Three Systems of Insular Functional Connectivity Identified with Cluster Analysis

BackgroundAnhedonia, which is defined as the inability to feel pleasure, is considered a core symptom of major depressive disorder (MDD). It can lead to several adverse outcomes in adolescents, including heightened disease severity, resistance to antidepressants, recurrence of MDD, and even suicide. Specifically, patients who suffer from anhedonia may exhibit a limited response to selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT). Previous researches have revealed a link between anhedonia and abnormalities within the reward circuitry, making the nucleus accumbens (NAc) a potential target for treatment. However, since the NAc is deep within the brain, repetitive transcranial magnetic stimulation (rTMS) has the potential to modulate this specific region. Recent advances have enabled treatment technology to precisely target the left dorsolateral prefrontal cortex (DLPFC) and modify the functional connectivity (FC) between DLPFC and NAc in adolescent patients with anhedonia. Therefore, we plan to conduct a study to explore the safety and effectiveness of using resting-state functional connectivity magnetic resonance imaging (fcMRI)-guided rTMS to alleviate anhedonia in adolescents diagnosed with MDD.MethodsThe aim of this article is to provide a study protocol for a parallel-group randomized, double-blind, placebo-controlled experiment. The study will involve 88 participants who will be randomly assigned to receive either active rTMS or sham rTMS. The primary object is to measure the percentage change in the severity of anhedonia, using the Snaith-Hamilton Pleasure Scale (SHAPS). The assessment will be conducted from the baseline to 8-week post-treatment period. The secondary outcome includes encompassing fMRI measurements, scores on the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Montgomery Asberg Depression Rating Scale (MADRS), the Chinese Version of Temporal Experience of Pleasure Scale (CV-TEPS), and the Chinese Version of Beck Scale for Suicide Ideation (BSI-CV). The Clinical Global Impression (CGI) scores will also be taken into account, and adverse events will be monitored. These evaluations will be conducted at baseline, as well as at 1, 2, 4, and 8 weeks.DiscussionIf the hypothesis of the current study is confirmed, (fcMRI)-guided rTMS could be a powerful tool to alleviate the core symptoms of MDD and provide essential data to explore the mechanism of anhedonia.Trial registrationClinicalTrials.gov NCT05544071. Registered on 16 September 2022.

The aim of this study is to investigate chemotherapy-induced alterations in the functional framework of the brain, and probe the relationship between these changes and executive function impairments in breast cancer patients. Thirty-three breast cancer patients (BC) after receiving chemotherapy and 31 matched healthy controls (HC) were enrolled in this study. All participants received resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) and neuropsychological background tests. The lower functional connectivity of the posterior cingulate cortex (PCC) was found in the left postcentral gyrus, left precentral gyrus, right superior temporal gyrus, right cingulate gyrus and right middle frontal gyrus. A significant negative correlation was found between the response time on the Trail Making Tests and the functional connectivity strength between the PCC and right middle frontal and right cingulate gyri in breast cancer patients. In addition, the strength of the functional connectivity between the PCC and right middle frontal gyrus had a negative correlation with the response times on the Stroop Interference Test in breast cancer patients. This study demonstrated that BC patients after receiving chemotherapy have abnormal functional connectivity. These findings suggest that functional connectivity changes might play an important role in chemotherapy-induced executive function impairments in breast cancer patients.

BackgroundPharmacological and nonpharmacological methods of inducing altered states of consciousness (ASCs) are becoming increasingly relevant in the treatment of psychiatric disorders. While comparisons between them are often drawn, to date no study has directly compared their neural correlates. MethodsTo address this knowledge gap, we directly compared 2 pharmacological methods (psilocybin 0.2 mg/kg orally [n = 23] and lysergic acid diethylamide [LSD] 100 μg orally [n = 25]) and 2 nonpharmacological methods (hypnosis [n = 30] and meditation [n = 29]) using resting-state functional connectivity magnetic resonance imaging and assessed the predictive value of the data using a machine learning approach. ResultsWe found that 1) no network reached significance in all 4 ASC methods; 2) pharmacological and nonpharmacological interventions of inducing ASCs showed distinct connectivity patterns that were predictive at the individual level; 3) hypnosis and meditation showed differences in functional connectivity when compared directly and also drove distinct differences when jointly compared with the pharmacological ASC interventions; and 4) psilocybin and LSD showed no differences in functional connectivity when directly compared with each other, but they did show distinct behavioral-neural relationships. ConclusionsOverall, these results extend our understanding of the mechanisms of action of ASCs and highlight the importance of exploring how these effects can be leveraged in the treatment of psychiatric disorders.

