OBJECTIVE: We evaluated whether transorbital ACS modulates BOLD activity in early visual cortex using high-resolution 7 Tesla functional magnetic resonance imaging (fMRI).
METHODS: In this feasibility study transorbital ACS in the alpha range and sham ACS was applied in a random block design in five healthy subjects for 20 min at 1 mA. Brain activation in the visual areas V1, V2 and V3 were measured using 7 Tesla fMRI-based retinotopic mapping at the time points before (baseline) and after stimulation. In addition, we collected data from one hemianopic stroke patient with visual cortex damage after ten daily sessions with 25-50 min stimulation duration.
RESULTS: In healthy subjects transorbital ACS increased the activated cortical surface area, decreased the fMRI response amplitude and increased coherence in the visual cortex, which was most prominent in the full field task. In the patient, stimulation improved contrast sensitivity in the central visual field. BOLD amplitudes and coherence values were increased in most early visual areas in both hemispheres, with the most pronounced activation detected during eccentricity testing in retinotopic mapping.
CONCLUSIONS: This feasibility study showed that transorbital ACS modifies BOLD activity to visual stimulation, which outlasts the duration of the AC stimulation. This is in line with earlier neurophysiological findings of increased power in EEG recordings and functional connectivity reorganization in patients with impaired vision. Accordingly, the larger BOLD response area after stimulation can be explained by more coherent activation and lower variability in the activation. Alternatively, increased neuronal activity can also be taken into account. Controlled trials are needed to systematically evaluate the potential of repetitive transorbital ACS to improve visual function after visual pathway stroke and to determine the cause-effect relationship between neural and BOLD activity changes.
METHODS: This is a prospective observational cohort study conducted in Sarawak General Hospital, Malaysia. Patients 12 years of age and older with mild to severe TBI who had a brain computed tomography (CT) done within eight hours of injury were enrolled in the study. A total of 334 patients were recruited from the 5th of August 2016 until the 8th of March 2018 in Sarawak General Hospital. In all 167 of them were administered with TXA and another 167 of the patients were not. The primary outcome expected is the number of good outcomes in isolated TBI patients given TXA. Good outcome is defined by Glasgow Outcome Score-Extended (GOSE) of five and above. Secondary outcome was clot expansion of an intracranial bleed seen on the first scan that had expanded by 25% or more on any dimension on the second scan.
RESULTS: The TXA did not show significant trend of good outcome in terms of GOSE (p=0.763). However, for moderate and severe acute subdural haemorrhage (SDH) subgroups, there was a significant difference (p=0.042). Clot expansion was present in 14 patients (12.7%) with TXA given and in 54 patients (38.8%) without TXA. The difference was statistically significant (p<0.001). Of the patients who received TXA, there was one case (0.6%) of deep vein thrombosis. Apart from that, TXA showed non-significant trend in reducing mortality (p=0.474).
CONCLUSIONS: Tranexamic acid reduces the rate of clot expansion in TBI by 26.1% (38.8-12.7%) without significantly increasing the risk of a thrombotic event. It can also improve the outcome of moderate and severe TBI patients with acute SDH.
Methods: We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25 mg bd, cilostazol 100 mg bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology, vascular function, and neuroimaging. LACI-1 was powered (80%, alpha 0.05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546.
Findings: LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) females, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6.4, 95%CI 1.2-11.7, p = 0.02), platelet count higher (MD 35.7, 95%CI 2.8, 68.7, p = 0.03) and white matter hyperintensities reduced more (Chi-square p = 0.007) with cilostazol versus no cilostazol.
Interpretation: Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified.
Funding: Alzheimer's Society (AS-PG-14-033).
MATERIALS AND METHODS: Five groups of rats were intravitreally administered with vehicle or Aβ(1-40) in doses of 1.0, 2.5, 5 and 10 nmol. Animals were sacrificed and eyes were enucleated at weeks 1, 2 and 4 post-injection. The retinae were subjected to morphometric analysis and TUNEL staining. Optic nerve sections were stained with toluidine blue and were graded for neurodegenerative effects. The estimation of BDNF and markers of oxidative stress in retina were done using ELISA technique.
RESULTS AND CONCLUSIONS: It was observed that intravitreal Aβ(1-40) causes significant retinal and optic nerve damage up to day 14 post-injection and there was increasing damage with increase in dose. However, on day 30 post-injection both the retinal and optic nerve morphology showed a trend towards normalization. The observations made for retinal cell apoptosis, retinal glutathione, superoxide dismutase activity and BDNF were in accordance with those of morphological changes with deterioration till day 14 and recovery by day 30 post-injection. The findings of this study may provide a guide for selection of appropriate experimental conditions for future studies.