Amygdala-hippocampal Complex Research Articles

Altered structural covariance of the cortex and hippocampal formation in patients with lung cancer after chemotherapy

ObjectiveIn this retrospective study, we aimed to investigate changes in brain morphology and structural topological networks in patients with lung cancer (LC) with or without chemotherapy. MethodsWe retrospectively recruited 191 participants for this cross-sectional study, including 113 patients with LC without chemotherapy (Ch-), 38 patients with LC with chemotherapy (Ch+), and 40 healthy controls (HC) matched for age, sex, and education. The gray matter volume (GMV) and cortical properties were compared among the three groups. We constructed the structural covariant network (SCN) based on cortical thickness, volumes of subcortical structures, and volumes of hippocampal subfields and the amygdala in all participants. The global and nodal topological properties of SCN were compared among groups. In addition, 23 patients with LC (8 Ch+ and 15 Ch-) who received two identical brain magnetic resonance scans were enrolled in the follow-up study. The paired t-test was used to compare group differences in brain morphology and topological properties in the structural network. ResultsThe GMV of the bilateral caudate and thalamus were smaller in the Ch- and Ch+ groups compared to the HC group using threshold-free cluster enhancement and permutation (P < 0.05, 5000 times permutations) for multiple comparison correction. The cortical SCN analysis suggested multiple enhanced nodal properties in several brain areas in Ch+ and Ch- compared to HC, mainly in the temporal gyrus, using permutations test and false discovery rate (FDR) (P < 0.05) corrections. Moreover, an increased sigma was found in the Ch+ compared with HC (P = 0.0238). The reduced nodal degree (P = 0.0002) and betweenness (P = 0.0008) in the right amygdala of Ch+ compared to HC were detected by subcortical SCN analysis. Furthermore, reduced gamma (P = 0.0342) and sigma (P < 0.0001) were found in Ch- compared with HC in the SCN analysis of subfields of the amygdala-hippocampal complex. In the follow-up study, reduced nodal degree (P < 0.0001) was found in the right anterior amygdala, and reduced clustering coefficient and local efficiency were found in patients with LC after the permutation test. ConclusionsOur study showed GMV defects and structural topological property abnormalities related to LC and chemotherapy. Such morphological changes associated with LC and chemotherapy could be used as imaging markers for clinical assessments and pathological indicators.

Interaction of perceived social support and childhood maltreatment on limbic responsivity towards negative emotional stimuli in healthy individuals

Childhood maltreatment (CM) is associated with increased limbic activity, while social support is linked to decreased limbic activity towards negative stimuli. Our study aimed to explore the interaction of perceived social support with CM, and their combined impact on limbic activity in negative emotion processing. A total of 130 healthy individuals (HC) underwent a negative emotional face processing paradigm. They were divided into two groups based on the Childhood Trauma Questionnaire: n = 65 HC without CM matched with n = 65 HC with CM. In a region-of-interest approach of the bilateral amygdala-hippocampus-complex (AHC), regression analyses investigating the association of CM and perceived social support with limbic activity and a social support x CM ANCOVA were conducted. CM was associated with increased AHC activity, while perceived social support tended to be associated with decreased AHC activity during negative emotion processing. The ANCOVA showed a significant interaction in bilateral AHC activity (pFWE ≤ 0.024) driven by a negative association between perceived social support and bilateral AHC activity in HC without CM. No significant association was observed in HC with CM. Exploratory analyses using continuous CM scores support this finding. Our results suggest that CM moderates the link between perceived social support and limbic activity, with a protective effect of perceived social support only in HC without CM. The lack of this effect in HC with CM suggests that CM may alter the buffering effect of perceived social support on limbic functioning, highlighting the potential need for preventive interventions targeting social perception of HC with CM.

Intimate partner violence perpetration among veterans: associations with neuropsychiatric symptoms and limbic microstructure.

Intimate partner violence (IPV) perpetration is highly prevalent among veterans. Suggested risk factors of IPV perpetration include combat exposure, post-traumatic stress disorder (PTSD), depression, alcohol use, and mild traumatic brain injury (mTBI). While the underlying brain pathophysiological characteristics associated with IPV perpetration remain largely unknown, previous studies have linked aggression and violence to alterations of the limbic system. Here, we investigate whether IPV perpetration is associated with limbic microstructural abnormalities in military veterans. Further, we test the effect of potential risk factors (i.e., PTSD, depression, substance use disorder, mTBI, and war zone-related stress) on the prevalence of IPV perpetration. Structural and diffusion-weighted magnetic resonance imaging (dMRI) data were acquired from 49 male veterans of the Iraq and Afghanistan wars (Operation Enduring Freedom/Operation Iraqi Freedom; OEF/OIF) of the Translational Research Center for TBI and Stress Disorders (TRACTS) study. IPV perpetration was assessed using the psychological aggression and physical assault sub-scales of the Revised Conflict Tactics Scales (CTS2). Odds ratios were calculated to assess the likelihood of IPV perpetration in veterans with either of the following diagnoses: PTSD, depression, substance use disorder, or mTBI. Fractional anisotropy tissue (FA) measures were calculated for limbic gray matter structures (amygdala-hippocampus complex, cingulate, parahippocampal gyrus, entorhinal cortex). Partial correlations were calculated between IPV perpetration, neuropsychiatric symptoms, and FA. Veterans with a diagnosis of PTSD, depression, substance use disorder, or mTBI had higher odds of perpetrating IPV. Greater war zone-related stress, and symptom severity of PTSD, depression, and mTBI were significantly associated with IPV perpetration. CTS2 (psychological aggression), a measure of IPV perpetration, was associated with higher FA in the right amygdala-hippocampus complex (r = 0.400, p = 0.005). Veterans with psychiatric disorders and/or mTBI exhibit higher odds of engaging in IPV perpetration. Further, the more severe the symptoms of PTSD, depression, or TBI, and the greater the war zone-related stress, the greater the frequency of IPV perpetration. Moreover, we report a significant association between psychological aggression against an intimate partner and microstructural alterations in the right amygdala-hippocampus complex. These findings suggest the possibility of a structural brain correlate underlying IPV perpetration that requires further research.

Consumption of ultra-processed foods is associated with depression, mesocorticolimbic volume, and inflammation

BackgroundThe consumption of ultra-processed foods and drinks (UPF) has been associated with depression and inflammation and preclinical studies showed that some UPF components disrupt the amygdala-hippocampal complex. We combine diet, clinical and brain imaging data to investigate the relationship between the UPF consumption, depressive symptoms, and brain volumes in humans, considering interactions with obesity, and the mediation effect of inflammation biomarkers. MethodsOne-hundred fifty-two adults underwent diet, depressive symptoms, anatomic magnetic resonance imaging assessments and laboratory tests. Relationships between the % of UPF consumption (in grams) of the total diet, depressive symptoms, and gray matter brain volumes were explored using several adjusted regression models, and in interaction with the presence of obesity. Whether inflammatory biomarkers (i.e., white blood cell count, lipopolysaccharide-binding protein, c-reactive protein) mediate the previous associations was investigated using R mediation package. ResultsHigh UPF consumption was associated with higher depressive symptoms in all participants (β = 0.178, CI = 0.008–0.261) and in those with obesity (β = 0.214, CI = −0.004–0.333). Higher consumption was also associated with lower volumes in the posterior cingulate cortex and the left amygdala, which in the participants with obesity also encompassed the left ventral putamen and the dorsal frontal cortex. White blood count levels mediated the association between UPF consumption and depressive symptoms (p = 0.022). LimitationsThe present study precludes any causal conclusions. ConclusionsUPF consumption is associated with depressive symptoms and lower volumes within the mesocorticolimbic brain network implicated in reward processes and conflict monitoring. Associations were partially dependent on obesity and white blood cell count.

Structural covariance network of the hippocampus-amygdala complex in medication-naïve patients with first-episode major depressive disorder.

