A parietal region processing numerosity of observed actions: An FMRI study.

When observing others' behavior, it is important to perceive not only the identity of the observed actions (OAs), but also the number of times they were performed. Given the mounting evidence implicating posterior parietal cortex in action observation, and in particular that of manipulative actions, the aim of this study was to identify the parietal region, if any, that contributes to the processing of observed manipulative action (OMA) numerosity, using the functional magnetic resonance imaging technique. Twenty-one right-handed healthy volunteers performed two discrimination tasks while in the scanner, responding to video stimuli in which an actor performed manipulative actions on colored target balls that appeared four times consecutively. The subjects discriminated between two small numerosities of either OMAs ("Action" condition) or colors of balls ("Ball" condition). A significant difference between the "Action" and "Ball" conditions was observed in occipito-temporal cortex and the putative human anterior intraparietal sulcus (phAIP) area as well as the third topographic map of numerosity-selective neurons at the post-central sulcus (NPC3) of the left parietal cortex. A further region of interest analysis of the group-average data showed that at the single voxel level the latter area, more than any other parietal or occipito-temporal numerosity map, favored numerosity of OAs. These results suggest that phAIP processes the identity of OMAs, while neighboring NPC3 likely processes the numerosity of the identified OAs.

Observing Others Speak or Sing Activates Spt and Neighboring Parietal Cortex.

To obtain further evidence that action observation can serve as a proxy for action execution and planning in posterior parietal cortex, we scanned participants while they were (1) observing two classes of action: vocal communication and oral manipulation, which share the same effector but differ in nature, and (2) rehearsing and listening to nonsense sentences to localize area Spt, thought to be involved in audio-motor transformation during speech. Using this localizer, we found that Spt is specifically activated by vocal communication, indicating that Spt is not only involved in planning speech but also in observing vocal communication actions. In addition, we observed that Spt is distinct from the parietal region most specialized for observing vocal communication, revealed by an interaction contrast and located in PFm. The latter region, unlike Spt, processes the visual and auditory signals related to other's vocal communication independently. Our findings are consistent with the view that several small regions in the temporoparietal cortex near the ventral part of the supramarginal/angular gyrus border are involved in the planning of vocal communication actions and are also concerned with observation of these actions, though involvements in those two aspects are unequal.

Increased interictal visual network connectivity in patients with migraine with aura.

OBJECTIVE: To evaluate the resting-state visual network functional connectivity in patients with migraine with aura and migraine without aura during the interictal period. POPULATION AND METHODS: Using resting-state functional magnetic resonance imaging, the resting-state visual network integrity was investigated in 20 patients with migraine with aura, 20 age- and sex-matched patients with migraine without aura and 20 healthy controls. Voxel-based morphometry and diffusion tensor imaging were used to assess whether between-groups differences in functional connectivity were dependent on structural or microstructural changes. RESULTS: Resting-state functional magnetic resonance imaging data showed that patients with migraine with aura, compared to both patients with migraine without aura and healthy controls, had a significant increased functional connectivity in the right lingual gyrus within the resting-state visual network (p < 0.05, cluster-level corrected). This abnormal resting-state visual network functional connectivity was observed in the absence of structural or microstructural abnormalities and was not related to migraine severity. CONCLUSIONS: Our imaging data revealed that patients with migraine with aura exhibit an altered resting-state visual network connectivity. These results support the hypothesis of an extrastriate cortex involvement, centred in the lingual gyrus, a brain region related to mechanisms underlying the initiation and propagation of the migraine aura. This resting-state functional magnetic resonance imaging finding may represent a functional biomarker that could differentiate patients experiencing the aura phenomenon from patients with migraine without aura, even between migraine attacks.

Abnormal Connectivity Within Executive Resting-State Network in Migraine With Aura.

