Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice.

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.

Modulation of startle and the startle-elicited P300 by the conditions of the cued continuous performance task in school-age boys.

OBJECTIVES: This study compares the modulation of the startle response by conditions requiring response preparation, production, and inhibition during a cued continuous performance task (CPT) in children to the results of previous studies in adults and evaluates the modulation of the startle-elicited P300 under the same conditions. The latter variable, reflecting the cognitive processing of the startling stimulus (SS), has not been studied under these conditions. METHODS: Normal boys completed a cued CPT in which the cue was the letter T, the go condition requiring a button press was an X following the T, and the no-go condition requiring response inhibition was a letter other than X following the T. SS were presented 450 ms following the letter of interest in each condition. The amplitudes of the startle-elicited P300 at Fz, Cz, and Pz and the startle blink were compared in the different CPT conditions. RESULTS: The startle blink, measured by orbicularis oculi electromyography, was not inhibited by the no-go CPT condition as is the case in adults. The vertical electro-oculogram was actually largest in the no-go condition. The startle-elicited P300 showed a central predominance and was significantly larger in the no-go condition and in the cue condition than in the go condition. CONCLUSIONS: The absence of inhibition of the startle response during the no-go condition probably reflects a relative inefficiency of prefrontal cortical mechanisms that mediate response inhibition in children compared to adults. The enhanced startle-elicited P300 in the no-go and cue conditions of the CPT reflects cognitive processing of the SS that has been influenced by response inhibition or its anticipation.

Prepulse inhibition of startle, intelligence and familial primary nocturnal enuresis.

UNLABELLED: Previous studies have shown a significant reduction of prepulse inhibition of startle in boys with primary nocturnal enuresis. Those enuretic boys who had higher IQs showed less prepulse inhibition. This study evaluates the association of prepulse inhibition and IQ in primary nocturnal enuresis in respect to family history of primary nocturnal enuresis. Prepulse inhibition of startle was studied in 83 boys with primary nocturnal enuresis and 57 non-enuretic boys using an interval of 120 ms between the onset of a 75 dB 1000 Hz tone and a 104 dB noise burst. Of the boys with primary nocturnal enuresis, 56 had a family history of primary nocturnal enuresis and 27 had no family history (no first-degree relative). Of the 57 non-enuretic boys, 42 also had no family history (no first-degree relative) of primary nocturnal enuresis, while 15 did have a positive family history. Associations between prepulse inhibition and IQ scores were compared among these four groups. Strong and significant associations between prepulse inhibition deficit and higher IQ scores in the enuretic group with familial primary nocturnal enuresis were unique in comparison to the other groups. CONCLUSIONS: The strong heritabilities of primary nocturnal enuresis, intelligence and prepulse inhibition suggest genetic mediation of the association of prepulse inhibition with intelligence in familial primary nocturnal enuresis.

Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis.

BACKGROUND: Children with primary nocturnal enuresis (PNE) wet the bed during all stages of sleep and irrespective of state of arousal, suggesting that during sleep, when voluntary, i.e., cortical control, is not available, the signal from the distended bladder is not registered in the subcortical centers inhibiting micturition. Deficient prepulse inhibition (PPI) of startle has been reported in PNE. This study evaluates the association of this PPI deficit in PNE with comorbidity with attention-deficit hyperactivity disorder (ADHD) and with intelligence. METHODS: Prepulse modulation of startle was studied in 96 boys with PNE and 105 nonenuretic boys using intervals of 60, 120, and 4000 msec between the onset of a 75-dB 1000-Hz tone and a 104-dB noise burst. Thirty-one percent of the enuretic and 36% of the nonenuretic boys were diagnosed with ADHD. RESULTS: After adjustment for presence or absence of ADHD, lower or higher IQ, age, and unmodulated startle amplitude, there was a significant association between PNE and deficient PPI of startle following the 120-msec prepulse interval. Those enuretic boys who also were ADHD or had higher performance IQs (> or = 110) showed the greatest PPI deficit. CONCLUSIONS: A common deficiency of inhibitory signal processing in the brain stem may underlie both deficient PPI and the inability to inhibit micturition in PNE. Strong familiarity for PNE, ADHD, and intelligence suggests a possible genetic mediation of these effects.

Transmission of primary nocturnal enuresis and attention deficit hyperactivity disorder.

Primary nocturnal enuresis (PNE) is a prevalent disorder among children with a complex mode of inheritance. Family, twin, and linkage studies have provided evidence that genetic factors underlie the familiality of PNE. Linkage investigations support the hypothesis that PNE is heterogeneous, and the genetic heterogeneity may be reflected in co-morbid clinical conditions such as attention deficit hyperactivity disorder (ADHD). This study used a family study method and examined the transmission of PNE in relatives of PNE and control probands with and without ADHD, to determine if these disorders co-occur due to common genetic susceptibilities or other, i.e. non-genetic, reasons. This study concluded that the pattern of inheritance found is consistent with the independent transmission of PNE and ADHD.