The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder (MDD). Each of these structures consists of several heterogeneous subfields. We aim to explore the topologic properties of the volume-based intrinsic network within the hippocampus-amygdala complex in medication-naïve patients with first-episode MDD. High-resolution T1-weighted magnetic resonance imaging scans were acquired from 123 first-episode, medication-naïve, and noncomorbid MDD patients and 81 age-, sex-, and education level-matched healthy control participants (HCs). The structural covariance network (SCN) was constructed for each group using the volumes of the hippocampal subfields and amygdala subregions; the weights of the edges were defined by the partial correlation coefficients between each pair of subfields/subregions, controlled for age, sex, education level, and intracranial volume. The global and nodal graph metrics were calculated and compared between groups. Compared with HCs, the SCN within the hippocampus-amygdala complex in patients with MDD showed a shortened mean characteristic path length, reduced modularity, and reduced small-worldness index. At the nodal level, the left hippocampal tail showed increased measures of centrality, segregation, and integration, while nodes in the left amygdala showed decreased measures of centrality, segregation, and integration in patients with MDD compared with HCs. Our results provide the first evidence of atypical topologic characteristics within the hippocampus-amygdala complex in patients with MDD using structure network analysis. It provides more delineate mechanism of those two structures that underlying neuropathologic process in MDD.

Should Reward Deficiency Syndrome (RDS) Be Considered an Umbrella Disorder for Mental Illness and Associated Genetic and Epigenetic Induced Dysregulation of Brain Reward Circuitry?

Reward Deficiency Syndrome (RDS) is defined as a breakdown of reward neurotransmission that results in a wide range of addictive, compulsive, and impulsive behaviors. RDS is caused by a combination of environmental (epigenetic) influences and DNA-based (genetic) neurotransmission deficits that interfere with the normal satisfaction of human physiological drives (i.e., food, water, and sex). An essential feature of RDS is the lack of integration between perception, cognition, and emotions that occurs because of (1) significant dopaminergic surges in motivation, reward, and learning centers causing neuroplasticity in the striato-thalamic-frontal cortical loop; (2) hypo-functionality of the excitatory glutamatergic afferents from the amygdala–hippocampus complex. A large volume of literature regarding the known neurogenetic and psychological underpinnings of RDS has revealed a significant risk of dopaminergic gene polymorphic allele overlap between cohorts of depression and subsets of schizophrenia. The suggestion is that instead of alcohol, opioids, gambling disorders, etc. being endophenotypes, the true phenotype is RDS. Additionally, reward deficiency can result from depleted or hereditary hypodopaminergia, which can manifest as a variety of personality traits and mental/medical disorders that have been linked to genetic studies with dopamine-depleting alleles. The carrying of known DNA antecedents, including epigenetic insults, results in a life-long vulnerability to RDS conditions and addictive behaviors. Epigenetic repair of hypodopaminergia, the causative basis of addictive behaviors, may involve precision DNA-guided therapy achieved by combining the Genetic Addiction Risk Severity (GARS) test with a researched neutraceutical having a number of variant names, including KB220Z. This nutraceutical formulation with pro-dopamine regulatory capabilities has been studied and published in peer-reviewed journals, mostly from our laboratory. Finally, it is our opinion that RDS should be given an ICD code and deserves to be included in the DSM-VI because while the DSM features symptomology, it is equally important to feature etiological roots as portrayed in the RDS model.

Active exploration of an environment drives the activation of the hippocampus-amygdala complex of domestic chicks.

In birds, like in mammals, the hippocampus critically mediates spatial navigation through the formation of a spatial map. This study investigates the impact of active exploration of an environment on the hippocampus of young domestic chicks. Chicks that were free to actively explore the environment exhibited a significantly higher neural activation (measured by c-Fos expression) compared with those that passively observed the same environment from a restricted area. The difference was limited to the anterior and the dorsolateral parts of the intermediate hippocampus. Furthermore, the nucleus taeniae of the amygdala showed a higher c-Fos expression in the active exploration group than in the passive observation group. In both brain regions, brain activation was correlated with the number of locations that chicks visited during the test. This suggests that the increase of c-Fos expression in the hippocampus is related to increased firing rates of spatially coding neurons. Furthermore, our study indicates a functional linkage of the hippocampus and nucleus taeniae of the amygdala in processing spatial information. Overall, with the present study, we confirm that in birds, like in mammals, hippocampus and amygdala functions are linked and likely related to spatial representations.

Integrated Information Coefficient Estimated from Neuronal Activity in Hippocampus-Amygdala Complex of Rats as a Measure of Learning Success.

