Ellen Binder

Sequential requirement of Sox4 and Sox11 during development of the sympathetic nervous system

The highly related transcription factors Sox4 and Sox11 are expressed in the developing sympathetic nervous system. In the mouse, Sox11 appears first, whereas Sox4 is prevalent later. Using mouse mutagenesis and overexpression strategies in chicken, we studied the role of both SoxC proteins in this tissue. Neither Sox4 nor Sox11 predominantly functioned by promoting pan-neuronal or noradrenergic differentiation of sympathetic neurons as might have been expected from studies in neuronal precursors of the central nervous system. The transcriptional network that regulates the differentiation of sympathetic neurons remained intact and expression of noradrenergic markers showed only minor alterations. Instead, Sox11 was required in early sympathetic ganglia for proliferation of tyrosine hydroxylase-expressing cells, whereas Sox4 ensured the survival of these cells at later stages. In the absence of both Sox4 and Sox11, sympathetic ganglia remained hypoplastic throughout embryogenesis because of consecutive proliferation and survival defects. As a consequence, sympathetic ganglia were rudimentary in the adult and sympathetic innervation of target tissues was impaired leading to severe dysautonomia.

Peripheral Nervous System Progenitors Can Be Reprogrammed to Produce Myelinating Oligodendrocytes and Repair Brain Lesions

Neural crest stem cells (NCSCs) give rise to the neurons and glia of the peripheral nervous system (PNS). NCSC-like cells can be isolated from multiple peripheral organs and maintained in neurosphere culture. Combining in vitro culture and transplantation, we show that expanded embryonic NCSC-like cells lose PNS traits and are reprogrammed to generate CNS cell types. When transplanted into the embryonic or adult mouse CNS, they differentiate predominantly into cells of the oligodendrocyte lineage without any signs of tumor formation. NCSC-derived oligodendrocytes generate CNS myelin and contribute to the repair of the myelin deficiency in shiverer mice. These results demonstrate a reprogramming of PNS progenitors to CNS fates without genetic modification and imply that PNS cells could be a potential source for cell-based CNS therapy.

In vivo role for CREB signaling in the noradrenergic differentiation of sympathetic neurons.

Signaling pathways involving cAMP and CREB have been implicated in several aspects of sympathetic neuron differentiation. Here, we used in vivo loss-of-function approaches in both mouse and chick embryos to characterize the physiological role of cAMP/CREB. Whereas sympathetic neuron development proceeds normally in CREB-deficient mouse embryos, a decrease in noradrenergic differentiation (TH, DBH) was observed in chick sympathetic ganglia in response to ACREB, a dominant-negative CREB variant which interferes with the function of all CREB family members. In contrast, expression of the generic neuronal marker SCG10 was not affected by ACREB. As the decrease in noradrenergic gene expression is compensated at later stages of development and TH expression in differentiated neurons is not CREB-dependent, a transient role for CREB is proposed, accelerating noradrenergic but not generic neuronal differentiation of sympathetic neurons.

Sensory-guided motor tasks benefit from mental training based on serial prediction

Mental strategies have been suggested to constitute a promising approach to improve motor abilities in both healthy subjects and patients. This behavioural effect has been shown to be associated with changes of neural activity in premotor areas, not only during movement execution, but also while performing motor imagery or action observation. However, how well such mental tasks are performed is often difficult to assess, especially in patients. We here used a novel mental training paradigm based on the serial prediction task (SPT) in order to activate premotor circuits in the absence of a motor task. We then tested whether this intervention improves motor-related performance such as sensorimotor transformation. Two groups of healthy young participants underwent a single-blinded five-day cognitive training schedule and were tested in four different motor tests on the day before and after training. One group (N=22) received the SPT-training and the other one (N=21) received a control training based on a serial match-to-sample task. The results revealed significant improvements of the SPT-group in a sensorimotor timing task, i.e. synchronization of finger tapping to a visually presented rhythm, as well as improved visuomotor coordination in a sensory-guided pointing task compared to the group that received the control training. However, mental training did not show transfer effects on motor abilities in healthy subjects beyond the trained modalities as evident by non-significant changes in the Jebsen-Taylor handfunctiontest. In summary, the data suggest that mental training based on the serial prediction task effectively engages sensorimotor circuits and thereby improves motor behaviour.

Using multi-level Bayesian lesion-symptom mapping to probe the body-part-specificity of gesture imitation skills

Abstract Past attempts to identify the neural substrates of hand and finger imitation skills in the left hemisphere of the brain have yielded inconsistent results. Here, we analyse those associations in a large sample of 257 left hemisphere stroke patients. By introducing novel Bayesian methods, we characterise lesion symptom associations at three levels: the voxel‐level, the single‐region level (using anatomically defined regions), and the region‐pair level. The results are inconsistent across those three levels and we argue that each level of analysis makes assumptions which constrain the results it can produce. Regardless of the inconsistencies across levels, and contrary to past studies which implicated differential neural substrates for hand and finger imitation, we find no consistent voxels or regions, where damage affects one imitation skill and not the other, at any of the three analysis levels. Our novel Bayesian approach indicates that any apparent differences appear to be driven by an increased sensitivity of hand imitation skills to lesions that also impair finger imitation. In our analyses, the results of the highest level of analysis (region‐pairs) emphasise a role of the primary somatosensory and motor cortices, and the occipital lobe in imitation. We argue that this emphasis supports an account of both imitation tasks based on direct sensor‐motor connections, which throws doubt on past accounts which imply the need for an intermediate (e.g. body‐part‐coding) system of representation. HighlightsNovel Bayesian lesion‐symptom analyses are proposed.Different levels of analysis emphasise different lesion sites for gesture imitation deficits.All levels argue against the body‐part‐specificity of gesture imitation skills.A direct sensor‐to‐motor pathway model of gesture imitation is supported.

Deep brain stimulation in rapidly progressive parkinson-dystonia syndrome due to mitochondrial disorder

Although Parkinson’s disease (PD) and dystonia can effectively be treated with drug therapy and deep brain stimulation (DBS), effective treatment for movement disorders in mitochondrial disorders are rare. In PD as drug therapy becomes less effective motor deficits such as tremor, rigidity and bradykinesia can effectively be treated with DBS at targets points like the subthalamic nucleus (STN) and the globus pallidus internus (GPI); in dystonia DBS in the GPI has been employed in both primary and secondary forms of dystonia. In this reportwedescribe apatientwith amitochondrial disorder (MD), who was treated with palliative GPI-DBS and later with bilateral DBS in the nucleus ventralis oralis anterior thalami (VOA)which resulted in reduced pain and rigidity. In this report we discuss the efficiency of DBS of two target points (GPI, VOA) in MD.

Reduced awareness for apraxic deficits in left hemisphere stroke.

Objective: Reduced awareness for motor or cognitive impairments has mainly been studied in relation to right-hemispheric deficits such as left-sided hemiparesis. However, recent studies suggest that also left hemisphere (LH) stroke can lead to reduced awareness for neurological/neuropsychological deficits, for example, aphasia. The aim of the current study was to characterize reduced awareness for apraxic as well as aphasic deficits in patients suffering from LH stroke. Method: After the assessment of apraxia and aphasia, patients (n = 32) were asked to rate their performance on a 1- to 5-point rating scale. An unawareness score (UAS) was computed as the difference between the examiners’ ratings and self-ratings, resulting in negative scores for patients who overestimated their performance in a given assessment, that is, exhibited reduced awareness for their stroke-related deficits. Results: Patients with apraxia (n = 14) and aphasia (n = 16) significantly overestimated their performance in the respective assessment. However, the level of awareness was not generally related to the severity of apraxia, and there were no group differences in other variables between patients with full (n = 7) and reduced awareness (n = 7) for apraxic deficits. The reduction of awareness for apraxic deficits did not differ significantly for buccofacial versus limb gestures. Conclusion: Data show that LH stroke can lead to reduced awareness not only for aphasic deficits but also for buccofacial and limb apraxia.

Action and semantic tool knowledge - Effective connectivity in the underlying neural networks

Evidence from neuropsychological and imaging studies indicate that action and semantic knowledge about tools draw upon distinct neural substrates, but little is known about the underlying interregional effective connectivity. With fMRI and dynamic causal modeling (DCM) we investigated effective connectivity in the left‐hemisphere (LH) while subjects performed (i) a function knowledge and (ii) a value knowledge task, both addressing semantic tool knowledge, and (iii) a manipulation (action) knowledge task. Overall, the results indicate crosstalk between action nodes and semantic nodes. Interestingly, effective connectivity was weakened between semantic nodes and action nodes during the manipulation task. Furthermore, pronounced modulations of effective connectivity within the fronto‐parietal action system of the LH (comprising lateral occipito‐temporal cortex, intraparietal sulcus, supramarginal gyrus, inferior frontal gyrus) were observed in a bidirectional manner during the processing of action knowledge. In contrast, the function and value knowledge tasks resulted in a significant strengthening of the effective connectivity between visual cortex and fusiform gyrus. Importantly, this modulation was present in both semantic tasks, indicating that processing different aspects of semantic knowledge about tools evokes similar effective connectivity patterns. Data revealed that interregional effective connectivity during the processing of tool knowledge occurred in a bidirectional manner with a weakening of connectivity between areas engaged in action and semantic knowledge about tools during the processing of action knowledge. Moreover, different semantic tool knowledge tasks elicited similar effective connectivity patterns.

Association of grey matter changes with stability and flexibility of prediction in akinetic-rigid Parkinson’s disease

Parkinson’s disease (PD), which is caused by degeneration of dopaminergic neurons in the midbrain, results in a heterogeneous clinical picture including cognitive decline. Since the phasic signal of dopamine neurons is proposed to guide learning by signifying mismatches between subjects’ expectations and external events, we here investigated whether akinetic-rigid PD patients without mild cognitive impairment exhibit difficulties in dealing with either relevant (requiring flexibility) or irrelevant (requiring stability) prediction errors. Following our previous study on flexibility and stability in prediction (Trempler et al. J Cogn Neurosci 29(2):298–309, 2017), we then assessed whether deficits would correspond with specific structural alterations in dopaminergic regions as well as in inferior frontal cortex, medial prefrontal cortex, and the hippocampus. Twenty-one healthy controls and twenty-one akinetic-rigid PD patients on and off medication performed a task which required to serially predict upcoming items. Switches between predictable sequences had to be indicated via button press, whereas sequence omissions had to be ignored. Independent of the disease, midbrain volume was related to a general response bias to unexpected events, whereas right putamen volume correlated with the ability to discriminate between relevant and irrelevant prediction errors. However, patients compared with healthy participants showed deficits in stabilisation against irrelevant prediction errors, associated with thickness of right inferior frontal gyrus and left medial prefrontal cortex. Flexible updating due to relevant prediction errors was also affected in patients compared with controls and associated with right hippocampus volume. Dopaminergic medication influenced behavioural performance across, but not within the patients. Our exploratory study warrants further research on deficient prediction error processing and its structural correlates as a core of cognitive symptoms occurring already in early stages of the disease.