Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats

BACKGROUND/AIMS: The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-D-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats. METHODS: Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli. RESULTS: Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components. CONCLUSIONS: Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders

Explore the Functional Connectivity between Brain Regions during a Chemistry Working Memory Task.

Previous studies have rarely examined how temporal dynamic patterns, event-related coherence, and phase-locking are related to each other. This study assessed reaction-time-sorted spectral perturbation and event-related spectral perturbation in order to examine the temporal dynamic patterns in the frontal midline (F), central parietal (CP), and occipital (O) regions during a chemistry working memory task at theta, alpha, and beta frequencies. Furthermore, the functional connectivity between F-CP, CP-O, and F-O were assessed by component event-related coherence (ERCoh) and component phase-locking (PL) at different frequency bands. In addition, this study examined whether the temporal dynamic patterns are consistent with the functional connectivity patterns across different frequencies and time courses. Component ERCoh/PL measured the interactions between different independent components decomposed from the scalp EEG, mixtures of time courses of activities arising from different brain, and artifactual sources. The results indicate that the O and CP regions' temporal dynamic patterns are similar to each other. Furthermore, pronounced component ERCoh/PL patterns were found to exist between the O and CP regions across each stimulus and probe presentation, in both theta and alpha frequencies. The consistent theta component ERCoh/PL between the F and O regions was found at the first stimulus and after probe presentation. These findings demonstrate that temporal dynamic patterns at different regions are in accordance with the functional connectivity patterns. Such coordinated and robust EEG temporal dynamics and component ERCoh/PL patterns suggest that these brain regions' neurons work together both to induce similar event-related spectral perturbation and to synchronize or desynchronize simultaneously in order to swiftly accomplish a particular goal. The possible mechanisms for such distinct component phase-locking and coherence patterns were also further discussed

Oscillation Phase Locking and Late ERP Components of Intracranial Hippocampal Recordings Correlate to Patient Performance in a Working Memory Task

In working memory tasks, stimulus presentation induces a resetting of intracranial temporal lobe oscillations in multiple frequency bands. To further understand the functional relevance of this phenomenon, we investigated whether working memory performance depends on the phase precision of ongoing oscillations in the hippocampus. We recorded intra-hippocampal local field potentials in individuals performing a working memory task. Two types of trials were administered. For high memory trials presentation of a list of four letters ( List ) was followed by a single letter memory probe ( Test ). Low memory load trials, consisting of four identical letters (AAAA) followed by a probe with the same letter (A), were interspersed. Significant phase locking of ongoing oscillations across trials, estimated by the Pairwise Phase Consistency Index (PPCI) was observed in delta (0.5-4 Hz), theta (5-7 Hz), and alpha (8-12 Hz) bands during stimulus presentation and recall but was increased in low memory load trials. Across patients however, higher delta PPCIs during recall in the left hippocampus were associated with faster reaction times. Because phase locking could also be interpreted as a consequence of a stimulus evoked potential, we performed event related potential analysis (ERP) and examined the relationship of ERP components with performance. We found that both amplitude and latency of late ERP components correlated with both reaction time and accuracy. We propose that, in the Sternberg task, phase locking of oscillations, or alternatively its ERP correlate, synchronizes networks within the hippocampus and connected structures that are involved in working memory

Pure phase-locking of beta/gamma oscillation contributes to the N30 frontal component of somatosensory evoked potentials

BACKGROUND: Evoked potentials have been proposed to result from phase-locking of electroencephalographic (EEG) activities within specific frequency bands. However, the respective contribution of phasic activity and phase resetting of ongoing EEG oscillation remains largely debated. We here applied the EEGlab procedure in order to quantify the contribution of electroencephalographic oscillation in the generation of the frontal N30 component of the somatosensory evoked potentials (SEP) triggered by median nerve electrical stimulation at the wrist. Power spectrum and intertrial coherence analysis were performed on EEG recordings in relation to median nerve stimulation. RESULTS: The frontal N30 component was accompanied by a significant phase-locking of beta/gamma oscillation (25-35 Hz) and to a lesser extent of 80 Hz oscillation. After the selection in each subject of the trials for which the power spectrum amplitude remained unchanged, we found pure phase-locking of beta/gamma oscillation (25-35 Hz) peaking about 30 ms after the stimulation. Transition across trials from uniform to normal phase distribution revealed temporal phase reorganization of ongoing 30 Hz EEG oscillations in relation to stimulation. In a proportion of trials, this phase-locking was accompanied by a spectral power increase peaking in the 30 Hz frequency band. This corresponds to the complex situation of 'phase-locking with enhancement' in which the distinction between the contribution of phasic neural event versus EEG phase resetting is hazardous. CONCLUSION: The identification of a pure phase-locking in a large proportion of the SEP trials reinforces the contribution of the oscillatory model for the physiological correlates of the frontal N30. This may imply that ongoing EEG rhythms, such as beta/gamma oscillation, are involved in somatosensory information processing.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

The oscillatory mechanisms of working memory maintenance

Working memory (WM) is a cognitive process which allows for maintenance of information that is no longer perceived. Although theoretical models have recognized that working memory involves interactions across cell assemblies in multiple brain areas, the exact neural mechanisms which support this process remain unknown. In this thesis I investigate the neural dynamics in the human hippocampus, the ventral, dorsal and frontal cortex as well as the long-range network connectivity across these brain areas to understand how such a distributed network allows for maintenance of various information pieces in WM. The results described here support a model in which working memory relies on dynamic interactions across frequencies (the cross-frequency coupling, CFC) in a distributed network of cortical areas coordinated by the prefrontal cortex. In particular, maintenance of information during a delay period selectively involves the hippocampus, dorsal and ventral visual stream as well as the prefrontal cortex each of which represents different features. The hippocampus contributes to this large network specifically by representing multiple items in working memory. In two independent experiments I observed that the low-frequency activity (a marker of neural inhibition) was linearly reduced across memory loads. Importantly, the hippocampus showed very prominent low-frequency power during maintenance of a single item suggesting that during this condition the neural processing was strongly inhibited. In turn, the broadband gamma activity was linearly increasing as a function of memory load. This pattern of results may be interpreted as reflecting an increased involvement of the hippocampus in representing longer sequences. Importantly, the low-frequency decrease was not static but fluctuated periodically between two different modes. One of the modes was characterized by the load-dependent power decreases and reduced cross-frequency coupling (memory activation mode) whereas the other mode was reflected by the load-independent high levels of power and increased coupling strength (load-independent mode). Crucially, these modes were temporally organized by the phase of an endogenous delta rhythm forming a “hierarchy of oscillations”. This periodicity was essential for the successful performance. Finally, during the memory activation mode the WM capacity limit was inter-individually correlated with the peak frequency change as predicted by the multiplexing model of WM. All these effects were subsequently replicated in an independent dataset. These results suggest that the hippocampus is involved in WM maintenance showing periodic fluctuations between two different oscillatory modes. Parameters of the hippocampal iEEG signal correlate with individual WM capacity, specifically during the memory activation mode. The ventral and dorsal visual stream each contributes to the distributed WM network by representing configuration and spatial information, respectively. Specifically, the alpha power in the ventral visual stream was decreased during maintenance of face identities. In turn, the alpha power was desynchronized in the dorsal visual stream while participants were maintaining face orientations. This shows that the alpha power double dissociates between the feature specific networks in the ventral and dorsal visual stream. These effects are further interpreted as reflecting selective involvement of the dorsal and ventral visual pathway depending on the maintained features. Importantly, each of the visual streams was selectively synchronized with the prefrontal cortex depending on the memory condition and the alpha power. This corroborates a central prediction from the gating by inhibition model which assumes that the increased alpha power serves as the mechanism for gating of information by inhibiting task redundant pathways. Moreover, during maintenance of information the phase of alpha modulated the amplitude of high-frequency activity both in the dorsal and ventral visual stream. Additionally,the low-frequency phase in the prefrontal cortex modulated high-frequency activity both in the dorsal and ventral visual stream. These results suggest that both the dorsal and ventral visual streams are selectively involved during maintenance of distinct features (i.e. face orientation and identity, respectively). They also indicate that the prefrontal cortex selectively gets synchronized with the visual regions depending on the alpha power in that region and the maintained feature. Finally, the activity in the prefrontal cortex influences processing across long distance as evident from changes in the phase synchrony with the visual cortical areas and by modulating gamma power in the visual cortical regions. It is also noted that the ventrolateral prefrontal cortex (vlPFC) contains information regarding abstract rules (i.e. response mapping). In particular, using a multivariate decoding approach I found that the local field potentials recorded from the vlPFC dissociate between different types of responses. At the same time I observed no evidence for the load-dependent or stimulus-specific changes in that brain region. The null effect should be treated with caution. Nevertheless, the current results suggest that the vlPFC may contribute to working memory by processing of abstract rules such as a mapping between the stimulus and the response. Furthermore, I found that the alpha power dependent duty cycle in the vlPFC constrains the duration of the gamma burst which has been suggested as a mechanism for neural inhibition. This finding is important because such a property of the alpha activity has never been observed in a brain region other than the primary sensory cortex. Together, the results presented in this thesis support a model according to which the working memory is a complex and highly dynamic process engaging hierarchies of oscillations across multiple cortical regions. In particular, the hippocampus is important for the multi-item WM. The dorsal and ventral visual streams are relevant for distinct visual features. Finally, the prefrontal cortex represents abstract rules and influences processing in other cortical regions likely providing a top down control over these regions

Oscillations and Episodic Memory: Addressing the Synchronization/Desynchronization Conundrum

Brain oscillations are one of the core mechanisms underlying episodic memory. However, while some studies highlight the role of synchronized oscillatory activity, others highlight the role of desynchronized activity. We here describe a framework to resolve this conundrum and integrate these two opposing oscillatory behaviors. Specifically, we argue that the synchronization and desynchronization reflect a division of labor between a hippocampal and a neocortical system, respectively. We describe a novel oscillatory framework that integrates synchronization and desynchronization mechanisms to explain how the two systems interact in the service of episodic memory

High-frequency neural oscillations and visual processing deficits in schizophrenia

Visual information is fundamental to how we understand our environment, make predictions, and interact with others. Recent research has underscored the importance of visuo-perceptual dysfunctions for cognitive deficits and pathophysiological processes in schizophrenia. In the current paper, we review evidence for the relevance of high frequency (beta/gamma) oscillations towards visuo-perceptual dysfunctions in schizophrenia. In the first part of the paper, we examine the relationship between beta/gamma band oscillations and visual processing during normal brain functioning. We then summarize EEG/MEG-studies which demonstrate reduced amplitude and synchrony of high-frequency activity during visual stimulation in schizophrenia. In the final part of the paper, we identify neurobiological correlates as well as offer perspectives for future research to stimulate further inquiry into the role of high-frequency oscillations in visual processing impairments in the disorder

Premotor and prefrontal contributions to modulating upper limb somatosensory input into non-primary motor areas

Upper limb motor control requires the use and integration of afferent somatosensory input from peripheral receptors to help plan and prepare movements. Cortical surface electroencephalography can be used to measure the earliest relay and processing of mixed somatosensory input in primary (SI) and secondary somatosensory (SII) cortices using parietal somatosensory evoked potentials (SEPs) that occur 20 to 100 milliseconds (ms) after median nerve stimulation. Moreover, somatosensory input into non-primary motor areas, such as premotor cortex (PMC) and supplementary motor area (SMA), can be measured by frontal N30 and N60 SEPs. Therefore, frontal N30 and N60 SEPs may provide an important neurophysiological link between somatosensory processing and upper limb motor control. Both PMC and SMA have intracortical connections with primary motor cortex (M1) and prefrontal cortex (PFC) as well as intercortical connections with their contralateral representations. However, it is not fully understood how somatosensory input in non-primary motor areas, represented by frontal SEPs, are modulated in the cortex by contralateral PMC and ipsilateral PFC. A modulatory role of contralateral M1 but not contralateral premotor areas on somatosensory input into non-primary motor areas has been established through contralateral movement paradigms. Furthermore, a modulatory role of the ipsilateral PFC on somatosensory input into non-primary motor areas has been identified through prefrontal lesion patients but it is unclear how PFC functionally modulates this somatosensory input during movement. Thus, the current thesis aimed to evaluate the contributions of the ipsilateral PFC as well as contralateral PMC on somatosensory processing in non-primary motor areas as well as SI/SII. SEP modulations were examined using experimental manipulations of top-down attention and cued contralateral movements to evaluate PFC and PMC contributions, respectively. In addition, continuous theta burst stimulation, a specific type of inhibitory non-invasive transcranial magnetic stimulation technique, was applied over PMC and PFC to evaluate their specific contributions to modulating somatosensory input into non-primary motor areas and SI/SII during a cued movement task. Understanding frontal SEP modulations and their association with upper limb motor control will have important applications for understanding dysfunctional upper limb motor control in various neurological disorders such as Parkinson’s disease (PD) that are known to have irregular frontal SEPs. The main findings from Chapters 2 and 3 revealed that frontal N30 and N60 SEPs were decreased during early response selection and increased during the late stages of preparing finger sequences to attended somatosensory input. In contrast, SI/SII input represented by parietal P50 and P100 SEPs were increased with attention. The main results of Chapter 4 showed that N30 and N60 SEPs were decreased and increased after transiently decreasing excitability in left PMC and right PFC, respectively. Collectively, the results of this thesis revealed temporally-specific modulations of somatosensory input into non-primary motor areas during contralateral upper limb movements that are a result of changes in activity in a network that includes the right PFC and left PMC

Neural Correlates of Auditory Perceptual Awareness and Release from Informational Masking Recorded Directly from Human Cortex: A Case Study.

