Proactive and reactive inhibition during overt and covert actions. An electrical neuroimaging study.

Response inhibition is the ability to suppress inadequate but automatically activated, prepotent or ongoing response tendencies. In the framework of motor inhibition, two distinct operating strategies have been described: “proactive” and “reactive” control modes. In the proactive modality, inhibition is recruited in advance by predictive signals, and actively maintained before its enactment. Conversely, in the reactive control mode, inhibition is phasically enacted after the detection of the inhibitory signal. To date, ample evidence points to a core cerebral network for reactive inhibition comprising the right inferior frontal gyrus (rIFG), the presupplementary motor area (pre-SMA) and the basal ganglia (BG). Moreover, fMRI studies showed that cerebral activations during proactive and reactive inhibition largely overlap. These findings suggest that at least part of the neural network for reactive inhibition is recruited in advance, priming cortical regions in preparation for the upcoming inhibition. So far, proactive and reactive inhibitory mechanisms have been investigated during tasks in which the requested response to be stopped or withheld was an “overt” action execution (AE) (i.e., a movement effectively performed). Nevertheless, inhibitory mechanisms are also relevant for motor control during “covert actions” (i.e., potential motor acts not overtly performed), such as motor imagery (MI). MI is the conscious, voluntary mental rehearsal of action representations without any overt movement. Previous studies revealed a substantial overlap of activated motor-related brain networks in premotor, parietal and subcortical regions during overtly executed and imagined movements. Notwithstanding this evidence for a shared set of cerebral regions involved in encoding actions, whether or not those actions are effectively executed, the neural bases of motor inhibition during MI, preventing covert action from being overtly performed, in spite of the activation of the motor system, remain to be fully clarified. Taking into account this background, we performed a high density EEG study evaluating cerebral mechanisms and their related sources elicited during two types of cued Go/NoGo task, requiring the execution or withholding of an overt (Go) or a covert (MI) action, respectively. The EEG analyses were performed in two steps, with different aims: 1) Analysis of the “response phase” of the cued overt and covert Go/NoGo tasks, for the evaluation of reactive inhibitory control of overt and covert actions. 2) Analysis of the “preparatory phase” of the cued overt and covert Go/NoGo EEG datasets, focusing on cerebral activities time-locked to the preparatory signals, for the evaluation of proactive inhibitory mechanisms and their related neural sources. For these purposes, a spatiotemporal analysis of the scalp electric fields was applied on the EEG data recorded during the overt and covert Go/NoGo tasks. The spatiotemporal approach provide an objective definition of time windows for source analysis, relying on the statistical proof that the electric fields are different and thus generated by different neural sources. The analysis of the “response phase” revealed that key nodes of the inhibitory circuit, underpinning inhibition of the overt movement during the NoGo response, were also activated during the MI enactment. In both cases, inhibition relied on the activation of pre-SMA and rIFG, but with different temporal patterns of activation in accord with the intended “covert” or “overt” modality of motor performance. During the NoGo condition, the pre-SMA and rIFG were sequentially activated, pointing to an early decisional role of pre-SMA and to a later role of rIFG in the enactment of inhibitory control of the overt action. Conversely, a concomitant activation of pre-SMA and rIFG emerged during the imagined motor response. This latter finding suggested that an inhibitory mechanism (likely underpinned by the rIFG), could be prewired into a prepared “covert modality” of motor response, as an intrinsic component of the MI enactment. This mechanism would allow the rehearsal of the imagined motor representations, without any overt movement. The analyses of the “preparatory phase”, confirmed in both overt and covert Go/NoGo tasks the priming of cerebral regions pertaining to putative inhibitory network, reactively triggered in the following response phase. Nonetheless, differences in the preparatory strategies between the two tasks emerged, depending on the intended “overt” or “covert” modality of the possible incoming motor response. During the preparation of the overt Go/NoGo task, the cue primed the possible overt response programs in motor and premotor cortex. At the same time, through preactivation of a pre-SMA-related decisional mechanism, it triggered a parallel preparation for the successful response selection and/or inhibition during the subsequent response phase. Conversely, the preparatory strategy for the covert Go/NoGo task was centred on the goal-oriented priming of an inhibitory mechanism related to the rIFG that, being tuned to the instructed covert modality of the motor performance and instantiated during the subsequent MI enactment, allowed the imagined response to remain a potential motor act. Taken together, the results of the present study demonstrate a substantial overlap of cerebral networks activated during proactive recruitment and subsequent reactive enactment of motor inhibition in both overt and covert actions. At the same time, our data show that preparatory cues predisposed ab initio a different organization of the cerebral areas (in particular of the pre-SMA and rIFG) involved with sensorimotor transformations and motor inhibitory control for executed and imagined actions. During the preparatory phases of our cued overt and covert Go/NoGo tasks, the different adopted strategies were tuned to the “how” of the motor performance, reflecting the intended overt and covert modality of the possible incoming action.

