(A) Local tissue oxygenation in the hippocampus of an awake, freely-moving rat (blue). Green denotes normoxia while red denotes severe hypoxia. (B) Representative oxygen profile before, during, and …
Both stimulations resulted in severe hypoxia. A 40 s seizure was elicited with MES stimulation and resulted in 104.1 min of severe hypoxia (red). Following 2 min of 3 Hz stimulation, hippocampal pO2 …
(A) Location of implants for simultaneous blood flow and pO2 recordings. These two probes were placed at opposing angles to leave room for cable attachment. (B) The simultaneous measurement of mean …
(A) Nifedipine (15 mg/kg) was administered immediately after a seizure. No differences were observed in seizure duration, however nifedipine initiated a quicker return to baseline pO2(n = 5). (B) …
(A) ASL-010, 26 year old female with drug resistant focal epilepsy. Ictal EEG recording on a longitudinal bipolar montage with left frontal seizure onset and spread to the right frontal region. …
(A) Cerebral blood flow from baseline and postictal ASL scans. Each point represents in individual. Group mean ± SEM are expressed in grey. Patient number is displayed on the left of the …
(A) COX-2 expression in sagittal section. Hippocampal inset is displayed (see B–D). Scale bar = 2 mm. (B–D) Contents of inset from (A). Many NeuN-expressing neurons (B) in DG and hilus express COX-2 …
(A) SC-560 (20 mg/kg) pre-administration did not significantly alter seizure duration or the resulting oxygen profile (n = 5). (B) Quantification of (A). No differences in the severe hypoxia were …
(A) COX-2 proteins from wild-type and mutant mice (PTGS2Y385F) displayed as a schematic. Both mice have functional peroxidase (POX). Mutants have a point mutation in the cyclooxygenase (COX) active …
(A) Experimental timeline for neocortex experiments. Rats were injected with vehicle or nifedipine 30 min prior to a baseline hang time measurement. Neocortical seizures (or sham) were then elicited …
(A) Seizure duration is not correlated with total area under curve (R square=0.000013, p=0.99). (B) Instead, the baseline pO2 is strongly correlated with the area below baseline (R square=0.52, ***p<…
(A) Pre-administration of nifedipine had no effect on area below baseline. (B) Post-administration of nifedipine significantly reduced the area below baseline (p<0.01).
Characteristics of patients recruited to ASL study.
Patient | Age | Age at Seizure Onset | Structural MRI findings |
---|---|---|---|
ASL-001 | 38 | 34 | Normal |
ASL-003 | 41 | 13 | Lesion in the right superior temporal gyrus, resolving? |
ASL-004 | 25 | 5 | Normal |
ASL-006 | 33 | 7 | Normal |
ASL-007 | 33 | 29 | Bilateral subependymal heterotopias along lateral ventricle right > left |
ASL-008 | 42 | 22 | Right amygdala enlargement, Right occipital cavernoma |
ASL-009 | 40 | 9 | Normal |
ASL-010 | 26 | 1 | Left frontal malformation of cortical development |
ASL-011 | 22 | 14 | Normal |
ASL-012 | 20 | 0.5 | Postsurgical changes in the right frontal lobe, right anterior temporal lobectomy |
Concordance of postictal ASL hypoperfusion with brain areas involved in the seizure. EEG localization of ictal activity was determined by an Epileptologist based on scalp EEG. GTC denotes when a …
Patient | EEG localization of seizure [duration (S)] | Area of maximal hypoperfusion for ASL quantification | ROI volume (cm3) | Concordant |
---|---|---|---|---|
ASL-001 | Left temporal [71] | Left temporal | 2.52 | yes |
ASL-003 | Unclear [26] | No Change | 1.45 | n/a |
ASL-004 | Left frontocentral [87] | Left superior posterior temporal | 0.31 | yes |
ASL-006 | Left fronotemporal [114] | Left insula, left anterior temporal | 1.46 | yes |
ASL-007 | GTC, Left hemisphere. Maximal posterior temporo-parietal [64] | Multifocal bihemispheric | 1.35 | yes |
ASL-008 | GTC, Right temporo-occipital [155] | Multifocal bihemispheric | 1.63 | yes |
ASL-009 | Left fronto-central [85] | Multifocal bihemispheric | 0.76 | yes |
ASL-010 | GTC, Bifrontal, maximum left [166] | Left frontal | 3.82 | yes |
ASL-011 | Left fronto-temporal [56] | No Change | 1.10 | n/a |
ASL-012 | Bitemporal right>left [30] | Multiple areas over right temporal posterior and superior to resection cavity | 2.19 | yes |
Investigation of mechanisms involved in postictal severe hypoxia.
