Dynamic integration and segregation of amygdala subregional functional circuits linking to physiological arousal.

The dynamical organization of brain networks is essential to support human cognition and emotion for rapid adaption to ever-changing environment. As the core nodes of emotion-related brain circuitry, the basolateral amygdala (BLA) and centromedial amygdala (CMA) as two major amygdalar nuclei, are recognized to play distinct roles in affective functions and internal states, via their unique connections with cortical and subcortical structures in rodents. However, little is known how the dynamical organization of emotion-related brain circuitry reflects internal autonomic responses in humans. Using resting-state functional magnetic resonance imaging (fMRI) with K-means clustering approach in a total of 79 young healthy individuals (cohort 1: 42; cohort 2: 37), we identified two distinct states of BLA- and CMA-based intrinsic connectivity patterns, with one state (integration) showing generally stronger BLA- and CMA-based intrinsic connectivity with multiple brain networks, while the other (segregation) exhibiting weaker yet dissociable connectivity patterns. In an independent cohort 2 of fMRI data with concurrent recording of skin conductance, we replicated two similar dynamic states and further found higher skin conductance level in the integration than segregation state. Moreover, machine learning-based Elastic-net regression analyses revealed that time-varying BLA and CMA intrinsic connectivity with distinct network configurations yield higher predictive values for spontaneous fluctuations of skin conductance level in the integration than segregation state. Our findings highlight dynamic functional organization of emotion-related amygdala nuclei circuits and networks and its links to spontaneous autonomic arousal in humans.

Functional coupling of the orbitofrontal cortex and the basolateral amygdala mediates the association between spontaneous reappraisal and emotional response.

Emotional regulation is known to be associated with activity in the amygdala. The amygdala is an emotion-generative region that comprises of structurally and functionally distinct nuclei. However, little is known about the contributions of different frontal-amygdala sub-region pathways to emotion regulation. Here, we investigated how functional couplings between frontal regions and amygdala sub-regions are involved in different spontaneous emotion regulation processes by using an individual-difference approach and a generalized psycho-physiological interaction (gPPI) approach. Specifically, 50 healthy participants reported their dispositional use of spontaneous cognitive reappraisal and expressive suppression in daily life and their actual use of these two strategies during the performance of an emotional-picture watching task. Results showed that functional coupling between the orbitofrontal cortex (OFC) and the basolateral amygdala (BLA) was associated with higher scores of both dispositional and actual uses of reappraisal. Similarly, functional coupling between the dorsolateral prefrontal cortex (dlPFC) and the centromedial amygdala (CMA) was associated with higher scores of both dispositional and actual uses of suppression. Mediation analyses indicated that functional coupling of the right OFC-BLA partially mediated the association between reappraisal and emotional response, irrespective of whether reappraisal was measured by dispositional use (indirect effect(SE)=-0.2021 (0.0811), 95%CI(BC)= [-0.3851, -0.0655]) or actual use (indirect effect(SE)=-0.1951 (0.0796), 95%CI(BC)= [-0.3654, -0.0518])). These findings suggest that spontaneous reappraisal and suppression involve distinct frontal- amygdala functional couplings, and the modulation of BLA activity from OFC may be necessary for changing emotional response during spontaneous reappraisal.

Infrared neural stimulation with 7T fMRI: A rapid in vivo method for mapping cortical connections of primate amygdala.

We have previously shown that INS-fMRI is a rapid method for mapping mesoscale brain networks in the macaque monkey brain. Focal stimulation of single cortical sites led to the activation of connected cortical locations, resulting in a global connectivity map. Here, we have extended this method for mapping brainwide networks following stimulation of single subcortical sites. As a testbed, we focused on the basal nucleus of the amygdala in the macaque monkey. We describe methods to target basal nucleus locations with submillimeter precision, pulse train stimulation methods, and statistical tests for assessing non-random nature of activations. Using these methods, we report that stimulation of precisely targeted loci in the basal nucleus produced sparse and specific activations in the brain. Activations were observed in the insular and sensory association cortices as well as activations in the cingulate cortex, consistent with known anatomical connections. What is new here is that the activations were focal and, in some cases, exhibited shifting topography with millimeter shifts in stimulation site. The precision of the method enables networks mapped from different nearby sites in the basal nucleus to be distinguished. While further investigation is needed to improve the sensitivity of this method, our analyses do support the reproducibility and non-random nature of some of the activations. We suggest that INS-fMRI is a promising method for mapping large-scale cortical and subcortical networks at high spatial resolution.

Correlates of Auditory Decision-Making in Prefrontal, Auditory, and Basal Lateral Amygdala Cortical Areas.

Spatial selective listening and auditory choice underlie important processes including attending to a speaker at a cocktail party and knowing how (or whether) to respond. To examine task encoding and the relative timing of potential neural substrates underlying these behaviors, we developed a spatial selective detection paradigm for monkeys, and recorded activity in primary auditory cortex (AC), dorsolateral prefrontal cortex (dlPFC), and the basolateral amygdala (BLA). A comparison of neural responses among these three areas showed that, as expected, AC encoded the side of the cue and target characteristics before dlPFC and BLA. Interestingly, AC also encoded the choice of the monkey before dlPFC and around the time of BLA. Generally, BLA showed weak responses to all task features except the choice. Decoding analyses suggested that errors followed from a failure to encode the target stimulus in both AC and dlPFC, but again, these differences arose earlier in AC. The similarities between AC and dlPFC responses were abolished during passive sensory stimulation with identical trial conditions, suggesting that the robust sensory encoding in dlPFC is contextually gated. Thus, counter to a strictly PFC-driven decision process, in this spatial selective listening task AC neural activity represents the sensory and decision information before dlPFC. Unlike in the visual domain, in this auditory task, the BLA does not appear to be robustly involved in selective spatial processing.SIGNIFICANCE STATEMENT We examined neural correlates of an auditory spatial selective listening task by recording single-neuron activity in behaving monkeys from the amygdala, dorsolateral prefrontal cortex, and auditory cortex. We found that auditory cortex coded spatial cues and choice-related activity before dorsolateral prefrontal cortex or the amygdala. Auditory cortex also had robust delay period activity. Therefore, we found that auditory cortex could support the neural computations that underlie the behavioral processes in the task.

An Amygdala Circuit Mediates Experience-Dependent Momentary Arrests during Exploration.

Exploration of novel environments ensures survival and evolutionary fitness. It is expressed through exploratory bouts and arrests that change dynamically based on experience. Neural circuits mediating exploratory behavior should therefore integrate experience and use it to select the proper behavioral output. Using a spatial exploration assay, we uncovered an experience-dependent increase in momentary arrests in locations where animals arrested previously. Calcium imaging in freely exploring mice revealed a genetically and projection-defined neuronal ensemble in the basolateral amygdala that is active during self-paced behavioral arrests. This ensemble was recruited in an experience-dependent manner, and closed-loop optogenetic manipulation of these neurons revealed that they are sufficient and necessary to drive experience-dependent arrests during exploration. Projection-specific imaging and optogenetic experiments revealed that these arrests are effected by basolateral amygdala neurons projecting to the central amygdala, uncovering an amygdala circuit that mediates momentary arrests in familiar places but not avoidance or anxiety/fear-like behaviors.

Anatomic alterations across amygdala subnuclei in medication-free patients with obsessive-compulsive disorder.

Background: The amygdala has been implicated in obsessive-compulsive disorder (OCD), a common, disabling illness. However, the regional distribution of anatomic alterations in this structure and their association with the symptoms of OCD remains to be established. Methods: We collected high-resolution 3D T1-weighted images from 81 untreated patients with OCD and no lifetime history of comorbid psychotic, affective or anxiety disorders, and from 95 age- and sex-matched healthy controls. We extracted the volume of the central nucleus of the amygdala (CeA) and the basolateral complex of the amygdala (BLA) and compared them across groups using FreeSurfer 6.0. In exploratory analyses, we evaluated other subnuclei, including the cortical medial nuclei, the anterior amygdaloid area, and the corticoamygdaloid transition area. Results: Patients with OCD had reduced amygdala volume bilaterally compared with healthy controls (left, p = 0.034; right, p = 0.002). Volume reductions were greater in the CeA (left: -11.9%, p = 0.002; right: -13.3%, p < 0.001) than in the BLA (left lateral nucleus: -3.3%, p = 0.029; right lateral nucleus: -3.9%, p = 0.018; right basal nucleus: -4.1%, p = 0.017; left accessory basal nucleus: -6.5%, p = 0.001; right accessory basal nucleus: -9.3%, p < 0.001). Volume reductions in the CeA were associated with illness duration. Exploratory analysis revealed smaller medial (left: -15.4%, p < 0.001, η2 = 0.101) and cortical (left: -9.1%, p = 0.001, η2 = 0.058; right: -15.4%, p < 0.001, η2 = 0.175) nuclei in patients with OCD compared with healthy controls. Limitations: Although the strict exclusion criteria used in the study helped us to identify OCD-specific alterations, they may have limited generalizability to the broader OCD population. Conclusion: Our results provide a comprehensive anatomic profile of alterations in the amygdala subnuclei in untreated patients with OCD and highlight a distinctive pattern of volume reductions across subnuclei in OCD. Based on the functional properties of the amygdala subnuclei established from preclinical research, CeA impairment may contribute to behavioural inflexibility, and BLA disruption may be responsible for altered fear conditioning and the affective components of OCD.

Amygdala subnucleus volumes in psychosis high-risk state and first-episode psychosis.

Structural and functional abnormalities of the amygdala in schizophrenia have been well documented. Post-mortem studies suggest that the lateral nucleus is particularly affected in schizophrenia. It is not known whether the amygdala subnuclei are differently affected at the time of the first-episode psychosis or already at high-risk state. 75 first-episode psychosis patients (FEP), 45 clinical high-risk patients (CHR) and 76 population controls participated in this cross-sectional case-control study. Participants underwent T1-weighted 3T MRI scans, from which the amygdala was segmented using a newly developed automated algorithm. Because early adverse events increase risk for psychosis and affect the amygdala, we also tested whether experiences of childhood maltreatment associate with the putative amygdala subnuclei abnormalities. Compared to the population controls, FEP had smaller volumes of the lateral, and basal nuclei. In CHR, only the lateral nucleus was significantly smaller compared to the control subjects. Experience of childhood maltreatment was inversely associated with lateral nucleus volumes in FEP but not in CHR. These results show that the lateral and basal nuclei of the amygdala are already affected in FEP. These volumetric changes may reflect specific cellular abnormalities that have been observed in post-mortem studies in schizophrenia in the same subnuclei. Decreased volume of the lateral nucleus in CHR suggest that a smaller lateral nucleus could serve as a potential biomarker for psychosis risk. Finally, we found that the lateral nucleus volumes in FEP may be sensitive to the effects of childhood maltreatment.

Adverse Childhood Experiences and Amygdalar Reduction: High-Resolution Segmentation Reveals Associations With Subnuclei and Psychiatric Outcomes.

The aim of the present study was 2-fold: (1) to utilize improved amygdala segmentation and exploratory factor analysis to characterize the latent volumetric structure among amygdala nuclei and (2) to assess the effect of adverse childhood experiences (ACEs) on amygdalar morphometry and current psychiatric symptoms. To investigate these aims, structural (T1) MRI and self-report data were obtained from 119 emerging adults. Regression analysis showed that higher ACE scores were related to reduced volume of the right, but not the left, amygdalar segments. Further, exploratory factor analysis yielded a two-factor structure, basolateral and central-medial nuclei of the right amygdala. Stractual equation modeling analyses revealed that higher ACE scores were significantly related to a reduced volume of the right basolateral and central-medial segments. Furthermore, reduction in the right basolateral amygdala was associated with increased anxiety, depressive symptoms, and alcohol use. This association supports an indirect effect between early adversity and psychiatric problems via reduced right basolateral amygdalar volume. The high-resolution segmentation results reveal a latent structure among amygdalar nuclei, which is consistent with prior work conducted in nonhuman mammals. These findings extend previous reports linking early adversity, right amygdala volume, and psychopathology.

Basolateral amygdala input to the medial prefrontal cortex controls obsessive-compulsive disorder-like checking behavior.

Obsessive-compulsive disorder (OCD) affects ∼1 to 3% of the world's population. However, the neural mechanisms underlying the excessive checking symptoms in OCD are not fully understood. Using viral neuronal tracing in mice, we found that glutamatergic neurons from the basolateral amygdala (BLAGlu) project onto both medial prefrontal cortex glutamate (mPFCGlu) and GABA (mPFCGABA) neurons that locally innervate mPFCGlu neurons. Next, we developed an OCD checking mouse model with quinpirole-induced repetitive checking behaviors. This model demonstrated decreased glutamatergic mPFC microcircuit activity regulated by enhanced BLAGlu inputs. Optical or chemogenetic manipulations of this maladaptive circuitry restored the behavioral response. These findings were verified in a mouse functional magnetic resonance imaging (fMRI) study, in which the BLA-mPFC functional connectivity was increased in OCD mice. Together, these findings define a unique BLAGlu→mPFCGABA→Glu circuit that controls the checking symptoms of OCD.

Aberrant Somatosensory Processing and Connectivity in Mice Lacking Engrailed-2.

Overreactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such as Fmr1 (fragile X mental retardation protein 1). Fmr1 knock-out mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity in Engrailed-2 knock-out (En2-/-) adult mice, which show a lower expression of Fmr1 and anatomical defects common to Fmr1 knock-outs. MRI-based resting-state functional connectivity in adult En2-/- mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, En2-/- but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation. En2-/- mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala compared with WT littermates. Conversely, when tested in a sensory maze, En2-/- and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in En2 mutants. Therefore, fearful responses to somatosensory stimuli in En2-/- mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes.SIGNIFICANCE STATEMENT Overreactivity to tactile stimuli is a common symptom in autism spectrum disorder (ASD) patients. Recent studies performed in mice bearing ASD-related mutations confirmed these findings. Here, we evaluated the behavioral response to whisker stimulation in mice lacking the ASD-related gene Engrailed-2 (En2-/- mice). Compared with WT controls, En2-/- mice showed reduced functional connectivity in the somatosensory cortex, which was paralleled by fear behavior, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala in response to repeated whisker stimulation. These results suggest that impaired somatosensory signal processing is a common feature in mice harboring ASD-related mutations.

Smaller volumes in the lateral and basal nuclei of the amygdala in patients with panic disorder.

The amygdala plays an important functional role in fear and anxiety. Abnormalities in the amygdala are believed to be involved in the neurobiological basis of panic disorder (PD). Previous structural neuroimaging studies have found global volumetric and morphological abnormalities in the amygdala in patients with PD. Very few studies, however, have explored for structural abnormalities in various amygdala sub-regions, which consist of various sub-nuclei, each with different functions. This study aimed to evaluate for volumetric abnormalities in the amygdala sub-nuclei, in order to provide a better understanding neurobiological basis of PD. Thirty-eight patients with PD and 38 matched healthy control (HC) participants underwent structural MRI scanning. The volume of the whole amygdala, as well as its consistent sub-nuclei, were calculated using FreeSurfer software. Relative volumes of these amygdala sub-regions were compared between the two groups. Results showed significantly smaller volumes in the right lateral and basal nuclei in the patients with PD compared with the HC. Lateral and basal nuclei are thought to play crucial role for processing sensory information related with anxiety and fear. Our results suggest that these particular amygdala sub-regions play a role in the development of PD symptoms.

In vivo quantification of amygdala subnuclei using 4.7 T fast spin echo imaging.

The amygdala (AG) is an almond-shaped heterogeneous structure located in the medial temporal lobe. The majority of previous structural Magnetic Resonance Imaging (MRI) volumetric methods for AG measurement have so far only been able to examine this region as a whole. In order to understand the role of the AG in different neuropsychiatric disorders, it is necessary to understand the functional role of its subnuclei. The main goal of the present study was to develop a reliable volumetric method to delineate major AG subnuclei groups using ultra-high resolution high field MRI. 38 healthy volunteers (15 males and 23 females, 21-60 years of age) without any history of medical or neuropsychiatric disorders were recruited for this study. Structural MRI datasets were acquired at 4.7 T Varian Inova MRI system using a fast spin echo (FSE) sequence. The AG was manually segmented into its five major anatomical subdivisions: lateral (La), basal (B), accessory basal (AB) nuclei, and cortical (Co) and centromedial (CeM) groups. Inter-(intra-) rater reliability of our novel volumetric method was assessed using intra-class correlation coefficient (ICC) and Dice's Kappa. Our results suggest that reliable measurements of the AG subnuclei can be obtained by image analysts with experience in AG anatomy. We provided a step-by-step segmentation protocol and reported absolute and relative volumes for the AG subnuclei. Our results showed that the basolateral (BLA) complex occupies seventy-eight percent of the total AG volume, while CeM and Co groups occupy twenty-two percent of the total AG volume. Finally, we observed no hemispheric effects and no gender differences in the total AG volume and the volumes of its subnuclei. Future applications of this method will help to understand the selective vulnerability of the AG subnuclei in neurological and psychiatric disorders.

