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High‐frequency oscillations (HFOs) are associated with normal brain function, but are also increasingly recognized as potential biomarkers of epileptogenic tissue. Considering the important role of interneuron activity in physiological HFO generation, we studied their modulation by midazolam (MDZ), an agonist of γ‐aminobutyric acid type A (GABAA)–benzodiazepine receptors. Here, we analyzed 80 intracranial electrode contacts in amygdala and hippocampus of 13 patients with drug‐refractory focal epilepsy who had received MDZ for seizure termination during presurgical monitoring. Ripples (80–250 Hz) and fast ripples (FRs; 250–400 Hz) were compared before and after seizures with MDZ application, and according to their origin either within or outside the individual seizure onset zone (SOZ). We found that MDZ distinctly suppressed all HFOs (ripples and FRs), whereas the reduction of ripples was significantly less pronounced inside the SOZ compared to non‐SOZ contacts. The rate of FRs inside the SOZ was less affected, especially in hippocampal contacts. In a few cases, even a marked increase of FRs following MDZ administration was seen. Our results demonstrate, for the first time, a significant HFO modulation in amygdala and hippocampus by MDZ, thus giving insights into the malfunction of GABA‐mediated inhibition within epileptogenic areas and its role in HFO generation. [ABSTRACT FROM AUTHOR]

This article discusses the role of the amygdala and hippocampus in emotional imagery. It challenges the notion that the amygdala is consistently activated during emotional processing, suggesting that conflicting results may be due to variations in task design and the proximity of the amygdala to other activated regions. The article presents evidence that the anterior hippocampus, rather than the amygdala, may play a key role in emotional processing in some contexts. The authors recommend including an amygdala perceptual localizer task and using sagittal views in future studies to accurately assess and confirm amygdala involvement. [Extracted from the article]

Immature neurons expressing the Bcl2 protein are present in various regions of the mammalian brain, including the amygdala and the entorhinal and perirhinal cortices. Their functional role is unknown but we have previously shown that neonatal and adult hippocampal lesions increase their differentiation in the monkey amygdala. Here, we assessed whether hippocampal lesions similarly affect immature neurons in the entorhinal and perirhinal cortices. Since Bcl2‐positive cells were found mainly in areas Eo, Er, and Elr of the entorhinal cortex and in layer II of the perirhinal cortex, we also used Nissl‐stained sections to determine the number and soma size of immature and mature neurons in layer III of area Er and layer II of area 36 of the perirhinal cortex. We found different structural changes in these regions following hippocampal lesions, which were influenced by the time of the lesion. In neonate‐lesioned monkeys, the number of immature neurons in the entorhinal and perirhinal cortices was generally higher than in controls. The number of mature neurons was also higher in layer III of area Er of neonate‐lesioned monkeys but no differences were found in layer II of area 36. In adult‐lesioned monkeys, the number of immature neurons in the entorhinal cortex was lower than in controls but did not differ from controls in the perirhinal cortex. The number of mature neurons in layer III of area Er did not differ from controls, but the number of small, mature neurons in layer II of area 36 was lower than in controls. In sum, hippocampal lesions impacted populations of mature and immature neurons in discrete regions and layers of the entorhinal and perirhinal cortices, which are interconnected with the amygdala and provide major cortical inputs to the hippocampus. These structural changes may contribute to some functional recovery following hippocampal injury in an age‐dependent manner. [ABSTRACT FROM AUTHOR]

Distinct neural effects of threat versus deprivation emerge by childhood, but little data are available in infancy. Withdrawn versus negative parenting may represent dimensionalized indices of early deprivation versus early threat, but no studies have assessed neural correlates of withdrawn versus negative parenting in infancy. The objective of this study was to separately assess the links of maternal withdrawal and maternal negative/inappropriate interaction with infant gray matter volume (GMV), white matter volume (WMV), amygdala, and hippocampal volume. Participants included 57 mother‐infant dyads. Withdrawn and negative/inappropriate aspects of maternal behavior were coded from the Still‐Face Paradigm at four months infant age. Between 4 and 24 months (M age = 12.28 months, SD = 5.99), during natural sleep, infants completed an MRI using a 3.0 T Siemens scanner. GMV, WMV, amygdala, and hippocampal volumes were extracted via automated segmentation. Diffusion weighted imaging volumetric data were also generated for major white matter tracts. Maternal withdrawal was associated with lower infant GMV. Negative/inappropriate interaction was associated with lower overall WMV. Age did not moderate these effects. Maternal withdrawal was further associated with reduced right hippocampal volume at older ages. Exploratory analyses of white matter tracts found that negative/inappropriate maternal behavior was specifically associated with reduced volume in the ventral language network. Results suggest that quality of day‐to‐day parenting is related to infant brain volumes during the first two years of life, with distinct aspects of interaction associated with distinct neural effects. [ABSTRACT FROM AUTHOR]

In temporal associations, a conditioned stimulus (CS) is separated by a time interval from the unconditioned stimulus (US), which activates the prelimbic cortex (PL) to maintain a CS representation over time. However, it is unknown whether the PL participates, besides the encoding, in the memory consolidation, and thus directly, with activity‐dependent changes or indirectly, by modulation of activity‐dependent changes in other brain regions. We investigated brain regions supporting the consolidation of associations with intervals and the influence of PL activity in this consolidation process. For this, we observed in Wistar rats the effect of pre‐training PL inactivation by muscimol in CREB (cAMP response element‐binding protein) phosphorylation, which is essential for memory consolidation, in subdivisions of the medial prefrontal cortex (mPFC), hippocampus, and amygdala 3 h after the training in the contextual fear conditioning (CFC) or CFC with 5‐s interval (CFC‐5s), fear associations without or with an interval between the CS and US, respectively. Both the CFC‐5s and CFC training increased phosphorylation of CREB in the PL and infralimbic cortex (IL); lateral (LA) and basolateral (BLA) amygdala; dorsal CA1 (dCA1); dorsal (dDG), and ventral dentate gyrus, and the CFC‐5s training in the central amygdala (CEA). PL activity was necessary for the CREB phosphorylation in the PL, BLA, CEA, dCA1, and dDG only in animals trained in the CFC‐5s. The cingulate cortex, ventral CA1, and ventral subiculum did not have learning‐induced phosphorylation of CREB. These results suggest that the mPFC, hippocampus, and amygdala support the consolidation of associations with or without intervals and that PL activity influences consolidation in the dorsal hippocampus and amygdala in temporal associations. Thereby, the PL contributes directly and indirectly by modulation to memory consolidation. The time interval engaged the PL early in recent memory consolidation. Results expanded PL's role beyond the time interval and remote memory consolidation. [ABSTRACT FROM AUTHOR]

