Supragenual Anterior Cingulate Cortex Research Articles

Interleukin 6 associates with reduced grey matter volume and resting-state connectivity in the anterior cingulate cortex in bipolar patients

High levels of peripheral IL-6, a pro-inflammatory cytokine, have been indicated as a key element of the bipolar disorder (BD), allowing to differentiate BD from major depression with high accuracy and to early detect poor responders to antidepressant treatments. IL-6 may contribute to BD pathophysiology through its effects on the neurobiological underpinnings of the disorder, such as grey matter (GM) volumes and resting state functional connectivity (rs-FC) abnormalities. In this study, we primary investigate the relationship between the peripheral plasmatic level of IL-6 and GM volumes, obtained with Voxel-Based Morphometry, in 84 BD inpatients. As secondary aims, we explored if IL-6 levels may be related to self-reported psychopathological dimensions of depression (i.e. symptoms severity and cognitive biases) and seed based rs-FC of brain regions structurally associated with the cytokine. Results showed that higher level of peripheral IL-6 was associated to lower GM volumes in supragenual anterior cingulate cortex, and reduced rs-FC between this area and medial orbito-frontal cortex in BD. Furthermore, in depressed patients IL-6 positively correlated to cognitive biases typically associated to depressive episodes, such as the perceived uncontrollability of negative events, or their generalization across future and situations. Our data provide additional evidence of detrimental effect of systemic inflammation on brain structure in BD and confirm the crucial role of anterior cingulate cortex as neural underpinning of the disorder. However, future studies are needed to replicate our findings in larger samples.

Functional brain response to painful mechanical stimulation and painful stimulation in areas of secondary mechanical hyperalgesia: A meta-analysis

This study evaluated brain activity in response to painful and nonpainful mechanical stimuli within an area of secondary mechanical hyperalgesia (SMH) compared to non-sensitized areas. We performed a meta-analysis summarizing responses to three different types of stimuli. Furthermore, we summarize reported results of contrast maps comparing brain responses to mechanical stimuli in SMH that in non-sensitized regions. We investigated 3 categories of brain responses to 1) nonpainful mechanical stimuli in 226 participants across 16 studies, 2) painful mechanical stimuli in 164 participants across 11 studies, 3) mechanical stimuli in SMH in 84 participants across 7 studies, and 4) contrast maps of brain responses to mechanical stimuli in SMH versus painful mechanical stimuli in 107 participants across 7 studies. We used GingerALE 3.0.2 to create meta-analytic statistical parametric maps. We generated summary Z-maps by subtracting negative maps from positive maps. Maps were Z-value thresholded at 3.29 and a cluster size of 272 mm3. Nonpainful mechanical stimuli activated bilateral parietal operculum (PO), right inferior frontal gyrus (IFG) and inferior parietal lobule. Painful mechanical stimuli activated bilateral PO, bilateral IFG pars opercularis, and deactivation in bilateral superior occipital gyri. Mechanical stimuli in SMH activated bilateral PO, bilateral dorsal anterior insula, left postcentral gyrus and supragenual anterior cingulate cortex. The contrast of mechanical stimuli in SMH versus painful mechanical stimuli included greater activation in right thalamus, left lateral periaqueductal gray, right dorsolateral prefrontal (DLPFC), right Rolandic opercular, bilateral primary somatosensory, anterior midcingulate, and right middle insular cortices. Contrast results revealed greater activation during SMH compared to painful mechanical stimulation in right thalamus, right DLPFC, and left lateral periaqueductal gray. These areas are involved in pain modulation (hyperalgesic and analgesic), while responses in mid insula and mid cingulate cortices are prominent in processing salient and painful stimuli. Neurosurgery Pain Research Institute, Postdoctoral Scholarship (TJM). This study evaluated brain activity in response to painful and nonpainful mechanical stimuli within an area of secondary mechanical hyperalgesia (SMH) compared to non-sensitized areas. We performed a meta-analysis summarizing responses to three different types of stimuli. Furthermore, we summarize reported results of contrast maps comparing brain responses to mechanical stimuli in SMH that in non-sensitized regions. We investigated 3 categories of brain responses to 1) nonpainful mechanical stimuli in 226 participants across 16 studies, 2) painful mechanical stimuli in 164 participants across 11 studies, 3) mechanical stimuli in SMH in 84 participants across 7 studies, and 4) contrast maps of brain responses to mechanical stimuli in SMH versus painful mechanical stimuli in 107 participants across 7 studies. We used GingerALE 3.0.2 to create meta-analytic statistical parametric maps. We generated summary Z-maps by subtracting negative maps from positive maps. Maps were Z-value thresholded at 3.29 and a cluster size of 272 mm3. Nonpainful mechanical stimuli activated bilateral parietal operculum (PO), right inferior frontal gyrus (IFG) and inferior parietal lobule. Painful mechanical stimuli activated bilateral PO, bilateral IFG pars opercularis, and deactivation in bilateral superior occipital gyri. Mechanical stimuli in SMH activated bilateral PO, bilateral dorsal anterior insula, left postcentral gyrus and supragenual anterior cingulate cortex. The contrast of mechanical stimuli in SMH versus painful mechanical stimuli included greater activation in right thalamus, left lateral periaqueductal gray, right dorsolateral prefrontal (DLPFC), right Rolandic opercular, bilateral primary somatosensory, anterior midcingulate, and right middle insular cortices. Contrast results revealed greater activation during SMH compared to painful mechanical stimulation in right thalamus, right DLPFC, and left lateral periaqueductal gray. These areas are involved in pain modulation (hyperalgesic and analgesic), while responses in mid insula and mid cingulate cortices are prominent in processing salient and painful stimuli. Neurosurgery Pain Research Institute, Postdoctoral Scholarship (TJM).

