Optical coherence tomography findings in primary headache disorders: is pain duration a clinical correlate?

OBJECTIVE: Ganglion cell layer thickness (GCLT) may be used as a potential marker for central neural changes. We compared GCLT by using spectral domain optical coherence tomography (SD-OCT) in patients with primary headache disorders and healthy controls. We seek whether there was any difference between the headache groups and whether any clinical parameters correlated to GCLT. METHODS: Fifty-three primary headache patients, 11 age and sex-matched healthy subjects were included in this cross-sectional study after power analysis. All subjects underwent SD-OCT. The duration of disorder, headache frequency, severity, duration of pain, presence of ocular pain, and accompanying symptoms have been collected. RESULTS: Mean GCLT of the headache group was 15.7 ± 3.8 µm (mean ± standard deviation), and the control group was 17.5 ± 2.4. The difference was not statistically significant. When we compared the controls, migraine and tension-type headache patients' GCLT values, we found a significant difference (ANOVA, p = 0.001). Migraine patients had thinner GCLT compared to all non-migraine headache patients (p = 0.01). Intraocular pressure values of migraine patients and non-migraine patients were not statistically significantly different (p = 0.13). The only clinical parameter that correlated with GCLT was pain duration (r = -0.43 and p = 0.01). The patients with white matter lesions had thinner GCLT (p = 0.046). CONCLUSION: Our results suggest that not long-term suffering from pain but migraine pathophysiology itself seems to affect neuroretinal tissue. Pain duration was moderately and inversely correlated to GCLT, meaning that the longer the headache, the thinner the ganglion cell layer is.

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 into how migraine starts in an otherwise healthy brain, remain 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 concentration of Na+/K+-ATPase blocker ouabain, allowing longer than 30-min intervals between CSDs or by knocking-down α2 subunit of Na+/K+-ATPase, which is crucial for K+ and glutamate re-uptake, with shRNA. Stimulation-triggered CSDs and extracellular K+ changes were monitored in vivo electrophysiologically and a K+-sensitive fluoroprobe (IPG-4), respectively. RESULTS: After priming with ouabain, photic stimulation significantly increased the CSD incidence compared with non-stimulated animals (44.0 vs. 4.9%, p < 0.001). Whisker stimulation also significantly increased the CSD incidence, albeit less effectively (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 with KCl but triggered 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 sensory stimulation after ouabain or shRNA treatment unlike controls. In line with the higher CSD susceptibility observed, K+ rise was more prominent after ouabain. To gain insight to preventive mechanisms reducing the probability of stimulus-evoked CSDs, we applied an A1-receptor antagonist (DPCPX) to the occipital cortex, because adenosine formed during stimulation from ATP can reduce CSD susceptibility. DPCPX induced spontaneous CSDs but only small-DC shifts along with suppression of EEG spikes during photic stimulation, suggesting that the inhibition co-activated with sensory stimulation could limit CSD ignition when K+ uptake was not sufficiently suppressed as with ouabain. CONCLUSIONS: 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 potential to trigger CSD when co-existing conditions bring extracellular K+ and glutamate concentrations over CSD-ignition threshold and stimulation-evoked inhibitory mechanisms are overcome.

Headache and cognitive disturbance correlate with ganglion cell layer thickness in patients who recovered from COVID-19.