Objective: To identify changes in regional cerebral blood flow (CBF) associated with premonitory symptoms (PS) of nitroglycerin (NTG)‐triggered migraine attacks. Background: PS could provide insights into attack initiation and alterations in neuronal function prior to headache onset. Methods: We undertook a functional imaging study using a double‐blind placebo‐controlled randomized approach in patients with migraine who spontaneously experienced PS, and in whom PS and migraine‐like headache could be induced by administration of NTG. All study visits took place in a dedicated clinical research facility housing a monitoring area with clinical beds next to a 3Tesla magnetic resonance imaging scanner. Fifty‐three patients with migraine were enrolled; imaging on at least one triggered visit was obtained from 25 patients, with 21 patients completing the entire imaging protocol including a placebo visit. Whole brain CBF maps were acquired using 3D pseudo‐continuous arterial spin labeling (3D pCASL). Results: The primary outcome was that patients with migraine not taking preventive treatment (n = 12) displayed significant increases in CBF in anterior cingulate cortex, caudate, midbrain, lentiform, amygdala and hippocampus (p < 0.05 family‐wise error‐corrected) during NTG‐induced PS. A separate region of interest analysis revealed significant CBF increases in the region of the hypothalamus (p = 0.006, effect size 0.77). Post hoc analyses revealed significant reductions in CBF over the occipital cortices in participants with a history of migraine with underlying aura (n = 14). Conclusions: We identified significant regional CBF changes associated with NTG‐induced PS, consistent with other investigations and with novel findings, withstanding statistical comparison against placebo. These findings were not present in patients who continually took preventive medication. Additional findings were identified only in participants who experience migraine with aura. Understanding this biological and treatment‐related heterogeneity is vital to evaluating functional imaging outcomes in migraine research. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co‐occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key brain region that is known to contribute to the aetiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from this brain region that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety‐ and fear‐related behaviours. However, it is not known if this pathway influences alcohol drinking‐related behaviours. Here, we employed a rodent operant self‐administration regimen that procedurally separates appetitive (e.g. seeking) and consummatory (e.g., drinking) behaviours, chemogenetics and brain region‐specific microinjections, to determine if BLA‐vHC circuitry influences alcohol and sucrose drinking‐related measures. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety‐like behaviours on the elevated plus maze. We then demonstrated that inhibiting the BLA‐vHC pathway significantly reduced appetitive drinking‐related behaviours for both alcohol and sucrose while having no effect on consummatory measures. Taken together, these findings provide the first indication that the BLA‐vHC circuit may regulate appetitive reward seeking directed at alcohol and natural rewards and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor‐related disorders. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder (AUD) and post‐traumatic stress disorder (PTSD) are highly comorbid, yet there is a lack of preclinical research investigating how prior ethanol (EtOH) dependence influences the development of a PTSD‐like phenotype. Furthermore, the neuroimmune system has been implicated in the development of both AUD and PTSD, but the extent of glial involvement in this context remains unclear. A rodent model was developed to address this gap in the literature. Methods: We used a 15‐day exposure to the 5% w/v EtOH low‐fat Lieber‐DeCarli liquid diet in combination with the stress‐enhanced fear learning (SEFL) paradigm to investigate the effects of chronic EtOH consumption on the development of a PTSD‐like phenotype. Next, we used a reverse transcription quantitative real‐time polymerase chain reaction to quantify mRNA expression of glial cell markers GFAP (astrocytes) and CD68 (microglia) following severe footshock stress in EtOH‐withdrawn rats. Finally, we tested the functional contribution of dorsal hippocampal (DH) astrocytes in the development of SEFL in EtOH‐dependent rats using astrocyte‐specific Gi designer receptors exclusively activated by designer drugs (Gi‐DREADD). Results: Results demonstrate that chronic EtOH consumption and withdrawal exacerbate future SEFL. Additionally, we found significantly increased GFAP mRNA expression in the dorsal and ventral hippocampus and amygdalar complex following the severe stressor in EtOH‐withdrawn animals. Finally, the stimulation of the astroglial Gi‐DREADD during EtOH withdrawal prevented the EtOH‐induced enhancement of SEFL. Conclusions: Collectively, results indicate that prior EtOH dependence and withdrawal combined with a severe stressor potentiate future enhanced fear learning. Furthermore, DH astrocytes significantly contribute to this change in behavior. Overall, these studies provide insight into the comorbidity of AUD and PTSD and the potential neurobiological mechanisms behind increased susceptibility to a PTSD‐like phenotype in individuals with AUD. [ABSTRACT FROM AUTHOR]

The amygdala is a key brain region involved in emotional memory formation. It is also responsible for memory modulation in other brain areas. Under extreme conditions, amygdala modulation may lead to the generation of abnormal plasticity and trauma‐related psychopathologies. However, the amygdala itself is a dynamic brain region, which is amenable to long‐term plasticity and is affected by emotional experiences. These alterations may modify the way the amygdala modulates activity and plasticity in other related brain regions, which in turn may alter the animal's response to subsequent challenges in what could be termed as "Behavioral metaplasticity."Because of the reciprocal interactions between the amygdala and other emotion processing regions, such as the medial prefrontal cortex (mPFC) or the hippocampus, experience‐induced intra‐amygdala metaplasticity could lead to alterations in mPFC‐dependent or hippocampus‐dependent behaviors. While initiated by alterations within the basolateral amygdala (BLA), such alterations in other brain regions may come to be independent of BLA modulation, thus establishing what may be termed "Trans‐regional metaplasticity." In this article, we review evidence supporting the notions of intra‐BLA metaplasticity and how this may develop into "Trans‐regional metaplasticity." Future research is needed to understand how such dynamic metaplastic alterations contribute to developing psychopathologies, and how this knowledge may be translated into promoting novel interventions in psychopathologies associated with fear, stress, and trauma. [ABSTRACT FROM AUTHOR]

Schizotypy and psychotic‐like experiences (PLE) form part of the wider psychosis continuum and may have brain structural correlates in nonclinical cohorts. This study aimed to compare the effects of differential schizotypy dimensions, PLE, and their interaction on hippocampal subfields and amygdala volumes in the absence of clinical psychopathology. In a cohort of 367 psychiatrically healthy individuals, we assessed schizotypal traits using the Oxford‐Liverpool Inventory of Life Experiences (O‐LIFE) and PLE using the short form of the Prodromal Questionnaire (PQ‐16). Based on high‐resolution structural MRI scans, we used automated segmentation to estimate volumes of limbic structures. Sex and total intracranial volume (Step 1), PLE and schizotypy dimensions (Step 2), and their interaction terms (Step 3) were entered as regressors for bilateral amygdala and hippocampal subfield volumes in hierarchical multiple linear regression models. Positive schizotypy, but not PLE, was negatively associated with left amygdala and subiculum volumes. O‐LIFE Impulsive Nonconformity, as well as the two‐way interaction between positive schizotypy and PLE, were associated with larger left subiculum volumes. None of the estimators for right hemispheric hippocampal subfield volumes survived correction for multiple comparisons. Our findings support differential associations of hippocampus subfield volumes with trait dimensions rather than PLE, and support overlap and interactions between psychometric positive schizotypy and PLE. In a healthy cohort without current psychosis risk syndromes, the positive association between PLE and hippocampal subfield volume occurred at a high expression of positive schizotypy. Further studies combining stable, transient, and genetic parameters are required. [ABSTRACT FROM AUTHOR]

Behavioral inhibition is a temperamental disposition to react warily when confronted by unfamiliar people, objects, or events. Behaviorally inhibited children are at greater risk of developing anxiety disorders later in life. Previous studies reported that individuals with a history of childhood behavioral inhibition exhibit abnormal activity in the hippocampus and amygdala. However, few studies have investigated the structural differences that may underlie these functional abnormalities. In this exploratory study, we evaluated rhesus monkeys exhibiting a phenotype consistent with human behavioral inhibition. We performed quantitative neuroanatomical analyses that cannot be performed in humans including estimates of the volume and neuron number of distinct hippocampal regions and amygdala nuclei in behaviorally inhibited and control rhesus monkeys. Behaviorally inhibited monkeys had larger volumes of the rostral third of the hippocampal field CA3, smaller volumes of the rostral third of CA2, and smaller volumes of the accessory basal nucleus of the amygdala. Furthermore, behaviorally inhibited monkeys had fewer neurons in the rostral third of CA2. These structural differences may contribute to the functional abnormalities in the hippocampus and amygdala of behaviorally inhibited individuals. These structural findings in monkeys are consistent with a reduced modulation of amygdala activity via prefrontal cortex projections to the accessory basal nucleus. Given the putative roles of the amygdala in affective processing, CA3 in associative learning and CA2 in social memory, increased amygdala and CA3 activity, and diminished CA2 structure and function, may be associated with increased social anxiety and the heritability of behavioral inhibition. The findings from this exploratory study compel follow‐up investigations with larger sample sizes and additional analyses to provide greater insight and more definitive answers regarding the neurobiological bases of behavioral inhibition. [ABSTRACT FROM AUTHOR]

Introduction: Several lines of evidence suggest that the amygdala–hippocampus is involved in the epileptogenic network of juvenile myoclonic epilepsy (JME). The aim of this study was to investigate the alterations in the individual nuclei of the amygdala and hippocampal subfields, and the intrinsic amygdala‐hippocampal network of patients with JME compared to healthy controls. Methods: This retrospective study conducted at a single tertiary hospital involved 35 patients with newly diagnosed JME, and 34 healthy subjects. We calculated the individual structural volumes of 18 nuclei in the amygdala, and 38 hippocampal subfields using three‐dimensional volumetric T1‐weighted imaging and FreeSurfer program. We also performed an analysis of the intrinsic amygdala‐hippocampal global and local network based on these volumes using a graph theory and Brain Analysis using Graph Theory (BRAPH) program. We investigated the differences in these volumes and network measures between patients with JME and healthy controls. Results: There were no significant volume differences in the nuclei of the amygdala and hippocampal subfields between patients with JME and healthy controls. However, we found significant differences in the global network between patients with JME and healthy controls. The mean clustering coefficient was significantly decreased in patients with JME compared to healthy controls (0.473 vs. 0.653, p =.047). In addition, specific regions in the hippocampal subfields showed significant differences in the local network between the two groups. The betweenness centrality of the right CA1‐head, right hippocampus–amygdala‐transition area, left hippocampal fissure, left fimbria, and left CA3‐head, was increased in patients with JME compared to healthy controls. Conclusion: The intrinsic amygdala‐hippocampal global and local networks differed in patients with JME compared to healthy controls, which may be related to the pathogenesis of JME, and memory dysfunction in patients with JME. [ABSTRACT FROM AUTHOR]

The extinction of contextual fear is commonly an essential requirement for successful exposure therapy for fear disorders. However, experimental work on extinction of contextual fear is limited, and there little or no directly relevant theoretical work. Here, we extend BACON, a neurocomputational model of context fear conditioning that provides plausible explanations for a number of aspects of context fear conditioning, to deal with extinction (calling the model BaconX). In this model, contextual representations are formed in the hippocampus and association of fear to them occurs in the amygdala. Representation creation, conditionability, and development of between‐session extinction are controlled by degree of confidence (assessed by the Bayesian weight of evidence) that an active contextual representation is in fact that of the current context (i.e., is "valid"). The model predicts that: (1) extinction which persists between sessions will occur only if at a sessions end there is high confidence that the active representation is valid. It follows that the shorter the context placement‐to‐US (shock) interval ("PSI") and the less is therefore learned about context, the longer extinction sessions must be for enduring extinction to occur, while too short PSIs will preclude successful extinction. (2) Short‐PSI deficits can be rescued by contextual exposure even after conditioning has occurred. (3) Learning to discriminate well between a conditioned and similar safe context requires representations of each to form, which may not occur if PSI was too short. (4) Extinction‐causing inhibition must be applied downstream of the conditioning locus for reasonable generalization properties to be generated. (5) Context change tends to cause return of extinguished contextual fear. (6). Extinction carried out in the conditioning context generalizes better than extinction executed in contexts to which fear has generalized (as done in exposure therapy). (7) BaconX suggests novel approaches to exposure therapy. [ABSTRACT FROM AUTHOR]

Background: The Alcohol and Addiction Research Domain Criteria (AARDoC) propose that alcohol use disorder is associated with neural dysfunction in three primary domains: incentive salience, negative emotionality, and executive function. Prior studies in heavy drinking samples have examined brain activation changes associated with alcohol and negative affect cues, representing the incentive salience and negative emotionality domains, respectively. Yet studies examining such cue‐induced changes in functional connectivity (FC) are relatively sparse. Methods: Nontreatment‐seeking heavy drinking adults (N = 149, 56.0% male, 48.6% non‐white, mean age 34.8 years (SD = 10.0)) underwent functional magnetic resonance imaging during presentation of alcohol, negative, and neutral pictures. We focused on FC changes involving the nucleus accumbens and amygdala in addition to activation and FC correlations with self‐reported AUD severity. Results: For alcohol cues versus neutral cues, we observed accumbens FC changes in the cerebellum and prefrontal cortex (PFC), and amygdala FC changes with occipital, parietal, and hippocampal regions. AUD severity correlated positively with activation in the cerebellum (p < 0.05), accumbens FC in the cingulate gyri, somatosensory gyri, and cerebellum (p < 0.05), and with amygdala FC in the PFC and inferior parietal lobule (p < 0.05) for alcohol cues versus neutral cues. For negative cues versus neutral cues, we observed accumbens FC changes in the lateral temporal, occipital, and parietal regions, and amygdala FC changes in the fusiform and lingual gyri (p < 0.05). Conclusions: The present findings provide empirical support for the AARDoC domains of incentive salience and negative emotionality and indicate that AUD severity is associated with salience and response control for reward cues. When covarying for differences in nonalcohol substance use and mood disorder diagnoses, AUD severity was also associated with emotional reactivity for negative cues. [ABSTRACT FROM AUTHOR]

Elucidating the neural mechanisms of memory in the brain is a central goal of neuroscience. Here, we discuss modern‐day transcriptomics methodologies, and how they are well‐poised to revolutionize our insight into memory mechanisms at unprecedented resolution and throughput. Focusing on the hippocampus and amygdala, two regions extensively examined in memory research, we show how single‐cell transcriptomics technologies have been leveraged to understand the naïve state of these brain regions. Building upon this foundation, we show that these technologies can be applied to single‐trial learning paradigms to comprehensively identify molecules and cells that participate in the encoding and retrieval of memory. Transcriptomics also provides an opportunity to understand the cell‐type organization of the human hippocampus and amygdala, and due to conservation of these brain regions between humans and rodents, to infer behavioral and causal contributions in the human brain by leveraging rodent cell‐type homologies and interventions. Ultimately, such transcriptomic technologies are poised to usher in a qualitatively novel understanding of memory in the brain. [ABSTRACT FROM AUTHOR]

Obese individuals exhibit brain functional abnormalities in multiple regions implicated in reward/motivation, emotion/memory, homeostatic regulation, and executive control when exposed to food cues and during rest. However, it remains unclear whether abnormal brain responses to food cues might account for or relate to their abnormal activity in resting state. This information would be useful for understanding the neural mechanisms behind hyperactive responses to food cues, a critical marker of obesity. Resting‐state functional magnetic resonance imaging (RS‐fMRI) and a cue‐reactivity fMRI task with high‐ (HiCal) and low‐caloric (LoCal) food cues were employed to investigate brain baseline activity and food cue‐induced activation differences in 44 obese participants (OB), in 37 overweight participants (OW), and in 37 normal weight (NW) controls. One‐way analyses of variance showed there was a group difference in the left hippocampus/amygdala activity during resting state and during food‐cue stimulation (pFWE < 0.05); post‐hoc tests showed the OB group had both greater basal activity and greater food cue‐induced activation than the OW and NW groups; OW had higher activity in the hippocampus/amygdala than the NW group, which was only significant during resting state. In the OB group, resting‐state activity in the left hippocampus/amygdala was positively correlated with activation induced by HiCal food cues, and both of these measures correlated with body mass index (BMI). Mediation analysis showed that the relationship between BMI and hippocampus/amygdala response to HiCal food cues was mediated by their resting‐state activity. These findings suggest a close association between obesity and brain functional abnormality in the hippocampus/amygdala. They also indicate that resting‐state activity in the hippocampus/amygdala may impact these regions' responses to food cues. [ABSTRACT FROM AUTHOR]

The hippocampus and amygdala are important structures in the posttraumatic stress disorder (PTSD); however, the exact relationship between these structures and stress or PTSD remains unclear. Moreover, they consist of several functionally distinct subfields/subregions that may serve different roles in the neuropathophysiology of PTSD. Here we present a subregional profile of the hippocampus and amygdala in 145 survivors of a major earthquake and 56 non‐traumatized healthy controls (HCs). We found that the bilateral hippocampus and left amygdala were significantly smaller in survivors than in HCs, and there was no difference between survivors with (n = 69) and without PTSD (trauma‐exposed controls [TCs], n = 76). Analyses revealed similar results in most subfields/subregions, except that the right hippocampal body (in a head‐body‐tail segmentation scheme), right presubiculum, and left amygdala medial nuclei (Me) were significantly larger in PTSD patients than in TCs but smaller than in HCs. Larger hippocampal body were associated with the time since trauma in PTSD patients. The volume of the right cortical nucleus (Co) was negatively correlated with the severity of symptoms in the PTSD group but positively correlated with the same measurement in the TC group. This correlation between symptom severity and Co volume was significantly different between the PTSD and TCs. Together, we demonstrated that generalized smaller volumes in the hippocampus and amygdala were more likely to be trauma‐related than PTSD‐specific, and their subfields/subregions were distinctively affected. Notably, larger left Me, right hippocampal body and presubiculum were PTSD‐specific; these could be preexisting factors for PTSD or reflect rapid posttraumatic reshaping. [ABSTRACT FROM AUTHOR]

Image labeling using convolutional neural networks (CNNs) are a template‐free alternative to traditional morphometric techniques. We trained a 3D deep CNN to label the hippocampus and amygdala on whole brain 700 μm isotropic 3D MP2RAGE MRI acquired at 7T. Manual labels of the hippocampus and amygdala were used to (i) train the predictive model and (ii) evaluate performance of the model when applied to new scans. Healthy controls and individuals with epilepsy were included in our analyses. Twenty‐one healthy controls and sixteen individuals with epilepsy were included in the study. We utilized the recently developed DeepMedic software to train a CNN to label the hippocampus and amygdala based on manual labels. Performance was evaluated by measuring the dice similarity coefficient (DSC) between CNN‐based and manual labels. A leave‐one‐out cross validation scheme was used. CNN‐based and manual volume estimates were compared for the left and right hippocampus and amygdala in healthy controls and epilepsy cases. The CNN‐based technique successfully labeled the hippocampus and amygdala in all cases. Mean DSC = 0.88 ± 0.03 for the hippocampus and 0.8 ± 0.06 for the amygdala. CNN‐based labeling was independent of epilepsy diagnosis in our sample (p =.91). CNN‐based volume estimates were highly correlated with manual volume estimates in epilepsy cases and controls. CNNs can label the hippocampus and amygdala on native sub‐mm resolution MP2RAGE 7T MRI. Our findings suggest deep learning techniques can advance development of morphometric analysis techniques for high field strength, high spatial resolution brain MRI. [ABSTRACT FROM AUTHOR]

Obesity is a chronic condition associated with adverse memory and emotional outcomes in humans and animal models. We have recently demonstrated that post‐weaning (i.e., periadolescent) high‐fat diet (HFD)‐induced obesity has opposite effect on hippocampal and amygdala‐dependent memory in rodents: while HFD consumption impairs spatial and relational memory, it enhances cue‐dependent emotional memory. However, it is still not clear whether this bidirectional HFD effect on memory is related to bidirectional alterations of hippocampal and amygdala synaptic plasticity and if it is influenced by the duration of diet intake. In the current study, we compared in male rats the impact of 2–3 and 6–7 months of HFD intake starting at weaning, thus covering adolescence, on in vivo long‐term potentiation (LTP) recorded simultaneously in the hippocampal area CA1 and the basolateral amygdala (BLA). As expected, 6–7 months of HFD intake abolished LTP in the CA1 and enhanced LTP in the BLA. However, 2–3 months of of HFD exposure enhanced LTP in both CA1 and BLA suggesting a transient compensatory mechanism in hippocampus. These results indicate that post‐weaning HFD intake progressively leads to bidirectional modulation of hippocampal and amygdala synaptic plasticity, as we previously demonstrated for related memory processes, yet with a different temporal dynamic. [ABSTRACT FROM AUTHOR]

Objective: Pharmacoresistance and the lack of disease‐modifying actions of current antiseizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant‐induced status epilepticus remain the models of choice to discover potential antiepileptogenic drugs, but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intra‐amygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug‐resistant temporal lobe epilepsy (TLE). Methods: Status epilepticus was induced via intra‐amygdala microinjection of kainic acid in C57BL/6 mice, and gene expression was analyzed via microarrays in hippocampal tissue at acute and chronic time‐points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug‐resistant TLE. Results: Intra‐amygdala kainic acid injection in mice triggered extensive dysregulation of gene expression that was ~3‐fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples from patients with TLE revealed a particularly high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signaling to be highly conserved across different models of epilepsy and patients. cAMP response element‐binding protein (CREB) was predicted as one of the main upstream transcription factors regulating gene expression during acute and chronic phases, and inhibition of CREB reduced seizure severity in the intra‐amygdala kainic acid model. Significance: Our findings suggest the intra‐amygdala kainic acid model faithfully replicates key molecular features of human drug‐resistant TLE and provides potential rational target approaches for disease‐modification through new insights into the unique and shared gene expression landscape in experimental epilepsy. [ABSTRACT FROM AUTHOR]

Forward models can predict sensory consequences of self‐action, which is reflected by less neural processing for actively than passively generated sensory inputs (BOLD suppression effect). However, it remains open whether forward models take the identity of a moving body part into account when predicting the sensory consequences of an action. In the current study, fMRI was used to investigate the neural correlates of active and passive hand movements during which participants saw either an on‐line display of their own hand or someone else's hand moving in accordance with their movement. Participants had to detect delays (0–417 ms) between their movement and the displays. Analyses revealed reduced activation in sensory areas and higher delay detection thresholds for active versus passive movements. Furthermore, there was increased activation in the hippocampus, the amygdala, and the middle temporal gyrus when someone else's hand was seen. Most importantly, in posterior parietal (angular gyrus and precuneus), frontal (middle, superior, and medial frontal gyrus), and temporal (middle temporal gyrus) regions, suppression for actively versus passively generated feedback was stronger when participants were viewing their own compared to someone else's hand. Our results suggest that forward models can take hand identity into account when predicting sensory action consequences. [ABSTRACT FROM AUTHOR]

This study determined the effects of intranasal pregnenolone (IN‐PREG) on acetylcholine (ACh) levels in selected areas of the rat brain, using in vivo microdialysis. Previous studies showed that PREG rapidly reaches the rodent brain after intranasal administration and that direct infusion of PREG and PREG‐S into the basal forebrain modulates ACh release in frontal cortex, amygdala, and hippocampus. In the present study, we investigated the effects of IN‐PREG on the cholinergic system in the rat brain. In the first experiment, IN‐PREG (5.6 and 11.2 mg/ml) or vehicle was applied bilaterally, and we hypothesized that IN‐PREG would increase ACh levels in amygdala, hippocampus, and frontal cortex, relative to baseline and vehicle. Dialysate was collected for 100 min, based on pilot data of duration of effect. Bilateral IN‐PREG (5.6 and 11.2 mg/ml) increased frontal cortex and hippocampal ACh relative to both baseline and vehicle. Moreover, 11.2 mg/ml PREG increased ACh in the amygdala relative to baseline, the lower dose, and vehicle. Therefore, in the second experiment, IN‐PREG (11.2 mg/ml) was applied only into one nostril, with vehicle applied into the other nostril, in order to determine whether ACh is predominantly increased in the ipsilateral relative to the contralateral amygdala. Unilateral application of IN‐PREG increased ACh in the ipsilateral amygdala, whereas no effect was observed on the contralateral side, suggesting that PREG was transported from the nostrils to the brain via the olfactory epithelial pathway, but not by circulation. The present data provide additional information on IN‐PREG action in the cholinergic system of frontal cortex, amygdala, and hippocampus. This may be relevant for therapeutic IN application of PREG in neurogenerative and neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: While many adolescents exhibit risky behavior, teenagers with a family history (FH+) of an alcohol use disorder (AUD) are at a heightened risk for earlier initiation of alcohol use, a more rapid escalation in frequency and quantity of alcohol consumption and developing a subsequent AUD in comparison with youth without such family history (FH−). Neuroanatomically, developmentally normative risk‐taking behavior parallels an imbalance between more protracted development of the prefrontal cortex (PFC) and earlier development of limbic regions. Magnetic resonance imaging (MRI)‐derived volumetric properties were obtained for these structures in FH+ and FH− adolescents. Methods: Forty‐two substance‐naïve adolescents (13‐ to 14‐year‐olds), stratified into FH+ (N = 19, 13 girls) and FH− (N = 23, 11 girls) age/handedness‐matched groups, completed MRI scanning at 3.0T, as well as cognitive and clinical testing. T1 images were processed using FreeSurfer to measure PFC and hippocampi/amygdalae subfields/nuclei volumes. Results: FH+ status was associated with larger hippocampal/amygdala volumes (p < 0.05), relative to FH− adolescents, with right amygdala results appearing to be driven by FH+ boys. Volumetric differences also were positively associated with family history density (p < 0.05) of having an AUD. Larger subfields/nuclei volumes were associated with higher anxiety levels and worse auditory verbal learning performance (p < 0.05). Conclusions: FH+ risk for AUD is detectable via neuromorphometric characteristics, which precede alcohol use onset and the potential onset of a later AUD, that are associated with emotional and cognitive measures. It is plausible that the development of limbic regions might be altered in FH+ youth, even prior to the onset of alcohol use, which could increase later risk. Thus, targeted preventative measures are warranted that serve to delay the onset of alcohol use in youth, particularly in those who are FH+ for an AUD. [ABSTRACT FROM AUTHOR]

Objective: Despite the growing knowledge on the functional relationship between an altered endocannabinoid (eCB) system and development of anorexia nervosa (AN), to date no studies have investigated the central eCB tone in the activity‐based anorexia (ABA) model that reproduces key aspects of human AN. Method: We measured levels of two major eCBs, anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG), those of two eCB‐related lipids, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), and the cannabinoid type‐1 receptor (CB1R) density in the brain of female ABA rats, focusing on areas involved in homeostatic and rewarding‐related regulation of feeding behavior (i.e., prefrontal cortex, nucleus accumbens, caudato putamen, amygdala, hippocampus and hypothalamus). Analysis was carried out also at the end of recovery from the ABA condition. Results: At the end of the ABA induction phase, 2‐AG was significantly decreased in ABA rats in different brain areas but not in the caudato putamen. No changes were detected in AEA levels in any region, whereas the levels of OEA and PEA were decreased exclusively in the hippocampus and hypothalamus. Furthermore, CB1R density was decreased in the dentate gyrus of hippocampus and in the lateral hypothalamus. After recovery, both 2‐AG levels and CB1R density were partially normalized in some areas. In contrast, AEA levels became markedly reduced in all the analyzed areas. Discussion: These data demonstrate an altered brain eCB tone in ABA rats, further supporting the involvement of an impaired eCB system in AN pathophysiology that may contribute to the maintenance of some symptomatic aspects of the disease. [ABSTRACT FROM AUTHOR]

Summary: Minocycline as a member of the tetracycline family is a lipophilic broad‐spectrum antibiotic, which can display some non‐antibiotic properties such as antioxidant, antiapoptosis, neuroprotection and modulation of pharmacological traits of drugs of abuse (ie, reward, sensitization and/or analgesia). Thus, the aim of the present study was to investigate the effect of intracerebroventricular (ICV) injection of minocycline on morphine‐induced memory impairment and motor function in male Wistar rats. The behavioural responses were measured by a passive avoidance test for evaluating memory, and in the open field for studying motor function. Furthermore, the expression of Phospho‐cAMP response element‐binding protein (P‐CREB) and c‐Fos were assessed using immunohistochemistry in the dorsal hippocampus and basolateral amygdala (BLA). Our results showed that morphine dose‐dependently impairs memory consolidation, but not motor function. Maximum effect was achieved with morphine at dose of 5 mg/kg. Pretreatment with ICV injection of minocycline (50 μg/rat) prevented morphine‐induced memory impairment, but there was no effect on motor function. The results of immunohistochemistry analysis demonstrated that morphine decreased expression of P‐CREB positive cells compared to saline control group in the BLA, but not in the dorsal hippocampus. On the other hand, pretreatment of animals with ICV injection of minocycline increased the expression of P‐CREB in both brain areas. Moreover, there was no significant change in the expression of c‐Fos positive cells in above‐mentioned regions. In summary, our results indicated that pretreatment with ICV injection of minocycline prevented morphine‐induced memory impairment and increased P‐CREB expression in the dorsal hippocampus and BLA, which may explain its memory improvement property. [ABSTRACT FROM AUTHOR]

Much of the theoretical focus in post‐traumatic stress disorder has been on the role of the amygdala, the hippocampus and the prefrontal cortex. Crucially, in unresolved traumatic experiences that underlie clinical presentations, this focus misses the brain areas key to the defence responses of fight, flight and freeze—and the associated affects of anger, fear and grief. The periaqueductal gray in the midbrain, with the hypothalamus, is essential for these somatic and emotional responses to traumatic experiences. We argue that when treatment approaches thought to work at the higher brain levels have been ineffective, it is because they have failed to engage the midbrain and hypothalamic sources of the affective responses to the trauma and to the memory of it. Basic affects have been so overwhelming that dissociation, or a similarly protective neurochemical capping mechanism, has prevented full resolution of the affective content of the adversity. Treatment with the Comprehensive Resource Model® (CRM) aims to clear the clinically relevant residues of adverse experiences by resolving the emotional responses accessed through the body memories. When the trauma has led to overwhelming distress, and/or dissociation, there is a necessity for robust resourcing to be in place before the emotional intensity of that distress is accessed. Resourcing needs to be as proximal to the re‐experience as possible to promote complete resolution and in some psychotherapy modalities, the supports provided are somewhat remote from the crucial moments of processing. Therefore, we describe how the CRM seeks to have robustly resourced states present concurrently with traumatised states to avoid overwhelming emotional distress. This allows safe entry into the deepest pain residual from the traumatic event so that it is not overwhelming during processing of the memory, and does not lead to further dissociation, allowing the individual to remain fully present throughout. This "stepping into the affect" can then be so rapidly effective that we also argue that CRM is not an exposure treatment; re‐orientation to the deepest content of the experience resolves the residual distress quickly and permanently through memory reconsolidation. Re‐learning at upper brain levels will then follow from the revoking of the affective power, which has previously driven stimulus/context and response learning in the amygdala, hippocampus and prefrontal cortex. [ABSTRACT FROM AUTHOR]

Emerging research suggests that normative variation in parenting quality relates to children's brain development. However, although the young brain is presumed to be especially sensitive to environmental influence, to our knowledge only two studies have examined parenting quality with infants as it relates to indicators of brain development, and both were cross‐sectional. This longitudinal study investigated whether different components of maternal sensitivity in infancy predicted the volume of two brain structures presumed to be particularly sensitive to early experience, namely the amygdala and the hippocampus. Three dimensions of sensitivity (Cooperation/Attunement, Positivity, Accessibility/Availability) were observed in 33 mother–infant dyads at 1 year of age and children underwent structural magnetic resonance imaging at age 10. Higher maternal Accessibility/Availability during mother–infant interactions was found to be predictive of smaller right amygdala volume, while greater maternal positivity was predictive of smaller bilateral hippocampal volumes. These longitudinal findings extend those of previous cross‐sectional studies and suggest that a multidimensional approach to maternal behavior could be a fruitful way to further advance research in this area, given that different facets of parenting might be differentially predictive of distinct aspects of neurodevelopment. [ABSTRACT FROM AUTHOR]

Objective: A subset of children with febrile status epilepticus (FSE) are at risk for development of temporal lobe epilepsy later in life. We sought a noninvasive predictive marker of those at risk that can be identified soon after FSE, within a clinically realistic timeframe. Methods: Longitudinal T2-weighted magnetic resonance imaging (T2WI MRI) of rat pups at several time points after experimental FSE (eFSE) was performed on a high-field scanner followed by long-term continuous electroencephalography. In parallel, T2WI MRI scans were performed on a 3.0-T clinical scanner. Finally, chronic T2WI MRI signal changes were examined in rats that experienced eFSE and were imaged months later in adulthood. Results: Epilepsy-predicting T2 changes, previously observed at 2 hours after eFSE, persisted for at least 6 hours, enabling translation to the clinic. Repeated scans, creating MRI trajectories of T2 relaxation times following eFSE, provided improved prediction of epileptogenesis compared with a single MRI scan. Predictive signal changes centered on limbic structures, such as the basolateral and medial amygdala. T2WI MRI changes, originally described on high-field scanners, can also be measured on clinical MRI scanners. Chronically elevated T2 relaxation times in hippocampus were observed months after eFSE in rats, as noted for post-FSE changes in children. Significance: Early T2WI MRI changes after eFSE provide a strong predictive measure of epileptogenesis following eFSE, on both high-field and clinical MRI scanners. Importantly, the extension of the acute signal changes to at least 6 hours after the FSE enables its inclusion in clinical studies. Chronic elevations of T2 relaxation times within the hippocampal formation and related structures are common to human and rodent FSE, suggesting that similar processes are involved across species. [ABSTRACT FROM AUTHOR]

Objective: Exposure to sexual assault is a significant risk factor to develop post‐traumatic stress disorder (PTSD) in females. The early neurobiological changes leading to the development of PTSD remain understudied and unclear in this population. Methods: Participants were 27 adult females recruited within a month following exposure to sexual assault (T1) and 20 age‐matched non‐exposed controls. Among the victims, 10 participants met (PTSD+) and 15 did not meet (PTSD−) DSM‐IV criteria for PTSD 6 months post‐trauma (T2). At both visits, hippocampal and amygdala volumes were extracted from magnetic resonance imaging scans, and indices of total diurnal cortisol changes were derived from individual areas under the curve relative to the ground (AUCg). Measures at T1 were compared between groups at T1, measures at T2 between groups at T2, and measures at T1 between groups at T2. Results: At T1, victims had significantly smaller bilateral hippocampal volumes, but not AUCg, than controls. At T2, neither hippocampal volume nor AUCg significantly differed among the groups. However, the PTSD+ group had significantly smaller hippocampal volumes at T1 than the control group, but not compared to the PTSD− group. Conclusions: This study indicates that having smaller hippocampal volumes is a risk factor to develop PTSD in females exposed to sexual assault. [ABSTRACT FROM AUTHOR]

Background: Adolescence is a transition period characterized by heightened emotional reactivity, which for some sets the stage for emerging depressive symptoms. Prior studies suggest that adolescent depression is associated with deviant cortical and subcortical brain structure. Longitudinal studies are, however, currently scarce, but critical to detect which adolescents are at risk for developing depressive symptoms. Methods: In this longitudinal study, a community sample of 205 participants underwent magnetic resonance imaging (MRI) in three biennial waves (522 scans) spanning 5 years across ages 8–25 years. Depressive symptomatology was assessed using self‐report at the third time point. Mixed models were used to examine the relations between structural brain development, specifically regional change in cortical thickness, surface area and subcortical volumes (hippocampus and amygdala), and depressive symptoms. Results: Accelerated frontal lobe cortical thinning was observed in adolescents who developed depressive symptoms at the third time point. This effect remained after controlling for parent‐reported affective problems at the first time point. Moreover, the effect was driven by specific lateral orbitofrontal and precentral regions. In addition, differential developmental trajectories of parietal cortical thickness and surface area in several regions were found for participants reporting higher depressive symptomatology, but these results did not survive correction for multiple comparisons. Volumes or developmental volume changes in hippocampus or amygdala were not related to depressive symptoms. Conclusions: This study showed that emerging depression is associated with cortical thinning in frontal regions within individuals. These findings move beyond detecting cross‐sectional correlations and set the stage for early detection, which may inform future intervention. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) is a sporadic adult‐onset neurodegenerative disease. It has recently been shown that patients with MSA accompanied by cognitive decline display numerous neuronal cytoplasmic inclusions (NCIs) in the limbic neurons. We examined potential mechanisms underlying the formation of these NCIs by determining of mitochondrial function and statuses of RNA processing by analyzing 12 pathologically confirmed cases of MSA. Among them, four had cognitive impairment Semiquantitative evaluation using immunohistochemistry analyses revealed a significantly greater NCI burden in the hippocampal cornu ammonis 1 (CA1) subfield, subiculum, and amygdala in the cases with cognitive impairments compared with those without cognitive impairment. Immunofluorescent staining revealed that limbic neurons with NCIs often accelerated production of reactive oxygen species (ROS) and degraded mitochondrial quality control. Immunofluorescent staining also revealed that neurons with these NCIs translocated heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the nucleus and aggregated abnormally at the perinuclear rim. Since the NCIs in the hippocampal neurons of MSA with cognitive impairments were more numerous, the neuronal mitochondrial dysfunction and altered ribostasis observed in NCI formation may be involved in the hippocampal degeneration of MSA. [ABSTRACT FROM AUTHOR]

