Neural substrates of the interaction between effort-expenditure reward decision-making and outcome anticipation.

OBJECTIVE: Reward anticipation is important for future decision-making, possibly due to re-evaluation of prior decisions. However, the exact relationship between reward anticipation and prior effort-expenditure decision-making, and its neural substrates are unknown. METHOD: Thirty-three healthy participants underwent fMRI scanning while performing the Effort-based Pleasure Experience Task (E-pet). Participants were required to make effort-expenditure decisions and anticipate the reward. RESULTS: We found that stronger anticipatory activation at the posterior cingulate cortex was correlated with slower reaction time while making decisions with a high-probability of reward. Moreover, the substantia nigra was significantly activated in the prior decision-making phase, and involved in reward-anticipation in view of its strengthened functional connectivity with the mammillary body and the putamen in trial conditions with a high probability of reward. CONCLUSIONS: These findings support the role of reward anticipation in re-evaluating decisions based on the brain-behaviour correlation. Moreover, the study revealed the neural interaction between reward anticipation and decision-making.

Out-of-phase transcranial alternating current stimulation modulates the neurodynamics of inhibitory control.

Transcranial alternating current stimulation (tACS) is an efficient neuromodulation technique that enhances cognitive function in a non-invasive manner. Using functional magnetic resonance imaging, we investigated whether tACS with different phase lags (0° and 180°) between the dorsal anterior cingulate and left dorsolateral prefrontal cortices modulated inhibitory control performance during the Stroop task. We found out-of-phase tACS mediated improvements in task performance, which was neurodynamically reflected as putamen, dorsolateral prefrontal, and primary motor cortical activation as well as prefrontal-based top-down functional connectivity. Our observations uncover the neurophysiological bases of tACS-phase-dependent neuromodulation and provide a feasible non-invasive approach to effectively modulate inhibitory control.

The influence of anterior cingulate GABA+ and glutamate on emotion regulation and reactivity in adolescents and adults.

During adolescence, emotion regulation and reactivity are still developing and are in many ways qualitatively different from adulthood. However, the neurobiological processes underpinning these differences remain poorly understood, including the role of maturing neurotransmitter systems. We combined magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (dACC) and self-reported emotion regulation and reactivity in a sample of typically developed adolescents (n = 37; 13-16 years) and adults (n = 39; 30-40 years), and found that adolescents had higher levels of glutamate to total creatine (tCr) ratio in the dACC than adults. A glutamate Í age group interaction indicated a differential relation between dACC glutamate levels and emotion regulation in adolescents and adults, and within-group follow-up analyses showed that higher levels of glutamate/tCr were related to worse emotion regulation skills in adolescents. We found no age-group differences in gamma-aminobutyric acid+macromolecules (GABA+) levels; however, emotion reactivity was positively related to GABA+/tCr in the adult group, but not in the adolescent group. The results demonstrate that there are developmental changes in the concentration of glutamate, but not GABA+, within the dACC from adolescence to adulthood, in accordance with previous findings indicating earlier maturation of the GABA-ergic than the glutamatergic system. Functionally, glutamate and GABA+ are positively related to emotion regulation and reactivity, respectively, in the mature brain. In the adolescent brain, however, glutamate is negatively related to emotion regulation, and GABA+ is not related to emotion reactivity. The findings are consistent with synaptic pruning of glutamatergic synapses from adolescence to adulthood and highlight the importance of brain maturational processes underlying age-related differences in emotion processing.

Anterior cingulate cortex and insomnia: A cingulate-striatum connection.

Insomnia is an important comorbidity of chronic pain. In this issue of Neuron, Li et al. report that chronic-pain-induced insomnia is mediated by the pyramidal neurons in the anterior cingulate cortex and their dopaminergic projections to the dorsal medial striatum.

White matter tracts adjacent to the human cingulate sulcus visual area (CSv).

Human cingulate sulcus visual area (CSv) was first identified as an area that responds selectively to visual stimulation indicative of self-motion. It was later shown that the area is also sensitive to vestibular stimulation as well as to bodily motion compatible with locomotion. Understanding the anatomical connections of CSv will shed light on how CSv interacts with other parts of the brain to perform information processing related to self-motion and navigation. A previous neuroimaging study (Smith et al. 2018, Cerebral Cortex, 28, 3685-3596) used diffusion-weighted magnetic resonance imaging (dMRI) to examine the structural connectivity of CSv, and demonstrated connections between CSv and the motor and sensorimotor areas in the anterior and posterior cingulate sulcus. The present study aimed to complement this work by investigating the relationship between CSv and adjacent major white matter tracts, and to map CSv's structural connectivity onto known white matter tracts. By re-analysing the dataset from Smith et al. (2018), we identified bundles of fibres (i.e. streamlines) from the whole-brain tractography that terminate near CSv. We then assessed to which white matter tracts those streamlines may belong based on previously established anatomical prescriptions. We found that a significant number of CSv streamlines can be categorised as part of the dorsalmost branch of the superior longitudinal fasciculus (SLF I) and the cingulum. Given current thinking about the functions of these white matter tracts, our results support the proposition that CSv provides an interface between sensory and motor systems in the context of self-motion.

Evolutionarily conserved neural responses to affective touch in monkeys transcend consciousness and change with age.

Affective touch-a slow, gentle, and pleasant form of touch-activates a different neural network than which is activated during discriminative touch in humans. Affective touch perception is enabled by specialized low-threshold mechanoreceptors in the skin with unmyelinated fibers called C tactile (CT) afferents. These CT afferents are conserved across mammalian species, including macaque monkeys. However, it is unknown whether the neural representation of affective touch is the same across species and whether affective touch's capacity to activate the hubs of the brain that compute socioaffective information requires conscious perception. Here, we used functional MRI to assess the preferential activation of neural hubs by slow (affective) vs. fast (discriminative) touch in anesthetized rhesus monkeys (Macaca mulatta). The insula, anterior cingulate cortex (ACC), amygdala, and secondary somatosensory cortex were all significantly more active during slow touch relative to fast touch, suggesting homologous activation of the interoceptive-allostatic network across primate species during affective touch. Further, we found that neural responses to affective vs. discriminative touch in the insula and ACC (the primary cortical hubs for interoceptive processing) changed significantly with age. Insula and ACC in younger animals differentiated between slow and fast touch, while activity was comparable between conditions for aged monkeys (equivalent to >70 y in humans). These results, together with prior studies establishing conserved peripheral nervous system mechanisms of affective touch transduction, suggest that neural responses to affective touch are evolutionarily conserved in monkeys, significantly impacted in old age, and do not necessitate conscious experience of touch.

Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behavior.

The anterior cingulate cortex (ACC) is critical for the perception and unpleasantness of pain.1,2,3,4,5,6 It receives nociceptive information from regions such as the thalamus and amygdala and projects to several cortical and subcortical regions of the pain neuromatrix.7,8 ACC hyperexcitability is one of many functional changes associated with chronic pain, and experimental activation of ACC pyramidal cells produces hypersensitivity to innocuous stimuli (i.e., allodynia).9,10,11,12,13,14 A less-well-studied projection to the ACC arises from a small forebrain region, the claustrum.15,16,17,18,19,20 Stimulation of excitatory claustrum projection neurons preferentially activates GABAergic interneurons, generating feed-forward inhibition onto excitatory cortical networks.21,22,23,24 Previous work has shown that claustrocingulate projections display altered activity in prolonged pain25,26,27; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,1,9,28 suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.

The memory trace of an intrusive trauma-analog episode.

