One of the deleterious effects of acute nerve agent exposure is the induction of status epilepticus (SE). If SE is not controlled effectively, it causes extensive brain damage. Here, we review the neuropathology observed after nerve agent‒induced SE, as well as the ensuing pathophysiological, neurological, and behavioral alterations, with an emphasis on their time course and longevity. Limbic structures are particularly vulnerable to damage by nerve agent exposure. The basolateral amygdala (BLA), which appears to be a key site for seizure initiation upon exposure, suffers severe neuronal loss; however, GABAergic BLA interneurons display a delayed death, perhaps providing a window of opportunity for rescuing intervention. The end result is a long‐term reduction of GABAergic activity in the BLA, with a concomitant increase in spontaneous excitatory activity; such pathophysiological alterations are not observed in the CA1 hippocampal area, despite the extensive neuronal loss. Hyperexcitability in the BLA may be at least in part responsible for the development of recurrent seizures and increased anxiety, while hippocampal damage may underlie the long‐term memory impairments. Effective control of SE after nerve agent exposure, such that brain damage is also minimized, is paramount for preventing lasting neurological and behavioral deficits.
This study examined event-related potentials (ERPs) and behavioral measures, considered to be sensitive to the selective processing of black versus white letter and non-letter patterns, in a group of seventy-four randomly selected 6 to 8 year old children. Results demonstrated faster and more accurate behavioral performance on the experimental task for the letter than for the non-letter patterns. The ERP measures provided complementary information regarding this letter facilitation effect, indicating that the selective neural processing of letter as compared to non-letter patterns was present in the electrophysiological waveform within the initial 100-140 ms after stimulus presentation. Later ERP measures (200-260 and 500-600 ms post-stimulus) in response to the letter stimuli showed greater differences as a function of task relevance over the left than over the right hemisphere. The results from the present study indicate a remarkably early facilitative influence of stimulus type (letter versus non-letter patterns) on the luminance discrimination of these stimuli and are consistent with an overlap of linguistic and perceptual processing.
Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M1 receptor antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly suppressed seizure severity and prevented the development of SE for about 40 minutes after exposure to paraoxon or soman, suggesting an important role of the M1 receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (a brain region that plays a key role in seizure initiation after nerve agent exposure), VU0255035 blocked the effects produced by bath application of paraoxon—namely, a brief barrage of spontaneous inhibitory postsynaptic currents, followed by a significant increase in the ratio of the total charge transferred by spontaneous excitatory postsynaptic currents over that of the inhibitory postsynaptic currents. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current Ih in basolateral amygdala principal cells, which could be one of the mechanisms underlying the increased glutamatergic activity, an effect that was also blocked in the presence of VU0255035. Thus, selective M1 antagonists may be an efficacious pretreatment in contexts in which there is risk for exposure to organophosphates, as these antagonists will delay the development of SE long enough for medical assistance to arrive.
Children with language-based learning impairments (LLIs) have major deficits in their recognition of some rapidly successive phonetic elements and nonspeech sound stimuli. In the current study, LLI children were engaged in adaptive training exercises mounted as computer “games” designed to drive improvements in their “temporal processing” skills. With 8 to 16 hours of training during a 20-day period, LLI children improved markedly in their abilities to recognize brief and fast sequences of nonspeech and speech stimuli.
Neurocognitive skills (e.g., processing speed, attention and memory) were hypothesized to be critical for workplace performance and by extension for the work-life balance of employees. Twenty-one employee volunteers underwent a neurocognitive training program – which consisted of an initial pre-test assessment, a six week "boost" or intervention period, and then a re-assessment to track the progress of each participant. A median split of the group created two training groups: a long-training group that averaged 30 hours of total training during the boost period; and a short-training group that averaged 7 hours of training. On pre-training measures of neurocognitive performance, group differences in performance did not reach statistical significance. Following training participants experienced a positive impact from the program as measured in three ways: standardized higher behavioral metrics, improved cognitive state metrics using EEG and positive self-reported data. From a quantitative perspective, participants' cognitive efficiency increased by 12% for the high-training group and 5% for the low-training group (cognitive efficiency refers to a behavioral measure which combines accuracy and speed). Qualitatively, study participants reported improvements in their productivity and mental performance post-study.
