Individual differences in theta-band oscillations in a spatial memory network revealed by electroencephalography predict rapid place learning

Spatial memory has been closely related to the medial temporal lobe (MTL) and theta-oscillations are thought to play a key role. However, it remains difficult to investigate MTL activation related to spatial memory with non-invasive electrophysiological methods in humans. Here, we combined the virtual delayed-matching-to-place (DMP) task, reverse-translated from the watermaze DMP task in rats, with high-density electroencephalography (EEG) recordings. Healthy young volunteers performed this computerised task in a virtual circular arena, which contained a hidden target whose location moved to a new place every four trials, allowing the assessment of rapid memory formation. Using behavioural measures as predictor variables for source reconstructed frequency specific EEG power, we found that inter-individual differences in ‘search preference’ during ‘probe trials’, a measure of 1-trial place learning known from rodent studies to be particularly hippocampus dependent, correlated predominantly with distinct theta-band oscillations (approx. 7 Hz), particularly in the right temporal lobe, the right striatum and inferior occipital cortex or cerebellum. This pattern was found during both encoding and retrieval/expression, but not in control analyses and could not be explained by motor confounds. Alpha-activity in sensorimotor and parietal cortex contralateral to the hand used for navigation also correlated (inversely) with search preference. This latter finding likely reflects movement-related factors associated with task performance, as well as a frequency difference in (ongoing) alpha-rhythm for high-performers vs low-performers that may contribute to these results indirectly. Relating inter-individual differences in ongoing brain activity to behaviour in a continuous rapid place learning task that is suitable for a variety of populations, we could demonstrate that memory related theta-band activity in temporal lobe can be measured with EEG recordings. This approach holds great potential for further studies investigating the interactions within this network during encoding and retrieval, as well as neuromodulatory impacts and age-related changes

Movement-related theta rhythm in humans: coordinating self-directed hippocampal learning.

The hippocampus is crucial for episodic or declarative memory and the theta rhythm has been implicated in mnemonic processing, but the functional contribution of theta to memory remains the subject of intense speculation. Recent evidence suggests that the hippocampus might function as a network hub for volitional learning. In contrast to human experiments, electrophysiological recordings in the hippocampus of behaving rodents are dominated by theta oscillations reflecting volitional movement, which has been linked to spatial exploration and encoding. This literature makes the surprising cross-species prediction that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. We examined the links between theta, spatial exploration, and memory encoding by designing an interactive human spatial navigation paradigm combined with multimodal neuroimaging. We used both non-invasive whole-head Magnetoencephalography (MEG) to look at theta oscillations and Functional Magnetic Resonance Imaging (fMRI) to look at brain regions associated with volitional movement and learning. We found that theta power increases during the self-initiation of virtual movement, additionally correlating with subsequent memory performance and environmental familiarity. Performance-related hippocampal theta increases were observed during a static pre-navigation retrieval phase, where planning for subsequent navigation occurred. Furthermore, periods of the task showing movement-related theta increases showed decreased fMRI activity in the parahippocampus and increased activity in the hippocampus and other brain regions that strikingly overlap with the previously observed volitional learning network (the reverse pattern was seen for stationary periods). These fMRI changes also correlated with participant's performance. Our findings suggest that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. These findings directly extend the role of the hippocampus in spatial exploration in rodents to human memory and self-directed learning

The Aha! Experience of Spatial Reorientation

The experience of spatial re-orientation is investigated as an instance of the wellknown phenomenon of the Aha! moment. The research question is: What are the visuospatial conditions that are most likely to trigger the spatial Aha! experience? The literature suggests that spatial re-orientation relies mainly on the geometry of the environment and a visibility graph analysis is used to quantify the visuospatial information. Theories from environmental psychology point towards two hypotheses. The Aha! experience may be triggered by a change in the amount of visual information, described by the isovist properties of area and revelation, or by a change in the complexity of the visual information associated with the isovist properties of clustering coefficient and visual control. Data from participants’ exploratory behaviour and EEG recordings are collected during wayfinding in virtual reality urban environments. Two types of events are of interest here: (a) sudden changes of the visuospatial information preceding subjects' response to investigate changes in EEG power; and (b) participants brain dynamics (Aha! effect) just before the response to examine differences in isovist values at this location. Research on insights, time-frequency analysis of the P3 component and findings from navigation and orientation studies suggest that the spatial Aha! experience may be reflected by: a parietal alpha power decrease associated with the switch of the representation and a frontocentral theta increase indexing spatial processing during decision-making. Single-trial time-frequency analysis is used to classify trials into two conditions based on the alpha/theta power differences between a 3s time-period before participants’ response and a time-period of equal duration before that. Behavioural results show that participants are more likely to respond at locations with low values of clustering coefficient and high values of visual control. The EEG analysis suggests that the alpha decrease/theta increase condition occurs at locations with significantly lower values of clustering coefficient and higher values of visual control. Small and large decreases in clustering coefficient, just before the response, are associated with significant differences in delta/theta power. The values of area and revelation do not show significant differences. Both behavioural and EEG results suggest that the Aha! experience of re-orientation is more likely to be triggered by a change in the complexity of the visual-spatial environment rather than a change in the amount, as measured by the relevant isovist properties

