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PubMed1975

Entrainment of motor-unit discharges as a neuronal mechanism of synchronization.

The neuronal mechanism which gives rise to the synchronization of motor-unit discharges has been inferred from an analysis of the interspike intervals of individual motor-unit discharges recorded from the soleus muscle. The motor units were divided into two groups on the basis of characteristic changes in their spike trains. The first group maintained a stationary discharge pattern throughout the process of synchronization with a firing rate of approximately 10 spikes/s. Small unidentified units simultaneously recorded gradually grouped around the individual spikes of the first group motor unit and with this process, high-frequency force oscillation appeared phase-locked with each of grouped discharges. The mean period of force oscillation was almost identical to the mean discharge interval. Therefore, the first group motor unit was considered as a pacemaker of this force-oscillation. The second group motor unit underwent from its initially stationary process to a transitional process characterized by spike dropouts from an otherwise regular spike train. When both groups of motor units were recorded by the same electrode, it was found that the firing rate of the second group motor unit discharges gradually approached that of the first group, and the spikes of the first and the second group motor units occurred near or at the same time. The number of double intervals decreased in a highly predictable fashion with an increase in a firing rate. It was furthermore observed that the spikes of a given motor unit whose discharges interval-to-period ratio is smaller at the beginning of transitional process was entrained to the first group motor-unit discharges with a faster time course than the unit whose discharge interval-to-period ratio is larger. The synchronizing process was described from the relations between shorter discharge interval-to-period ratios and the longer-to-shorter interval ratios obtained at several stages from the beginning of transitional process to the final synchronization. Their relations were best drawn by the second-order regression lines. The faster time course of synchronization was reflected in the larger value of coefficient a in the equation. The results of this and previous study (23) further provided evidence to justify that interaction of motor-unit discharges is responsible for the synchronization. Although the neuronal limiting device of the firing-rate control to approximately 10 spikes/s still remains unsolved, the possibility was considered that a disinhibitory neuronal network first acts to synchronize independently firing motoneurons and leads to the oscillation of the stretch reflex loop. This closed-loop system was considered as a site for the stored motor program and the use of disinhibitory neuronal network was discussed in relation to the Harmon's model of neuromimes.

Humans↗

PubMed2006

Stochastic approaches to understanding dissociations in inflectional morphology.

Computer modelling research has undermined the view that double dissociations in behaviour are sufficient to infer separability in the cognitive mechanisms underlying those behaviours. However, all these models employ multi-modal representational schemes, where functional specialisation of processing emerges from the training process. Targeted lesioning of different regions of functional specialisation leads to varied but predictable deficits in model performance. We argue that multi-modal representational schemes are not a necessary condition for the observation of double dissociations in an information processing system that shares resources across multiple tasks. Using a uni-modal representational system, we demonstrate that double dissociations may also result from stochastic processes. Lesioning experiments on a single-route, uni-modal connectionist model of regular and irregular noun and verb morphology confirm and extend earlier work demonstrating that selective impairment across tasks can result from damage to a distributed information processing system. A systematic investigation of the degree to which performance deteriorates across different inflectional classes reveals that simple and double dissociations can occur in this single-route, uni-modal model. An important prediction of the model is that double dissociations between regular and irregular inflection, resulting from stochastic processes should be extremely rare. However, they are particularly likely to occur when the researcher uses test batteries consisting of a small number of items. Given that cognitive neuropsychologists rarely provide details about the distribution of performance in a disordered population, it is concluded that a stochastic interpretation of double dissociations may have wider applicability than is normally supposed.