Drug | Principle known mechanism of action | Δ severity of hypoxia |
---|---|---|
Nifedipine (15 mg/kg) | L-type Ca2+ Channel Blocker | +78.82 ± 7.632% *** |
Nifedipine (15 mg/kg postictal) | +87.33 ± 10.49% ** | |
Acetaminophen (250 mg/kg) | COX-1/2 Inhibitor | +99.88 ± 0.12% *** |
Acetaminophen (150 mg/kg) | +88.88 ± 7.355% *** | |
Acetaminophen (50 mg/kg) | +48.85 ± 26.61% | |
Acetaminophen (250 mg/kg postictal) | −3.33 ± 17.29% | |
Ibuprofen (20 mg/kg) | +99.23 ± 0.396% *** | |
Celecoxib (20 mg/kg) | COX-2 Inhibitor | +67.26 ± 27.42% * |
SC-560 (20 mg/kg) | COX-1 Inhibitor | +19.42 ± 15.37% |
Celecoxib (20 mg/kg) + SC-560 (20 mg/kg) | COX-2 and COX-1 Inhibitors | +95.80 ± 4.21% *** |
Acetaminophen (250 mg/kg) + Nifedipine (15 mg/kg) | COX-1/2 Inhibitor + L-type Ca2+ Channel Blocker | +100 ± 0.00% *** |
CAY-10526 (2 mg/kg) | Prostaglandin E2 Synthesis Inhibitor | +41.72 ± 9.94% ** |
Seratrodast (10 mg/kg) | Thromboxane A2 Receptor Antagonist | −12.91 ± 44.08% |
Ozagrel (10 mg/kg) | Thromboxane A2 Synthesis Inhibitor | +21.24 ± 16.42% |
2-APB (3 mg/kg) | IP3r Antagonist + TRP Channel Blocker | +45.27 ± 18.44% * |
Chelerythrine Chloride (15 mg/kg) | PKC Inhibitor | +25.54 ± 29.90% |
Milrinone (3 mg/kg) | Phosphodiesterase-3 Inhibitor | −10.74 ± 34.31% |
Sildenafil (15 mg/kg) | Phosphodiesterase-5 Inhibitor | −19.34 ± 14.03% |
SKA-31 (10 mg/kg) | IKCa Channel Activator | −1.50 ± 12.68% |
Paxilline (2.5 mg/kg) | BKCa Channel Blocker | +19.55 ± 14.98% |
L-Arginine (500 mg/kg) | Nitric Oxide Precursor | −5.05 ± 14.08% |
Fasudil (10 mg/kg) | Rho Kinase Inhibitor | −53.07 ± 17.27% * |
All drugs were delivered by intraperitoneal injection pre-seizure (unless otherwise stated).
Statistics reported as different from chance (one sample T-test).
*p < 0.05, **p<0.01, ***p<0.001.
+ number indicates inhibition of hypoxia.
− number indicates potentiation of hypoxia.
Effect of Anti-Seizure drugs on postictal severe hypoxia.
Drug | Principal known mechanism of action | Δ severe hypoxia |
---|---|---|
Ethosuximide (300 mg/kg) | T-type Ca2+ Channel Blocker | +30.53 ± 19.31% * |
Topiramate (50 mg/kg) | Na+ Channel Blocker, GABA Enhancement, AMPA Inhibition | +4.34 ± 14.07% |
Bumetanide (2.5 mg/kg) | NKCC1 Transporter Inhibitor | −0.92 ± 14.72% |
Phenobarbital (30 mg/kg) | GABA Receptor Agonist | −1.22 ± 13.90% |
Levetiracetam (250 mg/kg) | Glutamate Release Inhibition | −14.85 ± 19.71% |
Phenytoin (75 mg/kg) | Na+ Channel Blocker | −15.76 ± 17.00% |
Lamotrigine (15 mg/kg) | Na+ Channel Blocker | −20.95 ± 17.13% |
Valproate (150 mg/kg) | Na+ Channel Blocker, GABA Enhancement | −24.89 ± 22.65% |
All drugs were delivered by intraperitoneal injection pre-seizure.
Statistics reported as different from chance (one sample T-test).
*p<0.05.
+ number indicates inhibition of hypoxia.
-number indicates potentiation of hypoxia.
Stereotaxic coordinates for surgical implantation.
Experiment | Anterior(+)/ Posterior(−) | Lateral Right(+)/Left(−) | Ventral (from brain surface) |
---|---|---|---|
Rat Dorsal Hippocampus | Electrode: −3.0 mm Optode: −3.5 mm | Electrode: 0.5 mm Optode: 3.5 mm | Electrode: 3.5 mm Optode: 3.5 mm |
Rat Dorsal Hippocampus with LDF | Electrode: −3.0 mm Optode: −5.0 mm LDF probe: −3.0 mm | Electrode: 0.5 mm Optode: 2.2 mm LDF probe: 3.5 mm | Electrode: 3.5 mm Optode: 3.5 mm LDF probe: 3.5 mm |
Rat Ventral Hippocampus | Electrode: −4.5 mm Optode: −3.0 mm | Electrode: 4.5 mm Optode: 3.5 mm | Electrode: 6.5 mm Optode: 3.5 mm |
Rat Ventral Hippocampus w/ Cannula | Electrode: −4.5 mm Optode: −3.0 mm Cannula: - 5.8 mm | Electrode: 4.5 mm Optode: 3.5 mm Cannula: −4.5 mm | Electrode: 6.5 mm Optode: 3.5 mm Cannula: 4.3 mm |
Rat Neocortex | Electrode:+1.0 mm Optode: 0 mm | Electrode: 0.5 mm Optode: 3.0 mm | Electrode: 3.6 mm Optode: 1.5 mm |
Mouse Ventral Hippocampus | Electrode: −2.9 mm Optode: −1.6 mm | Electrode: 3.0 mm Optode: 2.0 mm | Electrode: 3.0 mm Optode: 1.8 mm |