Negative myoclonus causes locomotory disability in progressive myoclonus epilepsy type EPM1- Unverricht-Lundborg disease.

OBJECTIVE: Patients with Unverricht-Lundborg disease/EPM1 develop increasing locomotory disability or ataxia in the course of their disease. To test our hypothesis that negative myoclonus is the reason for this increasing ataxia, we investigated a possible correlation over time. METHODS: In 15 patients with EPM1who were confirmed to have a mutation in the CSTB gene, polygraphic video-EEG-EMG recordings were performed in freely moving or standing patients. The criterion for the duration of the negative myoclonus was the measured length of the silent periods on the EMG. RESULTS: All 15 patients had documented negative myoclonus when standing and walking. The mean duration of silent periods significantly increased from 100 (SD: 19.1) ms at time point T1 to 128 (SD: 26.6) ms at T2 in seven of eight patients, based on two recordings and a mean interval of 12.8 (SD: 4.9) years. Using a cross-sectional approach, all 15 patients were classified based on whether they were ambulatory, could walk with aid, or needed a wheelchair. Ambulatory patients had a mean duration of 97.3 (SD: 16.5) ms, patients who could walk with aid had a mean duration of 106.7 (SD: 16) ms, and patients who were wheelchair-bound had a mean duration of 138 (SD: 23.6) ms. In addition to the prolongation of the silent periods, there was an observed increase in frequency of the negative myoclonus, becoming more continuous and tremulous. SIGNIFICANCE: Using simultaneous EEG/EMG recordings in freely moving or standing patients, we have shown that the locomotor disability or ataxia is due to negative myoclonus in voluntary innervated muscles. The reason for the progression is the prolongation of the silent periods as measured by the duration of the negative myoclonus and their increase in frequency.

Interfering with fear memories by eye movement desensitization and reprocessing.

OBJECTIVE: Pharmacologic and behavioral interventions that block reconsolidation of reactivated fear memory have demonstrated only limited success in modifying stronger and long-standing fear memories. Given the efficacy of Eye Movement Desensitization and Reprocessing (EMDR) in treating PTSD, pursuit eye movements are a promising and novel intervention for studies of human memory reconsolidation. Here, we examined the efficacy of pursuit eye movements in interfering with reconsolidation of conditioned fear memories. METHODS: We conducted a 3-day differential Pavlovian fear conditioning procedure in healthy adults, using videos of biologically prepared stimuli (tarantulas), partly reinforced with electrical shocks while recording skin conductance response (SCR) as a measure of autonomic conditioned responses. Fear conditioning was performed on Day 1. On Day 2, 38 participants were randomized into groups performing pursuit eye movements either immediately after fear memory reactivation, when the fear memory was stable, or 10 min later, when the fear memory was assumed to be more labile. On Day 3, fear memory strength was assessed by SCR to both reactivated and nonreactivated fear memories. RESULTS: Strong differential conditioning to the spider stimuli were observed during both fear acquisition and fear memory reactivation. Reactivated fear memory conditioned responses of participants performing pursuit eye movements after a 10-min delay were significantly smaller in the reinstatement phase (0.16 µS; 95% CI [0.02, 0.31]). CONCLUSIONS: Pursuit eye movements were effective in reducing fear-conditioned SCR in reinstatement. This result supports the theoretical proposition that EMDR can interfere with reactivated fear memory reconsolidation.

Functional impairment in Posttraumatic Stress Disorder: A systematic review and meta-analysis.

Posttraumatic Stress Disorder (PTSD) is a serious and debilitating condition often associated with significant impairments in daily functioning. To date, research on the complexity of functional impairment in individuals with PTSD is scarce and only limited. Yet, a quantitative synthesis and comprehensive review of existing evidence is needed to better characterize the magnitude of functional impairment in PTSD in distinct domains. We conducted a systematic literature search including observational studies comparing functioning of individuals with and without PTSD. Random effects meta-analyses were performed for the different functional domains according to the WHO International Classification of Functioning, Disability and Health (ICF). The protocol followed the MOOSE guidelines for systematic reviews. A total of thirty-four studies comprising 14 206 participants were included in the study. Compared to healthy individuals, subjects with PTSD showed significant (ps < 0.001) impairments with large to very large effect sizes (ds > 1) in all domains. Subjects with, compared to without, PTSD showed significant (ps < 0.001) impairments with medium to large effect sizes (ds > 0.5) in the domains General Tasks and Demands, Mobility, Self Care, Domestic Life, Interpersonal Interactions and Relationships, Major Life Areas and Community, Social and Civic Life. Significant impairments with small to medium effect sizes in the same domains were observed comparing PTSD to other mental disorders. In conclusion, PTSD has a significant impact on most areas of daily functioning as conceptualized in the International Classification of Functioning, Disability and Health (ICF) of the WHO. Early detection and targeted treatment of functional deficits is warranted in this patient population.

