Anterior Cingulate Cortex Regions Research Articles

501 Maternal PTSD and Child Brain Function During Implicit Emotion Regulation

OBJECTIVES/GOALS: Maternal mental health, such as post-traumatic stress disorder (PTSD), is closely linked to child mental health. PTSD in mothers is associated with their children’s emotional responses. We examined associations between maternal PTSD and child brain function during emotion regulation. METHODS/STUDY POPULATION: Eight children ages 10-12 years, whose mothers had trauma histories, performed the Emotional N-Back task during functional MRI scanning. Mothers and children each reported on their trauma exposure and PTSD symptom severity. BOLD response to fearful faces during the Emotional N-Back was extracted from two specific brain regions of interest, amygdala and anterior cingulate cortex. These regions are involved in emotional response and attentional control, which are processes intrinsic to emotion regulation. An independent samples t-test was conducted on children’s BOLD response to fearful faces, with maternal PTSD symptom severity (high, low) as the independent variable. A parallel analysis was conducted with child PTSD symptom severity (high, low) as the independent variable. RESULTS/ANTICIPATED RESULTS: We found a main effect of maternal PTSD within brain regions of relevance to implicit emotion regulation. Compared to children whose mothers reported low PTSD symptom severity (n=4), children whose mothers reported high PTSD symptom severity (n=4) showed greater responsiveness to fearful faces in anterior cingulate cortex (t=2.04, p=.09,d=1.44) and amygdala (t=2.44, p=.05, d=1.72) at trending significance. A parallel analysis with child PTSD symptom severity showed no differences in brain function by this factor (ps=.55-.61). DISCUSSION/SIGNIFICANCE: Our pilot study is the first, to our knowledge, to examine associations between maternal PTSD and brain function during emotion regulation in their children. This study lays a foundation for future work; our goal is to explore dysfunction in emotion regulation neurocircuitry as one mechanism linking maternal PTSD to their children’s mental health.

Localized alterations in cortical thickness and sulcal depth of the cingulo-opercular network in relation to lower reading fluency skills in children with dyslexia

The traditional models of reading development describe how language processing and word decoding contribute to reading comprehension and how impairments in word decoding, a defining feature of dyslexia, affect reading comprehension outcomes. However, these models do not include word and sentence reading (contextual reading) fluency, both of which engage executive functions, with notably decreased performance in children with dyslexia. In the current study, we compared cortical thickness and sulcal depth (CT/SD) in the cingulo-opercular (CO) executive functions brain network in children with dyslexia and typical readers and examined associations with word vs. contextual reading fluency. Overall, CT was lower in insular regions and higher in parietal and caudal anterior cingulate cortex regions in children with dyslexia. Children with dyslexia showed positive correlations between word reading fluency and CT/SD in insular regions, whereas no significant correlations were observed in typical readers. For sentence reading fluency, negative correlations with CT/SD were found in insular regions in children with dyslexia, while positive correlations with SD were found in insular regions in typical readers. These results demonstrate the differential relations between word and sentence reading fluency and anatomical circuitry supporting executive functions in children with dyslexia vs. typical readers. It also suggests that word and sentence reading fluency, relate to morphology of executive function-related regions in children with dyslexia, whereas in typical readers, only sentence reading fluency relates to morphology of executive function regions. The results also highlight the role of the insula within the CO network in reading fluency. Here we suggest that word and sentence reading fluency are distinct components of reading that should each be included in the Simple View of Reading traditional model.

TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging.

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis-dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined "behavioural tag/PRP". Interfering with the expression of these molecules resulted in impaired LTM after 24h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a "behavioural tag/PRP" combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.

Brain-based graph-theoretical predictive modeling to map the trajectory of anhedonia, impulsivity, and hypomania from the human functional connectome.

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task. Symptoms were assessed at baseline as well as at 3- and 6-month follow-ups. A whole-brain functional connectome was computed for each fMRI task, and the GPM was applied for symptom prediction using cross-validation. Prediction performance was evaluated by comparing the GPM to a corresponding null model. In addition, the GPM was compared to the connectome-based predictive modeling (CPM). Cross-sectionally, the GPM predicted anhedonia from the global efficiency (a graph theory metric that quantifies information transfer across the connectome) during the RL task, and impulsivity from the centrality (a metric that captures the importance of a region) of the left anterior cingulate cortex during resting-state. At 6-month follow-up, the GPM predicted (hypo)manic symptoms from the local efficiency of the left nucleus accumbens during the RL task and anhedonia from the centrality of the left caudate during resting-state. Notably, the GPM outperformed the CPM, and GPM derived from individuals with unipolar disorders predicted anhedonia and impulsivity symptoms for individuals with bipolar disorders. Importantly, the generalizability of cross-sectional models was demonstrated in an external validation sample. Taken together, across DSM mood diagnoses, efficiency and centrality of the reward circuit predicted symptoms of anhedonia, impulsivity, and (hypo)mania, cross-sectionally and prospectively. The GPM is an innovative modeling approach that may ultimately inform clinical prediction at the individual level.