Background: Widespread brain atrophy in alcohol‐dependent individuals (ALC) has been consistently documented in pathological and magnetic resonance imaging (MRI) studies. Longitudinal MRI studies have shown that the regional brain volume losses in ALC are partially reversible during abstinence from alcohol. The goal of this study was to determine volume reductions in cortical and subcortical regions functionally important to substance use behavior and their changes during short‐term (1 week to 1 month) and long‐term abstinence (1 to 7 months) from alcohol. The regions of interest (ROIs) were as follows: anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), insula, amygdala, and hippocampus. Methods: A total of 85 unique ALC were assessed at 1 week (n = 65), 1 month (n = 82), and 7 months (n = 36) of abstinence. In addition, 17 light/nondrinking healthy controls (CON) were assessed at baseline and follow‐up over a 10‐month interval. Regional brain volumes were derived from FreeSurfer. Cross‐sectional statistical analyses using 1‐way analysis of variance or Fisher's exact test were applied to identify group differences. Longitudinal statistical analyses using linear mixed models were applied to identify regional volume increases and nonlinear volume recovery trajectories. Results: We demonstrated significant regional volume reductions in ACC, DLPFC, and hippocampus. Older age was associated with smaller DLPFC and OFC, and higher average monthly drinking over 1 year prior to study was associated with smaller OFC. We also demonstrated significant volume increases of all ROIs except amygdala in ALC and significant nonlinear volume recovery trajectories of DLPFC, OFC, and insula. Conclusions: Results showed significant volume reductions in key regions of the executive control, salience, and emotion networks in ALC at entry into treatment and significant volume increases during short‐term and long‐term abstinence that were nonlinear over the entire abstinence period for the DLPFC, OFC, and insula. This gray matter plasticity during alcohol abstinence may have important neurobiological and neurocognitive implications in ALC, and it may contribute to an individual's ability to maintain abstinence from alcohol at different phases. [ABSTRACT FROM AUTHOR]

Abstract: Perceived stress has been associated with decreased hippocampal, amygdala, and prefrontal cortex volume, as well as decreased memory and executive functioning performance in adulthood. Parents' perceived stress has been linked to decreased hippocampal volume in young children. However, no studies have investigated the links between self‐perceived stress and brain structure or function in adolescents. Additionally, findings from previous research with younger or older samples are inconsistent, likely in part due to inconsistencies in participants' age range. In this study, we investigated the associations among self‐perceived stress, family socioeconomic factors (family income, parental education), subcortical (hippocampus, amygdala) volumes, prefrontal cortical thickness and surface area, and memory and executive functioning performance in adolescents. One hundred and forty‐three participants (12–20 years old) were administered a cognitive battery, a questionnaire to assess perceived stress, and a structural MRI scan. Higher levels of perceived stress were associated with decreased adolescent hippocampal volume. This study provides empirical evidence of how experience may shape brain development in adolescence—a period of plasticity during which it may be possible to intervene and prevent negative developmental outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Smaller hippocampal volumes are one of the most consistent findings in neuroimaging studies of post‐traumatic stress disorder (PTSD). However, very few prospective studies have assessed changes in hippocampal gray matter prior to and following therapy for PTSD, and no neuroimaging studies to date have longitudinally assessed military populations. Methods: A pilot study was conducted, assessing patients with combat‐related PTSD with structural MRI. Participants were then assigned either to a treatment group or waiting‐list control group. After the treatment group received multimodal psychological therapy for approximately 6 weeks, both groups completed a second neuroimaging assessment. Results: Region‐of‐interest analysis was used to measure gray matter volume in the hippocampus and amygdala. There was a group by time interaction; the therapy group (n = 6) showed a significant increase in hippocampal volume and a nonsignificant trend toward an increase in amygdala volume following therapy, while no change was observed in the waiting‐list group (n = 9). Conclusions: This study provides initial evidence for increases in gray matter volume in the hippocampus in response to therapy for combat‐related PTSD. [ABSTRACT FROM AUTHOR]

Background The ratio between amygdala:hippocampal (AH) volume has been associated with multiple psychiatric problems, including anxiety and aggression. Yet, little is known about its biological underpinnings. Here, we used a methylome-wide approach to test (a) whether DNA methylation in early life (birth, age 7) prospectively associates with total AH volume ratio in early adulthood, and (b) whether significant DNA methylation markers are influenced by prenatal risk factors. Methods Analyses were based on a subsample ( n = 109 males) from the Avon Longitudinal Study of Parents and Children, which included measures of prenatal risk, DNA methylation (Infinium Illumina 450k), T1-weighted brain scans and psychopathology in early adulthood (age 18-21). Amygdala and hippocampus measures were derived using Freesurfer 5.3.0. Methylation markers related to AH volume ratio across time were identified using longitudinal multilevel modeling. Results Amygdala:hippocampal volume ratio correlated positively with age 18 psychosis-like symptoms ( p = .007). Methylation of a probe in the gene SP6 associated longitudinally with (a) higher AH volume ratio (FDR q-value = .01) and (b) higher stressful life events during pregnancy ( p = .046). SP6 is expressed in the hippocampus and amygdala and has been implicated in cognitive decline in Alzheimer's disease. The association between SP6 DNA methylation, AH volume ratio and psychopathology was replicated in an independent dataset of 101 patients with schizophrenia and 111 healthy controls. Conclusions Our findings suggest that epigenetic alterations in genes implicated in neurodevelopment may contribute to a brain-based biomarker of psychopathology. [ABSTRACT FROM AUTHOR]

Aims Heart failure (HF) patients show significant lateralized neural injury, accompanied by autonomic, mood and cognitive deficits. Both gray and white matter damage occurs and probably develops from altered cerebral blood flow (CBF), a consequence of impaired cardiac output. However, the distribution of regional CBF changes in HF patients is unknown, but is an issue in determining mechanisms of neural injury. Our aim was to compare regional CBF changes in HF with CBF in control subjects using non-invasive pseudo-continuous arterial spin labelling (ASL) procedures. Methods and results We collected pseudo-continuous ASL data from 19 HF patients [mean age 55.5±9.1 years; mean body mass index 27.7±5.3 kg/m²; 13 male) and 29 control subjects (mean age 51.4±5.3 years; mean body mass index 25.7±3.6 kg/m²; 18 male), using a 3.0-Tesla magnetic resonance imaging (MRI) scanner. Whole-brain CBF maps were calculated, normalized to a common space, smoothed and compared between groups using ANCOVA (covariates; age, gender and gray matter volume). Reduced CBF appeared in multiple sites in HF patients in comparison with controls, with principally lateralized lower flow in temporal, parietal and occipital regions. Areas with decreased CBF included the bilateral prefrontal, frontal, temporal and occipital cortex, thalamus, cerebellum, corona radiate, corpus callosum, hippocampus and amygdala. Conclusions Heart failure patients showed lower, and largely lateralized, CBF in multiple autonomic, mood and cognitive regulatory sites. The reduced CBF is likely to contribute to the lateralized brain injury, leading to the autonomic and neuropsychological deficits found in the condition. [ABSTRACT FROM AUTHOR]

Objectives Volumetric studies on deep gray matter structures in bipolar disorder ( BP) have reported contrasting results. Childhood trauma, a relevant environmental stressor for BP, could account for the variability of the results, modulating differences in the amygdala and hippocampus in patients with BP compared with healthy controls (HC). Our study aimed to test this hypothesis. Methods We assessed 105 outpatients, diagnosed with bipolar disorder type I ( BP-I) or bipolar disorder type II ( BP- II) according to DSM- IV- TR criteria, and 113 HC subjects. History of childhood trauma was obtained using the Childhood Trauma Questionnaire ( CTQ). High-resolution magnetic resonance imaging was performed on all subjects and volumes of the amygdala, hippocampus, nucleus accumbens, caudate, pallidum, putamen, and thalamus were measured using FreeSurfer. Results Patients with BP showed a global reduction of deep gray matter volumes compared to HCs. However, childhood trauma modulated the impact of the diagnosis specifically on the amygdala and hippocampus. Childhood trauma was associated with bilateral decreased volumes in HCs and increased volumes in patients with BP. Conclusions The results suggest that childhood trauma may have a different effect in health and disease on volumes of gray matter in the amygdala and hippocampus, which are brain areas specifically involved in response to stress and emotion processing. [ABSTRACT FROM AUTHOR]

