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No description available.

Spike timing-dependent plasticity (STDP) has been suggested as one of the key mechanism underlying learning and memory. Due to its importance, timing-dependent plasticity studies have been approached in the living human brain by means of non-invasive brain stimulation (NIBS) protocols such as paired associative stimulation (PAS). However, contrary to STDP studies at a cellular level, functional plasticity induction in the human brain implies the interaction among target cortical networks and investigates plasticity mechanisms at a systems level. This thesis comprises of two independent studies that aim at understanding the importance of considering broad cortical networks when predicting the outcome of timing-dependent associative plasticity induction in the human brain. In the first study we developed a new protocol (ipsilateral PAS (ipsiPAS)) that required timing- and regional-specific information transfer across hemispheres for the induction of timing-dependent plasticity within M1 (see chapter 3). In the second study, we tested the influence of individual brain structure, as measured with voxel-based cortical thickness, on a standard PAS protocol (see chapter 4). In summary, we observed that the near-synchronous associativity taking place within M1 is not the only determinant influencing the outcome of PAS protocols. Rather, the online interaction of the cortical networks integrating information during a PAS intervention determines the outcome of the pairing of inputs in M1.

Existing neurocomputational and empirical data link deficient neuromodulation of the fronto-parietal and hippocampal-striatal circuitries with aging-related increase in processing noise and declines in various cognitive functions. Specifically, the theory of aging neuronal gain control postulates that aging-related suboptimal neuromodulation may attenuate neuronal gain control, which yields computational consequences on reducing the signal-to-noise-ratio of synaptic signal transmission and hampering information processing within and between cortical networks. Intervention methods such as cognitive training and non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been considered as means to buffer cognitive functions or delay cognitive decline in old age. However, to date the reported effect sizes of immediate training gains and maintenance effects of a variety of cognitive trainings are small to moderate at best; moreover, training-related transfer effects to non-trained but closely related (i.e., near-transfer) or other (i.e., far-transfer) cognitive functions are inconsistent or lacking. Similarly, although applying different tDCS protocols to reduce aging-related cognitive impairments by inducing temporary changes in cortical excitability seem somewhat promising, evidence of effects on short- and long-term plasticity is still equivocal. In this article, we will review and critically discuss existing findings of cognitive training- and stimulation-related behavioral and neural plasticity effects in the context of cognitive aging, focusing specifically on working memory and episodic memory functions, which are subserved by the fronto-parietal and hippocampal-striatal networks, respectively. Furthermore, in line with the theory of aging neuronal gain control we will highlight that developing age-specific brain stimulation protocols and the concurrent applications of tDCS during cognitive training may potentially facilitate short- and long-term cognitive and brain plasticity in old age.

Existing neurocomputational and empirical data link deficient neuromodulation of the fronto-parietal and hippocampal-striatal circuitries with aging-related increase in processing noise and declines in various cognitive functions. Specifically, the theory of aging neuronal gain control postulates that aging-related suboptimal neuromodulation may attenuate neuronal gain control, which yields computational consequences on reducing the signal-to-noise-ratio of synaptic signal transmission and hampering information processing within and between cortical networks. Intervention methods such as cognitive training and non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been considered as means to buffer cognitive functions or delay cognitive decline in old age. However, to date the reported effect sizes of immediate training gains and maintenance effects of a variety of cognitive trainings are small to moderate at best; moreover, training-related transfer effects to non-trained but closely related (i.e., near-transfer) or other (i.e., far-transfer) cognitive functions are inconsistent or lacking. Similarly, although applying different tDCS protocols to reduce aging-related cognitive impairments by inducing temporary changes in cortical excitability seem somewhat promising, evidence of effects on short- and long-term plasticity is still equivocal. In this article, we will review and critically discuss existing findings of cognitive training- and stimulation-related behavioral and neural plasticity effects in the context of cognitive aging, focusing specifically on working memory and episodic memory functions, which are subserved by the fronto-parietal and hippocampal-striatal networks, respectively. Furthermore, in line with the theory of aging neuronal gain control we will highlight that developing age-specific brain stimulation protocols and the concurrent applications of tDCS during cognitive training may potentially facilitate short- and long-term cognitive and brain plasticity in old age.

