[Therapeutic applications of classical serotonergic psyche-delics: neurobiological mechanisms and neural networks]. / Therapeutische toepassingen van klassieke serotonerge psychedelica: neurobiologische mechanismes en neurale netwerken.

BACKGROUND: Psychedelics have received renewed scientific attention in recent decades because of their potential to induce long-term changes in behaviour and cognition with potential therapeutic applications in various psychiatric indications. AIM: To provide a brief overview of the neurobiological action of classical serotonergic psychedelics, their impact on neural networks and implications for potential clinical applications. METHOD: We provide a non-exhaustive review of the current literature by subsequently and thematically outlining: 1. the empirical evidence concerning the action of psychedelics on the level of individual neuronal cells; 2.their effects on the level of neural networks; and 3. their influence on neuroplasticity and 4. different mechanistic hypotheses about the potential therapeutic effects of psychedelic substances. We illustrate this through key studies that provided important historical breakthroughs and show how these findings were integrated into the current theories. RESULTS: Studies evidence the central role of 5-HT2A receptors for the subjective effects of psychedelics, as well as affinity for many other receptors. Through a complex cascade of downstream effects, psychedelic substances lead to dynamic changes in different neural circuits and increased neuroplasticity which potentially persists even after the subjective effects have subsided. Several theoretical concepts offer complementary explanations for the relationship between the effects at neurobiological and psychological levels. CONCLUSION: Although the underlying neurobiological mechanisms are not yet fully understood and methodological challenges remain, the current research offers valuable insights into how a single or a few administrations of a psychedelic substance could lead to symptom improvements that can last for weeks, months, or even longer, if used in a supportive setting and in combination with psychotherapy.

[Neuroscientific and psychological explanations for the therapeutic effects of psychedelics]. / Neurowetenschappelijke en psycho­logische verklaringen voor de thera­peutische effecten van psychedelica.

BACKGROUND: Psychedelics have a strong therapeutic potential for the treatment of biomedical disorders, but the working mechanisms underlying psychedelics are only poorly understood.
AIM: To discuss different mechanisms underlying the therapeutic effects of classic psychedelics.
METHOD: To make a distinction between different levels of explanation: the pharmacological, the neurocognitive and the psychological level.
RESULTS: At the pharmacological level, classic psychedelics affect via the serotonin-receptor, the production of glutamate and brain-derived neurotrophic factor (bdnf), which stimulate neurogenesis. Psychedelics also have anti-flammatory properties and thereby have a protective effect on the brain. At the neurocognitive level, psychedelics have been associated with a reduced activation of the default mode network, which has been implicated in self-referential processing and rumination. At the same time, the brain's entropy increases, reflected in an increased connectivity between different brain areas. At the psychological level, the therapeutic efficacy of psychedelics has been attributed to the mystical experience, as well as to its awe-inducing potential, the feelings of connectedness and an enhanced awareness of emotions.
CONCLUSION: Psycholytic and psychedelic therapy act at different levels, but ultimately the combination of different mechanisms will help us to understand how psychedelics - in the right set and setting - can be used successfully in therapeutic practice.

Changing motor perception by sensorimotor conflicts and body ownership.

Experimentally induced sensorimotor conflicts can result in a loss of the feeling of control over a movement (sense of agency). These findings are typically interpreted in terms of a forward model in which the predicted sensory consequences of the movement are compared with the observed sensory consequences. In the present study we investigated whether a mismatch between movements and their observed sensory consequences does not only result in a reduced feeling of agency, but may affect motor perception as well. Visual feedback of participants' finger movements was manipulated using virtual reality to be anatomically congruent or incongruent to the performed movement. Participants made a motor perception judgment (i.e. which finger did you move?) or a visual perceptual judgment (i.e. which finger did you see moving?). Subjective measures of agency and body ownership were also collected. Seeing movements that were visually incongruent to the performed movement resulted in a lower accuracy for motor perception judgments, but not visual perceptual judgments. This effect was modified by rotating the virtual hand (Exp.2), but not by passively induced movements (Exp.3). Hence, sensorimotor conflicts can modulate the perception of one's motor actions, causing viewed "alien actions" to be felt as one's own.

Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1.

Donor T cells directed at hematopoietic system-specific minor histocompatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the clinical evaluation of the concept of mHag-based immunotherapy and subsequent broad implementation, the identification of more hematopoietic mHags with broad applicability is imperative. Here we describe novel mHag UTA2-1 with ideal characteristics for this purpose. We identified this antigen using genome-wide zygosity-genotype correlation analysis of a mHag-specific CD8(+) cytotoxic T lymphocyte (CTL) clone derived from a multiple myeloma patient who achieved a long-lasting complete remission after donor lymphocyte infusion from an human leukocyte antigen (HLA)-matched sibling. UTA2-1 is a polymorphic peptide presented by the common HLA molecule HLA-A*02:01, which is encoded by the bi-allelic hematopoietic-specific gene C12orf35. Tetramer analyses demonstrated an expansion of UTA2-1-directed T cells in patient blood samples after several donor T-cell infusions that mediated clinical GvT responses. More importantly, UTA2-1-specific CTL effectively lysed mHag(+) hematopoietic cells, including patient myeloma cells, without affecting non-hematopoietic cells. Thus, with the capacity to induce relevant immunotherapeutic CTLs, it's HLA-A*02 restriction and equally balanced phenotype frequency, UTA2-1 is a highly valuable mHag to facilitate clinical application of mHag-based immunotherapy.

I feel who I see: visual body identity affects visual-tactile integration in peripersonal space.

Recent studies have shown the importance of integrating multisensory information in the body representation for constituting self-consciousness. However, one idea that has received only scant attention is that our body representation is also constituted by knowledge of bodily visual characteristics (i.e. 'what I look like'). Here in two experiments we used a full body crossmodal congruency task in which visual distractors were presented on a photograph of the participant, another person, who was either familiar or unfamiliar, or an object. Results revealed that during the 'self-condition' CCEs were enhanced compared to the 'other condition'. The CCE was similar for unfamiliar and familiar others. CCEs for the object condition were significantly smaller. The results show that presentation of an irrelevant image of a body affects multimodal processing and that the effect is enhanced when that image is of the self. The results hold intriguing implications for body representation in social situations.

Pouring or chilling a bottle of wine: an fMRI study on the prospective planning of object-directed actions.

This fMRI study investigates the neural mechanisms supporting the retrieval of action semantics. A novel motor imagery task was used in which participants were required to imagine planning actions with a familiar object (e.g. a toothbrush) or with an unfamiliar object (e.g. a pair of pliers) based on either goal-related information (i.e. where to move the object) or grip-related information (i.e. how to grasp the object). Planning actions with unfamiliar compared to familiar objects was slower and was associated with increased activation in the bilateral superior parietal lobe, the right inferior parietal lobe and the right insula. The stronger activation in parietal areas for unfamiliar objects fits well with the idea that parietal areas are involved in motor imagery and suggests that this process takes more effort in the case of novel or unfamiliar actions. In contrast, the planning of familiar actions resulted in increased activation in the anterior prefrontal cortex, suggesting that subjects maintained a stronger goal-representation when planning actions with familiar compared to unfamiliar objects. These findings provide further insight into the neural structures that support action semantic knowledge for the functional use of real-world objects and suggest that action semantic knowledge is activated most readily when actions are planned in a goal-directed manner.

Imitation of hand and tool actions is effector-independent.

Following the theoretical notion that tools often extend one's body, in the present study, we investigated whether imitation of hand or tool actions is modulated by effector-specific information. Subjects performed grasping actions toward an object with either a handheld tool or their right hand. Actions were initiated in response to pictures representing a grip at an object that could be congruent or incongruent with the required action (grip-type congruency). Importantly, actions could be cued by means of a tool cue, a hand cue, and a symbolic cue (effector-type congruency). For both hand and tool actions, an action congruency effect was observed, reflected in faster reaction times if the observed grip type was congruent with the required movement. However, neither hand actions nor tool actions were differentially affected by the effector represented in the picture (i.e., when performing a tool action, the action congruency effect was similar for tool cues and hand cues). This finding suggests that imitation of hand and tool actions is effector-independent and thereby supports generalist rather than specialist theories of imitation.

Learning to use novel objects: a training study on the acquisition of novel action representations.

Many studies have suggested that the motor system is organized in a hierarchical fashion, around the prototypical end location associated with using objects. However, most studies supporting the hierarchical view have used well-known actions and objects that are highly over-learned. Accordingly, at present it is unclear if the hierarchical principle applies to learning the use of novel objects as well. In the present study we found that when learning to use a novel object subjects acquired an action representation of the end location associated with using the object, as evidenced by slower responses in an action observation task, when the object was presented at an incorrect end location. By showing the importance of knowledge about end locations when learning to use a novel object, the present study suggests that end locations are a fundamental organizing feature of the human motor system.

Neural evidence for impaired action selection in right hemiparetic cerebral palsy.

Recent studies suggest that in addition to low-level motor impairments, individuals with hemiparetic cerebral palsy (HCP) are characterized by anticipatory action planning deficits as well. In the present EEG study we investigated the neural and temporal dynamics of action planning in participants with right-sided HCP (n=10) and in left-handed control subjects (n=10). An anticipatory planning task was used in which participants were required to grasp and rotate a hexagonal knob over different angles (60 degrees, 120 degrees or 180 degrees). At a behavioral level, participants with HCP were slower in their movements and often selected an inappropriate grip when grasping the object. At a neural level, individuals with HCP showed a strong reduction in the amplitude of the P2 component, likely reflecting an impaired process of action selection. In addition, a strong correlation was observed between the P2 amplitude and grasping and rotation times. The P2 component was localized to sources in the dorsal posterior cingulate cortex (dPCC), an area that is known to be involved in orienting visual body parts in space. Together these findings suggest that anticipatory planning deficits in cerebral palsy arise mainly due to an impaired process of action selection.

Neural and temporal dynamics underlying visual selection for action.

The present study investigated the selection for action hypothesis, according to which a subject's action intention to perform a movement influences the way in which visual information is being processed. Subjects were instructed in separate blocks either to grasp or to point to a three-dimensional target-object and event-related potentials were recorded relative to stimulus onset. It was found that grasping compared with pointing resulted in a stronger N1 component and a subsequent selection negativity, which were localized to the lateral occipital complex. These effects suggest that the intention to grasp influences the processing of action-relevant features in ventral stream areas already at an early stage (e.g., enhanced processing of object orientation for grasping). These findings provide new insight in the neural and temporal dynamics underlying perception-action coupling and provide neural evidence for a selection for action principle in early human visual processing.

The N400-concreteness effect reflects the retrieval of semantic information during the preparation of meaningful actions.

The present ERP study investigated when and how action semantics, i.e. the conceptual knowledge that we acquired over the course of our lives, is activated during the preparation of object-directed actions. Subjects were required to grasp one of two objects and were implicitly instructed to either perform a meaningful action (e.g. moving a cup towards the mouth) or a meaningless action with the object (e.g. moving a cup towards the eye). A larger anterior N400 was found for the preparation of meaningful compared to meaningless actions, likely reflecting the retrieval of action semantic information in case a meaningful action was required with the object. The distribution and the latency of the anterior N400-effect were strongly related to standard N400-repetition effects, thereby further corroborating the semantic nature of the effect. In sum, the present study provides new insight in the neural and temporal dynamics underlying semantics for action.

The functional role of motor activation in language processing: motor cortical oscillations support lexical-semantic retrieval.

There is increasing experimental evidence that processing action-related language results in the automatic activation of associated regions of the motor and premotor cortex. However, the functional significance of motor activation in language processing is still under debate. In the present EEG study, we set out to investigate if language-induced motor activation primarily reflects the retrieval of lexical-semantic information or post-lexical motor imagery. The processing of action verbs was found accompanied by an early activation of motor-related brain areas, as reflected by a desynchronization in the mu- and beta-frequency bands which was localized to motor and premotor areas. A stronger motor activation was observed for verbs presented in an animal context (e.g. "The deer jumped over the stream") compared to a human context (e.g. "The athlete jumped over the fence") and motor resonance was directly modulated by the cloze probability of the noun-verb pairs. The onset of the motor effects preceded classical measures of semantic integration (i.e. the N400 component) and the strength of motor activation was found inversely related to the size of the N400 effect. These findings support the hypothesis that motor activation in language processing primarily supports the retrieval and integration of lexical-semantic information.

Lactic acid bacteria differ in their ability to induce functional regulatory T cells in humans.

BACKGROUND: Trials with probiotic lactic acid bacteria have yielded different results, which may be due to the strains used. Lactobacilli and bifidobacteria are known to be potent modulators of the immune system. The capacity of these bacteria used as probiotics to influence both T helper type 1 (Th1)- and Th2-mediated diseases has been shown before. However, the ability of strains to induce forkhead box P3 (FOXP3(+)) expressing regulatory T cells has not yet been investigated. OBJECTIVE: Test the inherent differences between strains in their capacity to induce functional regulatory T cells in human peripheral blood mononuclear cells (PBMC). METHODS: Human PBMC were co-cultured in vitro with either Bifidobacterium lactis W51, Lactobacillus acidophilus W55 or Lactobacillus plantarum W62 or an Escherichia coli control strain. The percentage of FOXP3(+) cells, the origin of the induced cells and the functionality of these cells were assessed. Results Probiotic strains differ in their capacity to induce regulatory T cells. FOXP3(+) cells were induced from CD25(-) cells and were able to suppress effector T cells. Naturally occurring regulatory T cells were not affected by co-culture with lactobacilli. IL-10 concentrations found in the supernatant showed a trend towards the same differences between strains. Blockade of IL-10 did not influence the up-regulation of FOXP3. No differences between lactic acid bacteria were found in IL-17, IFN-gamma or IL-13. CONCLUSIONS: Some probiotic strains are potent inducers of regulatory cells, while others are not. The clear differences between strains imply that an in vitro characterization of probiotic strains before application is recommended.

Short-term action intentions overrule long-term semantic knowledge.

In the present study, we investigated whether the preparation of an unusual action with an object (e.g. bringing a cup towards the eye) could selectively overrule long-term semantic representations. In the first experiment it was found that unusual action intentions activated short-term semantic goal representations, rather than long-term conceptual associations. In a second experiment the reversal of long-term priming effects was replicated, while reducing the need for internal verbalization as a possible strategy to accomplish the task. Priming effects in the first two experiments were found to involve the selection of object knowledge at a semantic level, rather than reflecting a general effect of action preparation on word processing (Experiment 3). Finally, in a fourth experiment short-term priming effects were shown to extend beyond a lexical level by showing faster responses to pictures representing the short-term action goal. Together, the present findings extend the 'selection-for-action' principle previously used in visual attention to a semantic level, by showing that semantic information is selectively activated in line with the short-term goal of the actor.

You'll never crawl alone: neurophysiological evidence for experience-dependent motor resonance in infancy.

Lately, neuroscience is showing a great interest in examining the functional and neural mechanisms which support action observation and understanding. Recent studies have suggested that our motor skills crucially affect the way in which we perceive the actions generated by others, by showing stronger motor resonance for observation of actions that are established in one's motor repertoire. In the present study we extend previous findings that were based on expert motor skills in adults to the natural development of actions in infants. To investigate the effect of natural motor experience on motor resonance during action observation, 14- to 16-month-old infants' EEG was recorded during observation of action videos. Stronger mu- and beta-desynchronizations were found for observation of crawling compared to walking videos and the size of the effect was strongly related to the infant's own crawling experience. This suggests that already early in life one's own action experience is closely related to how actions of others are perceived.

Conceptual knowledge for understanding other's actions is organized primarily around action goals.

Semantic knowledge about objects entails both knowing how to grasp an object (grip-related knowledge) and what to do with an object (goal-related knowledge). Considerable evidence suggests a hierarchical organization in which specific hand-grips in action execution are most often selected to accomplish a remote action goal. The present study aimed to investigate whether a comparable hierarchical organization of semantic knowledge applies to the recognition of other's object-directed actions as well. Correctness of either the Grip (hand grip applied to the object) or the Goal (end-location at which an object was directed) were manipulated independently in two experiments. In Experiment 1, subjects were required to attend selectively to either the correctness of the grip or the goal of the observed action. Subjects were faster when attending to the goal of the action and a strong interference of goal-violations was observed when subjects attended to the grip of the action. Importantly, observation of irrelevant goal- or grip-related violations interfered with making decisions about the correctness of the relevant dimension only when the relevant dimension was correct. In contrast, in Experiment 2, when subjects attended to an action-irrelevant stimulus dimension (i.e. orientation of the object), no interference of goal- or grip-related violations was found, ruling out the possibility that interference-effects result from perceptual differences between stimuli. These findings suggest that understanding the correctness of an action selectively recruits specialized, but interacting networks, processing the correctness of goal- and grip-specific information during action observation.

Semantics in action: an electrophysiological study on the use of semantic knowledge for action.

Recent studies have supported close interactions between language and action-related processes, suggesting comparable neural mechanisms. However, relatively little is known about the semantics involved in action planning. The present study investigated the activation of semantic knowledge in meaningful actions by recording event-related potentials (ERPs). Subjects prepared meaningful or meaningless actions with objects and made a semantic categorization response before executing the action. Words presented could be either congruent or incongruent with respect to the goal of the action. Preparation of meaningful actions elicited a larger anterior N400 for words incongruent to the present action goal as compared to congruent words, while no N400 effect was found when subjects prepared meaningless actions. These findings indicate that the preparation of meaningful actions with objects is accompanied by the activation of semantic information representing the usual action goals associated with those objects.