Insular Cortex Research Articles

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.

Disturbances of Interoception in Schizophrenia – Focus on Neuroimaging

Abstract: The current paper presents the most recent theoretical understanding of interoception (INTC) in light of the predictive processing framework and the Embodied Predictive Interoceptive Coding model and reviews recent experimental data on different interoceptive disturbances in schizophrenia (SCZ) such as lower interoceptive accuracy, nociceptive dysfunction reflected by reduced pain sensitivity, disturbed thermoregulation, impaired gastrointestinal regulation, cardiovascular and respiratory dysfunction, and immune disturbances. The immense clinical implications of these disturbances are discussed in the context of the high rates of morbidity and mortality in SCZ related to suicide and cardiac death. Next, the potential of INTC-related treatments is reviewed, and conclusions are made on the evidence for the use of vagus nerve stimulation, mindfulness-based interventions, and exercise therapy. The neuroimaging perspective is given in a brief account of the INTC-related findings in healthy individuals suggesting the right anterior insula and anterior cingulate cortex as key brain areas for interoceptive awareness, accuracy, and sensibility, by supporting higher-order representation and integration of visceral, and somatosensory interoception with exteroceptive information. In SCZ, on the other hand, neuroimaging research on specific interoceptive abilities is lacking but indirect evidence points to disrupted activation of major INTC network hubs. There is converging evidence of changes in these hubs in terms of both structure and function (volume reductions, aberrant activation, and connectivity). This narrative review identifies several gaps in contemporary INTC-related research in SCZ that need to be addressed in future experimental and clinical studies to elucidate the exact nature of the disturbances of interoceptive abilities in modalities other than cardioception; the interactions between different interoceptive modalities; the association between interoceptive abilities and other mental functions (such as emotion recognition and regulation, decision making, learning, memory, etc.); the efficacy of nonpharmacological and pharmacological INTC-based interventions; and the relation of disturbed interoceptive abilities with brain structure and function.

Ventral Striatum is Preferentially Correlated with the Salience Network Including Regions in Dorsolateral Prefrontal Cortex.

The ventral striatum (VS) receives input from the cerebral cortex and is modulated by midbrain dopaminergic projections in support of processing reward and motivation. Here we explored the organization of cortical regions linked to the human VS using within-individual functional connectivity MRI in intensively scanned participants. In two initial participants (scanned 31 sessions each), seed regions in the VS were preferentially correlated with distributed cortical regions that are part of the Salience (SAL) network. The VS seed region recapitulated SAL network topography in each individual including anterior and posterior midline regions, anterior insula, and dorsolateral prefrontal cortex (DLPFC) - a topography that was distinct from a nearby striatal seed region. The region of DLPFC linked to the VS is positioned adjacent to regions associated with domain-flexible cognitive control. The full pattern was replicated in independent data from the same two individuals and generalized to 15 novel participants (scanned 8 or more sessions each). These results suggest that the VS forms a cortico-basal ganglia loop as part of the SAL network. The DLPFC is a neuromodulatory target to treat major depressive disorder. The present results raise the possibility that the DLPFC may be an effective neuromodulatory target because of its preferential coupling to the VS and suggests a path toward further personalization.

Acute vestibular syndrome accompanying middle cerebral artery infarctions: a single-center study

Objectives: Acute vestibular syndrome (AVS) is a disease and disorder usually manifest with a single episode of sudden onset vestibular symptoms and signs, and may occur at any point along the vestibular pathway from the peripheral labyrinth to the vestibular cortex. This study presents the characteristics of the involved cortical area and clinical course in middle cerebral artery (MCA) territory infarction patients with central vestibular disorder. Methods: Files of patients diagnosed with acute ischemic stroke in the MCA territory were reviewed retrospectively between December 2020 and March 2022. All the patients were categorized into two groups (with or without AVS) and analyzed for comorbidities as well as smoking and drinking habits, and their data pertaining to the neurological examination, bedside neuro-otological examination, and laboratory and computerized tomography angiography findings were collected. Results: Seven hundred and sixty-eight patients with MCA territory infarction were included in the study. AVS incidence was calculated to be 13.3%. There was no statistically significant difference in the distribution of age and sex between patients with and without AVS. The involvement of the right side was significantly more prevalent in AVS patients. Distribution of patients with right-sided infarction: 11 with posterior superior temporal gyrus 17 with parieto-insular cortex, 16 with insular cortex and temporoparietal junction together, and 18 with more than one millimetric infarction in all three areas. Conclusions: Patients with acute vestibular syndrome, may have infarctions in the anterior circulation and most of them had no pathological neuro-otologic test findings.

