A poor metabolizer for cytochromes P450 2D6 and 2C19: a case report on antidepressant treatment

Scientific literature has never described a poor metabolizer for both the cytochrome P450 (CYP) 2D6 and the CYP 2C19. They are expected to be rare (<1% in different ethnic groups) and prone to adverse drug reactions with many antidepressants. In an ongoing pharmacogenetic study, after genotyping 1,576 subjects in three Kentucky state hospitals we have found one poor metabolizer for both CYP 2D6 and CYP 2C19, which corresponds to a prevalence of 0.06% (95% CI 0.01 to 0.36). The naturalistic antidepressant treatment of this poor metabolizer for both enzymes is described in this article. As genotyping reaches clinical practice, it will be interesting to prospectively establish whether mirtazapine is a reasonable choice as an antidepressant for these patients, as the data and this case suggest.     

Paradoxical facilitation of attention in healthy humans

Transcranial magnetic stimulation (TMS)-induced virtual lesions in healthy subjects can be used to test neurofunctional models of disease. The interhemispheric rivalry model of heminglect is well suited for such investigations, as simple predictions derived from clinical data can be tested without the caveats normally associated with lesion studies. One of these predictions is that release from contralateral inhibition should lead to increased parietal responsiveness, which, in turn, would enhance spatial attention. Here, we detail studies showing TMS-induced paradoxical functional facilitation of attention in healthy individuals and highlight their contribution to the understanding and treatment of neglect syndromes.     

Brain stimulation and conscious experience

Libet discovered that a substantial duration (> 0.5-1.0 s) of direct electrical stimulation of the surface of the somatosensory cortex at threshold currents is required before human subjects can report that a conscious somatosensory experience had occurred. Using a reaction time method we confirm that a similarly long stimulation duration at threshold currents is required for activation of elementary visual experiences (phosphenes) in human subjects following stimulation of the surface of the striate cortex. However, the reaction times for the subject to respond to the cessation of the visual experience after the end of electrical stimulation could be as brief as 225-242 ms. We also carried out extensive studies in cats under a variety of anesthetic conditions using the same electrodes and parameters of stimulation employed in the human studies to study the patterns of neuronal activity beneath the stimulating surface electrode. Whereas sufficiently strong currents can activate neurons within milliseconds, stimulating currents close to threshold activate sustained neural activity only after at least 350-500 ms. When currents are close to threshold, some neurons are inhibited for several hundreds of millisecond before the balance between inhibition and excitation shifts towards excitation. These results suggest that the prolonged latencies, i.e., latencies beyond 200-250 ms, for the emergence of conscious experience following direct cortical stimulation result from a delay in the sustained activation of underlying cortical neurons at threshold currents rather than being due to any unusually long duration in central processing time. Intracellular records from cortical neurological cells during repetitive electrical stimulation of the surface of the feline striate cortex demonstrate that such stimulation induces a profound depolarizing shift in membrane potential that may persist after each stimulus train. Such a depolarization is evidence that extracellular K+ concentrations have increased during electrical stimulation. Such an increase in extracellular K+ progressively increases cortical excitability until the threshold for sustained activation of cortical neurons is reached and then exceeded. Consequently, the long latency for threshold activation of cortical neurons depends upon a dynamically increasing cortical facilatory process that begins hundreds of milliseconds before there is sustained activation of such neurons. In some cases, this facilatory process must overcome an initial stimulus-induced inhibition before neuronal firing commences.     

Paradoxical effects of praise and criticism: Social,dimensional and temporal comparisons

Background. When developing a domain‐specific academic self‐concept, students are not restricted to social comparisons; they may also make temporal or dimensional comparisons. Aims. The main purpose of this study was to examine whether these different types of comparison trigger paradoxical effects of praise and criticism in the sense described by Meyer (1992) . University students participated in Study 1 (N=120) and Study 4 (N=83). The Study 2 sample consisted of 180 seventh to ninth grade students, and Study 3 investigated paradoxical effects with a sample of 130 elementary school students. Methods. Participants were presented with vignettes describing the results of 2 students (social comparison condition) versus 1 student in 2 subjects (dimensional comparison) versus 1 student in 2 subsequent tests (temporal comparison). In all cases, the results were identical. Participants were then informed about a teacher's response to these results (praise vs. criticism vs. neutral response), and were asked to estimate the ability of the 2 stimulus persons. Results. Study 1 and Study 2 revealed that dimensional, as well as social, comparisons following praise and criticism elicit paradoxical effects of perceived ability, reflected in corresponding estimations of student effort and teacher expectancies. There were no paradoxical effects following temporal comparisons. Study 3 did not reveal any paradoxical effects, thereby supporting the assumption that the occurrence of such effects depends on the level of cognitive development. Study 4 showed that the paradoxical effects found in Study 1 and 2 occur even when the sanctioned and the neutral achievement are presented independently. Conclusions. Dimensional comparisons, which have been largely overlooked in the past, play a major role in ability inferences.     

