Insular Cortex Research Articles

Food insecurity and adolescent impulsivity: The mediating role of functional connectivity in the context of family flexibility.

Adolescent food insecurity is a salient adversity hypothesized to affect neural systems associated with increased impulsive behavior. Family environments shape how adverse experiences influence development. In this study, hypotheses were tested regarding the conjoint effects of food insecurity and family flexibility on impulsivity via alterations in connectivity between regions within the salience and central executive networks. Such alterations are reflected in resting-state functional connectivity (rsFC) metrics between the anterior insula (AI) and the middle frontal gyrus (MFG). Hypotheses were tested in a longitudinal moderated mediation model with two waves of data from 142 adolescents (Time 1 [T1] Mage = 12.89, SD=0.85; Time 2 [T2] Mage = 15.01, SD=1.07). Data on past-year household food insecurity, family flexibility, and rsFC were obtained at T1. Impulsivity was self-reported by the adolescent at T1 and T2. Findings revealed that high T1 left-to-left rsFC between the AI and MFG was associated with increased impulsivity at T2. The interaction of family flexibility and food insecurity was associated with AI and MFG rsFC. In the context of low family flexibility, food insecurity was linked to high levels of AI and MFG rsFC. Conversely, in the context of optimal family flexibility, food insecurity was associated with low levels of AI and MFG rsFC. Conditional indirect analysis suggests that the links among food insecurity, rsFC, and impulsive behavior depend on family flexibility. RESEARCH HIGHLIGHTS: Adolescent food insecurity was associated with anterior insula and middle frontal gyrus connectivity only at certain levels of family flexibility. High family flexibility attenuated the link between food insecurity and neural connectivity, while low levels of family flexibility increased this risk. High left anterior insula and left middle frontal gyrus connectivity was associated with increased impulsivity 1 year later.

Evaluation of registration-based vs. manual segmentation of rhesus macaque brain MRIs.

With increasing numbers of magnetic resonance imaging (MRI) datasets becoming publicly available, researchers and clinicians alike have turned to automated methods of segmentation to enable population-level analyses of these data. Although prior research has evaluated the extent to which automated methods recapitulate "gold standard" manual segmentation methods in the human brain, such an evaluation has not yet been carried out for segmentation of MRIs of the macaque brain. Macaques offer the important opportunity to bridge gaps between microanatomical studies using invasive methods like tract tracing, neural recordings, and high-resolution histology and non-invasive macroanatomical studies using methods like MRI. As such, it is important to evaluate whether automated tools derive data of sufficient quality from macaque MRIs to bridge these gaps. We tested the relationship between automated registration-based segmentation using an open source and actively maintained NHP imaging analysis pipeline (AFNI) and gold standard manual segmentation of 4 structures (2 cortical: anterior cingulate cortex and insula; 2 subcortical: amygdala and caudate) across 37 rhesus macaques (Macaca mulatta). We identified some variability in the strength of correlation between automated and manual segmentations across neural regions and differences in relationships with demographic variables like age and sex between the two techniques.

Stress-induced cortisol response predicts empathy for pain: The role of task-based connectivity between the insula and sensorimotor cortex during acute stress

Empathy for pain is a key driver of prosocial behavior and is influenced by acute psychosocial stress. However, the role of task-based brain connectivity during acute stress have been neglected. Hence, we aimed to explore the relationship between the magnitude of cortisol response to acute stress and empathy for pain, as well as the neural connectivity mechanisms involved. In this study, 80 healthy participants (37 women and 43 men) were exposed to the acute psychosocial stress paradigm (ScanSTRESS) and were scanned by functional magnetic resonance imaging. Saliva samples were collected to measure the magnitude of cortisol stress response. Subsequently, the participants took part in a pain-video task to assess their empathy for pain. Six participants were excluded because of physical discomfort or excessive head movement in all runs during the task-dependent fMRI scan. Therefore, 33 women and 41 men were included in data analysis. We found that empathy for pain was negatively correlated with the magnitude of cortisol stress response (r = -0.268, p = 0.018) and that the task-based connectivity between the salience network and sensorimotor network, including its sub-network and sub-region, was negatively correlated with the magnitude of cortisol stress response, and positively correlated with empathy for pain. Furthermore, task-based connectivity between the insula and the paracentral lobule mediates the effect of the stress-induced cortisol response on empathy for pain (indirect effect = -0.0152, 95% CI = [- 0.036, -0.001], p = 0.036). Our research suggests that empathy is not only correlated with stress-induced glucocorticoids but also tied to the stress-induced reduced communication between basic and higher brain regions.

Mapping common and distinct brain correlates among cognitive flexibility tasks: concordant evidence from meta-analyses.

Cognitive flexibility allows individuals to switch between different tasks, strategies, or ideas; an ability that is important for everyday life. The Wisconsin card sorting test (WCST) and task switching paradigm (TSP) are popular measures of cognitive flexibility. Although both tasks require switching, the TSP requires participants to memorize switching rules and retrieve them when they view a cue (rule-retrieval), whereas the classic WCST requires participants to discover the switching rule via trial-and-error (rule-discovery). Many functional magnetic resonance imaging studies have examined brain responses to these tasks. Extant meta-analyses show concordance in activation in a widespread set of areas including frontal, parietal, and cingulate cortices. Critically, past meta-analyses have not specifically examined brain correlates associated with rule derivation (i.e., rule-discovery vs. rule-retrieval) in cognitive flexibility tasks. We examine for the first time common and distinct concordance in brain responses to rule-discovery (i.e., WCST) and rule-retrieval (i.e., TSP), as well as TSP subtypes using quantitative meta-analyses. We analyzed data from 69 eligible articles with a total of 1617 young-adult participants. Conjunction results show concordance in common fronto-parietal areas predominantly in the left hemisphere. Contrast analyses show that rule-discovery required increased involvement in multiple cortical and subcortical regions such as frontopolar (Brodmann Area 10), parietal, insular cortex, thalamus and caudate nucleus predominantly in the right hemisphere. No significant differences in concordance were observed among the three, task switching paradigm sub-types. We propose a neuroanatomical model of cognitive flexibility and discuss theoretical and practical applications.

Longitudinal evidence for a mutually reinforcing relationship between white matter hyperintensities and cortical thickness in cognitively unimpaired older adults

BackgroundFor over three decades, the concomitance of cortical neurodegeneration and white matter hyperintensities (WMH) has sparked discussions about their coupled temporal dynamics. Longitudinal studies supporting this hypothesis nonetheless remain scarce.MethodsWe applied global and regional bivariate latent growth curve modelling to determine the extent to which WMH and cortical thickness were interrelated over a four-year period. For this purpose, we leveraged longitudinal MRI data from 451 cognitively unimpaired participants (DELCODE; median age 69.71 [IQR 65.51, 75.50] years; 52.32% female). Participants underwent MRI sessions annually over a four-year period (1815 sessions in total, with roughly four MRI sessions per participant). We adjusted all models for demographics and cardiovascular risk.ResultsOur findings were three-fold. First, larger WMH volumes were linked to lower cortical thickness (σ = -0.165, SE = 0.047, Z = -3.515, P < 0.001). Second, individuals with higher WMH volumes experienced more rapid cortical thinning (σ = -0.226, SE = 0.093, Z = -2.443, P = 0.007), particularly in temporal, cingulate, and insular regions. Similarly, those with lower initial cortical thickness had faster WMH progression (σ = -0.141, SE = 0.060, Z = -2.336, P = 0.009), with this effect being most pronounced in temporal, cingulate, and insular cortices. Third, faster WMH progression was associated with accelerated cortical thinning (σ = -0.239, SE = 0.139, Z = -1.710, P = 0.044), particularly in frontal, occipital, and insular cortical regions.ConclusionsOur study suggests that cortical thinning and WMH progression could be mutually reinforcing rather than parallel, unrelated processes, which become entangled before cognitive deficits are detectable.Trial registrationGerman Clinical Trials Register (DRKS00007966, 04/05/2015).

Causal relationships between cortical brain structural alterations and migraine subtypes: a bidirectional Mendelian randomization study of 2,347 neuroimaging phenotypes

BackgroundPrevious studies have shown that migraines are associated with brain structural changes. However, the causal relationships between these changes and migraine, as well as its subtypes, migraine with aura (MA) and migraine without aura (MO), remain largely unclear.MethodsWe utilized genome-wide association study (GWAS) summary statistics from European cohorts for 2,347 cortical structural magnetic resonance imaging (MRI) phenotypes, derived from both T1-weighted and diffusion tensor imaging scans (n = 36,663), with migraine and its subtypes (n = 147,970–375,752). Cortical phenotypes included both macrostructural (e.g., cortical thickness, surface area) and microstructural (e.g., fractional anisotropy, mean diffusivity) features. Genetic correlations were first assessed to identify significant associations, followed by bidirectional Mendelian randomization (MR) analyses to determine causal relationships between these brain phenotypes and migraine, as well as its subtypes (MA and MO). Sensitivity analyses were applied to ensure the robustness of the results.ResultsGenetic correlation analysis identified 510 significant associations between cortical structural phenotypes and migraine across 401 distinct traits. Forward MR analysis revealed nine significant causal effects of cortical structural changes on migraine risk. Specifically, increased cortical thickness and local gyrification index in specific cortical regions were associated with a decreased risk of overall migraine, MA, and MO, while intracellular volume fraction and orientation diffusion index in specific regions increased the risk of MA and MO. Reverse MR analysis demonstrated that MA causally increased mean diffusivity in the insular and frontal opercular cortex. Sensitivity analyses confirmed the robustness of these findings, with no evidence of horizontal pleiotropy or heterogeneity.ConclusionThis study identifies causal relationships between cortical neuroimaging phenotypes and migraine, highlighting potential biomarkers for migraine diagnosis, treatment, and prevention.

Dissecting neural correlates of theory of mind and executive functions in behavioral variant frontotemporal dementia

Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

Endogenous opioid receptor system mediates costly altruism in the human brain

Functional neuroimaging studies suggest that a large-scale brain network transforms others’ pain into its vicarious representation in the observer, potentially modulating helping behavior. However, the neuromolecular basis of individual differences in vicarious pain and helping is poorly understood. We investigated the role of the endogenous μ-opioid receptor (MOR) system in altruistic costly helping. MOR density was measured using [11C]carfentanil. In a separate fMRI experiment, participants could donate money to reduce a confederate’s pain from electric shocks. Participants were generally willing to help, and brain activity was observed in amygdala, anterior insula, anterior cingulate cortex (ACC), striatum, primary motor cortex, primary somatosensory cortex and thalamus when witnessing others’ pain. Haemodynamic responses were negatively associated with MOR availability in emotion circuits. However, MOR availability positively associated with the ACC and hippocampus during helping. These findings suggest that the endogenous MOR system modulates altruism in the human brain.

Music in the Air and in the Body: An Interoceptive System's Perspective on Musical Emotions, Awareness, and Time.

Performing and perceiving music requires the integration of multimodal information, including sensations of one's own body. Research on musical engagement investigated emotional responses and the peripheral physiological activations involved, as well as bodily action tendencies, effects on time perception, and the role of awareness and focus of attention. The concept of interoception dedicates a central role to the insular cortex, as suggested by Craig and others, and offers a unifying framework for studying music as an activity that has always had a key role for individuals, groups, societies, with a strong bodily component. Chances and challenges of an interoceptive perspective on music are discussed.

Insights from Ecstatic Epilepsy: From Uncertainty to Metacognitive Feelings.

Ecstatic epilepsy is a rare form of focal epilepsy linked to the anterior insula in which patients experience a blissful state with a unique set of symptoms, including a feeling of physical well-being, mental clarity, a sense of oneness with the universe, and time dilation. In this chapter, we reflect on how these symptoms coincide with our current knowledge of the insula's functions and explore how this stunning natural model can further inform our understanding of the insula's role in the sentient self, uncertainty and surprise monitoring, and metacognitive feelings.

Characteristics of Functional Connections and Topographical Properties Distinguished the Healthy State and Obsessive-Compulsive Disorder

Background: Obsessive-compulsive disorder (OCD) is characterized by alterations in brain connectivity, particularly within the default mode network (DMN) and the salience network (SN). Investigating these connectivity differences can provide a deeper understanding of the neural mechanisms underlying OCD. Methods: This cross-sectional study involved 58 patients diagnosed with OCD and 38 healthy control subjects, totaling 96 participants. Resting-state functional MRI (fMRI) data were acquired and analyzed using the CONN toolbox to examine functional connectivity within intrinsic resting-state networks. Graph theory metrics were applied to evaluate node connections and the overall network topology. Clinical symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and their correlations with connectivity patterns and graph-theory parameters were analyzed. Results: The OCD patients and healthy controls were matched in terms of age, gender, marital status, socioeconomic status, and handedness. However, OCD patients had significantly worse general health, quality of life, and higher levels of depression and anxiety. Network analyses revealed altered whole-brain connectivity in OCD patients, particularly within the DMN and the frontoparietal network. The most significant between-group connectivity differences were observed between the posterior parietal cortex (PPC) and the precuneus. Disruptions in the DMN, specifically altered connectivity between the medial prefrontal cortex and posterior cingulate cortex, and changes in the SN involving the anterior insula and anterior cingulate cortex, were significantly correlated with the severity of OCD symptoms. Conclusions: The findings suggest that OCD is associated with distinct alterations in DMN connectivity, which may play a critical role in the disorder's pathophysiology. These disruptions offer potential targets for therapeutic intervention. Further research is needed to explore these connectivity changes in larger cohorts and at various stages of OCD to better understand their clinical significance.

Elucidating the neuropathological and molecular heterogeneity of amyloid-beta and tau in Alzheimer's disease through machine learning and transcriptomic integration.

Discerning functional brain network variations related to neuropathological aggregates in Alzheimer's disease (AD), including amyloid-beta (Abeta) and phosphorylated tau (p-tau), is crucial for understanding their link to cognitive decline and underlying molecular mechanisms. However, these variations are often confounded by normal aging-related changes, complicating interpretation. To address this challenge, we first defined Alzheimer's continuum cases (Abeta positive (A+), n = 129) and normal elderly (Abeta negative (A-), n = 160) using cerebral spinal fluid amyloid levels, and then applied a novel deep learning approach to resting-state connectivity using functional magnetic resonance imaging (fMRI) of the 289 subjects to disentangle A+-specific dimensions in brain network alterations from those shared with A- individuals. The identified A+-specific dimensions were further refined to predict individual Abeta and p-tau levels separately. We observed that resulting brain signatures, defined from A+-specific dimensions for predicting these two CSF biomarkers, were both attributed to the right superior temporal and anterior cingulate cortices and associated with attention and memory domains. When linking the brain signatures to gene expression data from a public transcriptomic atlas, we found that the brain signatures were associated with molecular pathways involving synaptic dysfunction and disruptions in pathways containing activity of excitatory neurons, astrocytes, and microglia. For A--shared dimensions, the Aβ-linked brain signature involved the left fusiform and right middle cingulate cortices, correlating with the language cognitive measurement and language-related molecular pathways. The p-tau-linked signature predominantly involved the right insula and inferior temporal cortices, correlating with the aging-related molecular pathways. Collectively, our findings provided new insights in understanding of Alzheimer's continuum pathological biomarkers.

The Role of the Insular Cortex and Serotonergic System in the Modulation of Long-Lasting Nociception.

The insular cortex (IC) is a brain region that both receives relevant sensory information and is responsible for emotional and cognitive processes, allowing the perception of sensory information. The IC has connections with multiple sites of the pain matrix, including cortico-cortical interactions with the anterior cingulate cortex (ACC) and top-down connections with sites of descending pain inhibition. We explored the changes in the extracellular release of serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), after inflammation was induced by carrageenan injection. Additionally, we explored the role of 5HT receptors (the 5HT1A, 5HT2A, and 5HT3 receptors) in the IC after inflammatory insult. The results showed an increase in the extracellular levels of 5HT and 5-HIAA during the inflammatory process compared to physiological levels. Additionally, the 5HT1A receptor was overexpressed. Finally, the 5HT1A, 5HT2A, and 5HT3 receptor blockade in the IC had antinociceptive effects. Our results highlight the role of serotonergic neurotransmission in long-lasting inflammatory nociception within the IC.

Functional connectivity in complex regional pain syndrome: A bicentric study

Brain imaging studies in complex regional pain syndrome (CRPS) have found mixed evidence for functional and structural changes in CRPS. In this cross-sectional study, we evaluated two patient cohorts from different centers and examined functional connectivity (rsFC) in 51 CRPS patients and 50 matched controls. rsFC was compared in predefined ROI pairs, but also in non-hypothesis driven analyses. Resting state (rs)fMRI changes in default mode network (DMN) and the degree rank order disruption index (kD) were additionally evaluated. Finally, imaging parameters were correlated with clinical severity and somatosensory function. Among predefined pairs, we found only weakly to moderately lower functional connectivity between the right nucleus accumbens and bilateral ventromedial prefrontal cortex in the infra-slow oscillations (ISO) band. The unconstrained ROI-to-ROI analysis revealed lower rsFC between the periaqueductal gray matter (PAG) and left anterior insula, and higher rsFC between the right sensorimotor thalamus and nucleus accumbens. In the correlation analysis, pain was positively associated with insulo-prefrontal rsFC, whereas sensorimotor thalamo-cortical rsFC was positively associated with tactile spatial resolution of the affected side. In contrast to previous reports, we found no group differences for kD or rsFC in the DMN, but detected overall lower data quality in patients. In summary, while some of the previous results were not replicated despite the larger sample size, novel findings from two independent cohorts point to potential down-regulated antinociceptive modulation by the PAG and increased connectivity within the reward system as pathophysiological mechanisms in CRPS. However, in light of the detected systematic differences in data quality between patients and healthy subjects, validity of rsFC abnormalities in CRPS should be carefully scrutinized in future replication studies.

A chronometric relationship between circuits underlying learning and error monitoring in the basal ganglia and salience network

Abstract Healthy individuals readily adjust their behaviour in response to errors using learning mechanisms. This raises the question of how error-related neural mechanisms underlie the learning process and its progress. In this study, 21 healthy participants performed a challenging functional magnetic resonance imaging (fMRI) task to answer this question. We assessed the evolution of error-related neural response as a function of learning progress. We tested the hypothesis that the dorsal anterior cingulate cortex (dACC) and anterior insula, key regions of the error monitoring neural circuitry, reflect both the performance of an action and its improvement. Given the nature of trial-and-error learning, we also expected an involvement of the striatum, particularly the putamen. We found that error-related neural activity (in the dACC and anterior insula) was similar following correct responses and errors in an initial learning period. However, as learning progressed, the activity continuously decreased in response to correct events and increased after errors. In opposition, during the initial learning phase, the putamen activity was modulated by errors, but, as it progressed, this region became unaffected by response outcomes. In sum, our study provides neural evidence for an interaction between the mechanisms underlying error monitoring and learning, contributing to clarifying how error-related neural responses evolve with learning.

Structural projections to the Nucleus Accumbens link to impulsive components of human risk preference

Abstract Functional responses in the Nucleus Accumbens (NAcc) to risk- and reward-related cues can predict real-life risk-taking behavior. Since NAcc activity depends on neurotransmission from connected brain regions, projections to the NAcc may also predict risk preference. To quantify risk preference, we employed latent variables previously derived in a comprehensive, independent study examining the psychometric structure of risk preference, which yielded a general risk preference factor as well as several specific factors, including a factor capturing impulsivity. Informed by previous work, we preregistered a set of hypotheses concerning the association between different risk preference factors and fractional anisotropy (or FA, which is sensitive to fiber coherence) for projections to the NAcc from Medial PreFrontal Cortex (MPFC), Anterior Insula, Amygdala, and an inferior tract from the Ventral Tegmental Area (iVTA). We tested our hypotheses in a community sample of 125 healthy human adults. As predicted, bilateral iVTA-NAcc tract FA showed a negative correlation with a psychometric factor that captured impulsivity, generalizing findings from prior research. Also as predicted, FA of the bilateral Amygdala-NAcc tract was positively associated with the impulsivity factor. Contrary to predictions, however, we observed no robust associations between the general risk preference factor and FA for projections from bilateral MPFC, right Anterior Insula, or bilateral Amygdala to the NAcc. Notably, exploratory unilateral analyses revealed an association between the general risk preference factor and left MPFC-NAcc tract FA. Taken together, these findings suggest that impulse control as a facet of risk preference maps onto specific neurobiological targets, while more general facets of risk preference may be supported by structural properties of lateral fronto-striatal projections. Although the exact associated functional mechanisms remain to be fully clarified, conNAcctomic approaches like the one presented here could pave the way for further research into the physiological foundations of risk preference and related constructs.

Persistent dysfunctions of brain metabolic connectivity in long-covid with cognitive symptoms.

Our study examines brain metabolic connectivity in SARS-CoV-2 survivors during the acute-subacute and chronic phases, aiming to elucidate the mechanisms underlying the persistence of neurological symptoms in long-COVID patients. We perfomed a cross-sectional study including 44 patients (pts) with neurological symptoms who underwent FDG-PET scans, and classified to timing infection as follows: acute (7 pts), subacute (17 pts), long-term (20 pts) phases. Interregional correlation analysis (IRCA) and ROI-based IRCA were applied on FDG-PET data to extract metabolic connectivity in resting state networks (ADMN, PDMN, EXN, ATTN, LIN, ASN) of neuro-COVID pts in acute/subacute and long-term groups compared with healthy controls (HCs). Univariate approach was used to investigate metabolic alterations from the acute to sub-acute and long-term phase. The acute/subacute phase was characterized by hyperconnectivity in EXN and ATTN networks; the same networks showed hypoconnectivity in the chronic phase. EXN and ATTN hypoconnectivity was consistent with clinical findings in long-COVID patients, e.g. altered performances in neuropsychological tests of executive and attention domains. The ASN and LIN presented hyperconnectivity in acute/subacute phase and normalized in long-term phase. The ADMN and PDMN presented a preseverved connectivity. Univariate analysis showed hypometabolism in fronto-insular cortex in acute phase, which reduced in sub-acute phase and disappeared in long-term phase. A compensatory EXN and ATTN hyperconnectivity was found in the acute/subacute phase and hypoconnectivity in long-term. Hypoconnectivity and absence of hypometabolism suggest that connectivity derangement in frontal networks could be related to protraction of neurological symptoms in long-term COVID patients.

Non-Invasive Brain Stimulation Beyond the Motor Cortex: A Systematic Review and Meta-Analysis Exploring Effects on Quantitative Sensory Testing in Clinical Pain.

Non-invasive brain stimulation (NIBS) has been investigated increasingly as a means of treating pain. The effectiveness of NIBS in the treatment of pain has traditionally focused upon protocols targeting the primary motor cortex (M1). However, over time, the effectiveness of M1 NIBS has been attributed to effects on interconnected cortical and subcortical sites rather than M1 itself. While previous reviews have demonstrated the effectiveness of non-M1 NIBS in improving subjective reports of pain intensity, the neurophysiological mechanisms underlying these effects remain incompletely understood. As chronic pain is associated with pain hypersensitivity and impaired endogenous descending pain modulation, it is plausible that non-M1 NIBS promotes analgesic effects by influencing these processes. The aim of this systematic review and meta-analysis was therefore to evaluate the effect of NIBS over non-M1 sites on quantitative sensory testing measures in clinical pain populations. A systematic search of electronic databases was conducted from inception to January 2024. Included articles (13trials, n = 565 participants) were appraised using PEDro and GRADE and a random effects model was used to meta-analyse outcomes where possible. A small number of studies found that NIBS applied to DLPFC may improve pain modulation in patients with fibromyalgia, and that stimulation of the posterior superior insula and prefrontal cortex could improve pain sensitivity in chronic neuropathic and osteoarthritic pain, respectively. However, findings varied between studies and there remains a paucity of primary research. This review indicates that current literature does not provide clear evidence that NIBS over non-M1 sites influences pain processing.

Pain Catastrophizing and Functional Activation During Occlusion in TMD Patients-An Interventional Study.

In temporomandibular disorder (TMD), the effects of standard interventions such as using an occlusal splint and its impact on pain relief and pain catastrophizing are poorly understood. Earlier work pointed to a crucial role of insula activation with changes in pain relief by occlusal splint treatment. We performed a functional imaging study using specially developed splint systems to allow for a placebo-controlled longitudinal design. Using functional MRI we examined 20 TMD patients during repetitive occlusal movements at baseline and over the course of splint therapy and also collected self-reported pain catastrophizing. For balancing performance between baseline and after intervention we used occlusion force measures in an individualized fMRI-splint system. Splint therapy lasted for approximately 7 weeks with one group selected by randomization wearing a palatine placebo splint over the first 3 weeks (delayed start; 11 individuals). As expected, fMRI activation in areas involved in pain processing (insula, primary and secondary somatosensory cortex) decreased with intervention. At baseline a positive correlation between activation of the left anterior insula and pain catastrophizing was present. Both parameters decreased over intervention while associations were primarily observable for patients with rather mild TMD.

The impact of cannabidiol placebo on amygdala-based neural responses to an acute stressor.

Cannabidiol (CBD) impacts brain regions implicated in anxiety reactivity and stress reactivity (e.g., amygdala, anterior cingulate cortex (ACC), anterior insula (AI)); however, placebo-controlled studies are mixed regarding CBD's anxiolytic effects. We previously reported that CBD expectancy alone can alter subjective, physiological, and endocrine markers of stress/anxiety; however, it is unclear whether these findings reflect altered brain reactivity. This study evaluated whether CBD expectancy independently alters amygdala resting-state functional connectivity (rsFC) with the ACC and AI following acute stress. Thirty-eight (20 females) healthy adults were randomly assigned to receive accurate or inaccurate information regarding the CBD content of a CBD-free oil administered during a single experimental session. Following a baseline resting state MRI scan, participants administered their assigned oil sublingually, engaged in a stress task (serial subtraction with negative feedback) inside the scanner, and underwent another resting state MRI scan. Amygdala rsFC with the ACC and AI was measured during each scan, and the subjective state was assessed at six time points. Outcomes were analyzed using ANCOVA. CBD expectancy (vs CBD-free expectancy) was associated with significantly weaker rsFC between the left amygdala and right ACC (p = 0.042), but did not systematically alter amygdala-AI rsFC (p-values > 0.05). We also replicated our previously reported CBD expectancy effects on subjective stress/anxiety in the scanner context. CBD placebo effects may be sufficient to alter neural responses relevant to its purported anxiolytic and stress-relieving properties. Future work is needed to replicate these results and determine whether CBD expectancy and pharmacology interact to alter neural anxiety reactivity and stress reactivity.