Search

The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. Rats with a loss of function mutation in the Cntnap2 gene show increased acoustic startle response (ASR) and decreased prepulse inhibition (PPI). The neural basis of this altered auditory processing in Cntnap2 knock-out rats is currently unknown. Auditory brainstem recordings previously revealed no differences between the genotypes. The next step is to investigate brainstem structures outside of the primary auditory pathway that mediate ASR and PPI, which are the pontine reticular nucleus (PnC) and pedunculopontine tegmentum (PPTg), respectively. Multi-unit responses from the PnC and PPTg in vivo of the same rats revealed sex-specific effects of loss of CASPR2 expression on PnC activity, but no effects on PPTg activity. Female Cntnap2

This study develops a fear-potentiated startle paradigm (FPS) and a machine learning approach to accurately predict PTSD symptoms using electrogram data. A three-phase fear-potentiated startle paradigm was designed to assess the conditioning, generalization, and extinction of fear. Electrooculogram and electrocardiogram signals were collected during the FPS. A total of 1107 Chinese firefighters participated in the study. The Chinese version PCL-C was administered to all subjects. A cutoff of 38 or higher is used to indicate PTSD symptoms. Electrogram features were extracted and selected to build a machine learning model to classify individuals. The machine learning model was 5-fold cross validated. The importance of the selected features was calculated. Classification performance metrics were evaluated for the machine learning model. The machine learning model can identify firefighters with a PCL-C score of 38 or above with sensitivity and specificity both above 0.85 when 5-fold cross validated on a 1107-person sample. The area under the receiver operating characteristic curve of the model is 0.93. Features related to fear generalization are found to be the most important. The proposed fear-potentiated startle paradigm and machine learning approach can accurately predict PTSD symptoms in Chinese firefighters, which can improve the screening and diagnosis of PTSD.

Data availability statement: The data that support the findings of this study are available from the corresponding author [LN], upon reasonable request. Footnotes: Rights retention strategy: For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. Copyright © The Author(s) 2022. Background: Prepulse-induced startle modulation occurs when a weak sensory stimulus (‘prepulse’) is presented before a startling sensory stimulus (‘pulse’), producing an inhibited (Prepulse Inhibition, PPI) or facilitated (Prepulse Facilitation, PPF) startle response. We recently identified several gaps and outlined future lines of enquiry to enable a fuller understanding of the neurobiology of PPI and PPF in healthy and clinical populations. However, before embarking on these studies, it is important to consider how task and population characteristics affect these phenomena in healthy humans. Methods: We examined PPI and PPF in separate tasks, with counterbalanced task order across participants in one session, using a range of stimulus onset asynchronies (SOAs), in 48 healthy adults (23 men, 25 women; 10 hormonal contraceptive users) to determine which SOAs produce the strongest PPI and PPF and also explored how sex and hormonal contraception might influence PPI and PPF under these experimental conditions. Results: Both PPI and PPF were affected by SOA, with greatest PPI observed at 60 and 120 ms, and greatest PPF at 4500 and 6000 ms. PPI was influenced by sex (more PPI in men than women) and hormonal contraception, whereas PPF was affected by task order (greater PPF when the PPF task followed, rather than preceded, the PPI task). Conclusions: Our findings indicate that studies of PPI and PPF need to consider, not only sex and hormonal status of study participants, but also task characteristics and presentation order to reduce variance and increase replicability across studies. Lido CTP Unilever; Biotechnology and Biological Sciences Research Council (BBSRC).

