Greater amygdala activity and dorsomedial prefrontal–amygdala coupling are associated with enhanced inflammatory responses to stress

Psychological stress is implicated in the etiology of many common chronic diseases and mental health disorders. Recent research suggests that inflammation may be a key biological mediator linking stress and health. Nevertheless, the neurocognitive pathways underlying stress-related increases in inflammatory activity are largely unknown. The present study thus examined associations between neural and inflammatory responses to an acute laboratory-based social stressor. Healthy female participants (n = 31) were exposed to a brief episode of stress while they underwent an fMRI scan. Blood samples were taken before and after the stressor, and plasma was assayed for markers of inflammatory activity. Exposure to the stressor was associated with significant increases in feelings of social evaluation and rejection, and with increases in levels of inflammation. Analyses linking the neural and inflammatory data revealed that heightened neural activity in the amygdala in response to the stressor was associated with greater increases in inflammation. Functional connectivity analyses indicated that individuals who showed stronger coupling between the amygdala and the dorsomedial prefrontal cortex (DMPFC) also showed a heightened inflammatory response to the stressor. Interestingly, activity in a different set of neural regions was related to increases in feelings of social rejection. These data show that greater amygdala activity in response to a stressor, as well as tighter coupling between the amygdala and the DMPFC, are associated with greater increases in inflammatory activity. Results from this study begin to identify neural mechanisms that might link stress with increased risk for inflammation-related disorders such as cardiovascular disease and depression.     

Structural integrity of the limbic–prefrontal connection: Neuropathological correlates of anxiety in Williams syndrome

Williams syndrome (WS) is a genetic condition characterized by a hypersocial personality and desire to form close relationships, juxtaposed with significant anxieties of nonsocial events. The neural underpinnings of anxiety in individuals with WS are currently unknown. Aberrations in the anatomical and microstructural integrity of the uncinate fasciculus (UF) have been recently implicated in social and generalized anxiety disorders. Based on these findings, we tested the hypothesis that the reported anxieties in individuals with WS share similar neuropathological correlates. Toward this end, diffusion tensor imaging (DTI) methods were employed to examine the microstructural integrity (fractional anisotropy, mean diffusivity, longitudinal diffusivity) of the UF in 18 WS and 15 typically developing adults (TD). Anxiety and sociability questionnaires were administered to determine associations with DTI indices of UF across groups. Results revealed comparable white matter integrity of the UF across groups, yet elevated subjective experience of anxiety in those with WS. Additionally, sociability and UF microstructural properties were dissociated across both groups. Whereas no relationships were found between DTI indices and anxiety in TD participants, strong negative associations were observed between these constructs in individuals with WS. Findings indicated that increased anxiety manifested by individuals with WS was associated with DTI measures of the UF and may signal structural or possibly physiological aberration involving this tract within the prefrontal-temporal network.     

Synaptic plasticity from amygdala to perirhinal cortex: a possible mechanism for emotional enhancement of visual recognition memory?

Emotionally salient experiences are better remembered than events that have little emotional context. Several lines of evidence indicate that the amygdala plays an important role in this emotional enhancement of memory. Visual recognition memory relies on synaptic plasticity in the perirhinal cortex, but little is known about the mechanisms involved in emotional enhancement of this form of memory. The results of the present study, performed in rat brain slices, show for the first time that the amygdala input to the perirhinal cortex undergoes synaptic plasticity. Stimulation in the amygdala resulted in long-term potentiation (LTP) in perirhinal cortex that was dependent on β-adrenoceptors and L-type voltage-dependent calcium channels (L-VDCCs) but was NMDAR-independent. In contrast, intracortical perirhinal stimulation resulted in LTP that was NMDAR-dependent but β-adrenoceptor- and L-VDCC-independent. In addition, the present results provide the first evidence that stimulation of the amygdala can reduce the threshold for LTP in the perirhinal cortex. Interestingly, this associative form of LTP requires β-adrenoceptor activation but not NMDA or L-VDCC activation. Knowing the mechanisms that control amygdala-perirhinal cortex interactions will allow better understanding of how emotionally charged visual events are remembered, and may help to understand how memories can consolidate and become intrusive in anxiety-related disorders.     

SWI phase asymmetries in deep gray matter of healthy adults: is there an association with handedness?

To explore the handedness effects on phase asymmetries in deep gray matter of healthy adults by using magnetic susceptibility-weighted imaging (SWI) phase. Thirty left-handed (16 men, 14 women; age range, 20 to 57 years) and 30 age- and sex-matched right-handed (16 men, 14 women; age range, 20 to 58 years) healthy adults were examined at 3.0 T MRI. For each subject, phase values were detected in bilateral frontal white matters (FWM), caudate nucleus (CA), putamen (PU), globus pallidus (GP), thalamus (TH), red nucleus (RN) and substantia nigra (SN) on phase images. Statistical analysis was performed with paired-samples t-test and independent-samples t-test. In both handedness groups, the corrected phase values in the left hemisphere were significantly lower than those in the right one in FWM, CA, PU, GP (P?<?0.05) and there was no significant hemispheric asymmetry in TH, RN and SN (P?>?0.05). Differences in corrected phase values in corresponding brain regions of the same hemisphere between left-handed and right-handed groups were not statistically significant (P?>?0.05). Hemispheric asymmetry of SWI phase in deep gray matter may not associate with handedness in adult brain.     

Aversive memory reactivation: A possible role for delta oscillations in the hippocampus–amygdala circuit

Memory labilization, the process by which memories become susceptible to update, is essential for memory reconsolidation and has been a target for novel therapies for traumatic memory-associated disorders. Maternal separation (MS) in male rats produced memories resistant to labilization in adulthood. Based on previous results, we hypothesized that temporal desynchronization between the dorsal hippocampus (DHc) and the basolateral amygdala (BLA), during memory retrieval, could be responsible for this impairment. Our goal was to investigate possible differences in oscillatory activity and synchrony between the DHc and BLA during fear memory reactivation, between MS and non-handled (NH) rats. We used male adult Wistar rats, NH or MS, with electrodes for local field potential (LFP) recordings implanted in the DHc and BLA. Animals were submitted to aversive memory reactivation by exposure to the conditioned context (Reat) or to pseudo-reactivation in a neutral context (pReat), and LFP was recorded. Plasticity markers linked to reconsolidation were evaluated one hour after reactivation. The power of delta oscillations and DHc-BLA synchrony in Reat animals was increased, during freezing. Besides, delta modulation of gamma oscillations amplitude in the BLA was associated with the increase in DHc Zif268 levels, an immediate early gene specifically associated with reconsolidation. Concerning early life stress, we found lower power of delta and strength of delta-gamma oscillations coupling in MS rats, compared to NH, which could explain the low Zif268 levels in a subgroup of MS animals. These results suggest a role for delta oscillations in memory reactivation that should be further investigated.     

Patient–therapist convergence in alliance ratings as a predictor of outcome in psychotherapy for generalized anxiety disorder

Objective: Although patients and therapists aligning over time on their perceptions of alliance quality is regarded as clinically important, few studies have examined the influence of such dyadic convergence on psychotherapy outcomes. This study tested whether early treatment convergence in patient–therapist alliance ratings was associated with subsequent worry and distress reduction in psychotherapy for generalized anxiety disorder (GAD), and whether treatment type and the dyad members’ initial alliance perceptions moderated these associations. Method: Data derived from a randomized trial for which patients with severe GAD received either 15 sessions of standard cognitive-behavioral therapy (CBT; n?=?43) or CBT integrated with motivational interviewing (n?=?42). Patients and therapists rated the alliance after each session. Patients rated worry after each session, and their distress multiple times. Results: As predicted, dyadic multilevel modeling revealed that early alliance convergence was associated with greater subsequent worry (p?=?.03) and distress (p?=?.01) reduction, and the combination of low initial patient-rated alliance and low convergence was associated with the worst outcome for the distress variable (p?=?.04). Conclusions: Results suggest that alliance convergence may be an important clinical process that bears on outcome, rendering it an important marker for therapist responsiveness.     

Discrimination of striatopallidum and extended amygdala in the rat: a role for parvalbumin immunoreactive neurons?

Synaptic effects of parvalbumin-immunoreactive (-ir) interneurons (PVs) upon medium spiny neurons may be essential to neural processing in the striatum and, in effect, may serve as an additional feature distinguishing striatum from extended amygdala. The present immunohistochemical study in the rat was done to evaluate the distributions of PVs in the striatum and extended amygdala. Numerous PVs occupy all structures currently regarded as having a striatal composition, including the caudate-putamen, nucleus accumbens, and olfactory tubercle, as well as structures that receive outputs from these, including the globus pallidus, ventral pallidum, entopeduncular nucleus and substantia nigra reticulata. The morphologies of striatal PVs and their distribution were similar to what has been previously reported. In addition, we found that the density of larger neostriatal PVs with extensive and densely immunoreactive dendritic and local axonal arbors is greatest laterally, particularly in striatal districts with slight calbindin-ir, including the striatal patch compartment. In contrast to the situation in striatum, few PVs were observed in the central and medial divisions of the extended amygdala, including the bed nucleus of stria terminalis, interstitial nucleus of the posterior limb of the anterior commissure and central and medial nuclei of the amygdala, or in mesopontine, peribrachial and medullary structures that receive extended amygdala output. The paucity of PVs may be a characteristic feature distinguishing extended amygdala and its projection areas from striatopallidum, as well as the general character of neural processing that occurs in each.     

Preventing anxiety in the children of anxious parents – feasibility of a brief,online, group intervention for parents of one- to three-year-olds

Background

The evidence suggests an increased risk of developing anxiety problems in children of anxious parents. The current study explored the feasibility and acceptability of an intervention with anxious parents of young children, to inform the possibility of further trials.

Methods

Participants were recruited through primary and secondary care psychological services and social media. Participants who had a current or recent anxiety disorder and a child aged 12–47 months were included. Assessments of parental and child outcomes occurred at baseline, after the intervention (week-2) and follow-up (week-8). The intervention was delivered in a small group format, in two sessions, one week apart, using videoconferencing.

Results

Out of 32 participants, 30 (94%) attended the full intervention. All found the intervention acceptable and reported it as useful and relevant. There was a reduction in parental depression (MD = 2.63, 95%CI 1.01–4.26), anxiety (MD = 3.93, 95%CI 2.49–5.37) and stress (MD = 4.60, 95% CI 3.02–6.18) and increases in parenting confidence.

Conclusions

The online group intervention was feasible and acceptable. There were moderate to large effects on parental mental health and no adverse effects on children (decline on outcome measures). This indicates that intervening early in parenting with anxious parents is possible and warrants further investigation to establish prevention efficacy with a larger, controlled trial.     

Gene–environment interactions in common mental disorders: an update and strategy for a genome-wide search

A decade of research has demonstrated the explanatory potential of interplay between genetic variants and environmental factors in the development of common mental disorders. Initial findings have undergone tests of replicability and specificity. Some gene–environment interactions have been confirmed, some have not replicated and yet other turned out to be more specific than initially thought. Specific and complementary roles of genetic factors have been delineated: a common functional length polymorphism in the serotonin transporter gene (5-HTTLPR) moderated the effect of childhood maltreatment on chronic depression in adulthood, but did not substantially influence the effects of adult stressful life events on the onset of new depressive episodes; in contrast, a common functional polymorphism in the brain-derived neurotrophic factor gene (BDNF) moderated the effect of stressful life events in adulthood in triggering new depressive episodes, but did not influence the effects of childhood maltreatment. Molecular mechanisms underlying gene–environment interactions are being uncovered, including DNA methylation and other epigenetic modifications. New gene–environment interactions continue to be reported, still largely from hypothesis-driven research. Statistical and biological prioritization strategies are proposed to facilitate a systematic discovery of novel gene–environment interactions in genome-wide analyses.     

Clinical anxiety,cortisol and interleukin-6: Evidence for specificity in emotion–biology relationships

Anxiety confers increased risk for inflammatory diseases, and elevated inflammatory activity in anxious individuals may contribute to this increased risk. One complication, however, is that anxiety could be associated with inflammatory activity either through a specific anxiety pathway or through a more general negative emotionality pathway. To investigate, we measured levels of the stress hormone cortisol, the pro-inflammatory cytokine interleukin-6 (IL-6), and the systemic inflammatory marker C-reactive protein (CRP), as well as depression and neuroticism, in clinically anxious and non-anxious adults. Compared with non-anxious participants, clinically anxious participants exhibited significantly lower levels of morning cortisol and significantly higher levels of IL-6, independent of age, sex, and depressive symptoms. These group differences were robust when controlling for neuroticism. Conversely, the groups had equivalent levels of CRP in all analyses. Results are indicative of anxiety-specific effects on inflammatory activity, and highlight a pathway by which anxiety may increase risk for inflammatory diseases.     

Tonic inhibition in principal cells of the amygdala: a central role for α3 subunit-containing GABAA receptors

GABAergic inhibition in the amygdala is essential in regulating fear and anxiety. Although fast "phasic" inhibition arising through the activation of postsynaptic GABA(A) receptors (GABA(A)Rs) has been well described in the amygdala, much less is known about extrasynaptic GABA(A)Rs mediating persistent or tonic inhibition and regulating neuronal excitability. Here, we recorded tonic currents in the basolateral (BLA) nucleus and the lateral (LA) nucleus of the amygdala. While all BLA principal cells expressed a robust GABAergic tonic current, only 70% of LA principal cells showed a tonic current. Immunohistochemical stainings revealed that the α3 GABA(A)R subunit is expressed moderately in the LA and strongly throughout the BLA nucleus, where it is located mostly at extrasynaptic sites. In α3 subunit KO mice, tonic currents are significantly reduced in BLA principal cells yet not in LA principal cells. Moreover, the α3 GABA(A)R-selective benzodiazepine site agonist and anxiolytic compound TP003 increases tonic currents and dampens excitability markedly in wild-type BLA principal cells but fails to do so in α3KO BLA cells. Interneurons of the LA and BLA nuclei also express a tonic current, but TP003-induced potentiation is seen in only a small fraction of these cells, suggesting that primarily other GABA(A)R variants underlie tonic inhibition in this cell type. Together, these studies demonstrate that α3 GABA(A)R-mediated tonic inhibition is a central component of the inhibitory force in the amygdala and that tonically activated α3 GABA(A)Rs present an important target for anxiolytic or fear-reducing compounds.     

Characterising youth with callous–unemotional traits and concurrent anxiety: evidence for a high-risk clinical group

Growing evidence supports the existence of two variants of youth with high callous–unemotional (CU) traits who present with markedly different risk profiles and outcomes, with potential implications for risk assessment and treatment formulation. So far, studies have identified variants of CU youth mainly using data-driven cluster approaches based on levels of CU traits and co-occurring anxiety. Yet, the extent to which this knowledge may be translated into clinical practice is unclear. To this end, the present study employed a severity-based, cut-off approach to systematically characterise CU groups across a range of clinically informative domains, including trauma history, psychiatric symptomatology, affective functioning, attachment style and behavioural risk. Analyses were based on multi-rated data from a community sample of high-risk youths (n = 155, M = 18 years). Consistent with previous studies, we found that, whereas variants show comparable levels of antisocial behaviour, those who present with both high CU and high anxiety report more severe childhood maltreatment, psychological distress, ADHD symptomatology and behavioural risk—including substance use, suicidal ideation and unsafe sex. In addition, these youth show greater attachment insecurity and affective dysregulation, as indexed by levels of irritability and alexithymia. Together, findings indicate that (1) trauma history is a key factor that differentiates variants of CU youth high vs. low on anxiety, and (2) differences in individual functioning across variants point to the need for tailored clinical assessment tools and intervention strategies. Importantly, the present findings indicate that variants of CU youth can be meaningfully differentiated using cut-off based approaches that parallel methods used in clinical assessments.