Neural oscillations as a translational tool in schizophrenia research: rationale, paradigms and challenges.

562093 research-article2015

JOP0010.1177/0269881114562093Journal of PsychopharmacologyPhillips and Uhlhaas

Review

Neural oscillations as a translational tool in schizophrenia research: Rationale, paradigms and challenges Keith G Phillips1 and Peter J Uhlhaas2

Journal of Psychopharmacology 2015, Vol. 29(2) 155–168 © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881114562093 jop.sagepub.com

Abstract Neural oscillations have received recently a great deal of interest in schizophrenia research because of the possibility to integrate findings from non-invasive electro/magnetoencephalographical recordings with pre-clinical research, which could potentially lead to the identification of pathophysiological mechanisms and novel treatment targets. In the current paper, we review the potential as well as the challenges of this approach by summarizing findings on alterations in rhythmic activity from both animal models and human data which have implicated dysfunctional neural oscillations in the explanation of cognitive deficits and certain clinical symptoms of schizophrenia. Specifically, we will focus on findings that have examined neural oscillations during 1) perceptual processing, 2) working memory and executive processes and 3) spontaneous activity. The importance of the development of paradigms suitable for human and animal models is discussed as well as the search for mechanistic explanation for oscillatory dysfunctions.

Keywords Schizophrenia, oscillations, cognition, animal models

Introduction Recently, neural oscillations and their synchronization (neural synchrony) have received considerable interest in psychiatric research (Uhlhaas and Singer, 2012). This is because transient synchronization of neuronal discharges has been proposed as one possible mechanism to dynamically bind widely distributed sets of neurons into functionally coherent ensembles during normal brain functioning (Singer, 1999). Accordingly, cognitive deficits and certain clinical symptoms in psychiatric disorders, such as schizophrenia (ScZ), may be considered in the context of dysfunctional rhythmic activity (Uhlhaas and Singer, 2010). In the following review, we will summarize the role of neural synchrony during normal brain functioning and the underlying neurobiological mechanisms, followed by a detailed overview of studies which have investigated neural oscillations in ScZpatients using non-invasive electro/magnetoencephalographical (EEG/MEG) recordings as well as in animal models of the disorder. In particular, we will examine the translational potential of current experimental paradigms that focus on sensory processing, working memory (WM) and executive functions as well as spontaneous activity.

spheres (Engel et al., 1991), and is modulated in a task- and attention-dependent way (Fries et al., 2001; Roelfsema et al., 1997). Furthermore, studies in human participants combining noninvasive recording techniques, such as EEG and MEG, with advanced methods of time series analysis have revealed that neural synchrony is associated with cognitive functions that require large-scale integration of distributed neural activity (Varela et al., 2001). Examples are attention-dependent stimulus selection, multimodal integration, WM, selective routing of activity and conscious processing of stimuli (Siegel et al., 2012; Uhlhaas et al., 2009). Synchronization in these studies was consistently associated with an oscillatory patterning of neuronal responses, most often in the beta (15–30 Hz) and gamma (30–200 Hz) frequency range. Subsequent research has indicated that such high-frequency oscillations are particularly effective in supporting precise synchronization of neuronal discharges (Fries et al., 2001). In general, there is a correlation between the distance over which synchronization is observed and the frequency of the synchronized oscillations. Short

Neural oscillations and cognition in largescale networks

1Lilly

First insights into the functional role of neural synchrony came from investigations on feature binding in vision (Gray et al., 1989). However, neural synchrony also seems relevant for large-scale integration of distributed neural activity since it occurs between distant cortical areas, for example, across visual areas in the two hemi-

Centre for Cognitive Neuroscience, Eli Lilly and Company, Windlesham, UK 2Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK Corresponding author: Peter J Uhlhaas, Institute of Neuroscience and Psychology, University of Glasgow, Hillead Str. 58, Glasgow, G12 8QB, UK. Email: [email protected]

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Table 1. Neural oscillations in cortical networks. Theta (4–7 Hz)

Alpha (8–12 Hz)

Beta (13–30 Hz)

Gamma (30–200 Hz)

Anatomy

Hippocampus, prefrontal cortex, sensory cortex

Thalamus, hippocampus reticular formation sensory cortex, motor cortex

All brain structures, retina, olfactory bulb

Neurotransmitters

GABA, glutamate, acetylcholine Memory, synaptic plasticity, top-down control, long-range synchronization

Glutamate, acetylcholine, serotonin Inhibition, attention, consciousness, top-down control, long-range synchronization

All cortical structures, subthalamic nucleus, hippocampus basal ganglia, olfactory bulb Glutamate, GABA, dopamine Sensory gating, attention, perception, motor control, long-range synchronization

Function

distance synchronization tends to occur at higher frequencies (beta/ gamma-band) than long-distance synchronization (von Stein and Sarnthein, 2000) (Table 1).

