Modulation Of Functional Connectivity Research Articles

Transient alteration of Awareness triggered by direct electrical stimulation of the brain

BackgroundAwareness is a state of consciousness that enables a subject to interact with the environment. Transient alteration of awareness (AA) is a disabling sign of many types of epileptic seizures. The brain mechanisms of awareness and its alteration are not well known. Objective/HypothesisTransient and isolated AA induced by electrical brain stimulation during a stereoelectroencephalography (SEEG) recording represents an ideal model for studying the associated modifications of functional connectivity and locating the hubs of awareness networks. MethodsWe investigated the SEEG signals-based brain functional connectivity (FC) changes vs background occurring during AA triggered by three thalamic and two insular stimulations in three patients explored by SEEG in the frame of presurgical evaluation for focal drug-resistant epilepsy. The results were compared to the stimulations of the same sites that did not induce clinical changes (negative stimulations). ResultsWe observed decreased node strength in the pulvinar, insula, and parietal associative cortices during the thalamic and insular stimulations that induced AA. The link strengths characterizing functional coupling between the thalamus and the insular, prefrontal, temporal, or parietal associative cortices were also decreased. In contrast, there was an increased synchronization between the precuneus and the temporal lateral cortex. These FC changes were absent during the negative stimulations. ConclusionOur study highlights the role of the pulvinar, insular, and parietal hubs in maintaining the awareness networks and paves the way for invasive or non-invasive neuromodulation protocols to reduce AA manifestations during epileptic seizures.

Neural correlates of motor learning: Network communication versus local oscillations

Abstract Learning new motor skills through training, also termed motor learning, is central for everyday life. Current training strategies recommend intensive task-repetitions aimed at inducing local activation of motor areas, associated with changes in oscillation amplitudes (“event-related power”) during training. More recently, another neural mechanism was suggested to influence motor learning: modulation of functional connectivity (FC), that is, how much spatially separated brain regions communicate with each other before and during training. The goal of the present study was to compare the impact of these two neural processing types on motor learning. We measured EEG before, during, and after a finger-tapping task (FTT) in 20 healthy subjects. The results showed that training gain, long-term expertise (i.e., average motor performance), and consolidation were all predicted by whole-brain alpha- and beta-band FC at motor areas, striatum, and mediotemporal lobe (MTL). Local power changes during training did not predict any dependent variable. Thus, network dynamics seem more crucial than local activity for motor sequence learning, and training techniques should attempt to facilitate network interactions rather than local cortical activation.

Distinct visual processing networks for foveal and peripheral visual fields.

This study investigates the systematic differences between foveal and peripheral vision, two crucial components of visual processing essential for navigating our surroundings. By simultaneously recording from a large number of neurons in the visual attentional neural network, we revealed substantial variations in the proportion and functional characteristics of foveal and peripheral units across different brain regions. We uncovered differential modulation of functional connectivity by attention and visual selectivity, elucidated the intricate interplay between foveal and peripheral processing in spatial attention and saccade selection, and linked neural responses to search behavior. Overall, our study contributes to a deeper understanding of how the brain processes and integrates visual information for active visual behaviors.

Change in Striatal Functional Connectivity Networks Across Two Years Due to Stimulant Exposure in Childhood ADHD: Results from the ABCD Sample.

