Migraine Aura-Catch Me If You Can with EEG and MRI-A Narrative Review.

Roughly one-third of migraine patients suffer from migraine with aura, characterized by transient focal neurological symptoms or signs such as visual disturbance, sensory abnormalities, speech problems, or paresis in association with the headache attack. Migraine with aura is associated with an increased risk for stroke, epilepsy, and with anxiety disorder. Diagnosis of migraine with aura sometimes requires exclusion of secondary causes if neurological deficits present for the first time or are atypical. It was the aim of this review to summarize EEG an MRI findings during migraine aura in the context of pathophysiological concepts. This is a narrative review based on a systematic literature search. During visual auras, EEG showed no consistent abnormalities related to aura, although transient focal slowing in occipital regions has been observed in quantitative studies. In contrast, in familial hemiplegic migraine (FHM) and migraine with brain stem aura, significant EEG abnormalities have been described consistently, including slowing over the affected hemisphere or bilaterally or suppression of EEG activity. Epileptiform potentials in FHM are most likely attributable to associated epilepsy. The initial perfusion change during migraine aura is probably a short lasting hyperperfusion. Subsequently, perfusion MRI has consistently demonstrated cerebral hypoperfusion usually not restricted to one vascular territory, sometimes associated with vasoconstriction of peripheral arteries, particularly in pediatric patients, and rebound hyperperfusion in later phases. An emerging potential MRI signature of migraine aura is the appearance of dilated veins in susceptibility-weighted imaging, which may point towards the cortical regions related to aura symptoms ("index vein"). Conclusions: Cortical spreading depression (CSD) cannot be directly visualized but there are probable consequences thereof that can be captured Non-invasive detection of CSD is probably very challenging in migraine. Future perspectives will be elaborated based on the studies summarized

Automated volumetry of hippocampal subfields in temporal lobe epilepsy

INTRODUCTION Hippocampal sclerosis is the most frequent pathological substrate in drug resistant temporal lobe epilepsy (TLE). Recently 4 types of hippocampal sclerosis (HS) have been defined in a task force by the International League Against Epilepsy (ILAE), based on patterns of cell loss in specific hippocampal subfields. Type 1 HS is most frequent and has the most favorable outcome after epilepsy surgery. We hypothesized that volume loss in specific hippocampal subfields determined by automated volumetry of high resolution MRI would correspond to cell loss in histological reports. MATERIAL AND METHODS In a group of well characterized patients with drug resistant TLE (N = 26 patients, 14 with right-sided focus, 12 with left-sided focus) volumes of the right and left hippocampus and the hippocampal subfields CA1, CA2 + 3, CA4 and dentate gyrus (DG) were estimated automatically using FreeSurfer version 6.0 from high-resolution cerebral MRI and compared to a large group of healthy controls (N = 121). HS subtype classification was attempted based on histological reports. RESULTS Volumes of the whole hippocampus and all investigated hippocampal subfields (CA1, CA2 + 3, CA4 and DG) were significantly lower on the ipsilateral compared the contralateral side (p < 0.001) and compared to the healthy controls (p < 0.001). Conversely, whole hippocampal and hippocampal subfield volumes were not significantly different from healthy control values on the contralateral side. In 12 of 20 patients the pattern of hippocampal volume loss in specific subfields was in accordance with HS types from histology. The highest overlap between automated MRI and histology was achieved for type 1 HS (in 10 of 12 cases). CONCLUSION The automated volumetry of hippocampal subfields, based on high resolution MRI, may have the potential to predict the pattern of cell loss in hippocampal sclerosis before operation

Adverse effects of Δ9-tetrahydrocannabinol on neuronal bioenergetics during postnatal development

