Neurofeedback in patients with frontal brain lesions: A randomized, controlled double-blind trial.

Background: Frontal brain dysfunction is a major challenge in neurorehabilitation. Neurofeedback (NF), as an EEG-based brain training method, is currently applied in a wide spectrum of mental health conditions, including traumatic brain injury. Objective: This study aimed to explore the capacity of Infra-Low Frequency Neurofeedback (ILF-NF) to promote the recovery of brain function in patients with frontal brain injury. Materials and methods: Twenty patients hospitalized at a neurorehabilitation clinic in Switzerland with recently acquired, frontal and optionally other brain lesions were randomized to either receive NF or sham-NF. Cognitive improvement was assessed using the Frontal Assessment Battery (FAB) and the Test of Attentional Performance (TAP) tasks regarding intrinsic alertness, phasic alertness and impulse control. Results: With respect to cognitive improvements, there was no significant difference between the two groups after 20 sessions of either NF or sham-NF. However, in a subgroup of patients with predominantly frontal brain lesions, the improvements measured by the FAB and intrinsic alertness were significantly higher in the NF-group. Conclusion: This is the first double-blind controlled study using NF in recovery from brain injury, and thus also the first such study of ILF NF. Although the result of the subgroup has limited significance because of the small number of participants, it accentuates the trend seen in the whole group regarding the FAB and intrinsic alertness (p = 0.068, p = 0.079, respectively). We therefore conclude that NF could be a promising candidate promoting the recoveryfrom frontal brain lesions. Further studies with larger numbers of patients and less lesion heterogeneity are needed to verify the usefulness of NF in the neurorehabilitation of patients with frontal brain injury (NCT02957695 ClinicalTrials.gov).

Identification of a lectin causing the degeneration of neuronal processes using engineered embryonic stem cells.

Unlike the mechanisms involved in the death of neuronal cell bodies, those causing the elimination of processes are not well understood owing to the lack of suitable experimental systems. As the neurotrophin receptor p75(NTR) is known to restrict the growth of neuronal processes, we engineered mouse embryonic stem (ES) cells to express an Ngfr (p75(NTR)) cDNA under the control of the Mapt locus (the gene encoding tau), which begins to be active when ES cell-derived progenitors start elongating processes. This caused a progressive, synchronous degeneration of all processes, and a prospective proteomic analysis showed increased levels of the sugar-binding protein galectin-1 in the p75(NTR)-engineered cells. Function-blocking galectin-1 antibodies prevented the degeneration of processes, and recombinant galectin-1 caused the processes of wild-type neurons to degenerate first, followed by the cell bodies. In vivo, the application of a glutamate receptor agonist, a maneuver known to upregulate p75(NTR), led to an increase in the amount of galectin-1 and to the degeneration of neurons and their processes in a galectin-1-dependent fashion. Section of the sciatic nerve also rapidly upregulated levels of p75(NTR) and galectin-1 in terminal Schwann cells, and the elimination of nerve endings was delayed at the neuromuscular junction of mice lacking Lgals1 (the gene encoding galectin-1). These results indicate that galectin-1 actively participates in the elimination of neuronal processes after lesion, and that engineered ES cells are a useful tool for studying relevant aspects of neuronal degeneration that have been hitherto difficult to analyze.

Region-specific integration of embryonic stem cell-derived neuronal precursors into a pre-existing neuronal circuit.

Enduring reorganization is accepted as a fundamental process of adult neural plasticity. The most dramatic example of this reorganization is the birth and continuously occurring incorporation of new neurons into the pre-existing network of the adult mammalian hippocampus. Based on this phenomenon we transplanted murine embryonic stem (ES)-cell derived neuronal precursors (ESNPs) into murine organotypic hippocampal slice cultures (OHC) and examined their integration. Using a precise quantitative morphological analysis combined with a detailed electrophysiology, we show a region-specific morphological integration of transplanted ESNPs into different subfields of the hippocampal tissue, resulting in pyramidal neuron-like embryonic stem cell-derived neurons (ESNs) in the Cornu Ammonis (CA1 and CA3) and granule neuron-like ESNs in the dentate gyrus (DG), respectively. Subregion specific structural maturation was accompanied by the development of dendritic spines and the generation of excitatory postsynaptic currents (EPSCs). This cell type specific development does not depend upon NMDA-receptor-dependent synaptic transmission. The presented integration approach was further used to determine the cell-autonomous function of the pan-neurotrophin receptor p75 (P75(NTR)), as a possible negative regulator of ESN integration. By this means we used p75(NTR)-deficient ESNPs to study their integration into a WT organotypic environment. We show here that p75(NTR) is not necessary for integration per se but plays a suppressing role in dendritic development.