Widely prescribed for Attention-Deficit/Hyperactivity Disorder (ADHD), stimulants (e.g., methylphenidate) have been studied for their chronic effects on the brain in prospective designs controlling dosage and adherence. While controlled approaches are essential, they do not approximate real-world stimulant exposure contexts where medication interruptions, dosage non-compliance, and polypharmacy are common. Brain changes in real-world conditions are largely unexplored. To fill this gap, we capitalized on the observational design of the Adolescent Brain Cognitive Development (ABCD) study to examine effects of stimulants on large-scale bilateral cortical networks' resting-state functional connectivity (rs-FC) with 6 striatal regions (left and right caudate, putamen, and nucleus accumbens) across two years in children with ADHD. Bayesian hierarchical regressions revealed associations between stimulant exposure and change in rs-FC of multiple striatal-cortical networks, affiliated with executive and visuo-motor control, which were not driven by general psychotropic medication. Of these connections, three were selective to stimulants versus stimulant naive: reduced rs-FC between caudate and frontoparietal network, and between putamen and frontoparietal and visual networks. Comparison with typically developing children in the ABCD sample revealed stronger rs-FC reduction in stimulant-exposed children for putamen and frontoparietal and visual networks, suggesting a normalizing effect of stimulants. 14% of stimulant-exposed children demonstrated reliable reduction in ADHD symptoms, and were distinguished by stronger rs-FC reduction between right putamen and visual network. Thus, stimulant exposure for a two-year period under real-world conditions modulated striatal-cortical functional networks broadly, had a normalizing effect on a subset of networks, and was associated with potential therapeutic effects involving visual attentional control.

Modulation of habenular and nucleus accumbens functional connectivity by ketamine in major depression.

Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Since ketamine elicits rapid antidepressant and antianhedonic effects in MDD, this study sought to investigate how serial ketamine infusion (SKI) treatment modulates static and dynamic functional connectivity (FC) in Hb and NAc functional networks. MDD participants (n=58, mean age=40.7 years, female=28) received four ketamine infusions (0.5mg/kg) 2-3 times weekly. Resting-state functional magnetic resonance imaging (fMRI) scans and clinical assessments were collected at baseline and 24h post-SKI. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Changes in FC pre-to-post SKI, and correlations with changes with mood and anhedonia were examined. Comparisons of FC between patients and healthy controls (HC) at baseline (n=55, mean age=32.6, female=31), and between HC assessed twice (n=16) were conducted as follow-up analyses. Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in mood ratings. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. No differences were observed between HC at baseline or over time. Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions in MDD. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.

Functional connectivity alterations in the thalamus among patients with bronchial asthma.

Bronchial Asthma (BA) is a common chronic respiratory disease worldwide. Earlier research has demonstrated abnormal functional connectivity (FC) in multiple cognition-related cortices in asthma patients. The thalamus (Thal) serves as a relay center for transmitting sensory signals, yet the modifications in the thalamic FC among individuals with asthma remain uncertain. This research employed the resting-state functional connectivity (rsFC) approach to explore alterations in thalamic functional connectivity among individuals with BA. After excluding participants who did not meet the criteria, this study finally included 31 patients with BA, with a gender distribution of 16 males and 15 females. Subsequently, we recruited 31 healthy control participants (HC) matched for age, gender, and educational background. All participants underwent the Montreal Cognitive Assessment (MoCA) and the Hamilton Depression Rating Scale (HAMD) assessment. Following this, both groups underwent head magnetic resonance imaging scans, and resting-state functional magnetic resonance imaging (rs-fMRI) data was collected. Based on the AAL (Automated Anatomical Labeling) template, the bilateral thalamic regions were used as seed points (ROI) for subsequent rsFC research. Pearson correlation analysis was used to explore the relationship between thalamic functional connectivity and neuropsychological scales in both groups. After controlling for potential confounding factors such as age, gender, intelligence, and emotional level, a two-sample t-test was further used to explore differences in thalamic functional connectivity between the two groups of participants. Compared to the HC group, the BA group demonstrated heightened functional connectivity (FC) between the left thalamus and the left cerebellar posterior lobe (CPL), left postcentral gyrus (PCG), and right superior frontal gyrus (SFG). Concurrently, there was a decrease in FC with both the Lentiform Nucleus (LN) and the left corpus callosum (CC). Performing FC analysis with the right thalamus as the Region of Interest (ROI) revealed an increase in FC between the right thalamus and the right SFG as well as the left CPL. Conversely, a decrease in FC was observed between the right thalamus and the right LN as well as the left CC. In our study, we have verified the presence of aberrant FC patterns in the thalamus of BA patients. When compared to HCs, BA patients exhibit aberrant alterations in FC between the thalamus and various brain areas connected to vision, hearing, emotional regulation, cognitive control, somatic sensations, and wakefulness. This provides further confirmation of the substantial role played by the thalamus in the advancement of BA.