Alzheimer Disease↗

PubMed2026

Multimodal Analysis Reveals Aberrant Expression of SUMO2 and Its Significant Association With Key Mechanisms of Metabolic Pathways in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. However, the role of small ubiquitin-like modifier 2 (SUMO2), a core member of the small ubiquitin-like modifier (SUMO) family, regarding its expression patterns and metabolism-related functions in HCC remains inadequately understood. METHODS: A multidimensional analytical framework was applied, integrating immunohistochemistry (153 HCC vs. 21 non-HCC samples), proteomics (159 paired samples), bulk transcriptomics (3240 HCC vs. 2267 non-HCC samples), single-cell RNA sequencing (RNA-seq) (10 HCC vs. 8 non-HCC samples), spatial transcriptomics, and external CRISPR/Cas9 functional genomics data. Systematic analyses included standardized mean difference (SMD), pathway enrichment, pseudotime trajectory inference, in silico knockout, cell-cell communication, metabolic flux scoring, immune infiltration, clinical correlation, drug sensitivity prediction, and molecular docking. RESULTS: At the protein level, immunohistochemistry (nuclear positivity) and external proteomic data collectively demonstrated consistent SUMO2 overexpression in HCC. Consistent upregulation was also observed at the mRNA level across large-scale cohorts. Single-cell RNA-seq and spatial transcriptomics localized SUMO2 enrichment to malignant hepatocytes and tumor-dominant regions. CRISPR-mediated SUMO2 knockout suppressed proliferation in multiple HCC cell lines. Mechanistically, high SUMO2 expression was significantly associated with metabolic reprogramming involving glycolysis/gluconeogenesis, pyruvate metabolism, and the tricarboxylic acid cycle. SUMO2-high malignant hepatocyte subpopulations exhibited enhanced activity of the macrophage migration inhibitory factor signaling axis and enhanced iron-sensor interactions. Further, the immune infiltration analysis revealed a negative correlation between SUMO2 expression and M1 macrophages and a positive correlation between follicular helper T cells and regulatory T cells. Clinically, elevated SUMO2 levels were found to be associated with adverse prognostic features. Furthermore, high SUMO2 expression was associated with increased sensitivity to dasatinib, and molecular docking simulations predicted potential binding between SUMO2 and dasatinib, with a Vina score of -8.5 kcal/mol. CONCLUSIONS: SUMO2 is aberrantly expressed at the protein, mRNA, single-cell, and spatial transcriptomic levels in HCC and is significantly associated with metabolic reprogramming and altered migration inhibitory factor (MIF)-mediated intercellular communication, suggesting its potential as a novel biomarker for diagnosis and treatment.

Humans↗

PubMed2003

Learning and inference in the brain.

This article is about how the brain data mines its sensory inputs. There are several architectural principles of functional brain anatomy that have emerged from careful anatomic and physiologic studies over the past century. These principles are considered in the light of representational learning to see if they could have been predicted a priori on the basis of purely theoretical considerations. We first review the organisation of hierarchical sensory cortices, paying special attention to the distinction between forward and backward connections. We then review various approaches to representational learning as special cases of generative models, starting with supervised learning and ending with learning based upon empirical Bayes. The latter predicts many features, such as a hierarchical cortical system, prevalent top-down backward influences and functional asymmetries between forward and backward connections that are seen in the real brain. The key points made in article are: (i). hierarchical generative models enable the learning of empirical priors and eschew prior assumptions about the causes of sensory input that are inherent in non-hierarchical models. These assumptions are necessary for learning schemes based on information theory and efficient or sparse coding, but are not necessary in a hierarchical context. Critically, the anatomical infrastructure that may implement generative models in the brain is hierarchical. Furthermore, learning based on empirical Bayes can proceed in a biologically plausible way. (ii). The second point is that backward connections are essential if the processes generating inputs cannot be inverted, or the inversion cannot be parameterised. Because these processes involve many-to-one mappings, are non-linear and dynamic in nature, they are generally non-invertible. This enforces an explicit parameterisation of generative models (i.e. backward connections) to afford recognition and suggests that forward architectures, on their own, are not sufficient for perception. (iii). Finally, non-linearities in generative models, mediated by backward connections, require these connections to be modulatory, so that representations in higher cortical levels can interact to predict responses in lower levels. This is important in relation to functional asymmetries in forward and backward connections that have been demonstrated empirically.

Bayes Theorem↗

PubMed2005

Hidden Markov event sequence models: toward unsupervised functional MRI brain mapping.

