Cortical Spreading Depression Can Be Triggered by Sensory Stimulation in Primed Wild Type Mouse Brain: a Mechanistic Insight to Migraine Aura Generation

Background: Unlike the spontaneously appearing aura in migraineurs, experimentally, cortical spreading depression (CSD), the neurophysiological correlate of aura is induced by non-physiological stimuli. Consequently, neural mechanisms involved in spontaneous CSD generation, which may provide insight how migraine starts in an otherwise healthy brain, remains largely unclear. We hypothesized that CSD can be physiologically induced by sensory stimulation in primed mouse brain. Methods: Cortex was made susceptible to CSD with partial inhibition of Na+/K+-ATPase by epidural application of a low dose of Na+/K+-ATPase blocker ouabain that does not induce repetitive CSDs or by knocking-down α2 subunit of Na+/K+-ATPase, which is crucial for K+ and glutamate re-uptake by astrocytes, with shRNA. Stimulation-induced CSDs and extracellular K+ changes were monitored in vivo electrophysiologically or with a K+-sensitive fluoroprobe (IPG-4). Results: After priming with ouabain, photic stimulation increased the CSD incidence compared with non-stimulated animals (44.0 vs. 4.9%, p<0.001). Whisker stimulation was less effective (14.9 vs. 2.4%, p=0.02). Knocking-down Na+/K+-ATPase (50% decrease in mRNA) lowered the CSD threshold in all mice tested but triggered stimulus-induced CSDs in 14.3% and 16.7% of mice with photic and whisker stimulation, respectively. Confirming Na+/K+-ATPase hypofunction, extracellular K+ significantly rose during stimulation after subthreshold ouabain or shRNA treatment unlike controls. In line with higher CSD susceptibility, K+ rise was more prominent after ouabain. To gain insight to preventive mechanisms reducing the incidence of stimulus-induced CSDs, we applied an A1-receptor (DPCPX) or GABA-A (bicuculine) antagonist over the occipital cortex, because adenosine formed during stimulation or inhibitory interneuron activity can reduce CSD susceptibility. DPCPX induced CSDs or CSD-like small-DC shifts during photic stimulation, whereas bicuculine was not effective. Conclusions: Our findings indicate that normal brain is well protected against CSD generation. For CSD to be ignited under physiological conditions, priming and predisposing factors are required as seen in migraine patients. Intense sensory stimulation has the potential to trigger a CSD when co-existing conditions can bring extracellular K+ and glutamate concentrations over threshold via reduced uptake of K+ and glutamate (e.g. inefficient fueling of α2-Na+/K+-ATPase due to reduced glycogen breakdown) or facilitated glutamate release (e.g. reduced presynaptic adenosinergic inhibition).

Temporal Onset Focal Seizures Induced by Intermittent Photic Stimulation

The study aimed to review the clinical, radiological, and pathological findings and electroencephalogram (EEG) of pediatric epilepsy patients with temporal onset focal seizures induced by intermittent photic stimulation (IPS). Four patients with temporal onset photosensitivity focal seizures were analyzed. Three (75%) of the four patients were female. The average age of seizure-onset was 4.4 years. The interictal EEG showed both generalized and focal spike and waves in one patient and focal or multifocal spike and waves alone in three patients. Photoparoxysmal response (PPR) was evoked in all patients and showed generalized discharges (patients 2–4), both generalized and posterior discharges (patient 1). Both generalized and focal discharges could coexist in interictal discharges and PPR. The sensitive frequencies of PPR and photoconvulsive response (PCR) were 12–30 and 10–16 Hz, respectively, which were close to the occipital rhythm. In all patients, the onset of PCR was recorded, namely, the left anterior and mesial temporal lobe (TL), the left posterior TL, and the whole left TL, which showed two forms: the seizure of two patients was the onset of slow waves in the temporal area without spreading generalized discharges (patients 1 and 4), and the other one was fast rhythmic activities in the temporal area, spreading to the occipital area or gradually evolving into the generalized discharges (patients 2 and 3). During follow-up, except for patient 3 who had occasional seizures, the seizures of the remaining patients were under control. Temporal onset focal seizures could be induced by IPS. Temporal onset photosensitivity seizures were mostly easy to control with antiseizure drugs.

Brain Dynamics Altered by Photic Stimulation in Patients with Alzheimer’s Disease and Mild Cognitive Impairment

Individuals with mild cognitive impairment (MCI) are at high risk of developing Alzheimer’s disease (AD). Repetitive photic stimulation (PS) is commonly used in routine electroencephalogram (EEG) examinations for rapid assessment of perceptual functioning. This study aimed to evaluate neural oscillatory responses and nonlinear brain dynamics under the effects of PS in patients with mild AD, moderate AD, severe AD, and MCI, as well as healthy elderly controls (HC). EEG power ratios during PS were estimated as an index of oscillatory responses. Multiscale sample entropy (MSE) was estimated as an index of brain dynamics before, during, and after PS. During PS, EEG harmonic responses were lower and MSE values were higher in the AD subgroups than in HC and MCI groups. PS-induced changes in EEG complexity were less pronounced in the AD subgroups than in HC and MCI groups. Brain dynamics revealed a “transitional change” between MCI and Mild AD. Our findings suggest a deficiency in brain adaptability in AD patients, which hinders their ability to adapt to repetitive perceptual stimulation. This study highlights the importance of combining spectral and nonlinear dynamical analysis when seeking to unravel perceptual functioning and brain adaptability in the various stages of neurodegenerative diseases.