Individual resting-state frontocingular functional connectivity predicts the intermittent theta burst stimulation response to stress in healthy female volunteers.

Intermittent theta burst stimulation (iTBS) delivered to the dorsolateral prefrontal cortex (DLPFC) has been investigated as a promising treatment for stress and stress-related mental disorders such as major depression, yet large individual differences in responsiveness demand further exploration and optimization of its effectiveness. Clinical research suggests that resting-state functional connectivity (rsFC) between the DLPFC and the anterior cingulate cortex (ACC) can predict iTBS treatment response in depression. The present study aimed to investigate whether rsFC between the left DLPFC and ACC subregions could predict the degree to which the stress system is affected by iTBS. After assessment of baseline resting-state fMRI data, 34 healthy female participants performed the Trier Social Stress Test on two separate days, each followed by active or sham iTBS over the left DLPFC. To evaluate iTBS effects on the stress-system, salivary cortisol was measured throughout the procedure. Our results showed that a stronger negative correlation between the left DLPFC and the caudal ACC was linked to a larger attenuation of stress-system sensitivity during active, but not during sham iTBS. In conclusion, based on individual rsFC between left DLPFC and caudal ACC, iTBS could be optimized to more effectively attenuate deregulation of the stress system.

Neural responses to social evaluative threat in the absence of negative investigator feedback and provoked performance failures.

Functional neuroimaging of social stress induction has considerably furthered our understanding of the neural risk architecture of stress-related mental disorders. However, broad application of existing neuroimaging stress paradigms is challenging, among others due to the relatively high intensity of the employed stressors, which limits applications in patients and longitudinal study designs. Here, we introduce a less intense neuroimaging stress paradigm in which subjects anticipate, prepare, and give speeches under simulated social evaluation without harsh investigator feedback or provoked performance failures (IMaging Paradigm for Evaluative Social Stress, IMPRESS). We show that IMPRESS significantly increases perceived arousal as well as adrenergic (heart rate, pupil diameter, and blood pressure) and hormonal (cortisol) responses. Amygdala and perigenual anterior cingulate cortex (pACC), two key regions of the emotion and stress regulatory circuitry, are significantly engaged by IMPRESS. We further report associations of amygdala and pACC responses with measures of adrenergic arousal (heart rate, pupil diameter) and social environmental risk factors (adverse childhood experiences, urban living). Our data indicate that IMPRESS induces benchmark psychological and endocrinological responses to social evaluative stress, taps into core neural circuits related to stress processing and mental health risk, and is promising for application in mental illness and in longitudinal study designs.

Swallowing Preparation and Execution: Insights from a Delayed-Response Functional Magnetic Resonance Imaging (fMRI) Study.

The present study sought to elucidate the functional contributions of sub-regions of the swallowing neural network in swallowing preparation and swallowing motor execution. Seven healthy volunteers participated in a delayed-response, go, no-go functional magnetic resonance imaging study involving four semi-randomly ordered activation tasks: (i) "prepare to swallow," (ii) "voluntary saliva swallow," (iii) "do not prepare to swallow," and (iv) "do not swallow." Results indicated that brain activation was significantly greater during swallowing preparation, than during swallowing execution, within the rostral and intermediate anterior cingulate cortex bilaterally, premotor cortex (left > right hemisphere), pericentral cortex (left > right hemisphere), and within several subcortical nuclei including the bilateral thalamus, caudate, and putamen. In contrast, activation within the bilateral insula and the left dorsolateral pericentral cortex was significantly greater in relation to swallowing execution, compared with swallowing preparation. Still other regions, including a more inferior ventrolateral pericentral area, and adjoining Brodmann area 43 bilaterally, and the supplementary motor area, were activated in relation to both swallowing preparation and execution. These findings support the view that the preparation, and subsequent execution, of swallowing are mediated by a cascading pattern of activity within the sub-regions of the bilateral swallowing neural network.

Regulated and unregulated forms of cortisol reactivity: a dual vulnerability model.

OBJECTIVE: To test in a laboratory setting the hypothesis that the most problematic daily outcomes should be particular to individuals displaying higher cortisol reactivity and deficits in executive functioning as assessed in a task-switching paradigm. METHODS: Thirty-eight volunteers completed a comprehensive assessment protocol. Individual differences in cortisol reactivity were quantified in an initial laboratory session involving a social stress speech task. Subsequently, individual differences in task-switching costs in a cognitive paradigm were assessed in a second session. Participants then reported on four problematic outcomes-error reactivity; worry; core aspects of negative emotionality; and aggression behavior frequency-for 15 consecutive days. RESULTS: Levels of cortisol reactivity did not predict task-switching costs. Instead, and as hypothesized, individual differences in cortisol reactivity and task-switching costs interacted to predict the problematic daily outcomes. The highest levels of such problematic outcomes were particular to high cortisol reactors also exhibiting greater task-switching costs. CONCLUSIONS: The findings support the dual vulnerability model proposed and are discussed from temperamental, health risk, and daily outcome perspectives. These findings indicate that cortisol is a risk factor, particularly when combined with deficiencies in task-switching.

Cerebral activations resulting from virtual dental treatment.

Pain, and anxiety of pain, for some people are serious problems in dental treatment. It is a common practical experience that even entering a dental surgery office, or the sound of a dental drill, may evoke vegetative correlates of toothache without any underlying disease. This everyday phenomenon suggests the hypothesis of a corresponding activation of pain-related brain areas by virtual dental treatment. Twenty healthy subjects viewed two different video clips presenting a dental treatment from the first-person perspective (simulation movie) and a moving hand holding an electrical toothbrush (control movie). Using functional magnetic resonance imaging, the cerebral hemodynamic responses that occurred during simulation and control movies were compared. Virtual dental treatment was associated with increased activity in pain-related brain areas such as the cingulate cortex, the insula, and primary and secondary somatosensory cortexes (SI, SII). The brain activation pattern indicates not only affective-motivational but also sensory-discriminative pain components during virtual dental treatment in all volunteers. Volunteers with a higher level of dental anxiety showed stronger activation of SI and SII. This may be a result of their higher anticipation of pain.

Stress evokes stronger medial posterior cingulate deactivations during emotional distraction in slower paced aging.

INTRODUCTION: Middle-aged offspring from long-lived families are thought to have a slower pace of aging, possibly related to HPA-axis function. Here, we investigated the neural and behavioral effects of social stress in offspring compared to their regular aging partners on emotional distraction during working memory (WM). METHODS: 104 middle-aged participants (53 males) consisting of offspring and their partners underwent the Trier Social Stress Test or a control procedure. Hereafter, a WM task with emotional distracters was performed using fMRI. Saliva cortisol levels were obtained during the procedure. RESULTS: Partners had higher overall cortisol levels than offspring. In addition, partners had decreased deactivations compared to offspring in the medial posterior cingulate cortex (mPCC) during emotional distraction, which were significantly correlated with lower accuracy during emotional distraction. DISCUSSION: mPCC-deactivations are known to be modulated by chronological aging, with more deactivations in the young than in the old. Here we show the same pattern in familial longevity versus regular aging after mild stress, with more deactivations related to better accuracy during emotional distraction. Functional mPCC deactivations might thus be related to pace of aging, and can be revealed by inducing mild stress.

The cortisol awakening response and anterior cingulate cortex function in maltreated depressed versus non-maltreated depressed youth.

Symptomatology of depression among children who have (vs. have not) experienced maltreatment is greater in severity, more resistant to conventional treatment, and associated with elevated risk for suicide. Recent evidence implicates perturbations in stress regulatory systems and heightened negative self-appraisals as factors that increase the severity of psychopathology experienced by depressed maltreated (vs. non-maltreated) youth. Likely explanatory mechanisms for these differences are disturbances in the function of the hypothalamic-pituitary axis (HPA) and persistent negative self-referential biases supported by prefrontal cortex function including the dorsal anterior cingulate cortex (dACC). The cortisol awakening response (CAR) and dACC activity during a self-appraisal task were assessed in maltreated and non-maltreated depressed youth. Hierarchical linear models were employed to model the CAR. Maltreatment group, dACC activity during positive and negative self-appraisals as well as other key predictors, were included in the models. Post hoc analyses explored explanations for significant differences. Results indicated that maltreated depressed youth exhibited a higher CAR compared to non-maltreated youth. At low levels of dACC activity during processing of negative self-descriptors maltreated and non-maltreated depressed youth's CAR did not differ. However, at elevated levels of dACC activity during processing of negative self-descriptors maltreated depressed youth exhibited significantly higher CAR compared to non-maltreated depressed youth.

Effects of mandibular advancement on brain activation during inspiratory loading in healthy subjects: a functional magnetic resonance imaging study.

Oral appliances have been a popular treatment option for subjects with obstructive sleep apnea. However, little information is available on how brain activation induced by respiratory challenge is modulated by mandibular advancement with these appliances. We hypothesized that the brain activation caused by respiratory stress may be alleviated by mandibular advancement. Respiratory stress was induced in 12 healthy subjects by resistive inspiratory loading. The effects of mandibular advancement during resistive inspiratory loading were assessed subjectively by using a visual analog scale. These effects were also evaluated objectively by using blood oxygenation level-dependent functional magnetic resonance imaging. The score for the visual analog scale significantly decreased with mandibular advancement. Cortical deactivation, in association with mandibular advancement, was localized to several specific regions, including the left cingulate gyrus and the bilateral prefrontal cortexes. These regions are known to be involved in respiratory control. Our results suggest that mandibular advancement with an oral appliance appears to be useful for reducing respiratory stress, based on both subjective and neuronal criteria.

Representational similarity analysis offers a preview of the noradrenergic modulation of long-term fear memory at the time of encoding.

Neuroimaging research on emotional memory has greatly advanced our understanding of the pathogenesis of anxiety disorders. While the behavioral expression of fear at the time of encoding does not predict whether an aversive experience will evolve into long-term fear memory, the application of multi-voxel pattern analysis (MVPA) for the analysis of BOLD-MRI data has recently provided a unique marker for memory formation. Here, we aimed to further investigate the utility of this marker by modulating the strength of fear memory with an α2-adrenoceptor antagonist (yohimbine HCl). Fifty-two healthy participants were randomly assigned to two conditions - either receiving 20mg yohimbine or a placebo pill (double-blind) - prior to differential fear conditioning and MRI-scanning. We examined the strength of fear associations during acquisition and retention of fear (48 h later) by assessing the similarity of BOLD-MRI patterns and pupil dilation responses. Additionally, participants returned for a follow-up test outside the scanner (2-4 weeks), during which we assessed fear-potentiated startle responses. Replicating our previous findings, neural pattern similarity reflected the development of fear associations over time, and unlike average activation or pupil dilation, predicted the later expression of fear memory (pupil dilation 48 h later). While no effect of yohimbine was observed on markers of autonomic arousal, including salivary α-amylase (sAA), we obtained indirect evidence for the noradrenergic enhancement of fear memory consolidation: sAA levels showed a strong increase prior to fMRI scanning, irrespective of whether participants had received yohimbine, and this increase correlated with the subsequent expression of fear (48 h later). Remarkably, this noradrenergic enhancement of fear was associated with changes in neural response patterns at the time of learning. These findings provide further evidence that representational similarity analysis is a sensitive tool for studying (enhanced) memory formation.

Afferent and efferent projections of the inferior area 6 in the macaque monkey.

The rostral part of the agranular frontal cortex (area 6) can be subdivided on the basis of its cytoarchitecture, enzymatic properties, and connections into two large sectors: a superior region, lying medial to the spur of the arcuate sulcus, and an inferior region, lying lateral to it. In this study we traced the afferent and efferent connections of the inferior region of area 6 by injecting small amounts of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) and fluorescent tracers (fast blue and diamidino yellow) into restricted parts of inferior area 6 and in physiologically determined fields of area 4. There is an ordered topographic pattern of connections between inferior area 6 and area 4. The region near the spur of the arcuate sulcus (hand field) projects to the area 4 hand field while the lateral part of inferior area 6 (mouth field) is connected with the corresponding field in area 4. The organization of the connections between the two fields is, however, different. The hand fields in area 6 and 4 have direct reciprocal projections, whereas the mouth field in the postarcuate cortex relays information to area 4 via a zone intermediate between the arcuate and the central sulcus. This zone corresponds to the cytochrome oxidase area F4 (Matelli, Luppino, and Rizzolatti: Behav. Brain Res. 18: 125-137, '85). The inferior area 6 also has topographically organized connections with the supplementary motor area. The inferior area 6 receives and sends fibers to a series of discrete cortical areas located in the lower cortical moiety (Sanides: The Structure and Function of the Nervous Tissue, Vol. 5. New York: Academic Press, pp 329-453, '72). These areas that form a broad ring around the central sulcus are the ventral bank of the principal sulcus and the adjacent area 46, the precentral operculum (PrOC), area SII (Jones and Burton: J. Comp. Neurol. 168:197-248, '76), the parietal operculum, and the rostral part of the inferior parietal lobule including the lower bank of the intraparietal sulcus. Finally, the inferior area 6 has sparse but consistent connections with insular and cingulate cortices. The functional significance of this complex pattern of connections is discussed.

A method for direct thalamic stimulation in fMRI studies using a glass-coated carbon fiber electrode.

Recent fMRI studies are of interest in exploring long-range interactions between different brain structures and the functional activation of specific brain regions by known neuroanatomical pathways. One of the experimental approaches requires the invasive implantation of an intracranial electrode to excite specific brain structures. In the present report, we describe a procedure for the production of a glass-coated carbon fiber electrode and the use of this electrode for direct activation of the brain in fMRI studies. The glass-coated carbon fiber microelectrode was implanted in the medial thalamus of anaesthetized rats and T2*-weighted gradient echo images in the sagittal plane obtained on a 4.7 T system (Biospec BMT 47/40) during electrical stimulation of the medial thalamus. The image quality obtained using this electrode was acceptable without reduction of the signal-to-noise ratio and image distortion. Cross-correlation analysis showed that the signal intensities of activated areas in the ipsilateral anterior cingulate cortex were significantly increased by about 4-5% during medial thalamus stimulation. The present study shows that glass-coated carbon fiber electrodes are suitable for fMRI studies and can be used to investigate functional thalamocingulate activation.

An analysis of the mechanisms underlying septal area control of hypothalamically elicited aggression in the cat.

This experiment was performed in order to examine several of the underlying mechanisms by which the septal area and adjacent regions regulate quiet biting attack behavior elicited from electrical stimulation of the hypothalamus in the cat. The results clearly indicate that stimulation of the septal area and anterior cingulate gyrus increased the latency for the occurrence of quiet biting attack behavior. Those sites within the septal area from which inhibition of attack can be produced are linked to sensory mechanisms associated with trigeminal reflexes activated during hypothalamic stimulation. Stimulation of these septal area sites decreased the lateral extent of the 'effective sensory fields' of the lipline established during hypothalamic stimulation, but did not appear to have any affect upon the latency of the hypothalamically elicited jaw-opening response. Deoxyglucose autoradiography revealed that the inhibition resulting from stimulation of the lateral septal area may be due to either the monosynaptic activation of the lateral hypothalamus or the disynaptic activation of this area utilizing a circuit involving the nuclei of the diagonal band of Broca.

"Stick out your tongue": tongue protrusion in neocortex and hypothalamic damaged rats.

Easily administered tests, analogues to the human neurological "stick out your tongue" tests, were devised to assess tongue use in normal, lateral hypothalamic (LH) and decorticate rats. LH and decorticate rats showed loss of tongue protrusion and licking immediately after surgery. Even though LH rats did not recover spontaneous eating dry food and drinking water, they showed extensive recovery of tongue protrusion and use. Decorticate rats regained the ability to eat dry food and drink water, but they showed minimal recovery of tongue protrusion and use. Comparisons of rats with variously located circumscribed neocortical lesions showed maximal tongue protrusion deficits followed orbital frontal cortex ablations. The results show: (1) that the tests developed and described are useful for routine examination of rats that have feeding abnormalities; (2) the feeding abnormalities of decorticate and LH rats can be dissociated; and (3) the orbital frontal cortex and corticofugal pathways passing through or adjacent to the LH may play a special role in the control of tongue and mouth use.