In complex acoustic environments, even salient supra-threshold sounds sometimes go unperceived, a phenomenon known as informational masking. The neural basis of informational masking (and its release) has not been well-characterized, particularly outside auditory cortex. We combined electrocorticography in a neurosurgical patient undergoing invasive epilepsy monitoring with trial-by-trial perceptual reports of isochronous target-tone streams embedded in random multi-tone maskers. Awareness of such masker-embedded target streams was associated with a focal negativity between 100 and 200 ms and high-gamma activity (HGA) between 50 and 250 ms (both in auditory cortex on the posterolateral superior temporal gyrus) as well as a broad P3b-like potential (between ~300 and 600 ms) with generators in ventrolateral frontal and lateral temporal cortex. Unperceived target tones elicited drastically reduced versions of such responses, if at all. While it remains unclear whether these responses reflect conscious perception, itself, as opposed to pre- or post-perceptual processing, the results suggest that conscious perception of target sounds in complex listening environments may engage diverse neural mechanisms in distributed brain areas

The role of multi-scale phase synchronization and cross-frequency interactions in cognitive integration

Neuronal processing is distributed into anatomically distinct, largely specialized, neuronal populations. These populations undergo rhythmic fluctuations in excitability, which are commonly known as neuronal oscillations. Electrophysiological studies of neuronal activity have shown that phase synchronization of oscillations within frequencies characterizes both resting state and task execution and that its strength is correlated with task performance. Therefore phase-synchronization within frequencies is thought to support communication between oscillating neuronal populations and thereby integration and coordination of anatomically distributed processing in cognitive functions. However, it has remained open if and how phase synchronization is associated with directional flow of information. Furthermore, oscillations and synchronization are observed concurrently in multiple frequencies, which are thought to underlie distinct computational functions. Little is known how oscillations and synchronized networks of different frequencies in the human brain are integrated and enable unified cognitive function and experience. In the first study of this thesis, we developed a measure of directed connectivity in networks of coupled oscillators, called Phase Transfer Entropy (Phase TE) and tested if Phase TE could detect directional flow in simulated data in the presence of noise and signal mixing. Results showed that Phase TE indeed reliably detected information flow under these conditions and was computationally efficient. In the other three studies, we investigated if two different forms of inter-areal cross-frequency coupling (CFC), namely cross-frequency phase synchrony (CFS) and phase-amplitude coupling (PAC), could support integration and coordination of neuronal processing distributed across frequency bands in the human brain. In the second study, we analyzed source-reconstructed magneto- and electroencephalographic (M/EEG) data to investigate whether inter-areal CFS could be observed between within-frequency synchronized networks and thereby support the coordination of spectrally distributed processing in visual working memory (VWM). The results showed that CFS was increased during VWM maintenance among theta to gamma frequency bands and the strength of CFS networks predicted individual VWM capacity. Spectral patterns of CFS were found to be different from PAC, indicating complementary roles for both mechanisms. In the third study, we analyzed source-reconstructed M/EEG data to investigate whether inter-areal CFS and PAC could be observed during two multi-object visual tracking tasks and thereby support visual attention. PAC was found to be significantly correlated with object load in both tasks, and CFS in one task. Further, patterns of CFS and PAC differed significantly between subjects with high and low capacity for visual attention. In the fourth study, we analyzed intracerebral stereo-electroencephalographic data (SEEG) and source-reconstructed MEG data to investigate whether CFS and PAC are present also in resting state. Further, in order to address concerns about observations of CFC being spurious and caused by non-sinusoidal or non-zero mean