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Habenula volume in post-traumatic stress disorder measured with high-resolution MRI
Jonathan B Savitz, Omer Bonne, Allison C Nugent, Meena Vythilingam, Wendy Bogers, Dennis S Charney, Wayne C Drevets
Biology of Mood & Anxiety Disorders , 2011, DOI: 10.1186/2045-5380-1-7
Abstract: High-resolution images (resolution of approximately 0.4 mm3) were acquired using a 3T scanner and a pulse sequence optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. PTSD and HC participants did not differ significantly in absolute or normalized habenula volume. Post hoc analyses controlling for the effects of comorbid major depressive disorder (MDD) and type and age of trauma exposure were not significant. Further, there was no association between PTSD severity and habenula volume.Our data suggest that PTSD is not associated with robust structural changes in the habenula. The modest size of the PTSD sample may have reduced statistical power thereby accounting for the negative results obtained.Post-traumatic stress disorder (PTSD) is associated with an impaired ability to extinguish conditioned fear responses to threatening stimuli. This deficit attributed is hypothesized to reflect deficient inhibition of the amygdala by the ventromedial prefrontal cortex (vmPFC) [1-3]. Nevertheless, additional neurocircuitry likely is involved in the pathophysiology of PTSD. The habenula receives projections from limbic regions, including the vmPFC, and modulates cortical function via its projections to the raphe and ventral tegmental area (VTA) [4]. Conditioned aversive stimuli have been shown to activate the habenula, inhibiting VTA-mediated dopamine release and potentially both inhibiting and facilitating raphe-mediated serotonin release [4]. Conceivably, therefore, the habenula may a key role in the inhibition of conditioned fear, and by extension, PTSD.The extant preclinical data appear consistent with this hypothesis. Rats exposed to chronic stress or undergoing dopamine depletion showed elevated glucose metabolism in the lateral habenula that was prevented by administration of an antidepressant [5]. Similarly, rats exposed to inescapable shock no longer developed learned helplessness after lesioning of the habenula
Error-Related Functional Connectivity of the Habenula in Humans  [PDF]
Jaime S. Ide,Chiang-Shan R. Li
Frontiers in Human Neuroscience , 2011, DOI: 10.3389/fnhum.2011.00025
Abstract: Error detection is critical to the shaping of goal-oriented behavior. Recent studies in non-human primates delineated a circuit involving the lateral habenula (LH) and ventral tegmental area (VTA) in error detection. Neurons in the LH increased activity, preceding decreased activity in the VTA, to a missing reward, indicating a feedforward signal from the LH to VTA. In the current study we used connectivity analyses to reveal this pathway in humans. In 59 adults performing a stop signal task during functional magnetic resonance imaging, we identified brain regions showing greater psychophysiological interaction with the habenula during stop error as compared to stop success trials. These regions included a cluster in the VTA/substantia nigra (SN), internal segment of globus pallidus, bilateral amygdala, and insula. Furthermore, using Granger causality and mediation analyses, we showed that the habenula Granger caused the VTA/SN, establishing the direction of this interaction, and that the habenula mediated the functional connectivity between the amygdala and VTA/SN during error processing. To our knowledge, these findings are the first to demonstrate a feedforward influence of the habenula on the VTA/SN during error detection in humans.
Claustrum projections to prefrontal cortex in the capuchin monkey, Cebus apella.  [PDF]
David H. Reser,Juliana G. Soares,Marcello Rosa
Frontiers in Systems Neuroscience , 2014, DOI: 10.3389/fnsys.2014.00123
Abstract: We examined the pattern of retrograde tracer distribution in the claustrum following intracortical injections into the frontal pole (area 10), dorsal (area 9), and ventral lateral (area 12) regions of the rostral prefrontal cortex in the tufted capuchin monkey (Cebus apella). The resulting pattern of labeled cells was assessed in relation to the complex three-dimensional geometry of the claustrum, as well as recent reports of claustrum-prefrontal connections in other primates. Claustrum-prefrontal projections were extensive, and largely concentrated in the ventral half of the claustrum, especially in the rostral 2/3 of the nucleus. Our data are consistent with a topographic arrangement of claustrum-cortical connections in which prefrontal and association cortices receive connections largely from the rostral and medial claustrum. Comparative aspects of claustrum-prefrontal topography across primate species and the implications of claustrum connectivity for understanding of cortical functional networks are explored, and we hypothesize that the claustrum may play a role in controlling or switching between resting state and task-associated cortical networks.