The easy-to-hard effect in human (Homo sapiens) and rat (Rattus norvegicus) auditory identification

The authors examined whether progressively training humans and rats to perform a difficult auditory identification task led to larger improvements than extensive training with highly similar sounds (the easy-to-hard effect). Practice improved humans' ability to distinguish sounds regardless of the training regimen. However, progressively trained subjects were more accurate and showed more generalization, despite significantly less training with the stimuli that were the most difficult to distinguish. Rats showed less capacity to improve with practice but still benefited from progressive training. These findings indicate that transitioning from an easier to a more difficult task during training can facilitate, and in some cases may be essential for, auditory perceptual learning. The results are not predicted by an explanation that assumes interaction of generalized excitation and inhibition but are consistent with a hierarchical account of perceptual learning in which the representational precision required to distinguish stimuli determines the mechanisms engaged during learning.     

Six-member stimulus classes generated by conditional-discrimination procedures

In conditional-discrimination procedures with three sets of stimuli, A, B, and C, three stimuli per set (A1A2A3, B1B2B3, and C1C2C3), subjects (children and adults) learned to select Set-B and Set-C comparisons conditionally upon Set-A samples (A1B1, A1C1, A2B2, A2C2, A3B3, A3C3). If the conditional-discrimination procedures also generated equivalence relations, three 3-member stimulus classes would be demonstrable, A1B1C1, A2B2C2, and A3B3C3. In addition to these three sets, the present experiments used three other sets of stimuli--D, E, and F. The subjects learned to select Set-E and Set-F comparisons conditionally upon Set-D samples (D1E1, D1F1, D2E2, D2F2, D3E3, D3F3). This established a second group of three 3-member stimulus classes, D1E1F1, D2E2F2, and D3E3F3. In all, two groups of three 3-member classes were established by teaching subjects 12 conditional discriminations. The two groups of 3-member classes were then combined (successfully for 5 of 8 subjects) into a single group of three 6-member classes by teaching the subjects three more conditional relations (E1C1, E2C2, and E3C3). With three other children, enlarging the classes one member at a time also produced 6-member classes. As a consequence of class formation, 60 untrained conditional relations emerged from 15 that had been explicitly taught. Six of the subjects also proved capable of naming the stimuli consistently in accord with their class membership, but two subjects demonstrated class formation even in the absence of consistent naming.     

Possible participation of D3 and D4 dopaminergic receptors on genital reflexes induced by cocaine in paradoxical sleep deprived male rats

Previous studies have demonstrated that paradoxical sleep deprivation (PSD) potentiates cocaine-induced genital reflexes in male rats and both D1 and D2 receptors may play a role in those effects, and to examine the possibility that such might involve other dopaminergic receptors, we investigated the effects of D3 and D4 receptor subtype antagonists on cocaine-induced reflexes in sleep-deprived rats. Separate groups of PSD rats received saline, D3 (U9919A; 0.75, 1.5 and 3 mg/kg) or D4 (L745870; 0.75, 1.5 and 3 mg/kg) antagonists prior to acute cocaine challenge. Results demonstrated that U9919A induced significant reduction in the number of animals that displayed erection and the frequency of erection at two smaller doses, while no significant difference was reported for the D4 receptor antagonist. Although our studies indicate that there is a relevant participation of D3 receptors in male sexual function, D4 receptors seem not to exert an essential role in this model.     

Inhibition of return: Unraveling a paradox

Although inhibition of return (IOR) is widely believed to aid search by discouraging reexamination of previously inspected locations, its impact actually appears to decline as the number of target locations increases. We test three possible reasons for this paradoxical result: (1) IOR is capacity-limited, (2) IOR is sensitive to subtle changes in target location probability, and (3) IOR decays with distance from a previously attended location. The present investigation provides strong support for the third explanation, indicating that a gradient of inhibition is centered on previously attended locations. We note that this inhibitory gradient resolves a paradox in the literature. Moreover, we speculate that the inhibitory gradient may reflect a “similarity space” within which target locations near to the cue are tagged with inhibition due to their similarity to the cued location. The farther the target location is away, the less similar it is to the cued location, and thus the less inhibition it receives.     

