Apparent reversal frequencies in squares and trapezia: the effect of invariant and variant information

Three studies of apparent reversals (ARs) in rotating rectangular and trapezoid arrays are reported, together with a mathematical analysis. Study 1 explores the effect of different degrees of outline suppression on the frequency and distribution of ARs in squares and trapezia. Study 2 examines how modifications in both types of array reduce AR frequency, demonstrates a manipulation whereby ARs in rotating squares are eliminated, and suggests that ARs in squares and trapezia are of different origins. In the mathematical analysis, an invariant characteristic of the transformations of rotating rectangles is reported, and from this a numerical index is developed that expresses the extent to which a rotating trapezium may appear to pause just before each point of oscillation. In study 3 it is shown that this measure is a better predictor of AR frequencies than the heuristic proposed by Braunstein.     

Androgens' performance-enhancing effects in the inhibitory avoidance and water maze tasks may involve actions at intracellular androgen receptors in the dorsal hippocampus

Androgens can have performance-enhancing effects in some cognitive tasks, but the mechanism of these effects has not been established. Experiments examined whether androgens' actions to bind to intracellular androgen receptors (ARs) in the hippocampus are necessary to enhance cognitive performance in the inhibitory avoidance and water maze tasks. If androgens' binding at ARs are essential, then blocking them through intrahippocampal administration of flutamide, an AR receptor antagonist, should attenuate androgens' performance-enhancing effects in the inhibitory avoidance and water maze tasks. In Experiments 1 and 2, flutamide was administered through intrahippocampal inserts to intact male rats immediately pre- and post-training in the inhibitory avoidance and water maze tasks. Both pre- and post-training administration of flutamide to the dorsal hippocampus, but not missed sites, produced significantly poorer performance in the inhibitory avoidance and water maze tasks, without influencing control measures such as flinch/jump threshold or swim speed. In Experiment 3, flutamide administration to the hippocampus was delayed two hours following training in the inhibitory avoidance and water maze tasks. There was no significant effect of delayed administration of flutamide on performance in either of these tasks. Together, these findings suggest that blocking ARs in the dorsal hippocampus with flutamide administration immediately pre- or post-training can produce decrements in cognitive performance, which implies that androgens' performance-enhancing effects may occur, in part, through binding at intracellular androgen receptors in the dorsal hippocampus.     

Selective antagonism of GABAA receptor subtypes: an in vivo approach to exploring the therapeutic and side effects of benzodiazepine-type drugs

Benzodiazepines (BZs) are clinically used as anxiolytic, hypnotic, anticonvulsant, and antispasmodic drugs. Research using transgenic mouse models has suggested that the effects of BZs involve multiple subtypes of the gamma-aminobutyric acid type A (GABAA) receptor, identified by specific a subunits (alpha1, alpha2, alpha3, alpha5). This review discusses the experimental uses of b-carboline-3-carboxylate-t-butyl ester (betaCCT), a drug that binds preferentially to the GABAA alpha1 subtype but exerts no action (ie, is a pharmacologic antagonist at the GABAA alpha1 subtype receptor). betaCCT blocks the anxiolytic-like effects of BZs, although studies in primates suggests this antagonism may reflect multiple receptor populations. betaCCT antagonized the ataxic but not muscle relaxant effects of BZs, a finding that implicates the GABAA alpha1 subtype receptor in ataxia but not muscle relaxation. The potential clinical utility of betaCCT is discussed, both in terms of treatment (ie, hepatic encephalopathy) and as a diagnostic imaging agent. Altogether, these results indicate that subtype-selective antagonists represent a useful approach to studying receptor mechanisms underlying the behavioral effects of BZ-type drugs.     