Prefrontal Control of the Amygdala during Real-Time fMRI Neurofeedback Training of Emotion Regulation  [PDF]
Vadim Zotev, Raquel Phillips, Kymberly D. Young, Wayne C. Drevets, Jerzy Bodurka
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079184
Abstract: We observed in a previous study (PLoS ONE 6:e24522) that the self-regulation of amygdala activity via real-time fMRI neurofeedback (rtfMRI-nf) with positive emotion induction was associated, in healthy participants, with an enhancement in the functional connectivity between the left amygdala (LA) and six regions of the prefrontal cortex. These regions included the left rostral anterior cingulate cortex (rACC), bilateral dorsomedial prefrontal cortex (DMPFC), bilateral superior frontal gyrus (SFG), and right medial frontopolar cortex (MFPC). Together with the LA, these six prefrontal regions thus formed the functional neuroanatomical network engaged during the rtfMRI-nf procedure. Here we perform a structural vector autoregression (SVAR) analysis of the effective connectivity for this network. The SVAR analysis demonstrates that the left rACC plays an important role during the rtfMRI-nf training, modulating the LA and the other network regions. According to the analysis, the rtfMRI-nf training leads to a significant enhancement in the time-lagged effect of the left rACC on the LA, potentially consistent with the ipsilateral distribution of the monosynaptic projections between these regions. The training is also accompanied by significant increases in the instantaneous (contemporaneous) effects of the left rACC on four other regions – the bilateral DMPFC, the right MFPC, and the left SFG. The instantaneous effects of the LA on the bilateral DMPFC are also significantly enhanced. Our results are consistent with a broad literature supporting the role of the rACC in emotion processing and regulation. Our exploratory analysis provides, for the first time, insights into the causal relationships within the network of regions engaged during the rtfMRI-nf procedure targeting the amygdala. It suggests that the rACC may constitute a promising target for rtfMRI-nf training along with the amygdala in patients with affective disorders, particularly posttraumatic stress disorder (PTSD).
Prefrontal Cortex Haemodynamics and Affective Responses during Exercise: A Multi-Channel Near Infrared Spectroscopy Study  [PDF]
Gavin D. Tempest, Roger G. Eston, Gaynor Parfitt
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095924
Abstract: The dose-response effects of the intensity of exercise upon the potential regulation (through top-down processes) of affective (pleasure-displeasure) responses in the prefrontal cortex during an incremental exercise protocol have not been explored. This study examined the functional capacity of the prefrontal cortex (reflected by haemodynamics using near infrared spectroscopy) and affective responses during exercise at different intensities. Participants completed an incremental cycling exercise test to exhaustion. Changes (Δ) in oxygenation (O2Hb), deoxygenation (HHb), blood volume (tHb) and haemoglobin difference (HbDiff) were measured from bilateral dorsal and ventral prefrontal areas. Affective responses were measured every minute during exercise. Data were extracted at intensities standardised to: below ventilatory threshold, at ventilatory threshold, respiratory compensation point and the end of exercise. During exercise at intensities from ventilatory threshold to respiratory compensation point, ΔO2Hb, ΔHbDiff and ΔtHb were greater in mostly ventral than dorsal regions. From the respiratory compensation point to the end of exercise, ΔO2Hb remained stable and ΔHbDiff declined in dorsal regions. As the intensity increased above the ventilatory threshold, inverse associations between affective responses and oxygenation in (a) all regions of the left hemisphere and (b) lateral (dorsal and ventral) regions followed by the midline (ventral) region in the right hemisphere were observed. Differential activation patterns occur within the prefrontal cortex and are associated with affective responses during cycling exercise.
Parallel organization of contralateral and ipsilateral prefrontal cortical projections in the rhesus monkey
Helen Barbas, Claus C Hilgetag, Subhash Saha, Caterina R Dermon, Joanna L Suski
BMC Neuroscience , 2005, DOI: 10.1186/1471-2202-6-32
Abstract: Commissural projection neurons constituted less than one third of the ipsilateral. Nevertheless, projections from the two hemispheres were strongly correlated in topography and relative density. We investigated to what extent the distribution of contralateral projections depended on: (a) geographic proximity of projection areas to the area homotopic to the injection site; (b) the structural type of the linked areas, based on the number and neuronal density of their layers. Although both measures were good predictors, structural type was a comparatively stronger determinant of the relative distribution and density of projections. Ipsilateral projection neurons were distributed in the superficial (II-III) and deep (V-VI) layers, in proportions that varied across areas. In contrast, contralateral projection neurons were found mostly in the superficial layers, but still showed a gradient in their distribution within cortical layers that correlated significantly with cortical type, but not with geographic proximity to the homotopic area.The organization of ipsilateral and contralateral prefrontal projections is similar in topography and relative density, differing only by higher overall density and more widespread laminar origin of ipsilateral than contralateral projections. The projections on both sides are highly correlated with the structural architecture of the linked areas, and their remarkable organization is likely established by punctuated development of distinct cortical types. The preponderance of contralateral projections from layer III may be traced to the late development of the callosal system, whose function may be compromised in diseases that have their root late in ontogeny.The primate cerebral cortex constitutes a vast communication network of ipsilateral and contralateral corticocortical connections. Although fewer in number, contralateral projection neurons, which course through the corpus callosum and the anterior commissure, have elaborate dendritic
Evidence for Broad Versus Segregated Projections from Cholinergic and Noradrenergic Nuclei to Functionally and Anatomically Discrete Subregions of Prefrontal Cortex  [PDF]
Daniel Chandler
Frontiers in Behavioral Neuroscience , 2012, DOI: 10.3389/fnbeh.2012.00020
Abstract: The prefrontal cortex (PFC) is implicated in a variety of cognitive and executive operations. However, this region is not a single functional unit; rather, it is composed of several functionally and anatomically distinct networks, including anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). These prefrontal subregions serve dissociable behavioral functions, and are unique in their afferent and efferent connections. Each of these subregions is innervated by ascending cholinergic and noradrenergic systems, each of which likewise has a distinct role in cognitive function; yet the distribution and projection patterns of cells in the source nuclei for these pathways have not been examined in great detail. In this study, fluorescent retrograde tracers were injected into ACC, mPFC, and OFC, and labeled cells were identified in the cholinergic nucleus basalis of Meynert (NBM) and noradrenergic nucleus locus coeruleus (LC). Injections into all three cortical regions consistently labeled cells primarily ipsilateral to the injection site with a minimal contralateral component. In NBM, retrogradely labeled neurons were scattered throughout the rostral half of the nucleus, whereas those in LC tended to cluster in the core of the nucleus, and were rarely localized within the rostral or caudal poles. In NBM, more than half of all retrogradely labeled cells possessed axon collaterals projecting two or more PFC subregions. In LC, however, only 4.3% of retrogradely labeled neurons possessed collaterals targeting any two prefrontal subregions simultaneously, and no cells were identified that projected to all three regions. Of all labeled LC neurons, 49.3% projected only to mPFC, 28.5% projected only to OFC, and 18.0% projected only to ACC. These findings suggest that subsets of LC neurons may be capable of modulating neuronal activity in individual prefrontal subregions independently, whereas assemblies of NBM cells may exert a more unified influence on the three areas, simultaneously. This work emphasizes unique aspects of the cholinergic and noradrenergic projections to functionally and anatomically distinct subregions of PFC and provides insights regarding global versus segregated regulation of prefrontal operations by these neuromodulatory pathways.
