Prenatal IV nicotine exposure produces a sex difference in sensorimotor gating of the auditory startle reflex in adult rats

Maternal smoking during pregnancy is associated with auditory processing deficits in children; these effects have been confirmed with animal models of continuous high-dose prenatal nicotine exposure. The present experiments utilized a novel, low-dose, intermittent, intravenous (IV) gestational nicotine exposure model to investigate potential deficits on the preattentive process of sensorimotor gating, as indexed by prepulse inhibition (PPI), in preweanling and adult rat offspring. Pregnant dams received bolus IV injections of nicotine (0.05 mg/kg/injection) 3×/day on gestational days 8-21. Auditory and tactile stimulus modalities were probed with tone and air puff prepulse stimuli, respectively. These prepulse stimuli preceded a 100 dB(A) startle tone by six different interstimulus intervals (ISIs; 0, 8, 40, 80, 120, 4000 ms) to define a curve of response inhibition. The magnitude of PPI increased with age, from 59 to 81% inhibition. Preweanlings (PNDs 14 and 18) and adults (PND 75) gestationally exposed to nicotine exhibited altered startle responding relative to controls, but the nature of the deficit became more localized at later ages. The entire curve of response inhibition in preweanlings exposed to prenatal nicotine (PND 14) was shifted up relative to controls, and notably, did not interact with prepulse stimulus modality, suggesting a generalized increased sensorimotor responsiveness as a function of prenatal nicotine. At PND 18, a shift in the response curve across all ISIs was again noted, but varied as a function of prepulse stimulus modality; the increased sensorimotor responsiveness was specific to the auditory, but not tactile, sensory modality. In adulthood, male and female animals prenatally exposed to nicotine were differentially sensitive to modulation by the ISIs, relative to control male and female animals. Specifically, despite robust PPI, adult females exposed to gestational nicotine were relatively insensitive to changes in ISI from 8 to 120 ms; in contrast, the robust PPI of nicotine-exposed males demonstrated a clear focal point of inhibition at 40 ms. These findings indicate that a low, daily dosing of IV prenatal nicotine produces long-lasting alterations in auditory PPI. An important implication of this research is that “chipping” with smoked-tobacco products during pregnancy may produce enduring changes in sensorimotor processing.     

Assessing appetitive,aversive, and negative ethanol-mediated reinforcement through an immature rat model

The motivational effects of drugs play a key role during the transition from casual use to abuse and dependence. Ethanol reinforcement has been successfully studied through Pavlovian and operant conditioning in adult rats and mice genetically selected for their ready acceptance of ethanol. Another model for studying ethanol reinforcement is the immature (preweanling) rat, which consumes ethanol and exhibits the capacity to process tactile, odor and taste cues and transfer information between different sensorial modalities. This review describes the motivational effects of ethanol in preweanling, heterogeneous non-selected rats. Preweanlings exhibit ethanol-mediated conditioned taste avoidance and conditioned place aversion. Ethanol's appetitive effects, however, are evident when using first- and second-order conditioning and operant procedures. Ethanol also devalues the motivational representation of aversive stimuli, suggesting early negative reinforcement. It seems that preweanlings are highly sensitive not only to the aversive motivational effects of ethanol but also to its positive and negative (anti-anxiety) reinforcement potential. The review underscores the advantages of using a developing rat to evaluate alcohol's motivational effects.     

Responses of primate locus coeruleus neurons to simple and complex sensory stimuli

Single and multiple unit recordings were obtained from locus coeruleus (LC) of unanesthetized, chair-restrained monkeys during presentation of a range of sensory stimuli. Tonic activity was higher during alertness or agitation than during behavioral inattentiveness and drowsiness. Low-level, simple auditory stimuli elicited no response, while more intense stimuli evoked phasic discharges in LC activity. The most pronounced responses were elicited by aversive air puffs and by multi-modal naturalistic stimuli such as interactions with the experimenter. The results suggest that sensory stimuli effective in eliciting LC discharge have specific stimulus attributes. It is proposed that the LC is tuned to specifically respond to stimuli which are conspicuous to that species: stimuli which by their physical or behavioral properties evoke a change in the focus of attention. The LC response would thereby contribute to adaptive behavioral responses to such unexpected imperative stimuli. This hypothesis is consistent with earlier suggestions that the LC contributes to behavioral functions such as vigilance and alarm and provides a rigorous framework for future experiments.     

