case study startle response

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Research Article

More Meditation, Less Habituation? The Effect of Mindfulness Practice on the Acoustic Startle Reflex

* E-mail: [email protected]

Affiliation Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

Affiliations Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom, National Institute of Health Research (NIHR) Biomedical Research Centre for Mental Health, South London and Maudsley National Health Services Trust, London, United Kingdom

Elena Antonova,
Paul Chadwick,
Veena Kumari

Published: May 6, 2015
https://doi.org/10.1371/journal.pone.0123512
Reader Comments

13 Jul 2015: Antonova E, Chadwick P, Kumari V (2015) Correction: More Meditation, Less Habituation? The Effect of Mindfulness Practice on the Acoustic Startle Reflex. PLOS ONE 10(7): e0133099. https://doi.org/10.1371/journal.pone.0133099 View correction

Mindfulness as a mode of sustained and receptive attention promotes openness to each incoming stimulus, even if repetitive and/or aversive. Mindful attention has been shown to attenuate sensory habituation in expert meditators; however, others were not able to replicate this effect. The present study used acoustic startle reflex to investigate the effect of mindfulness practice intensity on sensory habituation.

Auditory Startle Response (ASR) to 36 startling probes (12 trials x 3 block with 40ms inter-block intervals), was measured using electromyography (EMG) in three groups of participants (N = 12/group): meditation-naïve, moderate practice, and intensive practice.

Intensive practice group showed attenuated startle habituation as evidenced by significantly less habituation over the entire experiment relative to the meditation-naïve and moderate practice groups. Furthermore, there was a significant linear effect showing between-block habituation in meditation-naïve and moderate practice groups, but not in the intensive practice group. However, the Block x Group interaction between the intensive practice and the meditation-naive groups was not significant. Moderate practice group was not significantly different from the meditation-naïve in the overall measure of habituation, but showed significantly stronger habituation than both meditation-naïve and intensive practice groups in Block 1. Greater practice intensity was significantly correlated with slower overall habituation and habituation rate in Blocks 2 and 3 in the intensive, but not in the moderate, practice group.

Conclusions

The study provides tentative evidence that intensive mindfulness practice attenuates acoustic startle habituation as measured by EMG, but the effect is modest. Moderate practice, on the other hand, appears to enhance habituation, suggesting the effect of mindfulness practice on startle habituation might be non-liner. Better understanding of the effect of mindful attention on startle habituation may shed new light on sensory information processing capacity of the human brain and its potential for de-automatisation of hard-wired processes.

Citation: Antonova E, Chadwick P, Kumari V (2015) More Meditation, Less Habituation? The Effect of Mindfulness Practice on the Acoustic Startle Reflex. PLoS ONE 10(5): e0123512. https://doi.org/10.1371/journal.pone.0123512

Academic Editor: Suliann Ben Hamed, Centre de Neuroscience Cognitive, FRANCE

Received: May 22, 2014; Accepted: March 4, 2015; Published: May 6, 2015

Copyright: © 2015 Antonova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Data Availability: Data are available on request. All interested parties should submit the request for data access to the Psychiatry, Nursing and Midwifery Research Ethics Committee (PNM, RESC), King’s College London Psychiatry, quoting the reference: PNM/10/11-10. The contact details of the PNM RESC: Research Ethics Office, 5.12 Franklin Wilkins Building, (Waterloo Bridge Wing), Waterloo Campus, King’s College Lond.

Funding: This work was supported by the Templeton Positive Neuroscience Award to Dr Elena Antonova (Grant number: PAHWPZA) ( http://www.posneuroscience.org/research-awards.html ). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Mindfulness requires a mode of sustained attention that is open, receptive [ 1 ], and directed towards present moment experience [ 2 ]. At the advanced stages of practice, it aims to overcome a habitual process of selection and fixation on a particular sensory, emotional or conceptual content, whilst inhibiting the processing of other sensory or mental stimuli. Everything that arises in awareness on a moment-by-moment basis is attended to non-preferentially, non-judgementally, and without conceptual elaboration [ 3 ]. This receptive and non-preferential awareness when maintained unwaveringly is referred to as ‘open presence’ [ 4 ].

An early electroencephalography (EEG) study [ 5 ] observed that highly experienced Zen practitioners (three Zen masters), for whom mindfulness would have become a default mode of information processing, do not exhibit the phenomenon of alpha blocking habituation (a decrease in response with repeated presentation of identical stimuli that is not due to sensory adaption or motor fatigue) normally observed in healthy individuals. During mindful attention, the lack of habituation would result from the ability to maintain the freshness of attention for each incoming stimuli [ 6 ].

Becker and Shapiro [ 7 ] compared lay Zen practitioners with the practitioners of Yoga and Transcendental Meditation in the US, as well as two control groups of meditation-naïve individuals, one of which was asked to attend to each click and the other was asked to ignore each click. No difference between the groups was observed. However, the sample of Zen practitioners was fairly small (n = 10) and heterogeneous in terms of practice duration (mean 7.5 years, range 3–20 years). The duration and/or intensity of practice may have an effect on de-automatisation of habituation.

Habituation has been extensively studied using the acoustic startle reflex (ASR), a contraction of the skeletal musculature in response to an intensive acoustic stimulus typically measured by electromyography (EMG) of the orbicularis oculi muscle. It is a ubiquitous, cross-species phenomenon, allowing for rigorous experimental stimulus control and automated measurement [ 8 ]. The ASR shows rapid habituation in healthy adults normally evident by the 4 th -5 th presentation of the startling stimulus [ 9 ].

Levenson et al [ 10 ] reported a single-case study of an experienced Tibetan monk Matthieu Ricard (MR) measured on a set of physiological responses induced by unanticipated acoustic startle stimuli of 115-db 100-ms burst of white noise presented through hidden loudspeakers located behind MR’s head. The ASR was ranked by the experimenters based on facial muscle response. MR showed decreased initial reactivity during open presence as compared with a non-meditative state, as well as a group of control participants. Although the intensity of facial response to acoustic startle was diminished in MR during open presence, there was no observable habituation over 6 repetitions of the unanticipated startle.

The findings of this case study suggest that acoustic startle characteristics and startle habituation could be altered by long-term and/or intense mindfulness practice. However, the study used experimenters’ ratings, and although this could be a reliable method of quantifying the response by the experienced raters, the automated quantification is more practical and reliable, particularly in larger studies.

The purpose of this study was to investigate the effect of mindful attention on sensory habituation using the acoustic startle habituation paradigm and electromyography (EMG) for ASR quantification. We predicted that greater intensity of mindfulness practice would be associated with attenuated ASR habituation, whereas moderate practice would be unlikely to exert measurable effects on the hard-wired physiological mechanisms involved in sensory filtering.

The study was approved by the King’s College London Psychiatry, Nursing and Midwifery Research Ethics Committee (reference: PNM/10/11-10). All participants provided written informed consent prior to study participation.

Participants

Twenty seven lay mindfulness practitioners (25 males, 2 females) from the Tibetan Buddhist tradition practising Dzogchen or Mahamudra, a practice closely aligned both experientially and conceptually with mindfulness as formulated by Kabat-Zinn [ 11 ], [ 12 ], were recruited through UK Buddhist centres, retreats, and events. The inclusion criterion was at least 3 years of formal meditation practice of either Dzogchen or Mahamudra under the guidance of a teacher recognised by the Tibetan Buddhist tradition. Both female practitioners were post-menopausal and therefore were expected to have no difference in the startle reflex and its modulation as compared with males of similar age [ 13 ]. Fifteen healthy individuals (all male) with no experience of mindfulness practice either through meditation, yoga, martial arts, tai chi, or qigong were matched, on average, with meditators on age, years of education, and IQ as measured by a 2-subset version of Wechsler Abbreviated Scale of Intelligence [ 14 ]. All participants were right-handed, non-smokers, and were screened for mental illness, neurological abnormalities, head injury with the loss of consciousness, and past or current alcohol/drug abuse.

The data examination revealed poor psychophysiological data quality (>50% rejected responses) for 3 meditators and 3 meditation-naïve individuals; all data for these participants were excluded from analysis, with the final sample of 24 meditators and 12 meditation-naïve individuals.

Characteristics of the final sample.

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https://doi.org/10.1371/journal.pone.0123512.t001

Psychophysiological data collection

The eye blink startle response was indexed by recording electromyographic (EMG) activity of the right orbicularis oculi muscle by positioning two miniature silver/silver chloride electrodes (4 mm) filled with Dracard electrolyte paste (SLE, Croydon, UK). The ground electrode was placed on the right mastoid. Data were collected with participants sitting in a chair that promotes alert straight posture. The laboratory was moderately lit during data acquisition.

A commercial computerized human startle response monitoring system (Mark II, SR-Lab, San Diego, California) was used to deliver acoustic startle stimuli, and record and score the EMG activity. The startle system recorded EMG activity for 250 ms (sample interval 1 ms) from the onset of the pulse stimulus. The amplification gain control for EMG signal was kept constant for all participants. Recorded EMG activity was band-pass filtered, as recommended by the SR-Lab. Analogue bandpass filtering occurred before digitizing. The high-pass and low-pass cut-off frequencies were set at 100 Hz and 1 kHz, respectively. A 50-Hz notch filter was used to eliminate the 50-Hz interference. EMG data were scored off-line by the analytic software, providing measurements for latency to peak and amplitude of the startle response as used in our previous studies [ 15 – 18 ]. The analytic software contains a rolling average routine which smooth the rectified EMG response. Response onset was defined by a shift of 7.63 μV from the baseline value occurring within 20–120 ms from the onset of startle stimulus. The baseline value consisted of the average of the minimum and maximum values recorded during the first 18 ms. The latency to peak was defined as the latency to the point of maximal amplitude that occurred within 18–120 ms from the onset of startle stimuli.

Startle habituation paradigm and procedures

The startle habituation paradigm consisted of 3 blocks of 12 acoustic startle trials with the average inter-stimulus interval of 15 seconds within each block (range 9–21 sec), and an inter-block interval of 40 sec. The startling stimulus was a 40-ms presentation of 115 dB (A) SPL white noise (rise time <1 ms) over 70 dB (A) continuous background white noise. The startle probes were delivered via the head-phones (TDH-39P, Maico). The session lasted approximately 15 min.

Each participant was played 2 startle probes as a demonstration of the stimuli before the start of the experimental session; the startle response data for these probes were not used for the analysis. The session began with a 4-min acclimatization period consisting of 70 dB (A) continuous white noise. Meditators were instructed to use this period to settle into mindfulness practice. The meditation-naïve individuals were instructed to remain alert and aware of their surroundings. All participants were asked to maintain a soft gaze on a point in front of them designated on the wall with a blue sticker. The sticker was placed to direct the gaze slightly above the horizon. Both Dzogchen and Mahamudra traditions use this slightly upward gaze to promote open spacious awareness. The meditators were instructed ‘to rest in open presence, neither paying particular attention to the startling noises nor ignoring them or attempting to suppress an eye blink in response to them, but rather treating them non-preferentially as any other experience that arise in the moment’. Meditation-naïve individuals were instructed ‘to remain alert and awake throughout the experiment, neither paying particular attention to the startling noises nor ignoring them or attempting to suppress an eye blink in response to them, allowing natural response to occur, and to return their awareness to the surroundings if they caught themselves mind-wandering’. We deliberately chose not to give control participants a meditation instruction in relation to the quality of attention and awareness apart from asking them to remain alert and aware, as this might introduce ambiguity and effortful processing demands which we wished to avoid.

Startle habituation quantification

The habituation slopes for each of the 3 blocks of 12 trials and the overall habituation slope for 36 trials of the experiment were calculated for each participant.

Behavioural measure

To control for the possible role of sustained attention on startle habituation, both groups were assessed using Continuous Performance Task, identical pairs version (CPT-IP) [ 21 ] with d’prime as the dependent variable indexing ability to sustain attention.

Self-assessment measures

All participants completed the Mindfulness Attention Awareness Scale (MAAS) [ 2 ], a validated measure of dispositional mindfulness. Mindfulness practitioners also completed Freiburg Mindfulness Inventory (FMI)[ 22 ] designed to assess mindful attention in daily life in people who meditate. To further characterise the three groups of participants, we administered Beck Anxiety Inventory (BAI) [ 23 ], and Beck Depression Inventory-II (BDI-II) [ 24 ].

The group differences in initial reactivity (a square root of ASR amplitude to the first trial of the first block) and overall startle habituation (mean beta slope over 36 trials) were assessed using a one-way analysis of variance (ANOVA, p<.05). The group differences in latency to peak (in ms) and startle habituation (mean beta slopes) for Blocks 1, 2, & 3 were examined using 3 (Block) x 3 (Group) repeated-measures ANOVAs (p<.05). Lower order repeated measures ANOVAs were used to further probe significant main effects and their interactions, and where these were significant, were followed by planned group contrasts using t-tests (p<.05). The relationships between startle habituation and the self-report mindfulness measures were examined using Pearson product-moment correlations (p<.01).

Startle response characteristics and habituation

Fig 1 presents the mean startle amplitude of three groups over 36 trials.

https://doi.org/10.1371/journal.pone.0123512.g001

Table 2 and Fig 2 present mean latency to peak, initial reactivity, and startle habituation for MN , MP , and IP groups.

https://doi.org/10.1371/journal.pone.0123512.g002

https://doi.org/10.1371/journal.pone.0123512.t002

Initial reactivity.

Initial reactivity did not differ [p = 0.861] between the groups [raw ASR values MN : Mean (SD) = 813.17 (552.36) (393.27); MP : 934.17 (516.52); IP : 788.83 (490.76)] (the mean square root of ASR amplitude to the first trial of the first block as well as blocks 2 and 3 for each group is reported in Table 1 ). There were no correlations between initial reactivity and the IoP in either MP [p = .761] or IP [p = .868] groups.

Startle habituation.

Before proceeding with testing the main hypotheses, we examined whether the female participants habituation slope values were within the range of the respective group [ MP group female: overall slope = -2.83 (range: -5.04 —.69); Block 1 slope = -4.28 (range: -8.75 —.76); Block 2 slope = -1.19 (range: -5.05 – 1.46); Block 3 slope = -.0229 (range: -3.78–6.98); IP group female: overall slope = -.89 (range: -2.45 -. 09); Block 1 slope = -2.81 (range: -4.09 —.08); Block 2 slope = -.13 (range: -5.15 –. 32); Block 3 slope = -.13 (range: -4.12 -. 827)]. Having confirmed that the values for female participants did not constitute outlier values that could bias the results, we did not use gender as a covariate in the analysis of variance as the validity of these tests is dependent on the variables having normal distribution, whereas gender variable is categorical and highly unbalanced within the groups (N = 1 per meditators’ group).

One-way ANOVA revealed a significant main effect of Group for the overall startle habituation slope across 36 startle trials [F (2,33) = 4.98, p = .01]. Planned between-group contrasts showed that this effect was due to a significantly steeper habituation slope in MN [t (22) = -2.41, p = .02] and MP groups [t (22) = -3.31, p = .003] than in IP group, suggesting attenuated startle habituation in IP group across the entire experiment. MN vs MP difference was non-significant [p = .209].

