Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.

Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31

Using TMS-fMRI to investigate the neural correlates of visual perception

Introduction: Despite sustained attention, weak sensory event often evade our perceptual awareness. The neural mechanisms that determine whether a stimulus is consciously perceived remain poorly understood. Conscious visual perception is thought to rely on a widespread neural system encompassing primary and higher order visual areas, frontoparietal areas and subcortical regions such as the thalamus. This concurrent TMS-fMRI study applied TMS to the right anterior intraparietal sulcus (IPS) and in a sham control to investigate how perturbations to IPS influence the neural systems underlying visual perception of weak sensory events. Methods: 7 subjects took part in the concurrent TMS-fMRI experiment (3T Siemens Magnetom Tim Trio System, GE-EPI, TR = 3290ms, TE = 35ms, 40 axial slices, size = 3mm x 3mm x 3.3mm). The 2x2x2 factorial design manipulated: (i) visual target (present, absent), (ii) visual percept (yes, no) and (ii) TMS condition (IPS, Sham). In a visual target detection task, subjects fixated a cross in the centre of the screen. On 50 of the trials a weak visual target was presented in their left lower visual field. Subjects were instructed to answer 'yes' only when completely sure. Visual stimuli were individually tailored to yield a detection threshold of 70 in visual present trials. Bursts of 4 TMS pulses (10Hz) were applied in image acquisition gaps at 100ms after each trial onset over the right IPS (x=42.3, y=-50.3, z=64.4) and during a sham condition using a MagPro X100 stimulator (MagVenture, Denmark) and a MR-compatible figure of eight TMS coil (MRi-B88). Stimulation intensity was 69 for IPS and was adjusted during Sham stimulation to evoke similar side effects. Trials were presented in blocks of 12 that were interleaved with baseline periods of 13s. Each run consisted of 7 blocks with 4 runs per TMS condition, giving a total of 168 trials per condition. Each TMS condition was performed in different sessions and all conditions were counterbalanced across subjects. Behavioral responses were categorized in hit, miss, false alarm and correct rejection (CR). Performance measures for each category were computed separately for IPS- and Sham-TMS and averaged across subjects. While each condition was modelled at the 1st level (using SPM8), 2nd level random effects analyses (one-sample t-tests) were restricted to target present trials (i.e. hits, misses). We tested for the main effects of TMS, visual percept and their interaction. Results are reported at p<0.05 at cluster level corrected for the whole brain using an auxiliary uncorrected voxel threshold of p=0.01. Conclusions: Visual detection involves perceptual decisions based on uncertain sensory representations. As participants set a high criterion for determining whether they are aware of targets, missed trials were associated with more uncertainty as indexed by long response times and thereby placed more demands on decisional processes. TMS to IPS perturbed this neural system involved in perceptual decisions and awareness. Critically, while the right precentral/middle frontal gyrus associated with the frontal eye field usually discriminates between hits and misses, TMS-IPS abolishes this difference in activation indicating that IPS-FEF closely interact in perceptual awareness and decisions

Physical and perceptual factors that determine the mode of audio-visual integration in distinct areas of the speech processing system

Speech and non-speech stimuli differ in their (i) physical (spectro-temporal structure) and (ii) perceptual (phonetic/linguistic representation) aspects. To dissociate these two levels in audio-visual integration, this fMRI study employed original spoken sentences and their sinewave analogues that were either trained and perceived as speech (group 1) or non-speech (group 2). In both groups, all stimuli were presented in visual, auditory or audiovisual modalities. AV-integration areas were identified by superadditive and subadditive interactions in a random effects analysis. While no superadditive interactions were observed, subadditive effects were found in right superior temporal sulci for both speech and sinewave stimuli. The left ventral premotor cortex showed increased subadditive interactions for speech relative to their sinewave analogues irrespective of whether they were perceived as speech or non-speech. More specifically, only familiar auditory speech signal suppressed premotor activation that was elicited by passive lipreading in the visual conditions, suggesting that acoustic rather than perceptual/linguistic features determine AV-integration in the mirror neuron system. In contrast, AV-integration modes differed between sinewave analogues perceived as speech and non-speech in bilateral anterior STS areas that have previously been implicated in speech comprehension. In conclusion, physical and perceptual factors determine the mode of AV-integration in distinct speech processing areas

Penumbral Rescue by Normobaric O=O Administration in Patients with Ischemic Stroke and Target Mismatch ProFile (PROOF): Study Protocol of a Phase IIb Trial.

RATIONALE Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. AIMS PROOF investigates the use of normobaric oxygen therapy (NBO) within six hours of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior circulation occlusion. METHODS AND DESIGN Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. STUDY OUTCOMES Primary outcome is ischemic core growth (mL) from baseline to 24 hours (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 hours, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers are conducted. SAMPLE SIZE Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. DISCUSSION By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 hours on follow-up imaging reduces potential bias due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. TRIAL REGISTRATIONS ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31