Cortical Midline Research Articles

Zbtb20-Induced CA1 Pyramidal Neuron Development and Area Enlargement in the Cerebral Midline Cortex of Mice

Expression of the transcriptional repressor Zbtb20 is confined to the hippocampal primordium of the developing dorsal midline cortex in mice. Here, we show that misexpression of Zbtb20 converts projection neurons of the subiculum and postsubiculum (dorsal presubiculum) to CA1 pyramidal neurons that are innervated by Schaffer collateral projections in ectopic strata oriens and radiatum. The Zbtb20-transformed neurons express Bcl11B, Satb2, and Calbindin-D28k, which are markers of adult CA1 pyramidal neurons. Downregulation of Zbtb20 expression by RNA interference impairs the normal maturation of CA1 pyramidal neurons resulting in deficiencies in Calbindin-D28k expression and in reduced apical dendritic arborizations in stratum lacunosum moleculare. Overall, the results show that Zbtb20 is required for various aspects of CA1 pyramidal neuron development such as the postnatal extension of apical dendritic arbors in the distal target zone and the subtype differentiation of Calbindin-D28k-positive subsets. They further suggest that Zbtb20 plays a role in arealization of the midline cortex.

Multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice

BackgroundAgenesis of the corpus callosum is associated with many human developmental syndromes. Key mechanisms regulating callosal formation include the guidance of axons arising from pioneering neurons in the cingulate cortex and the development of cortical midline glial populations, but their molecular regulation remains poorly characterised. Recent data have shown that mice lacking the transcription factor Nfib exhibit callosal agenesis, yet neocortical callosal neurons express only low levels of Nfib. Therefore, we investigate here how Nfib functions to regulate non-cell-autonomous mechanisms of callosal formation.ResultsOur investigations confirmed a reduction in glial cells at the midline in Nfib-/- mice. To determine how this occurs, we examined radial progenitors at the cortical midline and found that they were specified correctly in Nfib mutant mice, but did not differentiate into mature glia. Cellular proliferation and apoptosis occurred normally at the midline of Nfib mutant mice, indicating that the decrease in midline glia observed was due to deficits in differentiation rather than proliferation or apoptosis. Next we investigated the development of callosal pioneering axons in Nfib-/- mice. Using retrograde tracer labelling, we found that Nfib is expressed in cingulate neurons and hence may regulate their development. In Nfib-/- mice, neuropilin 1-positive axons fail to cross the midline and expression of neuropilin 1 is diminished. Tract tracing and immunohistochemistry further revealed that, in late gestation, a minor population of neocortical axons does cross the midline in Nfib mutants on a C57Bl/6J background, forming a rudimentary corpus callosum. Finally, the development of other forebrain commissures in Nfib-deficient mice is also aberrant.ConclusionThe formation of the corpus callosum is severely delayed in the absence of Nfib, despite Nfib not being highly expressed in neocortical callosal neurons. Our results indicate that in addition to regulating the development of midline glial populations, Nfib also regulates the expression of neuropilin 1 within the cingulate cortex. Collectively, these data indicate that defects in midline glia and cingulate cortex neurons are associated with the callosal dysgenesis seen in Nfib-deficient mice, and provide insight into how the development of these cellular populations is controlled at a molecular level.

The neural temporal dynamics of the intensity of emotional experience

Despite the fact that emotions involve multiple time-varying components, little is known about the underlying neural basis of these temporal dynamics. In this paper, we assess these temporal dynamics by using time-varying hemodynamic response functions (HRF) to model BOLD responses to emotional stimuli. We show that these time-varying HRFs lead to a better fit to the BOLD data and yield larger areas of significant activation than do conventional gamma-based canonical HRFs. We also report for the first time that intensity of emotional experience is associated with both magnitude and duration of brain activation. Specifically, greater negative emotional intensity was associated with greater magnitude of activation in the occipital cortex and with longer duration of activation in regions along the cortical midline associated with self-referent processing: the anterior medial prefrontal cortex and the posterior cingulate cortex. These data significantly advance our understanding of how the brain processes emotion and suggest that the intensity of a negative emotional experience is due in part to elaborative self-referent processing that is captured by the duration of neural activity in cortical midline structures. These data also underscore the importance of using modeling techniques that will help elucidate the chronometry of both normal and psychopathological emotional processes.

Evaluative-feedback stimuli selectively activate the self-related brain area: An fMRI study

Evaluative-feedback, occurring in our daily life, generally contains subjective appraisal of one's specific abilities and personality characteristics besides objective right-or-wrong information. Traditional psychological researches have proved it to be important in building up one's self-concept; however, the neural basis underlying its cognitive processing remains unclear. The present neuroimaging study revealed the mechanism of evaluative-feedback processing at the neural level. 19 healthy Chinese subjects participated in this experiment, and completed the time-estimation task to better their performance according to four types of feedback, namely positive evaluative- and performance-feedback as well as negative evaluative- and performance-feedback. Neuroimaging findings showed that evaluative- rather than performance-feedback can induce increased activities mainly distributed in the cortical midline structures (CMS), including medial prefrontal cortex (BA 8/9)/anterior cigulate cortex (ACC, BA 20), precuneus (BA 7/31) adjacent to posterior cingulate gyrus (PCC, BA 23) of both hemispheres, as well as right inferior lobule (BA 40). This phenomenon can provide evidence that evaluative-feedback may significantly elicit the self-related processing in our brain. In addition, our results also revealed that more brain areas, particularly some self-related neural substrates were activated by the positive evaluative-feedback, in comparative with the negative one. In sum, this study suggested that evaluative-feedback was closely correlated with the self-concept processing, which distinguished it from the performance-feedback.

Dysfunction of a cortical midline network during emotional appraisals in schizophrenia.

A cardinal feature of schizophrenia is the poor comprehension, or misinterpretation, of the emotional meaning of social interactions and events, which can sometimes take the form of a persecutory delusion. It has been shown that the comprehension of the emotional meaning of the social world involves a midline paralimbic cortical network. However, the function of this network during emotional appraisals in patients with schizophrenia is not well understood. In this study, hemodynamic responses were measured in 14 patients with schizophrenia and 18 healthy subjects during the evaluation of descriptions of social situations with negative, positive, and neutral affective valence. The healthy and schizophrenia groups displayed opposite patterns of responses to emotional and neutral social situations within the medial prefrontal and posterior cingulate cortices--healthy participants showed greater activity to the emotional compared to the neutral situations, while patients exhibited greater responses to the neutral compared to the emotional situations. Moreover, the magnitude of the response within bilateral cingulate gyri to the neutral social stimuli predicted delusion severity in the patients with schizophrenia. These findings suggest that impaired functioning of cortical midline structures in schizophrenia may underlie faulty interpretations of social events, contributing to delusion formation.

Modeling the Impact of Lesions in the Human Brain

Lesions of anatomical brain networks result in functional disturbances of brain systems and behavior which depend sensitively, often unpredictably, on the lesion site. The availability of whole-brain maps of structural connections within the human cerebrum and our increased understanding of the physiology and large-scale dynamics of cortical networks allow us to investigate the functional consequences of focal brain lesions in a computational model. We simulate the dynamic effects of lesions placed in different regions of the cerebral cortex by recording changes in the pattern of endogenous (“resting-state”) neural activity. We find that lesions produce specific patterns of altered functional connectivity among distant regions of cortex, often affecting both cortical hemispheres. The magnitude of these dynamic effects depends on the lesion location and is partly predicted by structural network properties of the lesion site. In the model, lesions along the cortical midline and in the vicinity of the temporo-parietal junction result in large and widely distributed changes in functional connectivity, while lesions of primary sensory or motor regions remain more localized. The model suggests that dynamic lesion effects can be predicted on the basis of specific network measures of structural brain networks and that these effects may be related to known behavioral and cognitive consequences of brain lesions.

Modulation of cortical midline structures by implicit and explicit self-relevance evaluation

Recent neuroimaging work has observed activity in cortical midline structures (CMS) such as medial prefrontal and posterior cingulate cortices during self-referential processing. Moreover, items rated as self-relevant produce increased activity in these regions relative to items that are deemed not self-relevant. A common thread among previous reports has been reliance on experimental tasks that encourage or require online self-referential processing. In this paper, we report findings from two experiments that manipulated requirements for self-reflection. In Experiment 1, subjects rated trait adjectives for social desirability and for self-relevance. Results revealed increasing activity in CMS with increasing self-relevance, but only during explicit ratings of self-relevance. In Experiment 2, we examined CMS activity during passive viewing of personal semantic facts (such as subjects’ own first names). Taken together, these results suggest that highly self-relevant information captures attention through neural mechanisms that are comparable to those engaged during explicit self-reflection, namely via recruitment of CMS structures.

Posterior Cingulate and Lateral Parietal Gray Matter Volume in Older Adults with Depressive Symptoms

Depressive symptoms occurring late in life are an important risk factor for Alzheimer’s disease (AD). The latest research finds that onset of depressive symptoms in late life may herald the development of AD, not only for amnestic Mild Cognitive Impairment (aMCI) patients, but also for cognitively-normal older adults. Neuroimaging of brain structure, blood flow, and glucose metabolism indicates that depressive symptoms in late life are accompanied by structural and functional changes in limbic brain regions vulnerable to AD. The present cross-sectional study was guided by the hypothesis that compared to their non-depressed counterparts, older adults with mild to moderate depressive symptoms have less volume in limbic structures vulnerable to changes in AD—specifically, cortical midline structures such as anterior cingulate and posterior cingulate cortex as well as mesial temporal regions such as bilateral hippocampi and amygdalae. Consistent with our hypothesis, results of a voxel-based morphometry analysis revealed smaller retrosplenial, posterior cingulate, and precuneus gray matter volumes in depressed individuals relative to healthy controls. Right lateral parietal cortex—another region vulnerable to change in AD—was also smaller in the group with depressive symptoms. Contrary to our hypothesis, no volumetric differences were found in the anterior cingulate cortex or mesial temporal lobe. Results of this study show a relationship between geriatric depressive symptoms and brain volume in regions vulnerable to AD. Follow-up of participants over time will tell if brain changes detected here predict development of AD.

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.

Transverse patterning dissociates human EEG theta power and hippocampal BOLD activation

Theta oscillations (4-8 Hz) are often modulated in human electroencephalogram (EEG) studies of memory, whereas overlapping frequencies dominate rodent hippocampal EEG. An emerging parallelism between theta reactivity and hippocampal functional magnetic resonance imaging activation has suggested a homology between theta activity in humans and rodents, representing a process of cortico-hippocampal interaction involved in memory. In the present study, we investigated EEG reactivity during performance of a relational memory task that induces a negative hippocampal blood oxygenation level dependent (BOLD) signal change, compared to a nonrelational control condition. Relational trials induced theta increases and alpha decreases. Low Resolution Electromagnetic Brain Tomography estimates localized theta and alpha modulation to frontal midline and parietal midline cortices, respectively, both of which exhibit negative BOLD responses in this task. Thus, theta and alpha dynamics are dissociable from positive BOLD activation, and may, in fact, colocalize with negative BOLD responses.