Borderline personality disorder (BPD) is characterized by greater intensity of reactions to unpleasant emotional cues and a slower-than-normal return of these responses to baseline. Habituation is defined as decreased response to repeated stimulation. Affect-modulated startle (AMS), a translational psychophysiological approach, is mediated by the amygdala and used to study emotion processing in both humans and animals. This is the first study to examine the specificity of habituation anomalies in BPD during passive emotional and neutral picture processing.A total of 90 participants were studied: patients with BPD (n = 35), patients with schizotypal personality disorder (n = 26; included as a psychopathological comparison group), and healthy control subjects (n = 29). Participants received rigorous clinical assessments, and patients were unmedicated. AMS was examined during a series of intermixed unpleasant, neutral, and pleasant pictures.Compared with the other groups, patients with BPD showed greater overall AMS during unpleasant pictures and prolonged habituation of startle amplitude during unpleasant pictures from early to later trials. The groups did not differ in AMS during neutral or pleasant pictures or self-reported picture valence. Among the patients with BPD, prolonged habituation to unpleasant pictures was associated with greater symptom severity and suicidal/self-harming behavior.These findings 1) indicate that abnormal processing of and habituation to unpleasant pictures is observed in BPD but not schizotypal personality disorder, suggesting that these deficits are not simply characteristics of personality disorders in general; 2) are consistent with studies showing deficient amygdala habituation to unpleasant pictures in BPD; and 3) have significant implications for clinical assessment and treatment of BPD, e.g., alternative therapies for BPD such as gradual exposure to unpleasant emotional stimuli or amygdala neurofeedback may aid habituation deficits.

Hyperekplexia is a rare disorder characterized by exaggerated startle responses to unexpected sensory stimuli, recurrent apneas, and stiffness. Only few studies have been published on this disorder in populations with high rates of consanguinity.We retrospectively reviewed Saudi patients with genetically confirmed hereditary hyperekplexia using a standard questionnaire that was sent to nine major referral hospitals in Saudi Arabia.A total of 22 Saudi patients (11 males, 11 females) from 20 unrelated families who had hereditary hyperekplexia were included. Based on molecular studies, they were classified into different subtypes: SLC6A5 variant (12 patients, 54.5%), GLRB variant (seven patients, 31.8%), and GLRA1 variant (three patients, 13.7%). All patients were homozygous for the respective causal variant. The combined carrier frequency of hereditary hyperekplexia for the encountered founder mutations in the Saudi population is 10.9 per 10,000, which translates to a minimum disease burden of 13 patients per 1,000,000.Our study provides comprehensive epidemiologic information, prevalence figures, and clinical characteristics of a large cohort of patients with hereditary hyperekplexia.

Intolerance of uncertainty (IU) is a key transdiagnostic feature of internalizing psychopathology. An increasing body of research suggests that IU is associated with increased psychophysiological reactivity in anticipation of unpredictable threat. However, most studies examining the psychophysiological correlates of IU have been conducted in adults. There is a critical need to understand the relationship between IU and psychophysiological reactivity in anticipation of unpredictable threat during adolescence, a key developmental period associated with increased exploration of situations with uncertain outcomes. Thus, the present study examined the association between (1) youth IU and (2) parental IU (as an indicator of risk) in relation to youth defensive motivation (startle reflex) and attention (startle probe N100 and P300) in anticipation of unpredictable threat.The sample included 193 13 to 22-year-old (M = 17.33, SD = 1.97) females and a biological parent. Participants and their parent completed a self-report measure of prospective and inhibitory IU. Youth startle potentiation, probe N100 enhancement, and probe P300 suppression (indicating increased attention to threat) were measured in anticipation of predictable and unpredictable threat.Youth prospective IU and inhibitory IU were not related to youth psychophysiological reactivity to predictable or unpredictable threat. Greater parental prospective IU was associated with greater youth startle potentiation and probe N100 enhancement in anticipation of unpredictable threat.The present study suggests that parental IU, but not concurrent IU, is associated with heightened defensive motivation and attentional engagement in anticipation of unpredictable threat in youth.