Hearing Impairment: Reduced Pupil Dilation Response and Frontal Activation During Degraded Speech Perception.

A relevant aspect of listening is the effort required during speech processing, which can be assessed by pupillometry. Here, we assessed the pupil dilation response of normal-hearing (NH) and hard of hearing (HH) individuals during listening to clear sentences and masked or degraded sentences. We combined this assessment with functional magnetic resonance imaging (fMRI) to investigate the neural correlates of the pupil dilation response. Seventeen NH participants (Mage = 46 years) were compared to 17 HH participants (Mage = 45 years) who were individually matched in age and educational level. Participants repeated sentences that were presented clearly, that were distorted, or that were masked. The sentence intelligibility level of masked and distorted sentences was 50% correct. Silent baseline trials were presented as well. Performance measures, pupil dilation responses, and fMRI data were acquired. HH individuals had overall poorer speech reception than the NH participants, but not for noise-vocoded speech. In addition, an interaction effect was observed with smaller pupil dilation responses in HH than in NH listeners for the degraded speech conditions. Hearing impairment was associated with higher activation across conditions in the left superior temporal gyrus, as compared to the silent baseline. However, the region of interest analysis indicated lower activation during degraded speech relative to clear speech in bilateral frontal regions and the insular cortex, for HH compared to NH listeners. Hearing impairment was also associated with a weaker relation between the pupil response and activation in the right inferior frontal gyrus. Overall, degraded speech evoked higher frontal activation than clear speech. Brain areas associated with attentional and cognitive-control processes may be increasingly recruited when speech is degraded and are related to the pupil dilation response, but this relationship is weaker in HH listeners. https://doi.org/10.23641/asha.27162135.

High-resolution 7T fMRI reveals the visual zone of the human claustrum

Abstract The claustrum is a thin grey matter structure located between the insular cortex and the putamen. The function of the claustrum is largely unknown with diverse hypotheses ranging from multisensory integration and consciousness to attention and cognitive control. Much research on the function of the claustrum relies on invasive techniques in animal models, as the claustrum’s uniquely thin shape makes it difficult to image non-invasively in human subjects. In the current proof-of-concept study, we used high-resolution ultra-high field (7 Tesla) functional magnetic resonance imaging (fMRI) to measure activity in the human claustrum during the processing of naturalistic stimuli. We presented short video clips as visual only, auditory only or audiovisual conditions while participants performed a central fixation task. We found distinct visual responses in both the left and the right claustrum at a consistent spatial location across participants, hemispheres and sessions. We also found deactivations in response to auditory stimulation. These deactivations were confined to the right claustrum and did not overlap with visual activity. The deactivation in response to auditory stimulation demonstrates the complexity of claustrum’s functional organization and suggests functional differentiation within the claustrum. This is the first study to demonstrate sensory-specific effects within the human claustrum. It opens the possibility for studying the claustrum’s role in higher-level aspects of sensory processing in humans.

Association of RDoC dimensions with post-mortem brain transcriptional profiles in Alzheimer's Disease.

Neuropsychiatric symptoms are common in people with Alzheimer's disease (AD) across all severity stages. Their heterogeneous presentation and variable temporal association with cognitive decline suggest shared and distinct biological mechanisms. We hypothesized that specific patterns of gene expression associate with distinct NIMH Research Domain Criteria (RDoC) domains in AD. Post-mortem bulk RNAseq on the insula and anterior cingulate cortex from 60 brain donors representing the spectrum of canonical AD neuropathology combined with natural language processing approaches based on the RDoC Clinical Domains. Distinct sets of >100 genes (p FDR <0.05) were specifically associated with at least one clinical domain (Cognitive, Social, Negative, Positive, Arousal). In addition, dysregulation of immune response pathways was shared across domains and brain regions. Our findings provide evidence for distinct transcriptional profiles associated with RDoC domains suggesting that each dimension is characterized by specific sets of genes providing insight into the underlying mechanisms.

The expectations humans have of a pleasurable sensation asymmetrically shape neuronal responses and subjective experiences to hot sauce.

Expectations shape our perception, profoundly influencing how we interpret the world. Positive expectations about sensory stimuli can alleviate distress and reduce pain (e.g., placebo effect), while negative expectations may heighten anxiety and exacerbate pain (e.g., nocebo effect). To investigate the impact of the (an)hedonic aspect of expectations on subjective experiences, we measured neurobehavioral responses to the taste of hot sauce among participants with heterogeneous taste preferences. By identifying participants who "liked" versus those who strongly "disliked" spicy flavors and by providing contextual cues about the spiciness of the sauce to be tasted, we dissociated the effects of positive and negative expectations from sensory stimuli (i.e., visual and gustatory stimuli), which were the same across all participants. Our results indicate that positive expectations lead to modulations in the intensity of subjective experience. These modulations were accompanied by increased activity in brain regions previously linked to information integration and the placebo effect, including the anterior insula, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex, as well as a predefined "pleasure signature." In contrast, negative expectations decreased hedonic experience and increased neural activity in the previously validated "Neurological Pain Signature" network. These findings demonstrate that hedonic aspects of one's expectations asymmetrically shape how the brain processes sensory input and associated behavioral reports of one's subjective experiences of intensity, pleasure, and pain. Our results suggest a dissociable impact of hedonic information: positive expectations facilitate higher-level information integration and reward processing, while negative expectations prime lower-level nociceptive and affective processes. This study demonstrates the powerful role of hedonic expectations in shaping subjective reality and suggests potential avenues for consumer and therapeutic interventions targeting expectation-driven neural processes.

Clinical and imaging correlates of hyperorality in syndromes associated with frontotemporal lobar degeneration.

Empirical research investigating hyperorality in syndromes associated with frontotemporal lobar degeneration (FTLD) is limited. The present study aims to assess and describe hyperorality and its clinical and imaging correlates in patients with FTLD-associated syndromes. This retrospective longitudinal study included consecutive patients with FTLD who underwent a clinical, cognitive, and behavioral assessment. The presence and severity of hyperorality was assessed using the Frontal Behavior Inventory. A total of 712 patients with FTLD were included in the study. Hyperorality was reported by 29% (204 of 712 [95% CI: 25-32%]) of patients; was more frequent in those with severe dementia than in those with prodromal or mild to moderate dementia (P < 0.05); was associated with younger age (odds ratio [OR] = 0.96 [95% CI: 0.94-0.99]), (P = 0.003) and positive family history for dementia (OR = 2.03 [95% CI: 1.18-3.49], P = 0.010); was overall more probable in the behavioral variant of frontotemporal dementia (bvFTD) and frontotemporal dementia with amyotrophic lateral sclerosis phenotypes, and less probable in other language or motor phenotypes; and was associated with higher severity of neuropsychiatric symptoms (OR = 1.08 [95% CI: 1.06-1.10], P < 0.001) and with the presence of several behavioral symptoms (P < 0.05). Moreover, hyperorality severity increased over time only in patients with bvFTD (β = +0.15, P = 0.011) or semantic variant of primary progressive aphasia (β = +0.34, P = 0.010). Finally, the presence of hyperorality was significantly associated with greater atrophy in the right anterior insula and right orbitofrontal region (false discovery rate-corrected P < 0.05). Hyperorality is common in certain FTLD-associated syndromes. Understanding its correlates can help clinicians define pharmacological and educational interventions and clarify related anatomical circuits.

Gray matter volumetric changes in tinnitus: The impact of hearing loss and severity

Tinnitus is a phantom auditory sensation that commonly co-occurs with hearing loss. Both tinnitus and hearing loss can impact the quality of life, emotional well-being, and cognitive functioning of the affected individuals. While previous studies have highlighted structural alterations in hearing loss and/or tinnitus, the fundamental neural mechanisms underpinning tinnitus severity remain poorly understood. In this study, we conducted a voxel-based morphometry to investigate gray matter (GM) volume differences among groups of participants with varying tinnitus severity and hearing status, and controls within a large sample. We observed reduced GM volume in the left anterior insula and right planum polare in participants with hearing loss, regardless of their tinnitus status, compared to normal hearing controls. We noted decreased GM volume in the bilateral anterior and posterior insula for those with tinnitus and normal hearing compared to a normal hearing control group. Further, the tinnitus with hearing loss group showed decreased GM volume in the left planum polare, left inferior temporal gyrus, bilateral anterior temporal gyri, and right superior frontal gyrus compared to the normal hearing control group, suggesting a combined effect of hearing loss and tinnitus. While tinnitus severity did not show a significant overall effect, there was a significant positive correlation between tinnitus distress and GM volume in bilateral planum polare. Our findings enhance the understanding of structural brain changes related to hearing loss and tinnitus, and advance the overall knowledge of tinnitus pathophysiology, which can contribute to the development of more effective treatments for tinnitus.

8607 Gender Affirming Hormone Therapy: Influence of Brain Network Connectivity Changes on Affect

Abstract Disclosure: J. Andreano: None. A. Lopez: None. M. Misra: None. Background: Previous research indicates that acute gonadal treatments and fluctuations in ovarian hormone levels over the course of the menstrual cycle can alter patterns of communication between brain regions, as well as producing significant changes in self-reported affect. Recent research from our laboratory indicates changes in both brain connectivity and affect with gender affirming hormone therapy (GAHT). However, the relationship between these changes with GAHT are not well understood. Additionally, it is difficult to separate influences of GAHT and transgender identity in understanding differences in connectvity and affect from cisgender controls. A better understanding of the influence of GAHT on intrinsic network connectivity could point the way towards improved GAHT treatment regimens that minimize affective side effects. Objective: To assess relationships between changes in brain network connectivity and affective changes following GAHT, identifying regions in which changes of connectivity are associated with changes in self-reported affect, and to examine differences in brain network connectivity between transgender participants and cisgender controls. Methods: 14 transgender individuals receiving GAHT (estradiol n =7, testosterone n = 7)) were scanned using functional magnetic imaging (fMRI) at rest at two timepoints: baseline, prior to treatment, and 6 months into GAHT. Additionally, 20 cisgender controls (10 male, 10 female) were scanned once each. The time course of neural activity was computed for each voxel in the brain, then tested for correlation with each other voxel to develop a whole-brain connectome for each participant. Maps of average connectivity to two seeds known to associate with two major networks in the brain (posterior cingulate cortex for Default Mode Network, and anterior insula for Salience Network) were then generated for each participant. Within transgender participants, these maps were then compared between the baseline and 6 month timepoints. Additionally, baseline scans were also compared to scans from cisgender controls corresponding to biological sex. Results: Within-subjects analyses of transgender participants showed diverse associations between changes in seed-based connectivity and changes in self-reported anxiety and depression following GAHT in both the default mode and salience networks. Between subjects comparisons showed significantly higher connectivity within the salience network in trans men relative to cis women, as well as greater inter-network connectivity in this group. In contrast, cis men showed greater connectivity within both default mode and salience networks relative to trans women. Conclusions: Changes in affect following GAHT appear related to GAHT-induced changes in network connectivity; these influences appear independent of differences between cis and transgender individuals. Presentation: 6/2/2024

The role of loss aversion in social conformity: psychological and neural representations.

The impact of others' choices on decision-making is influenced by individual preferences. However, the specific roles of individual preferences in social decision-making remain unclear. In this study, we examine the contributions of risk and loss preferences as well as social influence in decision-making under uncertainty using a gambling task. Our findings indicate that while both individual preferences and social influence affect decision-making in social contexts, loss aversion plays a dominant role, especially in individuals with high loss aversion. This phenomenon is accompanied by increased functional connectivity between the anterior insular cortex and the temporoparietal junction. These results highlight the critical involvement of loss aversion and the anterior insular cortex-temporoparietal junction neural pathway in social decision-making under uncertainty. Our findings provide a computational account of how individual preferences and social information collectively shape our social decision-making behaviors.

HGGL-01 GLIOBLASTOMA MULTIFORM INVOLVING MULTIPLE BRAIN REGIONS ASSOCIATED WITH MUTATIONS IN EXON 4 OF ISOCITRATE DEHYDROGENASE 1 COMPLICATED BY ACUTE KIDNEY FAILURE: A CASE REPORT

Abstract Glioblastoma multiform (GBM), WHO grade 4, is the most aggressive primary brain tumor in adults associated with poor prognosis. We present a case of a 43-year-old female, Muyira, diagnosed with GBM involving multiple brain regions and harboring mutations in exon 4 of isocitrate dehydrogenase 1, who subsequently developed acute kidney failure. The patient initially presented with progressive neurological symptoms, including headache and cognitive decline. Multiplanar multiecho MRI of the brain was performed with IV contrast in orthogonal plane and revealed a moderate sized multilobulated heterogeneously and predominantly peripherally enhancing mass lesion with irregular margins and central non enhancing areas of necrosis arising from the right corona radiata, insular cortex, external capsule, lentiform nucleus, temporal, and frontal white matter with blood products. Perilesional edema was seen. Effacement of sulcal spaces. Right sylvian fissure, compression over right ventricle and midline shift of 8mm toward left side. There was dilatation of the left lateral ventricle with periventricular cerebrospinal fluid ooze. Uncal herniation was right side. On MR spectroscopy large choline, creatinine levels were seen in the lesion with reduced N-acetyl aspartate levels as compared to the normal parenchyma. Findings were suggestive of neoplastic lesion mostly high-grade glioma. Polymerase chain reaction sequencing confirmed the presence of missense mutation R132H in exon 4 of isocitrate dehydrogenase 1 gene. Despite maximal safe surgical resection, the patient developed acute kidney failure secondary to the nephrotoxic effects of gadolinium. Management of both the primary brain tumor and renal complication necessitated a multidisciplinary approach involving neurosurgery, oncology, nephrology, and supportive care. Despite aggressive interventions, the patient’s condition deteriorated, highlighting the challenges in managing concurrent life-threatening conditions in patients with advanced GBM.

Neurophysiological principles underlying predictive coding during dynamic perception-action integration

A major concept in cognitive neuroscience is that brains are “prediction machines”. Yet, conceptual frameworks on how perception and action become integrated still lack the concept of predictability and it is unclear how neural processes may implement predictive coding during dynamic perception-action integration. We show that distinct neurophysiological mechanisms of nonlinearly directed connectivities in the theta and alpha band between cortical structures underlie these processes. During the integration of perception and motor codes, especially theta band activity in the insular cortex and temporo-hippocampal structures is modulated by the predictability of upcoming information. Here, the insular cortex seems to guide processes. Conversely, the retrieval of such integrated perception-action codes during actions heavily relies on alpha band activity. Here, directed top-down influence of alpha band activity from inferior frontal structures on insular and temporo-hippocampal structures is key. This suggests that these top-down effects reflect attentional shielding of retrieval processes operating in the same neuroanatomical structures previously involved in the integration of perceptual and motor codes. Through neurophysiology, the present study connects predictive coding mechanisms with frameworks specifying the dynamic integration of perception and action.

Prophylactic (R,S)-ketamine and (2S,6S)-HNK decrease fear expression by differentially modulating fear neural ensembles

We previously reported that a single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) prior to stress attenuates learned fear. However, whether these drugs attenuate learned fear through divergent or convergent effects on neural activity remains to be determined. 129S6/SvEv male mice were injected with saline, (R,S)-ketamine, or (2S,6S)-HNK one week before a 3-shock contextual fear conditioning (CFC) paradigm. Five days later, mice were re-exposed to the aversive context, and euthanized one hour later to quantify active cells. Brains were processed for c-fos immunoreactivity, and neural networks were built with a novel, wide-scale imaging pipeline. We found that (R,S)-ketamine and (2S,6S)-HNK attenuate learned fear. Fear-related neural activity was altered in: dorsal CA3 following (2S,6S)-HNK; ventral CA3 and CA1, infralimbic (IL) and prelimbic (PL) regions, insular cortex (IC), retrosplenial cortex (RSP), piriform cortex (PIR), nucleus reuniens (RE), and periaqueductal grey (PAG) following both (R,S)-ketamine and (2S,6S)-HNK; and in the paraventricular nucleus of thalamus (PVT) following (R,S)-ketamine. Dorsal CA3 and ventral hippocampus activation correlated with freezing in the (R,S)-ketamine group, and RSP activation correlated with freezing in both (R,S)-ketamine and (2S,6S)-HNK groups. (R,S)-ketamine increased connectivity between cortical and subcortical regions while (2S,6S)-HNK increased connectivity within these regions. This work identifies novel nodes in fear networks, involving the RE, PIR, IC, PAG and RSP, that can be targeted with neuromodulatory strategies or pharmaceutical compounds to treat fear-induced disorders. This approach could be used to optimize target engagement and dosing strategies of existing medications.

The pivotal role of PACAP/PAC1R signaling from the anterior insular cortex to the locus coeruleus on anxiety-related behaviors of mice

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific receptor (PAC1R) are widely present in the central nervous system (CNS), and PACAP/PAC1R signaling has been implicated in anxiety-related behaviors. The locus coeruleus (LC), with its extensive noradrenergic (NA) projections throughout the CNS, is also implicated in anxiety. Although the LC exhibits a high expression of PAC1R, the precise role of PACAP/PAC1R signaling in the LC's involvement in anxiety remains unclear. Histochemical analysis confirmed high levels of PAC1R mRNA in the LC and showed that PAC1R gene transcripts were highly localized to NA neurons. Targeted deletion of PAC1R from these cells led to a hyperactive/low anxiety phenotype in the open field and elevated-plus maze tests. Retrograde neurocircuit tracing indicated PACAP neurons from the anterior insular cortex (aIC) and a few other regions projected axons to the LC. The selective activation of PACAP neurons in the aIC led to significantly increased anxiety behavior without a change in overall locomotor activity. Moreover, shRNA PACAP knockdown in the aIC in wild-type mice led to a selective decrease in anxiety. The present results identify an aIC to LC neurocircuit controlling anxiety that critically requires PACAP/PAC1R signaling.

Behavioral Changes and Long-Term Cortical Thickness Alterations in Women with Fibromyalgia

ObjectivesThe purpose of this study was to examine long-term brain and behavioral changes in patients with fibromyalgia (FM) compared to healthy individuals. MethodsData from 33 female volunteers with FM and 33 healthy controls women paired by age and school degree were used to analyze the cortical thickness from high-resolution T1-weighted magnetic resonance imaging (MRI) obtained through a 3T-MRI scanner. Additionally, the Toronto Alexithymia Scale, the Positive and Negative Affect Scale, the emotion regulation questionnaire (ERQ), and the Hamilton Depression and Anxiety rating scales were used to evaluate the behavioral changes. ResultsThe findings indicate significant cortical structure differences in the right cerebral hemisphere between groups in the insular anterior cortex precentral and postcentral gyrus (P < .001). The FM group scored higher for alexithymia (P < .01), negative affect (P < .01), anxiety (P < .01), and depression (P < .01) symptoms, on the other hand, scored lower for positive affect (P < .01). No differences were found on the left cerebral hemisphere. Furthermore, there was a negative correlation between the right insular anterior cortex and Toronto Alexithymia Scale (P < .001). ConclusionThis study showed long-term brain and behavioral changes in patients with FM, suggesting notable neurophysiological alterations associated with this chronic pain condition. It provides new insights into how FM may affect brain health and potential biomarkers for the condition.

Effects of total sleep deprivation on functional connectivity of the anterior cingulate cortex: Insights from resting-state fMRI in healthy adult males

Inadequate sleep significantly impacts an individual's health by compromising inhibitory control and self-regulation abilities. This study employed resting-state functional magnetic resonance imaging (fMRI) to assess the functional connectivity between the anterior cingulate cortex (ACC) and the whole brain in 16 healthy adult males after 36 h of total sleep deprivation. Additionally, this study investigated alterations in individuals' inhibitory control functions and physiological mechanisms following sleep deprivation. The results showed a significant increase in functional connectivity between the ACC, the left angular gyrus, and the right hippocampus following 36 h of continuous sleep deprivation. Conversely, functional connectivity was notably decreased between the ACC and the right insular cortex, right paracingulate gyrus, and bilateral putamen. Furthermore, changes in ACC functional connectivity were significantly correlated with alterations in behavioral performance in the go/no-go task after sleep deprivation. This study contributes to understanding brain network mechanisms in the anterior cingulate gyrus after sleep deprivation. It clarifies the relationship between functional connectivity changes in the anterior cingulate gyrus and inhibitory control post-sleep deprivation.