Background and aims Patterns of brain activation have demonstrated promise as prognostic indicators in substance dependent individuals (SDIs) but have not yet been explored in SDIs typical of community-based treatment settings. Design Prospective clinical outcome design, evaluating baseline functional magnetic resonance imaging data from the Balloon Analogue Risk Task (BART) as a predictor of 3-month substance use treatment outcomes. Setting Community-based substance use programs in Bloomington, Indiana, USA. Participants Twenty-three SDIs (17 male, aged 18-43 years) in an intensive outpatient or residential treatment program; abstinent 1-4 weeks at baseline. Measurements Event-related brain response, BART performance and self-report scores at treatment onset, substance use outcome measure (based on days of use). Findings Using voxel-level predictive modeling and leave-one-out cross-validation, an elevated response to unexpected negative feedback in bilateral amygdala and anterior hippocampus (Amyg/aHipp) at baseline successfully predicted greater substance use during the 3-month study interval ( P ≤ 0.006, cluster-corrected). This effect was robust to inclusion of significant non-brain-based covariates. A larger response to negative feedback in bilateral Amyg/aHipp was also associated with faster reward-seeking responses after negative feedback ( r(23) = −0.544, P = 0.007; r(23) = −0.588, P = 0.003). A model including Amyg/aHipp activation, faster reward-seeking after negative feedback and significant self-report scores accounted for 45% of the variance in substance use outcomes in our sample. Conclusions An elevated response to unexpected negative feedback in bilateral amygdala and anterior hippocampus (Amyg/aHipp) appears to predict relapse to substance use in people attending community-based treatment. [ABSTRACT FROM AUTHOR]

A Japanese woman showed slowly progressive memory disturbance since the age of 85 years. Later, disorientation gradually appeared. Head computed tomography revealed severe hippocampal atrophy, particularly in the posterior portion, and lateral ventricular dilatation, particularly in the inferior horn at the age of 99 years. The amygdala was relatively preserved from atrophy, and atrophy of the frontal lobe was relatively mild for her age. Apolipoprotein E gene analysis showed the ε3 homozygous phenotype. The woman died at the age of 101 years, and her clinical diagnosis was mild Alzheimer's disease. No apparent behavioural and psychological symptoms of dementia were observed during the disease course. Autopsy revealed severe hippocampal atrophy with numerous neurofibrillary tangles and ghost tangles, particularly in the hippocampal region, but senile plaques were rarely observed in the brain. The pathological findings were compatible with senile dementia of the neurofibrillary tangle type, whereas other neurodegenerative disorders were not recognized. The clinicopathologic findings of the present case are considered significant for the clinical diagnosis and pathogenesis of senile dementia of the neurofibrillary tangle type. [ABSTRACT FROM AUTHOR]

Several studies have recently demonstrated that the volumes of specific brain regions are reduced in children and adolescents with post-traumatic stress disorder ( PTSD) compared with those of healthy controls. Our study investigated the potential association between early traumatic experiences and altered brain regions and functions. We conducted a systematic review of the scientific literature regarding functional magnetic resonance imaging and a meta-analysis of structural magnetic resonance imaging studies that investigated cerebral region volumes in pediatric patients with PTSD. We searched for articles from 2000 to 2014 in the PsycINFO, PubMed, Medline, Lilacs, and ISI ( Web of Knowledge) databases. All data regarding the amygdala, hippocampus, corpus callosum, brain, and intracranial volumes that fit the inclusion criteria were extracted and combined in a meta-analysis that assessed differences between groups. The meta-analysis found reduced total corpus callosum areas and reduced total cerebral and intracranial volumes in the patients with PTSD. The total hippocampus (left and right hippocampus) and gray matter volumes of the amygdala and frontal lobe were also reduced, but these differences were not significant. The functional studies revealed differences in brain region activation in response to stimuli in the post-traumatic stress symptoms /PTSD group. Our results confirmed that the pediatric patients with PTSD exhibited structural and functional brain abnormalities and that some of the abnormalities occurred in different brain regions than those observed in adults. [ABSTRACT FROM AUTHOR]

Aim Using diffusional kurtosis imaging ( DKI) to assess the impact of emotional disorders on microstructural changes of the brain in children with haemophilia A. Materials and Methods Diffusional kurtosis imaging was acquired from haemophilia A ( n = 22) and controls ( n = 22) using a 3T scanner. A regression analysis of frontal, cingulate, hippocampus, insula and amygdala regions of interest ( ROIs) was conducted. Clinical data and results of psychological tests were collected. A paired t-test was used to analyse the differences between the two groups' ROIs, and the Spearman test was used to analyse the correlation between ROIs and psychological tests or clinical data. Results Fractional anisotropy ( FA) in the left middle cingulate and right hippocampus; mean diffusion ( MD) in the frontal lobe, right anterior cingulate and right middle cingulate showed varying degrees of increase in the ROI compared to controls ( P < 0.003). MD in the frontal lobe and the course of disease ( P < 0.05), FA in the right hippocampus and the social score of the self-consciousness scale ( P < 0.01) had a positive correlation. Conclusion Our study is the first to evaluate the relationship between emotion disorders and cognitive changes in the microstructure of the brain in children with haemophilia A, suggesting that DKI provides more information about tissue microstructural changes than do the conventional image method and traditional psychological tests. [ABSTRACT FROM AUTHOR]

Since stressful situations are considered risk factors for the development of depression and there are few studies evaluating prevention therapies for this disease, in the present study we evaluated the effect of previous physical exercise in animals subjected to chronic variable stress (CVS), an animal model of depression, on behavior tasks. We also investigated some parameters of oxidative stress and Na + , K + -ATPase activity, immunocontent and gene expression of alpha subunits in amygdala and hippocampus of rats. Young male rats were randomized into four study groups (control, exercised, stressed, exercised + stressed). The animals were subjected to controlled exercise treadmill for 20 min,three times a week, for two months prior to submission to the CVS (40 days). Results show that CVS impaired performance in inhibitory avoidance at 24 h and 7 days after training session. CVS induced oxidative stress, increasing reactive species, lipoperoxidation and protein damage, and decreasing the activity of antioxidant enzymes. The activity of Na + , K + -ATPase was decreased, but the immunocontents and gene expression of catalytic subunits were not altered. The previous physical exercise was able to improve performance in inhibitory avoidance at 24 h after training; additionally, exercise prevented oxidative damage, but was unable to reverse completely the changes observed on the enzymatic activities. Our findings suggest that physical exercise during the developmental period may protect against aversive memory impairment and brain oxidative damage caused by chronic stress exposure later in life. [ABSTRACT FROM AUTHOR]

Introduction Chronic stress induces dendritic atrophy and decreases spine density in excitatory hippocampal neurons, although there is also ample evidence indicating that the GABAergic system is altered in the hippocampus after this aversive experience. Chronic stress causes dendritic remodeling both in excitatory neurons and interneurons in the medial prefrontal cortex and the amygdala. Methods In order to know whether it also has an impact on the structure and neurotransmission of hippocampal interneurons, we have analyzed the dendritic arborization, spine density, and the expression of markers of inhibitory synapses and plasticity in the hippocampus of mice submitted to 21 days of mild restrain stress. The analyses were performed in GIN mice, a strain that displays EGFP-labeled interneurons. Results We observed a significant decrease in the dendritic arborization of interneurons in the CA1 region, which did not occur in those in CA3. We found neither changes in dendritic spine density in these regions nor alterations in the number of EGFP-positive interneurons. Nevertheless, the expression of glutamic acid decarboxylase 67 was reduced in different layers of CA1 and CA3 regions of the hippocampus. No significant changes were found in the expression of the polysialylated form of the neural cell adhesion molecule ( PSA- NCAM) or synaptophysin. Conclusions Chronic stress reduces the interneuronal dendritic arborization in CA1 region of the hippocampus but not in CA3. [ABSTRACT FROM AUTHOR]

Background: Studies have identified perturbations in facial processing in bipolar disorder and major depressive disorder (MDD), but their relationship to genetic risk and early development of illness is unclear. Methods: The Scottish Bipolar Family Study is a prospective longitudinal investigation examining young individuals (age 16-25) at familial risk of mood disorder. Participants underwent functional MRI using an implicit facial processing task employing angry and neutral faces. An explicit facial expression recognition task was completed outside the scanner. Clinical outcomes obtained 2 years after the scan were used to categorise participants into controls (n = 54), highrisk individuals who had developed MDD (HR MDD; n = 30) and high-risk individuals who remained well (HR Well, n = 43). Results: All groups demonstrated activation patterns typically observed during facial processing, including activation of the amygdala, hippocampus, fusiform gyrus and middle frontal regions. Notably, the HR MDD group showed reduced activation of the anterior cingulate gyrus versus both the control and HR Well group for angry faces, and versus the HR Well group for neutral faces. Outside the scanner, the HR MDD group was less accurate in recognising fearful expressions than the HR Well group. Conclusions: Here, we demonstrate functional abnormalities of the anterior cingulate cortex alongside facial emotional recognition deficits in high-risk individuals in the early stages of depression compared with both controls and at-risk individuals who remained well. These neural changes were associated with a current or future diagnosis of MDD and were not simply associated with increased familial risk. [ABSTRACT FROM AUTHOR]

