Effects of melatonin on prepulse inhibition,habituation and sensitization of the human startle reflex in healthy volunteers

Prepulse inhibition of the startle reflex (PPI) is an operational measure of sensorimotor gating, which is demonstrated to be impaired in patients with schizophrenia. In addition, a disruption of the circadian rhythm together with blunted melatonin secretion is regularly found in patients with schizophrenia and it is theorized that these may contribute to their attentional deficits. The aim of this study was to assess the effects of acute melatonin on healthy human sensorimotor gating. Twenty-one healthy male volunteers were administered melatonin or placebo after which their levels of PPI were assessed. Melatonin significantly reduced startle magnitude and ratings of alertness, but did not influence PPI, nor sensitization and habituation. However, when taking baseline scores in consideration, melatonin significantly increased PPI in low scoring individuals while significantly decreasing it in high scoring individuals in low intensity prepulse trialtypes only. In addition, subjective ratings of alertness correlated with PPI. The results suggest that melatonin has only minor influences on sensorimotor gating, habituation and sensitization of the startle reflex of healthy males. The data do indicate a relationship between alertness and PPI. Further research examining the effects of melatonin on these processes in patients with schizophrenia is warranted.     

DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in the ventral pallidum

Serotonin (5-HT)_2A receptors are known to be involved in prepulse inhibition of the startle response (PPI), a measure of sensorimotor inhibition that is deficient in schizophrenia, Huntington's disease, and obsessive compulsive disorder. In the present studies, the localization of the 5-HT_2A receptors responsible for modulating PPI was investigated using central injections of the hallucinogenic 5-HT₂ agonist DOI and the novel 5-HT_2A antagonist MDL 100,907. 5-HT_2A receptors are densely localized in the nucleus accumbens (NAC) and the ventral pallidum (VP), areas known to be important components of neural circuitry that mediates the ventral forebrain modulation of PPI. In the present studies, it was found that the infusion of DOI (0.0–5.0 μg/0.5 μl) into the VP disrupted PPI without having effects on startle reactivity. In contrast, similar infusions into the NAC had no effect on PPI or startle reactivity. The infusion of MDL 100,907 into the VP was found to increase PPI by itself and to attenuate the PPI-disruptive effects of systemically administered DOI. It is concluded that 5-HT_2A receptors within the VP are important for the modulation of PPI, presumably through interactions at intrinsic GABAergic or cholinergic interneurons.     

帕罗西汀对慢性不可预见应激大鼠惊跳反射和弱刺激抑制影响的初步研究

目的 探讨慢性不可预见应激大鼠的听觉惊跳反射和弱刺激抑制变化情况以及帕罗西汀对其的影响.方法 将24只大鼠按随机数字表法分为阴性对照组(8只)、慢性不可预见应激组(8只)和帕罗西汀组(8只).阴性对照组:静养21 d后给予蒸馏水灌胃;慢性不可预见应激组:先给予慢性不可预见应激21d后再给予蒸馏水灌胃21 d;帕罗西汀组:先给予慢性不可预见应激21 d后再给予帕罗西汀灌胃21 d.3组大鼠均接受体质量测量、自发活动、糖水偏好、惊跳反射和弱刺激抑制测试.结果 (1)慢性不可预见应激组大鼠体质量[(380.50±22.23)g]、10 min旷场自发活动[ (5765.57 ±2942.28) mm]、糖水摄入量[(19.09 ±7.16) ml/kg]均低于阴性对照组[(426.38±33.73)g、(12 272.15±2343.02) mm(42.58±11.68) ml/kg,P＜0.01];帕罗西汀组体质量[ (353.62 ±29.37)g]低于阴性对照组(P＜0.01).(2)惊跳反射实验结果3组大鼠之间差异无统计学意义(P＞0.05).(3)慢性不可预见应激组大鼠弱刺激抑制[( 30.50±14.84)％]小于阴性对照组和帕罗西汀组[ (57.80±13.32)％、(42.32±15.82)％],帕罗西汀组弱刺激抑制小于阴性对照组,差异均有统计学意义(P ＜0.01);82 dB时的弱刺激抑制高于70、64、58 dB时的弱刺激抑制(P＜0.01);76 dB时的弱刺激抑制高于64、58 dB时的弱刺激抑制(P ＜0.01);70 dB时的弱刺激抑制高于58 dB时的弱刺激抑制(P＜0.05).结论 随着弱刺激强度增加,弱刺激抑制逐渐增加;慢性不可预见应激大鼠存在弱刺激抑制的缺失,帕罗西汀能够缓解这一状况.     

Atypical alpha asymmetry in adults with ADHD

Introduction

A growing body of literature suggests atypical cerebral asymmetry and interhemispheric interaction in ADHD. A common means of assessing lateralized brain function in clinical populations has been to examine the relative proportion of EEG alpha activity (8-12 Hz) in each hemisphere (i.e., alpha asymmetry). Increased rightward alpha asymmetry has been associated with ADHD-like traits such as reduced reward responsiveness, a lack of inhibition toward aversive experience, and increased approach behaviors, and previous work has indicated increased rightward alpha asymmetry in children with ADHD. The current study explores whether increased rightward alpha asymmetry is also evident in adults with ADHD.

Method

We assessed low (8-10 Hz) and high (10-12 Hz) alpha asymmetry in adults with ADHD (n = 29) versus controls (n = 62) during baseline and cognitive activation conditions for nine homologous electrode pairs along the anterior-posterior axis. Result: Seven results emerged (p < .05) showing increased rightward alpha asymmetry in adults with ADHD. This occurred in three specific electrode pairs across two testing conditions, and five of six results occurred in the lower alpha band. Finally, post hoc analysis indicated that increased rightward alpha asymmetry was generally associated with greater numbers of ADHD symptoms—with a possible parietal association for inattentive and a fronto-temporal association for hyperactivity symptoms.

Conclusions

Increased rightward alpha asymmetry previously observed in children with ADHD appears to be a developmentally persistent feature of ADHD.     

Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle response in rats within a narrow time window

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle amplitude when a weak prepulse precedes a startle-inducing pulse. Prepulse inhibition has been shown to be disrupted by amphetamine at doses that also stimulate locomotor activity, and it has been suggested that the same neuroanatomical substrate, mesolimbic dopamine activation, mediates the effects of amphetamine on locomotor activity and PPI. Amphetamine stimulates locomotor activity and mesolimbic dopamine release over a 1- to 3-h period, whereas PPI is typically measured within the first 30 min following amphetamine treatment. The present study therefore determined whether delays in testing would alter the PPI-disruptive effect of amphetamine in male Wistar rats. Amphetamine dose dependently disrupted PPI when the test session occurred 10 min following amphetamine treatment and only when the prepulse intensity was 5-10 dB above background. Delays of 40 and 60 min post-amphetamine injection, however, resulted in a loss of the ability of amphetamine to disrupt PPI although locomotor activity was significantly stimulated by amphetamine at these time points. The data from the present study therefore do not readily fit with the notion that the effects of amphetamine on locomotion and PPI are mediated by the same substrate.     

