Psychol Sci. ISSN 1740-634X (online) PubMed In the next section we will explore the role of PFC in human threat processing research, from acquisition and encoding of threat, to its extinction and extinction recall. 2004;43:897905. Duman RS. 2018;48:1128. Thomas KM, Drevets WC, Dahl RE, Ryan ND, Birmaher B, Eccard CH, et al. Reviewer: 2017;82:e51e59. 2018;84:12937. Kostic VS, Filippi M. Neuroanatomical correlates of depression and apathy in Parkinson's disease: magnetic resonance imaging studies. Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: Symptom dimensions and emotion dysregulation in responses to scriptdriven trauma imagery. J Neurosci. Neuron. Cross-species comparisons can be more easily made with respect to connectivity patterns [23]. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. This pathway runs from the centromedial nucleus of the amygdala to the ventromedial nucleus of the hypothalamus. Its primary input is to the basal ganglia system. Admon R, Leykin D, Lubin G, Engert V, Andrews J, Pruessner J, et al. Gross JJ. Soc Cogn Affect Neurosci. 2017;37:486882. Hum Brain Mapp. Read more. Izquierdo A, Wellman CL, Holmes A. In comparing to the basolateral group, it is smaller, phylogenetically older, and functionally belongs to the olfactory system. [167] reported on fMRI task-based assessment while completing three tasks assessing emotional reactivity and regulation prior to prolonged exposure psychotherapy for PTSD. The .gov means its official. Tumors in your thalamus. Vision problems, including vision loss or light sensitivity. Thus, the precise role for the mPFC is not yet entirely clear. Amygdala reactivity and anterior cingulate habituation predict posttraumatic stress disorder symptom maintenance after acute civilian trauma. Emotion regulation: quantitative meta-analysis of functional activation and deactivation. Activity and connectivity of mood regulating circuit in depression: a functional magnetic resonance study. Resting-State Functional Connectivity in Treatment-Resistant Depression. Response variation following trauma: a translational neuroscience approach to understanding PTSD. The differences in these projection patterns suggest diverging functional roles for these adjacent structures. From rodent research showing that intra-amygdala infusion of the NMDA receptor agonist d-cycloserine, which enhances NMDA-dependent plasticity, facilitates extinction learning, and successful translation of this work to humans (see [104] for review), we know that the human amygdala plays a role in extinction learning. 2010;30:1572634. The hippocampus is mainly involved in memory, learning, and emotion. Social learning of fear. 2006;13:147. Impact of depressed mood on neuropsychological status in temporal lobe epilepsy. Behav Neurosci. However, few findings have been reliably and consistently reported. Major Depressive Disorder is a serious medical illness which is responsible for considerable morbidity and disability. Despite the large body of translational research, many questions remain unanswered and posttraumatic stress disorder remains difficult to treat. 2008;12:6571. Beginning with Brodmann, there have been debates about the existence and location of the mPFC in rodents due to the lack of a prominent granular layer [22; see Preuss and Wise, this issue]. In a study of 2,835 participants with definite HD, over 40% reported having active symptoms of depression (67). Differential frontalstriatal and paralimbic activity during reversal learning in major depressive disorder and obsessivecompulsive disorder. Functionally, it belongs to the limbic system. This is advantageous because the neural circuitry underlying threat and fear-related behaviors in mammals, including the amygdalahippocampusmedial prefrontal circuit, is among the most well-understood behavioral circuits in neuroscience [11,12,13,14]. Inhibition in this task correlated with a physiological measure of threat extinction in a fear-potentiated startle paradigm outside of the scanner. Nat Commun. Kohn N, Eickhoff SB, Scheller M, Laird AR, Fox PT, Habel U. Neural network of cognitive emotion regulationan ALE meta-analysis and MACM analysis. Padilla-Coreano N, Do-Monte FH, Quirk GJ. Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, et al. Often called the "gateway to consciousness," the thalamus regulates attention and alertness. In the case of bitemporal amnesia, the evidence suggests that the hippocampal formation plays a crucial role in memory functions; the possibility also needs to be considered that the hippocampal formation and amygdala may function conjointly in this regard. In the IL, threat extinction is associated with acetylation of histones near the Bdnf locus [61], changes to the p300/CBP complex (PCAF) [62], as well as deposition of DNA-modification marks such as 5-hydroxymethylcytosine and N6-methyl-2deoxyadenosine (m6dA) near loci of activity-dependent genes such as Bdnf. These structures also send their fibers back to the amygdala. Starkstein SE, Robinson RG, Honig MA, Parikh RM, Joselyn J, Price TR. 2021;31:96173. The amygdalofugal pathway and the stria terminalis together enable the amygdala to directly control the medial hypothalamus, the lateral hypothalamus and midbrain periaqueductal gray. J Neurosci. The BDNF-TrkB neurotrophic factor pathway has also been extensively studied with regards to mPFC and memory formation in mPFC. 2015;5:3. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Diminished medial prefrontal cortex activation during the recollection of stressful events is an acquired characteristic of PTSD. Research harnessing advances in technology to further probe the role of the prefrontal cortex in these processes, such as the use of optogenetics in rodents and brain stimulation in humans, will be highlighted, as well other fear regulation approaches that are relevant to the treatment of posttraumatic stress disorder and involve the prefrontal cortex, namely cognitive regulation and avoidance/active coping. Sheline YI, Price JL, Yan Z, Mintun MA. 2020;105:106276.e6. Nat Rev Neurosci. 2020;45:49198. The publisher's final edited version of this article is available at, Depression, Major depressive disorder, MDD, Unipolar depression, Limbic system, Resting state connectivity, Neuroimaging, fMRI, MRI, PET, Parkinsons disease, Stroke, Deep brain stimulation, DBS, Transcranial magnetic stimulation, TMS, Vagus nerve stimulation, VNS, Mood disorders, Psychiatry, Diagnostic and Statsitical Manual 4th Edition - Text Revision (DSM-IV-TR). Kerry J. Ressler or Elizabeth A. Phelps. In rodents, the PL and IL cortex are located adjacent to one another in the mPFC. In the meantime, to ensure continued support, we are displaying the site without styles In a small study of victims of urban violence, Rocha-Rego et al. Functional brain imaging, limbic function, and affective disorders. Neuron. Neuropsychopharmacology It includes parts of the cerebral cortex located near the center of the brain, including the cingulate gyrus and the hippocampus as well as the thalamus, hypothalamus and amygdala. Paralimbic frontal lobe hypometabolism in depression associated with Huntington's disease. The dorsomedial thalamus has been conceptualized as an integral part of the subcortical mood circuit with reciprocal connections to the dorsal and ventral prefrontal cortex as well as the striatum and the amygdala. Davis M, Walker DL, Myers KM. The main causes of damage to your thalamus include: Stroke in your thalamus. sleep. In humans, new tools such as fMRI-guided TMS, as one example, are beginning to allow relatively rapid translation of circuit function to targeted, precision-medicine approaches for individually guided care. Depress Anxiety. Sleep has been shown to enhance both threat learning, and the generalization of extinction learning in humans and other animals. Selective effects of psychotherapy on frontopolar cortical function in PTSD. Therefore, the current knowledge indicates that the pathophysiology of depression may be distributed across many brain regions and circuits. It is a structure that has different morphology in male comparing to female brain, it is as twice as large in men as in women. Amodio DM, Frith CD. Unfortunately, these associations may be less clear because the entire extent of stroke-affected areas may not be fully appreciated by neuroimaging methods alone (75). In a prospective study of Israeli soldiers, Admon et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Proceedings of the National Academy of Sciences. A more fundamental question regarding the discrepant findings may lie in whether higher brain functions and their abnormalities can be conceptualized solely in terms of activity in discrete brain regions. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, et al. 2014;24:298190. Consensus regarding biologic associations between depression and other neurological conditions, such as stroke, epilepsy, and brain tumors, are unfortunately much weaker. In humans, experimental studies of chronic stress are not possible due to ethical concerns; however, there is evidence that a history of childhood abuse is correlated with reduced gray matter volume in PFC regions, including the vmPFC and orbital frontal cortex [145]. However, there are other data to suggest that, more generally, PL encodes for the learning of rules, while IL allows for rule reversal [18]. Neural circuitry underlying the regulation of conditioned fear and its relation to extinction. Biol Psychiatry. Multiple large-scale neural networks underlying emotion regulation. In summary, while much remains to be learned, it is an extraordinarily exciting time for the field in which a great deal of convergence and replication has resulted in a fairly robust understanding of threat processing and its regulation by the PFC. The neurocircuitry of fear, stress, and anxiety disorders. Other targets and techniques that have been explored is the application of slow TMS on the right DLPFC (87). Depress Anxiety. 2021;38:7988. Active avoidance: neural mechanisms and attenuation of Pavlovian conditioned responding. Brain tumors have the advantage of assisting in the localization of depression due to their common association. 2019;10:116. The anterior extension of the amygdala is identified by the entorhinal sulcus. Google Scholar. There is limited consensus regarding specific brain regions that are associated with the manifestation of depression in epilepsy. J Neurosci. A review of the neuroimaging, neuropsychiatric and brain stimulation therapy studies of depression indicates that like other abnormalities of higher mental functions, the location of depression is difficult to determine. It contains 13 nuclei that are grouped into three functionally different divisions of nuclei: This group includes the lateral, basal and the accessory basal nucleus. One major limitation of fMRI for investigations of amygdala function in humans is that it is a relatively coarse measurement. Phelps EA, LeDoux JE. A few studies have reported an increased activation of the thalamus in depression (41, 42) but surprisingly most studies have noted no difference. Deep Brain Stimulation for Treatment-Resistant Depression: Follow-Up After 3 to 6 Years. Mayberg and colleagues (13) first noted a reciprocal relationship between the decreased metabolism of the prefrontal cortex and an increased metabolism in limbic regions such as striatum and thalamus in depression leading to the hypothesis that corticolimbic connectivity abnormality may be present in depression. Another study by the same group reported decrease in serotonin transporter and increase in dopamine transporter after chronic antidepressant treatment (49). In addition, mild acute stress in humans impairs the efficacy of previously acquired cognitive reappraisal strategies in reducing conditioned threat and subjective fear [146] and results in enhanced spontaneous recovery following extinction training [147]. Gottfried JA, Dolan RJ. CAS Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Nat Neurosci. 2016;9:52936. Fani N, King TZ, Shin J, Srivastava A, Brewster RC, Jovanovic T, et al. Drawing from neuroimaging findings of reduced metabolism of the prefrontal cortex in depression TMS therapy for depression has until present been restricted to the prefrontal cortex. [156] found that civilians with PTSD had decreased structural connectivity via the cingulum bundle, which supports the hippocampus-dACC pathway. Circuit-based corticostriatal homologies between rat and primate. Brain Stimul. Kheirbek MA, Drew LJ, Burghardt NS, Costantini DO, Tannenholz L, Ahmari SE, et al. 2013;49:188491. People with damaged amygdala express symptoms of so called Klver-Bucy syndrome. Part of the forebrain known as the diencephalon is also included in the limbic system. Regional brain imaging studies have investigated abnormalities in each of these brain subdivisions to investigate the location of depression in the brain. Biol Psychiatry. 2020;13:6502. Which of these competing memory representations is selectively strengthened depends on contextual factors such a recency of learning and replay [109]. Depression is associated with increased sensitivity to signals of disgust: A functional magnetic resonance imaging study. Menz MM, Rihm JS, Bchel C. REM sleep is causal to successful consolidation of dangerous and safety stimuli and reduces return of fear after extinction. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center. Lonsdorf TB, Haaker J, Kalisch R. Long-term expression of human contextual fear and extinction memories involves amygdala, hippocampus and ventromedial prefrontal cortex: a reinstatement study in two independent samples. Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies. Deen B, Pitskel NB, Pelphrey KA. Brain systems mediating aversive conditioning: an event-related fMRI study. An official website of the United States government. These kind of stimuli are of huge biological significance for evolutionary reasons and thus amygdala is one of the most important brain areas for those primitive behaviors. It is in part genetic, with at least 3040% risk heritability for PTSD following trauma [8,9,10], and in part depends on past personal history, including adult and childhood trauma and psychological factors which may differentially mediate fear and emotion regulation. Behav Neurosci. Introduction. 2001;62:1622. PL=prelimbic cortex, IL=infralimbic cortex; dACC=dorsal anterior cingulate cortex, vmPFC=ventromedial prefrontal cortex, dlPFC=dorsolateral prefrontal cortex. Studies in animal models have shown that acute stress leads to changes in neuronal signaling that impair function in the dlPFC [64] and IL cortex [66]. Meeting of minds: the medial frontal cortex and social cognition. Depression is the most common psychiatric illness in Parkinsons disease with a mean rate of 40%, and half of these cases meet criteria for major depression (64). The exact role of the striatum in depression still remains to be fully elucidated. Psychol Med. Our research supports the idea of the amygdala as a node that contributes to multiple behaviors, as it received a varied and wide range of input projections from the whole brain. Mol Psychiatry. The dorsal ACC has been implicated in cognitive aspects of emotion including conflict resolution of emotional stimuli with negative valence (1416), while the ventral (subgenual) ACC has extensive bilateral connection with limbic regions such as the amygdala and dorsomedial thalamus as well as cortical mood regulating areas such as the lateral and medial orbitofrontal cortex and the medial prefrontal cortex (14, 15). Fear extinction in the human brain: a meta-analysis of fMRI studies in healthy participants. 2019;22:75361. This ability is adaptive in that humans do not need to be physically harmed to learn about threats in the environment. One benefit of avoidance learning over extinction for controlling threat reactions is that avoidance learning results in a persistent reduction in the passive conditioned response, even when the avoidance action is no longer available [112]. Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR. One prominent theory of the amygdala's role in memory proposes that the amygdala boosts hippocampal encoding and consolidation of emotional stimuli by facilitating the release of norepinephrine . Fear-conditioned learning involving the amygdala has been thought to be one of the main causative factors; however, recent studies have reported abnormalities in the thalamus of PTSD patients, which may explain the mechanism of interventions such as eye movement desensitization and reprocessing (EMDR). Neuron. Specifically, in addition to increased activation of the cognitive control regions of the PFC mentioned above and modulation of the amygdala, Buhle et al. Milad MR, Quirk GJ. As with many other types of human data, sample size often limits interpretation, as small sample sizes are subject to both false positive and false negative biases. These include the intercalated cell masses and the amygdalohippocampal area. This finding is somewhat surprising given rodent research showing long-lasting changes in the amygdala lateral nucleus with threat learning. It could also be that the vmPFC is involved in cognitive reappraisal for some individuals more so than others. Projections to the amygdala are bidirectional, although there are differences in the projection patterns of PL and IL to the amygdaloid complex, and there is some controversy about whether PL and IL synapse onto functionally different cell types [28, 29]. Am J Psychiatry. The vHPC sends dense direct projections to the mPFC from CA1, but also bidirectional disynaptic indirect connections to the mPFC through the reuniens nucleus of the thalamus and the perirhinal cortex [38]. The amygdala communicates the salience of the threat cue to the mPFC (see Murray and Fellows, this issue, for further discussion of amygdala-PFC interactions). p300/CBP-associated factor selectively regulates the extinction of conditioned fear. Mol Brain. Inputs to the mPFC likely help to drive evolution of the memory trace over time. Subsequently, Winkelman et al. 1995;269:11158. The effect of cathodal tDCS on fear extinction: a cross-measures study. J Neurosci. Anand A, Li Y, Wang Y, Wu J, Gao S, Kalnin A, et al. An abundance of research suggests that the prefrontal cortex is central to fear processingthat is, how fears are acquired and strategies to regulate or diminish fear responses. Paradiso S, Hermann BP, Blumer D, Davies K, Robinson RG. Finally, the dmPFC is hypothesized to support abstracting affective meaning of stimuli or the processes of self-reflecting and identifying ones own affective reactions to stimuli [121, 126,127,128,129,130]. Therefore, depression could be said to be located in an abnormality of the brain stem monoamine neurons or their projections to the rest of the brain. Article Disrupted connections between regions are indicated by dashed lines. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Ferro JM, Caeiro L, Santos C. Poststroke emotional and behavior impairment: a narrative review. More than 20 years ago, Starkstein and colleagues (74) reported neural substrates associated with post-stroke depression. In another approach to this issue, Jovanovic et al. For instructed learning, the amygdala BOLD response is left-lateralized [83], and only patients with left, but not right, amygdala damage show impaired physiological evidence of threat learning, perhaps because of the verbally mediated nature of this learning [84]. Philos Trans R Soc Lond Biol Sci. It is known that innominate substance projects cholinergic neurons to the cortex of the brain that are important for the modulation of social behavior. At baseline, individuals with the greatest symptom improvement with therapy showed, among other findings, greater dorsal PFC and vmPFC activation during emotional conflict regulation. Norberg MM, Krystal JH, Tolin DF. Neuron. The documented role for sleep in memory consolidation is proposed to extend to both threat memories and extinction memories. Behav Neurosci. The amygdala is the most notably involved brain structure in emotional responses and the formation of emotional memories. Roberts AC, Clarke HF. Much like with threat acquisition, it may be that the involvement of the amygdala in extinction is more subtle and difficult to detect using standard fMRI techniques [106]. 2020;40:90716. J Neurosci Res. The mPFC receives massive inputs from subcortical structures, including the amygdala, hippocampus, ventral striatum, hypothalamus, periaqueductal gray, and cerebellum, among others, that allow it to integrate the behavioral state of the animal and adjust behavioral decisions on a moment-to-moment basis. Regina Bailey is a board-certified registered nurse, science writer and educator. Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, et al. The amygdala is part of the limbic system, a neural network that mediates many aspects of emotion and memory. These structures are involved in memory formation, regulation of appetite and satiety, attention, emotional responses, and sexual arousal. The exact significance of these volumetric abnormalities is not known. Sleep is another factor that has been shown to modulate threat control in humans. LaBar KS, LeDoux JE, Spencer DD, Phelps EA. Furthermore, deficient prefrontal perfusion in these regions, coupled with a reduction in problem-solving abilities and higher propensity to act on negative emotions, has been implicated in suicidal behavior (5). Corticoamygdala transfer of socially derived information gates observational learning. 2016;33:61422. Their translation across species will support both a scientific understanding of conservation of molecules and circuits across evolution for specific survival-related behaviors, as well as provide much more powerful targets for pharmacological and biological intervention using animal model systems targeting known conserved molecules and cell types for human therapeutic development. EAP, MAK, RJF, and ESL have nothing to disclose. Strobel C, Marek R, Gooch HM, Sullivan RKP, Sah P. Prefrontal and auditory input to intercalated neurons of the amygdala. Fear extinction as a model for translational neuroscience: ten years of progress. 2017;72:11128. This technique is thought to transmit electric impulses to the various brain regions which have vagal afferents. One report reviewing 42 studies of more than 4000 patients with gliomas concluded mild to moderate depressive symptoms may only rarely be due to tumor-associated structural or functional disruption of neuronal emotional networks (83). A time-dependent role of midline thalamic nuclei in the retrieval of fear memory. In the case of loss of hippocampal volume, a definite pathophysiology related to hypercortisolemia related neurotoxicity has been postulated (29). 2005;102:1070611. 1993;163:10913. I would honestly say that Kenhub cut my study time in half. Resolving Emotional Conflict: A Role for the Rostral Anterior Cingulate Cortex in Modulating Activity in the Amygdala. Hippocampal volume and 2-year outcome in depression. 2003;985:21832. Altered default mode network (DMN) resting state functional connectivity following a mindfulnessbased exposure therapy for posttraumatic stress disorder (PTSD) in combat veterans of Afghanistan and Iraq. Sheline YI, Gado MH, Price JL. Yehuda R, LeDoux J. Childhood maltreatment predicts reduced inhibitionrelated activity in the rostral anterior cingulate in PTSD, but not traumaexposed controls. Histologically in the mouse, PL and IL differ in the thickness of layer II/III and the prominence of layer separations between superficial II/III and layer V; however, this boundary is not easily demarcated [26, 27]. Zimmermann KS, Li C-C, Rainnie DG, Ressler, et al. Three Systems of Insular Functional Connectivity Identified with Cluster Analysis. 