Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia

European Neuropsychopharmacology (]]]]) ], ]]]–]]]

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Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia Ivan Cordona, María Jesús Nicolása, Sandra Arrietaa, Eneko Lopeteguia, Jon López-Azcáratea, Manuel Alegrea,b, Julio Artiedaa,b,n,1, Miguel Valenciaa,n,1 a

Neurophysiology Laboratory, Neuroscience Area, CIMA, Universidad de Navarra, Pamplona, Spain Neurophysiology Service, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain

b

Received 25 August 2014; received in revised form 6 January 2015; accepted 1 April 2015

KEYWORDS

Abstract

Schizophrenia; Animal models; Ketamine; Cortico-basal ganglia network; Cross-frequency coupling; Hyperlocomotion

Recent studies have suggested the implication of the basal ganglia in the pathogenesis of schizophrenia. To investigate this hypothesis, here we have used the ketamine model of schizophrenia to determine the oscillatory abnormalities induced in the rat motor circuit of the basal ganglia. The activity of free moving rats was recorded in different structures of the cortico-basal ganglia circuit before and after an injection of a subanesthesic dose of ketamine (10 mg/kg). Spectral estimates of the oscillatory activity, phaseamplitude cross-frequency coupling interactions (CFC) and imaginary event-related coherence together with animals' behavior were analyzed. Oscillatory patterns in the cortico-basal ganglia circuit were highly altered by the effect of ketamine. CFC between the phases of low-frequency activities (delta, 1–4; theta 4–8 Hz) and the amplitude of high-gamma ( 80 Hz) and high-frequency oscillations (HFO) ( 150 Hz) increased dramatically and correlated with the movement increment shown by the animals. Betweenstructure analyses revealed that ketamine had also a massive effect in the low-frequency mediated synchronization of the HFO’s across the whole circuit. Our findings suggest that ketamine administration results in an aberrant hypersynchronization of the whole cortico-basal circuit where the tandem theta/ HFO seems to act as the main actor in the hyperlocomotion shown by the animals. Here we stress the importance of the basal ganglia circuitry in the ketamine model of schizophrenia and leave the door open to further investigations devoted to elucidate to what extent these abnormalities also reflect the prominent neurophysiological deficits observed in schizophrenic patients. & 2015 Elsevier B.V. and ECNP. All rights reserved.

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Correspondence to: Neurophysiology Laboratory (2.33) CIMA, Avda. Pío XII 55, 31008 Pamplona (Navarra), Spain. Tel.: +34 948 194700. E-mail addresses: [email protected] (J. Artieda), [email protected] (M. Valencia). 1 These authors coordinated equally this work. http://dx.doi.org/10.1016/j.euroneuro.2015.04.004 0924-977X/& 2015 Elsevier B.V. and ECNP. All rights reserved.

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

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1.

Introduction

Schizophrenia is a mental disorder characterized by positive (hallucinations and paranoia) and negative symptoms (social withdrawal, poverty of speech and blunted affect), together with alterations in working memory and attention (Carter et al., 2010). To date, the antipsychotic medication (mostly D2 dopamine receptors antagonists) is able to treat the positive symptoms, but it has poor efficacy against the negative and cognitive ones. Much research has been carried out on the idea that dopaminergic dysfunction could lead to schizophrenia (Howes and Kapur, 2009). Although the initial findings pointed towards a general hyperactivity of dopamine receptors, more recent studies have found that, while striatal regions suffer from hyperdopaminergia (Abi-Dargham et al., 1998), the prefrontal cortex suffers from hypodopaminergia (Abi-Dargham et al., 2002). Newer theories suggest an origin related to misregulations in the glutamatergic system (Javitt, 2007). This is supported by the fact that in humans the administration of N-methyl-D-aspartate receptors (NMDAR) antagonists, such as phencyclidine (PCP) and ketamine, induce symptoms and cognitive deficits similar to schizophrenia (Lahti et al., 2001; Murray, 2002). In rodents, different NMDAR models of schizophrenia have been developed. One of the most common consists of the acute injection of subanesthetic doses (5–10 mg/kg) of ketamine (Kocsis et al., 2013). Ketamine injection produces hyperlocomotion, altered social interaction and impaired cognitive function. In particular, rodents hyperlocomotion has been associated with cognitive and perceptive disturbances that would mimic the cognitive dysfunction observed in humans (Adler et al., 1999). Among the NMDAR antagonists, ketamine is of particular interest due to its D2 dopamine affinity (Kapur and Seeman, 2002), having the potential to converge the dopaminergic and glutamatergic hypothesis into the same model (Frohlich and Van Horn, 2013). Many electrophysiological works have characterized this model in the hippocampus (Ehrlichman et al., 2009), cortex (Phillips et al., 2012) and nucleus accumbens (Hunt et al., 2006). These studies together with those carried out in patients have led to a general consensus about the idea of schizophrenia as a disorder where the synchronization of neural activity is altered. Likewise in Parkinson's or Alzheimer's disease, abnormalities in the oscillatory regime have been detected in schizophrenia (Alonso-Frech et al., 2006; Jeong, 2004; Uhlhaas and Singer, 2010). Among them, phase-amplitude cross-frequency coupling interactions (CFC) – where the phase of a slower activity determines the amplitude of higher frequency oscillations – have received much attention in the last years. CFC has been proposed as a potential mechanism to mediate into neural computation and synchronization between distant regions (Canolty and Knight, 2010). While it has been related to cognitive processing in humans (Canolty et al., 2006) and rodents (Tort et al., 2008), it has also been associated with the pathophysiology of different diseases (Ibrahim et al., 2014; López-Azcárate et al., 2010), including schizophrenia (Kocsis, 2012; Lakatos et al., 2013). Motivated by those studies which highlight the relevance of the basal ganglia circuits in the pathogenesis of schizophrenia (Perez-Costas et al., 2010; Simpson et al., 2010),