Intolerance of uncertainty (IU) represents a transdiagnostic risk factor for internalizing psychopathology. However, little is known regarding its psychophysiological correlates. IU is thought to render individuals hypersensitive to threatening events, even if the occurrence probability is low. To test this, we recruited 90 students who completed two NPU-threat tests separating temporal unpredictability from probabilistic unpredictability (i.e., probability of occurrence): First, a NPU version in which the timing of threat (i.e., shock) was either predictable or unpredictable but the shock probability was 100 % in each trial. Second, a probabilistic NPU version in which the timing of the shock was also either predictable or unpredictable, but the shock probability was 33 % in each trial. Startle reflex, event-related potentials N1 and P3 locked to auditory startle probes, and anxiety ratings were analyzed. As expected, temporally unpredictable threat modulated startle, N1, and anxiety ratings. IU predicted increased startle to lower shock probability, regardless of the temporal predictability. No evidence emerged for IU affecting N1 or P3. However, IU predicted anxiety ratings to threat conditions regardless of temporal or probabilistic predictability. Individual differences in IU shape startle responses to eventual threat: IU increases automatic defensive responding to unpredictable and potentially threatening situations if the threat probability is low. Individuals with higher IU may tend to “err on the side of caution” with a mismatch between physiological preparation and threat probability, such that the effects of IU are particularly observable in low threat probability conditions.

Fear memories are important for survival and are implicated in the etiology of fear disorders such as Post Traumatic Stress Disorder (PTSD). Fear memories are well studied pre-clinically and sex differences in rodent fear expression have been reported: females tend to freeze less than males. Whether this is a difference in fear learning or expression is debated. We aimed to differentiate between these possibilities with a task that allowed female rats to express fear memory by moving, rather than freezing. We assessed fear extinction after contextual fear conditioning in the isolated Shock Arm of a Y-maze in female and male rats by either placing them back in the isolated Shock Arm (Fear Extinction in the Shock Context) or allowing them to move freely in the Y-maze during extinction training and enter/avoid the Shock Arm (Avoidance Extinction). We confirmed that female rats freeze less than males during fear extinction in both settings. During Avoidance Extinction, however, both sexes had similar avoidance of the Shock Context, showing comparable fear memory and extinction. Additionally, female rats made more entries into the non-shock arms. Thus, female and male rats have similar fear learning but females express it with an active motor response. Furthermore, female rats also exhibited an active motor response under other anxiogenic conditions (Elevated Plus Maze) and had higher reactivity (Acoustic Startle Response) but not when fear-eliciting stimuli were present: cat hair and foot-shock. In summary, female rats have an active motor response to anxiogenic stimuli which we termed 'Anxioescapic' behavior strategy.

Intolerance of uncertainty is a transdiagnostic risk factor for fear-related disorders and is associated with higher levels of anxiety in children and adolescents. It is unclear how uncertainty relates to development of psychopathology in children who have experienced trauma in early life. The present study used a fear-potentiated startle paradigm in children to examine associations between uncertainty (assessed as unawareness of a change in reinforcement during fear extinction) and symptoms of anxiety and posttraumatic stress disorder (PTSD), as well as startle potentiation to threat and safety cues. Results showed that unaware children had strong positive associations between trauma exposure and PTSD symptoms, whereas aware children did not. Uncertainty interacted with anxiety in that children who were both unaware and had higher anxiety displayed higher fear-potentiated startle to safety cues and did not show discrimination between threat and safety during fear conditioning. These results suggest that anxious children who persist in associating a threat cue with an aversive event during extinction, after repeated presentations of the no longer reinforced conditioned stimulus, may express psychophysiological phenotypes related to PTSD.

