Fragile X syndrome (FXS) is the most common single gene (FMR1) disorder affecting cognitive and behavioral function in humans. This syndrome is characterized by a cluster of abnormalities including lower IQ, attention deficits, impairments in adaptive behavior and increased incidence of autism. Here, we show that young males with FXS have profound deficits in prepulse inhibition (PPI), a basic marker of sensorimotor gating that has been extensively studied in rodents. Importantly, the magnitude of the PPI impairments in the fragile X children predicted the severity of their IQ, attention, adaptive behavior and autistic phenotypes. Additionally, these measures were highly correlated with each other, suggesting that a shared mechanism underlies this complex phenotypic cluster. Studies in Fmr1-knockout mice also revealed sensorimotor gating and learning abnormalities. However, PPI and learning were enhanced rather than reduced in the mutants. Therefore, these data show that mutations of the FMR1 gene impact equivalent processes in both humans and mice. However, since these phenotypic changes are opposite in direction, they also suggest that murine compensatory mechanisms following loss of FMR1 function differ from those in humans.

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.

The current study evaluated the degree to which startle reflexes (SRs) in safe conditions versus danger conditions were predictive of the onset of anxiety disorders. Specificity of these effects to anxiety disorders was evaluated in comparison to unipolar depressive disorders and with consideration of level of neuroticism. A startle paradigm was administered at baseline to 132 nondisordered adolescents as part of a longitudinal study examining risk factors for emotional disorders. Participants underwent a repetition of eight safe-danger sequences and were told that delivery of an aversive stimulus leading to a muscle contraction of the arm would occur only in the late part of danger conditions. One aversive stimulus occurred midway in the safe-danger sequences. Participants were assessed for the onset of anxiety and unipolar depressive disorders annually over the next 3 to 4 years. Larger SR magnitude during safe conditions following delivery of the aversive stimulus predicted the subsequent first onset of anxiety disorders. Moreover, prediction of the onset of anxiety disorders remained significant above and beyond the effects of comorbid unipolar depression, neuroticism, and subjective ratings of intensity of the aversive stimulus. In sum, elevated responding to safe conditions following an aversive stimulus appears to be a specific, prospective risk factor for the first onset of anxiety disorders.

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This study of the maturation of prestimulation‐induced modulation of startle in 3 to 8 year old children and adults demonstrated significant effects of age on both startle magnitude and onset latency. Startle was evoked by 104dB(SPL) 50‐ms bursts of white noise, and the amplitude and onset latency of the blink reflex were measured after integration of the obicularis oculi EMG. Prestimulation with 75dB 1000 Hz tones resulted in severe inhibition of both amplitude and latency in adults when 20‐ms tones preceded the startling stimuli by 120 ms or 250 ms. Following sustained prestimulation for 2000 ms, the adults showed modest nonsignificant response facilitation. Eight‐year‐old children showed mature inhibitory and facilitatory startle amplitude modulation, but significantly less inhibition and more facilitation of onset latency compared to adults. Preschool children showed significantly less amplitude and latency inhibition and more facilitation than 8‐year‐olds and adults. In response to prestimulation 120 ms before startling stimuli, the preschool children actually showed latency facilitation. Modulation of startle by prestimulation is mediated by brainstem neuronal networks. These findings suggest that brainstem mechanisms which mediate startle response modulation undergo development during early childhood and do not mature until about 8 years of age.

Background-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 sample of 74 young autistic children was selected and defined by direct observation of specific behaviors and clinical assessment of the presence or absence of associated pathological conditions. Retrospective developmental data on these children and 38 age-matched normal children were gathered by means of a written inventory completed by the parents when the children were relatively young (mean age less than 4 years). The autistic children were reported to have had significant delays in the development of motor abilities, speech, communication, comprehension, and, to a lesser extent, perception during their 1st and 2nd years.

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