To evaluate the feasibility of recruitment, preliminary efficacy, and acceptability of auricular percutaneous electrical nerve field stimulation (PENFS) for the treatment of fibromyalgia in veterans, using neuroimaging as an outcome measure and a biomarker of treatment response. Randomized, controlled, single-blind. Government hospital. Twenty-one veterans with fibromyalgia were randomized to standard therapy (ST) control or ST with auricular PENFS treatment. Participants received weekly visits with a pain practitioner over 4weeks. The PENFS group received reapplication of PENFS at each weekly visit. Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) data were collected within 2weeks prior to initiating treatment and 2weeks following the final treatment. Analysis of rs-fcMRI used a right posterior insula seed. Pain and function were assessed at baseline and at 2, 6, and 12weeks post-treatment. At 12weeks post-treatment, there was a nonsignificant trend toward improved pain scores and significant improvements in pain interference with sleep among the PENFS treatment group as compared with the ST controls. Neuroimaging data displayed increased connectivity to areas of the cerebellum and executive control networks in the PENFS group as compared with the ST control group following treatment. There was a trend toward improved pain and function among veterans with fibromyalgia in the ST + PENFS group as compared with the ST control group. Pain and functional outcomes correlated with altered rs-fcMRI network connectivity. Neuroimaging results differed between groups, suggesting an alternative underlying mechanism for PENFS analgesia.

Chapter 11 - Cingulate role in Tourette syndrome

Increased Thalamocortical Connectivity in Schizophrenia Correlates With Sleep Spindle Deficits: Evidence for a Common Pathophysiology

Objective To study the resting-state functional connectivity(FC) changes of anterior cingulate cortex(ACC) and amygdala in adolescent patients with medication-naive first-episode major depressive disorder(MDD). Methods Medication-naive first-episode MDD adolescents(n=30) and pair-wise matched healthy controls(HCs, n=29) underwent resting-state functional magnetic resonance images(fMRI). To study whether there were different in FC changes between amygdala and ACC and whole brain regions, and whether abnormal FC was related to clinical characteristics. Results Compared with HCs, the adolescent MDD patients showed decreased FC between the left amygdala and right thalamus(MNI x, y, z: 15, -21, 18)(t=-2.85)and increased FC between the left amygdala and the bilateral temporal middle gyrus, left occipital gyrus, right medial prefrontal cortex(MPFC)(MNI x, y, z: 9, 66, 15)(t=2.80). The right amygdale showed decreased FC with bilateral middle frontal gyrus, left caudate(MNI x, y, z: -15, -9, 21)(t=-2.53), right thalamus(MNI x, y, z: 12, -36, 12)(t=-3.01), right cerebellum(MNI x, y, z: 3, -84, -33)(t=-2.45) and increased FC with right temporal middle gyrus, right MPFC(MNI x, y, z: 6, 69, 12)(t=2.41). The left ACC showed decreased FC with left cerebellum(MNI x, y, z: 12, -87, -24)(t=-2.36), left frontal inferior triangle gyrus, right frontal inferior orbital gyrus and increased FC with right frontal middle orbital gyrus.The right ACC showed decreased FC with left caudate(MNI x, y, z: -15, 21, 6)(t=-2.29), right temporal middle gyrus, right MPFC(MNI x, y, z: 9, 54, 36)(t=-2.29), right frontal inferior orbital gyrus, right angular(MNI x, y, z: 45, -51, 21)(t=-3.01), left dorsolateral prefrontal cortex(MNI x, y, z: -21, 33, 36)(t=-2.61). The increased FC between the left amygdale and bilateral temporal middle gyrus showed positive correlation with the score of HAMD(r=0.50, P<0.05; r=0.45, P<0.05). And the FC between the right amygdale and right middle frontal gyrus was positive correlation with duration of disease(r=0.63, P<0.05). Conclusion There is widespread FC disorder in amygdala and ACC in adolescents patients with first-episode depression.Abnormal FC changes may be the neuropathological mechanism of depression. Key words: Adolescent major depressive disorder; Resting-state fMRI; Functional connectivity; Amygdala; Anterior cingulated cortex

To identify the neural correlates of cognitive improvement in mild Alzheimer's disease (AD) subjects following 12 weeks of donepezil treatment. Resting-state functional connectivity magnetic resonance imaging (R-fMRI) was used to measure the hippocampal functional connectivity (HFC) in 14 mild AD and 18 age-matched normal (CN) subjects. AD subjects were scanned at baseline and after donepezil treatment. CN subjects were scanned only at baseline as a reference to identify regions correlated or anticorrelated to the hippocampus. Before each scan, participants underwent cognitive, behavioral, and functional assessments. After donepezil treatment, neural correlates of cognitive improvement measured by Mini-Mental State Examination scores were identified in the left parahippocampus, dorsolateral prefrontal cortex (DLPFC), and inferior frontal gyrus. Improvement in AD Assessment Scale-cognitive subscale scores correlated with the HFC changes in the left DLPFC and middle frontal gyrus. Stronger recovery in the network connectivity was associated with cognitive improvement. R-fMRI may provide novel insights into the brain's responses to AD treatment in clinical pharmacological trials, and also may predict clinical response.

Differences in the resting-state fMRI global signal amplitude between the eyes open and eyes closed states are related to changes in EEG vigilance

Mainero C, Boshyan J, Hadjikhani N. Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine. Annals of Neurology 2011;70:838-845. Objective: The periaqueductal gray matter (PAG), a known modulator of somatic pain transmission, shows evidence of interictal functional and structural abnormalities in migraineurs, which may contribute to hyperexcitability along spinal and trigeminal nociceptive pathways, and lead to the migraine attack. The aim of this study was to examine functional connectivity of the PAG in migraine. Methods: Using resting-state functional MRI, we compared functional connectivity between PAG and a subset of brain areas involved in nociceptive/somatosensory processing and pain modulation in 17 subjects with migraine, during a pain-free state, versus 17 genderand age-matched controls. We also assessed the relation between intrinsic resting-state correlations within PAG networks and the average monthly frequency of migraine attacks, as well as allodynia. Results: Our findings show stronger connectivity between the PAG and several brain areas within nociceptive and somatosensory processing pathways in migraineurs versus controls. In addition, as the monthly frequency of migraine attacks worsens, the strength of the connectivity in some areas within these pathways increases, whereas a significant decrease in functional resting-state connectivity between the PAG and brain regions with a predominant role in pain modulation (prefrontal cortex, anterior cingulate, amygdala) can be evidenced. Finally, migraineurs with a history of allodynia exhibit significantly reduced connectivity between PAG, prefrontal regions, and anterior cingulate compared to migraineurs without allodynia. Interpretation: These data reveal interictal dysfunctional dynamics within pain pathways in migraine manifested as an impairment of the descending pain modulatory circuits, likely leading to loss of pain inhibition, and hyperexcitability primarily in nociceptive areas. Comments: Functional neuroimaging techniques have helped elucidate the underlying physiology of migraines. Unlike traditional functional magnetic resonance imaging scans done during a task, resting state functional connectivity is a relatively new neuroimaging technique in which participants are scanned at rest, and the lowfrequency spontaneous fluctuations found to be highly correlated are thought to represent brain areas that are functionally connected at baseline. Mainero et al recently conducted this study to assess the functional connectivity of the periaqueductal gray (PAG) (a region previously implicated in the pathogenesis of migraine) to other brain regions in 17 migraineurs interictally compared with 17 age-/gendermatched controls. They found that compared with the controls, the migraineurs had increased resting state functional connectivity between the PAG, and somatosensory and nociceptive processing pathways. The connections between the PAG and the supramarginal gyrus, anterior insula, and hypothalamus were increased in migraineurs with more frequent attacks, while the connections between PAG and the prefrontal cortex, anterior cingulate, amygdala, and medial thalamus were decreased in migraineurs with more frequent attacks. The 5 migraineurs with allodynia also had significantly reduced connectivity between the PAG and the anterior insula, anterior cingulate, and prefrontal cortex vs genderand age-matched migraineurs without allodynia. This study is one of the first to use resting state functional connectivity analyses to compare the intrinsic neural connections in migraineurs vs controls. As expected, many of the connections between the PAG, and nociceptive and sensory processing pathways were increased in the migraineurs, and some of those connections were stronger in those with more frequent attacks. However, unexpectedly, those with more frequent migraines and those with allodynia had decreased connections between the PAG and areas involved in the cognitive modulation of pain. This suggests that From the Graham Headache Center, Faulkner/Brigham and Women’s Hospital, Boston, MA,

Inflammation is associated with decreased functional connectivity of insula in unmedicated bipolar disorder

To investigate the functional connectivity of the default-mode network (DMN) in patients with end-stage renal disease (ESRD) by using independent component analysis of resting-state functional magnetic resonance (MR) imaging and to correlate these DMN connectivity changes with neuropsychological test results and clinical biomarkers. Medical research ethics committee approval and written informed consent were obtained. Forty-six patients with ESRD, including 22 with minimal nephrotic encephalopathy (MNE) and 24 without nephrotic encephalopathy, and 23 healthy control subjects underwent resting-state functional MR imaging. All patients were asymptomatic and without history of neurologic or psychiatric disease. Independent component analysis was used to isolate the DMN. To display the voxels that contributed most strongly to an independent component, the intensity values in each spatial map were converted to z scores, which indirectly provided a measurement of functional connectivity in the DMN. Maps of the DMN were compared among the groups. Pearson correlation analysis was performed to correlate abnormal DMN functional connectivity with serum urea, creatinine, duration of dialysis, duration of disease, and neuropsychological test scores. Patients with ESRD showed significantly less functional connectivity in the posterior cingulate cortex, precuneus, and medial prefrontal cortex (MPFC) (P < .01) than did control subjects. Comparison of the two patient groups showed significantly reduced functional connectivity in the superior and MPFC in the MNE group (P < .01). The functional connectivity of the MPFC was positively correlated with digital symbol test score (R = 0.293, P = .048). Serum creatinine level was negatively correlated with functional connectivity of the posterior cingulate cortex and precuneus in patients with ESRD (R = -0.51, P = .002). Functional connectivity in the DMN was impaired in patients with ESRD, with further reduction in the MPFC with the development of MNE, which might explain the reduced performance of these patients on neurocognitive tests. Serum creatinine level might be associated with impairment of the DMN in patients with ESRD.

Objectives: This work aims to explore the changes of functional connectivity (FC) within the hippocampus network in patients with moderate and severe obstructive sleep apnea (OSA) and its correlation with neurocognitive dysfunction to explore the potential neurophysiological mechanism.Methods: A total of 32 treatment-naïve patients with moderate or severe OSA and 26 healthy controls (HCs), matched in age, gender, and education, underwent the evaluations of Epworth Sleep Scale, neurocognitive function, full-night polysomnography, and resting-state functional magnetic resonance imaging. The FC map of the hippocampus to other brain areas was compared among 15 OSA patients and 15 HCs with little head motion. Finally, the correlation between hippocampus FC strength and respiratory sleep parameters and neurocognitive assessments was analyzed.Results: Compared with HCs, the right hippocampus showed a significantly decreased FC with the bilateral insular lobe, right thalamus, and right anterior cingulate gyrus (ACG) and an increased FC with the right superior and middle temporal gyrus, left posterior cingulate gyrus, and left angular gyrus in the patients with OSA. The left hippocampus presented a significantly decreased FC with the left anterior cerebellum in patients with OSA. In addition, the aberrant right hippocampal FC with the right ACG was significantly correlated with disease severity and disrupted sleep architecture in the OSA group. Furthermore, after adjusting the related confounding factors, the FC strength between the right hippocampus, right insular lobe, and right thalamus was positively associated with the scores of Stroop Color–Word Test (SCWT) or Hopkins Verbal Learning Test—Revised (HVLT-R), while the FC between the right hippocampus and the right middle temporal gyrus was negatively correlated with the scores of HVLT-R. The right hippocampus FC with right superior temporal gyrus, left angular gyrus, and ACG were all negatively related to the scores of the symbol coding test (r = −0.642, p = 0.045; r = −0.638, p = 0.047; r = −0.753, p = 0.012), respectively. The FC between the left hippocampal and the left anterior cerebellar lobe showed a positive relationship with the scores of HVLT-R (r = 0.757, p = 0.011) and CPT-3D (r = −0.801, p = 0.005).Conclusion: The hippocampus presented abnormal FC with the cerebral and cerebellar regions extensively in OSA, and the correlation between abnormal hippocampal network FC and neurocognitive dysfunction in OSA suggests a promising insight to explore the potential biomarker and pathophysiologic mechanism of neurocognitive dysfunction of OSA.

Objective: The objective of this study was to investigate resting-state functional connectivity (FC) differences in insular sub-regions during the interictal phase in patients with migraine without aura (MWoA).Methods: Forty-nine MWoA patients (MWoA group) and 48 healthy individuals (healthy control group) were recruited for this study. All of the subjects underwent neurological examination and magnetic resonance imaging (MRI). The MRI data were processed using Brat 1.0 software to obtain a whole-brain FC diagram and using Rest 1.8 software to obtain the FC z-score of the sub-regions of both insulas (six sub-regions on each side). Therefore, there were a total of 12 regions of interest (ROIs) that were used as seed points for the statistical analysis.Results: There was abnormal FC between the insular sub-regions and multiple brain regions in the MWoA patients compared with the healthy control group, and a clear laterality was also observed. In addition, the FC z-score of certain sub-regions was negatively correlated with the disease duration.Conclusion: Different insular sub-regions are functionally associated with different regions of the brain and therefore have different functions. In MWoA, the FC between the insular sub-regions and other brain regions was mostly reduced, while a small amount was increased; additionally, the FC may be ipsilateral with a right-side advantage. Variations in the FC of insular sub-regions can be observed as an important indicator of MWoA.

Abnormal functional connectivity between the anterior cingulate and the default mode network in drug-naïve boys with attention deficit hyperactivity disorder