Pharmacogenetics,pharmacogenomics and personalized psychiatry: Are we there yet?

Previous studies suggest an important role for serotonergic (5-HT) modulation of the acoustic startle reflex (ASR) and prepulse inhibition (PPI). Acute challenge of brain serotonin by means of tryptophan depletion test (TDT) represents an established human challenge tool for temporary reduction of tryptophan (-TRP) levels and central nervous serotonin. Under these experimental conditions, PPI was found attenuated in males, but greater biochemical effects of TDT in the central nervous system of females are known. Therefore, in order to explore influence of 5-HT on various standard startle parameters in females, 16 young healthy females participated in a double-blind, cross-over TDT study. Acoustic stimuli were presented in 15 pulse-alone trials (100 dB, 40 ms) randomly followed by 25 pulse-alone or prepulse (70 dB, 30 ms; 120 ms interval) trials alongside electromyographic eyeblink recordings and mood state assessments. During 81% depletion of free plasma TRP, mean ASR magnitudes were significantly reduced compared to control (+TRP) condition while there were no differences in habituation or PPI nor did startle parameters correlate with mood states. Changes of plasma TRP and mood states correlated in tendency negatively in (-TRP) for depression and positively in (+TRP) for fatigue. In conclusion, this first study of startle parameters after TDT in a homogenous female population demonstrates that depletion of brain 5-HT in women only influences ASR.     

Patients with adverse mood effects from combined oral contraceptives have lower levels of prepulse inhibition than healthy controls

BACKGROUND: Negative mood symptoms remain one of the major reasons for discontinuation of oral contraceptive pills. The aim of this study was to compare acoustic startle response and prepulse inhibition (PPI) in women with different experience of oral contraceptive pills. METHODS: Thirty women currently on combined oral contraceptives (COCs) with no reports of adverse mood symptoms, 28 women currently on COCs and experiencing mood-related side effects from treatment, 27 women who had discontinued COC use for reasons other than adverse mood symptoms and 32 women who had discontinued COC use due to adverse mood effects were included. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of musculus Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78, or 86dB. RESULTS: Patients with adverse mood effects of COCs exhibited lower levels of PPI with 86dB prepulse compared to COC users with no adverse effects of COCs (p<0.05). There was no difference in PPI between the two groups of prior COC users. No significant difference was found between the groups regarding acoustic startle response. CONCLUSION: Relative to COC users with no reports of adverse mood symptoms, subjects suffering from COC-induced negative mood displayed deficits in PPI of acoustic startle. The fact that there was no difference in PPI between the two groups of prior COC users indicates that deficient PPI is related to adverse mood effects caused by COCs.     

Effects of personality trait emotionality on acoustic startle response and prepulse inhibition including N100 and P200 event-related potential

ObjectivesTo examine the association of personality trait-emotionality (behavioural inhibition system, BIS; behavioural activation system, BAS; anxiety and fear) and measures of auditory startle response (ASR) and prepulse inhibition (PPI) in a non-clinical sample.MethodsForty-seven women were tested for ASR and prepulse inhibition of the eyeblink component of the startle reflex as measured by electromyographic (EMG) responses of the left orbicularis oculi muscle and N100 and P200 components of the event-related potential (ERP) using sLORETA (standardized low resolution brain electromagnetic tomography). Startling stimuli (115 dB, 40 ms) were presented alone (pulse-alone) or were preceded by discrete (20 ms) prepulse stimuli (85 dB) at three prepulse-to-pulse intervals (30, 60 and 120 ms) over a steady background noise (70 dB). Measures of trait emotionality were assessed using a comprehensive battery of theoretically motivated personality scales.ResultsConsistent with previous reports, PPI (defined as percentage reduction in the amplitude of the ASR) increased as the prepulse-to-pulse interval increased. PPI measures were insensitive to individual differences in personality traits, while measures of ASR to pulse-alone stimuli disclosed significant effects. Higher BAS was associated with reduced N100 and P200 amplitudes to the pulse-alone stimulus, and with reduced current density for the N100 in the parietal lobe (BA40 and BA31). This effect indicated a smaller sensitivity or a higher avoidance level of these individuals for negative-startle stimuli. Higher trait anxiety was associated with larger ASR, suggesting an enhanced sensitivity to intense stimuli and a hasty style of reaction in anxious individuals. Lower self-report fear was associated with larger P200 amplitude, and enhanced current density in the medial and superior frontal gyrus (BA6). This effect indicates that prefrontal cortex may play an important role in inhibiting fear responses.ConclusionsOur findings are in good accordance with existing brain imaging studies and underline that ERP source localization is a useful alternative for identifying startle-relevant cortical regions.SignificanceThe present observations extend previous startle findings observed in clinical samples to normal personality individuals. These results imply that hypotheses derived from clinical data may hold important implications for understanding human emotion and motivation, especially in relation to fear and anxiety.     

Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women

OBJECTIVE: During the postpartum period, estradiol and progesterone levels decline from very high levels during late pregnancy to low levels within 48h of parturition. This period is associated with dysphoric states such as the postpartum blues. Animal studies have suggested an enhanced acoustic startle response and deficient prepulse inhibition (PPI) of startle response following progesterone withdrawal and during the postpartum period. The aim of the current study was to compare acoustic startle response and PPI in healthy third trimester pregnant women and healthy postpartum women. METHODS: Twenty-eight healthy pregnant and 21 healthy postpartum women (examined between 48h and 1 week after delivery) were recruited for the study. In addition, to evaluate the time-course of postpartum changes 11 early postpartum women (examined within 48h following delivery) were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78 or 86dB. RESULTS: Pregnant women exhibited lower levels of PPI compared to late postpartum women, p<0.05. There was no difference between pregnant women and postpartum women examined within 48h of delivery. There was no difference in startle response or habituation to startle response between pregnant women and either of the two groups of postpartum women. CONCLUSION: Healthy women display lower levels of PPI during late pregnancy when estradiol and progesterone levels are high compared to the late postpartum period when ovarian steroid levels have declined.     

Factors governing prepulse inhibition and prepulse facilitation of the acoustic startle response in mice

The influence of prepulses on the acoustic startle response (ASR) was measured in three inbred mouse strains, C57BL/6J, 129/SvHsd, and AKR/OlaHsd, and one hybrid strain produced by crossing wild mice and NMRI mice. Prepulse inhibition (PPI), i.e. reduction of ASR by prepulses, was maximal when the interval between prepulses and startle stimuli was in the range of 37.5-100 ms. Prepulse facilitation (PPF), i.e. increase of ASR by prepulses, was maximal when the prepulse preceded the startle stimulus by 12.5 ms. PPI increased with increasing prepulse SPL, PPF first increased then decreased when prepulse SPL was increased. Percent PPI was independent from startle stimulus SPL. All strains showed a long-term increase of PPI when tested for several days; one strain (129) also showed an increase of PPF over days. The present results clearly show that PPI and PPF are independent processes, which add to yield the final response change. PPF and the observed long-term changes of PPI and PPF are stronger expressed in mice than have been observed in rats under similar conditions. Since there were significant differences between the strains of mice with respect to PPI and PPF, genetically different strains of mice are a promising tool to study these two processes.     

Genetic variation of serotonin receptor function affects prepulse inhibition of the startle

Prepulse inhibition (PPI) is the attenuation of the startle response towards an instantaneous and intense stimulus when preceded by a weaker non-startling stimulus. Deficits in this sensorimotor gating process have been associated with the pathophysiology of schizophrenia and other psychiatric disorders. Among the neurotransmitters involved in PPI modulation, serotonin (5-HT) has so far received comparably little attention. While a recent pharmacological study suggests an important role of different 5-HT receptor (5-HTR) subtypes in PPI modulation, the mechanisms by which 5-HTR impact on PPI remain to be further elucidated. Therefore, we employed a molecular genetic approach in order to examine whether PPI is associated with two functional 5-HTR gene polymorphisms, 5-HTR1A C−1019G and 5-HTR2A T102C. In a sample of 81 healthy volunteers, we found no significant main effects of the polymorphisms, but a significant interaction effect on PPI at short (50 ms) and mid-long (150 ms) pulse–prepulse intervals. The presence of the 5-HTR2A T allele (reported to result in higher 5-HTR2A expression) led to attenuated PPI only in the absence of the 5-HTR1A G allele (reported to result in reduced 5-HTR1A autoreceptor expression). Our results may indicate that a higher 5-HTR2A expression together with a reduced 5-HTR1A autoreceptor expression and consequently, elevated firing rates of serotonergic neurons results in elevated 5-HTR2A activation by serotonin which could potently attenuate PPI. While further research into the molecular mechanisms underlying this interaction is needed, our results underscore the role of 5-HTR in PPI modulation and further implicate the 5-HTR1A G−1019C and the 5-HTR2A T102C polymorphisms in the pathophysiology of schizophrenia.     