Impaired linguistic processing and atypical brain laterality in adults with ADHD

Introduction: cognitive/behavioral testing, structural imaging, and functional imaging, has demonstrated atypical cerebral asymmetries in patients with attention-deficit/hyperactivity disorder (ADHD). However, few studies directly examined the nature of hemispheric specialization and interaction in this population. Methods: the present experiment applied techniques from behavioral laterality research to assess directly left/right brain dynamics in unmedicated adults with ADHD (n=21) and controls (n=22). We used a lateralized lexical decision task to assess hemispheric differences in word recognition and cross-callosal interhemispheric transfer of linguistic information. Results: analysis of variance indicated that ADHD subjects were impaired relative to controls in identifying words in both hemispheres (P=0.001). Furthermore, ADHD subjects exhibited decreased effects for ‘word regularity’ (P=004), enhanced effects of ‘word frequency’ (P=007), and an increased bias for ‘nonword’ responses overall (P=03), as well as during left visual field trials in particular (P=01). Conclusions: adult subjects with ADHD demonstrated poor linguistic processing. Group differences in sensitivity to semantic and phonological linguistic variables, along with differences in response biases, suggested that ADHD subjects had reduced left hemisphere and enhanced right hemisphere involvement during our task. These findings are relevant to current research investigating ‘endophenotypes’ in ADHD, as laterality indices may prove useful in etiological research, particularly molecular genetic investigations, and highlights the relevance of brain laterality research in clinical psychiatry.     

GLT-1 upregulation impairs prepulse inhibition of the startle reflex in adult rats

We tested the hypothesis that glutamate transporter GLT-1 (also known as EAAT2) plays a role in the regulation of prepulse inhibition (PPI) of the acoustic startle reflex, a simple form of information processing which is reduced in schizophrenia. To do this, we studied PPI in rats treated with ceftriaxone (200 mg/kg/day for 8 days), an antibiotic that selectively enhances GLT-1 expression and activity. We showed that ceftriaxone-induced GLT-1 upregulation is associated with impaired PPI of the startle, that this effect is reversed by dihydrokainate, a GLT-1 antagonist, that GLT-1 expression correlates negatively with PPI, and that PPI normalizes when GLT-1a levels return to baseline. Our data indicate that GLT-1 regulates PPI of the startle reflex.     

Reduced activation and inter-regional functional connectivity of fronto-striatal networks in adults with childhood Attention-Deficit Hyperactivity Disorder (ADHD) and persisting symptoms during tasks of motor inhibition and cognitive switching

Attention-Deficit Hyperactivity Disorder (ADHD) in children has been associated with fronto-striatal functional abnormalities during tasks of inhibitory control. In adults with ADHD, however, hardly any functional magnetic resonance imaging (fMRI) studies have investigated the neurofunctional correlates of the most compromised cognitive functions of motor response inhibition and no study has investigated cognitive flexibility. In this study we used fMRI to compare brain function and task-relevant inter-regional functional connectivity between 11 medication-naïve adults with persistent inattentive/hyperactive behaviours, followed up from childhood when they had been diagnosed with ADHD, and 14 age-matched healthy controls during a Stop and a cognitive Switch tasks. Whole-brain regression MR analyses were conducted within patients to correlate symptoms with brain activation. Despite comparable task performance, adults with childhood ADHD showed reduced activation compared to controls in bilateral inferior prefrontal cortex, caudate and thalamus during both tasks, as well as in left parietal lobe during the Switch task. Within patients, the severity of the behavioural symptoms was negatively correlated with more extensive activation of similar regions in fronto-striatal, parietal and cerebellar brain areas. In the Stop task, patients showed reduced inter-regional functional connectivity between right inferior fronto-frontal, fronto-striatal and fronto-parietal neural networks. The findings demonstrate that adults with childhood ADHD and persisting behavioural symptoms show strikingly similar patterns of fronto-striatal and parietal dysfunction to those observed in childhood ADHD during the same tasks of inhibitory control. This suggests that neuro-functional abnormalities in ADHD patients are likely to continue between childhood and early adulthood.     

Attention and executive functions profile in drug naive ADHD subtypes

Attention deficit hyperactivity disorder (ADHD) has been associated with executive functioning and sustained and divided attention deficits. In order to clarify the questions on neurocognitive impairment in ADHD, we investigated the presence of specific executive functions (EFs) and attention deficit patterns in ADHD clinical subtypes. 50 patients with ADHD and 44 controls were evaluated. All subjects were boys and performed a clinical-psychopathological and neuropsychological battery. Five main domains of EFs and attention were studied. Executive functions-related neurocognitive abilities were used as control tasks. ADHD patients, inattentive and combined subtypes differ from controls on response inhibition, divided attention, phonological, and visual object working memory and on variability of reaction times measured with CPT. Comparison of ADHD subtypes, in five main domains of EFs, did not show evidence of different executive functioning profiles. Response inhibition can predict performance on working memory tests but it cannot predict performance on divided attention/set shifting and on sustained attention. ADHD boys exhibit a selective impairment on executive functions and attention tasks. These data suggest the involvement of partially independent neural circuits which control inhibition and divided attention in ADHD. Since right prefrontal cortex seems to be crucial in controlling response inhibition, while left dorsolateral prefrontal cortex seems important in modulating divided attention, these areas are deputated to be involved in the pathogenesis of neuropsychological deficits in ADHD subtypes. In addition, this study candidates the impairment in phonological and visual-object working memory as a possible neuropsychological trait in ADHD males with inattentive or combined subtypes.     

Atypical EEG beta asymmetry in adults with ADHD

Background

Abnormal brain laterality (ABL) is well established in ADHD. However, its clinical specificity and association to cognitive and clinical symptoms is not yet understood. Previous studies indicate increased right hemisphere (RH) contribution in both ADHD and reading impaired samples. The current study investigates whether this ABL characteristic occurs in adults with ADHD absent comorbid language impairment.

Methods

EEG beta asymmetry was compared in 35 adult ADHD subjects and 104 controls during rest and active cognition. Group differences in beta asymmetry were then further evaluated for association to linguistic and attentional abilities, as well as association to beta asymmetry measures across different brain regions.

Results

Adults with ADHD showed pronounced rightward beta asymmetry (p = .00001) in inferior parietal regions (P8-P7) during a continuous performance task (CPT) that could not be attributed to linguistic ability. Among ADHD subjects only, greater rightward beta asymmetry at this measure was correlated with better CPT performance. Furthermore, this measure showed a lack of normal association (i.e., observed in controls) to left-biased processing in temporal-parietal (TP8-TP7) brain regions important for higher order language functions.

Conclusion

Adult ADHD involves abnormally increased right-biased contribution to CPT processing that could not be attributed to poor language ability. This appears to also involve abnormal recruitment of LH linguistic processing regions and represents an alternative, albeit less effective, CPT processing strategy. These findings suggest different pathophysiologic mechanisms likely underlie RH biased processing in ADHD and reading impaired samples.     

Increased prepulse inhibition of the acoustic startle response is associated with better strategy formation and execution times in healthy males

Prepulse inhibition (PPI) refers to the attenuation of the amplitude of the startle reflex in response to sudden intense stimuli (pulse) if preceded by a weaker sensory stimulus (prepulse). PPI reflects the ability to filter out irrelevant information in the early stages of processing so that attention can be directed to more salient environmental features. Inhibition at this early stage of information processing appears modulated by the prefrontal cortex in a "top-down" fashion and this may account for the normal inter-individual variability in PPI and in cognitive performance. PPI data were calculated from 82 healthy male subjects who were also tested in problem solving (Stockings of Cambridge; SoC), spatial working memory (SWM) and 5-choice reaction time (RT) tests from the Cambridge Neuropsychological Test Automated Battery. Correlations between PPI scores and cognitive test variables were examined. In addition PPI scores were divided in quartiles which were used as grouping factors in examining cognitive test performance. Compared to individuals in the lowest quartile those in the highest had (a) shorter execution but not reaction times on the 5-choice RT, (b) shorter subsequent but not initial thinking times in the SoC where they also solved more problems correctly with the minimum number of moves, and (c) better strategy but not errors scores in the SWM. Our findings suggest that greater PPI is associated with superior abilities in strategy formation and execution times. We suggest that this is due to more efficient early information processing.     

Prepulse inhibition of acoustic startle response in mild cognitive impairment and mild dementia of Alzheimer type

Amnestic mild cognitive impairment (MCI) describes the condition of memory-impaired individuals who otherwise function well and do not meet the clinical criteria for dementia. Such individuals are considered to represent a transitional stage between normal aging and dementia of Alzheimer type (DAT). Neurobiologic changes in amnestic MCI, and their significance for psychophysiologic function, are poorly understood. In this study, the authors compared acoustic prepulse inhibition (PPI) between subjects with amnestic MCI and mild DAT to characterize sensorimotor gating. The acoustic startle reflex, which the authors measured using an accelerometer and electromyogram, involves whole-body movement and eye blink in response to a sudden loud noise (115 dB). PPI is inhibition of this reflex by a softer noise (prepulse; 85 dB) preceding the startle stimulus by 30 ms. PPI was examined in 30 controls, 20 subjects with amnestic MCI, and 20 subjects with mild DAT. Neither amnestic MCI nor mild DAT affected startle movement amplitude. Subjects with amnestic MCI showed significantly enhanced PPI (gating facilitation), while subjects with mild DAT exhibited significantly less PPI than controls (gating deficit). This pattern of PPI changes suggests that neuropathologic changes in the limbic cortex, mainly the entorhinal cortex, at the earliest stage of DAT might be responsible for PPI abnormalities via disturbed regulation of the limbic cortico-striato-pallido-pontine circuitry. Startle PPI changes could be used as a biologic marker for amnestic MCI and mild DAT.     

A developmental influence of the N-methyl-D-aspartate receptor NR3A subunit on prepulse inhibition of startle.

BACKGROUND: The N-methyl-D-aspartate (NMDA) receptor is composed of various conformations of multiple subunits (including NR1, NR2A-D, and NR3A-B). Peak expression of the NR3A subunit occurs approximately 2-3 weeks postnatal, with low levels in adulthood. In the brain, the NR3A subunit is localized primarily in the amygdala, hippocampus, striatum, and cortex. These regions are involved in the modulation of prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating that is modulated by NMDA receptors. NR3A reduces NMDA current in native neurons expressing NR1 and NR2 subunits and forms glycine receptors when expressed with NR1 in the absence of NR2 in both oocyte and mammalian expression systems. METHODS: To examine the role of NR3A in vivo, NR3A knockout (KO), and overexpressing transgenic mice were generated. Adult NR3A overexpressing mice exhibited normal PPI; PPI in NR3A KO mice was tested repeatedly from weaning through adulthood. RESULTS: Male NR3A KO mice exhibited an increase in PPI at 3 and 4 weeks postnatal, whereas female NR3A KO mice did not differ from their WT counterparts at any age tested. CONCLUSIONS: This sex-specific increase in PPI is consistent with the antagonistic role of the NR3A subunit in NMDA receptor function and with the observation that estrogen modulates NMDA receptor function.     

Prepulse inhibition of acoustic startle in spontaneously hypertensive rats

Prepulse inhibition is modulated by dopaminergic drugs and is disrupted in attention-deficit hyperactivity disorder, as well as mental illnesses such as schizophrenia. Spontaneously hypertensive rats (SHR) have been proposed as an animal model of attention-deficit hyperactivity disorder and show marked alterations of dopaminergic regulation of behaviour. SHR showed significantly lower startle amplitude than Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats, but no difference in startle habituation. Baseline percentage prepulse inhibition was higher in SHR and WKY rats than in SD rats. Treatment with amphetamine caused significant disruption of prepulse inhibition in SHR and WKY rats, but not SD rats. In contrast, treatment with apomorphine caused prepulse-dependent disruption of prepulse inhibition in SD rats only. Both MK-801 and 8-OH-DPAT treatment caused disruption of prepulse inhibition in all three rat strains. This study shows differential changes in startle level and prepulse inhibition in SHR, however these rats are not uniformly different from either WKY rats or SD rats and WKY rats differ in a number of respects from SD rats. In conclusion, these data further reveal altered dopaminergic regulation of behaviour in SHR, but also shows that caution is needed about the control strain used to compare these animals with.     

Regulation of Prepulse Inhibition by Ventral Pallidal Projections

The acoustic startle reflex is inhibited by the presentation of a weak auditory prestimulus 30–500 ms prior to the startling stimulus. Previous studies have demonstrated that prepulse inhibition (PPI) of acoustic startle is regulated by GABAergic activity in the ventral pallidum. Ventral pallidal efferents include major projections to the pedunculopontine tegmental nucleus (PPTg), subthalamic nucleus (STN), and mediodorsal thalamus (MD). We used lesion and intracerebral infusion techniques to determine the relevance of these projections to the ventral pallidal regulation of PPI. Consistent with previous results, PPTg lesions significantly reduced PPI in all startle sessions, while MD lesions significantly reduced PPI only under certain experimental conditions. STN lesions failed to alter PPI, but they did significantly disrupt amphetamine-induced locomotion, verifying the behavioral effectiveness of these lesions. Infusion of the GABA-A agonist muscimol into either the PPTg or the MD significantly reduced PPI. Ventral pallidal projections to the PPTg and to the MD thus appear to regulate PPI, possibly via a GABAergic mechanism. Pallidal projections to the STN may regulate other behavioral processes such as locomotor activity, but they do not appear to regulate sensorimotor gating of the acoustic startle reflex.     

Endogenous neurotensin is involved in estrous cycle related alterations in prepulse inhibition of the acoustic startle reflex in female rats

Ovarian hormones regulate prepulse inhibition (PPI) of the acoustic startle reflex. Results from studies in intact female rodents investigating sex, estrous cycle and ovarian hormone regulation of PPI are inconsistent. In experiment #1, we investigated whether PPI in female rats is influenced by the time of day of testing and the estrous cycle stage of the rat. PPI was examined across the day of proestrus (P) and diestrus 1 (D1) in female rats and compared to males. PPI in males and P females was significantly higher than in D1 females. PPI in males and D1 females was significantly affected by the time of day of testing with PPI being reduced in the afternoon and evening compared to morning. PPI in P females was not significantly affected by the time of day of testing. Previous studies have demonstrated estrous cycle regulation of central nervous system neurotensin (NT) neurons and peripherally administered NT receptor agonists regulate PPI in a manner similar to antipsychotic drugs. Experiment #2 of this study was designed to examine whether endogenous NT is involved in estrous cycle regulation of PPI. The NT receptor antagonist SR 142948A reduced the high levels of PPI during D1 and P. In contrast, when tested at a time of day in which PPI was low in D1 females, administration of both the typical antipsychotic drug haloperidol and the NT receptor antagonist significantly increased PPI. These data support an effect of time of day and estrous cycle stage on PPI in female rats. The estrous cycle variations in PPI are mediated in part by endogenous NT.     

The neural basis of sustained and transient attentional control in young adults with ADHD

Differences in neural activation during performance on an attentionally demanding Stroop task were examined between 23 young adults with ADHD carefully selected to not be co-morbid for other psychiatric disorders and 23 matched controls. A hybrid blocked/single-trial design allowed for examination of more sustained vs. more transient aspects of attentional control. Our results indicated neural dysregulation across a wide range of brain regions including those involved in overall arousal, top-down attentional control, response selection, and inhibition. Furthermore, this dysregulation was most notable in lateral regions of DLPFC for sustained attentional control and in medial areas for transient aspects of attentional control. Because of the careful selection and matching of our two groups, these results provide strong evidence that the neural systems of attentional control are dysregulated in young adults with ADHD and are similar to dysregulations seen in children and adolescents with ADHD.