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Reliability of P50 suppression is vastly improved via dipole modeling
146A
BIOL PSYCHIATRY 1992;3 I:61A-252A
Neurophysiology
standard, 1.5 kHz, 80 dB target; (3) 1.4 kHz, 97 dB standard, 1.5 kHz, 97 dB target; and (4) 1.4 kHz, 80 dB standard, 1.5 kHz, 80 dB target. Subjects were required to press a button in response to target stimuli. Auditory sensitivity (A') did not differ significantly between groups. Midline P3 amplitudes were smaller in SZ (F(14,1) = 9.87, p = 0.007). Loudness manipulations modulated P3 amplitude (F(14,1) = 10.69, p = 0.006). The group by loudness interaction was significant (F(14,1) = 4.64, p = 0.049). Although the pitch main effect was not significa~L the group by pitch interaction was (F(14,1) = 6.64, p = 0.022). These interac:~oas ;effect an important finding: Whereas P3 ai~plitude in controls increased with greater discriminability, SZ amplitudes remained largely unaffected. These data are congruent with the hypothesis that SZ P3 amplitude has a ceiling determined by degree of tissue loss in neural generator sites, and is not due to decreased discriminability, physiological 'noise', or defective sensory processes.
197 DIPOLE SOURCE MODELING AND VALIDATION OF THE
AUDITORY P300 COMPONENT IN SCHIZOPHRENIA B.F. O'Donnell, M.E. Shenton, R.W. McCarley, B.N. Cuffin, S.F. Faux, R.S. Smith, D. Salisbury, R. Kikinis, F.A. Jolesz Harvard Medical School, Brockton VAMC, Brockton, MA 02140. Both amplitude reduction and topographic asymmetries (Lt < Rt) of the P300 component of the eve.~,related potential (ERP) have been reported in schizophrenia (SZ). Electrical source modeling of the 7300 component might provide insight into the anatomic generators of these abnormalities. This study combined source modeling of the P300 component with MRI measurement of specific temporal lobe structures in 15 right-handed, male, medicated subjects with Sz (DSM-III-R and RDC criteria) and 14 control subjects. The P300 component was recorded using an auditory oddball paradigm at 28 electrode sites. A three sphere head model with dipoles set as symmetric temporal lobe locations was used to model the P300 compc, nent peak. Dipole orientations were adjusted to obtain the best possible fit for each individual. The symmetric dipole model accounted for 81 ± 12% (mean ± SD) of the variance of P300 at 28 electrode sites in SZ, and 84 "+" 15% in control subjects. Dipole moments (strengths~ were reduced bilaterally in schizophrenia (ANOVA F(I,27) = 13. I, p = 0.001). For validation, quantitative semiautomated MRI image processing techniques were used to obtain volumes of the grey matter within the superior temporal gyms, hippocampus, amygdala, and parahippocampal gyrtt~. Left, but not right, P300 dipole moment was correlated with left superior temporal gyms volume (r = 0.57, p < 0.05) in SZ subjects. These lindings suggest that source modeling may be helpful in characterizing ERP abnormalities in schizophrenia, uad relating them to anatomic disturbances.
198 RELIABILITY OF P50 SUPPRESSION IS VASTLY IMPROVED VIA DIPOLE MODELING Valerie A. Cardenas, George Fein University of Cali]brnia, San Francisco, Abratech Corporation, and SFVAMC(il6R), San Francisco, CA 94121. Suppression of auditory P50-evoked responses to the second of paired clicks is important in psychiatric research. In normals, the response to the second click is reduced relative to the response to the first click, whereas schizophrenics show little or no amplitude reduction. Aberrant PS0 suppression has been proposed as a marker of the genetic vulnerability to schizophrenia. In practice, suppression is measured by the ratio of P50 amplitude to the first (conditioning) versus second (testing) click, with PS0 amplitude measured manually from the vertex recording. The independence of noise for each amplitude measurement results in multiplicative noise from the conditioning/testing (C/T) ratio, with consequent vel~, low reliability of C/T ratio. We found the reliability of C/T ratios in 12 normal individuals over six replications (two on each of 3 days) to be only 0.26. PS0 amplitude can also be measured using dipole modeling wherein the test and conditioning P50s are assumed to arise from the same underlying brain process. Dipole model parameters are estimated using topographic data from multiple electrodes. The SNR is increased by using a consistent
Neurophysiology
BIOL PSYCHIATRY 1992;31:6 !A-252A
147A
single model for both responses, and by spatial averag;ng across electrodes. Using a relatively simple dipole model, the reliability of the C/T ratio was increased to 0.59. The results sug~e.,~t ooth that the C/T ratio can be made reliable enough to support its use in clinical studies and that dipole modeling has potential benefits in increasing the reliability of evoked potential measures of ir,lportant neurophysiological pheno~nena.
199 REPEATED EVALUATION OF THE AEP P50 IN MONKEYS-AN INDICATION OF HABITUATION OR SENSITIZATION? K. Lifshitz, R.T. O'Keeffe, K.L. Lee, G. Linn Nathan Kline Institute, Orangeburg, NY 10962. As part of a broader study of fluphenazine decanoate effects on C. oreila monkeys, the auditory-evoked potential (AEP) was recorded every 6 weeks for 108 weeks, and once again after 6 months. EEG recordings were from 19 treated and 19 control animals. Scalp needle electrodes were used, and data from Cz referenced to balanced P3 and P4 were analyzed. Auditory stimuli were 30 ms, 1000 Hz, free-field tone pips at 85 dB SPL (human). Interstimulus intervals (ISI) were either !.5 sec ( _+ 10%) or 6.0 sec ( -+ 10%). Amplifier I/2 amplitude settings were 0.15 and 35 Hz. Mean latencies of PS0 were 39 and 45 ms for the 1.5 and 6 sec ISis. For the 1.5 sec ISI, the P50 showed an initial amplitude of about 4 In,V, increasing to about 9 ttV over the course of 18 measurements (each 6 weeks apart). For the 6.0 sec ISI, initial amplitude was about 9 ~V, increasing to 19 p,V. Increases followed linear trends; during fluphenazine treatment the rate of increase decreased. After a 6-month pause without EEG measurements, the P50 for the 1.5 sec ISI decreased to 5 p,V and for the 6 sec IS! to I I p,V. Nl00 and P200 did not show similar characteristics. P50 has been considered to be related to sensory "gating," but in this case it seems appropriate to th!nk in terms of memory and habituation or sensitization. Given the growth in amplitude of P50, sensitization is the easier term to describe this phenomenon.
200 COMBINED STARTLE AND P50 MEASURES OF SENSORY GATING: SUPPORT FOR A SHARED NEUROPHYSIOLOGY Steven B. Schwarzkopf, J. Steven Lamberti, John F. Crilly, Rebecca Martin, Jennifer Hirt, LeeAnn Holley Ohio State University, Columbus, OH 43210. Recent studies of sensory gating have employed acoustic startle response (ASR) testing and an auditoryevoked potential (AEP) paradigm. The ASR approach measures prepulse inhibition (PPl), the reduction of eye blink startle noted when a startle stimuli is preceded by a low intensity prepulse. AEP testing has assessed the reductioL of P50 AEP amplitude after the second (testing stimulus) versus initial click (conditioning stimulus) as a measure of sensory gating (CTR or conditioning/gsting ratio). These gating phenomena have not been assessed in the same individuals, making generalizations across paradigms tenuous. This study examined PPl and CTR in a control group to examine associations between these sensory gating parameters. Eighteen subjects were tested. EEG for PS0 measurement was recorded at CZ (linked ear reference) following 120 click pairs (peak intensity !15 db, 0.04 msec duration, 10 sec between clicks). Startle testing measured eye blink response after pulse along [P] stimuli (I 16 db, 30 msec duration) and prepulse-pulse pairs [PP-P]. Background noise level was 70 db and prepulses were 75, 80, and 85 db (preceding P by 100 msec, 30 msec duration). CTRs were calculated for the first 60, second 60, and all trials as per Nagamoto (1989). PPl was determined for each PP intensity and each of three trial blocks. Spearman correlations were used to assess associations between CTR and PPI measures. Sensory gating as measured by P50 CTR and PPl of acoustic startle were significantly correlated early in the test sessions (CTR for first 60 clicks, PPl in block 1, p < 0.05) with lower correlations (p > 0.10) later in testiug. Differential arousal levels (ASR > AEP) may contribute to poor correlations Inter in testing. High associations early in ~esting supports a shared neurophysiological basis for these sensory gating phenomena.
BIOL PSYCHIATRY 1992;3 I:61A-252A
Neurophysiology
standard, 1.5 kHz, 80 dB target; (3) 1.4 kHz, 97 dB standard, 1.5 kHz, 97 dB target; and (4) 1.4 kHz, 80 dB standard, 1.5 kHz, 80 dB target. Subjects were required to press a button in response to target stimuli. Auditory sensitivity (A') did not differ significantly between groups. Midline P3 amplitudes were smaller in SZ (F(14,1) = 9.87, p = 0.007). Loudness manipulations modulated P3 amplitude (F(14,1) = 10.69, p = 0.006). The group by loudness interaction was significant (F(14,1) = 4.64, p = 0.049). Although the pitch main effect was not significa~L the group by pitch interaction was (F(14,1) = 6.64, p = 0.022). These interac:~oas ;effect an important finding: Whereas P3 ai~plitude in controls increased with greater discriminability, SZ amplitudes remained largely unaffected. These data are congruent with the hypothesis that SZ P3 amplitude has a ceiling determined by degree of tissue loss in neural generator sites, and is not due to decreased discriminability, physiological 'noise', or defective sensory processes.
197 DIPOLE SOURCE MODELING AND VALIDATION OF THE
AUDITORY P300 COMPONENT IN SCHIZOPHRENIA B.F. O'Donnell, M.E. Shenton, R.W. McCarley, B.N. Cuffin, S.F. Faux, R.S. Smith, D. Salisbury, R. Kikinis, F.A. Jolesz Harvard Medical School, Brockton VAMC, Brockton, MA 02140. Both amplitude reduction and topographic asymmetries (Lt < Rt) of the P300 component of the eve.~,related potential (ERP) have been reported in schizophrenia (SZ). Electrical source modeling of the 7300 component might provide insight into the anatomic generators of these abnormalities. This study combined source modeling of the P300 component with MRI measurement of specific temporal lobe structures in 15 right-handed, male, medicated subjects with Sz (DSM-III-R and RDC criteria) and 14 control subjects. The P300 component was recorded using an auditory oddball paradigm at 28 electrode sites. A three sphere head model with dipoles set as symmetric temporal lobe locations was used to model the P300 compc, nent peak. Dipole orientations were adjusted to obtain the best possible fit for each individual. The symmetric dipole model accounted for 81 ± 12% (mean ± SD) of the variance of P300 at 28 electrode sites in SZ, and 84 "+" 15% in control subjects. Dipole moments (strengths~ were reduced bilaterally in schizophrenia (ANOVA F(I,27) = 13. I, p = 0.001). For validation, quantitative semiautomated MRI image processing techniques were used to obtain volumes of the grey matter within the superior temporal gyms, hippocampus, amygdala, and parahippocampal gyrtt~. Left, but not right, P300 dipole moment was correlated with left superior temporal gyms volume (r = 0.57, p < 0.05) in SZ subjects. These lindings suggest that source modeling may be helpful in characterizing ERP abnormalities in schizophrenia, uad relating them to anatomic disturbances.
198 RELIABILITY OF P50 SUPPRESSION IS VASTLY IMPROVED VIA DIPOLE MODELING Valerie A. Cardenas, George Fein University of Cali]brnia, San Francisco, Abratech Corporation, and SFVAMC(il6R), San Francisco, CA 94121. Suppression of auditory P50-evoked responses to the second of paired clicks is important in psychiatric research. In normals, the response to the second click is reduced relative to the response to the first click, whereas schizophrenics show little or no amplitude reduction. Aberrant PS0 suppression has been proposed as a marker of the genetic vulnerability to schizophrenia. In practice, suppression is measured by the ratio of P50 amplitude to the first (conditioning) versus second (testing) click, with PS0 amplitude measured manually from the vertex recording. The independence of noise for each amplitude measurement results in multiplicative noise from the conditioning/testing (C/T) ratio, with consequent vel~, low reliability of C/T ratio. We found the reliability of C/T ratios in 12 normal individuals over six replications (two on each of 3 days) to be only 0.26. PS0 amplitude can also be measured using dipole modeling wherein the test and conditioning P50s are assumed to arise from the same underlying brain process. Dipole model parameters are estimated using topographic data from multiple electrodes. The SNR is increased by using a consistent
Neurophysiology
BIOL PSYCHIATRY 1992;31:6 !A-252A
147A
single model for both responses, and by spatial averag;ng across electrodes. Using a relatively simple dipole model, the reliability of the C/T ratio was increased to 0.59. The results sug~e.,~t ooth that the C/T ratio can be made reliable enough to support its use in clinical studies and that dipole modeling has potential benefits in increasing the reliability of evoked potential measures of ir,lportant neurophysiological pheno~nena.
199 REPEATED EVALUATION OF THE AEP P50 IN MONKEYS-AN INDICATION OF HABITUATION OR SENSITIZATION? K. Lifshitz, R.T. O'Keeffe, K.L. Lee, G. Linn Nathan Kline Institute, Orangeburg, NY 10962. As part of a broader study of fluphenazine decanoate effects on C. oreila monkeys, the auditory-evoked potential (AEP) was recorded every 6 weeks for 108 weeks, and once again after 6 months. EEG recordings were from 19 treated and 19 control animals. Scalp needle electrodes were used, and data from Cz referenced to balanced P3 and P4 were analyzed. Auditory stimuli were 30 ms, 1000 Hz, free-field tone pips at 85 dB SPL (human). Interstimulus intervals (ISI) were either !.5 sec ( _+ 10%) or 6.0 sec ( -+ 10%). Amplifier I/2 amplitude settings were 0.15 and 35 Hz. Mean latencies of PS0 were 39 and 45 ms for the 1.5 and 6 sec ISis. For the 1.5 sec ISI, the P50 showed an initial amplitude of about 4 In,V, increasing to about 9 ttV over the course of 18 measurements (each 6 weeks apart). For the 6.0 sec ISI, initial amplitude was about 9 ~V, increasing to 19 p,V. Increases followed linear trends; during fluphenazine treatment the rate of increase decreased. After a 6-month pause without EEG measurements, the P50 for the 1.5 sec ISI decreased to 5 p,V and for the 6 sec IS! to I I p,V. Nl00 and P200 did not show similar characteristics. P50 has been considered to be related to sensory "gating," but in this case it seems appropriate to th!nk in terms of memory and habituation or sensitization. Given the growth in amplitude of P50, sensitization is the easier term to describe this phenomenon.
200 COMBINED STARTLE AND P50 MEASURES OF SENSORY GATING: SUPPORT FOR A SHARED NEUROPHYSIOLOGY Steven B. Schwarzkopf, J. Steven Lamberti, John F. Crilly, Rebecca Martin, Jennifer Hirt, LeeAnn Holley Ohio State University, Columbus, OH 43210. Recent studies of sensory gating have employed acoustic startle response (ASR) testing and an auditoryevoked potential (AEP) paradigm. The ASR approach measures prepulse inhibition (PPl), the reduction of eye blink startle noted when a startle stimuli is preceded by a low intensity prepulse. AEP testing has assessed the reductioL of P50 AEP amplitude after the second (testing stimulus) versus initial click (conditioning stimulus) as a measure of sensory gating (CTR or conditioning/gsting ratio). These gating phenomena have not been assessed in the same individuals, making generalizations across paradigms tenuous. This study examined PPl and CTR in a control group to examine associations between these sensory gating parameters. Eighteen subjects were tested. EEG for PS0 measurement was recorded at CZ (linked ear reference) following 120 click pairs (peak intensity !15 db, 0.04 msec duration, 10 sec between clicks). Startle testing measured eye blink response after pulse along [P] stimuli (I 16 db, 30 msec duration) and prepulse-pulse pairs [PP-P]. Background noise level was 70 db and prepulses were 75, 80, and 85 db (preceding P by 100 msec, 30 msec duration). CTRs were calculated for the first 60, second 60, and all trials as per Nagamoto (1989). PPl was determined for each PP intensity and each of three trial blocks. Spearman correlations were used to assess associations between CTR and PPI measures. Sensory gating as measured by P50 CTR and PPl of acoustic startle were significantly correlated early in the test sessions (CTR for first 60 clicks, PPl in block 1, p < 0.05) with lower correlations (p > 0.10) later in testiug. Differential arousal levels (ASR > AEP) may contribute to poor correlations Inter in testing. High associations early in ~esting supports a shared neurophysiological basis for these sensory gating phenomena.