In this Issue-November 15th| Volume 62, ISSUE 10, P1065-1066, November 15, 2007

In This Issue-November 15th

        Stress Response Related HPA Axis Disturbances

        Hypothalamic-pituitary-adrenal (HPA) -axis dysregulation is often a feature of stress-related neuropsychiatric disorders. Lyons et al. (pages 1171–1174) report that in nonhuman primates, small hippocampal volumes may be a risk factor for, and not just an effect of, impaired regulation of the HPA-axis response to stress.
        Carpenter et al. (pages 1080–1087) reported that individuals with moderate to severe levels of childhood maltreatment exhibited significantly decreased plasma cortisol and adrenocorticotropin hormone (ACTH) reactivity to a social stress test in comparison to subjects who reported no childhood maltreatment.

        Stress & PTSD: Physiology and Heritability

        Combat stress and chemical exposures during the Gulf War may have contributed to persisting endocrine dysregulation in soldiers. Golier et al. (pages 1175–1178) compared Gulf War veterans with and without posttraumatic stress disorder (PTSD) to a comparison group of non-deployed healthy subjects. The authors report that veterans without PTSD had lower ACTH levels and normal cortisol levels in 24-hour plasma samples. The reductions in ACTH were most pronounced among soldiers who had been exposed to pesticides or who had taken pyridostigmine bromide to protect from the effects of potential pesticide exposure, adjusting for the impact of PTSD.
        Habukawa et al. (pages 1179–1182) report that patients diagnosed with PTSD showed evidence of sleep maintenance impairments and increased awakening from rapid eye movement (REM) sleep, the stage of sleep where dreaming occurs. The awakenings from REM sleep were associated with reports of nightmares.
        In a study of twins who were also veterans, Fu et al. (pages 1088–1094) report that shared environmental factors associated with conduct disorder explain 10% of the risk for PTSD. In contrast, genetic factors associated with major depression explain 19% of the risk for PTSD. These findings suggest that distinct mechanisms account for the comorbidity of PTSD with conduct disorder and depression.
        Pervanidou et al. (pages 1095–1102) report a longitudinal study of the impact of psychological traumatization in children and adolescents involved in motor vehicle accidents. They found that evening salivary cortisol levels were initially elevated but declined over the subsequent 6 months. In contrast, noradrenaline levels were initially normal, but they increased gradually in patients who developed PTSD during this period. This progressive divergence in the secretion of these two important stress hormones may contribute to the natural history and pathophysiology of PTSD.
        Grillon et al. (pages 1183–1186) show that darkness increases the impact of social stress. Their study uses measurement of the startle response to assess the level of physiologic arousal. They found that social stress enhanced the ability of darkness to increase the startle response. This approach may be helpful in future studies attempting to understand the interplay of threatening contexts and social stress.

        Animal Studies Offer Potential New Treatment Options

        Bortolato et al. (pages 1103–1110) show that URB597, an inhibitor of brain anandamide hydrolysis, causes antidepressant-like effects in chronically stressed rats. Daily administration of URB597 for 5 weeks reversed the reduction in body weight gain and sucrose intake induced by stress to an extent comparable to the tricyclic antidepressant imipramine. The results suggest that anandamide deactivation may offer a target for the treatment of depression and other stress-related disorders.
        Burghardt et al. (pages 1111–1118) found that a single injection of a selective serotonin reuptake inhibitor, or SSRI, (citalopram or fluoxetine) led to an increase in conditioned fear expression in rats, while the antidepressant tianeptine and the norepinephrine reuptake inhibitor tomoxetine had no effect. The increase in fear expression was blocked with a concurrent injection of a 5-HT2C receptor antagonist, but not a 5-HT3 receptor antagonist. These data suggest that activation of 5-HT2C receptors may mediate the SSRI effects upon fear conditioning.
        Early life adverse experience alters adult emotional and cognitive development, although mediating mechanisms are not well understood. Sevelinges et al. (pages 1070–1079) found that learning particular fear-related associations to odor cues as an infant influenced the activity of fear circuitry, particularly the amygdala and olfactory bulb, when these animals were tested as adults. The altered responses of fear circuitry were specific to the learned odor cues and responses to novel odors were not changed.

        Neural Circuitry of Emotion: Impact of Treatments

        Oxytocin is known to reduce anxiety and stress in social interactions in animals and to reduce fear-related amygdala activation in humans. Using functional magnetic resonance imaging (fMRI), Domes et al. (pages 1187–1190) report that oxytocin reduces the extent of amygdala activation to both negative and positive facial expressions in healthy humans. These data suggest that oxytocin suppresses arousal generally, irrespective of stimulus valence.
        Goossens et al. (pages 1119–1125) showed that effective exposure-based therapy for spider phobia reduced the activation of a number of brain regions involved in the regulation of emotion including the anterior cingulate cortex, the insula, and amygdala, as assessed using fMRI.
        The amygdala has long been implicated in the expression of fear across species. Using structural and functional MRI in healthy human subjects, Milad et al. (pages 1191–1194) observed that the dorsal anterior cingulate is also involved in fear expression. Both the structure and the function of this brain region positively correlated with fear, i.e., the thicker and more active this brain region, the greater the fear responses that were observed.
        The brain circuits underlying novelty and familiarity are emerging from fMRI studies in humans. Activation of the relevant brain regions may be produced by having subjects complete cognitive tasks that elicit biases toward labeling objects as being new (novelty bias) or previously observed (familiarity bias). Sergerie et al. (pages 1126–1133) found that the tendency to over-report novelty was associated with activation of amygdala and prefrontal cortex while familiarity bias was associated with increased superior temporal gyrus activation.
        Excessive childhood behavioral inhibition is a risk factor for the development of anxiety and affective disorders in human infants and children. Kalin et al. (pages 1134–1139) report that lesions of the orbitofrontal cortex (OFC) in infant Rhesus monkeys decreased their threat-induced freezing behavior. These data implicate the OFC in some forms of childhood behavioral inhibition.
        A protein, the acid sensing ion channel-1a (ASIC1a), has been implicated in fear responses in animal studies. Coryell et al. (pages 1140–1148) found that mice that had this gene inactivated (ASIC1a−/− mice) expressed reduced fear, decreased acoustic startle, and inhibited fear response to predators. Acute ASIC1a inhibition had similar effects, indicating that ASIC1a modulates activity in the circuits underlying innate fear.

        Venlafaxine ER: An Effective Treatment for Social Phobia

        In children and adolescents with generalized social phobia, March et al. (pages 1149–1154) compared venlafaxine ER with placebo over 16 weeks of treatment in a randomized, controlled trial. Venlafaxine ER proved more effective than placebo, while being associated with more adverse events. Three subjects treated with venlafaxine ER experienced a suicidal event in contrast to none of the placebo-treated subjects.

        Fear-potentiated Startle Elevated in Smokers

        Grillon et al. (pages 1155–1161) report that in smokers, pre-pulse inhibition (PPI), a process that normally inhibits startle, functions normally. However, fear-potentiated startle was elevated, especially during withdrawal from nicotine. These data suggest that nicotine withdrawal may enhance physiologic reactivity to fear-inducing stimuli.

        D-cycloserine Effects Lost with Antidepressant Treatment

        D-cycloserine (DCS) has been shown to facilitate the loss of fear in both pre-clinical and clinical studies. Werner-Seidler and Richardson et al. (pages 1195–1197) now demonstrate that DCS does not facilitate the loss of fear in animals chronically exposed to an antidepressant. With the high degree of co-morbidity between anxiety and depression, this finding suggests that clinical trials of the efficacy of DCS as a pharmacological adjunct to exposure-based therapies should monitor concurrent antidepressant use among participants.

        Impact of Social Isolation

        Grippo et al. (pages 1162–1170) investigated the effects of isolation in prairie voles, a rodent species with social behaviors similar to humans. Isolation produced anxiety- and depression-like behaviors and it also raised resting heart rate and reduced heart rate variability, physiologic features of mood and anxiety disorders. This pattern of physiologic dysregulation also may have long-term implications for cardiac disease.