Optimised Multi-Channel Transcranial Direct Current Stimulation (MtDCS) Reveals Differential Involvement of the Right-Ventrolateral Prefrontal Cortex (rVLPFC) and Insular Complex in those Predisposed to Aberrant Experiences.

Research has shown a prominent role for cortical hyperexcitability underlying aberrant perceptions, hallucinations, and distortions in human conscious experience - even in neurotypical groups. The rVLPFC has been identified as an important structure in mediating cognitive affective states / feeling conscious states. The current study examined the involvement of the rVLPFC in mediating cognitive affective states in those predisposed to aberrant experiences in the neurotypical population. Participants completed two trait-based measures: (i) the Cortical Hyperexcitability Index_II (CHi_II, a proxy measure of cortical hyperexcitability) and (ii) two factors from the Cambridge Depersonalisation Scale (CDS). An optimised 7-channel MtDCS montage for stimulation conditions (Anodal, Cathodal and Sham) was created targeting the rVLPFC in a single-blind study. At the end of each stimulation session, participants completed a body-threat task (BTAB) while skin conductance responses (SCRs) and psychological responses were recorded. Participants with signs of increasing cortical hyperexcitability showed significant suppression of SCRs in the Cathodal stimulation relative to the Anodal and sSham conditions. Those high on the trait-based measures of depersonalisation-like experiences failed to show reliable effects. Collectively, the findings suggest that baseline brain states can mediate the effects of neurostimulation which would be missed via sample level averaging and without appropriate measures for stratifying individual differences.

Attenuated alpha oscillation and hyperresponsiveness reveals impaired perceptual learning in migraineurs.

BACKGROUND: Anomalous phantom visual perceptions coupled to an aversion and discomfort to some visual patterns (especially grating in mid-range spatial frequency) have been associated with the hyperresponsiveness in migraine patients. Previous literature has found fluctuations of alpha oscillation (8-14 Hz) over the visual cortex to be associated with the gating of the visual stream. In the current study, we examined whether alpha activity was differentially modulated in migraineurs in anticipation of an upcoming stimulus as well as post-stimulus periods. METHODS: We used EEG to examine the brain activity in a group of 28 migraineurs (17 with aura /11 without) and 29 non-migraineurs and compared their alpha power in the pre/post-stimulus period relative to the onset of stripped gratings. RESULTS: Overall, we found that migraineurs had significantly less alpha power prior to the onset of the stimulus relative to controls. Moreover, migraineurs had significantly greater post-stimulus alpha suppression (i.e event-related desynchronization) induced by the grating in 3 cycles per degree at the 2nd half of the experiment. CONCLUSIONS: These findings, taken together, provide strong support for the presence of the hyperresponsiveness of the visual cortex of migraine sufferers. We speculate that it could be the consequence of impaired perceptual learning driven by the dysfunction of GABAergic inhibitory mechanism.

Short-Term Immobilization Promotes a Rapid Loss of Motor Evoked Potentials and Strength That Is Not Rescued by rTMS Treatment.

Short-term limb immobilization results in skeletal muscle decline, but the underlying mechanisms are incompletely understood. This study aimed to determine the neurophysiologic basis of immobilization-induced skeletal muscle decline, and whether repetitive Transcranial Magnetic Stimulation (rTMS) could prevent any decline. Twenty-four healthy young males (20 ± 0.5 years) underwent unilateral limb immobilization for 72 h. Subjects were randomized between daily rTMS (n = 12) using six 20 Hz pulse trains of 1.5 s duration with a 60 s inter-train-interval delivered at 90% resting Motor Threshold (rMT), or Sham rTMS (n = 12) throughout immobilization. Maximal grip strength, EMG activity, arm volume, and composition were determined at 0 and 72 h. Motor Evoked Potentials (MEPs) were determined daily throughout immobilization to index motor excitability. Immobilization induced a significant reduction in motor excitability across time (-30% at 72 h; p < 0.05). The rTMS intervention increased motor excitability at 0 h (+13%, p < 0.05). Despite daily rTMS treatment, there was still a significant reduction in motor excitability (-33% at 72 h, p < 0.05), loss in EMG activity (-23.5% at 72 h; p < 0.05), and a loss of maximal grip strength (-22%, p < 0.001) after immobilization. Interestingly, the increase in biceps (Sham vs. rTMS) (+0.8 vs. +0.1 mm, p < 0.01) and posterior forearm (+0.3 vs. +0.0 mm, p < 0.05) skinfold thickness with immobilization in Sham treatment was not observed following rTMS treatment. Reduced MEPs drive the loss of strength with immobilization. Repetitive Transcranial Magnetic Stimulation cannot prevent this loss of strength but further investigation and optimization of neuroplasticity protocols may have therapeutic benefit.