Purpose: The StartReact effect, whereby movements are elicited by loud, startling acoustic stimuli (SAS), allows the evaluation of movements when initiated through involuntary circuitry, before auditory feedback. When StartReact is applied during poststroke upper extremity movements, individuals exhibit increased muscle recruitment, reaction times, and reaching distances. StartReact releases unimpaired speech with similar increases in muscle recruitment and reaction time. However, as poststroke communication disorders have divergent neural circuitry from upper extremity tasks, it is unclear if StartReact will enhance speech poststroke. Our objective is to determine if (a) StartReact is present in individuals with poststroke aphasia and apraxia and (b) SAS exposure enhances speech intelligibility. Method: We remotely delivered startling, 105-dB white noise bursts (SAS) and quiet, non-SAS cues to 15 individuals with poststroke aphasia and apraxia during repetition of six words. We evaluated average word intensity, pitch, pitch trajectories, vowel formants F1 and F2 (first and second formants), phonemic error rate, and percent incidence of each SAS versus non–SAS-elicited phoneme produced under each cue type. Results: For SAS trials compared to non-SAS, speech intensity increased (∆ + 0.6 dB), speech pitch increased (∆ + 22.7 Hz), and formants (F1 and F2) changed, resulting in a smaller vowel space after SAS. SAS affected pitch trajectories for some, but not all, words. Non-SAS trials had more stops (∆ + 4.7 utterances) while SAS trials had more sustained phonemes (fricatives, glides, affricates, liquids; ∆ + 5.4 utterances). SAS trials had fewer distortion errors but no change in substitution errors or overall error rate compared to non-SAS trials. Conclusions: We show that stroke-impaired speech is susceptible to StartReact, evidenced by decreased intelligibility due to altered formants, pitch trajectories, and articulation, including increased incidence of sounds that could not be produced without SAS. Future studies should examine the impact of SAS on voluntary speech intelligibility and clinical measures of aphasia and apraxia.

Fear is a phasic state of apprehension to an imminent threat, whereas anxiety is a more sustained state of expecting a potential threat leading to tension and worry. The NPU-threat test is a laboratory startle paradigm allowing a reliable and valid assessment of both, fear- and anxiety-potentiated reactions. It is suggested to differentiate between anxiety disorders, but little is known on associations with everyday life experiences of cognitive-emotional processes regarding anxiety in non-clinical samples. In the present project, the NPU-threat test was applied in three studies with (1) unselected healthy individuals, (2) participants with extreme manifestations of trait anxiety (low vs. high) and (3) individuals preparing for a high-stakes exam. Self-reported states of emotionality and worry were assessed during a four-day ambulatory assessment (AA). Overall, NPU-threat test measures did not significantly differ between studies, while the AA dependent measures were sufficiently sensitive to capture differences between groups. However, there was no significant association between psychophysiological measures of the NPU-threat test and AA state measures across participants. In participants recruited for low vs. high trait anxiety we found an association with AA worry and emotionality, but no interaction with potentiated startle. The present findings do not support the idea of a link between our laboratory biomarker and adaptive regulation of cognitive-emotional states in everyday life in healthy individuals. We speculate that an association between laboratory physiological measures and everyday experience of anxious states may be detectable in clinical samples.

Recent studies suggest that impaired glutathione synthesis and distorted dopaminergic transmission are important factors in the pathophysiology of schizophrenia. In the present study, on the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, L-buthionine-(S,R)- sulfoximine (BSO, 3.8 or 7.6 mmol/kg), and the dopamine uptake inhibitor, GBR 12,909 (5 mg/kg) alone or in combination, and prepulse inhibition of the acoustic startle response (PPI) was evaluated in adult 90-day-old rats. Moreover, the monoamine levels in the cortex and hippocampus of 16-day-old rats or 91-day-old rats were measured. The present results showed that administration of BSO at 3.8 mmol/kg led to a decreasing tendency in PPI for all tested prepulse intensities. In contrast, a combined treatment with BSO in both studied doses and GBR 12,909 did not induce significant deficits in PPI. Moreover, the results of biochemical studies indicated that treatment with BSO or GBR 12,909 alone induced a weak increase in the activity of dopaminergic, serotonergic, and noradrenergic systems in the frontal cortex and hippocampus of 16-day-old rats and 91-day-old rats. However, the combined administration of both substances allowed for maintaining the normal activity of monoaminergic systems in the rat brain. The most significant changes in the functioning of monoaminergic systems were observed in the frontal cortex of 16-day-old rats. Therefore, it seems that the frontal cortex of rat puppies is most sensitive to glutathione deficiencies resulting in increased oxidative stress in neurons. As a result, it can lead to cognitive and memory impairment.

