Associative Vocabulary Learning: Development and Testing of Two Paradigms for the (Re-) Acquisition of Action- and Object-Related Words

Despite a growing number of studies, the neurophysiology of adult vocabulary acquisition is still poorly understood. One reason is that paradigms that can easily be combined with neuroscientfic methods are rare. Here, we tested the efficiency of two paradigms for vocabulary (re-) acquisition, and compared the learning of novel words for actions and objects. Cortical networks involved in adult native-language word processing are widespread, with differences postulated between words for objects and actions. Words and what they stand for are supposed to be grounded in perceptual and sensorimotor brain circuits depending on their meaning. If there are specific brain representations for different word categories, we hypothesized behavioural differences in the learning of action-related and object-related words. Paradigm A, with the learning of novel words for body-related actions spread out over a number of days, revealed fast learning of these new action words, and stable retention up to 4 weeks after training. The single-session Paradigm B employed objects and actions. Performance during acquisition did not differ between action-related and object-related words (time*word category: p = 0.01), but the translation rate was clearly better for object-related (79%) than for action-related words (53%, p = 0.002). Both paradigms yielded robust associative learning of novel action-related words, as previously demonstrated for object-related words. Translation success differed for action- and object-related words, which may indicate different neural mechanisms. The paradigms tested here are well suited to investigate such differences with neuroscientific means. Given the stable retention and minimal requirements for conscious effort, these learning paradigms are promising for vocabulary re-learning in brain-lesioned people. In combination with neuroimaging, neuro-stimulation or pharmacological intervention, they may well advance the understanding of language learning to optimize therapeutic strategies

Die dopaminerge Beeinflussung der adulten Neurogenese: In vivo Untersuchungen im MPTP-Modell bei nicht-humanen Primaten

Auch im Gehirn adulter Säugetiere findet bis ins hohe Lebensalter die Bildung neuer Nervenzelle statt. Dieser Vorgang wird als adulte Neurogenese bezeichnet und beschränkt sich auf zwei Regionen, der Subventrikulären Zone (SVZ) und der Subgranulären Zone (SGZ) im Hippocampus. Um die jungen Zellen zukünftig eventuell für Reparaturvorgänge im pathologisch veränderten Gehirn nutzen zu können, müssen die physiologischen und pathophysiologischen endogenen Regulationsmechanismen bekannt sein. In dieser Arbeit sollte der Einfluss des Neurotransmitters Dopamin auf die subventrikuläre Neurogenese erforscht werden, indem Ursprung und Funktion der dopaminergen Innervation der SVZ bei nicht-menschlichen Primaten untersucht wurden. Durch Tracing Studien in drei Makaken konnte eine topographisch organisierte Innervation aus dem pars compacta der Substantia nigra, aber nicht aus dem angrenzenden retrorubralen Feld, in die SVZ dargestellt werden. Immunfärbungen gegen Tyrosin-Hydroxlase und 5-Bromo-2´-Deoxyuridin zeigten eine enge räumliche Nähe zwischen dopaminergen Fasern und proliferierenden subventrikulären Zellen. Im Folgenden sollten die pathophysiologischen Vorgänge bei der Parkinson Krankheit, die hauptsächlich bei über 60-Jährigen auftritt und durch eine Degeneration der dopaminergen nigralen Neurone gekennzeichnet ist, möglichst exakt simuliert werden. Die nigrale dopaminerge Innervation wurde bei drei mindestens 20 Jahren alten Makaken durch eine Behandlung mit 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridin zu einem großen Teil zerstört. Im Vergleich zu drei gleichaltrigen Kontrolltieren zeigte sich eine Abnahme von PCNA (proliferating cell nuclear antigen)-positiven proliferierenden Zellen um 44% sowie von PSA-NCAM (polysialylated neural cell adhesion molecule)-positiven Neuroblasten um 59% in der denervierten SVZ. Weiterhin konnten intraindividuell Unterschiede zwischen stark und schwach denervierten Teilen der SVZ nachgewiesen werden. Beide Ergebnisse weisen darauf hin, dass eine intakte nigro-subventrikuläre Innervation für das Aufrechterhalten der subventrikulären Neurogenese beim alten Individuum unerlässlich ist. Der hier erfolge Nachweis der Existenz einer dopaminerg kontrollierten Neurogenese in der SVZ adulter Primaten eröffnet die Perspektive, dieses System eventuell für die endogene Reparatur des zentralen Nervensystems bei neurodegenerativen Krankheiten nutzbar zu machen

tDCS Over the Motor Cortex Shows Differential Effects on Action and Object Words in Associative Word Learning in Healthy Aging