Differential levels of prefrontal cortex glutamate+glutamine in adults with antisocial personality disorder and bipolar disorder: A proton magnetic resonance spectroscopy study

As the main excitatory neurotransmitter in the central nervous system, glutamate, as measured in combination with glutamine (Glx), is implicated in several psychopathologies when levels are aberrant. One illness that shows heightened Glx levels is bipolar disorder (BD), an illness characterized by high impulsivity. In addition, although animal studies have reported elevated levels of Glx in aggressive and impulsive phenotypes, no study, to our knowledge, has reported Glx in the human cortex in relation to aggression. Here, we addressed the question of whether elevated levels of Glx would be present in patients with BD and antisocial personality disorder (ASPD), a condition associated with aggression and, like BD, also presents high impulsivity. We recruited individuals with ASPD (n = 18), individuals with BD (n = 16), and a healthy control group (n = 24). We used proton magnetic resonance spectroscopy to measure relative neurometabolite concentrations in the left dorsolateral prefrontal cortex (dlPFC) and supra-genual anterior cingulate cortex (ACC), two brain regions associated with impulsivity and behavior control. We found significantly elevated levels of Glx in the ASPD group relative to the BD and healthy control groups in the dlPFC (p = .014), and a positive correlation between Glx levels and aggression in the dlPFC in the ASPD group alone (r = .59, p = .026). These findings suggest a link between aggression in ASPD and Glx levels.

In need of constraint: Understanding the role of the cingulate cortex in the impulsive mind

Impulsive behavior often occurs without forethought and can be driven by strong emotions or sudden impulses, leading to problems in cognition and behavior across a wide range of situations. Although neuroimaging studies have explored the neurocognitive indicators of impulsivity, the large-scale functional networks that contribute to different aspects of impulsive cognition remain unclear. In particular, we lack a coherent account of why impulsivity is associated with such a broad range of different psychological features. Here, we use resting state functional connectivity, acquired in two independent samples, to investigate the neural substrates underlying different aspects of self-reported impulsivity. Based on the involvement of the anterior cingulate cortex (ACC) in cognitive but also affective processes, five seed regions were placed along the caudal to rostral gradient of the ACC. We found that positive urgency was related to functional connectivity between subgenual ACC and bilateral parietal regions such as retrosplenial cortex potentially highlighting this connection as being important in the modulation of the non-prospective, hastiness – related aspects of impulsivity. Further, two impulsivity dimensions were associated with significant alterations in functional connectivity of the supragenual ACC: (i) lack of perseverance was positively correlated to connectivity with the bilateral dorsolateral prefrontal cortex and right inferior frontal gyrus and (ii) lack of premeditation was inversely associated with functional connectivity with clusters within bilateral occipital cortex. Further analysis revealed that these connectivity patterns overlapped with bilateral dorsolateral prefrontal and bilateral occipital regions of the multiple demand network, a large-scale neural system implicated in the general control of thought and action. Together these results demonstrate that different forms of impulsivity have different neural correlates, which are linked to the functional connectivity of a region of anterior cingulate cortex. This suggests that poor perseveration and premeditation might be linked to dysfunctions in how the rostral zone of the ACC interacts with the multiple demand network that allows cognition to proceed in a controlled way.

How do resting state changes in depression translate into psychopathological symptoms? From ‘Spatiotemporal correspondence’ to ‘Spatiotemporal Psychopathology’

To review the recent findings in resting-state activity in major depressive disorder (MDD) and link them to psychopathological symptoms. MDD shows changes in resting state functional connectivity (rsFC) mainly within the default-mode network with a focus on especially the perigenual anterior cingulate cortex. rsFC in perigenual anterior cingulate cortex is abnormally high in MDD and decreased in the lateral prefrontal cortex with the central executive network (CEN). rsFC in other networks like the salience network, including the insula, amygdala, and supragenual anterior cingulate cortex and the sensorimotor network is also affected in MDD. Resting-state activity in MDD shows abnormal topographical and spatiotemporal pattern. The spatiotemporal alterations in resting state may translate into corresponding spatiotemporal changes underlying the sensorimotor, affective, and cognitive functions, and thus, the various symptoms. Such spatiotemporal correspondence between resting state changes and psychopathological symptoms may make necessary the development of what I describe as 'Spatiotemporal Psychopathology'.

How are different neural networks related to consciousness?

We aimed to investigate the roles of different resting-state networks in predicting both the actual level of consciousness and its recovery in brain injury patients. We investigated resting-state functional connectivity within different networks in patients with varying levels of consciousness: unresponsive wakefulness syndrome (UWS; n = 56), minimally conscious state (MCS; n = 29), and patients with brain lesions but full consciousness (BL; n = 48). Considering the actual level of consciousness, we compared the strength of network connectivity among the patient groups. We then checked the presence of connections between specific regions in individual patients and calculated the frequency of this in the different patient groups. Considering the recovery of consciousness, we split the UWS group into 2 subgroups according to recovery: those who emerged from UWS (UWS-E) and those who remained in UWS (UWS-R). The above analyses were repeated on these 2 subgroups. Functional connectivity strength in salience network (SN), especially connectivity between the supragenual anterior cingulate cortex (SACC) and left anterior insula (LAI), was reduced in the unconscious state (UWS) compared to the conscious state (MCS and BL). Moreover, at the individual level, SACC-LAI connectivity was more present in MCS than in UWS. Default-mode network (DMN) connectivity strength, especially between the posterior cingulate cortex (PCC) and left lateral parietal cortex (LLPC), was reduced in UWS-R compared with UWS-E. Furthermore, PCC-LLPC connectivity was more present in UWS-E than in UWS-R. Our findings show that SN (SACC-LAI) connectivity correlates with behavioral signs of consciousness, whereas DMN (PCC-LLPC) connectivity instead predicts recovery of consciousness.

Neural activity during interoceptive awareness and its associations with alexithymia-An fMRI study in major depressive disorder and non-psychiatric controls.

