Juergen Fell

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.

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.

Is synchronized neuronal gamma activity relevant for selective attention

Today, much evidence exists that sensory feature binding is accomplished by phase synchronization of induced neuronal gamma activity (30-80 Hz). Recent studies furthermore suggest that phase synchronization of induced gamma activity may represent a general mechanism enabling transient associations of neural assemblies and thus may play a central role in cortical information processing. Here, we describe findings indicating that synchronized gamma activity is moreover specifically involved in selective attention. While feature binding appears to depend primarily on induced gamma synchronization, attentional processes seem to involve both induced and evoked gamma oscillations. Yet it is still an open question, as to which top-down and bottom-up processes are associated with attentional modulation of gamma activity. A possible mechanism to project influences from attentional control structures to areas concerned with stimulus representation and vice versa, may be neuronal synchronization and the resulting firing rate changes of coincidence-detecting neurons in target areas.

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.

Rhinal-hippocampal theta coherence during declarative memory formation: interaction with gamma synchronization?

The hippocampus and the rhinal cortex, two substructures of the medial temporal lobe, together play a crucial role in human declarative memory formation. To investigate in detail the mechanism connecting these two structures transiently during memory formation we recorded depth EEG in epilepsy patients from within the hippocampus and the rhinal cortex. During this recording, patients performed a single‐trial word list‐learning paradigm with a free recall memory test following a distraction task. Rhinal–hippocampal EEG coherence and spectral power at both locations in the time interval up to 2 s after onset of word presentation were analysed in the frequency range 1–19 Hz. Successful as opposed to unsuccessful memory formation was associated with a general rhinal–hippocampal coherence enhancement, but without alterations in spectral power. Coherence increases in the theta range were correlated with the previously reported memory‐related changes in rhinal–hippocampal gamma phase synchronization. This correlation may suggest an interaction of the two mechanisms during declarative memory formation. While theta coherence might be associated with slowly modulated coupling related to an encoding state, rhinal–hippocampal gamma synchronization may be more closely related to actual memory processes by enabling fast coupling and decoupling of the two structures.

Lateralized Auditory Spatial Perception and the Contralaterality of Cortical Processing as Studied With Functional Magnetic Resonance Imaging and Magnetoencephalography

Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) were used to study the relationships between lateralized auditory perception in humans and the contralaterality of processing in auditory cortex. Subjects listened to rapidly presented streams of short FM‐sweep tone bursts to detect infrequent, slightly deviant tone bursts. The stimulus streams consisted of either monaural stimuli to one ear or the other or binaural stimuli with brief interaural onset delays. The onset delay gives the binaural sounds a lateralized auditory perception and is thought to be a key component of how our brains localize sounds in space. For the monaural stimuli, fMRI revealed a clear contralaterality in auditory cortex, with a contralaterality index (contralateral activity divided by the sum of contralateral and ipsilateral activity) of 67%. In contrast, the fMRI activations from the laterally perceived binaural stimuli indicated little or no contralaterality (index of 51%). The MEG recordings from the same subjects performing the same task converged qualitatively with the fMRI data, confirming a clear monaural contralaterality, with no contralaterality for the laterally perceived binaurals. However, the MEG monaural contralaterality (55%) was less than the fMRI and decreased across the several hundred millisecond poststimulus time period, going from 57% in the M50 latency range (20–70 ms) to 53% in the M200 range (170–250 ms). These data sets provide both quantification of the degree of contralaterality in the auditory pathways and insight into the locus and mechanism of the lateralized perception of spatially lateralized sounds. Hum. Brain Mapping 7:49–66, 1999.

Neural Bases of Cognitive ERPs: More than Phase Reset

Up to now, two conflicting theories have tried to explain the genesis of averaged event-related potentials (ERPs): Whereas one hypothesis claims that ERPs originate from an event-related activation of neural assemblies distinct from background dynamics, the other hypothesis states that ERPs are produced by phase resetting of ongoing oscillatory activity. So far, this question has only been addressed for early ERP components. Late ERP components, however, are generally thought to represent superimposed activities of several anatomically distinct brain areas. Thus, the question of which mechanism underlies the genesis of late ERP components cannot be easily answered based on scalp recordings. In contrast, two well-investigated late ERP components recorded invasively from within the human medial temporal lobe (MTL) in epilepsy patients, the so-called MTL-P300 and the anterior MTL-N400 (AMTL-N400), are based on single source activity. Hence, we investigated whether the MTL-P300 and the AMTL-N400 are based on an event-related activity increase, a phase reset of ongoing oscillatory activity or both. ERPs were recorded from the hippocampus and rhinal cortex in subjects performing a visual oddball paradigm and a visual word recognition paradigm. With wavelet techniques, stimulus-related phase-locking and power changes were analyzed in a frequency range covering 2 to 48 Hz. We found that the MTLP300 is accompanied by both phase reset and power increase and that both effects overlap partly in time. In contrast, the AMTL-N400 is initially associated with phase locking without power increase and only later during the course of the AMTL-N400 we observed an additional power increase. In conclusion, both aspects, event-related activation of neural assemblies and phase resetting of ongoing activity seem to be involved in the generation of late ERP components as recorded in cognitive tasks. Therefore, separate analysis of event-related power and phase-locking changes might reveal specific insights into the mechanisms underlying different cognitive functions.

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.

Medial frontal cortex and response conflict: Evidence from human intracranial EEG and medial frontal cortex lesion

The medial frontal cortex (MFC) has been implicated in the monitoring and selection of actions in the face of competing alternatives, but much remains unknown about its functional properties, including electrophysiological oscillations, during response conflict tasks. Here, we recorded intracranial EEG during a modified Flanker task from the MFC of two patients undergoing pre-surgical evaluation for the treatment of epilepsy. Performance on the task was associated with a suppression of beta (15-30 Hz) frequency oscillation power prior to and just following the response and an enhancement of theta (4-8 Hz) frequency power following the response. Beta (theta) power was anatomically distributed towards more dorsal/caudal (rostral/ventral) electrode sites along the cortex, suggesting an anatomical/functional specialization along the medial frontal wall for pre-response versus post-response action monitoring. Inter-site phase coherence analyses demonstrated that the ventral/rostral MFC theta oscillations were coupled with theta oscillations observed at scalp electrodes Fz and Cz. One patient was tested before and after having epileptogenic tissue in the MFC surgically removed; task performance increased from chance levels to near-perfect, and an ERP conflict effect was observed only following surgery. These findings provide novel evidence for the role of MFC oscillations and their relation to surface EEG-recorded potentials during action monitoring.