Erythropoietin reduces neural and cognitive processing of fear in human models of antidepressant drug action.

BACKGROUND: Erythropoietin (Epo) has neuroprotective and neurotrophic effects in animal models and affects cognitive and associated neural responses in humans. These effects have highlighted Epo as a candidate for treatment of psychiatric disease including schizophrenia and depression. The current study aimed to explore the effects of Epo on neural and behavioral measures of emotional processing relevant for depression and the effects of conventional antidepressant medication. METHODS: In the present study, we used functional magnetic resonance imaging to explore the effects of Epo (40,000 IU) versus saline on the neural processing of happy and fearful faces in 23 healthy volunteers. Facial expression recognition was assessed outside the scanner. RESULTS: One week after administration, Epo reduced neural response to fearful versus neutral faces in the occipito-parietal cortex consistent with reduced attention to fear. Erythropoietin additionally reduced recognition of fearful facial expressions without affecting recognition of other emotional expressions. These actions occurred in the absence of changes in hematological parameters. CONCLUSIONS: The present study demonstrates that Epo directly modulates brain responses to emotional information in humans in a manner consistent with the actions of conventional antidepressants. The characterization of the effects of Epo in a clinically depressed group is therefore warranted.     

Task instructions modulate neural responses to fearful facial expressions.

BACKGROUND: The amygdala, hippocampus, ventral, and dorsal prefrontal cortices have been demonstrated to be involved in the response to fearful facial expressions. Little is known, however, about the effect of task instructions upon the intensity of responses within these regions to fear-inducing stimuli. METHODS: Using functional magnetic resonance imaging, we examined neural responses to alternating, 30-sec blocks of fearful and neutral expressions in nine right-handed male volunteers during three different 5-min conditions: 1) passive viewing; 2) performance of a gender-decision task, with no explicit judgment of facial emotion; 3) performance of an emotionality judgment task - an explicitly emotional task. RESULTS: There was a significant effect of task upon activation within the left hippocampus and the left inferior occipital gyrus, and upon the magnitude of response within the left hippocampus, with maximal activation in these regions occurring during passive viewing, and minimal during performance of the explicit task. Performance of the gender-decision and explicit tasks, but not passive viewing, was also associated with activation within ventral frontal cortex. CONCLUSIONS: Neural responses to fearful facial expressions are modulated by task instructions.     

Anxiety and the neural processing of threat in faces

This study examined the relationship between social anxiety and the neural processing of threat in faces. Twenty-one adults with different levels of society anxiety were tested for their event-related potential responses to unattended threatening and nonthreatening faces, presented upright and upside-down, at three points in time: 160-210 ms (vertex positive potential), 300-350 ms (N3) and 440-500 ms (P3). Social anxiety was significantly correlated with the size of P3 to upright angry faces but not happy faces. This supports the theory that anxiety diverts attention towards goal-irrelevant threat cues, and suggests that this threat-related shift in attention starts to affect the processing of faces at 440-500 ms.     

Gender differences in the neural correlates of humor processing: implications for different processing modes

Humor is a complex phenomenon of human social cognition with large inter-individual variability. Gender differences in emotion processing are a common finding in functional neuroimaging studies, and have been documented in behavioral studies of humor, but have received limited attention in functional neuroimaging studies on humor. Using blood oxygenation level dependent (BOLD) contrasts with high-field (3T) functional magnetic resonance imaging (fMR) we investigated 29 healthy subjects (14 female, 15 male) during the processing of humorous cartoons. In women, the ventral system implicated ín detection and appraisal of emotion was activated, including amygdala, insula, and Anterior Cingulate Cortex (ACC). Men showed activation in both the ventral and dorsal processing systems. The results indicate that women process humor though limbic reactivity, involving appraisal of its emotional features, while men apply more evaluative, executive resources to humor processing.     

Effects of D-cycloserine on extinction: translation from preclinical to clinical work.

Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment.     

Early life adversity during the infant sensitive period for attachment: Programming of behavioral neurobiology of threat processing and social behavior

Animals, including humans, require a highly coordinated and flexible system of social behavior and threat evaluation. However, trauma can disrupt this system, with the amygdala implicated as a mediator of these impairments in behavior. Recent evidence has further highlighted the context of infant trauma as a critical variable in determining its immediate and enduring consequences, with trauma experienced from an attachment figure, such as occurs in cases of caregiver-child maltreatment, as particularly detrimental. This review focuses on the unique role of caregiver presence during early-life trauma in programming deficits in social behavior and threat processing. Using data primarily from rodent models, we describe the interaction between trauma and attachment during a sensitive period in early life, which highlights the role of the caregiver’s presence in engagement of attachment brain circuitry and suppressing threat processing by the amygdala. These data suggest that trauma experienced directly from an abusive caregiver and trauma experienced in the presence of caregiver cues produce similar neurobehavioral deficits, which are unique from those resulting from trauma alone. We go on to integrate this information into social experience throughout the lifespan, including consequences for complex scenarios, such as dominance hierarchy formation and maintenance.     

