Prepulse inhibition in fragile X syndrome: feasibility, reliability, and implications for treatment.

Pharmacological rescue of behavioral, cognitive and synaptic abnormalities in the animal models of fragile X syndrome (FXS) has prompted the initiation of clinical trials of targeted treatments in humans with this condition. Objective, well-validated outcome measures that are reflective of FXS deficits and can be modeled similarly in animal and human studies are urgently needed. A protocol measuring prepulse inhibition (PPI) of the startle reflex, including measures of test-retest stability, was evaluated in 61 individuals with the fragile X full mutation (40 males and 21 females; 19.18 +/- 7.18 years) and 63 age-matched normal controls (35 males and 28 females; 20.83 +/- 6.96 years) across two laboratory sites with identical equipment and protocols. Relative to controls, the fragile X group had PPI impairment of 26%, 22%, and 28% for 60, 120, and 240 ms prepulse interval trial types, respectively, P = 0.000002. PPI test-retest reliability in 29 of the participants was excellent for the 120 ms prepulse interval trials (intraclass correlations: FXS, 0.85; controls, 0.88, 0.89 overall). This study demonstrates the feasibility and reliability of PPI measurement in a developmentally disabled population and highlights its potential as an outcome measure to test the efficacy of targeted neurotherapeutic agents.

Baseline and affective startle modulation by angry and neutral faces in 4-8-year-old anxious and non-anxious children.

The present study examined the magnitudes of startle blink reflexes and electrodermal responses in 4-8-year-old high anxious children (N=14) and non-anxious controls (N=11). Responses were elicited by 16 auditory startle trials during a baseline phase prior to an affective modulation phase involving 12 startle trials presented during angry and neutral faces. Results showed significant response habituation across baseline trials and equivalent response magnitudes between groups during the baseline phase. The modulation of response magnitudes during angry and neutral faces did not differ significantly in either group. However, high anxious children showed larger responses overall compared with non-anxious control children during the affective modulation phase. Moreover, greater anxiety severity and larger startle reflexes were associated with poorer accuracy in rating neutral faces as neutral in high anxious children. Results may reflect elevated reactivity to threat contexts in 4-8-year-old high anxious versus non-anxious children.

Is aversive learning a marker of risk for anxiety disorders in children?

Aversive conditioning and extinction were evaluated in children with anxiety disorders (n=23), at-risk for anxiety disorders (n=15), and controls (n=11). Participants underwent 16 trials of discriminative conditioning of two geometric figures, with (CS+) or without (CS-) an aversive tone (US), followed by 8 extinction trials (4 CS+, 4 CS-), and 8 extinction re-test trials averaging 2 weeks later. Skin conductance responses and verbal ratings of valence and arousal to the CS+/CS- stimuli were measured. Anxiety disordered children showed larger anticipatory and unconditional skin conductance responses across conditioning, and larger orienting and anticipatory skin conductance responses across extinction and extinction re-test, all to the CS+ and CS-, relative to controls. At-risk children showed larger unconditional responses during conditioning, larger orienting responses during the first block of extinction, and larger anticipatory responses during extinction re-test, all to the CS+ and CS-, relative to controls. Also, anxiety disordered children rated the CS+ as more unpleasant than the other groups. Elevated skin conductance responses to signals of threat (CS+) and signals of safety (CS-; CS+ during extinction) are discussed as features of manifestation of and risk for anxiety in children, compared to the specificity of valence judgments to the manifestation of anxiety.

Developmental changes in startle reactivity in school-age children at risk for and with actual anxiety disorder.

