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PubMed2002

Antidepressant-like activity of VN2222, a serotonin reuptake inhibitor with high affinity at 5-HT1A receptors.

It has been suggested that drugs combining serotonin (5-hydroxytryptamine, 5-HT) transporter blockade and 5-HT1A autoreceptor antagonism could be a novel strategy for a shorter onset of action and higher therapeutic efficacy of antidepressants. The present study was aimed at characterizing the pharmacology of 1-(3-benzo[b]tiophenyl)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propanol (VN2222) a new synthetic compound with high affinity at both the 5-HT transporter and 5-HT1A receptors and devoid of high affinity at other receptors studied, with the only exception of alpha1-adrenoceptors. In keeping with the binding affinity at the 5-HT transporter, VN2222 inhibited 5-HT uptake in vitro both in rat cortical synaptosomes and in mesencephalic cultures and also in vivo when administered locally into the rat ventral hippocampus. After systemic administration, VN2222 exhibited an inverted U-shape effect so the inhibition of [3H]5-HT uptake ex vivo and the increase in 5-HT extracellular levels in microdialysis experiments was observed at low doses of 0.01-0.1 mg/kg whereas higher doses were ineffective. In studies related to 5-HT1A receptor function, 0.01-0.1 microM VN2222 produced a partial inhibition of forskolin-stimulated cAMP formation behaving as a weak agonist of 5-HT1A receptors. In body temperature studies, 5 mg/kg VN2222 produced a mild hypothermic effect in mice, suggesting a weak agonist activity at presynaptic 5-HT1A receptors; much lower doses (0.01-0.5 mg/kg) partially antagonized the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) possibly through 5-HT transporter blockade. In the learned helplessness test in rats, an animal model for antidepressants, 1-5 mg/kg VN2222 reduced significantly the number of escape failures. Consequently, VN2222 is a new compound with a dual effect on the serotonergic system, as 5-HT uptake blocker and 5-HT1A receptor partial agonist, and with a remarkable activity in an animal model of depression with high predictive validity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1979

Holistic versus analytic process models: a reply.

Two classes of stimulus process models are considered in this reply to Dykes and Cooper. It is shown that analytic models which assume that stimuli are initially processed in terms of constituent dimensions do not account for large amounts of published data. It is also shown that the holistic-discriminability model that Dykes and Cooper reject is nonetheless consistent with their results and predicts all of the data for which their analytic model was constructed to account.

Discrimination Learning↗

PubMed1988

Tolerance to morphine in the rat: associative and nonassociative effects.

Two experiments were conducted to examine the impact of dose level and interdose interval (IDI) on the development of tolerance to the analgesic effect of morphine. In Experiment 1, rats were administered a series of low- (5 mg/kg) or high- (30 mg/kg) dose injections of morphine either explicitly paired or unpaired with a distinctive context at a 48-hr IDI. The development of tolerance following this regimen was assessed by shifts in dose-response curves to the right when animals were tested on a tail-flick device in the distinctive context. Only animals that had received morphine paired with the distinctive context were tolerant to morphine; the magnitude of this associative tolerance was a positive function of the level of the conditioning dose. In Experiment 2, rats were exposed to a high dose of morphine (30 mg/kg) either paired or unpaired with a distinctive context at one of two IDIs (24 or 96 hr). Tolerance testing revealed that at the long IDI, only associative tolerance was evident, whereas at the short IDI, tolerance in the unpaired condition was more pronounced with a corresponding decline in the development of associative tolerance. The relevance of these findings for psychological theories of drug tolerance are discussed. The overall pattern of results are consistent with the predictions of an habituation model of drug tolerance.

Animals↗

PubMed2005

A comparative approach to cue competition with one and two strong predictors.

