Exaggerated Startle Response Research Articles

Hyperekplexia Masquerading as Epilepsy

Sir,Hyperekplexia is a rare neurogenetic disorder of glycineneurotransmission, characterized by an exaggerated startleresponse to tactile or acoustic stimuli and tonic spasms [1]. Anon-habituating startle response to nose tapping is consid-ered as clinical hallmark [2]. Glycine has an important rolein the central nervous system as an inhibitory neurotrans-mitter. Here, we describe this disorder in two sibs, referred tous as cases of epilepsy. This report describes the first familywith hyperekplexia from Bangladesh.Two male sibs from Bangladesh presented to ourhospital with complaint of startles and tonic spasms. Eldersib was aged 10 years and younger sib was aged 7 years atthe time of presentation. They were born to third degreeconsanguineous Muslim couple with an uneventful antena-tal and natal period. Both sibs also had history of neonatalonset exaggerated startle in response to auditory and tactilestimuli. Both sibs had history of nocturnal tonic spasms,which were brief, resulting in generalized hypertonia andaborted by flexing the head and trunk. Both sibs weretreated with multiple antiepileptics but there was noresponse. There was no history of similar symptoms inother family members of three generation pedigree.On clinical examination, both had normal anthropometryand intelligence, but had marked hyperactive behavior.Percussion over trigeminal afferent area (glabella and tip ofnose) produced a startle response, which was non-habituating. Auditory startle response was easily elicited.Rest of the examination was normal. Investigationsrevealed normal electroencephalogram and magnetic reso-nance imaging of brain.A diagnosis of hyperekplexia was made in view of earlyonset exaggerated startle response, episodic tonic spasms,non-habituating startle response, family history suggestingrecessive inheritance and normal investigations. Both sibswere treated with clonazepam 0.1–0.2 mg/kg/day whichcontrolled the tonic spasms completely and decreased thestartles significantly.A search for genetic mutations was performed inShimane University Hospital, Japan but none of GLRA1,SLC6A5, GLRB, GPHN, and ARHGEF9 genes mutationswere found in our patients. Absence of these mutationssuggest possible role of novel mutation in the present cases.Hyperekplexia should be distinguished from epilepsy asit is treatable. Clonazepam is the drug of choice, whichdramatically diminishes exaggerated startle response. Dur-ing attacks of tonic spasms, the limbs and head may beflexed towards the trunk in order to ameliorate thesymptoms (Vigevano maneuver) [3].References

Brain stimulation in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a complex, heterogeneous disorder that develops following trauma and often includes perceptual, cognitive, affective, physiological, and psychological features. PTSD is characterized by hyperarousal, intrusive thoughts, exaggerated startle response, flashbacks, nightmares, sleep disturbances, emotional numbness, and persistent avoidance of trauma-associated stimuli. The efficacy of available treatments for PTSD may result in part from relief of associated depressive and anxiety-related symptoms in addition to treatment of core symptoms that derive from reexperiencing, numbing, and hyperarousal. Diverse, heterogeneous mechanisms of action and the ability to act broadly or very locally may enable brain stimulation devices to address PTSD core symptoms in more targeted ways. To achieve this goal, specific theoretical bases derived from novel, well-designed research protocols will be necessary. Brain stimulation devices include both long-used and new electrical and magnetic devices. Electroconvulsive therapy (ECT) and Cranial electrotherapy stimulation (CES) have both been in use for decades; transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), deep brain stimulation (DBS), transcranial Direct Current Stimulation (tDCS), and vagus nerve stimulation (VNS) have been developed recently, over approximately the past twenty years. The efficacy of brain stimulation has been demonstrated as a treatment for psychiatric and neurological disorders such as anxiety (CES), depression (ECT, CES, rTMS, VNS, DBS), obsessive-compulsive disorder (OCD) (DBS), essential tremor, dystonia (DBS), epilepsy (DBS, VNS), Parkinson Disease (DBS), pain (CES), and insomnia (CES). To date, limited data on brain stimulation for PTSD offer only modest guidance. ECT has shown some efficacy in reducing comorbid depression in PTSD patients but has not been demonstrated to improve most core PTSD symptoms. CES and VNS have shown some efficacy in reducing anxiety, findings that may suggest possible utility in relieving PTSD-associated anxiety. Treatment of animal models of PTSD with DBS suggests potential human benefit. Additional research and novel treatment options for PTSD are urgently needed. The potential usefulness of brain stimulation in treating PTSD deserves further exploration.

