphetamines (including increased feelings of anxiety, irritability and agitation, sexual dysfunction, and insomnia) may exacerbate existing or underlying psychiatric conditions.24 In a recent study, Vourdas et al25 investigated the frequency of major and minor psychiatric disorders among patients with narcolepsy, as compared with a group of matched normal individuals, using a detailed

structured psychiatric Inhibitors,research,lifescience,medical diagnostic interview. This study took advantage of the recent introduction of the wake-promoting drug modafinil, which improves vigilance via a nondopaminergic/adrenergic mechanism and does not appear to induce psychosis. This study found little evidence for an increased frequency of psychotic disorders in narcolepsy. Although Inhibitors,research,lifescience,medical four patients (out of 45) had experienced episodes meeting criteria for probable psychotic disorder (in contrast to none of the controls), there were clear indications that the psychotic symptoms were related

to amphetamine use in the past, since they Inhibitors,research,lifescience,medical disappeared when the dose was lowered or medication was changed to modafinil. None of the patients taking modafinil showed psychotic symptoms. They found that 24% of patients had criteria for simple depression, a rate similar of that found in other surveys in Edoxaban narcolepsy1,2,7 and chronic medical disorders in general.26 Although some studies have shown a possible therapeutic role of stimulant medication for improving affect,27 others have shown that depression in narcolepsy is independent of pharmacological treatment or did not improve after treatment.1 Goswami28 reported that, despite treatment for excessive daytime sleepiness, narcolepsy patients remain at significant risk for psychiatric and psychosocial limitations. Beusterien et al8 have shown that treatment with modafinil produces higher scores than placebo for the physical role, energy/vitality, social function, and emotional role on the SF-36.

Better solubility will allow for faster absorption of drug, less will remain in the GI, and drug overlap will no longer be an issue. Figure 8 The 200mg/kg X3 Tandem dose predicted (2.5hr) versus obtained exposures from 1, 1.5, and 2.5hrs interval. Figure 9 The 200mg/kg X3 Tandem Dose Wagner-Nelson Plot (presented as mean values). The above data strongly support the tandem dose approach to increase exposure while minimizing compound usage. The present work supports the transit time theory in rats. We have also demonstrated Inhibitors,research,lifescience,medical that the ideal interval is dose Sepantronium Bromide nmr dependent. In summary, significantly improved exposures were obtained

by using the tandem dose with the appropriate interval. A simple calculation of dose efficiency Inhibitors,research,lifescience,medical was performed based on using 40% less drug (600mg/kg versus 1000mg/kg) and doubling the exposure. This tandem dose has improved the dose efficiency by approximately 300% for Compound 1. This conservative calculation was done by assuming a linear increase of both Cmax and AUC from 1000 to 2000mg/Kg doses for both compounds. This assumption is an overestimation since exposure increases of Compound

1 (s.i.d) were proven nonlinear beyond 300mg/Kg (and the actual nonlinear dose could be lower than Inhibitors,research,lifescience,medical 300mg/Kg). Thus, the true efficiency could be much higher. This novel tandem dose oral delivery approach using an optimized dosing interval achieves significantly higher in vivo exposure using less drug and requires no additional resources. It

is simple, cost effective, and well tolerated by animals and should be further utilized in industry. Regular b.i.d. or t.i.d. doses take up to Inhibitors,research,lifescience,medical 12 or 16 hours to administer. Depending on the dose, a simple X3 tandem dose can be administered within 2–5hrs (1 to 2.5hr interval). This easily fits into the traditional work day, and no additional staff or overtime is necessary. In theory, the tandem dose is not limited to three doses per day; a fourth dose can be given to further boost the exposure if needed without Inhibitors,research,lifescience,medical altering first the normal eight-hour work day [12]. Our current investigation of dosing interval further refines the tandem dosing strategy. This improved strategy can positively impact the preclinical oral delivery of low solubility compounds. 4. Conclusion In our research, we utilized this novel tandem dose strategy in rat and assessed the impact of dosing intervals on exposure. We successfully demonstrated that by using the tandem dose strategy with the appropriate dosing interval, significantly higher in vivo exposure can be reached without extraresources and investments. This method is well tolerated by the animal and achieves increased exposure with less drugs dosed. This novel approach allows the preclinical researcher to quickly evaluate the in vivo efficacy and safety of a new target.

