Sensorimotor gating in manic and mixed episode bipolar disorder

OBJECTIVES: Few studies have examined acoustic startle sensorimotor gating in bipolar disorder (BPD) despite the fact that patients with BPD have exhibited inhibitory dysfunctions on a variety of early information processing tasks. The present study aimed to expand the current literature through the investigation of electromyographic (EMG) measures of acoustic startle prepulse inhibition (PPI) in manic and mixed episode BPD. METHODS: Fourteen manic and 21 mixed episode BPD patients were compared to 32 healthy controls on acoustic startle measures of PPI using a 120-ms lead interval. RESULTS: Prepulse inhibition did not significantly differ across diagnostic groups (manic, mixed, control), and the presence of psychosis in the patient sample was not significantly related to PPI levels. With respect to startle response characteristics, patients in the mixed phase of the disorder showed prolonged prepulsed startle latency and attenuated responses to both probe-alone and prepulsed probes, though no differences in startle habituation were found across diagnostic groups. CONCLUSIONS: Although PPI deficits were not observed in either BPD sub-group, attenuated probe-alone and prepulsed startle magnitudes and reduced prepulse-induced latency facilitation in the mixed episode group is consistent with evidence that the mixed phase of BPD is associated with a more severe clinical outlook than other stages of the disorder. The absence of attenuated PPI in the patient sample may be due to the low incidence of psychosis in the BPD groups, though further studies are required to systematically assess the effects of symptom factors and clinical phase on sensorimotor gating in BPD.     

Assessment of sensorimotor gating following selective lesions of cholinergic pedunculopontine neurons

Sensorimotor gating is the state‐dependent transfer of sensory information into a motor system. When this occurs at an early stage of the processing stream it enables stimuli to be filtered out or partially ignored, thereby reducing the demands placed on advanced systems. Prepulse inhibition (PPI) of the acoustic startle reflex (ASR) is the standard measure of sensorimotor gating. A brainstem–midbrain circuitry is widely viewed as mediating both PPI and ASR. In this circuitry, the pedunculopontine tegmental nucleus (PPTg) integrates sensory input and cortico‐basal ganglia output and, via presumed cholinergic signaling, inhibits ASR‐generating neurons within the reticular formation. Non‐selective damage to all neuronal types within PPTg reduces PPI. We assessed whether this effect originates in the loss of cholinergic signaling by examining ASR and PPI in rats bearing non‐selective (excitotoxic) or selective cholinergic (Dtx‐UII) lesions of PPTg. Excitotoxic lesions had no effect on ASR but reduced PPI at all prepulse levels tested. In contrast, selective depletion of cholinergic neurons reduced ASR to the extent that PPI was not measurable with standard (10–20 s) inter‐trial intervals. Subsequent testing revealed appreciable ASRs could be generated when the inter‐trial interval was increased (180 s). Under these conditions, PPI was assessed and no deficits were found after lesions of cholinergic PPTg neurons. These results show that cholinergic output from PPTg is essential for rapidly regenerating the ASR, but has no influence on PPI. Results are discussed in terms of sensorimotor integration circuitry and psychiatric disorders that feature disrupted ASR and PPI.     

Sensorimotor gating and habituation of the startle response in schizophrenic patients randomly treated with amisulpride or olanzapine.

BACKGROUND: Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT2A/D2 and a pure D2/D3 antagonist on PPI and habituation of ASR in patients with schizophrenia. METHODS: The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise. RESULTS: Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect. CONCLUSIONS: Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D2 receptor blockade.     

Female schizophrenia patients have prepulse inhibition deficits.

BACKGROUND: Prepulse inhibition (PPI) of startle shows sexual dimorphism: women have lower levels of PPI than do men, and have menstrual cycle shifts in PPI. Many studies report PPI deficits in male schizophrenia patients; one recent report identified PPI deficits in male but not female patients. This study was designed to determine whether female schizophrenia patients have lower levels of PPI than normal females. METHODS: Twenty-five female schizophrenia patients, and 26 normal females were tested in a startle paradigm using 115 dB startle pulses and prepulses of 8 and 16 dB above a 70 dB background, with 30 and 120 msec prepulse intervals. RESULTS: Female patients had significantly less PPI compared with normal females, particularly when 16 dB prepulses were utilized. Patients also exhibited a nonsignificant trend towards lower levels of habituation compared to normal subjects. CONCLUSIONS: Under the present paradigmatic and subject acquisition conditions, female schizophrenia patients had PPI deficits compared to normal females.     