The relative validity effect (Wagner, Logan, Haberlandt, & Price, 1968) demonstrated that a strong cue or cause reduces responding to, or judgments of, a weaker cue or cause. We report two experiments with human subjects using relative validity preparations in which we investigate one- and two-cue competition effects. Previously, we investigated the effect using instrumental and Pavlovian conditioning preparations with rats. In the first experiment, we used a procedure analogous to the animal preparations. In the second experiment, we used a different probabilistic procedure. The results with humans and rats are very similar. In each species we find similar interference with processing the moderate predictor with one or with two strong competitors. These results are not well predicted by most associative models.

Adult↗

PubMed1997

A model of long-term memory storage in the cerebellar cortex: a possible role for plasticity at parallel fiber synapses onto stellate/basket interneurons.

By evoking changes in climbing fiber activity, movement errors are thought to modify synapses from parallel fibers onto Purkinje cells (pf*Pkj) so as to improve subsequent motor performance. Theoretical arguments suggest there is an intrinsic tradeoff, however, between motor adaptation and long-term storage. Assuming a baseline rate of motor errors is always present, then repeated performance of any learned movement will generate a series of climbing fiber-mediated corrections. By reshuffling the synaptic weights responsible for any given movement, such corrections will degrade the memories for other learned movements stored in overlapping sets of synapses. The present paper shows that long-term storage can be accomplished by a second site of plasticity at synapses from parallel fibers onto stellate/basket interneurons (pf*St/Bk). Plasticity at pf*St/Bk synapses can be insulated from ongoing fluctuations in climbing fiber activity by assuming that changes in pf*St/Bk synapses occur only after changes in pf*Pkj synapses have built up to a threshold level. Although climbing fiber-dependent plasticity at pf*Pkj synapses allows for the exploration of novel motor strategies in response to changing environmental conditions, plasticity at pf*St/Bk synapses transfers successful strategies to stable long-term storage. To quantify this hypothesis, both sites of plasticity are incorporated into a dynamical model of the cerebellar cortex and its interactions with the inferior olive. When used to simulate idealized motor conditioning trials, the model predicts that plasticity develops first at pf*Pkj synapses, but with additional training is transferred to pf*St/Bk synapses for long-term storage.

Animals↗

PubMed1994

Predicting community integration after traumatic brain injury with neuropsychological measures.

A neuropsychological test battery was administered to 23 subjects with traumatic brain injury during initial inpatient rehabilitation who were participating in the national Traumatic Brain Injury Model Systems study. Trails B and the Rey Auditory Verbal Learning Test total scores obtained during inpatient rehabilitation were significantly correlated with the Community Integration Questionnaire total score that was administered at one year postinjury. These findings suggest that performances on tests of cognitive speed and flexibility, complex attention, and memory during the acute phase of recovery may be useful for the later prediction of "real world" behavior and psychosocial outcome after one year postinjury.

Adolescent↗

PubMed1994

Artificial intelligence versus logistic regression statistical modelling to predict cardiac complications after noncardiac surgery.

The traditional approach to developing models predictive of cardiac events has been to perform logistic regression (LR) analysis on a variety of potential predictors. An alternative to use an artificial intelligence system called a neural network (NN) which simulates biological intelligence. To evaluate the potential applicability of the latter method, we compared the ability of LR and NN techniques to predict cardiac events after noncardiac surgery. A total of 200 patients (training group) underwent cardiac risk assessment before major noncardiac surgery using 17 clinical parameters and 7 quantitative indices based on dipyridamole-thallium imaging. There were 21 post-operative myocardial infarctions and/or cardiac deaths. Data from the training group were used to develop two predictive models: one based on backward stepwise LR multivariate statistical analysis and the other one using a neural network. Both models were then validated on a second group of 160 consecutive patients also referred for preoperative risk stratification (validation group). The NN consisted of 14 input, 29 hidden, and 1 output neurons and used a back-propagation algorithm (learning rate 0.2, training tolerance 0.5, sigmoid transfer function). The sensitivity, specificity, positive and negative predictive accuracies for the prediction of postoperative events in the validation group of 160 patients were, respectively, 67% (6/9), 82% (124/151), 18% (6/33), and 98% (124/127) for LR, and 67% (6/9), 96% (145/151), 50% (6/12), and 98% (145/148) for the NN, with a difference in specificity which attained statistical significance (p < 0.01). Artificial intelligence may provide a useful alternative to conventional LR statistical analysis for the purpose of preoperative cardiac risk assessment.

