Neural mapping of prepulse‐induced startle reflex modulation as indices of sensory information processing in healthy and clinical populations: A systematic review

Abstract Startle reflex is modulated when a weaker sensory stimulus (“prepulse”) precedes a startling stimulus (“pulse”). Prepulse Inhibition (PPI) is the attenuation of the startle reflex (prepulse precedes pulse by 30–500 ms), whereas Prepulse Facilitation (PPF) is the enhancement of the startle reflex (prepulse precedes pulse by 500–6000 ms). Here, we critically appraise human studies using functional neuroimaging to establish brain regions associated with PPI and PPF. Of 10 studies, nine studies revealed thalamic, striatal and frontal lobe activation during PPI in healthy groups, and activation deficits in the cortico‐striato‐pallido‐thalamic circuitry in schizophrenia (three studies) and Tourette Syndrome (two studies). One study revealed a shared network for PPI and PPF in frontal regions and cerebellum, with PPF networks recruiting superior medial gyrus and cingulate cortex. The main gaps in the literature are (i) limited PPF research and whether PPI and PPF operate on separate/shared networks, (ii) no data on sex differences in neural underpinnings of PPI and PPF, and (iii) no data on neural underpinnings of PPI and PPF in other clinical disorders.


| INTRODUCTION
The startle reflex is a rapid and involuntary motor response which is elicited by a sudden and intense sensory stimulus, such as a loud noise or unexpected touch to the body (Graham, 1975). As a protection/defensive response (Yeomans, Li, Scott, & Frankland, 2002), the startle response has been shown to become more intense when presented with threat of pain (Bradley, Silakowski, & Lang, 2008;Davis, 1989) and fear (Davis, Falls, Campeau, & Kim, 1993;Grillon et al., 1999). The startle reflex is seen across all mammals with a consistent motor response (Koch, 1999), typically as an eyeblink response in humans, and as a whole-body motor response in animals (Geyer, Swerdlow, Mansbach, & Braff, 1990;Swerdlow, Braff, & Geyer, 1999).
Although an automatic reflex, the startle response can be modified. For example, startle response will decrease with habituation (Hoffman & Searle, 1968;Tighe & Leaton, 2016) and increase with fear (Davis, Hitchcock, & Rosen, 1988) and negative affect (Bradley, Lang, & Cuthbert, 1993). Prepulse-pulse pairing, whereby a weak sensory stimulus ("prepulse") precedes a startling sensory stimulus ("pulse"), also modulates the startle reflex (Graham, 1975), demonstrating flexibility and plasticity of this brainstem reflex. Prepulsepulse pairing can inhibit, facilitate, or have no effect on the startle response, depending on the length of time between the pulse and prepulse (the stimulus onset asynchrony, SoA). The estimated temporal window for inhibiting the startle reflex, known as Prepulse Inhibition (PPI), is 30-500 ms (Graham, 1975). In humans, amplitude of the eye blink has been demonstrated to be inhibited by 50% or more (Hazlett et al., 2008), with maximal inhibition at 120 ms (Hazlett et al., 2001). To facilitate the startle reflex, known as Prepulse Facilitation (PPF), the SoA should be longer, at >500-6000 ms in humans (see Putnam & Vanman, 1999).