Social cues, mentalizing and the neural processing of speech accompanied by gestures

Body orientation and eye gaze influence how information is conveyed during face-to-face communication. However, the neural pathways underpinning the comprehension of social cues in everyday interaction are not known. In this study we investigated the influence of addressing vs. non-addressing body orientation on the neural processing of speech accompanied by gestures.While in an fMRI scanner, participants viewed short video clips of an actor speaking sentences with object- (O; e.g., shape) or person-related content (P; e.g., saying goodbye) accompanied by iconic (e.g., circle) or emblematic gestures (e.g., waving), respectively. The actor's body was oriented either toward the participant (frontal, F) or toward a third person (lateral, L) not visible.For frontal vs. lateral actor orientation (F > L), we observed activation of bilateral occipital, inferior frontal, medial frontal, right anterior temporal and left parietal brain regions. Additionally, we observed activity in the occipital and anterior temporal lobes due to an interaction effect between actor orientation and content of the communication (PF > PL) > (OF > OL).Our findings indicate that social cues influence the neural processing of speech-gesture utterances. Mentalizing (the process of inferring the mental state of another individual) could be responsible for these effects. In particular, socially relevant cues seem to activate regions of the anterior temporal lobes if abstract person-related content is communicated by speech and gesture. These new findings illustrate the complexity of interpersonal communication, as our data demonstrate that multisensory information pathways interact at both perceptual and semantic levels.     

Persistent disruption of a traumatic memory by postretrieval inactivation of glucocorticoid receptors in the amygdala.

BACKGROUND: Posttraumatic stress disorder (PTSD) is characterized by acute and chronic changes in the stress response, which include alterations in glucocorticoid secretion and critically involve the limbic system, in particular the amygdala. Important symptoms of PTSD manifest as a classical conditioning to fear, which recurs each time trauma-related cues remind the subject of the original insult. Traumatic memories based on fear conditioning can be disrupted if interfering events or pharmacological interventions are applied following their retrieval. METHODS AND RESULTS: Using an animal model, here we show that a traumatic memory is persistently disrupted if immediately after its retrieval glucocorticoid receptors are inactivated in the amygdala. The disruption of the memory is long lasting and memory retention does not re-emerge following strong reminders of the conditioned fear. CONCLUSIONS: We propose that a combinatorial approach of psychological and pharmacological intervention targeting the glucocorticoid system following memory retrieval may represent a novel direction for the treatment of PTSD.     

The Sustained Antidepressant Effects of Ketamine Are Independent of the Lateral Habenula

Ketamine is known to have a rapid and lasting antidepressant effect. Recent studies have shown that ketamine exerts it rapid antidepressant effect by blocking burst firing in the lateral habenula (LHb). Whether the sustained antidepressant effect of ketamine occurs through the same mechanism has not been explored. Here, using male rats, we found that local infusion of (R,S)-ketamine into the LHb resulted in a rapid antidepressant-like effect 1 h after infusion, which almost returned to baseline levels after 24 h. Intra-LHb injection of (S)-ketamine also showed a significant antidepressant-like effect 1 h after injection, which recovered at 24 h. No significant antidepressant-like effect was found at 1 or 24 h after the administration of (R)-ketamine into the LHb. Injection of (2R,6R)-hydroxynorketamine, a ketamine metabolite, into the LHb did not result in any obvious antidepressant-like effect 1 or 24 h after injection. Systemic administration of (R,S)-ketamine (intraperitoneally) significantly suppressed LHb bursting activity at 1 h, but the inhibitory effect was reversed 24 h after injection. No significant effect of (R,S)-ketamine on miniature excitatory postsynaptic potentials of LHb neurons was found at 1 or 24 h after systemic application. Our study demonstrated that the sustained antidepressant-like effect of ketamine may not depend on burst firing of LHb neurons.SIGNIFICANCE STATEMENT Ketamine exerts it rapid antidepressant effect by blocking burst firing in the lateral habenula (LHb). However, whether the sustained antidepressant effect of ketamine occurs through the same mechanism has not been explored. In the present study, we demonstrated that the sustained antidepressant effect of ketamine may not depend on the burst firing of LHb neurons. This finding may lead to a novel perspective on LHb in the antidepressant effect of ketamine.     

Mapping the time course of nonconscious and conscious perception of fear: an integration of central and peripheral measures

Neuroimaging studies using backward masking suggest that conscious and nonconscious responses to complex signals of fear (facial expressions) occur via parallel cortical and subcortical circuits. Little is known, however, about the temporal differentiation of these responses. Psychophysics procedures were first used to determine objective thresholds for both nonconscious detection (face vs. blank screen) and discrimination (fear vs. neutral face) in a backward masking paradigm. Event-related potentials (ERPs) were then recorded (n = 20) using these thresholds. Ten blocks of masked fear and neutral faces were presented under each threshold condition. Simultaneously recorded skin conductance responses (SCRs) provided an independent index of stimulus perception. It was found that Fear stimuli evoked faster SCR rise times than did neutral stimuli across all conditions, indicating that emotional content influenced responses, regardless of awareness. In the first 400 msec of processing, ERPs dissociated the time course of conscious (enhanced N4 component) from nonconscious (enhanced N2 component) perception of fear, relative to neutral. Nonconscious detection of fear also elicited relatively faster P1 responses within 100 msec post-stimulus. The N2 may provide a temporal correlate of the initial sensory processing of salient facial configurations, which is enhanced when top-down cortical feedback is precluded. By contrast, the N4 may index the conscious integration of emotion stimuli in working memory, subserved by greater cortical engagement. Hum. Brain Mapping 21:64-74, 2004.     

Risk–benefit analysis of antidepressant drug treatment in the elderly

Depression in the elderly is a significant health issue that has the potential to seriously affect physical and emotional well‐being. Therefore, the treatment of geriatric depression is necessary. Antidepressant treatment in older depressed patients is efficacious, but differences in the effectiveness of different classes of antidepressants have not been demonstrated. However, differences in tolerability profile are most recognizable in the elderly. With ageing, a series of changes occur in the elderly that modify both the pharmacokinetics and pharmacodynamics of antidepressants and may influence the efficacy, tolerability and safety of treatment in the elderly. Comorbidities require the use of other drugs, which increases the possibility of drug‐drug interactions. Given these aspects, individualized therapy for each elderly patient is needed to achieve acceptable risk–benefit ratio. Effective treatment of depression in the elderly, which may require combined pharmacological with psychosocial treatment, can decrease both morbidity and mortality; it also may lead to reduced demands on family members and on health‐care and social services.     

Antidepressant drug administration modifies the interactive relationship between alpha(2)-adrenergic sensitivity and levels of TNF in the rat brain

A reciprocally permissive interaction occurs between cellular responses elicited by the pleiotropic cytokine tumor necrosis factor-alpha (TNF) and alpha(2)-adrenergic receptor activation, such that each may adapt in response to modifications in the other's effects. Changes in presynaptic adrenergic sensitivity as well as neuronal sensitivity to TNF have been implicated in the mechanism of action of antidepressant drugs. The present study examines the influence of alpha(2)-adrenergic receptor activation on levels of TNF in regions of the brain associated with adrenergic function and the expression of mood. Additionally, the role of TNF as a neuromodulator is demonstrated by in vivo microinfusion of rrTNF proximal to the hippocampus. Administration to rats of an alpha(2)-adrenergic receptor agonist (clonidine) decreases levels of TNF in homogenates of rat locus coeruleus and hippocampus within 7.5 min. Chronic (14 days) administration of the antidepressant drugs desipramine or zimelidine transforms alpha(2)-adrenergic receptor-dependent decreases in TNF levels to increases in levels of TNF in the locus coeruleus. This transformation to an increase in total levels of TNF also occurs, although transiently, in the hippocampus following acute (1 day) antidepressant drug administration. The effect of TNF on presynaptic alpha(2)-adrenergic sensitivity was also investigated. Field stimulation of hippocampal slices from rats microinfused with rrTNF proximal to the hippocampus for 14 days demonstrates a decrease in fractional release of [3H]NE and an increase in alpha(2)-adrenergic autoreceptor sensitivity. These data demonstrate a mutual dependence between alpha(2)-adrenergic receptor activation and levels of TNF in the central nervous system that would culminate in an increase in neurotransmitter release following antidepressant drug administration.     

TMT-induced autonomic and behavioral changes and the neural basis of its processing

One of the main interests in the field of neuroscience is the investigation of the neural basis of fear. During recent years, an increasing number of studies have used trimethylthiazoline (TMT), a component of red fox feces, as a stimulus to induce fear in predator naive rats, mice, and voles. The aim of the present review is to summarize these studies. We present an overview to the autonomic and behavioral changes that are induced by TMT exposure. Then, we summarize the small number of studies that have examined the neural processing of the TMT stimulus. Finally, we compare these studies with those using a natural predator or predator odor to induce fear and discuss the possible use of TMT exposure in rodents as an animal model of unconditioned fear in humans.