Interactive processing of timbre dimensions: an exploration with event-related potentials

Abstract Timbre characterizes the identity of a sound source. On psychoacoustic grounds, it has been described as a multidimensional perceptual attribute of complex sounds. Using Garner's interference paradigm, we found in a previous behavioral study that three timbral dimensions exhibited interactive processing. These timbral dimensions acoustically corresponded to attack time, spectral centroid, and spectrum fine structure. Here, using event-related potentials (ERPs), we sought neurophysiological correlates of the interactive processing of these dimensions of timbre. ERPs allowed us to dissociate several levels of interaction, at both early perceptual and late stimulus identification stages of processing. The cost of filtering out an irrelevant timbral dimension was accompanied by a late negative-going activity, whereas congruency effects between timbre dimensions were associated with interactions in both early sensory and late processing stages. ERPs also helped to determine the similarities and differences in the interactions displayed by the different pairs of timbre dimensions, revealing in particular variations in the latencies at which temporal and spectral timbre dimensions can interfere with the processing of another spectral timbre dimension.     

Impulse control under emotion processing: an fMRI investigation in borderline personality disorder compared to non-patients and cluster-C personality disorder patients

Impulsivity is a characteristic syndromal and neurobehavioral feature of borderline personality disorder (BPD). Research suggests an important interaction between high negative emotions and low behavioral inhibition in BPD. However, knowledge about the generalizability across stimulus categories and diagnosis specificity is limited. We investigated neural correlates of hypothesized impaired response inhibition of BPD patients to negative, positive and erotic stimuli, by comparing them to non-patients and cluster-C personality disorder patients. During fMRI scanning, 53 BPD patients, 34 non-patients and 20 cluster-C personality disorder patients completed an affective go/no-go task, including social pictures. BPD patients showed more omission errors than non-patients, independent of the stimulus category. Furthermore, BPD patients showed higher activity in the inferior parietal lobule and frontal eye fields when inhibiting negative versus neutral stimuli. Activity of the inferior parietal lobule correlated positively with the BPD checklist subscale impulsivity. When inhibiting emotional stimuli, BPD patients showed an altered brain activity in the inferior parietal lobe and frontal eye fields, whereas previously shown dysfunctional prefrontal activity was not replicated. BPD patients showed a general responsivity across stimulus categories in the frontal eye fields, whereas effects in the inferior parietal lobe were specific for negative stimuli. Results of diagnosis specificity support a dimensional rather than a categorical differentiation between BPD and cluster-C patients during inhibition of social emotional stimuli. Supported by behavioral results, BPD patients showed no deficiencies in emotionally modulated response inhibition per se but the present findings rather hint at attentional difficulties for emotional information.

     

Perceptual grouping in disorganized schizophrenia

This study evaluated visual perceptual grouping in schizophrenia to test the hypothesis that the disorganization syndrome in schizophrenia is related to a deficit in cognitive coordination. Perceptual grouping was examined with three psychophysically well-controlled tasks in patients with disorganized schizophrenia (n=11), non-disorganized schizophrenia (n=24), psychotic disorders other than schizophrenia (n=31) and non-psychotic psychiatric disorders (n=35). These measures assessed processing of both concurrent and preceding stimulus context. Deficits in perceptual grouping were observed on all three tasks in disorganized schizophrenia patients. Dysfunctional perceptual grouping mechanisms produced both enhanced and impaired task performance suggesting that the pattern of performance observed was the result of a specific deficit in the grouping of stimulus elements. We interpret these data as further support for the hypothesis that the disorganization syndrome in schizophrenia reflects a widespread deficit in the cognitive coordination of contextually related stimuli, leading to dysfunctional grouping of stimulus features in vision, thought and language.     

Impaired engagement of the ventral attentional pathway in ADHD

In the cognitive theories of Attention Deficit Hyperactivity Disorder (ADHD) impaired behavioral adjustment has been linked to a deficit in learning to detect regularities or irregularities in the environment. In the neural level, the P3 component of event-related potential (ERP) is modulated by stimulus probability and has been suggested to index activation of the ventral attention network, which constitutes the reorienting system of the human brain. To explore the cortical basis of late positive ERP components and the engagement of the ventral attentional pathway in ADHD, we used ERP recordings complemented by spatiotemporally sensitive magnetoencephalography (MEG) measurements. We followed the activation evoked by frequent Go and infrequent NoGo stimuli in 10 ADHD adults and 13 control subjects. In the ERP recordings, a prominent positive deflection was detected after the infrequent visual stimuli (late positive component, LPC) in both subject groups. In ADHD adults the difference between the responses evoked by infrequent NoGo and frequent Go stimuli was markedly reduced compared to the control group during the LPC. The MEG recordings revealed that the activation detected during the LPC was localized bilaterally in the posterior temporal cortex. Activation of the left and right temporal regions was enhanced after infrequent NoGo stimuli in both subject groups. In ADHD adults, however, the effect of stimulus frequency was less pronounced. We suggest that the activation in the superior temporal cortices during the LPC reflects the action of ventral attention network. The engagement of this stimulus-driven reorienting system is defective in ADHD.     

Pharmacological treatment options for autism spectrum disorders in children and adolescents

Autism and other pervasive developmental disorders (PDDs) are frequently associated with dysfunctional behaviors and are characterized by deficits in socialization, communication, and behavioral rigidity. Despite the absence of a pharmacological cure for PDDs, many of the dysfunctional, coinciding behaviors may be treated pharmacologically. This article reviews what is known about the efficacy and tolerability of pharmacological interventions for the treatment of children and adolescents suffering from autistic spectrum disorders.     

Long-term behavioral consequences of stress exposure in adolescent versus young adult rats

Adolescence is a developmental time period marked by rapid changes in behavior and brain structure. Stress during adolescence has been shown to cause long-lasting behavioral changes, including increased anxiety- and depression-like behavior, in both rats and humans. These findings have led to the hypothesis that adolescence may be a particularly vulnerable or sensitive period for stress exposure. To investigate this hypothesis, we directly compared the effects of a 3-day stress exposure during either an adolescent (post natal day (PND) 27-29) or adult (PND 72-74) time window on exploratory behavior in male rats, measured 6 weeks post-stress (PND 72 or PND 117). Exploratory behavior was tested in both 'anxiogenic' and 'anxiolytic' environments, using the open field and novel object tests, respectively. We hypothesized that rats stressed as adolescents would show greater behavioral changes than rats stressed as adults. Contrary to our hypothesis, we found a decrease in exploratory behavior in the open-field test in both age groups. Furthermore, the magnitude of difference between stress and age-matched control animals was similar between age groups. In contrast, stress had no effect at either age in the novel object test, a more anxiolytic environment. Older adults showed decreased exploration in the novel object test compared to the younger adults, regardless of stress experience. These results suggest that adolescence is not a sensitive period for the effects of repeated variable stress on exploratory behavior in an anxiogenic environment.     

Effects of stress of postnatal development on corticosterone,serotonin and behavioral changes

Stressful events early in life are associated with later psychiatric disorders. We focused on developmental stage and evaluated changes in the corticosterone and serotonergic systems as well as in later anxiety-related behavioral tests. Stressed male Wistar rats were divided into two groups: stressed from postnatal day 11 (PND 11) to 15 and stressed from PND 16 to 20. The rats were exposed to an elevated open platform. Stress increased corticosterone in both experimental groups. In the hypothalamus, amygdala and hippocampus, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) increased in the rats stressed from PND 11 to 15, and decreased in the rats stressed from PND 16 to 20. In a later behavioral test, rats stressed from PND 11 to 15 traveled shorter distances and tended to spend less time in the center than control rats following restraint stress. There were no significant changes in 5-HT and 5-HIAA in hypothalamus, amygdala and hippocampus after restraint stress in adults. These findings indicate that stress reactions and later effects are different depending on the developmental stage during which the rats were stressed. Stress during the PND 11–15 period may enhance later anxiety-related behaviors without altering 5-HT and 5-HIAA content.     

Resting electrocortical activity in adults with dysfunctional anger: a pilot study

Although dysfunctional anger is not a DMS diagnosis, some individuals present with dysfunctional anger, to the exclusion of other psychiatric disorders, as the primary clinical feature. However, our understanding of the neural basis of dysfunctional anger is limited. Though previous work has examined electroencephalographic (EEG) activity in individuals with high trait anger, and in youth with disorders consistent with dysfunctional anger, no studies have assessed EEG activity in adults with dysfunctional anger. This study examined resting EEG by way of relative power in the beta and alpha bands, as well as absolute frontal and parietal alpha(1/2) asymmetry, in 15 adults with psychiatrist-assessed and psychometrically rated dysfunctional anger (Anger) and 14 control participants (Control). The Anger group had increased overall relative beta(1) power during both eyes-open and closed conditions. Inconsistent with most precedent literature, the Anger group also exhibited greater relative right fronto-cortical activation (alpha(1)-indexed frontal asymmetry) during the eyes-closed condition. This may reflect greater anxious arousal and/or compensatory activation of inhibitory tendencies associated with right frontal activation in individuals with dysfunctional anger. Enhanced beta(1) activity may index greater tonic cortical arousal or a chronic hypervigilant state, which may predispose individuals with dysfunctional anger to over-react to relatively innocuous stimuli.     

A prefrontal ERP involved in decision making during visual duration and size discrimination tasks

Recently, a late positive component (LPCt) with prefrontal dominance was identified in a duration discrimination task as a marker of decision-making processes (Paul et al., 2003). In the present study, LPCt amplitudes and latencies were measured in visual and size discrimination tasks for the purpose of determining the selectivity of this phenomenon. LPCt amplitudes were larger and latencies shorter for longer stimulus pairs, at a time of maximal behavioral performances. Wave amplitudes were also larger for smaller stimuli, but were not directly related to behavioral performances. These results indicate that the LPCt is not specific to temporal discrimination but can reflect more general decision-making processes.     

Cortical evoked potentials and behavioral reactivity to photic stimuli in freely moving rats

Averaged evoked potentials at the visual cortex (VER) were studied in relation to behavioral reactivity to photic stimuli during operant behavior for food reinforcement. The VERs showed highly systematic increases in late components with repetition of the sensory stimuli. Amplitude of late components related inversely to behavioral indices of reactivity, but the correlations between these measures were low to moderate. Control experiments involving other freely moving and curarized animals served to evaluate various behavioral and stimulus factors in the VER changes. The results were interpreted in terms of habituation of ‘arousal reactions’, for which additional supporting data were provided. Electrographic arousal, however, was viewed as a varying substrate of all behavior, which complicates relationships between VERs and any single index of behavioral reactivity to stimuli in freely moving subjects.     

Morphine- and ketocyclazocine-induced analgesia in the developing rat: differences due to type of noxious stimulus and body topography

Patterns of morphine- and ketocyclazocine-induced analgesia in limb withdrawal and tail-flick tests of thermal and mechanical nociception were examined in the preweanling rat. In the forepaw test, morphine was more effective than ketocyclazocine with both thermal and mechanical stimuli. Both drugs first induced analgesia between 3 and 5 days of age. In the tail-flick test, ketocyclazocine-induced analgesia preceded morphine's effects against both thermal and mechanical stimuli by several days. Ketocyclazocine produced robust analgesia between 7 and 10 days of age, while the effects of morphine did not peak until day 14. In the hindpaw, morphine was more effective than ketocyclazocine against a higher intensity mechanical stimulus, while ketocyclazocine was more effective against a lower intensity mechanical stimulus. Morphine-induced analgesia was reversed by lower doses of naloxone than was ketocyclazocine-induced analgesia, regardless of body part tested, against all noxious stimuli. These findings demonstrate differences in morphine- and ketocyclazocine-induced analgesia that are dependent upon age, body topography, stimulus type and intensity and imply different physiologic roles of mu- and chi-opioid receptors in analgesia.     

The influence of stimulus deviance on electrophysiologic and behavioral responses to novel events

This study investigated the role of stimulus deviance in determining electrophysiologic and behavioral responses to "novelty." Stimulus deviance was defined in terms of differences either from the immediately preceding context or from long-term experience. Subjects participated in a visual event-related potential (ERP) experiment, in which they controlled the duration of stimulus viewing with a button press, which served as a measure of exploratory behavior. Each of the three experimental conditions included a frequent repetitive background stimulus and infrequent stimuli that deviated from the background stimulus. In one condition, both background and deviant stimuli were simple, easily recognizable geometric figures. In another condition, both background and deviant stimuli were unusual/unfamiliar figures, and in a third condition, the background stimulus was a highly unusual figure, and the deviant stimuli were simple, geometric shapes. Deviant stimuli elicited larger N2-P3 amplitudes and longer viewing durations than the repetitive background stimulus, even when the deviant stimuli were simple, familiar shapes and the background stimulus was a highly unusual figure. Compared to simple, familiar deviant stimuli, unusual deviant stimuli elicited larger N2-P3 amplitudes and longer viewing times. Within subjects, the deviant stimuli that evoked the largest N2-P3 responses also elicited the longest viewing durations. We conclude that deviance from both immediate context and long-term prior experience contribute to the response to novelty, with the combination generating the largest N2-P3 amplitude and the most sustained attention. The amplitude of the N2-P3 may reflect how much "uncertainty" is evoked by a novel visual stimulus and signal the need for further exploration and cognitive processing.     

L’approche psychologique des troubles anxieux : information, soutien et psychothérapies

Anxiety disorders (panic disorder, generalized anxiety disorders, phobia) are very prevalent and have frequently serious consequences on social, familial and professional adaptation. Their treatments are in some cases based on pharmacotherapy, but in most cases on psychological approaches. In particular, cognitive-behavioral therapies have for a long time demonstrated their efficacy. The behavioral techniques consist on relaxation learning and on exposition to feared stimuli. The cognitive treatments aim to identify the dysfunctional process of thinking and to modify anxiogenic cognitive schemes. Social phobia are frequently treated with group therapy, including social skills training, exposure techniques and cognitive restructuration. These methods have to be applied by trained clinicians, but non-specialized physicians could play three key roles in the treatment process: diagnostic recognition, patients information and orientation towards specific psychological treatment.     

A PREFRONTAL ERP INVOLVED IN DECISION MAKING DURING VISUAL DURATION AND SIZE DISCRIMINATION TASKS

Recently, a late positive component (LPCt) with prefrontal dominance was identified in a duration discrimination task as a marker of decision-making processes (Paul et al., 2003). In the present study, LPCt amplitudes and latencies were measured in visual and size discrimination tasks for the purpose of determining the selectivity of this phenomenon. LPCt amplitudes were larger and latencies shorter for longer stimulus pairs, at a time of maximal behavioral performances. Wave amplitudes were also larger for smaller stimuli, but were not directly related to behavioral performances. These results indicate that the LPCt is not specific to temporal discrimination but can reflect more general decision-making processes.     

Striatal and midbrain connectivity with the hippocampus selectively boosts memory for contextual novelty

The role of contextual expectation in processing familiar and novel stimuli was investigated in a series of experiments combining eye tracking, functional magnetic resonance imaging, and behavioral methods. An experimental paradigm emphasizing either familiarity or novelty detection at retrieval was used. The detection of unexpected familiar and novel stimuli, which were characterized by lower probability, engaged activity in midbrain and striatal structures. Specifically, detecting unexpected novel stimuli, relative to expected novel stimuli, produced greater activity in the substantia nigra/ventral tegmental area (SN/VTA), whereas the detection of unexpected familiar, relative to expected, familiar stimuli, elicited activity in the striatum/globus pallidus (GP). An effective connectivity analysis showed greater functional coupling between these two seed areas (GP and SN/VTA) and the hippocampus, for unexpected than for expected stimuli. Within this network of midbrain/striatal–hippocampal interactions two pathways are apparent; the direct SN–hippocampal pathway sensitive to unexpected novelty and the perirhinal–GP–hippocampal pathway sensitive to unexpected familiarity. In addition, increased eye fixations and pupil dilations also accompanied the detection of unexpected relative to expected familiar and novel stimuli, reflecting autonomic activity triggered by the functioning of these two pathways. Finally, subsequent memory for unexpected, relative to expected, familiar, and novel stimuli was characterized by enhanced recollection, but not familiarity, accuracy. Taken together, these findings suggest that a hippocampal–midbrain network, characterized by two distinct pathways, mediates encoding facilitation and most critically, that this facilitation is driven by contextual novelty, rather than by the absolute novelty of a stimulus. This contextually sensitive neural mechanism appears to elicit increased exploratory behavior, leading subsequently to greater recollection of the unexpected stimulus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

A phenotype of early infancy predicts reactivity of the amygdala in male adults

One of the central questions that has occupied those disciplines concerned with human development is the nature of continuities and discontinuities from birth to maturity. The amygdala has a central role in the processing of novelty and emotion in the brain. Although there is considerable variability among individuals in the reactivity of the amygdala to novel and emotional stimuli, the origin of these individual differences is not well understood. Four-month old infants called high reactive (HR) demonstrate a distinctive pattern of vigorous motor activity and crying to specific unfamiliar visual, auditory and olfactory stimuli in the laboratory. Low-reactive infants show the complementary pattern. Here, we demonstrate that the HR infant phenotype predicts greater amygdalar reactivity to novel faces almost two decades later in adults. A prediction of individual differences in brain function at maturity can be made on the basis of a single behavioral assessment made in the laboratory at 4 months of age. This is the earliest known human behavioral phenotype that predicts individual differences in patterns of neural activity at maturity. These temperamental differences rooted in infancy may be relevant to understanding individual differences in vulnerability and resilience to clinical psychiatric disorder. Males who were HR infants showed particularly high levels of reactivity to novel faces in the amygdala that distinguished them as adults from all other sex/temperament subgroups, suggesting that their amygdala is particularly prone to engagement by unfamiliar faces. These findings underline the importance of taking gender into account when studying the developmental neurobiology of human temperament and anxiety disorders. The genetic study of behavioral and biologic intermediate phenotypes (or 'endophenotypes') indexing anxiety-proneness offers an important alternative to examining phenotypes based on clinically defined disorder. As the HR phenotype is characterized by specific patterns of reactivity to elemental visual, olfactory and auditory stimuli, well before complex social behaviors such as shyness or fearful interaction with strangers can be observed, it may be closer to underlying neurobiological mechanisms than behavioral profiles observed later in life. This possibility, together with the fact that environmental factors have less time to impact the 4-month phenotype, suggests that this temperamental profile may be a fruitful target for high-risk genetic studies.