Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis. However, it still lacks effective predictors and approaches. Here, a classical model of pharmacoresistant temporal lobe epilepsy (TLE) was established to screen pharmacoresistant and pharmaco-responsive individuals by applying phenytoin to amygdaloid-kindled rats. Ictal electroencephalograms (EEGs) recorded before phenytoin treatment were analyzed. Based on ictal EEGs from pharmacoresistant and pharmaco-responsive rats, a convolutional neural network predictive model was constructed to predict pharmacoresistance, and achieved 78% prediction accuracy. We further found the ictal EEGs from pharmacoresistant rats have a lower gamma-band power, which was verified in seizure EEGs from pharmacoresistant TLE patients. Prospectively, therapies targeting the subiculum in those predicted as "pharmacoresistant" individual rats significantly reduced the subsequent occurrence of pharmacoresistance. These results demonstrate a new methodology to predict whether TLE individuals become resistant to ASMs in a classic pharmacoresistant TLE model. This may be of translational importance for the precise management of pharmacoresistant TLE.
Epilepsy, Temporal Lobe/diagnosis* ; Animals ; Drug Resistant Epilepsy/drug therapy* ; Electroencephalography/methods* ; Rats ; Anticonvulsants/pharmacology* ; Neural Networks, Computer ; Male ; Humans ; Phenytoin/pharmacology* ; Adult ; Disease Models, Animal ; Female ; Rats, Sprague-Dawley ; Young Adult ; Convolutional Neural Networks

Humans ; Acupuncture Points ; Deglutition Disorders ; Electroacupuncture

OBJECTIVE Cognitive deficit is a com-mon comorbidity in temporal lobe epilepsy(TLE)and that is not well controlled by current therapeutics.Currently,how epileptic seizure affects cognitive performance remains largely unclear.The subiculum is the major out-put of the hippocampus,which projects to entorhinal cor-tex and other more distinct brain regions.Physiologically,the subiculum codes spatial working memory and naviga-tion information including place,speed,and trajectory.Importantly,prior studies have noted the importance of the subiculum in the beginning,spreading,and generaliz-ing process of hippocampal seizure.How seizure-activated neurons in subiculum participate in cognitive impairment remains largely elusive.METHODS In this study,we sought to label the subicular seizure-activated c-fos+ neu-rons with a special promoter with enhanced synaptic activity-responsive element E-SARE in the subiculum,combined with chemogenetics and designer receptors exclusively activated by designer drugs(DREADDs),Ca2+ fiber photometry approaches,and behavioral tasks,to reveal the role of these neurons in cognitive impairment in epilepsy.RESULTS We found that chemogenetic inhibi-tion of subicular seizure-tagged c-fos+ neurons(mainly CaMK Ⅱ α+ glutamatergic neurons)alleviates seizure generalization and improves cognitive performance in the hippocampal CA3 kindling TLE model.While inhibition of seizure-labeled c-fos+ GABAergic interneuron shows no effect on seizure and cognition.As a comparison,che-mogenetic inhibition of the whole subicular CaMK Ⅱ α+ neuron impairs cognitive function in na?ve mice in basal condition.Notably,inhibition of subicular seizure-tagged c-fos+ neurons enhances the recruitment of cognition-responsive c-fos+ neurons via increasing neural excitability during cognition tasks.CONCLUSION Our results dem-onstrate that subicular seizure-activated c-fos+ neurons contribute to cognitive impairment in TLE,suggesting sei-zure-tagged c-fos+ neurons as the potential therapeutic target to alleviate cognitive impairment in TLE.