Neurobiology of neural oscillations Importantly, signatures of neural oscillations can be readily quantified in non-invasive EEG/MEG-measurements in humans as well as in local field potentials (LFPs) and single-unit recordings in rodents. These clinical and pre-clinical techniques all share the advantage of a high temporal resolution for neuronal events that can be time locked to behavioural or pharmacological interventions. The spatial localization of the current sources responsible for generating these oscillations can be difficult to resolve especially using low density EEG recordings. The voltage responses recorded using EEG are, effectively, smoothed versions of the underlying LFPs mainly due to the distance and distorting effects of skin and muscles. Some of these difficulties can be overcome using new high density EEG recording techniques in combination with source modelling (Michel et al., 2004) or through the use of MEG that is much less dependent on the conductivity of the extracellular space (Gross et al., 2001). However, the underlying contribution of synaptic, neuronal spiking and other ionic process responsible for generating the field is likely to be similar between these clinical and preclinical techniques. Because of their shared characteristic and preserved mechanisms of generation across species (Buzsaki et al., 2013), parameters of rhythmic activity are an accessible and comparable biophysical signal ideally suited for translation research. In addition, recent advances in the development of signal-processing approaches have significantly expanded the repertoire to analyse neural oscillations in terms of their synchrony, amplitude and cross-frequency-coupling (Gross, 2014) (see Table 2). Moreover, there is consistent evidence for linking specific frequencies to distinct physiological mechanisms. Experimental and theoretical data indicate that the networks of mutually interacting GABAergic neurons, especially those expressing the calcium binding protein parvalbumin (PV), are crucially involved as pacemakers in the generation of high-frequency oscillations in local circuits (Buzsaki and Wang, 2012). Sohal and colleagues (2009) probed the influence of up- and down-regulation of PV interneurons on gamma-band oscillations in mice. Inhibition of PV interneurons led to an immediate suppression of 30–80 Hz

GABA, glutamate, acetylcholine Perception, attention, memory, consciousness, synaptic plasticity, motor control

oscillations while 10–30 Hz oscillations increased in power. In contrast, increasing PV-interneuron mediated feedback inhibition by boosting principal cell activity enhanced gamma-band power (Cardin et al., 2009). Recent studies have also examined the role of glutamatergic inputs to PV interneurons for the generation of coordinated network-activity. Thus, both N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been shown to exert significant effects on gamma-band oscillations through modulating excitatory transmission on PV cells (Fuchs et al., 2001; Korotkova et al., 2010). Low-frequency activity in the theta-frequency range has been linked to distinct rhythm generating mechanisms. Specifically, Klausberger et al. (2005) demonstrated that cholecystokinin(CCK) and PV-expressing interneurons have different contributions towards hippocampal network oscillations. While PV cells were closely linked to gamma-band activity, CCK interneurons fired with a frequency ~ 8 Hz at a characteristic time on the ascending phase of theta waves. In addition to relationships between specific GABAergic interneurons and rhythmic activity, there is also evidence on layer-specific expression of neural oscillations. Thus, gammaband oscillations are particularly prominent in superficial layers (layers 2/3) (Buffalo et al., 2011). In contrast, beta oscillations are largely found in infragranular layers and can be independent of excitatory or inhibitory synaptic transmission (Roopun et al., 2008).

Neural oscillations and the pathophysiology of ScZ Over the last decade, substantial evidence has demonstrated impairments in neural oscillations in ScZ and related disorders (Uhlhaas and Singer, 2010), which may allow critical insights into the pathophysiology of the syndrome (Spencer, 2008; Uhlhaas and Singer, 2012). Evidence suggests that the neurobiological mechanisms assuring the generation of rhythmic activity at low- and high-frequency oscillations during normal brain functioning are disturbed in ScZ and related disorders (Benes and Berretta, 2001; Lewis et al., 2012). Specifically, the mRNA of GAD67, which synthesizes GABA, is reduced in several cortical areas, including visual regions, in ScZ patients (Hashimoto et al., 2008). Moreover, this


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Phillips and Uhlhaas Table 2. Key concepts of neuronal oscillations. Measure

Definition

Neural oscillation Spectral power

Rhythmic neural activity within a circumscribed frequency range Reflects the amplitude of neural oscillations computed through a time-frequency transformation The phase of an oscillation refers to the momentary deflection of an oscillation, that is, the peak or trough Measures the covariance of phase-values between two signals through separating phase and amplitude components A measure of local integration (~ 1 cm) which is typically reflected in fluctuations of the oscillation amplitude Synchronizations between widely separated brain regions (> 2 cm) as reflected, for example, in phase synchrony Modulation of phase or amplitude between different oscillation frequencies

Phase Phase synchrony Local synchrony Long-range synchrony Cross-frequency coupling

Table 3. Constructs for translational research. Construct

Human data

Pre-clinical data

Translational value and challenges

Perception

Extensive evidence for impaired high-frequency oscillations during both visual and auditory perception in ScZ. Overall, the evidence points to a reduction of both amplitude and synchrony of rhythmic activity, especially at beta/ gamma-band frequencies. Preliminary evidence for reduced low- and high-frequency activity in EEG-recordings which may be related to deficits in WM in ScZ. In addition, cognitive control processes may be associated with gamma-band deficits in ScZ.

NMDA-antagonists reduce ASSRs. Similarly, ScZ-risk genes lead to a decrease in sensory-elicited gamma-band oscillations.

Perceptual processes represent a crucial area of research as sensory processing is disturbed in ScZ. A key challenge is the implementation of perceptual paradigms in rodent models of ScZ.

Genetic models of ScZ show impaired PFC-HPC synchrony at theta-band frequency. In addition, there is evidence for disturbance in thalamocortical interactions.

WM and executive functions represent an important construct in ScZ research. Further development of paradigms is required to examine reliably WM signatures in EEG/MEG recordings as well as in pre-clinical models. Examination of spontaneous activity in electrophysiology is an important parameter for the understanding of disturbances in rhythmic activity. Further studies need to provide a more detailed insight into the pattern of rhythmic activity during resting-state and sleep in ScZ.

WM and executive deficits

Spontaneous Activity

Conflicting evidence whether spontaneous high-frequency activity is altered in ScZ. There is further data to suggest that low-frequency power is increased during resting-state recordings. Moreover, there is evidence of reductions in sleep spindles and slow wave density.

Increases in spontaneous highfrequency oscillations are a hallmark of NMDA-antagonists and animal models of ScZ. Moreover, animal models show a disruption of delta/thetaband oscillations during sleep.

