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A recently reported behavioral screen in larval zebrafish for phenocopiers of known anesthetics and associated drugs yielded an isoflavone. Related isoflavones have also been reported as GABAA potentiators. From this, we synthesized a small library of isoflavones and incorporated an in vivo phenotypic approach to perform structure-behavior relationship studies of the screening hit and related analogs via behavioral profiling, patch-clamp experiments, and whole brain imaging. This revealed that analogs effect a range of behavioral responses, including sedation with and without enhancing the acoustic startle response. Interestingly, a subset of compounds effect sedation and enhancement of motor responses to both acoustic and light stimuli. Patch clamp recordings of cells with a human GABAA receptor confirmed that behavior-modulating isoflavones modify the GABA signaling. To better understand these molecules' nuanced effects on behavior, we performed whole brain imaging to reveal that analogs differentially effect neuronal activity. These studies demonstrate a multimodal approach to assessing activities of neuroactives.
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Hyperekplexia is a rare neurological disorder that is characterized by an excessive startle response to unexpected stimuli. Recently, heterogeneous causative genes have been identified. Most cases are diagnosed during the neonatal period from hypertonia or stiffness. Adult cases are relatively rare and can cause severe head injury, but they are often misdiagnosed, typically as epilepsy or psychiatric disorders, due to the rarity of the pathology. This report describes a genetically confirmed case of hyperekplexia in an adult with head trauma, highlighting the features of head trauma and discussing potential pitfalls in the diagnosis of adult patients with hyperekplexia.
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Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene and characterized by early-onset epilepsy, intellectual disability, and autistic features. To date, the etiological mechanisms underlying CDD are largely unknown and no effective therapies are available. The Cdkl5 knock-out (KO) mouse has been broadly employed in preclinical studies on CDD; Cdkl5-KO mice display neurobehavioral abnormalities recapitulating most CDD symptoms, including alterations in motor, sensory, cognitive, and social abilities. However, most available preclinical studies have been carried out on adult Cdkl5-KO mice, so little is known about the phenotypic characteristics of this model earlier during development. Furthermore, major autistic-relevant phenotypes, for example, social and communication deficits, have been poorly investigated and mostly in male mutants. Here, we assessed the autistic-relevant behavioral phenotypes of Cdkl5-KO mice during the first three post-natal weeks and in adulthood. Males and females were tested, the latter including both heterozygous and homozygous mutants. Cdkl5 mutant pups showed qualitative and quantitative alterations in ultrasonic communication, detected first at 2 weeks of age and confirmed later in adulthood. Increased levels of anxiety-like behaviors were observed in mutants at 3 weeks and in adulthood, when stereotypies, reduced social interaction and memory deficits were also observed. These behavioral effects of the mutation were evident in both sexes, being more marked and varied in homozygous than heterozygous females. These findings provide novel evidence for the autistic-relevant behavioral profile of the Cdkl5 mouse model, thus supporting its use in future preclinical studies investigating CDD pathology and autism spectrum disorders.
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Understanding how sensory processing demands affect the ability to ignore task-irrelevant, loud auditory stimuli (LAS) during a task is key to performance in dynamic environments. For example, tennis players must ignore crowd noise to perform optimally. We investigated how practice affects this ability by examining the effects of delivering LASs during preparatory phase of an anticipatory timing (AT) task on the voluntary and reflexive responses in two conditions: lower and higher visual processing loads. Twenty-four participants (mean age = 23.1, 11 females) completed the experiment. The AT task involved synchronizing a finger abduction response with the last visual stimulus item in a sequence of four Gabor grating patches briefly flashed on screen. The lower demand condition involved only this task, and the higher demand condition required processing the orientations of the patches to report changes in the final stimulus item. Our results showed that higher visual processing demands affected the release of voluntary actions, particularly in the first block of trials. When the perceptual load was lower, responses were released earlier by the LAS compared to the high-load condition. Practice reduced these effects largely, but high perceptual load still led to earlier action release in the second block. In contrast, practice led to more apparent facilitation of eyeblink latency in the second block. These findings indicate that a simple perceptual load manipulation can impact the execution of voluntary motor actions, particularly for inexperienced participants. They also suggest distinct movement preparation influences on voluntary and involuntary actions triggered by acoustic stimuli.