Affective valence and arousal in ADHD and normal boys during a startle habituation experiment.

OBJECTIVE: To measure two dimensions of emotion (affective valence and arousal) in 29 boys with attention-deficit hyper-activity disorder (ADHD) and 32 normal boys. METHOD: After a startle habituation experiment during which these subjects heard 40 startling sounds while watching a silent interesting movie, they were asked 12 questions (categorized a priori into questions relating to affective valence and to arousal) about their emotional reactions to these putatively unpleasant and pleasurable stimuli. Responses were recorded for the two dimensions of emotion, using two cartoon strips in each of which five expressions of a cartoon character varied linearly from happy to unhappy (affective valence dimension) and calm to excited (arousal dimension). RESULTS: Factor analyses of the 12 responses revealed four factors in which the highest loadings were for affective valence to the startle responses, affective valence to the silent movie, arousal, and scary feelings. Relative to the normal group, the responses of the ADHD group were significantly biased toward pleasurable valence to the startling stimuli and to the silent movie, with a trend toward hypoarousal. Startle magnitude and habituation were similar in both groups. The normal tonic heart rate acceleration throughout the experimental session was not sustained in the ADHD group. CONCLUSIONS: The self-reports of affective valence biased in the direction of pleasure and away from displeasure and the trend toward hypoarousal suggest an emotional dysfunction in ADHD.

Autonomic, electroencephalographic, and myogenic activity accompanying startle and its habituation during mid-childhood.

This study investigated (a) possible associations of the large individual variation in startle, with accompanying autonomic, central nervous system, and myogenic activities in a habituation paradigm; and (b) the patterns of habituation of these variables. Startle blinks to 40 noise bursts, heart rate, alpha activity, and orbicularis oculi electromyographic (EMG) activity preceding and following each startle response were measured in 40 normal 7-11-year-old boys. Startle amplitude and its habituation were independent of association with either initial values or successive changes in the autonomic, alpha, and EMG activities; whereas startle habituated, pre- and poststartle myogenic, alpha, and cardiac activities failed to habituate. Tonic cardiac activity was facilitated, suggesting sensitization of state, as proposed in the dual-process theory of habituation.

Habituation of P300 and reflex motor (startle blink) responses to repetitive startling stimuli in children.

Positive EEG deflections with the latency and scalp distribution of the P300 accompany startle in response to loud auditory stimuli in a non-task context. The purpose of this investigation is to determine if habituation would have effects on the P300 similar to those on the startle blink. Thirty-four normal 7 to 11-year-old boys from a startle habituation study had EEG recordings of sufficient quality to provide data for the current study. Startle was measured both as orbicularis oculi EMG and vertical EOG and P300 was recorded at Pz in response to 40,104 dB bursts of white noise presented at 23-s intervals. Both the startle response and the P300 habituated toward asymptotic levels after the first 28 trials, suggesting that both startle and the subsequent cognitive evaluation of the startling stimulus, reflected in the P300 response, are modulated by a common neurophysiological mechanism extrinsic to the direct startle pathway. A modest significant correlation between the P300 and the vertical EOG peak latencies for the initial trials suggests that the cognitive evaluation of the startling stimulus may also include evaluation of the reflex response to that stimulus. Analyses of the within-subject associations between startle and P300 initial amplitudes and rates of habituation showed that these parameters varied independently within the individual subject, suggesting that the P300 is not a component of the startle response. Rather, it reflects an evaluation of the startling stimulus, decreasing in amplitude as the surprising value of the startling stimulus decreases with habituation.

Urinary catecholamine excretion and behavioral differences in ADHD and normal boys.

Urinary catecholamine excretion was assessed in 15 boys with attention-deficit/hyperactivity disorder (ADHD) and 16 normal controls during a defined physical and mental task. Dihydroxyphenylalanine, dopamine, norepinephrine (NE), epinephrine (EPI), 3,4-dihydroxyphenylacetic acid, and 3,4-dihydroxyphenylglycol (DOPEG) concentrations were assayed by high-pressure liquid chromatography with electrochemical detection. The urinary concentration of DOPEG, an NE metabolite that has not been previously measured in ADHD, was significantly lower in the ADHD subjects than in the normal controls. There was also a trend for lower urinary EPI levels in the hyperactive boys. Stepwise multiple regression analyses demonstrated that DOPEG and EPI each contributed significantly to the variance in the behavioral symptoms within the full sample. The results are consistent with previous reports of abnormal metabolism of norepinephrine and epinephrine in ADHD. These neurochemical findings may be due to differences between ADHD and normal boys in neuronal (central or peripheral) or nonneuronal (e.g., adrenal, renal) activity. The results are also consistent with prior findings in normal children of an inverse relationship between EPI excretion and inattentive, restless behaviors. Together, these findings suggest caution in ascribing metabolite changes to ADHD or to ADHD-like behaviors that may be seen in normal children.

