Failure of extinction of fear responses in posttraumatic stress disorder: evidence from second-order conditioning

OBJECTIVES: Posttraumatic stress disorder (PTSD) is characterized by the re-experiencing of a traumatic event, although the trauma itself occurred in the past. The extinction of the traumatic response might be impeded if trauma reminders maintain fear responses by their association with the original trauma through second-order conditioning. METHOD: A differential conditioning paradigm with a trauma-specific picture, used as an acquired unconditioned stimulus, and graphic representations, used as conditioned stimuli, were employed in 14 PTSD patients, 15 trauma-exposed subjects without PTSD, and 15 healthy comparison subjects. The authors used event-related potentials of electroencephalogram (EEG), self-report measures, skin conductance responses, heart rate, and startle modulation to assess the differential conditioned response among subjects. RESULTS: Trauma-exposed subjects with and without PTSD but not healthy comparison subjects showed successful differential conditioning to the trauma-relevant cue indicative of second-order conditioning. Only PTSD patients exhibited enhanced conditioned responses to the trauma reminder during acquisition and impaired extinction as evident in more negative evaluations of the conditioned stimuli associated with a trauma reminder as well as enhanced peripheral and brain responses. CONCLUSIONS: These findings suggest that PTSD may be maintained by second-order conditioning where trauma-relevant cues come to serve as unconditioned stimuli, thus generalizing enhanced emotional responses to many previously neutral cues and impeding extinction. The extinction deficit in PTSD patients observed in this study underlines the need for therapies focusing on the extinction of learned responses, such as behavioral treatment, with or without the addition of pharmacological substances that enhance the extinction of a learned response.     

Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals

Posttraumatic stress disorder (PTSD) patients with histories of cocaine and alcohol abuse (CA-PTSD) were compared with normal volunteers. Positron emission tomography (PET) scans with 15O-butanol were used to compare regional cerebral blood flow (rCBF) between the groups during rest and during an auditory continuous performance task (ACPT). CA-PTSD patients had significantly higher rCBF in right amygdala and left parahippocampal gyrus than normals during the ACPT. Normals had higher rCBF at frontal cortex during the resting scan and during the ACPT. The role of the amygdala in attention and fear conditioning suggests that increased amygdala rCBF may be related to clinical features of PTSD. Cocaine use may be associated with increased amygdala rCBF in PTSD patients. Amygdala and frontal cortex attention system components may be reciprocally related and their relative contributions to processing of neutral stimuli perturbed in CA-PTSD.     

Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder

Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala–calcarine (P=0.01) and amygdala–thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala–ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.     

Learning fears by observing others: the neural systems of social fear transmission

Classical fear conditioning has been used as a model paradigm to explain fear learning across species. In this paradigm, the amygdala is known to play a critical role. However, classical fear conditioning requires first-hand experience with an aversive event, which may not be how most fears are acquired in humans. It remains to be determined whether the conditioning model can be extended to indirect forms of learning more common in humans. Here we show that fear acquired indirectly through social observation, with no personal experience of the aversive event, engages similar neural mechanisms as fear conditioning. The amygdala was recruited both when subjects observed someone else being submitted to an aversive event, knowing that the same treatment awaited themselves, and when subjects were subsequently placed in an analogous situation. These findings confirm the central role of the amygdala in the acquisition and expression of observational fear learning, and validate the extension of cross-species models of fear conditioning to learning in a human sociocultural context. Our findings also provides new insights into the relationship between learning from, and empathizing with, fearful others. This study suggests that indirectly attained fears may be as powerful as fears originating from direct experiences.     