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Sensory processing disruptions are a core symptom of autism spectrum disorder (ASD) and other neurological disorders. The acoustic startle response and prepulse inhibition (PPI) are common metrics used to assess disruptions in sensory processing and sensorimotor gating in clinical studies and animal models. However, often there are inconsistent findings on ASD-related PPI deficits across different studies. Here, we used a novel method for assessing changes in startle and PPI in rodents, using the Cntnap2 knock-out (KO) rat model for neurodevelopmental disorder/ASD that has consistently shown PPI disruptions in past studies. We discovered that not only sex and prepulse intensity but also the intensity of the startle stimulus profoundly impacts whether PPI deficits are evident in the Cntnap2 KO rat or not. We show that rats do not universally exhibit a PPI deficit; instead, impaired PPI is contingent on specific testing conditions. Notably, at lower startle stimulus intensities, Cntnap2 KO rats not only demonstrated intact PPI but also exhibited evidence of enhanced PPI compared with their wild-type counterparts. This finding emphasizes the importance of considering specific testing conditions when evaluating startle and PPI in the context of ASD and other neuropsychiatric conditions and might explain some of the inconsistencies between different studies.
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Estimulación Acústica , Modelos Animales de Enfermedad , Inhibición Prepulso , Reflejo de Sobresalto , Animales , Inhibición Prepulso/fisiología , Masculino , Femenino , Reflejo de Sobresalto/fisiología , Proteínas del Tejido Nervioso/genética , Proteínas de la Membrana/genética , Trastorno del Espectro Autista/fisiopatología , Filtrado Sensorial/fisiología , Ratas Transgénicas , RatasRESUMEN
Planned actions can be triggered involuntarily by a startling acoustic stimulus (SAS), resulting in very short reaction times (RT). This phenomenon, known as the StartReact effect, is thought to result from the startle-related activation of reticular structures. However, other sensory modalities also can elicit a reflexive startle response. Here, we assessed the effectiveness of an intense startling electric stimulus (SES) in eliciting the StartReact effect as compared to a SAS. We tested SES intensities at 15 and 25 times the perceptual threshold of each participant, as well as SAS intensities of 114 dB and 120 dB. The electrical stimulation electrodes were placed over short head of the biceps brachii on the arm not involved in the task. Intense electric and acoustic stimuli were presented on 20% of the trials in a simple RT paradigm requiring a targeted ballistic wrist extension movement. The proportion of trials showing short latency (≤ 120 ms) startle reflex-related activation in sternocleidomastoid was significantly lower on intense electrical stimulus trials compared to intense acoustic trials, and the startle response onset occurred significantly later on SES trials compared to SAS. However, when a startle reflex was observed, RTs related to the prepared movement were facilitated to a similar extent for both SES and SAS conditions, suggesting that the accelerated response latency associated with the StartReact effect is independent of stimulus type.
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Introduction: Startle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI. Methods: Using silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation. Results: Over time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9-13%). No significant neural activity for PPI was detected. Discussion: Startle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.
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Hyperekplexia (HPX) is a rare hereditary disorder characterized by an exaggerated startle reflex and neonatal hypertonia. It exhibits both autosomal dominant and autosomal recessive inheritance patterns, depending on the gene involved. It could be a fatal neurogenetic disorder, but it is treatable. We reported a nine-month-old female child with mild gross motor delay, an exaggerated startle reflex, and multiple episodes of transient hypertonia. Neurological and electrophysiological investigations and clinical presentation suggested the diagnosis of hereditary HPX. The child showed a good response to oral clonazepam, with a reduced frequency of such episodes and attainment of age-specific milestones.