ScZ: schizophrenia; NMDA: N-methyl-D-aspartate; ASSR: auditory steady-state response; WM: working memory; EEG: electroencephalographical; MEG: magnetoencephalographical.

decrease is a ccompanied by reduced expression of the GABA membrane transporter 1 (GAT1) (Lewis et al., 2005). Further investigation revealed cell-type specific impairments in GABAergic interneurons in post-mortem data. For example, GAD67 mRNA was not detectable in 50% of PV+ interneurons, whereas the overall number of cells was unchanged (Hashimoto et al., 2003). In addition to impaired PV-cell activity, reduced expression-levels of CCK mRNA were observed (Curley and Lewis, 2012), highlighting the potential contribution of distinct GABAergic interneurons towards rhythmic abnormalities in ScZ.

Additional parameters which are crucial for the generation of high-frequency oscillations are the AMPA- and NMDAreceptor-mediated activation of PV interneurons (Belforte et al., 2010; Carlen et al., 2011). Dysfunction of the NMDA-receptor has been implicated in the pathophysiology of ScZ through evidence from genetics (Kirov et al., 2012) as well as from studies which have tested the impact of NMDA-receptor blockade on cortical processes (Kantrowitz and Javitt, 2010). In healthy controls, ketamine, an antagonist of the NMDA-receptor, elicits the full range of psychotic symptoms and impairments in cognitive processes (Krystal et al., 2002).


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Evidence for neural oscillation abnormalities in ScZ and pre-clinical animal models In the following section, we review the evidence on the respective abnormalities in rhythmic activity in regard to three domains which have been extensively investigated in both human EEG/ MEG-recordings and pre-clinical research. Specifically, we will focus on 1) perception 3) WM and executive processes and 3) spontaneous activity.

Perception in ScZ Sensory perception represents a major domain of impairment in ScZ (Javitt, 2009; Uhlhaas and Mishara, 2007). Evidence suggests that disturbances in the processing of both visual and auditory information are associated with alterations in psychophysical, anatomical and neuroimaging parameters (Braus et al., 2002; Selemon et al., 1995; White et al., 2011). Neural oscillations, especially during visual perception, have been extensively investigated using invasive electrophysiology recordings in non-human primates (Lima et al., 2010; Ray and Maunsell, 2010). This research has produced a large body of evidence that has identified the relationship between the occurrence of high-frequency oscillations, stimulus variables and cognitive factors, such as attention, which provide a rich source of hypothesis generation for examining the mechanisms involved in sensory processing and oscillatory deficits in ScZ-patients (Tan et al., 2013).

Steady-state responses in ScZ. The majority of studies investigating rhythmic activity during auditory and visual perception in ScZ-patients have focused on steady-state responses (SSRs), which involve entrainment to the frequency and phase of a periodic stimulus (Brenner et al., 2009). Research investigating auditory and visual SSRs has observed reduced amplitude- and phase-modulation to repetitive stimulation at high (Krishnan et al., 2005; Kwon et al., 1999; Spencer et al., 2008b) but also at lower frequencies in ScZ (Hamm et al., 2011), suggesting a basic impairment of cortical circuits to engage in rhythmic activity. Similar impairments have been also observed in bipolar disorder (O’Donnell et al., 2004) and in autism spectrum disorders (Wilson et al., 2007). More recently, several groups have indicated that the 40 Hz auditory SSR in ScZ may also be associated with increased spectral power as a result of impaired phase-locking to auditory stimulation (Hamm et al., 2012). It is argued that such differences could be the result of different stimulus parameters and are consistent with the effects of NMDA-receptor antagonists, such as ketamine, which lead to an increase in the 40 Hz auditory SSRs in human EEGrecordings (Plourde, Baribeau, and Bonhomme, 1997). It is important to note, however, that while SSRs constitute a robust paradigm in eliciting neural oscillations, the functional relevance of SSR-elicited rhythmic activity remains unclear. One question is whether SSRs reflect simply the superposition of mid-latency ERPs and auditory brain stem activity as suggested by some theories (Bohórquez and Ozdamar, 2008). However, several findings indicate that the auditory SSR in the gamma-band range represents a truly cortically generated or at least modulated oscillation, rather

than a simple superposition of discrete evoked potentials to individual stimuli (reviewed in Brenner et al., 2009). This is supported by observations suggesting that the auditory SSR stabilizes over time (Ross et al., 2002), phase delay shortens with repeated stimuli (Santarelli and Conti, 1999) and the response can outlast the stimulus (Kwon et al., 1999).

Task-related spectral power and synchrony during auditory and visual perception in ScZ. Several studies have examined the integrity of evoked oscillations in ScZ using a variety of tasks. Evoked oscillations are phase- and time-locked to the stimulus onset, occurring ∼70–120 ms post stimulus onset. They are typically detected by averaging over a large number of single trials and then band-pass filtered at the frequency range of interest to assess the latency and peak amplitude of this averaged signal (Tallon-Baudry and Bertrand, 1999). Spencer et al. (2003; 2008a) reported reduced evoked gamma band-response during the encoding of simple visual stimuli and during the grouping of illusory contours in ScZ-patients. Induced beta/gamma spectral power was investigated by Uhlhaas and colleagues with Mooney faces, which involve the grouping of the fragmentary parts into coherent images based on the Gestalt principle of closure. EEG-response to Mooney faces revealed largely intact gamma-band activity in ScZ-patients relative to controls (Uhlhaas et al., 2006). However, subsequent studies with MEG reported prominent reduction in the 60—120 Hz spectral activity in both chronic as well as in unmedicated first episode ScZ-patients (Grützner, 2013; Sun et al., 2013). Differences between the findings from EEG and MEG-data may be due to the fact MEG has been found to be more sensitive in detecting low-amplitude high-frequency oscillatory activities than EEG (Muthukumaraswamy and Singh, 2013). In addition to the reduction in amplitude and consistency of evoked and induced spectral activity in ScZ patients, several studies have also assessed long-range neural synchrony through analysing phase synchronization between electrode pairs (Spencer et al., 2003; Uhlhaas et al., 2006). This is of particular relevance because of a large body of evidence suggesting that the functional networks underlying perception, attention, and executive processes rely on dynamic coordination through the interareal phase-locking of rhythmic activity (Varela et al., 2001). Complementing the observations of reductions in the amplitude of high-frequency activity, impairments in phase synchronization between electrodes have been observed in ScZ patients at beta/ gamma-band frequencies (Spencer et al., 2003; Uhlhaas et al., 2006). The significant reductions in phase synchrony observed in ScZ patients could indicate a global deficit in generating and sustaining synchrony both within local and also between distributed neural networks relevant for sensory processing.

Corollary discharge and predictive mechanisms in ScZ. Current models of perception have highlighted the idea that cortical circuits employ predictions to actively infer the causes of sensory perception (Friston, 2010). Converging evidence from psychophysical, neuroimaging and electrophysiological evidence suggests that this mechanism may be impaired in ScZ and underlies core clinical symptoms (Ford et al., 2007) (Figure 1). One example of predictive mechanisms is the ability of organisms to distinguish between self-generated (internal) and external


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Figure 1. Oscillatory measures during perceptual processing in schizophrenia. (a) Time-frequency maps of phase locking factor (PLF) for healthy controls (HC) and schizophrenia patients (SZ) during auditory steady-state response at 40 Hz. The time-frequency maps show responses at electrode Fz. Topographic maps are oriented so that the top of the map is anterior and the bottom is posterior. Adapted from Spencer et al. (2009). (b) Evoked oscillatory activity in schizophrenia patients and their unaffected co-twins. Electroencephalographic time–frequency analyses of evoked gamma-band power during an auditory oddball task for responses to the standard stimuli at electrode Cz in healthy twins, monozygotic twins concordant with schizophrenia (MZCCSCZ), MZ twins discordant with schizophrenia (MZDSSCZ) and unaffected co-twin members (MZDSWell Co-twins). Impaired evoked gamma-band power was significantly associated with schizophrenia and unaffected co-twins exhibited significantly reduced 30–60 Hz power as well compared with controls, highlighting the genetic contribution towards impairments in high-frequency oscillations in the disorder. Adapted from Hall et al. (2011). (c) High-frequency oscillations during perceptual organization in schizophrenia. Left panel: time–frequency representations and topographies of gamma-band spectral power of magnetoencephalographic (MEG) data in response to Mooney faces for controls (top) and chronic schizophrenia patients (bottom). The gamma-band signal is expressed as relative power change in the post-stimulus time window compared with baseline, averaged across all channels. The topographies (middle panel) display the results for a non-parametric analysis of variance indicating the main effects of group for both low (top) and high (bottom) gamma-band oscillations at the sensor level. Intensity of red indexes, increased activity in controls while stronger blue intensities suggest increased gamma-band power in schizophrenia patients relative to controls. The topographies depict corrected t-values and the channels that form a statistically significant cluster are indicated (*, p < 0.001; x, p < 0.05). Adapted from Grützner et al. (2013).

sensory/motor responses. Von Holst and Mittelstaedt (1950) and Sperry (1950) proposed that motor actions are accompanied by an efference copy of the action, which sends a ‘corollary discharge’ signal to the sensory cortex, signalling that impending sensations are self-initiated or self-generated. Several authors have argued that a failure of corollary discharge mechanisms underlies the impaired ability of ScZ patients to distinguish self-generated and externally-generated perceptions and actions (Blakemore et al., 2000; Feinberg, 1978; Ford and Mathalon, 2005). One study examined the coherence of theta oscillations between frontal and temporal lobes in ScZ patients with and without auditory hallucinations as participants either listened to their own played back speech or were instructed to talk aloud (Ford et al., 2002). In the controls and ScZ-patients without hallucinations, talking was associated with an increase in theta coherence between left frontal and temporal electrodes relative to the listening condition. In ScZ patients with hallucinations, this modulation was absent, suggesting

a failure in the preparation of temporal areas for speech production that could lead to the misattribution of self-generated speech to an external source. The same group also reported reduced gammaband oscillations before movement initiation in ScZ (Ford et al., 2008), suggesting that reduced neural oscillations could also underlie dysfunctions in sensorimotor communication and associated impairments in the initiation of willed action.

Sensory perception in pre-clinical animal models In contrast to the large body of work on sensory elicited oscillations in human EEG/MEG recordings, visual and auditory perception has been less investigated in pre-clinical models of ScZ. One reason for the absence of such data is the focus in current systems-neuroscience on the visual system of nonhuman primates. However, there is a renewed interest in


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studying the rodent visual cortex (Baker, 2013), which could also be utilized for assessing potential abnormalities in perceptual processing in ScZ.