2016;173:108393. DBS involves stimulation of a small brain region using sterotactically implanted electrodes connected to a subcutaneous stimulator device. Successful treatment appears to be accompanied by increased activation and functional connectivity of vmPFC/dlPFC regions with other cortical and subcortical areas. This work was supported by NIH (KJR: P50-MH115874, R01-MH108665; EAP: RO1- DA042855), the Frazier Institute at McLean Hospital (KJR), and the James S. McDonnell Foundation (EAP). A number of studies have also examined the role of activity within the PFC related to prediction of treatment response. The rodent mPFC is generally considered to consist of the medial precentral area (Fr2), the dorsal anterior cingulate cortex (dACC), prelimbic cortex (PL), and infralimbic cortex (IL) [24] (see Fig. Consistent with this suggestion, Milad et al. and transmitted securely. Proc Natl Acad Sci USA. Projections from the dorsal thalamus to the amygdala arise mainly from the midline thalamic nuclei and medial part of the medial geniculate nucleus and adjacent posterior thalamic nuclei. Amygdala could be considered as an interface between sensory world 21 and emotions. For example, Killgore et al. 2011;17:22736. Pain syndromes. Learn Mem. Price JL, Drevets WC. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. Emotion regulation: current status and future prospects. Erk S, Mikschl A, Stier S, Ciaramidaro A, Gapp V, Weber B, et al. Johnstone T, Van Reekum CM, Urry HL, Kalin NH, Davidson RJ. Neural Responses to Monetary Incentives in Major Depression. Fullana M, Harrison B, Soriano-Mas C, Vervliet B, Cardoner N, vila-Parcet A, et al. 2013;110:1513944. Large-scale functional brain network architecture changes associated with trauma-related dissociation. By this point, numerous functions of the amygdala have been described. Trends Cogn Sci. Advances in understanding the neural circuit of regulation of threat, fear, and PTSD symptoms may lead to novel and more robust treatment approaches. Furthermore, as we have learned with subcortical structures, different cell types residing within the same brain structure may have dramatically different, sometimes opposing, functions. [96] found vmPFC thickness to be positively correlated with extinction recall. The amygdala is one of the two almond-shaped groups of nuclei located deep within the temporal lobes, medial to the hypothalamus and adjacent to the hippocampus and inferior (temporal) horn of the lateral ventricle. The first study to demonstrate a role for the rodent ventromedial prefrontal cortex (vmPFC) came from Morgan et al., who lesioned the mPFC [30]. Another strategy that has been suggested to preserve the hypothesis regarding a regional neuroanatomical basis of depression is to not treat depression as a unitary illness, but to divide it into its different symptoms while exploring their anatomical basis. CAS Thalamic aphasia (jumbled words, meaningless speech). Benoit M, Robert PH. MacNamara A, Rabinak CA, Fitzgerald DA, Zhou XJ, Shankman SA, Milad MR, et al. Finally, in terms of connectivity, corticolimbic connectivity abnormalities are frequently cited as a cause of depression or for that matter a number of other psychiatric illnesses. Acute and sustained effects of cognitive emotion regulation in major depression. Imaging studies can be divided by the imaging modality used i.e. Kennedy SH, Giacobbe P, Rizvi SJ, Placenza FM, Nishikawa Y, Mayberg HS, et al. More recently, with the development of techniques to measure resting state connectivity a number of studies have reported corticolimbic abnormalities in depression. Initial rodent research on the neural circuitry of active avoidance found that while the passive expression of conditioned threat responses engages a pathway from the lateral nucleus to the central nucleus, when the animal engages in an action to avoid the unconditioned stimulus, projections from the lateral nucleus to the basal nucleus to the nucleus accumbens are involved. Neuroimaging research has provided insight into the brain regions involved in emotion regulation in humans. 2016;36:214860. When it leaves the centromedial nucleus, most of its fibers lie between the caudate nucleus and thalamus, followed by the vena terminalis. Conway CR, Sheline YI, Chibnall JT, George MS, Fletcher JW, Mintun MA. Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, et al. J Child Psychol Psychiatry. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.