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.

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 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. Here we used direct intracranial electroencephalogram (iEEG) 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 first show that spindles are modulated by the up-state of SOs. Critically, spindles were found to in turn cluster ripples in their troughs, providing fine-tuned temporal frames for the hypothesized transfer of hippocampal memory traces.

Recent findings indicate that the hippocampus supports not only longterm 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 multiitem 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. W orking memory (WM), the ability to maintain information about multiple items over a short time span, is indispensable for goal-directed behavior (1). Precise synchronization of neurons and neural networks results in oscillatory activity patterns in the gamma frequency range (25-100 Hz) and serves to facilitate neural communication and memory processing (2, 3). Data from animals and humans provide evidence that sustained increases of high-frequency activity (4-7) and theta (4-8 Hz) oscillations (8-10) are a neural correlate of WM maintenance. However, how multiple items can be simultaneously maintained without interference remains unknown. In animals, action potentials firing with respect to specific phases of ongoing theta oscillations accompany the encoding of sequences of spatial positions (11). In addition, firing rate is modulated by the phase of gamma band activity (12, 13). A related phase code based on interactions of theta phase and gamma oscillations has been suggested to support maintenance of multiple items in WM (14,15). Such crossfrequency coupling has been described in rodents (16,17) and recently in the human brain (18,19), but its link to multi-item WM has not been investigated.Here we address the question of whether multiple items are encoded by modulation of the amplitude of high-frequency oscillations by the phase of oscillations in a lower-frequency range in the human hippocampus. We used a modified Sternberg paradigm...

Deep brain stimulation (DBS) to different sites allows interfering with dysfunctional network function implicated in major depression.Because a prominent clinical feature of depression is anhedoniaFthe inability to experience pleasure from previously pleasurable activitiesFand because there is clear evidence of dysfunctions of the reward system in depression, DBS to the nucleus accumbens might offer a new possibility to target depressive symptomatology in otherwise treatment-resistant depression. Three patients suffering from extremely resistant forms of depression, who did not respond to pharmacotherapy, psychotherapy, and electroconvulsive therapy, were implanted with bilateral DBS electrodes in the nucleus accumbens. Stimulation parameters were modified in a double-blind manner, and clinical ratings were assessed at each modification. Additionally, brain metabolism was assessed 1 week before and 1 week after stimulation onset. Clinical ratings improved in all three patients when the stimulator was on, and worsened in all three patients when the stimulator was turned off. Effects were observable immediately, and no side effects occurred in any of the patients. Using FDG-PET, significant changes in brain metabolism as a function of the stimulation in fronto-striatal networks were observed. No unwanted effects of DBS other than those directly related to the surgical procedure (eg pain at sites of implantation) were observed. Dysfunctions of the reward systemFin which the nucleus accumbens is a key structureFare implicated in the neurobiology of major depression and might be responsible for impaired reward processing, as evidenced by the symptom of anhedonia. These preliminary findings suggest that DBS to the nucleus accumbens might be a hypothesis-guided approach for refractory major depression. Neuropsychopharmacology (2008) 33, 368-377; doi:10.1038/sj.npp.1301408; published online 11 April 2007 Keywords: deep brain stimulation; major depression; anhedonia; nucleus accumbens; brain stimulation; Cg25 INTRODUCTIONTraditional methods of alleviating depression largely stem from serendipitous observations of antidepressant effects of substances such as iproniazid (originally developed as a treatment for tuberculosis) or imipramine (originally developed as a treatment for schizophrenia). In particular, increasing levels of monoamine neurotransmitters in the synaptic cleft are associated with improvements of depressive symptoms. This insight led to a more targeted drug discovery process, resulting in drugs with fewer side effects, such as SSRIs. These medication treatments, in conjunction with certain methods of psychotherapy and electroconvulsive therapy, are effective at alleviating depressive symptomatology in most patients (Andrews and Nemeroff, 1994;Mann, 2005). However, these treatments do not work for all patients. A sizable minority of patients does not respond. Indeed, twelve percent of patients suffering from major depression have a poor outcome even after 5 years of treatment (Keller et al, 1992). Patien...

