Context-dependent interactions of left posterior inferior frontal gyrus in a local visual search task unrelated to language

The Embedded Figures Task (EFT) involves search for a target hidden in a complex geometric pattern. Even though the EFT is designed to probe local visual search functions, not language-related processes, neuropsychological studies have demonstrated a strong association between aphasia and impairment on this task. A potential explanation for this relationship was offered by a recent functional MRI study (Manjaly et al., 2003), which demonstrated that a part of the left posterior inferior frontal gyrus (pIFG), overlapping with Broca's region, is crucially involved in the execution of the EFT. This result suggested that pIFG, an area strongly associated with language-related functions, is also part of a network subserving cognitive functions unrelated to language. In this study, we tested this conjecture by analysing the data of Manjaly et al. for context-dependent functional interactions of the pIFG during execution of the EFT. The results showed that during EFT, compared to a similar visual matching task with minimal local search components, pIFG changed its interactions with areas commonly involved in visuospatial processing: Increased contributions to neural activity in left posterior parietal cortex, cerebellar vermis, and extrastriate areas bilaterally, as well as decreased contributions to bilateral temporo-parietal cortex, posterior cingulate cortex, and left dorsal premotor cortex were found. These findings demonstrate that left pIFG can be involved in nonlanguage processes. More generally, however, they provide a concrete example of the notion that there is no general one-to-one mapping between cognitive functions and the activations of individual areas. Instead, it is the spatiotemporal pattern of functional interactions between areas that is linked to a particular cognitive context

A role for Broca's area beyond language processing: Evidence from neuropsychology and fMRI

Broca's area (or, more generally, the left inferior frontal region) is implicated in many language and language-related tasks. This chapter addresses the question of whether it is legitimate to move from this assertion (supported by very large numbers of lesion studies and functional neuroimaging experiments) to the theoretical claim that the exclusive (or even the core) specialization of Broca's area is the mediation of language functions. It shows that particular neuroanatomical regions, including Broca's area, change their functions consequent upon the simultaneous activation of other regions that are effectively connected to a given region

The PhysiO Toolbox for Modeling Physiological Noise in fMRI Data

AbstractBackgroundPhysiological noise is one of the major confounds for fMRI. A common class of correction methods model noise from peripheral measures, such as ECGs or pneumatic belts. However, physiological noise correction has not emerged as a standard preprocessing step for fMRI data yet due to: (1) the varying data quality of physiological recordings, (2) non-standardized peripheral data formats and (3) the lack of full automatization of processing and modeling physiology, required for large-cohort studies.New methodsWe introduce the PhysIO Toolbox for preprocessing of physiological recordings and model-based noise correction. It implements a variety of noise models, such as RETROICOR, respiratory volume per time and heart rate variability responses (RVT/HRV). The toolbox covers all intermediate steps − from flexible read-in of data formats to GLM regressor/contrast creation − without any manual intervention.ResultsWe demonstrate the workflow of the toolbox and its functionality for datasets from different vendors, recording devices, field strengths and subject populations. Automatization of physiological noise correction and performance evaluation are reported in a group study (N=35).Comparison with existing methodsThe PhysIO Toolbox reproduces physiological noise patterns and correction efficacy of previously implemented noise models. It increases modeling robustness by outperforming vendor-provided peak detection methods for physiological cycles. Finally, the toolbox offers an integrated framework with full automatization, including performance monitoring, and flexibility with respect to the input data.ConclusionsThrough its platform-independent Matlab implementation, open-source distribution, and modular structure, the PhysIO Toolbox renders physiological noise correction an accessible preprocessing step for fMRI data

Individual treatment expectations predict clinical outcome after lumbar injections against low back pain

Subjective expectations are known to be associated with clinical outcomes. However, expectations exist about different aspects of recovery, and few studies have focused on expectations about specific treatments. Here, we present results from a prospective observational study of patients receiving lumbar steroid injections against low back pain (N=252). Patients completed questionnaires directly before (), directly after (), and 2 weeks after () the injection. In addition to pain intensity, we assessed expectations (and certainty therein) about treatment effects, using both numerical rating scales (NRS) and the Expectation for Treatment Scale (ETS). Regression models were used to explain (within-sample) treatment outcome (pain intensity at ) based on pain levels, expectations, and certainty at and . Using cross-validation, we examined the models’ ability to predict (out-of-sample) treatment outcome. Pain intensity significantly decreased ()two weeks after injections, with a reduction of the median NRS score from 6 to 3. NRS measures of pain, expectation and certainty from jointly explained treatment outcome (). Expectations at explained outcome on its own () and enabled out-of-sample predictions about outcome (), with a median error of 1.36 on a 0-10 NRS. Including measures from did not significantly improve models. Using the ETS as alternative measurement of treatment expectations (sensitivity analysis) gave consistent results. Our results demonstrate that treatment expectations play an important role for clinical outcome after lumbar injections and may represent targets for concomitant cognitive interventions. Predicting outcomes based on simple questionnaires might be useful to support treatment selection

Process of Assay Selection and Optimization for the Study of Case and Control Samples from a Phase IIb Efficacy Trial of a Candidate Tuberculosis Vaccine, MVA85A

