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The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Objective: Research on visual working memory has shown that individual stimulus features are processed in both specialized sensory regions and higher cortical areas. Much less evidence exists for auditory working memory. Here, a main distinction has been proposed between the processing of spatial and non-spatial sound features. Our aim was to examine feature-specific activation patterns in auditory working memory.
Methods: We collected fMRI data while 28 healthy adults performed an auditory delayed match-to-sample task. Stimuli were abstract sounds characterized by both spatial and non-spatial information, i.e., interaural time delay and central frequency, respectively. In separate recording blocks, subjects had to memorize either the spatial or non-spatial feature, which had to be compared with a probe sound presented after a short delay. We performed both univariate and multivariate comparisons between spatial and non-spatial task blocks.
Results: Processing of spatial sound features elicited a higher activity in a small cluster in the superior parietal lobe than did sound pattern processing, whereas there was no significant activation difference for the opposite contrast. The multivariate analysis was applied using a whole-brain searchlight approach to identify feature-selective processing. The task-relevant auditory feature could be decoded from multiple brain regions including the auditory cortex, posterior temporal cortex, middle occipital gyrus, and extended parietal and frontal regions.
Conclusion: In summary, the lack of large univariate activation differences between spatial and non-spatial processing could be attributable to the identical stimulation in both tasks. In contrast, the whole-brain multivariate analysis identified feature-specific activation patterns in widespread cortical regions. This suggests that areas beyond the auditory dorsal and ventral streams contribute to working memory processing of auditory stimulus features.
Working memory (WM) performance varies substantially among individuals but the precise contribution of different WM component processes to these functional limits remains unclear. By analyzing different types of responses in a spatial WM task, we recently demonstrated a functional dissociation between confident and not-confident errors reflecting failures of WM encoding and maintenance, respectively. Here, we use event-related brain potentials to further explore this dissociation. Healthy participants performed a delayed orientation-discrimination task and rated their response confidence for each trial. The encoding-related N2pc component was significantly reduced for confident errors compared to confident correct responses, which is indicative of an encoding failure. In contrast, the maintenance-related contra-lateral delay activity was similar for these response types indicating that in confident error trials, WM representations – potentially the wrong ones – were maintained accurately and with stability throughout the delay interval. However, contra-lateral delay activity measured during the early part of the delay period was decreased for not-confident errors, potentially reflecting compromised maintenance processes. These electrophysiological findings contribute to a refined understanding of the encoding and maintenance processes that contribute to limitations in WM performance and capacity.
Forgetting is a common phenomenon in everyday life. Although it often has negative connotations, forgetting is an important adaptive mechanism to avoid loading the memory storage with irrelevant information. A very important aspect of forgetting is its interaction with emotion. Affective events are often granted special and priority treatment over neutral ones with regards to memory storage. As a consequence, emotional information is more resistant to extinction than neutral information. It has been suggested that intentional forgetting serves as a mechanism to cope with unwanted or disruptive emotional memories and the main goal of this study was to assess forgetting of emotional auditory material using the item-method directed forgetting (DF) paradigm using a forgetting strategy based on mindfulness as a means to enhance DF. Contrary to our prediction, the mindfulness-based strategy not only did not improve DF but reduced it for neutral material. These results suggest that an interaction between processes such as response inhibition and attention is required for intentional forgetting to succeed.
Even though extensively investigated, the nature of working memory (WM) deficits in patients with schizophrenia (PSZ) is not yet fully understood. In particular, the contribution of different WM sub-processes to the severe WM deficit observed in PSZ is a matter of debate. So far, most research has focused on impaired WM maintenance. By analyzing different types of errors in a spatial delayed response task (DRT), we have recently demonstrated that incorrect yet confident responses (which we labeled as false memory errors) rather than incorrect/not-confident responses reflect failures of WM encoding, which was also impaired in PSZ. In the present study, we provide further evidence for a functional dissociation between confident and not-confident errors by manipulating the demands on WM maintenance, i.e., the length over which information has to be maintained in WM. Furthermore, we investigate whether these functionally distinguishable WM processes are impaired in PSZ. Twenty-four PSZ and 24 demographically matched healthy controls (HC) performed a spatial DRT in which the length of the delay period was varied between 1, 2, 4, and 6 s. In each trial, participants also rated their level of response confidence. Across both groups, longer delays led to increased rates of incorrect/not-confident responses, while incorrect/confident responses were not affected by delay length. This functional dissociation provides additional support for our proposal that false memory errors (i.e., confident errors) reflect problems at the level of WM encoding, while not-confident errors reflect failures of WM maintenance. Schizophrenic patients showed increased numbers of both confident and not-confident errors, suggesting that both sub-processes of WM—encoding and maintenance—are impaired in schizophrenia. Combined with the delay length-dependent functional dissociation, we propose that these impairments in schizophrenic patients are functionally distinguishable.
