Connectivity between the cerebrum and cerebellum during social and non-social sequencing using dynamic causal modelling

This analysis explores the effective connectivity of the cerebellum with the cerebral cortex during the generation of correct sequences of social and non-social events, using dynamic causal modelling (DCM). Our hypothesis is that during human evolution, the cerebellum’s function evolved from a mere coordinator of fluent sequences of motions and actions, to an interpreter of action sequences without overt movements that are important for social understanding. This requires efficient neural communication between the cerebellum and cerebral cortex. In a functional magnetic resonance imaging (fMRI) study, participants generated the correct chronological order of (non-)social events, including stories involving mechanical and social scripts, and true or false beliefs. Across all stories, a DCM analysis of these data revealed, as predicted, bidirectional (closed-loop) connections linking the bilateral posterior cerebellum with the bilateral temporo-parietal junction (TPJ) associated with behavior understanding, and this connectivity pattern was almost entirely significant. There was also a unidirectional connection from the right posterior cerebellum to the precuneus, but no direct connections with the dorsomedial prefrontal cortex (dmPFC). Moreover, all connections emanating from the bilateral posterior cerebellum were negative, indicative of some kind of error signal. Within the cerebral cortex, there were unidirectional connections from the bilateral TPJ to the dmPFC, as well as bidirectional connections between the precuneus and dmPFC, and between the bilateral TPJ. These results confirm that the effective connectivity between the posterior cerebellum and mentalizing areas in the cerebral cortex play a critical role in the understanding and construction of the correct order of social and non-social action sequences

The role of the cerebellum in social and non-social action sequences : a preliminary LF-rTMS study

An increasing number of studies demonstrated the involvement of the cerebellum in (social) sequence processing. The current preliminary study is the first to investigate the causal involvement of the cerebellum in sequence generation, using low-frequency repetitive transcranial magnetic stimulation (LF-rTMS). By targeting the posterior cerebellum, we hypothesized that the induced neuro-excitability modulation would lead to altered performance on a Picture and Story sequencing task, which involve the generation of the correct chronological order of various social and non-social stories depicted in cartoons or sentences. Our results indicate that participants receiving LF-rTMS over the cerebellum, as compared to sham participants, showed a stronger learning effect from pre to post stimulation for both tasks and for all types of sequences (i.e. mechanical, social scripts, false belief, true belief). No differences between sequence types were observed. Our results suggest a positive effect of LF-rTMS on sequence generation. We conclude that the cerebellum is causally involved in the generation of sequences of social and nonsocial events. Our discussion focuses on recommendations for future studies

The Click Test: A Novel Tool to Quantify the Age-Related Decline of Fast Motor Sequencing of the Thumb

International audienceAbstract : Background: The thumb plays a critical role for manual tasks during the activities of daily life and the incidence of neurological or musculoskeletal disorders affecting the voluntary movements of the thumb is high in the elderly. There is currently no tool to assess repetitive motor sequencing of the thumb during ageing.Objectives: To report a novel procedure (the Click Test) assessing the effects of ageing on fast motor sequencing of the thumb.Methods : Healthy subjects (n = 252; mean age +/- SD: 49.76 +/- 19.97 years; range: 19-89 years; F/M: 151/101) were asked to perform fast repeated flexion/extension movements of the thumb using a mechanical counter.Results: Motor performances (assessed by the number of clicks during 3 time periods: 15, 30 and 45 sec), significantly decreased as a function of age for both the dominant (age effect; p< 0.0001 for 15, 30 and 45 sec) and the non-dominant hand (p<0.0001 for 15, 30 and 45 sec). The number of clicks was significantly higher in males (gender effect; p<0.001) and was higher on the dominant side as compared to the non-dominant side (handedness effect: p<0.001). The Click Test is characterized by high repeatability (coefficients of variation from 3.20 to 4.47%), excellent intra-rater reliability (intra-class coefficients ICC ranging from 0.89 to 0.98), high inter-rater reproducibility (Pearson’s product correlation ranging from 0.85 to 0.96), high internal consistency (Cronbach alpha coefficient=0.95) and is highly correlated in terms of relative performances with the box and block test and the 9-hole peg test (positive linear correlation with the results of the box and block test: p<0.001 for 15, 30 and 45 sec for both the dominant and the non-dominant hand; negative linear correlation with the results of the 9-hole peg test: p<0.001 for 15, 30 and 45 sec for both the dominant and the non-dominant hand).Conclusion : The Click Test is an entirely novel and very low cost tool to reliably discriminate the ageing effects upon the performances during fast repetitive motor sequencing of the thumb. The potential clinical and research applications for motor functions are multiple, especially in acute and chronic neurological disorders affecting the thumb as well as in the field of rheumatology and orthopedics

