Volume 31, Issue 2

Cell assemblies and central pattern generators (CPGs) are related types of neuronal networks: both consist of interacting groups of neurons whose collective activities lead to defined functional outputs. In the case of a cell assembly, the functional output may be interpreted as a representation of something in the world, external or internal; for a CPG, the output ‘drives’ an observable (i.e. motor) behavior. Electrical coupling, via gap junctions, is critical for the development of CPGs, as well as for their actual operation in the adult animal. Electrical coupling is also known to be important in the development of hippocampal and neocortical principal cell networks. We here argue that electrical coupling – in addition to chemical synapses – may therefore contribute to the formation of at least some cell assemblies in adult animals.

The discovery of neural stem cells (NSCs) and their microenvironment, the NSC niche, brought new therapeutic strategies through neurogenesis and angiogenesis for stroke and most neurodegenerative diseases, including Alzheimer’s disease. Based on the close links between NSCs and endothelial cells, the integration of neurogenesis and angiogenesis of the NSC niche is also a promising area to the neurovascular unit (NVU) modeling and is now offering a powerful tool to advance our understanding of the brain. In this review, critical aspects of the NVU and model systems are discussed. First, we briefly describe the interaction of each part in the NSC niche. Second, we introduce the co-culture system, microfluidic platforms, and stem cell-derived 3D reconstitution used in NVU modeling based on the close relations between NSCs and endothelial cells, and various characteristics of cell interactions in these systems are also described. Finally, we address the challenges in modeling the NVU that can potentially be overcome by employing strategies for advanced biomaterials and stem cell co-culture use. Based on these approaches, researchers will continue to develop predictable technologies to control the fate of stem cells, achieve accurate screening of drugs for the nervous system, and advance the clinical application of NVU models.

Multiple sclerosis (MS) is a progressive and debilitating neurological condition in which the immune system abnormally attacks the myelin sheath insulating the nerves. Mesenchymal stem cells (MSCs) are found in most adult tissues and play a significant systemic role in self-repair. MSCs have promising therapeutic effects in many diseases, such as autoimmune diseases, including MS. MSCs have been tested in MS animal models, such as experimental autoimmune encephalomyelitis. Other studies have combined other agents with MSCs, genetically modified MSCs, or used culture medium from MSCs. In this review, we will summarize these studies and compare the main factors in each study, such as the source of MSCs, the type of animal model, the route of injection, the number of injected cells, and the mechanism of action.

Infantile spasms (IS) and seizures with focal onset have different clinical expressions, even when electroencephalography (EEG) associated with IS has some degree of focality. Oddly, identical pathology (with, however, age-dependent expression) can lead to IS in one patient vs. focal seizures in another or even in the same, albeit older, patient. We therefore investigated whether the cellular mechanisms underlying seizure initiation are similar in the two instances: spasms vs. focal. We noted that in-common EEG features can include (i) a background of waves at alpha to delta frequencies; (ii) a period of flattening, lasting about a second or more – the electrodecrement (ED); and (iii) often an interval of very fast oscillations (VFO; ~70 Hz or faster) preceding, or at the beginning of, the ED. With IS, VFO temporally coincides with the motor spasm. What is different between the two conditions is this: with IS, the ED reverts to recurring slow waves, as occurring before the ED, whereas with focal seizures the ED instead evolves into an electrographic seizure, containing high-amplitude synchronized bursts, having superimposed VFO. We used in vitro data to help understand these patterns, as such data suggest cellular mechanisms for delta waves, for VFO, for seizure-related burst complexes containing VFO, and, more recently, for the ED. We propose a unifying mechanistic hypothesis – emphasizing the importance of brain pH – to explain the commonalities and differences of EEG signals in IS versus focal seizures.

The purpose of the present study was to investigate the effects of transcranial direct current stimulation (tDCS) on motor recovery in adult patients with stroke, taking into account the parameters that could influence the motor recovery responses. The second aim was to identify the best tDCS parameters and recommendations available based on the enhanced motor recovery demonstrated by the analyzed studies. Our systematic review was performed by searching full-text articles published before February 18, 2019 in the PubMed database. Different methods of applying tDCS in association with several complementary therapies were identified. Studies investigating the motor recovery effects of tDCS in adult patients with stroke were considered. Studies investigating different neurologic conditions and psychiatric disorders or those not meeting our methodologic criteria were excluded. The main parameters and outcomes of tDCS treatments are reported. There is not a robust concordance among the study outcomes with regard to the enhancement of motor recovery associated with the clinical application of tDCS. This is mainly due to the heterogeneity of clinical data, tDCS approaches, combined interventions, and outcome measurements. tDCS could be an effective approach to promote adaptive plasticity in the stroke population with significant positive premotor and postmotor rehabilitation effects. Future studies with larger sample sizes and high-quality studies with a better standardization of stimulation protocols are needed to improve the study quality, further corroborate our results, and identify the optimal tDCS protocols.

Treatment-resistant schizophrenia (TRS) is a severe form of schizophrenia. The severity of illness is positively related to homocysteine levels, with high homocysteine levels due to the low activity of the transsulfuration pathway, which metabolizes homocysteine in synthesizing L-cysteine. Glutathione levels are low in schizophrenia, which indicates shortages of L-cysteine and low activity of the transsulfuration pathway. Hydrogen sulfide (H 2 S) levels are low in schizophrenia. H 2 S is synthesized by cystathionine β-synthase and cystathionine γ-lyase, which are the two enzymes in the transsulfuration pathway. Iron-sulfur proteins obtain sulfur from L-cysteine. The oxidative phosphorylation (OXPHOS) pathway has various iron-sulfur proteins. With low levels of L-cysteine, iron-sulfur cluster formation will be dysregulated leading to deficits in OXPHOS in schizophrenia. Molybdenum cofactor (MoCo) synthesis requires sulfur, which is obtained from L-cysteine. With low levels of MoCo synthesis, molybdenum-dependent sulfite oxidase (SUOX) will not be synthesized at appropriate levels. SUOX detoxifies sulfite from sulfur-containing amino acids. If sulfites are not detoxified, there can be sulfite toxicity. The transsulfuration pathway metabolizes selenomethionine, whereby selenium from selenomethionine can be used for selenoprotein synthesis. The low activity of the transsulfuration pathway decreases selenoprotein synthesis. Glutathione peroxidase (GPX), with various GPXs being selenoprotein, is low in schizophrenia. The dysregulations of selenoproteins would lead to oxidant stress, which would increase the methylation of genes and histones leading to epigenetic changes in TRS. An add-on treatment to mainline antipsychotics is proposed for TRS that targets the dysregulations of the transsulfuration pathway and the dysregulations of other pathways stemming from the transsulfuration pathway being dysregulated.