| PPI and PPF: prepulse characteristics, sensory modalities and impact of task instructions
The development of prepulse paradigm protocols applied within current human research have been adapted from animal models studying PPI Swerdlow, Braff, Taaid, & Geyer, 1994). This research uncovered the role of the prepulse in attenuating the startle response in rats by varying parameters of the acoustic prepulse, such as sound intensity, SoA and tone frequency (Hoffman & Searle, 1968;Ison, 1978). This has translated for human research, for example Braff, Geyer and Swerdlow (2001) found greater PPI in both healthy participants and schizophrenia patients when the prepulse presentation was discrete, rather than continuous, and prepulse frequency was white noise, rather than a tone. Investigations into prepulse characteristics has not been conducted for PPF. For PPF, animal and human research show differences in the SoA required to induce PPF. In animals, a much shorter temporal window is required for facilitation, with maximal PPF in hamsters at 100 ms SoA (Sasaki, Iso, Coffey, Inoue & Fukuda, 1998), and mice at <50 ms SoA (Plappert, Pilz & Schnitzler, 2004), rather than 500-6000 ms to facilitate startle reflex response in humans (Putnam & Vanman, 1999).
Prepulse paradigms can also implement different sensory modalities, with the prepulse and pulse stimuli being of the same or different modalities. Typically, an acoustic prepulse paradigm has been used, whereby quiet (prepulse) and loud (pulse) sounds are played. A tactile prepulse paradigm was presented by , administering a weak (prepulse) and a strong (pulse) puff of air. The "fMRIfriendly" paradigm was used to overcome the logistical difficulties of using auditory stimuli during functional magnetic resonance imaging (fMRI), such as the interference of background acoustic noise from the scanner and its application to clinical populations with hypersensitivity to noise.
PPI and PPF are theorised to reflect automatic processing of sensory information, thus researchers also developed an attention-toprepulse paradigm using sound stimuli. In comparison to no-task/ passive prepulse paradigms, whereby participants are not provided with instructions and passively experience the stimuli, the attentionto-prepulse paradigm presents participants with two different prepulses. The two prepulses will usually differ in tone and participants are asked to discriminate between them by paying attention to only one, for example, the higher tone, rather than the lower tone.
Employing task instructions applies differential stimulus significance which leads to different allocated attention. It is hypothesised that attending to the prepulse will enhance the inhibitory or facilitatory effect in healthy participants, in comparison to the ignored prepulses (Dawson et al., 1997;Filion, Dawson, & Schell, 1993;Hazlett et al., 1998). Neuroimaging studies have built upon this paradigm to assess the attentional effects on startle modulation (Hazlett et al., 1998(Hazlett et al., , 2001(Hazlett et al., , 2008. In addition, attention-to-prepulse paradigms typically use longer sounds as the prepulse, such as "short tone" and "long tone" prepulse sounds which are played for 5-7 s (Filion & Poje, 2003;Thorne, Dawson and Schell, 2005), whereas passive prepulse paradigms use short discrete sounds as the prepulse.

| PPI and PPF: assessment and reliability
Eyeblink is typically used as the physiological measure of startle reflex in humans and can be reliably indexed with electromyography (EMG), whereby electrodes measure orbicularis oculi muscle activity. EMG is a robust measure of startle reflex with high stability when comparing acoustic and tactile stimuli (Kumari, Gray, Geyer, et al., 2003) and high inter-rater reliability (Heidinger, Reilly, Wang, & Goldman, 2019). A large number of neuroimaging studies using the prepulse paradigm lack the physiological measure of PPI and PPF due to the logistical challenge of implementing EMG within the MRI scanner, meaning that it is difficult to infer modulation of the startle reflex without a simultaneous behavioural measure. However, recent developments have allowed for fMRI compatible EMG (Schulz-Juergensen, Wunberg, Wolff, Eggert, & Siniatchkin, 2013) or visual monitoring and eyetracking methods, such as infra-red goggles to measure eyeblink during scanning (He et al., 2019;Heidinger et al., 2019). Startle reflex is measured as whole-body startle in animals, typically in rats (Bubser & Koch, 1994;Geyer, Wilkinson, Humby, & Robbins, 1993) and mice (Ison & Allen, 2007), but eyeblink has also been used as a measure of startle reflex in a few animals. For example, Arnfred, Lind, Hansen and Hemmingsen (2004) used EMG integrated systems to measure PPI in minipigs and demonstrated very consistent findings with humans. However, this research does not exist for PPF.
Modulation of the startle response is measured as a change in eyeblink amplitude or whole-body response. This change will be present when comparing pulse-only trials, where the startle response will be at its normal level, to prepulse-pulse trials, where the response is modulated by the prepulse. Comparing the pulse-only trials to prepulse-pulse trials will produce a percentage change, with PPI reflecting a percentage of reduction in magnitude and PPF as a percentage increase in magnitude. The following equation is used: where a = startle amplitude at pulse only trials and b = startle amplitude at prepulse-pulse trials.
The current review will focus on the existing functional neuroimaging research of the startle reflex using prepulse paradigms to induce PPI and/or PPF in human populations, both adults and children. Previous reviews have focussed primarily on PPI Geyer et al., 1990;, the neural correlates of PPI (Fendt et al., 2001;Swerdlow et al., 2016)  Alzheimer's Disease (Jafari, Kolb, & Mohajerani, 2020) and other psychiatric disorders (Kohl, Heekeren, Klosterkötter, & Kuhn, 2013).
There are no current reviews of the PPF literature. ("prepulse inhibition" OR "PPI") AND ("fMRI" OR "functional magnetic resonance imaging"). This yielded eight of the papers included in the review. Two papers were hand searched as work cited from a searched article (Hazlett et al., 1998;Kumari, Gray, Geyer, et al., 2003) and included as they fit the inclusion criteria. Additional keywords ("sex differences" OR "gender differences"), ("PET" OR "positron emission tomography"), ("prepulse facilitation" OR "PPF"), were then added, and these produced the hand-searched papers, but no additional studies were found. Search terms were combined, and field-codes and wildcards were included, to increase the accuracy of the search. Research articles cited within each of the search results were also screened for relevance and included in the analysis if appropriate. See Figure 1 for the full search strategy. used schizophrenia patients with two control groups (healthy participants and participants with schizotypy), and two studies used participants with TS and a healthy control group. The PPI and PPF study used healthy participants. The findings of all reviewed PPI/PPF studies are presented in Table 1 and described in the Section 3.

