Schizophrenia
Abstract
Objectives: The M50 auditory evoked response is a popular measure for indicating auditory processing impairment in schizophrenia patients. It is used, for example, for computation of a ratio of brain responses occurring 50 ms after paired clicks (S2-evoked P50/S1-evoked P50) known to be a marker for sensory gating. Since, the dipoles used for estimation of the M50 response are complex models of brain activity they consists not only of amplitude but also of other parameters like position, orientation, latency, goodness of fit etc. It would be interesting to investigate how the additional parameters of the dipole model contribute to the evoked amplitudes and the gating ratios, and whether they are also correlates with the symptomatic and functional scores in schizophrenia patients. This interrelationship is the subject of this study. Additionally, the chosen parameters are investigated for changes caused by computer based training programs addressed to the auditory system.
Methods: A BEM model based on the Montreal Neurological Institute (MNI) brain was used for the estimation of the dipole parameters. The M50 auditory brain response was determined as the largest peak in the time interval of 40 to 80 ms. The time point with the best goodness of fit in this interval was chosen as a representative for the M50 component. In that time point amplitude, gating ratio, latency, orientation, localization and signal-to-noise ratio (SNR) were read out and used for further analysis. The effects of two cognitive trainings (“Cognitive exercise” (CE) and “Cognitive package” (Cogpack)) performed by 23 schizophrenia patients (4 female) were investigated and compared.
Results: The schizophrenia patients differed from the healthy controls in anterior-posterior asymmetry of the M50 dipole localization, sensory gating ratio and circular variance of the dipole orientations. It was shown that not only the dipole strength and sensory gating ratio but also other dipole parameters like dipole orientation, latency and signal-to-noise ratio (SNR) correlated with symptoms in schizophrenia. No significant changes due to training effect were observed except that the Cogpack group showed a decrease of circular variance for dipole orientations.
56 Conclusions: All parameters of a dipole model and not only the amplitudes could be important by investigating impairment in the auditory processing in schizophrenia. In the study of changes caused by trainings it would be interesting to consider the entire complex of parameters instead of just the gating ratios. This could help better understand the mechanisms behind the gating ratios.
Introduction
There are many findings on functional and structural differences between schizophrenia patients and healthy controls. For example, it is assumed that auditory filtering is deficient in schizophrenia, since sensory gating ratios are increased compared to controls (Thoma et. al., 2003). Another characteristic of schizophrenia is an altered structural hemispheric asymmetry (Petty, 1999). However, these findings are not always replicated (e.g. Edgar et al., 2008). One possible explanation for these unequivocal results might be different methodologies for source localization. The reporting of just one variable participating in a complex model is not enough to be able to draw conclusions about the processes underlying the reported differences between schizophrenia patients and healthy controls. Instead, as much as possible parameters participating in the dipole estimation should be reported. This could get a better insight into the auditory processing impairments in schizophrenia.
In this study a brighter range of dipole parameters were investigated for correlations of schizophrenia characteristics and for contribution to the sensory gating ratio and the M50 amplitude. Further, training-induced neuroplasticity in schizophrenia was investigated by tracing the changes in all dipole parameters.
Methods
Subjects
Data of 23 patients (20-49 years, 4 female) and 11 controls (23-44 years old, 1 female) were available. The patients group was split into two subgroups. One group of 13 patients (22-49 years, 3 female) was assigned to the Cognitive exercises (CE, Posit Science, San Francisco, USA) training program and another subgroup of 10 patients (20-46
57 years, 1 female) to the Cognitive Package (Cogpack, Marker Software, Ladenburg, Germany) training program.
Table 1: Demographic and clinical characteristics of schizophrenia patients
Characteristic CE Cogpack Group difference
N 13 10
Age (M±SD) 32±8.4 29±8.8 0.45a
Education (M±SD) 14±2.8 12±1.9 0.08a
Gender: Females/Males 3/10 1/9 0.41b
BPRS (M±SD) 47±9.4 47±6.5 0.83a
GAF (M±SD) 39±8.2 33±11.7 0.19a
BDI (M±SD) 14±11.7 15±14.3 0.82a
Hospitalizations (M±SD) 5±6.5 5±4.3 0.95a
Medication, number of patients receiving:
typical neuroleptics 0 0
atypical neuroleptics 11 8
both 2 2
Immediate recall (M±SD) 5±2 6±1.8 0.54a
Learning speed (M±SD) 11±2.1 13±2.4 0.18a
Delayed recall (M±SD) 10±3.4 10±5.3 0.91a
Note: BPRS: Brief Psychiatric Rating Scale, (Lukoff et al., 1986); GAF: Global Assessment of Functioning Scale (DSM-IV-TR; American Psychiatric Association, 2000); BDI: Beck Depression Inventory (Beck et al., 1996); M±SD: mean ± standard deviation; a Independent two-sample t-test; b Pearson’s Chi-square test
58 Data acquisition
MEG was recorded while participants were in a laying position, using a 148-channel magnetometer (MAGNES™ 2500 WH, 4D Neuroimaging, San Diego, USA). Data were continuously recorded with a sampling rate of 678.17 Hz and a real bandpass filter of 0.1 to 200 Hz. The subject’s nasion, left and right ear canal, and head shape were digitized with a Polhemus 3Space® Fasttrack prior to measurement.
Paradigm
Pairs of 3ms clicks were presented binaurally in an auditory paired-click design (500 ms interstimulus interval, random intertrial interval (ITI) between 7 and 9s).
Cognitive Training
Patients were trained for 4 weeks. The CE training was performed 5 times a week for an hour, the Cogpack was performed 3 times a week for 70 minutes. Overt cognitive performance of patients was assessed using a German equivalent of the California Verbal Learning Test (Verbaler Lern- und Merkfähigkeitstest, VMLT (Helmstaedter and Lux, 2001)). Based on serial learning of 15-word lists, the VMLT assesses immediate recall, learning speed (across 5 repetitions of the word list), and delayed recall (after 30 minutes including the distraction of introducing a second word list).
Data Pre-Processing
Raw data were bandpass filtered (5 – 55 Hz) and averaged with a baseline from –100 to 0 ms relative to the stimulus. Co-registration with structural data was performed based on fiducial landmarks (Nasion, left- and right- auricular points: LA, RA) using Curry V.6 (Compumedics Neuroscan, USA).
Dipole Fits
Single equivalent current dipole model (Curry V.6) with an Montreal Neurological Institute (MNI)-brain based boundary element volume conductor model (Appendix B) was used for the estimation of the dipole parameters.
Gating Ratios
M50 was defined as an upward-oriented dipole occurring immediately prior to M100 (latency for M50 between 40 and 80 ms post-stimulus). Gating ratios were calculated by
59 dividing the dipole moment of the second click source by the dipole moment of the first click source (S2/S1). Lower S2/S1 ratios imply a greater degree of sensory gating.
Asymmetry
The displacement of the right dipole localization in relation to the left dipole localization along the anterior-posterior coordinate axis was used as a measure for bilateral asymmetry measure of the M50 source position.
Orientations
The orientations were calculated in the 2-dimensional sagittal plane, since the MEG blind for radial sources. The Cartesian coordinates were transformed in polar coordinates in a circle with radius one and angles in radians. The circular variance was applied as s measure for the dispersion of the orientations.
Statistics
The correlations were estimated with the Pearson’s linear correlation index r. For the sensory gating ratio and asymmetry comparisons a repeated measures analysis of variance (RMANOVA) with between factor group and within factor hemisphere was used and for the investigation of the training effects RMANOVA with between factor – group, and within factor - training was applied.
Results
The detected differences between schizophrenia patients and healthy controls were:
1. Reduced anterior-posterior asymmetry in patients compared to controls (F(1, 31) = 5.32, p=0.03; Fischer LSD Post-hoc test: controls left vs. right: p=0.003) (Figure 1).
2. Significant higher gating ratios in patients compared to controls with no hemisphere effects (interaction group × hemisphere: F<1; group effect: F(1, 32) = 4.2, p=0.049).
3. Increased circular variance (CV) of the dipole orientations in the patients group assigned to the Cogpack training (CV(CE left) = 0.15; CV(Cogpack left) = 0.55;
CV(Controls left) = 0.31; CV(CE right) = 0.05; CV(Cogpack right) = 0.61;
CV(Controls right) = 0.33).
60 Figure 1. Anterior-posterior asymmetry differences between schizophrenia patients and healthy controls
Figure 2. Difference in the gating ratios between schizophrenia patients and healthy controls
61 Figure 3. Dipole orientations in the left hemisphere for the three groups. The orientations are presented as lines with unit length. The mean direction of the orientations is represented as a bit longer line.
Figure 4. Dipole orientations in the right hemisphere for the three groups. The orientations are presented as lines with unit length. The line which is longer than the other lines marks the mean direction of the orientations.
In the patients group the following correlations were found:
1. The S1 amplitude was not found to correlate with any clinical or functional score.
2. The S2 amplitude correlated significantly with immediate recall scores (r = -0.49, p = 0.04) showed a trend in the correlations with the BPRS scores (r = 0.41, p = 0.09) and with the BDI scores (r = 0.42, p = 0.08).
3. The dipole orientations correlated with the GAF scores (r = -0.59, p = 0.01) and with the delayed recall scores (r = -0.51, p = 0.03).
4. The M50 latency correlated with the GAF scores (r = -0.53, p = 0.02) and with the delayed recall scores (r = -0.48, p = 0.04).
5. Signal-to-noise ratio (SNR) correlated with the immediate recall scores (r = -0.54, p = 0.02).
62 6. The sensory gating ratio (SGR) correlated with the BPRS scores (r = 0.6, p =
0.009) and with the Immediate recall scores (r = -0.6, p = 0.009).
7. Neither the asymmetry nor the anterior-posterior coordinates of the dipoles correlated with any of the diagnostic and functional scores. Eight of the patients participated in this study had also an individual MRI datasets. A correlation between the left anterior-posterior dipole position with the number of hospitalizations was found: r = -0.74, p = 0.04.
Significant changes due to training effect were not found. The group x hemisphere x training interaction for the anterior-posterior dipole positions was not significant: F(2, 31) = 0.07, p = 0.93. The group x training interaction for the sensory gating ratios was also not significant: F(2, 31) = 0.36, p = 0.70. It was found that the circular variance of the dipole orientations in the Cogpack group was decreased after the training period compared with the circular variance before the training period (Table 2) additionally the mean orientation of the dipoles in the left hemisphere of the Cogpack group was normalized (after the training it was nearer to the dipole orientation in controls group) (Figure 5 and 6).
Table 2. Circular variance of the dipole orientations in the three groups and its change after the training period (4 weeks waiting time for the controls).
Circular variance (left) Circular variance (right)
Controls (pre) 0.31 0.33
Controls (post) 0.24 0.21
CE (pre) 0.15 0.05
CE (post) 0.23 0.28
Cogpack (pre) 0.55 0.61
Cogpack (post) 0.20 0.36
63 Figure 5. Mean directions of the dipole orientations in the left hemisphere (left) and right hemisphere (right) for the three groups in the first measurement. Controls are marked with green color, patients in the CE training group with red and patients in the Cogpack group with blue.
Figure 6. Mean directions of the dipole orientations in the left hemisphere (left) and right hemisphere (right) for the three groups in the second measurement. Controls are marked with green color, patients in the CE training group with red and patients in the Cogpack group with blue.
Patients’ illness status improved (GAF, F(1, 15)=12.99, p< .005; BPRS, F(1, 15)=18.69, p< .001; BDI, F(1, 16) = 10.57, p<.01) irrespective of type of training (for both scores, interactions F<1).
Patients generally improved in verbal learning and memory (immediate recall:
F(1, 18) = 22.34, p<.0005; learning speed: F(1, 18) = 5.49, p<.05; delayed recall: F(1, 18)
= 5.45, p<.05), where only the learning speed scores changed different in both patients groups (interaction: F(1, 18) = 20.59, p<.0005 with Post-hoc Fisher LSD test for the CE group: pre- vs. post-training p=0).
Discussion
The SGR is already known to correlate with symptoms in schizophrenia (right-hemisphere: Thoma et al., 2005; left-(right-hemisphere: Irwin et al., 2003). In this study not only the SGRs but also other dipole parameters have been shown to correlate with typical characteristics in schizophrenia. For example, the orientations of the dipoles correlated with the level of function (GAF scores) where orientations pointing directly upward mean highest functioning level and orientations pointing far downwards were marker for low functioning. A significant difference in the orientations between patients and controls was not found. Another dipole parameter showing dependency with schizophrenia scores was the latency of the M50 peak. It was found that later peaks
64 (near to 80 ms) implicated lower GAF scores and earlier peaks (near to 40 ms) implicated higher GAF scores. Except for a small subgroup of 8 patients who had individual MRI data sets no relationship between the anterior-posterior position of the dipole localizations and some of the symptomatic scores in schizophrenia were found.
This discrepancy between these two results could be due to the fact that in the case where no individual MRI datasets were available the co-registration of the functional (MEG) data and the structural (MRI) data happens on the basis of the fiducials which are individually measured in the functional data but are standard chosen in the structural data (MNI brain). In the subgroup of patients with individual MRI datasets not only a perfect co-registration of MEG- with MRI-data was possible but also comparison of inner brain structures (Study 1, Jordanov et al., 2010; Appendix C). Having said this, the interpretation of the anterior-posterior asymmetry impairment of the M50 localization in schizophrenia could not be considered as a crucial characteristic in patients group unless individual MRI data sets are used. No training effect was detected with respect to this measure may be due to the insufficient accuracy of the corresponding dipole parameter.
Prior to the training, bi-hemispheric circular variance of the dipole orientations was bigger in the patients group assigned to the Cogpack training than in the other two groups (patients in the CE training group and controls). Circular variance was substantially reduced after the training period. The Cogpack training seems to influence dipole orientations in the auditory cortex in schizophrenia patients.
Before the training period a significant difference in SGRs between schizophrenia patients and healthy controls was found. The statistical test with RMANOVA did not detect a significant time x group effects after the training period. Consequently, no training effect was found for any of both groups may be due to the small number of subjects.
In summary, not only the sensory gating ratios but also other dipole parameters could be considered as correlates of schizophrenia’s characteristics. As a measure for training induces neuroplasticity in schizophrenia a very sensitive and residual independent parameter of the dipole model should be chosen. This study suggests that the dipole orientation could be such measure.
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