Prepulse inhibition

Prepulse inhibition: preceding stimulus attenuates the startle response.

Prepulse Inhibition (PPI) is a neurological phenomenon in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong startling stimulus (pulse). The stimuli are usually acoustic, but tactile stimuli (e.g. via air puffs onto the skin) ^[1] and light stimuli ^[2] are also used.

The reduction of the amplitude of startle reflects the ability of the nervous system to temporarily adapt to a strong sensory stimulus when a preceding weaker signal is given to warn the organism. PPI is detected in numerous species ranging from mice to human. Although the extent of the adaptation affects numerous systems, the most comfortable to measure are the muscular reactions, which are normally diminished as a result of the nervous inhibition.

Deficits of prepulse inhibition manifest in the inability to filter out the unnecessary information; they have been linked to abnormalities of sensorimotor gating. Such deficits are noted in patients suffering from illnesses like schizophrenia and Alzheimer's disease, and in people under the influence of drugs, surgical manipulations, or mutations. Human studies of PPI have been summarised in reviews by Braff et al. (2001)^[3] and Swerdlow et al. (2008).^[4]

PPI and startle reflex apparatus for mice

Procedure

PPI measurement in human.

The main three parts of the procedure are prepulse, startle stimulus, and startle reflex. Different prepulse-to-pulse intervals, or lead intervals, are used: 30, 60, 120, 240 and 480 ms. Lead interval counts from the start of prepulse to the start of the pulse. With the interval exceeding 500 ms, prepulse facilitation - increased response - is most likely to follow.^[5]

A burst of white noise is usually used as the acoustic startle stimulus. Typical durations are 20 ms for prepulse and 40 ms for pulse. Background noise with 65-70 dB is used in human studies, and 30-40 dB in rodent experiments. Prepulse is typically set 3-12 dB louder than background. Startle response is measured in rodents using the so-called automated "startle chambers" or "stabilimeter chambers", with detectors recording whole-body reaction.^[5]

In humans, the movements of oculomotor muscles ("eye-blink reflex" or "eye-blink response" assessed using electromyographic recording of orbicularis oculi muscle and by oculography) could be used as a measure. Pulse-alone results are compared to prepulse-plus-pulse, and the percentage of the reduction in the startle reflex represents prepulse inhibition. Possible hearing impairment must be taken into account, as, for example, several strains of mice develop high frequency hearing loss when they mature.^[5]

Major features

• The magnitude of PPI is often significant, reaching as much as 65% in healthy subjects.
• Maximum inhibition is typically observed at 120 ms interval.^[6]
• Baseline startle response does not affect overall PPI levels – this finding was first discovered in rat studies^[7] and later duplicated in the studies of mice.^[8]
• The opposite reaction, Prepulse Facilitation (PPF), is typically noted when the interval between stimuli lasts longer than 500 ms. PPF is thought to reflect, at least partially, sustained attention.
• There is noted sex difference in prepulse inhibition, with men having higher PPI, while women having higher PPF.^[9]
• Monaural PPI is higher than binaural.^[10][11]
• Even the very first prepulse of a test session induces inhibition, which indicates that conditioning and learning are not necessary for this effect to occur. However, the lack of conditionality has been questioned.^[12]
• However a thousandth prepulse also induces inhibition; the phenomenon is highly robust^[13]
• It is thought that the short intervals used in PPI task do not give enough time for the activation of a volitional response.
• Prepulses could be attended or ignored, and attention affects the outcome. In one study, normal college students were instructed to attend to one of the kind of prepulses, high- or low-pitched, and ignore the other. Attended prepulse caused significantly greater inhibition at the 120 ms interval compared to the ignored one, and significantly greater facilitation at the 2000 ms interval.^[14]
• Louder background noise increases the amplitude of the startle response.
• Increased prepulse duration leads to increase in PPI.
• Steady background noise facilitates the startle response, while pulsed background produces inhibition.^[15]

History of Scientific Work

Prepulse inhibition was first described in 1862 by Sechenov and was rediscovered at least twice before Howard S. Hoffman discovered it again in 1963. Hoffman was the first to use the term prepulse. He continued his work on startle into the 1980s. His many papers on the reflex and its modification laid the groundwork for the widespread use of prepulse inhibition today in studies of schizophrenia and other disorders.^[16]