The effect of nicotine and trauma context on acoustic startle in smokers with and without posttraumatic stress disorder

Exaggerated startle response is a prominent feature of posttraumatic stress disorder (PTSD) although results examining differences in the acoustic startle response (ASR) between those with and without PTSD are mixed. One variable that may affect ASR among persons with PTSD is smoking. Individuals with PTSD are more likely to smoke and have greater difficulty quitting smoking. While smokers with PTSD report that smoking provides significant relief of negative affect and PTSD symptoms, the effects of smoking or nicotine deprivation on startle reactivity among smokers with PTSD are unknown. The purposes of the current study were to (1) examine baseline acoustic startle response (ASR) in smokers with and without PTSD under conditions of overnight abstinence, (2) evaluate the effect of smoking on ASR, and (3) evaluate the contextual effects of trauma versus neutral script presentations. ASR was measured among 48 smokers with and without PTSD in the context of a 2 (group: PTSD vs. non-PTSD) x 2 (context: trauma vs. neutral) x 3 (smoking condition: usual brand cigarette vs. denicotinized cigarette vs. no smoking) design. Effects of modest size indicated that (1) PTSD participants demonstrated higher ASR (2) compared to non-PTSD participants, PTSD participants reported greater negative affect following a trauma-related script, and (3) following a trauma-related script and smoking a usual brand cigarette, PTSD participants demonstrated higher ASR. Although many smokers with PTSD report that smoking reduces PTSD symptoms, results suggest that smoking may actually potentiate or maintain an exaggerated startle response.

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Diagnostic Pitfalls in a Patient With Posttraumatic Exaggerated Startle Response and Mutistic Stupor

Back to table of contents Previous article Next article LETTERFull AccessDiagnostic Pitfalls in a Patient With Posttraumatic Exaggerated Startle Response and Mutistic StuporAgorastos Agorastos M.D.Christoph Muhtz M.D.Michael Kellner M.D., Ph.D.,Agorastos Agorastos M.D.Search for more papers by this authorChristoph Muhtz M.D.Search for more papers by this authorMichael Kellner M.D., Ph.D.Search for more papers by this author,Published Online:1 Jul 2010https://doi.org/10.1176/jnp.2010.22.3.352.e18AboutSectionsView articleView PDFView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleTo the Editor: The differentiation of organic and psychogenic stupor is of major relevance in clinical practice. Mutistic stupor is a clinical manifestation of many psychiatric disorders in which the basal ganglia, frontal lobes, and limbic system are involved. 1 We report an unusual case of sporadic Creutzfeldt-Jakob disease with mutistic stupor, initially suspected as a posttraumatic dissociative reaction. Case ReportMrs. D, a 62-year-old Caucasian woman, presented to our hospital in December 2008 with mutistic stupor. Her daughter reported an acute onset of symptoms directly after a bombing attack very close to their house in Georgia. Since that point Mrs. D was reputedly numbed, showing avoidance behavior, hyperarousal, exaggerated startle, anxiety, disorientation, dissociation with memory loss, insomnia, and progressive mutism. One month earlier she was attacked by heavily armed criminals in her own apartment. Mrs. D had already been treated with sulpiride and risperidone without showing improvement but experienced extrapyramidal side effects (early dyskinesia, parkinsonism, and orofacial dystonic reactions). A subsequent vast exacerbation of the symptoms, with persisting mutism and akinesia, finally led to the admission in our clinic. Our patient showed a broad spectrum of posttraumatic-typical symptoms following exposure to traumatic events. The history of traumatization, the initial nonpathological neurological status, preadmission outpatient MRI, blood testing and lumbar puncture, as well as the nonspecific alterations of the initial EEG, underlined the hypothesis of a posttraumatic reaction. Only a subsequent conduction of all diagnostic measures and the later-on emerged myoclonias provided enough findings in order to revise this hypothesis: The control MRI displayed bilateral hyperintensities in the basal ganglia, the control EEG showed bi- and triphasic synchronized sharp wave complexes, and the liquor serology elevated 14-3-3 proteins, as typically reported in sporadic Creutzfeldt-Jakob disease patients. 2 , 3Discussion Sporadic Creutzfeldt-Jakob disease is a rare neurodegenerative disease with rapidly progressive course and extensively observed psychiatric symptoms, which appear mostly within 100 days of onset, often including exaggerated startle. 2 , 4 Approximately 10% of these patients are first admitted to psychiatric clinics with erroneous clinical diagnoses. 5 This case demonstrates that symptoms caused by the sporadic onset of Creutzfeldt-Jakob disease may mimic posttraumatic symptoms. Exaggerated startle response and stupor after severe traumatic experiences may sometimes have non-trauma-related etiopathogenesis and require a careful differential diagnostic procedure. Department for Psychiatry and Psychotherapy, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