SSR paradigms in pre-clinical research. Using the ventral hippocampal lesion neurodevelopmental model of ScZ (NVHL), Vohs et al. (2012) showed that there was a subtle but significant reduction in phase locking (PLF) at higher stimulation frequencies in lesioned animals although mean trial power was not affected. The NMDA receptor antagonist ketamine accentuated this reduction. Surprisingly, ketamine increased the mean trial power specifically within the 30–40Hz range in both NVHL and control animals, replicating findings observed in human EEG data (Plourde et al., 1997). The effects of NMDA-hypofunctioning were further investigated by Sivarao et al. (2013), who administered the NMDA antagonist MK-801 while recording EEG over the auditory cortex in anaesthetized animals. In contrast to the Vohs study, MK-801 produced a significant attenuation in both PLF and induced power to 40 Hz auditory stimuli while entrainment to other frequencies was not affected (Sivarao et al., 2013). Auditory SSR-deficits can also be reproduced by a 15q13.3 microdeletion, a copy number variation (CNV) that confers a high risk of developing ScZ (Fejgin et al., 2014). This rare CNV includes the gene encoding the nicotinic acetylcholine receptor alpha7 (Chrna7). Mice with a 15q13.3 microdeletion have increased gamma-band power at rest in the auditory cortex while the auditory SSR (ASSR) at 40 Hz is completely abolished. As cortical fast spiking interneurons can be positively modulated by nicotinic acetylcholine alpha7 receptors (Alkondon et al., 2000), the authors suggest a compromised function of fast spiking interneurons via reduced expression of Chrna7. This hypothesis is strengthened by experiments showing that nicotine can enhance the ASSR in both rodents (Sivarao et al., 2013) and human subjects (Harkrider and Champlin, 2001). The importance of cortical interneurons in modulating the ASSR was also highlighted in studies using mice that lack the NMDA-NR1 subunit in cortical GABAergic interneurons, of which a large majority affected are thought to be PV-positive (GluN1-IN KO). In a similar result to the 15q13.3 CNV mice, broadband gamma power was enhanced in the GluN1-IN KO mice during baseline recordings but a profound reduction of ASSR induced power and phase locking specifically at 40 Hz was seen. The most likely mechanism for this observation is a functional deficit in cortical PV neurons that receive thalamocortical afferents, leading to impairments in their feed-forward inhibition in response to acoustic stimuli. A number of these results are largely consistent with the data reported in ScZ patients, supporting the use of this relatively simple measure for translational research. However, the seemingly opposing effect of NMDA antagonists on phase-locking and induced power highlights the need for further work to fully understand how differences in stimulus parameters can impact on alterations in oscillatory signatures.

Task-related spectral power during auditory and visual perception in pre-clinical animal models of ScZ. Perceptual processing has not been comprehensively investigated in a pre-clinical model of ScZ so far. Ehrlichman et al. (2009) identified the effects of both amphetamine and ketamine on evoked hippocampal oscillations in response to simple tones. Ketamine

produced an enhancement of baseline gamma oscillations and a strong reduction in auditory-evoked theta oscillations. Similar to ketamine, amphetamine also produced a strong reduction in evoked theta oscillations without affecting the evoked gamma response (Ehrlichman et al., 2009). Auditory evoked gamma oscillations were, however, markedly impaired in the methylazoxymethanol acetate (MAM)-E17 neurodevelopmental model of ScZ (Lodge et al., 2009). In this study, a latent inhibition protocol was used where a novel or familiar tone is paired with a foot shock. MAM animals were impaired behaviourally, failing to show latent inhibition and auditory-evoked gamma and theta oscillations was markedly reduced. The authors suggest that the regionally selective reductions in PV interneurons in the medial prefrontal cortex (mPFC) of MAM-E17 rats might explain both the reduction in induced oscillatory response and behaviour.

WM and executive functions One critical mechanism to assure the representation of WM items during normal brain functioning is neural oscillations. This is because oscillatory activity facilitates the formation of neuronal assemblies through establishing transient temporal correlations that represent and sustain items in the absence of sensory inputs (Jensen et al., 2007). Evidence suggests that WM items are coded at different phases of low- and high-frequency oscillations (Roux and Uhlhaas, 2014) and that WM capacity is intimately related to oscillatory parameters (Jensen and Lisman, 1998). The findings of impaired perceptually-elicited impairments in high- and low-frequency oscillations are complemented by data indicating reduced high-frequency activity during WM and executive processes in ScZ. Haenschel et al. (2009) investigated gamma-band activity in EEG-data during a visual WM paradigm demonstrating significant reductions in gamma-band power at higher WM load conditions in early-onset ScZ patients. Similarly, Cho et al. (2006) reported a decrease in induced gamma-band power in chronic ScZ patients during a cognitive control task which involved the inhibition of a prepotent response. In addition to impairments at gamma-band frequencies, there is also evidence to suggest that theta-band oscillations may be related to WM impairments in ScZ. Schmiedt-Fehr and Basar-Eroglu (2011) reported abnormal evoked theta activity during WM and cognitive control, that is, the ability to adjust strategies flexibly in accordance with one’s intentions and goals. WM was examined in an N-back task and the authors manipulated cognitive control by monitoring simple actions during WM performance. In controls, theta activity was particularly prominent over frontal electrodes in the high cognitive control condition and increased with WM load. In contrast, ScZ patients did not show an increase in evoked theta activity in either the difficult high-control condition or with increased WM load.

Working memory and executive functions in pre-clinical animal models Recent studies have combined genetic animal models of ScZ with advanced in vivo electrophysiological recordings to examine the role of neural oscillations during WM and related cognitive processes. Several studies have used the hippocampal


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Phillips and Uhlhaas dependent T-maze delayed non-match to place paradigm, which requires animals to have both a memory of the rule and the maintenance of the spatial position of a particular target. However, it is currently unclear whether the cognitive and neural processes involved closely reflect WM in human observers. The synchronization of neuronal ensembles in hippocampal– entorhinal circuits at theta/gamma-band frequencies has been suggested to be important for this type of WM (Yamamoto et al., 2014) while potentially the rule memory/decision making can be driven by bursts of coherent theta oscillations in hippocampal– thalamocortical loops (Jones and Wilson, 2005). Recently, several investigators have examined how these networks are disrupted in animal models of ScZ. Hippocampal– mPFC network synchrony at theta frequencies was shown to be impaired in a mouse model of human 22q11.2 CNV carriers (Sigurdsson et al., 2010), a microdeletion which increases the risk of developing ScZ. This mouse model exhibited impaired learning on the T-maze task and showed reduced coherence between the hippocampal and mPFC, while theta power in the hippocampus was unaffected. In addition to hippocampal circuits involved in WM-related processes, Parnaudeau and colleagues (2013) selectively and reversibly decreased neuronal activity in the mediodorsal thalamus (MD) of mice with ‘designer receptor exclusively activated by a designer drug’ (DREADD) technology while recoding oscillatory and single unit activity in these brain structures. Beta synchrony between the MD and the mPFC was modulated by WM demands, which was reduced when a subtle reduction in cell firing of the MD was induced by DREADD, leading to impaired WM performance. Beta synchrony reductions have been observed in ScZ patients (Uhlhaas et al., 2006). However, these analyses are generally restricted to cortico-cortical networks and the contribution of thalamo-cortical deficits is unclear.