To investigate whether habituation rate differed across the blocks between and within the groups, 3 (Block) x 3 (Group) repeated measures ANOVA with mean beta slopes for 3 blocks was performed and revealed a significant main effect of Block [F (2,66) = 21.71, p<.0001] and a significant Block x Group interaction [F (4,66) = 6.05, p<.0001]. The main effect of Block was followed up with separate repeated measures ANOVA over Block in the three groups. There were significant main effects of Block in MN group [F (2,22) = 4.92, p = .02] and the MP group [F (2,22) = 22.44, p<.0001], but not in IP group [F (2,22) = 1.01, p = .381], showing non-significant habituation over the three blocks in IP group. Furthermore, the tests of within–subject linear contrasts were significant in MN [F (1,11) = 4.85, p = .05] and MP groups [F (1,11) = 29.33, p<.0001], but not in IP group [p = .234], further indicating gradual decrease in the ASR with repeated stimulation in MN and MP groups, but not in IP group.

The Block x Group interaction was investigated with 3 (Block) x 2 (Group) repeated measures ANOVAs. For MN vs MP groups comparison, the main effect of Block [F (2,44) = 57.75, p<.0001] and the Block x Group interaction [F (2,44) = 5.99, p = .005] were significant. Independent t -tests revealed significant differences in habituation for Block 1 between MN and MP groups [t (22) = 2.65, p = .01], but not for Block 2 [p = .15] or Block 3 [p = .28], suggesting that Block x Group interaction is driven by greater habituation in Block 1 in MP group compared with MN group. For MN vs IP group comparison, the main effect of Block was significant [F (2,44) = 5.35, p = .008], but the Block x Group interaction was not [p = .201]. Taken together with the results of the repeated measures ANOVAs investigating the main effect of Block reported above, this finding indicates that although MN group showed a significant linear decrease in ASR across the blocks and IP group did not, this within-block difference between two groups was not statistically significant. For MP vs IP group comparison, the main effect of Block [F (2,44) = 19.57, p<.0001] and the Block x Group interaction [F (2,44) = 10.67, p<.0001] were significant. Independent t -tests showed significant differences in habituation for Block 1 between MP and IP groups [t (22) = -4.121, p<.0001], but not for Block 2 [p = .43] or Block 3 [p = .51], indicating that Block x Group interaction is due to greater habituation in Block 1 in MP group compared with IP group.

There were no significant correlations between the habituation slopes and the IoP in the MP group. In IP group, there were significant inverse correlations between the IoP and the slopes for Block 2 and 3 [Block 1: r = -.478, p = .116; Block 2: r = -.799, p = .002; Block 3: r = -.68, p = .014], and the overall slope [r = -.840, p = .001], further confirming that greater practice intensity is associated with less habituation. (See Fig 3 for the scatterplot of the overall habituation slope and the IoP values for the MP and IP groups).

https://doi.org/10.1371/journal.pone.0123512.g003

Latency to peak.

There were no significant main effects or interactions, suggesting that latency to peak did not differ between three groups in any of the blocks or within the groups across three blocks.

Cognitive and psychological measures

Table 3 presents the means (SD) for CPT-IP and self-report questionnaires, as well as statistics for the comparison between three groups. The three groups had comparable d ’prime of CPT-IP, anxiety (BAI), depression (BDI-II), and dispositional mindfulness (MAAS). Further in relation to mindfulness, MP and IP groups could not be differentiated using FMI.

https://doi.org/10.1371/journal.pone.0123512.t003

There were no correlations between startle habituation slopes and any of the self-report measures.

The main aim of the present study was to investigate the effect of mindfulness practice intensity on acoustic startle habituation. The results suggest that intensive mindfulness practice somewhat attenuates habituation to startling stimuli, whereas moderate mindfulness practice might enhance habituation.

Startle habituation attenuation with intensive practice was evidenced by significantly less habituation in IP group over the entire experiment vs. MN and MP groups. There was also a significant linear effect showing between-block habituation in MN and MP groups, but not in IP group. Furthermore, greater practice intensity was significantly correlated with slower overall habituation and habituation rate in Blocks 2 and 3 in IP group, but not in MP group. However, the habituation rate across blocks in IP group was not significantly different from MN group when testing for Block x Group interaction, suggesting that the effect, although present, was not strong enough to emerge as significant group difference in the present sample, which was relatively small.

Our finding of attenuated ASR habituation in experienced mindfulness practitioners is in line with the finding by Kasamatsu and Hirai [ 5 ] of attenuated habituation to non-startling acoustic clicks in three Zen masters using EEG. The failure to replicate the lack of habituation to acoustic clicks in lay Zen practitioners by Becker and Shapiro [ 7 ] might be due to the heterogeneity of mindfulness expertise of the studied practitioners. Our study demonstrates that it is important to take into account the intensity of practice in addition to the total hours and/or years of practice, as more intensive practice is likely to result in greater and possibly more rapid psychophysiological changes. No significant correlation between the HoP and IoP in MP group and a strong significant correlation in IP group, as well as a significant positive correlation between the IoP and the habituation slopes in IP but not in MP groups in our study further supports the utility of the IoP index in quantifying practice expertise in the absence of more objective measures and in an attempt to derive such.

The attenuated startle habituation in IP group could not be explained by the greater ability to sustain attention/vigilance as measured by CPT-II, as we did not observe significant group differences on the CPT-II performance. In fact, we did not observe differences in CPT-II performance in another independent sample of mindfulness practitioners compared to meditation-naïve controls in a recently published study [ 25 ], in which we report greater attentional capacity in mindfulness practitioners. MacLean et al [ 26 ] have reported improved performance on a CPT paradigm that used short (target) and long (non-target) vertical lines in lay practitioners after intensive training (5 hr/day for 3 months) in focused attention meditation (mindfulness of the breath) under retreat conditions as compared to wait-list controls. However, MacCoon et al [ 27 ] did not observe differences in sustained attention using the same version of the CPT paradigm as MacLean after MBSR as compared with active control. It is possible that findings of MacLean et al are due to more intensive practice regime that either in MacCoon’s et al or in practitioners in our study. Alternatively, the version of CPT used in the present study, which requires discriminating 4 digit numbers quickly flashing up on the screen, might be more difficult and therefore less sensitive to mindfulness as a trait.

Intensive mindfulness practitioners did not differ from other two groups in other ASR characteristics, including initial ASR reactivity and response latency. In the single-case study by Levenson et al [ 10 ] described in the introduction, MR showed decreased initial reactivity (ranked by the experimenters based on facial muscle response, no EMG was used) during open presence as compared with a non-meditative state, as well as a group of control participants. The lack of attenuation in the initial reactivity in IP group might be due to the practitioners in our study being less experienced than MR. It is also possible that the difference is due to higher intensity of startling stimuli in Levenson et al study, which produces whole-body startle, and therefore might be more sensitive in differentiating meditators from meditation-naïve individuals than the auditory startle probes used in the present study. Future research should investigate whether the initial reactivity as measured by the EMG could be prominently diminished by the long-term intensive practice. It is important to note that although the intensity of facial response was diminished in MR during open presence, there was no observable habituation over 6 repetitions of the unanticipated startle, further collaborating our finding of the effect of intensive mindfulness practice on attenuating habituation.

Together, the measures of initial reactivity and startle habituation have the potential of being developed as objective measures of mindfulness expertise. Currently, the assessment of mindfulness expertise mostly rely on self-reports. In the present study meditators with intensive meditation practice were discriminated by an objective measure (ASR habituation), but not by self-report measures of mindfulness, either dispositional (no differences in MAAS scores between three groups), or practice-related (no difference in FMI scores between two groups of meditators). These findings contribute to the existing controversy in relation to assessing trait mindfulness using self-reported measures (see [ 28 ] for the discussion of relevant issues). In demonstrating that measureable psychophysiological changes occur in the brain’s receptivity to information input following intensive mindfulness practice, the present study takes a first step towards developing startle habituation as an objective measure of mindfulness expertise. Due to the cross-sectional design of the present study it is possible, however, that the observed association between attenuated ASR habituation and practice intensity could be explained by the fact that individuals who practice intensively might display reduced ASR prior to commencing mindfulness practice and this feature of their sensory processing somehow makes the practice more appealing and thus encourages more intense practice. The correlation between practice intensity and overall habituation could in principle be explained by this direction of causality, rather than more intensive practice leading to less habituation. Future studies adopting longitudinal design should address this issue, as well as to investigate at what point in the practice expertise the quantitative and qualitative shifts in the ASR characteristics occur.

Contrary to our prediction of unchanged startle habituation with moderate practice, MP group showed significantly stronger habituation in Block 1 compared to both MN and IP groups. Although from Fig 1 it might appear as if this effect is due to the higher initial reactivity in MP group followed by normal habituation response, this is an unlikely explanation for this result. Firstly, we used square root transformed values for the initial reactivity when calculating habituation beta slope. Secondly, we explored (not reported in the results) the correlation between the square root initial reactivity values and the habituation slope for Block 1 in MP group. Surprisingly, the correlation was positive (r = .458), i.e. higher initial reactivity was associated with less habituation in MP group, but it was not significant (p <.135). This suggests that the initial reactivity is unlikely to explain greater habituation in Block 1 in MP group. It is possible that mindfulness practice might have non-linear effects on startle habituation, with moderate practice enhancing and intensive practice attenuating it. The reasons for this should be elucidated in future research provided this effect is replicable and not a chance finding in the present study.

The finding that moderate mindfulness practice enhances habituation, if confirmed by further research, has implications for clinical applications of mindfulness, particularly for the management and/or treatment of schizophrenia. Habituation is considered to be critical for efficient information processing, and if disrupted, is thought to lead to sensory inundation and cognitive fragmentation as observed in schizophrenia [ 8 ] [ 29 ]. Reduced habituation in schizophrenia patients is observed across stimulus and measurement modalities [ 8 ] [ 30 ]. Attenuated startle habituation is well-documented in schizophrenia patients, both chronic [ 31 ], [ 29 ], [ 9 ] and first-episode [ 32 ], and was shown to be stable over the course of psychotic illness in a 6-year study [ 33 ]. The limited literature on mindfulness meditation and psychosis cautions against teaching mindfulness to people with a history of [ 34 ] or vulnerable to [ 35 ] psychosis precisely due to the concern that mindfulness would promote de-automatisation of a ‘hard-wired’ process of stimuli selection and inhibition, seen as an essential condition for efficient information processing. However, mindfulness practice does not result, per default , in psychotic syndrome and cognitive deficits characteristic of schizophrenia. On the contrary, dispositional mindfulness [ 2 ] and mindfulness developed through training [ 36 ] are associated with reduced anxiety and stress reactivity, increased behavioural flexibility, and overall well-being. Furthermore, mindfulness training enhances performance on cognitive tasks of executive function [ 37 ], orienting attention [ 38 ], sustained attention and cognitive flexibility [ 39 ], on which schizophrenia patients exhibit performance deficits [ 40 ]. Our finding that moderate mindfulness practice was associated with enhanced startle habituation supports the use of shorter and less intensive mindfulness practice for those vulnerable to or experiencing psychosis. Indeed, Chadwick et al [ 41 ] [ 42 ] used an adapted brief 10-min mindfulness meditation in their pilot studies of the effectiveness of mindfulness for people with schizophrenia diagnoses and treatment-resistant auditory hallucinations, or paranoia, or both. The case-study [ 35 ] reported the onset of psychotic experience following an intensive meditation retreat. These findings are consistent with the proposal that it might be the intensity of meditation practice rather than meditation per se that could potentially induce or exacerbate psychotic states in vulnerable individuals. Equally important research question is what affords intensive mindfulness practitioners information receptivity whilst maintaining the integrity of information processing and even enhancing it? Future research should elucidate possible cognitive and neural mechanisms that ‘protect’ mindfulness practitioners against information overload in the presence of diminished sensory information filtering.

Since habituation is a form of non-associative learning, whereby the central nervous system automatically disregards (filters out) repetitive stimuli that hold no information value, what would be possible advantages of attenuated habituation due to mindfulness practice? Buddhist psychology posits that one of the reasons for the discontent and dis-ease that even people with no psychiatric diagnosis often experience is a rapid habituation to sensory stimulation, leading to wanting new or higher intensity experiences. Indeed, in healthy meditation-naïve adults, faster habituation is associated with impulsivity, behavioural disinhibition, and sensation seeking [ 43 ]. One of the aims of the mindfulness practice is to maintain fresh and alert attention to each incoming stimulus, no matter its valence or familiarity. This leads to experiential novelty even of the most mundane and familiar stimuli. The meditator, for example, starts to notice that every breath is somewhat different from the previous one, or that physical pain, if looked at more closely, is not a solid monolith, but a mingling ever-changing flow of sensations. To borrow from William Blake: “How do you know but ev’ry Bird that cuts the airy way, Is an immense world of delight, clos’d by your senses five?”

The main limitation of the present study is a small sample size, which might have limited the power in testing the main hypothesis and/or resulted in chance findings. The inclusion of female participants in the groups of mindfulness practitioners might have potentially affected the results, although we have confirmed that their values did not fall into the extreme ends of the range in their respective groups.

Furthermore, the observed effect of intensive mindfulness practice on attenuating startle habituation might potentially be explained by other factors not controlled for in the present study. These might include considerable changes in life style of the practitioners who practice intensively, including living in urban vs country environment, which might differentially affect central nervous system arousal overtime, choice of jobs/occupations with differential stress levels, diet, etc.

In conclusion, the present study provides preliminary and tentative evidence for attenuated startle habituation with intensive mindfulness practice on a group level and using EMG measurement. Moderate practice, on the other hand, appears to enhance startle habituation, which might have significance for understanding meditation-induced psychosis reported in previous literature and suggests that more moderate practice regimes might be advisable for people vulnerable to or suffering from psychosis. The mechanisms that protect intensive mindfulness practitioners in the face of increased information receptivity, as well as relative merits and potential ‘dangers’ of such receptivity should be explored in future research. With further research, startle habituation has the potential to be developed as an objective measure of mindfulness expertise. Further study of sensory filtering in mindfulness experts may shed new light on sensory information capacity and receptivity of the human brain and the potential for de-automatisation of hard-wired processes such as habituation.

Author Contributions

Conceived and designed the experiments: EA PC VK. Performed the experiments: EA. Analyzed the data: EA VK. Wrote the paper: EA PC VK.

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Meditation and the startle response: a case study, by robert w. levenson, paul ekman, and matthieu ricard, emotion 2012, 12(3).

Posted 6 March 2013

This study investigates the effects of two type of meditation – open presence and focused – on a meditator’s defensive response to a startle stimulus during the meditation.

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Self-centeredness and selflessness: A theory of self-based psychological functioning and its consequences for happiness, by Michaël Dambrun and Matthieu Ricard, Review of General Psychology 2011, Vol. 15, No. 2
Measuring happiness: from fluctuating happiness to authenticdurable happiness, by Michaël Dambrun, Matthieu Ricard, et al, Frontiers in Personality Science and Individual Differences 2012
Buddhist and psychological perspectives on emotions and well-being, by Paul Ekman, Richard J. Davidson, Matthieu Ricard, and B. Alan Wallace, Current Directions in Psychological Science 2005, 14(2)
Long-term meditators self-induce high-amplitude gamma synchrony during mental practice, by Antoine Lutz, Matthieu Ricard, et al, Proceedings of the National Academy of Sciences of the United States of America 2004, 101(46)
The Dalai Lama: Happiness through wisdom and compassion, by Matthieu Ricard, International Journal of Wellbeing, 1(2)
Differential pattern of functional brain plasticity after compassion and empathy training
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Meditation and the startle response: A case study

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Understanding the Causes of Reduced Startle Reactivity in Stress-Related Mental Disorders

Submitted: 02 May 2012 Published: 20 March 2013

DOI: 10.5772/53066

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Author Information

Kevin d. beck.

Neurobehavioral Research Laboratory, Veteran Affairs New Jersey Health Care System, East Orange, NJ, USA
Stress & Motivated Behavior Institute, Department of Neurology & Neurosciences, University of Medicine & Dentistry of New Jersey – New Jersey Medical School, Newark, NJ, USA

Jennifer E. Catuzzi

University of Medicine & Dentistry of New Jersey – Graduate School of Biomedical Sciences, Newark, NJ, USA

*Address all correspondence to:

1. Introduction

Many questions have plagued the study of the etiology and subsequent treatment of mental illness. In part, it is simply because, as far as we know, some mental illnesses are somewhat unique to the human condition. Moreover, clinical studies have produced many different results concerning potential biomarkers for conditions such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). In this chapter, we review how we approached modeling a specific behavioral condition, suppression of the startle reflex, by examining whether one of two commonly associated peripheral biomarkers of anxiety and depression could potentially cause this rather specific symptom. The two peripheral systems under investigation were the hypothalamic-pituitary-adrenal (HPA) axis and the peripheral pro-inflammatory immune response, both of which have been implicated as a vulnerability factor, causal factor, or resultant (perpetuating) effect of PTSD and MDD.

Our general theory is that peripheral endocrine and immune signals, measured to be abnormal in patients with either PTSD or MDD (as well as other mental disorders), are actually perpetuating the behavioral features of these disorders. At the same time, if an individual has an immunosensitivity or has an overactive adrenal gland, s/he would be more likely to experience some of the symptoms associated with one of the particular mental illnesses. This may then lead the brain to compensate for those peripheral abnormalities, but, at the same time, cause other imbalances, which lead to the experience of a decline into mental illness. Thus, treating these peripheral markers as part of the “mental” disorder may be quite beneficial in normalizing certain aspects of the diagnosed abnormal behavior.

2. The startle reflex and mental health

2.1. the startle reflex as an assessment tool.

One of the major impediments to the mechanistic study of mental illness is establishing analogs of the abnormal behaviors expressed in humans in animal models, especially in sub-primate species. This has led some to adopt reflex-based measures such that the face and construct validity of the behavior change can be readily translated between the model and patient populations. Consequently, a popular measures for the study of anxiety disorders has been the potentiation of the startle reflex; however, there is growing evidence that a dampening of the startle response may be indicative of changes in physiology that underlie different mental disorders.

The startle reflex comprises a 3-synaptic sensory-motor neuronal pathway that serves as a defensive behavioral response to abrupt, usually intense, stimuli. The acoustic startle response (ASR) is the most commonly used form for studying this reflex. As shown in Figure 1 , the primary ASR circuit begins with neurons in the cochlear nerve, transmitting the representation of the acoustic stimulus from the cochlea of the inner ear to the cochlear nucleus (in the brainstem). Efferent pathways from the cochlear nucleus project to the nucleus reticularis pontis caudalis (PnC), in the pons, forming the second synapse in this reflex arc. The third synapse forms from the efferent projections from the PnC to various motor nuclei, through the recticulospinal spinal tracts to the muscles of the torso [ 1 ] and the muscles enervated by the facial nerve. These muscle enervations create a rapid cascade of near-immediate behavioral responses to abrupt acoustic stimuli, ranging from less than 10 ms to approximately 50 ms.

The ASR is modulated by several afferent connections originating from higher brain areas (midbrain, limbic, and cortical nuclei). At the level of the PnC, there are several inputs that can either enhance or inhibit the magnitude of an elicited ASR. In the area of fear and anxiety, the central amygdala and bed nucleus of the stria terminalis (BNST) are considered the 2 major excitatory modulation structures on this reflex [ 2 ]. Some have proposed that the BNST is the origin of anxiety-like behaviors whereas the nuclei of the amygdala are the origin of acute fear responses and explicit fear-learning [ 3 , 4 ]. The amygdala is predominately associated with causing classically conditioned fear-potentiated ASRs [ 5 ], and, in fact, has been specifically shown not to have a role in startle inhibition, at least via a learned conditioned inhibitor [ 6 ]. On the other hand, the process known as pre-pulse inhibition of the startle reflex (PPI) has elucidated neural pathways that can inhibit the expression of the ASR. For instance, the substantial nigra pars retriculata (SNR), pedunculopontine tegmentum (PPT) and laterodorsal tegmental nuclei (LDT) have inhibitory influence upon the PnC, thus reducing the measured ASR [ 7 - 10 ]. These three mid-brain nuclei (inhibitory) receive projections from various forebrain areas, including the amygdala, BNST, and medial prefrontal cortex (mPFC). Thus, limbic system modulation of the ASR can occur through direct enervation of the PnC (excitatory) or indirect enervation through mid-brain nuclei.

There are several nuclei within the midbrain/brainstem area that can directly modulate the intrinsic ASR circuit at the level of the nucleus reticularis pontis caudalis (PnC). Dashed red lines represent cholinergic inhibitory influences from the laterodorsal tegmental nuclei (LDT) and pedunculopontine tegmentum (PPT). Dashed black lines represent inhibitory GABAergic projections from the substantial nigra pars reticulata (SNR). A solid line from the parabrachial nucleus (PBN) is an example of a direct excitatory input to the PnC.

2.2. Abnormalities in the expression of the startle reflex in mental disorders

Over all other mental disorders, PTSD is associated with changes in the startle reflex. Commonly associated with exaggerated startle responses [ 11 - 14 ], higher or exaggerated startle reflex responses are a criteria symptom for the diagnosis of PTSD [ 15 ]. However, recent evidence suggests that this may not always be the case. In fact, others have reviewed the literature and found there are a significant number of reports where the startle responses in PTSD patients are not exaggerated [ 16 ]. More extreme, there are reports, albeit limited, where patients diagnosed with PTSD appeared to have blunted motor reflex responses to an acoustic stimulus [ 17 , 18 ]. These populations had distinctive qualities that were different than those studies that had found enhanced startle reactivity in their PTSD patients. First, the one study was exclusively female [ 18 ] and the other had a majority of female subjects [ 17 ], suggesting there may be a sex difference in the presentation of ASR in females as a result of experiencing trauma. However, others have reported enhanced startle responses in a different population of women diagnosed with PTSD following automobile accidents [ 19 ]. Thus, a second distinction between the two studies that observed suppressed startle reactions, which should be considered, is that the trauma was specifically associated with being the target of violence [ 17 , 18 ]. Although women with a PTSD diagnosis stemming from a prior rape have not always exhibited blunted startle responses [ 20 ], this discrepancy may be due to individual differences and/or methodological differences in being sensitive to such changes, as some have reported laterality effects in PTSD patients, notably of those having been raped in the past [ 21 ]. A third quality of at least one of these two reports is that the subjects also exhibited symptoms associated with major depressive disorder [ 18 ]. This suggests stressful experiences may not cause a uniform change in sensory reactivity, and the expression of the coping response to the trauma may have psychophysiological ramifications that are quite different, both in terms of effects upon sensory-motor responding to acoustic stimuli as well as the full expression of symptoms.

There is evidence that symptoms associated with depression may also include a blunted reaction to acoustic stimuli. Patients designated as “depressed”, having either a diagnosis of MDD or a significantly higher score on the Beck Depression Inventory (with or without additional neurological conditions), have been reported to exhibit blunted reactivity to acoustic stimuli, either with or without manipulations of affect [ 22 - 26 ]. Similarly, there is also evidence that bipolar disorder (BPD), the occurrence of at least one manic or mixed manic episode over the course of a patient’s lifetime, is characterized by blunted startle reactions as well, even during periods of remission [ 27 ]. A study by Carroll and colleagues found patients suffering from BPD exhibit attenuated baseline startle, most notably in those having experienced mixed episodes, not pure mania [ 28 ]. These data suggest there is a neurobiology of startle suppression that may provide critical insight to the underlying biological conditions that cause areas of the brain to improperly process information, in this case sensory-motor responses.

2.3. Animal models utilizing stress to dampen startle reactivity

Across the studies that have documented reductions in the expression of the startle reflex in rodents, the common-most feature is that the magnitude of the response is dampened following exposure to a stressor manipulation. Reduced startle amplitudes have been documented in rats following: repeated 20 min restraint [ 29 ]; inescapable tailshock [ 30 - 32 ]; predator exposure coupled with an intraperitoneal injection [ 33 ]; immune-challenge [ 34 , 35 ], and a single session of footshocks [ 36 ]. Interestingly, despite some differences in methodology, inescapable tailshock [ 30 ], inescapable footshock [ 36 ], and predator exposure with injection [ 33 ], all showed reduction in ASR measurements that could not be attributable to enhanced habituation to the acoustic stimuli. Yet, studies utilizing inescapable tailshock (in females) have established that exposure to the stressor condition causes a change in startle responsivity (the magnitude of the measured startle responses), not startle sensitivity (the threshold to elicit a certain percentage of startle responses). Thresholds for eliciting ASRs are not increased in the shocked females; instead, the magnitudes of the elicited startle responses are lower [ 31 , 32 ]. This suggests, at least for the female stress model, that the presumed increased inhibition upon the activity in the intrinsic ASR circuit is occurring through the motor response aspect of the reflex arc. The muscles are simply not as mobilized when this condition is induced. This model condition has been termed by some stress-induced startle suppression [ 32 , 34 ].

There are significant differences in the temporal characteristics of these different startle-suppression models in rodents. Inescapable tailshock causes a reduction in startle magnitude in female rats that is evident hours within exposure [ 31 , 32 ], possibly lasting up to a day later, when the bouts of shock are expanded to a few consecutive days [ 30 ]. The footshock-induced suppression of startle reactivity is evident 4 h following stressor exposure [ 36 ]. The immune-challenge models parallel these stressor manipulations by causing reductions in startle reactivity within a couple hours of administration of the challenge [ 34 , 35 ]. Thus, one interpretation of these data is that painful stressors are causing changes in the peripheral immune system, which, in turn, dampen startle reactivity during the time of their activity [ 34 ], on the range of hours. Following this logic, when females were tracked 4 and 8 days following tailshock, reductions in startle reactivity in the stressor-exposed rats did not reach statistical significance [ 30 ]. In contrast, the predator-exposure + injection model shows immediate suppression following the stressor exposure, which continues to be present 1 week later [ 33 ]. In addition, it is evident both under dark and light conditions [ 33 ], suggesting the change in the startle response is not occurring due to a change in reactivity to other stimuli that are known to modulate startle reactivity, such as light-enhanced startle [ 37 ]. Thus, this observance suggests that changes in ASR magnitude may be extended beyond the acute effects of stressor exposure that could be attributed to the short-term effects of immune signaling that would be in response to the injection (or possibly even shock).

3. Peripheral mechanisms of reduced startle reactivity

3.1. hypothalamic-pituitary adrenal (hpa)–axis.

Two interrelated mechanisms have been proposed as potential causes of startle suppression, the first being glucocorticoid hormone reception. Adamec and colleagues showed the reduction of startle magnitudes following combined cat exposure and saline injection could be blocked by substituting the saline injection with the glucocorticoid receptor antagonists RU-486 [ 33 ]. We subsequently tried to induce the effect in our female rats by administering the synthetic glucocorticoid agonist, dexamethasone. Startle responses were assessed 2 and 4 h following dexamethasone administration. As shown in Figure 2 , the dexamethasone did not appreciably change the magnitude of the elicited ASRs, nor did it affect the number of ASRs elicited (data not shown). These findings suggest that the reception of corticosterone at the glucorticoid receptor is not sufficient to reduce ASR magnitudes. One possibility is that RU-486 blocked the suppressed startle, in that model system, via a non-glucocorticoid mechanism, for example via progesterone receptor antagonism. A connection to progesterone will be discussed further below as it pertains to a pro-inflammatory response mechanism, in contrast to an anti-inflammatory glucocorticoid response, but this finding is supported by previous work that shows elevations in circulating corticosterone are not necessary for corticotrophin releasing hormone to increase ASR magnitudes, despite stimulating increased activity in the HPA-axis [ 38 ]. Likewise, the suppression of ASR magnitudes in Occidental low saccharine consuming rats is not recapitulated by substituting corticosterone administration for the shock exposure [ 36 ]. Therefore, a role of glucocorticoids in the suppression of ASR magnitudes may be limited.

In order to increase binding at the glucocorticoid receptors, the synthetic glucocorticoid analog, dexamethasone, was administered s.c. (0.1 mg/kg) to female Sprague Dawley rats (n= 8-9). The magnitudes of the elicited ASRs only differed across the Stimulus Intensity, F (1, 15) = 135.3, p <.001, not drug administration. Data are collapsed over the 2 startle test sessions. A cross (†) represents within-group difference from the highest stimulus intensity (p <.05, Fishers LSD).

3.2. Pro-inflammatory cytokines

The second mechanism, which is intertwined with the HPA-axis, is the peripheral pro-inflammatory immune response. We first showed that a ovarian hormone-dependent suppression of startle magnitudes could be induced by a single injection of the pro-inflammatory cytokine interleukin (IL)-1β [ 34 ], an effect that appears to parallel that observed following tailshock [ 31 ]. This effect was later replicated in male rats using lipopolysaccharide (LPS) [ 35 ]. Still, peripherally released IL-1β elicits the release of glucocorticoids from the adrenal through stimulation of the vagus nerve, paraventricular nucleus of the hypothalamus, and pituitary gland, which provides an anti-inflammatory response to the pro-inflammatory signal [ 39 - 44 ]. In order to further delineate that pro-inflammatory cytokines, and not anti-inflammatory glucocorticoids, are necessary for stress-induced startle suppression, we compared the effect of inescapable tailshock upon the induction of ASRs in two strains of rats, specifically chosen because of their pro-inflammatory and glucocorticoid responsiveness to stressors. Low-glucocorticoid/high-pro-inflammatory releasing Lewis (LEW) rats [ 45 - 49 ] and high-glucocorticoid releasing Wistar-Kyoto (WKY) rats [ 50 - 52 ] were compared. Females of each of these strains were exposed to inescapable tailshock and subsequently tested for startle reactivity 1 and 3 h later. If pro-inflammatory signaling, not anti-inflammatory glucocorticoid release is critical for eliciting startle suppression, then LEW rats would exhibit suppression of the ASR, and the WKY rats would not. As shown in Figure 3 , this is the case. This suggest the suppression of startle responsivity in female rats is more likely due to an overactive pro-inflammatory cytokine signaling response, instead of an overactive anti-inflammatory glucocorticoid response via the HPA-axis.

LEW rats exposed to the stressor differed from both their same-strain controls and the WKY groups on the measure of startle magnitude (responsivity). These impressions were confirmed by both main effects of Stimulus Intensity, F (1, 36) = 285.0, p <.0001, Strain, F (1, 36) = 6.4, p <.02, and Stressor exposure, F (1, 36) = 5.3, p <.03, as well as a marginal Strain x Stressor interaction, F (1, 36) = 3.3, p <.07. In addition to the expected differences in ASR magnitude due to Stimulus Intensity, F (2, 72) = 186.5, p <.0001, there were differences in the number of elicited startles across the two strains at the lowest stimulus intensity, with WKY rats having responded with more startles (4.5) than did the LEW rats (3.8) to 92 dBA stimulus. This impression was confirmed by a significant Strain x Stimulus Intensity interaction, F (2, 72) = 3.0, p <.05 (data not shown).

The hypothesis that pro-inflammatory cytokines are a necessary component in the suppression of startle responses following stress was further evaluated in the immune-sensitive Lewis rat strain by determining if elevations of peripheral IL-1β is sufficient to suppress startle reactivity in female rats. Startle responsivity has been found to be suppressed in female SD rats [ 34 ], but, we questioned whether immune-sensitive Lewis rats would show either greater effect sizes in the suppression of the startle magnitudes and/or reduced startle sensitivity as well. As shown in Figure 4 , both startle responsivity and sensitivity were reduced in female Lewis rats administered IL-1β. This confirms that pro-inflammatory signaling can influence both aspects of startle behavior, with sensitivity effects requiring a greater sensitivity to the pro-inflammatory signals or, possibly, greater elevations of the signal.

3.3. Prior immune challenge effects on stress-induced startle in SD rats

One consequence of the peripheral immune system having an effect on behavior, in this case sensory reactivity to acoustic stimuli, is that prior immune challenges may influence how future pro-inflammatory signaling or anti-inflammatory glucocorticoid responses influences behavior following stressor exposure. LPS is a commonly used endotoxin that elicits sickness behaviors due to a release of peripheral and central pro-inflammatory cytokines, followed by an increase in circulating glucocorticoids [ 53 , 54 ]. Others have shown that immune challenges days prior to shock exposure causes a greater increase in glucocorticoid release in response to shocks [ 55 , 56 ]; therefore, we used this known method of causing a sensitized glucocorticoid response to determine if a greater glucocorticoid release enhances or reduces the degree by which tailshock suppresses startle responsivity.

Female LEW rats (n = 16) exhibited significant differences in both startle sensitivity and startle responsivity measures following a single systemic injection of IL-1β (3 μg/kg, i.p.). Startle sensitivity was equally effected 1 and 3 h following administration and is shown collapsed over Session Time. Startle responsivity was only effected 1 h following administration; therefore, the 3 h time-point is not shown. An asterisk (*) represents a significant difference from saline-treated controls at the same stimulus intensity. A cross (†) represents a significant difference from saline-treated controls during the same test session (all p <.05, Fishers LSD).

We hypothesized that pro-inflammatory signaling causes stress-induced startle suppression; therefore, experiencing an immune challenge 3 days prior to shock would cause a sensitized anti-inflammatory release of glucocorticoids in response to inescapable shock, blocking the reduction of startle responsivity caused by the acute release of pro-inflammatory cytokines. As expected, the number of startle responses elicited did not differ based on prior treatment but did differ across stimulus intensity (data not shown); however, prior exposure to LPS reduced the effectiveness of inescapable shock to attenuate startle magnitudes (see Figure 5) . Although LPS has a short-term suppressing effect upon the startle response [ 35 ], it both causes an acute increase in pro-inflammatory cytokines (and sickness behaviors) followed by an increase in anti-inflammatory glucocorticoid signaling. This “priming” effect upon the anti-inflammatory glucocorticoid response to shock is a likely mechanism for “buffering” the behavior from being affected. Again, this suggests the glucocorticoid response may actually counteract the suppressive effects originating from peripheral pro-inflammatory cytokine signaling.

4. Central mechanisms of reduced startle reactivity

4.1. neuroanatomy and endocrine modulation of startle suppression.

As mentioned above, studies of pre-pulse inhibition of the ASR have elucidated neural circuitry that underlie the suppression of ASRs when they are immediately preceded by a salient auditory stimulus, for a review see [ 57 ]. Both the BNST and AMG have indirect projections to the PnC through the PPT [ 58 ]. Inputs from the PPT, LDT, and SNR to the PnC cause inhibition of the startle response [ 7 , 9 , 59 , 60 ]. More specifically, it appears the magnocellular portion of the PnC has muscarinic receptors to receive the inhibitory cholinergic signal from PPT and LDT [ 61 ] and GABA B receptors receive the inhibitory signal from the SNR [ 62 ]. The question is whether these areas could provide more tonic inhibition of the ASR, outside of the attentional processes associated with PPI. For instance, it is known that lesions to the medial septum and the fimbra-fornix increase startle reactivity because these areas provide tonic inhibition upon the amygdala [ 63 ]; thus, removal of inhibition upon the amygdala increases tonic excitatory activity to the PnC (from the amygdala). In contrast, lesions to the noradrenergic cell bodies of the LC reduce startle response magnitudes, as these neurons probably serve a tonic excitation function upon the PnC [ 64 ]. Thus, there are circuits within the brain that are situated such that they could provide more tonic changes in the ASR.

The expression of stress-induced startle suppression became evident 3 h following stressor exposure; however, this effect was blocked in those rats previously exposed to 30 µg/kg LPS (i.p.) 3 days earlier. These impressions were confirmed by a significant LPS x Stress x Session interaction, F (1, 28) = 10.2, p <.005. Hence, the pretreatment with LPS, which should have increased the glucocorticoid response to the inescapable tailshocks, blocked the suppression of startle responsivity following shock exposure. This suggests that prior experiences likely cause a more robust anti-inflammatory glucocorticoid response that actually reduces the influence of the peripheral immune pro-inflammatory immune response upon the areas of the brain capable of suppressing startle responsivity.

Specific to the female startle-suppression model, a central mechanism that caused this change in reactivity should be influenced by the presence/absence of ovarian hormones [ 31 , 32 ]. Ovarian hormones can have a significant impact on many of the neural structures associated with startle regulation. The cochlear nuclei [ 65 ], the nucleus accumbens [ 66 ], the hippocampus, [ 67 ] and the SNR [ 57 ] all exhibit changes in morphology, neurotransmission, and/or receptor expression with the presence of ovarian hormones. Yet, despite all these areas of influence, rodent studies usually do not find any differences in baseline startle reactivity across the estrus cycle or with hormone replacement [ 68 , 69 ]; however, see [ 70 ] for an example of oral-contraceptive usage effecting baseline startle in women. When significant arousal or stress occurs in the rodents, however, the modulatory actions of ovarian hormones on startle become evident. For example, Toufexis and colleagues have shown the magnitude of CRH-enhanced startle is attenuated when progesterone levels are increased [ 71 ]. CRH is thought to enhance startle reactivity in the BNST via CRF1-type receptors [ 72 - 75 ]. The result is an increase in excitatory afferents signaling to the PnC [ 76 ]. One possibility is that progesterone, or its metabolite allopregnanolone, may decrease the excitatory signaling from the BNST to the PnC by increasing GABA inhibition in this structure [ 77 ]. However, in vitro, BNST CRF-1 receptors increase local GABA activity [ 78 ]. Thus, it appears that progesterone or allopregnanolone should facilitate the actions of CRH on startle, unless they act through different mechanisms within the BNST or outside of the BNST. On the other hand, progesterone also affects how IL-1β influences sexual receptivity [ 79 ], and both glucocorticoid receptor activation [ 77 ] and progesterone-induced changes in central neuroadrenergic activity [ 80 ] have been suggested to attenuate startle reactivity selectively in female rats. As shown in Figure 6 , the administration of progesterone to ovariectomized rats appears to be necessary for IL-1β to suppress startle magnitudes. Thus, ovarian hormones are not sufficient to cause changes in startle reactivity in female rats. In fact, IL-1β appears to increase startle responsivity following estradiol pretreatment (17β-estradiol), whereas progesterone pretreatment sets the stage for IL-1β to suppress startle responsivity. Therefore, stress-induced startle suppression in female rats appears to necessitate a combination of the two factors, a peripheral pro-inflammatory immune response and the presence of progesterone.

Startle sensitivity and responsiveness were assessed 2 h following IL-1β administration. Hormone treatment occurred 2 h prior to IL-1β injection. Differences in startles elicited (sensitivity) and the magnitudes of those elicited startle responses (responsivity) each were assessed via a 5 (Condition) x 3 (Stimulus Intensity) repeated measures ANOVA. No significant differences in startle sensitivity were detected (data not shown). However, a significant main effect of Stimulus Intensity, F (2, 70) = 392.2, p <.001 and a significant Condition x Stimulus Intensity interaction, F [ 8 , 70 ] = 2.1, p <.05 were detected in the measure of startle responsivity (magnitude). An asterisk (*) represents a significant difference from all other groups. A single cross (†) represents a significant difference from the low estradiol dose group. A double cross (‡) represents a significant difference from both estradiol-treatment groups. All post-hoc tests used Fishers LSD (p <.05).

4.2. Evidence for limbic regulation of startle suppression

Peripheral IL-1β is known to have a significant impact on brain activity. Systemic IL-1 administration activates key afferent pathways in brainstem (lateral parabrachial nucleus and dorsomedial and ventrolateral medulla) and limbic system nuclei (BNST and central nucleus of the amygdala) [ 81 ]. In fact, peripheral IL-1β activates the amygdala and BNST more than i.c.v. administered IL-1β [ 82 ], probably because the vagal-mediated signals to these nuclei are more direct, to those nuclei via the NTS, than the diffusion of the IL-1β from the ventricles. Still, increasing peripheral IL-1β signaling increases NE and serotonin levels in these brain areas [ 83 ] and noradrenergic metabolism in the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus (LC), and amygdala [ 83 ]. In fact, as the IL-1β dose is increased, the amount of NE metabolism increases linearly in the amygdala, lasting as much as an hour [ 83 ]. It should be noted, this was not tested in the BNST. Yet, stimulation of α-adrenergic receptors also attenuate startle responses and facilitate non-associative habituation of the startle response [ 84 - 88 ]. IL-1β affects activity in the LC in a dose dependent manner as well, with low doses inhibiting activity and higher doses causing excitation; a process mediated by CRH at the time of IL-1β release [ 89 ]. Further, when the exposure to painful stimuli is prolonged or LPS is used to cause a significant pro-inflammatory response, additional release of central IL-1β occurs, especially in the hypothalamus [ 90 , 91 ]. These data suggest that activity in the limbic system, monoamine activity in particular, is significantly affected by peripheral immune signaling.

Based on the above logic, we hypothesized that the reduction in ASR magnitude occurring as a result of IL-1β administration to progesterone-pretreated female rats could be associated with changes in the central noradrenergic activity in one of the known modulatory nuclei of the acoustic startle response. Therefore, we measured norepinephrine levels in brain tissue-punches from 4 brain areas: BNST, amygdala, medial prefrontal cortex (mPFC), and dorsal hippocampus. As stated above, both the BNST and cAMG have direct excitatory projections to the PnC and indirect inhibitory connections via the PPT. The medial prefrontal cortex projects to the primary startle circuit via the LDT, whereas the dorsal hippocampus was included as an area that is both reactive to stress and ovarian hormone manipulation, but it is actually several synapses removed from the PPT. As shown in Figure 7 , differences due to hormone pretreatment and subsequent IL-1β administration were found in the BNST, not in any of the other 3 areas.

Significant effects of IL-1 treatment on NE levels in the BNST were observed in rats pretreated with progesterone (100 μg/kg, s.c.). This was confirmed by a significant Hormone x IL-1 interaction F (2, 42) = 4.5, p <.02. IL-1β treatment to oil-treated controls was associated with significantly lower NE levels than oil-treated saline-controls (*). IL-1β-administered rats, which were pretreated with either estradiol [20 μg/kg, s.c.) or progesterone, exhibited higher levels of NE compared to oil-pretreated rats that subsequently received IL-1β (†). In addition, the 2 hormone treated saline control conditions also differed from each other, with the estradiol-treated saline-controls exhibiting higher levels of NE than those pretreated with progesterone prior to saline administration (‡). All post-hoc tests utilized Fisher’s LSD (p <.05).

The role of the BNST in this cytokine-induced change in behavior is logical given recent work associating activity in this structure with changes in behavior associated with behavioral depression or sickness behavior. For example, an endotoxin-induced suppression of social interactions is both associated with increased activity in the BNST as well as reduced activity in the BNST when the suppressed behavior is blocked by IL-1ra [ 92 ]. Similarly, the behavioral depression exhibited in the forced-swim test can be reduced by stimulating the vagus nerve, leading to changes in brainstem nuclei activation (including the NTS) and also activation of the BNST [ 93 ]. Others have shown NE release is elevated with stressor exposure in the BNST, which is necessary for some stress-induced behaviors [ 94 , 95 ]. With particular attention to the startle reflex, the BNST is commonly associated with enhancing startle reactivity [ 2 , 96 ]. However, as shown in Figure 8) , there is an inhibitory pathway from the BNST to the PnC via the PPT that has been examined as a cholinergic mechanism for eliciting PPI [ 97 , 98 ]. Further, PPI has been shown to fluctuate over the estrus cycle, while not being sensitive to apomorphine disruption, implicating a non-dopaminergic mechanism for these hormone-induced changes in female pre-pulse inhibition, which could rule-out a role of the substantia nigra in this process [ 68 ]. In addition, the changes in measured NE levels in the BNST are consistent with previous studies citing peripheral IL-1β administration as a trigger for central noradrenergic activity [ 82 , 99 ].

Beyond the direct connections of the brainstem/midbrain nuclei, there are many other nuclei that indirectly influence the modulation of the ASR. Graphically represented here are the noradrenergic projections (in blue) from the nucleus of the solitary tract (NTS) and locus coeruleus (LC) to the various nuclei of the limbic system that then modulate the ASR via the inhibitory brainstem/midbrain nuclei. Input to the NTS via either the from the vagus nerve (X n.) or diffusion of IL-1β across the blood-brain barrier in the nearby area postrema is necessary for the noradrenergic changes in the brain in response to peripheral pro-inflammatory cytokine signaling. As above, red lines denote cholinergic pathways, and dashed lines represent inhibitory circuits. The orange represents CRH-mediated neural circuits. See text for further details.

There is evidence that could suggest a connection between the known effects of peripheral cytokine activity upon brain noradrenergic activity (most reported males) and an ovarian hormone influence upon these processes. For one, there is growing information pertaining to ovarian hormone influences on noradrenergic activity initiated from the NTS. Many of the brainstem noradrenergic nuclei, including the NTS, exhibit cyclic changes in estrogen and progesterone receptors [ 100 ]. Removal of ovarian hormones with or without hormone replacement particularly has a significant impact on NTS physiology. Specifically, the mRNA for prolactin-releasing peptide (PrRP) in noradrenergic neurons is decreased by ovariectomy and increased with subsequent replacement of either estradiol or progesterone [ 101 ]. Although the PrRP mRNA levels are reported to not change significantly across the estrus cycle in the NTS, an inspection of the data suggests the levels are a bit higher during proestrus [ 102 ]. PrRP labeling in the NTS is also preferentially sensitive to painful stressors, such as tailshock [ 103 ]. Estradiol has also been reported to increase neural inhibition in the NTS [ 104 ]. These data suggest ovarian hormone influences on NE NTS physiology could occur through changes in the regulation of a co-expressing neuropeptide. This could serve a filtering function for the vagal activity representing immune activity changes in the periphery, as the NTS projects its NE efferent connections to key areas involved in arousal and sensory reactivity, such as the BNST, AMG, hypothalamus, and parabrachial nucleus [ 105 ]. For example, core body temperature increases from peripheral IL-1β occur for a longer period of time during proestrus (compared to diestrus) apparently do to the actions of progesterone [ 106 ]. Although it is clear hypothalamic cyclooxygenase is the necessary mechanism for this effect [ 107 ] the noradrenergic input to the hypothalamus is required and may be changed as well [ 108 ]. Therefore, there are anatomical and pharmacological reasons to link NTS noradrenergic projections to the BNST as the primary pathway by which changes in vagal activity could influence startle responsivity through known inhibitory circuitry.

Other possible mechanism for startle suppression could occur as a cascade of effects that begin with the hormone-specific effects upon NE in the brain, but end with non-specific hormonal influences upon 5-HT. NE was shown above to be changed in the BNST following systemic increases in IL-1β, confirming the results of others showing noradrenergic activity increases within 30 minutes of a peripheral injection of IL-1β and may last 2 hours [ 109 , 110 ]. Importantly, as proposed above, the effect of systemic IL-1β injections on brain NE in rodents is dependent upon transmission in the vagus nerve [ 111 ]. The effects of peripheral IL-1β on 5-HT are quite different in terms of timing, route, and influence of ovarian hormones. First the increases observed in brain serotonin metabolism are evident 2-4 h following IL-1β administration and, at least in male rats, are reported to be less region specific (compared to NE activity changes) [ 110 ]. In addition, the effects of peripheral IL-1β on brain 5-HT are not dependent upon the vagus nerve in male mice but neither are the effects upon brain NE activity [ 112 ]. Thus, it is not known if 5-HT requires the same pathway as IL-1β to effect central 5-HT activity, but the difference in the temporal cascade would suggest such a difference is logical. Further, as shown in Figure 9 , the same peripheral IL-1β injections that elicited a hormone-dependent change in BNST NE levels caused an increase in 5-HT activity in both estradiol and progesterone-treated female rats. This somewhat conforms to the data previously describing less specificity in the upregulation of 5-HT activity, although we did not observe this pattern beyond the BNST.

Serotonin activity (5HIAA/5HT ratio) appears to be increased in the BNST of hormone-pretreated OVX female rats 2 h after a systemic injection of IL-1β, as suggested by a marginal effect of IL-1β, F (1, 42) = 3.6, p <.06.

5. Immune mechanisms following the acute pro-inflammatory response: Recovery or maintenance?

5.1. recovery of startle responsivity.

The peripheral immune system also has counter-inflammation mechanisms that could also be potential mechanisms for what appears to be a pro-inflammatory cytokine-mediated effect. Thus, another response to pro-inflammatory cytokine release, is the increase in the endogenous IL-1 receptor antagonist (IL-1ra), which has been shown to attenuate the reductions in food-intake elicited by systemic administration of LPS or IL-1β [ 113 ]. Our hypothesis was that elevations in IL-1ra, from systemic administration, would counteract the effects of IL-1β. Thus, IL-1ra was administered systemically, followed by an assessment of startle reactivity 1 and 3 h later. As shown in Figure 10 , the peripheral immune mechanism for stifling the pro-inflammatory response of IL-1β is sufficient to increase startle sensitivity. This suggests the nervous system is responsive to elevated acute pro-inflammatory signaling, suppressing startle, and elevations in the counter-active IL-1ra, increasing sensitivity to acoustic stimuli. These interactions illustrate the constant inter-relationship between the peripheral immune system and the nervous system regulation of sensory-motor activity.

Startle magnitudes in female SD rats (n = 7) were not affected by the administration of IL-1ra (10μg/kg); however, ASRs were elicited more often following the administration of IL-1ra. These impressions were confirmed by a significant main effect of Drug F (1, 12) = 9.7, p <.01. The higher sensitivity to the stimuli was superimposed upon the general difference in elicited startles across the three intensities, as reflected by a main effect of Stimulus Intensity, F (2, 24) = 67.4, p <.0001. An asterisk (*) represents a significant between-group difference from the vehicle-treated controls at the same intensity. A cross (†) represents a significant within-subject difference from the lowest intensity, and a double cross (‡) represents a significant within-subject difference from the highest intensity (all p <.05, Fishers LSD).

5.2. Immune influences on serotonin synthesis: A possible central mechanism of continued suppression?

Serotonin (5-HT) is an essential modulator of the startle reflex and disruption of serotonin synthesis and metabolism has been shown to result in startle suppression. As shown in Figure 11 , during the synthesis of serotonin, L-tryptophan is converted to 5-hydroxytryptophan (5-HTP) by the enzyme tryptophan hydroxylase. In a subsequent reaction, 5-HTP is converted to 5-HT by the enzyme L-aromatic amino acid decarboxylase. Disruption to any part of the 5-HT synthesis pathway is capable of reducing whole brain levels of serotonin resulting in unique abnormalities to the startle reflex. For example, when normal fasted women were tested after having ingested a tryptophan-free amino-acid mixture, the result was lower ASR magnitudes compared to those that received a mixture with L-tryptophan in its contents [ 114 ]. When a similar study was conducted in men, a non-significant trend for the same effect appears evident, although it was represented in the analysis as a failure to obtain significant PPI [ 115 ]. Alternatively, increasing tryptophan catabolism has also shown to affect PPI. Increasing levels of kynurenine, the first product of tryptophan degradation via indoleamine2, 3-dioxygenase, disrupts PPI in male Sprague-Dawley Rats [ 116 ]. Thus, the balance of serotonin and kynurenine is a likely secondary mechanism the body uses to modulate startle sensitivity and responsivity to stimuli.

The normal synthesis of serotonin (5-HT) involves the metabolism of tryptophan to 5-hydroxytryophan by tryptophan hydroxylase; however, in the presence of interferon-γ, another, competing enzyme, indolamine1,3-dioxygenase is upregulated. The result of this shift in the metabolism of tryptophan towards the formation of kynurenine is a reduction in the amount available for metabolism towards the formation of serotonin (i.e. serotonin depletion).

In addition to exhibiting reduced startle responses [ 18 ] women exhibiting PTSD, linked to previous intimate partner violence, also exhibit greater circulating levels of interferon (INF)-γ [ 117 ]. INF-γ is a downstream Th-1 mediated signal from the pro-inflammatory IL-1β signal and is a potent inhibitor of 5-HT synthesis, decreasing the amount of tryptophan available for 5-HT production. In the presence of IFN-γ, tryptophan is shunted to kynurenic acid synthesis by increasing activity of indoleamine2, 3-dioxygenase [ 118 ]. An intermediary signal between IL-1β and INF-γ is IL-2. Female rats treated with IL-1ra (to combat the induction of EAE) exhibit an attenuated IL-2 response [ 119 ], which would, presumably, decrease INF-γ signaling (see Figure 12) . There is limited experimental evidence that has focused upon delineating INF-γ or IL-2 effects on startle reactivity in rats, and those that have been conducted use an early development administration paradigm to assess later changes on behavior (e.g. [ 120 ]). However, one study conducted in mice did access acute IL-2 effects upon startle reactivity and reported no change in behavior [ 121 ]. Unfortunately, that study did not test more than one time-point and only utilized male mice.

The initiation of an inflammatory response begins with the non-specific macrophage pro-inflammatory response (Th0), which then diverges into either a Th1 (cell-based) or Th2 (humoral-mediated) response. There is evidence that suggests ovarian hormones may influence the path of the subsequent immune cascade from the Th0 response. To date, the Th1 response has been more intently studied for its possible role in effecting behavior (i.e. causing changes in behavior).

Given the lack of data pertaining to IFN-γ effects upon startle sensitivity and responsivity, we conducted a study focusing on determining whether IFN-γ could change ASR sensitivity or responsivity. As stated above, LEW rats exhibit greater pro-inflammatory responses to infection than do other strains; therefore, we tested whether acute administration of IFN-γ is sufficient to reduce startle reactivity, presumably from reducing serotonin availability. Although still preliminary, our results suggest IFN-γ may have a bi-potential effect on startle sensitivity. The higher dose of IFN-γ caused an apparent decrease in the percentage of startles elicited 1.5 h following injection, whereas the lower dose caused significantly more startles to be elicited than the high dose (see Figure 13) . This is an important distinction, for it suggests that reduced startle responding due to IFN-γ (and possibly low serotonin tone) is due to a decrease in the ability to sense a startling stimulus, rather than the ability to mount the physical response (although there are trends suggesting that responsivity may be decreased as well with higher doses). Hence, there may be more than a hypothetical link between stress, IL-1 release, and an identified difference in basal immune functioning in a population of women with PTSD that have also been described to have blunted startle responses. There may be instances where the downstream Th1-response is elevated, thus causing a seemingly similar “blunting” of the ASR but the suppression is different in form and occurs through different neural pathways.

6. Clinical applications

The suppression of startle reactions has only gained significant attention in the past decade, and, as researchers have looked for changes in startle responses (not just exaggerations), suppression has been observed in anxiety disorders (i.e. PTSD), MDD, and BPD. However, what does it mean when a specific, directional change in a reflex behavior is observed across these different diagnoses? The answer may lie in what is generally called comorbidity .

When one considers stress-related mental disorders, typically, anxiety disorders, MDD, BPD, and maybe even schizophrenia are cited as examples, but how distinct are anxiety disorders from MDD or MDD from BPD? In all cases, there is an overlap of various symptoms that could be experienced with any of these diagnoses. The DSM clinical criteria do provide some flexibility in categorizing subjects into the different classes of disorders. What that allows for are physiological conditions that are not specific to just one of these classes, and chronic or phasic abnormalities in the activities of the peripheral immune system could be common in some patients that meet the criteria for PTSD, the non-mania phase of BPD, or even MDD.

For example, there is a growing body of literature that suggests abnormal immune system signaling may be at the core of BPD. Several studies have shown abnormalities in the cytokine profiles of BPD patients, with differences present in both depressed and manic subpopulations [ 122 - 124 ]. Multiple studies have shown a characteristic increase in TNF-α among both bipolar depressed and manic patients [ 122 , 123 ], whereas patients suffering from bipolar mania commonly exhibit decrease in IL-1β, IL-2, and IFN-γ. When stimulated with LPS, a common procedure used to model behavioral depression in animals, the monocytes from non-lithium treated patients exhibit a decrease in the production of IL-1β and an increase in IL-6, compared to healthy controls. This abnormality was shown to be reversed in lithium treatment patients [ 125 ]. This suggests a by-product of lithium administration may be an influence on the pro-inflammatory response signals in the periphery. Additionally, Boufidou and colleges found that lithium is capable of down regulating the production of IL-2, IL-6, IL-10 and IFN-γ from peripheral blood lymphocytes in BPD patients, and a similar down regulation of pro-inflammatory cytokines was observed in previously non-medicated BDP after three months of lithium treatment [ 126 ]. These data further implicate a peripheral immune mechanism for BPD that is normalized by lithium treatment.

Startle sensitivity and responsivity were assessed 30 and 90 min following an acute systemic injection of IFN-γ (n = 16). Startle sensitivity was significantly altered by the specific dose administered. The low dose showed an increase in elicited startles over time, whereas the high dose showed a reduction in elicited startles over time, IFNγ x Session F (2, 29)= 3.3, p <.05. An asterisk represents a significant difference in the low-dose group at the 90 min test as compared to the same time high-dose and the 30-min low-dose test.

Based on the literature and the collected data from our laboratory, concerning the modulation of the ASR, we propose the following cascade of events may occur as a result of stressor exposure in our female rat model. First, the acute-phase (pro-inflammatory) response causes a transient reduction in startle responsivity (magnitude) that appears to last as long as IL-1 continues to be elevated above the levels of circulating IL-1ra. IL-1ra serves to normalize the response; thus, when the levels of IL-1ra are elevated to a sufficient degree, it causes an increase in ASR sensitivity (a rebound effect). However, in the cases where the stressor exposure is prolonged and/or severe enough to engage a downstream Th-1 response (i.e. increase IFN-γ signaling), then a reduction in ASR sensitivity occurs, whereby the sensory threshold for eliciting the response is increased. This could cause a chronic condition where ASRs are “blunted” in people with conditions ranging from PTSD to MDD to BPD.

The ASR could have a potential use as a functional index of abnormal peripheral immune functioning; thus, if the ASR is suppressed, it may represent an elevated level of pro-inflammatory or Th1 signaling in the patient. This could be of great importance from a therapeutic standpoint when one considers the suppressive effects of IL-1 upon sexual motivation in female rats are attenuated by indomethacin and ibuprofen [ 127 ]. Although blocking prostaglandin synthesis [ 128 ] or knocking-out the prostaglandin EP2 receptor does not change startle reactivity [ 129 ], prostaglandin EP1 knock-out mice do exhibit higher startle magnitudes compared to their wild-type control strain [ 130 ]. This suggests that EP1 receptors are in a position to serve as neuroimmune mechanisms to inhibit startle responsivity as well. Still, beyond the possible pharmacological implications, blunted reactivity to stimuli can have profound effects on other neural processes as well, and may explain some of the other symptoms associated with anxiety, MDD, or BPD. For instance, when the same dose of IL-1β, sufficient to blunt startle responsivity in female SD and Lewis rats, is administered to female SD rats prior to a simple associative learning procedure the rate of learning is slowed. This effect is attributed to a reduction in the neural representation of the unconditional reflexive response (i.e. the response is weaker), causing less optimal neural representation of the behavioral response to the predictive, conditional stimulus [ 131 ]. The implication is that associative learning may be impaired by either acute or chronic elevations in pro-inflammatory or Th1 cytokines. Interestingly, this pattern of effect is not observed in male rats, at these low to moderate dosages of IL-1β; in fact, these learning processes are facilitated [ 132 , 133 ]. Thus, the ASR can serve as a tool to better understand the blunting of sensory reactivity, but may also have implications for more complex associative learning processes as well. In Figure 14 , we present our theory as to how the ASR may be changed over time as a function of neuroimmune interactions between peripheral cytokine signaling (specifically the acute pro-inflammatory response and the downstream Th-1 response) and brain monoamines.

7. Conclusions

The evidence accumulated from these experiments favors a pro-inflammatory mechanism, over a HPA-axis glucocorticoid mechanism, as the necessary pathway that ultimately leads to the suppression of startle reactivity following stressor exposure. This finding adds to the ever-growing evidence that peripheral immune signaling has a significant role in influencing how the nervous systems functions. In this particular case, we have illustrated how a simple behavioral reflex can be dampened by pro-inflammatory signals, in the absence of any physical injury. This shows abnormal levels of peripheral immune signaling could lead to perceived symptoms reported by patients with PTSD, MDD, or BPD.

Biological differences in how different animals respond to stressor may reflect vulnerability factors for experiencing different symptoms associated with stress-related disorders, such as PTSD, MDD, and BPD. Thus, differences observed in the literature concerning startle reactivity in female PTSD patients (e.g. [ 18 , 19 ]) could be due to the types of stressor exposure or individual differences in biological responses. In addition, one cannot rule-out the role of coping mechanisms. In fact, one could hypothesize that the suppression of startle is an evolutionary selected response that keeps individuals within a species from continuing to fight a “losing battle”. If this were the case, then it would be logical for the immune system to play a role in that trigger-mechanism and not the HPA-axis. The HPA-axis is designed to maintain the fight-or-flight response [ 134 ], which would be in opposition to a behavioral suppression coping response. Others have proposed females are particularly selected to engage in alternative coping strategies that are in opposition to the fight-or-flight response [ 135 ], and one possibility is that signal reception of the peripheral immune response by the central nervous system is an early point of diversion in stress coping strategies between males and females. This could provide inherent propensities to respond differently, but, at the same time, could be modified by experience. Such propensities could translate into vulnerability factors for abnormal behaviors where that response becomes, potentially, maladaptive.