[Behavioral manifestations induced by electric stimulation of the anterior cingulate gyrus in man]. / Manifestations comportementales induites par la stimulation électrique du gyrus cingulaire antérieur chez l'homme

The electrical stimulation of a restricted part of area 24 in awake man elicits important behavioral changes. The present study is dealing with 83 epileptic patients whose brain activity was recorded in SEEG conditions, with a view to possible neurosurgery. In order to determine how seizures originate and propagate, 116 multileads electrodes (65 right, 51 left) were stereotaxically inserted in the anterior part of the cingular gyrus. 521 stimulations were performed. In 362 cases, this stimulation induced a particular behaviour which was characterized by an arousal, motor activities (involving fingers and hand, mouth, legs, eyes, associated movements of hand mouth, highly integrated movements), thymic modifications and hallucinatory manifestations. Topographical organization of the effective area in the cingular gyrus and the relation between the electrical responses and stimulation parameters are studied.

Meta-analysis on brain representation of experimental dental pain.

Functional magnetic resonance imaging (fMRI) has been widely used for investigating the brain representation associated with dental pain evoked by pulpal electrical stimulation. However, because of the heterogeneity of experimental designs and the small sample size of individual studies, the common brain representation regarding dental pain has remained elusive. We used imaging meta-analysis to investigate six dental pain-related fMRI studies (n = 87) and tested 3 hypotheses: (1) Dental pain is associated with the 'core' pain-related network; (2) pain-related brain activation is somatotopically organized in the somatosensory cortex; and (3) dental pain is associated with the cognitive-affective network related to pain. Qualitative and quantitative meta-analyses revealed: (1) common activation of the core pain-related network, including the somatosensory cortex, the insula, and the cingulate cortex; (2) inconsistency in somatotopically organized activation of the primary somatosensory cortex; and (3) common activation in the dorsolateral prefrontal cortex, suggesting a role of re-appraisal and coping in the experience of dental pain. In conclusion, fMRI combined with pulpal stimulation can effectively evoke activity in the pain-related network. The dental pain-related brain representation disclosed the mechanisms of how sensory and cognitive-affective factors shape dental pain, which will help in the development of more effective customized methods for central pain control.

Circadian and homeostatic modulation of functional connectivity and regional cerebral blood flow in humans under normal entrained conditions.

Diurnal rhythms have been observed in human behaviors as diverse as sleep, olfaction, and learning. Despite its potential impact, time of day is rarely considered when brain responses are studied by neuroimaging techniques. To address this issue, we explicitly examined the effects of circadian and homeostatic regulation on functional connectivity (FC) and regional cerebral blood flow (rCBF) in healthy human volunteers, using whole-brain resting-state functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). In common with many circadian studies, we collected salivary cortisol to represent the normal circadian activity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Intriguingly, the changes in FC and rCBF we observed indicated fundamental decreases in the functional integration of the default mode network (DMN) moving from morning to afternoon. Within the anterior cingulate cortex (ACC), our results indicate that morning cortisol levels are negatively correlated with rCBF. We hypothesize that the homeostatic mechanisms of the HPA axis has a role in modulating the functional integrity of the DMN (specifically, the ACC), and for the purposes of using fMRI as a tool to measure changes in disease processes or in response to treatment, we demonstrate that time of the day is important when interpreting resting-state data.

Tracing toothache intensity in the brain.

Identification of brain regions that differentially respond to pain intensity may improve our understanding of trigeminally mediated nociception. This report analyzed cortical responses to painless and painful electrical stimulation of a right human maxillary canine tooth. Functional magnetic resonance images were obtained during the application of five graded stimulus strengths, from below, at, and above the individually determined pain thresholds. Study participants reported each stimulus on a visual rating scale with respect to evoked sensation. Based on hemodynamic responses of all pooled stimuli, a cerebral network was identified that largely corresponds to the known lateral and medial nociceptive system. Further analysis of the five graded stimulus strengths revealed positive linear correlations for the anterior insula bilaterally, the contralateral (left) anterior mid-cingulate, as well as contralateral (left) pregenual cingulate cortices. Cerebral toothache intensity coding on a group level can thus be attributed to specific subregions within the cortical pain network.