Intrusive memories are a core symptom of posttraumatic stress disorder. Compared with memories of everyday events, they are characterized by several seemingly contradictory features: intrusive memories contain distinct sensory and emotional details of the traumatic event and can be triggered by various perceptually similar cues, but they are poorly integrated into conceptual memory. Here, we conduct exploratory whole-brain analyses to investigate the neural representations of trauma-analog experiences and how they are reactivated during memory intrusions. We show that trauma-analog movies induce excessive processing and generalized representations in sensory areas but decreased blood-oxygen-level-dependent (BOLD) responses and highly distinct representations in conceptual/semantic areas. Intrusive memories activate generalized representations in sensory areas and reactivate memory traces specific to trauma-analog events in the anterior cingulate cortex. These findings provide the first evidence of how traumatic events could distort memory representations in the human brain, which may form the basis for future confirmatory research on the neural representations of traumatic experiences.

Anterior cingulate cross-hemispheric inhibition via the claustrum resolves painful sensory conflict.

The anterior cingulate cortex (ACC) responds to noxious and innocuous sensory inputs, and integrates them to coordinate appropriate behavioral reactions. However, the role of the projections of ACC neurons to subcortical areas and their influence on sensory processing are not fully investigated. Here, we identified that ACC neurons projecting to the contralateral claustrum (ACC→contraCLA) preferentially respond to contralateral mechanical sensory stimulation. These sensory responses were enhanced during attending behavior. Optogenetic activation of ACC→contraCLA neurons silenced pyramidal neurons in the contralateral ACC by recruiting local circuit fast-spiking interneuron activation via an excitatory relay in the CLA. This circuit activation suppressed withdrawal behavior to mechanical stimuli ipsilateral to the ACC→contraCLA neurons. Chemogenetic silencing showed that the cross-hemispheric circuit has an important role in the suppression of contralateral nociceptive behavior during sensory-driven attending behavior. Our findings identify a cross-hemispheric cortical-subcortical-cortical arc allowing the brain to give attentional priority to competing innocuous and noxious inputs.

Astrocytes control recent and remote memory strength by affecting the recruitment of the CA1→ACC projection to engrams.

The maturation of engrams from recent to remote time points involves the recruitment of CA1 neurons projecting to the anterior cingulate cortex (CA1→ACC). Modifications of G-protein-coupled receptor pathways in CA1 astrocytes affect recent and remote recall in seemingly contradictory ways. To address this inconsistency, we manipulated these pathways in astrocytes during memory acquisition and tagged c-Fos-positive engram cells and CA1→ACC cells during recent and remote recall. The behavioral results were coupled with changes in the recruitment of CA1→ACC projection cells to the engram: Gq pathway activation in astrocytes caused enhancement of recent recall alone and was accompanied by earlier recruitment of CA1→ACC projecting cells to the engram. In contrast, Gi pathway activation in astrocytes resulted in the impairment of only remote recall, and CA1→ACC projecting cells were not recruited during remote memory. Finally, we provide a simple working model, hypothesizing that Gq and Gi pathway activation affect memory differently, by modulating the same mechanism: CA1→ACC projection.

Optogenetic stimulation of neurons in the anterior cingulate cortex induces changes in intravesical bladder pressure and the micturition reflex.

Lower urinary tract (LUT) function is controlled by the central nervous system, including higher-order cognitive brain regions. The anterior cingulate cortex (ACC) is one of these regions, but the role of its activity in LUT function remains poorly understood. In the present study, we conducted optogenetic experiments to manipulate neural activity in mouse ACC while monitoring bladder pressure to elucidate how the activity of ACC regulates LUT function. Selective optogenetic stimulation of excitatory neurons in ACC induced a sharp increase in bladder pressure, whereas activation of inhibitory neurons in ACC prolonged the interval between bladder contractions. Pharmacological manipulation of ACC also altered bladder contractions, consistent with those observed in optogenetic experiments. Optogenetic mapping of the cortical area responsible for eliciting the increase in bladder pressure revealed that stimulation to ACC showed more potent effects than the neighboring motor cortical areas. These results suggest that ACC plays a crucial role in initiating the bladder pressure change and the micturition reflex. Thus, the balance between excitation and inhibition in ACC may regulate the reflex bidirectionally.