here we set out to determine the CFC alterations produced by a subanesthetic dose of ketamine (10 mg/kg) on the motor circuit of the rat basal ganglia and relate them with the hyperlocomotion effects shown by the model. We show that the oscillatory architecture of the cortico-basal network is strongly affected by the effect of ketamine that seems to be closely related to the hyperlocomotion experienced by the animals. Specifically, we detect a strong correlation between the increase of locomotion and the alterations in the CFC interactions between the phase of delta (theta) oscillations and the amplitude of highfrequency activities (4 50 Hz) that may be of relevance for understanding schizophrenia.

2.

Experimental procedures

Here we studied a subset of recordings obtained from the experiments previously described in (Nicolás et al., 2011). During these recordings, we evaluated the effect of a low dose of ketamine (10 mg/kg) on the oscillatory activity of 13 male Wistar rats (250–300 g) measured on the motor cortex and three nuclei of the basal ganglia.

2.1.

Ethics statement

Animal care and surgery procedures were approved by the animal ethics committee; Comité de Ética para la Experimentación Animal, Universidad de Navarra, approval ID 088-06.

2.2.

Surgical electrode implantation

Recording electrodes were implanted along the basal ganglia motor circuit. They were located in motor cortex (Cx), caudate-putamen (CPU), subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr). Stereotactic coordinates were calculated according to the Paxinos and Watson neuroatlas (Paxinos and Watson, 2007). Coordinates were Cx (anterior (AP): 2.70 mm and lateral (L): 3.20 mm); CPU (AP: 0.20 mm, L:2.5 mm; ventral (V): 6 mm); STN (AP: 3.80 mm; L: 2.5 mm; V: 7.8 mm); SNr (AP: 5.80 mm, L:2 mm, V: 8 mm). Two different types of electrodes were used to record LFP from the different brain structures. Concentric microelectrodes with two contacts (SNE-100, Kopf Instruments, Tujunga, California, USA) were used for CPU, STN and SNr. Cortical activity was recorded by means of stainless steel screws placed in the skull. The active electrode was placed in the primary motor cortex and was referenced to an electrode placed in the auditory cortex.

2.3.

Recording procedure

The recordings started 5 days after surgery and took place inside a custom-made Faraday cage. Recordings started 45 min after connecting the cables in order to let the animals habituate to the Faraday cage. Then, the basal condition activity (before injection of ketamine) was recorded for 15 min. After that time, rats were injected a ketamine dose (10 mg/kg; Ketolar, Pfizer, Madrid, Spain) and activity was recorded along 60 min after injection. Animal's movement was tracked using a webcam placed on the top of the cage. Videos were analyzed semi-automatically with custom-made software running under Matlab (Mathworks, Natick, MA, USA). To rule out any possible sleep or awake-but-inactive effects on brain activity, only active periods (i.e. with locomotion) were selected for further analyses.

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

Coupling in the cortico-basal ganglia circuit 2.4.

Electrophysiological conditioning

Continuous recordings were carried out using Grass P511 amplifiers (Grass, Worwick, RI, USA). Local field potentials (LFPs) were filtered 0.3–1000 Hz, amplified 20,000 fold and sampled at 2500 Hz. After the signal acquisition, animals were sacrificed and the electrode position was located (see below). Misplaced electrodes were excluded from the analysis, as well as channels with suboptimal signal quality giving a total of: 13 Cx, 11 CPU, 8 STN and 7 SNr recordings studied.

2.5.