signal waveforms, we introduced a new approach to identify true inter-areal CFC connections and discard potentially spurious ones. We observed both inter-areal CFS and PAC, and showed that a significant part of connections was unambiguously true and non-spurious. Spatial profiles differed between CFS and PAC, but were consistent across datasets. Together, the results from studies II-IV provide evidence that inter-areal CFS and PAC, in complementary ways, connect frequency-specific phase-synchronized networks that involve functionally specialized regions across the cortex to support complex functions such as VWM and attention, and also characterize the resting state. Inter-areal CFC thus may be crucial for the coordination and integration of spectrally distributed processing and the emergence of introspectively coherent cognitive function.Keskeinen kysymys aivotutkimuksessa on, kuinka ajattelu ja kognitio syntyvät ihmisaivojen 10^15 hermosolussa. Informaation käsittely aivoissa tapahtuu suurissa hermosolupopulaatioissa, jotka ovat toiminnallisesti erikoistuneita ja anatomisesti eroteltuja eri aivoalueille. Niiden aktivaatiorakenteiden jaksollisia muutoksia kutsutaan aivorytmeiksi eli oskillaatioiksi. Hermosolupopulaatioiden välistä viestintää edesauttaa niiden toiminnan samantahtisuus eli synkronoituminen. Sähköfysiologisissa tutkimuksissa on havaittu aivorytmien synkronoituvan sekä lepomittausten että tehtävien suorituksen aikana siten että tämä synkronoituminen ennustaa kognitiivissa tehtävissä suoriutumista. Oskillaatioiden vaihesynkronia ei kuitenkaan kerro niiden välisen vuorovaikutuksen suunnasta. Tämän lisäksi oskillaatioita ja niiden välistä synkroniaa havaitaan yhtäaikaisesti lukuisilla eri taajuuksilla, joiden ajatellaan olevan vastuussa erillisistä laskennallisista ja kognitiivisista toiminnoista. Toistaiseksi on kuitenkin jäänyt kartoittamatta, miten informaation käsittely eri taajuuksilla yhdistetään yhtenäisiksi kognitiivisiksi toiminnoiksi, ja havaitaanko myös eri taajuisten oskillaatioverkkojen välillä synkroniaa. Väitöskirjan ensimmäisessä osatyössä on kehitetty uusi tapata mitata oskillaattoriverkkojen vuorovaikutusten suuntia, jonka toimivuus todennettiin simuloimalla synkronoituneita hermosolupopulaatioita. Väitöskirjan muissa osatöissä on tutkittu havaitaanko ihmisaivoissa eri taajuisten oskillaatioiden välistä synkronoitumista. Erityisesti tutkittiin kahta erilaista synkronian muotoa, joista ensimmäinen (’cross- frequency phase synchrony’,CFS) mittaa kahden oskillaation välistä vaihesuhdetta ja toinen (’phase-amplitude coupling’, PAC) vaiheen ja amplitudin suhdetta. Väitöskirjan toisessa osassa tutkittiin, selittääkö CFS koehenkilöiden suoriutumista näkötyömuistitehtävässä. Tutkimukseen osallistuneilta koehenkilöiltä mitattiin aivosähkökäyrä (EEG) ja aivomagneettikäyrä (MEG), joiden avulla selvitettiin havaitaanko aivoalueiden välistä synkroniaa (CFS). Tutkimustulokset osoittivat, että koehenkilöiden CFS oli korkeampi näkötyömuistitehtävän mielessä pitämisen aikana theta-taajuuksista gamma-taajuuksiin asti ja että CFS-verkkojen vahvuus ennusti yksilöllistä työmuistikapasiteettia. Kolmannessa tutkimuksessa analysoitiin MEG- ja EEG-aivokuvantamislaitteita käyttäen onko aivoalueiden välillä CFS:ä ja PAC:a kahdessa näkötarkkaavaisuustehtävässä. PAC lisääntyi tilastollisesti merkitsevästi tehtävän vaikeuden mukaan kummassakin tehtävässä, kun taas CFS lisääntyi yhdessä tehtävässä. Lisäksi CFS ja PAC taajuusparit olivat erilaisia hyvin suoriutuvien koehenkilöiden sekä heikosti suoriutuvien koehenkilöiden välillä. Neljännessä tutkimuksessa tutkittiin havaitaanko CFS:ä ja PAC:a aivojen lepotilassa. Aivokuoren aktiivisuutta mitattiin MEG:llä sekä epilepsiapotilailta aivoihin kirurgisesti asetetuilla elektrodeilla. CFS:ä sekä PAC:a havaittiin kummallakin menetelmällä. Lisäksi kehitimme menetelmän joka vähentää väärien havaintojen todennäköisyyttä ja lisää aitojen CFS ja PAC yhteyksien havaitsemista. Tulokset osoittavat, että merkittävä osuus yhteyksistä aivoalueiden välillä on aitoja. CFS- ja PAC-profiilit erosivat toisistaan, mutta olivat samanlaisia eri menetelmillä tutkittaessa. Yhdistettynä tulokset tutkimuksista II–IV viittaavat siihen, että CFS ja PAC yhdistävät eri taajuuksille ja aivoalueille hajautettua informaation käsittelyä. CFS:sää ja PAC:ia havaittiin aivojen lepotilassa mutta myös tarkkaavaisuus- ja näkötyömuistitehtävän aikana. CFS ja PAC saattavat mahdollistaa eri taajuisten aivorytmien ja hajautettujen prosessien koordinaation ja yhdistämisen