Marije ter Wal

Stereo-electroencephalography (SEEG) involves the implantation of depth electrodes in the brain to monitor epileptic seizures for surgical feasibility. As the electrodes advance into deeper limbic structures, the macro contacts distributed along the shaft record electrical activity from more lateral sites, while a bundled array of microwires simultaneously captures highly localised signals from the tip of the electrode. In a clinical setting these electrical signals are recorded relative to a reference signal, which may be sub-optimal for subsequent analyses that are unrelated to clinical objectives. Therefore, a secondary re-referencing operation is often undertaken to transform the signal in relation to a specific hypothesis. Despite a recent surge in SEEG studies, comparative studies on the much-understudied issue of re-referencing are sparse. Here, we analyse data collected from 16 human patients during an episodic memory task and comparatively apply a range of re-referencing methods to both macro contact and micro-wire data. We find that the choice of method changes the proportion of trials that survive artefact rejection, low frequency power, and the aperiodic background against which that power is read. In the hippocampal recordings, however, no method differed from any other in the size of a memory effect in power or spike–field coherence. This early transformative decision therefore bears on how the signal is described. We found no evidence that it changes the detectability of the behavioural effects tested here, and no method reversed the direction of a memory effect.

Place cells and concept neurons are defined by a rise in firing rate at a particular location or for a particular person or object. Neurons without such a rise remain unlabeled, although they keep firing during the task. Such neurons could still carry information in the timing of their spikes. Hippocampal theta provides a reference for this timing. We therefore asked whether the theta phase of a neuron’s spikes depends on location or on the viewed image, even when its firing rate does not. We analysed hippocampal neurons in humans navigating a virtual city, rats running on a linear track, and humans viewing images of animals, faces, and places. In both navigation datasets, more neurons than expected by chance fired at a consistent theta phase at particular locations. This phase tuning remained after we excluded neurons whose firing rate depended on location. In human navigation, the spike phases of these remaining neurons improved location decoding beyond the firing rates of all neurons. More phase-tuned neurons than expected by chance also fired at progressively earlier theta phases as participants passed each neuron’s preferred location. This pattern resembles phase precession, which classically occurs as an animal crosses the firing-rate field of a place cell. The neurons that showed it had no firing-rate field, so their phase shift was anchored to the location defined by phase tuning alone. During image viewing, more neurons than expected by chance changed the theta phase of their spikes after a particular image appeared. This effect remained after we removed, for each neuron, the images that changed its firing rate. Spike phases alone also predicted the image category above chance. Theta-relative spike timing therefore carries information about location and images that firing rate alone misses. We propose that weak input changes when a neuron fires within the theta cycle, whereas strong input also raises its firing rate.

The hippocampus is an essential hub for episodic memory processing. However, how human hippocampal single neurons code multi-element associations remains unknown. In particular, it is debated whether each hippocampal neuron represents an invariant element within an episode or whether single neurons bind together all the elements of a discrete episodic memory. Here we provide evidence for the latter hypothesis. Using single-neuron recordings from a total of 30 participants, we show that individual neurons, which we term episode-specific neurons, code discrete episodic memories using either a rate code or a temporal firing code. These neurons were observed exclusively in the hippocampus. Importantly, these episode-specific neurons do not reflect the coding of a particular element in the episode (that is, concept or time). Instead, they code for the conjunction of the different elements that make up the episode.