Abstract : Poisoning by organophosphorous compounds (OPs) can produce severe symptoms including seizures or status epilepticus (SE), and if left untreated results in long-term brain damage and neuropsychiatric symptoms or death. OPs produce their toxic effects by irreversibly inhibiting the enzyme acetyl cholinesterase (AChE), which subsequently causes a hyper stimulation of the muscarinic acetylcholine receptors (mAChRs) and the nicotinic acetylcholine receptors (nAChRs). The use of OP nerve agents in attacks in Syria recently highlighted the importance of developing treatments for all ages, but specifically, this attack highlighted the importance of developing treatments for seizures induced by OP intoxication for children. We developed an immature rat model appropriate for testing novel anticonvulsants against the nerve agent soman. Using postnatal day 21 male rats (P21), we found them to be highly susceptible to seizure induction and mortality induced by soman exposure. Soman exposure in P21 rats produced profound reduction in the activity of AChE in numerous brain regions but suggested that this reduction must occur specifically in the basolateral amygdala (BLA) to produce seizures as animals that did not experience seizures still retained higher Ache activity within the BLA. Seizures, if treated within 20 min or 60 min post-soma exposure could be arrested with the administration of atropine sulfate (ATS) or theGluK1-subunit containing Kainate (GluK1KR)/-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist LY293558, respectively. We also found an additional GluK1KR antagonist, UBP302 to be efficacious in arresting soman induced seizures when treatment was administered at 60 min post-exposure. Delayed post treatment with LY293558 blocked volumetric reductions in the amygdala and hippocampus induced by soman exposure that was observed 30 or 90 days post-soma exposure in rats that did not receive LY293558 treatment.
Neural processes associated with two aspects of visual-spatial attention were investigated with event-related potential (ERPs): those that direct spatial attention to a given point in space and those that modulate the processing of sensory input after attention has been directed. The subjects were 6- to 9-year-old children (51 boys and 35 girls). An arrow cue directed attention from the central to peripheral visual field; targets were then flashed in the attended or ignored visual field 600 msec after the cue. The directing of attention to the left vs. right visual field was associated with hemispheric differences in slow potentials prior to the presentation of the targets. The earliest potential, which started about 200 msec after the cue and was negative over the hemisphere contralateral to the direction of attention, was greatest over the parietal area and appeared to reflect processes directing attention per se. The last potential, which peaked 60 msec after the target and was positive over the hemisphere contralateral to the direction of attention, was greatest over the occipital-parietal region. It appeared to reflect the modulation of cortical excitability in the regions receiving input from the relevant and irrelevant visual fields. The effects of spatial attention on P1, N1, and P3 ERP components following the targets replicated previous results. Boys appeared more aroused (as indicated by CNVs) and reflected faster and greater selective processing (as indicated by reaction time, and N1-P1 latency and amplitude) than girls.
Developmental dyslexia, characterized by unexplained difficulty in reading, is associated with behavioral deficits in phonological processing. Functional neuroimaging studies have shown a deficit in the neural mechanisms underlying phonological processing in children and adults with dyslexia. The present study examined whether behavioral remediation ameliorates these dysfunctional neural mechanisms in children with dyslexia. Functional MRI was performed on 20 children with dyslexia (8–12 years old) during phonological processing before and after a remediation program focused on auditory processing and oral language training. Behaviorally, training improved oral language and reading performance. Physiologically, children with dyslexia showed increased activity in multiple brain areas. Increases occurred in left temporo-parietal cortex and left inferior frontal gyrus, bringing brain activation in these regions closer to that seen in normal-reading children. Increased activity was observed also in right-hemisphere frontal and temporal regions and in the anterior cingulate gyrus. Children with dyslexia showed a correlation between the magnitude of increased activation in left temporo-parietal cortex and improvement in oral language ability. These results suggest that a partial remediation of language-processing deficits, resulting in improved reading, ameliorates disrupted function in brain regions associated with phonological processing and produces additional compensatory activation in other brain regions.
Exposure to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the current US Food and Drug Administration–approved drug for the cessation of nerve agent–induced SE. Here, we compared the efficacy of DZP with that of UBP302 [(S)-3-(2-carboxybenzyl)willardiine; an antagonist of the kainate receptors that contain the GluK1 subunit] against seizures, neuropathology, and behavioral deficits induced by soman in rats. DZP, administered 1 hour or 2 hours postexposure, terminated the SE, but seizures returned; thus, the total duration of SE within 24 hours after soman exposure was similar to (DZP at 1 hour) or longer than (DZP at 2 hours) that in the soman-exposed rats that did not receive the anticonvulsant. Compared with DZP, UBP302 stopped SE with a slower time course, but dramatically reduced the total duration of SE within 24 hours. Neuropathology and behavior were assessed in the groups that received anticonvulsant treatment 1 hour after exposure. UBP302, but not DZP, reduced neuronal degeneration in a number of brain regions, as well as neuronal loss in the basolateral amygdala and the CA1 hippocampal area, and prevented interneuronal loss in the basolateral amygdala. Anxiety-like behavior was assessed in the open field and by the acoustic startle response 30 days after soman exposure. The results showed that anxiety-like behavior was increased in the DZP-treated group and in the group that did not receive anticonvulsant treatment, but not in the UBP302-treated group. The results argue against the use of DZP for the treatment of nerve agent–induced seizures and brain damage and suggest that targeting GluK1-containing receptors is a more effective approach.