The Body-Threat Assessment Battery (BTAB): A new instrument for the quantification of threat-related autonomic affective responses induced via dynamic movie clips.

We present a new instrument for the assessment of responses to threat-related imagery directed towards a human body - the Body-Threat Assessment Battery (BTAB). The BTAB consists of a series of high-definition dynamic clips depicting body-threats and matched non-threat baseline behaviours. For body-threat stimuli a perspective manipulation was included to assess the effects of viewing threats from the point-of-view of the observer (POV) or from an external/exocentric perspective (EXO). Green-screen technology was used so that extraneous background information could be removed and standardised in post-production. Categorical normative data for psychological ratings (valence, arousal and pain), psychophysiological, phasic skin conductance responses (SCRs) and tonic skin conductance levels (SCLs) were obtained for all stimuli. Body-threat stimuli evoked significantly higher psychological ratings of arousal and pain, with more negative ratings of valence, relative to baseline stimuli. In addition, threat stimuli also had an increased efficacy at evoking SCRs, and these were significantly stronger relative to baseline stimuli. There were no effects of perspective on psychophysiological or psychological responses to threat imagery. The findings are discussed in the context of the utility and scope of the BTAB for supporting neurocognitive investigations of aversive imagery and body-threats specifically in the study of embodiment, body-processing and self-consciousness.

Differences in early and late pattern-onset visual-evoked potentials between self- reported migraineurs and controls.

Striped patterns have been shown to induce strong visual illusions and discomforts to migraineurs in previous literature. Previous research has suggested that these unusual visual symptoms to be linked with the hyperactivity on the visual cortex of migraine sufferers. The present study searched for evidence supporting this hypothesis by comparing the visual evoked potentials (VEPs) elicited by striped patterns of specific spatial frequencies (0.5, 3, and 13 cycles-per-degree) between a group of 29 migraineurs (17 with aura/12 without) and 31 non-migraineurs. In addition, VEPs to the same stripped patterns were compared between non-migraineurs who were classified as hyperexcitable versus non-hyperexcitable using a previously established behavioural pattern glare task. We found that the migraineurs had a significantly increased N2 amplitude for stimuli with 13 cpd gratings but an attenuated late negativity (LN: 400 - 500 ms after the stimuli onset) for all the spatial frequencies. Interestingly, non-migraineurs who scored as hyperexcitable appeared to have similar response patterns to the migraineurs, albeit in an attenuated form. We propose that the enhanced N2 could reflect disruption of the balance between parvocellular and magnocellular pathway, which is in support of the cortical hyperexcitation hypothesis in migraineurs. In addition, the attenuation of the late negativity could reflect a top-down feedback mechanism to suppress visual processing of an aversive stimulus.

Covid-19: Race For A Vaccine.

Description The world is in the midst of a pandemic from COVID-19, a disease caused by the virus SARS-CoV-2. Despite broad mitigation efforts, new cases continue with 74 million cases and 1.6 million deaths worldwide. Regardless of previous research efforts, there is no commercially available vaccine for any coronavirus. Novel vaccine development has historically taken at least 10 years from discovery to availability with only a 6% market entry probability. With the global impact, there is an urgency to expedite a vaccine to protect the population. The U.S. government launched Operation Warp Speed with the goal to produce and deliver 300 million doses of safe and effective vaccines by January 2021. Efforts toward this goal have included coordinated government agency support, parallel clinical trial deployment, de-risking manufacturing earlier in the development process and real-time U.S. Food & Drug Administration evaluation of the safety and efficacy data. Safety is a priority and key analysis has not been eliminated during the compressed timeframe. The two frontrunner candidates show promising efficacy rates for preventing COVID-19 with Moderna reporting 94.1% efficacy and Pfizer reporting 95.0% efficacy. Despite the herculean efforts by scientists to develop an effective vaccine in such a short timeframe, several national surveys suggest that public confidence in these vaccines is low with less than 50% of the survey respondents willing to be vaccinated. According to experts, the U.S. needs the vaccine to be at least 70-80% effective and a 70-80% vaccination rate in order to return to normal. Significant education and promotion is planned in coordination with the Centers for Disease Control.

Evidence for distinct clusters of diverse anomalous experiences and their selective association with signs of elevated cortical hyperexcitability.

Visual cortical hyperexcitability is now known to be an underlying factor for aberrant visual experience, including hallucinations, and pattern or light induced visual discomfort. Such factors have also been observed in neurological and non-clinical groups (albeit in attenuated form) - consistent with the notion of a continuum of anomalous experiences. Utilizing an exploratory factor analysis (EFA) approach (n = 300), Study 1 developed a revised proxy screening measure for visual cortical hyperexcitability - the Cortical Hyperexcitability index - II(CHi-II). The EFA revealed a stable 3-factor solution which can be characterised as; (i) Heightened Visual Sensitivity and Discomfort (HVSD); (ii) Aura-like Hallucinatory Experience (AHE); and, (iii) Distorted Visual Perception (DVP). Study 2 tested both a self-reported migraine group and a control group on the CHi-II in conjunction with a computerised pattern-glare task that is known to reflect visual cortical hyperexcitability. The migraine group produced significantly elevated scores on both the AHE and HVSD factors of the CHi-II, relative to controls. Among the non-migraine group, subjects who scored higher in the pattern-glare task also produced significantly elevated scores on the AHE factor compared to those with low pattern-glare task scores. Collectively, these findings support the utility of the CHi-II as an indirect proxy measure for signs of cortical hyperexcitability and reveal new categorical distinctions for the nature of the anomalous perceptions. These perceptions may well reflect diverse neurocognitive underpinnings leading to advancements in our understanding of aberrations in conscious experience.

The depersonalized brain: New evidence supporting a distinction between depersonalization and derealization from discrete patterns of autonomic suppression observed in a non-clinical sample.

Depersonalization and Derealization are characterised by feelings of detachment from one's bodily self/surroundings and a general emotional numbness. We explored predisposition to trait-based experiences of depersonalization/derealization-type experiences and autonomic arousal toward simulated body-threats, which were delivered to the participant's own body (i.e. Self) and when observed being delivered to another individual (i.e. Other). Ninety participants took part in an "Implied Body-Threat Illusion" task (Dewe, Watson, & Braithwaite, 2016) and autonomic arousal was recorded via standardised skin conductance responses and finger temperature. Autonomic suppression in response to threats delivered to the Self correlated with increases in trait-based depersonalization-type experiences. In contrast, autonomic suppression for threats delivered to Others correlated with trait-based derealization-like experiences. Body-temperature and anticipatory arousal did not correlate reliably with predisposition to depersonalization- or derealization-type experiences. The theoretical implications of these findings are discussed in terms of a fronto-limbic autonomic suppression mechanism.

Predisposition to out-of-body experience (OBE) is associated with aberrations in multisensory integration: Psychophysiological support from a "rubber hand illusion" study.

It has been argued that disorders in body-ownership and aberrant experiences in self-consciousness are due to biases in multisensory integration. Here we examine whether such biases are also associated with spontaneous out-of-body experiences (OBEs) in a nonclinical population. One-hundred and 80 participants took part in a rubber hand illusion (RHI) experiment with synchronous and asynchronous visual and tactile stimulation. A realistic threat was delivered to the rubber hand after a fixed period of stimulation. Self-report exit questionnaires measured the subjective strength of the illusion and psychophysiological measures (skin conductance responses/finger temperature) provided an objective index of fear/anxiety toward the threat. Control participants reported a stronger RHI, and revealed larger threat-related skin conductance responses during synchronous compared with asynchronous brushing. For participants predisposed to OBEs, the magnitude of the skin conductance was not influenced by brushing synchrony-fear responses were just as strong in the asynchronous condition as they were in the synchronous condition. There were also no reliable effects of finger temperature for either group. Collectively, these findings are taken as support for the presence of particular biases in multisensory integration (perhaps via predictive coding mechanisms) in which imprecise top-down tuning occurs resulting in aberrant experiences in self-consciousness even in nonclinical hallucinators. (PsycINFO Database Record

Deliberate and spontaneous sensations of disembodiment: capacity or flaw?