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Human intracranial EEG (iEEG) recordings are primarily performed in epileptic patients for presurgical mapping. When patients perform cognitive tasks, iEEG signals reveal high-frequency neural activities (HFA, between around 40 Hz and 150 Hz) with exquisite anatomical, functional and temporal specificity. Such HFA were originally interpreted in the context of perceptual or motor binding, in line with animal studies on gamma-band (‘40Hz’) neural synchronization. Today, our understanding of HFA has evolved into a more general index of cortical processing: task-induced HFA reveals, with excellent spatial and time resolution, the participation of local neural ensembles in the task-at-hand, and perhaps the neural communication mechanisms allowing them to do so. This review promotes the claim that studying HFA with iEEG provides insights into the neural bases of cognition that cannot be derived as easily from other approaches, such as fMRI. We provide a series of examples supporting that claim, drawn from studies on memory, language and default-mode networks, and successful attempts of real-time functional mapping. These examples are followed by several guidelines for HFA research, intended for new groups interested by this approach. Overall, iEEG research on HFA should play an increasing role in cognitive neuroscience in humans, because it can be explicitly linked to basic research in animals. We conclude by discussing the future evolution of this field, which might expand that role even further, for instance through the use of multi-scale electrodes and the fusion of iEEG with MEG and fMRI.

High-frequency oscillations (ripples) have been described in the hippocampus and rhinal cortex of both animals and human subjects and have been linked to replay and consolidation of previously acquired information. More specifically, studies in rodents suggested that ripples are generated in the hippocampus and are then transferred into the rhinal cortex, and that they occur predominantly during negative half waves of neocortical slow oscillations. Recordings in human epilepsy patients used either microelectrodes or foramen ovale electrodes; it is thus unclear whether macroelectrodes, which are routinely used for pre-surgical investigations, allow the recording of ripples as well. Furthermore, no direct link between ripples and behavioural performance has yet been established. Here, we recorded intracranial electroencephalogram with macroelectrodes from the hippocampus and rhinal cortex contralateral to the seizure onset zone in 11 epilepsy patients during a memory consolidation task while they were having an afternoon 'nap', i.e. a sleep period of approximately 1 h duration. We found that ripples could reliably be detected both in the hippocampus and in the rhinal cortex and had a similar frequency composition to events recorded previously with microelectrodes in humans. Results from cross-correlation analysis revealed that hippocampal events were closely locked to rhinal events and were consistent with findings on transmission of ripples from the hippocampus into the rhinal cortex. Furthermore, hippocampal ripples were significantly locked to the phase of hippocampal delta band activity, which might provide a mechanism for the reported phase-locking to neocortical slow oscillations. Ripples occurred with the highest incidence during periods when subjects lay awake during the nap time. Finally, we found that the number of rhinal, but not hippocampal, ripples was correlated with the number of successfully recalled items (post-nap) learned prior to sleep. These data confirm previous recordings in animals and humans, but move beyond them in several respects: they are the first recordings of ripples in humans during a cognitive task and suggest that ripples are indeed related to behavioural performance; furthermore, they propose a mechanism for phase-locking of ripples to neocortical slow waves via phase coupling to hippocampal delta activity; finally, they show that ripples can be recorded reliably with standard macroelectrodes in the human brain.

Alzheimer's disease (AD) manifests with memory loss and spatial disorientation. AD pathology starts in the entorhinal cortex, making it likely that local neural correlates of spatial navigation, particularly grid cells, are impaired. Grid-cell-like representations in humans can be measured using functional magnetic resonance imaging. We found that young adults at genetic risk for AD (APOE-ε4 carriers) exhibit reduced grid-cell-like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid-cell-like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE-ε4 carriers. Our results provide evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset.