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Drevets WC. Neuroimaging abnormalities in the amygdala in mood disorders. Ann NY Acad Sci 985: 420-444
Annals of the New York Academy of Sciences
Abstract
Neuroimaging technology has been applied to investigate the pathophysiology of mood disorders in studies aimed at characterizing the anatomical correlates of depressive symptoms, the neurophysiological effects of antidepressant treatments, and the trait-like abnormalities that persist despite symptom remission. These studies have identified cerebral blood flow and metabolic differences between depressives and controls in the amygdala and anatomically related areas of the prefrontal cortex, striatum, and thalamus. Taken together with converging evidence from neuroendocrine, lesion analysis, and postmortem studies of clinically depressed subjects, these data suggest that emotional/stress-response systems that include the amygdala are pathologically activated in major depression and that this activity is associated with dysfunction of the prefrontal cortex and monoamine neurotransmitter systems that normally modulate such responses.
... An ancillary study of MGHP3 also includes neuroimaging assessment of subjects with histories of PP in order to ascertain patterns of neural circuitry seen in women with histories of PP compared to those without histories of postpartum psychotic illness. Assessment includes structural and functional (task-based and resting-state) MRI scans to explore whether women with a PP history show abnormalities in brain structure or function congruent with previous findings in other psychiatric disorders, such as cortical thinning [23] or amygdala overactivity [24]. ...
... The fMRI data will be used to measure neural responses to emotionally salient stimuli and the connectivity of brain networks [34] involved in affective responses, salience detection and sensorimotor function [35]. This arm of MGHP3 explores whether women with a history of PP show abnormalities in brain structure or function that are similar to those previously observed in psychotic disorders, mood disorders, or both [24,[35][36][37]. ...
Objective
Postpartum psychosis (PP) is a severe psychiatric disorder, with incomplete consensus on definition and diagnostic criteria. The Massachusetts General Hospital Postpartum Psychosis Project (MGHP3) was established to better ascertain the phenomenology of PP in a large cohort of diverse women spanning a wide geographical range (primarily in the US), including time of onset, symptom patterns, and associated comorbidities, psychiatric diagnoses pre- and post- the episode of PP, and also to identify genomic and clinical predictors of PP. This report describes the methods of MGHP3 and provides a status update.
Method
Data are collected from women who experienced PP within 6 months of childbirth and who provided this information within ten years of the study interview. Subject data are gathered during a one-time structured clinical interview conducted by phone, which includes administration of the Mini International Neuropsychiatric Interview for Psychotic Disorders Studies (Version 7.0.2), the MGHP3© Questionnaire, and other information including lifetime mental health history and use of psychiatric medications both prior to the episode of PP and during the subsequent time period prior to study interview. Subjects also provide a saliva sample to be processed for genomic analyses; a neuroimaging assessment is also conducted for a subset of participants.
Results
As of July 1, 2022, 311 subjects from 44 states and 7 countries were enrolled in MGHP3. Recruitment sources include social media, online advertisements, physician referral, community outreach, and partnership with PP advocacy groups.
Conclusions
The rigorous phenotyping, genetic sampling, and neuroimaging studies in this sample of women with histories of PP will contribute to better understanding of this serious illness. Findings from MGHP3 can catalyze ongoing discussions in the field regarding proper nosologic classification of PP as well as relevant treatment implications.
... Limbic structures that mediate emotional processing and their connections with frontal cortical regions are consistently reported to play an important role. One key hub within this network is the amygdala [5][6][7][8][9] . Removal or disruption of this region reduces fear and anxiety responses [10][11][12] . ...
... Positron-emission tomography in depressed patients shows abnormal metabolism in amygdala and connected subgenual frontal cortex 6,8,13 . Additionally, the amygdala is one of the key regions for regulating and expressing emotions 5,10,14,15 . ...
There has been increasing interest in using neuroimaging measures to predict psychiatric disorders. However, predictions usually rely on large brain networks and large disorder heterogeneity. Thus, they lack both anatomical and behavioural specificity, preventing the advancement of targeted interventions. Here we address both challenges. First, using resting-state functional magnetic resonance imaging, we parcellated the amygdala, a region implicated in mood disorders, into seven nuclei. Next, a questionnaire factor analysis provided subclinical mental health dimensions frequently altered in anxious-depressive individuals, such as negative emotions and sleep problems. Finally, for each behavioural dimension, we identified the most predictive resting-state functional connectivity between individual amygdala nuclei and highly specific regions of interest, such as the dorsal raphe nucleus in the brainstem or medial frontal cortical regions. Connectivity in circumscribed amygdala networks predicted behaviours in an independent dataset. Our results reveal specific relations between mental health dimensions and connectivity in precise subcortical networks.
... A similar pattern of c-Fos expression was noted in the LA/BL complex of the amygdala and subregions of the d/vHIPP which displays strong interconnections with the amygdala. These patterns are consistent with the role of these structures in the stress-induced depression and anxiety [126]. Furthermore, CSIS rats revealed activation of the striatum. ...
The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments.
... Besides, as a key subregion of the amygdala, BLA may communicate with the hippocampus and the PFC to modulate the long-term memory consolidation of life events by regulating and integrating the norepinephrine and glucocorticoid levels [68], which may contribute to the emotional arousal of daily life events and peer victimization perceiving for preadolescent migrant children. Indeed, the BLA-mPFC circuitry is considered to be one basis of depressive-like behaviors [69,70] and the activation of the BLA-mPFC neurons also has a prodepressive impact [71]. The higher BLA-SFG functional connectivity is possibly involved in perceiving peer victimization and maintaining threat-related information in preadolescent migrant children, and finally induces internalizing depressive symptoms tendency, while higher self-esteem and higher morning cortisol could provide both mental resources and endocrinal resources to ameliorate these negative effects, which may account for the above-moderating effects existing only in BLA-SFG connectivity. ...
Background: As a sense of an intense stressor, perceived peer victimization can cause adverse effects on mental health, like depressive symptoms. Yet, little is known about the neurobiological mechanisms underlying how perceived peer victimization causes and maintains depressive symptoms in preadolescence.
Methods: Here we investigate the effects of peer victimization on amygdala subregional functional connectivity in 101 preadolescent migrant children, and their relations to depressive symptoms and potential protective factors of self-esteem and daily cortisol. Further control analyses were conducted to verify whether there are any specific effects in migrant children compared to 54 age-matched preadolescent children from nonmigrant background.
Results: Children with higher perceived peer victimization exhibited greater intrinsic functional connectivity of the amygdala with the middle frontal gyrus extending into the superior frontal gyrus. Perceived peer victimization could account for an indirect association between amygdala hyperconnectivity and depressive symptoms. Moderated mediation analyses revealed that basolateral amygdala connectivity with the superior frontal gyrus acted as a neural marker linking peer victimization and greater risk for depressive symptoms only in preadolescent children with low self-esteem or low daily cortisol.
Conclusions: These findings suggest that considering neurobiological vulnerability and psychophysiological factors may gain a nuanced understanding of the adverse effects of perceived peer victimization on depressive symptoms, a risk for internalizing pathology. This study could inform personalized intervention strategies to prevent or ameliorate depressive symptoms in this disadvantaged population.
... Limbic brain structures such as the amygdala have become a focus for mental health researchers. This is largely due to amygdala dysfunction being widely implicated in depression due to its role in emotion regulation and sensory processing (Drevets, 2003;LeDoux, 2000). Previous studies focusing on amygdala circuitry have clearly demonstrated the potential of fMRI to enhance our understanding of treatment responsiveness and remission in depressed cohorts (Goldstein-Piekarski et al., 2016;Williams et al., 2015). ...
Background: Treatment resistance impacts almost 50% of depression patients, with amygdala dysfunction being widely implicated. The amygdala is a complex amalgamation of subnuclei with diverse functions but fMRI studies have typically focussed on identifying whole rather than subregional amygdala functional connectivity. This study used high resolution 3T fMRI data to investigate subregional alterations that may differentiate treatment-resistant cohorts from healthy individuals and depressed patients who respond to treatment.
Methods: Resting-state fMRI data were obtained in 35 participants diagnosed with Treatment-Resistant Depression (TRD), 38 healthy control participants (HC), and 35 treatment-sensitive participants (TSD). Seed-based functional connectivity analyses of the three main subregions bilaterally (laterobasal, centromedial and superficial), as well as the whole amygdala, were performed and comparisons made between groups.
Results: We found connectivity differences in the right laterobasal amygdala subregion in TRD compared to both groups. TRD patients displayed hypoconnectivity to the right fusiform gyrus relative to HC whereas hyperconnectivity to the left inferior frontal gyrus relative to TSD was identified. No connectivity differences were found for the whole amygdala or any of the other subregions bilaterally.
Limitations: Modest sample size and cross-sectional study design are limitations. A causal relationship between functional connectivity alterations and treatment resistance cannot be established.
Conclusion: Altered connectivity of the right laterobasal subregion is a distinguishing feature of TRD. These alterations may underlie severe impairments in emotion processing and social functioning that are characteristic of TRD. These results emphasise the need for further investigation of the functional role of the amygdala subregions in depression.
... An imaging study revealed larger amygdala volumes in the first depressive episode compared to recurrent major depression and healthy controls [107]. Increased amygdala activity is linked to symptoms of depression and negative emotions, which may be caused by dysfunction in the prefrontal cortex and monoamine neurotransmitter systems [108]. ...
... Greater levels of mindfulness have been associated with the downregulation of pain perception pathways involving the amygdala and the ACC [21,[32][33][34][35]. Mindfulness-based breathing intervention was reported to improve amygdala and prefrontal cortex connectivity, associated with less emotional reactivity to negative visual stimuli [36]. In line with amygdala functions [37,38], mindfulness interventions have been shown to stabilize mood and reduce depressive symptoms in chronic pain patients [39][40][41][42][43][44]. ...
In the context of chronic pain management, opioid-based treatments have been heavily relied upon, raising concerns related to addiction and misuse. Non-pharmacological approaches, such as Mindfulness-Based Pain Management, offer alternative strategies. We conducted a mechanistic clinical study to investigate the impact of an 8-week Mindfulness-Based Pain Management intervention on chronic pain, the modulation of inflammatory markers, stress physiology, and oxytocin, and their interplay with clinical pain symptoms and perception, in comparison to a patient wait-list active control. A total of 65 participants, including 50 chronic pain patients and 15 healthy controls, underwent salivary assays to assess endocrine markers, oxytocin, interleukin (IL)-1b, IL-6, IL-8, tumor necrosis factor (TNF)-a, and dehydroepiandrosterone sulphate (DHEA-S). Psychological assessments were also conducted to evaluate aspects of pain perception, mindfulness, mood, and well-being. Findings revealed significant differences between chronic pain patients and healthy controls in various clinical metrics, highlighting the psychological distress experienced by patients. Following Mindfulness-Based Pain Management, oxytocin levels significantly increased in chronic pain patients, that was not observed in the patient wait-list control group. In contrast, cytokine and DHEA-S levels decreased (not to statistically significant margins) supporting anti-inflammatory effects of Mindfulness-Based Pain Management. The fact DHEA-S levels, a marker of stress, did attenuate but not to statistically meaningful levels, suggests that pain reduction was not solely related to stress reduction, and that oxytocin pathways may be more salient than previously considered. Psychological assessments demonstrated substantial improvements in pain perception and mood in the intervention group. These results contribute to the growing body of evidence regarding the effectiveness of mindfulness-based interventions in chronic pain management and underscore oxytocin’s potential role as a therapeutic target.
... This suggests needing to compensate more when emotional information interferes with an inhibitory control task [184]. Amygdala dysfunction and abnormal communication between the amygdala and frontal lobes have been consistently implicated in the pathophysiology of both depression and anxiety disorders [111,[188][189][190][191][192][193]. Thus, concussion-related lesions affecting these regions may contribute to the emotional dysregulation often reported after a concussion. ...
Emotional dysregulation symptoms following a concussion are associated with an increased risk for emotional dysregulation disorders (e.g., depression and anxiety), especially in adolescents. However, predicting the emergence or worsening of emotional dysregulation symptoms after concussion and the extent to which this predates the onset of subsequent psychiatric morbidity after injury remains challenging. Although advanced neuroimaging techniques, such as functional magnetic resonance imaging and diffusion magnetic resonance imaging, have been used to detect and monitor concussion-related brain abnormalities in research settings, their clinical utility remains limited. In this narrative review, we have performed a comprehensive search of the available literature regarding emotional regulation, adolescent concussion, and advanced neuroimaging techniques in electronic databases (PubMed, Scopus, and Google Scholar). We highlight clinical evidence showing the heightened susceptibility of adolescents to experiencing emotional dysregulation symptoms following a concussion. Furthermore, we describe and provide empirical support for widely used magnetic resonance imaging modalities (i.e., functional and diffusion imaging), which are utilized to detect abnormalities in circuits responsible for emotional regulation. Additionally, we assess how these abnormalities relate to the emotional dysregulation symptoms often reported by adolescents post-injury. Yet, it remains to be determined if a progression of concussion-related abnormalities exists, especially in brain regions that undergo significant developmental changes during adolescence. We conclude that neuroimaging techniques hold potential as clinically useful tools for predicting and, ultimately, monitoring the treatment response to emotional dysregulation in adolescents following a concussion.