Diagnostic Pitfalls in a Patient With Posttraumatic Exaggerated Startle Response and Mutistic Stupor

To the Editor: The differentiation of organic and psychogenic stupor is of major relevance in clinical practice. Mutistic stupor is a clinical manifestation of many psychiatric disorders in which the basal ganglia, frontal lobes, and limbic system are involved. 1 We report an unusual case of sporadic Creutzfeldt-Jakob disease with mutistic stupor, initially suspected as a posttraumatic dissociative reaction.

The emotional brain and sleep: An intimate relationship

Research findings confirm our own experiences in life where daytime events and especially emotionally stressful events have an impact on sleep quality and well-being. Obviously, daytime emotional stress may have a differentiated effect on sleep by influencing sleep physiology and dream patterns, dream content and the emotion within a dream, although its exact role is still unclear. Other effects that have been found are the exaggerated startle response, decreased dream recall and elevated awakening thresholds from rapid eye movement (REM)-sleep, increased or decreased latency to REM-sleep, increased REM-density, REM-sleep duration and the occurrence of arousals in sleep as a marker of sleep disruption. However, not only do daytime events affect sleep, also the quality and amount of sleep influences the way we react to these events and may be an important determinant in general well-being. Sleep seems restorative in daily functioning, whereas deprivation of sleep makes us more sensitive to emotional and stressful stimuli and events in particular. The way sleep impacts next day mood/emotion is thought to be affected particularly via REM-sleep, where we observe a hyperlimbic and hypoactive dorsolateral prefrontal functioning in combination with a normal functioning of the medial prefrontal cortex, probably adaptive in coping with the continuous stream of emotional events we experience.

P01-187 - Psychiatric disorders amongst children of immigrants

ObjectivesAccording to European Statistical Office EUROSTAT, Romania represents the second source of immigrants in the European Union. Off the record, more than 2 million people work out of the country, sex ratio for immigrants being quite equal.Parents’ immigration seems to become a new mode of abuse against children. The most optimistic statistics highlight that almost 100,000 of children have been abandoned by one or both parents, the majority being ascertained to older family members.MethodsWe followed-up 96 teenagers registered in Mental Health Center and University Clinic of Psychiatry Craiova, aged between 15.4 and 19.8 (mean age 17.4 years).ResultsOf the 96 subjects included in the study, 59 were boys and 37 girls. Their mean age at parents’ departure was 8.2±1.9 years. In the total sample, the most prevalent symptoms at the onset were non-specific symptoms of stress response (i.e. exaggerated startle response, difficulties getting to sleep, difficulty in concentrating). Symptoms released after a delay of at least 6 months after the departure (more quickly at boys) and remaining members of the family decided to accompany the child to the psychiatrist more later, in several cases even at two years distance since the onset (earlier at boys, in which emotional response to abandon was noisier, often with dissocial behavior). Intensity of symptoms varied from mild to severe.ConclusionsHome alone generation begins now, after several years of opening to European world, to be a problem that us, Romanian adult psychiatrists, haven’t encountered before.