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Startle modulation paradigms, namely habituation and prepulse inhibition (PPI), can offer insight into the brain's early information processing mechanisms that might be impacted by regular meditation practice. Habituation refers to decreasing response to a repeatedly-presented startle stimulus, reflecting its redundancy. PPI refers to response reduction when a startling stimulus "pulse" is preceded by a weaker sensory stimulus "prepulse" and provides an operational measure of sensorimotor gating. Here, we examined habituation and PPI of the acoustic startle response in regular meditators (n = 32), relative to meditation-naïve individuals (n = 36). Overall, there was no significant difference between meditators and non-meditators in habituation or PPI, but there was significantly greater PPI in meditators who self-reported being able to enter and sustain non-dual awareness during their meditation practice (n = 18) relative to those who could not (n = 14). Together, these findings suggest that subjective differences in meditation experience may be associated with differential sensory processing characteristics in meditators.
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Concienciación , Habituación Psicofisiológica , Meditación , Inhibición Prepulso , Reflejo de Sobresalto , Humanos , Concienciación/fisiología , Masculino , Reflejo de Sobresalto/fisiología , Femenino , Adulto , Inhibición Prepulso/fisiología , Habituación Psicofisiológica/fisiología , Persona de Mediana Edad , Adulto Joven , Filtrado Sensorial/fisiologíaRESUMEN
Despite significant advances in the study of fear and fear memory formation, little is known about fear learning and expression in females. This omission has been proven surprising, as normal and pathological behaviors are highly influenced by ovarian hormones, particularly estradiol and progesterone. In the current study, we investigated the joint influence of serotonin (5-HT) neurotransmission and estrous cycle phases (low or high levels of estradiol and progesterone) on the expression of conditioned fear in a group of female rats that were previously divided according to their response to stressful stimuli into low or high anxiety-like subjects. The baseline amplitude of the unconditioned acoustic startle responses was high in high-anxiety female rats, with no effect on the estrous cycle observed. Data collected during the proestrus-estrus phase revealed that low-anxiety rats had startle amplitudes similar to those of high-anxiety rats. It is supposed that high-anxiety female rats benefit from increased estradiol and progesterone levels to achieve comparable potentiated startle amplitudes. In contrast, female rats experienced a significant decrease in hormone levels during the Diestrus phase. This decrease is believed to play a role in preventing them from displaying a heightened startle response when faced with strongly aversive stimuli. Data collected after 5-HT and 8-OH-DPAT were administered into the basolateral nuclei and dorsal periaqueductal gray suggest that 5-HT neurotransmission works with progesterone and estrogen to reduce startle potentiation, most likely by activating the serotonin-1A receptor subtype.
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Complejo Nuclear Basolateral , Estradiol , Miedo , Sustancia Gris Periacueductal , Progesterona , Receptor de Serotonina 5-HT1A , Reflejo de Sobresalto , Animales , Femenino , Ratas , Ansiedad/metabolismo , Ansiedad/fisiopatología , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/efectos de los fármacos , Condicionamiento Clásico/fisiología , Condicionamiento Clásico/efectos de los fármacos , Estradiol/farmacología , Estradiol/metabolismo , Ciclo Estral/fisiología , Miedo/fisiología , Miedo/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/efectos de los fármacos , Progesterona/farmacología , Progesterona/metabolismo , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Reflejo de Sobresalto/fisiología , Reflejo de Sobresalto/efectos de los fármacos , Serotonina/metabolismoRESUMEN
A context can be conceptualized as a stable arrangement of elements or as the sum of single elements. Both configural and elemental representations play a role in associative processes. This study aimed to explore the respective contributions of these two representations of a context in the acquisition of conditioned anxiety in humans. Virtual reality (VR) can be an ecologically valid tool to investigate context-related mechanisms, yet the influence of the sense of presence within the virtual environment remains unclear. Forty-eight healthy individuals participated in a VR-based context conditioning wherein electric shocks (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but not in the other (CTX-). During the test phase, nine elements from each context were presented singularly. We found a cluster of participants, who exhibited heightened anticipation of the US for anxiety-related elements as compared to the other group. In contrast to their clear elemental representation, these individuals showed diminished discriminative responses between the two context's configurations. Discriminative responses to the contexts were boosted in those individuals, who had a weaker elemental representation. Importantly, the individual sense of presence significantly influenced the conditioned responses. These findings align with the dual-representation view of context and provide insights into the role of presence in eliciting (conditioned) anxiety responses.