An investigation of prepulse inhibition in pediatric bipolar disorder

OBJECTIVES: Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, have been noted in psychopathologies including schizophrenia and adult bipolar disorder (BPD). Sensorimotor gating deficits may contribute to the emotional and behavioral dysregulation characteristic of pediatric BPD. The current study investigated possible PPI deficits in children with BPD. METHODS: Sixteen children with BPD (medicated, euthymic and non-psychotic) were compared with 13 control subjects on the magnitude of startle habituation, startle-alone response, and inhibition of startle following a 60 or 120-ms prepulse. RESULTS: Both groups displayed startle inhibition by a prepulse, with no significant between-group differences on the magnitude of inhibition after the 60- or 120-ms prepulse. In addition, there were no between-group differences on habituation or baseline startle response. PPI level was not significantly correlated with mood symptoms and did not differ based on comorbid attention deficit hyperactivity disorder. CONCLUSIONS: A lack of PPI deficits in our pediatric bipolar sample contrasts with previous results in adult bipolar and schizophrenic samples. These negative results may reflect the fact that our sample was medicated and was neither acutely manic nor psychotic. Deficits in sensorimotor gating may not be implicated in the emotional and behavioral dysregulation in pediatric BPD.     

Weak prepulses inhibit but do not elicit startle in rats and humans.

BACKGROUND: Inhibition of startle by weak prestimuli is called prepulse inhibition (PPI). It has recently been reported that 10- to 20-dB prepulses trigger eye-blink motor activity and PPI in normal human subjects. Motor activity after prepulses correlated negatively with PPI in four of nine possible conditions. We now report the relationship between prepulse-elicited startle (PPES) and PPI using weak prepulses. METHODS: We assessed PPI and PPES using 1- to 5-dB prepulses in humans and in rats after treatment with vehicle or apomorphine. RESULTS: Prepulses inhibited startle in an intensity-dependent fashion but elicited no startle activity in humans or rats. Apomorphine eliminated PPI in rats and produced a well-documented increase in stimulus-independent motor activity but did not stimulate PPES. CONCLUSIONS: In humans and rats, PPES is not a necessary condition for either the elicitation or the disruption of PPI.     

Impaired prepulse inhibition of acoustic startle in obsessive-compulsive disorder.

BACKGROUND: Animal and clinical studies suggest that impaired sensorimotor gating, as assessed with the prepulse inhibition (PPI) paradigm, may result from dysfunctional frontostriatal brain circuits and from neurochemical alterations which are also implied in the pathophysiology of obsessive-compulsive disorder (OCD). However, there is only preliminary evidence about impaired PPI in OCD so far. METHODS: Acoustic PPI was measured in 30 OCD patients and 30 matched healthy controls with a paradigm using different prepulse intensities. Psychopathology assessment included ratings for obsessions, compulsions, and depression. RESULTS: PPI was reduced in OCD patients, and this deficit was most pronounced for most intense (16 dB(A)) prepulses, where mean PPI was 39.6% in unmedicated patients (n = 4), 45.8% in medicated patients, and 58.9% in controls. No group differences were observed with regard to the habituation of acoustic startle magnitude. Startle measures were generally not associated with clinical measures, although such associations may have been obscured by medication effects. CONCLUSIONS: The present study confirms deficient central inhibitory functioning in patients with OCD and supports the model of deficient frontostriatal circuits in OCD. The relationship of PPI deficits to pharmacological and behavioral treatment and to possible subtypes of OCD merits further study.     

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.     

Disrupted sensory gating in pathological gambling.

BACKGROUND: Some neurochemical evidence as well as recent studies on molecular genetics suggest that pathologic gambling may be related to dysregulated dopamine neurotransmission. METHODS: The current study examined sensory (motor) gating in pathologic gamblers as a putative measure of endogenous brain dopamine activity with prepulse inhibition of the acoustic startle eye-blink response and the auditory P300 event-related potential. Seventeen pathologic gamblers and 21 age- and gender-matched healthy control subjects were assessed. Both prepulse inhibition measures were recorded under passive listening and two-tone prepulse discrimination conditions. RESULTS: Compared to the control group, pathologic gamblers exhibited disrupted sensory (motor) gating on all measures of prepulse inhibition. Sensory motor gating deficits of eye-blink responses were most profound at 120-millisecond prepulse lead intervals in the passive listening task and at 240-millisecond prepulse lead intervals in the two-tone prepulse discrimination task. Sensory gating of P300 was also impaired in pathologic gamblers, particularly at 500-millisecond lead intervals, when performing the discrimination task on the prepulse. CONCLUSIONS: In the context of preclinical studies on the disruptive effects of dopamine agonists on prepulse inhibition, our findings suggest increased endogenous brain dopamine activity in pathologic gambling in line with previous neurobiological findings.     

Sensorimotor gating of schizophrenia patients depends on Catechol O-methyltransferase Val158Met polymorphism

It has been recently shown that Catechol O-methyltransferase (COMT) Val(158)Met polymorphism strongly influences prepulse inhibition (PPI) of the acoustic startle response (ASR) in healthy human volunteers. Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val(158)Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val(158)Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val(158)Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes. These preliminary results imply that PPI is influenced by COMT Val(158)Met genotype in schizophrenia as well. In concert with other findings, our data suggest that PPI is a polygenic trait.     

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-elicited startle in prepulse inhibition.