Histological verification

To proceed with the histological verification, animals were anaesthetized (ketamine, 75 mg/kg+xylacine 11 mg/kg) and intracardially perfused with a solution of paraformaldehyde 4%, dissolved in Phosphate Buffer Solution (PBS) at 0.1 M and pH 7.4. After perfusion, the brain was taken out carefully and post-fixed during 24 h in PAF. Then it was passed to PBS Sacarose for at least 24 h. Brains were cut in coronal axis using a cryotome. Slides of 40 μm were obtained in order to process the brain and locate the recording sites. The slides were stained with thionine and then observed in a microscope to determine the location of the electrodes (Supplementary Figure 1).

2.6.

Data analysis

Analyses of electrophysiological data were performed in Matlab in fragments of 15 min (Mathworks, Natick, MA, USA).

2.7.

Spectral analysis

Power spectra estimation was performed by means of the Welch Periodogram (Halliday et al., 1995) and was estimated using a fast Fourier transform of 4 s length and a Hanning window, to achieve a resolution of 0.25 Hz per bin.

2.8.

2.10. Imaginary event related coherence (iERCoh) and phase locking value (PLV) analysis To study whether coherence was increased at specific moment of the delta–theta modulating phase we performed an event related coherence analysis as in López-Azcárate et al. (2013). iERCoh gives a measure of imaginary coherence associated with a specific event (Andrew and Pfurtscheller, 1996). Here we used the delta–theta activity troughs as triggers to compute the iERCoh in a window of 2 s around the trough. Since iERCoh accounts for amplitude and phase, we also computed the phase locking value (PLV) that only considers the phase of the signals (Lachaux et al., 1999). To evaluate statistical significance we created a distribution of 200 surrogates with trigger times randomly permutated. Assuming normality of this distribution, z-scores were obtained for iERcoh and PLV values.

2.11.

Statistics

Prior to any statistical analysis, all the variables were normalized by using the transformation described in Van Albada and Robinson (2007). In all cases except for locomotion, two-way repeated measures ANOVA (structure  time factors) followed by Tukey post-hoc tests were used to compare differences between periods of pre- and post-ketamine injection across structures. Missing values were imputed with the mean of the variables for all the other cases. CFC statistics were computed using the MI value obtained by filtering in the delta (1–4 Hz) and theta (4–8 Hz) ranges for the phase and in the low-gamma (40–60 Hz), high-gamma (70–100 Hz) and HFO (130–190 Hz) ranges for the amplitude signal. Changes in iERCoh were assessed by selecting the maxima of the iERCoh maps around t=0. Effect of ketamine on locomotion was assessed by means of one-way repeated measures ANOVA (time factor) followed by Tukey post-hoc tests. Finally, Pearson coefficient of correlation and multiple regression analyses were used to estimate the relationships among movement and the electrophysiological parameters.

Cross-frequency coupling (CFC)

To assess the phase-amplitude level of interaction between different frequency bands, the modulation index (MI) was used (as recently described in Tort et al. (2010)). The MI is a measure of strength of coupling and it is calculated by bandpass filtering two frequency ranges of interest: a low-frequency (phase-modulating) and a higher-frequency (amplitude-modulated) range. To obtain the comodulogram maps we estimated the MI for multiple pairs of bands (from 0.5 to 10 Hz in.25-Hz steps with 1-Hz bandwidth), and the amplitude signal filtering from 12 to 200 Hz in 2-Hz steps with 4Hz bandwidth. Mean normalized power of the activity time-associated to the phase peaks of delta–theta activity was also determined following the procedure described by Canolty et al. (2006).

2.9.

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Imaginary coherence (iCoh)

Coherence can be used to estimate functional relationships between different recording structures (Nunez et al., 1999). Since it has been shown to be affected by volume conduction effects (Nunez et al., 1997), the imaginary coherence (i.e., the imaginary part of coherence, iCoh) was used in this study (Nolte et al., 2004). This measure minimizes the volume conduction effects as it only takes into account time-lagged relationships (considering that volume conduction does not cause time lag) thus detecting true brain interactions. The statistics were derived from the transformed iCoh values (z-transformation) (Nolte et al., 2004).

3.

Results

We recorded the ECoG activity from the motor cortex and local field potentials from CPU, STN and SNr in free moving rats. Visual inspection of raw signals revealed that ketamine administration increased the amplitude of the oscillations at high frequencies (Figure 1, raw). Interestingly, ketamine incremented the occurrence of phasic increases in the amplitude of high-frequency oscillations (HFO) that coincided with the valley of the activity at low-frequencies (Figure 1, delta activity vs HFO), thus suggesting a degree of phase-amplitude CFC among these activities.