It is well documented that more women experience anxiety disorders and affective disorders, and there is a significant degree of comorbidity across these disorders – especially as cases become more severe [ 136 ]. There are many potential reasons for the higher rates reported in women. For instance, some have recently suggested there is a link between ovarian hormones and the occurrence of specific peptide isoforms that modulate stress responsiveness and fear conditioning [ 137 ]. The data presented here provide another example of how ovarian hormones can influence physiological processes associated with stress responsiveness. The role of progesterone in this immune model of startle suppression is particularly intriguing since progesterone can amplify the pro-inflammatory response through macrophage migration inhibitory factor [ 138 ]. This endocrine influence could, potentially, cause more Th1 signaling to occur, which, we hypothesize leads to an increase in IL-1β, causing more Th1 signaling to occur, eventually leading to an increase in IFN-γ release and subsequent reductions in sensitivity to auditory stimuli. If that same individual has central nervous system vulnerabilities, such as a particular peptide isoform, then, in addition to an apparent blunted startle response, the patient may also be exhibiting flashbacks due to enhanced neural processing of fear-associated memory. Thus, female vulnerability for anxiety and depression symptoms can be seen as a product of multiple mechanisms that modulate the female physiology and behavior in a manner that, at times, may even be counter to fight-or-flight, but, nonetheless lead to changes in nervous system functioning, causing the expression of a particular set of behavioral symptoms.

There is a growing literature pointing towards a complex interaction between the central nervous system and the peripheral immune system that underlies anxiety or affective disorder vulnerability and/or the presence of acute symptoms [ 139 - 143 ]. The utility of being able to use species-common measures, such as the startle response, has been advantageous to researchers in aiding them to understand how the brain functions under normal and abnormal conditions. Here we illustrate how such measures can be applied to the understanding of psychoneuroimmune interaction as they pertain to the influence of the peripheral immune system upon the brain and behavior. As we gain a greater understanding of the signaling cascades in the peripheral immune system, delineating how those signals affect the brain will continue to be important for our future understanding of the etiology of mental illnesses.

Acknowledgements

This research was supported by a U.S. Department of Veterans Affairs Merit Review research program to KDB and program support through the UMDNJ – Stress & Motivated Behavior Institute. The described experimentation was conducted with approval by the VANJHCS Institutional Animal Care and Use and Research and Development Committees, in accordance with the NIH Guide for the Care and Use of Animals. The authors want to thank Toni Marie Dispenziere, Tracey Longo, Ian Smith, and Paul William Ong for their technical assistance in conducting the experiments. Some of the described work was included in the undergraduate honors thesis of Mr. Ong. The authors also thank Dr. Victoria Luine for the use of the laboratory in the processing and measurement of the brain monoamine data.

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ICICT 2023: Proceedings of Eighth International Congress on Information and Communication Technology pp 217–232 Cite as

Content Moderator Startle Response: A Qualitative Study

Timir Bharucha 13 ,
Miriah E. Steiger 13 ,
Priyanka Manchanda 13 ,
Rainer Mere 14 &
Xieyining Huang 13
Conference paper
First Online: 01 September 2023

353 Accesses

Part of the book series: Lecture Notes in Networks and Systems ((LNNS,volume 695))

Commercial content moderators review user-generated content (UGC) to ensure the posts meet platform policies, guidelines, community standards, and regional laws. While the majority of posted UGC is deemed acceptable, a large amount of content remains, which is classified as non-compliant and may include gore, violence, suicide, child sexual abuse material (CSAM), and pornography, to name a few. Because of this, content moderators have a greater prevalence of their nervous system activating a startle response, which can impact emotional, psychological, and physiological processes. Prior research on content moderators has failed to explore moderators’ initial reactions to content from the start of employment through tenure as the subjection to material and habituation increases. This study takes an in-depth look at moderators’ experiences from recruiting, through training, and production to better understand the content moderators’ startle response and factors that enable startle habituation. The current study sample consisted of 78 total respondents—38 content moderators in the Philippines employed by TaskUs Inc. and 40 in Estonia employed by Sutherland Global Services. Employee tenure ranged from 0 to 6 months. Succeeding our analysis, transparency, understanding, and preparedness were major themes identified as the critical factors found within both companies when exploring the activation of the startle response and facilitation of habituation following content exposure. These themes were prevalent in the employment life-cycle's recruiting, training, and production phases.

Commercial content moderation
Startle response
Startle habituation
Employee life cycle

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Nielsen Norman Group (2000) Why you only need to test with 5 users. Nielsen Norman Group. Retrieved from https://www.nngroup.com/articles/why-you-only-need-to-test-with-5-users/#:~:text=Not%20true

Phelps BJ, Doyle-Lunders L, Harsin-Waite A, Hofman N, Knutson LM (2012) Demonstrating habituation of a startle response to loud noise. Behav Anal Today 13(1):17–19. https://doi.org/10.1037/h0100714

Reagh ZM, Knight DC (2013) Negative, but not positive emotional images modulate the startle response independent of conscious awareness. Emotion 13(4):782

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Acknowledgements

The authors express deep gratitude for those content moderators who participated in the research and so willingly shared their experiences. With this knowledge, we can better support the well-being of all reviewers. Additionally, the authors would like to thank content moderators worldwide for the tremendous and much-needed work that they do safeguarding the internet and social media platforms for the end-user.

The research study was conducted without any external funding (Table 1 ).

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Bharucha, T., Steiger, M.E., Manchanda, P., Mere, R., Huang, X. (2024). Content Moderator Startle Response: A Qualitative Study. In: Yang, XS., Sherratt, R.S., Dey, N., Joshi, A. (eds) Proceedings of Eighth International Congress on Information and Communication Technology. ICICT 2023. Lecture Notes in Networks and Systems, vol 695. Springer, Singapore. https://doi.org/10.1007/978-981-99-3043-2_18

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2015 Collectors' Edition - General articles

Without warning: the startle factor

‘#$@! we’re going to crash! This can’t be true! But what’s happening?’ were the last words from pilot David Robert on board Air France flight 447 as it crashed into the Atlantic ocean, in June 2009 killing all 228 on board.

In 2012, the French Bureau of Enquiry and Analysis for Civil Aviation Safety (BEA) found flight 447 crashed after temporary inconsistencies between the airspeed measurements—likely due to ice crystals obstructing the aircraft’s pitot tubes. This caused the autopilot to disconnect, after which the crew reacted incorrectly and put the aircraft into a stall.

The first officer’s initial response to pull back hard on the sidestick was consistent with impaired information processing, decision-making and problem solving typical of startle reaction. His persistence in maintaining full back pressure on the stick all the way down was also consistent with either multiple startles or continued degraded information processing following startle. BEA chief investigator Alain Bouillard equated the reaction to curling instinctively into a foetal position.

What is the startle response?

The startle response (also known as limbic hijack) is the physical and mental response to a sudden unexpected stimulus. More commonly known as ‘fight or flight’, this physiological reaction occurs in response to what you may perceive as a harmful event, attack, threat to your survival or simply fear. The fight or flight response evolved to enable us to react with appropriate actions: to run away, to fight, or sometimes freeze to be a less visible target.

The body responds with increased activity such as:

Circulation increasing blood supply to brain, muscles and to limbs (more O 2 ). Brain activity changes: we think less and react more instinctively.
Heart beats quicker and harder—coronary arteries dilate.
Blood pressure rises.
Lungs take in more oxygen and release more CO 2 .
Liver releases extra sugar for energy.
Muscles tense for action.
Sweating increases to speed heat loss.
Adrenal glands release adrenalin to fuel response.

In aviation, startle often occurs when the autopilot disengages and hands control to the pilot in a highly dynamic, time-critical condition. According to Human Factors SA psychologist Jo-Anne Hamilton, two systems in the brain—the reflexive fast system and the slow system—play different roles in our reaction to danger.

The reflexive fast system acts immediately—in one twelfth of a second—by sending information directly to the sense organs through the thalamus to the amygdala. The slow system sends sensory information to the hippocampus and cortex for further evaluation. It’s slower because it requires conscious processing.

Hamilton says that pilots in these non-routine, emergency and abnormal situations will have difficulties in recognising that a problem has occurred and difficulties in getting out of the normal mode of operations.

‘It may be a series of startle responses or more like one “big one” where the brain is kind of hijacked,’ Hamilton says. ‘Then we make a decision and once we make the next decision and our frontal cortex shuts down so our thinking capacity is not working so well—that leads us to the next decision etc and we go down into a tunnel.

‘And it’s extremely difficult once someone is in that tunnel—and you can see that from the Air France example—to stop, step back and say, “s**t, we are doing something really dumb here”.

‘We’ve evolved to confirm our decisions not to disconfirm them—it’s our natural human inclination.’

Automation versus stick & rudder

Arguments about whether pilots were better in the olden days have probably raged since the days of the Wright brothers. But hard numbers make one thing clear. Major in-flight events such as an engine failure are becoming rare in modern air transport aircraft. An airline pilot beginning their career today may never undergo such a test. But this safety improvement, paradoxically, brings its own dangers. Rare events are startling and underperformance—due to the effects of this startle on the body’s systems can be detrimental to the handling of such events.

According to Murray et al. (2012):

‘… one of the common themes as aircraft become more reliable is that pilots are surprised or startled by some event and as a result have either taken no action or alternatively taken the wrong action, which has created an undesired aircraft state, or in some cases, an accident. This surprise or startle is largely due to the enduring reliability of the aircraft and the aviation system, which has unwittingly created a conditioned expectation of normalcy among today’s pilots…The problem then is the level of expectation of novel or critical events is so low that the level of surprise or startle which pilots encounter during such events is higher than they would perhaps have had some decades ago when things went routinely wrong.’

In 2010, NASA’s Aviation Safety Program investigated loss of control. The NASA study determined that the, ‘deterioration of manual flying skills due to increased reliance upon automation is a strong contributor to manual handling errors…This deterioration in skill provides further encouragement to place even more emphasis on automation and less emphasis on manual flying. Thus, when piloting skill is needed to prevent or recover from a loss of control scenario, the basic manual flying skills are absent, either never having been fully developed or having atrophied to dangerous levels.’

Colgan Air Flight 3407 appears to fit this template. In 2009, the Bombardier Dash 8-Q400 was on instrument approach to Buffalo-Niagara International Airport, in the north-east US, when it stalled, dived and crashed into a house. Fifty people died. An NTSB investigation found the pilots had responded incorrectly to the stall warnings. Martin et al. (2012) agree that the cause was most likely due to the captain being, ‘initially very startled by the stick shaker and accompanied disengaging of the autopilot…His reactions were contrary to all previous stall training and could well have been induced by physiological effects from the startle reaction.’

Preventing startle

Of course, serious unusual events don’t always result in a startle response. In 2010, the crew of Qantas flight 32 prevented what could have been the world’s first A380 disaster after the plane experienced an uncontained engine failure.

QF32 captain Richard de Crespigny described how he handled the situation in his blog: ‘There was no startle effect, no panic on the flight deck. The cortex took and maintained control. We were able to “sit on our hands and initially do nothing”. Then we knew what we had to do.’

Hamilton believes training pilots for non-routine situations is essential and QF32’s de Crespigny and Chelsey Sullenberger of US Airways flight 1549 fame are a case in point—she describes them as ‘pilots’ pilots’.

‘When I heard about the landing on the Hudson I said to my colleague, “Sullenberger has done that before”. Obviously, he hasn’t done that before but when I read his book he says he had visualised the water landing I thought to myself: ‘wow that’s a pilot’s pilot”.’

Largely as the result of Colgan Air flight 3407, the US Federal Aviation Administration finalised a rule that will require airlines to provide pilots with simulated ‘extended envelope’ training by 2018. The full-motion simulator-based training is to include upset recovery manoeuvres as well as recovery from full stalls and stick pusher activations, among other abnormal events.

While CASA does not have a formal policy with regards to ‘startle factor training’ as a specific issue, training in non-technical skills is required to recognise and manage situations that can occur in a sudden event. The idea is to give flight crew the skills to manage a ‘startle’ type event.

Training in full flight simulators for ‘full stall recoveries and past stick shaker’ also requires adequate modelling of the flight simulator itself.

Part 61 Manual of Standards (MOS) addresses competency requirements for Non-technical skills 1 and Non-technical skills 2. Competency standards are required across a range of part 61 qualifications. In addition, each of the FAA-termed ‘extended envelope’ elements are covered as part of the type rating. The MOS flight review and proficiency checks also pick up the training and assessment of competency for areas such as upset recovery.

In addition to this, approved CAR 217 training and checking systems addresses the issues organisations feel are relevant to their operations. For example, the Air France 447 event led to Jetstar conducting their own specific training to address the icing event.

CASA will also introduce evidence based training (EBT) system guidance in the near future. EBT is specifically designed to address real time issues through training and assessment.

Training for startle situations—no matter how unlikely they may be—could prevent another Air France Flight 447 from happening in the future. Startle is a powerful mental force but it has two defences that every pilot can develop: confidence and competence.

Martin, W., Murray, P. and Bates, P. (2012). The Effects of Startle on Pilots During Critical Events: A Case Study Analysis. www98.griffith.edu.au
Langewiesche, W. (2014). Should Airplanes Be Flying Themselves? Vanity Fair.
Nottingham.ac.uk, (2012). What is the Fight or Flight response?
Jacobson, S. (2010). Aircraft Loss of Control Causal Factors and Mitigation Challenges.
Croft, J. (2014). Reconsidering Upset Recovery Training | Commercial Aviation content from Aviation Week. Aviationweek.com

Caught in the clouds

Power to the pedal

The bonfire of the inadequacies

[…] August 2015, Flight Safety Australia explored the crash and the startle response—the physical and mental response to a sudden unexpected […]

This is an interesting article. It raises quite a few questions and unresolved issues. “Evidence based” is necessarily retrospective. Will our ‘look back’ period be sufficient to isolate, then recognize the rare – but catastrophic events when our high risk, complex, tightly coupled systems have failed in the past? What kind of data are needed to identify obscured failures, and what investments are required to unravel the, then understand the accident chains to support’evidence based’ training? How will we incorporate into our failure modes training unknown and currently unknowable events that have yet to manifest, i.e., the “Black Swan” events that lie hidden in our environment, our technologies, our social systems, and elsewhere?

[…] Without warning: the startle factor | Flight Safety Australia Flight Safety Australia […]

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CONCEPTUAL ANALYSIS article

Role of institutions in public management: developing case studies for divergent policy systems provisionally accepted.

1 XIM University, India

The final, formatted version of the article will be published soon.

Public policy management has an intractable nature, and the institutional complexity of governance further exacerbates its practice. Transnational learning cutting across countries and policy areas can contribute to this policy knowledge in dealing with multifarious issues in public management. Understanding the institutional mix in public management in various contexts enhances the existing comprehension of how the national pattern of public management works differently in different socio-economic, cultural, and political settings. The present research aims to study the institutional framework in the form of state structure (unitary or federal) and the nature of executive government (majoritarian or consensual) in delineating the influence of institutions on public management processes in divergent policy systems. The paper undertakes four in-depth country case studies and the public management reforms as a response to institutional pressure are examined using the 4M strategy (Pollitt and Bouckaert, 2017)-Maintain (holding on to existing administrative structures and processes), Modernize (keeping service delivery and regulation up to date), Marketize (efficiency and user-responsive public management), and Minimize (reducing state-led regulation). The case studies highlight the differences in the broad direction and energy of implementation that characterize a particular policy style. The results of the study indicate that even though the institutional dimensions are not present in strict polarization, the impact of the institutional mix is evident in the dominant strategies of public management reforms adopted at the national level.

Keywords: political executive, Institutionalism and institutions, Public management, State Structure, Comparative politics

Received: 14 Jul 2023; Accepted: 05 Apr 2024.

Copyright: © 2024 Singh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Vaishali Singh, XIM University, Bhubaneswar, India

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Research Progress in the Study of Startle Reflex to Disease States

Junfeng zhang.