| Neuroimaging studies in healthy adults
Mapping neural networks in healthy participants allows researchers to develop a blueprint for normal functioning cognition and behaviour. In addition, it provides a baseline against which to evaluate neural abnormalities, both structural and functional, which may underlie cognitive deficits in a number of clinical populations.

| PPI
Early research using PET indicated a "top-down" influence for processing prepulse stimuli in humans, implicating cortical and limbic regions in modulating the startle response (Hazlett et al., 1998). Hazlett et al. (1998) designed an attention-toprepulse paradigm, whereby participants were presented with a pulse and three prepulses; a higher tone to attend to, a lower tone to ignore, and a novel prepulse. In healthy controls at 120 ms SoA, attended prepulses showed greater PPI, in comparison to ignored and novel prepulses, but novel prepulses had a greater inhibitory effect than ignored prepulses, although this effect was not seen on 240 ms SoA trials. A negative correlation was observed between glucose metabolism in the prefrontal cortex and PPI (120 ms SoA), with greater PPI reflecting greater relative glucose metabolism in these neural regions. Building upon this work, fMRI research has highlighted thalamic involvement during PPI in healthy participants. Hazlett et al. (2001) used an attention-to-prepulse paradigm, whereby participants attended to higher tone prepulses and ignored lower tone prepulses that were presented 120 ms SoA.
Greater BOLD response was seen in the thalamus, anterior nucleus and mediodorsal nucleus when participants attended to the prepulse, rather than to the ignored prepulse, and deactivation of these neural regions occurred during pulse-only trials.

| Summary of neuroimaging findings
Thalamic activity during PPI conditions was present in six of 10 studies of PPI in healthy groups. The role of the thalamus is evident in mediating the startle reflex and producing an inhibitory response in healthy adult populations (Kumari, Gray, Geyer, et al., 2003;Kumari, et al., 2007Kumari, et al., , 2008Buse et al., 2016). Comparing attention-to-prepulse paradigms with passive prepulse paradigms, it is evident that there is an attentional effect of the thalamus, with greater BOLD response in thalamic regions is observed when participants attend to prepulses, rather than ignoring prepulses (Hazlett et al., 2001(Hazlett et al., , 2008. On both paradigm types, pulse-only trials, where startle reflex is not modulated, compared to PPI trials, show a decrease in thalamic BOLD activity, further illustrating its role in normal functioning startle reflex and, therefore, sensorimotor gating.
The role of the striatum during PPI conditions was present in five of 10 studies of PPI in healthy groups (Campbell et al., 2007;Hazlett et al., 2008;Kumari et al., 2007;Kumari, Gray, Geyer, et al., 2003;Neuner et al., 2010). Frontal cortex activity has been documented in eight of 10 studies, demonstrating how higher order neural regions are recruited to modulate the startle reflex. This activity is evident during prepulse-pulse trials at 120 ms (Hazlett et al., 1998(Hazlett et al., , 2008Kumari, Gray, Geyer, et al., 2003;Kumari et al., 2007;Campbell et al., 2007;Zebardast et al., 2013), 140 ms SoA (Buse et al., 2016;Neuner et al., 2010), in comparison to pulse-only trials which elicit a brainstem response. Consistently, 30 ms SoA trials show increased BOLD response in the superior temporal gyrus in healthy adults (Kumari et al., 2007(Kumari et al., , 2008. This has similarly been seen on 480 ms SoA trials, with decreased BOLD response in the superior temporal gyrus in 120 ms SoA trials (Campbell et al., 2007