3.1. Ketamine increases the power of delta and theta oscillations in the cortico-basal ganglia network structures Prior to the CFC analysis, here we extended our previous study to investigate the effects of ketamine on the oscillations in the delta ( 1–4 Hz) and theta ( 4–8 Hz) ranges (Figure 2). Power spectral analysis revealed similar results to those reported by our group for the low-gamma ( 50 Hz), high-gamma ( 80 Hz) and high frequency oscillations (HFO, 150 Hz) (Nicolás et al., 2011). For the low

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

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Figure 1 Raw signals in pre and post-injection period (0–15 min after administration) of 10 mg/kg of ketamine. Raw and decomposed traces into predominant frequency bands of LFPs recorded from the motor cortex of a representative animal. Ketamine increases the amplitude of low-gamma (LG), high-gamma (HG) and high frequency oscillations (HFO) bands. Note the coincidence of phasic increases in the amplitude of the HFOs and the valley of the delta oscillations, mainly during the post-ketamine period.

Figure 2 Temporal evolution of Power Spectra in different bands. Power spectral analyses for each of the structures recorded (columns). (A) Grand average of all power spectra. LG, HG and HFO bands are increased after drug administration. (B) Focus on the delta and theta bands. Both bands increase their power during the first 15 min. Here and thereafter, colors denote the different time periods into which the recordings have been segmented: blue for 15–0 min basal (before ketamine injection), green for 0–15 min, red for 15–30 min, cyan for 30–45 min and magenta for 45–60 min after ketamine injection.

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

Coupling in the cortico-basal ganglia circuit frequency ranges, peaks in the delta and theta bands were also identified (Figure 2B). Statistical analyses (two-way repeated measures ANOVA) detected significant effects for the time factor in the delta (F(4,13) = 3.7, p= 0.01) and theta (F(4,13) = 3.65, p =0.011) ranges. Post-hoc multiple comparisons Tukey test (comparing pre-period vs. post-injection periods) revealed that ketamine increased the power of delta and theta bands during the first 15 min (po0.01) and after that time, power levels were back to basal. The structure factor was also significant for the theta range (F(3,13) = 8.65, p= 0.0002), where post-hoc analyses showed that the motor cortex presented significantly larger values of power than any of the other structures (po0.0001, with no differences among basal ganglia nuclei). No interaction effects were found neither for delta (F(12,13) = 1.23, p= 0.2679) nor for theta (F(12,13) = 1.64, p =0.087).

3.2. Ketamine alters the cross-frequency coupling patterns of the cortico-basal ganglia network structures Amplitudes of the gamma and HFO oscillations varied along the cycle of low-frequency oscillations in the delta and theta bands (see Figure 1). In order to delve into this relationship, we studied the phase-to-amplitude relationships and the effects induced by ketamine. In the basal condition, we found a pattern of modulation (Figure 3A, 15 to 0 min) with the phase of delta activity (mean 2.8, SD 0.9) modulating the amplitude of high-gamma (mean 80.75, SD 3.28) and HFO (mean 158.87, SD 13.94) oscillations. No consistent pattern was found for activities in the low-gamma range. The administration of ketamine caused a dramatic effect in the strength of coupling (MI) at the recorded structures (Figure 3A and B). Moreover, it also induced a shift of the modulating frequency, changing from delta to theta range and gradually returning into the delta range again. Two-way repeated measures ANOVA analyses on the MI values revealed no significant effects of time (F(4,13) = 1.21, p= 0.343), structure F(3,13) = 1.94, p= 0.1189) or interaction (F(12,13) = 0.61, p =0.8295) in the strength of CFC coupling between the phase of the delta/theta oscillations and the amplitude of the low-gamma activities. On the contrary, a significant time effect (i.e. ketamine effect, F(4,13) = 4.08, p= 0.0063) was detected for the high-gamma range. Posthoc analyses revealed that the MI increased significantly for the first 15 min after ketamine injection (po0.001) and then, MI were back to basal levels. In the HFO band significant time (F(4,13) = 15.14, po0.0001), structure (F(3,13) = 3.35, p= 0.0297) and interaction effects (F(4,13) = 4.42, po0.0001) were found. Interaction effects were further investigated by a series of one-way ANOVA tests (time factor, one per structure), revealing that there was a significant effect of ketamine for all structures (Cx: F(4,13) = 23.03, po0.0001; CPU: F(4,13) =7.55, po0.0001; STN: F(4,13) =7.17, p= 0.0001) but for the SNr, which did not reach the significance threshold (F(4,13) = 2.08, p= 0.097). Post-hoc analyses detected that in the Cx the effects on the coupling between delta/theta and HFO oscillations remained very significant for the whole recording (po0.001). In CPU and STN the changes in the MI values were also significant (po0.05) but lasted for 45 min.