Striatal reactivity to reward under threat-of-shock and working memory load in adults at increased familial risk for major depression: A preliminary study.

INTRODUCTION: Anhedonia, a core symptom of Major Depressive Disorder (MDD), manifests as a lack or loss of motivation as reflected by decreased reward responsiveness, at both behavioral and neural (i.e., striatum) levels. Exposure to stressful life events is another important risk factor for MDD. However, the mechanisms linking reward-deficit and stress to MDD remain poorly understood. Here, we explore whether the effects of stress exposure on reward processing might differentiate between Healthy Vulnerable adults (HVul, i.e., positive familial MDD) from Healthy Controls (HCon). Furthermore, the well-described reduction in cognitive resources in MDD might facilitate the stress-induced decrease in reward responsiveness in HVul individuals. Accordingly, this study includes a manipulation of cognitive resources to address the latter possibility. METHODS: 16 HVul (12 females) and 16 gender- and age-matched HCon completed an fMRI study, during which they performed a working memory reward task. Three factors were manipulated: reward (reward, no-reward), cognitive resources (working memory at low and high load), and stress level (no-shock, unpredictable threat-of-shock). Only the reward anticipation phase was analyzed. Imaging analyses focused on striatal function. RESULTS: Compared to HCon, HVul showed lower activation in the caudate nucleus across all conditions. The HVul group also exhibited lower stress-related activation in the nucleus accumbens, but only in the low working memory (WM) load condition. Moreover, while stress potentiated putamen reactivity to reward cues in HVul when the task was more demanding (high WM load), stress blunted putamen reactivity in both groups when no reward was at stake. CONCLUSION: Findings suggest that HVul might be at increased risk of developing anhedonic symptoms due to weaker encoding of reward value, higher difficulty to engage in goal-oriented behaviors and increased sensitivity to negative feedback, particularly in stressful contexts. These findings open new avenues for a better understanding of the mechanisms underlying how the complex interaction between the systems of stress and reward responsiveness contribute to the vulnerability to MDD, and how cognitive resources might modulate this interaction.

Increased Reward-Related Activation in the Ventral Striatum During Stress Exposure Associated With Positive Affect in the Daily Life of Young Adults With a Family History of Depression. Preliminary Findings.

Background: Being the offspring of a parent with major depression disorder (MDD) is a strong predictor for developing MDD. Blunted striatal responses to reward were identified in individuals with MDD and in asymptomatic individuals with family history of depression (FHD). Stress is a major etiological factor for MDD and was also reported to reduce the striatal responses to reward. The stress-reward interactions in FHD individuals has not been explored yet. Extending neuroimaging results into daily-life experience, self-reported ambulatory measures of positive affect (PA) were shown to be associated with striatal activation during reward processing. A reduction of self-reported PA in daily life is consistently reported in individuals with current MDD. Here, we aimed to test (1) whether increased family risk of depression is associated with blunted neural and self-reported reward responses. (2) the stress-reward interactions at the neural level. We expected a stronger reduction of reward-related striatal activation under stress in FHD individuals compared to HC. (3) the associations between fMRI and daily life self-reported data on reward and stress experiences, with a specific interest in the striatum as a crucial region for reward processing. Method: Participants were 16 asymptomatic young adults with FHD and 16 controls (HC). They performed the Fribourg Reward Task with and without stress induction, using event-related fMRI. We conducted whole-brain analyses comparing the two groups for the main effect of reward (rewarded > not-rewarded) during reward feedback in control (no-stress) and stress conditions. Beta weights extracted from significant activation in this contrast were correlated with self-reported PA and negative affect (NA) assessed over 1 week. Results: Under stress induction, the reward-related activation in the ventral striatum (VS) was higher in the FHD group than in the HC group. Unexpectedly, we did not find significant group differences in the self-reported daily life PA measures. During stress induction, VS reward-related activation correlated positively with PA in both groups and negatively with NA in the HC group. Conclusion: As expected, our results indicate that increased family risk of depression was associated with specific striatum reactivity to reward in a stress condition, and support previous findings that ventral striatal reward-related response is associated with PA. A new unexpected finding is the negative association between NA and reward-related ventral striatal activation in the HC group.