Emotional Disorders in Patients with Prefrontal Cortex Lesions

Wang Yiniu,Luo Yuejia,

心理科学进展 , 2004,
Abstract: A strong association between the prefrontal cortex in the brain and human emotion has been recognized. The effect of prefrontal cortex damage on emotional behavior has been abbreviated reviewed with pertinent clinical and neuroimaging observations in the past. Three clinical syndromes characterized by mood disorders, those are schizophrenia, major depression and anxiety disorders etc. They are dependent upon frontal system, especially prefrontal cortex dysfunction. There is convincing evidence that different facets of affective functioning, the experience of emotion, the expression of emotion, and the processing of emotionally laden information have distinct neural representation of prefrontal cortex.
Association between Sub-Threshold Affective Symptoms and Prefrontal Activation in Non-Clinical Population―An NIRS Study  [PDF]
Koichiro Fujimaki, Hidenori Takemoto, Shigeru Morinobu
Psychology (PSYCH) , 2014, DOI: 10.4236/psych.2014.59115

Only a few studies have examined the relationship between self-assessment of affective symptoms and brain activation in a non-clinical population. The aim of the present study was to assess this relationship and examine the underlying cortical mechanisms in a non-clinical population. Seventy-nine healthy male volunteers were assessed for affective symptoms using the Zung Self-rating Depression Scale (SDS), for apathy using the Apathy Scale (AS), and for feelings of stress using the Stress Arousal Checklist (SACL). Participants also performed a serial arithmetic task according to the Uchida-Kraepelin performance test while hemoglobin concentration changes were assessed on the surface of the prefrontal cortex (PFC) using 32-channel near-infrared spectroscopy (NIRS). The activity on the right side of PFC had a significant negative correlation with the SDS score. The AS and SACL scores were positively correlated with the SDS score. Furthermore, in a multiple regression analysis, SDS scores were predicted by the activity of the right PFC, AS scores, and SACL scores. These results suggest that the association between the cortical activation changes, apathy, and feelings of stress may objectively identify individuals with sub-threshold affective symptoms.

Role of Reuniens Nucleus Projections to the Medial Prefrontal Cortex and to the Hippocampal Pyramidal CA1 Area in Associative Learning  [PDF]
Lyndell Eleore, Juan Carlos López-Ramos, Rafael Guerra-Narbona, José M. Delgado-García
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023538
Abstract: We studied the interactions between short- and long-term plastic changes taking place during the acquisition of a classical eyeblink conditioning and following high-frequency stimulation (HFS) of the reuniens nucleus in behaving mice. Synaptic changes in strength were studied at the reuniens-medial prefrontal cortex (mPFC) and the reuniens-CA1 synapses. Input/output curves and a paired-pulse study enabled determining the functional capabilities of the two synapses and the optimal intensities to be applied at the reuniens nucleus during classical eyeblink conditioning and for HFS applied to the reuniens nucleus. Animals were conditioned using a trace paradigm, with a tone as conditioned stimulus (CS) and an electric shock to the trigeminal nerve as unconditioned stimulus (US). A single pulse was presented to the reuniens nucleus to evoke field EPSPs (fEPSPs) in mPFC and CA1 areas during the CS-US interval. No significant changes in synaptic strength were observed at the reuniens-mPFC and reuniens-CA1 synapses during the acquisition of eyelid conditioned responses (CRs). Two successive HFS sessions carried out during the first two conditioning days decreased the percentage of CRs, without evoking any long-term potentiation (LTP) at the recording sites. HFS of the reuniens nucleus also prevented the proper acquisition of an object discrimination task. A subsequent study revealed that HFS of the reuniens nucleus evoked a significant decrease of paired-pulse facilitation. In conclusion, reuniens nucleus projections to prefrontal and hippocampal circuits seem to participate in the acquisition of associative learning through a mechanism that does not required the development of LTP.
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