Prefrontal activity decline in women under a single dose of diazepam during rule-guided responses: an fMRI study.

Daily life events confront us with new situations demanding responses to usual and unusual rules. Diazepam (DZ), a clinically important drug, facilitates the inhibitory activity of the GABAergic system. Prefrontal cortex, rich in DZ receptors, coordinates necessary resources to direct actions according to rules. The balance between excitatory and inhibitory activity is critical to achieve optimal function of brain systems leading to complex functions. Major sex differences in the physiological mechanisms of the GABAergic system have been reported. However, the differential influence of DZ on men and women in neural activity during behavior directed by frontal lobes remains unexplored. The ability of healthy volunteers to select responses following usual/congruent and novel/incongruent rules, and brain correlates were measured with fMRI under the administration of DZ and a placebo. 10 mg of DZ was enough to decrease the performance in a different manner between men and women. While reaction times increased in both men and women, women committed more errors selecting responses than men under DZ. Men demonstrated increased activity, while women demonstrated decreased activity in frontal regions involved in response selection of rules. These findings could have important consequences in understanding the differential influences of DZ between the sexes in complex daily life situations. More importantly, this study emphasizes the importance of understanding the differential effects on men and women of drugs widely employed by society, thereby achieves better therapeutic results and avoids side effects that the present study revealed to be different between sexes.

Emotion regulation in bipolar disorder type I: an fMRI study.

BACKGROUND: Bipolar disorder type I (BD-I) is associated with emotion dysregulation. However, experimentally controlled studies of emotion regulation (ER), particularly those examining the brain correlates of the putative deficits, are scarce and their results inconsistent. METHOD: Nineteen euthymic BD-I patients and 17 healthy controls (HC) underwent functional magnetic resonance imaging while performing a visual ER 2 × 2 factorial task, with instruction (Look or Decrease) and valence (Negative or Neutral) as within-subject factors. Emotional ratings were collected after each picture presentation to assess regulation success. RESULTS: BD-I patients were successful at downregulating their emotions, although to a lesser degree than HC. Both groups engaged brain regions previously implicated in ER; however, unlike HC, patients engaged some of those regions, particularly the ventrolateral prefrontal cortex (VLPFC) in the Negative Look and Neutral Decrease conditions. Moreover, patients failed to show the reduced amygdala activation in the Negative Decrease condition observed in HC. CONCLUSION: Our findings suggest that BD-I patients are able to downregulate their emotions when instructed to do so. However, they also appear to engage their ER network, particularly the VLPFC, even when not required to do so. These findings may help explain their often-reported difficulty in regulating emotions in everyday life despite their attempts to do so.

Time course of the influence of musical expertise on the processing of vocal and musical sounds.

Previous functional magnetic resonance imaging (fMRI) studies have suggested that different cerebral regions preferentially process human voice and music. Yet, little is known on the temporal course of the brain processes that decode the category of sounds and how the expertise in one sound category can impact these processes. To address this question, we recorded the electroencephalogram (EEG) of 15 musicians and 18 non-musicians while they were listening to short musical excerpts (piano and violin) and vocal stimuli (speech and non-linguistic vocalizations). The task of the participants was to detect noise targets embedded within the stream of sounds. Event-related potentials revealed an early differentiation of sound category, within the first 100 ms after the onset of the sound, with mostly increased responses to musical sounds. Importantly, this effect was modulated by the musical background of participants, as musicians were more responsive to music sounds than non-musicians, consistent with the notion that musical training increases sensitivity to music. In late temporal windows, brain responses were enhanced in response to vocal stimuli, but musicians were still more responsive to music. These results shed new light on the temporal course of neural dynamics of auditory processing and reveal how it is impacted by the stimulus category and the expertise of participants.

Anterior cingulate cortical thickness is a stable predictor of recovery from post-traumatic stress disorder.

BACKGROUND: Decreased cortical thickness in frontal and temporal regions has been observed in individuals suffering from post-traumatic stress disorder (PTSD), compared to healthy controls and trauma-exposed participants without PTSD. In addition, individual differences, both functional and structural, in the anterior cingulate cortex (ACC) have been shown to predict symptom severity reduction. Although there is some evidence suggesting that activity in this region changes as a function of recovery, it remains unknown whether there are any structural correlates of recovery from PTSD. METHOD: Thirty participants suffering from moderate to severe PTSD underwent a magnetic resonance imaging (MRI) scan following an initial clinical assessment. A second assessment took place 6-9 months later. In addition, a subgroup of 25 participants completed a second MRI scan at that time. PTSD symptom severity changes over time were regressed against vertex-based cortical thickness. RESULTS: We found that cortical thickness in the right subgenual ACC (sgACC) predicted symptom improvement. Moreover, cortical thickness within this region of the ACC, measured 6-9 months later (n = 25), was also correlated with the same measure of symptom improvement. By contrast, no relationship was found between change in cortical thickness in this area and current PTSD symptom levels or degree of recovery. CONCLUSIONS: Our results suggest that sgACC thickness may be a stable marker of recovery potential in PTSD.

Behavioural and neural effects of diazepam on a rule-guided response selection task.

Diazepam (DZ), a clinically important drug, reduces alertness and can interfere with complex cognitive processes. The effect of DZ on the behavioural and neural correlates of rule-guided response selection has not been directly investigated. We studied DZ effects, compared to placebo (PL), on performance and brain responses, using fMRI, during rule implementation, when arbitrary stimulus-specific rules were involved. BOLD activity was measured in eighteen healthy volunteers during rule-guided response selection with DZ or PL administered in two counterbalanced sessions. A 10mg dose of DZ was sufficient to increase reaction times and to reduce accuracy in a rule-guided task but not in a motor task containing the same stimuli. With PL, implementing arbitrary rules activated right anterior cingulate/middle frontal gyri. Under DZ more brain areas were recruited during the task compared to PL, especially occipito-parietal cortices, as well as the left temporal lobe. For the congruent trials rules, more activity was observed in the right retrosplenial cortex when participants had taken DZ. These findings indicate that DZ might disrupt the neural activity necessary to implement novel rules, supporting the notion that DZ influence on behaviour goes beyond perceptual and motor processes that can potentially compromise complex cognitive functions.

Emotional face processing and flat affect in schizophrenia: functional and structural neural correlates.

BACKGROUND: There is a general consensus in the literature that schizophrenia causes difficulties with facial emotion perception and discrimination. Functional brain imaging studies have observed reduced limbic activity during facial emotion perception but few studies have examined the relation to flat affect severity. METHOD: A total of 26 people with schizophrenia and 26 healthy controls took part in this event-related functional magnetic resonance imaging study. Sad, happy and neutral faces were presented in a pseudo-random order and participants indicated the gender of the face presented. Manual segmentation of the amygdala was performed on a structural T1 image. RESULTS: Both the schizophrenia group and the healthy control group rated the emotional valence of facial expressions similarly. Both groups exhibited increased brain activity during the perception of emotional faces relative to neutral ones in multiple brain regions, including multiple prefrontal regions bilaterally, the right amygdala, right cingulate cortex and cuneus. Group comparisons, however, revealed increased activity in the healthy group in the anterior cingulate, right parahippocampal gyrus and multiple visual areas. In schizophrenia, the severity of flat affect correlated significantly with neural activity in several brain areas including the amygdala and parahippocampal region bilaterally. CONCLUSIONS: These results suggest that many of the brain regions involved in emotional face perception, including the amygdala, are equally recruited in both schizophrenia and controls, but flat affect can also moderate activity in some other brain regions, notably in the left amygdala and parahippocampal gyrus bilaterally. There were no significant group differences in the volume of the amygdala.

Influence of trait anxiety on brain activity during the acquisition and extinction of aversive conditioning.