Alpha and gamma-band oscillations in MEG-data: networks, function and development

Die Adoleszenz, d.h. die Reifungsphase des Jugendlichen zum Erwachsenen, stellt einen zentralen Abschnitt in der menschlichen Entwicklung dar, der mit tief greifenden emotionalen und kognitiven Veränderungen verbunden ist. Neure Studien (Bunge et al., 2002; Durston et al., 2002; Casey et al., 2005; Crone et al., 2006; Bunge and Wright, 2007) machen deutlich, dass sich die funktionelle Architektur des Gehirns während der Adoleszenz grundlegend verändert und dass diese Veränderungen mit der Reifung höherer kognitiven Funktionen in der Adoleszenz assoziiert sein könnten. Messungen des Gehirn-Volumens mit Hilfe der Magnet-Resonanz-Tomographie (MRT) zum Beispiel zeigen eine nicht-lineare Reduktion der grauen und eine Zunahme der weißen Substanz während der Adoleszenz (Giedd et al., 1999; Sowell et al., 1999, 2003). Des weiteren treten in dieser Zeit Veränderungen in exzitatorischen und inhibitorischen Neurotransmitter-Systemen auf (Tseng and O’Donnell, 2005; Hashimoto et al., 2009). Zusammen deuten diese Ergebnisse darauf hin, dass während der Adoleszenz ein Umbau der kortikalen Netzwerke stattfindet, der wichtige Konsequenzen für die Reifung neuronaler Oszillationen haben könnte. Im Anschluss an eine Einführung im Kapitel 2, fasst Kapitel 3 der vorliegenden Dissertation die Vorbefunde bezüglich entwicklungsbedingter Veränderungen in der Amplitude, Frequenz und Synchronisation neuronaler Oszillationen zusammen und diskutiert den Zusammenhang zwischen der Entwicklung neuronaler Oszillationen und der Reifung höhere kognitiver Funktionen während der Adoleszenz. Ebenso werden die anatomischen und physiologischen Mechanismen, die diesen Veränderungen möglicherweise zu Grunde liegen könnten, theoretisch vorgestellt. Die in Kapitel 4-6 vorgestellten eigenen empirischen Arbeiten untersuchen neuronale Oszillationen mit Hilfe der Magnetoencephalographie (MEG), um die Frequenzbänder und die funktionellen Netzwerke zu charakterisieren, die mit höheren kognitiven Prozessen und deren Entwicklung in der Adoleszenz assoziiert sind. Hierzu wurden drei Experimente durchgeführt, bei denen MEG-Aktivität während der Bearbeitung einer Arbeitsgedächtnisaufgabe und im Ruhezustand aufgezeichnet wurde. Die Ergebnisse dieser Experimente zeigen, dass Alpha Oszillationen und Gamma-Band Aktivität sowohl task-abhängig als auch im Ruhezustand gemeinsam auftreten. Darüber hinaus ergänzen die vorliegenden Untersuchungen Vorarbeiten, indem sie eine Wechselwirkung zwischen beiden Frequenzbändern aufgezeigt wird, die als ein Mechanismus für das gezielte Weiterleiten von Informationen dienen könnte. Die in Kapitel 6 vorgestellten Entwicklungsdaten weisen weiterhin darauf, dass in der Adoleszenz späte Veränderungen im Alpha und Gamma-Band stattfinden und dass diese Veränderungen involviert sind in die Entwicklung der Arbeitsgedächtnis-Kapazität und die Entwicklung der Fähigkeit, Distraktoren zu inhibieren. Abschliessend werden in Kapitel 7, die in dieser Dissertation vorgestellten Arbeiten, aus einer übergeordneten Perspektive im Gesamtzusammenhang diskutiert

Neuroimaging and behavioral investigations of memory consolidation during sleep on time scales from hours to months