Maturation of the fast component of vestibular nystagmus during childhood and young adulthood.

Primary nystagmus was evoked by constant angular acceleration at near-threshold levels (0.2, 0.4, and 0.6 degree/s2) in 34 normal human subjects (25 children aged 2-11 years and 9 young adults aged 17-21 years). Acceleration was carried out in complete darkness, and with subjects' eyes open. Analysis of response latencies showed that all subjects responded to acceleration magnitude as low as 0.2 degrees/s2. A decrease in response latency was associated with an increase in acceleration magnitude, and there was no significant effect of age on response latency or its relationship to acceleration. However, a relationship was found between age and the percentage of trials showing the presence of a set of three successive beats during acceleration: a significant increase in the frequency of such trials occurred with increasing age. The relationship of these findings to brainstem vestibular modulatory mechanisms is discussed.

Prestimulation-induced modulation of the P300 component of event related potentials accompanying startle in children.

Positive EEG deflections with the latency and scalp distribution of the P300 accompany startle in response to loud auditory stimuli in a non-task context. The purpose of this investigation is to determine if inhibitory and facilitatory prestimulation would have effects on the P300 similar to those on the startle blink. Prestimulation conditions were chosen to induce startle amplitude facilitation (4000 msec sustained tone), startle amplitude inhibition (120 msec prestimulation interval), and startle onset latency facilitation (60 msec prestimulation interval). Ninety-three boys (including normals and those with ADHD and/or enuresis) from a startle modulation study had EEG recordings of sufficient quality to provide data for the current study. Repeated measures analyses of variance demonstrated startle amplitude and P300 amplitude facilitation following the 4000 msec tone, startle amplitude and P300 amplitude inhibition following the 120 msec prestimulation interval, and startle onset latency and P300 peak latency facilitation (shorter latencies) following the 60 msec prestimulation interval. Hence, the vertex-recorded P300 elicited by startling stimuli was modulated by non-startling prestimulation in a manner that paralleled that of modulation of the brain-stem generated startle blink. Startle inhibition by prestimulation is mediated by an inhibitory pathway in the mesopontine lateral tegmentum. This brain-stem circuitry has a similar effect on the P300 even though the latter may be generated in more rostral structures. Alternatively, this automatically elicited P300 may represent a limbic or cortical reflection of the sensory processing taking place in the brain-stem. Either interpretation suggests a "bottom-up" as contrasted with a "top-down" mode of sensory processing. This P300 obeys the rules of startle modulation by brain-stem mechanisms rather than indexing cortical evaluation of stimuli for task relevance, stimulus probability, and prior uncertainty.

Startle modulation studies in autism.

We studied acoustic startle response and its modulation by prestimulation and by short-term and long-term habituation in 54 autistic patients and 72 normal age-matched controls. The startle response was measured as the amplitude and onset latency of the integrated orbicularis oculi EMG. There were no consistent significant differences between the autistic and control subjects in startle modulation by inhibitory or facilitatory prestimulation, short-term habituation of startle amplitude, long-term habituation of either startle amplitude or latency, or unmodulated startle amplitude. Differences between autistic and control subjects were limited to prolongation of unmodulated startle onset latencies in the autistics in all of the experimental paradigms (significant p = .005 only in the context of short-term habituation) and a statistically significant (p < .05) slower rate of short-term habituation of startle onset latency in the autistic patients, relative to the controls. Results provide only limited support for hypotheses of brainstem pathophysiology and no support for hypotheses of cerebellar pathophysiology in autism.

Prestimulation-induced startle modulation in attention-deficit hyperactivity disorder and nocturnal enuresis.

Startle modulation was induced by prestimulation in 43, 6-11 year old boys with attention-deficit hyperactivity disorder (ADHD), 13 of whom were or had been enuretic, 17 age-matched enuretic boys, and 42 age-matched normal boys, using 60-ms and 120-ms prestimulation intervals and a 4000-ms continuous tone. There was a significant multivariate effect of enuresis on startle amplitude modulation. This effect was attributed primarily to the reduction of amplitude inhibition following the 120-ms prestimulation interval regardless of whether or not enuresis was associated with ADHD. There was no effect of ADHD on startle modulation by prestimulation. The inhibition following the 120-ms prestimulation interval in the enuretic boys was reduced to the level of 5-year-old normal children, suggesting a maturational component of the deficient startle inhibition. The neurophysiologic dysfunction underlying the deficient startle inhibition in enuresis, but not ADHD, is discussed in terms of a possible dysfunction of mesopontine reticular mechanisms mediating preattentive processing of signals associated with spinal reflexes involved in urinary bladder control.