Curl Jr, Sir Harold W. Kroto, and Richard E. Smalley. Fullerenes, also known as buckyballs, are spherical molecules composed of carbon atoms. The see more discovery of fullerenes launched the field of nano-materials, one of the fastest-growing fields in chemistry today. In 1996, 11 years after the publication of the discovery, the three researchers were jointly awarded the Nobel Prize in chemistry. No controversy surrounded this discovery. In 1986, two IBM researchers, Karl Müller and Johannes Bednorz, discovered high-temperature Inhibitors,research,lifescience,medical superconductive materials. Although superconductivity was first discovered in 1911, nobody expected

to see this phenomenon at the relatively high temperatures of liquid nitrogen. In 1987, one year after publishing their discovery, the two researchers were awarded the Nobel Prize in physics. Again, no controversy surrounded this discovery, and, as the short period of time between the discovery and awarding of the prize shows, the discovery was enthusiastically embraced by the scientific community. Publication Inhibitors,research,lifescience,medical of the third discovery pre-dates the publication of the other two discoveries. I published the discovery of quasi-periodic crystals in 1984 and was awarded a Nobel Prize Inhibitors,research,lifescience,medical in 2011, 27 years after the discovery. Unlike the previous two discoveries,

this discovery was met with fierce opposition and a substantial amount of controversy. What was so controversial about this discovery that it raised the antagonism of so many people in the scientific community? Why would Linus Pauling, a twice-awarded Inhibitors,research,lifescience,medical Nobel Laureate and one of the greatest chemists of the twentieth century, state: “There is no such thing as quasi-crystals, only quasi-scientists”? In order to answer these questions, I must first give a short introduction to crystallography. For that purpose, I will define

three basic terms Inhibitors,research,lifescience,medical in crystallography: order, periodicity, and rotational symmetry. UNDERSTANDING CRYSTALLOGRAPHY Order Crystals are solids that have an atomic structure of an indefinitely extended, three-dimensional order. A simple two-dimensional ordered lattice is shown in Figure 1. The continued order of this lattice is evident in all directions. Figure 1 Example of rotation, order, and symmetry in an atomic lattice. Periodicity The periodicity of the lattice is defined by the lengths and mutual orientations of the three lattice vectors that enclose the pattern. As can unless be seen in Figure 1 (top left), periodicity exists when the distance between any two adjacent points on a straight vector is the same. Rotational Symmetry An object that has rotational symmetry is an object that looks identical after it is rotated. The lattice in Figure 1 is identical if we rotate it by 90°, 180°, 270°, or 360°. Therefore, this lattice has a four-fold rotational symmetry. Figure 2 shows objects that have two-, three-, five-, and six-fold rotational symmetry. Figure 2 Objects with a two-, three-, five-, and six-fold rotational symmetry.

0308). Only a trend toward greater preoperative disability was present in the UPDRS total score (P = 0.0982). There were no remarkable correlations between preoperative tremor subscore, asymmetry index, or dyskinesia subscore and change in weight. Furthermore, there was no significant correlation between change in the UPDRS Part 3 in the “practically defined off” state (Langston et al. 1992) and the change in weight

in the DBS patients. Importantly, UPDRS Part 3 “off” medication ratings were not available for the controls without DBS, therefore it was not possible to correlate changes in the UPDRS “off” and weight over time in patients with and without the DBS intervention. Discussion Our clinical practice is to initially place a DBS Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical electrode in the STN contralateral to the most severely affected side of

the body and then place a second stimulator in the opposite STN in a staged fashion when clinically needed. At 2 years postoperatively, PD patients with both unilateral and staged bilateral STN DBS show sustained weight gain, and the weight of the PD controls without DBS trend downwards over the same time interval. Although the mean weight gain was greater in patients who underwent staged bilateral STN DBS over 2 Inhibitors,research,lifescience,medical years versus those who remained unilateral over 2 years, the difference in weight gain between the groups was modest and not statistically significant. We Inhibitors,research,lifescience,medical therefore found no evidence for an equivalent amount of additional weight gain or a synergistic effect of the second subthalamic stimulator on body weight. These data may be useful for patients evaluating the potential risks and benefits of both unilateral and staged bilateral STN

DBS surgery for advanced PD. Our findings suggest that although weight gain likely occurs 5-FU ic50 following the second surgery, it is more modest than the weight gain following the first surgery, Inhibitors,research,lifescience,medical assuming that the first surgery is performed contralateral to the more severely affected hemibody. Furthermore, the total weight gain in patients who underwent bilateral STN DBS in this study is substantially less (approximately 5 kg) than that reported in other studies in which stimulators were placed Sodium butyrate bilaterally in a single procedure (approximately 10 kg) (Macia et al. 2004; Tuite et al. 2005; Novakova et al. 2007), suggesting a potential differential effect of initial bilateral STN DBS versus staged bilateral DBS on weight gain. The magnitude of the observed changes in body weight in patients undergoing staged bilateral STN DBS surgery parallels findings from studies of motor function, suggesting that like weight gain, motor improvement following staged placement of a second DBS electrode may not be as large as that following the unilateral procedure (Samii et al. 2007). Unexpectedly, staged bilateral STN DBS patients weighed an average of 10.9 kg less at baseline than both patients who remained unilateral for 2 years and the controls.

Inflammation and infection also influence plasma levels [Taylor et al. 2009a]. In addition, the fixed regression analysis we conducted was dominated by the large postmarketing naturalistic study which included 5629 patients [Pacia and Devinsky, 1994]. The mean doses used were not specified in the study and so a middle value for each dose

range was assumed. This approximation greatly reduced the capacity to demonstrate a dose-related effect. Owing to the paucity of useful data, we were unable to conduct a meta-regression Inhibitors,research,lifescience,medical analysis exploring the relationship between clozapine plasma level and AVL301 occurrence of seizures. Studies examining this relationship are scarce and our review only found three case reports, which suggest only that there is very substantial risk of seizures with clozapine plasma levels exceeding 1300 μg/l. Other limitations of our analysis include selection bias (the reporting only or mainly of cases), differences in reporting (case studies,

Inhibitors,research,lifescience,medical case series, retrospective population studies, Inhibitors,research,lifescience,medical study duration), the variability between study populations, the absence of data on patient risk factors (seizure history, neurological abnormalities, smoking status, etc.), the dearth of confirmatory observations of seizure occurrence and type (some seizures were clearly reported by patients or relatives), the subsequent drop-out rates, and the previously Inhibitors,research,lifescience,medical mentioned imprecision in reporting of individual or mean

doses. Can we say when to use an antiepileptic? Our regression model showed that seizure risk increases linearly with dose and that EEG abnormalities increase linearly with dose and plasma level and so there is Inhibitors,research,lifescience,medical no clear exponential rise in risk at any dose or level. Because results showed there was no dose or level at which risk increases at a greater rate, and as there is no safe dose or level at which seizures do not occur, we cannot make a recommendation on basis of risk of seizures except to keep the plasma level as low as possible. Dose, however, is affected by too many variables for a clear risk relationship to be established. not The plasma level for acute response to clozapine is in the range 200–504 μg/l [Taylor et al. 2009a]. In those not responding to clozapine, a plasma level target range of 350–500 μg/l has been suggested. When initiating clozapine, we suggest titrating slowly to 350 μg/l, as seizures are more common during the initiation phase [Pacia and Devinsky, 1994; Wilson and Claussen, 1994; Devinsky et al. 1991]. If there is no response, increase the dose to give a plasma level of 500 μg/l. Consideration should be given to introducing an AED if the clozapine plasma levels are above 500 μg/l, if there are clear epileptiform discharges on EEG, if the patient develops stuttering or speech difficulties, or if seizures occur.

2012). For example, patients with PD demonstrated higher

FA values in the left anterior and right posterior cingulate correlated with symptom severity (Han et al. 2008). Further, studies in patients with GAD demonstrated reduced FA in the uncinate fasciculus (Hettema et al. 2012) (connecting the amygdala and orbitofrontal cortex), a result also demonstrated in social phobia (SP) (Phan et al. 2009; Baur et al. 2011), and increased FA in the right postcentral gyrus (Zhang et al. 2011b). In PTSD, lowered FA has been found in areas including the left frontal gyrus, internal capsule, and midbrain (Kim et al. 2005; Schuff et al. 2011). Inhibitors,research,lifescience,medical Changes in integrity of white matter pathways connecting fear areas, including the uncinate fasciculus and corpus callosum, have been associated with trait anxiety states (Kim and Whalen 2009; Baur et al. 2011; Westlye et al. Inhibitors,research,lifescience,medical 2011). We are aware of only one study assessing the effect of AVL301 psychiatric disorders and smoking on white matter integrity. Zhang et al. (2010a), assessing patients with schizophrenia, demonstrated reductions in FA of the

Inhibitors,research,lifescience,medical left anterior thalamic radiation/anterior limb of the internal capsule that were both independent and additive in smokers and patients with schizophrenia, such that smokers with schizophrenia had the largest reductions Inhibitors,research,lifescience,medical in FA. No studies to our knowledge have yet been conducted in patients with anxiety disorders. In summary, gross and microstructural changes to key brain regions and white matter tracts are present in cigarette smokers and patients with anxiety disorders.

Changes to white matter microstructure in certain regions connecting fear response areas have been associated with trait anxiety states, and it is possible that cigarette smoke could negatively affect these pathways. Future Inhibitors,research,lifescience,medical research into these areas may provide important insights into anxiety pathogenesis. Neurotransmitter systems The importance of specific neurotransmitter systems has been extensively demonstrated in anxiety disorders, with current first-line pharmacological therapies interacting predominantly Bay 11-7085 with the serotonergic, noradrenergic, cannabinoid, cholinergic, and dopaminergic systems. In addition, some of these agents are also effective in enhancing smoking cessation (Jorenby et al. 1999), suggesting a plausible biological interaction between these systems and nicotine dependence. Many studies have demonstrated that nicotine and cigarette smoke affect diverse neurotransmitter systems. However, how these may predispose to increased anxiety is very complex, involving interaction between systems and differing effects of cigarette components. Much scientific work has explored the influence of nicotinic acetylcholine receptors (nAChRs) on brain function.

However, BNZ is associated with enhancing access to emotional memories (but not to procedural memory). Actually, until the 1970s, one of the major techniques to treat PTSD was via the “benzodiazepine interview,” which used BNZ (or sodium pentothal) in order to help the individual to go through full re-experience of the event. However,

how does this fit with our line of reasoning that reducing fear memory is beneficial? In a small study, Gelpin et al22 compared at 1-and 6-month follow-up individuals who received Inhibitors,research,lifescience,medical BNZ (clonazepam 2.6 mg/day or alprazolam 2.5 mg/day) with those who did not receive it. Out of the 13 who received BNZ, 9 developed PTSD, as compared with 3 of the 13 controls. These findings were also replicated by Mellman Inhibitors,research,lifescience,medical et al in a small study.23 In a unique animal model, which is based on setting affected (rats) apart from the unaffected,24 administration of alprazolam 1 hour after the exposure was associated with significantly more extreme behavioral response (the behavioral equivalent of PTSD) for the rats who were given alprazolam as compared with those