5 Two way repeated measures ANOVA test (time  structure) on the value of the modulatory frequency detected a significant effect on time (F(4,13) = 15.66, po0.0001) but not structure (F(4,13) = 2.52, p =0.0736) nor for interaction (F(4,13) = 0.98, p= 0.4752). Figure 4A illustrates the pattern of changes produced by ketamine. First, in basal condition ( 15 to 0 min), activities in the delta range entrained the amplitude of high-gamma and HFO bands. After ketamine injection, this modulating activity shifted significantly to the theta range (Post-hoc Tukey test, po0.0001 for time 0– 30 min and po0.001 for time 30–45 min) and gradually returned into the delta range (p40.05 for time 45–60 min). To further characterize this phenomenon, we investigated about the preferred phase of coupling for the gamma and HFO oscillations. We found that qualitatively, before and after ketamine administration, the amplitudes of highgamma and HFO oscillations were maximal at the troughs of the slow modulating activities (see Figure 4A, lower panels). Phase histograms (Figure 4B) confirmed that despite the aforementioned CFC changes in the modulating frequency and MI values, the preferred phase of coupling is not altered by the ketamine injection. These observations were consistent across all the recorded structures.

3.3. Ketamine alters the patterns of interaction among the cortico-basal ganglia network structures In a previous work we showed how ketamine alters the interactions in the cortico-basal ganglia network by increasing the imaginary coherence in the low-gamma, highgamma and HFO frequency bands (Nicolás et al., 2011). Here significant interactions (significance test against no correlation, po0.05) among all six possible pairs of structures recorded (Cx-CPU, Cx-STN, Cx-SNr, CPU-STN, CPU-SNr and STN-SNr) were also found in the delta and theta ranges (Figure 5). Interestingly, the two-way repeated measures ANOVA on the imaginary coherence detected a significant effect of ketamine on time for the theta band (F(4,13) = 4.13, p= 0.0059). Post-hoc test revealed that ketamine increased significantly the amount of interactions in this range for the whole post-injection period (po0.001). No significant effects were found in the case of the delta band (F(4,13) = 1.62, p= 0.1847). To investigate the combined effect of the alterations induced by ketamine in both the degree of interaction in the delta/theta range and in the CFC patters mediated by the phase of these oscillations we used a bivariate analysis based on an event-related coherence scheme that uses the phases of the low-frequency oscillations as trigger (LópezAzcárate et al., 2013). Following this scheme we have recently shown that in basal conditions and for the same set of structures recorded here, the interactions (i.e coherence) between structures in the gamma and HFO ranges are restricted to short-time bursts of coherent oscillations that only occur in precise phases of the delta waves. Accordingly, and in the same way that dopaminergic drugs modulate this phenomenon and alters the animals' behavior, here we expected that ketamine would also have a combined effect on these patterns of inter/intrafrequency coupling between multiple brain structures.

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

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Figure 3 Ketamine alters intra-site phase-to-amplitude CFC patterns. (A) Time-course of CFC patterns (grand average across all the animals) for pre and post-injection periods. The comodulograms show coupling interactions between the phase of the activity in the delta–theta range and the amplitudes of HG and HFO activities. During the basal period CFC at HG and HFO bands exist. After ketamine administration, a shift in the modulating (phase) frequency occurs; changing from delta (basal) to theta (first postketamine periods) and again to delta (last recording segment) and MI is greatly increased for HFO and HG. (B) MI values for all the structures and time segments. Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

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Figure 4 High-gamma and high frequency oscillations are phase-locked to delta–theta oscillations. (A) Example of the evolution of the CFC for the Cx of a representative animal. Comodulograms computed across the five different periods analyzed (upper panels) show that in basal condition, delta activity mainly modulates HG oscillations ( 15 to 0 min); then ketamine produces a shift in the modulation frequency to theta values (0–15 min) together with an increase in HFO and HG modulation. By the end of the recording, theta frequency shifts again to delta and modulation goes back to basal. These effects, together with the preferred phase of coupling can be observed by computing the average of the energy of oscillatory activity from 20 to 200 Hz using the troughs of the slow oscillations as a trigger (lower panel). (B) Distribution of preferred phases of coupling is consistent for all the time segments. Rows show the normalized amplitude for HFO and HG respectively. Ketamine does not change the preferred phase over time which peaks at the troughs of delta–theta activity.

In order to assess this hypothesis we selected the troughs of the low-frequency activity in one structure as the trigger for the computation of the iERCoh between high-frequency signals between two structures. Results showed that interstructure interactions in the high-gamma and HFO bands increased for very specific phases of the low frequency delta/theta activities and more importantly, that they were highly altered by ketamine (for an example, see Figure 6A). Phase-locking value analysis (PLV, see Section 2), a technique that takes into account only the phase of the signals confirmed the iERCoh findings (Figure 6B).

