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Biomedical subjects

M P Paulus

Publications and source records attributed to M P Paulus.

At least 19 recordsLinked to original sources
PubMed2004

Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach.

Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant--methamphetamine, and a mood stabilizer--valproate), with human data (linkage loci from human genetic studies, changes in postmortem brains from patients), as a bayesian strategy of crossvalidating findings. Topping the list of candidate genes, we have DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) located at 17q12, PENK (preproenkephalin) located at 8q12.1, and TAC1 (tachykinin 1, substance P) located at 7q21.3. These data suggest that more primitive molecular mechanisms involved in pleasure and pain may have been recruited by evolution to play a role in higher mental functions such as mood. The analysis also revealed other high-probability candidates genes (neurogenesis, neurotrophic, neurotransmitter, signal transduction, circadian, synaptic, and myelin related), pathways and mechanisms of likely importance in pathophysiology.

Animals↗
PubMed2001

Trait contributions of complex dysregulated behavioral organization in schizophrenic patients.

BACKGROUND: The "temporal architecture" of behavior is a construct that can be used to quantify the structure of behavioral sequences in the temporal domain-for example, by using a two-choice prediction task to investigate how past responses, stimuli, and outcomes influence the decision-making process. Using this task, previous investigations of the temporal architecture of the behavior in schizophrenic patients have identified an increased frequency of alternating highly predictable and highly unpredictable response sequences in the same test session in the same patient. Here, the hypothesis is tested that this dysregulation is stable over time and independent of psychosocial factors and symptomatic fluctuations. METHODS: Ninety-one schizophrenic patients were tested on a 128 trial version of the two-choice prediction task; of those, 58 subjects completed a retest session 40 days later. Three sets of measures were obtained: simple response biases, dynamical entropy, and mutual information functions. These measures were subjected to a factor analysis, and the reliability of the resulting factors was examined. RESULTS: First, three factors were obtained, which quantify 1) the level of dysregulation on this task; 2) the extent to which a win-stay/lose-shift strategy was used; and 3) the amount of simple response perseveration. Second, Crohnbach alpha for these factors was .699, .721, and .458, respectively. Third, there were no significant differences in the level of these factors within individual patients at the two time points. Fourth, neither symptom measures (Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms subscale scores) nor psychosocial or clinical variables (age, gender, illness duration, medication status) were able to predict the level of these factors at test or at retest. CONCLUSIONS: These results support the hypothesis that the fundamental dysregulation of the temporal architecture of behavior in schizophrenic patients is stable across time and independent of symptomatic status. Future studies will examine the heritability of this dysfunction.

Adult↗
PubMed2001

Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists.

Dopamine is known to regulate several behavioral phenomena, including sensorimotor gating and aspects of motor activity. The roles of dopamine D1 and D2 receptors in these behaviors have been documented in the rat literature, but few reports exist on their role in mice. We used dopamine transporter (DAT) (-/-) mice to examine the behavioral consequences of a chronically hyperdopaminergic state, challenging them with the preferential dopamine D2 receptor antagonist raclopride and D1 receptor antagonist SCH23390. At baseline, DAT (-/-) mice exhibited deficient sensorimotor gating as measured by prepulse inhibition (PPI) of the startle response, exhibited nonfocal preservative patterns of locomotion, and were hyperactive in a novel environment. Pretreatment with raclopride significantly increased PPI in the DAT (-/-) mice, whereas SCH23390 had no significant effect. Blockade of D2 receptors did not affect the predominantly straight patterns of motor behavior produced by the DAT (-/-) mice, but antagonism of D1 receptors significantly attenuated the preservative patterns, producing more of a meandering behavior seen in the DAT (+/+) control mice. Both D1 and D2 receptor antagonists decreased the hyperactivity seen in the DAT (-/-) mice. These findings support the role of the D2, but not the D1, receptor in the modulation of PPI in mice. Furthermore, D1 receptor activation appears to be the critical substrate for the expression of preservative patterns of motor behavior, whereas both D1 and D2 receptors appear to regulate the amount of motor activity.