Healthy aging is accompanied by a continuous decline in cognitive functions. For example, the ability to learn languages decreases with age, while the neurobiological underpinnings for the decline in learning abilities are not known exactly. Transcranial direct current stimulation (tDCS), in combination with appropriate experimental paradigms, is a well-established technique to investigate the mechanisms of learning. Based on previous results in young adults, we tested the suitability of an associative learning paradigm for the acquisition of action- and object-related words in a cohort of older participants. We applied tDCS to the motor cortex (MC) and hypothesized an involvement of the MC in learning action-related words. To test this, a cohort of 18 healthy, older participants (mean age 71) engaged in a computer-assisted associative word-learning paradigm, while tDCS stimulation (anodal, cathodal, sham) was applied to the left MC. Participants’ task performance was quantified in a randomized, cross-over experimental design. Participants successfully learned novel words, correctly translating 39.22% of the words after 1 h of training under sham stimulation. Task performance correlated with scores for declarative verbal learning and logical reasoning. Overall, tDCS did not influence associative word learning, but a specific influence was observed of cathodal tDCS on learning of action-related words during the NMDA-dependent stimulation period. Successful learning of a novel lexicon with associative learning in older participants can only be achieved when the learning procedure is changed in several aspects, relative to young subjects. Learning success showed large inter-individual variance which was dependent on non-linguistic as well as linguistic cognitive functions. Intriguingly, cathodal tDCS influenced the acquisition of action-related words in the NMDA-dependent stimulation period. However, the effect was not specific for the associative learning principle, suggesting more neurobiological fragility of learning in healthy aging compared with young persons

Die dopaminerge Beeinflussung der adulten Neurogenese: In vivo Untersuchungen im MPTP-Modell bei nicht-humanen Primaten

Auch im Gehirn adulter Säugetiere findet bis ins hohe Lebensalter die Bildung neuer Nervenzelle statt. Dieser Vorgang wird als adulte Neurogenese bezeichnet und beschränkt sich auf zwei Regionen, der Subventrikulären Zone (SVZ) und der Subgranulären Zone (SGZ) im Hippocampus. Um die jungen Zellen zukünftig eventuell für Reparaturvorgänge im pathologisch veränderten Gehirn nutzen zu können, müssen die physiologischen und pathophysiologischen endogenen Regulationsmechanismen bekannt sein. In dieser Arbeit sollte der Einfluss des Neurotransmitters Dopamin auf die subventrikuläre Neurogenese erforscht werden, indem Ursprung und Funktion der dopaminergen Innervation der SVZ bei nicht-menschlichen Primaten untersucht wurden. Durch Tracing Studien in drei Makaken konnte eine topographisch organisierte Innervation aus dem pars compacta der Substantia nigra, aber nicht aus dem angrenzenden retrorubralen Feld, in die SVZ dargestellt werden. Immunfärbungen gegen Tyrosin-Hydroxlase und 5-Bromo-2´-Deoxyuridin zeigten eine enge räumliche Nähe zwischen dopaminergen Fasern und proliferierenden subventrikulären Zellen. Im Folgenden sollten die pathophysiologischen Vorgänge bei der Parkinson Krankheit, die hauptsächlich bei über 60-Jährigen auftritt und durch eine Degeneration der dopaminergen nigralen Neurone gekennzeichnet ist, möglichst exakt simuliert werden. Die nigrale dopaminerge Innervation wurde bei drei mindestens 20 Jahren alten Makaken durch eine Behandlung mit 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridin zu einem großen Teil zerstört. Im Vergleich zu drei gleichaltrigen Kontrolltieren zeigte sich eine Abnahme von PCNA (proliferating cell nuclear antigen)-positiven proliferierenden Zellen um 44% sowie von PSA-NCAM (polysialylated neural cell adhesion molecule)-positiven Neuroblasten um 59% in der denervierten SVZ. Weiterhin konnten intraindividuell Unterschiede zwischen stark und schwach denervierten Teilen der SVZ nachgewiesen werden. Beide Ergebnisse weisen darauf hin, dass eine intakte nigro-subventrikuläre Innervation für das Aufrechterhalten der subventrikulären Neurogenese beim alten Individuum unerlässlich ist. Der hier erfolge Nachweis der Existenz einer dopaminerg kontrollierten Neurogenese in der SVZ adulter Primaten eröffnet die Perspektive, dieses System eventuell für die endogene Reparatur des zentralen Nervensystems bei neurodegenerativen Krankheiten nutzbar zu machen