Visual selective attention and visual working memory (WM) share the same capacity-limited resources. We investigated whether and how participants can cope with a task in which these 2 mechanisms interfere. The task required participants to scan an array of 9 objects in order to select the target locations and to encode the items presented at these locations into WM (1 to 5 shapes). Determination of the target locations required either few attentional resources (“popout condition”) or an attention-demanding serial search (“non pop-out condition”). Participants were able to achieve high memory performance in all stimulation conditions but, in the non popout conditions, this came at the cost of additional processing time. Both empirical evidence and subjective reports suggest that participants invested the additional time in memorizing the locations of all target objects prior to the encoding of their shapes into WM. Thus, they seemed to be unable to interleave the steps of search with those of encoding. We propose that the memory for target locations substitutes for perceptual pop-out and thus may be the key component that allows for flexible coping with the common processing limitations of visual WM and attention. The findings have implications for understanding how we cope with real-life situations in which the demands on visual attention and WM occur simultaneously. Keywords: attention, working memory, interference, encoding strategies
Das visuelle Arbeitsgedächtnis (AG) kann visuelle Information enkodieren, über eine kurze Zeitperiode aktiv halten und mit neu wahrgenommener Information vergleichen. Dadurch ermöglicht es eine Reihe höherer kognitiver Funktionen ( z.B. Kopfrechnen). Störungen des visuellen AGs sind ein relevantes Symptom neurologischer und psychiatrischer Erkrankungen. Die funktionellen und neuronalen Prozesse, die dem visuellen AG unterliegen, stellen eine fundamentale Frage der kognitiven Neurowissenschaft dar. Bisherige Forschung hat bereits einen großen Beitrag zum Verständnis der Vorgänge während der Enkodierungs- und Halte-Phase des AGs geleistet. Die neuronalen Korrelate der Wiedererkennung (WE) hingegen sind relativ unbekannt. Ziel der vorliegenden Studie war es, die neuronalen Mechanismen der WE anhand zweier Modulationen (Gedächtnisbelastung und Ähnlichkeit zwischen Merk- und Test-Stimulus) zu erforschen. Den neuronalen Grundlagen von Ähnlichkeit zwischen wurde bislang nahezu keine Beachtung geschenkt, ihre Untersuchung stellte deshalb eine wesentliche Motivation der Arbeit dar. Da erhöhte Gedächtnislast bei einer endlichen Anzahl an Stimuli zu einer erhöhten Anzahl an möglichen ähnlichen Test-Stimuli und auf diese Weise zu einer erhöhten Ähnlichkeit zwischen Merk- und Test-Stimulus führen kann, sind die Effekte beider Modulationen konfundiert. Es sollte deshalb zusätzlich der Nachweis für einen ähnlichkeitsunabhängigen Lasteffekt erbracht werden. Im Rahmen der vorliegenden Dissertation stand der zeitliche Ablauf der zu erwartenden kortikalen Aktivationen im Mittelpunkt des Interesses. Aus diesem Grund kam die Magnetenzephalographie (MEG) mit ihrem hervorragenden zeitlichen und guten räumlichen Auflösungsvermögen zum Einsatz. Die neuronale Aktivität von 17 Probanden wurde mittels MEG erfasst. Zusätzlich wurden Verhaltensdaten (VD) in Form von Reaktionszeit (RZ) und Korrektheit (KH) der Antworten aufgezeichnet. Als Stimuli dienten 15 verschiedene Farben, die einmal den gesamten Farbkreis abbildeten. 1 oder 3 verschiedenfarbige Quadrate dienten als Merk-Stimuli und ein farbiges Quadrat, das einem der vorher gezeigten glich (G), ihm ähnlich (Ä) oder unähnlich (U) war, folgte als Test-Stimulus. Die Probanden antworteten per Fingerheben aus einer Lichtschranke, ob der Test-Stimulus dem Merk-Stimulus glich (G) oder nicht glich (Ä, U). Insgesamt führten die 2 Belastungsmodulationen und die 3 Ähnlichkeitsmodulationen zu einem 2 x 3 Design, das eine Untersuchung der Haupteffekte und Interaktionen von Ähnlichkeit und Last ermöglichte. Die Ergebnisse der VD decken sich mit früheren Erkenntnissen, die mit ansteigender Gedächtnislast und Ähnlichkeit von einer signifikanten Verminderung der KH der Antworten sowie einer signifikanten Zunahme der RZ berichteten. Zusätzlich konnte eine signifikante Interaktion beider Modulationen beobachtet werden. Mit zunehmender Gedächtnislast verlängerte sich die RZ, bzw. verminderte sich die KH der Antworten für gleiche Testreize stärker als für ungleiche (Ä, U). Es konnten wesentliche neue Erkenntnisse über die neuronalen Korrelate der WE im visuellen AG gewonnen werden. Für die Ähnlichkeits-Modulation konnten drei zeitlich, räumlich und funktionell distinkte Ereigniskorrelierte-Felder (EKF)-Komponenten detektiert werden: eine frühe Komponente, die stärker auf U im Vergleich zu Ä und G Stimuli ansprach, eine mittlere, die mit der Schwierigkeit der Aufgabe assoziiert war sowie eine späte Komponente, die als Korrelat einer kategorialen Entscheidung interpretiert wurde. Diese Ergebnisse replizieren Befunde von Studien über die Entscheidungsfindung und die summierte Ähnlichkeit im Langzeitgedächtnis (LZG) und liefern gleichzeitig neue Hinweise für eine funktionelle Dissoziation verschiedener Komponenten der WE im visuellen AG. Die WE scheint aus der Berechnung der summierten Ähnlichkeit, der Entscheidungsfindung sowie der