Resting-State Functional Connectivity and Network Analysis of Cerebellum with Respect to Crystallized IQ and Gender

During the last years, it has been established that the prefrontal and posterior parietal brain lobes, which are mostly related to intelligence, have many connections to cerebellum. However, there is a limited research investigating cerebellum's relationship with cognitive processes. In this study, the network of cerebellum was analyzed in order to investigate its overall organization in individuals with low and high crystallized Intelligence Quotient (IQ). Functional magnetic resonance imaging (fMRI) data were selected from 136 subjects in resting-state from the Human Connectome Project (HCP) database and were further separated into two IQ groups composed of 69 low-IQ and 67 high-IQ subjects. Cerebellum was parcellated into 28 lobules/ROIs (per subject) using a standard cerebellum anatomical atlas. Thereafter, correlation matrices were constructed by computing Pearson's correlation coefficients between the average BOLD time-series for each pair of ROIs inside the cerebellum. By computing conventional graph metrics, small-world network properties were verified using the weighted clustering coefficient and the characteristic path length for estimating the trade-off between segregation and integration. In addition, a connectivity metric was computed for extracting the average cost per network. The concept of the Minimum Spanning Tree (MST) was adopted and implemented in order to avoid methodological biases in graph comparisons and retain only the strongest connections per network. Subsequently, six global and three local metrics were calculated in order to retrieve useful features concerning the characteristics of each MST. Moreover, the local metrics of degree and betweenness centrality were used to detect hubs, i.e., nodes with high importance. The computed set of metrics gave rise to extensive statistical analysis in order to examine differences between low and high-IQ groups, as well as between all possible gender-based group combinations. Our results reveal that both male and female networks have small-world properties with differences in females (especially in higher IQ females) indicative of higher neural efficiency in cerebellum. There is a trend toward the same direction in men, but without significant differences. Finally, three lobules showed maximum correlation with the median response time in low-IQ individuals, implying that there is an increased effort dedicated locally by this population in cognitive tasks

Constraint-induced Aphasia Therapy versus Intensive Semantic Treatment in Fluent Aphasia

Objective: To compare the effectiveness of two intensive therapy methods: Constraint- 4 Induced Aphasia Therapy (CIAT) and semantic therapy (BOX). Method: Nine patients with chronic fluent aphasia participated in a therapy programme 6 to establish behavioral treatment outcomes. Participants were randomly assigned to one of two groups (CIAT or BOX). Results: Intensive therapy significantly improved verbal communication. However, BOX 9 treatment showed a more pronounced improvement on two communication measures, namely on a standardized assessment for verbal communication, the Amsterdam Nijmegen Everyday Language Test (Blomert, Koster, & Kean, 1995) and on a subjective rating scale, the Communicative Effectiveness Index (Lomas et al., 1989). All 13 participants significantly improved on one (or more) subtests of the Aachen Aphasia Test (Graetz et al., 1992), an impairment-focused assessment. There was a treatment-specific effect. Therapy with BOX had a significant effect on language comprehension and on semantics, while of CIAT affected language production and phonology. Conclusion: The findings indicate that in patients with fluent aphasia (1) intensive treatment has a significant effect on language and verbal communication, (2) intensive therapy results in selective treatment effects and (3) an intensive semantic treatment shows a more striking mean improvement on verbal communication in comparison to communication-based CIAT-treatment

Mutational analysis of the RNA-binding domain of the Prunus necrotic ringspot virus (PNRSV) movement protein reveals its requirement for cell-to-cell movement

