Mismatch negativity predicts initial auditory-based targeted cognitive training performance in a heterogeneous population across psychiatric disorders.

Auditory-based targeted cognitive training (ATCT) programs are emerging pro-cognitive therapeutic interventions which aim to improve auditory processing to attenuate cognitive impairment in a "bottom up" manner. Biomarkers of early auditory information processing (EAIP) like mismatch negativity (MMN) and P3a have been used successfully to predict gains from a full 40 h course of ATCT in schizophrenia (SZ). Here we investigated the ability of EAIP biomarkers to predict ATCT performance in a group of subjects (n = 26) across SZ, MDD, PTSD and GAD diagnoses. Cognition was assessed via the MATRICS Consensus Cognitive Battery (MCCB) and MMN/P3a were collected prior to completing 1 h of "Sound Sweeps," a representative ATCT exercise. Baseline and final performance over the first two levels of cognitive training served as the primary dependent variables. Groups had similar MMN, but the SZ group had attenuated P3a. MMN and MCCB cognitive domain t-scores, but not P3a, were strongly correlated with most ATCT performance measures, and explained up to 61% of variance in ATCT performance. Diagnosis was not a significant predictor for ATCT performance. These data suggest that MMN can predict ATCT performance in heterogeneous neuropsychiatric populations and should be considered in ATCT studies across diagnostically diverse cohorts.

Preliminary Evidence that Memantine Enhances Prepulse Effects on Startle Magnitude and Latency in Patients with Alzheimer's Disease.

BACKGROUND: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer's disease (AD); conceivably, its acute impact on PPI might be used to predict a patient's sensitivity to MEM's therapeutic effects. OBJECTIVE: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients. METHODS: 18 carefully screened individuals with AD (mean age = 72.8 y; M:F=9 : 9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency. RESULTS: Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p < 0.04; d = 0.40); this comparison reached a large effect size for the 60 ms interval (d = 0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency ("latency facilitation") and this effect was amplified after MEM (p = 0.03; d = 0.41; for 60 ms intervals, d = 0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures. CONCLUSION: MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient's neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a "biomarker" measured at the outset on treatment can predict sensitivity to MEM's therapeutic effects.

Effects of the first prepulse on the blink response to a startling noise.

Startle is inhibited when a startling stimulus follows 30-300 ms after a weak prepulse. Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is deficient in several neuropsychiatric disorders. Previous reports argue both for and against a learned component to the inhibitory effects of prepulses, but this issue has yet to be fully investigated using stimuli that most commonly detect PPI deficits in clinical populations. If the inhibitory impact of a prepulse is learned, PPI should not be evident when the prepulse is the first stimulus experienced by the subject. Eyeblink electromyography in normal adults was recorded after either a 118 dB(A) 40-ms noise pulse alone (PA) or the same pulse preceded 120 ms by an 86 dB(A) 5-ms noise prepulse (pp+P). In 25 subjects (Order 1), Trial 1 was a PA, and Trial 2 was a pp+P; 23 subjects experienced the opposite order (Order 2). In 34 subjects, Trials 1 and 2 were both PA (control order). Background was 70 dB(A). Startle magnitude increased from Trial 1 to 2 if no prepulse was presented (control order). Compared with the control order, startle inhibition by prepulses was evident in both Orders 1 and 2, and was more robust in Order 2 (first trial=pp+P). Startle magnitude was significantly lower on pp+P than on PA trials in Order 2 but not Order 1 (F<1). Prepulses inhibit startle on the first pairing with a startling pulse, an effect that cannot be explained by learning.

Effects of prepulse intensity, duration, and bandwidth on perceived intensity of startling acoustic stimuli.

Intense abrupt stimuli can elicit a startle reflex; a weak "prepulse" 30-300 ms earlier can reduce both startle and perceived stimulus intensity. Prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, is used to understand brain disorders characterized by gating deficits. Compared to startle, PPI of perceived stimulus intensity (PPIPSI) may provide information that is distinct, and easier to acquire and analyze. To develop this experimental measure, we examined PPIPSI under different stimulus conditions. Both PPI and PPIPSI exhibited a non-linear relationship to prepulse intensity, with prepulses 15 dB(A) above background causing maximal inhibition of both measures. A 50 ms broadband noise prepulse produced maximal PPI and PPIPSI, whereas 5 and 20 ms pure tone prepulses produced maximal PPIPSI and PPI, respectively. PPIPSI is a robust, parametrically sensitive and "low tech" measure of sensory gating that may become a valuable tool for understanding the biology of certain mental disorders.