INTRODUCTION: Hallucinations that involve shifts in the subjectively experienced location of the self, have been termed "out-of-body experiences" (OBEs). Early psychiatric accounts cast OBEs as a specific instance of depersonalisation and derealisation disorder (DPD-DR). However, during feelings of alienation and lack of body realism in DPD-DR the self is experienced within the physical body. Deliberate forms of "disembodiment" enable humans to imagine another's visuo-spatial perspective taking (VPT), thus, if a strong relationship between deliberate and spontaneous forms of disembodiment could be revealed, then uncontrolled OBEs could be "the other side of the coin" of a uniquely human capacity. METHODS: We present a narrative review of behavioural and neuroimaging work emphasising methodological and theoretical aspects of OBE and VPT research and a potential relationship. RESULTS: Results regarding a direct behavioural relationship between VPT and OBE are mixed and we discuss reasons by pointing out the importance of using realistic tasks and recruiting genuine OBEers instead of general DPD-DR patients. Furthermore, we review neuroimaging evidence showing overlapping neural substrates between VPT and OBE, providing a strong argument for a relationship between the two processes. CONCLUSIONS: We conclude that OBE should be regarded as a necessary implication of VPT ability in humans, or even as a necessary and potentially sufficient condition for the evolution of VPT.

Uncomfortably numb: new evidence for suppressed emotional reactivity in response to body-threats in those predisposed to sub-clinical dissociative experiences.

INTRODUCTION: Depersonalisation and derealisation disorders refer to feelings of detachment and dissociation from one's "self" or surroundings. A reduced sense of self (or "presence") and emotional "numbness" is thought to be mediated by aberrant emotional processing due to biases in self-referent multi-sensory integration. This emotional "numbing" is often accompanied by suppressed autonomic arousal to emotionally salient stimuli. METHODS: 118 participants completed the Cambridge Depersonalisation scale [Sierra, & Berrios, 2000. The Cambridge Depersonalisation Scale: A new instrument for the measurement of depersonalisation. Psychiatry Research, 93, 153-164)] as an index of dissociative anomalous experience. Participants took part in a novel "Implied Body-Threat Illusion" task; a pantomimed injection procedure conducted directly onto their real body (hand). Objective psychophysiological data were recorded via standardised threat-related skin conductance responses and finger temperature measures. RESULTS: Individuals predisposed to depersonalisation/derealisation revealed suppressed skin conductance responses towards the pantomimed body-threat. Although the task revealed a reliable reduction in finger temperature as a fear response, this reduction was not reliably associated with measures of dissociative experience. CONCLUSIONS: The present findings significantly extend previous research by revealing emotional suppression via a more direct body-threat task, even for sub-clinical groups. The findings are discussed within probabilistic and predictive coding frameworks of multi-sensory integration underlying a coherent sense of self.

Stimulating the aberrant brain: Evidence for increased cortical hyperexcitability from a transcranial direct current stimulation (tDCS) study of individuals predisposed to anomalous perceptions.

Findings from neurological and clinical groups have shown that increased predisposition to anomalous experience/aura reflects an elevation in aberrant neural processes in the brain. However, studies of anomalous experiences in non-clinical/non-neurological groups are less clear on this matter and are more typically confined to subjective questionnaire measures alone. The current investigation, the first to our knowledge, carried out a transcranial Direct Current Stimulation (tDCS) study of cortical hyperexcitability, and its association with anomalous experience in non-clinical/non-neurological groups. Sixty participants completed; (i) both excitatory (anodal) and inhibitory (cathodal) brain stimulation conditions of the visual cortex; (ii) a computerised pattern-glare task, where observers reported phantom visual distortions from viewing highly irritable visual patterns (a metric of cortical hyperexcitability), and; (iii) questionnaire measures of predisposition to anomalous perceptions. There were no reliable signs of cortical hyperexcitability (via pattern-glare tasks) when collapsed across the whole sample. However, a significant positive correlation between predisposition to anomalous experience and elevated signs of cortical hyperexcitability was observed. Crucially, there was a significant negative correlation between tDCS stimulatory conditions. A visual cortex that reacted more strongly to excitatory stimulation, responded less well to inhibitory suppression, and this pattern was related to predisposition to anomalous perceptions. Both findings are consistent with the presence of a hyperexcitable cortex. Collectively the present findings provide objective evidence that the brains of individuals predisposed to anomalous experiences/hallucinations can be hyperexcitable - even in the non-clinical/non-neurological population. These data are consistent with continuum models of anomalous experience and have important implications for contemporary theories of aberrations in self-consciousness.

The Cortical Hyperexcitability Index (CHi): a new measure for quantifying correlates of visually driven cortical hyperexcitability.

INTRODUCTION: Aberrations of visual experience, including visual hallucinations and visual distortions, are known to be associated with increased cortical hyperexcitability. As a consequence, the presence, intensity and frequency of certain experiences may well be indicative of an underlying increase in cortical hyperexcitability. METHODS: The current study presents a new proxy measure of cortical hyperexcitability, the Cortical Hyperexcitability Index (CHi). Two hundred and fifty healthy participants completed the CHi with the results subjected to exploratory factor analysis (EFA). RESULTS: The EFA revealed a three-factor model as the most parsimonious solution. The three factors were defined as: (1) heightened visual sensitivity and discomfort; (2) negative aura-type visual aberrations; and (3) positive aura-type visual aberrations. The identification of three factors suggests that multiple mechanisms underlie the notion of cortical hyperexcitability, providing researchers with new and greater precision in delineating these underlying features. CONCLUSIONS: The factorial structure of the CHi and the increased precision could aid the interpretation of findings from neuroscientific (i.e., brain imaging/stimulation) examinations of cortical processes underlying aberrant perceptions across a host of clinical, neurological and pathological conditions. As a consequence, the CHi is a useful and comprehensive proxy measure of cortical hyperexcitability with considerable scientific and clinical utility.

Surface-based constraints on target selection and distractor rejection: evidence from preview search.

In preview search when an observer ignores an early appearing set of distractors, there can subsequently be impeded detection of new targets that share the colour of this preview. This "negative carry-over effect" has been attributed to an active inhibitory process targeted against the old items and inadvertently their features. Here we extend negative carry-over effects to the case of stereoscopically defined surfaces of coplanar elements without common features. In Experiment 1 observers previewed distractors in one surface (1000ms), before being presented with the target and new distractors divided over the old and a new surface either above or below the old one. Participants were slower and less efficient to detect targets in the old surface. In Experiment 2 in both the first and second display the items were divided over two planes in the proportion 66/33% such that no new planes appeared following the preview, and there was no majority of items in any one plane in the final combined display. The results showed that participants were slower to detect the target when it occurred in the old majority surface. Experiment 3 held constant the 2D properties of the stimuli while varying the presence of binocular depth cues. The carry-over effect only occurred in the presence of binocular depth cues, ruling out any account of the results in terms of 2-D cues. The results suggest well formed surfaces in addition to simple features may be targets for inhibition in search.

Autonomic emotional responses to the induction of the rubber-hand illusion in those that report anomalous bodily experiences: evidence for specific psychophysiological components associated with illusory body representations.

We present the first study to examine indicators of autonomic arousal associated with shifts in body image and as a function of predisposition to report spontaneous anomalous bodily experiences (ABEs) from nonclinical samples. Participants completed the Temporal-Lobe Experience subscale of the Cardiff Anomalous Perception scale-a measure associated with anomalous experiences resulting from temporal lobe dysfunction (Bell, Halligan, & Ellis, 2006) followed by a rubber-hand illusion experiment. We examined: (a) the time taken to induce the illusion, (b) effects on the tonic skin conductance level, and (c) phasic skin conductance responses in the form of nonspecific skin conductance responses (NS-SCRs) in the period leading up to the declaration of the illusion. The illusion took significantly longer to induce in those reporting high levels of ABEs, relative to those reporting low levels of such experiences. A significant increase in the tonic skin conductance level and the frequency of NS-SCRs occurred in the period leading directly up to the declaration of the illusion. Both measures were significantly increased for those reporting higher-levels of ABEs. The data question generic notions of "weak" body representations subserving increasing malleability in body image. Instead, they lend general support for a "dysconnection" account of anomalous bodily experiences-at least for some nonclinical hallucinators. Theoretical considerations are discussed.

Fractionating the unitary notion of dissociation: disembodied but not embodied dissociative experiences are associated with exocentric perspective-taking.

It has been argued that hallucinations which appear to involve shifts in egocentric perspective (e.g., the out-of-body experience, OBE) reflect specific biases in exocentric perspective-taking processes. Via a newly devised perspective-taking task, we examined whether such biases in perspective-taking were present in relation to specific dissociative anomalous body experiences (ABE) - namely the OBE. Participants also completed the Cambridge Depersonalization Scale (CDS; Sierra and Berrios, 2000) which provided measures of additional embodied ABE (unreality of self) and measures of derealization (unreality of surroundings). There were no reliable differences in the level of ABE, emotional numbing, and anomalies in sensory recall reported between the OBE and control group as measured by the corresponding CDS subscales. In contrast, the OBE group did provide significantly elevated measures of derealization ("alienation from surroundings" CDS subscale) relative to the control group. At the same time we also found that the OBE group was significantly more efficient at completing all aspects of the perspective-taking task relative to controls. Collectively, the current findings support fractionating the typically unitary notion of dissociation by proposing a distinction between embodied dissociative experiences and disembodied dissociative experiences - with only the latter being associated with exocentric perspective-taking mechanisms. Our findings - obtained with an ecologically valid task and a homogeneous OBE group - also call for a re-evaluation of the relationship between OBEs and perspective-taking in terms of facilitated disembodied experiences.

Signs of increased cortical hyperexcitability selectively associated with spontaneous anomalous bodily experiences in a nonclinical population.

INTRODUCTION: The current study examined the presence of cortical hyperexcitability, in nonclinical hallucinators, reporting different forms of anomalous bodily experiences (ABEs). Groups reporting visual out-of-body experiences and nonvisual sensed-presence experiences were examined. It was hypothesised that only those hallucinators whose experiences contained visual elements would show increased signs of visual cortical hyperexcitability. METHODS: One hundred and eighty-two participants completed the "Pattern-glare task" (involving the viewing of striped gratings with spatial frequencies irritable to visual cortex)-a task known to reflect degrees of cortical hyperexcitability associated with hallucinatory/aura experiences in neurological samples. Participants also completed questionnaire measures of anomalous "temporal-lobe experience" and predisposition to anomalous visual experiences. RESULTS: Those reporting increased levels of anomalous bodily experiences provided significantly elevated scores on measures of temporal-lobe experience. Only the visual OBE group reported significantly elevated levels of cortical hyperexcitability as assessed by the pattern-glare task. CONCLUSIONS: Collectively, the results are consistent with there being an increased degree of background cortical hyperexcitability in the cortices of individuals predisposed to some ABE-type hallucinations, even in the nonclinical population. The present study also establishes the clinical utility of the pattern-glare task for examining signs of aberrant visual connectivity in relation to visual hallucinations.

Evidence for elevated cortical hyperexcitability and its association with out-of-body experiences in the non-clinical population: new findings from a pattern-glare task.

Individuals with no history of neurological or psychiatric illness can report hallucinatory Out-of-Body Experiences (OBEs) and display elevated scores on measures of temporal-lobe dysfunction (Braithwaite et al., 2011). However, all previous investigations of such biases in non-clinical populations are based on indirect questionnaire measures. Here we present the first empirical investigation that a non-clinical OBE group is subject to pattern-glare, possibly as a result of cortical hyperexcitability (Wilkins et al., 1984). Fifty-nine students at the University of Birmingham viewed a series of square-wave gratings with spatial frequencies of approximately .7, 3 and 11 cycles-per-degree, both black/white and of contrasting colours. The illusions and discomfort reported when viewing gratings with mid-range spatial frequency have been hypothesized to reflect cortical hyperexcitability (Wilkins, 1995; Huang et al., 2003). Participants also completed the Cardiff Anomalous Perception Scale (CAPS: Bell et al., 2006) which included experiential measures of disruptions in 'Temporal-lobe Experience'. Participants who reported OBEs also reported significantly more visual illusions/distortions and significantly greater discomfort as a result of viewing the mid-frequency gratings. There were no such differences with respect to gratings with relatively lower or higher spatial frequency. The OBE group also produced significantly elevated scores on the CAPS measures of Temporal-lobe Experience, relative to controls. Collectively, the results are consistent with there being a neural 'vulnerability' in the cortices of individuals pre-disposed to some hallucinations, even in the non-clinical population.