Animals↗
PubMed2001

Prefrontal, parietal, and temporal cortex networks underlie decision-making in the presence of uncertainty.

Decision-making in the presence of uncertainty, i.e., selecting a sequence of responses in an uncertain environment according to a self-generated plan of action, is a complex activity that involves both cognitive and noncognitive processes. Using functional magnetic resonance imaging, the neural substrates of decision-making in the presence of uncertainty are examined. Normal control subjects show a significant activation of a frontoparietal and limbic neural system during a two-choice prediction task relative to a two-choice response task. The most prevalent response strategy during the two-choice prediction task was "win-stay/lose-shift," where subjects will repeat the previous response if it successfully predicted the stimulus and switch to the alternative response otherwise. Increased frequency of responses that are consistent with this strategy is associated with activation in the superior temporal gyrus. In comparison, increased frequency of response inconsistent with win-stay/lose-shift is associated with parietal cortex activation. These results support the hypothesis that subjects use a frontoparietal neural system to establish a contingency based decision-making strategy even in the presence of random reinforcement.

Adult↗
PubMed2001

Strain-specific effects of amphetamine on prepulse inhibition and patterns of locomotor behavior in mice.

Several reports describe substantive behavioral differences between strains of mice both at baseline and in response to pharmacological manipulations. For example, mouse strain differences have been reported in prepulse inhibition (PPI) and patterns of locomotor activity, two behavioral processes that are altered by dopamine (DA) agonists such as amphetamine. Here, we characterized acoustic and tactile startle reactivity, acoustic PPI, and both the amounts and spatial patterns of locomotor activity in C57BL/6J, 129SvEv (129S6), and 129SvJ (129X1) mice at baseline and in amphetamine dose-response studies. Because hearing loss is common in numerous strains of mice, we also assessed cross-modal PPI using a light prepulse with an airpuff startle stimulus. The results establish that these three inbred strains of mice display both intra- and cross-modal PPI, and that amphetamine decreases PPI and startle reactivity in a dose-, sensory modality-, and strain-specific manner. Furthermore, the amount of locomotor activity and the spatial pattern of motor sequences are altered differentially after treatment with amphetamine in C57BL/6J and 129X1 mice, but not in 129S6 mice. Given that amphetamine releases presynaptic DA, these findings are consistent with the role of DA in the modulation of PPI and motor patterns in mice. These findings highlight the importance of selecting appropriate strains of mice for behavioral, pharmacological, and genetic studies.

Acoustic Stimulation↗
PubMed2000

Environmental enrichment and isolation rearing in the rat: effects on locomotor behavior and startle response plasticity.

BACKGROUND: Laboratory rats exhibit behavioral changes that reflect a continuum of early life experience, from isolation-reared to socially reared to enrichment-reared conditions. In this study, we further characterize the behavioral effects of isolation, social, and enriched rearing on locomotor activity, patterns of movement and exploration, startle reactivity, prepulse inhibition (PPI), and habituation in adult rats. METHODS: Male Sprague-Dawley rat pups (21 days old) were housed under enrichment (three per cage with toys and exposure to enriched environments), normal social (three per cage), or isolation (one per cage) conditions. Eight weeks later, locomotor and exploratory behaviors, acoustic startle reactivity, PPI, and habituation were measured in the three groups. RESULTS: Enrichment-reared rats exhibited reduced exploration and rapid habituation of locomotor activity, increased startle reactivity, and normal PPI and startle habituation compared with socially reared controls. Isolation-reared rats exhibited increased exploration and normal habituation of locomotor activity, increased startle reactivity, reduced PPI, and normal startle habituation. CONCLUSIONS: Isolation- and enrichment-reared rats exhibited opposite changes in some behaviors and similar changes in other behaviors. Specifically, rats raised in enriched conditions appear more efficient at assimilating stimuli from their environment than do rats reared in isolation. Nevertheless, both enrichment- and isolation-rearing conditions increased startle reactivity, whereas only isolation rearing led to disruptions of PPI in adulthood. These results suggest that isolation- and enrichment-rearing conditions produce some common and some differential effects on how rats process environmental stimuli. For studies of isolation-rearing effects on PPI, however, the complex and resource-intensive enrichment condition seems to offer few advantages over the normal social condition.