Subcallosal cingulate deep brain stimulation evokes two distinct cortical responses via differential white matter activation.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.

Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain.

Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders.

The anterior cingulate cortex controls the hyperactivity in subthalamic neurons in male mice with comorbid chronic pain and depression.

Neurons in the subthalamic nucleus (STN) become hyperactive following nerve injury and promote pain-related responses in mice. Considering that the anterior cingulate cortex (ACC) is involved in pain and emotion processing and projects to the STN, we hypothesize that ACC neurons may contribute to hyperactivity in STN neurons in chronic pain. In the present study, we showed that ACC neurons enhanced activity in response to noxious stimuli and to alterations in emotional states and became hyperactive in chronic pain state established by spared nerve injury of the sciatic nerve (SNI) in mice. In naïve mice, STN neurons were activated by noxious stimuli, but not by alterations in emotional states. Pain responses in STN neurons were attenuated in both naïve and SNI mice when ACC neurons were inhibited. Furthermore, optogenetic activation of the ACC-STN pathway induced bilateral hyperalgesia and depression-like behaviors in naive mice; conversely, inhibition of this pathway is sufficient to attenuate hyperalgesia and depression-like behaviors in SNI mice and naïve mice subjected to stimulation of STN neurons. Finally, mitigation of pain-like and depression-like behaviors in SNI mice by inhibition of the ACC-STN projection was eliminated by activation of STN neurons. Our results demonstrate that hyperactivity in the ACC-STN pathway may be an important pathophysiology in comorbid chronic pain and depression. Thus, the ACC-STN pathway may be an intervention target for the treatment of the comorbid chronic pain and depression.

How is helping behavior regulated in the brain?

In humans and other animals, individuals can actively respond to the specific needs of others. However, the neural circuits supporting helping behaviors are underspecified. In recent work, Zhang, Wu, and colleagues identified a new role for the anterior cingulate cortex (ACC) in the encoding and regulation of targeted helping behavior (allolicking) in mice.

Bilingual Language Control in the Brain: Evidence from Structural and Effective Functional Brain Connectivity.

Experience in bilingual language control is often accompanied by changes in the structure and function of the brain. Brain structural changes are also often closely related to changes in functions. Previous studies, however, have not directly explored the relationship between structural connectivity and effective functional connectivity of the brain during bilingual language control, and whether the two types of connectivity are associated with behavioral performance of language control. Using behavioral performance, functional, and diffusion imaging techniques, we found that: (1) during language control, the left dorsal lateral prefrontal cortex (dlPFC), left caudate nucleus (CN), inferior parietal lobe, precuneus, and dorsal anterior cingulate cortex (dACC)/pre-SMA were significantly activated. (2) In the language control model with left dlPFC, dACC/pre-SMA, and left CN as ROIs (selected based on activation results and language control models from previous studies), stimuli first enter dACC/pre-SMA and then to left CN. At the left CN, a bidirectional effective connectivity is formed with left dlPFC. (3) There is a nonlinear relationship between effective connectivity during language control and the structural connectivity of the second language learners' brains. Specifically, the fiber density between dACC/pre-SMA and left dlPFC has a positive influence on the bidirectional effective connectivity between left dlPFC and left CN. Findings of the present study contribute evidence toward functional effective connectivity during bilingual language control; toward structural connectivity in the brains of second language learners; as well as toward nonlinear relationships between functional effective connectivity, structural connectivity, and behavioral performance in relation to bilingual language control.

Cortical signatures of sleep are altered following effective deep brain stimulation for depression.

Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) is an experimental therapy for treatment-resistant depression (TRD). Chronic SCC DBS leads to long-term changes in the electrophysiological dynamics measured from local field potential (LFP) during wakefulness, but it is unclear how it impacts sleep-related brain activity. This is a crucial gap in knowledge, given the link between depression and sleep disturbances, and an emerging interest in the interaction between DBS, sleep, and circadian rhythms. We therefore sought to characterize changes in electrophysiological markers of sleep associated with DBS treatment for depression. We analyzed key electrophysiological signatures of sleep-slow-wave activity (SWA, 0.5-4.5 Hz) and sleep spindles-in LFPs recorded from the SCC of 9 patients who responded to DBS for TRD. This allowed us to compare the electrophysiological changes before and after 24 weeks of therapeutically effective SCC DBS. SWA power was highly correlated between hemispheres, consistent with a global sleep state. Furthermore, SWA occurred earlier in the night after chronic DBS and had a more prominent peak. While we found no evidence for changes to slow-wave power or stability, we found an increase in the density of sleep spindles. Our results represent a first-of-its-kind report on long-term electrophysiological markers of sleep recorded from the SCC in patients with TRD, and provides evidence of earlier NREM sleep and increased sleep spindle activity following clinically effective DBS treatment. Future work is needed to establish the causal relationship between long-term DBS and the neural mechanisms underlying sleep.

The brain's go-getter circuit: Anterior cingulate cortex to nucleus accumbens and its disruption by stress.

In this issue of Neuron, Fetcho, Parekh, et al.1 show that neurons in the anterior cingulate cortex (ACC) projecting to the nucleus accumbens (NAc) are essential for integrating reward and effort evaluation in mice, and that this circuit is sensitive to exposure to stress hormones.

Inter-individual, hemispheric and sex variability of brain activations during numerosity processing.

Numerosity perception is a fundamental and innate cognitive function shared by both humans and many animal species. Previous research has primarily focused on exploring the spatial and functional consistency of neural activations that were associated with the processing of numerosity information. However, the inter-individual variability of brain activations of numerosity perception remains unclear. In the present study, with a large-sample functional magnetic resonance imaging (fMRI) dataset (n = 460), we aimed to localize the functional regions related to numerosity perceptions and explore the inter-individual, hemispheric, and sex differences within these brain regions. Fifteen subject-specific activated regions, including the anterior intraparietal sulcus (aIPS), posterior intraparietal sulcus (pIPS), insula, inferior frontal gyrus (IFG), inferior temporal gyrus (ITG), premotor area (PM), middle occipital gyrus (MOG) and anterior cingulate cortex (ACC), were delineated in each individual and then used to create a functional probabilistic atlas to quantify individual variability in brain activations of numerosity processing. Though the activation percentages of most regions were higher than 60%, the intersections of most regions across individuals were considerably lower, falling below 50%, indicating substantial variations in brain activations related to numerosity processing among individuals. Furthermore, significant hemispheric and sex differences in activation location, extent, and magnitude were also found in these regions. Most activated regions in the right hemisphere had larger activation volumes and activation magnitudes, and were located more lateral and anterior than their counterparts in the left hemisphere. In addition, in most of these regions, males displayed stronger activations than females. Our findings demonstrate large inter-individual, hemispheric, and sex differences in brain activations related to numerosity processing, and our probabilistic atlas can serve as a robust functional and spatial reference for mapping the numerosity-related neural networks.

Cortical regulation of helping behaviour towards others in pain.

Humans and animals exhibit various forms of prosocial helping behaviour towards others in need1-3. Although previous research has investigated how individuals may perceive others' states4,5, the neural mechanisms of how they respond to others' needs and goals with helping behaviour remain largely unknown. Here we show that mice engage in a form of helping behaviour towards other individuals experiencing physical pain and injury-they exhibit allolicking (social licking) behaviour specifically towards the injury site, which aids the recipients in coping with pain. Using microendoscopic imaging, we found that single-neuron and ensemble activity in the anterior cingulate cortex (ACC) encodes others' state of pain and that this representation is different from that of general stress in others. Furthermore, functional manipulations demonstrate a causal role of the ACC in bidirectionally controlling targeted allolicking. Notably, this behaviour is represented in a population code in the ACC that differs from that of general allogrooming, a distinct type of prosocial behaviour elicited by others' emotional stress. These findings advance our understanding of the neural coding and regulation of helping behaviour.