Activity-Dependent Gating of Parvalbumin Interneuron Function by the Perineuronal Net Protein Brevican.

Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive. We show that the PNN protein Brevican is a critical regulator of interneuron plasticity. We find that Brevican simultaneously controls cellular and synaptic forms of plasticity in PV+ cells by regulating the localization of potassium channels and AMPA receptors, respectively. By modulating Brevican levels, experience introduces precise molecular and cellular modifications in PV+ cells that are required for learning and memory. These findings uncover a molecular program through which a PNN protein facilitates appropriate behavioral responses to experience by dynamically gating PV+ interneuron function.

Ictal EEG source imaging in frontal lobe epilepsy leads to improved lateralization compared with visual analysis.

PURPOSE: To investigate the utility of EEG source imaging to lateralize ictal patterns in frontal lobe epilepsy, which were nonlateralized by standard EEG analysis. METHODS: Prospective analysis of 17 seizures in 8 patients with unilateral frontal lobe epilepsy MRI lesions and nonlateralizing ictal scalp EEG. We applied four EEG source imaging techniques (phase maps, symmetric dipoles, low-resolution brain electromagnetic tomography analysis, and classical low-resolution brain electromagnetic tomography analysis recursively applied) to the averaged seizure pattern. We tested (1) the ability of these techniques to lateralize seizure patterns, (2) the agreement of the lateralization result with MRI lesion side and subdural EEG recordings, individually for each method and for concordance of all. RESULTS: We found lateralizing results in 5 of 17 seizures when analyzing phase maps, 8 of 17 when analyzing dipoles, and 5 of 17 in both classical low-resolution brain electromagnetic tomography analysis recursively applied and low-resolution brain electromagnetic tomography analysis. No discordance with the MRI lesion side was seen when analyzing phase maps, whereas dipole analysis was discordant to the MRI lesion in two seizures, classical low-resolution brain electromagnetic tomography analysis recursively applied in one, and low-resolution brain electromagnetic tomography analysis in two. Agreement between all imaging methods was found in three seizures (three patients), all in line with the side of the MRI lesion. CONCLUSIONS: Advanced EEG review methods and source localization provide useful lateralizing information in difficult frontal lobe epilepsy seizure patterns.

Gene therapy in status epilepticus.

Gene therapy in human disease has expanded rapidly in recent years with the development of safer and more effective viral vectors, and presents a novel approach to the treatment of epilepsy. Studies in animals models have demonstrated that overexpression of inhibitory peptides can modify seizure threshold, prevent the development of epilepsy, and modify established epilepsy. More recently there has been a flurry of studies using optogenetics in which light-activated channels expressed in neurons can transiently change neuronal excitability on exposure to light, thereby enabling the development of closed loop systems to detect and stop seizure activity. The treatment of status epilepticus presents its own challenges. Because of both the delay in gene expression following transfection and also the necessity of using focal transfection, there are a limited number of situations in which gene therapy can be used in status epilepticus. One such condition is epilepsia partialis continua (EPC). We have used gene therapy in a model of EPC and have shown that we can "cure" the condition. Recent evidence suggesting that gene therapy targeting subcortical regions can modify generalized or more diffuse epilepsies, indicates that the range of situations in status epilepticus in which gene therapy could be used will expand.

Adult-onset NREM parasomnia with hypnopompic hallucinatory pain: a case report.

We report the case of a 43-year-old woman presenting with nocturnal episodes of pain and screaming during sleep starting at age 30. There was no childhood or family history of parasomnia. The events had gradually become more frequent over the years, occurring in the first half of the night within 2 h of sleep onset. There were no triggers, and she had partial amnesia for the events. A diagnosis of adult-onset sleep terrors was made on clinical grounds and supported polysomnographically. Seizures and periodic limb movements were excluded as triggering factors. There was some mild sleep disordered breathing (predominantly non-desaturating hypopnea with a propensity for REM sleep of debatable significance). Imaging of the brain and spine and neurophysiological investigations ruled out lesions, entrapments, or neuropathies as possible causes of pain. Treatment (clonazepam, paroxetine, or gabapentin) was poorly tolerated and made no difference to the nocturnal episodes, while trazodone worsened them. This is the first report of hypnopompic psychic pain in association with a NREM parasomnia. We hypothesize that the pain may represent a sensory hallucination analogous to the more commonly recognized visual NREM parasomnia-associated hypnopompic visual hallucinations and that, as such, it may arise during arousal of the sensory neocortex as confabulatory response.

Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.

Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy.

Oscillatory dynamics in the hippocampus support dentate gyrus­CA3 coupling.

Gamma oscillations in the dentate gyrus and hippocampal CA3 show variable coherence in vivo, but the mechanisms and relevance for information flow are unknown. We found that carbachol-induced oscillations in rat CA3 have biphasic phase-response curves, consistent with the ability to couple with oscillations in afferent projections. Differences in response to stimulation of either the intrinsic feedback circuit or the dentate gyrus were well described by varying an impulse vector in a two-dimensional dynamical system, representing the relative input to excitatory and inhibitory neurons. Responses to sinusoidally modulated optogenetic stimulation confirmed that the CA3 network oscillation can entrain to periodic inputs, with a steep dependence of entrainment phase on input frequency. CA3 oscillations are therefore suited to coupling with oscillations in the dentate gyrus over a broad range of frequencies.