Differential modulation of resting-state functional connectivity between amygdala and precuneus after acute physical exertion of varying intensity: indications for a role in affective regulation.

Physical activity influences psychological well-being. This study aimed to determine the impact of exercise intensity on psychological well-being and alterations in emotion-related brain functional connectivity (FC). Twenty young, healthy, trained athletes performed a low- and high-intensity interval exercise (LIIE and HIIE) as well as a control condition in a within-subject crossover design. Before and after each condition, Positive And Negative Affect Scale (PANAS) was assessed as well as resting-state functional MRI (rs-fMRI). Voxel-wise FC was examined for bilateral amygdala seed region to whole-brain and emotion-related anatomical regions (e.g., insula, temporal pole, precuneus). Data analyses were performed using linear mixed-effect models with fixed factors condition and time. The PANAS Positive Affect scale showed a significant increase after LIIE and HIIE and a significant reduction in Negative Affect after the control condition. In rs-fMRI, no significant condition-by-time interactions were observed between the amygdala and whole brain. Amygdala-precuneus FC analysis showed an interaction effect, suggesting reduced post-exercise anticorrelation after the control condition, but stable, or even slightly enhanced anticorrelation for the exercise conditions, especially HIIE. In conclusion, both LIIE and HIIE had positive effects on mood and concomitant effects on amygdala-precuneus FC, particularly after HIIE. Although no significant correlations were found between amygdala-precuneus FC and PANAS, results should be discussed in the context of affective disorders in whom abnormal amygdala-precuneus FC has been observed.

Structural and functional correlates of disability, motor and cognitive performances in multiple sclerosis: Focus on the globus pallidus

ObjectivesTo explore structural and functional alterations of external (GPe) and internal (GPi) globus pallidus in people with multiple sclerosis (pwMS) compared to healthy controls (HC) and analyze their relationship with measures of clinical disability, motor and cognitive impairment. MethodsSixty pwMS and 30 HC comparable for age and sex underwent 3.0T MRI, including conventional, diffusion tensor MRI and resting state (RS) functional MRI. Expanded Disability Status Scale (EDSS) scores were rated and timed 25-foot walk (T25FW) test, nine-hole peg test (9HPT), and paced auditory serial addition test (PASAT) were administered. Two operators segmented the GP into GPe and GPi. Volumes, T1/T2 ratio, diffusivity indices and seed-based RS functional connectivity (FC) of the GP and its components were assessed. ResultsPwMS had no atrophy or altered diffusivity measures of the GP. Compared to HC, pwMS had higher T1/T2 ratio in both GP regions, which correlated with EDSS score (r = 0.26–0.39, p = 0.01–0.05). RS FC analysis highlighted component-specific functional alterations in pwMS: the GPe had decreased RS FC with fronto-parietal cortices, whereas the GPi had decreased intra-GP RS FC and increased RS FC with the thalamus. Worse EDSS, 9HPT, T25FW and PASAT scores were associated with GP RS FC modifications (r=-0.51‒0.51, p < 0.001). ConclusionsStructural GP involvement in MS was homogeneous across its portions. Increased T1/T2 ratio values, possibly representing iron accumulation, were related to more severe disability. RS FC alterations of the GPe and GPi were consistent with their roles within the basal ganglia network and correlated with worse functional status, suggesting less efficient communication between structures.

Resting state functional connectivity modifications in monoaminergic circuits underpin fatigue development in patients with multiple sclerosis.

Dysregulation of monoaminergic networks might have a role in the pathogenesis of fatigue in multiple sclerosis (MS). We investigated longitudinal changes of resting state (RS) functional connectivity (FC) in monoaminergic networks and their association with the development of fatigue in MS. Eighty-nine MS patients and 49 age- and sex-matched healthy controls (HC) underwent neurological, fatigue, and RS functional MRI assessment at baseline and after a median follow-up of 1.3 years (interquartile range = 1.01-2.01 years). Monoaminergic-related RS FC was estimated with an independent component analysis constrained to PET atlases for dopamine (DA), noradrenaline (NA), and serotonin (5-HT) transporters. At baseline, 24 (27%) MS patients were fatigued (F) and 65 were not fatigued (NF). Of these, 22 (34%) developed fatigue (DEV-FAT) at follow-up and 43 remained not fatigued (NO-FAT). At baseline, F-MS patients showed increased monoaminergic-related RS FC in the caudate nucleus vs NF-MS and in the hippocampal, postcentral, temporal, and occipital cortices vs NF-MS and HC. Moreover, F-MS patients exhibited decreased RS FC in the frontal cortex vs NF-MS and HC, and in the thalamus vs NF-MS. During the follow-up, no RS FC changes were observed in HC. NO-FAT patients showed limited DA-related RS FC modifications, whereas DEV-FAT MS patients showed increased DA-related RS FC in the left hippocampus, significant at time-by-group interaction analysis. In the NA-related network, NO-FAT patients showed decreased RS FC over time in the left superior frontal gyrus. This region showed increased RS FC in both DEV-FAT and F-MS patients; this divergent behavior was significant at time-by-group interaction analysis. Finally, DEV-FAT MS patients presented increased 5-HT-related RS FC in the angular and middle occipital gyri, while this latter region showed decreased 5-HT-related RS FC during the follow-up in F-MS patients. In MS patients, distinct patterns of alterations were observed in monoaminergic networks based on their fatigue status. Fatigue was closely linked to specific changes in the basal ganglia and hippocampal, superior frontal, and middle occipital cortices.

Modulations of resting-static functional connectivity on insular by electroacupuncture in subjective tinnitus.

To explore the modulations of electroacupuncture in subjective tinnitus (ST) by comparing the difference of functional connectivity (FC) in ST patients and healthy volunteers between the insular (INS) and the whole brain region. A total of 34 ST patients were selected into electroacupuncture group (EG) and 34 age- and sex-matched normal subjects were recruited into control group (CG). The EG received acupuncture at SI19 (Tinggong), GB11 (Touqiaoyin), TE17 (Yifeng), GV20 (Baihui), GV15 (Yamen), GV14 (Dazhui), SJ13 (Zhongzhu), among which the points of SI19 and GB11 were connected to the electroacupuncture instrument with the density wave of 2/50 Hz, and 3 treatments per week for 10 sessions in total. The severity of tinnitus was evaluated by Tinnitus Handicap Inventory (THI), the hearing status was recorded using pure tone audiometry, and resting-state functional magnetic resonance imaging (rs-fMRI) was performed on the brain before and after treatment, the CG received no intervention yet only rs-fMRI data were collected. With the electroacupuncture treatment, the total THI score, average air conduction threshold of patients of EG were significantly lower than before (p < 0.01), and the total effective rate was 88.24%. Compared with CG, FC of ST patients between INS and left superior temporal gyrus and right hippocampal significantly decreased before treatment, while FC of ST patients between INS and right superior frontal gyrus, left middle frontal gyrus and right anterior cuneus significantly decreased after treatment (voxel p < 0.001, cluster p < 0.05, corrected with GRF). FC of ST patients between the INS and right middle frontal gyrus, left superior frontal gyrus and right paracentral lobule showed a significant decrease after treatment (voxel p < 0.001, cluster p < 0.05, corrected with GRF). In addition, THI score in EG was negatively correlated with the reduction of FC value in INS-left superior frontal gyrus before treatment (r = -0.41, p = 0.017). Therefore, this study suggests that abnormal FC of INS may be one of the significant central mechanisms of ST patients and can be modulated by electroacupuncture. Electroacupuncture treatment can effectively reduce or eliminate tinnitus symptoms in ST patients and improve the hearing by decreasing FC between the INS and the frontal and temporal brain regions.

