Early Schizophrenia and Bipolar Disorder Patients Display Reduced Neural Prepulse Inhibition

Background: Altered sensorimotor gating has been demonstrated by Prepulse Inhibition (PPI) tests in patients with psychosis. Recent advances in signal processing methods allow assessment of neural PPI through electroencephalogram (EEG) recording during acoustic startle response measures (classic muscular PPI). Simultaneous measurements of muscular (eye-blink) and neural gating phenomena during PPI test may help to better understand sensorial processing dysfunctions in psychosis. In this study, we aimed to assess simultaneously muscular and neural PPI in early bipolar disorder and schizophrenia patients. Method: Participants were recruited from a population-based case-control study of first episode psychosis. PPI was measured using electromyography (EMG) and EEG in pulse alone and prepulse + pulse with intervals of 30, 60, and 120 ms in early bipolar disorder (n = 18) and schizophrenia (n = 11) patients. As control group, 15 socio-economically matched healthy subjects were recruited. All subjects were evaluated with Rating Scale, Hamilton Rating Scale for Depression, and Young Mania Rating Scale questionnaires at recruitment and just before PPI test. Wilcoxon ranked sum tests were used to compare PPI test results between groups. Results: In comparison to healthy participants, neural PPI was significantly reduced in PPI 30 and PPI60 among bipolar and schizophrenia patients, while muscular PPI was reduced in PPI60 and PPI120 intervals only among patients with schizophrenia. Conclusion: The combination of muscular and neural PPI evaluations suggested distinct impairment patterns among schizophrenia and bipolar disorder patients. Simultaneous recording may contribute with novel information in sensory gating investigations.

Looming Effects on Attentional Modulation of Prepulse Inhibition Paradigm

In a hazardous environment, it is fundamentally important to successfully evaluate the motion of sounds. Previous studies demonstrated “auditory looming bias” in both macaques and humans, as looming sounds that increased in intensity were processed preferentially by the brain. In this study on rats, we used a prepulse inhibition (PPI) of the acoustic startle response paradigm to investigate whether auditory looming sound with intrinsic warning value could draw attention of the animals and dampen the startle reflex caused by the startling noise. We showed looming sound with a duration of 120 ms enhanced PPI compared with receding sound with the same duration; however, when both sound types were at shorter duration/higher change rate (i.e., 30 ms) or longer duration/lower rate (i.e., more than 160 ms), there was no PPI difference. This indicates that looming sound–induced PPI enhancement was duration dependent. We further showed that isolation rearing impaired the abilities of animals to differentiate looming and receding prepulse stimuli, although it did not abolish their discrimination between looming and stationary prepulse stimuli. This suggests that isolation rearing compromised their assessment of potential threats from approaching objects and receding objects.

Cognitive behavioral markers of neurodevelopmental trajectories in rodents

Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms: drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a ‘U-shaped’ developmental trajectory; lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders.

Instantaneous radiated power of brain activity: application to prepulse inhibition and facilitation for body dysmorphic disorder

Background Global measures of neuronal activity embrace the advantage of a univariate, holistic and unique description of brain activity, reducing the spatial dimensions of electroencephalography (EEG) analysis at the cost of lower precision in localizing effects. In this work, the instantaneous radiated power (IRP) is proposed as a new whole-brain descriptor, reflecting the cortical activity from an exclusively electromagnetic perspective. Considering that the brain consists of multiple elementary dipoles, the whole-brain IRP takes into account the radiational contribution of all cortical sources. Unlike conventional EEG analyses that evaluate a large number of scalp or source locations, IRP reflects a whole-brain, event-related measure and forces the analysis to focus on a single time-series, thus efficiently reducing the EEG spatial dimensions and multiple comparisons. Results To apply the developed methodology in real EEG data, two groups (25 controls vs 30 body dysmorphic disorder, BDD, patients) were matched for age and sex and tested in a prepulse inhibition (PPI) and facilitation (PPF) paradigm. Two global brain descriptors were extracted for between-groups and between-conditions comparison purposes, namely the global field power (GFP) and the whole-brain IRP. Results showed that IRP can replicate the expected condition differences (with PPF being greater than PPI responses), exhibiting also reduced levels in BDD compared to control group overall. There were also similar outcomes using GFP and IRP, suggesting consistency between the two measures. Finally, regression analysis showed that the PPI-related IRP (during N100 time-window) is negatively correlated with BDD psychometric scores. Conclusions Investigating the brain activity with IRP significantly reduces the data dimensionality, giving insights about global brain synchronization and strength. We conclude that IRP can replicate the existing evidence regarding sensorimotor gating effects, revealing also group electrophysiological alterations. Finally, electrophysiological IRP responses exhibited correlations with BDD psychometrics, potentially useful as supplementary tool in BDD symptomatology.

