Nikolai Axmacher

The role of phase synchronization in memory processes

In recent years, studies ranging from single-unit recordings in animals to electroencephalography and magnetoencephalography studies in humans have demonstrated the pivotal role of phase synchronization in memory processes. Phase synchronization — here referring to the synchronization of oscillatory phases between different brain regions — supports both working memory and long-term memory and acts by facilitating neural communication and by promoting neural plasticity. There is evidence that processes underlying working and long-term memory might interact in the medial temporal lobe. We propose that this is accomplished by neural operations involving phase–phase and phase–amplitude synchronization. A deeper understanding of how phase synchronization supports the flexibility of and interaction between memory systems may yield new insights into the functions of phase synchronization in general.

Nucleus Accumbens Deep Brain Stimulation Decreases Ratings of Depression and Anxiety in Treatment-Resistant Depression

BACKGROUND While most patients with depression respond to combinations of pharmacotherapy, psychotherapy, and electroconvulsive therapy (ECT), there are patients requiring other treatments. Deep brain stimulation (DBS) allows modulation of brain regions that are dysfunctional in depression. Since anhedonia is a feature of depression and there is evidence of dysfunction of the reward system, DBS to the nucleus accumbens (NAcc) might be promising. METHODS Ten patients suffering from very resistant forms of depression (treatment-resistant depression [TRD]), not responding to pharmacotherapy, psychotherapy, or ECT, were implanted with bilateral DBS electrodes in the NAcc. The mean (+/-SD) length of the current episode was 10.8 (+/-7.5) years; the number of past treatment courses was 20.8 (+/-8.4); and the mean Hamilton Depression Rating Scale (HDRS) was 32.5 (+/-5.3). RESULTS Twelve months following initiation of DBS treatment, five patients reached 50% reduction of the HDRS (responders, HDRS = 15.4 [+/-2.8]). The number of hedonic activities increased significantly. Interestingly, ratings of anxiety (Hamilton Anxiety Scale) were reduced in the whole group but more pronounced in the responders. The [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography data revealed that NAcc-DBS decreased metabolism in the subgenual cingulate and in prefrontal regions including orbital prefrontal cortex. A volume of interest analysis comparing responders and nonresponders identified metabolic decreases in the amygdala. CONCLUSIONS We demonstrate antidepressant and antianhedonic effects of DBS to NAcc in patients suffering from TRD. In contrast to other DBS depression studies, there was also an antianxiety effect. These effects are correlated with localized metabolic changes.

Cross-frequency coupling supports multi-item working memory in the human hippocampus

Recent findings indicate that the hippocampus supports not only long-term memory encoding but also plays a role in working memory (WM) maintenance of multiple items; however, the neural mechanism underlying multi-item maintenance is still unclear. Theoretical work suggests that multiple items are being maintained by neural assemblies synchronized in the gamma frequency range (25–100 Hz) that are locked to consecutive phase ranges of oscillatory activity in the theta frequency range (4–8 Hz). Indeed, cross-frequency coupling of the amplitude of high-frequency activity to the phase of slower oscillations has been described both in animals and in humans, but has never been linked to a theoretical model of a cognitive process. Here we used intracranial EEG recordings in human epilepsy patients to test pivotal predictions from theoretical work. First, we show that simultaneous maintenance of multiple items in WM is accompanied by cross-frequency coupling of oscillatory activity in the hippocampus, which is recruited during multi-item WM. Second, maintenance of an increasing number of items is associated with modulation of beta/gamma amplitude with theta band activity of lower frequency, consistent with the idea that longer cycles are required for an increased number of representations by gamma cycles. This effect cannot be explained by a difference in theta or beta/gamma power. Third, we describe how the precision of cross-frequency coupling predicts individual WM performance. These data support the idea that working memory in humans depends on a neural code using phase information.

Sustained Neural Activity Patterns during Working Memory in the Human Medial Temporal Lobe

In contrast to classical findings that the medial temporal lobe (MTL) specifically underlies long-term memory, previous data suggest that MTL structures may also contribute to working memory (WM). However, the neural mechanisms by which the MTL supports WM have remained unknown. Here, we exploit intracranial EEG to identify WM-specific sustained activity patterns with the highest temporal and spatial resolution currently available in humans. Using a serial Sternberg paradigm, we found a positive shift of the direct current (DC) potential and a long-lasting decrease in MTL gamma-band activity during maintenance of a single item, reflective of a sustained reduction in neural activity. Maintenance of an increasing number of items elicited an incrementally negative shift of the DC potential and an increase in MTL gamma-band activity. In addition, the paradigm was conducted in healthy control subjects using functional magnetic resonance imaging. This confirmed that our results were not caused by pathological processes within the MTL, and that this region was indeed specifically activated during the task. Our results thus provide direct evidence for sustained neural activity patterns during working memory maintenance in the MTL, and show that these patterns depend on WM load.

Interactions between Medial Temporal Lobe, Prefrontal Cortex, and Inferior Temporal Regions during Visual Working Memory: A Combined Intracranial EEG and Functional Magnetic Resonance Imaging Study

It is a fundamental question whether the medial temporal lobe (MTL) supports only long-term memory encoding, or contributes to working memory (WM) processes as well. Recent data suggest that the MTL is activated whenever multiple items or item features are being maintained in WM. This may rely on interactions between the MTL or the prefrontal cortex (PFC) and content-specific areas in the inferior temporal (IT) cortex. Here, we investigated the neural mechanism through which the MTL, PFC, and IT cortex interact during WM maintenance. First, we quantified phase synchronization of intracranial EEG data in epilepsy patients with electrodes in both regions. Second, we used directional coupling analysis to study whether oscillatory activity in the IT cortex drives the MTL or vice versa. Finally, we investigated functional connectivity in functional magnetic resonance imaging data of healthy subjects with seeds in the MTL and PFC. With increasing load, EEG phase synchronization between the IT cortex and anterior parahippocampal gyrus and within the MTL increased. Coupling was bidirectional in all load conditions, but changed toward an increased top-down (anterior parahippocampal gyrus → IT) coupling in the high gamma range (51–75 Hz) with increasing load. Functional connectivity between the MTL seed and the visual association cortex increased with load, but activity within the MTL and the PFC correlated with fewer voxels, suggesting that more specific neural networks were engaged. These data indicate that WM for multiple items depends on an increased strength of top-down control of activity within the IT cortex by the MTL.

Hierarchical nesting of slow oscillations, spindles and ripples in the human hippocampus during sleep

During systems-level consolidation, mnemonic representations initially reliant on the hippocampus are thought to migrate to neocortical sites for more permanent storage, with an eminent role of sleep for facilitating this information transfer. Mechanistically, consolidation processes have been hypothesized to rely on systematic interactions between the three cardinal neuronal oscillations characterizing non–rapid eye movement (NREM) sleep. Under global control of de- and hyperpolarizing slow oscillations (SOs), sleep spindles may cluster hippocampal ripples for a precisely timed transfer of local information to the neocortex. We used direct intracranial electroencephalogram recordings from human epilepsy patients during natural sleep to test the assumption that SOs, spindles and ripples are functionally coupled in the hippocampus. Employing cross-frequency phase-amplitude coupling analyses, we found that spindles were modulated by the up-state of SOs. Notably, spindles were found to in turn cluster ripples in their troughs, providing fine-tuned temporal frames for the hypothesized transfer of hippocampal memory traces.