Theta and gamma oscillations in the medial temporal lobe are suggested to play a critical role for human memory formation via establishing synchrony in neural assemblies. Arguably, such synchrony facilitates efficient information transfer between neurons and enhances synaptic plasticity, both of which benefit episodic memory formation. However, to date little evidence exists from humans that would provide direct evidence for such a specific role of theta and gamma oscillations for episodic memory formation. Here, we investigate how oscillations shape the temporal structure of neural firing during memory formation in the medial temporal lobe. We measured neural firing and local field potentials in human epilepsy patients via micro-wire electrode recordings to analyze whether brain oscillations are related to co-incidences of firing between neurons during successful and unsuccessful encoding of episodic memories. The results show that phase-coupling of neurons to faster theta and gamma oscillations correlates with co-firing at short latencies (~20–30 ms) and occurs during successful memory formation. Phase-coupling at slower oscillations in these same frequency bands, in contrast, correlates with longer co-firing latencies and occurs during memory failure. Thus, our findings suggest that neural oscillations play a role for the synchronization of neural firing in the medial temporal lobe during the encoding of episodic memories.

Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding and recall of cue-object associative memories. We find no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz). Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but significantly more for remembered than forgotten trials, providing a potential mechanistic underpinning for the theta oscillations found in behavioral responses.

Neural circuits contain a wide variety of interneuron types, which differ in their biophysical properties and connectivity patterns. The two most common interneuron types, parvalbumin-expressing and somatostatin-expressing cells, have been shown to be differentially involved in many cognitive functions. These cell types also show different relationships with the power and phase of oscillations in local field potentials. The mechanisms that underlie the emergence of different oscillatory rhythms in neural circuits with more than one interneuron subtype, and the roles specific interneurons play in those mechanisms, are not fully understood. Here, we present a comprehensive analysis of all possible circuit motifs and input regimes that can be achieved in circuits comprised of excitatory cells, PV-like fast-spiking interneurons and SOM-like low-threshold spiking interneurons. We identify 18 unique motifs and simulate their dynamics over a range of input strengths. Using several characteristics, such as oscillation frequency, firing rates, phase of firing and burst fraction, we cluster the resulting circuit dynamics across motifs in order to identify patterns of activity and compare these patterns to behaviors that were generated in circuits with one interneuron type. In addition to the well-known PING and ING gamma oscillations and an asynchronous state, our analysis identified three oscillatory behaviors that were generated by the three-cell-type motifs only: theta-nested gamma oscillations, stable beta oscillations and theta-locked bursting behavior, which have also been observed in experiments. Our characterization provides a map to interpret experimental activity patterns and suggests pharmacological manipulations or optogenetics approaches to validate these conclusions.

The hippocampus is an essential hub for episodic memory processing. However, how human hippocampal single neurons code multi-element associations remains unknown. Some argue that each hippocampal neuron codes for an invariant element within an episode. Instead, others have proposed that hippocampal neurons bind together all elements present in a discrete episodic memory. Here, we provide evidence for the latter. We show that individual neurons, which we term Episode Specific Neurons (ESNs), code discrete episodic memories using either a rate code or a temporal firing code. We find evidence for these neurons exclusively in the hippocampus. Importantly, these ESNs do not reflect the coding of a particular element in the episode (i.e., concept or time). Instead, they code for the conjunction of the different elements that make up the episode. One-Sentence Summary: Individual neurons in the hippocampus code for discrete episodic memories.

1. Summary: Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding or retrieval of cue-object associative memories. We found no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz), while responses from later forgotten trials do not lock to the behavioral oscillation. Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but only for correctly remembered trials, providing a mechanistic underpinning for the theta oscillations found in behavioral responses.

The processing steps that lead up to a decision, i.e., the transformation of sensory evidence into motor output, are not fully understood. Here, we combine stereoEEG recordings from the human cortex, with single-lead and time-resolved decoding, using a wide range of temporal frequencies, to characterize decision processing during a rule-switching task. Our data reveal the contribution of rostral inferior parietal lobule (IPL) regions, in particular PFt, and the parietal opercular regions in decision processing and demonstrate that the network representing the decision is common to both task rules. We reconstruct the sequence in which regions engage in decision processing on single trials, thereby providing a detailed picture of the network dynamics involved in decision-making. The reconstructed timeline suggests that the supramarginal gyrus in IPL links decision regions in prefrontal cortex with premotor regions, where the motor plan for the response is elaborated.