Association of low baseline levels of erythrocyte folate with treatment nonresponse at three months in rheumatoid arthritis patients receiving methotrexate.

OBJECTIVE: To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). METHODS: A prospective derivation cohort (n = 285) and validation cohort (n = 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B12 , serum folate, erythrocyte vitamin B6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype. RESULTS: In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (ß = -0.15, P = 0.037) and the validation cohort (ß = -0.20, P = 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P = 0.049; validation cohort, P = 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P = 0.066; validation cohort, P = 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events. CONCLUSION: A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months.

Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Building memories: remembering and forgetting of verbal experiences as predicted by brain activity.

A fundamental question about human memory is why some experiences are remembered whereas others are forgotten. Brain activation during word encoding was measured using blocked and event-related functional magnetic resonance imaging to examine how neural activation differs for subsequently remembered and subsequently forgotten experiences. Results revealed that the ability to later remember a verbal experience is predicted by the magnitude of activation in left prefrontal and temporal cortices during that experience. These findings provide direct evidence that left prefrontal and temporal regions jointly promote memory formation for verbalizable events.

Functional-anatomic correlates of object priming in humans revealed by rapid presentation event-related fMRI.

Human functional-anatomic correlates of object repetition were explored in a cohort of 20 subjects using fMRI. Subjects performed an object classification task where the target objects were either novel or repeated. Objects appeared rapidly, one every 2 s, in a randomly intermixed task design similar to traditional behavioral, event-related potential (ERP), and single-unit physiological studies. Recently developed event-related fMRI methods were used to analyze the data. Clear effects of repetition were observed. Brain areas in midlevels of the processing hierarchy, including extrastriate visual cortex extending into inferotemporal cortex and left dorsal prefrontal cortex, showed reductions in the amount of activation after repetition. By contrast, early visual areas and output motor areas were activated equally by both novel and repeated objects and did not show effects of repetition, suggesting that the observed correlates of repetition were anatomically selective. We discuss these findings in relation to previous positron emission tomography (PET) and fMRI studies of item repetition and single-unit physiological studies; we also address the broad impact that rapid event-related fMRI is likely to have on functional neuroimaging.

The resting brain and our self: self-relatedness modulates resting state neural activity in cortical midline structures.

The resting brain shows high neural activity in various regions, the default-mode network, chief among them the cortical midline structures (CMS). The psychological correlate of high resting state neural activity in CMS remains however unclear though speculatively it has been associated with processing of internally-oriented self-relatedness. We used functional MRI to examine internally-oriented self-relatedness during the resting state period. This was indirectly done by letting subjects perceive emotional pictures followed by a fixation cross; the very same pictures were then rated subjectively according to their degree of self-relatedness in a postscanning session. This allowed us to correlate the picture ratings of self-relatedness with signal changes in the subsequent resting state period, i.e. fixation period. The emotional pictures' degree of self-relatedness parametrically modulated subsequent resting state signal changes in various CMS, including ventro- and dorsomedial prefrontal cortex and posterior cingulate cortex. This modulation could be distinguished from effects of emotion dimensions (e.g. valence, intensity) and evoked effects of self-relatedness during the stimulus period itself the latter being observed rather in subcortical regions, e.g. amygdala, ventral striatum, and tectum. In sum, our findings suggest that resting state neural activity in CMS is parametrically and specifically modulated by the preceding stimulus's degree of self-relatedness. This lends further support to the presumed involvement of these regions in processing internally-oriented self-relatedness as distinguished from externally-oriented self-relatedness.

Increased pre-SMA activation in early PD patients during simple self-initiated hand movements.

The slowness of movement, termed bradykinesia, is one of the main symptoms of Parkinson's disease (PD). This symptom may be due to the inability of PD patients to maximise the speed of internally driven movements. The mesial premotor areas and in particular the pre-supplementary motor area (pre-SMA) seem to play a crucial role in the temporal initiation of movements in humans and animals. However, this activation seems to be debatable in imaging studies of PD patients. We performed a motor paradigm with temporally self-initiated movements in nine de novo PD patients before and after initiation of dopaminergic medication. The main finding was an increased activation of the pre-SMA in de novo PD patients compared with healthy age-matched control subjects. This result indicates the contribution of the pre-SMA in the temporal initiation of self-generated movements and in the disease pathology of PD. Increased bilateral activation of the superior cerebellum, mainly on the ipsilateral side, and a decreased activation of the ipsilateral inferior cerebellum in PD patients were also present. These findings provide new insights into the activation pattern of the cerebellum in PD patients.

The neural bases of the pseudohomophone effect: Phonological constraints on lexico-semantic access in reading.