Good vibrations: Cross-frequency coupling in the human nucleus accumbens during reward processing

The nucleus accumbens is critical for reward-guided learning and decision-making. It is thought to “gate” the flow of a diverse range of information (e.g., rewarding, aversive, and novel events) from limbic afferents to basal ganglia outputs. Gating and information encoding may be achieved via cross-frequency coupling, in which bursts of high-frequency activity occur preferentially during specific phases of slower oscillations. We examined whether the human nucleus accumbens engages such a mechanism by recording electrophysiological activity directly from the accumbens of human patients undergoing deep brain stimulation surgery. Oscillatory activity in the gamma (40–80 Hz) frequency range was synchronized with the phase of simultaneous alpha (8–12 Hz) waves. Further, losing and winning small amounts of money elicited relatively increased gamma oscillation power prior to and following alpha troughs, respectively. Gamma–alpha synchronization may reflect an electrophysiological gating mechanism in the human nucleus accumbens, and the phase differences in gamma–alpha coupling may reflect a reward information coding scheme similar to phase coding.

Medial Temporal Theta/Alpha Power Enhancement Precedes Successful Memory Encoding: Evidence Based on Intracranial EEG

Not only poststimulus, but also prestimulus neural activity has been shown to be predictive for later successful memory encoding. However, it is still not clear which medial temporal lobe processes precede effective memory formation. Here, our aim was to investigate whether such prestimulus markers for successful memory encoding can be specified based on intracranial recordings directly from the hippocampus and rhinal cortex. For this purpose, we analyzed subsequent memory effects during a continuous word recognition paradigm in 31 presurgical epilepsy patients. We found that rhinal and hippocampal theta and successive alpha power enhancement before word presentation predicted successful memory encoding. Previous studies suggest that stimulus-triggered hippocampal theta activity is particularly related to memory retrieval and activation of a mnemonic context, whereas the alpha rhythm reflects inhibitory top-down control of task processing and executive functioning. In line with these suggestions, we propose that the observed medial temporal theta and alpha power increases before stimulus presentation reflect activation of contextual information and inhibitory top-down control processes preparing for stimulus-triggered memory processing.

Memory consolidation by replay of stimulus-specific neural activity.

Memory consolidation transforms initially labile memory traces into more stable representations. One putative mechanism for consolidation is the reactivation of memory traces after their initial encoding during subsequent sleep or waking state. However, it is still unknown whether consolidation of individual memory contents relies on reactivation of stimulus-specific neural representations in humans. Investigating stimulus-specific representations in humans is particularly difficult, but potentially feasible using multivariate pattern classification analysis (MVPA). Here, we show in healthy human participants that stimulus-specific activation patterns can indeed be identified with MVPA, that these patterns reoccur spontaneously during postlearning resting periods and sleep, and that the frequency of reactivation predicts subsequent memory for individual items. We conducted a paired-associate learning task with items and spatial positions and extracted stimulus-specific activity patterns by MVPA in a simultaneous electroencephalography and functional magnetic resonance imaging (fMRI) study. As a first step, we investigated the amount of fMRI volumes during rest that resembled either one of the items shown before or one of the items shown as a control after the resting period. Reactivations during both awake resting state and sleep predicted subsequent memory. These data are first evidence that spontaneous reactivation of stimulus-specific activity patterns during resting state can be investigated using MVPA. They show that reactivation occurs in humans and is behaviorally relevant for stabilizing memory traces against interference. They move beyond previous studies because replay was investigated on the level of individual stimuli and because reactivations were not evoked by sensory cues but occurred spontaneously.

Intracranial EEG Correlates of Expectancy and Memory Formation in the Human Hippocampus and Nucleus Accumbens

The human brain is adept at anticipating upcoming events, but in a rapidly changing world, it is essential to detect and encode events that violate these expectancies. Unexpected events are more likely to be remembered than predictable events, but the underlying neural mechanisms for these effects remain unclear. We report intracranial EEG recordings from the hippocampus of epilepsy patients, and from the nucleus accumbens of depression patients. We found that unexpected stimuli enhance an early (187 ms) and a late (482 ms) hippocampal potential, and that the late potential is associated with successful memory encoding for these stimuli. Recordings from the nucleus accumbens revealed a late potential (peak at 475 ms), which increases in magnitude during unexpected items, but no subsequent memory effect and no early component. These results are consistent with the hypothesis that activity in a loop involving the hippocampus and the nucleus accumbens promotes encoding of unexpected events.