Cortical midline involvement in autobiographical memory

Recollecting autobiographical memories of personal past experiences is an integral part of our everyday lives and relies on a distributed set of brain regions. Their occurrence externally in the real world (‘realness’) and their self-relevance (‘selfness’) are two defining features of these autobiographical events. Distinguishing between personally experienced events and those that happened to other individuals, and between events that really occurred and those that were mere figments of the imagination, is clearly advantageous, yet the respective neural correlates remain unclear. Here we experimentally manipulated and dissociated realness and selfness during fMRI using a novel paradigm where participants recalled self (autobiographical) and non-self (from a movie or television news clips) events that were either real or previously imagined. Distinct sub-regions within dorsal and ventral medial prefrontal cortex, retrosplenial cortex and along the parieto-occipital sulcus preferentially coded for events (real or imagined) involving the self. By contrast, recollection of autobiographical events that really happened in the external world activated different areas within ventromedial prefrontal cortex and posterior cingulate cortex. In addition, recall of externally experienced real events (self or non-self) was associated with increased activity in areas of dorsomedial prefrontal cortex and posterior cingulate cortex. Taken together our results permitted a functional deconstruction of anterior (medial prefrontal) and posterior (retrosplenial cortex, posterior cingulate cortex, precuneus) cortical midline regions widely associated with autobiographical memory but whose roles have hitherto been poorly understood.

Self-reflection across time: cortical midline structures differentiate between present and past selves

The processing of personal changes across time and the ability to differentiate between representations of present and past selves are crucial for developing a mature sense of identity. In this study, we explored the neural correlates of self-reflection across time using functional magnetic resonance imaging (fMRI). College undergraduates were asked to reflect on their own psychological characteristics and those of an intimate other, for both the present time period (i.e. at college) and a past time period (i.e. high school years) that involved significant personal changes. Cortical midline structures (CMS) were commonly recruited by the four reflective tasks (reflecting on the present self, past self, present other and past other), relative to a control condition (making valence judgments). More importantly, however, the degree of activity in CMS also varied significantly according to the target of reflection, with the ventral and dorsal medial prefrontal cortex and the posterior cingulate cortex being more recruited when reflecting on the present self than when reflecting on the past self or when reflecting on the other person. These findings suggest that CMS may contribute to differentiate between representations of present and past selves.

The resting brain and our self: Self-relatedness modulates resting state neural activity in cortical midline structures

The resting brain shows high neural activity in various regions, the default-mode network, chief among them the cortical midline structures (CMS). The psychological correlate of high resting state neural activity in CMS remains however unclear though speculatively it has been associated with processing of internally-oriented self-relatedness. We used functional MRI to examine internally-oriented self-relatedness during the resting state period. This was indirectly done by letting subjects perceive emotional pictures followed by a fixation cross; the very same pictures were then rated subjectively according to their degree of self-relatedness in a postscanning session. This allowed us to correlate the picture ratings of self-relatedness with signal changes in the subsequent resting state period, i.e. fixation period. The emotional pictures' degree of self-relatedness parametrically modulated subsequent resting state signal changes in various CMS, including ventro- and dorsomedial prefrontal cortex and posterior cingulate cortex. This modulation could be distinguished from effects of emotion dimensions (e.g. valence, intensity) and evoked effects of self-relatedness during the stimulus period itself the latter being observed rather in subcortical regions, e.g. amygdala, ventral striatum, and tectum. In sum, our findings suggest that resting state neural activity in CMS is parametrically and specifically modulated by the preceding stimulus's degree of self-relatedness. This lends further support to the presumed involvement of these regions in processing internally-oriented self-relatedness as distinguished from externally-oriented self-relatedness.

The trans-species concept of self and the subcortical–cortical midline system

The nature of the self has been one of the central problems in philosophy and most recently in neuroscience. Here, we suggest that animals and humans share a 'core self' represented in homologous underlying neural networks. We argue that the core self might be constituted by an integrative neuronal mechanism that enables self-related processing (SRP). Because mammalian organisms are capable of relating bodily states, intrinsic brain states (e.g. basic attentional, emotional and motivational systems) and environmental stimuli to various life-supporting goal-orientations, SRP appears to be a core ability preserved across numerous species. Recent data suggest that SRP is operating via a central integrative neural system made up of subcortical-cortical midline structures (SCMSs), that are homologous across mammalian species.