We investigated phonological processing in normal readers to answer the question to what extent phonological recoding is active during silent reading and if or how it guides lexico-semantic access. We addressed this issue by looking at pseudohomophone and baseword frequency effects in lexical decisions with event-related functional magnetic resonance imaging (fMRI). The results revealed greater activation in response to pseudohomophones than for well-controlled pseudowords in the left inferior/superior frontal and middle temporal cortex, left insula, and left superior parietal lobule. Furthermore, we observed a baseword frequency effect for pseudohomophones (e.g., FEAL) but not for pseudowords (e.g., FEEP). This baseword frequency effect was qualified by activation differences in bilateral angular and left supramarginal, and bilateral middle temporal gyri for pseudohomophones with low- compared to high-frequency basewords. We propose that lexical decisions to pseudohomophones involves phonology-driven lexico-semantic activation of their basewords and that this is converging neuroimaging evidence for automatically activated phonological representations during silent reading in experienced readers.

Perceptual specificity in visual object priming: functional magnetic resonance imaging evidence for a laterality difference in fusiform cortex.

Seeing an object on one occasion may facilitate or prime processing of the same object if it is later again encountered. Such priming may also be found -- but at a reduced level -- for different but perceptually similar objects that are alternative exemplars or 'tokens' of the initially presented object. We explored the neural correlates of this perceptual specificity using event-related functional magnetic resonance imaging (fMRI) procedures, contrasting neural activity when participants made object classification decisions (size judgments) regarding previously presented objects (repeated same), alternative exemplars of previously presented objects (repeated different), or entirely new objects (novel). Many frontal regions (including bilateral frontal operculum, bilateral posterior inferior frontal/precentral, left anterior inferior frontal, and superior frontal cortices) and multiple late visual and posterior regions (including middle occipital, fusiform, fusiform-parahippocampal, precuneus, and posterior cingulate, all bilaterally), demonstrated reduced neural activity for repeated compared to novel objects. Greater repetition-induced reductions were observed for same than for different exemplars in several of these regions (bilateral posterior inferior frontal, right precuneus, bilateral middle occipital, bilateral fusiform, bilateral parahippocampal and bilateral superior parietal). Additionally, right fusiform (occipitotemporal) cortex showed significantly less priming for different versus same exemplars than did left fusiform. These findings converge with behavioral evidence from divided visual field studies and with neuropsychological evidence underscoring the key role of right occipitotemporal cortex in processing specific visual form information; possible differences in the representational-functional role of left fusiform are discussed.

Characterization of grass pollen reactive T-cell lines derived from lesional atopic skin.

Since it has been hypothesized that atopic dermatitis represents a cellular immune reaction to exogenous aeroallergens, we investigated whether lesional skin contains allergen-specific T-cells and which lymphokines they might secrete. Using phytohaemagglutinin or grass pollen for the cloning procedure, we established a series of T-cell lines from the skin of two patients. When rechallenged with the allergen, three out of 12 dermal lines which had been cloned with the pollen extract and three out of 20 epidermal lines cloned with PHA were found to proliferate specifically. With one exception, allergen-specific lines were CD4+, CD8-, alpha/beta receptor +. The reaction pattern to the single components of the grass allergen extract was assessed with the line UH-D3. Further, the proliferative response to Lolium perennis was inhibited by HLA-DR antibody, indicating its dependence on structures of the MHC class II complex. Only one out of four CD4+ allergen-reactive lines secreted considerable interferon-gamma activity but all secreted interleukin-4. The relative predominance of IL-4 points to a possible role of skin-derived T-cells in the synthesis of IgE. The identification of allergen-specific T-cells in lesional skin of patients with atopic dermatitis is consistent with the hypothesis that their dermatitis represents a T-cell-mediated immune reaction.

Selective attention to conjunctions of color and shape of alphanumeric versus non-alphanumeric stimuli: a comparative electrophysiological study.

We compared multi-dimensional selection on the basis of the color, the global shape and the local shape of alphanumeric (letters) and non-alphanumeric (non-letters) stimuli. We investigated whether letters are selected on the basis of name codes or on the basis of highly familiar local shape codes. Participants responded to a single conjunction of color, global shape and local shape occurring in a randomized stream of other conjunctions of these attributes. Dependent variables were reaction time and measures derived from event-related brain potentials (onset latencies and peak amplitudes of the occipital selection negativity, SN). The SN results showed that, for both letters and non-letters, color and global shape were selected first and local shape was selected later. Reaction times were faster, and SN to the local shape occurred earlier for letters than for non-letters. The SN to the local shape of letters was larger than the SN to the local shape of non-letters. In contrast, the SN to the global shape of letters was smaller than the SN to the global shape of non-letters. Selection of the global shape of letters, but not of non-letters, depended on whether they occurred in the relevant color. Selection of the color of both letters and non-letters was independent of shape relevance, and selection of the local shape of both letters and non-letters was independent of color relevance. These results suggest that, (1) both letter and non-letter shapes are initially analyzed in a feature-specific manner; and (2) letters are selected for task-directed processing on the basis of highly familiar local shape codes and not on the basis of name codes.

Is our self based on reward? Self-relatedness recruits neural activity in the reward system.

Every organism has to evaluate incoming stimuli according to their current and future significance. The immediate value of stimuli is coded by the reward system, but the processing of their long-term relevance implements a valuation system that implicates self-relatedness. The neuronal relationship between reward and self-relatedness remains unclear though. Using event-related functional MRI, we investigated whether self-relatedness induces neural activity in the reward system. Self-relatedness induced signal changes in the same regions that were recruited during reward including the bilateral nucleus accumbens (NACC), ventral tegmental area (VTA) and ventromedial prefrontal cortex (VMPFC). The fMRI signal time courses revealed no differences in early BOLD signals between reward and self-relatedness. In contrast, both conditions differed in late BOLD signals with self-relatedness showing higher signal intensity. In sum, our findings indicate sustained recruitment of the reward system during self-relatedness. These findings may contribute to a better understanding of the reward-based nature of our self.

Selective activation of a parietofrontal circuit during implicitly imagined prehension.

It is generally held that motor imagery is the internal simulation of movements involving one's own body in the absence of overt execution. Consistent with this hypothesis, results from numerous functional neuroimaging studies indicate that motor imagery activates a large variety of motor-related brain regions. However, it is unclear precisely which of these areas are involved in motor imagery per se as opposed to other planning processes that do not involve movement simulation. In an attempt to resolve this issue, we employed event-related fMRI to separate activations related to hand preparation-a task component that does not demand imagining movements-from grip selection-a component previously shown to require the internal simulation of reaching movements. Our results show that in contrast to preparation of overt actions, preparation of either hand for covert movement simulation activates a large network of motor-related areas located primarily within the left cerebral and right cerebellar hemispheres. By contrast, imagined grip selection activates a distinct parietofrontal circuit that includes the bilateral dorsal premotor cortex, contralateral intraparietal sulcus, and right superior parietal lobule. Because these areas are highly consistent with the frontoparietal reach circuit identified in monkeys, we conclude that motor imagery involves action-specific motor representations computed in parietofrontal circuits.

Functional-anatomic study of episodic retrieval. II. Selective averaging of event-related fMRI trials to test the retrieval success hypothesis.

In a companion paper (R. L. Buckner et al., 1998, NeuroImage 7, 151-162) we used fMRI to identify brain areas activated by episodic memory retrieval. Prefrontal areas were shown to differentiate component processes related to retrieval success and retrieval effort in block-designed paradigms. Importantly, a right anterior prefrontal area was most active during task blocks involving greatest retrieval success, consistent with an earlier PET study by M. D. Rugg et al. (1996, Brain 119, 2073-2083). However, manipulation of these variables within the context of blocked trials confounds differences related to varying levels of retrieval success with potential shifts in subjects' strategies due to changes in the probability of target events across blocks. To test more rigorously the hypothesis that certain areas are directly related to retrieval success, we adopted recently developed procedures for event-related fMRI. Fourteen subjects studied words under deep encoding and were then tested in a mixed trial paradigm where old and new words were randomly presented. This recognition testing procedure activated similar areas to the blocked trial paradigm, with all areas showing similar levels of activation across old and new items. Of critical importance, significant activation was detected in right anterior prefrontal cortex for new items when subjects correctly indicated they were new (correct rejections). These findings go against the retrieval success hypothesis as formally proposed and provide an important constraint for interpretation of this region's role in episodic retrieval. Furthermore, anterior prefrontal activation was found to occur late, relative to other brain areas, suggesting that it may be involved in retrieval verification or monitoring processes or perhaps even in anticipation of subsequent trial events (although an alternative possibility, that the late onset is mediated by a late vascular response, cannot be ruled out). These findings and their relation to the results obtained in the companion blocked-trial paradigm are discussed.

Control of semantic interference in episodic memory retrieval is associated with an anterior cingulate-prefrontal activation pattern.

Prefrontal activation is a consistent finding in functional neuroimaging studies of episodic memory retrieval. In the present study we aimed at a further analysis of prefrontal neural systems involved in the executive control of context-specific properties in episodic memory retrieval using an event-related fMRI design. Nine subjects were asked to learn two 20-item word lists that consisted of concrete nouns assigned to four semantic categories. Ten items of both word lists referred to the same semantic category. Subjects were instructed to determine whether nouns displayed in random order corresponded to the first 20-item target list. The interference evoked by the retrieval of semantically related items of the second list resulted in significantly longer reaction times compared to the noninterference condition. Contrasting the interference against the noninterference retrieval condition demonstrated an activation pattern that comprised a right anterior cingulate and frontal opercular area and a left-lateralized dorsolateral prefrontal region. Trial averaged time series revealed that the PFC areas were selectively activated at the interference condition and did not respond to the familiarity of learned words. These findings suggest a functionally separable role of prefrontal cortical areas mediating processes associated with the executive control of interfering context information in episodic memory retrieval.