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Ansiedad , Condicionamiento Clásico , Realidad Virtual , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Condicionamiento Clásico/fisiología , ElectrochoqueRESUMEN
Prepulse inhibition (PPI) is a well-established phenomenon wherein a weak sensory stimulus attenuates the startle reflex triggered by a subsequent strong stimulus. Within the circuit, variations in target responses observed for PPI paradigms represent prepulse-induced excitability changes. However, little is known about the mechanism of PPI. Here, we focused on short-latency PPI of the trigeminal blink reflex R1 signal with an oligosynaptic reflex arc through the principal sensory trigeminal nucleus and the facial nucleus. As the facial nucleus is facilitatory to any input, R1 PPI is the phenomenon in the former nucleus. Considering that GABAergic modulation may be involved in PPI, this study investigated whether the PPI mechanism includes GABA-A equivalent inhibition, which peaks at approximately 30 ms in humans. In 12 healthy volunteers, the reflex was elicited by electrical stimulation of the supraorbital nerve, and recorded at the ipsilateral lower eyelid by accelerometer. Stimulus intensity was 1.5 times the R1 threshold for test stimulus and 0.9 times for the prepulse. The prepulse-test interval (PTI) was 5-150 ms. Results showed significant inhibition at 40-and 80-150-ms PTIs but not at 20-, 30-, 50-, 60-, and 70-ms PTIs, yielding two distinct inhibitions of different time scales. This corresponds well to the early and late components of inhibitory post synaptic potentials by GABA-A and GABA-B receptor activation. Thus, the data support the contribution of inhibitory post synaptic potentials elicited by the prepulse to the observed PPI. As inhibitory function-related diseases may impair the different inhibition components to varying degrees, methods deconvoluting each inhibitory component contribution are of clinical importance.
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Objectives: Bilateral stimulation is a core element of Eye Movement Desensitization and Reprocessing Therapy, a psychotherapeutic intervention for the treatment of Posttraumatic Stress Disorder (PTSD). Promising previous findings showed measurable physiological effects of bilateral stimulation in healthy individuals, but studies that replicated these findings in PTSD patients are sparse. Methods: 23 patients with PTSD and 30 healthy controls were confronted with affective standard scripts (pleasant, neutral, unpleasant) while bilateral tactile stimulation was applied. Monolateral and no stimulation served as control conditions. Noise-induced startle reflex response (valence measure) and galvanic skin response (arousal measure) were used for physiological responses and the valence and arousal scale of the Self-Assessment-Manikin for subjective responses. Results: Both groups showed a subjective distress reduction for unpleasant scripts and a subjective attention increase for positive scripts under bilateral stimulation. In healthy individuals, this was also for physiological measures, and a general startle-reducing effect of bilateral stimulation in the absence of affective stimuli was found. In PTSD patients, however, the effects were restricted on the subjective level, and no concomitant physiological effects were observed. Conclusions and significance: The findings indicate, that generalizing the effects of BLS in healthy individuals to PTSD patients may be problematic. The herein-reported group differences can be explained by PTSD-specific peculiarities in emotion processing and cognitive processing style.
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The article describes the main diagnostic criteria and principles of posttraumatic stress disorder (PTSD) diagnostic with the consideration of risk factors and specific clinical features. The main biomarkers search trends and existing limitations are considered. The role of the psychophysiological arousal symptoms claster is highlighted in the clinical picture of PTSD as well as in connection with the main cluster of re-experiencing symptoms activation and slowing of sanogenesis process. The necessity of PTSD detection in somatic medicine is thoroughly described. The article presents therapeutic algorithms of the latest international and Russian PTSD treatment clinical guidelines based on the individual combination of psychotherapy and psychopharmacotherapy treatment choice. Additionally the accumulated during the last decades national clinical experience of the anxiety disorders treatment, including the symptoms of psychophysiological arousal is highlighted that determined the list of the recommended drugs indicating the evidence level, in the PTSD treatment standards and guidelines. The treatment choices possibilities with the consideration of different PTSD symptoms cluster expression and comorbid states and individual case distress level specific are presented. Main evidence based psychotherapeutic methods are described.