A comparison of two methods for the administration of paradoxical intention

Recent research in the treatment of insomnia by paradoxical intention has utilized two different methods of instruction. Studies utilizing the random assignment of subjects to treatment groups employ a procedure in which clients are provided with a straight-forward explanation based on the present authors' understanding of the use of paradoxical intention with insomnia (type A administration). In contrast, controlled case studies have employed reframing, a procedure which explains the need for the paradoxical intention in a manner which best suits the specific understanding of the individual client (type B administration). The present study employed the type B method in a design employing the random assignment of clients to groups. Three additional groups (type A administration, placebo control, no-treatment control) completed the design. The results indicated that the type A method was superior to the type B procedure when the same method for administering paradoxical intention was applied to a randomized group of individuals.     

Implicit diagnosticity in an information-buying task. How do we use the information that we bring with us to a problem?

Past research suggests that people may make use of diagnosticity information when explicit data regarding P(D | H) and P(D | ? H) are given to them. However, people fall victim to pseudodiagnosticity biases and ignore P(D | ? H) when such data must be actively sought. This series of four experiments utilized judgment problems in which subjects have knowledge of P(D | ? H) but must recognize the relevance of that knowledge for the judgment at hand. It was hypothesized that subjects who genuinely understood the role of P(D | ? H) in hypothesis testing would respond to this manipulation of implicit diagnosticity by exhibiting greater confidence and lesser information buying when given evidence of relatively high diagnosticity. In the first three studies, subjects attempted to judge the guilt or innocence of suspects in several fictional crimes. In the fourth experiment, subjects attempted to judge the club membership status of students at their own university. Greater amounts of information were bought when the only available information was of low diagnosticity. Subjects also expressed greater confidence in judgments made using highly diagnostic information. However, within the legal scenario, sensitivity to diagnosticity was dependent upon the implication of the cues received. Results are discussed with respect to Bayesian probability, expected value theory, and a confidence criterion model of information purchasing.     

Interference in letter identification: A test of feature-specific inhibition

The role of perceptual interference in letter identification was investigated in three experiments designed to test the feature-specific inhibition model proposed by Bjork and Murray (1977). According to their extension of Estes’ (1972, 1974) interactive channels model, input channels leading to the same feature detector inhibit one another more than do channels leading to different detectors. The model therefore predicts perceptual interference between two letters to be a function of the degree of their feature overlap. Experiment 1 confirmed the feature-specific inhibition model and Bjork and Murray’s finding that the accuracy of report is lower when a briefly presented target letter is flanked by an identical letter than when flanked by another target letter or by a nontarget letter. Results from Experiment 2 indicated that single-target performance is a function of the degree of feature similarity between the target letter and background characters in a stimulus display. Experiment 3 ruled out a spatial-uncertainty explanation of feature-specific inhibition in a new paradigm that does not require subjects to process a poststimulus cue. The results of these experiments are discussed in relation to recent studies exhibiting strong effects of noise letters at the response stage of processing. It is suggested that discrepancies between feature-specific interference and response-interference studies may be a function of the particular mode of stimulus presentation and of the dependent measures that are used.     

Identity-based inhibitory processing during focused attention

Recent data suggest that the operating principles governing inhibition of distractor-related activity may deviate from dominant models describing inhibitory processing during selective attention. Here we aimed to gain a better understanding of these data in order to determine whether they actually defy premises of current models. In addition to providing evidence against noninhibitory accounts of the data (see especially Experiment 6), the results support three main novel findings that challenge current theories. First, the data provide evidence that inhibition overpowered excitation from ongoing external input (Experiments 1–4), which suggests that inhibitory control processes are more powerful than current models indicate. Second, negative effects emerged even when targets appeared alone (Experiment 5), which suggests that selection does not play an essential role in triggering inhibitory processing. Third, relatively early distractor-related activity was affected, which supports a role for inhibition prior to action control (Experiment 3). These findings suggest a need to revise current models describing inhibition of distracting information during selective attention.     