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.     

Effects of age-related hearing loss on startle reflex and prepulse inhibition in mice on pure and mixed C57BL and 129 genetic background

The present study examined the developmental course of the age-related hearing loss and its consequences on the expression of acoustic startle reflex (ASR) and prepulse inhibition (PPI) generated by white-noise bursts in 129S2/SvPas (129) and C57BL/6J (C57) mouse strains and their F(1) hybrids. Auditory brainstem responses (ABR), ASR and PPI were assessed at various time points: 6, 28, 41 and 94 weeks. Both parental strains showed marked ABR threshold shifts with age, with C57 mice having the most pronounced deficits. By contrast, the hybrids displayed only minor hearing loss with age. The time courses of ASR and PPI varied considerably between the mouse strains. From 6 to 41 weeks of age, ASR and PPI elicited by weak stimuli (70-90dB) increased in C57 mice, whereas the startle responses to intense stimuli (95-120dB) declined progressively. In 129 and hybrid mice, PPI levels remained relatively stable during the first year, but a progressive increase of ASR was observed in the hybrids for intense stimuli (95-120dB). When animals reached 94 weeks of age, marked deterioration of ASR was observed in all strains, while deficits in PPI were only seen in 129 and C57 mice. These findings show that the time course and the severity of the hearing loss vary considerably between 129, C57 strains and their hybrids, thus suggesting a marked heterogeneity in the genetic mechanisms underlying deafness in mice. They also demonstrate that the age-related hearing loss may have complex consequences on auditory behavioral performances depending of the severity of the deficits, the genetic background as well as the stimuli parameters.     

Opiate-dopamine interactions in the neural substrates of acoustic startle gating in the rat

1. The acoustic startle reflex (ASR) was measured in adult male Dawley rats using startling acoustic stimuli presented either alone or 60-500 msec after a weak acoustic prepulse. 2. The inhibition of the ASR by the prepulse, termed "prepulse inhibition" (PPI), was blocked in animals treated either with the indirect dopamine (DA) agonist d-amphetamine (AMPH) or with the direct DA receptor agonist apomorphine (APO). 3. Pretreatment with the opiate receptor antagonist naloxone (NAL) prevented the AMPH-induced loss of PPI, but did not diminish the APO-induced loss of PPI. 4. The opiate heroin had no significant effect on PPI. 5. Dopaminergic mechanisms that modulate PPI in the rat may be regulated by opiate systems that act presynaptic to the DA receptor; brain opiate receptors may not have direct effects on startle gating independent of this opiate-DA interaction.     

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.     

Prepulse inhibition of the startle response in risperidone-treated patients: comparison with typical antipsychotics

Individuals with schizophrenia are known to show deficits in prepulse inhibition (PPI) of the startle response. PPI refers to a response suppression in reaction to a strong startling stimulus, if preceded briefly by a weak non-startling stimulus and represents a well-established animal model to investigate information processing deficits in schizophrenia. This study examined PPI of the startle acoustic response in schizophrenic patients given typical antipsychotics or a second generation atypical antipsychotic, risperidone, using a naturalistic between-subjects design. Two groups of male schizophrenic patients: (i) stable on a range of typical antipsychotics (n = 20), and (ii) stable on risperidone (n = 10) were tested for PPI (prepulse-to-pulse intervals: 30, 60, and 120 ms, prepulses 15 dB above the background) of the acoustic startle response, and compared with a group of healthy male subjects (n = 20). Patients on typical antipsychotics showed significantly less PPI with 30 and 60 ms prepulse trials than healthy subjects. Risperidone-treated patients did not differ from healthy subjects for PPI with any prepulse trials. Further longitudinal within-subject studies are now required to examine whether risperidone is superior to typical antipsychotics in improving information processing functions, as assessed by PPI of the acoustic startle response, in treatment-responsive male patients with schizophrenia.     

