Pre-pulse inhibition

When using sound stimuli, the amplitude of the so-called “ acoustic startle response ” ( ASR ) is measured . Non-sonic stimuli and their combinations are sometimes used - in this case they speak of a sensory startle response (SSR ). A stimulus can be a flash of light, a light click on an over- nose ( English glabellar tap ), a breath of air. A combination of different types of stimuli is practiced, for example, sound pre-pulse and click, or light pre-pulse and sound pulse.

Measurement of PPI in rodents takes place in the so-called " startle chambers ", equipped with motion detectors. In humans, the reaction of the oculomotor muscles is usually measured. When using sound, possible hearing impairments are taken into account.

Various interpulse intervals are used - 30, 60, 120, 240 and 480 ms. The interval duration is calculated from the beginning of the pre-pulse to the beginning of the pulse. At intervals longer than 500 ms, the reverse reaction usually occurs - prepulse facilitation (PPF ). The typical pre-pulse duration is 20 ms, and the pulse duration is 40 ms. An acoustic test usually uses background white noise . The pre-pulse volume, as a rule, is set above the background by 3-12 decibels , while acoustic stimuli are also usually white noise.

• The amplitude of inhibition reaches 65% in healthy people.
• Maximum inhibition is usually observed at an inter-pulse interval of 120 ms. ^[2]
• The basic reaction of fright does not affect the strength of inhibition - this was first noted in experiments with rats, ^[3] then confirmed in experiments on mice. ^[four]

• The reverse reaction, pre-pulse amplification, usually accompanies the inter-pulse intervals lasting more than 500 ms. PPF is believed to some extent reflect the ability to maintain attention .
• In men, on average, pre-pulse inhibition is stronger, while in women, pre-pulse amplification is more pronounced. ^[five]

• PPI is more pronounced when using only one ear than when using both. ^{[6] [7]}

• Inhibition of the reaction occurs at the first signal even during the first test, therefore, for the emergence of the PPI reaction, training and conditioning are not required. However, the lack of the impact of training on the PPI response is challenged. ^[eight]

• It is believed that the brevity of the delay between signals does not allow the use of volitional control in the response.
• At the same time, it is possible to set the task to ignore some pre-pulses and respond to others. In one study, healthy subjects demonstrated enhanced responses of PPI and PPF at intervals of 120 ms and 2000 ms to stimuli of a given type, and weakened responses to stimuli that needed to be ignored. ^[9]
• The amplitude of the fright reaction increases with an increase in background noise , as well as with an elongation of the pre-pulse.
• With stable background noise, the fright response is stronger than with pulsating. ^[ten]

Studies of PPI disorders are conducted in humans and many other species. PPI deficiencies in schizophrenia are the most studied, although they are typical not only for this disease. They are also noted in panic disorder , (Ludewig, et al., 2005) schizotypal personality disorder , ^[11] obsessive-compulsive disorder, (Swerdlow et al., 1993), Huntington’s disease, ^[12] enuresis , attention deficit (Ornitz et al. 1992), and Tourette’s syndrome (Swerdlow et al. 1994; Castellanos et al. 1996). According to one study, people with temporal lobe epilepsy and psychosis have PPI deficiency, while deviations are not found in the form of the disease without psychosis. ^[13] Therefore, PPI deficiencies are associated not with a specific disease, but with disorders in certain neural connections.

PPI Deficiency in Schizophrenia

A decrease in PPI has been described in many schizophrenia studies. The first mention dates back to 1978 . ^[14] Abnormalities were also noted in healthy relatives of patients. ^{[15] [16]} One study showed that when focusing on a prepulse, patients did not experience PPI enhancement. ^[17] Dopamine , which plays a significant role in schizophrenia, regulates the sensorimotor filtering of information in rodents. ^{[18] [19]} These findings fit into hypothetical descriptions of the dopamine mechanisms of the disease, possibly being associated with processes of sensory overload and fragmentation of cognitive processes.

Antipsychotics have been shown to increase PPI in patients, while atypical antipsychotics show a greater effect. Sexual differences in response in patients do not differ from those in healthy people: in men, inhibition is stronger. Patients showed a specific PPI deficiency at an interval of 60 ms; even with therapy, this interval gives a reduced inhibition reaction. ^[20]

It was noted that smokers have higher PPIs than non-smokers, with the strongest inhibition recorded in most smokers. ^{[20] [21]} This finding is consistent with evidence of patients' addiction to cigarettes . About 70% of patients smoke, ^[22] and many smoke more than 30 cigarettes per day. ^[23] Perhaps this somehow improves the condition of patients. In some works, the association of schizophrenia with the CHRNA7 and CHRFAM7A genes encoding the nicotinic receptor subunits is noted, but in other works this correlation is not found. ^{[24] [25]} Contrary to expectations, mouse alpha receptor subunit alpha7 subunits have normal PPI. ^[26]

Animal PPI Models

Active studies of PPI in animals are ongoing to better understand and model schizophrenia. ^{[27] The} methods for generating schizophrenia-like PPI disorders, according to a review by Geyer et al., Fit into four models: ^[28]

• Disruption of PPI by dopamine receptor agonists. Used when searching for antipsychotics.
• Use of 5-HT2 Serotonin Receptor Agonists
• Use of NMDA Antagonists
• Intervention in the development process (raising an animal in isolation, deprivation of communication with the mother). Various drugs are tested on such animals, and increased inhibition is considered a sign of a possible antipsychotic effect.

• FABP7 , a marker of radial glia - association with PPI in mice, association with schizophrenia in humans. ^[29]

• 5-HT2A encoding a serotonin receptor . ^[thirty]

• Point knockout of the NCDN gene in mice reduces PPI by 20%. ^[31]

• Prepulse Inhibition Deficits Predict Functional Difficulties in Schizophrenia - Schizophrenia Research Forum. Review of publication. ^[1] Translation: Pre-pulse inhibition (PPI) and the level of functioning of patients with schizophrenia (inaccessible link) .