Novel vitreous substitutes: the next frontier in vitreoretinal surgery.

PURPOSE OF REVIEW: After removing the native vitreous during vitreoretinal surgery, an adequate substitute is required to ensure homeostasis of the eye. Current clinically used endotamponades (silicone oil, gases, semifluorinated alkanes) are effective in promoting retinal reattachment, but lead to complications such as emulsification, prolonged inflammation, blurred vision, raised intraocular pressure, cataract formation or the need for revision surgery. The aim of this review is to provide an update on novel vitreous substitutes with a focus on polymer-based systems. RECENT FINDINGS: Polymeric hydrogels provide favourable properties such as high water content, optical transparency, suitable refractive indices and densities, adjustable rheological properties, injectability, biocompatibility and their ability to tamponade the retina via viscosity and swelling pressure, comparable to the native human vitreous body. Here, vitreous replacement strategies can be divided into chemically or physically crosslinked hydrogel systems that are applied as preformed or in-situ gelling matrices. SUMMARY: Several hydrogel-based vitreous substitutes have already been positively evaluated in preclinical tests and have the potential to enter the clinical phase soon.

Cardiac cycle phases affect auditory-evoked potentials, startle eye blink and pre-motor reaction times in response to acoustic startle stimuli.

Startle stimuli evoke lower responses when presented during the early as compared to the late cardiac cycle phase, an effect that has been called 'cardiac modulation of startle' (CMS). The CMS effect may be associated with visceral-afferent neural traffic, as it is reduced in individuals with degeneration of afferent autonomic nerves. The aim of this study was to investigate whether the CMS effect is due a modulation of only early, automatic stages of stimulus processing by baro-afferent neural traffic, or if late stages are also affected. We, therefore, investigated early and late components of auditory-evoked potentials (AEPs) to acoustic startle stimuli (105, 100, 95 dB), which were presented during the early (R-wave +230 ms) or the late cardiac cycle phase (R +530 ms) in two studies. In Study 1, participants were requested to ignore (n = 25) or to respond to the stimuli with button-presses (n = 24). In Study 2 (n = 23), participants were asked to rate the intensity of the stimuli. We found lower EMG startle response magnitudes (both studies) and slower pre-motor reaction times in the early as compared to the late cardiac cycle phase (Study 1). We also observed lower N1 negativity (both studies), but higher P2 (Study 1) and P3 positivity (both studies) in response to stimuli presented in the early cardiac cycle phase. This AEP modulation pattern appears to be specific to the CMS effect, suggesting that early stages of startle stimulus processing are attenuated, whereas late stages are enhanced by baro-afferent neural traffic.

Respiratory modulation of intensity ratings and psychomotor response times to acoustic startle stimuli.

Respiratory interoception may play an important role in the perception of respiratory symptoms in pulmonary diseases. As the respiratory cycle affects startle eye blink responses, startle modulation may be used to assess visceral-afferent signals from the respiratory system. To ascertain the potential impact of brainstem-relayed signals on cortical processes, we investigated whether this pre-attentive respiratory modulation of startle (RMS) effect is also reflected in the modulation of higher cognitive, evaluative processing of the startle stimulus. Twenty-nine healthy volunteers received 80 acoustic startle stimuli (100 or 105 dB(A); 50 ms), which were presented at end and mid inspiration and expiration, while performing a paced breathing task (0.25 Hz). Participants first responded to the startle probes by 'as fast as possible' button pushes and then rated the perceived intensity of the stimuli. Psychomotor response time was divided into 'reaction time' (RT; from stimulus onset to home button release; represents stimulus evaluation) and 'movement time' time (MT; from home button release to target button press). Intensity judgments were higher and RTs accelerated during mid expiration. No effect of respiratory cycle phase was found on eye blink responses and MTs. We conclude that respiratory cycle phase affects higher cognitive, attentional processing of startle stimuli.

Visceral-afferent signals from the cardiovascular system, but not urinary urge, affect startle eye blink.

The aim of the current study was to investigate if startle methodology is suitable to reflect urinary urgency. Eighteen healthy men were tested on two separate days, each including an ingestion of fluid until 80% of the subjective urge to micturate was reached. EMG responses to acoustic startle stimuli were assessed before and after micturition, as well as in the early and late cardiac cycle phases (230 vs. 530 ms after a cardiac R-wave). Sonographic assessment confirmed bladder-filling status. Emotional arousal, stress, urge and unpleasantness ratings, as well as mean blood pressure were higher before than after micturition. Startle eye blink responses were lower during the early than during the late cardiac cycle phase, but were not affected by bladder filling status. We conclude that startle methodology is suitable for the investigation of afferent signals from the cardiovascular system, but not to reflect urinary urgency. This result may be due to different neurophysiological mechanisms underlying afferent signals from the bladder compared to other visceral organs or interference with affective states or sympathetic activation associated with bladder filling. Notwithstanding, the present research protocol of fluid intake, sonographic assessment of the bladder, and subjective reports, can be applied to examine effects of urinary urge on physiological and psychological processes.

Gastric modulation of startle eye blink.

Previous assessment methods of gastric interoception either rely on self-reports, or imply invasive procedures. We investigated the reliability of startle methodology as a non-invasive alternative for the assessment of afferent gastric signals. Twenty-four participants were tested on three separate days, on which they were requested to ingest water (either 0, 300 or 600ml), after 8h of fasting. On each assessment day, eye blink responses (EMG) to 10 acoustic startle stimuli (105dB) were assessed at 4 measurement points (before, 0, 7, 14min. after ingestion). Increased normogastric responses (EGG), ratings of satiety and fullness, and higher heart rate variability (RMSSD) suggested effective non-invasive induction of gastric distention. Startle responses were lower directly after ingestion of 600ml as compared to earlier and later measurements. These results suggest that startle methodology provides a reliable method to investigate afferent gastric signals. It could be useful to study possible dissociations between subjective reports and objective afferent gastric signals in eating or somatoform disorders.

Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress.

The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity.

Cardiac modulation of startle is altered in depersonalization-/derealization disorder: Evidence for impaired brainstem representation of baro-afferent neural traffic.

Patients with depersonalization-/derealization disorder (DPD) show altered heartbeat-evoked brain potentials, which are considered psychophysiological indicators of cortical representation of visceral-afferent neural signals. The aim of the current investigation was to clarify whether the impaired CNS representation of visceral-afferent neural signals in DPD is restricted to the cortical level or is also present in sub-cortical structures. We used cardiac modulation of startle (CMS) to assess baro-afferent signal transmission at brainstem level in 22 DPD and 23 healthy control individuals. The CMS paradigm involved acoustic startle stimuli (105dB(A), 50ms) elicited 0, 100, 200, 300, 400 and 500ms after a cardiac R-wave. In healthy control individuals, we observed lower startle responses at 100 and 300ms than at 0 and 400ms after an R-wave. In DPD patients, no effect of the cardiac cycle on startle response magnitude was found. We conclude that the representation of visceral-afferent neural signals at brainstem level may be deficient in DPD. This effect may be due to increased peripheral sympathetic tone or to dysregulated signal processing at brainstem level.

Acoustic startle reactivity while processing reward-related food cues during food deprivation: evidence from women in different menstrual cycle phases and men.

Previous research has shown that food deprivation enhances the acoustic startle reflex when it is elicited during presentation of visual food cues. Frustrative nonreward may explain this effect, since visual food cues are also rated to be more appetitive and arousing during food deprivation. However, the impact of menstrual cycle and sex on this effect remains unclear, and it is also not known whether this effect is influenced by hunger and motivation to eat. According to a within-study design, 20 healthy women in different menstrual cycle phases and 14 healthy men participated twice, in normal and food-deprived conditions. After 18 h of food deprivation, acoustic startle was attenuated by appetitive nonfood foreground pictures, but enhanced by presentation of food pictures. No differences between menstrual cycle phases and sexes appeared. The effect correlated with hunger changes, suggesting that motivational factors play a role.

Cold pressor stress affects cardiac attenuation of startle.

Stress may affect cardio-afferent neural traffic. We investigated whether acute autonomic stress has an impact on cardiac modulation of startle (CMS), a 'background' methodology for assessing baro-afferent signal transmission. Therefore, 38 healthy volunteers received acoustic startle stimuli (105 dB) at 6 different latencies relative to the R-wave (R +0, 100, 200, 300, 400, and 500 ms; randomized order), both before and immediately after either a cold pressor (n = 19) or a control intervention (n = 19). Blood pressure was enhance d significantly in the cold pressor group right after the intervention (+13.7/5.7 mmHg), reflecting sustained autonomic activation after the stress procedure. Before stress, startle responses were lowest for latencies of R +200 and +300 ms, corroborating previous findings. After the cold pressor test, startle responsiveness was lowest for earlier latencies (R +0, +100 and +200 ms). Stress facilitation of pre-ejection baro-afferent traffic originating from atrial mechano-sensitive receptors may be associated with this time shift effect. We conclude that the cardiac modulation of startle is sensitive to altered temporal baro-afferent feedback characteristics induced by stress and autonomic activation.

Cardiac modulation of startle: effects on eye blink and higher cognitive processing.

Cardiac cycle time has been shown to affect pre-attentive brainstem startle processes, such as the magnitude of acoustically evoked reflexive startle eye blinks. These effects were attributed to baro-afferent feedback mechanisms. However, it remains unclear whether cardiac cycle time plays a role in higher startle-related cognitive processes, as well. Twenty-five volunteers responded first by 'fast as possible' button pushes (reaction time, RT), and second, rated perceived intensity of 60 acoustic startle stimuli (85, 95, or 105 dB; 50 ms duration; binaural; instantaneous rise time), which were presented either 230 or 530 ms after the R-wave, and eye blink responses were measured by EMG. RT was divided into evaluation and motor response time according to previous research. Increasing stimulus intensity enhanced startle eye blink, intensity ratings, and RT components. Eye blinks and intensity judgments were lower when startle was elicited at a latency of R+230 ms, but RT components were differentially affected: the evaluative component was attenuated, and the motor component was accelerated when stimuli were presented 230 ms after the R-wave. We conclude that the cardiac cycle affects the attentive processing of acoustic startle stimuli.

Lateralization effects on the cardiac modulation of acoustic startle eye blink.

Cardiac modulation of startle eye blink has been introduced as a methodology to reflect baro-afferent signal transmission. Recent studies showed that affective startle modulation is specific to left-ear presentation that may be due to hemispheric specificity in processing emotional-relevant stimuli, similar to the processing of visceral- and baro-afferent stimuli. To explore whether cardiac modulation of startle eye blink is lateralized as well, 37 healthy volunteers received 160 unilateral acoustic startle probes of 105 dB(A) intensity presented to both ears, one at a time. They were elicited 0, 100, 230, and 530 ms after the R-wave of the cardiac cycle. Startle response magnitude was significantly diminished at a latency of 230 ms, which may be due to the baro-afferent neural feedback at this temporal location, but only for left-ear presentation. This lateralization effect in the cardiac modulation of startle eye blink may reflect the previously described advantages of right-hemispheric brain structures in relaying viscero- and baro-afferent signal transmission.