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Resting state theta band source distribution and functional connectivity in remitted schizophrenia
Neuroscience Letters 630 (2016) 199–202
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
Resting state theta band source distribution and functional connectivity in remitted schizophrenia D. Shreekantiah Umesh ∗ , Sai Krishna Tikka (MD DPM), Nishant Goyal (MD DPM), S.Haque Nizamie (MD DPM), Vinod Kumar Sinha (MD DPM) KS Mani Center for Cognitive Neurosciences, Central Institute of Psychiatry, Kanke, Ranchi, 834006 Jharkhand, India
h i g h l i g h t s • • • • •
Increased resting theta activity is one of the most consistent observations occurring during all the phases of schizophrenia illness. Resting state theta oscillations during the remission phase are yet unclear. Low-resolution brain electromagnetic tomography (LORETA) is an electrophysiological approach, which address the restricted spatial resolution of EEG. Statistically significant and increased theta band current source density was found in the dominant anterior cingulate cortex. Connectivity analysis showed increased theta band connectivity between the inferior parietal lobe bilaterally and between the left inferior parietal lobe and right middle frontal gyrus.
a r t i c l e
i n f o
Article history: Received 17 June 2016 Received in revised form 27 July 2016 Accepted 27 July 2016 Available online 30 July 2016 Keywords: Current source distribution Functional connectivity Remitted schizophrenia
a b s t r a c t Increased resting theta activity is one consistent observation occurring during all the phases of schizophrenia. However, the resting theta oscillations during the remission phase are yet unclear. We studied resting theta current source density and functional connectivity in remitted schizophrenia and compared with healthy controls. Significantly increased current source density was found in the dominant anterior cingulate cortex. Increased connectivity between the inferior parietal lobe bilaterally and between the left inferior parietal lobe and right middle frontal gyrus was also found. It may be concluded that schizophrenia patients have aberrant regional theta band current source density and functional connectivity even during remission. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Increased resting state theta activity is a sign of focal brain pathology, which is reported in various neurological and psychiatric disorders. In schizophrenia, increased resting theta activity is one of the most consistent observation occurring either locally or globally, in drug naive, first-episode, and chronic patients [16,22]. However, when these subjects are exposed to various tasks and paradigms with simultaneous electroencephalographic (EEG) recording, most studies report a consistently reduced theta activity [4]. Low-resolution brain electromagnetic tomography (LORETA) is an electrophysiological approach, which address the restricted
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (D. Shreekantiah Umesh), [email protected] (S.K. Tikka), [email protected] (N. Goyal), [email protected] (S.Haque Nizamie), vinod [email protected] (V.K. Sinha). http://dx.doi.org/10.1016/j.neulet.2016.07.055 0304-3940/© 2016 Elsevier Ireland Ltd. All rights reserved.
spatial resolution of EEG. It provides a 3-dimensional tomography of brain’s electrical activity or current source density [17,18]. Typically, different cortical and subcortical regions mainly prefrontal cortex, hippocampus and sensory cortex are involved in the generation of theta oscillations [25]. Using standardized LORETA (sLORETA), Mientus et al. [15] found enhanced low-frequency activity (delta band) in the anterior cingulate cortex and fusiform gyrus in unmedicated schizophrenia patients and reflected a possibility of cortical hypoactivation. Also, functional disconnection of various large-scale neural networks, represented by theta oscillations, might also be related to psychopathology. König et al. [13] found schizophrenia patients have diminished theta synchronization in the anterior and midline frontal regions suggesting a “floppy” functional connectivity that may be attributed to working memory deficits. Additionally, antipsychotic drugs also increase in delta and theta frequencies in the anterior cingulate and medial frontal cortex in medicated schizophrenia patients as compared to drug naïve [24].
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Table 1 Sociodemographic and clinical characteristics of remitted schizophrenia patients. Variables
SZ
HC
t
p
Age (in years ±SD) Duration of illness (years) Age of onset (years) Chlorpromazine equivalent dose (mg/day)
29.80 (7.68) 5.37 ± 3.31 23.47 ± 7.35 443.65 ± 215.94
29.75 (7.71)
0.001
0.999
PANSS
Positive Syndrome Scale Negative Syndrome Scale General Psychopathology PANSS Total Score
7.800 ± 0.894 10.600 ± 1.095 20.700 ± 1.763 40.250 ± 3.176
SANS
SANS Total Score Affective Flattenning Alogia Apathy Anhedonia Attention
24.750 ± 4.689 6.800 ± 1.609 3.200 ± 0.894 4.900 ± 1.209 7.300 ± 0.923 2.400 ± 0.598
SZ: schizophrenia, HC: Healthy controls.
Fig. 1. illustrates increased resting state theta band current source density for the maximum t threshold (Left anterior cingulate gyrus).
Studying schizophrenia patients in remission is critical in understanding the electrophysiological activity of the brain in terms of a ‘trait phenomenon’. Moreover, none of the studies have focussed on resting state electrical activity of the brain using standardized LORETA (sLORETA) by following stringent remission criteria for schizophrenia [2]. We attempted to study the current source density and functional connectivity of resting state theta activity in remitted schizophrenia patients and compared with the healthy controls. Also, we focused on the long-range functional connectivity (theta band) using lagged linear connectivity analysis to extend the hypothesis of functional dysconnectivity in remitted schizophrenia.
2. Methodology Twenty consented age-matched right-handed male schizophrenia patients and 20 healthy controls were included in the study. Institute’s ethical committee approved the study protocol. Patients scoring ≤ 3 (mild) on items 1–3 of the positive sub-scale, on items 1, 4, and 6 of the negative sub-scale, and on items 5 and 9 of the general psychopathology subscale in Positive and Negative syndrome scale (PANSS) [12] and score ≤2 (mild) on all the items of Scale for the Assessment of Negative Symptoms (SANS) for a period of 6 months were included [2] (refer Table 1). All the patients were on antipsychotic medications and those scoring > 0.3 on SimpsonAngus Extrapyramidal Side Effects Scale [21] were excluded. The healthy controls who scored <3 on General Health Questionairre-12 (GHQ-12) [8] were included in the study.
2.1. EEG recording and analysis All participants underwent 192 channels EEG recording (International 10-5 system) in a sound attenuated room at K.S Mani Centre for Cognitive Neurosciences, Central Institute of Psychiatry Ranchi, Jharkhand India. The acquisition was done in a resting state with eyes closed for 10 min. The data was collected between 9 AM to 12 PM and participants were refrained from caffeine and nicotine before the recording. Eye movement potentials were monitored using right and left electrooculogram (EOG) channels. Electrode impedance was kept <5k. EEG was filtered (time constant- 0.1 s, high-frequency filter–120 Hz) and digitized (sampling rate- 512 Hz) using Neurofax EEG–1100 K (Nihon-Kohden, Tokyo, Japan). First sixty-second epochs of artefact-free EEG data was visually selected from two independent investigators (SKT and NG) after carefully excluding segments with eye movement, blink and electromyogram (EMG), movement, electrode artefacts and drowsiness changes. Selected EEG epochs were recomputed against a common average reference. Out of 192 channels, 19 channels (Fp1, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1 and O2) were selected and re-referenced to the average. Matlab7.1® (The Math Works Inc, Massachusetts, U.S.A.) was used for EEG pruning and analyses.
2.2. sLORETA analysis For source localization, sLORETA was used to estimate the 3-dimensional intracerebral current source density distribution
D. Shreekantiah Umesh et al. / Neuroscience Letters 630 (2016) 199–202
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Fig. 2. illustrates increased theta band connectivity from left inferior parietal lobe to right middle frontal gyrus and between inferior parietal lobes of both hemispheres for the maximum t threshold.
[LORETA-KEY software package as provided at http://www.uzh.ch/ keyinst/NewLORETA/Software/Software.htm]. The software uses a three-shell spherical head model registered to a standardized stereotactic space available as a digitized MRI from the Brain Imaging Centre (Montreal Neurological Institute, MNI305) with a grid of 7 mm, producing a total of 2394 voxels. EEG theta band time-averaged LORETA images were computed and used for further analysis. Statistical comparisons of LORETA-estimated current source density were performed between the schizophrenia group and healthy controls. The localization of the differences in activity between the groups was assessed by voxel-by-voxel non-paired ttests of the LORETA images, based on the log-transformed power of the estimated electric current density. This resulted in ‘t-statistic’ 3-dimensional images (Refer Fig. 1). In order to correct for multiple comparisons, a nonparametric single-threshold test was applied [10]. The null hypothesis of no current sources was rejected if at least one t value (i.e. voxel, t MAX) was above the critical threshold for p = 0.05, determined by 5000 randomizations [24]. The connectivity analysis was performed by the computation of lagged linear connectivity. This connectivity measure is a much more appropriate measure of electrophysiological brain connectivity as it decomposes connectivity into instantaneous and lagged components [5] and it is resistant to non-physiological artefacts, in particular, volume conduction and low spatial resolution. It is thought to represent the connectivity between two signals after the instantaneous zero-lag contribution (artefactual component) has been excluded [11]. For connectivity analysis, 19 Regions of Interest (ROIs) were defined corresponding to the site of the electrode (one for each scalp electrode) [5,11]. Following this, the ‘single nearest voxel’ option was chosen in this way, each ROI consisted of a single voxel, the closest to each predefined channel. 3. Results 3.1. sLORETA analysis The thresholds for significance were T = 2.89 corresponding to p < 0.05. Significant difference in current source density was observed in theta band in Left anterior cingulate cortex (ACC), Brodmann area (BA) 32 [(X, Y, Z = −5, 35, 20) (refer Fig. 1)] (T = 2.684 p < 0.05). No significant differences were observed in the other brain regions as it exceeded the maximum threshold. 3.2. Connectivity analysis The thresholds for significance were T = 1.86 corresponding to p < 0.05. In Schizophrenia patients, a significantly increased lagged linear connectivity (T = 1.694, p < 0.05) was observed in the theta
band between the cortical areas explored by P3 [(X, Y, Z = −40, −70, 45) left inferior parietal lobe], P4 [(X Y Z = 45 −70 45) right inferior parietal lobe] and F4 [(X, Y, Z = 45, 40, 30) right middle frontal gyrus (dorsolateral prefrontal cortex)] electrode sites [6] (refer Fig. 2). No significant differences were observed for other electrode pairs. 3.3. Correlation analysis The sLORETA correlation analyses revealed a trend level significantly increased lagged linear connectivity between the right precuneus and left middle frontal gyrus correlated with total PANSS score (r = 0.25, p = 0.063). No significant correlation was observed for SANS. 4. Discussion We aimed to explore the EEG current source density and functional connectivity in theta band using scalp EEG power spectra in remitted schizophrenia patients and compared with healthy controls. During rest, an increased current source density in theta band in the left ACC was observed in remitted schizophrenia patients. Broadly, an increased current source density in theta frequency band in ACC may reflect regional cortical hypo-functioning. Moreover, abnormal ACC activity is found in schizophrenia. Studies have reported that ACC is hyperactive at rest, which is unable to activate further in response to increasing task demands [1,9,20]. Also, ACC forms a functional bridge between the limbic structures and the frontal lobe and offers the capacity to integrate cognitive activity with affective experience which may underlie psychopathology [23]. Our study hints towards increased theta band current source distribution in ACC at rest even when the patients have remitted. Also, we may speculate that grey matter reductions may progress with illness duration as earlier studies report reduced grey matter volume in ACC not only during the acute phase of illness but also in the premorbid phase [7,19] suggesting it to be a ‘trait phenomenon’. Nonetheless, an increase in slow frequency activity in the ACC has been described as an outcome of antipsychotic treatment [14]. An increase in theta frequency in the ACC and the medial frontal cortex are found in patients receiving clozapine and olanzapine compared to drug naïve [24]. Our study does not delineate whether increased theta band current source density is a resultant of the diseased state of the brain or an effect of chronic antipsychotic treatment, which is indeed a limitation of the present study. We also showed increased theta band functional connectivity between the right and left inferior parietal lobes and, between the left inferior parietal lobe and right middle frontal cortex. These distinct brain regions are the subsets of the ‘default mode network’, which is impaired in schizophrenia patients. In a recent
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study, Andreou et al. [3] found increased resting state thetaband connectivity across the frontal midline, sensorimotor and the left temporo-parietal junction. Our findings further support that theta-band hyperconnectivity may be a specific pathophysiological mechanism that might underlie residual psychopathology in schizophrenia patients despite in remission. Expectedly, theta band connectivity was positively correlated with total PANSS score. We propose that ongoing psychopathological processes may positively influence theta band connectivity or vice-versa. The study has certain limitations. Larger sample size must be considered before drawing an absolute conclusion. Scalp EEG recordings have an intrinsic limitation in terms of spatial resolution. As discussed earlier, the influence of antipsychotic medication on findings of the present study is a confound. As controlling for the medication status in patients during remission is ethically challenging, our study could not eliminate this confound. Future studies may focus on recruiting a larger sample, including drug-free remitted schizophrenia subject may broaden the understanding of neural underpinning of resting theta oscillations. Conflict of interest None. Acknowledgement None. References [1] R. Adams, A.S. David, Patterns of anterior cingulate activation in schizophrenia: a selective review, Neuropsychiatr. Dis. Treat. 3 (2007) 87. [2] N.C. Andreasen, W.T. Carpenter Jr., J.M. Kane, R.A. Lasser, S.R. Marder, D.R. Weinberger, Remission in schizophrenia: proposed criteria and rationale for consensus, Am. J. Psychiatry 162 (2005) 441–449. [3] C. Andreou, G. Leicht, G. Nolte, N. Polomac, S. Moritz, A. Karow, I.L. Hanganu-Opatz, A.K. Engel, C. Mulert, Resting-state theta-band connectivity and verbal memory in schizophrenia and in the high-risk state, Schizophr. Res. 161 (2015) 299–307. [4] E. Basar, B. Guntekin, Review of delta, theta, alpha, beta, and gamma response oscillations in neuropsychiatric disorders, Suppl. Clin. Neurophysiol. 62 (2013) 303–341. [5] L. Canuet, R. Ishii, R.D. Pascual-Marqui, M. Iwase, R. Kurimoto, Y. Aoki, S. Ikeda, H. Takahashi, T. Nakahachi, M. Taakeda, Resting-state EEG source localization and functional connectivity in schizophrenia-like psychosis of epilepsy, PLoS One 6 (2011) e27863. [6] L. Canuet, I. Tellado, V. Couceiro, C. Fraile, L. Fernandez-Novoa, R. Ishii, M. Takeda, R. Cacabelos, Resting-state network disruption and APOE genotype in Alzheimer’s disease: a lagged functional connectivity study, PLoS One 7 (2012) e46289.
[7] A. Fornito, M. Yücel, B. Dean, S.J. Wood, C. Pantelis, Anatomical abnormalities of the anterior cingulate cortex in schizophrenia: bridging the gap between neuroimaging and neuropathology, Schizophr. Bull. 35 (2009) 973–993. [8] D.P. Goldberg, R. Gater, N. Sartorius, T. Ustun, M. Piccinelli, O. Gureje, C. Rutter, The validity of two versions of the GHQ in the WHO study of mental illness in general health care, Psychol. Med. 27 (1997) 191–197. [9] M.M. Haznedar, M.S. Buchsbaum, C. Luu, E.A. Hazlett, B.V. Siegel, J. Lohr, J. Wu, R.J. Haier, W.E. Bunney, Decreased anterior cingulate gyrus metabolic rate in schizophrenia, Am. J. Psychiatry 154 (1997) 682–684. [10] A.P. Holmes, R. Blair, J. Watson, I. Ford, Nonparametric analysis of statistic images from functional mapping experiments, J. Cereb. Blood Flow Metab. 16 (1996) 7–22. [11] C. Imperatori, B. Farina, M.I. Quintiliani, A. Onofri, P.C. Gattinara, M. Lepore, V. Gnoni, E. Mazzucchi, A. Contardi, G. Della Marca, Aberrant EEG functional connectivity and EEG power spectra in resting state post-traumatic stress disorder: a sLORETA study, Biol. Psychol. 102 (2014) 10–17. [12] S.R. Kay, A. Flszbein, L.A. Opfer, The positive and negative syndrome scale (PANSS) for schizophrenia, Schizophr. Bull. 13 (1987) 261. [13] T. Koenig, D. Lehmann, N. Saito, T. Kuginuki, T. Kinoshita, M. Koukkou, Decreased functional connectivity of EEG theta-frequency activity in first-episode, neuroleptic-naive patients with schizophrenia: preliminary results, Schizophr. Res. 50 (2001) 55–60. [14] L. McCormick, L. Decker, P. Nopoulos, B.-C. Ho, N. Andreasen, Effects of atypical and typical neuroleptics on anterior cingulate volume in schizophrenia, Schizophr. Res. 80 (2005) 73–84. [15] S. Mientus, J. Gallinat, Y. Wuebben, R.D. Pascual-Marqui, C. Mulert, K. Frick, H. Dorn, W.M. Herrmann, G. Winterer, Cortical hypoactivation during resting EEG in schizophrenics but not in depressives and schizotypal subjects as revealed by low resolution electromagnetic tomography (LORETA), Psychiatry Res. 116 (2002) 95–111. [16] L.V. Moran, L.E. Hong, High vs low frequency neural oscillations in schizophrenia, Schizophr. Bull. (2011) sbr056. [17] R.D. Pascual-Marqui, Standardized low-resolution brain electromagnetic tomography (sLORETA): technical details, Methods Find. Exp. Clin. Pharmacol. 24 (2002) 5–12. [18] R.D. Pascual-Marqui, C.M. Michel, D. Lehmann, Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain, Int. J. Psychophysiol. 18 (1994) 49–65. [19] P. Salgado-Pineda, R. Landin-Romero, E. Fakra, P. Delaveau, B. Amann, O. Blin, Structural abnormalities in schizophrenia: further evidence on the key role of the anterior cingulate cortex, Neuropsychobiology 69 (2014) 52–58. [20] B.V. Siegel Jr., M.S. Buchsbaum, A. Najafi, M. Wu, Activity in 70 unmedicated male schizophrenic patients, Am. J. Psychiatry 1 (1993) 1325. [21] G. Simpson, J. Angus, A rating scale for extrapyramidal side effects, Acta Psychiatr. Scand. 45 (1970) 11–19. [22] S.R. Sponheim, B.A. Clementz, W.G. Iacono, M. Beiser, Resting EEG in first-episode and chronic schizophrenia, Psychophysiology 31 (1994) 37–43. [23] A.K. Stark, H.B. Uylings, E. Sanz-Arigita, B. Pakkenberg, Glial cell loss in the anterior cingulate cortex a subregion of the prefrontal cortex, in subjects with schizophrenia, Am. J. Psychiatry 161 (2004) 882–888. [24] B. Tislerova, M. Brunovsky, J. Horacek, T. Novak, M. Kopecek, P. Mohr, V. Krajca, LORETA functional imaging in antipsychotic-naive and olanzapine-, clozapine-and risperidone-treated patients with schizophrenia, Neuropsychobiology 58 (2008) 1–10. [25] P.J. Uhlhaas, W. Singer, Abnormal neural oscillations and synchrony in schizophrenia, Nat. Rev. Neurosci. 11 (2010) 100–113.
Contents lists available at ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
Resting state theta band source distribution and functional connectivity in remitted schizophrenia D. Shreekantiah Umesh ∗ , Sai Krishna Tikka (MD DPM), Nishant Goyal (MD DPM), S.Haque Nizamie (MD DPM), Vinod Kumar Sinha (MD DPM) KS Mani Center for Cognitive Neurosciences, Central Institute of Psychiatry, Kanke, Ranchi, 834006 Jharkhand, India
h i g h l i g h t s • • • • •
Increased resting theta activity is one of the most consistent observations occurring during all the phases of schizophrenia illness. Resting state theta oscillations during the remission phase are yet unclear. Low-resolution brain electromagnetic tomography (LORETA) is an electrophysiological approach, which address the restricted spatial resolution of EEG. Statistically significant and increased theta band current source density was found in the dominant anterior cingulate cortex. Connectivity analysis showed increased theta band connectivity between the inferior parietal lobe bilaterally and between the left inferior parietal lobe and right middle frontal gyrus.
a r t i c l e
i n f o
Article history: Received 17 June 2016 Received in revised form 27 July 2016 Accepted 27 July 2016 Available online 30 July 2016 Keywords: Current source distribution Functional connectivity Remitted schizophrenia
a b s t r a c t Increased resting theta activity is one consistent observation occurring during all the phases of schizophrenia. However, the resting theta oscillations during the remission phase are yet unclear. We studied resting theta current source density and functional connectivity in remitted schizophrenia and compared with healthy controls. Significantly increased current source density was found in the dominant anterior cingulate cortex. Increased connectivity between the inferior parietal lobe bilaterally and between the left inferior parietal lobe and right middle frontal gyrus was also found. It may be concluded that schizophrenia patients have aberrant regional theta band current source density and functional connectivity even during remission. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Increased resting state theta activity is a sign of focal brain pathology, which is reported in various neurological and psychiatric disorders. In schizophrenia, increased resting theta activity is one of the most consistent observation occurring either locally or globally, in drug naive, first-episode, and chronic patients [16,22]. However, when these subjects are exposed to various tasks and paradigms with simultaneous electroencephalographic (EEG) recording, most studies report a consistently reduced theta activity [4]. Low-resolution brain electromagnetic tomography (LORETA) is an electrophysiological approach, which address the restricted
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (D. Shreekantiah Umesh), [email protected] (S.K. Tikka), [email protected] (N. Goyal), [email protected] (S.Haque Nizamie), vinod [email protected] (V.K. Sinha). http://dx.doi.org/10.1016/j.neulet.2016.07.055 0304-3940/© 2016 Elsevier Ireland Ltd. All rights reserved.
spatial resolution of EEG. It provides a 3-dimensional tomography of brain’s electrical activity or current source density [17,18]. Typically, different cortical and subcortical regions mainly prefrontal cortex, hippocampus and sensory cortex are involved in the generation of theta oscillations [25]. Using standardized LORETA (sLORETA), Mientus et al. [15] found enhanced low-frequency activity (delta band) in the anterior cingulate cortex and fusiform gyrus in unmedicated schizophrenia patients and reflected a possibility of cortical hypoactivation. Also, functional disconnection of various large-scale neural networks, represented by theta oscillations, might also be related to psychopathology. König et al. [13] found schizophrenia patients have diminished theta synchronization in the anterior and midline frontal regions suggesting a “floppy” functional connectivity that may be attributed to working memory deficits. Additionally, antipsychotic drugs also increase in delta and theta frequencies in the anterior cingulate and medial frontal cortex in medicated schizophrenia patients as compared to drug naïve [24].
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Table 1 Sociodemographic and clinical characteristics of remitted schizophrenia patients. Variables
SZ
HC
t
p
Age (in years ±SD) Duration of illness (years) Age of onset (years) Chlorpromazine equivalent dose (mg/day)
29.80 (7.68) 5.37 ± 3.31 23.47 ± 7.35 443.65 ± 215.94
29.75 (7.71)
0.001
0.999
PANSS
Positive Syndrome Scale Negative Syndrome Scale General Psychopathology PANSS Total Score
7.800 ± 0.894 10.600 ± 1.095 20.700 ± 1.763 40.250 ± 3.176
SANS
SANS Total Score Affective Flattenning Alogia Apathy Anhedonia Attention
24.750 ± 4.689 6.800 ± 1.609 3.200 ± 0.894 4.900 ± 1.209 7.300 ± 0.923 2.400 ± 0.598
SZ: schizophrenia, HC: Healthy controls.
Fig. 1. illustrates increased resting state theta band current source density for the maximum t threshold (Left anterior cingulate gyrus).
Studying schizophrenia patients in remission is critical in understanding the electrophysiological activity of the brain in terms of a ‘trait phenomenon’. Moreover, none of the studies have focussed on resting state electrical activity of the brain using standardized LORETA (sLORETA) by following stringent remission criteria for schizophrenia [2]. We attempted to study the current source density and functional connectivity of resting state theta activity in remitted schizophrenia patients and compared with the healthy controls. Also, we focused on the long-range functional connectivity (theta band) using lagged linear connectivity analysis to extend the hypothesis of functional dysconnectivity in remitted schizophrenia.
2. Methodology Twenty consented age-matched right-handed male schizophrenia patients and 20 healthy controls were included in the study. Institute’s ethical committee approved the study protocol. Patients scoring ≤ 3 (mild) on items 1–3 of the positive sub-scale, on items 1, 4, and 6 of the negative sub-scale, and on items 5 and 9 of the general psychopathology subscale in Positive and Negative syndrome scale (PANSS) [12] and score ≤2 (mild) on all the items of Scale for the Assessment of Negative Symptoms (SANS) for a period of 6 months were included [2] (refer Table 1). All the patients were on antipsychotic medications and those scoring > 0.3 on SimpsonAngus Extrapyramidal Side Effects Scale [21] were excluded. The healthy controls who scored <3 on General Health Questionairre-12 (GHQ-12) [8] were included in the study.
2.1. EEG recording and analysis All participants underwent 192 channels EEG recording (International 10-5 system) in a sound attenuated room at K.S Mani Centre for Cognitive Neurosciences, Central Institute of Psychiatry Ranchi, Jharkhand India. The acquisition was done in a resting state with eyes closed for 10 min. The data was collected between 9 AM to 12 PM and participants were refrained from caffeine and nicotine before the recording. Eye movement potentials were monitored using right and left electrooculogram (EOG) channels. Electrode impedance was kept <5k. EEG was filtered (time constant- 0.1 s, high-frequency filter–120 Hz) and digitized (sampling rate- 512 Hz) using Neurofax EEG–1100 K (Nihon-Kohden, Tokyo, Japan). First sixty-second epochs of artefact-free EEG data was visually selected from two independent investigators (SKT and NG) after carefully excluding segments with eye movement, blink and electromyogram (EMG), movement, electrode artefacts and drowsiness changes. Selected EEG epochs were recomputed against a common average reference. Out of 192 channels, 19 channels (Fp1, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1 and O2) were selected and re-referenced to the average. Matlab7.1® (The Math Works Inc, Massachusetts, U.S.A.) was used for EEG pruning and analyses.
2.2. sLORETA analysis For source localization, sLORETA was used to estimate the 3-dimensional intracerebral current source density distribution
D. Shreekantiah Umesh et al. / Neuroscience Letters 630 (2016) 199–202
201
Fig. 2. illustrates increased theta band connectivity from left inferior parietal lobe to right middle frontal gyrus and between inferior parietal lobes of both hemispheres for the maximum t threshold.
[LORETA-KEY software package as provided at http://www.uzh.ch/ keyinst/NewLORETA/Software/Software.htm]. The software uses a three-shell spherical head model registered to a standardized stereotactic space available as a digitized MRI from the Brain Imaging Centre (Montreal Neurological Institute, MNI305) with a grid of 7 mm, producing a total of 2394 voxels. EEG theta band time-averaged LORETA images were computed and used for further analysis. Statistical comparisons of LORETA-estimated current source density were performed between the schizophrenia group and healthy controls. The localization of the differences in activity between the groups was assessed by voxel-by-voxel non-paired ttests of the LORETA images, based on the log-transformed power of the estimated electric current density. This resulted in ‘t-statistic’ 3-dimensional images (Refer Fig. 1). In order to correct for multiple comparisons, a nonparametric single-threshold test was applied [10]. The null hypothesis of no current sources was rejected if at least one t value (i.e. voxel, t MAX) was above the critical threshold for p = 0.05, determined by 5000 randomizations [24]. The connectivity analysis was performed by the computation of lagged linear connectivity. This connectivity measure is a much more appropriate measure of electrophysiological brain connectivity as it decomposes connectivity into instantaneous and lagged components [5] and it is resistant to non-physiological artefacts, in particular, volume conduction and low spatial resolution. It is thought to represent the connectivity between two signals after the instantaneous zero-lag contribution (artefactual component) has been excluded [11]. For connectivity analysis, 19 Regions of Interest (ROIs) were defined corresponding to the site of the electrode (one for each scalp electrode) [5,11]. Following this, the ‘single nearest voxel’ option was chosen in this way, each ROI consisted of a single voxel, the closest to each predefined channel. 3. Results 3.1. sLORETA analysis The thresholds for significance were T = 2.89 corresponding to p < 0.05. Significant difference in current source density was observed in theta band in Left anterior cingulate cortex (ACC), Brodmann area (BA) 32 [(X, Y, Z = −5, 35, 20) (refer Fig. 1)] (T = 2.684 p < 0.05). No significant differences were observed in the other brain regions as it exceeded the maximum threshold. 3.2. Connectivity analysis The thresholds for significance were T = 1.86 corresponding to p < 0.05. In Schizophrenia patients, a significantly increased lagged linear connectivity (T = 1.694, p < 0.05) was observed in the theta
band between the cortical areas explored by P3 [(X, Y, Z = −40, −70, 45) left inferior parietal lobe], P4 [(X Y Z = 45 −70 45) right inferior parietal lobe] and F4 [(X, Y, Z = 45, 40, 30) right middle frontal gyrus (dorsolateral prefrontal cortex)] electrode sites [6] (refer Fig. 2). No significant differences were observed for other electrode pairs. 3.3. Correlation analysis The sLORETA correlation analyses revealed a trend level significantly increased lagged linear connectivity between the right precuneus and left middle frontal gyrus correlated with total PANSS score (r = 0.25, p = 0.063). No significant correlation was observed for SANS. 4. Discussion We aimed to explore the EEG current source density and functional connectivity in theta band using scalp EEG power spectra in remitted schizophrenia patients and compared with healthy controls. During rest, an increased current source density in theta band in the left ACC was observed in remitted schizophrenia patients. Broadly, an increased current source density in theta frequency band in ACC may reflect regional cortical hypo-functioning. Moreover, abnormal ACC activity is found in schizophrenia. Studies have reported that ACC is hyperactive at rest, which is unable to activate further in response to increasing task demands [1,9,20]. Also, ACC forms a functional bridge between the limbic structures and the frontal lobe and offers the capacity to integrate cognitive activity with affective experience which may underlie psychopathology [23]. Our study hints towards increased theta band current source distribution in ACC at rest even when the patients have remitted. Also, we may speculate that grey matter reductions may progress with illness duration as earlier studies report reduced grey matter volume in ACC not only during the acute phase of illness but also in the premorbid phase [7,19] suggesting it to be a ‘trait phenomenon’. Nonetheless, an increase in slow frequency activity in the ACC has been described as an outcome of antipsychotic treatment [14]. An increase in theta frequency in the ACC and the medial frontal cortex are found in patients receiving clozapine and olanzapine compared to drug naïve [24]. Our study does not delineate whether increased theta band current source density is a resultant of the diseased state of the brain or an effect of chronic antipsychotic treatment, which is indeed a limitation of the present study. We also showed increased theta band functional connectivity between the right and left inferior parietal lobes and, between the left inferior parietal lobe and right middle frontal cortex. These distinct brain regions are the subsets of the ‘default mode network’, which is impaired in schizophrenia patients. In a recent
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study, Andreou et al. [3] found increased resting state thetaband connectivity across the frontal midline, sensorimotor and the left temporo-parietal junction. Our findings further support that theta-band hyperconnectivity may be a specific pathophysiological mechanism that might underlie residual psychopathology in schizophrenia patients despite in remission. Expectedly, theta band connectivity was positively correlated with total PANSS score. We propose that ongoing psychopathological processes may positively influence theta band connectivity or vice-versa. The study has certain limitations. Larger sample size must be considered before drawing an absolute conclusion. Scalp EEG recordings have an intrinsic limitation in terms of spatial resolution. As discussed earlier, the influence of antipsychotic medication on findings of the present study is a confound. As controlling for the medication status in patients during remission is ethically challenging, our study could not eliminate this confound. Future studies may focus on recruiting a larger sample, including drug-free remitted schizophrenia subject may broaden the understanding of neural underpinning of resting theta oscillations. Conflict of interest None. Acknowledgement None. References [1] R. Adams, A.S. David, Patterns of anterior cingulate activation in schizophrenia: a selective review, Neuropsychiatr. Dis. Treat. 3 (2007) 87. [2] N.C. Andreasen, W.T. Carpenter Jr., J.M. Kane, R.A. Lasser, S.R. Marder, D.R. Weinberger, Remission in schizophrenia: proposed criteria and rationale for consensus, Am. J. Psychiatry 162 (2005) 441–449. [3] C. Andreou, G. Leicht, G. Nolte, N. Polomac, S. Moritz, A. Karow, I.L. Hanganu-Opatz, A.K. Engel, C. Mulert, Resting-state theta-band connectivity and verbal memory in schizophrenia and in the high-risk state, Schizophr. Res. 161 (2015) 299–307. [4] E. Basar, B. Guntekin, Review of delta, theta, alpha, beta, and gamma response oscillations in neuropsychiatric disorders, Suppl. Clin. Neurophysiol. 62 (2013) 303–341. [5] L. Canuet, R. Ishii, R.D. Pascual-Marqui, M. Iwase, R. Kurimoto, Y. Aoki, S. Ikeda, H. Takahashi, T. Nakahachi, M. Taakeda, Resting-state EEG source localization and functional connectivity in schizophrenia-like psychosis of epilepsy, PLoS One 6 (2011) e27863. [6] L. Canuet, I. Tellado, V. Couceiro, C. Fraile, L. Fernandez-Novoa, R. Ishii, M. Takeda, R. Cacabelos, Resting-state network disruption and APOE genotype in Alzheimer’s disease: a lagged functional connectivity study, PLoS One 7 (2012) e46289.
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