This work was supported by a grant from FWF (P 34121-B; EK), GW Pharmaceuticals, as well as funding from the Swedish Research Council (2018-02838; TH), the European Research Council (SECRET-CELLS, ERC-2015-AdG-695136; TH), and the Wellcome Trust (grant no. 094476/Z/10/Z, which funded the purchase of the TripleTOF 5600 mass spectrometer at the BSRC Mass Spectrometry and Proteomics Facility, University of St. Andrews).Ongoing societal changes in views on the medical and recreational roles of cannabis increased the use of concentrated plant extracts with a Δ9-tetrahydrocannabinol (THC) content of more than 90%. Even though prenatal THC exposure is widely considered adverse for neuronal development, equivalent experimental data for young age cohorts are largely lacking. Here, we administered plant-derived THC (1 or 5 mg/kg) to mice daily during P5–P16 and P5–P35 and monitored its effects on hippocampal neuronal survival and specification by high-resolution imaging and iTRAQ proteomics, respectively. We found that THC indiscriminately affects pyramidal cells and both cannabinoid receptor 1+ (CB1R)+ and CB1R– interneurons by P16. THC particularly disrupted the expression of mitochondrial proteins (complexes I–IV), a change that had persisted even 4 months after the end of drug exposure. This was reflected by a THC-induced loss of membrane integrity occluding mitochondrial respiration and could be partially or completely rescued by pH stabilization, antioxidants, bypassed glycolysis, and targeting either mitochondrial soluble adenylyl cyclase or the mitochondrial voltage-dependent anion channel. Overall, THC exposure during infancy induces significant and long-lasting reorganization of neuronal circuits through mechanisms that, in large part, render cellular bioenergetics insufficient to sustain key developmental processes in otherwise healthy neurons.Publisher PDFPeer reviewe

Genetic Manipulation of sn-1-Diacylglycerol Lipase and CB₁Cannabinoid Receptor Gain-of-Function Uncover Neuronal 2-Linoleoyl Glycerol Signaling in Drosophila melanogaster

Introduction: In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabinoid receptors (CB(1)R). Even though the insect genome codes for inaE, which is a DAGL ortholog (dDAGL), its products and their functions remain unknown particularly because insects lack chordate-type cannabinoid receptors. Materials and Methods: Gain-of-function and loss-of-function genetic manipulations were carried out in Drosophila melanogaster, including the generation of both dDAGL-deficient and mammalian CB(1)R-overexpressing flies. Neuroanatomy, dietary manipulations coupled with targeted mass spectrometry determination of arachidonic acid and 2-linoleoyl glycerol (2-LG) production, behavioral assays, and signal transduction profiling for Akt and Erk kinases were employed. Findings from Drosophilae were validated by a CB(1)R-binding assay for 2-LG in mammalian cortical homogenates with functionality confirmed in neurons using high-throughput real-time imaging in vitro. Results: In this study, we show that dDAGL is primarily expressed in the brain and nerve cord of Drosophila during larval development and in adult with 2-LG being its chief product as defined by dietary precursor availability. Overexpression of the human CB(1)R in the ventral nerve cord compromised the mobility of adult Drosophilae. The causality of 2-LG signaling to CB(1)R-induced behavioral impairments was shown by inaE inactivation normalizing defunct motor coordination. The 2-LG-induced activation of transgenic CB(1)Rs affected both Akt and Erk kinase cascades by paradoxical signaling. Data from Drosophila models were substantiated by showing 2-LG-mediated displacement of [(3)H]CP 55,940 in mouse cortical homogenates and reduced neurite extension and growth cone collapsing responses in cultured mouse neurons. Conclusions: Overall, these results suggest that 2-LG is an endocannabinoid-like signal lipid produced by dDAGL in Drosophila

Functional Differentiation of Cholecystokinin-Containing Interneurons Destined for the Cerebral Cortex

Although extensively studied postnatally, the functional differentiation of cholecystokinin (CCK)-containing interneurons en route towards the cerebral cortex during fetal development is incompletely understood. Here, we used CCKBAC/DsRed mice encoding a CCK promoter-driven red fluorescent protein to analyze the temporal dynamics of DsRed expression, neuronal identity, and positioning through high-resolution developmental neuroanatomy. Additionally, we developed a dual reporter mouse line (CCKBAC/DsRed::GAD67gfp/+) to differentiate CCK-containing interneurons from DsRed+ principal cells during prenatal development. We show that DsRed is upregulated in interneurons once they exit their proliferative niche in the ganglionic eminence and remains stably expressed throughout their long-distance migration towards the cerebrum, particularly in the hippocampus. DsRed+ interneurons, including a cohort coexpressing calretinin, accumulated at the palliosubpallial boundary by embryonic day 12.5. Pioneer DsRed+ interneurons already reached deep hippocampal layers by embryonic day 14.5 and were morphologically differentiated by birth. Furthermore, we probed migrating interneurons entering and traversing the cortical plate, as well as stationary cells in the hippocampus by patch-clamp electrophysiology to show the first signs of Na+ and K+ channel activity by embryonic day 12.5 and reliable adult-like excitability by embryonic day 18.5. Cumulatively, this study defines key positional, molecular, and biophysical properties of CCK+ interneurons in the prenatal brain