There is growing evidence that stress leads to contrasting patterns of structural plasticity in the hippocampus and amygdala, two brain areas implicated in the cognitive and affective symptoms of stress-related psychiatric disorders. Acute stress has been shown to trigger a delayed increase in the density of dendritic spines in the basolateral amygdala (BLA) of rodents. However, the physiological correlates of this delayed spinogenesis in the BLA remain unexplored. Furthermore, NMDA receptors (NMDARs) have been known to underlie chronic stress-induced structural plasticity in the hippocampus, but nothing is known about the role of these receptors in the delayed spinogenesis, and its physiological consequences, in the BLA following acute stress. Here, using whole-cell recordings in rat brain slices, we find that a single exposure to 2-h immobilization stress enhances the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs) recorded from principal neurons in the BLA 10 days later. This was also accompanied by faster use-dependent block of NMDA receptor currents during repeated stimulation of thalamic inputs to the BLA, which is indicative of higher presynaptic release probability at these inputs 10 days later. Furthermore, targeted in vivo infusion of the NMDARantagonist APV into the BLA during the acute stress prevents the increase in mEPSC frequency and spine density 10 days later. Together, these results identify a role for NMDARs during acute stress in both the physiological and morphological strengthening of synaptic connectivity in the BLA in a delayed fashion. These findings also raise the possibility that activation of NMDA receptors during stress may serve as a common molecular mechanism despite the divergent patterns of plasticity that eventually emerge after stress in the amygdala and hippocampus. [ABSTRACT FROM AUTHOR]

Self-esteem is a widely studied construct in psychology that is typically measured by the Rosenberg Self-Esteem Scale (RSES). However, a series of cross-sectional and longitudinal studies have suggested that a simple and widely used unidimensional factor model does not provide an adequate explanation of RSES responses due to method effects. To identify the neural correlates of the method effect, we sought to determine whether and how method effects were associated with the RSES and investigate the neural basis of these effects. Two hundred and eighty Chinese college students (130 males; mean age = 22.64 years) completed the RSES and underwent magnetic resonance imaging (MRI). Behaviorally, method effects were linked to both positively and negatively worded items in the RSES. Neurally, the right amygdala volume negatively correlated with the negative method factor, while the hippocampal volume positively correlated with the general self-esteem factor in the RSES. The neural dissociation between the general self-esteem factor and negative method factor suggests that there are different neural mechanisms underlying them. The amygdala is involved in modulating negative affectivity; therefore, the current study sheds light on the nature of method effects that are related to self-report with a mix of positively and negatively worded items. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is a new investigational therapy that has generated positive results in refractory depression. Although the neurochemical and behavioral effects of DBS have been examined, less attention has been paid to the influence of DBS on the network dynamics between different brain areas, which could contribute to its therapeutic effects. Herein, we set out to identify the effects of 1 h DBS in the infralimbic cortex (IL) on the oscillatory network dynamics between hippocampus and basolateral amygdala (BLA), two regions implicated in depression and its treatment. Urethane-anesthetized rats with bilaterally implanted electrodes in the IL were exposed to 1 h constant stimulation of 130 Hz of frequency, 60 μA of constant current intensity and biphasic pulse width of 80 μsec. After a period of baseline recording, local field potentials (LFP) were recorded with formvar-insulated stainless steel electrodes. DBS of the IL increased the power of slow wave (SW, <1.5 Hz) and theta (3–12 Hz) frequencies in the hippocampus and BLA. Furthermore, IL DBS caused a precise coupling in different frequency bands between both brain structures. The increases in SW band synchronization in hippocampus and BLA after DBS suggest that these changes may be important for the improvement of depressive behavior. In addition, the augmentation in theta synchrony might contribute to improvement in emotional and cognitive processes. [ABSTRACT FROM AUTHOR]

Multinodular and vacuolating neuronal tumors (MVNT) have been referred to as distinctive neuronal tumors whose characteristic features include multiple nodules localized in the subcortical white matter. MVNT are composed of vacuolating dysplastic neurons reactive to HuC/HuD. A significant overexpression of alpha-internexin (INA) limited to the stroma of nodules was reported in one tumor. Since genetic analyses have failed to demonstrate any consistent alterations, the nosological position as well as the nature of MVNT, namely, neoplastic or dysplastic, remains unclear. We herein present another example of MVNT involving the amygdala and anterior hippocampus in a 41-year-old man. In addition to the nodular lesions described earlier, we found INA-positive ribbon-like lesions that replaced neuropil and extended along the hippocampal gray matter. We also identified dysplastic neurons infiltrating into the CA4 hilus of the hippocampus. Intense INA expression was present in the stroma as well as the cytoplasmic membrane of dysplastic neurons and their processes. While the invasiveness suggested a neoplasm, a relatively restrictive, either nodular or ribbon-like growth pattern with INApositive abnormal neuropil suggested a hamartoma. Such quasi-tumors should be accommodated in the World Health Organization classification of tumors of the central nervous system, as are dysembryoplastic neuroepithelial tumor and Lhermitte-Duclos disease. [ABSTRACT FROM AUTHOR]

Objectives Results from magnetic resonance imaging ( MRI) studies are heterogeneous with regard to hippocampal and amygdala volume alterations in bipolar disorder ( BD). Lithium treatment may influence both structures. It is unknown if lithium treatment has distinct effects on hippocampal subfield volumes and if subfield volumes change over the course of illness in BD. Methods MRI scans were obtained for 34 lithium-treated patients with BD (Li+), 147 patients with BD who were not treated with lithium (Non-Li), and 300 healthy controls. Hippocampal total and subfield volumes and amygdala volumes were automatically estimated using Freesurfer. General linear models were used to investigate volume differences between groups and the effects of illness course and lithium treatment. Results The Non-Li BD group displayed significantly smaller bilateral cornu ammonis ( CA) 2/3 and CA4/dentate gyrus ( DG) subfields, total hippocampal volumes, right CA1 and right subiculum subfields, and left amygdala volume compared to healthy controls. There were no differences between the Li+ BD and either the Non-Li BD or the healthy control groups. In patients with numerous affective episodes, Non-Li BD patients had smaller left CA1 and CA2/3 volumes compared to Li+ BD patients and healthy controls. There were positive associations between lithium treatment duration and left amygdala volume. Conclusions Hippocampal subfield and amygdala volumes were reduced in Non-Li BD patients compared to healthy controls, whereas the Li+ BD volumes were no different from those in Non-Li BD patients or healthy controls. Over the course of BD, lithium treatment might counteract reductions specifically in the left CA1 and CA2/3 hippocampal subfields and amygdala volumes, in accordance with the suggested neuroprotective effects of lithium. [ABSTRACT FROM AUTHOR]

Objective: Using a hypothesis-driven approach, subcortical and cortical regions implicated in anxiety disorders in the general population were examined in children with recent-onset epilepsy with versus without anxiety compared to controls. This study reports frequency of anxiety disorders while examining familial, clinical, and demographic variables associated with anxiety in children with epilepsy. Method: Participants included 88 children with epilepsy aged 8-18 years: 25 with a current anxiety disorder and 63 children with epilepsy and no current anxiety disorder. Forty-nine controls without anxiety disorders were included. T1 volumetric magnetic resonance imaging (MRI) scans were collected; subcortical volumes and cortical thickness were computed using the FreeSurfer image analysis suite. Analyses focused on adjusted measures of subcortical volumes and cortical thickness. Results: Relative to controls, larger left amygdala volumes were found in the Epilepsy with Anxiety group compared to the Epilepsy without Anxiety group (p = 0.027). In the hippocampus, there were no significant differences between groups. Examination of cortical thickness demonstrated that the Epilepsy with Anxiety group showed thinning in left medial orbitofrontal (p = 0.001), right lateral orbitofrontal (p = 0.017), and right frontal pole (p = 0.009). There were no differences between groups in age, sex, IQ, age of onset, medications, or duration of epilepsy. There were more family members with a history of anxiety disorders in the Epilepsy with Anxiety group compared to the Epilepsy without Anxiety group (p = 0.005). Significance: Anxiety is a common psychiatric comorbidity in children with recentonset epilepsy with volumetric enlargement of the amygdala and thinner cortex in orbital and other regions of prefrontal cortex, suggesting structural abnormalities in brain regions that are part of the dysfunctional networks reported in individuals with anxiety disorders in the general population. These findings are evident early in the course of epilepsy, are not related to chronicity of seizures, and may be linked to a family history of anxiety and depressive disorders. [ABSTRACT FROM AUTHOR]