Alpha3-integrins are required for hippocampal long-term potentiation and working memory

Integrins comprise a large family of heterodimeric, transmembrane cell adhesion receptors that mediate diverse neuronal functions in the developing and adult CNS. Recent pharmacological and genetic studies have suggested that beta1-integrins are critical in synaptic plasticity and memory formation. To further define the role of integrins in these processes, we generated a postnatal forebrain and excitatory neuron-specific knockout of alpha3-integrin, one of several binding partners for beta1 subunit. At hippocampal Schaffer collateral-CA1 synapses, deletion of alpha3-integrin resulted in impaired long-term potentiation (LTP). Basal synaptic transmission and paired-pulse facilitation were normal in the absence of alpha3-integrin. Behavioral studies demonstrated that the mutant mice were selectively defective in a hippocampus-dependent, nonmatch-to-place working memory task, but were normal in other hippocampus-dependent spatial tasks. The impairment in LTP and working memory is similar to that observed in beta1-integrin conditional knockout mice, suggesting that alpha3-integrin is the functional binding partner for beta1 for these processes in the forebrain.     

Hypnotic susceptibility, visual distraction, and reports of Necker cube apparent reversals

Subjects, either susceptible (n = 50) or resistant (n = 50) to hypnotic suggestion, were asked to report on frequency of apparent reversals (ARs) to the Necker cube illusion. Such reports were made in the presence or absence of various types of visual, geometric surrounds (squares, triangles, crosses, or parallelograms). In agreement with a number of previous experiments, susceptible subjects reported perceiving more ARs than did resistant subjects. This difference held whether visual surrounds were present or absent. The presence of surrounds did serve to reduce AR reports regardless of hypnotic susceptibility level. The results are examined in terms of the ability of subjects to selectively attend when confronted with potential visual distractors.     

Latency and frequency reports to the Necker cube illusion: effects of hypnotic susceptibility and mental arithmetic

An experiment (N = 32) was conducted to assess latency of first apparent reversal (AR) and AR frequency while observing the Necker cube illusion. Subjects who were either high in hypnotic susceptibility (susceptibles) or low in hypnotic susceptibility (resistant subjects) observed the cube either while performing or not performing mental addition problems. Susceptibles reported perceiving the first AR more quickly and a greater frequency of ARs than did resistant subjects. Also, latency of the first AR was negatively correlated with AR frequency. These results were interpreted in terms of the ability of susceptibles to allocate concentrative or selective attention in a manner that was conducive to faster performance, when faced with competing tasks.     

Effects of alpha and beta adrenergic antagonists on aggressive behavior in male mice

The effects of a variety of alpha and beta adrenergic antagonists were examined on the social encounters of isolated male mice with anosmic male partners. A range of alpha antagonists, including phentolamine, prazosin, and yohimbine, all suppressed social aggression. A range of beta antagonists, including propranolol, atenolol, metaprolol, and ICI 118, 551, also reduced this type of attack. Ethological assessment of the lowest effective dose of these adrenergic antagonists revealed a marked inhibitor action on offensive, social, and nonsocial behavior, while defensive responses and immobility were enhanced. It is concluded that the noradrenergic system has a significant non-specific role in mediating intermale aggression via both alpha and beta adrenergic receptor subtypes. © 1993 Wiley-Liss, Inc.     

HIV-1 infection and its impact on the HPA axis, cytokines, and cognition

Immediately after infection, Human immunodeficiency virus, type 1 (HIV-1) enters the central nervous system (CNS) and is localized in highest concentration in the hippocampus and basal ganglia. Since these areas are associated with HPA axis and autonomic activities as well as cognition, it has been hypothesized that these functions will be impacted adversely in HIV-1 infection. In the treatment of HIV infection, although the highly potent antiretroviral (HAART) drugs have been effective in reducing peripheral viral load and prolonging life expectancy, these drugs do not cross the blood-brain barrier in therapeutic concentrations. Therefore, it has been proposed that the beneficial effects of HAART on the CNS will be limited. Our investigations on seropositive individuals, showing hypo-reactivity of the autonomic system and HPA axis activity suggest that HIV-1 infection is a model of chronic stress. Furthermore, an elevated baseline TNF-alpha level as well as its increased reactivity to an alpha-adrenergic challenge among HIV-1+ individuals, may lead to additional neurodegeneration. It is proposed that the effects of HIV-1 infection on the brain will have implications for neurocognitive and mental health functioning in seropositive individuals even in patients undergoing HAART therapy. These outcomes may result in the need to develop facilities for long term "care-giving".     