Evaluating first seizures in adults in primary care.

A seizure is defined as the clinical manifestation resulting from an excessive and abnormal discharge of a population of neurones. The individual lifetime risk of developing a non-febrile seizure is about 5% and around a third of patients will experience further seizures and be diagnosed as having epilepsy. When assessing a possible first seizure, assuming that the patient has recovered and is not in an emergency situation, the first question is whether the paroxysmal event was a seizure. There are many seizure imitators, some of which can be fatal if missed. These include cardiac syncope due to arrhythmias, valvular abnormalities or ischaemia, hypotension, hypoglycaemia and TIAs. Ultimately, the diagnosis of a seizure is clinical and is best established by taking an accurate history. An accurate description of the paroxysmal event is paramount. So the patient should ideally bring a witness to the consultation, allow the clinician to contact a witness by phone, or provide a written description of the paroxysm. Further features to be established include type of seizure (generalised or partial) and timing (early morning or nocturnal). The past medical history should be probed for previous syncopal events or possible seizures. Once a putative diagnosis of a seizure has been made, the second question is whether the seizure was provoked or not. Examination should include assessment of the level of consciousness and orientation, and the cardiovascular and nervous systems. In the patient who has fully recovered from a first seizure NICE recommends measuring plasma glucose, and electrolytes including calcium, and a 12-lead ECG. Referral to an emergency department for urgent neuroimaging and lumbar puncture should be considered if the patient has not fully recovered, and/or if risk factors are present. If the patient has fully recovered, guidelines recommend referral to a first seizure clinic for review by an epilepsy specialist.

Treatment options in juvenile myoclonic epilepsy.

OPINION STATEMENT: Juvenile myoclonic epilepsy (JME) is characterized by excellent response to treatment, if diagnosed correctly. Lifestyle advice is an integral part of the treatment of JME; it should include recommendations on avoidance of common triggers such as sleep deprivation and alcohol excess and emphasis on the importance of compliance with medication. The drug of first choice in the treatment of JME is sodium valproate, which has a response rate of up to 80%. Valproate should be avoided in women of childbearing age because of significantly increased risks of fetal malformations and neurodevelopmental delay. Levetiracetam or lamotrigine are alternative first-line options if valproate is contraindicated. With limited data from trials to support either of these drugs, the choice should take into account comorbidity factors and patient priorities. Because of its low side effect profile, excellent tolerability, and lack of interactions with other drugs, levetiracetam is our preferred alternative first-line agent. Lamotrigine is another first-line option but may exacerbate myoclonus. The failure of valproate or failure of two first-line antiepileptic drugs suggests that combination therapy is indicated. Drug interactions and the patient's gender, age, and comorbidities need to be considered. Levetiracetam, lamotrigine, and valproate are suitable adjuncts, with a synergistic effect reported from the combination of valproate and lamotrigine. Clonazepam is a useful adjunct for myoclonus and can be used in combination with lamotrigine to avoid lamotrigine's myoclonic effects. In women of childbearing potential, valproate should be considered if levetiracetam and lamotrigine have failed to control seizures at this stage. Topiramate is a cost-effective alternative monotherapy, but because of its poor tolerability, we recommend it as add-on treatment only. Zonisamide should remain a second-line adjunct in the treatment of JME, owing to the lack of supportive data. Phenobarbital is the most cost-effective drug and can be used to control the seizures of JME when antiepileptic drugs are limited or too costly. Carbamazepine, oxcarbazepine, and phenytoin can exacerbate absences and myoclonus and are therefore contraindicated, although they can improve control of tonic-clonic seizures when these are refractory to other medication. Gabapentin, pregabalin, tiagabine, and vigabatrin are contraindicated and can worsen seizures. (Tiagabine and vigabatrin have been reported to induce absence status epilepticus.) Surgical alternatives in refractory cases are rarely contemplated but may include vagus nerve stimulation and callosotomy. Deep brain stimulation is an experimental technique that may prove useful in managing refractory cases of JME.

Failure of caspase inhibition in the double-lesion rat model of striatonigral degeneration (multiple system atrophy).

In the present study we assessed the neuroprotective effects of the pan-caspase inhibitor z-VAD.fmk [N-benzyloxycarbony-valine-alanine-aspartate-(OMe)-fluoromethylketone], and the caspase-3 inhibitor Ac-DEVD.CHO (acetyl-aspartate-chloromethylketone) in the double-lesion rat model of striatonigral degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). Male Wistar rats were divided into three groups, receiving either Ac-DEVD.CHO, z-VAD.fmk or normal saline before lesion surgery, comprising a sequential unilateral quinolinic acid (QA) lesion of the striatum followed by a 6-hydroxydopamine (6-OHDA) lesion of the ipsilateral medial forebrain bundle. At 2 weeks post lesion, all rats underwent testing of spontaneous nocturnal locomotor behavior in an automated Photobeam Activity System (FlexField). Immunohistochemistry was performed with tyrosine hydroxylase, dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein and glial fibrillary acidic protein antibodies. Morphometry was performed using computerized image analysis. Behavioral and morphological analysis failed to show striatal or nigral protection in caspase inhibitor-treated animals. Our findings suggest that anti-apoptotic strategies are unrewarding in the SND rat model and, therefore, alternative neuroprotective interventions such as anti-glutamatergic agents or inhibitors of microglial activation should be explored instead.