BACKGROUND: We examined how individual differences in trait anxiety (TA) influence the neural responses associated with the acquisition and extinction of anticipatory anxiety elicited through a context conditioning paradigm, with particular focus on the amygdala and the subgenual anterior cingulate cortex (sgACC). METHOD: During two sessions of echo-planar functional magnetic resonance imaging (fMRI), 18 healthy volunteers completed a decision-making task with two randomly alternating 28-s to 32-s background screen colour blocks. One of the colours was associated with the presentation of an aversive noise (CTX+) and the other colour was 'safe' (CTX-). In the first session (Acquisition), 33% of CTX+ colour blocks were paired with noise and in the second session (Extinction) no noise was presented. RESULTS: The amygdala displayed an increased response to CTX+ compared to CTX- colour blocks during the Acquisition and Extinction sessions and the ACC displayed an increased response to CTX+ compared to CTX- colour blocks during Extinction only. In addition, a greater conditioned response (CTX+ minus CTX-) was observed in the ACC when comparing the Extinction and Acquisition sessions. Correlation analyses further showed that higher levels of TA were associated with a higher conditioned response in the amygdala during Extinction as well as a greater differential conditioned response (i.e. Extinction>Acquisition) in the ACC. CONCLUSIONS: Our results support the idea that individuals with high levels of anxiety-relevant traits and vulnerable to developing an anxiety disorder display a more resilient anxiety response during extinction that is characterized by hyper-responsivity in the amygdala.

Affective response to one's own moral violations.

Morality depends on a set of cultural rules that regulate interpersonal behaviour and provide a basis for social cohesion. The interpretation of moral transgressions and their affective consequences depends on whether the action is intentional or accidental, and whether one is the agent of or witness to the action. We used event-related functional magnetic resonance imaging (fMRI) to investigate whether the amygdala is involved in judging one's own moral violation of social norms. In this study, participants (n = 12) were asked to make evaluations regarding the degree of inappropriateness of social behaviours described in stories in which they themselves, or someone else, transgressed social norms either intentionally or accidentally. Consistent with our hypothesis, the amygdala was activated when participants considered stories narrating their own intentional transgression of social norms. This result suggests the amygdala is important for affective responsiveness to moral transgressions.

Activations related to "mirror" and "canonical" neurones in the human brain: an fMRI study.

In the macaque monkey ventral premotor cortex (F5), "canonical neurones" are active when the monkey observes an object and when the monkey grasps that object. In the same area, "mirror neurones" fire both when the monkey observes another monkey grasping an object and when the monkey grasps that object. We used event-related fMRI to investigate where in the human brain activation can be found that reflects both canonical and mirror neuronal activity. There was activation in the intraparietal and ventral limbs of the precentral sulcus when subjects observed objects and when they executed movements in response to the objects (canonical neurones). There was activation in the dorsal premotor cortex, the intraparietal cortex, the parietal operculum (SII), and the superior temporal sulcus when subjects observed gestures (mirror neurones). Finally, activations in the ventral premotor cortex and inferior frontal gyrus (area 44) were found when subjects imitated gestures and executed movements in response to objects. We suggest that in the human brain, the ventral limb of the precentral sulcus may form part of the area designated F5 in the macaque monkey. It is possible that area 44 forms an anterior part of F5, though anatomical studies suggest that it may be a transitional area between the premotor and prefrontal cortices.

Neural response to emotional faces with and without awareness: event-related fMRI in a parietal patient with visual extinction and spatial neglect.

This study examined whether differential neural responses are evoked by emotional stimuli with and without conscious perception, in a patient with visual neglect and extinction. Stimuli were briefly shown in either right, left, or both fields during event-related fMRI. On bilateral trials, either a fearful or neutral left face appeared with a right house, and it could either be extinguished from awareness or perceived. Seen faces in left visual field (LVF) activated primary visual cortex in the damaged right-hemisphere and bilateral fusiform gyri. Extinguished left faces increased activity in striate and extrastriate cortex, compared with right houses only. Critically, fearful faces activated the left amygdala and extrastriate cortex both when seen and when extinguished; as well as bilateral orbitofrontal and intact right superior parietal areas. Comparison of perceived versus extinguished faces revealed no difference in amygdala for fearful faces. Conscious perception increased activity in fusiform, parietal and prefrontal areas of the left-hemisphere, irrespective of emotional expression; while a differential emotional response to fearful faces occurring specifically with awareness was found in bilateral parietal, temporal, and frontal areas. These results demonstrate that amygdala and orbitofrontal cortex can be activated by emotional stimuli even without awareness after parietal damage; and that substantial unconscious residual processing can occur within spared brain areas well beyond visual cortex, despite neglect and extinction.

An fMRI study of intentional and unintentional (embarrassing) violations of social norms.

The aim of this investigation was to identify neural systems supporting the processing of intentional and unintentional transgressions of social norms. Using event-related fMRI, we addressed this question by comparing neural responses to stories describing normal behaviour, embarrassing situations or violations of social norms. Processing transgressions of social norms involved systems previously reported to play a role in representing the mental states of others, namely medial prefrontal and temporal regions. In addition, the processing of transgressions of social norms involved systems previously found to respond to aversive emotional expressions (in particular angry expressions); namely lateral orbitofrontal cortex (Brodmann area 47) and medial prefrontal cortex. The observed responses were similar for both intentional and unintentional social norm violations, albeit more pronounced for the intentional norm violations. These data suggest that social behavioural problems in patients with frontal lobe lesions or fronto-temporal dementia may be a consequence of dysfunction within the systems identified in light of their possible role in processing whether particular social behaviours are, or are not, appropriate.

Modulation of auditory neural responses by a visual context in human fear conditioning.

Responses to a stimulus signaling danger depend not only on the nature of that stimulus, but also on the context in which it is presented. A large body of work has been conducted in experimental animals investigating the neural correlates of contextual modulation of fear responses. However, much less is known about this process in humans. In this study we used functional MRI in a fear conditioning paradigm to explore this phenomenon. Responses to acoustic conditioned stimuli in auditory cortex were modulated by the presence of a visual context which signaled the likelihood of receiving an aversive unconditioned stimulus. Furthermore, the presence of the aversive visual context was associated with enhanced activity in parietal cortex, which may reflect an increase in attention to the presence of environmental threat stimuli.

Effects of attention and emotion on face processing in the human brain: an event-related fMRI study.

We used event-related fMRI to assess whether brain responses to fearful versus neutral faces are modulated by spatial attention. Subjects performed a demanding matching task for pairs of stimuli at prespecified locations, in the presence of task-irrelevant stimuli at other locations. Faces or houses unpredictably appeared at the relevant or irrelevant locations, while the faces had either fearful or neutral expressions. Activation of fusiform gyri by faces was strongly affected by attentional condition, but the left amygdala response to fearful faces was not. Right fusiform activity was greater for fearful than neutral faces, independently of the attention effect on this region. These results reveal differential influences on face processing from attention and emotion, with the amygdala response to threat-related expressions unaffected by a manipulation of attention that strongly modulates the fusiform response to faces.

Auditory processing across the sleep-wake cycle: simultaneous EEG and fMRI monitoring in humans.

We combined fMRI and EEG recording to study the neurophysiological responses associated with auditory stimulation across the sleep-wake cycle. We found that presentation of auditory stimuli produces bilateral activation in auditory cortex, thalamus, and caudate during both wakefulness and nonrapid eye movement (NREM) sleep. However, the left parietal and, bilaterally, the prefrontal and cingulate cortices and the thalamus were less activated during NREM sleep compared to wakefulness. These areas may play a role in the further processing of sensory information required to achieve conscious perception during wakefulness. Finally, during NREM sleep, the left amygdala and the left prefrontal cortex were more activated by stimuli having special affective significance than by neutral stimuli. These data suggests that the sleeping brain can process auditory stimuli and detect meaningful events.

Amygdala-hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging.

Previous functional neuroimaging studies have characterized brain systems mediating associative learning using classical delay conditioning paradigms. In the present study, we used event-related functional magnetic resonance imaging to characterize neuronal responses mediating aversive trace conditioning. During conditioning, neutral auditory tones were paired with an aversive sound [unconditioned stimulus (US)]. We compared neuronal responses evoked by conditioned (CS+) and nonconditioned (CS-) stimuli in which a 50% pairing of CS+ and the US enabled us to limit our analysis to responses evoked by the CS+ alone. Differential responses (CS+ vs CS-), related to conditioning, were observed in anterior cingulate and anterior insula, regions previously implicated in delay fear conditioning. Differential responses were also observed in the amygdala and hippocampus that were best characterized with a time x stimulus interaction, indicating rapid adaptation of CS+-specific responses in medial temporal lobe. These results are strikingly similar to those obtained with a previous delay conditioning experiment and are in accord with a preferential role for medial temporal lobe structures during the early phase of conditioning. However, an additional activation of anterior hippocampus in the present experiment supports a view that its role in trace conditioning is to maintain a memory trace between the offset of the CS+ and the delayed onset of the US to enable associative learning in trace conditioning.

Differential effects of amygdala lesions on early and late plastic components of auditory cortex spike trains during fear conditioning.

In auditory fear conditioning, pairing of a neutral acoustic conditioned stimulus (CS) with an aversive unconditioned stimulus (US) results in an enhancement of neural responses to the CS in the amygdala and auditory cortex. It is not clear, however, whether cortical plasticity governs neural changes in the amygdala or vice versa, or whether learning in these two structures is determined by independent processes. We examined this issue by recording single-cell activity in the auditory cortex (areas Te1, Te1v, and Te3) of freely behaving, amygdalectomized rats using a movable bundle of microwires. Amygdala damage did not affect short-latency (0-50 msec) tone responses, nor did it interfere with conditioning-induced increases of these onset responses. In contrast, lesions of the amygdala interfered with the development of late (500-1500 msec) conditioned tone responses that were not present before conditioning. Furthermore, whereas onset conditioned responses in the control group remained elevated after 30 extinction trials (presentation of CS alone), onset responses in lesioned animals returned to their preconditioning firing level after approximately 10 extinction trials. These results suggest that the amygdala enables the development of long-latency (US anticipatory) responses and prevents the extinction of short-latency onset responses to threatening stimuli. The findings further suggest that auditory cortex cells may participate differently in explicit and implicit memory networks.

Affective computing.

by Rosalind Picard, MIT Press, 1997. $27.50 (xii+292 pages) ISBN 0 262 16170 2.

Fear conditioning enhances different temporal components of tone-evoked spike trains in auditory cortex and lateral amygdala.

Single neurons were recorded in freely behaving rats during fear conditioning from areas of auditory cortex that project to the lateral nucleus of the amygdala (LA). The latency and rate of conditioning and extinction were analyzed, and the results were compared to previous recordings from LA itself. Auditory cortex neurons took more trials to learn, and they responded more slowly than LA neurons within trials. Short-latency plasticity in LA, therefore, reflects inputs from the auditory thalamus rather than the auditory cortex. Unlike LA cells, some auditory cortex cells showed late conditioned responses that seemed to anticipate the unconditioned stimulus, while others showed extinction-resistant memory storage. Thus, rapid conditioning of fear responses to potentially dangerous stimuli depends on plasticity in the amygdala, while cortical areas may be particularly involved in higher cognitive (mnemonic and attentional) processing of fear experiences.

Stimulus generalization of fear responses: effects of auditory cortex lesions in a computational model and in rats.

The conditioning of fear responses to a simple acoustic stimulus (pure tone) paired with footshock can be mediated by the transmission of auditory information to the lateral nucleus of the amygdala from either the auditory thalamus or the auditory cortex. We examined the processing capacity of the thalamo-amygdala pathway by making lesions of the auditory cortex and testing the extent to which conditioned fear responses generalized to tones other than the one paired with footshock. Two studies were performed, one in an anatomically constrained computational model of the fear conditioning network and the other in rats. Stimulus generalization was unaffected in both. These findings support the validity of the model as an approach to studying the neural basis of conditioned fear learning, and in addition suggest that the thalamo-amygdala pathway, possibly by the use of population coding, is capable of performing at least crude stimulus discriminations.