Objective: Alexithymia relates to difficulties recognizing and describing emotions. It has been linked to subjectively increased interoceptive awareness (IA) and to psychiatric illnesses such as major depressive disorder (MDD) and somatization. MDD in turn is characterized by aberrant emotion processing and IA on the subjective as well as on the neural level. However, a link between neural activity in response to IA and alexithymic traits in health and depression remains unclear.Methods: A well-established fMRI task was used to investigate neural activity during IA (heartbeat counting) and exteroceptive awareness (tone counting) in non-psychiatric controls (NC) and MDD. Firstly, comparing MDD and NC, a linear relationship between IA-related activity and scores of the Toronto Alexithymia Scale (TAS) was investigated through whole-brain regression. Secondly, NC were divided by median-split of TAS scores into groups showing low (NC-low) or high (NC-high) alexithymia. MDD and NC-high showed equally high TAS scores. Subsequently, IA-related neural activity was compared on a whole-brain level between the three independent samples (MDD, NC-low, NC-high).Results: Whole-brain regressions between MDD and NC revealed neural differences during IA as a function of TAS-DD (subscale difficulty describing feelings) in the supragenual anterior cingulate cortex (sACC; BA 24/32), which were due to negative associations between TAS-DD and IA-related activity in NC. Contrasting NC subgroups after median-split on a whole-brain level, high TAS scores were associated with decreased neural activity during IA in the sACC and increased insula activity. Though having equally high alexithymia scores, NC-high showed increased insula activity during IA compared to MDD, whilst both groups showed decreased activity in the sACC.Conclusions: Within the context of decreased sACC activity during IA in alexithymia (NC-high and MDD), increased insula activity might mirror a compensatory mechanism in NC-high, which is disrupted in MDD.

Prefrontal thinning affects functional connectivity and regional homogeneity of the anterior cingulate cortex in depression.

Major depressive disorder (MDD) is associated with structural and functional alterations in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Enhanced ACC activity at rest (measured using various imaging methodologies) is found in treatment-responsive patients and is hypothesized to bolster treatment response by fostering adaptive rumination. However, whether structural changes influence functional coupling between fronto-cingulate regions and ACC regional homogeneity (ReHo) and whether these functional changes are related to levels of adaptive rumination and treatment response is still unclear. Cortical thickness and ReHo maps were calculated in 21 unmedicated depressed patients and 35 healthy controls. Regions with reduced cortical thickness defined the seeds for the subsequent functional connectivity (FC) analyses. Patients completed the Response Style Questionnaire, which provided a measure of adaptive rumination associated with better response to psychotherapy. Compared with controls, depressed patients showed thinning of the right anterior PFC, increased prefrontal connectivity with the supragenual ACC (suACC), and higher ReHo in the suACC. The suACC clusters of increased ReHo and FC spatially overlapped. In depressed patients, suACC ReHo scores positively correlated with PFC thickness and with FC strength. Moreover, stronger fronto-cingulate connectivity was related to higher levels of adaptive rumination. Greater suACC ReHo and connectivity with the right anterior PFC seem to foster adaptive forms of self-referential processing associated with better response to psychotherapy, whereas prefrontal thinning impairs the ability of depressed patients to engage the suACC during a major depressive episode. Bolstering the function of the suACC may represent a potential target for treatment.

Functional connectivity and neuronal variability of resting state activity in bipolar disorder--reduction and decoupling in anterior cortical midline structures.

The cortical midline structures seem to be involved in the modulation of different resting state networks, such as the default mode network (DMN) and salience network (SN). Alterations in these systems, in particular in the perigenual anterior cingulate cortex (PACC), seem to play a central role in bipolar disorder (BD). However, the exact role of the PACC, and its functional connections to other midline regions (within and outside DMN) still remains unclear in BD. We investigated functional connectivity (FC), standard deviation (SD, as a measure of neuronal variability) and their correlation in bipolar patients (n = 40) versus healthy controls (n = 40), in the PACC and in its connections in different frequency bands (standard: 0.01-0.10 Hz; Slow-5: 0.01-0.027 Hz; Slow-4: 0.027-0.073 Hz). Finally, we studied the correlations between FC alterations and clinical-neuropsychological parameters and we explored whether subgroups of patients in different phases of the illness present different patterns of FC abnormalities. We found in BD decreased FC (especially in Slow-5) from the PACC to other regions located predominantly in the posterior DMN (such as the posterior cingulate cortex (PCC) and inferior temporal gyrus) and in the SN (such as the supragenual anterior cingulate cortex and ventrolateral prefrontal cortex). Second, we found in BD a decoupling between PACC-based FC and variability in the various target regions (without alteration in variability itself). Finally, in our subgroups explorative analysis, we found a decrease in FC between the PACC and supragenual ACC (in depressive phase) and between the PACC and PCC (in manic phase). These findings suggest that in BD the communication, that is, information transfer, between the different cortical midline regions within the cingulate gyrus does not seem to work properly. This may result in dysbalance between different resting state networks like the DMN and SN. A deficit in the anterior DMN-SN connectivity could lead to an abnormal shifting toward the DMN, while a deficit in the anterior DMN-posterior DMN connectivity could lead to an abnormal shifting toward the SN, resulting in excessive focusing on internal contents and reduced transition from idea to action or in excessive focusing on external contents and increased transition from idea to action, respectively, which could represent central dimensions of depression and mania. If confirmed, they could represent diagnostic markers in BD.

