Katja Ludewig

Deficits in prepulse inhibition and habituation in never-medicated, first-episode schizophrenia.

BACKGROUND Prepulse inhibition (PPI) is the normal suppression of the startle reflex when an intense startling stimulus is preceded by a barely detectable prepulse. Habituation of the acoustic startle reflex is decrement in response when the same stimulus is presented repeatedly. These factors have been proposed as neurophysiologic measures of sensorimotor gating or filtering and discussed as trait-linked markers for information-processing deficits in schizophrenia-spectrum disorders. The aim of this study was to examine whether first-episode schizophrenia patients also exhibit deficits in PPI and habituation. METHODS Never-medicated male schizophrenic and schizophreniform patients in their first psychotic episode (n=24) were compared with age-matched healthy men (n=21) in an acoustic startle paradigm assessing PPI (30-, 60-, 120-, 240-, and 2000-msec interstimulus intervals) and habituation. RESULTS Compared with control subjects, first-episode patients exhibited significant deficits in both PPI in the 60-msec prepulse condition and startle habituation. Patients also exhibited less facilitation in the 2000-msec prepulse condition. CONCLUSIONS In combination with other studies, these findings indicate that PPI and habituation may be sensitive intermediate phenotypic markers for information-processing deficits in schizophrenic patients.

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.

Stability of the acoustic startle reflex, prepulse inhibition, and habituation in schizophrenia

Prepulse inhibition (PPI) of the acoustic startle reflex has been proposed as a neurophysiological measure of sensorimotor gating. There is high test-retest reliability of both startle magnitude and PPI in non-psychiatric subjects. The present study examined the stability of the acoustic startle reflex and its modulation in patients with schizophrenia. Startle measurements were performed in 19 chronic schizophrenic patients on stable medications and 24 healthy control subjects, three times at one-month intervals. PPI trials with various intervals between the prepulse and the startle stimulus (30, 60. 120, 240, and 2000 ms) were used. Intraclass correlation coefficients (ICC) were computed to assess stability. There was a good test-retest reliability of PPI in both schizophrenic patients (Mean ICC: 0.75) and control subjects (Mean ICC: 0.71). Acoustic startle magnitude was the most stable measure across sessions (Mean ICC schizophrenics: 0.89; Mean ICC controls: 0.89). In both groups, a good test-retest reliability was found in the startle latencies. Habituation and prepulse-induced shortening of latencies exhibited moderate stability. Schizophrenic patients exhibited significantly less PPI than control subjects in the 60 ms prepulse condition. This PPI deficit was evident in all three sessions. These results indicate that PPI is a stable neurobehavioral measure in chronic schizophrenic patients in the absence of changes in clinical state.

The acoustic startle reflex and its modulation: effects of age and gender in humans.

The acoustic startle reflex and its modulation by prepulse inhibition (PPI) and habituation are used in many studies in different fields of neuropsychiatric research. The aim of this study was to examine the effects of age and gender on PPI, startle magnitude, and habituation in healthy human volunteers. Twenty-seven male and 28 female participants of four different age groups (range: 20-60 years) were investigated in an acoustic startle paradigm using a startle stimulus of 115 dB and a prepulse of 86 dB (16 dB over the white noise background) with five different lead intervals (30, 60, 120, 240, and 2000 ms). Seventeen males and 16 female participants were tested three times at monthly intervals. Aged participants showed significantly lower startle magnitude and significantly more habituation than younger participants, but there was no effect of age on PPI or prepulse facilitation. Moreover, there were no effects of gender on startle magnitude, PPI, prepulse facilitation, or habituation measures. Healthy males and females exhibited stable startle magnitudes and PPI across sessions. The results demonstrated that PPI and startle are reliable measures of sensory information processing in both genders and that startle magnitude and habituation are age-dependent measures.

Decision-making strategies by panic disorder subjects are more sensitive to errors

BACKGROUND Decision-making is a complex process, which can be assessed experimentally by the two-choice prediction task. Error-rate, i.e. the frequency of incorrect predictions during this task, is an important factor for the response selection during decision-making. This investigation examined whether the frequency of incorrect predictions has an augmented effect on the number of different strategies underlying decision-making in patients with panic disorder. METHODS Patients with a DSM-IV diagnosis of panic disorder (PD; N=18), unipolar major depressive disorder (MDD; N=18) and normal comparison subjects (C; N=35) were tested with the two-choice prediction task using three error-rate conditions (20, 50, or 80%). The dynamical entropy of the response sequences was used to quantify the number of different strategies generated during the different error-rates. RESULTS At 20% error-rates, panic disorder subjects when compared to MDD and C subjects generated more strategies and switched more frequently between strategies as measured by the dynamical entropy and the range of local dynamical entropies. Response bias measures during the two-choice prediction task and post-test self-assessment did not differ between panic disorder subjects and MDD or C subjects. LIMITATIONS First, panic disorder subjects were medicated. Second, the frequency and intensity of panic attacks and the degree of avoidance behaviors, was not assessed. Third, subjects were tested once only. CONCLUSIONS Panic disorder subjects show uniformly high response sequence unpredictability in the presence of low error-rates, which is consistent with continued search for an optimal response strategy even when the error-rate is low.

A neural network approach to the acoustic startle reflex and prepulse inhibition.

Prepulse inhibition (PPI) is the normal suppression of the startle reflex when an intense stimulus is preceded by a weak non-startling prestimulus. PPI is widely used as a model for sensorimotor gating processes and has been shown to be impaired in various neuropsychiatric disorders, including schizophrenia. We have reproduced startle-like behavior and basic PPI modifications with a neural network. The network design was constrained by the attempt (1) to use as few connections as possible and (2) to relate neuroanatomical structures to the simulated network. Performance of the network was evaluated by the behavior of the simulated motor neurons in response to prepulse and pulse stimuli presented with various lead intervals and prepulse intensities. A delayed inhibitory pathway via the pedunculopontine nucleus (PPTg) to the caudal pontine reticular nucleus was found to be a necessary but insufficient requirement to reproduce basic PPI output patterns. Additional requirements included (a) a low threshold at or below the caudal pontine reticular formation, (b) signal amplification in the inhibitory pathway and (c) prolongation of activity in the inhibitory pathway. On the grounds of the most appropriate output patterns of the simulations, we propose a mechanism of sustained activation in the PPTg due to recursive connections. Relations between stimuli, behavior (motor output) and the underlying architecture are discussed. Potentially, this modeling technique can be extended to investigate the impact of drugs and higher brain regions on PPI.

Behavioural dysregulation of decision-making in deficit but not nondeficit schizophrenia patients

This study aimed to determine whether deficit but not nondeficit schizophrenia showed dysregulation of decision-making. In a two-choice prediction task, the subject is asked to predict whether a stimulus appears on the left or right side of a computer screen. Schizophrenia patients were divided into 12 patients with and 12 patients without deficit syndrome and compared to 12 healthy control subjects. Dynamical entropy and mutual information analyses were used to determine underlying strategies and the degree to which sequences of responses are nonrandom. When compared to controls, deficit but not nondeficit schizophrenia patients showed a dysregulation of decision-making characterized by an increased oscillation between highly predictable and highly unpredictable response sequences. Moreover, in deficit patients, the previous choice was more predictive of the current response. Therefore, the two-choice prediction task may be useful in differentiating between deficit and nondeficit schizophrenia.