... 5-HT release in the BL facilitates fear memory formation and impairs extinction in mice, an effect that is inhibited by the administration of a cocktail of 5-HT1A and 5-HT2A receptor antagonists (Sengupta & Holmes, 2019). Imaging studies in humans have shown that the amygdala is activated by anxietyrelated stimuli (Zald, 2003) and is overactivated in patients with anxiety and mood disorders (Drevets, 2003;Rauch et al., 2003). The fact that chronic administration of selective serotonin reuptake inhibitors (SSRIs) to depressed patients normalizes the activity of the amygdala and leads to clinical improvement along a time course that is consistent with the delayed onset of clinical efficaciousness of SSRIs strongly suggests that one of the main sites of therapeutic action of the SSRIs is the amygdala (Drevets et al., 2002;Sheline et al., 2001). ...
This review discusses neuroanatomical aspects of the three main monoaminergic systems innervating the basolateral nuclear complex (BNC) of the amygdala (serotonergic, noradrenergic, and dopaminergic systems). It mainly focuses on immunohistochemical (IHC) and in situ hybridization (ISH) studies that have analyzed the relationship of specific monoaminergic inputs and their receptors to specific neuronal subtypes in the BNC in order to better understand the anatomical substrates of the monoaminergic modulation of BNC circuitry. First, light and electron microscopic IHC investigations identifying the main BNC neuronal subpopulations and characterizing their local circuitry, including connections with discrete PN compartments and other INs, are reviewed. Then, the relationships of each of the three monoaminergic systems to distinct PN and IN cell types, are examined in detail. For each system, the neuronal targets and their receptor expression are discussed. In addition, pertinent electrophysiological investigations are discussed. The last section of the review compares and contrasts various aspects of each of the three monoaminergic systems. It is concluded that the large number of different receptors, each with a distinct mode of action, expressed by distinct cell types with different connections and functions, should offer innumerable ways to subtlety regulate the activity of the BNC by therapeutic drugs in psychiatric diseases in which there are alterations of BNC monoaminergic modulatory systems, such as in anxiety disorders, depression, and drug addiction. It is suggested that an important area for future studies is to investigate how the three systems interact in concert at the neuronal and neuronal network levels.
... Amygdaloid nuclei dysregulation has been implicated in various neurological and psychiatric disorders with impaired sensory perception, mood, cognition, and social behavior in both pediatric and adult patient populations (Schumann et al., 2011;Yan, 2012). Altered amygdaloid activity and/or connectivity can occur in general anxiety disorder, social anxiety and panic disorders, posttraumatic stress disorder, borderline personality disorder with pronounced affective lability, schizophrenia, bipolar disorder, depression, and autism spectrum disorder (Andrews et al., 2022;Drevets, 2003;Holt et al., 2008;Li et al., 2018;Yan, 2012). ...
Visualizing nerve cells has been fundamental for the systematic description of brain
structure and function in humans and other species. Different approaches aimed to
unravel the morphological features of neuron types and diversity. The inherent complexity of the human nervous tissue and the need for proper histological processing
have made studying human dendrites and spines challenging in postmortem samples. In
this study, we used Golgi data and open-source software for 3D image reconstruction
of human neurons from the cortical amygdaloid nucleus to show different dendrites
and pleomorphic spines at different angles. Procedures required minimal equipment
and generated high-quality images for differently shaped cells. We used the “singlesection” Golgi method adapted for the human brain to engender 3D reconstructed
images of the neuronal cell body and the dendritic ramification by adopting a neuronal tracing procedure. In addition, we elaborated 3D reconstructions to visualize
heterogeneous dendritic spines using a supervised machine learning-based algorithm
for image segmentation. These tools provided an additional upgrade and enhanced
visual display of information related to the spatial orientation of dendritic branches and
for dendritic spines of varied sizes and shapes in these human subcortical neurons. This
same approach can be adapted for other techniques, areas of the central or peripheral
nervous system, and comparative analysis between species.
... Individuals in a putatively positive internal state tend to interpret ambiguous cues more optimistically, expecting positive outcomes (e.g., rewards), while individuals in a putatively negative state tend to interpret the same cues more pessimistically (Paul et al., 2005;Mendl et al., 2010;Rygula et al., 2013). In humans, emotional cognitive bias occurs in anxiety and mood disorders and has been partially attributed to changes in the activity of the amygdala (Drevets, 2003;Victor et al., 2010;Ramasubbu et al., 2014;Yang and Wang, 2017;Zhang et al., 2018). ...
Background: The amygdala is crucial for emotional cognitive processing. Affective or emotional states can bias cognitive processes, including attention, memory, and decision-making. This can result in optimistic or pessimistic behaviors that are partially driven by the activation of the amygdala. The resulting emotional cognitive bias is a common feature of anxiety and mood disorders, both of which are interactively influenced by genetic and environmental factors. It is also known that emotional cognitive biases can be influenced by environmental factors. However, little is known about the effects of genetics and/or gene-environment interactions on emotional cognitive biases. We investigated the effects of the genetic background and environmental enrichment on the transcriptional profiles of the mouse amygdala following a well-established cognitive bias test.
Methods: Twenty-four female C57BL/6J and B6D2F1N mice were housed either in standard (control) conditions or in an enriched environment. After appropriate training, the cognitive bias test was performed on 19 mice that satisfactorily completed the training scheme to assess their responses to ambiguous cues. This allowed us to calculate an “optimism score” for each mouse. Subsequently, we dissected the anterior and posterior portions of the amygdala to perform RNA-sequencing for differential expression and other statistical analyses.
Results: In general, we found only minor changes in the amygdala’s transcriptome associated with the levels of optimism in our mice. In contrast, we observed wide molecular effects of the genetic background in both housing environments. The C57BL/6J animals showed more transcriptional changes in response to enriched environments than the B6D2F1N mice. We also generally found more dysregulated genes in the posterior than in the anterior portion of the amygdala. Gene set overrepresentation analyses consistently implicated cellular metabolic responses and immune processes in the differences observed between mouse strains, while processes favoring neurogenesis and neurotransmission were implicated in the responses to environmental enrichment. In a correlation analysis, lipid metabolism in the anterior amygdala was suggested to influence the levels of optimism.
Conclusions: Our observations underscore the importance of selecting appropriate animal models when performing molecular studies of affective conditions or emotional states, and suggest an important role of immune and stress responses in the genetic component of emotion regulation.
... There are several studies about the function of the amygdala as related to affective dysfunctions in many psychiatric disorders [152][153][154][155][156][157]. The human amygdala gets input from all sensory modalities, and the visual modality is the most significant for emotional aspects of social interactions. ...
Here we present a complex hypothesis about the psychosomatic mechanism of serotonergic psychedelics. Serotonergic psychedelics affect gut microbes that produce a temporary increase of 5-HT by their host enterochromaffin cells (ECs). This increased 5-HT production—which is taken up and distributed by platelets—may work as a hormone-like regulatory signal that could influence membrane permeability in the host organs and tissues and in the brain. Increased plasma 5-HT levels could enhance permeability of the blood-brain barrier (BBB). Transiently increased permeability of the BBB allows for plasma 5-HT to enter the central nervous system (CNS) and be distributed by the volume transmission. Next, this gut-derived 5-HT could modulate excitatory and inhibitory neurotransmission and produce special network disintegration in the CNS. This transient perturbation of the normal neural hierarchy allows patients access to suppressed fear information and perform an emotional reset, in which the amygdale may have a key role.
... It should be noted that the hippocampus, amygdala and medial prefrontal cortex are anatomically and physiologically connected with projections to each other and cooperate together to initiate a relatively wide range of behaviors including anxiety behavior [71]. For example, CA1 forms the main output of the hippocampus [72] and projects to the medial prefrontal cortex and the amygdala [73,74], and in practice, CA1-prefrontal cortex inputs activate in anxiety-related behaviors [75] and activation of ventral CA1-basolateral amygdala synapses considerably increases anxiety-related behaviors [76,77]. It has been shown that corticosterone secretion following stress increases the excitability and firing of CA1 hippocampal pyramidal cells [78][79][80] which may be result in activation of ventral CA1-basolateral amygdala and CA1-prefrontal cortex circuitry and subsequently may thus initiate anxiety-like behavior, which could be an explanation for anxiety behavior seen in the Stress group of our study with noting to the increase of corticosterone in the stress group. ...
There is a disagreement on whether extremely low frequency electromagnetic fields (ELF-EMF) have a beneficial or harmful effect on anxiety-like behavior. Prenatal stress induces frequent disturbances in offspring physiology such as anxiety-like behavior extending to adulthood. This study was designed to evaluate the effects of prenatal stress and ELF-EMF exposure before and during pregnancy on anxiety-like behavior and some anxiety-related pathways in the hippocampus of female rat offspring. A total of 24 female rats 40 days of age were distributed into four groups of 6 rats each: control, Stress (rats whose mothers underwent chronic stress), EMF (rats whose mothers were exposed to electromagnetic fields) and EMF/S (rats whose mothers were simultaneously exposed to chronic stress and ELF-EMF). The rats were given elevated plus-maze and open field tests and then their brains were dissected and their hippocampus were subjected to analysis. ELISA was used to measure 24(S)-hydroxy cholesterol, corticosterone, and serotonin levels. Cryptochrome2, steroidogenic acute regulatory protein, 3B-Hydroxy steroid dehydrogenase, N-methyl-D-aspartate receptor 2(NMDAr2) and phosphorylated N-methyl-D-aspartate receptor 2(PNMDAr2) were assayed by immunoblotting. Anxiety-like behavior increased in all treatment groups at the same time EMF increased anxiety induced by maternal stress in the EMF/S group. The stress group showed decreased serotonin and increased corticosterone levels. ELF-EMF elevated the PNMDAr2/NMDAr2 ratio and 24(S)-hydroxy cholesterol compared to the control group but did not change corticosterone. EMF did not restore changes induced by stress in behavioral and molecular tests. The results of the current study, clarified that ELF-EMF can induce anxiety-like behavior which may be attributed to an increase in the PNMDAr2/NMDAr2 ratio and 24(S)-OHC in the hippocampus, and prenatal stress may contribute to anxiety via a decrease in serotonin and an increase in corticosterone in the hippocampus. We also found that anxiety-like behavior induced by maternal stress exposure, is exacerbated by electromagnetic fields radiation.
... Decreased share of TP-PTD and a weak expression of TP also confirm the altered signaling, which correlates with abnormal social behavior. In line with hypotheses that amygdala hyperactivity underlies anxiety 51,52 , in vivo photoactivation of basolateral amygdala-vCA1 synapses significantly increases anxiety-related behaviors, while photoinhibition produces robust anxiolytic effects 53 . As far as hippocampal cells response was not recorded after amygdala stimulation the existence of Hip-amygdala disconnection is not clear. ...
Autism spectrum disorders (ASD) are neurodevelopmental disorders, that are characterized by core symptoms, such as alterations of social communication and restrictive or repetitive behavior. The etiology and pathophysiology of disease is still unknown, however, there is a strong interaction between genetic and environmental factors. An intriguing point in autism research is identification the vulnerable time periods of brain development that lack compensatory homeostatic corrections. Valproic acid (VPA) is an antiepileptic drug with a pronounced teratogenic effect associated with a high risk of ASD, and its administration to rats during the gestation is used for autism modeling. It has been hypothesized that valproate induced damage and functional alterations of autism target structures may occur and evolve during early postnatal life. Here, we used prenatal and postnatal administrations of VPA to investigate the main behavioral features which are associated with autism spectrum disorders core symptoms were tested in early juvenile and adult rats. Neuroanatomical lesion of autism target structures and electrophysiological studies in specific neural circuits. Our results showed that prenatal and early postnatal administration of valproate led to the behavioral alterations that were similar to ASD. Postnatally treated group showed tendency to normalize in adulthood. We found pronounced structural changes in the brain target regions of prenatally VPA-treated groups, and an absence of abnormalities in postnatally VPA-treated groups, which confirmed the different severity of VPA across different stages of brain development. The results of this study clearly show time dependent effect of VPA on neurodevelopment, which might be explained by temporal differences of brain regions’ development process. Presumably, postnatal administration of valproate leads to the dysfunction of synaptic networks that is recovered during the lifespan, due to the brain plasticity and compensatory ability of circuit refinement. Therefore, investigations of compensatory homeostatic mechanisms activated after VPA administration and directed to eliminate the defects in postnatal brain, may elucidate strategies to improve the course of disease.
... In addition to DMN and CCN, limbic system, which includes cingulate, hypothalamus, hippocampus, amygdala, is considered as an emotional regulation as well as an important role in depression [34], especially the amygdala networks [35]. Amygdala networks include emotion regulation, sensory information adjustment, and the process of visceral information in response to emotional stimuli, which involved in crucial functions associated with depression [36]. ...
Depression is one of the most common mental health problems in adolescents, which can lead to serious negative influence on school maladaptation, social adaptation, healthy development, even increase the risk of self-injury and suicide. Increasing number of studies demonstrate that both brain changes and environmental factors are relevant to depressive symptoms and disorder in adolescents. The present study is interested in the brain changes related to adolescent depression and how the environmental factors interact with the brain under the depression. Specifically, this study reviewed the influence of the alter in brain structure (e.g., white matter abnormality) and large-scale brain functional networks (e.g., default mode network) of adolescent depression. Moreover, the present review also introduced some environmental factors (e.g., parenting style) and how they can predict adolescent depression by affecting related brain structure and function. Finally, the limitations of the present study and suggestions for future studies are also conducted.
... The amygdala is known to play a large part in processing negative emotions, such as the initiation of fear and stress responses [112,113], and is centrally implicated in MDD [21,[114][115][116]. In the amygdala, previous work has reported the volume increase in some studies for patients with depression compared to controls [117], increased BOLD response in unipolar depression [103], and reduced activation after treatment to masked fearful faces [118]. ...
Investigation of brain changes in functional connectivity and functional network topology from receiving 8-week selective serotonin reuptake inhibitor (SSRI) treatments is conducted in 12 unmedicated adolescents with major depressive disorder (MDD) by using wavelet-filtered resting-state functional magnetic resonance imaging (fMRI). Changes are observed in frontal-limbic, temporal, and default mode networks. In particular, topological analysis shows, at the global scale and in the 0.12–0.25 Hz band, that the normalized clustering coefficient and smallworldness of brain networks decreased after treatment. Regional changes in clustering coefficient and efficiency were observed in the bilateral caudal middle frontal gyrus, rostral middle frontal gyrus, superior temporal gyrus, left pars triangularis, putamen, and right superior frontal gyrus. Furthermore, changes of nodal centrality and changes of connectivity associated with these frontal and temporal regions confirm the global topological alternations. Moreover, frequency dependence is observed from FDR-controlled subnetworks for the limbic-cortical connectivity change. In the high-frequency band, the altered connections involve mostly frontal regions, while the altered connections in the low-frequency bands spread to parietal and temporal areas. Due to the limitation of small sample sizes and lack of placebo control, these preliminary findings require confirmation with future work using larger samples. Confirmation of biomarkers associated with treatment could suggest potential avenues for clinical applications such as tracking treatment response and neurobiologically informed treatment optimization.
... The amygdala receives sensory information from the cortex, thalamus, hypothalamus, and brainstem (8). Previous studies have shown that amygdala dysfunction may be related to the pathogenesis of depression (9). Tang et al. (10) have also reported that the volume change rates of the left amygdala in patients with MCI and HCs were −1.32 ± 1.1% per year and −0.81 ± 0.73% per year, respectively. ...
Convergent evidence indicates that individuals with symptoms of depression exhibit altered functional connectivity (FC) of the amygdala, which is a key brain region in processing emotions. At present, the characteristics of amygdala functional circuits in patients with mild cognitive impairment (MCI) with and without depression are not clear. The current study examined the features of amygdala FC in patients with MCI with depression symptoms (D-MCI) using resting-state functional magnetic resonance imaging. We acquired resting-state functional magnetic resonance imaging data from 16 patients with D-MCI, 18 patients with MCI with no depression (nD-MCI), and 20 healthy controls (HCs) using a 3T scanner and compared the strength of amygdala FC between the three groups. Patients with D-MCI exhibited significant FC differences in the amygdala–medial prefrontal cortex and amygdala–sensorimotor networks. These results suggest that the dysfunction of the amygdala–medial prefrontal cortex network and the amygdala–sensorimotor network might be involved in the neural mechanism underlying depression in MCI.
... However, with advances in neuroimaging and suitable adjustments to standard methods, it is now possible to investigate the structural and functional connectivity of subcortical regions located deep inside the brain. In this first section, we will focus on the connectivity of the amygdala, a region that has been studied in-depth across mammalian species and which plays a central role in psychiatric disorders ( Drevets, 2003 ;Murray et al., 2011 ). Some of the neuroimaging challenges and advances discussed in this section similarly apply to other forebrain subcortical structures. ...
Mapping the structural and functional connectivity of the central nervous system has become a key area within neuroimaging research. While detailed network structures across the entire brain have been probed using animal models, non-invasive neuroimaging in humans has thus far been dominated by cortical investigations. Beyond the cortex, subcortical nuclei have traditionally been less accessible due to their smaller size and greater distance from radio frequency coils. However, major neuroimaging developments now provide improved signal and the resolution required to study these structures. Here, we present an overview of the connectivity between the amygdala, brainstem, cerebellum, spinal cord and the rest of the brain. While limitations to their imaging and analyses remain, we also provide some recommendations and considerations for mapping brain connectivity beyond the cortex.
... It is worth noting that the neuroesthetic studies reporting amygdala activation included such judgment tasks Zeki, 2011, 2013;Jacobs et al., 2016) which were not included in those studies that did not report amygdala activation. The amygdala has also been shown to be recruited in several tasks that require emotional decision-making, such as expression and perception of fear, appetitive processes, or social judgments, and it is part of the stress-response system (Drevets, 2003). Mood disorders, like major depression or bipolar disorder have been associated with elevated resting cerebral blood flow in this region, with downregulation depending on cognitive control areas, like the OFC, to reappraise contextual value (Dolan, 2007). ...
A worldwidemental health crisis is expected, as millions worldwide fear death and disease while being forced into repeated isolation. Thus, there is a need for new proactive approaches to improve mental resilience and prevent mental health conditions. Since the 1990s, art has emerged as an alternative mental health therapy in the United States and Europe, becoming part of the social care agenda. This article focuses on how visual esthetic experiences can create similar patterns of neuronal activity as those observed when the reward system is activated. The activation of the reward structures could have a stress buffering effect, given the interdependence observed between the reward and stress systems. Therefore, could visual esthetic experiences stimulate mental resilience? And if this were the case, could art-based interventions be offered for mental health in the context of COVID-19 and beyond?
... Symptoms of depression are associated with hyperactivity of the amygdala and decreased activity in the dorsolateral prefrontal cortex (dlPFC; Siegle et al., 2007). Hyperactivity of the amygdala contributes to increased attention to negative information (Drevets, 2003), while decreased dlPFC functioning contributes to cognitive control deficits (Fales et al., 2008). The combination of amygdala activation and decreased functioning of the dlPFC results in a troublesome rumination loop (Siegle et al., 2007). ...
Background
Cognitive Control Training (CCT) may reduce symptoms of depression. The mechanisms behind CCT are unclear, however. This study examined the adaptive Paced Auditory Serial Addition Task's (aPASAT) effect on depressive symptoms, while examining potential mechanisms by which changes may occur.
Methods
Seventy-two participants were randomly assigned to 1 of 3 conditions: the aPASAT, an active control condition, and a no training control. Participants in the aPASAT and active control conditions each practiced a cognitive task over a 2-week period. The aPASAT is paced and time-pressured, whereas the active control was self-paced and developed to be less stressful.
Results
Linear trend analysis revealed that, when accounting for age, CCT decreased depressive symptoms as the stress involved in the training task increased, as predicted. Against prediction, self-reported distress tolerance was unrelated to this pattern.
Limitations
This study did not include data to evaluate performance on the training tasks. Additionally, though the task in the active control condition was developed to be less stressful, participant stress was not directly measured.
Conclusions
Findings suggest that cognitive control training may reduce depressive symptoms and that the stressful component of the aPASAT may be important in that reduction.
... As an important component of the limbic system (Sokolowski and Corbin, 2012), the amygdala plays a key role in responding to emotional stimuli; its involvement in the pathophysiological response to stress had been well recognized (Drevets, 2003;Barry et al., 2017;Kedo et al., 2018). In addition, the amygdala also plays an important role in the arousal and execution of sexual behavior (Kühn and Gallinat, 2011;Seok et al., 2016). ...
Often associated with sexual dysfunction (SD), chronic stress is the main contributing risk factor for the pathogenesis of depression. Radix bupleuri had been widely used in traditional Chinese medicine formulation for the regulation of emotion and sexual activity. As the main active component of Radix bupleuri, saikosaponin D (SSD) has a demonstrated antidepressant effect in preclinical studies. Herein, we sought to investigate the effect of SSD to restore sexual functions in chronically stressed mice and elucidate the potential brain mechanisms that might underly these effects. SSD was gavage administered for three weeks during the induction of chronic mild stress (CMS), and its effects on emotional and sexual behaviors in CMS mice were observed. The medial posterodorsal amygdala (MePD) was speculated to be involved in the manifestation of sexual dysfunctions in CMS mice. Our results revealed that SSD not only alleviated CMS-induced depressive-like behaviors but also rescued CMS-induced low sexual motivation and poor sexual performance. CMS destroyed astrocytes and activated microglia in the MePD. SSD treatment reversed the changes in glial pathology and inhibited neuroinflammatory and oxidative stress in the MePD of CMS mice. The neuronal morphological and functional deficits in the MePD were also alleviated by SSD administration. Our results provide insights into the central mechanisms involving the brain associated with sexual dysfunction. These findings deepen our understanding of SSD in light of the psychopharmacology of stress and sexual disorders, providing a theoretical basis for its potential clinical application.
... As mentioned before, amygdala, prefrontal cortex and thalamus may be concerned with depression mood in ESRD patients. The amygdala is the main core region for modulating emotions, which was considered as an important starting region for investigating abnormalities of the regulatory circuit (Drevets 2003;Price 2003). Hence, we focused on three fiber bundles: the bilateral amygdala to the prefrontal cortex and the bilateral amygdala to the thalamus. ...
Depression is one of the common incidental symptoms in end-stage renal disease (ESRD) patients, empirically overlooked. Reproducible results observed that altered interregional white matter (WM) connections between depression-related brain regions (thalamus, amygdala, and prefrontal cortex (PFC)) in the human brain were closely associated with depression. Whether the depressive tendency of ESRD patients is also association with the WM connections is remains unknown. To address this problem, 56 ESRD patients before dialysis initiation and 56 healthy controls (HCs) were scanned with diffusion tensor imaging. According to the diagnostic and statistical manual of mental disorders, ESRD patients were separated into with and without depressive tendency groups. Twenty-five essential metabolites were tested in ESRD. The tractography atlas-based analysis and multiple regression analysis were implemented to gain features which could map the depressive tendency variability across ESRD. For metabolites, the levels of thrombocytes and calcium have significant differences between with and without depressive tendency groups. For WM microstructure, depressive tendency ESRD patients had abnormal WM diffusion properties along the fiber tracts of the amygdala-PFC. Compared with the features which were extracted from the group-difference of WM or metabolites, only WM features combinations (1000 bootstrap samples; 5000 permutation tests) along the fiber tract of the amygdala-PFC was a significant predictor of either with or without depressive tendency. Our findings suggested that the advanced neuroprotection may be planned before dialysis initiation, and the WM characteristics of amygdala-PFC may be a potential neuromarkers for the early diagnosis of depressive tendency in ESRD patients before dialysis initiation.
... Several moods and anxiety disorders such as depression cause a negative bias in the perception of facial emotions (Gur et al., 1992;Rubinow and Post, 1992;Murphy et al., 1999). Functional imaging studies have reported a decrease in the volume and activity of the ACC and an increase in activity in the amygdala in depressed patients (Drevets et al., 1997;Drevets, 2003). These previous findings together with our present results suggest that the ACC probably functions in the processing of facial emotions, and dysfunction of the neural network including the ACC and the amygdala leads to the negative bias of the perception of others' emotions in depressive patients. ...
Appropriate processing of others’ facial emotions is a fundamental ability of primates in social situations. Several moods and anxiety disorders such as depression cause a negative bias in the perception of facial emotions. Depressive patients show abnormalities of activity and gray matter volume in the perigenual portion of the anterior cingulate cortex (ACC) and an increase of activation in the amygdala. However, it is not known whether neurons in the ACC have a function in the processing of facial emotions. Furthermore, detecting predators quickly and taking avoidance behavior are important functions in a matter of life and death for wild monkeys. the existence of predators in their vicinity is life-and-death information for monkeys. In the present study, we recorded the activity of single neurons from the monkey ACC and examined the responsiveness of the ACC neurons to various visual stimuli including monkey faces, snakes, foods, and artificial objects. About one-fourth of the recorded neurons showed a significant change in activity in response to the stimuli. The ACC neurons exhibited high selectivity to certain stimuli, and more neurons exhibited the maximal response to monkey faces and snakes than to foods and objects. The responses to monkey faces and snakes were faster and stronger compared to those to foods and objects. Almost all of the neurons that responded to video stimuli responded strongly to negative facial stimuli, threats, and scream. Most of the responsive neurons were located in the cingulate gyrus or the ventral bank of the cingulate sulcus just above or anterior to the genu of the corpus callosum, that is, the perigenual portion of the ACC, which has a strong mutual connection with the amygdala. These results suggest that the perigenual portion of the ACC in addition to the amygdala processes emotional information, especially negative life-and-death information such as conspecifics’ faces and snakes.
Background
Bright light therapy (BLT) demonstrates efficacy in alleviating subthreshold depression (StD) among young adults. The amygdala plays a critical role in depression.
Methods
StD subjects were divided into BLT group (N=47) and placebo group (N=42). Depression severity was assessed using HAM-D, Centre for Epidemiologic Studies Depression Scale (CES-D) and Beck Depression Inventory (BDI) pre-/post-8-week intervention. Structural/resting-state fMRI scan was conducted. Seed-based static FC (sFC) and dynamic FC (dFC) analyses of the bilateral amygdala and their subfields were conducted.
Results
Compared to placebo, BLT showed reduced depression scale, and increased sFC of right basolateral amygdala (BLA)/superficial amygdala (SFA)-right middle temporal gyrus (MTG) and dFC of right centralmedial amygdala (CMA) and right inferior orbital frontal gyrus, and decreased sFC of right amygdalostriatal transition/CMA- left thalamus and dFC of right SFA- right medial prefrontal cortex after intervention; while the whole amygdala and its subnuclei volume did not change significantly after BLT. Right BLA-MTG sFC changes positively correlated with BDI improvement. Baseline amygdala sFC/dFC predicted post-BLT symptom changes. BLT-induced right BLA sFC alterations spatially correlated with 5-HT1A/5-HT2A receptor distributions, and right CMA dFC changes with 5-HT1A.
Conclusions
Findings suggest BLT modulates amygdala-thalamocortical circuits and serotonergic pathways, highlighting FC biomarkers for treatment efficacy assessment.
Trial Registration ClinicalTrials.gov Identifier
ChiCTR2000032633.
Emotions affect a large proportion of psychiatric disorders and are involved in practically all psychopathological symptoms and syndromes. Unfortunately, many of the questions about emotions cannot be answered today or are hotly debated; this concerns the various research directions: Research is being conducted in Affective Neuroscience, Psychiatry, Psychology, and also in the Humanities. Another question that should be posed at the beginning is: Is the conscious experience of emotions the decisive factor, i.e., the experience of mood or the unconscious effects of emotionality, or could it also be the physical and mental phenomena associated with them? What can we consider as established when we try to explain the disturbance of emotions?
Human brain organoids are 3-dimensional brain-like tissues derived from human pluripotent stem cells and hold promising potential for modeling neurological, psychiatric, and developmental disorders. While the molecular and cellular aspects of human brain organoids have been intensively studied, their functional properties such as organoid neural networks (ONNs) are largely understudied. Here, we summarize recent research advances in understanding, characterization, and application of functional ONNs in human brain organoids. We first discuss the formation of ONNs and follow up with characterization strategies including microelectrode array (MEA) technology and calcium imaging. Moreover, we highlight recent studies utilizing ONNs to investigate neurological diseases such as Rett syndrome and Alzheimer’s disease. Finally, we provide our perspectives on the future challenges and opportunities for using ONNs in basic research and translational applications.
Background
The human stress response is characterized by increases in neuromodulators, including norepinephrine (NE) and cortisol. Both neuromodulators can enter the brain and affect neurofunctional responses. Two brain areas associated with stress are the amygdala and the hippocampus. The precise influence of NE and cortisol on the amygdala and hippocampal resting state functional connectivity (RSFC) is poorly understood.
Aims
To investigate the influence of NE and cortisol on the amygdala and hippocampal RSFC.
Methods
We recruited 165 participants who received 10 mg yohimbine and/or 10 mg hydrocortisone in a randomized, placebo-controlled design. With seed-based analyses, we compared RSFC of the hippocampus and amygdala separately between the three groups that received medication versus placebo.
Results
We found no differences between yohimbine and placebo condition or between hydrocortisone and placebo condition regarding amygdala or hippocampal FC. Compared with placebo, the yohimbine/hydrocortisone condition showed increased amygdala and hippocampal RSFC with the cerebellum. Also, they had increased hippocampal RSFC with the amygdala and cerebral white matter.
Discussion
The group with elevated NE and cortisol showed significantly increased RSFC between the amygdala, hippocampus, and cerebellum compared to placebo. These three brain areas are involved in associative learning and emotional memory, suggesting a critical role for this network in the human stress response. Our results show that NE and cortisol together may influence the strength of this association. Compared to placebo, we found no differences in the groups receiving only one medication, suggesting that increasing one neuromodulator alone may not induce differences in neurofunctional responses. The study procedure has been registered at clinicaltrials.gov (ID: NCT04359147).
The impact of companion animals on human psychological health has garnered widespread attention. Research demonstrates that companion animals contribute positively in various ways, including reducing depression, anxiety, stress, and fostering positive emotions in humans. Recent studies have revealed significant changes in the activity levels of human emotion-related cortical areas (such as the frontal cortex and amygdala) and neurotransmitter (e.g., oxytocin, cortisol) secretion due to interaction with companion animals. However, research in this domain is still in a nascent stage, with many unknowns in the cognitive neural mechanisms involved. This paper proposes that to understand the cognitive mechanisms through which companion animals affect human psychological health, we need to examine changes in emotional cognitive processing. It aims to uncover the neurological underpinnings of how companion animals enhance human psychological well-being from the perspective of brain connectivity. This approach is expected to provide theoretical support and direction for future research and practical applications in this field.
The comorbidity of chronic pain and depression poses tremendous challenges for the treatment of either one because they exacerbate each other with unknown mechanisms. As the posterior insular cortex (PIC) integrates multiple somatosensory and emotional information and is implicated in either chronic pain or depression, we hypothesize that the PIC and its projections may contribute to the pathophysiology of comorbid chronic pain and depression. We show that PIC neurons were readily activated by mechanical, thermal, aversive, and stressful and appetitive stimulation in naive and neuropathic pain male mice subjected to spared nerve injury (SNI). Optogenetic activation of PIC neurons induced hyperalgesia and conditioned place aversion in naive mice, whereas inhibition of these neurons led to analgesia, conditioned place preference (CPP), and antidepressant effect in both naive and SNI mice. Combining neuronal tracing, optogenetics, and electrophysiological techniques, we found that the monosynaptic glutamatergic projections from the PIC to the basolateral amygdala (BLA) and the ventromedial nucleus (VM) of the thalamus mimicked PIC neurons in pain modulation in naive mice; in SNI mice, both projections were enhanced accompanied by hyperactivity of PIC, BLA, and VM neurons and inhibition of these projections led to analgesia, CPP, and antidepressant-like effect. The present study suggests that potentiation of the PIC→BLA and PIC→VM projections may be important pathophysiological bases for hyperalgesia and depression-like behavior in neuropathic pain and reversing the potentiation may be a promising therapeutic strategy for comorbid chronic pain and depression.
The amygdala is a hub of emotional circuits involved in the regulation of cognitive and emotional behaviors and its critically involved in emotional reactivity, stress regulation, and fear memory. Growing evidence suggests that the amygdala plays a key role in the consolidation of emotional memories during sleep. Neuroimaging studies demonstrated that the amygdala is selectively and highly activated during rapid eye movement sleep (REM) and sleep deprivation induces emotional instability and dysregulation of the emotional learning process. Regulation of dendritic spines during sleep represents a morphological correlate of memory consolidation. Several studies indicate that dendritic spines are remodeled during sleep, with evidence for broad synaptic downscaling and selective synaptic upscaling in several cortical areas and the hippocampus. Currently, there is a lack of information regarding the regulation of dendritic spines in the amygdala during sleep. In the present work, we investigated the effect of 5 h of sleep deprivation on dendritic spines in the mouse amygdala. Our data demonstrate that sleep deprivation results in differential dendritic spine changes depending on both the amygdala subregions and the morphological subtypes of dendritic spines. We observed decreased density of mushroom spines in the basolateral amygdala of sleep deprived mice, together with increased neck length and decreased surface area and volume. In contrast, we observed greater densities of stubby spines in sleep deprived mice in the central amygdala, indicating that downscaling selectively occurs in this spine type. Greater neck diameters for thin spines in the lateral and basolateral nuclei of sleep deprived mice, and decreases in surface area and volume for mushroom spines in the basolateral amygdala compared to increases in the cental amygdala provide further support for spine type-selective synaptic downscaling in these areas during sleep. Our findings suggest that sleep promotes synaptic upscaling of mushroom spines in the basolateral amygdala, and downscaling of selective spine types in the lateral and central amygdala. In addition, we observed decreased density of phosphorylated cofilin immunoreactive and growth hormone immunoreactive cells in the amygdala of sleep deprived mice, providing further support for upscaling of dendritic spines during sleep. Overall, our findings point to region-and spine type-specific changes in dendritic spines during sleep in the amygdala, which may contribute to consolidation of emotional memories during sleep.
Background
Major depressive disorder (MDD) is a highly prevalent (8–15%), severely disabling disorder and is associated with enormous socioeconomic impact. Antidepressant medication for the treatment of MDD has proven effective in RCTs; however, placebo response is also substantial. Given the potential benefits of modulating the placebo response in patient care and pharmacological research, understanding the mechanisms underlying placebo response is of high clinical relevance. The placebo response is mediated by treatment expectation, i.e. an individual’s belief about whether and how much they will improve as a consequence of their treatment. The mechanisms and moderators of treatment expectation effects in MDD are poorly understood. Initial brain imaging studies on placebo responses in MDD point towards the relevance of the lateral prefrontal cortex and the rostral anterior cingulate cortex (rACC). In this project, we will investigate the neural mechanisms underlying the antidepressant effects of treatment expectation associated with the fast-acting antidepressant esketamine in patients with MDD. Esketamine is an NMDA receptor antagonist inducing antidepressant effects within hours.
Methods
We will employ a fully balanced placebo design with the factors “treatment” (i.v. esketamine / placebo) and verbally induced “expectation” (high / low) combined with fMRI (resting state, emotion and reward processing paradigms) to investigate the psychological and neural mechanisms underlying the antidepressant effects of expectation, and how these interact with the pharmacological effects of esketamine.
Discussion
The insights gained by this project promise fundamental implications for clinical treatment and future drug trials. Unraveling the mechanisms underlying expectation effects on antidepressant treatment may inform (1) strategies to modulate these effects and thus improve assay sensitivity in RCTs and (2) novel treatment regiments aiming to maximize the synergistic effects of expectation and pharmacological treatment in the clinical care of patients with MDD.
Trial registration
This trial has been prospectively registered with the EU Clinical Trials Register: EudraCT-No.: 2020–000784-23 (November 17, 2020).
Stress is an inevitable part of life and, simultaneously, a stimulus that can trigger various neuropsychiatric disorders. Therefore, proper stress management is essential for maintaining a healthy life. In this study, we investigated the suppression of stress-induced cognitive deficit by controlling changes in synaptic plasticity caused by stress and confirmed that ethyl pyruvate (EP) has such an effect. Corticosterone, a stress hormone, suppresses long-term potentiation (LTP) in mouse acute hippocampal slices. EP blocked the LTP inhibitory effect of corticosterone by regulating GSK-3β function. Restraint stress for 2 weeks increased the anxiety levels and caused the cognitive decline in the experimental animals. Administration of EP for 14 days did not affect the increase in anxiety caused by stress but improved cognitive decline caused by stress. In addition, the decrease in neurogenesis and synaptic function deficits in the hippocampus, which cause of cognitive decline due to stress, were improved by EP administration. These effects appear via regulation of Akt/GSK-3β signaling, as in in vitro studies. These results suggest that EP prevents stress-induced cognitive decline through the modulation of Akt/GSK-3β-mediated synaptic regulation.
There is intriguing evidence suggesting that ketamine might have distinct acute and delayed neurofunctional effects, as its acute administration transiently induces schizophrenia-like symptoms, while antidepressant effects slowly emerge and are most pronounced 24 h after administration. Studies attempting to characterize ketamine's mechanism of action by using blood oxygen level dependent (BOLD) imaging have yielded inconsistent results regarding implicated brain regions and direction of effects. This may be due to intrinsic properties of the BOLD contrast, while cerebral blood flow (CBF), as measured with arterial spin labeling, is a single physiological marker more directly related to neural activity. As effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release, a combination of these approaches should be particularly suited to offer novel insights. In total, 75 healthy participants were investigated in a double blind, placebo-controlled, randomized, parallel-group study and underwent two scanning sessions (acute/post 24 h.). Acute ketamine administration was associated with higher perfusion in interior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC), but no other investigated brain region. Inhibition of glutamate release by pretreatment with lamotrigine abolished ketamine's effect on perfusion. At the delayed time point, pretreatment with lamotrigine was associated with lower perfusion in IFG. These findings underscore the idea that regionally selective patterns of CBF changes reflect proximate effects of modulated glutamate release on neuronal activity. Furthermore, region-specific sustained effects indicate both a swift restoration of disturbed homeostasis in DLPFC as well changes occurring beyond the immediate effects on glutamate signaling in IFG.
While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood control.
Accumulated evidence has demonstrated abnormal amygdala activation in bipolar disorder (BD). The olfactory bulb (OB) has vigorous connections with the amygdala. Although odor-related functions of the OB decreased during the evolutionary process, we hypothesized that an evolved OB with increased activation in emotion regulation may be one of the main factors affecting amygdala functions in BD. Our aim was to investigate metabolism in the OB and amygdala in patients with BD. Twenty-six patients diagnosed with BD according to DSM-5 diagnostic criteria were included in this cross-sectional study. Metabolism in the OB and amygdala was assessed using fluorodeoxyglucose positron emission tomography/CT in patients with BD. The OB and amygdala metabolism was compared with the patients’ Z scores. Both OB and amygdala metabolic activities were significantly higher than in the controls. A positive correlation was detected between right/left amygdala metabolism and right OB metabolism (p < 0.05, r:467 and r:662, respectively). This study increased our understanding of the etiopathogenesis of BD. In BD, the main cause of hypermetabolism in the amygdala may be increased metabolism in the OB. During evolution, the OB may have assumed a dominant role in emotional processing rather than olfactory functions.
Objective
Major depressive disorder (MDD) is a highly prevalent mood disorder affecting over 300 million people worldwide. Biased processing of negative information and neural hyper-responses to negative events are hallmarks of depression. The present study combined cross-sectional and longitudinal experiments to explore both persistent and resolved neural hyper-responses to negative outcomes from risky decision-making in current and remitted MDD patients.
Methods
A total of 264 subjects participated in the cross-sectional study, including 117 patients with medication-naive first-episode current depression, 45 remitted patients with only one episode of depression, and 102 healthy controls. Participants completed a modified balloon analog risk task during functional MRI. In the longitudinal arm of the study, 42 current MDD patients were followed up and 26 remitted patients were studied again after 8-week of antidepressant treatment.
Results
Current MDD patients showed hyper-responses to loss outcomes in multiple limbic regions including the amygdala and ventral anterior cingulate cortex (vACC). Amygdala but not vACC hyperactivity correlated with depression scores in current MDD patients. Furthermore, amygdala hyperactivity resolved while vACC hyperactivity persisted in remitted MDD patients in both cross-sectional and longitudinal studies.