The effects of galangin in prepulse inhibition test and experimental schizophrenia models

Objective: Acetylcholinesterase inhibitors are the focus of interest in the management of schizophrenia. We aimed to investigate the effects of acute galangin administration, a flavonoid compound with acetylcholinesterase inhibiting activity, on schizophrenia-associated cognitive deficits in rats and schizophrenia models in mice. Methods: Apomorphine-induced prepulse inhibition (PPI) disruption for cognitive functions, nicotinic, muscarinic and serotonergic mechanism involvement, and brain acetylcholine levels were investigated in Wistar rats. Apomorphine-induced climbing, MK-801-induced hyperlocomotion, and catalepsy tests were used as schizophrenia models in Swiss albino mice. The effects of galangin were compared with acetylcholinesterase inhibitor donepezil, and typical and atypical antipsychotics haloperidol and olanzapine, respectively. Results: Galangin (50,100 mg/kg) enhanced apomorphine-induced PPI disruption similar to donepezil, haloperidol, and olanzapine (p<0.05). This effect was not altered in the combination of galangin with the nicotinic receptor antagonist mecamylamine (1 mg/kg), the muscarinic receptor antagonist scopolamine (0.05 mg/kg), or the serotonin-1A receptor antagonist WAY-100635 (1 mg/kg) (p>0.05). Galangin (50,100 mg/kg) alone increased brain acetylcholine concentrations(p<0.05), but not in apomorphine-injected rats (p>0.05). Galangin (50 mg/kg) decreased apomorphine-induced climbing and MK-801-induced hyperlocomotion similar to haloperidol and olanzapine (p<0.05), but did not induce catalepsy, unlike them. Conclusion: We suggest that galangin may help enhance schizophrenia-associated cognitive deficits, and nicotinic, muscarinic cholinergic and serotonin-1A receptors are not involved in this effect. Galangin also exerted an antipsychotic-like effect without inducing catalepsy and may be considered as an advantageous antipsychotic agent.

Effects of Magnitude of Leading Stimulus on Prepulse Inhibition of Auditory Evoked Cerebral Responses: An Exploratory Study

An abrupt change in a sound feature (test stimulus) elicits a specific cerebral response, which is attenuated by a weaker sound feature change (prepulse) preceding the test stimulus. As an exploratory study, we investigated whether and how the magnitude of the change of the prepulse affects the degree of prepulse inhibition (PPI). Sound stimuli were 650 ms trains of clicks at 100 Hz. The test stimulus was an abrupt sound pressure increase (by 10 dB) in the click train. Three consecutive clicks, weaker (−5 dB, −10 dB, −30 dB, or gap) than the baseline, at 30, 40, and 50 ms before the test stimulus, were used as prepulses. Magnetic responses to the ten types of stimuli (test stimulus alone, control, four types of tests with prepulses, and four types of prepulses alone) were recorded in 10 healthy subjects. The change-related N1m component, peaking at approximately 130 ms, and its PPI were investigated. The degree of PPI caused by the −5 dB prepulse was significantly weaker than that caused by other prepulses. The degree of PPI caused by further decreases in prepulse magnitude showed a plateau level between the −10 dB and gap prepulses. The results suggest that there is a physiologically significant range of sensory changes for PPI, which plays a role in the change detection for survival.

Prepulse inhibition predicts subjective hearing in rats

Auditory studies in animals benefit from quick and accurate audiometry. The auditory brainstem response (ABR) and prepulse inhibition (PPI) have been widely used for hearing assessment in animals, but how well these assessments predict subjective audiometry still remains unclear. Human studies suggest that subjective audiometry is consistent with the ABR-based audiogram, not with the PPI-based audiogram, likely due to top-down processing in the cortex that inhibits PPI. Here, we challenged this view in Wistar rats, as rodents exhibit less complexity of cortical activities and thereby less influence of the cerebral cortex on PPI compared to humans. To test our hypothesis, we investigated whether subjective audiometry correlates with ABR- or PPI-based audiograms across the range of audible frequencies in Wistar rats. The subjective audiogram was obtained through pure-tone audiometry based on operant conditioning. Our results demonstrated that both the ABR-based and PPI-based audiograms significantly correlated to the subjective audiogram. We also found that ASR strength was information-rich, and adequate interpolation of this data offered accurate audiometry. Thus, unlike in humans, PPI could be used to predict subjective audibility in rats.