Neural substrates of emotionally valenced episodic memory: A PET study using film stimuli

Abstract  To reveal the pathogenetic mechanism of post-traumatic stress disorder (PTSD), we modeled the 're-experience' symptom of PTSD in healthy subjects, and investigated its neural substrates using PET activation experiments on an emotionally (fear) valenced episodic memory task and several contrast tasks. Ten right-handed healthy male volunteers underwent H₂¹⁵O-PET. Each subject was required to watch a horror film the previous day. During the PET scan, the subject was shown part of the film for 60 s immediately before the terrifying climax scene and told to recall the following scene. The subject did not watch the scene directly, but re-experienced fear induced by the trigger. The rCBF in this task compared with that in control tasks was analyzed with SPM99. The subjective emotional state of the subject in each task was evaluated using an analog scale. The main cerebral areas where rCBF significantly correlated with the task of emotionally valenced episodic memory, compared with the novel emotional task, were the left retrosplenial cortex (Brodmann's area: BA 31), the left visual association cortex (BA 19) and the right prefrontal cortex (BA 10). Although the retrosplenial cortex or the posterior cingulate gyrus has been regarded as engaged in processing either only emotion or only episodic memory, this area is considered to be involved in processing 'emotionally valenced episodic memory'.     

Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: an fMRI study

Biological models of posttraumatic stress disorder (PTSD) suggest that patients will display heightened amygdala but decreased medial prefrontal activity during processing of fear stimuli. However, a rapid and automatic alerting mechanism for responding to nonconscious signals of fear suggests that PTSD may display heightened rather than decreased MPFC under nonconscious processing of fear stimuli. This study used functional magnetic resonance imaging to examine blood oxygenation level-dependent signal changes during nonconscious presentation (16.7 ms, masked) of fearful and neutral faces in 15 participants with PTSD and 15 age and sex-matched healthy control participants. Results indicate that PTSD participants display increased amygdala and MPFC activity during nonconscious processing of fearful faces. These data extend existing models by suggesting that the impaired MPFC activation in PTSD may be limited to conscious fear processing. Hum Brain Mapp, 2008. (c) 2007 Wiley-Liss, Inc.     

Latent class growth analyses reveal overrepresentation of dysfunctional fear conditioning trajectories in patients with anxiety-related disorders compared to controls

Recent meta-analyses indicated differences in fear acquisition and extinction between patients with anxiety-related disorders and comparison subjects. However, these effects are small and may hold for only a subsample of patients. To investigate individual trajectories in fear acquisition and extinction across patients with anxiety-related disorders (N = 104; before treatment) and comparison subjects (N = 93), data from a previous study (Duits et al., 2017) were re-analyzed using data-driven latent class growth analyses. In this explorative study, subjective fear ratings, shock expectancy ratings and startle responses were used as outcome measures. Fear and expectancy ratings, but not startle data, yielded distinct fear conditioning trajectories across participants. Patients were, compared to controls, overrepresented in two distinct dysfunctional fear conditioning trajectories: impaired safety learning and poor fear extinction to danger cues. The profiling of individual patterns allowed to determine that whereas a subset of patients showed trajectories of dysfunctional fear conditioning, a significant proportion of patients (≥50 %) did not. The strength of trajectory analyses as opposed to group analyses is that it allows the identification of individuals with dysfunctional fear conditioning. Results suggested that dysfunctional fear learning may also be associated with poor treatment outcome, but further research in larger samples is needed to address this question.     

Effects of repeated anodal transcranial direct current stimulation on auditory fear extinction in C57BL/6J mice

BackgroundTrauma-based psychotherapy is a first line treatment for post-traumatic stress disorder (PTSD) but not all patients achieve long-term remission. Transcranial direct current stimulation (tDCS) received considerable attention as a neuromodulation method that may improve trauma-based psychotherapy.ObjectiveWe explored the effects of repeated anodal tDCS over the prefrontal cortex (PFC) on fear extinction in mice as a preclinical model for trauma-based psychotherapy.MethodsWe performed auditory fear conditioning with moderate or high shock intensity on C57BL6/J mice. Next, mice received anodal tDCS (0.2 mA, 20 min) or sham stimulation over the PFC twice daily for five consecutive days. Extinction training was performed by repeatedly exposing mice to the auditory cue the day after the last stimulation session. Early and late retention of extinction were evaluated one day and three weeks after extinction training respectively.ResultsWe observed no significant effect of tDCS on the acquisition or retention of fear extinction in mice subjected to fear conditioning with moderate intensity. However, when the intensity of fear conditioning was high, tDCS significantly lowered freezing during the acquisition of extinction, regardless of the extinction protocol. Moreover, when tDCS was combined with a strong extinction protocol, we also observed a significant improvement of early extinction recall. Finally, we found that tDCS reduced generalized fear induced by contextual cues when the intensity of conditioning is high and extinction training limited.ConclusionsOur data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD.     