Conclusions
These findings provide consistent evidence supporting differential patterns of the amygdala and vACC hyper-responses to negative outcomes during depression remission. Amygdala hyperactivity may be a symptomatic and state-dependent marker of depressive neural responses, while vACC hyperactivity may reflect a persistent and state-independent effect of depression on brain function. These findings offer new insights into the neural underpinnings of depression remission and prevention of depression recurrence.
Objectives:
In this study, we aimed to evaluate the clinical significance of osmophobia and its effect on quality of life in people with migraine.
Methods:
A total of 145 people with migraine were included in this cross-sectional study. Patients were evaluated with the migraine data form, the Migraine 24-Hour Quality of Life Questionnaire (24-HrMQoLQ), the Migraine Disability Assessment Scale (MIDAS), the Patient Health Questionnaire-9 (PHQ-9), the Insomnia Severity Index (ISI), the Generalized Anxiety Disorder-7 (GAD-7), the Allodynia Symptom Checklist (ASC), and the Fatigue Severity Scale (FSS). To evaluate the presence of osmophobia retrospectively, a semi-structured interview was conducted with the patients by the neurologist.
Results:
The mean 24-Hr-MQoLQ of patients with osmophobia was significantly lower than those without osmophobia. The decrease in the 24-Hr-MQoLQ was statistically significant in the areas of feeling and concerns and social functionality. The mean of the MIDAS scale was higher significantly in patients with osmophobia than those without osmophobia. In addition, the mean ISI, PHQ-9, FSS and ASC scores of patients with osmophobia were statistically significantly higher than those without osmophobia.
Conclusions:
Both 24-h and 3-month quality of life of people with migraine with osmophobia were more affected than those without osmophobia. At the same manner, insomnia, depression, fatigue and allodynia were observed at higher rates in people with migraine with osmophobia than in migraine without osmophobia. Osmophobia, which is one of the specific symptoms that distinguishes migraine from other headache disorders, deserves further and multifaceted investigation.
The hippocampus and amygdala limbic structures are critical to the etiology of major depressive disorder (MDD). However, there are no high-resolution characterizations of the role of their subregions in the whole brain network (connectome). Connectomic examination of these subregions can uncover disorder-related patterns that are otherwise missed when treated as single structures. 38 MDD patients and 40 healthy controls (HC) underwent anatomical and diffusion imaging using 7-Tesla MRI. Whole-brain segmentation was performed along with hippocampus and amygdala subregion segmentation, each representing a node in the connectome. Graph theory analysis was applied to examine the importance of the limbic subregions within the brain network using centrality features measured by node strength (sum of weights of the node’s connections), Betweenness (number of shortest paths that traverse the node), and clustering coefficient (how connected the node’s neighbors are to one another and forming a cluster). Compared to HC, MDD patients showed decreased node strength of the right hippocampus cornu ammonis (CA) 3/4, indicating decreased connectivity to the rest of the brain, and decreased clustering coefficient of the right dentate gyrus, implying it is less embedded in a cluster. Additionally, within the MDD group, the greater the embedding of the right amygdala central nucleus (CeA) in a cluster, the greater the severity of depressive symptoms. The altered role of these limbic subregions in the whole-brain connectome is related to diagnosis and depression severity, contributing to our understanding of the limbic system involvement in MDD and may elucidate the underlying mechanisms of depression.
Mania, the diagnostic hallmark of bipolar disorder, is an episodic disturbance of mood, sleep, behavior, and perception. Improved understanding of the neurobiology of mania is expected to allow for novel avenues to address current challenges in its diagnosis and treatment. Previous research focusing on the impairment of functional neuronal circuits and brain networks has resulted in heterogenous findings, possibly due to a focus on bipolar disorder and its several phases, rather than on the unique context of mania. Here we present a comprehensive overview of the evidence regarding the functional neuroanatomy of mania. Our interpretation of the best available evidence is consistent with a convergent model of lateralized circuit dysfunction in mania, with hypoactivity of the ventral prefrontal cortex in the right hemisphere, and hyperactivity of the amygdala, basal ganglia, and anterior cingulate cortex in the left hemisphere of the brain. Clarification of dysfunctional neuroanatomic substrates of mania may contribute not only to improve understanding of the neurobiology of bipolar disorder overall, but also highlights potential avenues for new circuit-based therapeutic approaches in the treatment of mania.
Early screening is essential for effective intervention and treatment of individuals with mental disorders. Functional magnetic resonance imaging (fMRI) is a noninvasive tool for depicting neural activity and has demonstrated strong potential as a technique for identifying mental disorders. Due to the difficulty in data collection and diagnosis, imaging data from patients are rare at a single site, whereas abundant healthy control data are available from public datasets. However, joint use of these data from multiple sites for classification model training is hindered by cross-domain distribution discrepancy and diverse label spaces. Herein, we propose few-shot domain-adaptive anomaly detection (FAAD) to achieve cross-site anomaly detection of brain images based on only a few labeled samples. We introduce domain adaptation to mitigate cross-domain distribution discrepancy and jointly align the general and conditional feature distributions of imaging data across multiple sites. We utilize fMRI data of healthy subjects in the Human Connectome Project (HCP) as the source domain and fMRI images from six independent sites, including patients with mental disorders and demographically matched healthy controls, as target domains. Experiments showed the superiority of the proposed method compared with binary classification, traditional anomaly detection methods, and several recognized domain adaptation methods.
Links between olfactory sensory function and affect have been well established. A robust literature exists in both humans and animals showing that disrupting olfaction sensory function can elicit disordered mood state, including serve as a model of depression. Despite this, considerably less is known regarding the directionality and neural basis of this relationship, e.g. whether disruptions in sensory function precede and contribute to altered mood or if altered mood state precipitates changes in olfactory perception. Further, the neural basis of altered olfactory function in depression remains unclear. In conjunction with clinical studies, animal models represent a valuable tool to understand the relationship between altered mood and olfactory sensory function. Here, we review the relevant literature assessing olfactory performance in depression in humans and in rodent models of depressive-like behavioral states. Rodents allow for detailed characterization of alterations in olfactory perception, manipulation of experiential events that elicit depressive-like phenotypes, and allow for interrogation of potential predictive markers of disease and the cellular basis of olfactory impairments associated with depressive-like phenotypes. We synthesize these findings to identify paths forward to investigate and understand the complex interplay between depression and olfactory sensory function.
Objectives
Vigilance is characterized by alertness and sustained attention. The hyper-vigilance states are indicators of stress experience in the resting brain. Neurexan (Nx4) has been shown to modulate the neuroendocrine stress response. Here, we hypothesized that the intake of Nx4 would alter brain vigilance states at rest.
Method
In this post-hoc analysis of the NEURIM study, EEG recordings of three, 12 min resting-state conditions in 39 healthy male volunteers were examined in a randomized, placebo-controlled, double-blind, cross-over clinical trial. EEG was recorded at three resting-state sessions: at baseline (RS0), after single-dose treatment with Nx4 or placebo (RS1), and subsequently after a psychosocial stress task (RS2). During each resting-state session, each 2-s segment of the consecutive EEG epochs was classified into one of seven different brain states along a wake-sleep continuum using the VIGALL 2.1 algorithm.
Results
In the post-stress resting-state, subjects exhibited a hyper-stable vigilance regulation characterized by an increase in the mean vigilance level and by more rigidity in the higher vigilance states for a longer period of time. Importantly, Nx4-treated participants exhibited significantly lower mean vigilance level compared to placebo-treated ones. Also, Nx4- compared to placebo-treated participants spent comparably less time in higher vigilance states and more time in lower vigilance states in the post-stress resting-state.
Conclusion
Study participants showed a significantly lower mean vigilance level in the post-stress resting-state condition and tended to stay longer in lower vigilance states after treatment with Nx4. These findings support the known stress attenuation effect of Nx4.
Depression and related mood disorders constitute an enormous burden on health, quality of life, and the global economy, and women have roughly twice the lifetime risk of men for experiencing depression. Here, we review sex differences in human brain physiology that may be connected to the increased susceptibility of women to major depressive disorder (MDD). Moreover, we summarize decades of preclinical research using animal models for the study of mood dysfunction that uncover some of the potential molecular, cellular, and circuit-level mechanisms that may underlie sex differences and disease etiology. We place particular emphasis on a series of recent studies demonstrating the central contribution of the circuit projecting from ventral hippocampus to nucleus accumbens and how inherent sex differences in the excitability of this circuit may predict and drive depression-related behaviors. The findings covered in this review underscore the continued need for studies using preclinical models and circuit-specific strategies for uncovering molecular and physiological mechanisms that could lead to potential sex-specific diagnosis, prognosis, prevention, and/or treatments for MDD and other mood disorders.
Sleep disturbances and memory dysfunction are key characteristics across psychiatric disorders. Recent advances have revealed insight into the role of sleep in memory consolidation, pointing to key overlap between memory consolidation processes and structural and molecular abnormalities in psychiatric disorders. Ongoing research regarding the molecular mechanisms involved in memory consolidation has the potential to identify therapeutic targets for memory dysfunction in psychiatric disorders and aging. Recent evidence from our group and others points to extracellular matrix molecules, including chondroitin sulfate proteoglycans and their endogenous proteases, as molecules that may underlie synaptic dysfunction in psychiatric disorders and memory consolidation during sleep. These molecules may provide a therapeutic targets for decreasing strength of reward memories in addiction and traumatic memories in PTSD, as well as restoring deficits in memory consolidation in schizophrenia and aging. We review the evidence for sleep and memory consolidation dysfunction in psychiatric disorders and aging in the context of current evidence pointing to the involvement of extracellular matrix molecules in these processes.
Objective
Globally, mood disorders are highly prevalent, and are associated with increased morbidity and mortalities. Magnetic resonance imaging is widely used in the study of mood disorders. However, bibliometric analyses of the state of this field are lacking.
Methods
A literature search in the web of science core collection (WoSCC) for the period between 1945 and 2020 returned 3073 results. Data extracted from these publications include, publication year, journal names, countries of origin, institutions, author names and research areas. The bibliometric method, CiteSpace V and key words analysis were used to visualize the collaboration network and identify research trends, respectively.
Results
Since it was first reported in 1999, the use of magnetic resonance imaging in studies on mood disorders has been increasing. Biological psychiatry is the core journal that has extensively published on this topic, while the UNIV PITTSBURGH, USA, has the highest published papers on this topic. Keyword analysis indicated that studies on depression, bipolar disorders, and schizophrenia, with a focus on specific brain regions, including amygdala, prefrontal cortex and anterior cingulate cortex are key research topics.
Conclusion
Brain structure and network, sex differences, and treatment-associated brain changes are key topics of future research.
Anti-CD4 IgG autoantibodies have been implicated in CD4+ T cell reconstitution failure, leaving people with HIV (PWH) at heightened risk of HIV-associated comorbidities, such as neurocognitive impairment. Seventeen PWH on stable anti-retroviral therapy (ART) and 10 HIV seronegative controls had plasma anti-CD4 IgG antibodies measured by enzyme-linked immunosorbent assay. Neuropsychological (NP) tests assessed cognitive performance, and brain volumes were measured by structural magnetic resonance imaging. Anti-CD4 IgG levels were elevated (p = 0.04) in PWH compared with controls. Anti-CD4 IgG correlated with global NP z-scores (rho = − 0.51, p = 0.04). A relationship was observed between anti-CD4 IgG and putamen (β = − 0.39, p = 0.02), pallidum (β = − 0.38, p = 0.03), and amygdala (β = − 0.42, p = 0.05) regional brain volumes. The results of this study suggest the existence of an antibody-mediated relationship with neurocognitive impairment and brain abnormalities in an HIV-infected population.
Mood disorders such as depression and bipolar disorder are common mental illnesses, affecting millions of patients worldwide. The application of newly available brain imaging methods to the study of mood disorders holds substantial promise in uncovering the brain mechanisms affected in these illnesses. This comprehensive and authoritative text features contributions from leading international experts, providing easily accessible information on the study of the brain mechanisms involved in the causation of mood disorders and the available treatments. Topics covered include the potential of magnetoencephalography (MEG), neuroimaging brain inflammation in depression, electrophysiology studies in mood disorders, and the applications of machine learning, filling an important gap in available neuropsychiatric literature and highlighting new developments. An invaluable resource for practitioners in the fields of psychiatry, neurology, primary care medicine, and related mental health professions, as well as researchers, students, graduate and post-graduate trainees.
Depression is a mental and neurological disease that reduces the desire for exploration. Dysregulation of the information transmission between medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) is associated with depression. However, which direction of information transmission (mPFC-BLA or BLA-mPFC) related to the decline of exploratory interests in depression is unclear. Therefore, it is important to determine what specific changes occur in mPFC and BLA information transmission in depressed rats during exploratory behavior. In the present study, local field potentials (LFPs) were recorded via multi-electrodes implanted in the mPFC and BLA for the control and depression groups of rats when they were exploring in an open field. The theta band was determined to be the characteristic band of exploratory behavior. The direct transfer function (DTF) was used to calculate the mPFC and BLA bidirectional information flow (IF) to measure information transmission. Compared with the control group, the theta IF of mPFC-BLA in the depression group was significantly reduced, and there was no significant difference in theta IF of BLA-mPFC between the two groups. Our results indicated that the reduction of mPFC-BLA information transmission can inhibit the exploratory behavior of depressed rats.