Spontaneous oscillations in ScZ An important issue for the interpretation of deficits in neural oscillations in ScZ is the question whether there is a constitutive impairment of mechanisms generating rhythmic activity or whether the deficit is apparent only during task performance. Accordingly, examination of spontaneously occurring neural oscillations could potentially provide important, complementary insights into the nature of aberrant oscillatory dynamics in ScZ. Spontaneous rhythmic activity can be obtained during different states and contexts. These typically involve the recording of EEG/MEG-data during an eyes-closed/eyes-open condition during which the participant is asked not explicitly to perform a cognitive task. In addition, rhythmic activity occurs during sleep and is modulated during its different stages (Steriade et al., 2001). A third example is rhythmic activity that occurs prior to or between stimulus presentations. Such pre-stimulus or background activity has received increasing attention in cognitive neuroscience, highlighting that on-going dynamics are a fundamental feature of large-scale networks (Deco et al., 2011).

Resting-state neural oscillations in ScZ patients. Neural oscillations, especially at alpha-frequencies, are a prominent feature of resting-state measurements. MEG resting-state has revealed resting-state networks similar to that observed using functional magnetic resonance imaging (fMRI) (Brookes et al.,

2011) which involve interactions at alpha (8–14 Hz) and beta band (15–30 Hz) oscillations in the visual cortex and defaultmode regions (Hipp et al., 2012). In addition, the phase of alphaband oscillations strongly modulates the amplitude of broad-band (30–70 Hz) gamma-band activity, suggesting an important modulatory role of alpha-band in the modulation of cortical excitability levels (Roux et al., 2013). There is preliminary evidence to suggest that the pattern of spontaneously occurring gamma-band activity may differ from neural oscillations associated with cognitive processing. Kikuchi et al. (2011) examined resting-state EEG-data in medicationnaïve, first-episode ScZ patients and healthy controls and found significantly elevated gamma-band power over frontal electrodes, a finding which was, however, not observed in chronic ScZ patients (Rutter et al., 2009). The interpretation and comparability of these findings is complicated by the fact that it is currently unclear whether the generating mechanisms underlying high-frequency activity during rest are similar to those observed during task-related oscillations. For example, resting-state spectra during normal brain functioning do not exhibit a clear oscillatory peak at higher frequencies but, rather, a broad-banded modulation of spectral power. It is questionable, however, whether broad-band spectral power increases actually reflect oscillatory processes. Instead, it is more likely that such phenomena reflect the sum of local synaptic events and action potentials and hence just the level of local cortical activation (Uhlhaas et al., 2011). In addition to changes in high-frequency activity, the majority of studies examining low-frequency (delta-, theta- and alpha-band) oscillations have reported an increase in the power of low-frequency, which has been shown to be accompanied by reductions in the coherence of oscillations at theta and alpha frequencies (Hinkley et al., 2011). However, such findings may be associated with chronic ScZ and less pronounced in firstepisode or participants at high-risk for the development of ScZ (Ranlund et al., 2014).

Neural oscillations during sleep in ScZ. In addition to neural oscillations during wakeful states, ScZ patients also exhibit impaired altered oscillatory signatures during sleep. These manifest as reductions in sleep spindles (Ferrarelli et al., 2010b) and slow wave density (Sekimoto et al., 2007) as well as slow wave power (Göder et al., 2006; Keshavan et al., 1998). A number of studies have attempted to link the deficits in slow waves and spindles to cognitive impairments observed in ScZ (Forest et al., 2007; Keshavan et al., 1998, 2011; Sarkar et al., 2010). The reductions in spindle density in ScZ patients were shown to specifically correlate with sleep-dependent procedural learning (Wamsley et al., 2011). The generation of slow waves and spindles and also the mechanisms by which this oscillatory activity is synchronized across a range of brain regions and timescales requires precision in both cortico-cortical and cortico-thalamic circuits. Gardner et al. (2014) (reviewed in Gardner et al. 2014) argued that both slow wave and sleep spindles during sleep might be a useful indicator for understanding cortico-cortical and cortico-thalamic circuit dysfunctions in ScZ.

Pre-stimulus activity in ScZ. Divergent findings exist on the presence of disturbances in pre-stimulus activity in ScZ at


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gamma-band frequencies. Spencer (2012) examined baseline activity in the 40 Hz ASSR paradigm in chronic ScZ patients. Baseline activity at 40 Hz was significantly elevated in the auditory cortex in ScZ patients relative to controls, which correlated with the levels of auditory hallucinations. However, Uhlhaas et al. (Grützner et al., 2013; Sun et al., 2013) could not confirm these findings in both chronic and first-episode ScZ patients. Thus, further investigations are required to determine to what extent high-frequency oscillations reflect a dysfunctional process that is most apparent during task-related activity versus an impairment in the intrinsic dynamics of cortical circuits in ScZ.

Spontaneous oscillations in pre-clinical models of ScZ In contrast with the existing EEG/MEG-data from ScZ patients, examination of activity in pre-clinical research has so far focused on rhythmic activity during at-rest periods and during sleep in animal models.