RATIONALE AND OBJECTIVES: Most methods used in functional MRI (fMRI) brain mapping require restrictive assumptions about the shape and timing of the fMRI signal in activated voxels. Consequently, fMRI data may be partially and misleadingly characterized, leading to suboptimal or invalid inference. To limit these assumptions and to capture the broad range of possible activation patterns, a novel statistical fMRI brain mapping method is proposed. It relies on hidden semi-Markov event sequence models (HSMESMs), a special class of hidden Markov models (HMMs) dedicated to the modeling and analysis of event-based random processes. MATERIALS AND METHODS: Activation detection is formulated in terms of time coupling between (1) the observed sequence of hemodynamic response onset (HRO) events detected in the voxel's fMRI signal and (2) the "hidden" sequence of task-induced neural activation onset (NAO) events underlying the HROs. Both event sequences are modeled within a single HSMESM. The resulting brain activation model is trained to automatically detect neural activity embedded in the input fMRI data set under analysis. The data sets considered in this article are threefold: synthetic epoch-related, real epoch-related (auditory lexical processing task), and real event-related (oddball detection task) fMRI data sets. RESULTS: Synthetic data: Activation detection results demonstrate the superiority of the HSMESM mapping method with respect to a standard implementation of the statistical parametric mapping (SPM) approach. They are also very close, sometimes equivalent, to those obtained with an "ideal" implementation of SPM in which the activation patterns synthesized are reused for analysis. The HSMESM method appears clearly insensitive to timing variations of the hemodynamic response and exhibits low sensitivity to fluctuations of its shape (unsustained activation during task). Real epoch-related data: HSMESM activation detection results compete with those obtained with SPM, without requiring any prior definition of the expected activation patterns thanks to the unsupervised character of the HSMESM mapping approach. Along with activation maps, the method offers a wide range of additional fMRI analysis functionalities, including activation lag mapping, activation mode visualization, and hemodynamic response function analysis. Real event-related data: Activation detection results confirm and validate the overall strategy that consists in focusing the analysis on the transients, time-localized events that are the HROs. CONCLUSION: All the experiments performed on synthetic and real fMRI data demonstrate the relevance of HSMESMs in fMRI brain mapping. In particular, the statistical character of these models, along with their learning and generalizing abilities are of particular interest when dealing with strong variabilities of the active fMRI signal across time, space, experiments, and subjects.

Adolescent↗

PubMedDate not supplied

[From acute victimization at chronic victimization: socio-cognitive approach of differential tolerance threshold].

BACKGROUND: Work, for many years reduced to a purely instrumental dimension, proves to be a true microcosm of society, with its informal modes, its emotional networks and its series of evils and dilemmas. This human apprehension of the professional sphere tends to reveal a pole with multiple facets, some of which have long been concealed, but whose individual, social and economic extent can't let people ignore them. This social perception, which contributes to regard work as sacred and makes it impervious to any aggression, should be abandoned. Bearing this in mind, our study endeavours to show that "work" and "victim" are far more overlapping than antagonistic realities; it aims at determining the impact of two aggressive methods via the professional pole, namely: moral harassment at work and armed attacks within bank premises. Such an approach tends to unify health psychology, occupational psychology and victimology, thus opening a breach in the stereotyped view which crystallizes the professional sphere into a kind of representative noose devoid of the most human bases. We then suggest, as a first hypothesis, that the nature of the victimization process, resulting from specific aggressive scenarios, would determine different psychological, physiological and relational consequences, apprehended under the generic expression of tolerance threshold. In other words, "mobbing", through its proactive, intentional and obsessional dimension would tend to lower the victims' threshold more than hold-ups, which are characterized by a reactive aspect, and obey unfavourable socio-economic contingencies. Our research also aims at apprehending this dynamic relationship binding victimization types to tolerance thresholds through two analysing factors. These psychological mediators are derived from Lazarus and Folkman's "transactional model of stress", which postulates that stress would rise from the perception people get of the transaction between the requirements of the situation and their own resources. These modulators would correspond to the social evaluation of the stressor and the adjustment strategies adopted by the victims. We then postulate the fact that these interfering variables would determine a connection between the type of victimization and the series of signs and symptoms generated. In other words, the aversive modes would refer to a process of significance via these interpolated socio-cognitive factors, thus forming a trace of the traumatic event according to the tolerance threshold expressed. More precisely, our assumption consists in postulating that the insidious and latent aspect of harassment which is supposed to support a dispositional attribution of the harasser's intrigues as well as the preferential adoption of coping strategies centred on emotional control, would lower the victims' tolerance threshold further, than a visible and instantaneous hold-up which is supposed to condition an essentially situational perception and the adoption of strategies mainly directed towards the problem. METHOD: Since this study is the subject of a comparative research strategy, its required the constitution of three independent samples: ten harassment victims; seven armed attack victims; ten witnesses, all salaried employees; they had not been subjected to either type of attack but were questioned about a working life event seen as stressful. The three groups, set up according to sex and age considerations, agreed to be subjected to a semi-directive interview. Considering the exploratory nature of this present research, the process proved to be most suitable since, through the filter of the people's subjectivity, it clearly determined the meaning granted by the victim to the aversive situation. In order to comply with a standardization preoccupation, each interview was identically structured using a preset question grid and similar operating conditions. The data collected were then subjected to four levels of analysis. An analysis of contents, centred on a logic-semantic frequency dimension of speech, obtained a simplified representation of the whole of the data. This first level of analysis, supplemented by descriptive statistics, validated, in the second stage, the significance of the differences in the semantic categories. In the third stage, an "analysis of adjacency" associated with a factorial analysis of the correspondences, delineated the differentiating values of the three groups of subjects. A final stage of analysis, centred on a multiaxial dimension [DSM IV ], permitted the constitution of clinical pictures. RESULTS: In accordance with the general assumption, the results show that the victims reveal a dominating presence of mobbing signs related to depression and anxiety symptomatology with an acute emotional threshold. Hold-up victims also show undoubted but significantly less harmful consequences. These victims have turned out to be more centred on the anxious pole and the social and family fields. Moreover, while the victims of harassment unanimously evoke the emergence of a break-up in dynamics conveying a freeze of the social matrix, some of the victims of armed attacks express "secondary benefits" through the setting-up of gregarious dynamics on professional as well as on family level. DISCUSSION: Considering these results, there seems to be a double induction of such a difference. The social evaluation tends to be a first explanatory inference as for the expressed tolerance level. As a matter of fact, the frequential analysis reveals a different perception of the attacker. The supernumerary evocation of dispositional factors, supposing a personal motivation marked with intrigues concealed behind an apparent legitimacy, draws a very personological profile of the harasser. This majority of intrinsic determinants reveals an increase in the causal weight of the harasser; at the same time, it disregards the possible influence of extrinsic factors. In that respect, the harasser is seen as the only instigator of the attacks, which consequently worsens his/her responsibility and culpability. No difference appears between the harasser himself and the hypothetical causes of the aversive situation: the harasser is seen as the source of the attacks and the attacks as the concretization of the harasser's state of mind. On the basis of this report, the victims of harassment tend to amalgamate the personality and the situation. The victims of armed attacks, as for them, are characterized by a more situational evaluation of the stressor, revealing an apparent will to segment the aversive situation: on the one hand the act, and the other the attacker, as though, eventually, the latter was but one element depending on a specific situation. The majority enunciation of extrinsic factors supposes an obvious intention to diffuse the hold-up man's responsibility over contextual attributes. The second inference lies in the strategies used to adjust to the situation. Whatever the type of victimization, the passive coping system reveals as dominating. However, this tendency seems to be more moderate with hold-up victims, who tend to counterbalance the strategies centred on emotional control with strategies directed towards an active resolution of the problem. CONCLUSION: Considering these first results, which call for further study, our impression is that it seems to be relevant to consider the setting-up of psychological therapy programs adapted to the very nature of each victimization case.

Adaptation, Psychological↗