Treatment-resistant depression (TRD) is a serious problem in adolescents. Development and optimization of novel interventions for these youth will require a deeper knowledge of the neurobiology of depression. A well-established phenomenon of depression is an attention bias toward negativity and away from positivity that is evidenced behaviorally and neurally, but it is unclear how symptom reduction is related to changes to this bias. Neurobiological research using a treatment probe has promise to help discover the neural changes that accompany symptom improvement. Ketamine has utility for such research because of its known rapid and strong antidepressant effects in the context of TRD. Our previous study of six open-label ketamine infusions in 11 adolescents with TRD showed variable response, ranging from full remission, partial response, non-response, or clinical worsening. In this study, we examined the performance of these participants on Word Face Stroop (WFS) fMRI task where they indicated the valence of affective words superimposed onto either congruent or incongruent emotional faces before and after the ketamine infusions. Participants also completed a clinical assessment (including measurement of depression symptomology and anhedonia/pleasure) before and after the ketamine infusions. Following ketamine treatment, better WFS performance correlated with self-reported decreased depressive symptoms and increased pleasure. Analyses of corticolimbic, corticostriatal and default mode (DMN) networks showed that across networks, decreased activation during all conditions (congruent negative, congruent positive, incongruent negative, and incongruent positive) correlated with decreases in depressive symptoms and with increases in pleasure. These findings suggest that in adolescents with TRD, clinical improvement may require an attenuation of the negativity bias and re-tuning of these three critical neural networks to attenuate DMN and limbic regions activation and allow more efficient recruitment of the reward network. Lower activation across conditions may facilitate shifting across different salient emotional stimuli rather than getting trapped in downward negative spirals.
The functional neuroanatomy of unipolar major depression was investigated using positron emission tomography to measure differences in regional cerebral blood flow (BF). A relatively homogeneous subject group was obtained using criteria for familial pure depressive disease (FPDD), which are based upon family history as well as upon symptoms and course. Because of the absence of certain knowledge about the pathophysiology of mood disorders and their underlying functional neuroanatomy, we used data obtained from the subtraction of composite images from one-half of depressed and control subjects to identify candidate regions of interest. The major cortical region defined in this manner was statistically tested on a second set of subjects. Using this strategy, we found increased BF in an area that extended from the left ventrolateral prefrontal cortex onto the medial prefrontal cortical surface. Based upon the connectivity between these portions of the prefrontal cortex and the amygdala and evidence that the amygdala is involved in emotional modulation, activity was measured in the left amygdala and found to be significantly increased in the depressed group. A separate group of subjects with FPDD who were currently asymptomatic were also imaged to determine whether these findings represented abnormalities associated with the depressed state, or with a trait difference that might underlie the tendency to become depressed. Only the depressed group had increased activity in the left prefrontal cortex, suggesting that this abnormality represents a state marker of FPDD. Both the depressed and the remitted groups demonstrated increased activity in the left amygdala, though this difference achieved significance only in the depressed group. This suggests that the abnormality involving the left amygdala may represent a trait marker of FPDD, though further assessment in a larger sample size is necessary to establish this. These data along with other evidence suggest that a circuit involving the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and medial thalamus is involved in the functional neuroanatomy of depression.
To determine the relationship between cerebral Glc metabolism and glutamatergic neuronal function, we used 13C NMR spectroscopy to measure, simultaneously, the rates of the tricarboxylic acid cycle and Gln synthesis in the rat cortex
in vivo. From these measurements, we calculated the rates of oxidative Glc metabolism and glutamate–neurotransmitter cycling between
neurons and astrocytes (a quantitative measure of glutamatergic neuronal activity). By measuring the rates of the tricarboxylic
acid cycle and Gln synthesis over a range of synaptic activity, we have determined the stoichiometry between oxidative Glc
metabolism and glutamate–neurotransmitter cycling in the cortex to be close to 1:1. This finding indicates that the majority
of cortical energy production supports functional (synaptic) glutamatergic neuronal activity. Another implication of this
result is that brain activation studies, which map cortical oxidative Glc metabolism, provide a quantitative measure of synaptic
glutamate release.
1. Intracellular current-clamp recordings obtained from neurons of the basolateral nucleus of the amygdala (BLA) were used to characterize postsynaptic potentials elicited through stimulation of the stria terminalis (ST) or the lateral amygdala (LA). The contribution of glutamatergic receptor subtypes to excitatory postsynaptic potentials (EPSPs) were analyzed by the use of the non N-methyl-D-aspartate (non-NMDA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the NMDA antagonist, (DL)-2-amino-5-phosphonovaleric acid (APV). 2. Basic membrane properties of BLA neurons determined from membrane responses to transient current injection showed that at the mean resting membrane potential (RMP; -67.2 mV) the input resistance (RN) and time constant for membrane charging (tau) were near maximal, and that both values were reduced with membrane hyperpolarization, suggesting an intrinsic regulation of synaptic efficacy. 3. Responses to stimulation of the ST or LA consisted of an EPSP followed by either a fast inhibitory postsynaptic potential (f-IPSP) only, or by a fast- and subsequent slow-IPSP (s-IPSP). The EPSP was graded in nature, increasing in amplitude with increased stimulus intensity, and with membrane hyperpolarization after DC current injection. Spontaneous EPSPs were also observed either as discrete events or as EPSP/IPSP waveforms. 4. In physiological Mg2+ concentrations (1.2 mM), at the mean RMP, the EPSP consisted of dual, fast and slow, glutamatergic components. The fast-EPSP (f-EPSP) possessed characteristics of kainate/quisqualate receptor activation, namely, the EPSP increased in amplitude with membrane hyperpolarization, was insensitive to the NMDA receptor antagonist, APV (50 microM), and was blocked by the non-NMDA receptor antagonist, CNQX (10 microM). In contrast, the slow-EPSP (s-EPSP) decreased in amplitude with membrane hyperpolarization, was insensitive to CNQX (10 microM), and was blocked by APV (50 microM), indicating mediation by NMDA receptor activation. 5. In the presence of CNQX (10 microM), ST stimulation evoked an APV-sensitive s-EPSP. In contrast, LA stimulation evoked a f-IPSP, which when blocked by subsequent addition of bicuculline methiodide (BMI; 30 microM) revealed a temporally overlapping APV-sensitive s-EPSP. These data suggest that EPSP amplitude and duration are determined, in part, by the shunting of membrane conductance caused by a concomitant IPSP. 6. Superfusion of either CNQX or APV in BLA neurons caused membrane hyperpolarization and blockade of spontaneous EPSPs and IPSPs, suggesting that these compounds may act to block tonic excitatory amino acid (EAA) release within the nucleus, and that a degree of feed-forward inhibition occurs within the nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)
Statistical parametric maps (SPMs) are potentially powerful ways of localizing differences in regional cerebral activity. This potential is limited by uncertainties in assessing the significance of these maps. In this report, we describe an approach that may partially resolve this issue. A distinction is made between using SPMs as images of change significance and using them to identify foci of significant change. In the first case, the SPM can be reported nonselectively as a single mathematical object with its omnibus significance. Alternatively, the SPM constitutes a large number of repeated measures over the brain. To reject the null hypothesis, that no change has occurred at a specific location, a threshold adjustment must be made that accounts for the large number of comparisons made. This adjustment is shown to depend on the SPM's smoothness. Smoothness can be determined empirically and be used to calculate a threshold required to identify significant foci. The approach models the SPM as a stationary stochastic process. The theory and applications are illustrated using uniform phantom images and data from a verbal fluency activation study of four normal subjects.
Experiments were conducted to determine if the actions of antidepressant drugs in a pharmacological screen would be localized to specific brain regions. Rats were infused in discrete brain regions with drugs of different pharmacological properties and processed in the forced swim test. Infusion of imipramine and pargyline into the amygdala produced behavioral responses similar to i.p. injections of the drugs. The regions of the amygdala from which positive responses could be elicited were highly selective. From cannula placements and diffusion studies with autoradiography it appears that a locus of action of imipramine and pargyline is confined to the central, basolateral and/or lateral nuclear regions of the amygdala. Behavioral responses of rats in which imipramine was infused into the anterior amygdala or caudate-putamen did not differ from saline controls. When infused into regions of the amygdala in which imipramine was active, iprindole, an "atypical" antidepressant, did not produce a behavioral response in the forced swim test. Two "false positives" in the forced swim test, atropine and amphetamine, were also not active when infused into the amygdala. These results indicate that the amygdala is a critical site of action for certain antidepressant drugs in the forced swim test, and that behavioral activation in the test induced by iprindole, amphetamine and atropine involve brain regions other than the amygdala.
The amygdala is a central component of the limbic brain system and is known to be vital to understanding aspects of emotion, memory and social behaviour. Dysfunction of the structure is also thought to contribute to a variety of disorders, including autism, Alzheimer's Disease and schizophrenia. The nature of its contribution to these fundamental aspects of behaviour and cognition, and its relationship with other regions of the brain has remained elusive. However, since Aggleton's first book on the subject - The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (1992) - there have been major advances in our understanding of the processes involved and a dramatic rise in the volume of research. Scientists are now able to define its contribution in an increasingly precise manner. Leading experts from around the world have contributed chapters to this comprehensive and unique review, describing current thinking on this enigmatic brain structure. This is a book for all those with an interest in the neural basis of emotion and memory.
Signals detected with functional brain imaging techniques are based on the coupling of neuronal activity with energy metabolism. Techniques such as position emission tomography (PET) and functional magnetic resonance imaging (fMRI) allow the visualization of brain areas that are activated by a variety of sensory, motor or cognitive tasks. Despite the technological sophistication of these brain imaging techniques, the precise mechanisms and cell types involved in coupling and in generating metabolic signals are still debated. Recent experimental data on the cellular and molecular mechanisms that underlie the fluorodeoxyglucose (FDG)-based PET imaging point to a critical role of a particular brain cell type, the astrocytes, in coupling neuronal activity to glucose utilization. Indeed, astrocytes possess receptors and reuptake sites for a variety of neurotransmitters, including glutamate, the predominant excitatory neurotransmitter in the brain. In addition, astrocytic end-feet, which surround capillaries, are enriched in the specific glucose transporter GLUT-1. These features allow astrocytes to 'sense' synaptic activity and to couple it with energy metabolism. In vivo and in vitro data support the following functional model: in response to glutamate released by active neurons, glucose is predominantly taken up by astrocytic end-feet; glucose is then metabolized to lactate which provides a preferred energy substrate for neurons. These data support the notion that astrocytes markedly contribute to the FDG-PET signal.
Is there a relationship between perimenopausal reproductive function and the onset of mood disorders? The perimenopause is a time of considerable variability in reproductive function and, in some women, is associated with an increased susceptibility to depression. Whether the variability in ovarian hormone secretion during the perimenopause has any causal role in the development of depression remains unclear. Recent epidemiologic data confirm that the perimenopause is a time of increased susceptibility to the onset of depression. Additionally, although similar to major depressive disorder in phenomenology, course, and family and personal history of mood disorder, perimenopausal depression may be distinguished by an antidepressant response to estradiol therapy. This article presents background information relevant to the controversy surrounding the putative relationship between reproductive aging and mood disorders, reviews the endocrinology of the perimenopause, and describes several emerging methodologic issues that may help reconcile conflicting findings in past observational studies and recent randomized controlled trials. Studies examining the prevalence, presentation, and treatment response characteristics of mood disorders occurring during the perimenopause are described as well. The article concludes with recommendations for the evaluation and treatment of women with perimenopausal depression.
Background:
To determine whether elevations of plasma norepinephrine (NE) in major depression represent increased sympathetic nervous system (SNS) activity and to assess the effects of desipramine hydrochloride on sympathetic function.Methods:
SNS activity was assessed in depressed patients and controls by an isotope-dilution, plasma NE Kinetic technique using mathematical modeling and compartmental analysis. This approach provided estimates of the rate of NE appearance into an extravascular compartment, which is the site of endogenous NE release from SNS nerves, the corresponding rate of NE appearance into plasma, and the rate of NE clearance from plasma.Results:
Norepinephrine appearance into the extravascular and vascular compartments was significantly elevated in 17 depressed patients compared with that in 36 controls. The rate of NE clearance from plasma was similar in both groups. This is compatible with increased SNS activity in major depression. Desipramine, given for 2 days, significantly reduced the concentration of NE in plasma of patients and controls by markedly suppressing the rates of extravascular and vascular NE appearance, compatible with a short-term reduction in SNS activity. Desipramine prolonged the rate of NE clearance from plasma, consistent with a blockade of NE re-uptake into SNS nerve terminals. The initial suppression of SNS activity by desipramine was reversed by long-term (28 days) treatment of patients, with extravascular and vascular NE appearance rates returning to approximately basal levels. An associated rise in plasma NE concentrations compared with the baseline was attributable to a progressive reduction in plasma NE clearance.Conclusion:
Sympathetic nervous system activity is elevated in major depression and is suppressed by short-term desipramine administration. The demonstration of SNS reactivation occurring with prolonged desipramine treatment is compatible with the theory that long-term treatment desensitizes CNS α2-adrenergic receptors and emphasizes the value of examining the temporal course of responses to pharmacological challenges of neuroendocrine systems. Previously reported elevations of plasma NE during prolonged administration of tricyclic antidepressants are probably the result of a reduction in plasma NE clearance, not an increase in SNS activity.
Background: Alterations in amygdala function have been implicated in the pathophysiological characteristics of adult anxiety and depressive disorders. Studies with healthy adults and children, as well as with adults who have amygdala lesions, have found facial expressions of emotion to be useful probes of amygdala activity. Our study examined the amygdala response to fearful and neutral facial expressions in healthy, anxious, and depressed children. We hypothesized that children with anxiety and depression may show atypical amygdala responses to emotional stimuli. Methods: Twelve children (8-16 years of age) with generalized anxiety or panic disorder and 12 healthy comparison children underwent noninvasive functional magnetic resonance imaging while viewing photographs of fearful and neutral facial expressions. In a second comparison, 5 girls with major depressive disorder were compared with 5 anxious and 5 healthy girls from the previous sample. Results: Children with anxiety disorders showed an exaggerated amygdala response to fearful faces compared with healthy children, whereas depressed children showed a blunted amygdala response to these faces. In addition, the magnitude of the amygdala’s signal change between fearful and neutral faces was positively correlated with the severity of everyday anxiety symptoms. Conclusions: Our results suggest that amygdala function is affected in both anxiety and depression during childhood and adolescence. Moreover, this disruption appears to be specific to the child’s own rating of everyday anxiety.
Prior magnetic resonance imaging (MRI) studies report both medial and lateral cortical temporal changes and disturbed temporal lobe asymmetries in schizophrenic patients compared with healthy controls. The specificity of temporal lobe (TL) changes in schizophrenia is unknown. We determined the occurrence and specificity of these TL changes. Forty-six schizophrenic patients were compared to 60 normal controls and 27 bipolar subjects on MRI measures of bilateral volumes of anterior and posterior superior temporal gyrus (STG), amygdala, entorhinal cortex, and multiple medial temporal structures, as well as global brain measures. Several regional comparisons distinguished schizophrenia from bipolar disorder. Entorhinal cortex, not previously assessed using MRI in schizophrenia, was bilaterally smaller than normal in schizophrenia but not in bipolar disorder. Schizophrenic but not bipolar patients had an alteration of normal posterior STG asymmetry. Additionally, left anterior STG and right amygdala were smaller than predicted in schizophrenia but not bipolar disorder. Left amygdala was smaller and right anterior STG larger in bipolar disorder but not schizophrenia.
The role of the amygdala in major depression was investigated. Resting regional cerebral metabolic rate (rCMR(glu)) was measured with [18F]fluorodeoxyglucose positron emission tomography (PET) in two samples of subjects using two different PET cameras. The samples consisted of 10 and 17 medication-free depressives and 11 and 13 controls, respectively. Using coregistration of PET and magnetic resonance images, regions were individually delineated for the amygdala and thalamus, the latter of which was used as a control region. Within the depressed groups, right amygdalar rCMR(glu) was positively correlated with negative affect. Thalamic rCMR(glu) was not related to negative affect, and amygdalar rCMR(glu) accounted for a significant portion of variance in depressives' negative affect scores over and above the contribution of thalamic rCMR(glu).
This chapter attempts to define the anatomical organization of the prefrontal cortex (OMPFC) in macaque monkeys, including its architectonic structure and intrinsic and extrinsic connections, in hopes that this will enable more complete analysis of its function. Lesions of the OMPFC, such as reported in the classical case of Phineas Gage and in similar contemporary cases, have been reported to produce disturbances in emotional reactions to sensory stimuli, and disruption of social conduct so severe that they constitute a radical change in personality. Although the basis for this deficit remains unclear, it has been suggested that it is related to disconnection of pathways between the cortex and autonomic systems that govern visceral responses normally associated with affective stimuli. The results indicate that the OMPFC, like other cortical regions, is composed of a number of relatively discrete cortical areas. Each of these areas has distinct structure and connections, and presumably plays a distinct functional role within the overall function of the region.
Reviews convergent findings suggesting that dysregulation of hypothalamic and/or extrahypothalamic corticotropin-releasing factor (CRF) neurons may be involved in the pathophysiology of major depression and other psychiatric disorders. The findings discussed pertain to elevated CSF CRF concentrations in drug-free depressed patients; to normalization of CSF CRF concentrations with recovery from major depression; and to a blunted adrenocorticotropic hormone response to CRF in depressed patients. CRF receptor downregulation in the frontal cortex of suicide victims and enlargement of both the pituitary and adrenal glands in depressed patients are also cited as implicating dysregulation of CRF in the pathogenesis of depression. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
presents an emerging view of the brain basis of perception of others' intentions / the central concept of links between sensory representation of social events and somatic response is introduced, together with empirical evidence for the role of particular neural structures in mediating social perception / the role of somatosensory signals in assigning motivational significance to current social experience is considered / addresses the absence of "theory of mind" in autism (PsycINFO Database Record (c) 2012 APA, all rights reserved)
[the author] presents a theory of emotion based on his research on the neurophysiology of emotional processes in primates / the theory, in brief, is that emotions are states produced by reinforcing stimuli / unit recording studies aimed at identifying sites in the brain involved in processing reinforcing stimuli are described / the research points to the amygdala and the orbitofrontal cortex as key areas in the brain's system for computing the reinforcing value of stimuli (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The World Health Organization ranks depression as one of the top three health conditions in terms of burden of disease. This chapter discusses the diagnosis and treatment of major depressive disorder, dysthymic disorder, bipolar disorder (manic-depressive illness), and cyclothymic disorder. In addition, an overview of current knowledge regarding the etiology and natural history of these disorders is presented. Though these disorders occur in children and young adolescents, our comments are generally limited to older adolescents and adults. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Abnormalities in amygdala and hippocampus have been shown to coexist in schizophrenia (SZ). In the hippocampus, compelling evidence suggests that a disruption of GABA neurotransmission is present mainly in sectors CA4, CA3, and CA2. The amygdala sends important inputs to the hippocampus and is also believed to have a defective GABA system in schizophrenia. To explore the possibility that changes in the hippocampal GABAergic system could be related to an increased inflow of activity originating in the amygdala, a “partial” animal model has been developed. In awake, freely moving, rats a GABAA receptor antagonist was infused locally into the basolateral nuclear complex of the amygdala (BLn). Within 2 hours, a decreased density of both the 65- and 67-kDa isoforms of glutamate decarboxylase (GAD65 and GAD67) -immunoreactive (IR) terminals was detected on neuron somata in sectors CA3 and CA2, but not in CA1, CA4, or dentate gyrus. An increase of GAD67-IR somata was also found in the dentate gyrus and CA4. In anterograde tracer studies, amygdalo-hippocampal projection fibers were exclusively found in CA3 and CA2, but not CA1. Taken together, these results indicate that activation of amygdalo-hippocampal afferents is associated with the induction of significant changes in the GABA system of the hippocampus, with a subregional distribution that is remarkably similar to that found in SZ. Under pathologic conditions, an excessive discharge of excitatory activity emanating from the amygdala could be capable of altering inhibitory modulation along the trisynaptic pathway. This mechanism may potentially contribute to disturbances of GABAergic function in the major psychoses. Such “partial” rodent modelling provides an important strategy for deciphering the effect of altered cortico-limbic circuits in SZ. J. Comp. Neurol. 431:129–138, 2001. © 2001 Wiley-Liss, Inc.
Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. For example, both stress and chronic administration of corticosterone produce dendritic atrophy in hippocampal neurons (Woolley C, Gould E, McEwen BS. 1990. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225–231; Watanabe Y, Gould E, McEwen BS, 1992b. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 588:341–345). Prefrontal cortex is also a target for glucocorticoids involved in the stress response (Meaney MJ, Aitken DH. 1985. [3H]Dexamethasone binding in rat frontal cortex. Brain Res 328:176–180); it shows neurochemical changes in response to stress (e.g., Luine VN, Spencer RL, McEwen BS. 1993. Effect of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function. Brain Res 616:55–70; Crayton JW, Joshi I, Gulati A, Arora RC, Wolf WA. 1996. Effect of corticosterone on serotonin and catecholamine receptors and uptake sites in rat frontal cortex. Brain Res 728:260–262; Takao K, Nagatani T, Kitamura Y, Yamawaki S. 1997. Effects of corticosterone on 5-HT1A and 5-HT2 receptor binding and on the receptor-mediated behavioral responses of rats. Eur J Pharmacol 333:123–128; Sandi C, Loscertales M. 1999. Opposite effects on NCAM expression in the rat frontal cortex induced by acute vs. chronic corticosterone treatments. Brain Res 828:127–134), and mediates many of the behaviors that are altered by chronic corticosterone administration (e.g., Lyons DM, Lopez JM, Yang C, Schatzberg AF. 2000. Stress-level cortisol treatment impairs inhibitory control of behavior in monkeys. J Neurosci 20:7816–7821). To determine if glucocorticoid-induced morphological changes also occur in medial prefrontal cortex, the effects of chronic corticosterone administration on dendritic morphology in this corticolimbic structure were assessed. Adult male rats received s.c. injections of either corticosterone (10 mg in 250 μL sesame oil; n = 8) or vehicle (250 μL; n = 8) daily for 3 weeks. A third group of rats served as intact controls (n = 4). Brains were stained using a Golgi-Cox procedure and pyramidal neurons in layer II-III of medial prefrontal cortex were drawn; dendritic morphology was quantified in three dimensions. Sholl analyses demonstrated a significant redistribution of apical dendrites in corticosterone-treated animals: the amount of dendritic material proximal to the soma was increased relative to intact rats, while distal dendritic material was decreased relative to intact animals. Thus, chronic glucocorticoid administration dramatically reorganized apical arbors in medial prefrontal cortex. This reorganization likely reflects functional changes and may contribute to stress-induced changes in cognition. © 2001 John Wiley & Sons, Inc. J Neurobiol 49: 245–253, 2001
Integration of the hypothalamo–pituitary–adrenal stress response occurs by way of interactions between stress-sensitive brain circuitry and neuroendocrine neurons of the hypothalamic paraventricular nucleus (PVN). Stressors involving an immediate physiologic threat (`systemic' stressors) are relayed directly to the PVN, probably via brainstem catecholaminergic projections. By contrast, stressors requiring interpretation by higher brain structures (`processive' stressors) appear to be channeled through limbic forebrain circuits. Forebrain limbic sites connect with the PVN via interactions with GABA-containing neurons in the bed nucleus of the stria terminalis, preoptic area and hypothalamus. Thus, final elaboration of processive stress responses is likely to involve modulation of PVN GABAergic tone. The functional and neuroanatomical data obtained suggest that disease processes involving inappropriate stress control involve dysfunction of processive stress pathways.
The processes whereby our brains continue to learn about a changing
world in a stable fashion throughout life are proposed to lead to
conscious experiences. These processes include the learning of top-down
expectations, the matching of these expectations against bottom-up
data, the focusing of attention upon the expected clusters of information,
and the development of resonant states between bottom-up and top-down
processes as they reach an attentive consensus between what is expected
and what is there in the outside world. It is suggested that all
conscious states in the brain are resonant states and that these
resonant states trigger learning of sensory and cognitive representations.
The models which summarize these concepts are therefore called Adaptive
Resonance Theory, or ART, models. Psychophysical and neurobiological
data in support of ART are presented from early vision, visual object
recognition, auditory streaming, variable-rate speech perception,
somatosensory perception, and cognitive-emotional interactions, among
others. It is noted that ART mechanisms seem to be operative at all
levels of the visual system, and it is proposed how these mechanisms
are realized by known laminar circuits of visual cortex. It is predicted
that the same circuit realization of ART mechanisms will be found
in the laminar circuits of all sensory and cognitive neocortex. Concepts
and data are summarized concerning how some visual percepts may be
visibly, or modally, perceived, whereas amodal percepts may be consciously
recognized even though they are perceptually invisible. It is also
suggested that sensory and cognitive processing in the What processing
stream of the brain obey top-down matching and learning laws that
are often complementary to those used for spatial and motor processing
in the brain's Where processing stream. This enables our sensory
and cognitive representations to maintain their stability as we learn
more about the world, while allowing spatial and motor representations
to forget learned maps and gains that are no longer appropriate as
our bodies develop and grow from infanthood to adulthood. Procedural
memories are proposed to be unconscious because the inhibitory matching
process that supports these spatial and motor processes cannot lead
to resonance.
Unilateral partial ablations were made in the medial granular frontal cortex of 6 adult squirrel monkeys. Fiber degeneration was traced using the Nauta-Gygax and Fink-Heimer selective silver impregnation techniques into the cingulum, uncinate fascicle, corpus callosum, internal capsule and sublenticular (ventral extracapsular) bundle. Corticocortical projections were observed to the lateral orbital, parietal, rostral inferior temporal, and entorhinal cortices, as well as to the hippocampus proper. Subcortical projections were observed to the basal amygdaloid nucleus, lateral hypothalamus, lateral dorsal, anterior ventral, mediodorsal, pulvinar, and intralaminar nuclei of the thalamus. Preterminal and terminal fiber degeneration were notably sparse in most of the neostriatum, except the dorsolateral region of the caudate nucleus. Fiber degeneration traversed the medial crus cerebri of the midbrain, where fibers of passage ascended into the tegmentum through the medial substantia nigra. Preterminal and terminal degeneration were present in the mesencephalic reticular formation lateral and dorsal to the red nucleus and a few degenerating fibers were followed into the dorsolateral periaqueductal gray. Degeneration was observed as far caudal as the reticulotegmental nucleus of the rostral pons. On the basis of its connections, the medial prefrontal cortex resembles the remainder of the prefrontal lobe and probably also has an important role in cortical and subcortical limbic mechanisms.