Neural correlates of experienced moral emotion: An fMRI investigation of emotion in response to prejudice feedback

Guilt, shame, and embarrassment are quintessential moral emotions with important regulatory functions for the individual and society. Moral emotions are, however, difficult to study with neuroimaging methods because their elicitation is more intricate than that of basic emotions. Here, using functional MRI (fMRI), we employed a novel social prejudice paradigm to examine specific brain regions associated with real-time moral emotion, focusing on guilt and related moral-negative emotions. The paradigm induced intense moral-negative emotion (primarily guilt) in 22 low-prejudice individuals through preprogrammed feedback indicating implicit prejudice against Black and disabled people. fMRI data indicated that this experience of moral-negative emotion was associated with increased activity in anterior paralimbic structures, including the anterior cingulate cortex (ACC) and anterior insula, in addition to areas associated with mentalizing, including the dorsomedial prefrontal cortex, posterior cingulate cortex, and precuneus. Of significance was prominent conflict-related activity in the supragenual ACC, which is consistent with theories proposing an association between acute guilt and behavioral inhibition. Finally, a significant negative association between self-reported guilt and neural activity in the pregenual ACC suggested a role of self-regulatory processes in response to moral-negative affect. These findings are consistent with the multifaceted self-regulatory functions of moral-negative emotions in social behavior.

A morphometric study of glia and neurons in the anterior cingulate cortex in mood disorder

The anterior cingulate cortex (ACC) is a key region for the pathophysiology and treatment of depression. However, it remains unclear whether and how the morphology of the ACC is altered in subjects with mood disorders. A post mortem morphometric study of the supragenual ACC (Brodmann area 24b) in seven subjects with mood disorder and nine comparison subjects. We measured glial and neuronal density, and neuronal size and shape. We also quantified the astrocytic marker, glial fibrillary acidic protein (GFAP), using immunoautoradiography. Cortical and layer thickness did not differ between groups. Subjects with mood disorder had a decreased density of glial cells across all layers, and a reduction in GFAP in white matter. The density of pyramidal neurons was decreased selectively in layer Vb, and their size was increased in layers V and VI. The shape of pyramidal neurons also differed in mood disorder, in layers Va and VI. These data provide further evidence for morphometric alterations in glia and pyramidal neurons in mood disorder. They represent a possible cellular basis for the aberrant functioning and connectivity of the ACC apparent from neuroimaging and other studies.

Involvement of glutamate in rest‐stimulus interaction between perigenual and supragenual anterior cingulate cortex: A combined fMRI‐MRS study

The brain shows a high degree of activity at rest. The significance of this activity has come increasingly into focus. At present, however, the interaction between this activity and stimulus-induced activity is not well defined. The interaction between a task-negative (perigenual anterior cingulate cortex, pgACC) and task-positive (supragenual anterior cingulate cortex, sgACC) region during a simple task was thus investigated using a combination of fMRI and MRS. Negative BOLD responses in the pgACC were found to show a unidirectional effective connectivity with task-induced positive BOLD responses in the sgACC. This connectivity was shown to be related specifically with glutamate levels in the pgACC. These results demonstrate an interaction between deactivation from resting-state and resting-state glutamate levels in a task-negative region (pgACC), and task-induced activity in a task-positive region (sgACC). This provides insight into the neuronal and biochemical mechanisms by means of which the resting state activity of the brain potentially impacts upon subsequent stimulus-induced activity.

Increased Activation of the Supragenual Anterior Cingulate Cortex during Visual Emotional Processing in Male Subjects with High Degrees of Alexithymia: An Event-Related fMRI Study

Background: One of the most prominent neurobiological models of alexithymia assumes an altered function of the anterior cingulate cortex (ACC) as the crucial neural correlate of alexithymia. So far functional imaging studies have yielded inconclusive results. Therefore, we tested this hypothesis in healthy alexithymics and nonalexithymics in an event-related fMRI study. Methods:Thirty high- and 30 low-alexithymic right-handed male subjects (selected by the 20-item Toronto Alexithymia Scale, TAS-20) were investigated with event-related fMRI using a picture viewing paradigm. The stimuli consisted of happy, fearful and neutral facial expressions (Ekman-Friesen) as well as positive, negative and neutral pictures from the International Affective Picture System. Results: Contrasting the high-alexithymic with the low-alexithymic group we observed increased activation of the supragenual ACC for different emotional valences as well as for different emotional stimuli. Moreover, there was a positive correlation of the ACC with the individual TAS-20 scores but no correlations with the individual Beck Depression Inventory scores. Additionally, there was no difference in activity of the amygdala. Conclusions: We demonstrated that the supragenual ACC is constantly activated more strongly in alexithymic subjects and that this activation is related to the symptoms of alexithymia and not to associated symptoms such as depression. Therefore, our findings support the hypothesis of an altered function of the ACC in alexithymia.

High-frequency heart rate variability and cortico-striatal activity in men and women with social phobia

Identifying brain systems that regulate or modulate autonomic nervous system functions may identify pathways through which psychosocial factors can influence health and disease. Reduced high-frequency heart rate variability (HF-HRV) characterizes anxiety disordered patients and is predictive of adverse myocardial events. Sex differences in the prevalence of anxiety disorders and cardiac diseases implicate the possibility of sex specific neural regulation of HF-HRV. We investigated the correlation between HF-HRV and regional cerebral blood flow (rCBF) in 28 subjects (15 women) with social phobia undergoing a stressful public speaking task. Regional CBF was measured with [15O] water positron emission tomography. Stress induced rCBF correlated positively with HF-HRV in the right supra genual anterior cingulate cortex Brodmann's area (BA) 32, the right head of the caudate nucleus and bilaterally in the medial prefrontal cortex (BA10), extending into the dorsolateral prefrontal cortex (BA46) in the left hemisphere. Men showed larger positive co-variation in the caudate than women. These findings underscore the importance of the emotional division of the anterior cingulate cortex, the prefrontal cortex and the striatum in cardiovagal activity. The study replicates and extends results from published functional neuroimaging studies on cardioregulatory or modulatory areas in healthy subjects to men and women with social phobia. Moreover, caudate functions, possibly related to dopaminergic neurotransmission, have sexually dimorphic effects on vagal modulation of the heart.

A preliminary study of functional connectivity in comorbid adolescent depression

Major depressive disorder (MDD) begins frequently in adolescence and is associated with severe outcomes, but the developmental neurobiology of MDD is not well understood. Research in adults has implicated fronto-limbic neural networks in the pathophysiology of MDD, particularly in relation to the subgenual anterior cingulate cortex (ACC). Developmental changes in brain networks during adolescence highlight the need to examine MDD-related circuitry in teens separately from adults. Using resting state functional magnetic resonance imaging (fMRI), this study examined functional connectivity in adolescents with MDD ( n = 12) and healthy adolescents ( n = 14). Seed-based connectivity analysis revealed that adolescents with MDD have decreased functional connectivity in a subgenual ACC-based neural network that includes the supragenual ACC (BA 32), the right medial frontal cortex (BA 10), the left inferior (BA 47) and superior frontal cortex (BA 22), superior temporal gyrus (BA 22), and the insular cortex (BA 13). These preliminary data suggest that MDD in adolescence is associated with abnormal connectivity within neural circuits that mediate emotion processing. Future research in larger, un-medicated samples will be necessary to confirm this finding. We conclude that hypothesis-driven, seed-based analyses of resting state fMRI data hold promise for advancing our current understanding of abnormal development of neural circuitry in adolescents with MDD.

Inhibition-related activity in subgenual cingulate is associated with symptom severity in major depression

Individuals with major depressive disorder (MDD) show impaired inhibitory control over negative thoughts. However, the brain mechanism underlying impaired inhibitory control in MDD has been incompletely described. The objective of this study was to examine brain function during inhibitory and error processing in a unique population of young, healthy, unmedicated MDD individuals. We hypothesized that MDD subjects would show clinically relevant alterations in brain activation in medial prefrontal and anterior cingulate cortex (ACC) during both inhibitory and error processing. Subjects performed an individualized parametric stop-signal task during functional magnetic resonance imaging (fMRI). MDD subjects ( n = 15) met DSM-IV criteria for current MDD. Healthy control (HC) subjects ( n = 16) had no lifetime history of MDD or other psychiatric disorder. The groups were not significantly different in several socio-demographic variables or in behavioral performance. A group by trial difficulty interaction on error-related activation in bilateral inferior frontal gyrus and left supragenual ACC was observed, suggesting a demand-specific failure of this circuitry in MDD. Additionally, a group by trial difficulty interaction on inhibition-related activation in subgenual ACC was observed. Among MDD individuals, inhibition-related subgenual activation correlated with depressive symptom severity, implicating subgenual ACC in inhibitory control processes related to clinical depression.

Increased self‐focus in major depressive disorder is related to neural abnormalities in subcortical‐cortical midline structures

Patients with major depressive disorder (MDD) often show a tendency to strongly introspect and reflect upon their self, which has been described as increased self-focus. Although subcortical-cortical midline structures have been associated with reflection and introspection of oneself in healthy subjects, the neural correlates of the abnormally increased attribution of negative emotions to oneself, i.e. negative self-attribution, as hallmark of the increased self-focus in MDD remain unclear. The aim of the study was, therefore, to investigate the neural correlates during judgment of self-relatedness of positive and negative emotional stimuli thereby testing for emotional self-attribution. Using fMRI, we investigated 27 acute MDD patients and compared them with 25 healthy subjects employing a paradigm that focused on judgment of self-relatedness when compared with mere perception of the very same emotional stimuli. Behaviourally, patients with MDD showed significantly higher degrees of self-relatedness of specifically negative emotional stimuli when compared with healthy subjects. Neurally, patients with MDD showed significantly lower signal intensities in various subcortical and cortical midline regions like the dorsomedial prefrontal cortex (DMPFC), supragenual anterior cingulate cortex, precuneus, ventral striatum (VS), and the dorsomedial thalamus (DMT). Signal changes in the DMPFC correlated with depression severity and hopelessness whereas those in the VS and the DMT were related to judgment of self-relatedness of negative emotional stimuli. In conclusion, we present first evidence that the abnormally increased negative self-attribution as hallmark of the increased self-focus in MDD might be mediated by altered neural activity in subcortical-cortical midline structures.

Reduced Brainstem Inhibition during Anticipated Pelvic Visceral Pain Correlates with Enhanced Brain Response to the Visceral Stimulus in Women with Irritable Bowel Syndrome