Posttraumatic Stress Disorder and Male-Perpetrated Intimate Partner Violence

ALTHOUGH THE RELATIONSHIP BETWEEN POSTTRAUmatic stress disorder (PTSD) and aggression is generally well established within the literature, research investigating the relationship between PTSD and male-perpetrated intimate partner violence (IPV) has only begun to emerge. Preliminary findings suggest a link between trauma exposure, PTSD symptomatology, and maleperpetrated IPV, which may have important clinical implications for batterer intervention programs. To the extent that IPV associated with PTSD has an etiology distinct from non–PTSD-related IPV, prevention and intervention programs may need to be tailored to address the potentially unique IPV risk factors among men with PTSD. Because of the lack of research on the association of PTSD and IPV perpetrated by women, this Commentary will focus on male-perpetrated IPV. Most US studies examining the relationship between PTSD and male-perpetrated IPV have been conducted with male veterans. Findings from these studies indicate that male veterans with greater PTSD symptomatology often self-report higher levels of anger, hostility, aggressiveness, anger reactivity, and IPV perpetration than veterans without significant PTSD symptomatology. The association between PTSD and IPV perpetration has also been found among civilian men. Rosenbaum and Leisring found that civilian male batterers referred to a group batterers treatment program who met diagnostic criteria for PTSD based on the PTSD Checklist-Civilian Version self-reported greater generalized aggressivity and significantly higher rates of IPV perpetration on the Conflict Tactics Scale than civilian male batterers without PTSD. In a study examining IPV rates within a nonclinical civilian male sample recruited from a college campus, Jakupcak and Tull reported similar findings, with higher self-reported rates of IPV perpetration, trait and internal anger, and hostility found among civilian men with PTSD symptomatology compared with civilian men without PTSD symptoms. Prior research investigating the relationship between PTSD and aggression has often included PTSD as a single construct. However, findings from a 3-wave longitudinal study examining the course of PTSD symptoms over a 12-month period in young adults who experienced community violence highlight the importance of considering how the 3 PTSD symptom clusters differentially change over time, influence other PTSD symptoms, and affect behavior, including aggression. Although debate exists as to the nature and number of factors, PTSD is currently characterized by 3 distinct symptom clusters consisting of (1) reexperiencing symptoms (eg, nightmares, flashbacks); (2) avoidance symptoms (eg, avoidance of trauma-related stimuli); and (3) hyperarousal symptoms (eg, hypervigilance, exaggerated startle response). These 3 symptom clusters have been examined as they relate to aggressive behavior. Overall, hyperarousal symptoms appear to play an especially prominent role in the initiation of aggressive behavior. For example, in a study examining the association between aggression and each of the 3 PTSD symptom clusters among male Vietnam veterans participating in a larger multisite psychophysiological project on PTSD, Taft et al found hyperarousal symptoms to have the strongest positive relationship with aggressive behavior in comparison with the other 2 PTSD symptom clusters. Additionally, the authors found that hyperarousal symptoms were both directly related to aggression and indirectly associated with aggression through alcohol problems, as measured by the CAGE questionnaire for assessing alcoholism. Conversely, findings from the same study show that reexperiencing symptoms may not directly influence aggressive behavior, but may indirectly affect aggression via their positive relationship on physiological reactivity (ie, heart rate and skin conductance) to trauma cues and negative affect on alcohol problems. Mixed findings exist regarding the role of PTSD avoidance symptoms and subsequent aggressive behavior. A study comparing male Vietnam veterans seeking inpatient PTSD treatment with a mixed diagnostic group of male inpatient Vietnam veterans without PTSD found a positive relationship between avoidance/numbing symptoms and aggression when assessing PTSD symptom clusters using the brief Mississippi Scale for Combat-Related PTSD. However, additional evidence from the study by Taft et al suggests a potential negative association between avoidance/numbing

Clinical changes and EEG patterns preceding the onset of periodic sharp wave complexes in Creutzfeldt-Jakob disease.

The conversion of EEG findings and the evolution of clinical signs was investigated in 7 CJD patients who underwent serial EEG recordings along the course. At the onset of PSWC (mean 8.7 weeks), 5 patients had already progressed to akinetic mutism (characterized by loss of verbal contact and directed responses); and a CJD-typical-movement disorder (myoclonia, exaggerated startle reaction or focal dyskinesia) had started in 5 patients. When akinetic mutism commenced (on average at 7.5 weeks), runs of frontal intermittent non-peaked rhythmical delta activity (FIRDA) were found in all cases. These were later replaced by PSWC in 6 patients (interval 1 to 3 weeks). Occurrence of PSWC was often negatively related to external stimuli (2 of 6 cases), and sedative medication (all patients tested). We conclude that the selection of EEG recording dates to detect PSWC in CJD-candidates should be guided by detailed information about movement disorders and conscious level. Regarding the short survival time after their onset (average 8 weeks), PSWC usually mark the terminal stage of CJD. To detect PSWC, especially, EEG registrations in advanced stages are often necessary. In earlier disease stages, FIRDA-like EEG activities should be regarded as compatible with this diagnosis, and encourage further EEG studies for the demonstration of PSWC in a more advanced stage of CJD.