When pain persists beyond healing time and becomes a "false alarm" of bodily threat, protective strategies, such as avoidance, are no longer adaptive. More specifically, generalization of avoidance based on conceptual knowledge may contribute to chronic pain disability. Using an operant robotic-arm avoidance paradigm, healthy participants (N = 50), could perform more effortful movements in the threat context (eg, pictures of outdoor scenes) to avoid painful stimuli, whereas no pain occured in the safe context (eg, pictures of indoor scenes). Next, we investigated avoidance generalization to conceptually related contexts (ie, novel outdoor/indoor scenes). As expected, participants avoided more when presented with novel contexts conceptually related to the threat context than in novel exemplars of the safe context. Yet, exemplars belonging to one category (outdoor/indoor scenes) were not interchangeable; there was a generalization decrement. Posthoc analyses revealed that contingency-aware participants (n = 27), but not non-aware participants (n = 23), showed the avoidance generalization effect and also generalized their differential pain-expectancy and pain-related fear more to novel background scenes conceptually related to the original threat context. In contrast, the fear-potentiated startle response was not modulated by context. PERSPECTIVE: This article provides evidence for contextual modulation of avoidance behavior and its generalization to novel exemplars of the learned categories based on conceptual relatedness. Our findings suggest that category-based generalization is a plausible mechanism explaining why patients display avoidance behavior in novel situations that were never directly associated with pain. ispartof: The Journal of Pain vol:23 issue:4 pages:1-12 ispartof: location:United States status: Published online

Background: Fear conditioning and extinction are well-characterized cross-species models of fear-related posttraumatic stress disorder (PTSD) symptoms, and recent animal data suggest that 3,4-methylenedioxymethamphetamine (MDMA) enhances fear extinction retention. Aims: This study investigated the effect of MDMA on fear learning, extinction training, and retention in healthy humans. Methods: The study involved a randomized placebo-controlled, two-group, parallel design trial in a sample of healthy adults, age 21–55 recruited from a major metropolitan area. The experimental paradigm included a fear acquisition session followed by an extinction training session 24 hours later, and 2 hours after study drug administration. Fear extinction retention was measured 48 hours after extinction training. Participants ( N = 34; 70.6% male and 29.4% female) were randomly assigned in 1:1 ratio to 100 mg MDMA or placebo. All randomized participants completed the trial and were included in primary analyses. Safety was monitored via adverse events and vital signs. MDMA was well-tolerated with no serious adverse events. Results: Results indicated a significant main effect of session between extinction training and retention with no significant group differences. Significantly more participants in the MDMA group retained extinction learning compared to the placebo group (χ2 = 7.29, p = 0.007). Conclusion: Although we did not observe the hypothesized facilitation of extinction retention, the findings from this initial human trial provide compelling rationale to continue to explore the potential for MDMA to impact extinction retention. Clinical Trials Registry Name and Identifier: Evaluation of MDMA on Startle Response (NCT0318176) https://clinicaltrials.gov/ct2/show/NCT03181763?term = MDMA&draw = 2&rank = 9

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

Latah is a culture-specific syndrome characterized by exaggerated startle response, echolalia, palilalia, echopraxia, coprolalia, forced obedience and involuntary vocalization in response to startle. Latah is stimulus-induced and is associated with behavior and psychiatric features. The aim of this review is to provide a comprehensive description on latah from a regional perspective based on previous literature and clinical experiences and highlight the clinical characteristics of latah from a movement disorders perspective. The pathophysiology of latah is complex and poorly understood although psychological stressors have been implicated. In view of the distressing psychosocial impact of latah, this neuropsychiatric startle syndrome warrants further studies to understand the pathophysiology and identify the appropriate treatments.