Antipsychotic effects on prepulse inhibition in normal 'low gating' humans and rats.

Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg p.o.) on PPI in 20 normal men with a 'low PPI' trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20-30 ms) in 'low gating' human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals <120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal 'low gating' appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.

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.

Amphetamine effects on prepulse inhibition across-species: replication and parametric extension.

Despite the similarities of prepulse inhibition (PPI) of the startle reflex and its apparent neural regulation in rodents and humans, it has been difficult to demonstrate cross-species homology in the sensitivity of PPI to pharmacologic challenges. PPI is disrupted in rats by the indirect dopamine (DA) agonist amphetamine, and while studies in humans have suggested similar effects of amphetamine, these effects have been limited to populations characterized by smoking status and specific personality features. In the context of a study assessing the time course of several DA agonist effects on physiological variables, we failed to detect PPI-disruptive effects of amphetamine in a small group of normal males. The present study was designed to reexamine this issue, using a larger sample and a paradigm that should be more sensitive for detecting drug effects. PPI in rats was shown to be disrupted by the highest dose of amphetamine (3.0 mg/kg) at relatively longer prepulse intervals (>30 ms). In humans, between-subject comparisons of placebo (n=15) vs 20 mg amphetamine (n=15) failed to detect significant PPI-disruptive effects of amphetamine, but significant PPI-disruptive effects at short (10-20 ms) prepulse intervals were detected using within-subject analyses of postdrug PPI levels relative to each subject's baseline PPI. Post hoc comparisons failed to detect greater sensitivity to amphetamine among subjects characterized by different personality and physiological traits. Bioactivity of amphetamine was verified by autonomic and subjective changes. These results provide modest support for cross-species homology in the PPI-disruptive effects of amphetamine, but suggest that these effects in humans at the present dose are subtle and may be best detected using within-subject designs and specific stimulus characteristics.

Effects of amantadine and bromocriptine on startle and sensorimotor gating: parametric studies and cross-species comparisons.

BACKGROUND: We recently reported that prepulse inhibition (PPI) in humans was increased by the dopamine (DA) agonist/ N-methyl- D-aspartate (NMDA) antagonist amantadine (200 mg), but was not significantly altered by the DA agonist bromocriptine (1.25-2.5 mg). PPI-enhancing effects of DA agonists occur in rats under specific stimulus conditions, including short prepulse intervals (<30 ms). We characterized the effects of amantadine and bromocriptine on PPI across species, assessing: (1) dose-response effects on PPI in rats over 10- to 120-ms prepulse intervals; (2) drug effects on PPI in humans, using this same range of prepulse intervals; and (3) drug effects on measures related to PPI, including PPI of perceived stimulus intensity (PPIPSI), and startle habituation. METHODS: Drug effects on PPI were assessed in male Sprague Dawley rats ( n=90) and humans ( n=49); startle habituation and PPIPSI were also studied in humans. RESULTS: Amantadine and bromocriptine exhibited dose- and stimulus-dependent effects on PPI in rats, increasing PPI with short (10-20 ms) prepulse intervals, and decreasing PPI with long (60-120 ms) prepulse intervals. In humans, amantadine increased PPI with both short (20 ms) and long (120 ms) prepulse intervals. Bromocriptine had no significant effect on PPI in humans, but tended to increase PPI at short (20 ms) intervals. Amantadine eliminated PPIPSI. CONCLUSIONS: Amantadine modifies prepulse effects on startle in rats and humans, and disrupts prepulse effects on perceived stimulus intensity in humans; bromocriptine has clear effects on PPI in rats, but not in humans. The divergent effects of amantadine on sensorimotor and sensory effects of prepulses may reflect a divergence of brain circuitry regulating these processes.