New lessons from knockout mice: The role of serotonin during development and its possible contribution to the origins of neuropsychiatric disorders

Serotonin (5-HT) modulates numerous processes in the central nervous system that are relevant to neuropsychiatric function and dysfunction. It exerts significant effects on anxiety, mood, impulsivity, sleep, ingestive behavior, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several psychiatric conditions but efforts to more clearly understand the mechanisms of this influence have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of 5-HT as well as several enzymes that control its synthesis and metabolism. Pharmacologic agents that target specific receptors have provided clues regarding the function of these receptors in the human brain. 5-HT is also an important modulator of neural development and several groups have employed a genetic strategy relevant to behavior. Several inactivation mutations of specific 5-HT receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases, knockout mice have been used to confirm what has already been suspected based on pharmacologic studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior.     

Rôle du contrôle exécutif dans le raisonnement par analogie chez l’enfant et le primate non humain

Analogical reasoning (AR) is a cornerstone of human cognition. Two main theories have historically been proposed to account for the ontogeny of AR. They propose that analogical skills are constrained by children's logical skills or limited knowledge of the relations to be considered. We adopt an alternative perspective in this review paper suggesting that AR abilities depend on the efficiency of executive control. We present convergent data collected in children and monkeys highlighting the role of three main executive functions: inhibitory control, cognitive flexibility and working memory updating. The analysis of children's reasoning suggests that the contribution of relational knowledge and executive control to analogical reasoning cannot be considered independently.     

Pharmacological treatment effects on eye movement control

The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second- generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson’s disease, and Huntington’s disease are also reviewed. While greater recognition and investigation into pharmacological treatment effects in these disorders is needed, both beneficial and adverse drug effects are identified. This raises the important caveat for oculomotor studies of neuropsychiatric disorders that performance differences from healthy individuals cannot be attributed to illness effects alone. In final sections of this review, studies are presented that illustrate the utility of eye movements for use as potential biomarkers in pharmacodynamic and pharmacogenetic studies. While more systematic studies are needed, we conclude that eye movement measurements hold significant promise as tools to investigate treatment effects on cognitive and sensorimotor processes in clinical populations and that their use may be helpful in speeding the drug development pathway for drugs targeting specific neural systems and in individualizing pharmacological treatments.     

Pharmacological treatment effects on eye movement control

The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second- generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson’s disease, and Huntington’s disease are also reviewed. While greater recognition and investigation into pharmacological treatment effects in these disorders is needed, both beneficial and adverse drug effects are identified. This raises the important caveat for oculomotor studies of neuropsychiatric disorders that performance differences from healthy individuals cannot be attributed to illness effects alone. In final sections of this review, studies are presented that illustrate the utility of eye movements for use as potential biomarkers in pharmacodynamic and pharmacogenetic studies. While more systematic studies are needed, we conclude that eye movement measurements hold significant promise as tools to investigate treatment effects on cognitive and sensorimotor processes in clinical populations and that their use may be helpful in speeding the drug development pathway for drugs targeting specific neural systems and in individualizing pharmacological treatments.     