Artificial Intelligence↗

PubMed2026

SeqQC-former: A sequence-quality fusion framework for QC-aware review prioritization of candidate somatic SNVs in cancer genomics.

The accurate prioritization of candidate somatic single-nucleotide variants (SNVs) remains a challenge due to the substantial variability in sequencing quality across genomic loci. SeqQC-Former is a sequence-quality fusion framework that integrates the local nucleotide context with read-level quality-control (QC) covariates derived from matched tumor-normal sequencing data. This integration generates QC-aware prioritization scores for the downstream review of candidate variants. Unlike conventional variant callers, SeqQC-Former is designed not to infer biological truth but to support post-calling review and prioritization under heterogeneous sequencing conditions. The framework was trained and evaluated on a SEQC2-derived dataset comprising 89,447 candidate loci, including 1378 positive and 88,069 negative loci. In chromosome-held-out validation, which aims to reduce potential genomic-position leakage, SeqQC-Former demonstrated strong discrimination (AUROC = 0.9479; AUPRC = 0.9448), indicating good generalization to previously unseen chromosomes. Given that the SEQC2-derived labels contain QC-associated information; these results should be interpreted as an evaluation of QC-aware prioritization capability rather than an independent validation of biological variant correctness. Ablation analyses revealed that structured QC covariates provided the dominant predictive signal under the current SEQC2-derived labeling regime. SeqQC-Former achieved a significantly higher AUROC than classical machine-learning baselines, as determined by DeLong's test (p < 0.01). Application to 53,164 glioblastoma variants demonstrated that external predictions were sensitive to QC scaling and threshold selection, underscoring that model outputs should be interpreted as QC-dependent prioritization scores rather than calibrated probabilities or definitive biological classifications. Overall, SeqQC-Former offers a reproducible post-calling QC-aware prioritization framework for large-scale somatic SNV review and underscores the importance of explicitly modeling sequencing-quality information when interpreting structured cancer genomics datasets.

Humans↗

PubMed2004

Modeling the effects of repetitions, similarity, and normative word frequency on old-new recognition and judgments of frequency.

Judgments of frequency for targets (old items) and foils (similar; dissimilar) steadily increase as the number of times a target is studied increases, but discrimination of targets from similar foils does not steadily improve, a phenomenon termed registration without learning (D. L. Hintzman & T. Curran, 1995; D. L. Hintzman, T. Curran, & B. Oppy, 1992). The present experiment explores this phenomenon with words of differing normative word frequency. The retrieving-effectively-from-memory model (REM; R. M. Shifrrin & M. Steyvers, 1997, 1998) predicts that low-frequency words will be better recognized than high-frequency words because low-frequency words have more distinctive memory representations. A corollary of this assumption predicts that the typical recognition word-frequency effect will be disrupted when similar foils are tested. These predictions were confirmed, but to fit both the recognition and the judgment-of-frequency data, the authors used a "dual-process" extension of the REM model.

Attention↗

PubMedDate not supplied

Absence of ketamine effects on memory and other cognitive functions in schizophrenia patients.

Glutamatergic dysfunction may play an important role in both the pathophysiology of schizophrenia, and impaired memory commonly observed in that disorder. NMDA receptor antagonists impair learning/memory in animal models, putatively based on its ability to block long-term potentiation (LTP) in the hippocampus. Although well studied in animal models, research in humans is limited and confounded by administration of NMDA antagonists before the learning experience. Based on presumed glutamatergic dysfunction, it was predicted that the NMDA antagonist ketamine would not effect memory in schizophrenic subjects. Bolus injections of ketamine (0.5 mg/kg) or placebo were given to seven patients with schizophrenia in this double-blind cross-over study. Immediately prior to injection, subjects were administered verbal and figural memory tests. Delayed recalls were obtained 30-45 min postinjection. In order to rule out drug-induced generalized cognitive impairments, other cognitive tasks were administered pre- and postinjection. The results indicate no differences between the drug and placebo conditions for either memory task, and no changes on the other cognitive tasks observed.