In basal condition, the iERCoh was mainly detected in the high-gamma range, centered on the troughs of the delta–theta activity. After ketamine injection, coherence in the HFO band was remarkably increased. The two-way repeated measures ANOVA (time  pair of structures) on the iERCoh values of the HG and HFO bands revealed an effect of the time factor (F(4,13) =4.16, p=0.0057 and F(4,13) =21, po0.0001); the pair factor was only significant for the HFO band (F(11,13) =6.25, p=0.0016) and no interaction was detected in any of the two frequency ranges (F(44,13) =1.16, p=0.319 and F(44,13) =1.26, p=0.246). Post-hoc Tukey tests detected a significant increase

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

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Figure 5 Ketamine alters delta–theta coherence between structures. Delta and theta iCoh for all possible pairs of structures studied. Coherence values in the theta band are increased after ketamine administration reaching those of delta band.

(respect to basal) in the iERCoh for the HFO band that lasted for the whole recording (po0.001). In the case of the HG range significant differences (po0.001) were only found for the first 15 min after the injection of the drug. Post-hoc analyses on the pair factor for the HFO range detected that the pair Cx-CPU presented the largest degree of interaction (po0.0001, against all the other pairs). In all cases, the coherence was maximal at the troughs of the low-frequency activity and the effect was gradually reduced with the distance to the trough. All these results suggest that the phase of the delta (theta) activities does not only shape the amplitudes of the HG and HFO oscillations (phase-amplitude CFC), but also could modulate the interactions at these frequencies by gating the periods of transient communication among structures. In order to compare the differential effects of ketamine on these low-frequency mediated interactions of the highgamma and HFO activities, we performed a two-way repeated measures ANOVA (time  pair of structures) with the ratios of HFO/high-gamma event-related values for those pairs of structures showing changes in the iERCoh. The results confirmed that the increase in the HFO coherence at the troughs of the delta–theta was significantly larger than the one produced in the high-gamma band (F(4,13) = 12.71, po0.0001). The pair of structures factor was also significant (F(4,13) = 6.52, p= 0.0012), but no interaction was found (F(4,13) = 0.9, p= 0.5525)

3.4.

Locomotor activity

During basal condition, animals moved sparingly. Consistent with the previous reports (Caixeta et al., 2013; Hunt et al., 2006; Nicolás et al., 2011), the subanesthesic dose of ketamine produced a pattern of hyperlocomotion in the

rodents inducing predominant circling and stereotypic head movements (Figure 7A). The one way-repeated measures ANOVA analysis revealed a significant effect of time in locomotion activity (F(4,13) = 20.73, po0.0001) (Figure 7B) and post-hoc Tukey test confirmed that ketamine induced a significant increase in the amount of locomotion shown by the animals in the post-injection period (po0.0001 for time 0–45 min; po0.01 for time 45–60 min). Pearson's correlations between the amount of movement and the MI values and iERCoh values in the high-gamma and HFO frequency were estimated (Tables 1 and 2). Specifically, we analyzed the correlations between the movement at every time slot and their corresponding MI (iERCoh) values, pooled across the whole set of animals and time slots. In the HFO band, the Cx was the only structure where the strength of CFC coupling correlated with movement while in the high-gamma band we only detected significant correlations for the structures in the basal ganglia nuclei (CPU, STN and SNr). Finally, the degree of prediction that the MI values at the different structures offered for the amount of movement shown by the animals was assessed by a multiple linear regression analysis with forward selection. This analysis showed that the MI at CPU and STN for the highgamma range together with the MI at Cx in the HFO were the variables that best predicted the amount of movement shown by the animals (F= 20.69; po0.0001). Forward selection in the regression model did not show any significant additive effect for the remaining variables. For the iERCoh estimates, statistical analysis detected that iERCoh values between a number of pairs of structures correlated positively with the movement. The highest values of correlation were found in the HFO band where all the pairs showed a great significance. iERCoh values in

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

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Figure 6 Between-structure HFO synchronization is increased by the effect of ketamine. Time–frequency maps representing the ERCoh (A) and PLV (B) between the motor cortex and CPU using the Cx delta–theta phase trough time points as trigger for the analysis (see methods) of a representative animal. In basal condition ( 15 to 0 min, left column) and for the HG band, phasic events of interaction between structures are detected only for specific phases (the troughs) of the delta wave (superimposed white traces). After ketamine administration interactions in the HFO band are greatly increased (45–60 min, right column). Similar results are obtained when choosing the activity of the second structure to set the trigger (data not shown).