Salicylate increases the gain of the central auditory system

High doses of salicylate, the anti-inflammatory component of aspirin, induce transient tinnitus and hearing loss. Systemic injection of 250 mg/kg of salicylate, a dose that reliably induces tinnitus in rats, significantly reduced the sound evoked output of the rat cochlea. Paradoxically, salicylate significantly increased the amplitude of the sound-evoked field potential from the auditory cortex (AC) of conscious rats, but not the inferior colliculus (IC). When rats were anesthetized with isoflurane, which increases GABA-mediated inhibition, the salicylate-induced AC amplitude enhancement was abolished, whereas ketamine, which blocks N-methyl-d-aspartate receptors, further increased the salicylate-induced AC amplitude enhancement. Direct application of salicylate to the cochlea, however, reduced the response amplitude of the cochlea, IC and AC, suggesting the AC amplitude enhancement induced by systemic injection of salicylate does not originate from the cochlea. To identify a behavioral correlate of the salicylate-induced AC enhancement, the acoustic startle response was measured before and after salicylate treatment. Salicylate significantly increased the amplitude of the startle response. Collectively, these results suggest that high doses of salicylate increase the gain of the central auditory system, presumably by down-regulating GABA-mediated inhibition, leading to an exaggerated acoustic startle response. The enhanced startle response may be the behavioral correlate of hyperacusis that often accompanies tinnitus and hearing loss.

A Novel GLRA1 Mutation Associated with An Atypical Hyperekplexia Phenotype

Hyperekplexia (MIM #149400) is a rare neurological disorder characterized by an exaggerated startle response, infantile hypertonia and hyperreflexia without spasticity, a hesitant gait that usually improves by 3 years of age, and nocturnal myoclonus. Familial hyperekplexia is usually autosomal dominant resulting from mutations in the inhibitory glycine receptor subunit alpha 1 (GLRA1) gene on chromosome 5q. We identified a 3-generation family with progressively severe phenotypes of hyperekplexia. All affected family members were found to be heterozygous for a novel arginine271proline mutation in GLRA1. Long-term follow-up of the affected members of the third generation, now aged 6 and 7 years, reveals enhanced startle responses and persistent hypertonia of the extremities without clonus or a catch, tight heel cords and abnormal toe-walking gait, and plantar flexor reflexes. The 7-year-old child recently reponded well to a benzodiazepine. Future studies are warranted to examine whether this new missense mutation is solely responsible for this atypical phenotype.

Onset of activity and time to response on individual CAPS-SX17 items in patients treated for post-traumatic stress disorder with venlafaxine ER: a pooled analysis

This pooled analysis of data from two randomized, placebo-controlled trials of venlafaxine extended release (ER) assessed onset of activity and time to response on the 17 symptoms of post-traumatic stress disorder (PTSD) listed in DSM-IV and measured by the 17-item Clinician-Administered PTSD Scale (CAPS-SX17). The intent-to-treat (ITT) population comprised 687 patients (placebo, n=347; venlafaxine ER, n=340). Significant (p<0.05) separation between venlafaxine ER and placebo was observed on most CAPS-SX17 items, with earliest onset of activity and response (week 2) on items 5 (physiological reactivity on exposure to cues) and 14 (irritability or anger outbursts), and (week 4) items 1 (intrusive recollections) and 4 (psychological distress at exposure to cues). Onset of activity and response occurred later (generally, weeks 6-8) on items 9 (diminished interest/participation in activities), 10 (detachment or estrangement), 11 (restricted range of affect), 12 (sense of foreshortened future), all associated with numbing, 15 (difficulty concentrating), 16 (hypervigilance), 17 (exaggerated startle response), associated with hyperarousal, and 6 (avoidance of thoughts/feelings or conversations). Significant differences between venlafaxine ER and placebo were largely absent throughout the treatment period and at the primary week-12 end-point for items 2 (distressing dreams), 7 (avoidance of activities, places or people), 8 (inability to recall important aspect of trauma) and 13 (difficulty falling/staying asleep). These results indicate that symptoms of physiological reactivity and psychological distress in response to cues, and irritability/anger outbursts show early and robust improvement with venlafaxine ER treatment, while symptoms of numbing and hyperarousal take longer. The early and persistent effect of venlafaxine ER over placebo on anger/irritability is noteworthy in view of the clinical significance of these symptoms in PTSD.