Adult↗

PubMed1988

A model of automatic attention attraction when mapping is partially consistent.

A model is described to account for the data of Durso, Cooke, Breen, and Schvaneveldt (1987). On the basis of the relative frequency of an item's presentation as a target, the item develops an automatic tendency to attract attention. When stimuli are then displayed, each calls the attention system to a degree determined by its present strength. We assume that attention eventually drifts to the strongest stimulus (which is then given as a response), but in a time determined inversely by the difference in strength between the two strongest stimuli. A version of this model in which the strengths were freely estimated parameters predicted the various elements of the data with good accuracy. In other versions of the model, strength values were derived from assumptions concerning the learning of automatism. Two of these models, quite different in character, captured the major qualitative features of the data. Further empirical tests of the models are suggested.

Attention↗

PubMed1984

Statistical modeling of clinical intake decisions.

Modeled the intake decisions of four clinicians and a group of clinicians at a community mental health center by principal components-discriminant function analysis. The models of two clinicians and the group-based models withstood replication by the jackknife technique of discriminant analysis. Results showed that clinicians' written notes can be used to predict their decisions. We learned, for example, that the cues that are most important in arriving at intake decisions were therapy history, interview site, level of functioning, diagnosis, and behavioral disturbance.

Adult↗

PubMed2004

Predicting extubation outcome in preterm newborns: a comparison of neural networks with clinical expertise and statistical modeling.

Even though ventilator technology and monitoring of premature infants has improved immensely over the past decades, there are still no standards for weaning and determining optimal extubation time for those infants. Approximately 30% of intubated preterm infants will fail attempted extubation, requiring reintubation and resuming of mechanical ventilation. A machine-learning approach using artificial neural networks (ANNs) to aid in extubation decision making is hereby proposed. Using expert opinion, 51 variables were identified as being relevant for the decision of whether to extubate an infant who is on mechanical ventilation. The data on 183 premature infants, born between 1999 and 2002, were collected by review of medical charts. The ANN extubation model was compared with alternative statistical modeling using multivariate logistic regression and also with the clinician's own predictive insight using sensitivity analysis and receiver operating characteristic curves. The optimal ANN model used 13 parameters and achieved an area under the receiver operating characteristic curve of 0.87 (out-of-sample validation), comparing favorably with multivariate logistic regression. It also compared well with the clinician's expertise, which raises the possibility of being useful as an automated alert tool. Because an ANN learns directly from previous data obtained in the institution where it is to be used, this makes it particularly amenable for application to evidence-based medicine. Given the variety of practices and equipment being used in different hospitals, this may be particularly relevant in the context of caring for preterm newborns who are on mechanical ventilation.

Decision Making↗

PubMed1976

Complementary molecular models of learning and memory.

The functional capabilities of the brain are formally characterizable interms of a finite system along with a memory space which it can manipulate. Two types of learning are possible: (1) modification-based learning, associated with alternate realizations of the finite system; (2) memory-based learning, associated with the assimilation, manipulation, and retrieval of memories. Constructive models which fulfill these conditions and which at the same time operate on the basis of molecular information processing principles have certain general features. We describe these features in terms of two interfaced submodels, the first for the finite system and the second for the memory space. The finite system may be realized by networks of neurons in which the specificity of enzyme molecules controls the nerve impulse. Such a realization is amenable to modification-based learning mediated by processes analogous to those of natural evolution and selective theories of antibody synthesis. The memory space is realizable by networks of neurons in which the conformation of dendritic receptor molecules controls the nerve impulse. In this case certain neurons firing in response to an external input undergo sensitization at the dendrites and in such a way that they are loadable and later callable by reference neurons, thereby allowing for reconstruction of manipulation of the firing pattern associated with this input. The overall construction makes a large number of biochemical, anatomical, physiological, and psychological predictions which are either testable or in good agreement with fact.