BACKGROUND: Retinal abnormalities are being increasingly reported in COVID-19, in addition to the well-known symptoms of this disease accounting for the neurological involvement. In this study, we aimed to investigate whether ganglion cell layer thickness (GCLT) was different in recovered COVID-19 patients compared to controls in the subacute stage and to determine whether it correlated with COVID-19-related neurological symptoms or pneumonia. METHODS: This study involved 40 patients who had recovered from COVID-19 and 40 age- and sex-matched healthy controls. All the participants underwent ophthalmological examination, spectral domain optical coherence tomography and neurological examination. The clinical and biochemical properties of the patients were noted and their correlations with GCLT were sought. RESULTS: The duration after COVID-19 infection was 113 ± 62 (mean ± SD) days. At this subacute stage, there was no significant difference between the GCLT measurements of the COVID-19 patients and the controls (14 ± 4.0 µm [median ± IQR] vs 16 ± 4.8 µm, respectively). When we analyzed the relationships with neurological symptoms in the patient group, we found that patients with cognitive symptoms had lower GCLT values compared to those without (13 ± 3 µm vs. 16 ± 4 µm, respectively; p = 0.002). Patients who suffered headache during the acute infection also had lower GCLT values compared to those without (14 ± 4 µm vs. 18 ± 5 µm, respectively; p = 0.015). The GCLT values did not differ significantly with respect to anosmia, ageusia, sleep disturbances, having had COVID-19 pneumonia, or smoking status. Age, duration after COVID-19, and blood levels of thyroid stimulating hormone, glucose, vitamin D and vitamin B12 were not in correlation with GCLT in our study. CONCLUSION: Our findings highlight an association between GCLT values and neurological symptoms such as cognitive disturbance (brain fog) and headache in patients who had recovered after non-severe COVID-19 infection. Neuroretinal involvement by SARS-CoV2 might be linked to central neurological symptoms. The patients with lower GCLT values may benefit from close monitoring for neurological problems.

Subacute neurological sequelae in mild COVID-19 outpatients.

Introduction: Neurological aspect of COVID-19 is less understood compared to its respiratory and systemic effects. We aimed to define subacute neurological sequelae in patients who recovered from mild COVID-19. Materials and Methods: This study enrolled long COVID patients who had mild infection, were non-hospitalized, and admitted to our hospital with neurological complaints occurring after COVID-19. The evaluation included detailed history of the symptoms, neurological examination, blood tests and necessary investigations relevant to their personal medical situation, and also a retrospective inquiry about their respiratory and neurological status during the acute phase of infection. Descriptive statistical measures, Chi-square and Student's t-test were utilized. Result: We identified 50 patients (29F/21M) with a mean age of 36.9 ± 1.6 (mean ± SEM). The average time from COVID-19 to admission was 99 days(min-max= 15-247). Most frequent neurological complaints were headache (42%) and cognitive dysfunction (42%). Sleep disturbance (36%), prolonged anosmia (30%), prolonged ageusia (22%), fatigue (22%), and dizziness (8%) followed. Most patients with headache experienced headache also as an acute manifestation of COVID-19 (p= 0.02). Acute-stage sleep disorders were found to be more associated with subacute cognitive symptoms than other central symptoms (p= 0.008). The most common neurological symptom in the acute phase was headache (74%). Six patients, despite the absence of any acute-stage neurological symptoms, presented with emergence of subacute neurological sequela. There were only five patients with pulmonary involvement during the acute stage, who were not different from the rest of the cohort in terms of neurological sequelae. There was no increase of inflammatory markers in the blood tests at the subacute stage, or no association of the symptoms to biochemical parameters. Conclusions: This study gives a description of neurological sequelae of mild COVID-19 at the subacute stage, in a relatively young group, and reveals that cognitive disturbances, as well as headache, are quite frequent.

Confocal reflectance microscopy for metal and lipid nanoparticle visualization in the brain.

Aim: A requirement for nanoparticle (NP) research is visualization of particles within cells and tissues. Limitations of electron microscopy and low yields of NP fluorescent tagging warrant the identification of alternative imaging techniques. Method: Confocal reflectance microscopy (CRM) in combination with fluorescence imaging was assessed for visualizing rhodamine B-conjugated silver and fluorescein isothiocyanate-conjugated lipid core-stearylamine NP uptake in vitro and in vivo. Results: CRM successfully identified cellular uptake and blood-brain barrier penetration of NPs owing to their distinguishing refractive indices. NP-dependent reflectance signals in vitro were dose and incubation time dependent. Finally, CRM facilitated the distinction between nonspecific fluorescence signals and NPs. Conclusion: These findings demonstrate the value of CRM for NP visualization in tissues, which can be performed with a standard confocal microscope.

Nanoparticles (NPs) are extremely small materials utilized in the healthcare sector mainly for the delivery of drugs into tissues that are not easily accessible with regular pharmaceuticals. One such tissue is the brain, which has a barrier between it and the bloodstream that prevents the passage of most drugs. For NP research, the successful entry of NPs into target tissues must be demonstrated, but this is complicated by the small size and weak labeling of NPs. In this article, the authors demonstrate a low-cost, complementary microscopy technique that is readily available in most biological research laboratories and that can be used to detect and analyze the entry of different NP types into brain tissue and their uptake by brain tumor cells. These data create new opportunities for research on NP-assisted drug delivery to the central nervous system.