INDICATED PREVENTION OF PSYCHOTIC DISORDERS WITH LONG-CHAINOMEGA-3 FATTY ACIDS: A RANDOMIZED, PLACEBO-CONTROLLED TRIAL

Mindful self-awareness is central to mindfulness meditation and plays a key role in its salutary effects. It has been related to decreased activation in cortical midline structures (CMS) and amygdala, and increased activation in somatosensory regions. However, findings in untrained individuals are contradictory, and scarce in experienced meditators.Using fMRI, we investigated experienced mindfulness meditators (LTM, n = 21, average 4652 practice-hours) and matched meditation-naïve participants (MNP, n = 19) during short periods of mindful self-awareness (FEEL) and self-referential thinking (THINK).We report somatosensory activations and decreases in CMS during FEEL for both groups, but significantly stronger decreases in prefrontal CMS in LTM. LTM further showed decreases in language-related and amygdala regions, but the latter was not significantly different between groups. Overall, higher activations in amygdala and mid-line regions during FEEL were related to levels of depressiveness.Neural patterns of mindful self-awareness emerge already in MNP but more pronounced in LTM. Specifically, meditation training might reduce self-reference and verbalization during mindful awareness. We further corroborate the suggested link between mindfulness and healthy self-related functions on the neural level. Longitudinal studies need to corroborate these findings.

Coupling of Theta Oscillations between Anterior and Posterior Midline Cortex and with the Hippocampus in Freely Behaving Rats

Theta oscillations in the hippocampus support cognitive processing. Theta-range rhythmicity has also been reported in frontal and posterior cortical areas--where it tends to show consistent phase-relations with hippocampal rhythmicity. Theta-range rhythmicity may, then, be important for cortico-cortical and/or cortico-hippocampal interactions. Here, we surveyed the rat frontal and posterior midline cortices for theta-related oscillations and examined their relationships with hippocampal activity in freely moving rats. Variation in electroencephalography across 4 general classes of spontaneous behavior demonstrated different profiles of theta-like activities through the rat midline cortices. Analysis of cortico-cortical and cortico-hippocampal coherences showed distinct, behavior-dependent, couplings of theta and delta oscillations. Increased theta coherence between structures was most obvious during nonautomatic behaviors and least during immobility or grooming. Extensive coupling of theta oscillations throughout the rat midline cortices and hippocampus occurred during rearing, and exploratory behavior. Such increases in coherence could reflect binding of cortico-hippocampal pathways into temporary functional units by behavioral demands. Extensive coupling of frontal delta, which lacked coherence with posterior areas (including the hippocampus), suggests that different frequencies of rhythmicity may act to bind groups of structures into different functional circuits on different occasions.

Are our emotional feelings relational? A neurophilosophical investigation of the James–Lange theory

The James–Lange theory considers emotional feelings as perceptions of physiological body changes. This approach has recently resurfaced and modified in both neuroscientific and philosophical concepts of embodiment of emotional feelings. In addition to the body, the role of the environment in emotional feeling needs to be considered. I here claim that the environment has not merely an indirect and thus instrumental role on emotional feelings via the body and its sensorimotor and vegetative functions. Instead, the environment may have a direct and non-instrumental, i.e., constitutional role in emotional feelings; this implies that the environment itself in the gestalt of the person–environment relation is constitutive of emotional feeling rather than the bodily representation of the environment. Since the person–environment relation is crucial in this approach, I call it the relational concept of emotional feeling. After introducing the relational concept of emotional feeling, the present paper investigates the neurophilosophical question whether current neuroimaging data on human emotion processing and anatomical connectivity are empirically better compatible with the “relational” or the “embodied” concept of emotional feeling. These data lend support to the empirical assumption that neural activity in subcortical and cortical midline regions code the relationship between intero- and exteroceptive stimuli in a relational mode, i.e. their actual balance, rather than in a translational mode, i.e., by translating extero- into interoceptive stimulus changes. Such intero-exteroceptive relational mode of neural coding may have implications for the characterization of emotional feeling with regard to phenomenal consciousness and intentionality. I therefore conclude that the here advanced relational concept of emotional feeling may be considered neurophilosophically more plausible and better compatible with current neuroscientific data than the embodied concept as presupposed in the James–Lange theory and its modern neuroscientific and philosophical versions.