Anger arousal,deindividuation, and aggression

We tested the notion that angered persons' aggression would be increased through a process of excitation transfer when they are deindividuated, but that individuated subjects would be most aggressive in circumstances under which they could use the information that they had ingested an arousing drug as a pretext for their aggression. Sixty-two male undergraduates participated under either deindividuated or individuated conditions, ingested either 350 mg of caffeine or a placebo, were informed that they had either taken a stimulant or a nonarousing drug, and were all angered by a confederate. According to prediction, when deindividuated and aroused by caffeine the amount of noxious stimulation subjects delivered to the provocateur was greater if they believed that the drug they had taken was nonarousing than if they thought it was a stimulant; in contrast, individuated subjects' aggression was greater when aroused subjects believed the drug was a stimulant. The results are discussed in terms of excitation transfer and the effect of aggression inhibition on the use of information about one's arousal.     

Stuttering, emotions, and heart rate during anticipatory anxiety: a critical review

Persons who stutter often report their stuttering is influenced by emotional reactions, yet the nature of such relation is still unclear. Psychophysiological studies of stuttering have failed to find any major association between stuttering and the activity of the sympathetic nervous system. A review of published studies of heart rate in relation to stressful speech situations indicate that adults who stutter tend to show a paradoxical reduction of heart rate compared with nonstuttering persons. Reduction of heart rate has also been observed in humans and mammals during anticipation of an unpleasant stimulus, and is proposed to be an indication of anticipatory anxiety resulting in a "freezing response" with parasympathetic inhibition of the heart rate. It is suggested that speech-related anticipatory anxiety in persons who stutter is likely to be a secondary, conditioned reaction based on previous experiences of stuttering. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe how the autonomic nervous system is modulated by emotional responses; (2) explain how anticipatory fear often results in inhibition of heart rate due to parasympathetic activation; (3) discuss why emotional reactions in persons who stutter may be secondary to negative experiences of speech problems.     

Employing paradoxical intention in the treatment of agoraphobia

The present study assessed the efficacy of paradoxical intention in ameliorating the travel restriction of agoraphobics. A combined score indicating proximity to two difficult target locations represented the dependent variable. A multiple baseline across subjects was used with each of two groups of five clients. This was accomplished by sequentially staggering introduction of treatment. At the conclusion of baseline phase. Group A received 6 weeks of gradual exposure followed by paradoxical intention to criterion. Group B received paradoxical intention to criterion immediately after baseline. Results indicated that paradoxical intention produced greater movement toward targets for clients in Group B when compared both with their baseline and with the performance of Group A following an equal period of gradual exposure.     

Effects of tobacco smoking, schizotypy and number of pre-exposures on latent inhibition in healthy subjects

Latent inhibition is a slowing of learning about a stimulus that when previously experienced had no consequences. This study investigated the effects of tobacco smoking and personality traits on a latent inhibition task. Two-hundred and five healthy adults performed an auditory masking task during which half of them were pre-exposed to bursts of white noise. All subjects were then asked to detect an association of the white noise with a change on a computer screen. Subjects who had heard the white noises before were slower to learn the association than subjects who had not, i.e. they showed latent inhibition. Latent inhibition was stronger when subjects were pre-exposed to 10 rather than 6 bursts of white noise. Latent inhibition was reduced in subjects who smoked tobacco and in non-smoking subjects who scored highly on a schizotypy questionnaire. These two effects were independent. We conclude that tobacco smoking should be taken into account in interpreting the results of human latent inhibition studies.     

Subject strategies in part-whole transfer in free recall

The effect of instructing subjects as to the nature of the relationship between the two lists of a part-to-whole transfer situation has been studied in a number of cases with conflicting results. Some studies have shown that instructions to the subject produce positive transfer, while in others only slight effects from instructions may be noted. Detailed analysis of subject output protocols in a part-to-whole experiment demonstrated that subjects who maintained their List 1 organization showed positive transfer to the whole list. Reanaiysis of several studies in the literature supported the conclusion that subjects who maintain their organization will show positive transfer under these conditions. In a second experiment, it is demonstrated that subjects can be instructed to maintain their List 1 organization during List 2 and that such instruction enhances the amount of positive transfer obtained. The results are viewed as consistent with a hierarchical version of an organization theory for recall performance.     

Backward conditioning in Pavlovian type studies

Authors of almost all learning texts have indicated that unconditional/ stimulus-conditional stimulus (UCS-CS) trials (backward conditioning) utilized in classical conditioning experiments will not result in establishing a conditional response (CR) (excitation). Recently, it has been proposed that backward conditioning can take place although whether UCS-CS trials result in excitation or inhibition has been left unspecified. It is proposed that the diversity of findings can be attributed to inadequate methodology and the use of a classical-instrumental transfer paradigm. When only traditional Pavlovian conditioning studies are examined, the experimental findings suggest that UCS-CS trials will result in inhibition.