Local GABA concentration is related to network-level resting functional connectivity

Anatomically plausible networks of functionally inter-connected regions have been reliably demonstrated at rest, although the neurochemical basis of these ‘resting state networks’ is not well understood. In this study, we combined magnetic resonance spectroscopy (MRS) and resting state fMRI and demonstrated an inverse relationship between levels of the inhibitory neurotransmitter GABA within the primary motor cortex (M1) and the strength of functional connectivity across the resting motor network. This relationship was both neurochemically and anatomically specific. We then went on to show that anodal transcranial direct current stimulation (tDCS), an intervention previously shown to decrease GABA levels within M1, increased resting motor network connectivity. We therefore suggest that network-level functional connectivity within the motor system is related to the degree of inhibition in M1, a major node within the motor network, a finding in line with converging evidence from both simulation and empirical studies

Cortical activation changes underlying stimulation-induced behavioural gains in chronic stroke

Transcranial direct current stimulation, a form of non-invasive brain stimulation, is showing increasing promise as an adjunct therapy in rehabilitation following stroke. However, although significant behavioural improvements have been reported in proof-of-principle studies, the underlying mechanisms are poorly understood. The rationale for transcranial direct current stimulation as therapy for stroke is that therapeutic stimulation paradigms increase activity in ipsilesional motor cortical areas, but this has not previously been directly tested for conventional electrode placements. This study was performed to test directly whether increases in ipsilesional cortical activation with transcranial direct current stimulation are associated with behavioural improvements in chronic stroke patients. Patients at least 6 months post-first stroke participated in a behavioural experiment (n = 13) or a functional magnetic resonance imaging experiment (n = 11), each investigating the effects of three stimulation conditions in separate sessions: anodal stimulation to the ipsilesional hemisphere; cathodal stimulation to the contralesional hemisphere; and sham stimulation. Anodal (facilitatory) stimulation to the ipsilesional hemisphere led to significant improvements (5–10%) in response times with the affected hand in both experiments. This improvement was associated with an increase in movement-related cortical activity in the stimulated primary motor cortex and functionally interconnected regions. Cathodal (inhibitory) stimulation to the contralesional hemisphere led to a functional improvement only when compared with sham stimulation. We show for the first time that the significant behavioural improvements produced by anodal stimulation to the ipsilesional hemisphere are associated with a functionally relevant increase in activity within the ipsilesional primary motor cortex in patients with a wide range of disabilities following stroke

B cell–intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans

Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21–induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Human frontal eye fields and visual search

This thesis tested whether the human frontal eye fields (FEFs) have visuospatial functions that are dissociable from FEF oculomotor functions. Functional magnetic resonance imaging (fMRI) was used to localize the FEFs, and transcranial magnetic stimulation (TMS) was applied in a series of experiments to transiently disrupt information processing in the FEFs. It was shown that TMS applied over the right FEFs degrades subjects' performance on a visual conjunction search task in which eye movements were not required and were not made. A TMS timing protocol subsequently showed that computations in the FEFs that occur between 40 and 80ms after the onset of a visual search array are critical for accurate performance. This suggests that, as in the monkey, the human FEFs may accumulate and use visual evidence from extrastriate cortex, which forms the basis for accurate visuospatial discrimination. A training protocol showed that the right FEFs are no longer critical for accurate visuospatial discrimination performance once a search task has been extensively practised. This study further suggested that the FEFs may have a previously unknown role in the perception of left-right rotated shapes. A study on feature and spatial priming indicated that these two phenomena have distinct causal mechanisms. The left FEFs appear to access a spatial memory signal during the process of saccade programming. When TMS is applied during this period, the spatial priming benefit is abolished. Altogether, this thesis presents evidence that visuospatial and oculomotor functions can be dissociated in the human FEFs. The data on timing and the effects of learning correspond well with results reported in monkeys. The priming experiment offers the first evidence that the left FEFs are crucial for spatial priming, while the learning study suggests the novel hypothesis that the FEFs are crucial for left-right rotated shape perception.</p

Harm reduction initiatives for drug users and the general population: what value to society?

This paper charts the benefits of harm reduction measures for drug users and society in general in Ireland. It points out that extensive changes have occurred in Irish drug policy, with the expansion of the Drug Treatment Services in response to the Government Strategy to prevent drug misuse in 1991 and the National AIDS Strategy Commission report in 1992 and the introduction of the methadone protocol in 1998. The paper shows that approximately 7000 individuals receive methadone treatment, with over 55 methadone clinics in the Eastern region of the country. Needle exchange programmes have also expanded, with 14 serving the Dublin area. The paper shows that in Britain it has been estimated that for every £1 spent on treatment there is a return of more than £3 in terms of savings associated with reduced crime. The paper points out that more progress needs to be made in regard to high-risk sexual behaviour, not just focussing on drug misuers, but also those who exchange sex to support addiction. The paper suggests practical interventions including outreach, peer and social interventions, sex education, legal access to sterile injecting equipment and low threshold agonist pharmacology, in the form of methadone treatment programmes