Animals↗
PubMed2000

The genetic liability to stress and postweaning isolation have a competitive influence on behavioral organization in rats.

Rats housed in social isolation postweaning (isolates) show profound behavioral and neurobiological differences when compared to socially housed rats (socials). Fischer rats (F344) relative to Lewis rats are hyperresponsive and significantly more susceptible to stressful stimuli. This investigation tested the hypothesis that the behavioral effects of postweaning isolation are more pronounced in a strain of rats with high susceptibility to stress compared to a strain with low susceptibility to stress. Seventy male Sprague-Dawley, Lewis, and F344 rats were housed individually or in groups at weaning on Day 21 and tested on Day 85 in the Behavioral Pattern Monitor. There was no interaction between strain and postweaning isolation for measures of locomotor activity and exploratory behavior (holepoking). However, the postweaning isolation-induced increase in the frequency of repetitive straight movements, a measure of behavioral organization, was more pronounced in Lewis isolates compared to Sprague-Dawley and F344 isolates. These results do not support the hypothesis that rats with a higher susceptibility to stress show more pronounced changes in behavior following postweaning isolation; instead, increased susceptibility to stress may counteract the repetitive movement patterns induced by social isolation.

Animals↗
PubMed2000

Recurrent erosions of the cornea: epidemiology and treatment.

PURPOSE: To evaluate the epidemiologic characteristics of a large clinical population of patients with recurrent erosions of the cornea. The efficacy of different modalities of treatment was also evaluated. METHODS: A retrospective chart review of all patients with the diagnosis of recurrent corneal erosion treated between January 1990 and December 1998 was performed. RESULTS: Clinically confirmed recurrent erosions were identified in 104 patients. There were 36 males and 68 females. A history of trauma was present in 47 patients (45%), 30 patients (29%) had epithelial basement membrane dystrophy (EBMD), and 18 patients (17%) had both a history of trauma and evidence of EBMD. More than 87% of all erosions occurred on the inferior third of the cornea. Conservative therapy was used as the primary treatment in 52 patients with a recurrence rate of 6%. Corneal stromal micropuncture was performed on 38 patients with a recurrence rate of 40%. Eleven patients had epithelial debridement with a recurrence rate of 18%. Four patients had a superficial keratectomy with a diamond bur with a recurrence rate of 25%. Only one patient had an excimer phototherapeutic keratectomy, and she had a minor recurrence posttreatment. CONCLUSIONS: In our series, the distribution of trauma and EBMD in patients with recurrent erosions of the cornea is roughly equivalent. Conservative therapy was effective in approximately one half of the patients. All surgical treatment modalities were associated with recurrences. Those patients with both EBMD and trauma were more likely to have a recurrence after treatment. More effective treatment modalities for recurrent erosions of the cornea need to be investigated.

Administration, Topical↗
PubMed1999

Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli.

The involvement of dopamine neurotransmission in behavioral responses to novelty is suggested by reports that reward is related to increased dopamine activity, that dopamine modulates exploratory behavior in animals, and that Parkinson's disease patients report diminished responses to novelty. Some studies have reported that polymorphisms of the human dopamine D4 receptor (D4R) gene are associated with personality inventory measures of the trait called "novelty-seeking". To explore a potential role for the D4R in behavioral responses to novelty, we evaluated D4R-knock-out (D4R-/-) and wild-type (D4R+/+) mice in three approach-avoidance paradigms: the open field, emergence, and novel object tests. These three paradigms differ in the degree to which they elicit approach, or exploratory behavior, and avoidance, or anxiety-related behavior. Thus, we used these three tests to determine whether the D4R primarily influences the exploratory or the anxious component of responses to approach-avoidance conflicts. D4R-/- mice were significantly less behaviorally responsive to novelty than D4R+/+ mice in all three tests. The largest phenotypic differences were observed in the novel object test, which maximizes approach behavior, and the smallest phenotypic differences were found in the open field test, which maximizes avoidance behavior. Hence, D4R-/- mice exhibit reductions in behavioral responses to novelty, reflecting a decrease in novelty-related exploration.

Analysis of Variance↗
PubMed1999

The nonlinear, complex sequential organization of behavior in schizophrenic patients: neurocognitive strategies and clinical correlations.

BACKGROUND: Thought disorder is a hallmark of schizophrenia and can be inferred from disorganized behavior. Measures of the sequential organization of behavior are important because they reflect the cognitive processes of the selection and sequencing of behavioral elements, which generate observable and analyzable behavioral patterns. In this context, sequences of choices generated by schizophrenic patients in a two-choice guessing task fluctuate significantly, which reflects an "oscillating dysregulation" between highly predictable and highly unpredictable subsequences within a single test session. In this study, we aimed to clarify the significance of dysregulation by seeing whether demographic, clinical, neuropsychological, and psychological measures predict the degree of dysregulation observed on this two-choice task. METHODS: Thirty schizophrenic patients repeatedly performed a LEFT or RIGHT key press that was followed by a stimulus, which occurred randomly on the left or right side of the computer screen. Thus, the stimulus location had nothing to do with the key press behavior. The range of key press sequence predictabilities as measured by the dynamical entropy was used to quantify the dysregulation of response sequences and reflects the range of fixity and randomness of the responses. A factor analysis was performed and step-wise multiple regression analyses were used to relate the factor scores to demographic, clinical, symptomatic, Wisconsin Card Sorting Test (WCST), and Rorschach variables. RESULTS: The LEFT/RIGHT key press sequences were determined by three factors: 1) the degree of win-stay/lose-shift strategy; 2) the degree of contextual influence on the current choice; and 3) the degree of dysregulation on the choice task. Demographic and clinical variables did not predict any of the three response patterns on the choice task. In contrast, the WCST and Rorschach test predicted performance on various factors of choice task response patterns. CONCLUSIONS: Schizophrenic patients employ several rules, i.e., "win-stay/lose-shift" and "decide according to the previous choice," that fluctuate significantly when generating sequences on this task, confirming that a basic behavioral dysregulation occurs in a single schizophrenic subject across a single test session. The organization or the "temporal architecture" of the behavioral sequences is not related to symptoms per se, but is related to deficits in executive functioning, problem solving, and perceptual organizational abilities.

Adult↗
PubMed1999

Behavioral organization is independent of locomotor activity in 129 and C57 mouse strains.

Assessing locomotor behavior is a standard methodology to characterize the behavioral phenotype of a genetic manipulation. Typically, levels of locomotor activity are measured using various methods that are based on the frequency of photobeam breaks or distance traveled as assessed by video-tracking systems. Locomotor behavior, however, is multi-dimensional and reflects the combined influences of multiple processes. Here, we examine the number of independent dimensions of locomotor behavior in mice based on measures derived from a video-tracking system. In addition, we test the hypothesis that locomotor behavior varies substantially across mouse strains. 84 mice were tested for 30 min in a 41 x 41 cm enclosure. Based on previous investigations in rats, we also assessed the spatial and dynamical aspects of locomotor behavior using the spatial scaling exponent, d, and the dynamical entropy, h. A principal component analysis and a one-way repeated measure ANOVA were conducted. C57 mouse strains differ substantially from 129 mouse strains on almost all measures of locomotor behavior. The principal component analysis revealed that two independent factors influence this set of measures. The first factor reflects the amount or level of locomotor activity, the second factor quantifies the degree of spatial and dynamical organization of behavior. These strain differences and the existence of at least two independent dimensions when measuring locomotor behavior may help to parse the effects of gene manipulations relative to strain differences in mutant mice.

Algorithms↗
PubMed1999

Long-range correlations in choice sequences of schizophrenic patients.

Schizophrenic patients significantly greater than normals exhibit long-range correlations in sequences of choices in a simple binary choice task. Moreover, schizophrenic patients also are significantly less influenced by external stimuli than are normal comparison subjects. These effects are not significantly correlated with each other, suggesting that they do not result from a uniform attentional deficit nor are they due to simple perseverative responding or any other uniform process. The interdependence of responses over many trials suggests that the response history of many previous behavioral responses contributes significantly to the temporal architecture of schizophrenic patients. In agreement with others (Lyon et al., 1994), we find that similar organizational principles apply to physical, economical, or biological systems and seem to play an important role in human psychopathology.

Adult↗
PubMed1998

Differential movement patterns but not amount of activity in unconditioned motor behavior of Fischer, Lewis, and Sprague-Dawley rats.

Histocompatible Fischer 344 and Lewis rats have been shown to differ on a wide variety of behavioral, chemical, and molecular measures. This investigation aimed to clarify strain differences in unconditioned motor behavior with respect to the amount and patterns of movements. Twenty female Fischer 344, Lewis, and Sprague-Dawley were tested in the Behavioral Pattern Monitor for 30 min. The locomotor activity and movement patterns, quantified by counts of photobeam breaks and the spatial scaling exponent, d, were assessed. The level of locomotor activity did not differ significantly between Fischer, Lewis, and Sprague-Dawley rats. In contrast, movement patterns differed significantly between the strains. Specifically, Sprague-Dawley rats exhibited significantly more straight movements than both Fischer and Lewis rats. Moreover, Lewis rats showed significantly more straight movements compared to Fischer rats during the first 10 min in the enclosures. Differences in movement patterns across strains may provide an important behavioral variable to further explore the genetic and developmental aspects of behavior.

Animals↗
PubMed1998

Modulation of phencyclidine-induced changes in locomotor activity and patterns in rats by serotonin.

To test the hypothesis that serotonergic modulation of the effects of phencyclidine (PCP) are due to circuit- rather than receptor-based interactions between glutamatergic and serotonergic systems, multivariate profiles of rat behavior were assessed after treatments with the 5-hydroxytryptamine (5-HT) 5-HT2 receptor antagonist ketanserin (1.0 mg/kg), the 5-HT2 receptor agonist (1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (DOI; 0.27 mg/kg), various doses of PCP (0.75 to 10.125 mg/kg), or combinations thereof. Ketanserin blocked all effects of DOI, but reduced the effects of PCP only on locomotion. Depending on the dose, PCP was observed to increase or decrease locomotion and the roughness of the rats' patterns of locomotion. In any case, DOI always increased the activity and decreased the roughness of locomotor paths in PCP-treated rats. Thus, co-administration of DOI and PCP did not yield a shift in the dose-effect curve for either drug, but instead resulted in a new behavioral profile consistent with a circuit-based dynamic interaction.

Amphetamines↗
PubMed1998

A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders.

BACKGROUND: Investigations of unipolar major depressive disorder (MDD) have focused primarily on major depressive episode remission/recovery and relapse/recurrence. This is the first prospective, naturalistic, long-term study of the weekly symptomatic course of MDD. METHODS: The weekly depressive symptoms of 431 patients with MDD seeking treatment at 5 academic centers were divided into 4 levels of severity: (1) depressive symptoms at the threshold for MDD; (2) depressive symptoms at the threshold for minor depressive or dysthymic disorder (MinD); (3) subsyndromal or subthreshold depressive symptoms (SSDs), below the thresholds for MinD and MDD; and (4) no depressive symptoms. The percentage of weeks at each level, number of changes in symptom level, and medication status were analyzed overall and for 3 subgroups defined by mood disorder history. RESULTS: Patients were symptomatically ill in 59% of weeks. Symptom levels changed frequently (1.8/y), and 9 of 10 patients spent weeks at 3 or 4 different levels during follow-up. The MinD (27%) and SSD (17%) symptom levels were more common than the MDD (15%) symptom level. Patients with double depression and recurrent depression had more chronic symptoms than patients with their first lifetime major depressive episode (72% and 65%, respectively, vs 46% of follow-up weeks). CONCLUSION: The long-term weekly course of unipolar MDD is dominated by prolonged symptomatic chronicity. Combined MinD and SSD level symptoms were about 3 times more common (43%) than MDD level symptoms (15%). The symptomatic course is dynamic and changeable, and MDD, MinD, and SSD symptom levels commonly alternate over time in the same patients as a symptomatic continuum of illness activity of a single clinical disease.

Adult↗
PubMed1998

Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse.

BACKGROUND: The study tested whether level of recovery from major depressive episodes (MDEs) predicts duration of recovery in unipolar major depressive disorder (MDD) patients. METHODS: MDD patients seeking treatment at five academic centers were followed naturalistically for 10 years or longer. Patients were divided on the basis of intake MDE recovery into residual depressive symptoms (SSD; N=82) and asymptomatic (N=155) recovery groups. They were compared on time to first episode relapse/recurrence, antidepressant medication, and comorbid mental disorders. Recovery level was also compared to prior history of recurrent MDEs ( > 4 lifetime episodes) as a predictor of relapse/recurrence. RESULTS: Residual SSD compared to asymptomatic recovery patients relapsed to their next MDE > 3 times faster (median=68 vs. 23 weeks) and to any depressive episode > 5 times faster (median=33 vs. 184 weeks). Residual SSD recovery status was significantly associated with early episode relapse (OR=3.65) and was stronger than history of recurrent MDEs (OR=1.64). Rapid relapse in the SSD group could not be attributed to higher comorbidity or lower antidepressant treatment. LIMITATIONS: Although inter-rater agreement on weekly depressive symptom ratings was very high (ICC > 0.88), some error may exist in assigning recovery levels. Antidepressant treatments were recorded, but were not controlled. CONCLUSIONS: MDE recovery is a powerful predictor of time to episode relapse/recurrence. Residual SSD recovery is associated with very rapid episode relapse which supports the idea that SSD is an active state of illness. Asymptomatic recovery is associated with prolonged delay in episode recurrence. These findings of this present study have important implications for the goals of treatment of MDD and for defining true MDE recovery.

Adult↗
PubMed1998

Isolation rearing affects sequential organization of motor behavior in post-pubertal but not pre-pubertal Lister and Sprague-Dawley rats.

OBJECTIVE: Dopaminergic and serotonergic modulation potently influences the sequential organization of rat movements in a simple unconditioned motor paradigm. Rats reared in social isolation post-weaning differ profoundly from their socially reared litter mates on behavioral, neurochemical, and neuroanatomical measures. This investigation examined (1) whether social isolation significantly affects the sequential organization of rat movements, (2) whether these changes occur at different ages, and (3) whether these changes differ across strains. METHOD: male Lister and Sprague Dawley rats reared in isolation post-weaning and socially reared controls were tested at 2 and 8 weeks post-weaning, in the Behavioral Pattern Monitor for 30-min sessions. The amount of activity and the spatial patterns of movements as measured by both the spatial scaling exponent and the fluctuation spectrum of local spatial scaling exponents were assessed in 10-min intervals. RESULTS: Habituation of locomotor activity was significantly attenuated in isolation reared rats during the 30-min sessions irrespective of strain. Spatial patterns of movements were significantly affected by isolation rearing in movements in post-pubertal but not pre-pubertal Lister and Sprague-Dawley rats. The spatial scaling exponent and the fluctuation spectrum analysis revealed a shift towards straight, distance-covering, and repetitive movements rather than a complex re-organization of the behavioral repertoire. CONCLUSIONS: Isolation rearing profoundly affects the sequential organization of movements in post-pubertal rats, suggesting that emerging behavioral dysfunctions parallel developmentally those found in patients with schizophrenia.

Animals↗