Cross-modal plasticity occurs when the function of remaining senses is enhanced following deprivation or loss of a sensory modality. Auditory neural responses are enhanced in the auditory cortex, including increased sensitivity and frequency selectivity, following short-term visual deprivation in adult mice (Petrus et al. Neuron 81:664-673, 2014). Whether or not these visual deprivation-induced neural changes translate into improved auditory perception and performance remains unclear. As an initial investigation of the effects of adult visual deprivation on auditory behaviors, CBA/CaJ mice underwent binocular enucleation at 3-4 weeks old and were tested on a battery of learned behavioral tasks, acoustic startle response (ASR), and prepulse inhibition (PPI) tests beginning at least 2 weeks after the enucleation procedure. Auditory brain stem responses (ABRs) were also measured to screen for potential effects of visual deprivation on non-behavioral hearing function. Control and enucleated mice showed similar tone detection sensitivity and frequency discrimination in a conditioned lick suppression test. Both groups showed normal reactivity to sound as measured by ASR in a quiet background. However, when startle-eliciting stimuli were presented in noise, enucleated mice showed decreased ASR amplitude relative to controls. Control and enucleated mice displayed no significant differences in ASR habituation, PPI tests, or ABR thresholds, or wave morphology. Our findings suggest that while adult-onset visual deprivation induces cross-modal plasticity at the synaptic and circuit levels, it does not substantially influence simple auditory behavioral performance.

The underlying mechanisms of trauma-related disorders are challenging to discover and the disorders are difficult to treat, in part due to the complex and varied expressions of response to traumatic stress. These challenges will be easier to overcome as more is understood about the variability in response to trauma. Incorporating assessment of variability into animal models of traumatic stress may allow better translation to clinical research and treatment development. In this study, we characterized variability in behavioral responses following traumatic stress exposure using a predator exposure (PE) animal model. Elevated plus maze (EPM) and acoustic startle response (SR) were used to study avoidance and arousal symptoms in male Sprague-Dawley rats. Behavioral data were compared between control (

Converging lines of evidence suggest that autonomic and nociceptive pathways linked with the locus coeruleus are disrupted in complex regional pain syndrome (CRPS). To investigate this, pupillary dilatation to arousal stimuli (which reflects neural activity in the locus coeruleus) and pupillary reflexes to light were assessed in a cross-sectional study of 33 patients with CRPS. Moderately painful electrical shocks were delivered to the affected or contralateral limb and unilateral 110 dB SPL acoustic startle stimuli were delivered via headphones. To determine whether the acoustic startle stimuli inhibited shock-induced pain, startle stimuli were also administered bilaterally 200 ms before or after the electric shock. The pupils constricted briskly and symmetrically to bright light (500 lux) and dilated symmetrically in dim light (5 lux). However, the pupil on the CRPS-affected side was smaller than the contralateral pupil before and after the delivery of painless and painful arousal stimuli. Auditory sensitivity was greater on the affected than unaffected side but acoustic startle stimuli failed to inhibit shock-induced pain. Together, these findings suggest that neural activity in pathways linked with the locus coeruleus is compromised on the affected side in patients with CRPS. This may contribute to autonomic disturbances, auditory discomfort and pain. Perspective: The locus coeruleus is involved not only in modulation of pain but also regulates sensory traffic more broadly. Hence, fatigue of neural activity in the ipsilateral locus coeruleus might not only exacerbate pain and hyperalgesia in CRPS but could also contribute more generally to hemilateral disturbances in sensory processing.

Background Nanoparticles (NPs) are increasingly incorporated in everyday products. To investigate the effects of early life exposure to orally ingested TiO2 NP, male and female Sprague–Dawley rat pups received four consecutive daily doses of 10 mg/kg body weight TiO2 NP (diameter: 21 ± 5 nm) or vehicle control (water) by gavage at three different pre-weaning ages: postnatal day (PND) 2–5, PND 7–10, or PND 17–20. Cardiac assessment and basic neurobehavioral tests (locomotor activity, rotarod, and acoustic startle) were conducted on PND 20. Pups were sacrificed at PND 21. Select tissues were collected, weighed, processed for neurotransmitter and metabolomics analyses. Results Heart rate was found to be significantly decreased in female pups when dosed between PND 7–10 and PND 17–20. Females dosed between PND 2–5 showed decrease acoustic startle response and when dosed between PND 7–10 showed decreased performance in the rotarod test and increased locomotor activity. Male pups dosed between PND 17–20 showed decreased locomotor activity. The concentrations of neurotransmitters and related metabolites in brain tissue and the metabolomic profile of plasma were impacted by TiO2 NP administration for all dose groups. Metabolomic pathways perturbed by TiO2 NP administration included pathways involved in amino acid and lipid metabolism. Conclusion Oral administration of TiO2 NP to rat pups impacted basic cardiac and neurobehavioral performance, neurotransmitters and related metabolites concentrations in brain tissue, and the biochemical profiles of plasma. The findings suggested that female pups were more likely to experience adverse outcome following early life exposure to oral TiO2 NP than male pups. Collectively the data from this exploratory study suggest oral administration of TiO2 NP cause adverse biological effects in an age- and sex-related manner, emphasizing the need to understand the short- and long-term effects of early life exposure to TiO2 NP.

The neurotransmitter serotonin has been critically implicated in the pathogenesis of several mental disorders. The serotonin transporter (5-HTT) is a key regulator of serotonergic neurotransmission and its genetic variability is associated with increased risk of psychopathology. One well known polymorphic locus in the 5-HTT gene affecting its expression is a tandem repeat in the promoter region (5-HTTLPR). It has been reported that 5-HTT is functionally coupled with the neuronal nitric oxide synthase (NOS1 or nNOS), an enzyme catalyzing the production of nitric oxide (NO). We have previously demonstrated that a tandem repeat polymorphism in the promoter of NOS1 exon 1f (Ex1f-VNTR) is associated with sensorimotor gating, a marker of inhibitory processing and a well established endophenotype of several neuropsychiatric disorders. Here we investigated the combined genetic effects of NOS1 Ex1f-VNTR and 5-HTTLPR on sensorimotor gating, measured by prepulse inhibition (PPI) of the acoustic startle reflex, in 164 healthy adults. We found no evidence for the interaction between NOS1 Ex1f-VNTR and 5-HTTLPR on PPI. PPI was associated with NOS1 Ex1f-VNTR, but not 5-HTTLPR. Our data suggest that while NOS1 plays a role in sensorimotor gating, the nitrergic pathway of gating regulation does not involve the action of 5-HTT.

Opioid use disorder (OUD) has been linked to exaggerated attentional, affective, and arousal responses to opioid-related stimuli, as well as altered responses to other affective (eg, naturally rewarding or aversive) stimuli, particularly blunted responses to pleasant/rewarding stimuli. Both exaggerated responses to drug-related stimuli and reduced response to pleasant stimuli may influence the course of OUD and its treatment, however interpretation of studies thus far is limited by methodological issues. In the present study, we examined subjective ratings, and attenuation of the P3 component of the acoustic startle-evoked event-related potential (as a measure of attention), while viewing neutral, pleasant, unpleasant, and drug-related images. Participants prescribed opioid agonist treatment (OAT) for OUD (n = 82) were compared to a carefully-matched control group (n = 33) and to recently-abstinent participants with OUD (n = 22). Relative to controls, participants prescribed OAT gave higher positive valence ratings of drug images, and blunted valence responses to other affective images, but groups did not differ in terms of arousal ratings or P3 amplitude. Within the OAT group, linear modeling of associations between frequency of recent illicit opioid use and startle P3 amplitude found an association between increased recent illicit opioid use and reduced attention to pleasant, relative to unpleasant, images. The latter finding may have implications for interventions targeting cognitive biases in people with substance use disorder. In particular, they suggest that enhancing attention to pleasant stimuli may be as, if not more important, than the typical approach of trying to reduce attentional bias to drug-related stimuli.

