'Negativity bias' in risk for depression and anxiety: brain-body fear circuitry correlates, 5-HTT-LPR and early life stress.

The INTEGRATE Model draws on the framework of 'integrative neuroscience' to bring together brain-body and behavioral concepts of emotion, thinking and feeling and their regulation. The key organizing principle is the drive to 'minimize danger and maximize reward' that determines what is significant to us at each point in time. Traits of 'negativity bias' reflect the tendency to perceive danger rather than reward related information, and this bias influences emotion, thinking and feeling processes. Here, we examined a self-report measure of Negativity Bias in relation to its impact on brain and body correlates of emotion processing. The contributions of the serotonin transporter (5-HTT-LPR) allelic variants and early life stress to both negativity bias and these correlates were also examined. Data were accessed in collaboration with the Brain Resource International Database (BRID) which provides standardized data across these domains of measurement. From an initial sample of 303 nonclinical subjects from the BRID, subjects scoring one standard deviation below (n=55) and above (n=47) the mean on the measure of negativity bias were identified as 'Negativity Bias' and 'Positivity Bias' groups for analysis, respectively. These subjects had been genotyped for 5-HTT-LPR Short allele versus LL homozygote status, and completed the early life stress scale, and recording of startle responses and heart rate for conscious and nonconscious fear conditions. A matched subset (n=39) of BRID subjects completed functional MRI with the same facial emotion tasks. The Negativity Bias (compared to Positivity Bias) group was distinguished by both arousal and brain function correlates: higher startle amplitude, higher heart rate for conscious and nonconscious fear conditions, and heightened activation in neural circuitry for both fear conditions. Regions of heightened activation included brainstem and bilateral amygdala, anterior cingulate and ventral and dorsal medial prefrontal cortex (mPFC) for conscious fear, and brainstem and right-sided amygdala, anterior cingulate and ventral, mPFC for nonconscious fear. The 5-HTT-LPR Short allele (versus LL) conferred a similar pattern of arousal and neural activation. For those with the 5-HTT-LPR Short allele, the addition of early life stress contributed to enhanced negativity bias, and to further effects on heart rate and neural activation for nonconscious fear in particular. These findings suggest that traits of negativity bias impact brain-body arousal correlates of fear circuitry. Both genetic variation and life stressors contribute to the impact of negativity bias. Given that negativity bias is a feature of conditions such as depression and associated biological alterations, the findings have implications for translation into clinical decision support.

The neural networks of inhibitory control in posttraumatic stress disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) involves deficits in information processing that may reflect hypervigilence and deficient inhibitory control. To date, however, no PTSD neuroimaging study has directly examined PTSD-related changes in executive inhibition. Our objective was to investigate the hypothesis that executive inhibitory control networks are compromised in PTSD. METHODS: Functional magnetic resonance imaging (fMRI) was used during a Go/No-Go inhibition task completed by a sample of patients with PTSD (n = 23), a matched sample of healthy (i.e. without trauma exposure) control participants (n = 23) and a sample of control participants with trauma exposure who did not meet criteria for PTSD (n = 17). RESULTS: Participants with PTSD showed more inhibition-related errors than did individuals without trauma exposure. During inhibition, control participants activated a right-lateralized cortical inhibitory network, whereas patients with PTSD activated only the left lateral frontal cortex. PTSD was associated with a reduction in right cortical activation and increased activation of striatal and somatosensory regions. CONCLUSION: The increased inhibitory error and reduced right frontal cortical activation are consistent with compromised inhibitory control in PTSD, while the increased activation of brain regions associated with sensory processing and a greater demand on inhibitory control may reflect enhanced stimulus processing in PTSD, which may undermine cortical control mechanisms.

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.

Fronto-limbic and autonomic disjunctions to negative emotion distinguish schizophrenia subtypes.

Schizophrenia patients show a disconnection in amygdala-medial prefrontal cortex and autonomic arousal systems for processing fear. Concurrent functional magnetic resonance imaging [fMRI] and skin conductance recording were used to determine whether these disturbances are specific to fear, or present in response to other signals of danger. We also examined whether these disturbances distinguish a specific symptom profile. During scanning, 27 schizophrenia (13 paranoid, 14 nonparanoid) and 22 matched healthy control subjects viewed standardized facial expressions of fear, anger and disgust (versus neutral). Skin conductance responses [SCRs]were acquired simultaneously to assess phasic increases in arousal. 'With-arousal' versus 'without-arousal' responses were analysed using non-parametric methods. For controls, 'with-arousal' responses were associated with emotion-specific activity for fear (amygdala), disgust (insula) and anger (anterior cingulate), together with common medial prefrontal cortex [MPFC] engagement, as predicted. Schizophrenia patients displayed abnormally increased phasic arousal, with concomitant reductions in emotion-specific regions and MPFC. These findings may reflect a general disconnection between central and autonomic systems for processing signals of danger. This disjunction was most apparent in patients with a profile of paranoia, coupled with poor social function and insight. Heightened autonomic sensitivity to signals of fear, threat or contamination, without effective neural mechanisms for appraisal, may underlie paranoid delusions which concern threat and contamination, and associated social and interpersonal difficulties.

The mellow years?: neural basis of improving emotional stability over age.

Contrary to the pervasive negative stereotypes of human aging, emotional functions may improve with advancing age. However, the brain mechanisms underlying changes in emotional function over age remain unknown. Here, we demonstrate that emotional stability improves linearly over seven decades (12-79 years) of the human lifespan. We used both functional magnetic resonance imaging and event-related potential recording to examine the neural basis of this improvement. With these multimodal techniques, we show that better stability is predicted by a shift toward greater medial prefrontal control over negative emotional input associated with increased activity later in the processing sequence (beyond 200 ms after stimulus) and less control over positive input, related to a decrease in early activity (within 150 ms). This shift was independent from gray matter loss, indexed by structural magnetic resonance data. We propose an integrative model in which accumulated life experience and the motivation for meaning over acquisition in older age contribute to plasticity of medial prefrontal systems, achieving a greater selective control over emotional functions.

Trauma modulates amygdala and medial prefrontal responses to consciously attended fear.

Effective fear processing relies on the amygdala and medial prefrontal cortex (MPFC). Post-trauma reactions provide a compelling model for examining how the heightened experience of fear impacts these systems. Post-traumatic stress disorder (PTSD) has been associated with excessive amygdala and a lack of MPFC activity in response to nonconscious facial signals of fear, but responses to consciously processed facial fear stimuli have not been examined. We used functional MRI to elucidate the effect of trauma reactions on amygdala-MPFC function during an overt fear perception task. Subjects with PTSD (n = 13) and matched non-traumatized healthy subjects (n = 13) viewed 15 blocks of eight fearful face stimuli alternating pseudorandomly with 15 blocks of neutral faces (stimulus duration 500 ms; ISI 767 ms). We used random effects analyses in SPM2 to examine within- and between-group differences in the MPFC and amygdala search regions of interest. Time series data were used to examine amygdala-MPFC associations and changes across the first (Early) versus second (Late) phases of the experiment. Relative to non-traumatized subjects, PTSD subjects showed a marked bilateral reduction in MPFC activity (in particular, right anterior cingulate cortex, ACC), which showed a different Early-Late pattern to non-traumatized subjects and was more pronounced with greater trauma impact and symptomatology. PTSD subjects also showed a small but significant enhancement in left amygdala activity, most apparent during the Late phase, but reduction in Early right amygdala response. Over the time course, trauma was related to a distinct pattern of ACC and amygdala connections. The findings suggest that major life trauma may disrupt the normal pattern of medial prefrontal and amygdala regulation.

Pathways for fear perception: modulation of amygdala activity by thalamo-cortical systems.

Effective perception of fear signals is crucial for human survival and the importance of the amygdala in this process is well documented. Animal, lesion and neuroimaging studies indicate that incoming sensory signals of fear travel from thalamus to amygdala via two neural pathways: a direct subcortical route and an indirect pathway via the sensory cortex. Other lines of research have demonstrated prefrontal modulation of the amygdala. However, no study to date has examined the prefrontal modulation of the thalamo-cortico-amygdala pathways in vivo. We used psychophysiological and physiophysiological interactions to examine the functional connectivity within thalamus, amygdala and sensory (inferior occipital, fusiform) cortices, and the modulation of these networks by the anterior cingulate cortex (ACC). Functional magnetic resonance imaging (fMRI) data were acquired for 28 healthy control subjects during a fear perception task, with neutral as the 'baseline' control condition. Main effect analysis, using a region of interest (ROI) approach, confirmed that these regions are part of a distributed neural system for fear perception. Psychophysiological interactions revealed an inverse functional connectivity between occipito-temporal visual regions and the left amygdala, but a positive connectivity between these visual region and the right amygdala, suggesting that there is a hemispheric specialization in the transfer of fear signals from sensory cortices to amygdala. Physiophysiological interactions revealed a dorsal-ventral division in ACC modulation of the thalamus-sensory cortex pathway. While the dorsal ACC showed a positive modulation of this pathway, the ventral ACC exhibited an inverse relationship. In addition, both the dorsal and ventral ACC showed an inverse interaction with the direct thalamus-amygdala pathway. These findings suggest that thalamo-amygdala and cortical regions are involved in a dynamic interplay, with functional differentiation in both lateralized and ventral/dorsal gradients. Breakdowns in these interactions may give rise to affect-related symptoms seen in a range of neuropsychiatric disorders.

BOLD, sweat and fears: fMRI and skin conductance distinguish facial fear signals.

It is not known how the brain and autonomic systems interact during perception of facial signals of danger. We recorded blood-oxygen-level-dependent (BOLD) activity using fMRI and simultaneous skin conductance measures of autonomic arousal in healthy subjects. Distinct response profiles were elicited for fear (enhanced arousal with amygdala activity), anger (rapid onset, slow recovery arousal responses with anterior cingulate) and disgust (delayed arousal responses with insula and basal ganglia activity). The findings suggest that fear, anger and disgust perception involves specific interactions in the neural arousal systems for emotion and motivation.

The dynamics of cortico-amygdala and autonomic activity over the experimental time course of fear perception.

Human neuroimaging studies implicate the amygdala, medial prefrontal and somatosensory-related cortices as key neural components in the perception of facial fear signals. Yet, their temporal sequence and interaction with autonomic arousal is not known. We used simultaneous functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) recording in 22 healthy subjects to examine central and autonomic responses to repeated fearful expressions. Phasic SCRs followed a U-shape pattern across early, middle and late presentations of fear stimuli. fMRI data revealed a concomitant temporal sequence of preferential somatosensory insula, dorsomedial prefrontal cortex and left amygdala engagement. These findings suggest that sustained cortico-amygdala and autonomic responses may serve to prime the emotional content of fear signals, and differentiate them from initial stimulus novelty.

Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia.

OBJECTIVE: The authors investigated impaired differentiation of limbic-prefrontal systems by autonomic arousal in schizophrenia. It was predicted that paranoid patients would be distinguished by a disjunction of hyperarousal but reduced amygdala and medial prefrontal activity relative to both healthy comparison subjects and patients with nonparanoid schizophrenia. METHOD: Pictures depicting facial expressions of fear were presented to 27 schizophrenia patients (13 paranoid, 14 nonparanoid) and 22 matched healthy comparison subjects in an implicit perception task to evoke limbic activity. Simultaneous functional magnetic resonance imaging and skin conductance arousal recordings were acquired during presentation of faces expressing fear or neutral emotion. Responses to fear stimuli were further examined by contrasting those that were associated with a skin conductance response ("with arousal") and those that were not ("without arousal"). RESULTS: In the comparison subjects, arousal dissociated amygdala/medial prefrontal ("visceral") networks and hippocampus/lateral prefrontal ("context") networks for fear perception. Excessive arousal responses were elicited in the schizophrenia subjects, but there was an associated reduction in amygdala/medial prefrontal activity. This disjunction was pronounced in paranoid patients relative to both healthy subjects and nonparanoid patients. Paranoid patients also showed a relatively greater prefrontal deficit for "without-arousal" responses. CONCLUSIONS: This is the first study to reveal a functional disconnection in autonomic and central systems for processing threat-related signals in patients with paranoid schizophrenia. Paranoid cognition may reflect an internally generated cycle of misattribution regarding incoming fear signals due to a breakdown in the regulation of these systems.