Introduction: Successful storage of memory can be divided into three fundamental processes: encoding, consolidation and retrieval. During encoding, information is acquired e.g. in a learning session of an experiment. New mnemonic traces are formed in the brain. When the information needs to be remembered e.g. at the retrieval session of an experiment, memory needs to be recovered. Since encoding does not lead to instantaneous permanent storage of the learned material, a form of memory stabilization is necessary. A person’s freshly acquired memory is initially fragile until the memory trace is reinforced through a process of consolidation. While learning and retrieval must occur during wakefulness, memory consolidation can occur during sleep. One question that is still under debate in sleep literature is whether a period of sleep, in comparison to wakefulness, significantly and persistently benefits the consolidation of recently and explicitly acquired declarative information (such that memory retrieval after a period of sleep is significantly better than retrieval after a period of wakefulness). A further problem regarding the benefit of sleep for memory is the discrepancy between functional and behavioral findings: Sleep associated changes are possibly a covert process and changes on the anatomical level are not necessarily congruent with behavioral results. Another question concerns memory consolidation in the long run. In humans, the medial temporal lobe, especially the hippocampus, is an important brain structure involved in declarative memory retrieval. Through the process of consolidation, declarative memory has been found to become independent of the hippocampus over time. Yet, human imaging studies investigating memory retrieval for a longer period of time (several months) are scarce. Another gap of knowledge lies in the role of the hippocampus. Several different hypotheses about its role exist: The multiple trace theory, established by Nadel and Moscovitch (1997), states that personally experienced episodes stay hippocampus dependent, whereas semanticized memories become independent over time. O’Keefe et al. (1978) proposed that the hippocampus is permanently accessed for spatial memory retrieval. According to Eichenbaum (2000), the hippocampus binds new information coupled with an episode into a network of existing memory traces. This thesis focuses on long-term memory. The major focus lies on declarative memory, whereas the minor focus lies on non-declarative memory. All five studies of this thesis investigate declarative memory and the last study (study 5) additionally investigates non-declarative memory. Study 1: Objective: To investigate the relation between episodic (declarative) memory and sleep versus sleep deprivation on the functional and behavioral level. The aim is to do the investigation on a time scale of 2 ½ months. Methods: The analysis was based on a between-group (factor: sleep / wake), within-subject (factor: autobiographical task / spatial task) design. Each subject learned two episodic memory tasks (word associations): an autobiographical task and a spatial task. Brain activity (using a 3T MRT) and behavioral performances were measured at 3 times: 1) Immediately after learning; 2) after a night of sleep/wake and two recovery nights of sleep; 3) 2 ½ months after learning. Results: No sleep related changes in hippocampal activation could be concluded from the neuroimaging results. Supporting this, behavioral results (free recall) showed no difference between sleep and sleep deprivation groups. Recall results showed no difference between the sleep group and the sleep deprivation group. Study 2: Presuming that sleep supports hippocampus dependent declarative memory, but given the results of study 1, it was important to investigate the role of the hippocampus. Objective: This study focused on the role of the hippocampus in declarative memory retrieval, given the different hypotheses (mentioned above) about its role. Methods: Using a between-group design, hippocampal involvement during free recall at an early stage after encoding was compared between sequential, spatial and autobiographical learning strategies. (Study 2 was not a sleep-study). Free recall performance of concrete nouns was measured on the functional as well as behavioral level. Results: Not all episodic memory traces depended equally on the hippocampus when information was retrieved in free recall: Whereas recall of autobiographical memory relied on the hippocampus after consolidation, recall of spatially and sequentially associated information did not. Functional conjunction analyses showed that brain areas mutually involved in all tasks tested, were: the precuneus (medial parietal cortex), medial occipital gyrus and superior parietal lobe (SPL). Studies 3 – 5: The specific mechanisms underlying the process of memory consolidation are still not clarified. It has been suggested that a positive effect of sleep on memory occurs when a sensitive set of requirements is met, although to date, pinpointing the exact requirements has not been possible from sleep literature. Study 3: Objective: The question to be answered was: Is the type of retrieval, that is, cued recall or recognition, crucial for an effect of sleep on declarative memory? Methods: The following parameters were applied: i) Cued recall and recognition as the type of retrieval test; ii) Circadian rhythm: Learning either in the morning or in the evening; iii) The retention period between learning and the post-conditional test was kept constant at 12 hours; iv) Interference learning was used; v) The learning material was restricted to non-sense syllables. Results: A beneficial effect of sleep on memory retrieval 12 hours after learning non-sense syllables occurred only when syllables were tested via cued recall. However, results were influenced by circadian rhythm effects with better test scores in the morning than in the evening. Study 4: Objective: Same as in study 3, but controlling for the circadian rhythm effects by using nap sleep instead of nocturnal sleep. Methods: Circadian rhythm effects were controlled by choosing a 60 minute nap sleep paradigm, in which encoding and retrieval both took place at the same time of day (in the afternoon), for both the sleep and wake conditions. The two types of retrieval in relation to nap sleep and wakefulness were examined: cued recall and recognition. The following parameters were applied: i) Cued recall and recognition for the type of retrieval test; ii) Circadian rhythm: Learning in the afternoon; iii) The retention period between learning and the post-conditional test was kept constant at three hours (including a 60 minute nap or time spent awake); iv) Interference learning was used; v) The learning material consisted of concrete German nouns. Results: subjects did not perform significantly better after a period of napping compared to a period of wakefulness, neither for words tested via cued recall nor words tested via recognition. A sleep benefit on the behavioral level did not show to be specific to the type of retrieval test. Study 5: Objective: To examine whether a sleep benefit occurs between a critical period of 12 to 144 hours post learning. In addition to declarative memory, the relation between sleep and procedural memory is tested, using a motor sequence (finger tapping) task. Methods: Subjects learned a procedural and a declarative task. The following parameters were applied: i) Free recall for the declarative and procedural retrieval tests; ii) In contrast to the other studies, total sleep deprivation and daytime wakefulness were used as wake condition iii) The retention period between learning and testing was 12, 72 or 144 hours (3 groups); iv) Interference learning was not used for the declarative task (a main and new motor sequence task were learned); v) The learning material was restricted to non-sense syllables. Results: No beneficial post-learning effect of sleep could be detected in the declarative and procedural tasks over the retention interval of up to six days. Results of study 5 demonstrated that sleep after learning did not lead to better performance of motor skills than wakefulness after learning. Conclusion: From the results of the five studies of this thesis, it can be concluded that declarative and procedural memories are consolidated equally well over a period of wakefulness compared to a period of sleep. The type of retrieval, circadian rhythm, retention period, interference, and the type of material might all contribute to a set of variables influencing the benefit of sleep on memory. It can also be assumed that the human brain is capable of compensating a night of sleep deprivation without significant behavioral deficits during retrieval of verbal declarative and motor skill tasks, whether memory is tested shortly after encoding (a few hours), after days or after months