Cognitive factors such as fear of pain and symptom-related anxiety play an important role in chronic pain states. The current study sought to characterize abnormalities in preparatory brain response before aversive pelvic visceral distention in irritable bowel syndrome (IBS) patients and their possible relationship to the consequences of distention. The brain functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to anticipated and delivered mild and moderate rectal distention was recorded from 14 female IBS patients and 12 healthy controls. During cued anticipation of distention, activity decreased in the insula, supragenual anterior cingulate cortex (sACC), amygdala, and dorsal brainstem (DBS) of controls. IBS patients showed less anticipatory inactivation. Group differences were significant in the right posterior insula and bilateral DBS. Self-rated measures of negative affect during scanning were higher in patients than controls (p < 0.001), and the anticipatory BOLD decreases in DBS were inversely correlated with these ratings. During subsequent distention, both groups showed activity increases in insula, dorsal ACC, and DBS and decreases in the infragenual ACC. The increases were more extensive in patients, producing significant group differences in dorsal ACC and DBS. The amplitude of the anticipatory decrease in the pontine portion of DBS was associated with greater activation during distention in right orbitofrontal cortex and bilateral sACC. Both regions have been associated previously with corticolimbic inhibition and cognitive coping. Deficits in preparatory inhibition of DBS, including the locus ceruleus complex and parabrachial nuclei, may interfere with descending corticolimbic inhibition and contribute to enhanced brain responsiveness and perceptual sensitivity to visceral stimuli in IBS.

Cortical selective vulnerability in motor neuron disease: a morphometric study.

Neuroimaging and neuropsychological studies have revealed that the primary motor cortex (PMC) and the extramotor cortical areas are functionally abnormal in motor neuron disease (MND, amyotrophic lateral sclerosis), but the nature of the cortical lesions that underlie these changes is poorly understood. In particular, there have been few attempts to quantify neuronal loss in the PMC and in other cortical areas in MND. We used SMI-32, an antibody against an epitope on non-phosphorylated neurofilament heavy chain, to analyse the size and density of SMI-32-positive cortical pyramidal neurons in layer V of the PMC, the dorsolateral prefrontal cortex (DLPFC) and the supragenual anterior cingulate cortex (ACC) in 13 MND and eight control subjects. There was a statistically significant reduction in the density of SMI-32-immunoreactive (IR) pyramidal neurons within cortical layer V in the PMC, the DLPFC and the ACC in MND subjects compared with controls [t (19) = 2.91, P = 0.009; estimated reduction 25%; 95% CI = 8%, 40%]. In addition, we studied the density and size of interneurons immunoreactive for the calcium-binding proteins calbindin-D(28K) (CB), parvalbumin (PV) and calretinin (CR) in the same areas (PMC, DLPFC and ACC). Statistically significant differences in the densities of CB-IR neurons were observed within cortical layers V (P = 0.003) and VI (P = 0.001) in MND cases compared with controls. The densities of CR- and PV-IR neurons were not significantly different between MND and control cases, although there were trends towards reductions of CR-IR neuronal density within the same layers and of PV-IR neuronal density within cortical layer VI. Loss of pyramidal neurons and of GABAergic interneurons is more widespread than has been appreciated and is present in areas associated with neuroimaging and cognitive abnormalities in MND. These findings support the notion that MND should be considered a multisystem disorder.

A quantitative morphometric study of the human anterior cingulate cortex

Morphometric alterations in the anterior cingulate cortex (ACC) have been reported in schizophrenia and mood disorders. Parameters affected include glial and neuronal density, neuronal size and cortical thickness. Some data, especially in mood disorders, suggest that the left subgenual ACC is preferentially involved. Qualitative studies show that the ACC cytoarchitecture is heterogeneous, but there are few quantitative data. We performed a quantitative morphometric study of five anatomical levels within the ACC (caudal and rostral subgenual [area 24b sg], rostral and intermediate supragenual [area 24b] and caudal supragenual [area 24b′]) in both hemispheres of five normal brains. We measured cortical depth, layer depths, neuronal density, neuronal size, and glial density, using the optical disector and nucleator. Relative to the subgenual ACC, the supragenual ACC was thicker, with a deeper layer V. Supragenual neurons were substantially larger in all layers, and were less densely packed in layers V and VI, than subgenual neurons. Glial density, and the glia to neuron ratio, was higher in supragenual than subgenual ACC. Only minor differences were seen between left and right ACC, between caudal and rostral subgenual ACC, and between the three supragenual levels. These data complement the qualitative descriptions of the heterogeneity of human ACC cytoarchitecture, connections, and functions, especially between supragenual and subgenual regions. Our findings also indicate that care must be taken when selecting ACC tissue to be used for morphometric studies of psychiatric disorders, since the normal anatomical variation is of a similar magnitude as the reported disease-related alterations.