Sex differences in the acoustic startle response and prepulse inhibition in Wistar rats

The prepulse inhibition paradigm (PPI) is based on the phenomenon that the acoustic startle response (ASR) to an acoustic stimulus is reduced when the stimulus is preceded by a weak prepulse. It has been shown that PPI is dramatically disrupted in patients with schizotypic disorders. Since PPI can be easily tested in animals as well as in humans it is a widely used model to investigate the neurobiological mechanisms underlying those disorders. In humans it has been demonstrated that men show increased PPI at weak prepulses relative to women. Only very few studies have investigated PPI sex differences in rats and these report negative findings. Studies are reported on here where consistent differences have been found in ASR and PPI between adult male and female Wistar rats. Compilation of data from a series of experiments demonstrates that ASR and PPI are both greater in males than in females in this rat strain, a finding which is largely in line with the human evidence. This study therefore adds weight to the argument that PPI of the ASR provides an animal model with high validity for the study of important human disorders which are characterized by sensorimotor gating deficits.     

Effects of background and prepulse characteristics on prepulse inhibition and facilitation: implications for neuropsychiatric research.

BACKGROUND: Both prepulse inhibition (PPI) and prepulse facilitation (PPF) deficits have been reported in schizophrenia patients, but the use of different experimental parameters across laboratories makes direct comparisons of results difficult. We assessed the effects of different parameters on PPI and PPF in normal subjects. METHODS: Eyeblink startle was measured in 14 healthy male subjects, using 115 dB[A] white noise startle pulses and 86 dB[A] prepulses. Analyses compared the effects of: 1) background noise level (ambient 54 vs. 70 dB[A]) on PPI and PPF, 2) prepulse duration (discrete 20 msec vs. continuous) on PPF, 3) prepulse frequency (1000 Hz vs. white noise) on PPI and PPF, and 4) prepulse interval (2000 vs. 4500 msec) on PPF. RESULTS: Compared to an experimentally delivered 70 dB[A] background, ambient 54 dB[A] background led to significantly more PPI (with discrete white noise prepulses), and more PPF (with continuous prepulses). Continuous and longer (4500 msec) prepulses induced more PPF than did discrete and shorter (2000 msec) prepulses. CONCLUSIONS: Paradigmatic differences appear likely to be responsible for divergent findings in studies of PPI and PPF in normal and schizophrenia subjects. The present study should guide investigators in the selection of parameters for assessing PPI and PPF in studies of normal subjects and schizophrenia patients. Attention to the 4 factors of 1) background noise, 2) prepulse duration, 3) frequency, and 4) interval will facilitate comparability of results across different laboratories, especially when using PPI/PPF in schizophrenia research as neural substrate probes, as biomarkers, and as endophenotypes.     

Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion

This study investigated the relationship between depressive symptom response during tryptophan (TRP) depletion and a functional polymorphism of the promoter region of the serotonin (5-HT) transporter gene (SLC6A4).(1) Forty-three subjects in remission from a major depressive episode who underwent TRP depletion were genotyped. DNA was extracted from blood lymphocytes or from cheek cells.(2) The two common alleles are designated long (l) and short (s). Depressive symptoms were measured with the 25-item Hamilton Depression Rating Scale (HDRS).(3) There was a significant association between the l homozygous genotype and the depressive response to TRP depletion, with a significant main effect of time (F = 8.763, df = 3, 38, P = <0.001), and time x l homozygous allele interaction (F = 3.676, df = 3, 38, P = 0.02). Individuals whose genotype predicted increased 5-HT transporter activity may be more susceptible to depressive changes in response to transient 5-HT perturbations. The use of endophenotypic markers for affective disorders such as the mood response to TRP depletion may facilitate studies of complex genetic traits such as depression by decreasing its heterogeneity.     

Behavioral effects of tryptophan depletion in seasonal affective disorder associated with the serotonin transporter gene?

There is some evidence that the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) may be involved in the pathogenesis of seasonal affective disorder (SAD). Short-term tryptophan (TRP) depletion was carried out in 18 drug-free remitted patients who met DSM-IV criteria for SAD. Behavioral effects were measured with the Hamilton Depression Rating Scale (HDRS) both 24 h before and 24 h after TRP depletion. Some of the patients showed behavioral responses such as lowered mood, feelings of guilt, loss of interest, agitation, loss of energy, fatigue, social withdrawal, increased appetite, and carbohydrate craving. It was the aim of our study to investigate whether the genotypes of the serotonin transporter gene were associated with symptoms of transient depressive relapse after TRP depletion. In addition, we matched the SAD patients with healthy control subjects to see if alleles and genotypes of the serotonin transporter gene were associated with SAD. High molecular weight DNA was isolated from peripheral blood leukocytes using standard methods. For the 5-HTT receptor gene, a 17-bp repetitive element of intron 2 was genotyped (variable number tandem repeat, VNTR). Alterations in HDRS scores after TRP depletion showed no significant association with alleles or genotypes of the 5-HTT gene, although heterozygotes showed a trend toward increased HDRS scores. The serotonin transporter is known to play a critical role in the termination of serotonergic neurotransmission by sodium-dependent uptake of 5-HT into the presynaptic neuron. The present study in a small group of SAD patients was unable to demonstrate that the 5-HTT gene plays a role in the pathogenesis of SAD or in short-term depressive relapse after TRP depletion.     