Behavioral Responses to Uncertainty in Weight-Restored Anorexia Nervosa - Preliminary Results.

Impaired decision-making under conditions of uncertainty seems to contribute to the expression and maintenance of anorexia nervosa (AN), but it is not clear whether this impairment is a disease state that would remit with treatment, or a persisting trait in patients with AN. To examine this question, a longitudinal study was conducted in 12 female inpatients with AN (age M = 22.2, SE = 1.36), before (Time-1) and after reaching a body mass index of >17.5 kg/m2 (Time-2). Intolerance of uncertainty (IU) was assessed via a decision-making task, the wheel of fortune (WOF). Weight gain at Time-2 was accompanied with significant changes in uncertainty-related performance compared to Time-1 [(Time × Uncertainty), p < 0.05]. At Time-1, reaction times (RTs) varied in function of uncertainty, while at Time-2, uncertainty did not modulate RTs. These findings support a change in decision-making under uncertainty with successful weight-rehabilitation in AN. While IU was present in underweight patients, it became non-significant after weight restoration.

Striatal responsiveness to reward under threat-of-shock and working memory load: A preliminary study.

INTRODUCTION: Reward and stress are important determinants of motivated behaviors. Striatal regions play a crucial role in both motivation and hedonic processes. So far, little is known on how cognitive effort interacts with stress to modulate reward processes. This study examines how cognitive effort (load) interacts with an unpredictable acute stressor (threat-of-shock) to modulate motivational and hedonic processes in healthy adults. MATERIALS AND METHODS: A reward task, involving stress with unpredictable mild electric shocks, was conducted in 23 healthy adults aged 20-37 (mean age: 24.7 ± 0.9; 14 females) during functional magnetic resonance imaging (fMRI). Manipulation included the use of (a) monetary reward for reinforcement, (b) threat-of-shock as the stressor, and (c) a spatial working memory task with two levels of difficulty (low and high load) for cognitive load. Reward-related activation was investigated in a priori three regions of interest, the nucleus accumbens (NAcc), caudate nucleus, and putamen. RESULTS: During anticipation, threat-of-shock or cognitive load did not affect striatal responsiveness to reward. Anticipated reward increased activation in the ventral and dorsal striatum. During feedback delivery, both threat-of-shock and cognitive effort modulated striatal activation. Higher working memory load blunted NAcc responsiveness to reward delivery, while stress strengthened caudate nucleus reactivity regardless reinforcement or load. CONCLUSIONS: These findings provide initial evidence that both stress and cognitive load modulate striatal responsiveness during feedback delivery but not during anticipation in healthy adults. Of clinical importance, sustained stress exposure might go along with dysregulated arousal, increasing therefore the risk for the development of maladaptive incentive-triggered motivation. This study brings new insight that might help to build a framework to understand common stress-related disorders, given that these psychiatric disorders involve disturbances of the reward system, cognitive deficits, and abnormal stress reactivity.

Psychiatric Symptom Profiles Predict Functional Impairment.

Objective: Mental illness often interferes with daily functioning and an individual's pattern of psychiatric signs and symptoms may predict risk of future disability. Understanding the linkage between psychiatric symptoms and impaired functioning is critical for accurate rehabilitation planning and legal assessment. Here, we investigated the stability of functional impairment measures over 18 months and their association with psychiatric symptoms. Moreover, we developed a clinical self-report measure that allows estimation of functional impairment levels over 18 month observation periods. Methods: Consecutively treated outpatients and daycare patients (N = 155) from several psychiatric units in Switzerland completed the Dissociative Experiences Scale, Somatoform Dissociation Questionnaire, Multidimensional Inventory for Dissociation, Beck Depression Inventory, Brief Symptom Inventory, and WHO Disability Assessment Schedule at baseline, 6, 12, and 18 month follow-up examinations. The association between symptoms functional impairment over time was investigated using longitudinal linear mixed models. Penalized regression was used to identify questionnaire items that best predicted functional impairment. Results: We found high stability in the extent of functional impairment over 18 months. Fear of negative evaluation, fatigue, concentration problems, negative alterations in mood, and dissociative symptoms showed the strongest association with functional impairment measures. The empirically derived scale for functional impairment prediction explained between 0.62 and 0.77 of the variance in disability across various life domains. Conclusion: Given the capability for somatic and mental symptoms associated with social anxiety, depression, and dissociation to predict future disability, these symptoms have strong potential for guiding rehabilitation planning and prognostic evaluation in insurance medicine. The Functional Impairment Prediction Scale may serve as a valuable, empirical-based extension in legal assessments of how work capacity is affected by psychological factors.