| Neuroimaging studies: clinical populations
This literature search yielded functional neuroimaging research in clinical populations using prepulse paradigms only in two clinical populations: schizophrenia and TS.

PPI
Using the attention-to-prepulse paradigm, Hazlett et al. (1998) found that participants with schizophrenia did not show differential PPI between the attended and ignored prepulse at 120 and at 240 ms SoA, the latter being the same findings as the control group. The clinical group showed lower glucose metabolism during PPI at 120 ms SoA in the superior, middle and inferior prefrontal cortex and supramarginal, angular and superior parietal lobe, in comparison to the control group. PPI was also negatively correlated with higher glucose metabolism in the anterior prefrontal cortex (Brodmann area 10) when participants with schizophrenia were presented with the attended prepulses.
Comparing a healthy control group with participants diagnosed with schizophrenia, this tactile prepulse paradigm design by Kumari, Gray, Geyer, et al. (2003) highlighted that PPI in the clinical group was lower, compared to the controls. There was significantly less BOLD activity in striatal, thalamic, hippocampal, frontal and supramarginal gyrus/inferior parietal lobe during 120 ms SoA when compared to pulse-only trials in the clinical group, as compared to healthy controls.
A linear relationship was also found between PPI and BOLD activity in the CSPT circuitry in participants with schizophrenia, which corresponded with the level of observed PPI. Kumari et al. (2007) explored the neural correlates in a group of medicated schizophrenia participants (typical and atypical antipsychotics), and a healthy control group. The study reported lower PPI in the clinical group, in comparison to healthy controls, and also less PPI in participants taking typical antipsychotics, in comparison to healthy controls. Participants on atypical antipsychotics (risperidone and olanzapine) also showed this, but not to a statistically significant level.
Patients showed reduced BOLD response in the temporal lobe, thalamic and striatal regions on 120 ms SoA trials, compared to pulseonly trials. Thalamic activity was significantly associated with PPI across all clinical groups. Differences between the clinical groups based on medication type showed reduced BOLD response at 120 ms SoA in the anterior and posterior cingulate, right temporal gyrus and thalamus in the typical antipsychotic group, compared to healthy controls. This was similarly seen in participants taking risperidone. Interestingly, participants taking olanzapine most resembled the neural activity exhibited by the control group at 120 ms SoA, with neural activations in the pre-and postcentral gyrus, left middle temporal gyrus, extending to the globus pallidus/caudate, hippocampal and thalamic regions. The strongest BOLD response was observed in the right superior/middle temporal gyrus. PPI differences are still present in the medicated schizophrenia groups, compared to controls, but the reduction of PPI is less pronounced in the atypical medication groups, highlighting a possibility of "greater PPI-improving effects" (Kumari et al., 2007, pg. 471).
Findings by Hazlett et al. (2008) Kumari et al., 2004). Early research from Hazlett et al. (1998) using the attention-to-prepulse paradigm demonstrated differences in PPF between healthy controls and a group of unmedicated schizophrenia participants, with healthy controls showing more PPF when attending to prepulses at 4500 ms SoA.
The clinical group failed to show this differential effect between attended and ignored prepulses, but did show more PPF during novel prepulses, rather than ignored. However, neural findings accompanying these behavioural effects were not presented by these authors.