Bisherige Studien liefern Hinweise für das Auftreten von aktiven Prozessen der Reihenfolgekoordination in Doppelaufgaben. Diese Prozesse sind notwendig für die Regulation der Bearbeitungsreihenfolge von zwei Aufgaben. Bisher ist jedoch wenig über die kognitiven und neuronalen Mechanismen bekannt, die diesen Prozessen zugrunde liegen. Ziel der vorliegenden Dissertation war deshalb die Überprüfung eines Modells aktiver Reihenfolgekoordination in Doppelaufgaben. Das Modell nimmt an, dass diese Prozesse auf Repräsentationen zurückgreifen, die Informationen über die Verarbeitungssequenz zweier Aufgaben enthält. Zusätzlich macht das Modell Annahmen über (1) den Ort der Verarbeitung und (2) den genauen Inhalt dieser Repräsentationen. Weiterhin enthält das Modell die Annahmen, dass (3) der präfrontale Kortex kausal in Reihenfolgekoordination involviert ist und dass (4) diese Prozesse von unterschiedlichen Kriterien beeinflusst werden. In dieser Dissertation wurde das Model in einer Reihe von vier Studien überprüft. Dazu wurde ein Doppelaufgabenparadigma mit zufällig wechselnder Aufgabenreihenfolge verwendet. Ich konnte zeigen, dass die Reihenfolgerepräsentationen im Arbeitsgedächtnis aufrechterhalten und aktiv verarbeitet werden. Ich konnte weiterhin zeigen, dass diese Repräsentationen nur Information über die Sequenz der Aufgaben enthalten. Spezifische Aufgabeninformation wird hingegen separat repräsentiert. Durch den Einsatz transkranieller Magnetstimulation konnte ich zudem nachweisen, dass der präfrontale Kortex eine kausale Rolle für Reihenfolgekoordination spielt. Darüber hinaus konnte ich zeigen, dass Anforderungen an Reihenfolgekoordinationsprozesse in Situationen, in denen Probanden ein von außen vorgegebenes Reihenfolgekriterium befolgen, erhöht sind im Vergleich zu Situationen, in denen Probanden ein auf einer freien Wahl basierendes Kriterium nutzen können. Die Implikationen dieser Ergebnisse werden unter Berücksichtigung des vorgeschlagenen Modells diskutiert. / Evidence from behavioral as well as neurophysiological studies indicates the occurrence of active task-order coordination processes in dual-task situations. These processes are required for planning and regulating the processing sequence of two tasks that overlap in time. So far, however, the cognitive and neural mechanisms underlying active task-order coordination are highly underspecified. To tackle this issue, in the present dissertation I tested a model of task-order coordination in dual-task situations. This model assumes that task-order coordination relies on representations that contain information about the processing sequence of the two component tasks. In addition, the model includes assumptions about the (1) locus of processing as well as (2) the exact content of these order representations. The model further assumes that (3) the lateral prefrontal cortex is causally involved in implementing task-order coordination processes and that (4) these processes are affected by different order criteria. I tested this model in a series of four studies by applying a dual-task paradigm with randomly changing task order. I demonstrated that task-order representations are actively maintained and processed in working memory during dual tasking. Moreover, I found that these order representations only contain information about the processing sequence of tasks, whereas specific component task information is represented separately. By applying transcranial magnetic stimulation, I also provided evidence for the causal role of the lateral prefrontal cortex for task-order coordination. Furthermore, I showed that the demands on task-order coordination are increased when participants have to adhere to an external and mandatory order criterion compared to when they can use an internally generated order criterion that is based on free choice. The implications of these results as well as an outlook for future research will be discussed in the framework of the proposed model.