Cortical and white matter substrates supporting visuospatial working memory

ObjectiveIn tasks involving new visuospatial information, we rely on working memory, supported by a distributed brain network. We investigated the dynamic interplay between brain regions, including cortical and white matter structures, to understand how neural interactions change with different memory loads and trials, and their subsequent impact on working memory performance. MethodsPatients undertook a task of immediate spatial recall during intracranial EEG monitoring. We charted the dynamics of cortical high-gamma activity and associated functional connectivity modulations in white matter tracts. ResultsElevated memory loads were linked to enhanced functional connectivity via occipital longitudinal tracts, yet decreased through arcuate, uncinate, and superior-longitudinal fasciculi. As task familiarity grew, there was increased high-gamma activity in the posterior inferior-frontal gyrus (pIFG) and diminished functional connectivity across a network encompassing frontal, parietal, and temporal lobes. Early pIFG high-gamma activity was predictive of successful recall. Including this metric in a logistic regression model yielded an accuracy of 0.76. ConclusionsOptimizing visuospatial working memory through practice is tied to early pIFG activation and decreased dependence on irrelevant neural pathways. SignificanceThis study expands our knowledge of human adaptation for visuospatial working memory, showing the spatiotemporal dynamics of cortical network modulations through white matter tracts.

Modulation of smoker brain activity and functional connectivity by tDCS: A go/no-go task-state fMRI study

BackgroundTranscranial direct current stimulation (tDCS) applied to particular brain areas may reduce a smoker's smoking cravings. Most studies on tDCS mechanisms are performed on brains in the resting state. Therefore, brain activity changes induced by tDCS during tasks need to be further studied. MethodsForty-six male smokers were randomised to receive anodal tDCS of the left/right dorsolateral prefrontal cortex (DLPFC) or sham tDCS. A go/no-go task was performed before and after stimulation, respectively. Brain activity and functional connectivity (FC) changes during the task state before and after tDCS were used for comparison. ResultsThis study revealed that the anodal stimulation over one DLPFC area caused decreased activity in the ipsilateral precuneus during the go task state. Right DLPFC stimulation increased the FC between the bilateral DLPFCs and the right anterior cingulate cortex (ACC), which is closely associated with cognition and inhibition of executive functions. Additionally, the study showed variations in brain activity depending on whether the anode was positioned over the right or left DLPFC (R-DLPFC or L-DLPFC). ConclusionDuring the go task, tDCS might exert a suppressive effect on some brain areas, such as the precuneus. Stimulation on the R-DLPFC might strengthen the FC between the right ACC and the bilateral DLPFCs, which could enhance the ability of behavioural decision-making and inhibition to solve conflicts effectively. Stimulating the L-DLPFC alone could increase the FC of bilateral DLPFCs with some brain regions associated with response inhibition.

Attention-related power and functional connectivity modulation associated with long-term alpha neurofeedback training

Electroencephalography (EEG) based Neurofeedback training (NFT) is a non-invasive, brain-modulation technique that can improve the subject’s attention. In this research, the effectiveness of long-term NFT on the subject’s attention is explored. Real-time frontal lobe alpha band (8–13 Hz) power was used as feedback. The subjects were divided into the NFT group (n = 25) which received training and the control group (n = 25) which did not. All the subjects participated in the attention network task (ANT) at three stages i.e., before, mid, and at the end of NFT sessions. The EEG and behavioral data (Response time (RT) of the ANT task) were recorded for all subjects. The EEG data were pre-processed using a manual artifact removal procedure to avoid event-related information loss. Alpha band modulation can affect other bands such as theta (4–8 Hz) and beta (13–30 Hz) hence event-related functional connectivity (FC) and band power (BP) were analyzed in these bands as well. In event-related analysis, a significant increase (ANOVA & T-Test: P < 0.05) in theta and alpha power and FC within the NFT group was observed after NFT sessions whereas the changes observed within the control group were not significant. The RT of the subjects in the NFT group decreased. The increase in event-related power and connectivity within the theta and alpha band and the decrease in RT in the NFT group indicate the effectiveness of NFT sessions in the enhancement of attention.

