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The effects of amphetamine on shifts in visual attention
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BIOLPSYCHIATRY 1994;35:615--747
91. PREVALENCE AND CORRELATES OF STABLE NEGATIVE SYMPTOM SUBTYPES IN GERIATRIC CHRONIC SCHIZOPHRENIC INPATIENTS K.M. Putnam1'2, P.D. Harvey !, M. Parrella2, L.
White 2, P. Powchik l, & M. Davidson 1,2 tThe Mount Sinai School of Medicine, NY, NY, 10029; 2pilgrim Psychiatric Center, West Brentwood, NY, 11717 Although negative symptoms of schizcbphrenia have been studied in detail over the past 20 years, with substantial attention paid to the correlates of those symptoms, less attention has been paid to the stability characteristics of those symptoms, in the studies that have been conducted on the "deficit subtype", it has been reported that patients with stable deficit symptoms have specific cognitive and functional impairments. These studies have largely been conducted on relatively young patients, with less attention paid to geriatric patients with a long-term course of continu. ous hospitalization. In order to address the issue of the stability of negative subtypes in chronically institutionalized patients, a sample of 149 geriatric schizophrenic inpatients were examined with ratings of clinical symptoms (the Positive and Negative Syndrome Scale; PANSS) and a cognitive assessment battery at two assessments one year apart. Patients were characterized on the basis of their symptom presentation at the two assessments into groups who had stable negative subtypes (n=95; 64%), negative subtypes at one assessment only (n=31; 21%), or non-negative subtypes at both assessments (n-23; 15%). Patients with stable negative subtypes had significantly lower MiniMental State Scores at the 2nd as. sessment than the patients with mixed or non-negative subtypes (m- ! 3. I vs. 21.6 vs. 24.4). Similar findings were found for the entire cognitive battery, including verbal learning, delayed recall, praxis, and naming per. formance. Although the stable negative patients had lower premorbid education (m-8.9 vs 10.0 vs. 10.5) than the other two groups of patients, this difference did not account for the other differences in cognitive perform. ante. These data suggest that a majority of the patients in long-term inpa. tient care have stable negative symptoms and that this presentation is associated with substantial cognitive impairments. The presence of any negative symptoms, even unstable ones, was associated with reductions in cognitive functioning and reduced educational attainment, suggesting an intrinsic relationship between negative symptoms and intellectual functions in geriatric schizophrenic patients.
92. DIABETES MELLITUS AND COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA
THURSDAY, MAY 19
plasma glucose levels, i 2 (i 7%) of the patients were diagnosed to have NIDDM. MMSE total score was less than 24 in 50 (70.4%) of the patients, and less than ! 8 in 23 (32.4%) of the patients. There was no difference in MMSE total score, or MMSE items of delayed recall, orientation, language, and visuospatial ability between patients with NIDDM and nondiabetic patients (p>0.40 for all comparisons). The f'mdings indicate that the prevalence of NIDDM in these patients is much higher than that of the general population in Italy, but this does not contribute to severe cognitive impairment. This "dementia" likely is integral to the schizophrenic disease process. Additional data will be presented on the relations of NIDDM to negative symptoms and neurological abnormalities.
93. COGNITIVE CONTROL FUNCTIONS IN MEMORY-IMPAIRED SUBJECTS: A NEUROPHARMACOLOGICAL MODEL H. WeingartnerI, K. Sirocco I, M. Eckardt2, D. Hommer2, & D.N. Johnson I 1Cognitive Neurosciences Section; 2Section on Brain Imaging and Electrophysiology, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, DICBR, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892 Triazolam and ethanol treated normal controls demonstrate similar selective impairments in memory and perception on tasks that require the use of cognitive control functions. Following the administration of 0.375 mg of triazolam or 1.05 g/kg of ethanol, subjects are impaired when they are required to judge the accuracy and source of what is remembered or to perceive and evaluate the extent to which drug treatments induce sedation. This effect is independent of other indices of memory performance (e.g., the amount of information recalled). Furthermore, the inability to monitor and judge memory performance is potentiated when the drug state in which the subject is asked to remember is different from that which was present when the information was first generated or presented to the subjeet. in contrast, indirect tests of memory and cognitive functions that are carried out relatively automatically are not impaired under the triazolam or ethanol treatment conditions. These findings model the types of cognitive dysfunctions that are expressed in amnestic disorder patients and in some alcoholic patients. The findings also provide evidence that the triazolam and ethanol induced selective impairments in memory are part of a more generalized disruption of cognitive control functions. These functions maybe important in a wide variety of operations including attention, perception, decision processes, and memory. Pharmacological modeling of impairments in control functions in memory and associated functions provides a useful framework for the study of impaired cognition in clinical populations.