Estudio de la actividad cerebral durante la percepción y procesamiento afectivo de las expresiones faciales de la emoción

Las expresiones faciales de la emoción constituyen estímulos altamente relevantes en la interacción humana, dado que son señales comunicativas que nos permiten inferir el estado interno de otras personas. La función comunicativa de las expresiones faciales de la emoción ha sido objeto de gran interés y existe abundante literatura sobre el tema. Muchos autores han investigado los mecanismos involucrados en la percepción y decodificación de las expresiones faciales desde distintas perspectivas. En estudios realizados con medidas de la actividad cerebral de alta resolución temporal (electroencefalografía-EEG- y magnetoencefalografía-MEG) que se centran en el curso temporal del procesamiento perceptivo de las expresiones faciales de la emoción se ha encontrado una sensibilidad temprana a diversas emociones. Por ejemplo, el componente N170 ha mostrado sensibilidad diferenciada a las expresiones faciales de la emoción (ver revisión de Hinojosa, Mercado & Carretié, 2015). Un procedimiento utilizado habitualmente para investigar el procesamiento afectivo es el paradigma de priming afectivo, en el que primes y targets emocionales se presentan secuencialmente. La técnica de potenciales evocados (event-related potentials-ERP) se ha empleado habitualmente para explorar estos procesos y los estudios se han centrado en dos componentes principales: el N400 y el Potencial Tardío Positivo (Late Positive Potential-LPP). Se ha encontrado que el N400 es altamente sensible a la incongruencia semántica, mientras que su sensibilidad a la incongruencia afectiva no está tan clara. Por el contrario, se ha observado modulación del LPP debida a la incongruencia afectiva en ausencia de efectos en N400 (Herring et al., 2011)...

Please Stop Rubbing Your Relationship In My Face(book): An Investigation of Online Romantic Social Comparison

It is well-documented that social networking sites such as Facebook set the stage for social comparison. Such comparison has been linked to a number of negative outcomes including envy, negative moods, and lower self-esteem. The present research aims to extend current understanding of online social comparison by investigating how it pertains to romantic relationships. I hypothesized that for individuals high in attachment anxiety (compared to those low in this construct), online romantic social comparison might be related to negative consequences—which, in the current project, was operationalized as lower mood/affect and state self-esteem. Further, I hypothesized that there would be an interaction between attachment anxiety and relationship insecurities on these negative outcomes, such that the expected difference of attachment anxiety would be more pronounced under conditions priming relationship insecurities, relative to a control condition. Two experiments were conducted, one of which focused on single individuals, and the second focusing on individuals who were themselves in dating relationships. The paradigms of each entailed experimental manipulation of a key relationship-related variable (for single individuals, pessimism for future relationships; for dating individuals, the presence or absence of rejection threat), subsequent exposure to romantic content from Facebook, and finally, measures of affect and state self-esteem. I discovered partial support for the hypothesis that some single individuals—particularly those with higher, rather than lower, attachment anxiety—do indeed report feeling more negative moods and lower state self-esteem following exposure to romantic online content, in contrast to single individuals who had instead viewed neutral online content. The association between attachment anxiety and negative outcome was especially pertinent if individuals had been primed to believe that their own future romantic prospects were grim, or if attention had been drawn to their singleness. Among dating individuals, less support for hypotheses was found; however, exploratory post-hoc analyses revealed a promising (albeit weak) trend indicating that reinvestigation of the current hypotheses would be prudent.

Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine

Advanced metastatic melanoma is incurable by standard treatments, but occasionally responds to immunotherapy. Recent trials using dendritic cells (DC) as a cellular adjuvant have concentrated on defined peptides as the source of antigens, and rely on foreign proteins as a source of help to generate a cell-mediated immune response. This approach limits patient accrual, because currently defined, non-mutated epitopes are restricted by a small number of human leucocyte antigens. It also fails to take advantage of mutated epitopes peculiar to the patient's own tumour, and of CD4(+) T lymphocytes as potential effectors of anti-tumour immunity. We therefore sought to determine whether a fully autologous DC vaccine is feasible, and of therapeutic benefit. Patients with American Joint Cancer Committee stage IV melanoma were treated with a fully autologous immunotherapy consisting of monocyte-derived DC, matured after culture with irradiated tumour cells. Of 19 patients enrolled into the trial, sufficient tumour was available to make treatments for 17. Of these, 12 received a complete priming phase of six cycles of either 0.9X10(6) or 5X10(6) DC/intradermal injection, at 2-weekly intervals. Where possible, treatment continued with the lower dose at 6-weekly intervals. The remaining five patients could not complete priming, due to progressive disease. Three of the 12 patients who completed priming have durable complete responses (average duration 3 5 months +), three had partial responses, and the remaining six had progressive disease (WHO criteria). Disease regression was not correlated with dose or with the development of delayed type hypersensitivity responses to intradermal challenge with irradiated, autologous tumour. However, plasma S-100B levels prior to the commencement of treatment correlated with objective clinical response (P = 0.05) and survival (log rank P < 0.001). The treatment had minimal side-effects and was well tolerated by all patients. Mature, monocyte-derived DC preparations exposed to appropriate tumour antigen sources can be reliably produced for patients with advanced metastatic melanoma, and in a subset of those patients with lower volume disease their repeated administration results in durable complete responses.

Maintaining and updating semantic context in schizophrenia: an investigation of the effects of multiple remote primes

Conflicting findings regarding the ability of people with schizophrenia to maintain and update semantic contexts have been due, arguably, to vagaries within the experimental design employed (e.g. whether strongly or remotely associated prime-target pairs have been used, what delay between the prime and the target was employed, and what proportion of related prime-target pairs appeared) or to characteristics of the participant cohort (e.g. medication status, chronicity of illness). The aim of the present study was to examine how people with schizophrenia maintain and update contextual information over an extended temporal window by using multiple primes that were either remotely associated or unrelated to the target. Fourteen participants with schizophrenia and 12 healthy matched controls were compared across two stimulus onset asynchronies (SOAs) (short and long) and two relatedness proportions (RP) (high and low) in a crossed design. Analysis of variance statistics revealed significant two- and three-way interactions between Group and SOA, Group and Condition, SOA and RP, and Group, SOA and RP. The participants with schizophrenia showed evidence of enhanced remote priming at the short SOA and low RP, combined with a reduction in the time course over which context could be maintained. There was some sensitivity to biasing contextual information at the short SOA, although the mechanism over which context served to update information appeared to be different from that in the controls. The participants with schizophrenia showed marked performance decrements at the long SOA (both low and high RP). Indices of remote priming at the short (but not the long) SOA correlated with both clinical ratings of thought disorder and with increasing length of illness. The results support and extend the hypothesis that schizophrenia is associated with concurrent increases in tonic dopamine activity and decreases in phasic dopamine activity. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Addition of cue exposure to cognitive-behaviour therapy for alcohol misuse: a randomized trial with dysphoric drinkers

Aim To test whether addition of moderation-orientated cue exposure (CE) or CE after dysphoric mood induction ( emotional CE, ECE) improved outcomes above those from cognitive-behaviour therapy alone (CBT) in people who drank when dysphoric. Design Multi-site randomized controlled trial comparing CBT with CBT + CE and CBT + ECE. Setting Out-patient rooms in academic treatment units in Brisbane and Sydney, Australia. Participants People with alcohol misuse and problems controlling consumption when dysphoric (n = 163). Those with current major depressive episode were excluded. Intervention Eight weekly 75-minute sessions of individual treatment for alcohol problems were given to all participants, with CBT elements held constant across conditions. From session 2, CBT + CE participants resisted drinking while exposed to alcohol cues, with two priming doses of their preferred beverage being given in some sessions. After an initial CE session, CBT + ECE participants recalled negative experiences before undertaking CE, to provide exposure to emotional cues of personal relevance. Measurements Alcohol consumption, related problems, alcohol expectancies, self-efficacy and depression. Results Average improvements were highly significant across conditions, with acceptable maintenance of effects over 12 months. Both treatment retention and effects on alcohol consumption were progressively weaker in CBT + CE and CBT + ECE than in CBT alone. Changes in alcohol dependence and depression did not differ across conditions. Conclusions These data do not indicate that addition of clinic-based CE to standard CBT improves outcomes. A different approach to the management of craving may be required.

Systemic activation of dendritic cells by Toll-like receptor ligands or malaria infection impairs cross-presentation and anti-viral immunity

The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.

Acquisition of negative valence and modified attentional processing by non fear relevant stimuli

The current research examined valence and attentional processing of a priori fear relevant stimuli and investigated the extent to which these characteristics can be acquired by non fear relevant stimuli across an aversive learning episode. The first experiment compared pictures of snakes and spiders with pictures of birds and fish using affective priming, visual search and detection of a dot probe. Snakes and spiders were more negative than birds and fish as indexed by affective priming, and were preferentially attended to in the visual search task. The second experiment exposed the non fear relevant animal pictures, birds and fish, in an aversive learning episode involving an aversive shock US. Skin conductance responding was measured during acquisition. After acquisition, conditioned non fear relevant animal stimuli, CS1, and non conditioned, non fear relevant animal stimuli, CS, were compared across affective priming, visual search and dot probe tasks. During acquisition, skin conductance responses were larger during CS1 than during CS across all three response intervals. After acquisition, CS1 non fear relevant animal pictures were more negative than CS non fear relevant animal pictures as indexed by affective priming, and were preferentially attended to in a dot probe task. These studies provide evidence that negative valence and modified attentional processing can be acquired in a brief aversive learning episode.

Higher-order CpG-DNA stimulation reveals distinct activation requirements for marginal zone and follicular B cells in lupus mice

Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded CpG-oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG-ODN capable of forming higher-order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell-activating factor, or simultaneous co-engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF-1, IL-6 and IL-12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self-derived hypomethylated double-stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co-engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9-induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.

Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome

Recent large-scale analyses of mainly full-length cDNA libraries generated from a variety of mouse tissues indicated that almost half of all representative cloned sequences did flat contain ail apparent protein-coding sequence, and were putatively derived from non-protein-coding RNA (ncRNA) genes. However, many of these clones were singletons and the majority were unspliced, raising the possibility that they may be derived from genomic DNA or unprocessed pre-rnRNA contamination during library construction, or alternatively represent nonspecific transcriptional noise. Here we Show, using reverse transcriptase-dependent PCR, microarray, and Northern blot analyses, that many of these clones were derived from genuine transcripts Of unknown function whose expression appears to be regulated. The ncRNA transcripts have larger exons and fewer introns than protein-coding transcripts. Analysis of the genomic landscape around these sequences indicates that some cDNA clones were produced not from terminal poly(A) tracts but internal priming sites within longer transcripts, only a minority of which is encompassed by known genes. A significant proportion of these transcripts exhibit tissue-specific expression patterns, as well as dynamic changes in their expression in macrophages following lipopolysaccharide Stimulation. Taken together, the data provide strong support for the conclusion that ncRNAs are an important, regulated component of the mammalian transcriptome.