Fear conditioning in adolescents with anxiety disorders: results from a novel experimental paradigm

OBJECTIVE: Considerable research examines fear conditioning in adult anxiety disorders but few studies examine youths. Adult data suggest that anxiety disorders involve elevated fear but intact differential conditioning. We used a novel paradigm to assess fear conditioning in pediatric anxiety patients. METHOD: Sixteen individuals with anxiety disorders and 38 healthy comparisons viewed two photographs of actresses displaying neutral expressions. One picture served as the conditioned stimulus (CS), paired with a fearful expression and a shrieking scream (CS+), whereas the other picture served as a CS unpaired with the aversive outcome (CS-). Conditioning was indexed by self-reported fear. Subjects participated in two visits involving conditioning and extinction trials. RESULTS: Both groups developed greater fear of the CS+ relative to CS-. Higher fear levels collapsed across each CS characterized anxious relative to healthy subjects, but no significant interaction between group and stimulus type emerged. Fear levels at visit 1 predicted avoidance of visit 2. Fear levels to both CS types showed stability even after extinction. CONCLUSIONS: Consistent with adult data, pediatric anxiety involves higher fear levels following conditioning but not greater differential conditioning. Extending these methods to neuroimaging studies may elucidate neural correlates of fear conditioning. Implications for exposure therapies are discussed.     

Retrieval and emotional processing of traumatic memories in posttraumatic stress disorder: peripheral and central correlates

Posttraumatic stress disorder (PTSD) is thought to be characterized by dysfunctional memory processes, i.e., the automatic re-experiencing of the traumatic event and the inability to consciously recall facts about the traumatic event, as well as altered emotional processing of trauma-relevant cues. The present study examined the cerebral mechanisms underlying the cued recall of trauma-specific memories and the emotional processing of the presented cues in 16 PTSD patients, 15 trauma-exposed subjects without PTSD and 16 healthy controls. Subjects received questions about their specific trauma as well as other disastrous and neutral events while the electroencephalogram and heart rate were measured. The PTSD patients showed no impairment in trauma-specific declarative memory compared to non-PTSD subjects but had some deficits in general declarative memory as assessed by the Wechsler Memory Scale-Revised. Compared to healthy control subjects, PTSD patients displayed increased P300 and late positive complex amplitudes to trauma-specific questions, indicating enhanced emotional processing of these cues. In line with their behavioral performance, both trauma-exposed groups showed decreased terminal contingent negative variation amplitudes to trauma-specific questions over frontal electrodes reflecting altered memory retrieval. Within-group comparisons revealed that only the PTSD group but not the other groups showed a differentiation between trauma-specific and neutral questions with respect to the LPC, tCNV and P300. Concordantly with previous studies, PTSD patients showed elevated resting heart rate compared to the healthy controls. These findings are discussed in the context of current models of the role of declarative memory in the development and maintenance of PTSD.     