OBJECTIVE Epilepsy is considered a cir-cuit-level dysfunction associated with imbalanced excita-tion-inhibition,it is therapeutically necessary to identify key brain regions and related circuits in epilepsy.The subic-ulum is an essential participant in epileptic seizures,but the circuit mechanism underlying its role remains largely elusive.METHODS Here we deconstruct the diversity of subicular circuits in mouse models of epilepsy.Fiber pho-tometry was used to detect intrinsic activities of subicular PV,SST-positive interneurons and CaMK Ⅱ α-positive pyramidal neurons.Optogenetics and chemogenetics were used to selectively active or inactive subicular neu-rons or their projecting terminals.We also used in vivo and in vitro electrophysiology to record membrane charac-teristics of single neuron in distinct sub-regions of the subiculum.Finally,single pulse test was used to detect synaptic transmission strength between the subiculum and its downstream target.RESULTS First,we found that two majority of subicular interneurons,which inner-vate local pyramidal neurons to constrain their excitability,PV and SST-positive neurons showcase distinct calcium dynamics during hippocampal seizures.This could be attributed to distinct neural inputs from para-hippocampal regions of these two neuronal types.During epileptogen-esis,PV and SST neurons undergo different circuit reor-ganization patterns,that is,remarkable increase of exter-nal input to subicular PV neurons are seen after seizures,while SST cells receive decimated neural input.As their downstream targets,excitatory subicular pyramidal neu-rons are also intrinsically activated during hippocampal seizures.Moreover,we found that the subiculum hetero-geneously controls the generalization of hippocampal sei-zures by projecting to different downstream regions.No-tably,anterior thalamus projecting subicular neurons bidi-rectionally mediate seizures,while entorhinal cortex-pro-jecting subicular neurons act oppositely in seizure modu-lation.These two subpopulations are structurally and functionally dissociable.An intrinsically enhanced hyper-polarization-activated current and robust bursting intensity in anterior thalamus-projecting neurons facilitate synaptic transmission,thus contributing to the generalization of hippocampal seizures.CONCLUSION These results demonstrate that subicular neurons and circuits have diverse roles in epilepsy,suggesting the necessity to pre-cisely target specific subicular circuits for effective treat-ment of epilepsy.

OBJECTIVE Trigeminal pain is mostly uni-lateral orofacial,but pain sensitization often spreads to contralateral orofacial or distal body regions.Widespread trigeminal pain has more severe intensity,longer dura-tion,and wider distribution,accompanied by more serious comorbid emotional syndrome.Unfortunately,the first-line analgesics for neuropathic pain has limited effect on widespread pain along with unavoidable side effects.In-depth understanding of the pathogenesis of wide-spread trigeminal pain is urgently needed.METHODS Trigeminal pain was induced by partial transection of the infraorbital nerve(p-IONX)and evaluated by measur-ing nociceptive thresholds to mechanical or heat stimula-tion.Neuronal activity was evaluated by single-unit and patch clamp recordings.HMGB1 expression was mea-sured by immunohistochemistry.Antagonism of HMGB1 was achieved by injecting anti-HMGB1 monoclonal anti-body(mAb)intracerebrally or intraperitoneally.RESULTS P-IONX model induced not only orofacial algesia but also somatic algesia in hind paw.Spontaneous firing frequency of glutamatergic neurons in the ventral posteromedial tha-lamic nucleus(VPMGlu)as well as the amplitude and fre-quency of sEPSCs significantly increased after p-IONX.Moreover,calcium signal recording showed that VPMGlu became to be activated by the noxious mechanical stimu-lation given on the hind paw,suggesting that VPMGlu recruited somatic afferents after p-IONX.We further explored the upstream brain regions of VPMGlu by virus retrograde tracing.We found the afferents from the grac-ile nucleus/cuneate nucleus(Gr/Cu),which are involved in the conduction of somatic sensation,markedly increased.And chemogenetical inhibiting Gr/Cu-VPM circuit alleviated the widespread neuropathic pain.In addition,the expression of HMGB1 in the VPM was sig-nificantly increased after p-IONX.Local administration of anti-HMGB1 mAb in the VPM relieved widespread neuro-pathic pain in mice receiving p-IONX.CONCLUSION These results demonstrate that the remodeling of affer-ent neurons in VPM underlie the spreading of wide-spread trigeminal neuropathic pain.Highly expressed HMGB1 in VPM plays an important role in these patho-logical changes after nerve injury and systemic adminis-tration of anti-HMGB1 mAb concurrently relieves wide-spread pain.

Humans ; Spinal Cord Injuries/complications* ; Paralysis/etiology* ; Nervous System Diseases ; Brain

Brain/diagnostic imaging* ; Head

Humans ; Astrocytes ; Neocortex ; Epilepsy/therapy* ; Tosylarginine Methyl Ester