Basolateral amygdala-ventromedial prefrontal cortex connectivity predicts cognitive behavioural therapy outcome in adults with obsessive-compulsive disorder.

BACKGROUND: Cognitive behavioural therapy (CBT), including exposure and ritual prevention, is a first-line treatment for obsessive-compulsive disorder (OCD), but few reliable predictors of CBT outcome have been identified. Based on research in animal models, we hypothesized that individual differences in basolateral amygdala-ventromedial prefrontal cortex (BLA-vmPFC) communication would predict CBT outcome in patients with OCD. METHODS: We investigated whether BLA-vmPFC resting-state functional connectivity (rs-fc) predicts CBT outcome in patients with OCD. We assessed BLA-vmPFC rs-fc in patients with OCD on a stable dose of a selective serotonin reuptake inhibitor who then received CBT and in healthy control participants. RESULTS: We included 73 patients with OCD and 84 healthy controls in our study. Decreased BLA-vmPFC rs-fc predicted a better CBT outcome in patients with OCD and was also detected in those with OCD compared with healthy participants. Additional analyses revealed that decreased BLA-vmPFC rs-fc uniquely characterized the patients with OCD who responded to CBT. LIMITATIONS: We used a sample of convenience, and all patients were receiving pharmacological treatment for OCD. CONCLUSION: In this large sample of patients with OCD, BLA-vmPFC functional connectivity predicted CBT outcome. These results suggest that future research should investigate the potential of BLA-vmPFC pathways to inform treatment selection for CBT across patients with OCD and anxiety disorders.

The Basolateral Amygdalae and Frontotemporal Network Functions for Threat Perception.

Although the amygdalae play a central role in threat perception and reactions, the direct contributions of the amygdalae to specific aspects of threat perception, from ambiguity resolution to reflexive or deliberate action, remain ill understood in humans. Animal studies show that a detailed understanding requires a focus on the different subnuclei, which is not yet achieved in human research. Given the limits of human imaging methods, the crucial contribution needs to come from individuals with exclusive and selective amygdalae lesions. The current study investigated the role of the basolateral amygdalae and their connection with associated frontal and temporal networks in the automatic perception of threat. Functional activation and connectivity of five individuals with Urbach-Wiethe disease with focal basolateral amygdalae damage and 12 matched controls were measured with functional MRI while they attended to the facial expression of a threatening face-body compound stimuli. Basolateral amygdalae damage was associated with decreased activation in the temporal pole but increased activity in the ventral and dorsal medial prefrontal and medial orbitofrontal cortex. This dissociation between the prefrontal and temporal networks was also present in the connectivity maps. Our results contribute to a dynamic, multirole, subnuclei-based perspective on the involvement of the amygdalae in fear perception. Damage to the basolateral amygdalae decreases activity in the temporal network while increasing activity in the frontal network, thereby potentially triggering a switch from resolving ambiguity to dysfunctional threat signaling and regulation, resulting in hypersensitivity to threat.

Accumulation of Polyribosomes in Dendritic Spine Heads, But Not Bases and Necks, during Memory Consolidation Depends on Cap-Dependent Translation Initiation.

Translation in dendrites is believed to support synaptic changes during memory consolidation. Although translational control mechanisms are fundamental mediators of memory, little is known about their role in local translation. We previously found that polyribosomes accumulate in dendritic spines of the adult rat lateral amygdala (LA) during consolidation of aversive pavlovian conditioning and that this memory requires cap-dependent initiation, a primary point of translational control in eukaryotic cells. Here we used serial electron microscopy reconstructions to quantify polyribosomes in LA dendrites when consolidation was blocked by the cap-dependent initiation inhibitor 4EGI-1. We found that 4EGI-1 depleted polyribosomes in dendritic shafts and selectively prevented their upregulation in spine heads, but not bases and necks, during consolidation. Cap-independent upregulation was specific to spines with small, astrocyte-associated synapses. Our results reveal that cap-dependent initiation is involved in local translation during learning and that local translational control varies with synapse type.SIGNIFICANCE STATEMENT Translation initiation is a central regulator of long-term memory formation. Local translation in dendrites supports memory by providing necessary proteins at synaptic sites, but it is unknown whether this requires initiation or bypasses it. We used serial electron microscopy reconstructions to examine polyribosomes in dendrites when memory formation was blocked by an inhibitor of translation initiation. This revealed two major pools of polyribosomes that were upregulated during memory formation: one pool in dendritic spine heads that was initiation dependent and another pool in the bases and necks of small spines that was initiation independent. Thus, translation regulation differs between spine types and locations, and translation that occurs closest to individual synapses during memory formation is initiation dependent.

Functional connectivity in the resting brain as biological correlate of the Affective Neuroscience Personality Scales.

According to Jaak Panksepp's Affective Neuroscience Theory and the derived self-report measure, the Affective Neuroscience Personality Scales (ANPS), differences in the responsiveness of primary emotional systems form the basis of human personality. In order to investigate neuronal correlates of personality, the underlying neuronal circuits of the primary emotional systems were analyzed in the present fMRI-study by associating the ANPS to functional connectivity in the resting brain. N=120 healthy participants were invited for the present study. The results were reinvestigated in an independent, smaller sample of N=52 participants. A seed-based whole brain approach was conducted with seed-regions bilaterally in the basolateral and superficial amygdalae. The selection of seed-regions was based on meta-analytic data on affective processing and the Juelich histological atlas. Multiple regression analyses on the functional connectivity maps revealed associations with the SADNESS-scale in both samples. Functional resting-state connectivity between the left basolateral amygdala and a cluster in the postcentral gyrus, and between the right basolateral amygdala and clusters in the superior parietal lobe and subgyral in the parietal lobe was associated with SADNESS. No other ANPS-scale revealed replicable results. The present findings give first insights into the neuronal basis of the SADNESS-scale of the ANPS and support the idea of underlying neuronal circuits. In combination with previous research on genetic associations of the ANPS functional resting-state connectivity is discussed as a possible endophenotype of personality.

Bidirectional Control of Social Behavior by Activity within Basolateral and Central Amygdala of Primates.

UNLABELLED: Both hypoactivity and hyperactivity in the amygdala are associated with perturbations in social behavior. While >60 years of experimental manipulations of the amygdala in animal models have shown that amygdala is critical for social behavior, many of these studies contradict one another. Moreover, several questions remain unaddressed. (1) What effect does activation of amygdala have on social behavior? (2) What is the effect of transient silencing, rather than permanent damage? (3) Is there a dissociation between the roles of the central (CeA) and basolateral amygdala (BLA) in regulating social behavior? (4) Can the prosocial effects of amygdala manipulations be explained by anxiolytic effects? We focally manipulated activity within the CeA or BLA in macaques by intracerebral microinjection of muscimol (to inactivate) or bicuculline (to activate) to these amygdaloid subregions. Social interactions were observed in pairs of highly familiar monkeys. We compared these effects to those achieved with systemic diazepam. Activation of the BLA but not CeA suppressed social behavior. Inhibition of either structure increased social behavior, although the effect was greater following inhibition of the BLA. Systemic diazepam was without effect. These studies, which are the first to bidirectionally manipulate the primate amygdala for effects on social behavior, revealed that (1) the amygdala, as a critical regulator of the social network, is bidirectionally sensitive to perturbations in activity, and (2) increased sociability after amygdala inactivation cannot be solely explained by decreased fear. SIGNIFICANCE STATEMENT: Many previous studies reported loss of social interactions following permanent damage to the amygdala in nonhuman primates. In contrast, we report that transient inhibition of the basolateral amygdala triggered a profound increase in social interactions in dyads of monkeys highly familiar with each other. We compared these effects to those of systemic diazepam, which failed to increase social behavior. While it has been suggested that suppression of "fear" could underlie the prosocial effects of amygdala manipulations, our data strongly suggest that impairment in fear processing per se cannot account for the prosocial effects of amygdala inhibition. Furthermore, our studies are the first to examine activation of the amygdala and to assess the separate roles of the amygdaloid nuclei in social behavior in primates.

Preferential recruitment of the basolateral amygdala during memory encoding of negative scenes in posttraumatic stress disorder.

BACKGROUND: The vast majority of functional neuroimaging studies in posttraumatic stress disorder (PTSD) have examined the amygdala as a unitary structure. However, an emerging body of studies indicates that separable functions are subserved by discrete amygdala subregions. The basolateral subdivision (BLA), as compared with the centromedial amygdala (CMA), plays a unique role in learning and memory-based processes for threatening events, and alterations to the BLA have been implicated in the pathogenesis of PTSD. We assessed whether PTSD is associated with differential involvement of the BLA versus the CMA during successful encoding of emotionally charged events. METHODS: Participants with PTSD (n=11) and a trauma-exposed comparison (TEC) group (n=11) viewed a series of photos that varied in valence (negative versus positive) and arousal (high versus low) while undergoing functional magnetic resonance imaging (fMRI). Subsequently, participants completed an old/new recognition memory test. RESULTS: Using analytic methods based on probabilistic cytoarchitectonic mapping, PTSD was associated with greater activation of the BLA, as compared to the CMA, during successful encoding of negative scenes, a finding which was not observed in the TEC group. Moreover, this memory-related activity in the BLA independently predicted PTSD status. Contrary to hypotheses, there was no evidence of altered BLA activity during memory encoding of high arousing relative to low arousing scenes. CONCLUSIONS: Task-related brain activation in PTSD does not appear to be consistent across the entire amygdala. Importantly, memory-related processing of negative information in PTSD is associated with preferential recruitment of the BLA.

Deep brain stimulation of the basolateral amygdala for treatment-refractory combat post-traumatic stress disorder (PTSD): study protocol for a pilot randomized controlled trial with blinded, staggered onset of stimulation.

BACKGROUND: Combat post-traumatic stress disorder (PTSD) involves significant suffering, impairments in social and occupational functioning, substance use and medical comorbidity, and increased mortality from suicide and other causes. Many veterans continue to suffer despite current treatments. Deep brain stimulation (DBS) has shown promise in refractory movement disorders, depression and obsessive-compulsive disorder, with deep brain targets chosen by integration of clinical and neuroimaging literature. The basolateral amygdala (BLn) is an optimal target for high-frequency DBS in PTSD based on neurocircuitry findings from a variety of perspectives. DBS of the BLn was validated in a rat model of PTSD by our group, and limited data from humans support the potential safety and effectiveness of BLn DBS. METHODS/DESIGN: We describe the protocol design for a first-ever Phase I pilot study of bilateral BLn high-frequency DBS for six severely ill, functionally impaired combat veterans with PTSD refractory to conventional treatments. After implantation, patients are monitored for a month with stimulators off. An electroencephalographic (EEG) telemetry session will test safety of stimulation before randomization to staggered-onset, double-blind sham versus active stimulation for two months. Thereafter, patients will undergo an open-label stimulation for a total of 24 months. Primary efficacy outcome is a 30% decrease in the Clinician Administered PTSD Scale (CAPS) total score. Safety outcomes include extensive assessments of psychiatric and neurologic symptoms, psychosocial function, amygdala-specific and general neuropsychological functions, and EEG changes. The protocol requires the veteran to have a cohabiting significant other who is willing to assist in monitoring safety and effect on social functioning. At baseline and after approximately one year of stimulation, trauma script-provoked 18FDG PET metabolic changes in limbic circuitry will also be evaluated. DISCUSSION: While the rationale for studying DBS for PTSD is ethically and scientifically justified, the importance of the amygdaloid complex and its connections for a myriad of emotional, perceptual, behavioral, and vegetative functions requires a complex trial design in terms of outcome measures. Knowledge generated from this pilot trial can be used to design future studies to determine the potential of DBS to benefit both veterans and nonveterans suffering from treatment-refractory PTSD. TRIAL REGISTRATION: PCC121657, 19 March 2014.