Locus Coeruleus Activity Mediates Hyperresponsiveness in Posttraumatic Stress Disorder.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) are hyperresponsive to unexpected or potentially threatening environmental stimuli. Research in lower animals and humans suggests that sensitization of the locus coeruleus-norepinephrine system may underlie behavioral and autonomic hyperresponsiveness in PTSD. However, direct evidence linking locus coeruleus system hyperactivity to PTSD hyperresponsiveness is sparse. METHODS: Psychophysiological recording and functional magnetic resonance imaging were used during passive listening to brief, 95-dB sound pressure level, white noise bursts presented intermittently to determine whether behavioral and autonomic hyperresponsiveness to sudden sounds in PTSD is associated with locus coeruleus hyperresponsiveness. RESULTS: Participants with PTSD (n = 28) showed more eye-blink reflexes and larger heart rate, skin conductance, and pupil area responses to loud sounds (multivariate p = .007) compared with trauma-exposed participants without PTSD (n = 26). PTSD participants exhibited larger responses in locus coeruleus (t = 2.60, region of interest familywise error corrected), intraparietal sulcus, caudal dorsal premotor cortex, and cerebellar lobule VI (t ≥ 4.18, whole-brain familywise error corrected). Caudal dorsal premotor cortex activity was associated with both psychophysiological response magnitude and levels of exaggerated startle responses in daily life in PTSD participants (t ≥ 4.39, whole-brain familywise error corrected). CONCLUSIONS: Behavioral and autonomic hyperresponsiveness in PTSD may arise from a hyperactive alerting/orienting system in which processes related to attention and motor preparation localized to lateral premotor cortex, intraparietal sulcus, and posterior superior cerebellar cortex are modulated by atypically high phasic noradrenergic influences originating in the locus coeruleus.

How fat will it make me? Estimation of weight gain in anorexia nervosa.

This study investigates the subjective estimation of weight gain in patients with anorexia nervosa (AN) when being confronted with food cues both in a general (self-unrelated) and in an intent-to-eat (self-related) condition. Looking at the presentation of different snack pictures with different nutrition values (high-low calories), AN patients (N = 24) and age-matched healthy women (N = 27) estimated the weight gain when they imagined eating the presented portions of snack pictures once a day in addition to the normal daily nutrition in the following two conditions: 1) a general condition without specific additional instruction, 2) an intent-to-eat condition, in which they were instructed to imagine that they would eat the snack themselves. Compared to healthy women, patients with AN estimated a higher weight gain only in the intent-to-eat condition, i.e. when they imagined eating the snacks themselves, but not in the general, not self-related condition. In the patient group, mean estimations of weight gain were associated with the "drive for thinness". This study suggests cognitive abnormalities related to the effects of food intake on the weight gain in AN, and that these cognitive anomalies could be related to the fear of gaining weight, one central symptom of AN. It appears that the self-reflective disturbed cognition, rather than the general cognition, could be the main driver underlying anorexia and that the overestimation of the energetic content of food is related to the drive for thinness.

Effects of Posture and Stimulus Spectral Composition on Peripheral Physiological Responses to Loud Sounds.

In the "loud-tone" procedure, a series of brief, loud, pure-tone stimuli are presented in a task-free situation. It is an established paradigm for measuring autonomic sensitization in posttraumatic stress disorder (PTSD). Successful use of this procedure during fMRI requires elicitation of brain responses that have sufficient signal-noise ratios when recorded in a supine, rather than sitting, position. We investigated the modulating effects of posture and stimulus spectral composition on peripheral psychophysiological responses to loud sounds. Healthy subjects (N = 24) weekly engaged in a loud-tone-like procedure that presented 500 msec, 95 dB sound pressure level, pure-tone or white-noise stimuli, either while sitting or supine and while peripheral physiological responses were recorded. Heart rate, skin conductance, and eye blink electromyographic responses were larger to white-noise than pure-tone stimuli (p's < 0.001, generalized eta squared 0.073-0.076). Psychophysiological responses to the stimuli were similar in the sitting and supine position (p's ≥ 0.082). Presenting white noise, rather than pure-tone, stimuli may improve the detection sensitivity of the neural concomitants of heightened autonomic responses by generating larger responses. Recording in the supine position appears to have little or no impact on psychophysiological response magnitudes to the auditory stimuli.