Using facial expressions as CSs and fearsome and disgusting pictures as UCSs: affective responding and evaluative learning of fear and disgust in blood-injection-injury phobia

Two experiments examine use of an evaluative conditioning (EC) paradigm in the acquisition of fear and disgust responding to neutral facial expressions. In Experiment 1, 60 participants were randomly assigned to one of three evaluative learning conditions in which neutral facial expressions were paired with fearsome, disgusting, or neutral pictures. No statistically significant differences were detected between the three conditions. However, significant differences emerged within subjects as post-exposure of fear and disgust ratings were higher among expressions that were paired with pictorial stimuli. Experiment 2 sought to examine if an analogue sample of BII phobics would be more susceptible than nonphobic controls to fear and disgust EC utilizing a similar experimental design, given the co-occurrence of fear and disgust in BII-phobic responding. Results failed to demonstrate an EC effect specific to the analogue phobic group, although both groups showed an evaluative shift toward disgust for those facial expressions paired with BII-relevant pictures. Consistent with previous findings, examination of picture rating data suggested that analogue BII phobics rated the BII pictures as significantly more disgusting than fearful. The role of EC processes and a priori expectancy biases in the associative learning of disgust in BII phobia is discussed.     

Neurofunctional correlates of posttraumatic stress disorder: a PET symptom provocation study

Summary Patients with combat-related posttraumatic stress disorder (PTSD) show altered cognitive and affective processing and symptomatic responding following exposure to trauma reminders. Previous symptom provocation studies using brain imaging have involved Vietnam veterans. In this study neural correlates were investigated in patients with PTSD resulting from trauma in more recent war zones. ¹⁵Oxygen water and positron emission tomography were used to measure regional cerebral blood flow (rCBF) in patients with war- and combat-related chronic PTSD during exposure to combat and neutral sounds. Self-reports and heart rate confirmed symptomatic responding during traumatic stimulation. The war-related condition, as compared to the neutral, increased rCBF in the right sensorimotor areas (Brodmann areas 4/6), extending into the primary sensory cortex (areas 1/2/3), and the cerebellar vermis. RCBF also increased in the right amygdala and in the periaqueductal gray matter adjacent to the pons. During provocation rCBF was lowered in the right retrosplenial cortex (areas 26/29/30 extending into area 23). Symptom provocation in PTSD promote sensorimotor, amygdaloid and midbrain activation. We conclude that perceptually induced symptom activation in PTSD is associated with an emotionally determined motor preparation and propose that subcortically initiated rather than cortically controlled memory mechanisms determine this pattern. Received: 14 November 2001 / Accepted: 1 March 2002     

Individual variation in the propensity to attribute incentive salience to an appetitive cue predicts the propensity to attribute motivational salience to an aversive cue

It has been proposed that animals that attribute high levels of incentive salience to reward-related cues may be especially vulnerable to addiction. Individual variation has also been observed in the motivational value attributed to aversive cues, which may confer vulnerability to anxiety disorders such as post-traumatic stress disorder (PTSD). There may be a core behavioral trait that contributes to individual variation in the motivational value assigned to predictive cues regardless of emotional valence. To test this hypothesis, we used a Pavlovian conditioned approach procedure to classify rats based on whether they learned to approach and interact with a cue predicting food reward (sign-trackers) or learned upon cue presentation to go to the location of impending food delivery (goal-trackers), and then examined Pavlovian fear conditioning in the same animals. It has recently been proposed that sign-trackers are more vulnerable to substance abuse because they attribute greater incentive motivational value to drug cues. Here we show that sign-trackers also have a tendency to be more fearful of discrete cues that predict footshock. In addition, we found that goal-trackers exhibited greater contextual fear when placed back into the original fear-conditioning context in the absence of temporally discrete cues. These results suggest that there may be a subset of individuals who tend to attribute high levels of motivational salience to predictive cues regardless of emotional valence, which may predispose them to a number of psychiatric comorbidities including PTSD and substance abuse. Other individuals use contexts to appropriately modify their reactions to such salient stimuli.     