Meaning selection and the subcortex: Evidence of reduced lexical ambiguity repetition effects following subcortical lesions

Recent research indicates that individuals with nonthalamic subcortical (NS) lesions call experience difficulties processing lexical ambiguities in a variety of contexts. This study examined how prior processing of a lexical ambiguity influences subsequent meaning activation in 10 individuals with NS lesions and 10 matched healthy controls. Subjects made speeded lexical decisions oil related or unrelated targets following homophone primes. Homophones were repealed with different targets biasing the same or different meanings oil the second presentation. The effects of prime-target relatedness, interstimulus interval (200 or 1250 ms), and same vs different meaning repetition were examined Both the patient and control groups showed printing when the same homophone meaning was biased oil repetition. When a different meaning was biased on the second presentation. no priming was evident in the controls, while facilitation remained present for the NS group, consistent with aberrant meaning selection and deactivation processes. These findings are discussed in terms of age and task-related repetition effects and current conceptions of frontal-subcortical involvement in cognition.

Phosphoinositide regulation of neuroexocytosis: adding to the complexity

Exocytosis of neurotransmitter containing vesicles supports neuronal communication. The importance of molecular interactions involving specific lipids has become progressively more evident and the lipid composition of both the synaptic vesicle and the pre-synaptic plasma membrane at the active zone has significant functional consequences for neurotransmitter release. Several classes of lipids have been implicated in exocytosis including polyunsaturated fatty acids and phosphoinositides. This minireview will focus on recent developments regarding the role of phosphoinositides in neurosecretion.

Relationship between bicarbonate retention and bone characteristics in broiler chickens

Determination of the bicarbonate retention factor (BRF) is an important step during development of the indicator amino acid oxidation technique for use in a new model. A series of 4-h oxidation experiments were performed to determine the BRF of broilers aged 7, 14, 21, 28, 35, and 42 d using 4 birds per age group. A priming dose of 1.2 mu Ci of (NaHCO3)-C-14, followed by eight half-hourly doses of 1 mu Ci of (NaHCO3)-C-14 were given orally to each of 4 birds per age. The percentage of 14 C dose expired by the bird at a steady state was measured. These birds, as well as 12 additional birds matched for age and BW, were killed, and femur bone mineral density was measured by quantitative computed tomography to determine the relationship between bone development and bicarbonate retention at each age. There was a correlation (r = 0.50; P < 0.05) between total cross-sectional femur bone mineral density and bicarbonate retention at each age. A prediction equation (Y = 6.95 x 10(-2) X - 3.51 x 10(5)X(2) + 27.58; P < 0.0001, R-2 = 0.79) where Y = bicarbonate retention and X = BW was generated to predict Y as a function of X. Bicarbonate retention values peaked at 28 d, during the stage of the most rapid bone deposition and the highest growth rate. A constant BRF was found from 1,900 to 2,700 g of BW of 35.15 +/- 1.095% (mean SEM). This retention factor will allow the accurate correction of oxidation of C-14-labeled substrates in broilers of different ages and BW in future indicator amino acid oxidation studies.

Signal integration between IFN gamma and TLR signalling pathways in macrophages

Macrophages are major effector cells of the innate immune system, and appropriate regulation of macrophage function requires the integration of multiple signalling inputs derived from the recognition of host factors (e.g. interferon-gamma/IFN gamma) and pathogen products (e.g. toll-like receptor/TLR agonists). The profound effects of IFN gamma pre-treatment (priming) on TLR-induced macrophage activation have long been recognised, but many of the mechanisms underlying the priming phenotype have only recently been identified. This review summarises the known mechanisms of integration between the IFN gamma and TLR signalling pathways. Synergy occurs at multiple levels, ranging from signal recognition to convergence of signals at the promoters of target genes. In particular, the cross-talk between the IFN gamma and LPS and CpG DNA signalling pathways is discussed. (c) 2006 Elsevier GmbH. All rights reserved.