Altered Pain Perception and Fear-Learning Deficits in Subjects With Posttraumatic Stress Disorder.

There is growing evidence that fear-learning abnormalities are involved in the development of posttraumatic stress disorder (PTSD) and chronic pain. More than 50% of PTSD patients suffer from chronic pain. This study aimed to examine the role of fear-learning deficits in the link between pain perception and PTSD. We included 19 subjects with PTSD and 21 age- and sex-matched healthy control subjects in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs flashed upon a screen in front of each subject. The unconditioned stimulus was either a low or high temperature impulse delivered through a thermal contact thermode on the subjects' hand. A designation of 'CS-' was assigned to CS always followed by nonpainful low-temperature stimuli; a designation of 'CS+' was given to CS that were randomly followed by either a low or a more painful high temperature. Skin conductance was used as a physiological marker of fear. In healthy control subjects, CS+ induced more fear than CS-, and a low-temperature stimulus induced less subjective pain after CS- than after CS+. PTSD subjects failed to demonstrate such adaptive conditioning. Fear ratings after CS presentation were significantly higher in the PTSD group than in the control group. There were significant interaction effects between group and the type of CS on fear and pain ratings. Fear-learning deficits are a potentially promising, specific psychopathological factor in altered pain perception associated with PTSD. Deficits in safety learning may increase fear and, consequently, pain sensations. These findings may contribute to elucidating the pathogenesis behind the highly prevalent comorbidity that exists between PTSD and pain disorders, and to developing new treatments. PERSPECTIVE: This study provides new insights into the pathogenesis of chronic pain in patients with PTSD. The findings may help to develop new treatment strategies for this highly prevalent comorbidity in PTSD.

Delayed extinction fails to reduce skin conductance reactivity to fear-conditioned stimuli.

A brief 10-min time delay between an initial and subsequent exposure to extinction trials has been found to impair memory reconsolidation in fear-conditioned rodents and humans, providing a potential means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder (PTSD). The present study used videos of biologically prepared, conditioned stimuli (tarantulas) to test the efficacy of delayed extinction in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, the delayed-extinction intervention failed to reduce reactivity to the conditioned stimulus paired with the extinction delay. These results are partially consistent with other recent, mixed findings and point to a need for testing other candidate interventions designed to interfere with the reconsolidation process.

Discriminative evaluative conditioning in the long-term after severe accidental injury.

Impairments in classical fear conditioning and deficits in discriminative learning are observed in posttraumatic stress disorder (PTSD). However, it is unknown whether similar impairments can be found with types of discriminative learning other than classical conditioning, such as evaluative conditioning (EC), in which the valence of a stimulus can be transferred to other stimuli. In this study, we investigated whether EC is also influenced by traumatic experiences independently of presence of PTSD. We tested 14 accident survivors with remitted PTSD, 14 survivors without PTSD, and 16 non-trauma controls. We used behavioral measures, psychophysiological indicators, and subjective ratings for tasks. General effects of learning were observed across groups and conditioning/extinction. Trauma controls had slower reaction times (RTs) to the aversive conditioned stimulus compared to appetitive conditioned and neutral stimuli, as well as slower RTs and increased accuracy during conditioning than during extinction. Remitted PTSD participants showed opposite results, demonstrating decreased accuracy and slower RTs during conditioning as compared to during extinction. No discriminative effect was found in the non-trauma controls and the remitted PTSD participants. These results suggest that a traumatic experience influences EC, and that this influence differs between individuals who have and have not developed PTSD after traumatic exposure.

Blunted responses to reward in remitted post-traumatic stress disorder.

BACKGROUND: Recent evidence suggests blunted responses to rewarding stimuli in patients with post-traumatic stress disorder (PTSD). However, it is not clear whether these alterations in reward processing normalize in remitted PTSD patients. METHODS: We tested behavioral and physiological responses to monetary reward in a spatial memory task in 13 accident survivors with remitted PTSD, 14 accident survivors who never had PTSD, and 16 nontrauma-exposed subjects. All accident survivors were recruited from two samples of severely physically injured patients, who had participated in previous prospective studies on the incidence of PTSD after accidental injury approximately 10 years ago. Reaction time, accuracy, skin conductance responses, and self-reported mood were assessed during the task. RESULTS: Accident survivors who never had PTSD and nontrauma exposed controls reported significantly higher positive mood in the reinforced versus nonreinforced condition (P < 0.045 and P < 0.001, respectively), while there was no effect of reinforcement in remitted PTSD subjects. CONCLUSIONS: Our findings suggest an alteration of the reward system in remitted PTSD. Further research is needed to investigate whether altered reward processing is a residual characteristic in PTSD after remission of symptoms or, alternatively, a preexisting risk factor for the development of PTSD after a traumatic event.