Modulatory influence of continuous tone, tone offset, and tone onset on the human acoustic startle response.

Startle modulation in young adult men, by continuous background tone and its offset, a 2-s sustained tone and its offset, and the onset of a 25-ms tone pip were compared. Tone (75dB 1000 Hz) offset and onset occurred either 2000 ms or 100-120 ms before the startle stimuli (104dB (SPL), 50-ms white noise bursts). Blink amplitude and latency were unaffected by continuous background tone. Blink amplitude was reliably inhibited by 100-ms offset of both the continuous background tone and the 2-s sustained tone or 120-ms onset of the tone pip, whereas effects on latency were more variable. Facilitation of blink amplitude and latency was significant but weak and only following the 2-s sustained tone, and only with respect to one of two experimental contexts. These findings support those of others and suggest that startle inhibition results from activation of neurons responding to transient environmental changes. The degree of inhibition appears to be related to stimulus value. Startle amplitude facilitation following long sustained prestimulation intervals is dependent on experimental context. Overall latency and amplitude modulation tend to be concordant, leading to the conclusion that the mechanism(s) underlying both are context dependent and linked in the adult human.

Maturation of prestimulation-induced startle modulation in girls.

This study of the maturation of prestimulation-induced modulation of startle in 4- to 8-year-old girls and young women demonstrated significant effects of age on both startle amplitude and onset latency modulation. Prestimulation with nonstartling tones resulted in strong inhibition of both amplitude and latency of the startle blink reflex in adults when 25-ms tones preceded the startling stimuli by 120 ms or 250 ms. Following sustained prestimulation for 2000 ms, the adults showed weak nonsignificant response facilitation. Eight-year-old girls showed mature inhibitory startle amplitude modulation, but significantly less inhibition of onset latency compared to adults. Preschool girls showed significantly less amplitude and latency inhibition and more facilitation than 8-year-olds and adult women. These findings in female subjects were very similar to those obtained by Ornitz, Guthrie, Kaplan, Lane, and Norman (1986) in male subjects. Gender differences were limited to the 8-year-old age group. The 8-year-old girls showed significantly less startle amplitude inhibition than 8-year-old boys following the 120-ms and 250-ms prestimulation intervals and less latency facilitation following 2000 ms of sustained prestimulation. In general, these findings suggest that brainstem mechanisms that mediate startle response modulation undergo development during early childhood and do not mature until about 8 years of age in both male and female subjects. The results are discussed in relation to studies of gender effects on development of other neurophysiological variables and to maturation of the nervous system.

Maturation of startle facilitation by sustained prestimulation.

The startle response to a 104dB (SPL) 50-ms burst of white noise was facilitated by prestimulation with a nonstartling tone sustained for 2 s prior to the startling stimulus in 3, 4, 5, and 8 year old children and young adults. Both startle amplitude and onset latency showed significantly greater facilitation in the preschool children than in the 8-year-olds and adults. The results of this experiment, which used a fixed prestimulation interval, were compared to those of an earlier study in which the prestimulation interval was varied. The maturational changes in startle facilitation in response to the 2-s prestimulation interval were similar in the two experiments. Hence the maturational effect on startle facilitation was independent of the uncertainty (as to when the startling stimulus would be given), which might be associated with variable prestimulation intervals. These findings suggest that the neuronal mechanisms that mediate startle facilitation undergo development during early childhood and mature about 8 years of age, and that this maturational sequence is relatively independent of attentional effects.

Startle modulation in children with posttraumatic stress disorder.

Startle responses to bursts of white noise were recorded as blink reflexes 17-21 months after a traumatic event in six children with posttraumatic stress disorder (PTSD) and in six normal control children. A seventh child with PTSD was studied on four occasions during the 2 years following a stressful event. The startle responses were modulated by nonstartling acoustic prestimulation in order to study the inhibitory and facilitatory modulation of startle reaction by brainstem mechanisms. The children with PTSD experienced a significant loss of the normal inhibitory modulation of startle response, suggesting that the traumatic experience had induced a long-lasting brainstem dysfunction.

Long-term habituation and sensitization of the acoustic startle response in the normal adult human.

The development and independence of short-term and long-term habituation (and short-term sensitization) of the acoustic startle response to repetitive stimuli has been repeatedly demonstrated in the experimental animal. Although short-term habituation (and sensitization) of acoustic startle has been studied in humans, neither long-term habituation nor sensitization has been demonstrated. In this study, long-term habituation (response amplitude decrement) of the blink component of the acoustic startle response occurred in normal men across five consecutive daily sessions of repetitive acoustic stimulation. Long-term sensitization (onset latency shortening) developed after the third day. Both the long-term habituation and sensitization were independent of the day. Both the long-term habituation and sensitization were independent of the short-term habituation, which developed within each daily session.