S. MukherjeeI, P. Decina2, & P.L. Scapicchio 2 tDepanment of Psychiatry, Medical College of Georgia, 1515 Pope Avenue, Augusta, GA 30912-3800; Ospedale Santa Maria lm,nacolata, Guidonia, Italy
94. THE EFFECTS OF AMPHETAMINE ON SHIFTS IN VISUAL ATTENTION
Many studies indicate that diabetes mellitus is more common among those with psychiatric disorders, such as schizophrenia and mood disorders. if and how this comorbidity influences the course of schizophrenia remains to be systematically investigated. In view of reports that noninsulin-dependent diabetes mellitus (NIDDM) is associated with greater cognitive deficits, and that many elderly schizophrenic patients, especially the institutionalized, manifest cognitive deficits that clinically resemble dementia, we examined in 71 (40 men, 31 women) institutionalized elderly schizophrenic patients the prevalence of NIDDM and its relation to cognitive status. Their mean age was 63.65 yrs (SD 7.5), with no gender effect on age. Cognitive function was assessed with the MiniMental State Examination (MMSE). Based on fasting and postprandial
M.J. Moran, G.K. Thaker, S.L. Cassady, D.L. Ross, & D. LaPorte Maryland Psychiatric Research Center, University of Maryland at Baltimore, Baltimore, MD 21228 Schizophrenic patients consistently exhibit deficits in sustained visual attention. Recently, an asymmetric deficit in the ability to shift covert visual attention has also been demonstrated in schizophrenic patients. This deficit is manifested by a slower reaction time to a right visual field (RVF) target when covert attention is first invalidly cued to the left (Posner et ai,
THURSDAY,, MAY 19
1988). This asymmetry has been attributed to left hemispheric dopamine dysregnlation (Early et al, 1989). However, inconsistent replication of this finding in schizophrenic patients may be due to neuroleptic effects. To test this hypothesis, one could administer a pharmacologic probe to new roleptic-naive schizophrenia spectrum personality disordered (SSPD) subjects, who would then be expected to exhibit abnormalities similar to schizophrenic patients in the visual attention task. Normal controls (n-0) and SSPD subjects (n-9) were administered d-amphetamine 30 mg in a placebo controlled, double blind study and tested approximately 3 hours post-drag. SSPD subjects showed a slower reaction time to invalidly cued RVF targets than did normals. Implications of this finding will be discussed.
95. THE EFFECT OF TRIAZOLAM ON VISUAL ATTENTION AND INFORMATION PROCESSING D.N. Johnson & H. Weingartner Cognitive Neurosciences Section, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, DICBR, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892 This study was designed to examine the effects of triazolam on attention in normal volunteers. Previous research has shown that benzodiazepines selectively influence memory, impairing explicit functions but sparing implicit functions. We used a cued visual search task to evaluate visual information processing and attention with manipulations designed to separately elicit controlled and automatic attention allocation. Treatment (.375 mg triazolam and placebo), Cue-Validity (valid and invalid) and Cue-Type (central and peripheral) were manipulated in a donhle-blind within-snhjects design. ANOVA revealed that for the placebo and drug conditions, subjects were significantly faster on cue-valid as compared to cue-invalid trials, and subjects were significantly slower in the triazolam condition than in the placebo condition. Treatment interacted with CueValidity, with a larger difference between cue.valid and cue-invalid trials under triazolam as compared to placebo. No other main effects or interactions were significant. These results lead us to two conclusions: I) The lack of an interaction between Treatment and Cue-Type supports the argument that the effect of triazolam is not at the level of attention allocation, and 2) The interaction between Treatment and Cue-Validity is consistent with either a triazolam produced deficit in attention switching or in decision making. We hope to fmd the functional locus of this effect in futu~ studies. The approach taken in this research illustrates how pharmacological tools can be used to explore different forms of attention, and can serve as a framework for understanding the determinants of impaired attention and the relation of attention to other cognitive functions.