Figure 7 Ketamine increases locomotion activity. (A) Time course of locomotion activity of a representative animal. The injection of 10 mg/kg produces an increase in locomotion activity. The peak of movement is reached during the first period and gradually decreases with time. (B) Boxplot of the evolution of total locomotion. Compared to basal, the rat moves significantly more during the whole recording period. Significance levels are shown with one (*po0.05,) or two (**po0.001) asterisks.

the high-gamma band also correlated in most of the pairs, although the value of the correlation coefficient was lower. Multiple linear regression analysis with forward selection detected that the iERCoh values that better predicted the degree of movement were the iERCoh values in the CPU-Cx pair for the high-gamma range and the pairs Cx-CPU Cx-STN and STN-Cx in the HFO band (F= 11.75; po0.0001).

4.

Discussion

In the current study, we have used the rodent model of ketamine to assess to what extent the acute blocking of NMDA receptors interferes in the architecture of the oscillatory activity of the motor circuit of the rat cortico-basal ganglia, and how this disturbance results in the behavioral alterations.

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

10

I. Cordon et al.

Table 1 Linear correlations between intra-structure modulation index (MI) values and amount of movement for the administration of 10 mg/kg of ketamine.

Cx CPU STN SNr n

High-gamma

HFO

r =.075 r =.389n r =.578n r =.699n

r =.633nn r =.080 r =.501 r =.183

po.05. po0.001.

nn

Table 2 Linear correlations between the ERCoh values and movement for the administration of 10 mg/kg of ketamine. The first element of the pair represents the structure from which the delta–theta activity was taken as trigger to calculate the ERCoh.

Cx-CPU Cx-STN Cx-SNr CPU-Cx CPU-STN CPU-SNr STN-Cx STN-CPU STN-SNr SNr-Cx SNr-CPU SNr-STN

High-gamma

HFO

0.185 0.3152n 0.4882n 0.2604 0.3919n 0.4718n 0.2324 0.5164n 0.7864n 0.4222n 0.5236n 0.743n

0.5296n 0.7948nnn 0.825nnn 0.5018nn 0.7282nnn 0.6069n 0.8318nnn 0.807nnn 0.9151nnn 0.8175nnn 0.6965nn 0.743nnn

n

po.05. po0.001. nnn po0.0001. nn

The administration of subanesthesic doses of ketamine is an established rat model of schizophrenia and induces an increase in locomotion together with an increase in the power of gamma (30–80 Hz) and high-frequency (around 150 Hz) oscillations in otherwise healthy rats (Caixeta et al., 2013; Hunt et al., 2006; Nicolás et al., 2011). Previous experiments have also shown changes in the power of delta and theta oscillations (Hunt and Kasicki, 2013). Oscillations in the theta range have been associated with memory and learning and a role in enhancing coordination across distributed brain areas during information processing has also been attributed to them. They appear when rats are engaged in active motor behavior or when they remain motionless but alert (Buzsáki, 2002; O’Neill et al., 2013; Tort et al., 2008). Our results confirm that ketamine induces a significant increase in the power of the theta oscillations. Nevertheless, and despite the significant increase in the amount of movement during the whole recording time, changes in the theta power only lasted for the first 15 min after the drug administration. Interestingly, some studies have reported significant effects of ketamine on the power of

theta oscillation (Páleníček et al., 2011; Sebban et al., 2002) while others have shown the contrary (Hunt et al., 2011; Phillips et al., 2012); here we have found that there is a transitory effect that lasts for several minutes and then it loses its significance. All these results suggest that factors such as the methodology of recording/analysis, drug dose and electrode placement could account for these differences. Cross-frequency interactions have been proposed as a potential mechanism to process information and bind neuronal assemblies at different spatial and temporal scales (Canolty and Knight, 2010). Coupling between the phase of low-frequency oscillations and the amplitude of higher frequency activities has already been found in humans and rodents, both under physiologic and pathological conditions (Canolty et al., 2006; López-Azcárate et al., 2010; Tort et al., 2008). In schizophrenia and its models, only a few studies have explored potential abnormalities in these CFC patterns (Caixeta et al., 2013; Kirihara et al., 2012; Lakatos et al., 2013). Kirihara et al. (2012) studied the CFC patterns in schizophrenic patients during auditory steady-state stimulation (ASSR) and did not find differences compared to the responses observed in healthy subjects. However, Lakatos et al. (2013) showed that impairment in delta/ gamma coupling in the auditory system occurs in schizophrenia as well as impaired modulation within the motor system during the execution of auditory tasks. Further experiments are necessary to elucidate whether CFC changes in schizophrenic subject are task-dependent. In rodents, Caixeta et al. (2013) have investigated the effect of different doses of ketamine in the CFC patterns of the rat hippocampus. Our results agree with and extend their findings, together with an exaggerated increase in the theta-mediated high-gamma and HFO CFC, we also detected a shift in the frequency of the modulating activity from the delta to the theta range. Moreover, our results show a sort of topographic correlation between the increase of locomotion and the changes observed in the CFC patterns. While hyperlocomotion correlates better with the CFC increase between theta/HFO in the cortex, in subcortical structures (CPU, STN and SNr) correlations are stronger between theta/high-gamma. This is also supported by the results of the stepwise multiple regression analysis, where the increase in locomotion is completely explained by the combined effect of the changes in the MI of CPU and STN at the high-gamma range together with those of the HFO in the Cx (being the MI at the Cx the variable that better explains the model by itself). Interestingly, a similar behavior for the high-gamma band has also been observed in parkisonian patients (Lalo et al., 2008) and could suggest that HFO activity would be more related to cortical-mediated activity while processing at the subcortical level could be more dependent on gamma oscillations. Together with the changes in theta power and in the CFC patterns, we also detected that ketamine does result in an increase of theta band coherence across the whole circuit. This could be of key importance because the phase of theta oscillations seems to play also a key role in the modulation of the amplitude of gamma and HFO activities. This fact would suggest a combined effect of ketamine on the organization of the oscillatory activity across the whole circuit. In this line, different studies (Colgin et al., 2009; Tort et al., 2008) have shown how inter-site CFC could serve to manage information

Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004

Coupling in the cortico-basal ganglia circuit across different spatial locations where low-frequency activities would pace the exchange of chunks of information via gamma oscillations. As a result, CFC could be used as a bidirectional communication system where independent channels would exchange functional information for cognitive processing across different brain areas (Canolty and Knight, 2010). Recently we have shown that the phase of delta oscillations provides gamma and HFO oscillations with gating periods of transient communication between structures that are altered by dopaminergic modulation (López-Azcárate et al., 2013). Indeed, the iERCoh analysis revealed a dramatic increase of synchronization between structures at the trough of the theta oscillations (mainly in the HFO band) that strongly correlated with movement. This suggests the presence of a subtle architecture in the oscillatory activity of basal ganglia that is altered by the ketamine effect and points to the tandem theta/HFO oscillations as the main actor in the hyperlocomotion induced by ketamine. The amplitude of the HFO oscillations does not occur randomly, but in phasic bursts that appear at very specific phases of the delta and theta oscillations. During these phasic events, the HFO (and gamma) oscillations are coherent across the whole motor circuit of the cortico-basal ganglia, where not only the amplitudes but also the phases are synchronized. After ketamine administration, these physiological mechanisms turn aberrant and could result in hyperlocomotion and likely in the perceptive disturbances of this schizophrenia model. Similar aberrant cross-structure interactions have been already reported in Parkinson's disease patients (Hemptinne et al., 2013). In summary, our findings suggest that ketamine induces an aberrant pattern in the oscillatory activity of the corticobasal ganglia circuit that seems to be closely related to the hyperlocomotion experienced by the rodents. This work stresses the importance of the basal ganglia circuitry in this model and would be in agreement with some theories about the implication of these nuclei in schizophrenia (PerezCostas et al., 2010; Simpson et al., 2010). To our knowledge, this is the first report of cross-frequency coupling in the cortico-basal ganglia motor circuit in the ketamine rodent model of schizophrenia. We consider that it represents one-step further in the characterization of this model and leaves the door open to further investigations focusing on the interactions between dopamine receptors (main modulators of this circuit) and NMDA blockade. Although translating our results to patients is hard and the functional role of these oscillatory changes remains unclear, what seems apparent is that schizophrenia is accompanied of a number of abnormalities in the architecture of brain activity that should be considered in further investigations about the pathophysiology of the disease.

Role of funding source The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Contributors This work was supported by the UTE Proyecto CIMA, the Spanish Ministry of Science and Innovation (Project Ref. BFU2010- 18608), the

11 Fondo de Investigaciones Sanitarias (Project Ref. FIS 070034) and the Gobierno de Navarra (Jerónimo de Ayanz Programme). Miguel Valencia acknowledges financial support from the Spanish Ministry of Science and Innovation, Juan de la Cierva (Project Ref. JCI-2010-07876).

Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Financial disclosures The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgment This work was supported by the UTE Proyecto CIMA, the Spanish Ministry of Science and Innovation (Project Ref. BFU2010-18608), the Fondo de Investigaciones Sanitarias (Project Ref. FIS 070034) and the Gobierno de Navarra (Jerónimo de Ayanz Programme). Miguel Valencia acknowledges financial support from the Spanish Ministry of Science and Innovation, Juan de la Cierva (Project Ref. JCI-2010-07876).

Appendix A.

Supporting information

Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/ j.euroneuro.2015.04.004.

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Please cite this article as: Cordon, I., et al., Coupling in the cortico-basal ganglia circuit is aberrant in the ketamine model of schizophrenia. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.04.004