Neural bases of behavior selection without an objective correct answer.

Life choice (e.g. occupation choice) often includes situations with two or more possible answers. How does the brain respond to such conflict-ridden situations? We investigated whether the dorsal anterior cingulate cortex (dACC) evaluates the degree of conflict between possible answers. Additionally, we investigated whether the medial prefrontal cortex (MPFC) or the medial temporal lobe (MTL) has a function in behavior selection with plural possible answers. We used an occupational choice task (e.g. which occupation do you think you could do better?-dancer or chemist) with two possible answers and a word-length task (e.g. which word is longer?-dentist or comedian) that has a correct answer. The conflicts in each task were manipulated. Results showed that the dACC and the MTL were activated when the conflict during occupational choice was large, and that the MPFC and posterior cingulate cortex were activated more in the occupational choice task than in the word-length task. Our results show that the dACC evaluates the degree of conflict between possible answers, and that the MTL, MPFC, and posterior cingulate cortex have a function in behavior selection without an objective correct answer. It is thought that the MTL functions to reduce conflict when a large-conflict is detected in the dACC. Furthermore, the MPFC and posterior cingulate are thought to have a function of biasing any of the plural answers in behavior selection without an objective answer.

Functions of the orbitofrontal and pregenual cingulate cortex in taste, olfaction, appetite and emotion.

Complementary neurophysiological recordings in macaques and functional neuroimaging in humans show that the primary taste cortex in the rostral insula and adjoining frontal operculum provides separate and combined representations of the taste, temperature, and texture (including viscosity and fat texture) of food in the mouth independently of hunger and thus of reward value and pleasantness. One synapse on, in the orbitofrontal cortex, these sensory inputs are for some neurons combined by learning with olfactory and visual inputs. Different neurons respond to different combinations, providing a rich representation of the sensory properties of food. The representation of taste and other food-related stimuli in the orbitofrontal cortex of macaques is found from its lateral border throughout area 13 to within 7 mm of the midline, and in humans the representation of food-related and other pleasant stimuli is found particularly in the medial orbitofrontal cortex. In the orbitofrontal cortex, feeding to satiety with one food decreases the responses of these neurons to that food, but not to other foods, showing that sensory-specific satiety is computed in the primate (including human) orbitofrontal cortex. Consistently, activation of parts of the human orbitofrontal cortex correlates with subjective ratings of the pleasantness of the taste and smell of food. Cognitive factors, such as a word label presented with an odour, influence the pleasantness of the odour, and the activation produced by the odour in the orbitofrontal cortex. Food intake is thus controlled by building a multimodal representation of the sensory properties of food in the orbitofrontal cortex, and gating this representation by satiety signals to produce a representation of the pleasantness or reward value of food which drives food intake. A neuronal representation of taste is also found in the pregenual cingulate cortex, which receives inputs from the orbitofrontal cortex, and in humans many pleasant stimuli activate the pregenual cingulate cortex, pointing towards this as an important area in motivation and emotion.

The emission pattern of vocalizations and directionality of the sonar system in the echolocating bat, Pteronotus parnelli.

The radiation patterns of the first three harmonics (approx. 30, 60, 90 kHz) of the mustached bat biosonar signal were measured from vocalizations elicited by cortical microstimulation. The primary foci of the acoustic beam patterns were in front of the mouth but somewhat below the horizontal plane. The prominent second and third harmonics showed sharp cutoffs between 20 degrees and 30 degrees lateral to the midline. Sidelobes were found, suggesting the influence of some vocal tract interference. When compared with previously measured estimates of the directionality of the auditory system, the vocal emission patterns are roughly complementary: Regions of maximum auditory sensitivity are found in areas of submaximal power for the sonar pulse beam pattern. The result is that, for the two most important harmonics, the "biosonar system" (i.e., vocal beam pattern plus receiver directionality) has a broader and more uniform directionality than either component alone. Therefore, within a limited region of space, echo amplitude will vary less as a function of angular displacement. This reduces the confounding influences of absolute sound pressure level on interaural intensity differences.