Facial emotion recognition in schizophrenia: intensity effects and error pattern

OBJECTIVE: The authors used color photographs of emotional and neutral expressions to investigate recognition patterns of five universal emotions in schizophrenia. METHOD: Twenty-eight stable outpatients with schizophrenia (19 men and nine women) and 61 healthy subjects (29 men and 32 women) completed an emotion discrimination test that presented mild and extreme intensities of happy, sad, angry, fearful, disgusted, and neutral faces, balanced for gender and ethnicity. Analyses evaluated accuracy of identifying emotions as a function of intensity, diagnosis, and gender of poser and rater. RESULTS: Patients performed worse than comparison subjects on recognition of all emotions and neutral faces combined, including mild and extreme expressions. For specific emotions, patients performed worse on recognition of fearful, disgusted, and neutral expressions. For all emotions except disgust, recognition of extreme intensity was better than recognition of mild intensity. However, patients showed less benefit from increased intensity for all emotions combined, and the difference was most pronounced for fear. Thus, patients were more impaired than healthy comparison subjects in identifying high-intensity expressions, even though this was an easier task than identifying low-intensity expressions. In the comparison of patterns of errors, patients and healthy subjects differed only in misattributions of neutral expressions; patients overattributed disgusted expressions and underattributed happy expressions. CONCLUSIONS: Patients with schizophrenia were impaired in overall emotion recognition, particularly fear and disgust, and did not benefit from increased emotional intensity. Error patterns indicate that patients misidentified neutral cues as negatively valenced.     

Ventral medial prefrontal cortex and emotional perseveration: the memory for prior extinction training

Several years ago, we found that lesions of ventral medial prefrontal cortex (mPFCv) disrupted performance during the extinction component of a classical fear conditioning task without affecting acquisition performance. We called this emotional perseveration, hypothesizing that mPFCv may normally act to inhibit fear responses to a conditioned stimulus (CS) when the CS no longer signals danger. Subsequent studies have supported this hypothesis, showing that mPFCv is crucial for the memory of prior extinction training. The present study examined the effects of mPFCv lesions made after training. Such lesions resulted in reduced freezing to contextual stimuli and normal responding to the CS presented alone during a retention test. Rats were then subjected to extinction trials (CS without US) over multiple days. In contrast to pre-training lesions, post-training lesions had little effect on extinction rate. All rats were given additional training. Lesioned rats expressed greater fear reactions than controls, indicating that prior extinction was less effective in them. Lesioned rats also showed resistance to extinction during reextinction trials, confirming our earlier finding that lesions made before training weaken the effectiveness of extinction trials. These results suggest three conclusions. First, an intact mPFCv during acquisition may protect the animal from prolonged responding during extinction trials following brain insult. Second, changes in mPFCv may predispose subjects toward enhanced fear reactions that are difficult to extinguish when reexposed to fearful stimuli, due to a diminished capacity to benefit from the fear-reducing impact of prior extinction experience. Third, contextual cues processed by mPFCv may influence extinction performance.     

An antisense oligonucleotide reverses the footshock-induced expression of fos in the rat medial prefrontal cortex and the subsequent expression of conditioned fear-induced immobility.

The immediate-early genes, including c-fos, have been proposed to be involved in learning and memory. In this report, we examine stress-induced Fos-like immunoreactivity (Fos-li) in subregions of the prefrontal cortex during a conditioned fear paradigm. During the acquisition phase, the rats were conditioned to fear a formerly neutral tone by pairing the tone with a mild footshock. The rats were then tested for fearful behavior by reexposure to the tone without additional footshock. During acquisition, Fos-li was increased in the medial prefrontal cortex (infralimbic and prelimbic) but not the anterior cingulate and M1 motor cortex. However, during the extinction phase, no significant increase in Fos-li was observed in any region. These findings indicate that acquisition, but not extinction, of conditioned fear is associated with an increase in Fos-li in subregions of the medial prefrontal cortex. In other animals, an antisense oligonucleotide directed against the c-fos mRNA was injected into the infralimbic/prelimbic cortex 12 or 72 hr before the acquisition session. Antisense treatment given 12, but not 72, hr earlier suppressed Fos production without altering behavior during the acquisition session. Three days after the acquisition session, rats were tested for fearful behavior as before. The antisense oligonucleotide blockade of Fos production during acquisition was associated with a significantly less fearful response during the extinction session. These results support a role for Fos in the medial prefrontal cortex during the acquisition of aversive learning.     