Human frontal eye fields and visual search

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Inducing affective learning biases with cognitive training and prefrontal tDCS: a proof-of-concept study

Background Cognitive models of mood disorders emphasize a causal role of negative affective biases in depression. Computational work suggests that these biases may stem from a belief that negative events have a higher information content than positive events, resulting in preferential processing of and learning from negative outcomes. Learning biases therefore represent a promising target for therapeutic interventions. In this proof-of-concept study in healthy volunteers, we assessed the malleability of biased reinforcement learning using a novel cognitive training paradigm and concurrent transcranial direct current stimulation (tDCS). Methods In two studies, young healthy adults completed two sessions of negative (n = 20) or positive (n = 20) training designed to selectively increase learning from loss or win outcomes, respectively. During training active or sham tDCS was applied bilaterally to dorsolateral prefrontal cortex. Analyses tested for changes both in learning rates and win- and loss-driven behaviour. Potential positive/negative emotional transfer of win/loss learning was assessed by a facial emotion recognition task and mood questionnaires. Results Negative and positive training increased learning rates for losses and wins, respectively. With negative training, there was also a trend for win (but not loss) learning rates to decrease over successive task blocks. After negative training, there was evidence for near transfer in the form of an increase in loss-driven choices when participants performed a similar (untrained) task. There was no change in far transfer measures of emotional face processing or mood. tDCS had no effect on any aspect of behaviour. Discussion and Conclusions Negative training induced a mild negative bias in healthy adults as reflected in loss-driven choice behaviour. Prefrontal tDCS had no effect. Further research is needed to assess if this training procedure can be adapted to enhance learning from positive outcomes and whether effects translate to affective disorders

Frontal cortex stimulation reduces vigilance to threat: Implications for the treatment of depression and anxiety

The difficulty in treating mood disorders has brought about clinical interest in alternative treatments, such as transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). However, the optimal parameters for stimulation and underlying mechanisms of action are unclear. Psychiatric treatments have acute effects on emotional processing that predict later therapeutic action. Such effects have been proposed as cognitive biomarkers for screening novel treatments for depression and anxiety.This study assessed the effect of tDCS on a battery of emotional processing measures sensitive to antidepressant action. To refine optimal stimulation parameters, DLPFC stimulation using two common electrode montages was compared with sham. Sixty healthy volunteers received 20 minutes of active or sham DLPFC stimulation before completing computerized emotional processing tasks, including a dot-probe measure of vigilance to threat.Relative to sham stimulation, participants receiving simultaneous anodal stimulation of left DLPFC and cathodal stimulation of right DLPFC (bipolar-balanced montage) showed reduced vigilance to threatening stimuli. There was no such significant effect when the cathode was placed on the supraorbital ridge (bipolar-unbalanced montage). There were no effects of tDCS on other measures of emotional processing.Our findings provide the first experimental evidence that modulating activity in the DLPFC reduces vigilance to threatening stimuli. This significant reduction in fear vigilance is similar to that seen with anxiolytic treatments in the same cognitive paradigm. The finding that DLPFC tDCS acutely alters the processing of threatening information suggests a potential cognitive mechanism that could underwrite treatment effects in clinical populations

Frontal cortex stimulation reduces vigilance to threat: Implications for the treatment of depression and anxiety

The difficulty in treating mood disorders has brought about clinical interest in alternative treatments, such as transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). However, the optimal parameters for stimulation and underlying mechanisms of action are unclear. Psychiatric treatments have acute effects on emotional processing that predict later therapeutic action. Such effects have been proposed as cognitive biomarkers for screening novel treatments for depression and anxiety.This study assessed the effect of tDCS on a battery of emotional processing measures sensitive to antidepressant action. To refine optimal stimulation parameters, DLPFC stimulation using two common electrode montages was compared with sham. Sixty healthy volunteers received 20 minutes of active or sham DLPFC stimulation before completing computerized emotional processing tasks, including a dot-probe measure of vigilance to threat.Relative to sham stimulation, participants receiving simultaneous anodal stimulation of left DLPFC and cathodal stimulation of right DLPFC (bipolar-balanced montage) showed reduced vigilance to threatening stimuli. There was no such significant effect when the cathode was placed on the supraorbital ridge (bipolar-unbalanced montage). There were no effects of tDCS on other measures of emotional processing.Our findings provide the first experimental evidence that modulating activity in the DLPFC reduces vigilance to threatening stimuli. This significant reduction in fear vigilance is similar to that seen with anxiolytic treatments in the same cognitive paradigm. The finding that DLPFC tDCS acutely alters the processing of threatening information suggests a potential cognitive mechanism that could underwrite treatment effects in clinical populations