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Guías de Práctica Clínica como Asunto , Psicoterapia , Trastornos por Estrés Postraumático , Trastornos por Estrés Postraumático/terapia , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/fisiopatología , Humanos , Nivel de Alerta/fisiología , Federación de RusiaRESUMEN
Prepulse inhibition (PPI) of the startle reflex serves as a pre-cognitive marker of sensorimotor gating, and its deficit may predict cognitive impairments. Startle reflex is modulated by many factors. Among them, stress has been a topic of interest, but its effects on both pre-cognitive and cognitive variables continue to yield divergent results. This study aims to analyze the effect of acute stress on PPI of the startle reflex and cognitive function (working memory, attention, inhibition, and verbal fluency). Participants were exposed to the MAST stress induction protocol or a stress-neutral task: stress group (n = 54) or control group (n = 54). Following stress induction, participants' startle responses were recorded, and cognition was assessed. The results revealed that participants in the stress group exhibited greater startle magnitude, lower PPI, and lower scores in working memory tests compared with the control group. Additionally, a correlation was found between working memory and PPI across all the participants, independent of stress group. These findings support the notion that after stress, both greater startle magnitude and diminished PPI could play an adaptive role by allowing for increased processing of stimuli potentially dangerous and stress-related. Similarly, our results lend support to the hypothesis that lower PPI may be predictive of cognitive impairment. Considering the impact of stress on both pre-cognitive (PPI) and cognitive (working memory) variables, we discuss the possibility that the effect of stress on PPI occurs through motivational priming and emphasize the relevance of considering stress in both basic and translational science.
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Memoria a Corto Plazo , Inhibición Prepulso , Reflejo de Sobresalto , Estrés Psicológico , Humanos , Memoria a Corto Plazo/fisiología , Masculino , Femenino , Reflejo de Sobresalto/fisiología , Inhibición Prepulso/fisiología , Adulto Joven , Estrés Psicológico/fisiopatología , Adulto , Atención/fisiologíaRESUMEN
Herein, we present the case of a 21-year-old man with a history of generalized tonic seizures since the age of 4 years. These seizures occurred either spontaneously or could be provoked by auditory stimuli such as the sounds of a vacuum cleaner or an electric shaver. Despite trials with 10 different anti-seizure medications, his seizures remained refractory. Interictal electroencephalography (EEG) revealed generalized epileptiform activity, whereas ictal EEG showed a generalized attenuation pattern. Magnetic resonance imaging revealed extensive chronic infarctions, predominantly in the bilateral cerebral watershed areas. At the age of 17, the patient underwent a one-stage complete callosotomy, which only achieved remission of auditory-provoked seizures. Based on this experience and published reports, we propose that the posterior corpus callosum, particularly the isthmus and anterior splenium, may be involved in seizures caused by unexpected sound stimuli.
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Estimulación Acústica , Cuerpo Calloso , Electroencefalografía , Epilepsia Refleja , Humanos , Masculino , Adulto Joven , Cuerpo Calloso/cirugía , Cuerpo Calloso/diagnóstico por imagen , Epilepsia Refleja/fisiopatología , Epilepsia Refleja/etiología , Epilepsia Refleja/cirugía , Adulto , Reflejo de Sobresalto/fisiología , Imagen por Resonancia MagnéticaRESUMEN
The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure of sensorimotor gating, defined as the reduction of ASR when a high intensity sound (pulse) is preceded in milliseconds by a weaker stimulus (prepulse). Brainstem nuclei are associated with the mediation of ASR and PPI, whereas cortical and subcortical regions are associated with their modulation. However, it is still unclear how the modulatory units can influence PPI. In the present work, we developed a computational model of a neural circuit involved in the mediation (brainstem units) and modulation (cortical and subcortical units) of ASR and PPI. The activities of all units were modeled by the leaky-integrator formalism for neural population. The model reproduces basic features of PPI observed in experiments, such as the effects of changes in interstimulus interval, prepulse intensity, and habituation of ASR. The simulation of GABAergic and dopaminergic drugs impaired PPI by their effects over subcortical units activity. The results show that subcortical units constitute a central hub for PPI modulation. The presented computational model offers a valuable tool to investigate the neurobiology associated with disorder-related impairments in PPI.
