Marcus Heldmann

Background and Objectives: X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative movement disorder caused by a retrotransposon insertion with a polymorphic hexanucleotide repeat expansion in the TAF1 gene. While the disease predominantly affects males, female carriers may exhibit a variable phenotypic expression. Neurobiological alterations in asymptomatic female mutation carriers (fMC) remain largely unexplored. We aimed to investigate whether fMC exhibit neurodegenerative changes despite the absence of overt clinical manifestations and to assess their clinical, genetic, and longitudinal correlates using multimodal MRI. Methods: In this cross-sectional and longitudinal multimodal study, 103 female relatives of XDP patients underwent clinical, genetic, and MRI assessments. Forty-two were identified as fMC and 61 as healthy controls (HC). Structural T1-weighted MRI was analyzed using voxel-based morphometry and subcortical volumetry, while susceptibility-weighted imaging assessed iron deposition. Clinical evaluation included standardized motor and cognitive testing. Longitudinal follow-up MRI was available for a subset of participants (20 fMC, 13 HC). Results: fMC exhibited significant striatal atrophy compared to HC, with volume reductions in the caudate (-19.4%), putamen (-18.6%), and pallidum (-28.6%) (all p<0.001), despite the absence of overt movement disorders or cognitive deficits, accompanied by relative cerebellar hypertrophy. In fMC striatal volumes decreased with increasing age (putamen: rho=−0.382, p=0.012; caudate: rho=−0.631, p<0.001) and virtual time from genetically determined estimated age at onset (putamen: rho=−0.406, p=0.008; caudate: rho=−0.660, p<0.001). Susceptibility-weighted imaging revealed increased iron deposition in the caudate in fMC, which increased with greater local atrophy (rho=0.718, p<0.001). No significant longitudinal progression was detected over follow-up intervals of up to 25.5 months. Discussion: Asymptomatic female carriers of the XDP-associated TAF1 variant exhibit significant striatal neurodegeneration and iron accumulation, indicating a dominant-negative effect despite X-linked inheritance. Future longitudinal studies should focus on non-motor features and integrate genetic, imaging, and clinical markers to improve risk stratification and identify the subset of female carriers most likely to benefit from future disease-modifying therapies.

Zusammenfassung.Hintergrund: Besondere Schwierigkeiten im Rechtschreiben weisen ohne geeignete Intervention oftmals eine hohe Stabilität und langfristige Persistenz auf. Digitale Trainingsprogramme bieten vielfältige Übungsmöglichkeiten, wobei die Texteingabe in der Regel über Tastatur erfolgt. Studien verweisen auf die positive Rolle der Handschrift beim Orthografieerwerb. Im Rahmen eines vom BMBF geförderten Forschungsprojektes wurde daher ein Tablet-basiertes Rechtschreibtrainingsprogramm mit handschriftlicher Eingabemöglichkeit und direktem Feedback über die Wortkorrektheit entwickelt und angewendet. Methoden: Nach einer erfolgreichen Machbarkeitsstudie 2015/2016 im häuslichen Umfeld (n = 9, zweite bis fünfte Klasse) wurde das weiterentwickelte Programm in der Hauptstudie 2019/2020 mit rechtschreibschwachen Kindern (Prozentrang PR >≤ 16 im DERET) der dritten und vierten Jahrgangsstufe im schulischen sowie häuslichem Kontext eingesetzt (Covid19-bedingter Ortswechsel). Ergebnisse: Bei Kindern mit einer sehr niedrigen Rechtschreibausgangsleistung (Prozentrang >≤ 16) zeigte sich eine signifikante Verbesserung der Rechtschreibfertigkeiten in der Trainings- (n = 14) im Vergleich zur Kontrollgruppe (n = 27) – bei hoher Programmakzeptanz. Diskussion: Die Kombination von digitalem Medium und handschriftlicher Eingabemöglichkeit mit direktem Fehlschreibungs-Feedback ermöglicht rechtschreibschwachen Kindern eine effektive und gut in den schulischen bzw. häuslichen Alltag integrierbare Unterstützung beim Orthografieerwerb.

