Prepulse inhibition of startle in adults with ADHD

Prepulse inhibition of startle (PPI) is a measure of sensorimotor gating, a pre-conscious regulator of attention. PPI is impaired in adults with schizophrenia and several other neuropsychiatric disorders associated with attentional abnormalities. The core feature of ADHD involves deficits in attention and, like schizophrenia, ADHD is associated with dysregulation of cortical-striatal circuits and dopamine transmission. Therefore, PPI may be disrupted in ADHD. While ADHD persists into adulthood in approximately half the children with ADHD, there has not been any published report of PPI in ADHD adults. In this study, PPI was measured in a sample of ADHD adults and compared to a sample of healthy comparison (HC) subjects. Twenty unmedicated adults with ADHD (11 inattentive subtype, 9 combined subtype) and 17 HC subjects were administered an eyeblink startle PPI paradigm. The PPI of ADHD adults was not significantly different from that of HC subjects in any of the PPI conditions. There was no significant effect of ADHD subtype nor of gender. The lack of PPI deficits in ADHD adults has important implications and suggests that, despite the presence of PPI dysregulation in a large number of disparate neuropsychiatric disorders, it is not a general feature of all neuropsychiatric disorders with attention abnormalities. Furthermore, the attentional deficiency in ADHD may have a neurobiological substrate somewhat distinct from schizophrenia and other neuropsychiatric disorders that are associated with PPI deficits. This distinction may be related to a relative sparing of pre-conscious attentional functions in ADHD compared to other disorders with PPI impairment.     

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.     

Effects of antipsychotics on prepulse inhibition of the startle response in drug-na?ve schizophrenic patients.

BACKGROUND: Disturbances in sensorimotor gating measured by prepulse inhibition of the startle response (PPI) have frequently been reported in medicated and unmedicated schizophrenia spectrum patients and in their relatives, suggesting that the deficit represents a stable vulnerability marker for schizophrenia. Clinical data on the effects of antipsychotics on PPI disturbances are scarce, but from preclinical studies, antipsychotics have been shown to influence PPI. To differentiate pathogenetic mechanisms from drug related effects, longitudinal clinical studies on the effect of antipsychotic treatment on PPI in drug-naive first-episode schizophrenic patients are needed. METHODS: First-episode schizophrenic patients never previously medicated with antipsychotics were examined at inclusion and after 3 months of treatment with the atypical antipsychotic compound, risperidone, or the typical drug, zuclopenthixol. Healthy controls were used as a comparison group. RESULTS: The results confirm deficits in PPI in drug-naive first-episode patients. No effect of antipsychotic treatment on PPI dysfunction was observed in any of the treatment groups. CONCLUSIONS: The data are the first to show the possible effect of treatment with antipsychotic drugs on PPI disturbances in a longitudinal study of drug-naive schizophrenic patients. The data do not support any influence of treatment with antipsychotic drugs on sensorimotor gating deficits. Instead, the results point to the impairment in PPI as a stable vulnerability indicator.     

Prepulse inhibition of the startle reflex in schizophrenia remains stable with short-term quetiapine

Purpose

To study the short-term effect of treatment with quetiapine on prepulse inhibition (PPI) deficits of the startle reflex in schizophrenia patients.

Subjects and methods

Using PPI, we studied a group of 21 schizophrenia patients and 16 controls. Seventeen of the patients were re-tested with PPI after 21 days of treatment with quetiapine.

Results

At baseline, an almost significant decrease in PPI was found in the patients as compared to the controls. PPI measurements did not change in the patients after 21 days of treatment with quetiapine, despite their clinical improvement.

Conclusion

Our results suggest that short-term quetiapine treatment may not modify PPI measures in schizophrenia patients.     

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.     

Prepulse inhibition and habituation of the startle response are stable neurobiological measures in a normal male population.

Prepulse inhibition (PPI) and habituation of the startle response are operational measures of sensorimotor gating and information processing. Changes in the normal inhibition and habituation of the startle response may provide trait markers for illnesses such as schizophrenia that have altered neurotransmitter control of the neural circuitry that modulates these measures. The stability of PPI and habituation was assessed in 10 normal male subjects. Prepulse inhibition was found to be most stable in the more intense prepulse conditions, and habituation was most stable in the early portion of the test session. These data support the hypothesis that PPI and habituation are relatively stable neurobiological markers.     