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BACKGROUND: 22q11.2 deletion syndrome (22q11DS) is one of the most robust genetic predictors of psychosis and other psychiatric illnesses. In this study, we examined 22q11DS subjects' acoustic startle responses (ASRs), which putatively index psychosis risk. Latency of the ASR is a presumptive marker of neural processing speed and is prolonged (slower) in schizophrenia. ASR measures correlate with increased psychosis risk, depend on glutamate and dopamine receptor signaling, and could serve as translational biomarkers in interventions for groups at high psychosis risk. METHODS: Startle magnitude, latency, and prepulse inhibition were assessed with a standard acoustic startle paradigm in 31 individuals with 22q11.2DS and 32 healthy comparison (HC) subjects. Surface electrodes placed on participants' orbicularis oculi recorded the electromyographic signal in ASR eyeblinks. Individuals without measurable startle blinks in the initial habituation block were classified as non-startlers. RESULTS: Across the startle session, the ASR magnitude was significantly lower in 22q11DS subjects than HCs because a significantly higher proportion of 22q11DS subjects were non-startlers. Latency of the ASR to pulse-alone stimuli was significantly slower in 22q11DS than HC subjects. Due to the overall lower 22q11DS startle response frequency and magnitudes prepulse inhibition could not be analyzed. CONCLUSIONS: Reduced magnitude and slow latency of 22q11DS subjects' responses suggest reduced central nervous system and neuronal responsiveness. These findings are consistent with significant cognitive impairments observed in 22q11DS subjects. Further research is needed to untangle the connections among basic neurotransmission dysfunction, psychophysiological responsiveness, and cognitive impairment.
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Parpadeo , Síndrome de DiGeorge , Inhibición Prepulso , Reflejo de Sobresalto , Humanos , Masculino , Femenino , Reflejo de Sobresalto/fisiología , Adulto , Adolescente , Adulto Joven , Síndrome de DiGeorge/fisiopatología , Inhibición Prepulso/fisiología , Parpadeo/fisiología , Tiempo de Reacción/fisiología , Electromiografía , Estimulación AcústicaRESUMEN
Elevated arousal in anxiety is thought to affect attention control. To test this, we designed a visual short-term memory (VSTM) task to examine distractor suppression during periods of threat and no-threat. We hypothesized that threat would impair performance when subjects had to filter out large numbers of distractors. The VSTM task required subjects to attend to one array of squares while ignoring a separate array. The number of target and distractor squares varied systematically, with high (four squares) and low (two squares) target and distractor conditions. This study comprised two separate experiments. Experiment 1 used startle responses and white noise as to directly measure threat-induced anxiety. Experiment 2 used BOLD to measure brain responses. For Experiment 1, subjects showed significantly larger startle responses during threat compared to safe period, supporting the validity of the threat manipulation. For Experiment 2, we found that accuracy was affected by threat, such that the distractor load negatively impacted accuracy only in the threat condition. We also found threat-related differences in parietal cortex activity. Overall, these findings suggest that threat affects distractor susceptibility, impairing filtering of distracting information. This effect is possibly mediated by hyperarousal of parietal cortex during threat.
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Atención , Imagen por Resonancia Magnética , Memoria a Corto Plazo , Reflejo de Sobresalto , Humanos , Masculino , Femenino , Adulto Joven , Imagen por Resonancia Magnética/métodos , Memoria a Corto Plazo/fisiología , Atención/fisiología , Reflejo de Sobresalto/fisiología , Adulto , Percepción Visual/fisiología , Encéfalo/fisiología , Estimulación Luminosa/métodos , Miedo/fisiología , Miedo/psicología , Adolescente , Mapeo Encefálico/métodos , Oxígeno/sangre , Ansiedad/fisiopatología , Ansiedad/psicología , Tiempo de Reacción/fisiologíaRESUMEN
BACKGROUND: Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. METHODS: Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging. RESULTS: We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. CONCLUSIONS: Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments.