Cingulate microstimulation induces negative decision-making via reduced top-down influence on primate fronto-cingulo-striatal network.

The dorsolateral prefrontal cortex (dlPFC) is crucial for regulation of emotion that is known to aid prevention of depression. The broader fronto-cingulo-striatal (FCS) network, including cognitive dlPFC and limbic cingulo-striatal regions, has been associated with a negative evaluation bias often seen in depression. The mechanism by which dlPFC regulates the limbic system remains largely unclear. Here we have successfully induced a negative bias in decision-making in female primates performing a conflict decision-making task, by directly microstimulating the subgenual cingulate cortex while simultaneously recording FCS local field potentials (LFPs). The artificially induced negative bias in decision-making was associated with a significant decrease in functional connectivity from cognitive to limbic FCS regions, represented by a reduction in Granger causality in beta-range LFPs from the dlPFC to the other regions. The loss of top-down directional influence from cognitive to limbic regions, we suggest, could underlie negative biases in decision-making as observed in depressive states.

Neuromodulation of inhibitory control using phase-lagged transcranial alternating current stimulation.

BACKGROUND: Transcranial alternating current stimulation (tACS) is a prominent non-invasive brain stimulation method for modulating neural oscillations and enhancing human cognitive function. This study aimed to investigate the effects of individualized theta tACS delivered in-phase and out-of-phase between the dorsal anterior cingulate cortex (dACC) and left dorsolateral prefrontal cortex (lDLPFC) during inhibitory control performance. METHODS: The participants engaged in a Stroop task with phase-lagged theta tACS over individually optimized high-density electrode montages targeting the dACC and lDLPFC. We analyzed task performance, event-related potentials, and prestimulus electroencephalographic theta and alpha power. RESULTS: We observed significantly reduced reaction times following out-of-phase tACS, accompanied by reduced frontocentral N1 and N2 amplitudes, enhanced parieto-occipital P1 amplitudes, and pronounced frontocentral late sustained potentials. Out-of-phase stimulation also resulted in significantly higher prestimulus frontocentral theta and alpha activity. CONCLUSIONS: These findings suggest that out-of-phase theta tACS potently modulates top-down inhibitory control, supporting the feasibility of phase-lagged tACS to enhance inhibitory control performance.

Interoceptive training impacts the neural circuit of the anterior insula cortex.

Interoception is the perception of afferent information that arises from anywhere and everywhere within the body. Recently, interoceptive accuracy could be enhanced by cognitive training. Given that the anterior insula cortex (AIC) is a key node of interoception, we hypothesized that resting functional connectivity (RSFC) from AIC was involved in an effect of interoceptive training. To address this issue, we conducted a longitudinal intervention study using interoceptive training and obtained RSFC using fMRI before and after the intervention. A heartbeat perception task evaluated interoceptive accuracy. Twenty-two healthy volunteers (15 females, age 19.9 ± 2.0 years) participated. After the intervention, interoceptive accuracy was enhanced, and anxiety levels and somatic symptoms were reduced. Also, RSFC from AIC to the dorsolateral prefrontal cortex (DLPFC), superior marginal gyrus (SMG), anterior cingulate cortex (ACC), and brain stem, including nucleus tractus solitarius (NTS) were enhanced, and those from AIC to the visual cortex (VC) were decreased according to enhanced interoceptive accuracy. The neural circuit of AIC, ACC, and NTS is involved in the bottom-up process of interoception. The neural circuit of AIC, DLPFC, and SMG is involved in the top-down process of interoception, which was thought to represent the cognitive control of emotion. The findings provided a better understanding of neural underpinnings of the effect of interoceptive training on somatic symptoms and anxiety levels by enhancing both bottom-up and top-down processes of interoception, which has a potential contribution to the structure of psychotherapies based on the neural mechanism of psychosomatics.

The neurocomputational link between defensive cardiac states and approach-avoidance arbitration under threat.

Avoidance, a hallmark of anxiety-related psychopathology, often comes at a cost; avoiding threat may forgo the possibility of a reward. Theories predict that optimal approach-avoidance arbitration depends on threat-induced psychophysiological states, like freezing-related bradycardia. Here we used model-based fMRI analyses to investigate whether and how bradycardia states are linked to the neurocomputational underpinnings of approach-avoidance arbitration under varying reward and threat magnitudes. We show that bradycardia states are associated with increased threat-induced avoidance and more pronounced reward-threat value comparison (i.e., a stronger tendency to approach vs. avoid when expected reward outweighs threat). An amygdala-striatal-prefrontal circuit supports approach-avoidance arbitration under threat, with specific involvement of the amygdala and dorsal anterior cingulate (dACC) in integrating reward-threat value and bradycardia states. These findings highlight the role of human freezing states in value-based decision making, relevant for optimal threat coping. They point to a specific role for amygdala/dACC in state-value integration under threat.

Brain activity during Stroop task performance at age 74 after exposure to the Dutch famine during early gestation.

OBJECTIVE: Poorer performance on the Stroop task has been reported after prenatal famine exposure at age 58, potentially indicating cognitive decline. We investigated whether brain activation during Stroop task performance at age 74 differed between individuals exposed to famine prenatally, individuals born before and individuals conceived after the famine. METHOD: In the Dutch famine birth cohort, we performed a Stroop task fMRI study of individuals exposed (n = 22) or unexposed (born before (n = 18) or conceived after (n = 25)) to famine in early gestation. We studied group differences in task-related mean activation of the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC) and posterior parietal cortex (PPC). Additionally, we explored potential disconnectivity of the DLPFC using psychophysiological interaction analysis. RESULTS: We observed similar activation patterns in the DLPFC, ACC and PPC in individuals born before and individuals exposed to famine, while individuals conceived after famine had generally higher activation patterns. However, activation patterns were not significantly different between groups. Task-related decreases in connectivity were observed between left DLPFC-left PPC and right DLPFC-right PPC, but were not significantly different between groups. CONCLUSIONS: Although not statistically significant, the observed patterns of activation may reflect a combined effect of general brain aging and prenatal famine exposure.

The anterior cingulate cortex is involved in intero-exteroceptive integration for spatial image transformation of the self-body.

Spatial image transformation of the self-body is a fundamental function of visual perspective-taking. Recent research underscores the significance of intero-exteroceptive information integration to construct representations of our embodied self. This raises the intriguing hypothesis that interoceptive processing might be involved in the spatial image transformation of the self-body. To test this hypothesis, the present study used functional magnetic resonance imaging to measure brain activity during an arm laterality judgment (ALJ) task. In this task, participants were tasked with discerning whether the outstretched arm of a human figure, viewed from the front or back, was the right or left hand. The reaction times for the ALJ task proved longer when the stimulus presented orientations of 0°, 90°, and 270° relative to the upright orientation, and when the front view was presented rather than the back view. Reflecting the increased reaction time, increased brain activity was manifested in a cluster centered on the dorsal anterior cingulate cortex (ACC), suggesting that the activation reflects the involvement of an embodied simulation in ALJ. Furthermore, this cluster of brain activity exhibited overlap with regions where the difference in activation between the front and back views positively correlated with the participants' interoceptive sensitivity, as assessed through the heartbeat discrimination task, within the pregenual ACC. These results suggest that the ACC plays an important role in integrating intero-exteroceptive cues to spatially transform the image of our self-body.

Spatiotemporal brain hierarchies of auditory memory recognition and predictive coding.

Our brain is constantly extracting, predicting, and recognising key spatiotemporal features of the physical world in order to survive. While neural processing of visuospatial patterns has been extensively studied, the hierarchical brain mechanisms underlying conscious recognition of auditory sequences and the associated prediction errors remain elusive. Using magnetoencephalography (MEG), we describe the brain functioning of 83 participants during recognition of previously memorised musical sequences and systematic variations. The results show feedforward connections originating from auditory cortices, and extending to the hippocampus, anterior cingulate gyrus, and medial cingulate gyrus. Simultaneously, we observe backward connections operating in the opposite direction. Throughout the sequences, the hippocampus and cingulate gyrus maintain the same hierarchical level, except for the final tone, where the cingulate gyrus assumes the top position within the hierarchy. The evoked responses of memorised sequences and variations engage the same hierarchical brain network but systematically differ in terms of temporal dynamics, strength, and polarity. Furthermore, induced-response analysis shows that alpha and beta power is stronger for the variations, while gamma power is enhanced for the memorised sequences. This study expands on the predictive coding theory by providing quantitative evidence of hierarchical brain mechanisms during conscious memory and predictive processing of auditory sequences.

Modulation of hippocampal theta oscillations via deep brain stimulation of the parietal cortex depends on cognitive state.