96. ATrENTIONAL EFFECTS OF SINGLE DOSE TRIAZOLAM C.S. Carter, R.J. Maddock, M.R. Chaderjian, & R. Post Department of PsychiaUy, University of Pittsburgh, and the Departments of Psychiatry and Psychology, University of California at Davis
81OL PSYCHIATRY 641 1994;35:615-747
While the effects of benzodiazepines on human memory have been extensively studied little is known about the effects of these agents on attentional processes. We studied the effects of a single dose of triazolam on selective visual-spatial attention using a double blind, placebo controlled design. In each of 2 sessions 1i normal volunteers ingested either 0.25 mg of triazolam or placebo. Attentional performance was evaluated using 2 versions of the covert orienting paradigm which measured automatic (exogenous) and controlled (endogenous) components of attentional orienting, respectively. Triazolam selectively modified performance on automatic orienting to exogenous cues. Specifically, triazolam increased the facilitation of target detection seen at shorter (! 50 msec) cue-target intervals and decreased the inhibition seen at longer (800 msec) cue-target intervals. This may indicate an increase in facilitation and a reduction in inhibition or a slowing of the time course of the biphasic attentional effect normally resulting from exogenous cuing. Since the neural mechanisms serving automatic orienting to exogenous cues and the control of saccadic eye movements appear to be tightly coupled a slowing of automatic ori. enting may be analogous to the slowing of saccadic eye movement velocities produced by benzodiazepines. These results suggest that the contribution of impaired selective attention to the cognitive impairment associ. ated with the ingestion of single doses of triazolam is significant and worthy of further investigation.
97. EFFECTS OF THE NOVEL CHOLINOMIMETIC SDZ ENS 163 ON SCOPOLAMINE-INDUCED COGNITIVE IMPAIRMENT N. R. Cutlerl, R. Polinsky 2, R.D. Seifert i, J.J. Sramek l, M.Moore2, T.S. Wardlel, & D.C. Jones t tCalifornia Clinical Trials, Beverly Hills, CA 9021 I; 2Clinical Pharmacology, Drug Safety Department, Sandoz Pharmaceuticals Corp., East Hanover, NJ 07936 SDZ ENS 163 acts as an antagonist at presynaptic muscarinic receptors and as an agonist at postsynaptic muscarinic receptors. This study was designed to evaluate the effects ofSDZ ENS 163 on cognitive impairment induced by scopolamine. 18 healthy male volunteers (mean age 29 years; range 20 to 38) were randomly assigned to receive single doses of orally administered SDZ ENS 163 50mr or matching placebo followed by normal saline (NS) or 0.4mr scopolamine IV push over I minute, according to a replicated 2x2 Latin square crossover design. The four study administration days were separated by 48 hours. Cognitive performance was assessed by repeated evaluations using the Computerized Neuropsychological Test Battery (CN'rB) (Veroff et al., 1991). Serial saliva samples were collected and weighed. Safety was assessed by continuous and repeated telemetry evaluations of vital signs and observation of adverse events. No statistically significant treatment group order effect was found (p=NS). In general, subjects demonstrated statistically significant (F~-0.05) decreases in cognitive performance when administered SDZ ENS 163/scopolamine and placebo/scopolamine, as manifested in a decline in word-list learning with selective reminding, simple reaction time, visual memory, and choice reaction time sub-tests of the CNTB. No differences were observed in the number of word intrusions, perseverations, or delayed recall. SDZ ENS ! 63 did not antagonize the significantly reduced salivary flow induced by scopolamine. Adverse events were mild and self-limited, and included drowsiness, dizziness, dry mouth, and hypersalivation. In this single dose, cross-over paradigm, SDZ ENS 163 did not prevent or ameliorate scopolamine-induced impairment; possible reasons for the lack of effect will be discussed.
BIOLPSYCHIATRY 1994;35:615--747
91. PREVALENCE AND CORRELATES OF STABLE NEGATIVE SYMPTOM SUBTYPES IN GERIATRIC CHRONIC SCHIZOPHRENIC INPATIENTS K.M. Putnam1'2, P.D. Harvey !, M. Parrella2, L.
White 2, P. Powchik l, & M. Davidson 1,2 tThe Mount Sinai School of Medicine, NY, NY, 10029; 2pilgrim Psychiatric Center, West Brentwood, NY, 11717 Although negative symptoms of schizcbphrenia have been studied in detail over the past 20 years, with substantial attention paid to the correlates of those symptoms, less attention has been paid to the stability characteristics of those symptoms, in the studies that have been conducted on the "deficit subtype", it has been reported that patients with stable deficit symptoms have specific cognitive and functional impairments. These studies have largely been conducted on relatively young patients, with less attention paid to geriatric patients with a long-term course of continu. ous hospitalization. In order to address the issue of the stability of negative subtypes in chronically institutionalized patients, a sample of 149 geriatric schizophrenic inpatients were examined with ratings of clinical symptoms (the Positive and Negative Syndrome Scale; PANSS) and a cognitive assessment battery at two assessments one year apart. Patients were characterized on the basis of their symptom presentation at the two assessments into groups who had stable negative subtypes (n=95; 64%), negative subtypes at one assessment only (n=31; 21%), or non-negative subtypes at both assessments (n-23; 15%). Patients with stable negative subtypes had significantly lower MiniMental State Scores at the 2nd as. sessment than the patients with mixed or non-negative subtypes (m- ! 3. I vs. 21.6 vs. 24.4). Similar findings were found for the entire cognitive battery, including verbal learning, delayed recall, praxis, and naming per. formance. Although the stable negative patients had lower premorbid education (m-8.9 vs 10.0 vs. 10.5) than the other two groups of patients, this difference did not account for the other differences in cognitive perform. ante. These data suggest that a majority of the patients in long-term inpa. tient care have stable negative symptoms and that this presentation is associated with substantial cognitive impairments. The presence of any negative symptoms, even unstable ones, was associated with reductions in cognitive functioning and reduced educational attainment, suggesting an intrinsic relationship between negative symptoms and intellectual functions in geriatric schizophrenic patients.
92. DIABETES MELLITUS AND COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA
THURSDAY, MAY 19
plasma glucose levels, i 2 (i 7%) of the patients were diagnosed to have NIDDM. MMSE total score was less than 24 in 50 (70.4%) of the patients, and less than ! 8 in 23 (32.4%) of the patients. There was no difference in MMSE total score, or MMSE items of delayed recall, orientation, language, and visuospatial ability between patients with NIDDM and nondiabetic patients (p>0.40 for all comparisons). The f'mdings indicate that the prevalence of NIDDM in these patients is much higher than that of the general population in Italy, but this does not contribute to severe cognitive impairment. This "dementia" likely is integral to the schizophrenic disease process. Additional data will be presented on the relations of NIDDM to negative symptoms and neurological abnormalities.
93. COGNITIVE CONTROL FUNCTIONS IN MEMORY-IMPAIRED SUBJECTS: A NEUROPHARMACOLOGICAL MODEL H. WeingartnerI, K. Sirocco I, M. Eckardt2, D. Hommer2, & D.N. Johnson I 1Cognitive Neurosciences Section; 2Section on Brain Imaging and Electrophysiology, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, DICBR, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892 Triazolam and ethanol treated normal controls demonstrate similar selective impairments in memory and perception on tasks that require the use of cognitive control functions. Following the administration of 0.375 mg of triazolam or 1.05 g/kg of ethanol, subjects are impaired when they are required to judge the accuracy and source of what is remembered or to perceive and evaluate the extent to which drug treatments induce sedation. This effect is independent of other indices of memory performance (e.g., the amount of information recalled). Furthermore, the inability to monitor and judge memory performance is potentiated when the drug state in which the subject is asked to remember is different from that which was present when the information was first generated or presented to the subjeet. in contrast, indirect tests of memory and cognitive functions that are carried out relatively automatically are not impaired under the triazolam or ethanol treatment conditions. These findings model the types of cognitive dysfunctions that are expressed in amnestic disorder patients and in some alcoholic patients. The findings also provide evidence that the triazolam and ethanol induced selective impairments in memory are part of a more generalized disruption of cognitive control functions. These functions maybe important in a wide variety of operations including attention, perception, decision processes, and memory. Pharmacological modeling of impairments in control functions in memory and associated functions provides a useful framework for the study of impaired cognition in clinical populations.