| Tourette syndrome
TS is characterised as a childhood neuropsychiatric disorder and is associated with sensorimotor gating deficits, such as premonitory urges and motor and phonetic tics which result in impairments in gating sensory, cognitive and motor information (Leckman, 2002). Age of onset is typically prepubertal and it is more common in boys, than girls. TS is less common in adulthood with reduced severity in symptoms by the age of 20 years (Bloch et al., 2006;Leckman et al., 1998).
Due to the nature of the symptoms of TS, it is important to understand abnormalities in the integration of sensory and motor systems. Sowell et al. (2008) identified thinning of somatosensory cortices and connectivity between motor and sensory cortices in participants with TS, illustrating structural differences to healthy controls. Functional neuroimaging research has identified both striatal regions and the hippocampus as playing a key role in TS (Bloch, Leckman, Zhu, & Peterson, 2005;Kalanithi et al., 2005) and, as these regions form part of the CSPT network, it indeed may be that this pathophysiology may lead to sensorimotor disturbances in TS. Reduced PPI has been observed in TS populations, in comparison to healthy controls, but PPF has yet to be studied in a TS population.

PPI
The "fMRI-friendly" startle paradigm by Swerdlow, Karban, et al. (2001), was developed and studied by presenting children with TS with acoustic and tactile prepulses and pulses. The clinical group showed reduced PPI at 120 ms SoA, in comparison to the control, when presented with both modalities. Acoustic PPI was greater than the tactile PPI in both groups, but the general consensus was that PPI impairments can be explored using both stimulus modalities. The "fMRI-friendly" tactile design seems to dominate the existing literature for TS populations, with no current studies to investigate the neural correlates of PPI in TS using auditory stimulation. are also in line with those from structural MRI studies, which showed a positive association between PPI and grey matter volumes in most of these regions , and with PPI and superior parietal cortex and frontal cortex (Hammer et al., 2013). Neuroimaging findings at peak PPI, 120 ms SOA in both acoustic and tactile stimulation (Campbell et al., 2007;Hazlett et al., 2008;Kumari et al., 2007), reveal the recruitment of higher order control from the CSPT neural circuitry to mediate the automatic brainstem response. The neurobiology of PPI at longer/peak lead interval PPI appears to overlap with that of the P50 suppression (Oranje, Geyer, Bocker, Kenemans, & Verbaten, 2006). P50 suppression (i.e., a smaller P50 evoked potential to the second stimulus when two sensory stimuli are presented by a 500 ms interval) is another paradigm used widely to document inhibitory deficits in people with schizophrenia (Patterson et al., 2008).
PPF-related neural activity in the left superior medial gyrus, right middle frontal gyrus, anterior and middle cingulate cortex and cerebellum has been identified in the only fMRI study of PPF (Neuner et al., 2010). PET research by Hazlett et al. (1998) presented PPI and PPF behavioural findings from healthy controls and schizophrenia patients, but only detailed PPI-related neural activity at 120 ms, rather than PPF-related neural activity at 4500 ms.
It is clear that there has been little exploration into whether star-

| Mapping neural correlates of PPI and PPF
One of the major gaps in the field is mapping the neural correlates of PPF and establishing whether there is one shared or two separate neural pathways for PPI and PPF. In animal research, it is assumed that PPI and PPF demonstrate independent processes due to the different effect produced by the prepulse, such as prepulse intensity and SoA (Plappert et al., 2004). Kumari, Gray, Gupta, et al. (2003) provides behavioural evidence for an overlap of neural circuitry with some distinct areas involved in the underlying process of PPI and PPF as women showed a smooth transition from PPI to PPF, indicating a general shift from PPI to PPF on a shared neural network. However, this was not seen in men. In addition, fMRI research has suggested an overlap in neural networks for PPI and PPF (Neuner et al., 2010). PPF requires more investigation to clarify the core networks of startle  (Damestani et al., 2021;Wiesinger, Menini, & Solana, 2019), will allow for auditory stimulation and neural responses resulting from this stimulation, rather than scanning conditions, or also to build upon the earlier interventions of developing an "fMRI-friendly" prepulse paradigm (Swerdlow, Karban, et al., 2001).