The angular gyrus (AG) and posterior cingulate cortex (PCC) demonstrate extensive structural and functional connectivity with the hippocampus and other core recollection network regions. Consequently, recent studies have explored neuromodulation targeting these and other regions as a potential strategy for restoring function in memory disorders such as Alzheimer's Disease. However, determining the optimal approach for neuromodulatory devices requires understanding how parameters like selected stimulation site, cognitive state during modulation, and stimulation duration influence the effects of deep brain stimulation (DBS) on electrophysiological features relevant to episodic memory. We report experimental data examining the effects of high-frequency stimulation delivered to the AG or PCC on hippocampal theta oscillations during the memory encoding (study) or retrieval (test) phases of an episodic memory task. Results showed selective enhancement of anterior hippocampal slow theta oscillations with stimulation of the AG preferentially during memory retrieval. Conversely, stimulation of the PCC attenuated slow theta oscillations. We did not observe significant behavioral effects in this (open-loop) stimulation experiment, suggesting that neuromodulation strategies targeting episodic memory performance may require more temporally precise stimulation approaches.

Organization of corticocortical and thalamocortical top-down inputs in the primary visual cortex.

Unified visual perception requires integration of bottom-up and top-down inputs in the primary visual cortex (V1), yet the organization of top-down inputs in V1 remains unclear. Here, we used optogenetics-assisted circuit mapping to identify how multiple top-down inputs from higher-order cortical and thalamic areas engage V1 excitatory and inhibitory neurons. Top-down inputs overlap in superficial layers yet segregate in deep layers. Inputs from the medial secondary visual cortex (V2M) and anterior cingulate cortex (ACA) converge on L6 Pyrs, whereas ventrolateral orbitofrontal cortex (ORBvl) and lateral posterior thalamic nucleus (LP) inputs are processed in parallel in Pyr-type-specific subnetworks (Pyr←ORBvl and Pyr←LP) and drive mutual inhibition between them via local interneurons. Our study deepens understanding of the top-down modulation mechanisms of visual processing and establishes that V2M and ACA inputs in L6 employ integrated processing distinct from the parallel processing of LP and ORBvl inputs in L5.

Dynamical and individualised approach of transcranial ultrasound neuromodulation effects in non-human primates.

Low-frequency transcranial ultrasound stimulation (TUS) allows to alter brain functioning with a high spatial resolution and to reach deep targets. However, the time-course of TUS effects remains largely unknown. We applied TUS on three brain targets for three different monkeys: the anterior medial prefrontal cortex, the supplementary motor area and the perigenual anterior cingulate cortex. For each, one resting-state fMRI was acquired between 30 and 150 min after TUS as well as one without stimulation (control). We captured seed-based brain connectivity changes dynamically and on an individual basis. We also assessed between individuals and between targets homogeneity and brain features that predicted TUS changes. We found that TUS prompts heterogenous functional connectivity alterations yet retain certain consistent changes; we identified 6 time-courses of changes including transient and long duration alterations; with a notable degree of accuracy we found that brain alterations could partially be predicted. Altogether, our results highlight that TUS induces heterogeneous functional connectivity alterations. On a more technical point, we also emphasize the need to consider brain changes over-time rather than just observed during a snapshot; to consider inter-individual variability since changes could be highly different from one individual to another.

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.

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.

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.

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.

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.

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.

Optogenetic Inhibition of Rat Anterior Cingulate Cortex Impairs the Ability to Initiate and Stay on Task.

Our prior research has identified neural correlates of cognitive control in the anterior cingulate cortex (ACC), leading us to hypothesize that the ACC is necessary for increasing attention as rats flexibly learn new contingencies during a complex reward-guided decision-making task. Here, we tested this hypothesis by using optogenetics to transiently inhibit the ACC, while rats of either sex performed the same two-choice task. ACC inhibition had a profound impact on behavior that extended beyond deficits in attention during learning when expected outcomes were uncertain. We found that ACC inactivation slowed and reduced the number of trials rats initiated and impaired both their accuracy and their ability to complete sessions. Furthermore, drift-diffusion model analysis suggested that free-choice performance and evidence accumulation (i.e., reduced drift rates) were degraded during initial learning-leading to weaker associations that were more easily overridden in later trial blocks (i.e., stronger bias). Together, these results suggest that in addition to attention-related functions, the ACC contributes to the ability to initiate trials and generally stay on task.

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.

Mapping Early Brain-Body Interactions: Associations of Fetal Heart Rate Variation with Newborn Brainstem, Hypothalamic, and Dorsal Anterior Cingulate Cortex Functional Connectivity.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal ANS development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with postbirth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic, and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks of gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40 and 46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower- and higher-order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants.

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.