The first phase IIb safety and efficacy trial of a new tuberculosis vaccine since that for BCG was completed in October 2012. BCG-vaccinated South African infants were randomized to receive modified vaccinia virus Ankara, expressing the Mycobacterium tuberculosis antigen 85A (MVA85A), or placebo. MVA85A did not significantly boost the protective effect of BCG. Cryopreserved samples provide a unique opportunity for investigating the correlates of the risk of tuberculosis disease in this population. Due to the limited amount of sample available from each infant, preliminary work was necessary to determine which assays and conditions give the most useful information. Peripheral blood mononuclear cells (PBMC) were stimulated with antigen 85A (Ag85A) and purified protein derivative from M. tuberculosis in an ex vivo gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) and a Ki67 proliferation assay. The effects of a 2-h or overnight rest of thawed PBMC on ELISpot responses and cell populations were determined. Both the ELISpot and Ki67 assays detected differences between the MVA85A and placebo groups, and the results correlated well. The cell numbers and ELISpot responses decreased significantly after an overnight rest, and surface flow cytometry showed a significant loss of CD4(+) and CD8(+) T cells. Of the infants tested, 50% had a positive ELISpot response to a single pool of flu, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) (FEC) peptides. This pilot work has been essential in determining the assays and conditions to be used in the correlate study. Moving forward, PBMC will be rested for 2 h before assay setup. The ELISpot assay, performed in duplicate, will be selected over the Ki67 assay, and further work is needed to evaluate the effect of high FEC responses on vaccine-induced immunity and susceptibility to tuberculosis disease

Alternate aerosol and systemic immunisation with a recombinant viral vector for tuberculosis, MVA85A: A phase I randomised controlled trial

BACKGROUND:There is an urgent need for an effective tuberculosis (TB) vaccine. Heterologous prime-boost regimens induce potent cellular immunity. MVA85A is a candidate TB vaccine. This phase I clinical trial was designed to evaluate whether alternating aerosol and intradermal vaccination routes would boost cellular immunity to the Mycobacterium tuberculosis antigen 85A (Ag85A). METHODS AND FINDINGS:Between December 2013 and January 2016, 36 bacille Calmette-Guérin-vaccinated, healthy UK adults were randomised equally between 3 groups to receive 2 MVA85A vaccinations 1 month apart using either heterologous (Group 1, aerosol-intradermal; Group 2, intradermal-aerosol) or homologous (Group 3, intradermal-intradermal) immunisation. Bronchoscopy and bronchoalveolar lavage (BAL) were performed 7 days post-vaccination. Adverse events (AEs) and peripheral blood were collected for 6 months post-vaccination. The laboratory and bronchoscopy teams were blinded to treatment allocation. One participant was withdrawn and was replaced. Participants were aged 21-42 years, and 28/37 were female. In a per protocol analysis, aerosol delivery of MVA85A as a priming immunisation was well tolerated and highly immunogenic. Most AEs were mild local injection site reactions following intradermal vaccination. Transient systemic AEs occurred following vaccination by both routes and were most frequently mild. All respiratory AEs following primary aerosol MVA85A (Group 1) were mild. Boosting an intradermal MVA85A prime with an aerosolised MVA85A boost 1 month later (Group 2) resulted in transient moderate/severe respiratory and systemic AEs. There were no serious adverse events and no bronchoscopy-related complications. Only the intradermal-aerosol vaccination regimen (Group 2) resulted in modest, significant boosting of the cell-mediated immune response to Ag85A (p = 0.027; 95% CI: 28 to 630 spot forming cells per 1 × 106 peripheral blood mononuclear cells). All 3 regimens induced systemic cellular immune responses to the modified vaccinia virus Ankara (MVA) vector. Serum antibodies to Ag85A and MVA were only induced after intradermal vaccination. Aerosolised MVA85A induced significantly higher levels of Ag85A lung mucosal CD4+ and CD8+ T cell cytokines compared to intradermal vaccination. Boosting with aerosol-inhaled MVA85A enhanced the intradermal primed responses in Group 2. The magnitude of BAL MVA-specific CD4+ T cell responses was lower than the Ag85A-specific responses. A limitation of the study is that while the intradermal-aerosol regimen induced the most potent cellular Ag85A immune responses, we did not boost the last 3 participants in this group because of the AE profile. Timing of bronchoscopies aimed to capture peak mucosal response; however, peak responses may have occurred outside of this time frame. CONCLUSIONS:To our knowledge, this is the first human randomised clinical trial to explore heterologous prime-boost regimes using aerosol and systemic routes of administration of a virally vectored vaccine. In this trial, the aerosol prime-intradermal boost regime was well tolerated, but intradermal prime-aerosol boost resulted in transient but significant respiratory AEs. Aerosol vaccination induced potent cellular Ag85A-specific mucosal and systemic immune responses. Whilst the implications of inducing potent mucosal and systemic immunity for protection are unclear, these findings are of relevance for the development of aerosolised vaccines for TB and other respiratory and mucosal pathogens. TRIAL REGISTRATION:ClinicalTrials.gov NCT01954563

A Phase I, Open-Label Trial, Evaluating the Safety and Immunogenicity of Candidate Tuberculosis Vaccines AERAS-402 and MVA85A, Administered by Prime-Boost Regime in BCG-Vaccinated Healthy Adults

MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing Mycobacterium tuberculosis antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB.In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS-402.Most related adverse events (AEs) were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN-γ, TNF-α and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A.Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries