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    Overall Comparison

    Controls were significantly faster in absolute RT on both COR (p<0.001, t=7.97) and UNC (p<0.001, t=3.62) trials (Table 1). In controls, COR was significantly faster than UNC (p<0.05, t=2.22) while the reverse was true for patients whose UNC was faster than COR (p<0.05, t=2.14). There was no overall difference in RT in right vs. left for either controls or patients under either condition. There were also no sex differences in RT.


    CONTROLS: COR N=367 trials, mean of 153.1±49.0ms

    PATIENTS: COR N=356 trials, mean of 181.5±46.8ms

    CONTROLS: UNC N=368 trials, mean of 161.5±53.7ms

    PATIENTS: UNC N=360 trials, mean of 171.4±41.7ms

    Comparison of Individual Subjects

    The disparate distributions between patients and controls were significantly different (Wilcoxon's U test; p<0.05, U=39.5). Eight of 13 (62%) patients had faster UNC trials, five reaching statistical significance . Only two controls had UNC faster, neither reaching statistical significance. Nine controls (70%) had faster COR; three reached the 0.05 level and another just missed it. Four patients (30%) had faster COR; only the fastest (22ms faster) patient reached statistical significance. The average difference (COR minus UNC, computed from individual data) for controls of -8.86±15.2ms (COR faster) and patients of +9.49±20.9ms (UNC faster) also tested significantly different (p<0.02, t=2.56).

    Age Effect

    Figure 4 and Table 2 break down subjects into young and old groups. Within both groups of subjects, young and old ages differed significantly (controls: p<0.005, t=3.77; patients: p<0.005, t=4.04) while between groups the respective young and old ages did not differ.

    Age vs. reaction time



    YOUNG: COR N=195 trials, mean of 148.4±46.4ms; UNC N=200 trials, mean of 151.8±42.0ms

    OLD: COR N=172 trials, mean of 158.3±51.2ms; UNC N=168 trials, mean of 178.0±61.3ms


    YOUNG: COR N=221 trials, mean of 167.3±39.6ms; UNC N=215 trials, mean of 164.5±38.3ms

    OLD: COR N=134 trials, mean of 205.5±48.0ms; UNC N=145 trials, mean of 189.2±42.0ms

    Within both patients and controls, COR-UNC (COR minus UNC RTs) differences were significant in the old groups but not in the young (controls: p<0.005, t=3.22; patients: p<0.005, t=3.02). Between patients and controls, COR=UNC differences were significantly different in the old group but not in the young (p<0.05, t=4.70).

    The absolute RT had a tendency to increase with age from young to old in both the control and patient groups. All comparisons reached the 0.001 level of significance except COR controls young to old, which slowed the least, just missing the 0.05 level of significance. After 41 years-old, there was almost complete segregation of patients vs. controls. None of the 8 patients over 41 years of age had faster COR trials while 9 of 10 controls had faster COR (p<0.01, X2=14.4). This amounted to 94%, without overlap at 3ms minimal difference, and 88% at 6ms. There was a significant difference in comparing the correlation coefficient of age vs. COR-UNC difference for controls (R=-0.49) and for patients (R=+0.52) (p<0.02, Z=2.51). In both patients and controls, the effect of age on laterality failed to show significant differences in either the COR or UNC conditions.

    Effect of Sequence on RT

    In order to test the effects of practice and fatigue on RT, varying sequences were employed. In patients, whether the UNC condition was given in the initial or final trials, the RT was faster, and in controls it was considerable slower. Although none reached the 0.05 level of significance, trends were consistent with the significant overall results when the data for the varying sequences were combined. In the patient group, when the COR trials were first, all RTs in this sequence set were significantly slower then when the UNC trials were first (COR initial vs. final; p<0.05, t=2.02; UNC initial vs. UNC final; p<0.001, t=3.46). In controls, there were no significant differences in this regard. Thus, initial COR conditions in patients seemed to have an effect of overall slowing, although UNC patients still maintained a faster position.

    Medication Data

    Medication was recorded as equivalents of haloperidol (HPD) and trihexyphenidyl (THP). Fig 7 displays the relationship of medication dose to reaction time.

    Relationship of medication dose to reaction time


    Increasing dose was associated with slower absolute RT for both conditions (COR, R =+0.62, p<0.05, t=2.59; UNC, R=+0.53, p almost =0.05, t=2.06) (Figs.7 and 8). For the COR-UNC difference, however, R =+0.31 and was not significant. Although it did not reach the 0.05 Ievel, the four patients on no THP tended to have faster UNC RT (p=0.07, t=1.96). The high-dose THP group did have significantly faster UNC trials (p<0.005, t=2.88).


    In contrast to THP, increasing dose was associated with faster absolute RT (COR, R =-0.58, p<0.05, t=2.38; UNC, R=-0.63, p<0.05, t=2.68). For HPD, the COR-UNC difference (R=-O.15) was not significant. The low-dose HPD group, however, did show a significant COR-UNC difference (p<0.005, t = 3.01).

    BPRS vs. RT

    There was a trend toward decreasing absolute RT for both the COR and UNC conditions as BPRS severity increased, the COR trials reaching significant correlation (COR, R=-0.62, p<0.05, t=2.61). For UNC (R=-0.52, p<0.1, t=2.0), this did not reach the 0.05 Ievel. For BPRS, the severity vs. COR-UNC difference (R=-0.33) was not significant.

    Diagnostic/Symptom Analyses

    Because of a low N, results of both diagnostic and symptom breakdown were felt to have no meaning. We did note, however, that anxiety was the only symptom, with an overall trend for faster COR RT although it did not reach significance.

    Hospital Duration

    There was no significant correlation of either COR (R=+0.31) and UNC (R =+0.31) absolute RT or COR-UNC differences (R=+0.10) with hospital duration.


    The major finding of this study is a significant inability of SZ subjects to utilize the COR trials in the service of faster RT, consistent with studies previously cited. Overall, the absolute RT in SZ patients was also, as in prior studies, slower than controls.

    Age had a significant effect on the way SZ patients and controls responded to prior time information. Young controls seemed to be able to react quickly in either the COR or UNC conditions while older controls seemed more dependent on prior time information. In patients, however, only the young were able to benefit from prior time information. Older patients, in contrast, could not extract benefit from prior time information and in fact were slower under these conditions.

    The strong association of faster UNC trials with age in the SZ group may be an indicator of basic SZ pathology. Alternatively, this may be due to an interaction of the normal aging process with a prior static neurological insult. In either case, the results point to altered information processing expressed to greater degrees in older SZ patients. Because of almost complete separation in response to experimental conditions of patients and controls over 40 years old, this test may prove to have some value in confirming the diagnosis of SZ in older age groups. More definitive results would come from future studies stratifying subjects by age before testing rather than post-hoc analyses that were done in this study.

    By employing varying sequences, we concluded that for both patients and controls, the effects of fatigue or practice were small relative to the effect of whether there was prior time information or not. No matter what sequence was employed, results were consistent with the significant trends seen in the groups as a whole. Intra-sequence comparisons may not have reached the 0.05 Ievel because the N was one-half of that as a whole. Initial COR conditions seemed to disturb the ability of these patients to react in that both COR and UNC trials in this sequence set were significantly slower. One explanation might be that the initial COR trials impaired their ability to establish a mental set for preparation and that they perseverated on this in the later UNC trials.

    Voluntary attention and motivation factors can also be assumed to be small, since if they were a major influence, one would expect even performance in both COR and UNC conditions rather than a selectively poor COR performance. All subjects willingly agreed to be subjects, participation was completely optional, and no reward was given to participate in the study. SZ patients have also been shown to have intact voluntary attention and motivation in studies of saccadic latency as well as in studies of smooth pursuit (Iacono and Tuason,1981; Levin et al., 1981,1982; Holzman,1987).

    Additionally, differences between patients and controls are too large to be due to errors in the RT measurement itself.

    Analysis of medication dose pointed to significant associations with absolute RT. Increasing THP dose was associated with slower absolute RT while increasing HPD dose was associated with faster absolute RT. Regarding medication effect on response to foreperiod conditions, even those patients who took no THP continued to have faster UNC trials. Along with a nonsignificant R (for THP COR-UNC difference), this supports a conclusion that THP alone was not responsible for the faster UNC trials in SZ patients. Only in the low-dose HPD group were UNC trials significantly faster. This may mean that at low neuroleptic doses, SZ patients have more trouble using the correlated cue. At higher doses, there was no significant difference between COR and UNC trials, and it seems that although some patients may have been "normalized" in their ability to use the COR prior time information in the service of faster COR trials.

    Alternatively, it might be that some aspect of the patients' symptomatology and the prescribers' dosing in regards to the symptomatology contributed to the HPD effects. This logic also applies to THP dosing, where drug-induced parkinsonism may have been responsible for increased absolute RT and was treated with higher THP doses. There was no association, however, of THP with COR-UNC difference and higher COR-UNC differences were seen only in the low-dose HPD group.

    We conclude, therefore, that while there may be other explanations for a more normal pattern of information processing with higher HPD doses, the main finding of a significant inability of SZ subjects to utilize the COR trials in the service of faster RT seems to be independent of medication dosing. The way to discern medication effects more clearly would be to test drug-free patients, or those whose drug dosages are assigned at random. This is important in light of the fact that patients were medicated and controls were not. Enhancement of information processing with antipsychotic medication warrants further study. This is important since it could provide a measurement of treatment response as well as support a role for medication in improved cognitive functioning.

    In neurotransmitter terms, either a low HPD or a high THP dose reflects a relatively high D/A (dopamine/acetylcholine) ratio in the central nervous system. In this model, a high D/A ratio correlates with slow overall RT and poor ability to use foreperiod cuing in order to form a mental set. Lower D/A ratios would be associated with RT profiles more consistent with the control data. The findings of this study are thus consistent with the hyperdopaminergic theories of SZ (Andreasen, 1988). Further study might employ various drug regimens and/ or challenges in order to learn more about the role of neurochemistry in this area.

    Another effect of antipsychotics may be to alter time perception. Maricq (1983) studied the effects of metamphetamine and HPD on time estimation in the rat and found that metamphetamine, which increases dopamine transmission, Ieads to an increase in the speed of the internal clock and vice versa with HPD. If dopamine is increased in SZ patients and affects temporal processing as Maricq suggests, then there may be erroneous estimation of foreperiod as cued by the COR signal. In the present study, slow COR RT at low HPD doses and improvement at higher doses would be consistent with Maricq's finding that when he gave rats a mix of metamphetamine and HPD, the opposing effects on time estimation were neutralized. Additionally, antipsychotics have been shown to speed up rather than slow information processing (Holzman, I 987).

    Unfortunately, because of a low N, neither the diagnostic nor the symptom analyses were felt to have any meaning. Because there was a trend for anxiety to cause a faster COR RT, there was no evidence that this symptom was responsible for the SZ patients' poor ability to form a mental set.

    Poor ability of SZ patients to use the COR warning cue may relate to various areas of cognitive difficulty that are suspected to be awry in SZ. Because both manual and saccadic RTS Show this phenomena, the function in question must be common to both systems and lie proximal to the motor output stage in which these systems differ.

    Areas in the frontal lobe concerned with sequential thinking and the ability to change expectations to new data are likely to be activated under the conditions of this study. Various lines of evidence including CT, MRI, and cytoarchitectural studies have pointed to early cerebral changes before the onset of clinical symptoms (Andreasen, 1988). In our study, we found significant, though divergent, age-related changes between SZ patients and normals so that the normal aging process coupled to an earlier defect may be a cause for these results. Although the limitations of this study could not provide brain imaging correlation, we propose a comparison of those patients who do and do not show slower RTS under COR conditions. We also propose a prospective study to follow the time course of subjects' response to foreperiod conditions in order to clarify individual progression with age.

    Evoked potential studies may provide another clue towards delineating the steps in information processing that are put to use by our study. N100 abnormalities are seen in conditions of divided attention or longer rates of stimulus presentation (Holzman, 1987). In our experiment, divided attention consists of that to the light and sound present in both COR and UNC groups. P300, however, reflecting cognitive processing of the stimuli, would more likely be included in the COR trials, where there is information about foreperiod duration. It may also be that the information reaching the cortex (reflected by NlOO) is more poorly filtered at the P300 stage when there is meaning to be processed. Correlation of our experimental conditions with evoked potential would be useful for a further understanding of this matter.

    Mather (1986) studied saccadic eye movements of normals in the dark and concluded that SZ patients, although having normal oculomotor RTs, process visuospatial information less efficiently than normals. We suggest that because our study illuminates a temporal processing deficit (only temporal conditions change between COR and UNC trials), there may be a general sensory information processing deficit common to both spatial and temporal types of stimuli.

    One limitation of this study is that it did not separately analyze the responses to the I,3, and 5s intervals. Other studies using manual responses had reported that SZ patients were unable to improve RTS in regular compared to irregular series of preparatory intervals when these intervals were greater than 2s in one study and greater than 4s in another (Huston et al.,1937; Rodnick and Shakow, 1940). Having done so, perhaps we would have found less overlap with controls at the longer foreperiods.

    Another limitation is the relatively small number of patients in this study. This limits the reliability of the conclusions that can be drawn from analysis of some of the data variables, such as diagnosis, symptomatology, BPRS severity, and medications. Many Japanese SZ patients are often concurrently on a benzodiazepine and could not be included in this study. This may also bias the pathology in the sample that was studied although in what way we do not know. Although DSM-III-R criteria were used, another shortcoming was the absence of research diagnoses. The limitations of uncontrolled medication dosing were discussed earlier.

    Future research in this area needs to address further the effects of diagnosis, symptom cluster, severity, and medication. Studies should include nonsymptomatic relatives of SZ patients to search for genetic links and state vs. trait variables. Other psychiatric diagnoses need to be studied to discern specificity. Prospective studies to follow the progression with age and correlation with tests of brain structure and function are also needed. This study presented the foreperiod signal via a speaker system that simultaneously stimulated both ears. Presentation of the warning signal via earphone to one ear at a time would provide more conclusive evidence as to the question laterality.

    A summary of the conclusions of the present study are as follows:

    (a) Measurement of saccadic latency is an accurate and reliable method to study the effect of foreperiod on RT.

    (b) SZ subjects had significantly slower COR trials, where there was prior time information about duration of foreperiod, while controls had significantly faster COR trial sets. This is interpreted as a general information processing deficit in SZ patients' ability to establish a mental set necessary to prepare by expectancy. This may relate to sequencing difficulty in the frontal lobes, stages of information processing associated with the NIOO and P300 evoked potential waves, abnormalities in time perception, and relatively high levels of dopamine in the central nervous system.

    (c) Significantly slower absolute RTS were found in the SZ group, consistent with past data of slow RT in SZ patients.

    (d) Increasing age was associated with increasingly significant slower COR trials in SZ patients and increasingly significant slower UNC trials in controls. These findings may be due to a normal aging process in controls while in SZ patients it may be associated with progression of the SZ pathology. Alternatively, it could be an interaction of normal aging with a prior static SZ deficit, or possibly a combination of both. This inability to establish a mental set necessary for preparation with increasing age may prove useful in confirming the diagnosis of SZ in older patients.

    (e) In both groups, increasing age was associated with significantly slower absolute RTS undcr all conditions. While low neuroleptic dose and low BPRS were also associated with slow absolute RTs, the fact that controls on no medication and with no symptoms had incrcasing RT with age points strongly toward age as an important factor.

    (f) Both HPD and THP had significant and opposing associations with absolute RT. Absolute RT quickened with higher doses of HPD and slowed with increasing doses of THP. While THP had little recognizable influence on experimental conditions, HPD at higher doses may enhance the ability of some subjects to use prior time information in the service of establishing a mental set about the occurrence of a future event. Medication, however, was uncontrolled and confounding interactions could not be ruled out as causative for the observed medication effects. Enhancement of information processing with antipsychotics warrants further study since this could provide a measurement of treatment response and support a role for medication in improved cognitive functioning. The overall finding of slower COR RT in SZ patients, however, remained independent of medication dose in this study.