The present study examined the development of elevated startle reactivity in anticipation of mild anxiogenic procedures in school-age children with current anxiety disorders and in those at-risk for their development due to parental anxiety. Startle blink reflexes and skin conductance responses were assessed in 7 to 12 year old anxious children (N=21), non-anxious children at-risk for anxiety by virtue of parental anxiety disorder status (N=16) and non-anxious control children of non-anxious parents (N=13). Responses were elicited by 28 auditory startle stimuli presented prior to undertaking mild anxiogenic laboratory procedures. Results showed that group differences in startle reactivity differed as a function of children's age. Relative to control children for whom age had no effect, startle reflex magnitude in anticipation of anxiogenic procedures increased across the 7 to 12 years age range in children at-risk for anxiety disorders, whereas elevations in startle reactivity were already manifest from a younger age in children with anxiety disorders. These findings may suggest an underlying vulnerability that becomes manifest with development in offspring of anxious parents as the risk for anxiety disorders increases.

When the orbicularis oculi response to a startling stimulus is zero, the vertical EOG may reveal that a blink has occurred.

OBJECTIVE: Startle blink reflexes in humans are typically measured as orbicularis oculi electromyographic activity (ooEMG) in response to startling stimuli. When ooEMG activity cannot be measured, responses are scored as 'zero'. However, inhibition of the levator palpebrae is also involved in every blink. The present study examines whether or not during 'zero' startle responses, defined by absence of orbicularis oculi contraction, a startle blink defined by lid movement (i.e. indirect evidence of cessation of tonic levator palpebrae activity) might occur. METHODS: Both ooEMG and vertical electro-oculogram (vEOG) were recorded in 55 children and adolescents during acoustic startle stimulation. Zero ooEMG responses and their accompanying vEOG were tabulated. Fourteen participants who had 3 or more zero ooEMG responses associated with measurable vEOG responses were selected for more detailed study. RESULTS: For these 14 subjects, of 25.4% of usable trials scored as zero in ooEMG, 86.8% of these were accompanied by measurable vEOG responses (for all 55 subjects, 7.9% of trials had zero ooEMG responses, and 70.8% of these zero trials were accompanied by measurable vEOGs). Mean vEOG amplitude and peak latency were comparable whether associated with small ooEMG responses or ooEMGs scored as zero. These 14 participants had smaller and shorter ooEMG responses than the remainder of the sample, but other parameters of ooEMG and vEOG recordings did not differ. A single-case example shows how recording of ooEMG may have resulted in the decision that this participant was a putative 'startle non-responder' when concomitant recording of vEOG showed blink responding in the form of lid movement on 100% of trials. CONCLUSIONS: These results suggest that in absence of orbicularis oculi contraction, cessation of the tonic activity of the levator palpebrae can occur thereby permitting the eyelid to drop in response to an auditory startle stimulus, as measured by vEOG recordings. SIGNIFICANCE: These findings suggest that some degree of independence in the innervation of the orbicularis oculi and levator palpebrae muscle is demonstrated when the ooEMG is putatively 'zero'. This requires re-evaluation of the construct of startle response probability.

Differentiating between reflex and spontaneous blinks using simultaneous recording of the orbicularis oculi electromyogram and the electro-oculogram in startle research.

The present study documents the differences between reflex and spontaneous blinks by recording the vertical electro-oculogram (EOG) along with the orbicularis oculi electromyogram (OO-EMG). EOG and OO-EMG were applied without fixation of the head in 15 freely moving children during an auditory startle experiment. Results revealed that the easily-recorded EOG shows the same relationships between orbicularis oculi contraction and velocity of lid movement in startle blinks as the head-constraining methods, e.g. the magnetic search coil, used in previous studies. The OO-EMG onset occurred before the EOG onset in most reflex blinks while no such pattern occurred for spontaneous blinks. In comparison with spontaneous blinks, reflex blinks showed a shorter duration between onset and peak and between onset and offset in OO-EMG and EOG. In addition, reflex blinks showed greater OO-EMG activity and smaller EOG-recorded lid movements compared with spontaneous blinks. Simultaneous recording of OO-EMG and EOG can distinguish reflex from spontaneous blinks and lid saccades in populations, e.g. children, that cannot tolerate head restraint and in experiments permitting or requiring movement.