One possible reason it was discovered and rediscovered is that it got confused with Pavlovian conditioning. Another is that it didn't fit nicely into theories of the times.^[17]

Disruption of PPI

Disruptions of PPI are studied in humans and many other species. The most studied are deficits of PPI in schizophrenia, although this disease is not the only one to be associated with such deficits. They have been noted in panic disorder (Ludewig, et al., 2005), schizotypal personality disorder,^[18] obsessive-compulsive disorder(Swerdlow et al., 1993), Huntington's disease,^[19] nocturnal enuresis and attention deficit disorder (Ornitz et al. 1992), and Tourette's syndrome (Swerdlow et al. 1994; Castellanos et al. 1996). According to one study, people who have temporal lobe epilepsy with psychosis also show decreases in PPI, unlike those who have TLE without psychosis.^[20] Therefore, PPI deficits are not typical to specific disease, but rather tell of disruptions in a specific brain circuit.

PPI deficit in schizophrenia

PPI deficits represent a well-described finding in schizophrenia, with the first report dating back to 1978.^[21] The abnormalities are also noted in unaffected relatives of the patients.^[22][23] In one study, patients failed to show increased PPI to attended prepulses.^[24] Dopamine, which plays a major role in schizophrenia, had been shown to regulate sensorimotor gating in rodent models.^[25][26] These findings fit to the dopamine hypothesis of schizophrenia. In theory, PPI disruption in schizophrenia may be related to the processes of sensory flooding and cognitive fragmentation.

Antipsychotic medication have been shown to increase PPI in patients, with atypical antipsychotics having more effect. Patients display the same gender difference in PPI as healthy people: males have higher PPI compared to females. One notable finding is that patients are specifically deficient in PPI with 60 ms prepulse intervals relative to intervals of other lengths; this remains so even under antipsychotic treatment.^[27]

The other fact is the influence of cigarette smoking. Non-smoking patients have lower PPI compared to smokers, and heavy smokers have the highest PPI.^[27][28] This finding runs in accord with the high rates of smoking among schizophrenic patients, estimated at 70%,^[29] with many patients smoking more than 30 cigarettes a day.^[30] Some studies show association of schizophrenia with the CHRNA7 and CHRFAM7A genes, which code for alpha7 subunit of nicotinic receptors, but other studies are negative.^[31][32] Contrary to the predictions, nicotine receptor alpha7 subunit knockout mice do not show disruptions in PPI.^[33]

Disruption of PPI in rodents

Murine models are widely used to test hypotheses linking genetic components of various diseases with sensorimotor gating. While some of the hypotheses stand to the test, others are not, as some mice models show unchanged or increased PPI contrary to the expectations, as in the tests of COMT-deficient mice.^[34]

Certain surgical procedures also disrupt PPI in animals, helping to unravel the underlying circuitry.

Many animal studies of PPI are undertaken in order to understand and model the pathology of schizophrenia.^[35] Schizophrenia-like PPI disruption techniques in rodents have been classified in one review^[36] into four models:

• PPI impairment driven by dopamine-receptor agonists, most validated for antipsychotic studies;
• PPI impairment by 5-HT2 receptor agonists;
• PPI impairment by NMDAR antagonists;
• PPI impairment by developmental intervention (isolation rearing, maternal deprivation).

Diverse chemical compounds are tested on animals with such deficits. Compounds that are able to restore PPI could be further investigated for their potential antipsychotic role.

An updated summary of both preclinical and clinical findings with PPI can be found in a recent comprehensive review.^[4]

See also

• Latent inhibition

References

External links

• Table listing the action of different chemical compounds on PPI in mice - from the review by Geyer et al., 2002
• Losing Your (Prepulse) Inhibitions—All About α3 GABAA? - Schizophrenia Research Forum
• Prepulse Inhibition Deficits Predict Functional Difficulties in Schizophrenia - Schizophrenia Research Forum
• An Analysis of Nicotine Exacerbation of Reductions in PPI in a Rodent Model of Schizophrenia - a master's thesis with a thorough review of schizophrenia PPI disruption models in rodents