Testing the "Sexually Abused-Abuser Hypothesis" in Adolescents: A Population-Based Study.

A long-standing belief in the literature on sex offenders is that sexually victimized youths are at increased risk of becoming sex offenders themselves. The present study tested the link between past sexual abuse, either with or without contact, and sexually offending behavior in a representative sample of male and female adolescents while controlling for other types of abuse, mental health problems, substance use, and non-sexual violent behaviors. Self-reported data were collected from a nationally representative sample of 6,628 students attending 9th grade public school in Switzerland (3,434 males, 3,194 females, mean age = 15.50 years, SD = 0.66 years). Exposure to contact and non-contact types of sexual abuse was assessed using the Child Sexual Abuse Questionnaire and sexually offending behavior by the presence of any of three behaviors indicating sexual coercion. Two-hundred-forty-five males (7.1 %) and 40 females (1.2 %) reported having sexually coerced another person. After controlling for non-sexual abuse, low parent education, urban versus rural living, mental health problems, substance use, and non-sexual violent behavior, male adolescents who were victims of contact sexual abuse and non-contact sexual abuse were significantly more likely to report coercive sexual behaviors. Females who experienced contact or non-contact sexual abuse were also found at increased risk of committing sexual coercion after controlling for covariates. The present findings demonstrate a strong relationship between past sexual abuse, with and without physical contact, and sexual-offending behavior in male and female adolescents. Reducing exposure to non-contact sexual abuse (like Internet-based sexual exploitation) should become a new area of sexual violence prevention in youths.

Prereactivation propranolol fails to reduce skin conductance reactivity to prepared fear-conditioned stimuli.

Pharmacologic blockade of memory reconsolidation has been demonstrated in fear-conditioned rodents and humans and may provide a means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder. Studying the efficacy of potential interventions in clinical populations is challenging, creating a need for paradigms within which candidate reconsolidation-blocking interventions can be readily tested. We used videos of biologically prepared conditioned stimuli (tarantulas) to test the efficacy of propranolol in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, subsequent propranolol failed to reduce reactivity to the reactivated conditioned stimulus. These results are consistent with other recent findings and point to a need for testing other candidate drugs.

Prefrontal GABA and glutathione imbalance in posttraumatic stress disorder: preliminary findings.

Although posttraumatic stress disorder (PTSD) is associated with a variety of structural and functional brain changes, the molecular pathophysiological mechanisms underlying these macroscopic alterations are unknown. Recent studies support the existence of an altered excitation-inhibition balance in PTSD. Further, there is preliminary evidence from blood-sample studies suggesting heightened oxidative stress in PTSD, potentially leading to neural damage through excessive brain levels of free radicals. In this study we investigated PTSD (n=12) and non-PTSD participants (n=17) using single-voxel proton magnetic resonance spectroscopy (MRS) in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). We found significantly higher levels of γ-amino butyric acid (GABA) (a primary inhibitory neurotransmitter) and glutathione (a marker for neuronal oxidative stress) in PTSD participants. Atypically high prefrontal inhibition as well as oxidative stress may be involved in the pathogenesis of PTSD.

Cortical and cerebellar modulation of autonomic responses to loud sounds.

Detecting unexpected environmental change causes modulation of autonomic activity essential for survival. Understanding the neural mechanisms associated with responses to loud sounds may provide insights into the pathophysiology of posttraumatic stress disorder (PTSD), since individuals with PTSD exhibit heightened autonomic responses to unexpected loud sounds. We combined fMRI with autonomic psychophysiological assessment to investigate central and peripheral reactivity to loud tones in 20 healthy participants. Activity in anterior insula, pregenual anterior cingulate cortex, anterior midcingulate cortex, supplementary motor area, supramarginal gyrus, and cerebellar lobules VIII-IX was associated with both tones and concomitant skin conductance responses. Since regions signaling unexpected external events modulate autonomic activity, heightened loud tone autonomic responses in PTSD may reflect sensitization of this "salience" network.