Hippocampal neurophysiology during exploratory behaviour and sleep in rats heterozygous for the psychiatric risk gene cacna1c

Genome-wide association studies reveal that calcium channel gene variants confer risk for psychiatric disorders across diagnostic categories. One consistently implicated gene is CACNA1C, a gene encoding the α1 pore-forming subunit of the L-type calcium channel. Recent rodent research highlights an important role for Cacna1c in hippocampal synaptic plasticity and related cognition, yet little is known about the effects of reduced Cacna1c gene dosage on hippocampal neurophysiology in vivo. Using tetrodes targeted to the dorsal CA1 I recorded single unit and local field potential activity in rats heterozygous for Cacna1c during free exploration and rest. Cacna1c heterozygous rats displayed enlarged place-fields and an associated reduction in place-cell spatial information content during runs on a linear track in a familiar and novel orientation, while place-cell activity during exploration of a novel open-field was intact. In addition, while 6-10Hz theta and 25-140Hz gamma rhythms were comparable in frequency and power in heterozygotes, their dependence on locomotion was compromised. Phase-amplitude coupling between theta and slow-gamma was also attenuated in Cacna1c heterozygous rats running on the track in a novel orientation. Hippocampal recordings at rest revealed intact 120-250Hz sharp-wave ripple oscillations, yet an enhanced participation of individual neurons in sharp-wave ripple events in Cacna1c heterozygotes. Despite the elevation in ripple-associated activity, coactivity between cell pairs during sharp-wave ripple events was markedly impaired. Changes to neurophysiology during sleep-associated oscillations appeared independent of global sleep architecture, since Cacna1c heterozygotes showed normal circadian activity patterns. Finally, combining genetic L-type calcium channel hypofunction with NMDA receptor blockade using systemic ketamine administration, did not exacerbate hippocampal deficits in Cacna1c heterozygotes, indicating a divergence of these biological pathways. This research reveals an important role for CACNA1C in hippocampal neurophysiology that may contribute to cognitive deficits associated with psychiatric ris