The goal of the brain is to provide right on time a suitable earlier-acquired model for the future behavior. How a complex structure of neuronal activity underlying a suitable model is selected or fixated is not well understood. Here we propose the integrated information Φ as a possible metric for such complexity of neuronal groups. It quantifies the degree of information integration between different parts of the brain and is lowered when there is a lack of connectivity between different subsets in a system. We calculated integrated information coefficient (Φ) for activity of hippocampal and amygdala neurons in rats during acquisition of two tasks: spatial task followed by spatial aversive task. An Autoregressive Φ algorithm was used for time-series spike data. We showed that integrated information coefficient Φ is positively correlated with a metric of learning success (a relative number of rewards). Φ for hippocampal neurons was positively correlated with Φ for amygdalar neurons during the learning requiring the cooperative work of hippocampus and amygdala. This result suggests that integrated information coefficient Φ may be used as a prediction tool for the suitable level of complexity of neuronal activity and the future success in learning and adaptation and a tool for estimation of interactions between different brain regions during learning.

Electroconvulsive therapy in treatment resistant depression

Electroconvulsive therapy (ECT) is a treatment modality for patients with treatment resistant depression (TRD), defined as failure of two adequate antidepressant medication trials. We provide a qualitative review of ECT's effectiveness for TRD, methods to optimize ECT parameters to improve remission rates and side effect profiles, and ECT's proposed neurobiological mechanisms. Right unilateral (RUL) electrode placement has been shown to be as effective for major depression as bilateral ECT, and RUL is associated with fewer cognitive side effects. There is mixed evidence on how to utilize ECT to sustain remission (i.e., continuation ECT, psychotropic medications alone, or a combination of ECT and psychotropic medications). Related to neurobiological mechanisms, an increase in gray matter volume in the hippocampus-amygdala complex is reported post-ECT. High connectivity between the subgenual anterior cingulate and the middle temporal gyrus before ECT is associated with better treatment response. Rodent models have implicated changes in neurotransmitters including glutamate, GABA, serotonin, and dopamine in ECT's efficacy; however, findings in humans are limited. Altogether, while ECT remains a highly effective therapy, the neurobiological underpinnings associated with improvement of depression remain uncertain.

Beyond olfaction: Beneficial effects of olfactory training extend to aging-related cognitive decline.

Studies on olfactory training (OT) outcomes have mostly been limited to olfactory performance, while direct neural connections between olfactory system and amygdala-hippocampal complex allow expecting OT to have psychological effects. To address this hypothesis, we examined olfactory, cognitive and emotional effects of OT in the group of 68 subjects aged between 50 and 88 years (Mage = 62.8 ± 8.9 years; 28 males) who are likely to experience an age-related decline in olfactory and cognitive performance. We diversified stimuli used in the OT to verify whether odor mixtures result in more effective activation of olfactory receptor neurons than single molecule odors. Subjects were randomly assigned to one of the experimental conditions: (a) simple OT utilizing single-molecule odors; (b) mixtures OT using odor mixtures; (c) control group without OT. Results indicate beneficent effects of the simple OT on cognitive assessment, cognitive decline symptoms, and olfactory sensitivity. OT can be adapted from otorhinolaryngological practice to successfully serve neurocognitive research and in supporting the cognitive-related aging process. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Altered Metabolic Interrelationships in the Cortico-Limbic Circuitry in Military Service Members with Persistent Post-Traumatic Stress Disorder Symptoms Following Mild Traumatic Brain Injury.

Introduction: Comorbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are common in military service members. The aim of this study is to investigate brain metabolic interrelationships in service members with and without persistent PTSD symptoms after mTBI by using 18F-fluorodeoxyglucose (FDG) positron emission tomography. Methods: Service members (n = 408) diagnosed with mTBI were studied retrospectively. Principal component analysis was applied to identify latent metabolic systems, and the associations between metabolic latent systems and self-report measures of post-concussive and PTSD symptoms were evaluated. Participants were divided into two groups based on DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, fourth edition-Text Revision) criteria for PTSD, and structural equation modeling was performed to test a priori hypotheses on metabolic interrelationships among the brain regions in the cortico-limbic circuitry responsible for top-down control and bottom-up emotional processing. The differences in metabolic interrelationships between age-matched PTSD-absent (n = 204) and PTSD-present (n = 204) groups were evaluated. Results: FDG uptake in the temporo-limbic system was positively correlated with post-concussive and hyperarousal symptoms. For the bottom-up emotional processing, the insula and amygdala-hippocampal complex in the PTSD-present group had stronger metabolic interrelationships with the bilateral rostral anterior cingulate, left lingual, right lateral occipital, and left superior temporal cortices, but a weaker relationship with the right precuneus cortex, compared with the PTSD-absent group. For the top-down control, the PTSD-present group had decreased metabolic engagements of the dorsolateral prefrontal cortex on the amygdala. Discussion: Our results suggest altered metabolic interrelationships in the cortico-limbic circuitry in mTBI subjects with persistent PTSD symptoms, which may underlie the pathophysiological mechanisms of comorbid mTBI and PTSD. Impact statement This is the first 18F-fluorodeoxyglucose positron emission tomography study to investigate brain metabolic interrelationships in service members with persistent post-traumatic stress disorder (PTSD) symptoms after mild traumatic brain injury (mTBI). We identified that the temporo-limbic metabolic system was associated with post-concussive and hyperarousal symptoms. Further, brain metabolic interrelationships in the cortico-limbic circuitry were altered in mTBI subjects with significant PTSD symptoms compared with those without them.

Neurophysiological phenotypes of pharmacoresistant temporal lobe epilepsy

Patients with a drug-resistant form of epilepsy can be treated by neurosurgery through the destruction or separation of the epileptic focus. If the results of clinical, neuro-imaging and neurophysiological methods are discordant, then the localization of the epileptogenic zone is performed based on the results of long-term invasive monitoring of the bioelectrical activity of the cortex and deep structures of the brain. The aim of this work was the retrospective analysis of the results of invasive monitoring of the bioelectrical activity of the brain to clarify the mechanisms of the formation of patterns of interictal and ictal activity in structural epilepsy. The study included 35 patients (18 men, 17 women) with drug-resistant temporal lobe epilepsy, who were treated at the Polenov Neurosurgical Institute. The examination included video-EEG monitoring, long-term invasive monitoring of bioelectrical activity of the cortex, and deep brain structures. The patients were divided into two groups according to the type of surgical treatment: 1) micro-surgical resection of the epileptic focus, including the zone of structural changes (24 patients); 2) stereotactic destruction of the amygdala-hippocampal complex (6 patients). The follow-up of the outcomes of the surgical treatment took place over 2-3 years. Depending on the results of the surgical treatment, the patients were divided into two groups: 1) patients with a favorable outcome (Engel 1–2) — 15 patients and 2) patients with no positive dynamics and a relatively poor outcome (Engel 3–4) — 15 patients. The results obtained showed that the patterns of interictal and ictal activity in their totality determine the neurophysiology, i.e the phenotype of temporal lobe epilepsy, reflecting the interference of pathogenetic and sanogenetic mechanisms. The localization of the epileptogenic zone should be based on the cumulative assessment of interictal and ictal activity. The presence of more than one focus of interictal activity, the secondary spread of epileptiform activity from the primary focus, are prognostically unfavorable factors.

Psychopathological Syndromes Across Affective and Psychotic Disorders Correlate With Gray Matter Volumes.

More than a century of research on the neurobiological underpinnings of major psychiatric disorders (major depressive disorder [MDD], bipolar disorder [BD], schizophrenia [SZ], and schizoaffective disorder [SZA]) has been unable to identify diagnostic markers. An alternative approach is to study dimensional psychopathological syndromes that cut across categorical diagnoses. The aim of the current study was to identify gray matter volume (GMV) correlates of transdiagnostic symptom dimensions. We tested the association of 5 psychopathological factors with GMV using multiple regression models in a sample of N = 1069 patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for MDD (n = 818), BD (n = 132), and SZ/SZA (n = 119). T1-weighted brain images were acquired with 3-Tesla magnetic resonance imaging and preprocessed with CAT12. Interactions analyses (diagnosis × psychopathological factor) were performed to test whether local GMV associations were driven by DSM-IV diagnosis. We further tested syndrome specific regions of interest (ROIs). Whole brain analysis showed a significant negative association of the positive formal thought disorder factor with GMV in the right middle frontal gyrus, the paranoid-hallucinatory syndrome in the right fusiform, and the left middle frontal gyri. ROI analyses further showed additional negative associations, including the negative syndrome with bilateral frontal opercula, positive formal thought disorder with the left amygdala-hippocampus complex, and the paranoid-hallucinatory syndrome with the left angular gyrus. None of the GMV associations interacted with DSM-IV diagnosis. We found associations between psychopathological syndromes and regional GMV independent of diagnosis. Our findings open a new avenue for neurobiological research across disorders, using syndrome-based approaches rather than categorical diagnoses.

Interaction of FKBP5 variant rs3800373 and city living alters the neural stress response in the anterior cingulate cortex

Psychosocial stress effects of urban living are associated with substantially increased risk for schizophrenia, mood and anxiety disorders, by altering stress-induced activity in the amygdala and pregenual anterior cingulate cortex (ACC). Genetic factors are likely to modulate the impact of city living on stress processing. Growing evidence suggests a key role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of stress-related disorders. Here we investigated the interaction of city living and genetic variation in FKBP5 (rs3800373) on neural activity in stress-sensitive brain systems. Functional magnetic resonance imaging was performed in 31 healthy young adults using the Montreal Imaging Stress Task. Subjects were divided into groups depending on the number of inhabitants of their current residency. There was a significant main effect of city living on neural activity in the amygdala-hippocampus complex, replicating prior findings. Moreover, we found an interaction between rs3800373 and city living modulating responses in the bilateral subgenual ACC and right pregenual ACC. Specifically, only city dwellers carrying the FKBP5 minor risk allele showed increased stress responses in the subgenual and pregenual ACC when compared to those living in small towns. A significant gene-environment interaction on neural stress responses in the amygdala or hippocampus was only found in FKBP5 major allele carriers. These results point to a potential role of the FKBP5 rs3800373 minor risk allele in predisposing those who live in bigger cities to changes of functional responsivity in the pre- and subgenual ACC, thereby increasing the risk for developing stress-related mental disorders.

Facial Emotion Perception in Borderline Personality Disorder: Differential Neural Activation to Ambiguous and Threatening Expressions and Links to Impairments in Self and Interpersonal Functioning

BackgroundMany individuals with borderline personality disorder (BPD) perceive emotional expressions in faces intended to convey no emotion and display a heightened sensitivity to facial expressions conveying threat, such as fear. In BPD, the amygdala activates in response to ambiguous and threatening facial expressions, although the differential sensitivity of this brain region to higher and lower intensities of fearful expressions and the relationship of this neural activity to personality impairments have not yet been investigated. MethodsIn the present study, we examined brain activation during an implicit facial emotion task with neutral faces and fearful expressions displayed at 50% and 100% intensity in patients with BPD (n=45) and healthy controls (HC; n=25). ResultsOn neutral faces, higher brain activation was found in BPD compared to HC in the right temporal pole, amygdala, hippocampus, pallidum, and orbitofrontal cortex, whereas no significant whole-brain group differences were observed for either intensity of fearful expressions. A region-of-interest analysis focused on the amygdala-hippocampal complex showed greater activation for neutral and 50%-intensity fearful faces in BPD. Severity of personality impairment in the domains of empathy and identity were associated with higher precuneus activity during neutral and 100%-fearful face processing. LimitationsBrain activation differences of this naturalistic severely ill inpatient sample may be influenced by comorbid Axis-I disorders often seen in samples of BPD. Conclusions: These findings suggest a heightened amygdala-hippocampal response to neutral faces and moderate-intensity fearful expressions in BPD, while self and interpersonal impairments are associated with task-based activations in regions implicated in self-referential processes.

Childhood Maltreatment Alters the Neural Processing of Chemosensory Stress Signals.

Accumulating evidence suggests that childhood maltreatment (CM) confers risk for psychopathology later in life by inducing hypervigilance to social threat cues such as fearful faces. However, it remains unclear whether the modulatory impact of CM extents to the olfactory domain of social communication in humans. To address this question, we examined whether CM modulates the neural processing of chemosensory threat signals in sweat and whether CM affects the stress-reducing effects of oxytocin (OXT) in this context. In a randomized, double-blind within-subject functional MRI study design, 58 healthy participants (30 females) received intranasal OXT (40 IU) or placebo (PLC) and completed a forced-choice emotion recognition task with faces of varying emotion intensities (neutral to fearful) while exposed to sweat stimuli and a non-social control odor. Axillary sweat samples were collected from 30 healthy male donors undergoing an acute psychosocial stressor (stress) and ergometer training (sport) as control in a pre-study. CM was assessed by the 25-item Childhood Trauma Questionnaire (CTQ). The final fMRI analysis included 50 healthy participants (26 females). Regression analysis showed a stress-specific association of CTQ scores with amygdala hyperreactivity, hippocampal deactivation, and increased functional connectivity between the amygdala and the hippocampus, medial orbitofrontal cortex, and the anterior cingulate cortex (ACC) under PLC. Furthermore, we observed a positive association of CTQ scores and the dampening effects of OXT on stress-related amygdala responses. Our findings suggest that CM may induce hypervigilance to chemosensory threat cues in a healthy sample due to inefficient frontolimbic inhibition of amygdala activation. Future studies should investigate whether increased recruitment of the intralimbic amygdala-hippocampus complex reflects a compensatory mechanism that prevents the development of psychopathology in those who have experienced CM. Furthermore, the results reveal that the stress-specific effects of OXT in the olfactory domain are more pronounced in participants with increasing levels of CM exposure.

Effect of childhood physical abuse on social anxiety is mediated via reduced frontal lobe and amygdala-hippocampus complex volume in adult clinical high-risk subjects

BackgroundChildhood adverse experiences (CAE) are associated with clinical psychiatric disorders and symptoms, and with volumetric abnormalities in the amygdala-hippocampus complex (AmHiC) and frontal lobe (FroL) in adulthood. AimTo study whether CAE are associated with reduced AmHiC and FroL and whether these structures mediate the effect of CAE on social anxiety and depression. MethodIn seven European centres, 374 patients with recent onset of psychosis (n = 127), clinical high-risk to psychosis (n = 119) or recent onset of depression (n = 128) were scanned with MRI and their FroL and AmHiC volumes were measured. They all completed self-report scales for assessment of CAE, social anxiety and depression. ResultsOf the CAE domains, physical abuse was associated specifically with reduced grey and white matter volumes of FroL and AmHiC in psychotic and high-risk patients. After controlling intracranial volume, PhyAb associated significantly with FroL and its grey matter volume in high-risk patients only. In mediation analyses, the effect of physical abuse on social anxiety was mediated via reduced FroL grey mater volume in high-risk patients. In them, when the effects of AmHiC and depression were controlled, the effect of physical abuse on social anxiety was mediated via FroL grey matter volume reduction. ConclusionsChildhood physical abuse is associated with reduced frontal lobe and amygdala-hippocampus complex volume in adult subjects with psychotic symptoms. Reduced frontal lobe and amygdala-hippocampus complex volume mediate the effect of physical abuse on social anxiety in high-risk patients. The effect of physical abuse on depression-independent social anxiety is mediated via reduced frontal lobe.