High-frequency oscillations in distributed neural networks reveal the dynamics of human decision making

We examine the relative timing of numerous brain regions involved in human decisions that are based on external criteria, learned information, personal preferences, or unconstrained internal considerations. Using magnetoencephalography (MEG) and advanced signal analysis techniques, we were able to non-invasively reconstruct oscillations of distributed neural networks in the high-gamma frequency band (60–150 Hz). The time course of the observed neural activity suggested that two-alternative forced choice tasks are processed in four overlapping stages: processing of sensory input, option evaluation, intention formation, and action execution. Visual areas are activated first, and show recurring activations throughout the entire decision process. The temporo-occipital junction and the intraparietal sulcus are active during evaluation of external values of the options, 250–500 ms after stimulus presentation. Simultaneously, personal preference is mediated by cortical midline structures. Subsequently, the posterior parietal and superior occipital cortices appear to encode intention, with different subregions being responsible for different types of choice. The cerebellum and inferior parietal cortex are recruited for internal generation of decisions and actions, when all options have the same value. Action execution was accompanied by activation peaks in the contralateral motor cortex. These results suggest that high-gamma oscillations as recorded by MEG allow a reliable reconstruction of decision processes with excellent spatiotemporal resolution.

Effects of Working Memory Load on Oscillatory Power in Human Intracranial EEG

Studies of working memory load effects on human EEG power have indicated divergent effects in different frequency bands. Although gamma power typically increases with load, the load dependency of the lower frequency theta and alpha bands is uncertain. We obtained intracranial electroencephalography measurements from 1453 electrode sites in 14 epilepsy patients performing a Sternberg task, in order to characterize the anatomical distribution of load-related changes across the frequency spectrum. Gamma power increases occurred throughout the brain, but were most common in the occipital lobe. In the theta and alpha bands, both increases and decreases were observed, but with different anatomical distributions. Increases in theta and alpha power were most prevalent in frontal midline cortex. Decreases were most commonly observed in occipital cortex, colocalized with increases in the gamma range, but were also detected in lateral frontal and parietal regions. Spatial overlap with group functional magnetic resonance imaging results was minimal except in the precentral gyrus. These findings suggest that power in any given frequency band is not a unitary phenomenon; rather, reactivity in the same frequency band varies in different brain regions, and may relate to the engagement or inhibition of a given area in a cognitive task.

Que PASA? The posterior-anterior shift in aging.

A consistent finding from functional neuroimaging studies of cognitive aging is an age-related reduction in occipital activity coupled with increased frontal activity. This posterior-anterior shift in aging (PASA) has been typically attributed to functional compensation. The present functional magnetic resonance imaging sought to 1) confirm that PASA reflects the effects of aging rather than differences in task difficulty; 2) test the compensation hypothesis; and 3) investigate whether PASA generalizes to deactivations. Young and older participants were scanned during episodic retrieval and visual perceptual tasks, and age-related changes in brain activity common to both tasks were identified. The study yielded 3 main findings. First, inconsistent with a difficulty account, the PASA pattern was found across task and confidence levels when matching performance among groups. Second, supporting the compensatory hypothesis, age-related increases in frontal activity were positively correlated with performance and negatively correlated with the age-related occipital decreases. Age-related increases and correlations with parietal activity were also found. Finally, supporting the generalizability of the PASA pattern to deactivations, aging reduced deactivations in posterior midline cortex but increased deactivations in medial frontal cortex. Taken together, these findings demonstrate the validity, function, and generalizability of PASA, as well as its importance for the cognitive neuroscience of aging.