S. MukherjeeI, P. Decina2, & P.L. Scapicchio 2 tDepanment of Psychiatry, Medical College of Georgia, 1515 Pope Avenue, Augusta, GA 30912-3800; Ospedale Santa Maria lm,nacolata, Guidonia, Italy
94. THE EFFECTS OF AMPHETAMINE ON SHIFTS IN VISUAL ATTENTION
Many studies indicate that diabetes mellitus is more common among those with psychiatric disorders, such as schizophrenia and mood disorders. if and how this comorbidity influences the course of schizophrenia remains to be systematically investigated. In view of reports that noninsulin-dependent diabetes mellitus (NIDDM) is associated with greater cognitive deficits, and that many elderly schizophrenic patients, especially the institutionalized, manifest cognitive deficits that clinically resemble dementia, we examined in 71 (40 men, 31 women) institutionalized elderly schizophrenic patients the prevalence of NIDDM and its relation to cognitive status. Their mean age was 63.65 yrs (SD 7.5), with no gender effect on age. Cognitive function was assessed with the MiniMental State Examination (MMSE). Based on fasting and postprandial
M.J. Moran, G.K. Thaker, S.L. Cassady, D.L. Ross, & D. LaPorte Maryland Psychiatric Research Center, University of Maryland at Baltimore, Baltimore, MD 21228 Schizophrenic patients consistently exhibit deficits in sustained visual attention. Recently, an asymmetric deficit in the ability to shift covert visual attention has also been demonstrated in schizophrenic patients. This deficit is manifested by a slower reaction time to a right visual field (RVF) target when covert attention is first invalidly cued to the left (Posner et ai,
THURSDAY,, MAY 19
1988). This asymmetry has been attributed to left hemispheric dopamine dysregnlation (Early et al, 1989). However, inconsistent replication of this finding in schizophrenic patients may be due to neuroleptic effects. To test this hypothesis, one could administer a pharmacologic probe to new roleptic-naive schizophrenia spectrum personality disordered (SSPD) subjects, who would then be expected to exhibit abnormalities similar to schizophrenic patients in the visual attention task. Normal controls (n-0) and SSPD subjects (n-9) were administered d-amphetamine 30 mg in a placebo controlled, double blind study and tested approximately 3 hours post-drag. SSPD subjects showed a slower reaction time to invalidly cued RVF targets than did normals. Implications of this finding will be discussed.
95. THE EFFECT OF TRIAZOLAM ON VISUAL ATTENTION AND INFORMATION PROCESSING D.N. Johnson & H. Weingartner Cognitive Neurosciences Section, Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, DICBR, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892 This study was designed to examine the effects of triazolam on attention in normal volunteers. Previous research has shown that benzodiazepines selectively influence memory, impairing explicit functions but sparing implicit functions. We used a cued visual search task to evaluate visual information processing and attention with manipulations designed to separately elicit controlled and automatic attention allocation. Treatment (.375 mg triazolam and placebo), Cue-Validity (valid and invalid) and Cue-Type (central and peripheral) were manipulated in a donhle-blind within-snhjects design. ANOVA revealed that for the placebo and drug conditions, subjects were significantly faster on cue-valid as compared to cue-invalid trials, and subjects were significantly slower in the triazolam condition than in the placebo condition. Treatment interacted with CueValidity, with a larger difference between cue.valid and cue-invalid trials under triazolam as compared to placebo. No other main effects or interactions were significant. These results lead us to two conclusions: I) The lack of an interaction between Treatment and Cue-Type supports the argument that the effect of triazolam is not at the level of attention allocation, and 2) The interaction between Treatment and Cue-Validity is consistent with either a triazolam produced deficit in attention switching or in decision making. We hope to fmd the functional locus of this effect in futu~ studies. The approach taken in this research illustrates how pharmacological tools can be used to explore different forms of attention, and can serve as a framework for understanding the determinants of impaired attention and the relation of attention to other cognitive functions.