Prospective investigation of cerebellar cognitive affective syndrome in a previously non-demented population of acute cerebellar stroke.

OBJECTIVE: In this prospective study, we aimed to investigate the presence and evolution of cerebellar cognitive affective syndrome in a cohort of isolated cerebellar stroke with no known cognitive or psychiatric impairment. We tried to distinguish the unconfounded effect of cerebellar lesions on neuropsychological processing. METHODS: After a meticulous exclusion procedure based on possible confounders, we recruited 14 patients and 13 age-matched healthy controls to the study, prospectively. All of the patients had a detailed initial neuropsychological assessment at the first week and a follow-up assessment at the 4th month after stroke. RESULTS: The prevalence of cognitive or behavioral-affective abnormalities in our cohort were 86% and 64% respectively. The patients exhibited mild and transient affective-behavioral abnormalities except for depressive symptoms that persisted in the subacute stage. They scored lower in general cognitive performance as revealed by mini mental test (p=0.001). Memory, executive functions, attention and working memory, central processing speed, and linguistic abilities were impaired (p<0.001; p=0.001; p=0.007; p=0.05; p<0.001 respectively). Improvement was evident only in memory domain of the cognitive functions in the subacute stage. Cognitive impairment was more likely with a medial or posterolateral infarct (p=0.014). Behavioral-affective abnormalities were not associated with a specific location in our cohort. Age seemed to negatively correlate with the recovery in general cognitive performance on the follow-up. CONCLUSIONS: These findings show that acute denervation of cerebellocortical projections leads to mild affective-behavioral abnormalities, and full-blown cerebellar cognitive affective syndrome is rare. However, cognition was significantly affected after an acute cerebellar infarct even in a previously healthy, non-demented pure population.

Improving Microcirculatory Reperfusion Reduces Parenchymal Oxygen Radical Formation and Provides Neuroprotection.

BACKGROUND AND PURPOSE: Reperfusion is the most significant determinant of good outcome after ischemic stroke. However, complete reperfusion often cannot be achieved, despite satisfactory recanalization. We hypothesized that microvascular protection was essential for achieving effective reperfusion and, hence, neuroprotection. To test this hypothesis, we have developed an in vivo model to differentially monitor parenchymal and vascular reactive oxygen species (ROS) formation. By comparing the ROS-suppressing effect of N-tert-butyl-α-phenylnitrone (PBN) with its blood-brain barrier impermeable analog 2-sulfo-phenyl-N-tert-butylnitrone (S-PBN), we assessed the impact of vascular ROS suppression alone on reperfusion and stroke outcome after recanalization. METHODS: The distal middle cerebral artery was occluded for 1 hour by compressing with a micropipette and then recanalized (n=60 Swiss mice). ROS formation was monitored for 1 hour after recanalization by intravital fluorescence microscopy in pial vasculature and cortical parenchyma with topically applied hydroethidine through a cranial window. PBN (100 mg/kg) or S-PBN (156 mg/kg) was administered shortly before recanalization, and suppression of the vascular and parenchymal hydroethidine fluorescence was examined (n=22). Microcirculatory patency, reperfusion, ischemic tissue size, and neurological outcome were also assessed in a separate group of mice 1 to 72 hours after recanalization (n=30). RESULTS: PBN and S-PBN completely suppressed the reperfusion-induced increase in ROS signal within vasculature. PBN readily suppressed ROS produced in parenchyma by 88%. S-PBN also suppressed the parenchymal ROS by 64% but starting 40 minutes later. Intriguingly, PBN and S-PBN comparably reduced the size of ischemic area by 65% and 48% (P>0.05), respectively. S-PBN restored the microvascular patency and perfusion after recanalization, suggesting that its delayed parenchymal antioxidant effect could be secondary to improved microcirculatory reperfusion. CONCLUSIONS: Promoting microvascular reperfusion by protecting vasculature can secondarily reduce parenchymal ROS formation and provide neuroprotection. The model presented can be used to directly assess pharmacological end points postulated in brain parenchyma and vasculature in vivo.