| Understanding sexual dimorphism in PPI and PPF
At present, it is unclear how sex can affect the underlying neural substrates of startle modulation using the prepulse paradigm. Sex differences have been identified across the literature in both humans and animals (Kumari, 2011), with women demonstrating less PPI than men (Aasen, Kolli, & Kumari, 2005;Abel, Waikar, Pedro, Hemsley, & Geyer, 1998;Kumari et al., 2004), even after removing confounds such as personality characteristics attributed to the men and women (Kumari, Gray, Gupta, et al., 2003), and smoking .
Sex differences in PPI may result from reproductive hormones. For example, post-menopausal women and pre-pubescent girls (>8 years) do not show reduced PPI, in comparison to men (Kumari et al., 2008;Ornitz, Guthrie, Sadeghpour, & Sugiyama, 1991), and women in the early follicular stage of their menstrual cycle, show more PPI than women in the luteal phase (Kumari et al., 2010). Women in their third trimester of pregnancy display low PPI compared to postpartum women, linked to higher than normal hormone levels (Kask, Bäckström, Gulinello, & Sundström-Poromaa, 2008). Alternatively, PPF is higher in women than men, including post-menopausal women and pre-menopausal women, in comparison to men, and also higher in pre-pubescent girls (>8 years) compared to prepubescent boys (>8 years) (Kumari et al., 2008;Kumari, Gray, Gupta, et al., 2003;Ornitz et al., 1991). Women in the early follicular stage of their menstrual cycle show less PPF than women in the luteal phase (Kumari et al., 2010).
Sexual dimorphism in startle modulation may also be a result of the combination of hormones on the neural system. For example, oestrogen influences dopaminergic activity in the nucleus accumbens and striatum (Becker, 2000), which are essential in inhibiting the startle response. Progesterone is also involved in dopaminergic activity by increasing and decreasing basal and amphetamine-stimulated dopamine and cholinergic activity, which plays a role in PPI in humans and animals Rupprecht et al., 1999).
Sex differences have been noted in a number of clinical disorders, including schizophrenia and TS. For example, in schizophrenia, there are less severe cases, later age of onset and often better outcomes for women with schizophrenia, rather than men with schizophrenia (see Leung, Chue, & Psych, 2000;McGrath et al., 2004), and TS is more prevalent in males than females (see Leckman et al., 1998;. Both disorders show widely documented PPI deficits, suggesting that outlining the effect of sex on PPI-related neural substrates will explain the sexual dimorphism of these clinical disorders.  (Buse et al., 2016) and enuresis (Ornitz, Hanna, & de Traversay, 1992).

| Longitudinal research: a study of normal or aberrant development
To expand the field, researchers may wish to conduct longitudinal research, implementing functional neuroimaging techniques to compliment the changes in development of PPI and PPF, as seen from preto post-puberty. Indeed, observing these changes in a population where hormonal change occurs in puberty will allow us to study the effect of hormones and sexual dimorphism on PPI and PPF (Abel et al., 1998;Kumari, Gray, Gupta, et al., 2003, Kumari et al., 2004Aasen et al., 2005;Kumari, 2008Kumari, , 2010Kumari, , 2011 (Cadenhead, Swerdlow, Shafer, Diaz, & Braff, 2000;Kumari et al., 2005), and individuals with gene polymorphisms with variations associated with lower PPI (Quednow et al., 2018). Therefore, assessing a cohort who are clinically high-risk for developing psychosis-spectrum disorders would advance the field, assessing PPI and PPF with complimentary neural findings.
In addition to psychosis-spectrum disorders, longitudinal studies can explore high-risk clinical groups and the pre-manifestation of disorders, such as Huntington's disease, that show sensorimotor gating disturbances (Uc, Skinner, Rodnitzky, & Garcia-Rill, 2003). For example, the pre-diagnostic stage of Huntington's disease shows no detectable clinical abnormalities (see Walker, 2007), thus PPI could be used as a biomarker and a marker of clinical severity (de Tommaso et al., 2001), with complimentary neuroimaging findings to explore where neural function also shows deficit.

| Translation of animal models to clinical research
The development of the prepulse paradigm using surgical and pharmacological manipulation in rodent models has helped shape clinical understanding for disorders which display sensorimotor gating issues. Davis, Gendelman, Tischler, and Gendelman (1982) identified key forebrain regions which inhibit the startle reflex and this modulatory effect has been shown across all mammals, indicating a translational model for understanding PPI in human research (Swerdlow & Geyer, 1998). PPI impairments have been noted when the CSPT network is damaged, specifically the hippocampus, medial prefrontal cortex and basolateral amygdala (Swerdlow & Geyer, 1998 and clinical research (Harrison, 2004). In addition, damage to the medial prefrontal cortex after 6-hydroxydopamine lesion in rats causes PPI deficits (Bubser & Koch, 1994), and low levels of dopamine in the prefrontal cortex have also been noted in schizophrenia patients, which would explain the sensorimotor gating issues (Howes & Kapur, 2009).
Research of PPF in animal models is lacking, but some researchers have observed facilitatory effects when rats were injected with ketamine, a NMDA receptor antagonist that can produce a psychosis-like state in humans (Domino, 1968). Ketamine research supports the notion that clinical psychosis disorders, such as schizophrenia, may be a result of a glutamate deficiency in the hippocampus and prefrontal cortex (Tsai et al., 1995). Therefore, ketamine will reduce PPI and effectively enhance PPF (De Bruin, Ellenbroek, Cools, Coenen, & Van Luijtelaar, 1999;Mansbach & Geyer, 1991). Yet, in human studies, researchers have identified mixed findings in the relationship between PPI and low doses of ketamine, with some studies illustrating an increase in PPI (Abel, Allin, Hemsley, & Geyer, 2003;Duncan et al., 2001), and others a decrease in PPI (van Berckel, Oranje, van Ree, Verbaten, & Kahn, 1998). Using functional neuroimaging techniques combined with pharmacological research could shed further light on differences in neural processing of schizophrenia and the effects of dopamine and glutamate antagonists on the healthy brain, particularly with regard to startle modulation and sensory information processing.

| Further avenues to investigate PPI and PPF deficits in clinical disorders
Sensorimotor gating impairments have been linked to psychosis, thus impairments in schizophrenia have been widely documented (e.g., Kumari et al., 2007;Kumari, Gray, Geyer, et al., 2003). Similar impairments have been noted in patients with bipolar disorder who show normal PPI when they are not in the manic phase, which infers a state dependent deficit. Individuals with depression and ADHD, on the other hand, do not show differences in PPI, compared to a healthy control (see Hornix, Havekes, & Kas, 2019). However, in a review by Kohl et al. (2013), several non-psychotic disorders have documented PPI deficits, including OCD, TS and Huntington's disease. These sensorimotor impairments may be a result of pathophysiology in the neural networks underlying the gating mechanism, thus inhibitory issues may stem from abnormalities in the CSPT circuitry. For example, hyperactivity in the striatum in OCD patients has been linked to PPI deficits (see Stein, 2002), but for autism, anxiety, substance disorders and post-traumatic stress disorder (PTSD), the PPI literature is unclear (Kohl et al., 2013).
Behavioural research has documented reduced PPF in participants with schizophrenia (Kumari et al., 2007;Storozheva et al., 2012) and in a small number of children with TS (Swerdlow, Karban, et al., 2001), but greater PPF response in women with fibromyalgia, in comparison to female healthy controls (Berryman et al., 2021). However, investigations into PPF differences in clinical groups, compared to healthy controls, are sparse. As neuroimaging research is beginning to investigate whether a shared neural network underlies PPI and PPF, studying PPF in clinical populations that show PPI deficits is essential to establish whether PPF deficits are present, and also to provide further insight into neural dysfunctions which may underly the disorder.

| CONCLUSION
This review has highlighted the existing functional neuroimaging literature on startle modulation using a prepulse paradigm. There was evidence of thalamic, striatal and frontal lobe activation during PPI in healthy groups, and activation deficits at some level in the CSPT cir-

ACKNOWLEDGEMENT
We would like to thank Dr Timo Giesbrecht for his suggestions and support.

CONFLICT OF INTEREST
The authors declare no conflict of interest.