The possibility that certain of the afferents of the primate amygdaloid complex use an excitatory amino acid transmitter was evaluated by injecting D-[3H]-aspartate into the amygdala of two Macaca fascicularis monkeys. The distribution of D-[3H]-aspartate labeled neurons was compared with those labeled with the nonselective retrograde tracer WGA-HRP injected at the same location as the isotope. Retrogradely labeled cells of both types were observed in a variety of cortical and subcortical structures observed in a variety of cortical and subcortical structures and in discrete regions within the amygdala. D-[3H]-aspartate labeled neurons were observed in layers III and V of the frontal, cingulate, insular and temporal cortices. In the hippocampal formation, heavily labeled cells were observed in the CA1 region and in the deep layers of the entorhinal cortex. Of the subcortical afferents, the claustrum and the midbrain peripeduncular nucleus contained the greatest number of D-[3H]-aspartate labeled cells. Subcortical afferents that are not thought to use excitatory amino acids, such as the cholinergic neurons of the basal nucleus of Meynert, did not retrogradely transport the isotope. Within the amygdala, the most conspicuous labeling was in the paralaminar nucleus which forms the rostral and ventral limits of the amygdala. When the D-[3H]-aspartate injection involved the basal nucleus, many labeled cells were also observed in the lateral nucleus. Retrograde transport of D-[3H]-aspartate injected into the amygdala, therefore, appears to demonstrate a subpopulation of inputs that may use an excitatory amino acid transmitter.
Synopsis
Using positron emission tomography (PET) and ¹⁵ Oxygen, regional cerebral blood flow (rCBF) was measured in 33 patients with primary depression, 10 of whom had an associated severe cognitive impairment, and 23 age-matched controls. PET scans from these groups were analysed on a pixel-by-pixel basis and significant differences between the groups were identified on Statistical Parametric Maps (SPMs). In the depressed group as a whole rCBF was decreased in the left anterior cingulate and the left dorsolateral prefrontal cortex ( P < 0·05 Bonferroni-corrected for multiple comparisons). Comparing patients with and without depression-related cognitive impairment, in the impaired group there were significant decreases in rCBF in the left medial frontal gyrus and increased rCBF in the cerebellar vermis ( P < 0·05 Bonferroni-corrected). Therefore an anatomical dissociation has been described between the rCBF profiles associated with depressed mood and depression-related cognitive impairment. The pre-frontal and limbic areas identified in this study constitute a distributed anatomical network that may be functionally abnormal in major depressive disorder.
We previously investigated the functional neuroanatomy of familial pure depressive disease (FPDD) using positron emission tomography (PET) measurements of regional blood flow and obtained evidence that flow is increased in the left prefrontal cortex, amygdala, and medial thalamus and is decreased in the medial caudate. These data along with other evidence suggested that circuits involving the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and medial thalamus are involved in the pathophysiology of FPDD. One of these circuits, the limbic-thalamo-cortical circuit, which includes the amygdala, the medio-dorsal thalamus, and parts of the ventral and medial prefrontal cortex, may be engaged in abnormal reverberatory activity that maintains the cognitive and emotional set of depression. Using this hypothesis as a neural model to investigate antidepressant treatment mechanisms, we review evidence that the changes in dopaminergic, serotonergic, and noradrenergic function induced by somatic antidepressant therapies may yield modulatory effects on limbic-thalamo-cortical activity. We also discuss preliminary findings of treatment-associated changes in this circuit in studies comparing PET images acquired before and during antidepressant treatment.
Volumetric measurements of subcortical and temporal structures were done on a sample of 54 schizophrenic patients, who were compared with 48 bipolar patients and 47 normal controls. We observed the male schizophrenic patients to have significant enlargement in the putamen and lesser enlargement in the caudate. We found the right temporal lobe to be larger than the left across all diagnostic groups, although bipolar females failed to have this asymmetry. We did not replicate the finding of decreased hippocampal, amygdala, or temporal lobe volume in our schizophrenic patients. Nor did we find significant differences between our bipolar patients and controls in the structures measured, with the exception of the right hippocampus. Our findings are consistent with a developmental defect in pruning of subcortical brain regions or with a compensatory synaptic increase secondary to decreased input from other brain regions such as the prefrontal cortex or anterior temporal lobe structures. Coupled with the lack of temporal lobe asymmetry in bipolar females, these findings suggest that different types of gender-specific neurodevelopmental abnormalities may occur in affective versus schizophrenic psychosis, which may reflect the effects of hormonal influences on brain development in predisposed individuals.
Sleep deprivation is a rapid, nonpharmacologic antidepressant intervention that is effective for a subset of depressed patients. The objective of this study was to identify which brain structures' activity differentiates responders from nonresponders and to study how metabolism in these brain regions changes with mood.
Regional cerebral glucose metabolism was assessed by positron emission tomography (PET) with [18F]deoxyglucose (FDG) before and after total sleep deprivation in 15 unmedicated awake patients with unipolar major depression and 15 normal control subjects, who did the continuous performance test during FDG uptake.
After sleep deprivation, four patients showed a 40% or more improvement on the Hamilton Rating Scale for Depression. Before sleep deprivation the depressed responders had a significantly higher cingulate cortex metabolic rate than the depressed nonresponders, and this normalized after sleep deprivation. The normal control subjects and nonresponding depressed patients showed no change in cingulate metabolic rate after sleep deprivation.
Overactivation of the limbic system as assessed by PET scans may characterize a subset of depressed patients. Normalization of activity with sleep deprivation is associated with a decrease in depression.
This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, 125I-iodopindolol (125I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of rats with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of 125I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce 125I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of 125I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of 125I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of 125I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus. Repeated treatment of rats with citalopram, sertraline, or trazodone or with drugs lacking clinical antidepressant efficacy caused no significant effects on the binding of 125I-IPIN to either subtype of beta adrenoceptor in any region of brain. These results demonstrate that amygdaloid beta-1 adrenoceptors are particularly susceptible to regulation by certain antidepressant treatments and implicate the amygdala as an important site of action for antidepressants with pharmacological activity on noradrenergic neurons.
The neural connections from the basolateral nucleus of the amygdala (BLA) to the medial prefrontal cortex (MPC) in urethane-anesthetized rats were investigated. Extracellular recordings were made from 200 neurons with spontaneous firing in the MPC, and the BLA was electrically stimulated. The most frequent response to BLA stimulation was inhibition (63.5%). Excitatory responses were found in 17 units (8.5%), while 56 neurons (28%) did not change their spontaneous firing after BLA stimulation. Inhibitory responses showed a wide range of latencies, suggesting the coexistence of mono- and polysynaptic pathways. On the contrary, the excitatory responses seem to be mediated by a monosynaptic pathway. BLA projections to the MPC play a predominantly inhibitory role in the spontaneous activity of prefrontal neurons. This inhibition may modulate central motor systems and motivated behaviors.
We studied 10 patients with melancholia before and after sleep deprivation and 8 controls with Tc-99m-hexamethylpropylenamineoxime (HMPAO) single photon emission computed tomography (SPECT). All depressed subjects showed relative hypoperfusion in the left anterolateral prefrontal cortex under both conditions. Only responders showed relative hyperperfusion in parts of the limbic system and a reduction of blood flow in these regions after sleep deprivation.
The neurobiologic mechanisms whereby the long-term administration of different antidepressant treatments enhance the efficacy of 5-HT synaptic transmission was investigated using an electrophysiologic paradigm in chloral hydrate anesthetized rats. Repeated electroconvulsive shocks (ECS; administered every other day for 14 days) as well as the sustained 21-day administration of the tricyclic antidepressant imipramine (10 mg/kg/day) and of the selective 5-hydroxytryptamine (5-HT) reuptake blocker paroxetine (5 mg/kg/day), increased the suppressant effect of the electrical stimulation of the afferent 5-HT pathway on the firing activity of CA3 hippocampus pyramidal neurons. The long-term treatments with imipramine and ECS, but not with paroxetine, increased the responsiveness of postsynaptic CA3 hippocampus pyramidal neurons to the microiontophoretic application of 5-HT and to that of the selective 5-HT1A receptor ligand 8-OH-DPAT. In contrast, the long-term treatment with paroxetine, but not with imipramine or ECS, attenuated the negative feedback exerted by terminal 5-HT autoreceptors on 5-HT release. This was indicated by two series of experiments. First, the capacity of the acute intravenous injection of the terminal 5-HT autoreceptor antagonist methiothepin to increase the efficacy of the stimulation was abolished in paroxetine-treated rats. Second, the decreased suppressant effect on pyramidal neuron firing activity usually obtained by increasing the frequency of the stimulation from 1 to 5 Hz (shown to be due to an increase in terminal 5-HT autoreceptor activation at the higher frequency) was also reduced in paroxetine-treated rats. The present data confirm and extend those of previous electrophysiologic studies showing that an enhanced 5-HT synaptic transmission is a common end result of long-term administration of various types of antidepressant treatments. Furthermore, they suggest that the mechanisms underlying this enhanced synaptic transmission differ according to the type of treatment administered. Tricyclic antidepressants and ECS enhance 5-HT synaptic transmission by increasing the sensitivity of postsynaptic 5-HT1A receptors, whereas selective 5-HT reuptake blockers produce this effect by reducing the function of terminal 5-HT autoreceptors, thereby increasing the amount of 5-HT released per stimulation-triggered action potential.
Depression is a frequent finding in patients with Parkinson's disease (PD). Regional cerebral glucose metabolism was measured in depressed and nondepressed patients with PD and in age-comparable normal control subjects using 2-[18F]-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Relative metabolic activity in the caudate and orbital-inferior region of the frontal lobe was significantly lower in the depressed patients with PD as compared to both nondepressed patients and control subjects. There was a significant inverse correlation between relative glucose metabolism in the orbital-inferior area of the frontal lobe and depression scores. This study suggests that depression in PD is associated with dysfunction in the caudate and orbital-inferior area of the frontal lobe. This metabolic pattern is unlike that seen in patients with PD who have other behavioral deficits such as dementia, and suggests that disruption of basal ganglia circuits involving the inferior region of the frontal lobe may affect the regulation of mood.
Since the inception of the 14C-deoxyglucose method and its extension to in vivo imaging of regional cerebral glucose metabolism in humans by positron emission tomography, uncertainty has persisted concerning the type of work to which regional metabolism is coupled, as well as the distribution of this work within the neuron. 14C-deoxyglucose studies indicate that functionally-coupled neural metabolism is more apparent in axon terminals and perhaps dendrites than neuronal perikarya. Moreover, it appears that most of the metabolism in axon terminals is accounted for by Na+-K+-ATPase activity. Nevertheless, cytochrome oxidase histochemistry reveals the presence of intensely reactive mitochondria in soma-dendrite regions opposite presynaptic axon terminals, thereby indicating that continuous temporal and spatial summation of postsynaptic graded potentials is associated with increased metabolism. While the situation concerning the relative postsynaptic metabolic prices of EPSP's and IPSP's remains uncertain, the presence of elevated levels of cytochrome oxidase activity within certain classes of presynaptic terminals indicates that active excitation and inhibition is associated with increases in presynaptic metabolism. This observation has been confirmed in 14C-deoxyglucose studies. Nevertheless, studies of neonatal hippocampus indicate that, before metabolic activity shifts to dendritic and telodendritic regions of electrophysiological activity, metabolism is high in somal foci of biosynthesis.
The extent and distribution of biochemical abnormalities thought to reflect disorders of subpopulations of neurons have been determined in the cerebral cortex from brains of patients with Alzheimer-type dementia and depressive illness who died of natural causes. In dementia, loss of gray matter from areas of the parietal and temporal lobes is most obvious. In depression, these areas are not affected, but the pars opercularis and temporal pole are smaller than in controls. Results expressed per unit mass of total protein indicate selective reductions in both disorders of serotonin 2 recognition sites in all areas examined and of somatostatin content in only the temporal pole of the six areas examined. In dementia alone a selective loss was found of somatostatin content of the superior parietal lobule and of serotonin 1A sites and choline acetyltransferase activity in all areas examined. Results for depression expressed per entire area indicate additionally reduced somatostatin content and serotonin 1A sites in the pars opercularis and serotonin 1A sites in the temporal pole. These multiple analyses performed on each sample provide further support for a prominent disorder of pyramidal neurons in dementia as well as more evidence for alterations in cortical neurons in depression, either as a result of the disease itself or its treatment.
Empirical studies have recently demonstrated that major and minor depressive disorders occur in 30-50% of stroke patients, and last more than one year without treatment, although they do respond to tricyclic antidepressants. These mood disorders are not strongly associated with severity of impairment, demographic characteristics, social supports or prior personal history, but major depression is often strongly associated with left frontal or left basal ganglia lesions and pre-existing subcortical atrophy. While the aetiology of these mood disorders remains unknown, serotonergic or noradrenergic dysfunction may play a role. Mania is a rare complication of stroke: the clinical presentation and response to treatment are usually the same as mania without brain injury. Post-stroke mania is strongly associated with both a right hemisphere lesion in a limbic-connected area and a second predisposing factor, such as genetic loading for affective disorder, pre-existing subcortical atrophy or seizure disorder. This disorder may be mediated through frontal lobe dysfunction. The lesion method represents a potentially fruitful technique for investigating the mechanisms of affective disorder.
Corticosteroids in human plasma and urine increase after amygdala stimulation, and plasma corticosteroids decrease after hippocampus stimulation. Five subjects underwent unilateral temporal lobectomy, and histopathologic localization of electrode sites was attempted. Localization was successful for six sites: three in basolateral amygdala and three in hippocampus.