Mild traumatic brain injury impacts associations between limbic system microstructure and post-traumatic stress disorder symptomatology.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals, yet the neuropathological mechanisms that contribute to this disorder remain to be fully determined. Moreover, it is unclear how exposure to mild traumatic brain injury (mTBI), a condition that is often comorbid with PTSD, particularly among military personnel, affects the clinical and neurological presentation of PTSD. To address these issues, the present study explores relationships between PTSD symptom severity and the microstructure of limbic and paralimbic gray matter brain regions, as well as the impact of mTBI comorbidity on these relationships. Structural and diffusion MRI data were acquired from 102 male veterans who were diagnosed with current PTSD. Diffusion data were analyzed with free-water imaging to quantify average CSF-corrected fractional anisotropy (FA) and mean diffusivity (MD) in 18 limbic and paralimbic gray matter regions. Associations between PTSD symptom severity and regional average dMRI measures were examined with repeated measures linear mixed models. Associations were studied separately in veterans with PTSD only, and in veterans with PTSD and a history of military mTBI. Analyses revealed that in the PTSD only cohort, more severe symptoms were associated with higher FA in the right amygdala-hippocampus complex, lower FA in the right cingulate cortex, and lower MD in the left medial orbitofrontal cortex. In the PTSD and mTBI cohort, more severe PTSD symptoms were associated with higher FA bilaterally in the amygdala-hippocampus complex, with higher FA bilaterally in the nucleus accumbens, with lower FA bilaterally in the cingulate cortex, and with higher MD in the right amygdala-hippocampus complex. These findings suggest that the microstructure of limbic and paralimbic brain regions may influence PTSD symptomatology. Further, given the additional associations observed between microstructure and symptom severity in veterans with head trauma, we speculate that mTBI may exacerbate the impact of brain microstructure on PTSD symptoms, especially within regions of the brain known to be vulnerable to chronic stress. A heightened sensitivity to the microstructural environment of the brain could partially explain why individuals with PTSD and mTBI comorbidity experience more severe symptoms and poorer illness prognoses than those without a history of brain injury. The relevance of these microstructural findings to the conceptualization of PTSD as being a disorder of stress-induced neuronal connectivity loss is discussed.

Multiple extinction contexts modulate the neural correlates of context-dependent extinction learning and retrieval.

Exposure therapy is a successful treatment for patients with anxiety and fear-related disorders. Extinction of conditioned fear comprises one important mechanism underlying the effects of exposure therapy. Yet, relapses frequently occur in the long-term, probably related to difficulties in generalizing the extinction of conditioned fear to new contexts, leading to renewal of conditioned fear. Extinction training in multiple extinction contexts depicts a promising opportunity to reduce this renewal of conditioned fear. However, the underlying neural correlates are unknown yet. In this functional magnetic resonance imaging study, 49 healthy men participated in a fear conditioning paradigm with fear acquisition training in context A on a first day, extinction training in a single context (B1) or in four different contexts (B1-B4) one day later, and fear and extinction recall and reinstatement in context B1 and a novel context C on a third day one week later. Multiple extinction contexts led to a stronger differential activation decrease in the hippocampus during extinction learning compared to a single extinction context. One week later, the multiple context group compared with the single context group showed reduced differential amygdala activation during fear renewal in the novel context C compared with the extinction context B1. Furthermore, multiple extinction contexts diminished amygdala activation during a subsequent reinstatement test in context B1. However, there were no significant differences in differential conditioned SCRs. These results indicate that the use of multiple extinction contexts during extinction training leads to reduced conditioned responses in the amygdala-hippocampus complex.

Brain structural effects of treatments for depression and biomarkers of response: a systematic review of neuroimaging studies.

Antidepressive pharmacotherapy (AD), electroconvulsive therapy (ECT) and cognitive behavioural therapy (CBT) are effective treatments for major depressive disorder. With our review, we aim to provide a systematic overview of neuroimaging studies that investigate the effects of AD, ECT and CBT on brain grey matter volume (GMV) and biomarkers associated with response. After a systematic database research on PubMed, we included 50 studies using magnetic resonance imaging and investigating (1) changes in GMV, (2) pre-treatment GMV biomarkers associated with response, or (3) the accuracy of predictions of response to AD, ECT or CBT based on baseline GMV data. The strongest evidence for brain structural changes was found for ECT, showing volume increases within the temporal lobe and subcortical structures - such as the hippocampus-amygdala complex, anterior cingulate cortex (ACC) and striatum. For AD, the evidence is heterogeneous as only 4 of 11 studies reported significant changes in GMV. The results are not sufficient in order to draw conclusions about the structural brain effects of CBT. The findings show consistently that higher pre-treatment ACC volume is associated with response to AD, ECT and CBT. An association of higher pre-treatment hippocampal volume and response has only been reported for AD. Machine learning approaches based on pre-treatment whole brain patterns reach accuracies of 64-90% for predictions of AD or ECT response on the individual patient level. The findings underline the potential of brain biomarkers for the implementation in clinical practice as an additive feature within the process of treatment selection.