Phencyclidine (PCP)-induced deficits of prepulse inhibition in monkeys

Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating which occurs in both rodents and humans. PPI is deficient in severe neuropsychiatric disorders such as schizophrenia. We investigated PPI in 10 adult monkeys (Cebus apella). Stimuli were 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse of either 8 or 16 dB above the 70 dB background noise. Experiments included a pretreatment baseline session and a session following treatment with either phencyclidine (PCP, 0.12 mg/kg, i.m.) or saline. Comparison of peak amplitudes indicated a significant intensity-dependent decrease in startle response that was similar to that observed in humans under similar experimental conditions. PCP treatment significantly disrupted PPI, but did not reduce responses to startle pulses alone. These results provide the first demonstration of PPI in monkeys. The ability of PCP to induce schizophrenia-like deficits in PPI suggests that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.     

Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects

Prepulse inhibition (PPI) of the startle reflex refers to the ability of a weak prestimulus, the prepulse, to inhibit the response to a closely following strong sensory stimulus, the pulse. PPI is found to be deficient in a number of psychiatric and neurological disorders associated with abnormalities at some level in the limbic and cortico-pallido-striato-thalamic circuitry. We applied whole-brain functional magnetic resonance imaging to elucidate the neural correlates of PPI using airpuff stimuli as both the prepulse and the pulse in groups of (i) healthy subjects and (ii) schizophrenic patients. Cerebral activation during prepulse-plus-pulse stimuli with stimulus-onset asynchronies of 120 ms was contrasted with activation during pulse-alone stimuli. In healthy subjects, PPI was associated with increased activation bilaterally in the striatum extending to hippocampus and thalamus, right inferior frontal gyrus and bilateral inferior parietal lobe/supramarginal gyrus, and with decreased activation in the right cerebellum and left medial occipital lobe. All activated regions showed significantly greater response in healthy subjects than schizophrenic patients, who also showed a trend for lower PPI. The findings demonstrate involvement of the striatum, hippocampus, thalamus, and frontal and parietal cortical regions in PPI. Dysfunctions in any of these regions may underlie observations of reduced PPI in schizophrenia.     

A large single ethnicity study of prepulse inhibition in schizophrenia: Separate analysis by sex focusing on effect of symptoms

Deficits in sensorimotor gating, as measured with prepulse inhibition (PPI), have been considered an endophenotype of schizophrenia. However, the question remains whether these deficits are related to current symptoms. This single site study aimed to explore clinical features related to the modulation of startle reflex in a large sample of Japanese patients with schizophrenia (DSM-IV). The subjects comprised 181 patients and 250 healthy controls matched for age and sex. Schizophrenia symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Startle reflex to acoustic stimuli was recorded using a startle stimulus of 115 dB and a prepulse of four different conditions (intensity: 86 dB or 90 dB; lead interval: 60 ms or 120 ms). Patients exhibited significantly reduced startle magnitude (p < 0.001), habituation (p = 0.001), and PPI (90 dB, 60 ms, p = 0.016; 90 dB, 120 ms, p = 0.001) compared with controls. Patients of both sexes exhibited significantly lower habituation and PPI (90 dB, 120 ms) compared with the same sex controls. We could not detect a significant correlation with any clinical variable in the entire patients, however, when men and women were examined separately, there was a negative correlation with the PANSS cognitive domain (ρ = −0.33, p = 0.008) in men, but not in women. Moreover, when patients were subdivided into four clusters, two clusters with high positive symptoms showed significant PPI deficits in men. Our results suggest that sensorimotor gating is impaired in schizophrenia of both sexes, and PPI deficits may be related to thought disturbance and disorganization in male patients with schizophrenia.     

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.     

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.