Prepulse inhibition of the startle response in men with schizophrenia: effects of age of onset of illness, symptoms, and medication

BACKGROUND: Prepulse inhibition of the startle reflex response refers to the ability of a weak prestimulus to transiently inhibit the response to a closely following strong sensory stimulus. This effect represents an operational index of sensorimotor gating and is found to be deficient in schizophrenia. Prepulse inhibition deficits in schizophrenia seem to be partially normalized by typical antipsychotics and more fully by some atypical antipsychotics. Early onset of schizophrenia, particularly in men, has been associated with abnormal brain maturation, profound neuropsychological deficits, and less responsiveness to antipsychotic medication. We evaluated the effects of the age of onset of illness, current positive and negative symptoms, and the type of medication (typical vs atypical) on prepulse inhibition of the startle response in schizophrenia. METHODS: Thirty-eight male schizophrenic patients and 20 healthy male controls underwent testing for prepulse inhibition of the acoustic startle response. RESULTS: Earlier onset of illness was associated with reduced prepulse inhibition, while adult onset of illness was not. No significant relationships occurred between current symptoms and prepulse inhibition. Patients given typical, but not atypical, antipsychotics exhibited less prepulse inhibition compared with healthy controls. CONCLUSION: Early onset of illness is associated with profound deficits in prepulse inhibition of the startle response in men with schizophrenia.     

Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis.

BACKGROUND: Children with primary nocturnal enuresis (PNE) wet the bed during all stages of sleep and irrespective of state of arousal, suggesting that during sleep, when voluntary, i.e., cortical control, is not available, the signal from the distended bladder is not registered in the subcortical centers inhibiting micturition. Deficient prepulse inhibition (PPI) of startle has been reported in PNE. This study evaluates the association of this PPI deficit in PNE with comorbidity with attention-deficit hyperactivity disorder (ADHD) and with intelligence. METHODS: Prepulse modulation of startle was studied in 96 boys with PNE and 105 nonenuretic boys using intervals of 60, 120, and 4000 msec between the onset of a 75-dB 1000-Hz tone and a 104-dB noise burst. Thirty-one percent of the enuretic and 36% of the nonenuretic boys were diagnosed with ADHD. RESULTS: After adjustment for presence or absence of ADHD, lower or higher IQ, age, and unmodulated startle amplitude, there was a significant association between PNE and deficient PPI of startle following the 120-msec prepulse interval. Those enuretic boys who also were ADHD or had higher performance IQs (> or = 110) showed the greatest PPI deficit. CONCLUSIONS: A common deficiency of inhibitory signal processing in the brain stem may underlie both deficient PPI and the inability to inhibit micturition in PNE. Strong familiarity for PNE, ADHD, and intelligence suggests a possible genetic mediation of these effects.     

Prepulse inhibition deficits in patients with panic disorder

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is reduced in several neuropsychiatric disorders that are characterized by deficits in inhibition or gating of intrusive or irrelevant stimuli. Clinically, panic disorder (PD) patients have been described as having difficulties in inhibition of responding to sensory and cognitive events. Because such difficulties may be due to failures in early stages of information processing, we examined PPI in patients with PD. Acoustic startle reactivity, habituation, and PPI (30-, 60-, 120-, 240-, and 2,000-ms interstimulus intervals) were assessed in patients with panic disorder (m/f = 10, 10) and age- and gender-matched healthy controls (m/f = 11, 10). PD patients were assessed with structured clinical interview for DSM-IV criteria with benzodiazepine treatment as an exclusion criterion. Panic disorder patients exhibited normal startle reactivity, reduced habituation, and significantly reduced PPI in the 30-, 60-, and 240-ms prepulse conditions. Within the PD group, the patients with high trait and state anxiety exhibited less PPI than patients with low trait and state anxiety. Furthermore, in PD patients, decreased PPI correlated significantly with high trait but not state anxiety. These data indicate that early stages of sensory information processing are abnormal in patients with PD. These observed deficits in PPI could reflect a more generalized difficulty in suppressing or gating information in panic disorder. The correlation between high trait anxiety and deficient PPI supports the hypothesis that sensorimotor gating abnormalities are an enduring feature of subjects with PD.     

Prepulse inhibition of the acoustic startle reflex in pigs and its disruption by d-amphetamine

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating. The dopamine receptor agonist-mediated disruption of PPI in rats is widely used as a model of the sensorimotor gating deficiencies demonstrated in schizophrenia patients. As a possible tool for validation of a pig model of psychosis, we wished to verify the existence of PPI in landrace pigs and investigate the potential disruption of PPI by d-amphetamine (AMPH) in these animals. PPI of the acoustic startle reflex and its potential disruption by AMPH were investigated using three doses 0.5-1.5mg/kg with a paradigm including two levels of prepulses (82 and 88dB) and a prepulse (PP) interval of 60 and 120ms. We found an average PPI of the startle reflex of 25.6% and both of the investigated PP intensities and PP intervals were equally effective in this PP-inhibitive paradigm. AMPH significantly disrupted PPI and, in spite of only the 0.5mg/kg dose proved statistically significant, the results indicate this to be dose-related. We have demonstrated the phenomenon of PPI of the startle reflex in landrace pigs and its disruption by d-amphetamine. Studies of sensorimotor gating defects could be a valuable additional tool in assessing pig models of neuropsychiatric disorders.     

Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics

Alterations of electrocardiogram results and cases of sudden cardiac death have been reported since the beginning of neuroleptic treatment. In particular, a temporal association exists between some antipsychotics and prolongation of the heart rate-corrected QT interval (QTc), an event that may increase the risk for developing a potentially fatal ventricular tachycardia arrhythmia known as torsades de pointes if it significantly exceeds normal intraindividual and interindividual variation. Although the incidence of serious adverse cardiac events in response to antipsychotic medications is relatively low, any possibility for the occurrence of cardiotoxicity warrants continued study. The present article reviews important differences among antipsychotic drugs in the potential for, and occurrence of, serious adverse cardiac outcomes and suggests that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute significantly to a QTc prolongation that could result in potentially fatal ventricular arrhythmias.     

Differences of satisfaction with medication between patients with schizophrenia treated with typical antipsychotics and atypical antipsychotics

Many studies have demonstrated that atypical antipsychotics are superior to typical antipsychotics in that they have fewer side-effects and produce better improvement of cognitive deficits and quality of life in patients with schizophrenia. However, most of these studies dealt with objective indices assessed by researchers rather than subjective indices that are indeed important to patients themselves. In 126 patients with schizophrenia, annoyance of side-effects and psychotic symptoms, satisfaction with medication, wish to change medication, and knowledge of atypical antipsychotics were assessed using questionnaires. Patients treated with typical antipsychotics complained less of annoyance of poor attention and concentration than those treated with atypical antipsychotics, which can be explained by increased awareness of these symptoms by the patients due to the improvement of cognitive function. There were no significant differences between the two groups in other variables. The present results that satisfaction and annoyance were similar between patients treated with typical antipsychotics and those with atypical antipsychotics, may partly explain why patients hesitated and rejected changing or shifting from typical to atypical antipsychotics. But because 98 of 126 patients did not know about atypical antipsychotics, it is important to educate the patients on the merits of atypical antipsychotics.     

Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington''s disease.

The corpus striatum serves a critical function in inhibiting involuntary, intrusive movements. Striatal degeneration in Huntington's disease results in a loss of motor inhibition, manifested by abnormal involuntary choreiform movements. Sensorimotor inhibition, or "gating", can be measured in humans using the startle reflex: the startle reflex is normally inhibited when the startling stimulus is preceded 30-500 ms earlier by a weak prepulse. In the present study, prepulse inhibition (PPI) was measured in patients with Huntington's disease to quantify and characterise sensorimotor gating. Compared with age matched controls, patients with Huntington's disease exhibit less PPI. Startle gating deficits are evident in patients with Huntington's disease when startle is elicited by either acoustic or tactile stimuli. Even with stimuli that elicit maximal PPI in normal subjects, patients with Huntington's disease exhibit little or no PPI, and their pattern of startle gating does not show the normal modulatory effects usually elicited by changing the prepulse interval or intensity. Startle amplitude and habituation and latency facilitation are largely intact in these patients, although reflex latency is significantly slowed. In patients with Huntington's disease, startle reflex slowing correlates with cognitive impairment measured by the dementia rating scale, and with the performance disruptive effects of interference measured by the Stroop test. These findings document a profound disruption of sensorimotor gating in patients with Huntington's disease and are consistent with preclinical findings that identify the striatum and striatopallidal GABAergic efferent circuitry as critical substrates for sensorimotor gating of the startle reflex.     

Physiogenomic comparison of weight profiles of olanzapine- and risperidone-treated patients

Atypical antipsychotics induce pre-diabetic symptoms in some but not all patients, characterized most notably by elevated weight. The side effect profiles of the various drugs in the class differ, however, raising the possibility of drug-specific mechanisms for similar side effects. We used physiogenomic analysis, an approach previously employed to study the genetics of drug and diet response, to discover and compare genetic associations with weight profiles observed in patients treated with olanzapine and risperidone as an approach to unraveling contrasting mechanistic features of both drugs. A total of 29 single nucleotide polymorphisms (SNPs) were selected from 13 candidate genes relevant to two potential pharmacological axes of psychotropic-related weight profiles, appetite peptides and peripheral lipid homeostasis. We applied physiogenomic analysis to a cross-section of 67 and 101 patients being treated with olanzapine and risperidone, respectively, and assessed genetic associations with the weight profiles. Weight profiles in patients treated with olanzapine were significantly associated with SNPs in the genes for apolipoprotein E, apolipoprotein A4 and scavenger receptor class B, member 1. Weight profiles in patients treated with risperidone were significantly associated with SNPs in the genes for leptin receptor, neuropeptide Y receptor Y5 and paraoxonase 1. These results are consistent with contrasting mechanisms for the weight profile of patients treated with these drugs. Genes associated with olanzapine weight profiles may be related to peripheral lipid homeostatic axes, whereas those associated with risperidone's may be related to brain appetite peptide regulation. Future physiogenomic studies will include neurotransmitter receptor SNPs and validation in independent samples.     

Prepulse inhibition and recovery of trigemino-cervical reflex in patients with cervical dystonia

ObjectiveWe aimed to analyze the prepulse inhibition (PPI) and recovery rate (R) of the trigeminocervical reflex (TCR) in patients with cervical dystonia (CD).MethodsWe enrolled 15 patients with CD and 16 healthy subjects. TCR was recorded over splenius capitis after infraorbital nerve stimulation. For TCR-PPI, we applied a prepulse stimulus to the left second finger 100 ms prior to the test stimulus and the percentage of change of response to test stimulus was calculated. For TCR-R, we applied paired infraorbital stimuli at interstimulus interval (ISIs) of 300 ms and the percentage of change of the second compared to the first response was calculated.ResultsTCR-PPI and TCR-R values were higher (less inhibition and greater recovery) on both sides in the patient group compared to healthy subjects. There was high correlation between TCR-PPI and TCR-R on both sides in patients with dystonia (p < 0.005). We did not find any significant relationship between TCR-R or TCR-PPI and side of dystonic posture.ConclusionsWe showed disturbed modulation of TCR in CD patients. In CD, a general inhibition of the inhibitory pathways and facilitation of the excitatory pathways occur. Although TCR was recorded directly on the affected muscles in CD, symmetric abnormal TCR findings in CD suggest that these findings are probably secondary to altered function of higher order centers rather than being directly related to the pathophysiological process.     

Prepulse inhibition deficits of the startle reflex in neonatal ventral hippocampal-lesioned rats: reversal by glycine and a glycine transporter inhibitor.

BACKGROUND: Neonatal ventral hippocampal (NVH) lesions in rats induce behavioral abnormalities at adulthood thought to simulate some aspects of the positive, negative, and cognitive deficits classically observed in schizophrenic patients. Such lesions induce a postpubertal emergence of prepulse inhibition (PPI) deficits of the startle reflex reminiscent of the sensorimotor gating deficits observed in a majority of schizophrenic patients. To study the potential involvement of the glycinergic neurotransmission in such deficits, we investigated the capacity of glycine (an obligatory N-methyl-D-aspartate [NMDA] receptor co-agonist) and ORG 24598 (a selective glycine transporter 1 inhibitor) to reverse NVH lesion-induced PPI deficits in rats.METHODS: Ibotenic acid was injected bilaterally into the ventral hippocampus of 7-day-old pups. Prepulse inhibition of the startle reflex was measured at adulthood. RESULTS: Glycine (.8 and 1.6 g/kg IP) and ORG 24598 (10 mg/kg IP) fully and partially reversed lesion-induced PPI deficits, respectively. CONCLUSIONS:These findings confirm that an impaired glutamatergic neurotransmission may be responsible for PPI deficits exhibited by NVH-lesioned rats and support the hypoglutamatergic hypothesis of schizophrenia. They also suggest that drugs acting either directly at the NMDA receptor glycine site or indirectly on the glycine transporter 1 could offer promising targets for the development of novel therapies for schizophrenia.     

Effects of typical and atypical antipsychotics on prepulse inhibition and latent inhibition in chronic schizophrenia.

BACKGROUND: Prepulse inhibition and latent inhibition are the two animal paradigms currently dominating neuropharmacological research on attentional deficits in schizophrenia. Both paradigms have been shown to have a reasonable amount of face, predictive, and construct validity, but responsiveness to typical and atypical antipsychotics differs between the two, as indicated by animal and human studies. The relationship between the paradigms in schizophrenic patients is still unclear.METHODS: We tested prepulse inhibition and auditory latent inhibition in a sample of 33 chronic schizophrenic patients medicated either with atypical (n = 17) or typical (n = 16) antipsychotics.RESULTS: Latent inhibition was found to be intact in both patient groups. Prepulse inhibition was intact in the group receiving atypicals, but deficient in the group receiving typicals (at 60 msec lead interval condition).CONCLUSIONS: The direct comparison supports the hypothesis that atypical and typical antipsychotics have different effects on prepulse inhibition than on latent inhibition in schizophrenic patients; however, the results may also be explained by a greater sensitivity of the prepulse inhibition method. Because it is crucial to understand why there are considerable differences between the two paradigms and between human and animal studies, research should focus more strongly on comparative approaches.     

Prepulse inhibition and fear-potentiated startle are altered in tissue inhibitor of metalloproteinase-2 (TIMP-2) knockout mice

The ability to discriminate between potential dangers and recall those stimuli is essential for survival. This emotional learning requires the involvement of higher brain structures, including the amygdala, hippocampus and related cortical structures. Long-term changes in synaptic transmission and structure are important for the establishment and consolidation of fear memory. The structural changes associated with this synaptic plasticity likely require alterations in the composition of the extracellular matrix (ECM). ECM integrity is maintained by the opposing action of matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). To date, no studies have examined the role of MMPs or TIMPs in conditioned fear. Here, we show that neither male nor female mice deficient in TIMP-2 (knockout) exhibit prepulse inhibition of the startle reflex, suggesting deficits in pre-attentional sensorimotor gating. In addition, knockout mice and mice expressing a mutant truncated TIMP-2 (knock-down) show deficits in fear-potentiated startle. This is the first report of a phenotype for the TIMP-2(-/-) mice and suggests that TIMP-2 may play a role in the synaptic plasticity underlying learning and memory.     

Elevated prolactin in pediatric patients on typical and atypical antipsychotics

As part of systematic treatment trials of haloperidol, clozapine, and olanzapine with a total of 35 children and adolescents with early onset psychosis, prolactin was measured at baseline and week 6 of treatment. The National Institute of Mental Health patients--13 females, 22 males (mean age, 14.1+/-2.3 years; range, 9.1-19 years) with childhood onset schizophrenia (n = 32), or Psychotic Disorder not otherwise specified (NOS) (n = 3) with onset of psychosis before age 13--were recruited for open or double-blind trials of haloperidol, clozapine, or olanzapine. Baseline serum prolactin was measured after a 3-week washout period and after 6 weeks of treatment. Mean prolactin concentration after 6 weeks of treatment was significantly elevated on all three drugs; however, on clozapine, mean prolactin remained within the normal range. Prolactin was increased above the upper limit of normal for 100% of 10 patients on haloperidol, 70% of 10 patients on olanzapine, and 0% of 15 patients on clozapine (chi2 analyses: H > C, p = 0.004; O > C, p = 0.001). Given the potential endocrine and possible cardiac correlates of hyperprolactinemia, these more robust prolactin elevations in pediatric patients after short-term exposure to olanzapine than those reported for adults justify longer observation intervals with bigger samples to establish treatment safety of atypical antipsychotics in adolescents.