App-Based Mindfulness Meditation Training and an Audiobook Intervention Reduce Symptom Severity but Do Not Modify Backward Inhibition in Adolescent Obsessive-Compulsive Disorder: Evidence from an EEG Study.

(1) Background: 1-2% of children and adolescents are affected by Obsessive-Compulsive Disorder (OCD). The rigid, repetitive features of OCD and an assumed disability to inhibit recent mental representations are assumed to have led to a paradoxical advantage in that the Backward Inhibition (BI) effect was recently found to be lower in adolescents with OCD as compared to healthy controls. It was hypothesized that app-based mindfulness meditation training could reduce the disability to inhibit recent mental representations and thus increase the BI-effect by adapting cognitive flexibility and inhibition abilities according to healthy controls. (2) Methods: 58 adolescents (10-19 years) with OCD were included in the final sample of this interviewer-blind, randomized controlled study. Participants were allocated to an intervention group (app-based mindfulness meditation training) or an (active) control group (app-based audiobook) for eight weeks. Symptom (CY-BOCS), behavioral (reaction times and mean accuracy), and neurophysiological changes (in EEG) of the BI-effect were analyzed in a pre-post design. (3) Results: The intervention and the control group showed an intervention effect (Reliable Change Index: 67%) with a significant symptom reduction. Contrary to the hypothesis, the BI-effect did not differ between pre vs. post app-based mindfulness meditation training. In addition, as expected the audiobook application showed no effects. Thus, we observed no intervention-specific differences with respect to behavioral (reaction times and mean accuracy) or with respect to neurophysiological (perceptual [P1], attentional [N1], conflict monitoring [N2] or updating and response selection [P3]) processes. However, in an exploratory approach, we revealed that the BI-effect decreased in participants who did not benefit from using an app, regardless of group. (4) Conclusions: Both listening to an app-based mindfulness meditation training and to an audiobook reduce symptom severity in adolescent OCD as measured by the CY-BOCS; however, they have no specific effect on BI. The extent of the baseline BI-effect might be considered as an intra-individual component to predict the benefit of both mindfulness meditation training and listening to an audiobook.

A ventral stream-prefrontal cortex processing cascade enables working memory gating dynamics.

The representation of incoming information, goals and the flexible processing of these are required for cognitive control. Efficient mechanisms are needed to decide when it is important that novel information enters working memory (WM) and when these WM 'gates' have to be closed. Compared to neural foundations of maintaining information in WM, considerably less is known about what neural mechanisms underlie the representational dynamics during WM gating. Using different EEG analysis methods, we trace the path of mental representations along the human cortex during WM gate opening and closing. We show temporally nested representational dynamics during WM gate opening and closing depending on multiple independent neural activity profiles. These activity profiles are attributable to a ventral stream-prefrontal cortex processing cascade. The representational dynamics start in the ventral stream during WM gate opening and WM gate closing before prefrontal cortical regions are modulated. A regional specific activity profile is shown within the prefrontal cortex depending on whether WM gates are opened or closed, matching overarching concepts of prefrontal cortex functions. The study closes an essential conceptual gap detailing the neural dynamics underlying how mental representations drive the WM gate to open or close to enable WM functions such as updating and maintenance.

Human photoreceptors switch from autonomous axon extension to cell-mediated process pulling during synaptic marker redistribution.

Photoreceptors (PRs) are the primary visual sensory cells, and their loss leads to blindness that is currently incurable. Although cell replacement therapy holds promise, success is hindered by our limited understanding of PR axon growth during development and regeneration. Here, we generate retinal organoids from human pluripotent stem cells to study the mechanisms of PR process extension. We find that early-born PRs exhibit autonomous axon extension from dynamic terminals. However, as PRs age from 40 to 80 days of differentiation, they lose dynamic terminals on 2D substrata and in 3D retinal organoids. Interestingly, PRs without motile terminals are still capable of extending axons but only by process stretching via attachment to motile non-PR cells. Immobile PR terminals of late-born PRs have fewer and less organized actin filaments but more synaptic proteins compared with early-born PR terminals. These findings may help inform the development of PR transplantation therapies.

Time-On-Task Effects on Working Memory Gating Processes-A Role of Theta Synchronization and the Norepinephrine System.

Performance impairment as an effect of prolonged engagement in a specific task is commonly observed. Although this is a well-known effect in everyday life, little is known about how this affects central cognitive functions such as working memory (WM) processes. In the current study, we ask how time-on-task affects WM gating processes and thus processes regulating WM maintenance and updating. To this end, we combined electroencephalography methods and recordings of the pupil diameter as an indirect of the norepinephrine (NE) system activity. Our results showed that only WM gate opening but not closing processes showed time-on-task effects. On the neurophysiological level, this was associated with modulation of dorsolateral prefrontal theta band synchronization processes, which vanished with time-on-task during WM gate opening. Interestingly, also the modulatory pattern of the NE system, as inferred using pupil diameter data, changed. At the beginning, a strong correlation of pupil diameter data and theta band synchronization processes during WM gate opening is observed. This modulatory effect vanished at the end of the experiment. The results show that time-on-task has very specific effects on WM gate opening and closing processes and suggests an important role of NE system in the time-on-task effect on WM gate opening process.

Distinguishing Multiple Coding Levels in Theta Band Activity During Working Memory Gating Processes.

Cognitive control and working memory (WM) processes are essential for goal-directed behaviour. Cognitive control and WM are probably based on overlapping neurophysiological mechanisms. For example, theta-band activity (TBA) plays an important role in both functions. For cognitive control processes, it is known that different aspects of information about stimulus content, motor processes and stimulus-response relationships are encoded simultaneously in the TBA. All this information is probably processed during WM gating processes and must be controlled during them. However, direct data for this are lacking. This question is investigated in this study by combining methods of EEG temporal signal decomposition, time-frequency decomposition and beamforming. We show that portions of stimulus-related information, motor response-related information and information related to the interaction between the stimulus and motor responses in the TBA are influenced in parallel and to a similar extent by WM gate opening and gate closing processes. Nevertheless, it is stimulus-related information in the theta signal in particular that modulates behavioural performance in WM-gating. The data suggest that the identified processes are implemented in specific neuroanatomical structures. In particular, the medial frontal cortex, temporal cortical regions and insular cortex are involved in these dynamics. The study shows that principles of information coding relevant to cognitive control processes are also crucial for understanding WM gating.

Growth Factors as Axon Guidance Molecules: Lessons From in vitro Studies.

Growth cones at the tips of extending axons navigate through developing organisms by probing extracellular cues, which guide them through intermediate steps and onto final synaptic target sites. Widespread focus on a few guidance cue families has historically overshadowed potentially crucial roles of less well-studied growth factors in axon guidance. In fact, recent evidence suggests that a variety of growth factors have the ability to guide axons, affecting the targeting and morphogenesis of growth cones in vitro. This review summarizes in vitro experiments identifying responses and signaling mechanisms underlying axon morphogenesis caused by underappreciated growth factors.

RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex.

Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.

Familiar growth factors have diverse roles in neural network assembly.

The assembly of neuronal circuits during development depends on guidance of axonal growth cones by molecular cues deposited in their environment. While a number of families of axon guidance molecules have been identified and reviewed, important and diverse activities of traditional growth factors are emerging. Besides clear and well recognized roles in the regulation of cell division, differentiation and survival, new research shows later phase roles for a number of growth factors in promoting neuronal migration, axon guidance and synapse formation throughout the nervous system.