Impaired memory consolidation in rats produced with beta-adrenergic blockade

Despite abundant evidence that systemic administration of adrenergic drugs and hormones can produce retrograde memory enhancement, the literature contains no clear demonstration that postlearning systemic administration of adrenergic antagonists produces retrograde amnesia. Here we demonstrate retrograde amnesia for a stressful learning task (a spatial water maze) with systemic administration of the beta-adrenergic antagonist propranolol (5 mg/kg). The amnesic effect of the drug depended on the degree of learning in the subjects: Propranolol caused a robust retrograde amnesia in "good learners," but did not significantly affect memory in "poor learners." The findings provide critical additional support for the hypothesis that postlearning adrenergic activation modulates memory consolidation processes after emotionally stressful events and help explain previous failures to detect memory impairment after systemic administration of adrenergic blocking drugs.     

重视非抗心律失常药物的致心律失常作用

抗心律失常药物的致心律失常作用近年来已得到心血管科医生的广泛关注,但在临床实践中观察,对于一些非抗心律失常药,如抗生素、精神类药物等,在发挥他们相应的药理效应同时,可引起心动过缓、心动过速、传导阻滞,甚至致命性心律失常,而其致心律失常效应往往没有引起关注,强化非心脏药物致心律失常作用的意识,了解其可能的机制及促发因素都是必要的。     

Impaired Memory Consolidation in Rats Produced with β-Adrenergic Blockade

Despite abundant evidence that systemic administration of adrenergic drugs and hormones can produce retrograde memory enhancement, the literature contains no clear demonstration that postlearning systemic administration of adrenergic antagonists produces retrograde amnesia. Here we demonstrate retrograde amnesia for a stressful learning task (a spatial water maze) with systemic administration of the β-adrenergic antagonist propranolol (5 mg/kg). The amnesic effect of the drug depended on the degree of learning in the subjects: Propranolol caused a robust retrograde amnesia in “good learners,” but did not significantly affect memory in “poor learners.” The findings provide critical additional support for the hypothesis that postlearning adrenergic activation modulates memory consolidation processes after emotionally stressful events and help explain previous failures to detect memory impairment after systemic administration of adrenergic blocking drugs.     

Cortical alpha rhythm, biofeedback, and the determinants of subjective state

A critical assumption in the rationale for the clinical application of voluntary control over central nervous system (CNS) activity is that there exists a direct relationship between specific CNS activities and specific subjective mood states. The experiment reported here was based on the idea that a joint manipulation of both cognitive and physiological (i.e., alpha electroencephalographic [EEG]) variables would provide information required for an explication of the processes involved in subjective mood change. Three main variables were considered in the present experiment. First, the instructions were designed to induce a "set" or expectations for either positive or negative changes in subjective mood. Second, the type of feedback (alpha or not alpha) was varied. Those in the not-alpha feedback condition received feedback contingent on the absence of alpha activity, whereas those in the alpha feedback condition received feedback contingent on the presence of alpha activity. Third, an estimate of each individual's baseline alpha density was obtained, and on this basis subjects were classified as high-baseline or low-baseline subjects. Baseline alpha density, alpha density during training, and subjective mood were all considered as continuous variables. The results of the present study indicate that biofeedback of the cortical alpha rhythm is neither a sufficient nor a necessary condition for changes in subjective mood. In addition, the type of instructions designed to set subjects for positive or negative alterations in subjective states is predictive of changes in subjective state reported during alpha biofeedback training as well as of success at controlling and changing EEG during feedback training. The data presented here permit a direct examination of the actual relationship of EEG changes to changes in subjective mood state. Similar shifts in subjective mood state can be obtained with either increases or decreases in alpha activity. Further, both positive and negative subjective experiences can be associated with increases in alpha activity.     

Diagnostic value of alpha 1-acid glycoprotein in the cerebrospinal fluid

Samples from 1415 neurological patients were used to study the diagnostic value of acid alpha 1-glycoprotein in the lumbar cerebrospinal fluid. The value of analysis for this substance is considered to lie in the detection of non-specific acute-phase reactions of various causes in the CNS with special reference to barrier problems. The large number of pathologically elevated values associated with acute inflammations of the meninges and cerebral parenchyme is particularly striking. The results of the studies are analyzed on the basis of comprehensive control investigations (n = 559).