who got saline.25 Hence, some pilot human data, plus a signal from animal studies suggest that early administration of BNZ might interfere with the normal potent spontaneous recovery. Hypothalamic-pituitary-adrenal axis, PTSD, and BNZ Glucocorticoids were found to reduce Inhibitors,research,lifescience,medical phobic fear in humans.26 Individuals with arachnophobia who were PKA inhibitor ic50 injected with Cortisol 1 hour before exposure reported less fear (as measured on a visual analog scale) as Inhibitors,research,lifescience,medical compared with individuals who got saline. Stress is associated with activation of the hypothalamicpituitary-adrenal (HPA) axis, and consequently with secretion of hydrocortisone. What is the effect of BNZ on this normal, primary cornerstone of the normal response to stress? What is the effect of BNZ on Cortisol? Why does administration of BNZ seem to interfere with the normal recovery process? Administration of BNZ abolishes the expected activation (the normal response) of the HPA axis. Inhibitors,research,lifescience,medical The HPA axis is the main component in the

neuroendocrine response to acute and chronic stress (Figure 4). In response to stress, a chain of reactions aminophylline stimulates the adrenal cortex to synthesize and release glucocorticoids, in particular Cortisol. These hormones are instrumental in adaptation to stress.27 A main function appears to be in the regulation and containment of the sympathetic and parasympathetic responses to stress (ie, changes in heart rate, blood pressure, respiration), responses that help the body accommodate to an immediate demand. In animal studies, it has been demonstrated that blunted HPA-axis response increased PTSD-like reactions in rats exposed to trauma,28 which strengthens the notion that an intervention aimed at bolstering this natural response with an early intervention immediately after the trauma could help reduce PTSD (Figure 5). Figure 4. The hypothaiamic-pituitary-adrenal axis. Figure 5.

In each session, about 240 volumes were recorded. For each run, the functional scanning was always preceded by five dummy scans to insure tissue steady-state magnetization. After functional scanning, a high-resolution (HR) 3D T1-weighted sequence for anatomical images was performed (12 min). HR T1 images were P450 inhibitor clinical trial acquired for coregistration of

the functional images (data matrix = 256 × 256, slice-thickness = 1 mm, FOV = 256 mm2, TR = 2.3 sec, TE = 2.98 msec). The whole experiment lasted for about 1 h. Preprocesing Inhibitors,research,lifescience,medical of fMRI data was carried out with Statistical Parametric Mapping SPM2 (Wellcome trust Centre for Neuroimaging, London, UK, http://www.fil.ion.ucl.ac.uk/spm/). First, the functional images were checked for motion-related artifacts per participant per experimental session. The exclusion criterion was set to 3 mm deviation from the initial position of the head at the beginning of a session according to the six movement parameters. Inhibitors,research,lifescience,medical Then, all functional images were corrected for slice timing, spatially realigned, normalized to the Montreal Neurological Institute (MNI)

template, and smoothed using a Gaussian filter of 8 mm. A high-pass filter was used to remove low-frequency drifts. Random-effects analyses were conducted using SPM8 (Wellcome Inhibitors,research,lifescience,medical trust Centre for Neuroimaging, London, UK, http://www.fil.ion.ucl.ac.uk/spm/). At single-subject level, we modeled each experimental condition (related, unrelated, filler pairs, neutral, and symbol trials) as separate events using the canonical hemodynamic response function (HRF) supplied by SPM8 and its temporal Inhibitors,research,lifescience,medical derivative to correct for the implied impreciseness in timing, resulting in two regressors per experimental condition. The onset of the second word of each pair (i.e., the target word, or the presentation of the symbol string) was defined as the onset of

the HRF used in the regressor. For Experiment 1, we added two regressors for incorrect and missed trials to explain variance introduced Inhibitors,research,lifescience,medical by error trials. Six realignment parameters (three translation, three rotation) estimated during preprocessing were added as regressors of no interest. We computed individual contrast images for the critical conditions (related, unrelated) by subtracting the Thiamine-diphosphate kinase activation associated with the symbol condition from the related and unrelated condition for each linguistic task, respectively. We used the symbol condition as visual baseline condition in both tasks to subtract out any activation associated with motor responses in Experiment 1 and with activation related to basic processing of visual stimuli for both linguistic tasks. Otherwise, a comparison of both linguistic tasks would have resulted in a main effect of semantic categorization in motor brain areas. These individual contrast estimates for the critical conditions for both linguistic tasks were subjected to a group analysis.