BACKGROUND: Prepulse inhibition (PPI) has become a major experimental paradigm in the study of psychiatric disorders. In this study, a potential confound in measurement and interpretation of PPI, namely startle reactions to so-called "nonstartling" prepulses, was examined. METHODS: Prepulses of 80, 85, and 90 dB(A) were presented on their own or followed by a pulse of 115 dB(A) (lead interval: 120 msec). RESULTS: Even at only 80 dB(A), prepulses presented alone elicited a response in about 50% of trials; and, except in the first stage of the experiment, responses became more frequent as prepulse intensity increased. Importantly, PPI at 80 and 85 dB(A) was negatively correlated with response probability to prepulses presented alone. CONCLUSIONS: Prepulses reliably activate the very startle system that they are thought to inhibit, and a high level of responsiveness to prepulses is associated with relatively lower levels of PPI. These findings might hold important implications for clinical and psychopharmacologic studies of PPI, and we suggest that the extent and influence of prepulse-elicited startles should be routinely examined.     

Verbal fluency in adults with high functioning autism or Asperger syndrome

The semantic and phonemic fluency performance of adults with high functioning autism (HFA), Asperger syndrome and a neurotypical control group were compared. All participants were matched for age and verbal ability. Results showed that the participants with HFA were significantly impaired in their performance of both semantic fluency tasks and the phonemic fluency task using the letter M. The Asperger group was only impaired in their performance of the semantic fluency task ‘professions’. The social components of the ‘professions’ task may have influenced the performance of the two disorder groups for this subtest negatively. The fluency deficits could not be attributed to a lack of the use of strategies or to difficulties in switching between strategies. The impairment in two of the three verbal fluency subtests in the HFA group can be attributed to the relatively low processing speed found in this group.     

Impaired Sensorimotor Gating Using the Acoustic Prepulse Inhibition Paradigm in Individuals at a Clinical High Risk for Psychosis

Many robust studies have investigated prepulse inhibition (PPI) in patients with schizophrenia. Recent evidence indicates that PPI may help identify individuals who are at clinical high risk for psychosis (CHR). Selective attention to prepulse stimulus can specifically enhance PPI in healthy subjects; however, this enhancement effect is not observed in patients with schizophrenia. Modified PPI measurement with selective attentional modulation using perceived spatial separation (PSS) condition may be a more robust and sensitive index of PPI impairment in CHR individuals. The current study investigated an improved PSSPPI condition in CHR individuals compared with patients with first-episode schizophrenia (FES) and healthy controls (HC) and evaluated the accuracy of PPI in predicting CHR from HC. We included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes. The measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI conditions were applied using 60- and 120-ms lead intervals. Compared with HC, the CHR group had lower PSSPPI level (Inter-stimulus interval [ISI] = 60 ms, P < .001; ISI = 120 ms, P < .001). PSSPPI showed an effect size (ES) between CHR and HC (ISI = 60 ms, Cohen’s d = 0.91; ISI = 120 ms, Cohen’s d = 0.98); on PSSPPI using 60-ms lead interval, ES grade increased from CHR to FES. The area under the receiver operating characteristic curve for PSSPPI was greater than that for PSCPPI. CHR individuals showed a PSSPPI deficit similar to FES, with greater ES and sensitivity. PSSPPI appears a promising objective approach for preliminary identification of CHR individuals.     

Involvement of nucleus accumbens dopaminergic transmission in acoustic startle: observations concerning prepulse inhibition in rats with entorhinal cortex lesions

The relationship between the entorhinal cortex and prepulse inhibition (PPI) as well as the nucleus accumbens dopaminergic participation in acoustic startle were examined in rats. After the entorhinal cortex was damaged bilaterally using ibotenic acid, a microdialysis probe was placed in the nucleus accumbens for detection of dopamine before, during and after acoustic startle stimuli. In rats with bilateral entorhinal cortex lesions PPI was reduced, and extracellular dopamine in the nucleus accumbens was elevated with or without acoustic stimuli. The entorhinal cortex and the sensorimotor gating system thus may be related via dopaminergic connections in the nucleus accumbens, even though dopamine release did not coincide completely with acoustic startle stimuli.     

Neural correlates of altered sensorimotor gating in boys with Tourette Syndrome: A combined EMG/fMRI study

Objectives: It has been hypothesised that altered sensorimotor gating might be a core problem in Tourette Syndrome (TS). However, the underlying neurophysiological mechanisms are elusive. Methods: We applied functional magnetic resonance imaging (fMRI) to investigate the neural correlates of altered sensorimotor gating by means of prepulse inhibition (PPI) in 22 boys with TS and 22 healthy boys using tactile PPI. The electromyography of the startle response was recorded simultaneously to the acquisition of the fMRI images. Results: As expected, PPI of the startle response was reduced in boys with TS compared to the healthy boys. We found decreased PPI-related blood oxygen level-dependent (BOLD) activity in boys with TS in the middle frontal gyrus, postcentral gyrus, superior parietal cortex, cingulate gyrus and caudate body. In boys with TS PPI of the startle response was positively correlated to PPI-related BOLD activity in the superior parietal cortex. Conclusions: Our findings indicate that deficient sensorimotor gating in boys with TS is associated with reduced recruitment of brain regions responsible for the higher-order integration of somatosensory stimuli. Due to our strict sample selection we were able to reduce confounding by neural adaptation processes, long-term medication, gender or comorbidities.