Association of Age and Response to Methylphenidate HCL Treatment in Adult ADHD: A Proton Magnetic Resonance Spectroscopy Study.

This study investigated the age-dependent effects of methylphenidate (MPH) on brain metabolites including choline (Cho), N-acetyl aspartate (NAA) and creatine (Cr) levels in the dorsolateral prefrontal cortex (DLPFC), striatum, cerebellum, and anterior cingulate cortex (ACC) regions of the brain in adult patients with attention deficit hyperactivity disorder (ADHD). The study was included 60 patients with ADHD between the ages of 18 and 60 years. The patients were grouped with respect to their ages as follows: 18-24 years, 25-30 years, and 31 and over years. Levels of NAA, Cr and Cho in DLPFC, ACC, cerebellum and striatum were measured with magnetic resonance spectroscopy (MRS). Subjects were then given 10 mg of oral MPH and the same metabolite levels were measured 30 minutes apart. Twelve (20%) of the cases were female and 48 (80%) were male. The age distribution of the cases is as follows: 15 subjects between the ages of 18-24, 26 subjects between the ages of 25-30 and 19 subjects over the age of 30. NAA levels were higher after MPH in the DLPFC of the 18-24 age group (p = 0.016) and in the cerebellum of the 25-30 age group (p = 0.041). No increase in Cho and Cr levels was observed after treatment compared to before (p > 0.05). It is thought that treatment of MPH can be effective on metabolites in different brain regions and this effect can vary upon age adult ADHD patients. After MPH treatment, both the 18-24 age group (in the DLPFC) and the 25-30 age group (in the cerebellum) was detected significantly higher NAA levels compared to pre-treatment levels. This increase in NAA levels suggested that pharmacotherapy, especially at early ages, may be effective on neuronal damage.

Heterogeneous Brain Abnormalities in Schizophrenia Converge on a Common Network Associated With Symptom Remission.

There is a huge heterogeneity of magnetic resonance imaging findings in schizophrenia studies. Here, we hypothesized that brain regions identified by structural and functional imaging studies of schizophrenia could be reconciled in a common network. We systematically reviewed the case-control studies that estimated the brain morphology or resting-state local function for schizophrenia patients in the literature. Using the healthy human connectome (n = 652) and a validated technique "coordinate network mapping" to identify a common brain network affected in schizophrenia. Then, the specificity of this schizophrenia network was examined by independent data collected from 13 meta-analyses. The clinical relevance of this schizophrenia network was tested on independent data of medication, neuromodulation, and brain lesions. We identified 83 morphological and 60 functional studies comprising 7389 patients with schizophrenia and 7408 control subjects. The "coordinate network mapping" showed that the atrophy and dysfunction coordinates were functionally connected to a common network although they were spatially distant from each other. Taking all 143 studies together, we identified the schizophrenia network with hub regions in the bilateral anterior cingulate cortex, insula, temporal lobe, and subcortical structures. Based on independent data from 13 meta-analyses, we showed that these hub regions were specifically connected with regions of cortical thickness changes in schizophrenia. More importantly, this schizophrenia network was remarkably aligned with regions involving psychotic symptom remission. Neuroimaging abnormalities in cross-sectional schizophrenia studies converged into a common brain network that provided testable targets for developing precise therapies.

Identifying risk loci for obsessive-compulsive disorder and shared genetic component with schizophrenia: A large-scale multi-trait association analysis with summary statistics

Due to limited samples, no genetic loci have been identified for obsessive-compulsive disorder (OCD) in genome-wide association studies. Additionally, although co-morbidities between OCD and schizophrenia (SCZ) were observed, their common genetic etiology was not completely known. Here, we conducted a comprehensive investigation regarding the genetic architecture of OCD and the common genetic foundation shared by OCD and SCZ using summary statistics data (2688 cases and 7037 controls for OCD; 53,386 cases and 77,258 controls for SCZ). We discovered significant genetic correlation between OCD and SCZ (r̂g=0.296, P = 2.82 × 10−11). We then performed two multi-trait association analyses to detect OCD-associated loci and colocalization analysis to detect causal variants. Parallel gene-level analyses were also implemented. We identified 323 OCD-relevant variants located within 12 loci, with four loci shared the same causal variants between OCD and SCZ. Further, the gene-level analyses discovered 8 OCD-associated genes. Finally, multiple functional analyses at both SNP and gene levels showed that these genetic association signals had significant enrichments in the regions of left ventricle and anterior cingulate cortex, and suggested an important role of pathways involving regulation of telomere maintenance, histone phosphorylation, and GnRH secretion. Overall, this study identified new genetic loci for OCD and provided substantial evidence supporting common genetic foundation underlying OCD and SCZ. The findings advanced our understanding of genetic architecture and pathophysiology of OCD as well as shedding light on shared genetic etiology of the two disorders.

Spectroscopic abnormalities in the pregenual anterior cingulate cortex in obsessive-compulsive disorder using proton magnetic resonance spectroscopy: a controlled study

BackgroundThe main aim of the present study is to determine the role of metabolites observed using proton magnetic resonance spectroscopy (1H-MRS) in obsessive-compulsive disorder (OCD). As the literature describing biochemical changes in OCD yields conflicting results, we focused on accurate metabolite quantification of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline-containing compounds (tCh), and myo-inositol (mI) in the anterior cingulate cortex (ACC) to capture the small metabolic changes between OCD patients and controls and between OCD patients with and without medication.MethodsIn total 46 patients with OCD and 46 healthy controls (HC) matched for age and sex were included in the study. The severity of symptoms in the OCD was evaluated on the day of magnetic resonance imaging (MRI) using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Subjects underwent 1H-MRS from the pregenual ACC (pgACC) region to calculate concentrations of tNAA, tCr, tCho, and mI. Twenty-eight OCD and 28 HC subjects were included in the statistical analysis. We compared differences between groups for all selected metabolites and in OCD patients we analyzed the relationship between metabolite levels and symptom severity, medication status, age, and the duration of illness.ResultsSignificant decreases in tCr (U = 253.00, p = 0.022) and mI (U = 197.00, p = 0.001) in the pgACC were observed in the OCD group. No statistically significant differences were found in tNAA and tCho levels; however, tCho revealed a trend towards lower concentrations in OCD patients (U = 278.00, p = 0.062). Metabolic concentrations showed no significant correlations with the age and duration of illness. The correlation statistics found a significant negative correlation between tCr levels and YBOCS compulsions subscale (cor = -0.380, p = 0.046). tCho and YBOCS compulsions subscale showed a trend towards a negative correlation (cor = -0.351, p = 0.067). Analysis of subgroups with or without medication showed no differences.ConclusionsPatients with OCD present metabolic disruption in the pgACC. The decrease in tCr shows an important relationship with OCD symptomatology. tCr as a marker of cerebral bioenergetics may also be considered as a biomarker of the severity of compulsions. The study failed to prove that metabolic changes correlate with the medication status or the duration of illness. It seems that a disruption in the balance between these metabolites and their transmission may play a role in the pathophysiology of OCD.

The contribution of the cingulate cortex: treating depressive symptoms in first-episode drug naïve schizophrenia.

Our previous study has shown the cingulate cortex abnormalities in first-episode drug naïve (FEDN) schizophrenia patients with comorbid depressive symptoms. However, it remains largely unknown whether antipsychotics may induce morphometric change in cingulate cortex and its relationship with depressive symptoms. The purpose of this study was to further clarify the important role of cingulate cortex in the treatment on depressive symptoms in FEDN schizophrenia patients. In this study, 42 FEDN schizophrenia patients were assigned into depressed patients group (DP, n=24) and non-depressed patients group (NDP, n=18) measured by the 24-item Hamilton Depression Rating Scale (HAMD). Clinical assessments and anatomical images were obtained from all patients before and after 12-week treatment with risperidone. Although risperidone alleviated psychotic symptoms in all patients, depressive symptoms were decreased only in DP. Significant group by time interaction effects were found in the right rostral anterior cingulate cortex (rACC) and other subcortical regions in the left hemisphere. After risperidone treatment, the right rACC were increased in DP. Further, the increasing volume of right rACC was negatively associated with improvement in depressive symptoms. These findings suggested that the abnormality of the rACC is the typical characteristics in schizophrenia with depressive symptoms. It's likely key region contributing to the neural mechanisms underlying the effects of risperidone treatment on depressive symptoms in schizophrenia.

Interoceptive Awareness of the Breath Preserves Attention and Language Networks amidst Widespread Cortical Deactivation: A Within-Participant Neuroimaging Study.

Interoception, the representation of the body's internal state, serves as a foundation for emotion, motivation, and wellbeing. Yet despite its centrality in human experience, the neural mechanisms of interoceptive attention are poorly understood. The Interoceptive/Exteroceptive Attention Task (IEAT) is a novel neuroimaging paradigm that compares behavioral tracking of the respiratory cycle (Active Interoception) to tracking of a visual stimulus (Active Exteroception). Twenty-two healthy participants completed the IEAT during two separate scanning sessions (N = 44) as part of a randomized control trial of Mindful Awareness in Body-oriented Therapy (MABT). Compared to Active Exteroception, Active Interoception deactivated somatomotor and prefrontal regions. Greater self-reported interoceptive sensibility (MAIA scale) predicted sparing from deactivation within the anterior cingulate cortex (ACC) and left-lateralized language regions. The right insula-typically described as a primary interoceptive cortex-was only specifically implicated by its deactivation during an exogenously paced respiration condition (Active Matching) relative to self-paced Active Interoception. Psychophysiological interaction (PPI) analysis characterized Active Interoception as promoting greater ACC connectivity with lateral prefrontal and parietal regions commonly referred to as the Dorsal Attention Network (DAN). In contrast to evidence relating accurate detection of liminal interoceptive signals such as the heartbeat to anterior insula activity, interoceptive attention towards salient signals such as the respiratory cycle may involve reduced cortical activity but greater ACC-DAN connectivity, with greater sensibility linked to reduced deactivation within the ACC and language-processing regions.Significance StatementInteroception, the representation of the body's internal state, is poorly understood compared to the external senses, with existing neuroimaging studies failing to match task difficulty between interoceptive and exteroceptive tasks. The present study used a novel fMRI task to compare interoceptive and exteroceptive attention and explore whether this distinction was moderated by self-reported interoceptive awareness. The results implicate three novel interoceptive mechanisms: interoceptive attention reduces widespread cortical activity while increasing prefrontal connectivity, wherein greater self-reported interoceptive awareness is linked to preserved activation of the anterior cingulate cortex and language regions. Rather than increasing activation of interoceptive cortex, interoceptive attention to the breath may involve attending to body representations typically ignored in favor of exteroceptive information and other forms of cognition.

Anterior insula and dorsal anterior cingulate cortex as a hub of self-regulation: combining activation likelihood estimation meta-analysis and meta-analytic connectivity modeling analysis.

Self-regulation, which is an individual's ability to control their emotions and behaviors in pursuit of goals, is a complex cognitive function that relies on distributed brain networks. Here, we used activation likelihood estimation (ALE) to conduct two large-scale meta-analyses of brain imaging studies of emotional regulation and behavioral regulation. We used single analysis of ALE to identify brain activation regions associated with behavioral regulation and emotion regulation. The conjunction results of the contrast analysis of the two domains showed that the crucial brain regions of dorsal anterior cingulate cortex (dACC), bilateral anterior insula (AI), and right inferior parietal lobule (IPL) are nested within the brain areas of the two regulation domains at the spatial and functional level. In addition, we assessed the coactivation pattern of the four common regions using meta-analytic connectivity modeling (MACM). The coactivation brain patterns based on the dACC and bilateral AI overlapped with the two regulation brain maps in a high proportion. Furthermore, the functional characters of the identified common regions were reverse-inferenced using the BrainMap database. Collectively, these results indicate that the brain regions of dACC and bilateral AI, playing a crucial role as a hub to other brain regions and networks by effective connectivity in self-regulation, are spatially nested in the brain network of behavioral regulation and emotion regulation.

Molecular differences in brain regional vulnerability to aging between males and females.

Aging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive. Using the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer's disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases. This integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD.

Interhemispheric neural characteristics of noxious mechano-nociceptive stimulation in the anterior cingulate cortex.

Pain is an unpleasant sensory and emotional experience. One of the most critical regions of the brain for pain processing is the anterior cingulate cortex (ACC). Several studies have examined the role of this region in thermal nociceptive pain. However, studies on mechanical nociceptive pain have been very limited to date. Although several studies have investigated pain, the interactions between the two hemispheres are still not clear. This study aimed to investigate nociceptive mechanical pain in the ACC bilaterally. Local field potential (LFP) signals were recorded from seven male Wistar rats' ACC regions of both hemispheres. Mechanical stimulations with two intensities, high-intensity noxious (HN) and non-noxious (NN) were applied to the left hind paw. At the same time, the LFP signals were recorded bilaterally from awake and freely moving rats. The recorded signals were analyzed from different perspectives, including spectral analysis, intensity classification, evoked potential (EP) analysis, and synchrony and similarity of two hemispheres. By using spectro-temporal features and support vector machine (SVM) classifier, HN vs. no-stimulation (NS), NN vs. NS, and HN vs. NN were classified with accuracies of 89.6, 71.1, and 84.7%, respectively. Analyses of the signals from the two hemispheres showed that the EPs in the two hemispheres were very similar and occurred simultaneously; however, the correlation and phase locking value (PLV) between the two hemispheres changed significantly after HN stimulation. These variations persisted for up to 4 s after the stimulation. In contrast, variations in the PLV and correlation for NN stimulation were not significant. This study showed that the ACC area was able to distinguish the intensity of mechanical stimulation based on the power activities of neural responses. In addition, our results suggest that the ACC region is activated bilaterally due to nociceptive mechanical pain. Additionally, stimulations above the pain threshold (HN) significantly affect the synchronicity and correlation between the two hemispheres compared to non-noxious stimuli.

Functional Connectivity Modifications in Monoaminergic Circuits Occur in Fatigued MS Patients Treated With Fampridine and Amantadine (P10-3.008)

<h3>Objective:</h3> To investigate changes over time of fatigue severity and concomitant modifications of resting state (RS) functional connectivity (FC) in monoaminergic networks in 45 fatigued multiple sclerosis (MS) patients after different symptomatic treatments. <h3>Background:</h3> Fatigue is common and disabling in MS. Symptomatic treatments for fatigue rely on drugs reinforcing monoaminergic synaptic transmission, suggesting a role of monoaminergic network abnormalities in fatigue pathogenesis. <h3>Design/Methods:</h3> MS patients were randomly, blindly assigned to treatment with fampridine (n=15), amantadine (n=15) or placebo (n=15) and underwent clinical, neuropsychological and 3T RS fMRI at baseline (T0) and after four weeks (W4) of treatment. Fifteen matched healthy controls (HC) were acquired twice. Dopamine-, noradrenaline- and serotonin-related RS FC was derived by independent component analysis (ICA), constrained to PET atlases for dopamine, noradrenaline and serotonin transporters, obtained in HCs’ brain. Changes in modified fatigue impact scale (MFIS) score and monoaminergic-related RS FC were assessed. <h3>Results:</h3> MS patients showed baseline abnormalities <i>vs</i> HC in all three networks, with decreased monoamine-related RS FC in temporal, occipital, insular and cerebellar regions, and increased RS FC in frontal, parietal and subcortical areas. At W4, MFIS scores decreased in all patients’ groups, with no time-by-treatment interaction. At W4, fampridine and amantadine patients showed increased dopamine- and noradrenaline-related RS FC in the insular cortex, as well as increased serotonin-related RS FC in the precuneus/posterior cingulate cortex. Amantadine patients also showed increased dopamine- and noradrenaline-related RS FC in the anterior cingulate cortex (ACC). Conversely, placebo patients mostly showed increased noradrenaline-related RS FC in the precuneus and middle cingulate cortex. Fampridine and placebo groups showed trends towards significant correlations between RS FC modifications and MFIS improvements (r=−0.49: −0.52, p=0.07–0.08). <h3>Conclusions:</h3> Fatigue improved in all groups. Concomitant monoaminergic-related RS FC modifications were found in insular, ACC and parietal regions for fampridine and amantadine MS patients, and in medial parietal regions for placebo patients. <b>Disclosure:</b> Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Dr. Lamanna has nothing to disclose. Bruno Colombo has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis, Biogen, Sanofi Genzyme, TEVA and Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck . Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS).

Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. Our results highlight the need for a standardized tDCS protocol in MDD clinical trials.

Lesions to both somatic and affective pain pathways lead to decreased salience network connectivity.

Human pain is a salient stimulus composed of two main components: a sensory/somatic component, carrying peripheral nociceptive sensation via the spinothalamic tract and brainstem nuclei to the thalamus and then to sensory cortical regions, and an affective (suffering) component, where information from central thalamic nuclei is carried to the anterior insula, dorsal anterior cingulate cortex and other regions. While the sensory component processes information about stimulus location and intensity, the affective component processes information regarding pain-related expectations, motivation to reduce pain and pain unpleasantness. Unlike investigations of acute pain that are based on the introduction of real-time stimulus during brain recordings, chronic pain investigations are usually based on longitudinal and case-control studies, which are limited in their ability to infer the functional network topology of chronic pain. In the current study, we utilized the unique opportunity to target the CNS's pain pathways in two different hierarchical locations to establish causality between pain relief and specific connectivity changes seen within the salience and sensorimotor networks. We examined how lesions to the affective and somatic pain pathways affect resting-state network topology in cancer patients suffering from severe intractable pain. Two procedures have been employed: percutaneous cervical cordotomy (n = 15), hypothesized to disrupt the transmission of the sensory component of pain along the spinothalamic tract, or stereotactic cingulotomy (n = 7), which refers to bilateral intracranial ablation of an area in the dorsal anterior cingulate cortex and is known to ameliorate the affective component of pain. Both procedures led to immediate significant alleviation of experienced pain and decreased functional connectivity within the salience network. However, only the sensory procedure (cordotomy) led to decreased connectivity within the sensorimotor network. Thus, our results support the existence of two converging systems relaying experienced pain, showing that pain-related suffering can be either directly influenced by interfering with the affective pathway or indirectly influenced by interfering with the ascending spinothalamic tract.

The effects of low intensity focused ultrasound on neuronal activity in pain processing regions in a rodent model of common peroneal nerve injury

BackgroundNon-invasive, external low intensity focused ultrasound (liFUS) offers promise for treating neuropathic pain when applied to the dorsal root ganglion (DRG). ObjectiveWe examine how external liFUS treatment applied to the L5 DRG affects neuronal changes in single-unit activity from the primary somatosensory cortex (SI) and anterior cingulate cortex (ACC) in a common peroneal nerve injury (CPNI) rodent model. MethodsMale Sprague Dawley rats were divided into two cohorts: CPNI liFUS and CPNI sham liFUS. Baseline single-unit activity (SUA) recordings were taken 20 min prior to treatment and for 4 h post treatment in 20 min intervals, then analyzed for frequency and compared to baseline. Recordings from the SI and ACC were separated into pyramidal and interneurons based on waveform and principal component analysis. ResultsFollowing CPNI surgery, all rats (n = 30) displayed a significant increase in mechanical sensitivity. In CPNI liFUS rats, there was a significant increase in pyramidal neuron spike frequency in the SI region compared to the CPNI sham liFUS animals beginning at 120 min following liFUS treatment (p < 0.05). In the ACC, liFUS significantly attenuated interneuron firing beginning at 80 min after liFUS treatment (p < 0.05). ConclusionWe demonstrate that liFUS changed neuronal spiking in the SI and ACC regions 80 and 120 min after treatment, respectively, which may in part correlate with improved sensory thresholds. This may represent a mechanism of action how liFUS attenuates neuropathic pain. Understanding the impact of liFUS on pain circuits will help advance the use of liFUS as a non-invasive neuromodulation option.

Modelling transcranial ultrasound neuromodulation: an energy-based multiscale framework

Several animal and human studies have now established the potential of low intensity, low frequency transcranial ultrasound (TUS) for non-invasive neuromodulation. Paradoxically, the underlying mechanisms through which TUS neuromodulation operates are still unclear, and a consensus on the identification of optimal sonication parameters still remains elusive. One emerging hypothesis based on thermodynamical considerations attributes the acoustic-induced nerve activity alterations to the mechanical energy and/or entropy conversions occurring during TUS action. Here, we propose a multiscale modelling framework to examine the energy states of neuromodulation under TUS. First, macroscopic tissue-level acoustic simulations of the sonication of a whole monkey brain are conducted under different sonication protocols. For each one of them, mechanical loading conditions of the received waves in the anterior cingulate cortex region are recorded and exported into a microscopic cell-level 3D viscoelastic finite element model of a neuronal axon embedded in extracellular medium. Pulse-averaged elastically stored and viscously dissipated energy rate densities during axon deformation are finally computed under different sonication incident angles and are mapped against distinct combinations of sonication parameters of the TUS. The proposed multiscale framework allows for the analysis of vibrational patterns of the axons and its comparison against the spectrograms of stimulating ultrasound. The results are in agreement with literature data on neuromodulation, demonstrating the potential of this framework to identify optimised acoustic parameters in TUS neuromodulation. The proposed approach is finally discussed in the context of multiphysics energetic considerations, argued here to be a promising avenue towards a scalable framework for TUS in silico predictions. Statement of significanceLow-intensity transcranial ultrasound (TUS) is poised to become a leading neuromodulation technique for the treatment of neurological disorders. Paradoxically, how it operates at the cellular scale remains unknown, hampering progress in personalised treatment. To this end, models of the multiphysics of neurons able to upscale results to the organ scale are required. We propose here to achieve this by considering an axon submitted to an ultrasound wave extracted from a simulation at the organ scale. Doing so, information pertaining to both stored and dissipated axonal energies can be extracted for a given head/brain morphology. This two-scale multiphysics energetic approach is a promising scalable framework for in silico predictions in the context of personalised TUS treatment.

Low-Intensity Focused Ultrasound Alleviates Chronic Neuropathic Pain-Induced Allodynia by Inhibiting Neuroplasticity in the Anterior Cingulate Cortex.

Low-intensity focused ultrasound (LIFU) is a potential noninvasive method to alleviate allodynia by modulating the central nervous system. However, the underlying analgesic mechanisms remain unexplored. Here, we assessed how LIFU at the anterior cingulate cortex (ACC) affects behavior response and central plasticity resulting from chronic constrictive injury (CCI). The safety of LIFU stimulation was assessed by hematoxylin and eosin (H&E) and Fluoro-Jade C (FJC) staining. A 21-day ultrasound exposure therapy was conducted from day 91 after CCI surgery in mice. We assessed the 50% mechanical withdrawal threshold (MWT50) using Von Frey filaments (VFFs). The expression levels of microtubule-associated protein 2 (MAP2), growth-associated protein 43 (GAP43), and tau were determined via western blotting (WB) and immunofluorescence (IF) staining to evaluate the central plasticity in ACC. The regions of ACC were activated effectively and safely by LIFU stimulation, which significantly increased the number of c-fos-positive cells (P < 0.05) with no bleeding, coagulative necrosis, and neuronal loss. Under chronic neuropathic pain- (CNP-) induced allodynia, MWT50 decreased significantly (P < 0.05), and overexpression of MAP2, GAP43, and tau was also observed. After 3 weeks of treatment, significant increases in MWT50 were found in the CCI+LIFU group compared with the CCI group (P < 0.05). WB and IF staining both demonstrated a significant reduction in the expression levels of MAP2, GAP43, and tau (P < 0.05). LIFU treatment on ACC can effectively attenuate CNP-evoked mechanical sensitivity to pain and reverse aberrant central plasticity.

The effect of long-term methadone maintenance treatment on coupling among three large-scale brain networks in male heroin-dependent individuals: A resting-state fMRI study

PurposeMethadone maintenance treatment (MMT) is considered as an effective and mainstream therapy for heroin dependence. However, whether long-term MMT would improve the coupling among the three core large-scale brain networks (salience, default mode, and executive control) and its relationship with the craving for heroin is unknown. MethodsForty-four male heroin-dependent individuals during long-term MMT, 27 male heroin-dependent individuals after short-term detoxification/abstinence (SA), and 26 demographically matched healthy controls (HC) underwent resting-state functional magnetic resonance imaging. We analyzed the difference in coupling among the salience, default mode, and executive control networks among the three groups and examined how the coupling among these large-scale networks was associated with craving before and after drug-cue exposure. ResultsCompared with the SA group, the MMT group showed lower craving before and after cue exposure and stronger connectivity between the dorsal anterior cingulate cortex (a key node of the salience network) and key regions of the bilateral executive control network, including the bilateral dorsolateral prefrontal cortex, posterior parietal cortex, and dorsomedial prefrontal cortex. Among the heroin-dependent individuals, the functional connectivity was negatively correlated with the craving before and after heroin-cue exposure. ConclusionOur findings suggest that long-term MMT could increase the coupling between the salience and bilateral executive control networks and decrease craving for heroin. These findings contribute to the understanding of the neural mechanism of MMT, from the perspective of large-scale brain networks.