96. ATrENTIONAL EFFECTS OF SINGLE DOSE TRIAZOLAM C.S. Carter, R.J. Maddock, M.R. Chaderjian, & R. Post Department of PsychiaUy, University of Pittsburgh, and the Departments of Psychiatry and Psychology, University of California at Davis
81OL PSYCHIATRY 641 1994;35:615-747
While the effects of benzodiazepines on human memory have been extensively studied little is known about the effects of these agents on attentional processes. We studied the effects of a single dose of triazolam on selective visual-spatial attention using a double blind, placebo controlled design. In each of 2 sessions 1i normal volunteers ingested either 0.25 mg of triazolam or placebo. Attentional performance was evaluated using 2 versions of the covert orienting paradigm which measured automatic (exogenous) and controlled (endogenous) components of attentional orienting, respectively. Triazolam selectively modified performance on automatic orienting to exogenous cues. Specifically, triazolam increased the facilitation of target detection seen at shorter (! 50 msec) cue-target intervals and decreased the inhibition seen at longer (800 msec) cue-target intervals. This may indicate an increase in facilitation and a reduction in inhibition or a slowing of the time course of the biphasic attentional effect normally resulting from exogenous cuing. Since the neural mechanisms serving automatic orienting to exogenous cues and the control of saccadic eye movements appear to be tightly coupled a slowing of automatic ori. enting may be analogous to the slowing of saccadic eye movement velocities produced by benzodiazepines. These results suggest that the contribution of impaired selective attention to the cognitive impairment associ. ated with the ingestion of single doses of triazolam is significant and worthy of further investigation.
97. EFFECTS OF THE NOVEL CHOLINOMIMETIC SDZ ENS 163 ON SCOPOLAMINE-INDUCED COGNITIVE IMPAIRMENT N. R. Cutlerl, R. Polinsky 2, R.D. Seifert i, J.J. Sramek l, M.Moore2, T.S. Wardlel, & D.C. Jones t tCalifornia Clinical Trials, Beverly Hills, CA 9021 I; 2Clinical Pharmacology, Drug Safety Department, Sandoz Pharmaceuticals Corp., East Hanover, NJ 07936 SDZ ENS 163 acts as an antagonist at presynaptic muscarinic receptors and as an agonist at postsynaptic muscarinic receptors. This study was designed to evaluate the effects ofSDZ ENS 163 on cognitive impairment induced by scopolamine. 18 healthy male volunteers (mean age 29 years; range 20 to 38) were randomly assigned to receive single doses of orally administered SDZ ENS 163 50mr or matching placebo followed by normal saline (NS) or 0.4mr scopolamine IV push over I minute, according to a replicated 2x2 Latin square crossover design. The four study administration days were separated by 48 hours. Cognitive performance was assessed by repeated evaluations using the Computerized Neuropsychological Test Battery (CN'rB) (Veroff et al., 1991). Serial saliva samples were collected and weighed. Safety was assessed by continuous and repeated telemetry evaluations of vital signs and observation of adverse events. No statistically significant treatment group order effect was found (p=NS). In general, subjects demonstrated statistically significant (F~-0.05) decreases in cognitive performance when administered SDZ ENS 163/scopolamine and placebo/scopolamine, as manifested in a decline in word-list learning with selective reminding, simple reaction time, visual memory, and choice reaction time sub-tests of the CNTB. No differences were observed in the number of word intrusions, perseverations, or delayed recall. SDZ ENS ! 63 did not antagonize the significantly reduced salivary flow induced by scopolamine. Adverse events were mild and self-limited, and included drowsiness, dizziness, dry mouth, and hypersalivation. In this single dose, cross-over paradigm, SDZ ENS 163 did not prevent or ameliorate scopolamine-induced impairment; possible reasons for the lack of effect will be discussed.