Cortisol suppression by dexamethasone reduces exaggerated fear responses in posttraumatic stress disorder

PTSD symptoms are associated with heightened fear responses in laboratory fear conditioning paradigms. This study examined the effects of dexamethasone administration on hypothalamic-pituitary-adrenal (HPA) function and fear-potentiated startle (FPS) in trauma-exposed individuals with and without PTSD. We used an established fear discrimination procedure, in which one visual stimulus (CS+, danger cue) was paired with aversive airblasts to the throat (unconditioned stimulus, US), and another stimulus (CS-, safety cue) was presented without airblasts. In addition to FPS, the dexamethasone suppression test (DST) was performed. The study sample (N=100) was recruited from a highly traumatized civilian population in Atlanta, GA. Half of the subjects (n=54, 16 PTSD, 38 controls) underwent conditioning at baseline and the other half (n=46, 17 PTSD, 29 controls) after DST, in a cross-sectional design. We found a significant interaction effect of diagnostic group and dexamethasone treatment. Under baseline conditions, subjects with PTSD showed more than twice as much fear-potentiated startle to the danger cue compared to traumatized controls, F(1,53)=8.08, p=0.006. However, there was no group difference in subjects tested after dexamethasone suppression. Furthermore, there was a significant treatment effect in PTSD subjects but not in controls, with dexamethasone reducing fear-potentiated startle to the CS+, F(1,32)=4.00, p=0.05. There was also a positive correlation between PTSD subjects' FPS and cortisol levels, r=0.46, p=0.01. These results suggest that transient suppression of HPA function via dexamethasone suppression may reduce exaggerated fear in patients with PTSD.     

Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study

Recall of fear extinction, which is thought to aid in recovery from a psychologically traumatic event, is hypothesized to be deficient in post-traumatic stress disorder (PTSD), but this has not yet been demonstrated in the laboratory, nor has its origin been investigated. To address these two issues, 14 pairs of monozygotic twins discordant for combat exposure, in 7 of which the combat-exposed twin had PTSD, underwent a two-day fear conditioning and extinction procedure. On Day 1, subjects viewed colored light conditioned stimuli, some of which were paired with mild electric shock, followed by extinction of the conditioned responses. On Day 2, recall of Day 1 extinction learning (i.e., extinction retention) was assessed. Skin conductance response (SCR) was the dependent measure. There were no group differences during acquisition or extinction learning. However, a significant PTSD Diagnosis (in the exposed twin) x combat Exposure interaction emerged during extinction recall, with the PTSD combat veterans having larger SCRs than their own co-twins, and than the non-PTSD combat veterans and their co-twins. These results indicate that retention of extinction of conditioned fear is deficient in PTSD. Furthermore, they support the conclusion that this deficit is acquired as a result of combat trauma leading to PTSD, rather than being a predisposing factor to developing PTSD upon the stress of combat.     

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.     

Amygdala hyperfunction in phobic fear normalizes after exposure.

BACKGROUND: The amygdala is implicated as a key brain structure in fear processing. Studies exploring this process using the paradigm of fear conditioning have implicated the amygdala in fear acquisition and in generating behavioral fear responses. As such, fear extinction could be expected to induce a reduction in amygdala activity. However, exposure in specific phobia has never been shown persistently to reduce amygdala activity. METHODS: By means of event-related functional magnetic resonance imaging, responses to phobia-related, general threat, and neutral pictures were measured before and 2 weeks after an intensive exposure session in 20 subjects with specific phobia for spiders and compared with healthy control subjects. RESULTS: Phobic subjects showed increased amygdala activity at baseline. This hyperactivity was significantly reduced 2 weeks after exposure therapy. Furthermore, a significant reduction of hyperactivity in anterior cingulate cortex and insula was found postexposure. CONCLUSIONS: To our knowledge, this is the first study demonstrating the effect of exposure on the amygdala in specific phobia. Our findings suggest that exposure therapy can have an effect on subcortical structures.