Identification of a de novo Lys304Gln mutation in the glycine receptor α‐1 subunit gene in a Korean infant with hyperekplexia

Startle disease or hyperekplexia (STHE; MIM 149400) is a rare disorder that is characterized by marked muscular hypertonia in infancy and an exaggerated startle response to unexpected acoustic or tactile stimuli. Mutations in the gene encoding the alpha-1 subunit of the inhibitory glycine receptor (GLRA1) were reported as causes of STHE. Recently, we encountered a Korean male infant with generalized stiffness that was observed from the first 3 days of life. The abnormal startle response was evident from the fourth week of life, and he showed marked improvement in the startle response and muscle hypertonia after being administered phenobarbital and clonazepam. Direct sequencing analysis of the infant and his parents revealed a de novo variation (c.910A>C) in the GLRA1 gene, resulting in a novel Lys304Gln missense mutation.

Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder

People who are exposed to horrific, life-threatening experiences are at risk for developing post-traumatic stress disorder (PTSD). Some of the symptoms of PTSD include persistent anxiety, exaggerated startle, cognitive impairments and increased sensitivity to yohimbine, an α2-adrenergic receptor antagonist. We have taken into account the conditions known to induce PTSD, as well as factors responsible for long-term maintenance of the disorder, to develop an animal model of PTSD. Adult male Sprague–Dawley rats were administered a total of 31 days of psychosocial stress, composed of acute and chronic components. The acute component was a 1-h stress session (immobilization during cat exposure), which occurred on Days 1 and 11. The chronic component was that on all 31 days the rats were given unstable housing conditions. We found that psychosocially stressed rats had reduced growth rate, reduced thymus weight, increased adrenal gland weight, increased anxiety, an exaggerated startle response, cognitive impairments, greater cardiovascular and corticosterone reactivity to an acute stressor and heightened responsivity to yohimbine. This work demonstrates the effectiveness of acute inescapable episodes of predator exposure administered in conjunction with daily social instability as an animal model of PTSD.

HYPEREKPLEXIA CAUSED BY DOMINANT-NEGATIVE SUPPRESSION OF GLYRA1 FUNCTION

Hyperekplexia (HE; startle disease; OMIM#149400) is a rare inheritable neurologic disorder characterized by an exaggerated response to sudden stimuli, muscular rigidity, and hyperreflexia, leading to chronic injuries due to unprotected falls. All symptoms are present at birth but gradually decline during the first year of life, although an exaggerated startle response remains during adulthood.1 Dysfunctional inhibitory neurotransmission by glycine (Gly) plays a central role in HE pathogenesis. All patients with HE carry mutations in genes encoding either for α1 (GLYRA1) or β (GLYRB) Gly receptor subunits, presynaptic Gly transporters (SLC6A5), or proteins involved in Gly receptor (GLYR) clustering, such as gephyrin (GPHN) and collybistin (ARHGEF9).1,2 GLYRA1 subunits interact in a heteropentameric complex with homologous β subunits (3α12β). Each subunit comprises an extracellular N-terminus, four α-helical transmembrane segments (TM1 to TM4), and an extracellular C-terminus; TM2 segments are thought to align the Cl− selective pore.1 Different GLYRA1 missense and nonsense mutations have been associated with autosomal dominant, autosomal recessive, and sporadic forms of HE. Missense mutations may show incomplete penetrance and impair channel gating, trafficking, and stability.3 Nonsense mutations have been reported only in recessive cases, in compound heterozygosity with a missense mutation, or in homozygosity in the offspring of consanguineous nonaffected parents and appear unable to cause the startle phenotype in heterozygosis.4,5 A recessive form of HE linked to a GLYRA1 null allele has been described,6 suggesting a nonpathogenic role for haplotype insufficiency. In this study, we investigated the functional consequences of a de novo …

Behavioral interventions for trauma and posttraumatic stress disorder.