Brain↗

PubMed1981

Intention and uncertainty at later stages of childbearing: the United States 1965 and 1970.

While births may be dichotomous, fertility intentions are not inherently so. Intentions are predictions about the future and, as such, are couched in considerable uncertainty. Ignoring this uncertainty hides much of what could be learned from data on fertility intentions. This paper presents a model which allows analysis of the full range of intentions. This paper presents a model which allows analysis of the full range of intentions. After selecting a sample of women in the later stage of childbearing (e.g., those who intend fewer than two additional children) from the 1965 and 1970 National Fertility Studies, it is shown that: (1) substantial portions of women at this stage of the reproductive life cycle were indeed uncertain of their parity-specific intention; (2) this certainty, like more firm intentions, varies by age and parity as the model predicts; and (3) there were significant shifts in the level of certainty between 1965 and 1970. Specifically, while intentions for third, fourth, and fifth births declined, more women "didn't know" if they intended to have another child or not. Among those not intending another child, more seemed uncertain of this intention in 1970 than did comparable women in 1965. In contrast, those intending another child seemed more certain. These changes in intention and uncertainty indicate that the observed decline in intended parity was tentative. Post-1970 evidence suggests that this tentative decline has become an equivocal one.

Adolescent↗

PubMed2004

Evaluation of DNA intercalation potential of pharmaceuticals and other chemicals by cell-based and three-dimensional computational approaches.

To what extent noncovalent chemical-DNA interactions, in particular weak nonbonded DNA intercalation, contribute to genotoxic responses in mammalian cells has not been fully elucidated. Moreover, with the exception of predominantly flat, multiple-fused-ring structures, our ability to predict intercalation ability of novel compounds is nearly completely lacking. Computational programs such as DEREK and MCASE recognize primarily those molecules that can form irreversible covalent adducts with DNA since their learning sets, for the most part, have not been populated by compounds for which a relationship between noncovalent interaction and genotoxicity exists. We describe here a novel three-dimensional (3D) computational DNA-docking model for prediction of DNA intercalative activity of molecules with both classical and nonclassical intercalating structures. The 3D docking results show a remarkable concordance with results obtained from testing these molecules directly in the Chinese hamster V79 cell-based bleomycin amplification system suggesting that either or both of these approaches may have utility in defining noncovalent chemical-DNA interactions. The ability to predict and/or demonstrate cellular DNA intercalation of novel molecules may well provide fresh insights into the nature and mechanistic basis of structurally unexpected genotoxicity observed during safety testing.

Animals↗

PubMed2001

Predicting spontaneous recovery of memory.

Long after a new language has been learned and forgotten, relearning a few words seems to trigger the recall of other words. Neural-network models indicate that this form of spontaneous recovery may result from the storage of distributed representations, which are thought to mediate human memory. Here we use a psychomotor learning task to show that a corresponding effect of spontaneous memory recovery occurs in human subjects.

Humans↗

PubMed2000

Blocking and the detection of odor components in blends.

Recent studies of olfactory blocking have revealed that binary odorant mixtures are not always processed as though they give rise to mixture-unique configural properties. When animals are conditioned to one odorant (A) and then conditioned to a mixture of that odorant with a second (X), the ability to learn or express the association of X with reinforcement appears to be reduced relative to animals that were not preconditioned to A. A recent model of odor-based response patterns in the insect antennal lobe predicts that the strength of the blocking effect will be related to the perceptual similarity between the two odorants, i.e. greater similarity should increase the blocking effect. Here, we test that model in the honeybee Apis mellifera by first establishing a generalization matrix for three odorants and then testing for blocking between all possible combinations of them. We confirm earlier findings demonstrating the occurrence of the blocking effect in olfactory learning of compound stimuli. We show that the occurrence and the strength of the blocking effect depend on the odorants used in the experiment. In addition, we find very good agreement between our results and the model, and less agreement between our results and an alternative model recently proposed to explain the effect.

1-Octanol↗