    Acknowledgment: This research was supported by a grant from the Matsumae International Foundation, Kasumigaseki, Tokyo, Japan. The authors would like to thank the administration of the Minakawa Hospital for access to their patient population, Dean Shogo Sasaki and Chairman of psychiatry Dr. Tetsuya lwasaki of the Tokai University School of Medicine who supplied experimental equipment, and Drs. Fumio Matsuda and Toshiyuki Watanabe for clinical data collection.


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    バーガー ダグラス 

    New York 医科大学精神科、New York 州、USA

    Neuropsychiatry, Neuropsychology & Behavorial Neurology, (新雑誌名: Cognitive and Behavioral Neurology) 3:2, 80-97; 1990.

    (これはDr. バーガーの東京大学医学部の博士論文である。)

    本研究は精神分裂病患者の情報処理に関して、警報音の長さを予め知らされている場合と知らされていない場合の2つの条件下でサッケード反応潜時を測定したものである。先行研究では精神分裂病患者の無条件用手反応潜時は正常者より遅いことが指摘されている。また、精神分裂病患者では、正常者とは反対に、警報音の持続時間に関する情報を予め与えられた場合の方が与えられていない場合よりも成績が悪化するとされている。この現象を、"FOREPERIOD EFFECT" と呼ぶ。本研究で明らかになる与えられた情報がサッケード系に及ぼす影響と、先行研究で明らかにされている用手系に及ぼす影響とを比較することによって、"FOREPERIOD EFFECT" 現象の原因として、視覚系に欠陥があるか、用手系に欠陥があるか、両系に共通している欠陥があるかを検討することも可 能である。




    警報音の長さと周波数(音の高さ)が組み合わせられた場合は、被験者はある周波数の警報音を聞くだけで、警報音の長さ(光刺激がいつ動くか)を予測出来る条件になる(本試行に入る前に数回練習する)。一方、警報音の長さと周波数が組み関係していない場合では、被験者は警報音の長さ(光刺激がいつ動くか)を予測出来ない条件になる。警報音と光刺激と眼電図によるサッケード運動を、データ レコーダーに記録し、測定する際POLYGRAPHに表示して、コンピュターを用いてサッケード反応潜時を測定した。予測出来る条件、予測出来ない条件の両方とも30回の試行(左右同数ずつ)を行い、患者群、正常群ともに半数は左向き15回、右向き15回の順序で刺激を与え、残り半数は逆になるようにした。

    また、疲労と慣れの影響を見るために、予測出来るかどうかの条件の順序についても、患者群と正常群の半数ずつ、逆になるようにした。 従って、患者群、正常群とも全部で4種類の試行条件を設定したことになる。試行間には約15秒間の休憩をおき, 条件間には1−2分間の休憩をおいた。


    本研究の結果の解釈としては、正常者に較べて精神分裂病患者の情報処理には欠陥があり、また、年齢が増えるとと共にこの欠陥が大きくなると考えられた。我々の仮説では、情報処理と時間知覚に対する神経伝達物質の影響、前頭葉の異常、誘発電位で測 定される情報処理の諸段階が、精神分裂病患者における情報処理障害に関わっている可能性がある。年齢の増加とこの欠陥の関連では、精神分裂病の病理の進展、又は年齢の増加と精神分裂病の既成病理との相互影響という原因が推定される。


    薬物の影響については、先行研究で高ドパミン状態が時間知覚に影響することが明らかにされているので、本研究では、精神分裂病のドパミン仮説に従って、薬物の投与量が増えると精神分裂病患者の時間知覚あるいは情報処理が正常化される可能性がある ことが示唆された。

    本研究のまとめ:a.) 精神分裂病患者には、心理的な準備に向けて精神機能を整えるための情報処理における欠陥が認められる。b.) この欠陥は高年齢群の精神分裂病患者においてその診断を確定するために有用である可能性がある。c.) 情報処理に対する抗精神病薬の効果を考えると今後も引き続き研究を進める必要がある。

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