Diesterified Derivatives of 5-Iodo-2′-Deoxyuridine as Cerebral Tumor Tracers

With the aim to develop beneficial tracers for cerebral tumors, we tested two novel 5-iodo-2′-deoxyuridine (IUdR) derivatives, diesterified at the deoxyribose residue. The substances were designed to enhance the uptake into brain tumor tissue and to prolong the availability in the organism. We synthesized carrier added 5-[125I]iodo-3′,5′-di-O-acetyl-2′-deoxyuridine (Ac2[125I]IUdR), 5-[125I]iodo-3′,5′-di-O-pivaloyl-2′-deoxyuridine (Piv2[125I]IUdR) and their respective precursor molecules for the first time. HPLC was used for purification and to determine the specific activities. The iodonucleoside tracer were tested for their stability against human thymidine phosphorylase. DNA integration of each tracer was determined in 2 glioma cell lines (Gl261, CRL2397) and in PC12 cells in vitro. In mice, we measured the relative biodistribution and the tracer uptake in grafted brain tumors. Ac2[125I]IUdR, Piv2[125I]IUdR and [125I]IUdR (control) were prepared with labeling yields of 31–47% and radiochemical purities of >99% (HPLC). Both diesterified iodonucleoside tracers showed a nearly 100% resistance against degradation by thymidine phosphorylase. Ac2[125I]IUdR and Piv2[125I]IUdR were specifically integrated into the DNA of all tested tumor cell lines but to a less extend than the control [125I]IUdR. In mice, 24 h after i.p. injection, brain radioactivity uptakes were in the following order Piv2[125I]IUdR>Ac2[125I]IUdR>[125I]IUdR. For Ac2[125I]IUdR we detected lower amounts of radioactivities in the thyroid and stomach, suggesting a higher stability toward deiodination. In mice bearing unilateral graft-induced brain tumors, the uptake ratios of tumor-bearing to healthy hemisphere were 51, 68 and 6 for [125I]IUdR, Ac2[125I]IUdR and Piv2[125I]IUdR, respectively. Esterifications of both deoxyribosyl hydroxyl groups of the tumor tracer IUdR lead to advantageous properties regarding uptake into brain tumor tissue and metabolic stability

Differential effects of BDNF val(66)met in repetitive associative learning paradigms

In healthy young subjects, the brain derived neurotropic factor (BDNF) val(66)met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF-genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val(66)met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results

Differential effects of BDNF val(66)met in repetitive associative learning paradigms

In healthy young subjects, the brain derived neurotropic factor (BDNF) val(66)met polymorphism negatively affects behavioural outcome in short-term motor cortex or hippocampus-based learning paradigms. In repetitive training paradigms over several days this effect can be overcome, in tests involving other brain areas even positive effects were found. To further specify the role of this polymorphism in cognitive processes, we used an associative vocabulary learning paradigm over four consecutive days and tested 38 young healthy subjects and 29 healthy elderly subjects. As a control paradigm, we designed a nonverbal haptic Braille letter-learning paradigm based on the same principles. Behavioural outcome was then associated with the BDNF-genotype. In the vocabulary learning task, met carrier (met/val and met/met) benefitted more from the repetitive training than val/val subjects. This was paralleled by a higher reduction of delayed answers during the course of the study, an effect that was also present in the haptic paradigm. However, in a group of healthy elderly subjects, no similar tendency was found. We conclude that the BDNF val(66)met polymorphism alters highly circumscribed answer behaviours in young healthy subjects. This might partly explain the high variability of previously published results

Inverse autonomic stress reactivity in depressed patients with and without prior history of depression

Background: There is a considerable association between major depressive disorder (MDD) and cardiovascular disease, most possibly relying on abnormalities in the autonomic nervous system (ANS)-related cardiac reactivity, although the exact underlying pathophysiological pathway is unclear. This study tends to shed some additional light on this background by investigating ANS reactivity in MDD with respect to previous depression history through an objective stress challenge paradigm. Methods: The study assessed the effects of an overnight hypothalamus-pituitary-adrenal (HPA) axis stimulation with metyrapone (MET) on baseline ANS activity through linear and non-linear heart rate variability (HRV) measures in the morning of two continuous days in a group of 14 physically healthy, antidepressant-free patients with clinical, non-psychotic MDD, to investigate differences in autonomic reactivity with respect to prior MDD history. Results: The main findings of this study include statistically significant time × group interactions with respect to several HRV measures, suggesting substantial differences on autonomic reactivity between patients with and without depression history. Hereby, recurrent-episode MDD patients showed lower vagal activity, while first-episode MDD patients increased PNS activity after HPA axis stimulation. Conclusions: These findings indicate that HPA axis stimulation in MDD patients leads to inverse vagal response according to MDD history. We suggest that chronic stress system overactivation, as found in MDD, might lead to a progressive inversion of the original stress response through HPA axis and ANS divergence over the course of a recurrent illness. HRV could, thus, represent a significant biomarker in MDD with temporal sensitivity