The movement protein (MP) of Prunus necrotic ringspot virus (PNRSV) is required for cell-to-cell movement. MP subcellular localization studies using a GFP fusion protein revealed highly punctate structures between neighboring cells, believed to represent plasmodesmata. Deletion of the RNA-binding domain (RBD) of PNRSV MP abolishes the cell-to-cell movement. A mutational analysis on this RBD was performed in order to identify in vivo the features that govern viral transport. Loss of positive charges prevented the cell-to-cell movement even though all mutants showed a similar accumulation level in protoplasts to those observed with the wild-type (wt) MP. Synthetic peptides representing the mutants and wild-type RBDs were used to study RNA-binding affinities by EMSA assays being approximately 20-fold lower in the mutants. Circular dichroism analyses revealed that the secondary structure of the peptides was not significantly affected by mutations. The involvement of the affinity changes between the viral RNA and the MP in the viral cell-to-cell movement is discussed

Transcranial direct current stimulation (tDCS) modulation of picture naming and word reading:A meta-analysis of single session tDCS applied to healthy participants

Recent reviews quantifying the effects of single sessions of transcranial direct current stimulation (or tDCS) in healthy volunteers find only minor effects on cognition despite the popularity of this technique. Here, we wanted to quantify the effects of tDCS on language production tasks that measure word reading and picture naming. We reviewed 14 papers measuring tDCS effects across a total of 96 conditions to a) quantify effects of conventional stimulation on language regions (i.e., left hemisphere anodal tDCS administered to temporal/frontal areas) under normal conditions or under conditions of cognitive (semantic) interference; b) identify parameters which may moderate the size of the tDCS effect within conventional stimulation protocols (e.g., online vs offline, high vs. low current densities, and short vs. long durations), as well as within types of stimulation not typically explored by previous reviews (i.e., right hemisphere anodal tDCS or left/right hemisphere cathodal tDCS). In all analyses there was no significant effect of tDCS, but we did find a small but significant effect of time and duration of stimulation with stronger effects for offline stimulation and for shorter durations (< 15 min). We also found some indication of publication bias towards reporting positive effects. We encourage further experimentation in order resolve the disparity between the current popularity of tDCS and its poor efficacy in healthy participants

The regulation and deregulation of Wnt signaling by PARK genes in health and disease

Wingless/Int (Wnt) signaling pathways are signal transduction mechanisms that have been widely studied in the field of embryogenesis. Recent work has established a critical role for these pathways in brain development, especially of midbrain dopaminergic neurones. However, the fundamental importance of Wnt signaling for the normal function of mature neurones in the adult central nervous system has also lately been demonstrated by an increasing number of studies. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide and is currently incurable. This debilitating disease is characterized by the progressive loss of a subset of midbrain dopaminergic neurones in the substantia nigra leading to typical extrapyramidal motor symptoms. The aetiology of PD is poorly understood but work performed over the last two decades has identified a growing number of genetic defects that underlie this condition. Here we review a growing body of data connecting genes implicated in PD--most notably the PARK genes--with Wnt signaling. These observations provide clues to the normal function of these proteins in healthy neurones and suggest that deregulated Wnt signaling might be a frequent pathomechanism leading to PD. These observations have implications for the pathogenesis and treatment of neurodegenerative diseases in general

Consensus Paper: Cerebellum and Social Cognition.

The traditional view on the cerebellum is that it controls motor behavior. Although recent work has revealed that the cerebellum supports also nonmotor functions such as cognition and affect, only during the last 5 years it has become evident that the cerebellum also plays an important social role. This role is evident in social cognition based on interpreting goal-directed actions through the movements of individuals (social "mirroring") which is very close to its original role in motor learning, as well as in social understanding of other individuals' mental state, such as their intentions, beliefs, past behaviors, future aspirations, and personality traits (social "mentalizing"). Most of this mentalizing role is supported by the posterior cerebellum (e.g., Crus I and II). The most dominant hypothesis is that the cerebellum assists in learning and understanding social action sequences, and so facilitates social cognition by supporting optimal predictions about imminent or future social interaction and cooperation. This consensus paper brings together experts from different fields to discuss recent efforts in understanding the role of the cerebellum in social cognition, and the understanding of social behaviors and mental states by others, its effect on clinical impairments such as cerebellar ataxia and autism spectrum disorder, and how the cerebellum can become a potential target for noninvasive brain stimulation as a therapeutic intervention. We report on the most recent empirical findings and techniques for understanding and manipulating cerebellar circuits in humans. Cerebellar circuitry appears now as a key structure to elucidate social interactions

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field