Die transkranielle Magnetstimulation (TMS) ist ein nichtinvasives Hirnstimulationsverfahren, mit welchem sowohl die funktionelle Untersuchung umschriebener kortikaler Regionen als auch die Modulation der Erregbarkeit ebendieser sowie die Induktion neuroplastischer Phänomene möglich ist. Sie wurde in der Vergangenheit insbesondere bei der Erforschung des humanen zentralmotorischen Systems angewandt. Dabei zeigte sich, dass ein einzelner über dem primärmotorischen Areal (M1) applizierter TMS-Puls multiple deszendierende Erregungswellen im Kortikospinaltrakt induzieren kann. Von diesen Undulationen besitzt die D-Welle (direkte Welle) die kürzeste Latenz und sie rekurriert auf eine direkte Aktivierung kortikospinaler Neurone, wohingegen I-Wellen (indirekte Wellen) längere Latenzen besitzen und durch transsynaptische Aktivierung dieser Zellen entstehen. Bemerkenswert ist das periodische Auftreten der letztgenannten Erregungswellen mit einer Periodendauer von etwa 1,5 ms. Zwar sind die genauen Mechanismen noch unbekannt, welche der Entstehung dieser I-Wellen sowie dem Phänomen der I-Wellen-Fazilitierung, das sich in geeigneten TMS-Doppelpulsprotokollen offenbart, zugrunde liegen, jedoch existieren hierzu verschiedene Erklärungsmodelle. Im Mittelpunkt der vorliegenden Arbeit steht die repetitive Anwendung eines TMS-Doppelpulsprotokolls, bei dem das Interpulsintervall (IPI) im Bereich der I-Wellen-Periodizität liegt (iTMS) und das gleichsam durch eine Implementierung der I-Wellen-Fazilitierung in der repetitiven TMS charakterisiert ist. Da gezeigt werden konnte, dass iTMS mit einem IPI von 1,5 ms (iTMS_1,5ms) die kortikospinale Erregbarkeit signifikant intra- und postinterventionell zu steigern vermag, und die I-Wellen-Periodizität interindividuellen Schwankungen unterliegt, wurde in der hier vorgestellten Studie an Normalprobanden der Einfluss einer individuellen Anpassung des IPIs (resultierend in der iTMS_adj) auf die intrainterventionelle kortikospinale Erregbarkeit untersucht. In der Tat stellte sich heraus, dass die iTMS_adj der iTMS_1,5ms diesbezüglich überlegen ist. Dieses Ergebnis unterstreicht das Potential einer Individualisierung der interventionellen TMS für erregbarkeitsmodulierende Effekte und macht dasjenige der ohnehin auf physiologische Prozesse abgestimmten iTMS explizit, was insbesondere für klinische Anwendungen relevant sein mag.

Spike timing-dependent plasticity (STDP) has been suggested as one of the key mechanism underlying learning and memory. Due to its importance, timing-dependent plasticity studies have been approached in the living human brain by means of non-invasive brain stimulation (NIBS) protocols such as paired associative stimulation (PAS). However, contrary to STDP studies at a cellular level, functional plasticity induction in the human brain implies the interaction among target cortical networks and investigates plasticity mechanisms at a systems level. This thesis comprises of two independent studies that aim at understanding the importance of considering broad cortical networks when predicting the outcome of timing-dependent associative plasticity induction in the human brain. In the first study we developed a new protocol (ipsilateral PAS (ipsiPAS)) that required timing- and regional-specific information transfer across hemispheres for the induction of timing-dependent plasticity within M1 (see chapter 3). In the second study, we tested the influence of individual brain structure, as measured with voxel-based cortical thickness, on a standard PAS protocol (see chapter 4). In summary, we observed that the near-synchronous associativity taking place within M1 is not the only determinant influencing the outcome of PAS protocols. Rather, the online interaction of the cortical networks integrating information during a PAS intervention determines the outcome of the pairing of inputs in M1.