Indication of increased phase coupling between theta and gamma EEG rhythms associated with the experience of auditory verbal hallucinations

Neuroscience Letters 534 (2013) 242–245

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Indication of increased phase coupling between theta and gamma EEG rhythms associated with the experience of auditory verbal hallucinations Elias Koutsoukos a,b,∗ , Elias Angelopoulos a,b , Antonis Maillis a,b , George N. Papadimitriou a , Costas Stefanis b a b

Signal Processing Laboratory, University Mental Health Research Institute, Athens, Greece Dept. of Psychiatry, Eginition Hospital, Athens University Medical School, Athens, Greece

h i g h l i g h t s  Synergy between theta and gamma EEG rhythms is associated with cognitive processes.  Auditory verbal hallucinations are considered to be autonomous cognitive processes.  Theta–gamma EEG rhythms interaction was found during auditory verbal hallucinations.

a r t i c l e

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Article history: Received 1 October 2012 Received in revised form 21 November 2012 Accepted 2 December 2012 Keywords: Auditory verbal hallucinations EEG phase synchrony Theta-gamma coupling Schizophrenia

a b s t r a c t Electroencephalographic oscillations, with different spectral contents, recorded in various brain sites are assumed to play an important role in the information processes underlying cognition as well as the abnormal brain functioning observed in nosological entities that affect neuronal connectivity such as schizophrenia. In the present study we investigated the interaction of EEG rhythms during the experience of auditory verbal hallucinations (AVHs). For this purpose we analyzed data obtained from patients suffering from persistent AVHs, focusing on the mode that the phase of theta oscillations modulate the amplitude of the broad gamma EEG oscillations. Our results indicate increased phase coupling between theta and gamma rhythms observed in the left frontotemporal cortices during AVHs, under eyes closed condition. The average differences of theta-gamma coupling between hallucinatory and resting stages in the left temporal area were found to be statistically significant. These results suggest that a theta–gamma interaction may be involved in the production and experience of AVHs in patients suffering from schizophrenia. © 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Oscillatory activity located at various brain regions and frequency bands is assumed to play an important role in the integration of the information routing underlying the cognitive processes. The strength of these activities is usually modulated by different behavioral states and task demands. The cohered and functionally coupled activity between neuronal areas associates specific rhythms with the range of the involved neuronal assemblies, in a top down processing. [10,17,18,29,32]. Early experimental findings [13] have revealed that EEG is hierarchically organized with the phase of delta band (1–4 Hz) to modulate theta (4–8 Hz) amplitude and theta phase to modulate gamma

∗ Corresponding author at: Signal Processing Laboratory, University Mental Health Research Institute, 2 Soranou Efessiou, 11527 Athens, Greece. Tel.: +302 106170901; fax: +302 106170904. E-mail address: [email protected] (E. Koutsoukos). 0304-3940/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2012.12.005

(30–50 Hz) amplitude. The proposed oscillatory hierarchy controls the baseline excitability and thus stimulus-related responses in the neuronal ensemble. Recent studies consider the important role of hippocampus in the neuronal circuitry communication [16,24]. In this brain area, oscillations in the theta and gamma frequency range occur together and interact in several ways, indicating that they are part of a common functional system. It is argued that these oscillations form a coding scheme that is used in the hippocampus to organize the readout from long-term memory of the discrete sequence of upcoming places, as cued by current position. In general, brain electrical oscillations are the result of phasic and synchronous firing of selectively distributed neural networks that form dynamic assemblies interacting in specific tasks. In humans fast oscillations in the region of gamma band have been found to be involved in attention, perception, learning and memory [3,8,11,28]. On the other hand oscillations with lower frequency content were found also underlying the memory processes [12,27]. Although brain oscillations reflect the “echo” of the functioning neuronal circuitry, under specific circumstances their interaction

E. Koutsoukos et al. / Neuroscience Letters 534 (2013) 242–245

could characterize abnormal brain functioning usually observed in nosological entities such as schizophrenia where the neuronal connectivity is disturbed [19,34]. Auditory verbal hallucinations (AVHs), the perception of voices in the absence of auditory stimuli, are common and distressing symptoms reported by 50–80% of patients with schizophrenia [21]. The results in a number of imaging and electrophysiological studies on the origins of AVH, are not consistent and the underlying pathophysiology still remains unclear. Neuroimaging studies have associated occurrences of AVHs with activation of diverse brain regions involved in speech generation, speech perception, and verbal memory [7,9,15,22,23,31]. Many of these studies have found prominent activation during AVHs in the right as well as left hemisphere [15,22] with considerable inter-subject variation concerning the cortical areas involved [7]. The “symptom-capture” approach [23] as a method to explain AVHs by imaging the dynamical changes of the brain functioning by means of EEG activity, blood flow and metabolism is adequate to isolate the “envelope of the symptom”, using EEG, functional magnetic resonance imaging or positron emission tomography, in periods associated with the appearance of auditory hallucinations. These studies report that auditory hallucinations are associated with activation of speech production areas, primary and secondary auditory cortices, and various polymodal association cortices [9,22]. Results obtained from electrophysiological studies showed that AVHs are associated with increased beta frequency oscillations generated in speechrelated areas [14] and increased ␣-band coherence between the left and right superior temporal cortices [26]. In a previous study [1] in schizophrenic patients with persistent AVHs, both intra- and inter-hemispheric phase coupling of alpha oscillations were found significantly increased compared with these of healthy controls and non-hallucinatory schizophrenic patients. This alpha band overcoupling was pronounced in tight time windows associated with the experience of AVHs indicating functional disturbance of the speech related areas. In the present study we investigated the possible interaction of brain oscillations during the experience of AVHs. For this purpose we analyzed data obtained from patients suffering from persistent AVHs, focusing in the interaction between the phase of theta and the envelope of the broad gamma EEG oscillations in a limited time window during the subjective denotation of acusmata.

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1.2. Data analysis EEG signals were band-pass filtered in two frequency bands the low (4–10 Hz) and the high (30–60 Hz). During the narrow band filtering provision has been taken regarding the zero phase lag and the resulted edge distortions of the filtered signals. The main issue was to figure out how the phase of a time series interacts or modulates the amplitude of another time series. The low-frequency signal defined after the filtering could be considered as an original time series. But, the high-frequency signal requires some treatment in order to be capable for phase computation. The following procedure derives a new time series that describes the power of high frequency amplitude vs. time. The squared magnitude of the Hilbert transform is used to extract the power time series of the high frequency signal as defined in Eq. (1). ph (t) = real[h(t)2 ] + imag[h(t)2 ]

(1)

The new time series ph (t), following subsequent normalization, removing of trends including DC and smoothing, exhibits morphological and spectral similarities with those of the low frequency signal pl (t). Thus ph (t) reflects the variation of high frequency energy envelope through the time. 1 i e [ϕlt − ϕht ]| n n

CI = |

(2)

t=1

The magnitude of CI, appeared in Eq. (2), expresses the coupling index obtained from the phase difference [ϕlt − ϕht ] for a specific time window t. A total number of 40 hallucinatory events have been included in our analysis. The above procedure applied repeatedly on EEG segments lasted 1.5–2 s prior to the marked end of the AVH. In the practice the coupling index was computed in a window defined from the time where the amplitude and the phase of pl (t) and ph (t) are consistent for 500 ms (2–4 cycles per second of theta rhythm). This experimental condition involves a number of limitations regarding the temporal accuracy between the marks and the AVH occurrences. The manually annotated AVHs, in any case, could not be considered as external-world trigger pulses essentially required

1.1. Brief review of the general procedure In this study we processed EEG data acquired from eight patients (4 males, 4 females, mean age: 35 ± 2, duration of illness: 14 ± 6 years) suffering from schizophrenia and exhibited drug-resistant spontaneous AVHs. After a detailed description of the experimental protocol, all subjects gave written informed consent, and University Mental Health Research Institute ethics committee approval was obtained. Recruitment and inclusion in the study details have been reported elsewhere [1]. All participants were selected from a larger sample of subjects suffering from schizophrenia with basic concern the ability to cooperate in the experimental procedure. Provision has been taken for the EEG recordings, since the demands for the high frequency surface recordings impose special shielding and control of the electromagnetic level of noise. Recordings from (Fp1, Fp2, F7, F3, Fz, F4, F8, FT7, FC3, FCz, FC4, FT8, T7, C3, Cz, C4, T8, TP7, CP3, CPz, CP4, TP8, P7, P3, Pz, P4, P8, O1, Oz, O2) sites have been performed in a light and sound attenuated double-skin Faraday cage. The skin resistance of each electrode was kept ≤5 k for the entire session and EEG signals were acquired by a Synamps (Neuroscan Labs) amplifier module sampled at 500 Hz. The patients were instructed to denote the experience of any AVH by pressing a miniature optical switch with the middle finger of their dominant hand to indicate the experience of AVHs.

Fig. 1. (a) shows the raw EEG of the specific case. The filtered gamma activity and the respected energy envelope are plotted in (b) with black and red lines respectively. The spectral distribution of the high frequency component is illustrated in (c). The relation of the gamma envelope and the theta component is shown in plot (d) with red and black lines respectively. Black box locates the phase convergence of theta and gamma-energy signals approximately 1 s prior the marker (thick black line) that marks the existence of an AVH.

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Fig. 2. Averaged coupling index of EEG segments recorded in periods that participants pressed the button in the absence and during the AVHs experience (a) and (b) respectively.

to detect evoked or induced EEG activity. In our study their physiological meaning was to locate a broad (1.5–2 s) window associated with the AVHs. Thus the temporal anchoring was more or less relative and not critical. For statistical reasons the computed CI under AVHs have been compared with those obtained from EEG segments recorded at periods where the same subjects were instructed to voluntarily press the button (dummy pressings) in the absence of hallucinations in a separate session of the experiment. The followed experimental design allowed us to detect the amount of coupling between EEG oscillations located in the theta and gamma EEG bands in schizophrenic patients exhibiting AVHs. 2. Results Spectral and coupling-index properties of forty EEG segments recorded during the experience of AVHs, under eyes closed condition, were analyzed and compared with those of forty EEG segments obtained from hallucination free periods (dummy pressings). Fig. 1 shows the subsequent steps followed for the detection of an AVH-related theta-gamma modulation occurrence recorded at T7 electrode. The black box shown in Fig. 1(d) indicates phase convergence between two EEG oscillations. In the specific example the theta wave (6 Hz) and the gamma-envelope (35 Hz) exhibited coupling index of 0.78 one second prior to the marker. As it is expected, these “in-phase” occurrences are not systematic and their transient nature imposed some type of time locking for the detection and the subsequent comparison. Fig. 2(b) illustrates the averaged coupling index of 40 examined cases where the EEG segments were located at 1.5–2 s prior to the marked AVH experience as denoted by patient’s feedback. On the contrary, Fig. 2(a) illustrates the averaged coupling index of EEG segments recorded in periods that participants pressed the button in the absence of AVHs. The CI differences between these two stages were found to be statistically significant with the higher averaged values to be localized in the left frontotemporal (F7, FT7, T7, TP7) areas. In the case of electrode site T7 the level of significance was (ANOVA F(1,78) = 137.42; p < 0.05). 3. Discussion Electrophysiological brain oscillations in multiple frequency bands, ranging from the lower part of delta to higher part of gamma, have been associated with various cognitive and perceptual processes [2,30]. Although these oscillations could characterize the activity of specific neural networks involved in specific brain functioning, synergy between rhythms, in terms of phase coupling, has been reported in several brain regions under specific

cognitive tasks [5,6,13,20]. In general, brain oscillations not only underlie the normal brain functioning but also is suggested to be relevant with pathophysiological brain states. In a recent study [33], schizophrenia involves abnormal oscillations and synchrony related to cognitive dysfunctions and some of the symptoms of the disorder. Indications for direct relationship between phase synchronization and coherence in pairs of EEG signals recorded from frontal, temporal, central and parietal brain areas and positive and negative symptoms of schizophrenia have also been reported [4]. More specifically, recent findings [34] indicate that functional changes of a left-lateralized frontotemporoparietal resting-state networks associated with language processing and speech monitoring may underlie and modulate persistent AVHs and symptom intensity. Previous studies [1,26] have shown detectable spectral and phasic alterations of the oscillatory activity during the experience of persistent AVHs. Based on this consideration we extended our previous study by focusing on the possible interaction between high-low EEG spectral content in the case of AVHs. The increased phase coupling between theta and gamma rhythms observed in left frontotemporal cortices during AVHs were found to be significant, compared with the coupling of the resting EEG recorded from the same individuals. Since AVH could be considered arbitrary (in the absence of external stimuli) cognitive process, the increased phase coupling differences found, may partly reflect the AVH underlying mechanism. The increased synchrony found in speech related areas associated with AVHs symptoms [1] can be conceptualized with the notion that the functional engagement of different cortical areas causes segregation or increased information flow across specialized brain areas [25]. In analogy, the increased inter-rhythm coupling found in the present study, imply binding of different oscillations related to AVHs production in a speech related area, with theta phase to drive or modulate gamma amplitude during the production of acusmata. An issue that should be considered in our methodology is the confounding factors related with the ability of the patient to precisely report the initiation and completion of the hallucinatory experience. However, in order to limit subjectivity errors, we carefully selected patients with insight, high level of education and good social functioning to improve the cooperation during the experimental procedure.

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