Resting-state activity in pre-clinical models. Alterations in high-frequency activity, especially in gamma-band power, are a frequently reported phenotype in ScZ-genetic models such as15q13.3 CNVs, ErbB4-PV and NR1-PV KOs (Del Pino et al., 2013; Fejgin et al., 2014; Gandal et al., 2012; Korotkova et al., 2010). Similar increases have been also observed in pharmacological models incorporating an NMDAR-R hypofunction (Páleníček et al., 2011; Phillips et al., 2011; Pinault, 2008) (Figure 2). As outlined in Neurobiology of neural oscillations, above, PV interneurons are strongly implicated in the generation of gammafrequency oscillations, with KO mice lacking NMDA-NR1 subunits specifically on PV+cells exhibiting elevated gamma power (Korotkova et al., 2010). It is therefore plausible that blockade of NMDARs located on PV interneurons is involved in mediating the induction of gamma oscillations following NMDAR antagonism, and ultimately the generation of aberrant gamma frequency oscillations in ScZ. Supporting this hypothesis, mice with NR1 subunits knocked-out from PV interneurons are less susceptible to MK801 induced gamma frequency oscillations (Carlén et al., 2011). Emerging evidence from pharmacological models indicates that high-frequency oscillations (HFOs; 130–180Hz), a hitherto under-researched class of oscillations, could also be implicated in network dysfunctions in ScZ. In rodents, HFOs can be induced by systemic administration of either NMDAR antagonists (Hunt et al., 2006; Phillips et al., 2011) or 5HT-2a agonists (Goda et al., 2013), with the nucleus accumbens being one region implicated in their generation (Hunt et al., 2010). To date HFOs are infrequently discussed in the literature related to pre-clinical ScZ models or in EEG/MEG-data. Neural oscillations during sleep in pre-clinical animal models of ScZ. A number of genetic models with links to ScZ have reported abnormalities in circadian control of sleep states, including a truncated version of DISC-1 (Sawamura et al., 2008) and the blind-drunk mutant mice (Oliver et al., 2012). However, only one study has systematically looked at EEG changes during sleep in a rodent model of ScZ. Phillips et al. (2012) showed that fragmented

non-rapid eye movement (NREM) sleep in the MAM-E17 rat neurodevelopmental model of ScZ is associated with reduced slow wave power and reduced coherence between cortical areas. The reduction in the proportion of cortical pyramidal cells exhibiting up–down state fluctuations in this model might reflect an impaired ability of cortical networks to maintain, synchronize or propagate delta waves through larger areas of cortical tissue, potentially explaining the deficit in slow waves seen in the Phillips study. The density of PV-positive interneurons was also shown to be selectively reduced in the MAM-E17 model (Phillips et al., 2012), therefore impairments in E–I balance may also drive some of the deficits seen. Although the basic properties of spindles were unaffected in this model, their number was significantly reduced particularly over frontal regions, again mirroring the results seen in ScZ (Ferrarelli et al., 2007, 2010). Pre-clinical studies have shown that these specific sleep patterns can be correlated across different brain areas. Simultaneous recordings in the cortex and hippocampus showed that there is a precise temporal coordination of slow waves, spindles and hippocampal ripple oscillations (Siapas and Wilson, 1998; Sirota et al., 2003). This coordination perseveres across species and has been recorded in both rodents and humans (Clemens et al., 2007; Molle et al., 2002, 2006). It has been suggested that these slow wave–spindle–ripple episodes may constitute an important mechanism of cortico-hippocampal communication during sleep, providing a temporal window for plasticity to occur and allowing information to be moved from short-term hippocampal to longerterm neocortical stores. Importantly, the most striking result from the Phillips study shows that the impaired antero-posterior propagation of cortical delta waves in the MAM-E17 model is associated with driving a mis-timing of spindle oscillations to slow waves during NREM sleep. A breakdown in the cortical–thalamic–hippocampal temporal coordination as a result of the impaired slow wave activity culminates in hippocampal ripple events failing to coordinate with spindles in directly connected neocortical regions, suggesting a mechanism that drives some of the cognitive deficits seen in this model.

Neural oscillations in ScZ patients and animal models: prospects and challenges of translational work Neural oscillations, animal models and the symptoms of ScZ Neural oscillations have been linked to the profound impairments in sensory processing and cognitive functions in both ScZ patients and animal models of the disorder. One distinct advantage of this approach is that experimental paradigms are available that can be implemented in both EEG/MEG settings as well as in invasive electrophysiological recordings (Table 3). Currently, little evidence is available that has linked abnormal rhythmic activity to clinical symptoms of psychosis, such as the characteristic delusions and hallucinations. The reasons for this are twofold: 1) there are obvious limitations to animal models in terms of modelling the more complex features of psychosis and 2) the contribution of neural oscillations towards clinical symptoms in ScZ is unclear, which does not yet allow testable


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Figure 2. Ketamine induced power changes in rat hippocampal and prefrontal cortical local field potential (LFP). (a) Schematic illustration highlighting the position of a 32 channel Neuronexus silicon probe implanted in rat dorsal hippocampus. (b) Representative LFP traces from a single rat following doses of vehicle and 10 mg/kg ketamine (intraperitoneally). (c) Mean spectral power within the theta (4–12 Hz) and gamma (40–80Hz) bands across all recording sites. Note that ketamine decreases theta power, whilst increasing gamma power (n=3). (d) Spectrogram of rat medial prefrontal cortical (mPFC) LFP from a single recording session. In addition to strong induction of gamma power as observed in the hippocampus, cortical data also demonstrate that ketamine can induce high-frequency oscillations (HFOs) at ~160 Hz. (e) Mean ketamine induced mPFC power (n=10). Changes of greatest magnitude are observed in the gamma band, but additional peaks are also observed in the HFO range. Adapted from Phillips et al. (2012). RSA: retrosplenial agranular cortex; M1: primary motor cortex; M2: secondary motor cortex; CA1: cornu ammonis area 1; DG: dentate gyrus; PoDG: polymorph layer of the dentate gyrus; mPFC: medial prefrontal cortex medial.

predictions. While correlations between different symptom domains, that is, negative, positive and disorganized features, have been reported (Uhlhaas and Singer, 2010), the precise role of rhythmic activity towards the emergence of hallucinations or thought disorders has not been established. One possible way to examine the role of neural oscillations in the generation of clinical symptoms in ScZ could be the examination of corollary discharge mechanisms (see Corollary discharge and predictive mechanisms in ScZ, above). Previous evidence has consistently implicated a deficit in this process in ScZ, which could underlie the generation of positive symptoms (Mathalon and Ford, 2008). Moreover, corollary discharge paradigms can be implemented in both pre-clinical research and EEG/MEG para-

digms, thus allowing for the targeted search of pathophysiological mechanisms underlying hallucinations and delusions.

Heterogeneity, medication effects and illness-stages in ScZ ScZ is a heterogeneous disorder characterized by distinct but overlapping groups of symptoms and cognitive dysfunctions. As a result of this phenotypic complexity, modelling the full spectrum in pre-clinical research remains challenging and an important task for future research. In addition, ScZ is likely to involve ongoing changes in the neurobiological signatures during the course of the disorder as the


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result of adaptive changes in large-scale networks due to symptoms expression and illness chronicity. Chronic and acute ketamine models have been proposed to address some of the differences between chronic and recent-onset ScZ (Jentsch and Roth, 1999), which is in part consistent with changes in glutamatergic neurotransmission during the course of the disorder (Marsman et al., 2013). However, the ongoing changes are likely to impact on other transmitter-systems as well as, such GABA, which are important for E–I-balance and the generation of neural oscillations. Animal models are likely to be important for determining the effects of antipsychotic medication on brain structure and function, a topic which has received increased attention in recent years (Ho et al., 2011; Tost et al., 2010). In addition, recent studies indicate that trials with novel compounds for the treatment of ScZ that are tested in chronic patients may fail because of long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy (Gill et al., 2014), highlighting the importance of animal models for disentangling the effects of antipsychotics on neural circuits and development of novel treatments.

Neural oscillations and translational paradigms One distinct advantage of neural oscillations is the availability of measures describing the amplitude and synchrony of rhythmic activity that can be obtained from animal models of ScZ as well as from human participants. While behavioural and cognitive parameters are established in both pre-clinical and patient studies, they allow for only limited insights into the underlying biology, a prerequisite for the development of novel therapeutic targets. Similarly, blood oxygenation level dependent (BOLD) signals as well as anatomical measures, such as MRI and diffusion tensor imaging (DTI), are potentially suitable for this goal. However, the physiological basis of these signals is less clear and fMRI/MR-techniques for rodents are not frequently employed in pre-clinical research. One essential prerequisite for exploiting fully the translational potential of neural oscillations are paradigms that can easily be implemented in patient settings and rodent electrophysiology. Our review has indicated that currently only few paradigms are available. While perceptual tasks have been systematically employed in human participants, there is currently only a small body of work that has tested the suitability of such approaches in rodent electrophysiology. Similarly, signatures of hippocampal–cortical interactions are an important read-out for current animal models of ScZ (Colgin, 2011), yet it is currently unclear to what extent such processes can be reliably assessed in EEG/MEG-data. In MEG, magnetic fields decay rapidly with increasing distance and thus source localization of subcortical activity remains challenging. A limited number of MEG studies, nevertheless, have reported on thalamic and other subcortical sources (Poch et al., 2011; Ribary et al., 1991). More recently, we have shown that MEG resting-state data can be used to examine the influence between the phase of thalamic alpha and cortical gamma-band activity (Roux et al., 2013), highlighting the suitability of MEG and possibly also EEG to examine cortico–subcortical interactions. Accordingly, development, implementation and testing of electrophysiological paradigms that can be used to obtain signatures of neural oscillations in both pre-clinical animal models and EEG/MEG recordings is an important task for the field. These

tasks need to fulfil a number of criteria. Specifically, they should 1) reflect a meaningful physiological and behavioural construct that is relevant for understanding the pathophysiology of ScZ, 2) lead to robust signatures of rhythmic activity in circumscribed circuits and 3) show high test–retest reliability.

Conclusions In this paper, we have attempted to review findings investigating neural oscillations in ScZ patients and pre-clinical animal models of the disorder. In particular, we have focused on data obtained during perceptual processing, WM and higher cognitive functions, as well as spontaneous activity. Overall, there is currently moderate correspondence between findings obtained in EEG/MEG recordings in ScZ and observations from invasive electrophysiological studies as well as in vitro data. This is due to the fact that only a small number of paradigms as well as parameters of oscillatory signatures have been systematically assessed in both ScZ patients and pre-clinical research. Accordingly, this finding highlights the need to further systematically investigate the patterns as well as the mechanisms underlying abnormal oscillations and synchrony in ScZ. In our view, further identification of such paradigms is critical for efforts aimed at identifying novel and more effective targets to correct circuit abnormalities in ScZ and related disorders. The investigation of neural oscillations in ScZ has already led to a considerable interest in the pre-clinical field for future drug development and as read-out for the assessment of treatment effects. For this approach to be successful, development of translational paradigms is essential and will likely lead to important and novel insights into the relevance of neural oscillations in the pathophysiology of ScZ.

Declaration of Conflicting Interests The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Keith Phillips is an employee of Eli Lilly and Company.

Funding The authors received no financial support for the research, authorship, and/or publication of this article.

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