Context and explicit threat cue modulation of the startle reflex: preliminary evidence of distinctions between adolescents with principal fear disorders versus distress disorders.

Anxiety and depression are prevalent, impairing disorders. High comorbidity has raised questions about how to define and classify them. Structural models emphasise distinctions between "fear" and "distress" disorders while other initiatives propose they be defined by neurobiological indicators that cut across disorders. This study examined startle reflex (SR) modulation in adolescents with principal fear disorders (specific phobia; social phobia) (n=20), distress disorders (unipolar depressive disorders, dysthymia, generalised anxiety disorder; post-traumatic stress disorder) (n=9), and controls (n=29) during (a) baseline conditions, (b) threat context conditions (presence of contraction pads over the biceps muscle), and (c) an explicit threat cue paradigm involving phases that signalled safety from aversive stimuli (early and late stages of safe phases; early stages of danger phases) and phases that signalled immediate danger of an aversive stimulus (late stages of danger phases). Adolescents with principal fear disorders showed larger SRs than other groups throughout safe phases and early stages of danger phases. SRs did not differ between groups during late danger phases. Adolescents with principal distress disorders showed attenuated SRs during baseline and context conditions compared to other groups. Preliminary findings support initiatives to redefine emotional disorders based on neurobiological functioning.

Human fear conditioning and extinction: timing is everything or is it?

A differential fear conditioning paradigm was used with 107 healthy undergraduate participants to evaluate the effect of conditioned stimulus (CS) temporal properties on fear acquisition and extinction. Two minute duration CSs were used for Day 1 fear acquisition. Participants were randomized to receive either 1, 2, or 4min CS durations during Day 2 extinction. Extinction re-test was examined on Day 3 using the original acquisition CS duration (2min). Findings indicated that participants who were aware of the CS+/unconditioned stimulus (US) contingency (n=52) develop a temporal expectation about when the unconditioned stimulus will be delivered. Although the shorter duration CS resulted in greater fear reduction during extinction, cessation of fear responding at re-test was the same for CS extinction durations ranging from half the CS acquisition duration to twice the CS acquisition duration. Thus, extinction performance did not predict extinction at re-test, which could have important implications for optimizing exposure therapy for anxiety disorders.

Brief report: Sensorimotor gating in idiopathic autism and autism associated with fragile X syndrome.

Prepulse inhibition (PPI) may useful for exploring the proposed shared neurobiology between idiopathic autism and autism caused by FXS. We compared PPI in four groups: typically developing controls (n = 18), FXS and autism (FXS+A; n = 15), FXS without autism spectrum disorder (FXS-A; n = 17), and idiopathic autism (IA; n = 15). Relative to controls, the FXS+A (p < 0.002) and FXS-A (p < 0.003) groups had impaired PPI. The FXS+A (p < 0.01) and FXS-A (p < 0.03) groups had lower PPI than the IA group. Prolonged startle latency was seen in the IA group. The differing PPI profiles seen in the FXS+A and IA indicates these groups may not share a common neurobiological abnormality of sensorimotor gating.

Does neuroticism in adolescents moderate contextual and explicit threat cue modulation of the startle reflex?

BACKGROUND: This study evaluated the relationship between neuroticism (N), a probable risk factor for emotional disorders, and modulation of startle reflexes (SRs). METHODS: One hundred thirty-two adolescents with varying levels of N but without anxiety or depressive disorders were evaluated in contextual cue and explicit threat cue paradigms. RESULTS: Within the explicit threat cue paradigm, N potentiated SRs more in conditions that were intermediately associated with threat of an aversive biceps contraction than conditions that were the furthest from and conditions that were the closest to the same threat. Also, N potentiated SRs across the entire experiment, regardless of experimental conditions, in male and not in female subjects. CONCLUSIONS: These results suggest that adolescents with high levels of N show greater sensitivity to contexts intermediately associated with threat. Results are discussed in comparison with other studies of groups at risk for anxiety and depressive disorders.