1 First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300380, People’s Republic of China

2 National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300380, People’s Republic of China

3 State Key Laboratory of Component-based Chinese Medicine, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China

Jiangwei Shi

The startle reflex is considered a primitive physiological reflex, a defense response that occurs in the organism when the body feels sudden danger and uneasiness, characterized by habituation and sensitization effects, and studies on the startle reflex often deal with pre-pulse inhibition (PPI) and sensorimotor gating. Under physiological conditions, the startle reflex is stable at a certain level, and when the organism is in a pathological state, such as stroke, spinal cord injury, schizophrenia, and other diseases, the reflex undergoes a series of changes, making it closely related to the progress of disease. This paper summarizes the startle reflex in physiological and pathological states by reviewing the databases of PubMed, Web of Science, Cochrane Library, EMBASE, China Biology Medicine, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodical, Wanfang Data, and identifies and analyzes the startle reflex and excessive startle reaction disorder.

Introduction

The startle reflex in humans is a conserved systemic motion response that is ubiquitous in mammals. It is the reflex contraction of the skeletal and facial muscles to sudden intense stimuli, and includes eye blinking, limb flexion, trunk shrugs, and autonomic symptoms (such as increased heart rate, sweating). 1 It originates from the brainstem, descends along the reticular tract to the spinal cord, 2 and finally stimulates the muscles through motor neurons, the strength of which are measured by electromyography (EMG). 3 The startle reflex is considered a defensive (relative to directional) response, which is habitual. 5 As the number and frequency of startles increase, the body becomes habitual, and the degree of startle reflex decreases. This kind of reaction exists to a certain extent to protect the human body. The startle reflex is an effective tool for studying the basic characteristics of the central nervous system. It has the characteristics of cross-species consistency, simple neural circuits, and sensitivity to experimental operations. 5 Throughout our review, we found that the degree of attention to the startle reflex has increased in the past five years, but review articles were mostly limited to the habituation, sensitization, pre-pulse inhibition (PPI), and sensorimotor gating of the startle reflex. Thereafter, we focused on summarizing the startle reflex in clinical disease states, and distinguishing the startle reflex from hyperekplexia.

In this article, the truncation and Boolean logic operators were used to search the databases of PubMed, Web of Science, Cochrane Library, EMBASE, China Biology Medicine, China National Knowledge Infrastructure, VIP Database for Chinese Technical Periodical, Wanfang Data according to the combination of subject words and free words. Herein, we summarized the startle reflex in physiological and pathological states and analyzed both the reflex and excessive startle reaction disorder. The search keywords were as follows: “startle reflex,” “startle response,” “mechanism,” “pathology,” “physiology,” “pre-pulse suppression,” “sensorimotor gating,” “disease,” “rare diseases,” “hyperekplexia,” “stroke,” “spinal cord injuries,” “schizophrenia,” and “autistic disorder.”

Classifications

Mammalian sensory organs are diverse; thus the startle reflex can be classified as auditory, visual, tactile, or olfactory. Among them, the most widely studied in clinical research is the auditory startle reflex (ASR), 6 which may be related to the difference in the processing time of stimulation among the known sensory modalities. For example, the total processing time for sound stimuli is shorter than that for visual stimuli, possibly because of the faster conduction time in the ear and the shorter distance from the ear to the auditory cortex. The tactile startle reflex often causes a local reaction as compared to the auditory startle reflex, contributing to a certain incubation period, resulting in an atypical response; therefore, there are few related studies. 7 Unless specified, the startle reflex described in this article is the auditory startle reflex. The ASR is most prominent in the facial, neck, and shoulder muscles, and rarely in the lower body. Surface EMG records obtained from the orbicularis (OOC), sternocleidomastoid (SCM), biceps brachii (BB), and tibialis anterior (TA) muscles were used as research indicators. 8

Measurement Methods

The startle reflex is important when studying the input and output of brainstem information, and there are many methods for measuring it. The most common and original method for measuring the startle reflex is the EMG system. With professional training and equipment (wired sensors), EMG detects the electrical signals of the target activity, obtaining objective and relevant data on the startle reflex. Other novel measurement methods include the new optical non-invasive method, 9 mobile acoustic startle reflex monitoring system (MARS), 10 and video freeze monitoring system. 5 The Balogiannis team 9 believe that the new optical non-invasive method is simple and reliable, making it superior to traditional EMG systems in terms of effectiveness, accuracy, and reliability. MARS 10 is the first mobile phone-based monitoring system. Through the use of smartphone applications for visual recording, ASR can be detected and monitored in healthy people. The diagnosis and monitoring of ASR in stroke, traumatic brain injury, and mood disorders has opened up new prospects and horizons, and the same went for that in remote or isolated conditions. The video freeze system 5 (Georgia Medical Association Co., Ltd., Vermont, USA) uses a standard digital camera to shoot videos and automatically evaluates the rodents’ shock response to sound. The system is also equipped with stimuli, such as sounds and lights, that are required for various startle modes, which is a new tool for studying startle reflex. These multiple measurement methods enable more efficient and realistic evaluation of the startle reflex.

Related Mechanisms

Sensorimotor gating.

Sensorimotor gating and startle reflex are both important components of the brainstem reflex, and it is necessary to understand one to study the other. Sensorimotor gating is a control mechanism for the effective transmission of sensory information to the motor system. 11 It usually occurs in the early stages of central nervous system processing, so that unnecessary stimuli are filtered out or partially ignored, and the central nervous system is less trivial, thereby optimizing the exchange of brain information, and efficiently using limited resources to process important information. Disruption of sensorimotor gating is prominent in many neurological and psychiatric diseases, including Parkinson’s disease (PD), schizophrenia, and Tourette’s syndrome.

PPI is a standard measurement method for sensorimotor gating. It is considered to be a potential biomarker reflecting brain function in disease states. 12 It is a stable physiological marker of the nervous system that accompanies human growth, and develops until its full maturation at approximately 8 years of age. It is mainly mediated by the brainstem and affected by the cortex - striatum - globus pallidus - pontine systems. 5 It is usually defined as a decrease in startle reflex due to weak sensation or pre-stimulus. Whenever a weaker stimulus (“pre-pulse,” such as a sound of about 85 decibels) appears before a strong stimulus, it results in a reduced startle amplitude to the strong stimulus (“pulse,” such as a sound of about 118 decibels). Simultaneously, PPI adjusts sensory input by filtering out irrelevant content or distracting stimuli to prevent sensory information overflow, thereby selectively and efficiently processing relevant information. 13

Neural Circuits

At present, the neural circuits of the startle reflex are still unclear. Fang et al 14 explored the neural circuit of the startle reflex by analyzing the retina- superior colliculus (SC)-lateral posterior nucleus (LP)-primary visual cortex (V1) pathway. The retina transmits visual information to the SC, which uploads information to the LP, which activates the L1 inhibitory neurons to inhibit the V1 response, and process different types of visual information. This pathway increases the incoming threshold of sensory information by screening important information, enabling the brain to receive more accurate information in the shortest time, and issuing commands in a timely manner during emergencies. 15 The pulvinar nucleus of the thalamus is an important part in this pathway, and is mutually and extensively connected with the prefrontal cortex, sensory cortex, superior colliculus, and amygdala, playing a very important role in multimodal sensory processing, emotional response, and defensive behavior. 16 , 17 In addition, abnormal pulvinar nucleus activity is associated with excessive startling. 18

It is relatively simple that the primary auditory startle reflex neural pathway in mammals. External sound activates primary auditory neurons in the cochlear root and cochlear nucleus (CN) that transmit the auditory signals to giant neurons of the caudal pontine reticular nucleus (PnC) in the brainstem, then the PnC giant neurons directly activate spinal motor neurons (MNs), which finally form the CN-PnC-MNs pathway. 19 PPI is activated by midbrain structures primarily including the inferior colliculus (IC), superior colliculus (SC), and peduncular tegmentum (PPTg). 20 The PPI pathway is also affected by midbrain and corticolimbic structures. The basolateral amygdala (BLA) activates the nucleus accumbens (NAcc), which in turn inhibits the ventral pallidus (VP), and ultimately the VP inhibits PPTg. 21 The above together form the cortico-striato-pallido-pontine (CSPP) network. 22 More current studies suggest that in addition to the CSPP pathway regulating the startle reflex, there are other pathways. It has been observed that the damage of the BLA leads to an excessive enhancement of the startle reflex, so the startle reflex pathway was investigated from the central nucleus of the amygdala (CeA), and a CeA-PnC pathway independent of the CSPP was found. 23 This pathway does not affect the threshold level of startle reflex, but modulates the magnitude and duration of startle reflex. 24 So far, studies have identified two neural pathways related to the auditory startle reflex, the CSPP neural pathway that mediates PPI and the CeA-PnC pathway that uses the lentiform nucleus as an initiation signal. In the future, more neural pathways and mechanisms may be developed.

Startle Reflex in Disease States

The strengthening or weakening of the startle reflex can reflect the pathological conditions of the body; related in-depth studies are of great significance in diagnosing and treating clinical diseases. In certain disease states, such as central nervous system traumatic diseases (traumatic brain injury, stroke), neurodegenerative diseases (Alzheimer’s disease and PD), and some mental system diseases (schizophrenia), the central nervous system is reorganized, altering the startle reflex. 6 For different diseases, the startle reflex is different. For neurological diseases, the startle reflex is often strengthened, which often helps patients to participate in active activities and is conducive to later recovery. For mental disorders, declining habituation of the startle reflex allows patients to maintain a high level of arousal to external stimuli, which can interfere with the body’s ability to pay attention, process, and remember information.

Startle Reflex After Stroke

A quarter of stroke patients have an increased startle reflex. 25 Honeycutt et al 26 believed that compared with normal subjects, stroke patients have an increased startle reflex, which manifests as increased limb activity when stimulated, suggesting that the startle reflex is relevant to the recovery of motor function in patients after stroke, but whether the startle reflex can be used as a treatment for movement disorders remains to be studied. Sheng Li et al 27 studied the ASR response of the damaged biceps brachii in 16 patients with post-stroke hemiplegia, and reported that the auditory evoked potential response of the injured biceps muscle showed different patterns at different stages of stroke. For patients with post-stroke spasticity, the frequency, amplitude, and duration of the auditory startle reflex increase, suggesting a connection between spasticity and startle reflex.

The main pathway of the startle reflex is the reticulospinal tract, beginning from the medulla oblongata and pons, and running parallel to the corticospinal tract that innervates skeletal muscle movement. 28 A large number of overlapping neurons in the descending pathways terminate in the gray matter layers VII and VIII of the lateral cord and anterior cord, and primarily regulate muscle tension in both limbs. 29 After stroke onset, the integrity of the central nervous tissues and functions of the corticospinal tract are damaged, reducing human motor function to varying degrees. At this time, the compensatory excitement of the reticular spinal tract 30 can replace the corticospinal cord to a certain extent, which also helps to recover movement after stroke. In contrast, it can also lead to spasticity, 31 confirming the important role of the reticulospinal tract in spasticity. Therefore, the startle reflex can be used as a tool to monitor the excitability of the reticulospinal tract. 32 The whole process of post-stroke exercise recovery can be divided broadly into three main stages, and subdivided into six stages according to Brunnstrom as follows: fistula soft stage (stage I), spasticity stage (stages II–IV), and chronic recovery stage (stages V–VI), with the startle reflex different in each stage. 33 In the soft stage, the startle reflex exists as normal, suggesting an intact reticular spinal cord pathway; in the spastic period, the startle reflex is exaggerated, indicating increased excitability of the reticulospinal tract; in the recovery period, the startle reflex is reduced, indicating reduced compensatory excitement of the spinal tract, and restored motor function of the corticospinal tract. The extent of exaggeration of the reflex in ther spastic phase depends on the severity and location of the sports injury. 34

The startle reflex pathway plays different roles in different stages of exercise recovery, especially for spasticity. The startle reflex pathway can be used to develop a personalized rehabilitation plan for each Brunnstrom stage to promote exercise recovery. It is also a follow-up point when studying spastic development after stroke onset.

Startle Reflex After Spinal Cord Injury

Spinal cord injury (SCI) can cause changes in the functions of the central and peripheral nervous systems, 35 such as increase excitability above the lesion, 36 and damage to the bottom segmental motor neuron of the corticospinal tract and injury plane. The possibility of interrupted neuron regeneration after SCI is extremely small. At this time, functional recovery usually requires reorganization of multiple levels of the central nervous system and backup nerve pathways. 37 Reorganization can occur at multiple levels, including the cerebral cortex, brainstem, or spinal cord, 38 as well as different neural pathways. Aside from the corticospinal tract, the human motor nervous system has five other descending conduction pathways as follows: red nucleus, vestibular, tectorial, reticular, and medial longitudinal tracts. 37 After SCI, the corticospinal tract is damaged; thus, the other normal brainstem spinal cord bundles initiate a compensatory mechanism, and the enhancement of the startle reflex also indicates reorganization of the reticulospinal pathway. 39 At this time, the startle reflex can be used to monitor the reorganization of neural pathways in SCI patients.

Regarding whether the degree of enhancement of the startle reflex is related to the damaged plane and degree of SCI, the probability of ASR in patients with SCI was higher than that in normal subjects. 39 The incubation period of ASR in patients with high-level SCI is significantly shorter than that in patients with low-level SCI, but the difference in ASR latency was not statistically significant between complete and incomplete SCI patients. The number of cervical SCI is greater than that of thoracolumbar SCIs; hence, the reorganization and plasticity of the central nervous system are more obvious. Therefore, the degree of enhancement of the startle reflex may be related to the number of damaged neuronal reorganizations, rather than the extent of the disease. After SCI, the reticular spinal cord is reorganized, and the enhanced startle reflex can guide the treatment and prognosis; simultaneously, it can increase the patients’ belief in rehabilitation, as suggested by Kumru. 7 The exaggerated stimulus response, especially the auditory startle reflex, may help enhance the voluntary movement of patients with SCI and facilitate the effective development of later rehabilitation training.

Startle Reflex in Schizophrenia

Schizophrenia is a psychiatric disorder characterized by impairments in the integration of information and cognition, including thinking, distraction, and information processing deficits, and affects approximately 1% of the world’s population. 5 However, its etiology is not well understood. After onset, the level of sensorimotor gating in the brain gradually decreases. The existence of this mechanism is to filter the influence of unnecessary information on the human body. When sensorimotor gating is reduced, an increase in unnecessary interference will stimulate the symptoms of patients with schizophrenia, which is generally regarded as a measure of responsiveness to external environmental stimuli, and it represents a method of studying reactivity and habituation. One physiological mechanism which is lacking in schizophrenia is PPI, which is modulated by the cortico-striatal-pallidal-pontine pathway and involved neurotransmitters. 5

There are different opinions about whether the startle reflex in patients with schizophrenia is decreased or increased. Existing studies divide the users into three drug groups according to use: typical antipsychotics, atypical antipsychotics, and control. Most studies 40 reported a reduced startle reflex in the typical antipsychotic group. Psychiatric drugs (such as clozapine) can alleviate the difference between patients with schizophrenia and normal subjects, proving the effect of drugs on schizophrenia. However, some previous studies 41 report conflicting results. Other studies believe that patients with schizophrenia experience different emotions, thereby exhibiting different startle reflexes. When the subjects are in a state of disgust or anxiety, the degree of startle increases, and when they are in a delusional state, their shock amplitude is significantly higher. However, in patients with mainly negative symptoms, particularly flat emotions, their ASR sensitivity may be lower, possibly because of the weakened ability of these patients to express emotional stimuli. 42 Therefore, the startle reflex is generally regarded as a measure of the response to external environmental stimuli. Research on the startle reflex will help to understand schizophrenia and help standardize clinical medication regimens.

Startle Reflex for Other Diseases

Many diseases can cause changes in the startle reflex of the human body. These changes help us understand the pathogenesis and principles of the disease. The startle reflex can also be used as a detection tool to guide clinical treatment and prognosis.

The latency of the ASR in children with autism spectrum disorder (ASD) is prolonged, and the PPI level decreases, which may be related to the impaired adaptive function of children with autism in multiple areas, including social, communication, occupation, or other important areas of daily life. 43 Impaired adaptability can easily lead to an increased risk of adverse behaviors in such patients.

One of the earliest clinical symptoms of Tay-Sachs disease is the enhanced startle reflex. 44 The brains of patients with Tay-Sachs disease show an enhanced stem electrophysiological response, suggesting that the enhanced startle reflex is related to changes in the physiological state of the brainstem. In addition, augmented startle reflex characteristics of Tay–Sachs disease are also observed in GM1 gangliosidosis, metachromatic leukodystrophy, and Krabbe disease. 45 These diseases need to be distinguished, and brainstem research should be strengthened.

Regarding the relationship between myoclonus and brain stem reticular structure in patients with progressive myoclonic epilepsy (PME), the frequency of ASR in PME patients was significantly reduced, the average latency was longer, and the reduced startle reflex suggested that the reticular structures were less excitable, which is attributable to atrophy and degenerative changes. 46–48

Yavuz et al 49 found that the neural pathways of ASR in patients with coexisting essential tremor and Parkinson’s disease (ET-PD) with obvious dyskinesia were significantly abnormal, while the ASR in patients with pure essential tremor (TE) or PD was similar to that in healthy subjects, indicating that ET-PD is a unique disease, and cortical and brainstem structural abnormalities show close associations.

Urbach-Wiethe disease is a rare genetic disorder that causes near-complete calcification of the basolateral amygdala (BLA). The study of a single individual 50 confirmed that when the BLA function is impaired, the patient’s learning ability for challenging tasks is weaker than that of the startle reflex. The slower learning system is not enough to quickly stimulate the defensive response, whereas the excessive startle reflex to fear stimuli will be detrimental to the patient’s emotional stability. This suggests that the BLA is essential for coordinating the adverse effects and effective changes produced by excessive startle.

Startle Reflex Modulation Measurement can be used to objectively assess indicators in patients with Alzheimer’s disease, which is considered the only objective physiological measure of emotion that is sensitive to emotional valence. 51 For patients with Alzheimer’s disease, especially those in the advanced stage, it is almost impossible to participate in daily living activities through accurate verbal expression and physical behavior. Using the startle reflex can summarize their emotional responses to various stimuli. 52 This process can connect the patient with the surrounding environment, giving nursing workers or family members more useful information to facilitate high-quality patient care.

Difference Between Startle Reflex and Hyperekplexia

Hyperekplexia is easily confused with the startle reflex. The startle reflex is the symmetrical contraction response of the body when the body is stimulated, whereas hyperekplexia is a rare neurological disorder caused by abnormal glycinergic neurotransmission which usually develops in the neonatal period, with genetic predisposition. 53 When faced with sudden visual, auditory, or tactile stimuli, patients with hyperekplexia experience jitters, tremors, stiffness, and other phenomena. In severe cases, it may suffocate and require resuscitation to save lives. Older children often fall down after repeated attacks, while physical examination showed increased muscle tone and positive nose percussion tests.

The disease is similar to reflex epilepsy, abnormal brain development, tetanus, convulsions, and other diseases. Hyperekplexia patients may simultaneous develop reflex epilepsy; 54 therefore, abnormal electroencephalography (EEG) during the ictal period cannot be used to diagnose epilepsy alone. If the startle response symptoms persist despite antiepileptic drug intake, hyperekplexia may be considered, and genetic testing can be performed to confirm the diagnosis. For diseases that are easily misdiagnosed, EEG and other brain imaging examinations are conducive to early differential diagnosis, and gene sequencing can confirm the diagnosis. After the startle reaction, the abdominal pressure can be increased, resulting to umbilical hernia, inguinal hernia, and hip dislocation. 55 Clonazepam has a good effect on this disease. Tao Dongying et al 56 found that clinical symptoms in children significantly improved after taking low-dose clonazepam for 2 days, the muscle stiffness disappeared, and no falls occurred again. The Vigevano strategy can alleviate attacks and reduce mortality. 57 , 58 However, the specific diagnosis and treatment of this disease still depends on individual conditions, and there is no clear and systematic treatment plan.

The triggering conditions of the startle reflex are similar to those of hyperekplexia, both of which are caused by the sudden stimulation of the human body by the external environment, such as sound, light, and touch. The phenomenon is similar, and the body contraction response exists; however, hyperekplexia is a disease other than contraction. Additionally, there are other phenomena, such as shaking, tremors, and stiffness, which may even affect life. The startle reflex can occur at all ages, and will change accordingly under different diseases, whereas hyperekplexia is an independent neurological disease that frequently occurs in newborns have a complete disease system of “concept-genesis-diagnosis-differential diagnosis-treatment-prognosis”. In clinical practice, attention should be paid to differentiation between the two.

As a defensive response of the human body, the startle reflex is an important tool to check whether the excitability of the brainstem network structure is normal and whether the nerve conduction pathway is intact. It is of great value to study disease pathogenesis, diagnosis, treatment, and prognosis. The highlights of this review include: (1) PPI is a measure of sensorimotor gating, which can be used as a starting point for research on central nervous system diseases. So far, studies have identified two neural pathways related to the auditory startle reflex, the CSPP neural pathway and the CeA-PnC pathway. In future research, more neural pathways and mechanisms may be developed; (2) the startle reflex is enhanced for patients with post-stroke spasticity, suggesting that the compensatory effect of the reticulospinal tract on the corticospinal tract may be beneficial to the recovery of patients after stroke; (3) there is no difference in the startle reflex between patients with complete and incomplete SCI, and cervical SCIs are more reorganized than thoracoc SCIs, while the startle reflex in patients with lumbar SCIs is enhanced, suggesting that the reorganization of the nervous system after spinal cord injury may be related to the level of injury, and not the extent; (4) the startle reflex is enhanced in schizophrenia patients, so the startle reflex can be used as a criterion for evaluating the efficacy of schizophrenia drugs; (5) the study of the startle reflex in rare diseases helps to understand its pathogenesis, clinical treatment, and prognosis; (6) the startle reflex is a physiological or pathological phenomenon in mammals, whereas hyperekplexia is a genetic pathology commonly seen in newborns.

In conclusion, the startle reflex has important guiding value for studying various stages of various diseases. There is still plenty of room for research on the startle reflex. Afferent pathways in the brainstem are different, and so are other types of startle reflexes. Randomized controlled studies are needed to fully understand the startle reflex.

Funding Statement

This work was supported by the financial support from the National Natural Science Foundation of China (No. 81503672).

Abbreviations

EMG, electromyography; PPI, prepulse inhibition; CBM, China Biology Medicine; CNKI, China National Knowledge Infrastructure; VIP, VIP Database for Chinese Technical Periodical; ASR, acoustic startle reflex; OOC, orbicularis; SCM, sternocleidomastoid; BB, biceps brachii; TA, tibialis anterior; MARS, mobile acoustic startle reflex monitoring system; PD, Parkinson’s Disease; SC, superior colliculus; LP, lateral posterior nucleus; V1, Primary Visual Cortex; CN, cochlear nucleus; PnC, caudal pontine reticular nucleus; MNs, motor neurons; IC, inferior colliculus; PPTg, pedunculopontine tegmental nucleus; BLA, Basolateral amygdaloid nucleus, anterior part; NAcc, nucleus accumbens; VP, ventral pallidus; CSPP, cortico-striato-pallido-pontine; CeA, Central amygdaloid nucleus; SCI, spinal cord injuries; ASD, Autism Spectrum Disorder; PME, progressive myoclonic epilepsy; ET-PD, Coexisting Essential Tremor Parkinson’s Disease; ET, essential tremor; BLA, basolateral amygdala; EEG, electroencephalography.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

The authors report no conflicts of interest in this work.

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Meditation and the Startle Response: A Case Study
In this study, we examined the capacity of two different kinds of meditation to modulate the autonomic, somatic, and facial aspects of the defensive startle response to an aversive auditory stimulus. A single subject, MR, a Buddhist monk with four decades of meditation experience was studied. A single case experimental design was utilized in ...
Meditation and the startle response: A case study.
The effects of two kinds of meditation (open presence and focused) on the facial and physiological aspects of the defensive response to an aversive startle stimulus were studied in a Buddhist monk with approximately 40 years of meditation experience. The participant was exposed to a 115-db, 100-ms acoustic startle stimulus under the 2 meditation conditions, a distraction condition (to control ...
Recent advances in studying brain‐behavior interactions using
The neural basis of the startle response has been studied in most cases in the hindleg reflex, i.e., the whole-body startle response. In fact, in the only study that has investigated the blink reflex in rodents, a processing pathway via the midbrain reticular formation was observed for the blink reflex (Hori et al., 1986) which is different ...
More Meditation, Less Habituation? The Effect of Mindfulness ...
The findings of this case study suggest that acoustic startle characteristics and startle habituation could be altered by long-term and/or intense mindfulness practice. However, the study used experimenters' ratings, and although this could be a reliable method of quantifying the response by the experienced raters, the automated ...
Meditation and the startle response: a case study
The startle response (an aversive reflex) is enhanced during a fear state and is diminished in a pleasant emotional context and the effect is found when affects are prompted by pictures or memory images, changes appropriately with aversive conditioning, and may be dependent on right-hemisphere processing. Expand.
Meditation and the Startle Response: A Case Study
A thought-provoking example consists of a case study that examined the startle refl ex, an innate and involuntary response to sudden loud noises, in a practitioner with over 40 years of meditation ...
Meditation and the startle response: A case study, by Robert W
Meditation and the startle response: A case study, by Robert W. Levenson, Paul Ekman, and Matthieu Ricard, Emotion 2012, 12(3) Posted 6 March 2013. This study investigates the effects of two type of meditation - open presence and focused - on a meditator's defensive response to a startle stimulus during the meditation. Download the article
Meditation and the startle response: a case study.
Figure 2. Average physiological and facial behavioral response to unanticipated startle across six replications of open presence meditation, focused meditation, and distraction conditions in Ricard. All responses are scaled so that greater activation is in the upwards direction. - "Meditation and the startle response: a case study."
Meditation and the startle response: A case study
Meditation and the startle response: A case study. Matthieu Ricard. 2012, Emotion. See Full PDF Download PDF. See Full PDF ...
The startle syndromes: Physiology and treatment
Startle syndromes are paroxysmal and show stimulus sensitivity, placing them in the differential diagnosis of epileptic seizures. Startle syndromes form a heterogeneous group of disorders with three categories: hyperekplexia (HPX), stimulus-induced disorders, and neuropsychiatric syndromes. HPX is characterized by an exaggerated motor startle ...
Meditation and the startle response: A case study
My Research and Language Selection Sign into My Research Create My Research Account English; Help and support. Support Center Find answers to questions about products, access, use, setup, and administration.; Contact Us Have a question, idea, or some feedback? We want to hear from you.
Understanding the Causes of Reduced Startle Reactivity in Stress
The acoustic startle response (ASR) is the most commonly used form for studying this reflex. As ... a second distinction between the two studies that observed suppressed startle reactions, ... this is the case. This suggest the suppression of startle responsivity in female rats is more likely due to an overactive pro-inflammatory cytokine ...
Startle response
In animals, including humans, the startle response is a largely unconscious defensive response to sudden or threatening stimuli, such as sudden noise or sharp movement, and is associated with negative affect. Usually the onset of the startle response is a startle reflex reaction. The startle reflex is a brainstem reflectory reaction (reflex) that serves to protect vulnerable parts, such as the ...
Startle Response
Startle responses are rapid movements that occur very quickly following an abrupt, unexpected, strong sensory stimulus, such as a loud sound produced by a slamming door. Startle or escape responses are shared by almost all animals, including both invertebrates and vertebrates [ 1 ]. In many cases, they are thought to serve protective functions ...
Content Moderator Startle Response: A Qualitative Study
Previous studies on startle response pointed to the emotional, cognitive, and physiological impairment the phenomenon could have on the individual in ... Murray PS, Bates PR (2012) The effects of startle on pilots during critical events: a case study analysis. In: Aviation psychology and applied human factors—working toward sezo accidents ...
Without warning: the startle factor
The startle response (also known as limbic hijack) is the physical and mental response to a sudden unexpected stimulus. More commonly known as 'fight or flight', this physiological reaction occurs in response to what you may perceive as a harmful event, attack, threat to your survival or simply fear. The fight or flight response evolved to ...
Affective Modulation of the Startle Response among Children at High and
The startle response is a reflexive, cross-species fight-or-flight response to ... Vrana SR, Constantine JA, Westman JS. Startle reflex modification as an outcome measure in the treatment of phobia: Two case studies. Behavioral Assessment. 1992; 14:279-291. [Google Scholar] Vrana SR, Spence EL, Lang PJ. The startle probe response: A new ...
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The paper undertakes four in-depth country case studies and the public management reforms as a response to institutional pressure are examined using the 4M strategy (Pollitt and Bouckaert, 2017)-Maintain (holding on to existing administrative structures and processes), Modernize (keeping service delivery and regulation up to date), Marketize ...
Research Progress in the Study of Startle Reflex to Disease States
Introduction. The startle reflex in humans is a conserved systemic motion response that is ubiquitous in mammals. It is the reflex contraction of the skeletal and facial muscles to sudden intense stimuli, and includes eye blinking, limb flexion, trunk shrugs, and autonomic symptoms (such as increased heart rate, sweating). 1 It originates from the brainstem, descends along the reticular tract ...
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More Meditation, Less Habituation? The Effect of Mindfulness Practice on the Acoustic Startle Reflex

Conclusions

Introduction

Participants

Characteristics of the final sample.

Psychophysiological data collection

Startle habituation paradigm and procedures

Startle habituation quantification

Behavioural measure

Self-assessment measures

Startle response characteristics and habituation

Initial reactivity.

Startle habituation.

Latency to peak.

Cognitive and psychological measures

Author Contributions

Matthieu Ricard

Articles about science

Meditation and the startle response: A case study

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Understanding the Causes of Reduced Startle Reactivity in Stress-Related Mental Disorders

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Jennifer E. Catuzzi

1. Introduction

2. The startle reflex and mental health

2.2. Abnormalities in the expression of the startle reflex in mental disorders

2.3. Animal models utilizing stress to dampen startle reactivity

3. Peripheral mechanisms of reduced startle reactivity

3.2. Pro-inflammatory cytokines

3.3. Prior immune challenge effects on stress-induced startle in SD rats

4. Central mechanisms of reduced startle reactivity

4.2. Evidence for limbic regulation of startle suppression

5. Immune mechanisms following the acute pro-inflammatory response: Recovery or maintenance?

5.2. Immune influences on serotonin synthesis: A possible central mechanism of continued suppression?

6. Clinical applications

7. Conclusions

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Research Progress in the Study of Startle Reflex to Disease States

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Introduction

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Startle Reflex in Disease States

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Startle Reflex in Schizophrenia

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Abbreviations

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