Abstract Optimal therapy for Posttraumatic Stress Disorder (PTSD) follows logically from an understanding of etiological models describing the development and maintenance of the disorder. Accordingly, the present article provides a brief overview of PTSD with particular attention paid to etiology. Exposure-based interventions have consistently been shown to promote superior posttraumatic adjustment relative to alternate treatment approaches. In addition to describing exposure therapy for PTSD, we briefly review the supporting treatment-outcome literature. Misconceptions surrounding exposure therapy are presented and discussed. Finally, cultural considerations and complex presentations are considered. Keywords: Posttraumatic Stress Disorder (PTSD), peritraumatic reaction, intense fear, helplessness, horror ********** In order to meet diagnostic criteria for posttraumatic stress disorder (PTSD), an individual must experience, witness or be confronted with an event that involves actual or threatened serious injury or death, or a threat to the physical integrity of self or others. Further, the peritraumatic reaction to the event must involve intense fear, helplessness or horror (American Psychiatric Association; APA, 2000, pp.467). Although resiliency in the face of trauma is the norm, exposure to events that may potentially elicit PTSD is not uncommon. By way of example, one large scale epidemiological study of nearly 6,000 U.S. citizens indicated that approximately 61% of men and 51% of women have experienced at least one potentially traumatic event in their lives (Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995). Events that frequently precipitate PTSD include combat, natural disasters, sexual assault, violent crime, or witnessing or experiencing significant accidents or injuries. According to the most recent version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR; APA, 2000), in order for an individual to meet diagnostic criteria for PTSD he or she must have at least one symptom of re-experiencing, three or more avoidance symptoms, and two or more persistent symptoms of heightened arousal related to traumatic exposure. Re-experiencing may include recurrent and intrusive distressing recollections of the event, recurrent dreams of the event, acting or feeling as if the event were re-occurring, intense psychological distress at exposure to internal or external cues which represent the event, or physiological reactivity with exposure to internal or external cues that represent an aspect of the event. The second symptom cluster, characterized by avoidance, involves efforts to avoid thoughts, feelings, conversations, activities, places or people that are associated with recollections of the trauma, an inability to recall important aspects of the trauma, diminished interest in activities, feelings of detachment from others, a restricted range of affect, or a sense of a foreshortened future. The hyperarousal symptoms that constitute the third cluster include difficulty falling or staying asleep, irritability or outbursts of anger, difficulty concentrating, hypervigilance, and an exaggerated startle response. In order to meet diagnostic criteria for PTSD the symptoms outlined above must persist for at least one month following the trauma and must significantly interfere with an individual's social, educational, or occupational functioning. Although exposure to potentially traumatic events is not uncommon in the general population, results from the National Comorbidity Survey indicate that PTSD affects only 7.8% of the population, with the rate for women (10.4%) being more than twice the rate for men (5.0%) (Keane & Barlow, 2002; Kessler et al., 1995). It is important to note that the elevated rate of PTSD for women is most likely due to the increased rate of victimization among women. In a national study of exposure to crime among women in the United States, 36% of women reported being directly affected by crime at some point in their lives, with rape or molestation being the most frequently experienced crime (Keane & Barlow, 2002; Resnick, Kilpatrick, Dansky, Saunders, & Best, 1993). …

Hyperekplexia in two siblings

Hyperekplexia is a rare, hereditary, non-epileptic disorder characterized by an exaggerated startle reaction to unexpected auditory, somatosensory and visual stimuli. The authors describe a one-day-old term neonate, who presented with jitteriness and episodic tonic spasms, and his elder sister with hyperekplexia. Hyperekplexia though is a rare disorder is one of the differential diagnoses for refractory tonic spasms in infancy. The prognosis is generally good in hereditary hyperekplexia. Recent molecular studies have revealed many associated mutations in the glycine receptor alpha and beta subunit genes.

Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease

Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.

Anisomycin, a Protein Synthesis Inhibitor, Disrupts Traumatic Memory Consolidation and Attenuates Posttraumatic Stress Response in Rats

Paradoxical changes in memory represent a troublesome characteristic of posttraumatic stress disorder (PTSD). Exceptionally vivid intrusive memories of some aspects of the trauma are mingled with patchy amnesia regarding other important aspects. Molecular studies of the memory process suggest that the conversion from labile short-term memory into long-term fixed traces involves protein synthesis. This study assessed the effects of administration of anisomycin, a protein synthesis inhibitor, after initial exposure, after exposure to a cue associated with triggering experience, and after reexposure to the triggering trauma in an animal model of PTSD. Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in rats that were exposed to predator stress, with and without microinjection of anisomycin. Microinjection of anisomycin before and after stress exposure reduced anxiety-like and avoidant behavior, reduced the mean startle amplitude, and reversed the stress-induced habituation deficit 7 days later. The persistent anxiety-like behaviors that were seen after stress exposure do not appear to be sensitive to anisomycin after reexposure to a cue associated with the event or after reexposure to the index experience. Disruption of the process of traumatic memory consolidation may be useful for mitigating PTSD symptoms.