Sex, head and neck posture, and cervical muscle preparation are contributing factors in the severity of head and neck injuries. However, it is unknown how these factors modulate the head kinematics. In this study, twenty-four (16 male and 8 female) participants experienced 50 impulsive forces to their heads with and without an acoustic warning. Female participants demonstrated a 71 ms faster (p = 0.002) muscle activation onset compared to males after warning. The magnitude of muscle activation was not significant between sexes. Females exhibited 21% (p < 0.008) greater peak angular velocity in all force directions and 18% (p < 0.04) greater peak angular acceleration in sagittal plane compared to males. Females exhibited 15% (p = 0.03) greater peak linear acceleration compared to males only in sagittal flexion. Preparation attenuated head kinematics significantly (p < 0.03) in 11 out of 18 investigated head kinematics for both sexes. A warning eliciting a startle response 420 ms prior to the impact resulted in significant attenuation of all measured head kinematics in sagittal extension (p < 0.037). In conclusion, both sex and warning type were significant factors in head kinematics. These data provide insight into the complex relationship of muscle activation and sex, and may help identify innovative strategies to reduce head and neck injury risk in sports.

Trauma exposure has been repeatedly linked to psychophysiological threat reactivity, although the directionality of this association has been inconsistent. Several factors likely contribute to inconsistent findings including type of trauma and threat paradigm. The present study therefore examined the impact of trauma type on psychophysiological reactivity to predictable (P-) and unpredictable (U-) threat in young adults (N = 112). Participants were classified into three groups: history of interpersonal or noninterpersonal trauma, or no history of trauma. Startle eyeblink potentiation was recorded during a well-validated threat-of-shock paradigm. Results indicated individuals with interpersonal trauma exposure displayed exaggerated startle reactivity to U-threat (only) compared with both other groups. In contrast, individuals with noninterpersonal trauma exhibited blunted startle reactivity to U-threat (only) compared with both other groups. Findings reveal that trauma and threat type influence threat reactivity and that those with a history of interpersonal trauma may uniquely display exaggerated sensitivity to stressors that are uncertain.

Experiments in rodent animal models help to reveal the characteristics and underlying mechanisms of pathologies related to hearing loss such as tinnitus or hyperacusis. However, a reliable understanding is still lacking. Here, four different rat strains (Sprague Dawley, Wistar, Long Evans, and Lister Hooded) underwent comparative analysis of electrophysiological (auditory brainstem responses, ABRs) and behavioral measures after noise trauma induction to differentiate between strain-dependent trauma effects and more consistent changes across strains, such as frequency dependence or systematic temporal changes. Several hearing- and trauma-related characteristics were clearly strain-dependent. Lister Hooded rats had especially high hearing thresholds and were unable to detect a silent gap in continuous background noise but displayed the highest startle amplitudes. After noise exposure, ABR thresholds revealed a strain-dependent pattern of recovery. ABR waveforms varied in detail among rat strains, and the difference was most prominent at later peaks arising approximately 3.7 ms after stimulus onset. However, changes in ABR waveforms after trauma were small compared to consistent strain-dependent differences between individual waveform components. At the behavioral level, startle-based gap-prepulse inhibition (gap-PPI) was used to evaluate the occurrence and characteristics of tinnitus after noise exposure. A loss of gap-PPI was found in 33% of Wistar, 50% of Sprague Dawley, and 75% of Long Evans rats. Across strains, the most consistent characteristic was a frequency-specific pattern of the loss of gap-PPI, with the highest rates at approximately one octave above trauma. An additional range exhibiting loss of gap-PPI directly below trauma frequency was revealed in Sprague Dawley and Long Evans rats. Further research should focus on these frequency ranges when investigating the underlying mechanisms of tinnitus induction.

Previous studies have shown that activating the attachment system attenuates fear learning. This study aimed to explore whether attachment priming can also impact on fear extinction processes, which underpin the management of anxiety disorders. In this study, 81 participants underwent a standard fear conditioning and extinction protocol on day 1 and returned 24 h later for an extinction recall and reinstatement test. Half the participants were primed to imagine their closest attachment figure prior to undergoing extinction training, while the other half were instructed to imagine a positive situation. Fear-potentiated startle and subjective expectancies of shock were measured as the primary indicators of fear. Attachment priming led to less relapse during the reinstatement test at the physiological but not subjective levels. These findings have translational potential to imply that activating awareness of attachment figures might augment long-term safety memories acquired in existing treatments to reduce relapse of fear.