Background: X-Linked dystonia-parkinsonism (XDP) is a movement disorder characterized by the presence of both dystonia and parkinsonism with one or the other more prominent in the initial stages and later on manifesting with more parkinsonian features towards the latter part of the disease. XDP patients show oculomotor abnormalities indicating prefrontal and striatal impairment. This study investigated oculomotor behavior in non-manifesting mutation carriers (NMC). We hypothesized that oculomotor disorders occur before the appearance of dystonic or parkinsonian signs. This could help to functionally identify brain regions already affected in the prodromal stage of the disease. Methods: Twenty XDP patients, 13 NMC, and 28 healthy controls (HC) performed different oculomotor tasks typically affected in patients with parkinsonian signs. Results: The error rate for two types of volitional saccades, i.e., anti-saccades and memory-guided saccades, was increased not only in XDP patients but also in NMC compared to HC. However, the increase in error rates of both saccade types were highly correlated in XDP patients only. Hypometria of reflexive saccades was only found in XDP patients. Initial acceleration and maintenance velocity of smooth pursuit eye movements were only impaired in XDP patients. Conclusions: Despite being asymptomatic, NMC already showed some oculomotor deficits reflecting fronto-striatal impairments, typically found in XDP patients. However, NMC did not show saccade hypometria and impaired smooth pursuit as seen in advanced Parkinson’s disease and XDP, suggesting oculomotor state rather than trait signs in these mutation carriers. Neurodegeneration may commence in the striatum and prefrontal cortex, specifically the dorsolateral prefrontal cortex.

Precise control of movement and timing play a key role in musical performance. This motor skill requires coordination across multiple joints, muscles, and limbs, which is acquired through extensive musical training from childhood on. Thus, making music can be a strong driver for neuroplasticity. We here present the rare case of a professional french horn player with a congenital bilateral amelia of the upper limbs. We were able to show a unique cerebral and cerebellar somatotopic representation of his toe and feet, that do not follow the characteristic patterns of contralateral cortical and ipsilateral cerebellar layout. Although being a professional horn player who trained his embouchure muscles, including tongue, pharyngeal, and facial muscle usage excessively, there were no obvious signs for an expanded somatosensory representation in this part of the classic homunculus. Compared to the literature and in contrast to control subjects, the musicians foot movement-related activations occurred in cerebellar areas that are typically more related to hand than to foot activation.

In humans, food is considered a powerful primary reinforcer, whereas money is a secondary reinforcer, as it gains a value through learning experience. Here, we aimed to identify the neural regions supporting the processing of food-related reinforcers, relate it to the neural underpinnings of monetary reinforcers, and explore their modulation by metabolic state (hunger vs satiety). Twenty healthy male participants were tested in two experimental sessions, once hungry and once satiated, using functional magnetic resonance imaging. Participants performed an associative learning task, receiving food or monetary rewards (in the form of images) on separate blocks. Irrespective of incentive type, both food and monetary rewards engaged ventral striatum, medial orbitofrontal cortex and amygdala, regions that have been previously associated with reward processing. Food incentives additionally engaged the opercular part of the inferior frontal gyrus and the insula, collectively known as a primary gustatory cortex. Moreover, in response to negative feedback (here, reward omission), robust activation was observed in anterior insula, supplementary motor area and lateral parts of the prefrontal cortex, including middle and inferior frontal gyrus. Furthermore, the interaction between metabolic state and incentive type resulted in supramarginal gyrus (SMG) activity, among other motor and sensory-related regions. Finally, functional connectivity analysis showed correlation in the hungry state between the SMG and mesolimbic regions, including the hippocampus, midbrain and cingulate areas. Also, the interaction between metabolic state and incentive type revealed coupling between SMG and ventral striatum. Whereas general purpose reward-related regions process incentives of different kinds, the current results suggest that the SMG might play a key role in integrating the information related to current metabolic state and available incentive type.

Hypo‐ and hyperthyroidism have effects on brain structure and function, as well as cognitive processes, including memory. However, little is known about the influence of thyroid hormones on brain perfusion and the relationship of such perfusion changes with cognition. The present study aimed to demonstrate the effect of short‐term experimental hyperthyroidism on brain perfusion in healthy volunteers and to assess whether perfusion changes, if present, are related to cognitive performance. It is known that an interaction exists between brain perfusion and cerebral oxygen consumption rate and it is considered that neural activation increases cerebral regional perfusion rate in brain areas associated with memory. Measuring cerebral blood flow may therefore represent a proxy for neural activity. Therefore, arterial spin labelling (ASL) measurements were conducted and later analysed to evaluate brain perfusion in 29 healthy men before and after ingesting thyroid hormones for 8 weeks. Psychological tests concerning memory were performed at the same time‐points and the results were correlated with the imaging results. In the hyperthyroid condition, perfusion was increased in the posterior cerebellum in regions connected with cerebral networks associated with cognitive control and the visual cortex compared to the euthyroid condition. In addition, these perfusion changes were positively correlated with changes of performance in the German version of the Auditory Verbal Learning Task [AVLT, Verbaler Lern‐und‐Merkfähigkeits‐Test (VLMT)]. Cerebellar perfusion and function therefore appears to be modulated by thyroid hormones, likely because the cerebellum hosts a high number of thyroid hormone receptors.

Background: The generation of random sequences is considered to tax executive functions and has been reported to be impaired in Parkinson’s disease (PD) previously. Objective: To assess the neurophysiological markers of random number generation in P