OBJECTIVE: To evaluate the executive control network connectivity integrity in patients with migraine with aura, in the interictal period, in comparison to patients with migraine without aura and healthy controls. METHODS: Using resting-state functional magnetic resonance imaging, we compared executive control network functional connectivity in 20 patients with migraine with aura vs 20 sex and age-matched patients with migraine without aura and 20 healthy controls, and assessed the correlation between executive control network functional connectivity and clinical features of patients with migraine. We used voxel-based morphometry and diffusion tensor imaging to investigate potential structural or microstructural changes. RESULTS: Neuropsychological data revealed no significant executive dysfunction in patients with migraine. Resting-state functional magnetic resonance imaging showed significant group differences in right middle frontal gyrus (Talairach coordinates x, y, z: +26, +2, +48) and dorsal anterior cingulate cortex (Talairach coordinates x, y, z: +6, +13, +49), indicating that these areas had a decreased component activity in both patients with migraine with and without aura when compared with healthy controls. Conversely, there were no significant differences in the executive control network functional connectivity between patients with migraine with and without aura (P < .05, cluster-level corrected). These functional abnormalities are independent of structural and microstructural changes and did not significantly correlate with clinical parameters. CONCLUSIONS: Our data demonstrate a disrupted executive control network functional connectivity in patients with migraine with and without aura, in the interictal period. Although this functional phenomenon is present in the absence of clinically relevant executive deficits, it may reflect a vulnerability to executive high-demanding conditions of daily living activities in patients with migraine.

Disrupted default mode network connectivity in migraine without aura.

BACKGROUND: Resting-state functional magnetic resonance imaging (RS-fMRI) has demonstrated disrupted default mode network (DMN) connectivity in a number of pain conditions, including migraine. However, the significance of altered resting-state brain functional connectivity in migraine is still unknown. The present study is aimed to explore DMN functional connectivity in patients with migraine without aura (MwoA) and investigate its clinical significance. METHODS: To calculate and compare the resting-state functional connectivity of the DMN in 20 patients with MwoA, during the interictal period, and 20 gender- and age-matched HC, Brain Voyager QX was used. Voxel-based morphometry was used to assess whether between-group differences in DMN functional connectivity were related to structural differences. Secondary analyses explored associations between DMN functional connectivity, clinical and neuropsychological features of migraineurs. RESULTS: In comparison to HC, patients with MwoA showed decreased connectivity in prefrontal and temporal regions of the DMN. Functional abnormalities were unrelated to detectable structural abnormalities or clinical and neuropsychological features of migraineurs. CONCLUSIONS: Our study provides further evidence of disrupted DMN connectivity in patients with MwoA. We hypothesize that a DMN dysfunction may be related to behavioural processes such as a maladaptive response to stress which seems to characterize patients with migraine.

The Effect of Physical Exercise on People with Psychosis: A Qualitative Critical Review of Neuroimaging Findings.

Recently, genuine motor abnormalities have been recognized as prodromal and predictive signs of psychosis onset and progression. Therefore, physical exercise could represent a potentially relevant clinical tool in promoting the reshaping of neural connections in motor circuitry. The aim of this review is to provide an overview of the literature on neuroimaging findings as a result of physical treatment in psychosis cohorts. Twenty-one studies, all research articles, were included and discussed in this narrative review. Here, we first outlined how the psychotic brain is susceptible to structural plastic changes after aerobic physical training in pathognomic brain areas (i.e., temporal, hippocampal and parahippocampal regions). Secondly, we focused on functional changes, both region-specific and in terms of connections, to gain insights into the involvement of distant but inter-related neural regions in the plastic process occurring after treatment. Third, we attempted to bridge neural plastic changes occurring after physical interventions with clinical and cognitive outcomes of psychotic patients in order to assess the relevance of such neural reshaping in the psychiatric rehabilitation field. In conclusion, we suggest that the current state of the art is presenting physical intervention as effective in promoting neural changes for patients with psychosis; it is not only useful at the onset of the pathology but also in improving the course of the illness and its functional outcome. However, more evidence is needed to improve our knowledge of the efficacy of physical exercise in plastically reorganizing the psychotic brain in the long term, especially within regions lacking specific investigations, such as motor circuitry.

Neuropsychological Evaluation and Functional Magnetic Resonance Imaging Tasks in the Preoperative Assessment of Patients with Brain Tumors: A Systematic Review.

BACKGROUND: Current surgical treatment of gliomas relies on a function-preserving, maximally safe resection approach. Functional Magnetic Resonance Imaging (fMRI) is a widely employed technology for this purpose. A preoperative neuropsychological evaluation should accompany this exam. However, only a few studies have reported both neuropsychological tests and fMRI tasks for preoperative planning-the current study aimed to systematically review the scientific literature on the topic. METHODS: PRISMA guidelines were followed. We included studies that reported both neuropsychological tests and fMRI. Exclusion criteria were: no brain tumors, underage patients, no preoperative assessment, resting-state fMRI only, or healthy sample population/preclinical studies. RESULTS: We identified 123 papers, but only 15 articles were included. Eight articles focused on language; three evaluated cognitive performance; single papers studied sensorimotor cortex, prefrontal functions, insular cortex, and cerebellar activation. Two qualitative studies focused on visuomotor function and language. According to some authors, there was a strong correlation between performance in presurgical neuropsychological tests and fMRI. Several papers suggested that selecting well-adjusted and individualized neuropsychological tasks may enable the development of personalized and more efficient protocols. The fMRI findings may also help identify plasticity phenomena to avoid unintentional damage during neurosurgery. CONCLUSIONS: Most studies have focused on language, the most commonly evaluated cognitive function. The correlation between neuropsychological and fMRI results suggests that altered functions during the neuropsychological assessment may help identify patients who could benefit from an fMRI and, possibly, functions that should be tested. Neuropsychological evaluation and fMRI have complementary roles in the preoperative assessment.

Impact of Physical Exercise Alone or in Combination with Cognitive Remediation on Cognitive Functions in People with Schizophrenia: A Qualitative Critical Review.

Physical exercise and cognitive remediation represent the psychosocial interventions with the largest basis of evidence attesting their effectiveness in improving cognitive performance in people living with schizophrenia according to recent international guidance. The aims of this review are to provide an overview of the literature on physical exercise as a treatment for cognitive impairment in schizophrenia and of the studies that have combined physical exercise and cognitive remediation as an integrated rehabilitation intervention. Nine meta-analyses and systematic reviews on physical exercise alone and seven studies on interventions combining physical exercise and cognitive remediation are discussed. The efficacy of physical exercise in improving cognitive performance in people living with schizophrenia is well documented, but more research focused on identifying moderators of participants response and optimal modalities of delivery is required. Studies investigating the effectiveness of integrated interventions report that combining physical exercise and cognitive remediation provides superior benefits and quicker improvements compared to cognitive remediation alone, but most studies included small samples and did not explore long-term effects. While physical exercise and its combination with cognitive remediation appear to represent effective treatments for cognitive impairment in people living with schizophrenia, more evidence is currently needed to better understand how to implement these treatments in psychiatric rehabilitation practice.

Metacognitive interpersonal therapy in borderline personality disorder: Clinical and neuroimaging outcomes from the CLIMAMITHE study-A randomized clinical trial.

Different psychotherapeutic approaches demonstrated their efficacy but the possible neurobiological mechanism underlying the effect of psychotherapy in borderline personality disorder (BPD) patients is poorly investigated. We assessed the effects of metacognitive interpersonal therapy (MIT) on BPD features and other dimensions compared to structured clinical management (SCM). We also assessed changes in amygdala activation by viewing emotional pictures after psychotherapy. One hundred forty-one patients were referred and 78 BPD outpatients were included and randomized to MIT or SCM. Primary outcome was emotional dysregulation assessed with the Difficulties in Emotion Regulation Scale (DERS). We also assessed BPD symptomatology, number of PD criteria, metacognitive abilities, state-psychopathology, depression, impulsiveness, interpersonal functioning, and alexithymia. A subset of 60 patients underwent functional magnetic resonance imaging before and after 1 year of psychotherapy to assess amygdala activation by viewing standardized emotional pictures (secondary outcome). DERS scores decreased in both groups (time effect p < .001). The Cohen's d effect size for change (baseline posttreatment) on DERS was very large (d = 0.84) in MIT, and large (d = 0.76) in SCM. Both groups significantly improved in depressive symptoms, state-psychopathology, alexithymia, and interpersonal functioning. MIT showed larger effect on metacognitive functions than SCM (Time × Group p < .001). Both interventions showed a significant effect on BPD symptomatology although SCM group showed a larger decrease. On the contrary, MIT group showed larger decrease in impulsivity and number of PD criteria. Interestingly, both MIT and SCM modulated amygdala activation in BPD patients. MIT is a valid and effective psychotherapy for BPD with an impact on amygdala activation. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Magnetic resonance neurography and diffusion tensor imaging of the sciatic nerve in hereditary transthyretin amyloidosis polyneuropathy.

The therapeutic advance in hereditary transthyretin amyloidosis (ATTRv amyloidosis) requires quantitative biomarkers of nerve involvement in order to foster early diagnosis and monitor therapy response. We aimed at quantitatively assessing Magnetic Resonance Neurography (MRN) and Diffusion Tensor Imaging (DTI) properties of the sciatic nerve in subjects with ATTRv-amyloidosis-polyneuropathy (ATTRv-PN) and pre-symptomatic carriers (ATTRv-C). Twenty subjects with pathogenic variants of the TTR gene (mean age 62.20 ± 12.04 years), 13 ATTRv-PN, and 7 ATTRv-C were evaluated and compared with 20 healthy subjects (mean age 60.1 ± 8.27 years). MRN and DTI sequences were performed at the right thigh from the gluteal region to the popliteal fossa. Cross-sectional-area (CSA), normalized signal intensity (NSI), and DTI metrics, including fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) of the right sciatic nerve were measured. Increased CSA, NSI, RD, and reduced FA of sciatic nerve differentiated ATTRv-PN from ATTRv-C and healthy subjects at all levels (p < 0.01). NSI differentiated ATTRv-C from controls at all levels (p < 0.05), RD at proximal and mid-thigh (1.04 ± 0.1 vs 0.86 ± 0.11 p < 0.01), FA at mid-thigh (0.51 ± 0.02 vs 0.58 ± 0.04 p < 0.01). According to receiver operating characteristic (ROC) curve analysis, cutoff values differentiating ATTRv-C from controls (and therefore identifying subclinical sciatic involvement) were defined for FA, RD, and NSI. Significant correlations between MRI measures, clinical involvement and neurophysiology were found. In conclusion, the combination of quantitative MRN and DTI of the sciatic nerve can reliably differentiate ATTRv-PN, ATTRv-C, and healthy controls. More important, MRN and DTI were able to non-invasively identify early subclinical microstructural changes in pre-symptomatic carriers, thus representing a potential tool for early diagnosis and disease monitoring.

Neuro-Environmental Interactions: a time sensitive matter.

The assessment of resting state (rs) neurophysiological dynamics relies on the control of sensory, perceptual, and behavioral environments to minimize variability and rule-out confounding sources of activation during testing conditions. Here, we investigated how temporally-distal environmental inputs, specifically metal exposures experienced up to several months prior to scanning, affect functional dynamics measured using rs functional magnetic resonance imaging (rs-fMRI). We implemented an interpretable XGBoost-Shapley Additive Explanation (SHAP) model that integrated information from multiple exposure biomarkers to predict rs dynamics in typically developing adolescents. In 124 participants (53% females, ages: 13-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of six metals (manganese, lead, chromium, cupper, nickel and zinc) in biological matrices (saliva, hair, fingernails, toenails, blood and urine) and acquired rs-fMRI scans. Using graph theory metrics, we computed global efficiency (GE) in 111 brain areas (Harvard Oxford Atlas). We used a predictive model based on ensemble gradient boosting to predict GE from metal biomarkers, adjusting for age and biological sex. Model performance was evaluated by comparing predicted versus measured GE. SHAP scores were used to evaluate feature importance. Measured versus predicted rs dynamics from our model utilizing chemical exposures as inputs were significantly correlated ( p < 0.001, r = 0.36). Lead, chromium, and copper contributed most to the prediction of GE metrics. Our results indicate that a significant component of rs dynamics, comprising approximately 13% of observed variability in GE, is driven by recent metal exposures. These findings emphasize the need to estimate and control for the influence of past and current chemical exposures in the assessment and analysis of rs functional connectivity.

Occipital atrophy signature in prodromal Lewy bodies disease.

INTRODUCTION: Dementia with Lewy bodies (DLB) is typically characterized by parietal, temporal, and occipital atrophy, but less is known about the newly defined prodromal phases. The objective of this study was to evaluate structural brain alterations in prodromal DLB (p-DLB) as compared to healthy controls (HC) and full-blown dementia (DLB-DEM). METHODS: The study included 42 DLB patients (n = 20 p-DLB; n = 22 DLB-DEM) and 27 HC with a standardized neurological assessment and 3-tesla magnetic resonance imaging. Voxel-wise analyses on gray-matter and cortical thickness were implemented to evaluate differences between p-DLB, DLB-DEM, and HC. RESULTS: p-DLB and DLB-DEM exhibited reduced occipital and posterior parieto-temporal volume and thickness, extending from prodromal to dementia stages. Occipital atrophy was more sensitive than insular atrophy in differentiating p-DLB and HC. Occipital atrophy correlated to frontotemporal structural damage increasing from p-DLB to DLB-DEM. DISCUSSION: Occipital and posterior-temporal structural alterations are an early signature of the DLB continuum and correlate with a long-distance pattern of atrophy.

Neuro-environmental interactions: a time sensitive matter.

Introduction: The assessment of resting state (rs) neurophysiological dynamics relies on the control of sensory, perceptual, and behavioral environments to minimize variability and rule-out confounding sources of activation during testing conditions. Here, we investigated how temporally-distal environmental inputs, specifically metal exposures experienced up to several months prior to scanning, affect functional dynamics measured using rs functional magnetic resonance imaging (rs-fMRI). Methods: We implemented an interpretable XGBoost-shapley additive explanation (SHAP) model that integrated information from multiple exposure biomarkers to predict rs dynamics in typically developing adolescents. In 124 participants (53% females, ages, 13-25 years) enrolled in the public health impact of metals exposure (PHIME) study, we measured concentrations of six metals (manganese, lead, chromium, copper, nickel, and zinc) in biological matrices (saliva, hair, fingernails, toenails, blood, and urine) and acquired rs-fMRI scans. Using graph theory metrics, we computed global efficiency (GE) in 111 brain areas (Harvard Oxford atlas). We used a predictive model based on ensemble gradient boosting to predict GE from metal biomarkers, adjusting for age and biological sex. Results: Model performance was evaluated by comparing predicted versus measured GE. SHAP scores were used to evaluate feature importance. Measured versus predicted rs dynamics from our model utilizing chemical exposures as inputs were significantly correlated (p < 0.001, r = 0.36). Lead, chromium, and copper contributed most to the prediction of GE metrics. Discussion: Our results indicate that a significant component of rs dynamics, comprising approximately 13% of observed variability in GE, is driven by recent metal exposures. These findings emphasize the need to estimate and control for the influence of past and current chemical exposures in the assessment and analysis of rs functional connectivity.

Topological network properties of resting-state functional connectivity patterns are associated with metal mixture exposure in adolescents.

Introduction: Adolescent exposure to neurotoxic metals adversely impacts cognitive, motor, and behavioral development. Few studies have addressed the underlying brain mechanisms of these metal-associated developmental outcomes. Furthermore, metal exposure occurs as a mixture, yet previous studies most often consider impacts of each metal individually. In this cross-sectional study, we investigated the relationship between exposure to neurotoxic metals and topological brain metrics in adolescents. Methods: In 193 participants (53% females, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of four metals (manganese, lead, copper, and chromium) in multiple biological media (blood, urine, hair, and saliva) and acquired resting-state functional magnetic resonance imaging scans. Using graph theory metrics, we computed global and local efficiency (global:GE; local:LE) in 111 brain areas (Harvard Oxford Atlas). We used weighted quantile sum (WQS) regression models to examine association between metal mixtures and each graph metric (GE or LE), adjusted for sex and age. Results: We observed significant negative associations between the metal mixture and GE and LE [ßGE = -0.076, 95% CI (-0.122, -0.031); ßLE= -0.051, 95% CI (-0.095, -0.006)]. Lead and chromium measured in blood contributed most to this association for GE, while chromium measured in hair contributed the most for LE. Discussion: Our results suggest that exposure to this metal mixture during adolescence reduces the efficiency of integrating information in brain networks at both local and global levels, informing potential neural mechanisms underlying the developmental toxicity of metals. Results further suggest these associations are due to combined joint effects to different metals, rather than to a single metal.

Executive resting-state network connectivity in migraine without aura.

BACKGROUND: Converging neuropsychological evidence suggests that in migraine executive functions (EF) may be affected during interictal periods. OBJECTIVE: To evaluate the functional connectivity of the fronto-parietal networks (FPN) known to be associated with EF, in migraine without aura (MwoA) patients, in the interictal period, in comparison to healthy controls (HC). METHODS: Using resting-state functional MRI (RS-fMRI), we compared functional connectivity within the FPN in 14 patients with MwoA versus 14 sex- and age-matched HC, and assessed the correlation between functional connectivity within FPN, clinical features of MwoA patients, and EF. We used voxel-based morphometry to assess whether between-group differences in functional connectivity were dependent on structural differences. RESULTS: Neuropsychological data revealed no significant executive dysfunction in MwoA patients. RS-fMRI showed that MwoA patients, compared to HC, had significant functional connectivity reduction within the right FPN and specifically in the middle frontal gyrus (MFG) and the dorsal anterior cingulate cortex. In addition, we found that MFG reduced connectivity was negatively correlated with the pain intensity of migraine attacks. There were no structural differences between the two groups. CONCLUSIONS: Our data suggest that, even in the absence of clinically evident EF deficits, MwoA is associated with reduced FPN functional connectivity. This study provides further insights into the complex scenario of migraine mechanisms.

The Luria-Nebraska Neuropsychological Battery Neuromotor Tasks: From Conventional to Image-Derived Measures.

Background: Sensorimotor difficulties significantly interfere with daily activities, and when undiagnosed in early life, they may increase the risk of later life cognitive and mental health disorders. Subtests from the Luria-Nebraska Neuropsychological Battery (LNNB) discriminate sensorimotor impairments predictive of sensorimotor dysfunction. However, scoring the LNNB sensorimotor assessment is highly subjective and time consuming, impeding the use of this task in epidemiologic studies. Aim: To train and validate a novel automated and image-derived scoring approach to the LNNB neuro-motor tasks for use in adolescents and young adults. Methods: We selected 46 adolescents (19.6 +/− 2.3 years, 48% male) enrolled in the prospective Public Health Impact of Metal Exposure (PHIME) study. We visually recorded the administration of five conventional sensorimotor LNNB tasks and developed automated scoring alternatives using a novel mathematical approach combining optic flow fields from recorded image sequences on a frame-by-frame basis. We then compared the conventional and image-derived LNNB task scores using Pearson's correlations. Finally, we provided the accuracy of the novel scoring approach with Receiver Operating Characteristic (ROC) curves and the area under the ROC curves (AUC). Results: Image-derived LNNB task scores strongly correlated with conventional scores, which were assessed and confirmed by multiple administrators to limit subjectivity (Pearson's correlation ≥ 0.70). The novel image-derived scoring approach discriminated participants with low motility (

Aberrant Structural Connectivity of the Triple Network System in Borderline Personality Disorder Is Associated with Behavioral Dysregulation.

BACKGROUND: Core symptoms of Borderline Personality Disorder (BPD) are associated to aberrant connectivity of the triple network system (salience network [SN], default mode network [DMN], executive control network [ECN]). While functional abnormalities are widely reported, structural connectivity (SC) and anatomical changes have not yet been investigated. Here, we explored the triple network's SC, structure, and its association with BPD clinical features. METHODS: A total of 60 BPD and 26 healthy controls (HC) underwent a multidomain neuropsychological and multimodal MRI (diffusion- and T1-weighted imaging) assessment. Metrics (fractional anisotropy [FA], mean diffusivity [MD], cortical thickness) were extracted from SN, DMN, ECN (triple network), and visual network (control network) using established atlases. Multivariate general linear models were conducted to assess group differences in metrics and associations with clinical features. RESULTS: Patients showed increased MD in the anterior SN, dorsal DMN, and right ECN compared to HC. Diffusivity increases were more pronounced in patients with higher behavioral dysregulation, i.e., suicidal attempting, self-harm, and aggressiveness. No differences were detected in network structure. CONCLUSIONS: These results indicate that the triple network system is impaired in BPD at the microstructural level. The preferential involvement of anterior and right-lateralized subsystems and their clinical association suggests that these abnormalities could contribute to behavioral dysregulation.

Distributed changes in default-mode resting-state connectivity in multiple sclerosis.

BACKGROUND: The default-mode network (DMN) has been increasingly recognized as relevant to cognitive status. OBJECTIVES: To explore DMN changes in patients with relapsing-remitting (RR) multiple sclerosis (MS) and to relate these to the cognitive status. METHODS: Eighteen cognitively impaired (CI) and eighteen cognitively preserved (CP) RRMS patients and eighteen healthy controls (HCs), matched for age, sex and education, underwent neuropsychological evaluation and anatomical and resting-state functional MRI (rs-fMRI). DMN functional connectivity was evaluated from rs-fMRI data via independent component analysis. T2 lesion load (LL) was computed by a semi-automatic method and global and local atrophy was estimated by SIENAX and SPM8 voxel-based morphometry analyses from 3D-T1 images. RESULTS: When the whole group of RRMS patients was compared with HCs, DMN connectivity was significantly weaker in the anterior cingulate cortex, whereas it was significantly weaker in the core but stronger at the periphery of the posterior cingulate cortex. These findings were more evident in CP than CI patients. Observed DMN changes did not correlate with global atrophy or T2-LL, but were locally associated with regional grey matter loss. CONCLUSION: Relapsing-remitting multiple sclerosis patients show a consistent dysfunction of DMN at the level of the anterior node. DMN distribution changes in the posterior node may reflect a possible compensatory effect on cognitive performance.

Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease with Transcranial Magnetic Stimulation (NEST4AD): Rationale and Study Design.

BACKGROUND: Default mode network (DMN) dysfunction is well established in Alzheimer's disease (AD) and documented in both preclinical stages and at-risk subjects, thus representing a potential disease target. Multi-sessions of repetitive transcranial magnetic stimulation (rTMS) seem capable of modulating DMN dynamics and memory in healthy individuals and AD patients; however, the potential of this approach in at-risk subjects has yet to be tested. OBJECTIVE: This study will test the effect of rTMS on the DMN in healthy older individuals carrying the strongest genetic risk factor for AD, the Apolipoprotein E (APOE) ɛ4 allele. METHODS: We will recruit 64 older participants without cognitive deficits, 32 APOE ɛ4 allele carriers and 32 non-carriers as a reference group. Participants will undergo four rTMS sessions of active (high frequency) or sham DMN stimulation. Multimodal imaging exam (including structural, resting-state, and task functional MRI, and diffusion tensor imaging), TMS with concurrent electroencephalography (TMS-EEG), and cognitive assessment will be performed at baseline and after the stimulation sessions. RESULTS: We will assess changes in DMN connectivity with resting-state functional MRI and TMS-EEG, as well as changes in memory performance in APOE ɛ4 carriers. We will also investigate the mechanisms underlying DMN modulation through the assessment of correlations with measures of neuronal activity, excitability, and structural connectivity with multimodal imaging. CONCLUSION: The results of this study will inform on the physiological and cognitive outcomes of DMN stimulation in subjects at risk for AD and on the possible mechanisms. These results may outline the design of future non-pharmacological preventive interventions for AD.