Evidenzevaluation unter schwierigeren Bedingungen zu bestehen. Es gelang außerdem der Nachweis eines ähnlichkeitsunabhängigen Effektes der Lastmodulation. Es konnte eine bilateral parieto-okzipitale sowie eine linksseitig fronto-temporale Aktivierung erfasst werden, die wahrscheinlich allgemeinen Schwierigkeitseffekten entsprechen. Unter ansteigender Gedächtnisbelastung kam es zu einer Zunahme der Amplitude beider Aktivitäten. Diese Ergebnisse bestätigen Befunde über die Amplitudenentwicklung während der Halte-Phase, die als Heranziehung zusätzlicher Ressourcen unter schwierigeren Bedingungen gedeutet wurden. Die EKF-Daten konnten jedoch keine Bestätigung des in den VD nachgewiesenen Interaktionseffektes bringen. Vielversprechende Ansätze für zukünftige Studien bieten eine präzisere Bestimmung der räumlichen Verteilung sowie eine weitere Evaluation der kognitiven Funktion der neuronalen Aktivität der Ähnlichkeit, da die Ähnlichkeit zwischen Merk- und Test-Stimulus eine entscheidende Rolle bei der Beschränkung der WE-Leistung einzunehmen scheint.
The pathophysiology of schizophrenia is still poorly understood. Investigating the neurophysiological correlates of cognitive dysfunction with functional neuroimaging techniques such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is widely considered to be a possible solution for this problem. Working memory impairment is one of the most prominent cognitive impairments found in schizophrenia. Working memory can be divided into a number of component processes, encoding, maintenance and retrieval. They appear to be differentially affected in schizophrenia, but little is known about the neurophysiological disturbances which contribute to deficits in these component processes. The aim of this dissertation was to elucidate the neurophysiological underpinnings of the component processes of working memory and their disturbance in schizophrenia. In the first study the the neurophysiological substrates of visual working memory capacity limitations were investigated during encoding, maintenance and retrieval in 12 healthy subjects using event-related fMRI. Subjects had to encode up to four abstract visual shapes and maintain them in working memory for 12 seconds. Afterwards a test stimulus was presented, which matched one of the previously shown shapes in fifty percent of the trials. A bilateral inverted U-shape pattern of BOLD activity with increasing memory load in areas closely linked with selective attention, i.e. the frontal eye fields and areas around the intraparietal sulcus, was observed already during encoding. The increase of the number of stored items from memory load three to memory load four in these regions was negatively correlated with the increase of BOLD activity from memory load three to memory load four. These results point to a crucial role of attentional processes for the limited capacity of working memory. In the second study, the contribution of early perceptual processing deficits during encoding and retrieval to working memory dysfunction was investigated in 17 patients with schizophrenia and 17 healthy control subjects using EEG and event-related fMRI. A slightly modified version of the working memory task used in the fist study was employed. Participants only had to encode and maintain up to three items. In patients the amplitude of the P1 event-related potential was significantly reduced already during encoding in all memory load conditions. Similarly, BOLD activity in early visual areas known to generate the P1 was significantly reduced in patients. In controls, a stronger P1 amplitude increase with increasing memory load predicted better performance. These findings indicate that in addition to later memory related processing stages early visual processing is disturbed in schizophrenia and contributes to working memory dysfunction by impairing the encoding of information. In the third study, which was based on the same data set as the second study, cortical activity and functional connectivity in 17 patients with schizophrenia and 17 to healthy control subjects during the working memory encoding, maintenance and retrieval was investigated using event-related fMRI. Patients had reduced working memory capacity. During encoding activation in the left ventrolateral prefrontal cortex and extrastriate visual cortex was reduced in patients but positively correlated with working memory capacity in controls. During early maintenance patients switched from hyper- to hypoactivation with increasing memory load in a fronto-parietal network which included left dorsolateral prefrontal cortex. During retrieval right ventrolateral prefrontal hyperactivation was correlated with encoding-related hypoactivation of left ventrolateral prefrontal cortex in patients. Cortical dysfunction in patients during encoding and retrieval was accompanied by abnormal functional connectivity between fronto-parietal and visual areas. These findings indicate a primary encoding deficit in patients caused by a dysfunction of prefrontal and visual areas. The findings of these studies suggest that isolating the component processes of working memory leads to more specific markers of cortical dysfunction in schizophrenia, which had been obscured in previous studies. This approach may help to identify more reliable biomarkers and endophenotypes of schizophrenia.