3T vs. 7T fMRI: capturing early human memory consolidation after motor task utilizing the observed higher functional specificity of 7T.

Functional magnetic resonance imaging (fMRI) visualizes brain structures at increasingly higher resolution and better signal-to-noise ratio (SNR) as field strength increases. Yet, mapping the blood oxygen level dependent (BOLD) response to distinct neuronal processes continues to be challenging. Here, we investigated the characteristics of 7 T-fMRI compared to 3 T-fMRI in the human brain beyond the effect of increased SNR and verified the benefits of 7 T-fMRI in the detection of tiny, highly specific modulations of functional connectivity in the resting state following a motor task. 18 healthy volunteers underwent two resting state and a stimulus driven measurement using a finger tapping motor task at 3 and 7 T, respectively. The SNR for each field strength was adjusted by targeted voxel size variation to minimize the effect of SNR on the field strength specific outcome. Spatial and temporal characteristics of resting state ICA, network graphs, and motor task related activated areas were compared. Finally, a graph theoretical approach was used to detect resting state modulation subsequent to a simple motor task. Spatial extensions of resting state ICA and motor task related activated areas were consistent between field strengths, but temporal characteristics varied, indicating that 7 T achieved a higher functional specificity of the BOLD response than 3 T-fMRI. Following the motor task, only 7 T-fMRI enabled the detection of highly specific connectivity modulations representing an "offline replay" of previous motor activation. Modulated connections of the motor cortex were directly linked to brain regions associated with memory consolidation. These findings reveal how memory processing is initiated even after simple motor tasks, and that it begins earlier than previously shown. Thus, the superior capability of 7 T-fMRI to detect subtle functional dynamics promises to improve diagnostics and therapeutic assessment of neurological diseases.

Differential Corticospinal Excitability and Cortical Functional Connectivity Modulation by Spinal Cord Transcutaneous Stimulation-based Motor Training versus Motor Training alone in Able-bodied and SCI participants: A Multiple Case Study.

Spinal cord transcutaneous stimulation (scTS) has shown its potential for boosting motor, sensory, and autonomic function recovery after a spinal cord injury. Despite the demonstrated benefits, little is known about the exact neuromodulatory mechanisms triggered by scTS and the cortex involvement in the beneficial effects observed. Here, we examine the effects of scTS-based motor training and motor training alone on sensorimotor cortical functional connectivity and corticospinal excitability in able-bodied and SCI participants.Clinical Relevance- The results show preliminary evidence of differential cortical involvement and modulation by scTS-based motor training in uninjured and spinal-cord injured individuals. A better understanding of scTS mechanisms of action could help optimize the intervention design and potentiate its benefits.

Functional connectivity modifications in monoaminergic circuits occur in fatigued MS patients treated with fampridine and amantadine.

Monoaminergic network dysfunction may have a role in multiple sclerosis (MS) fatigue pathogenesis. To investigate modifications of fatigue severity and resting state (RS) functional connectivity (FC) in monoaminergic networks of 45 fatigued MS patients after different symptomatic treatments. Patients were randomly, blindly assigned to fampridine (n = 15), amantadine (n = 15) or placebo (n = 15) treatment and underwent clinical and 3T-MRI evaluations at baseline (t0) and week 4 (w4), i.e. after four weeks of treatment. Fifteen healthy controls (HC) were enrolled. Dopamine-, noradrenaline- and serotonin-related RS FC was assessed by PET-guided constrained independent component analysis. At t0, MS patients showed widespread monoamine-related RS FC abnormalities. At w4, fatigue scores decreased in all groups (p = range < 0.001-0.002). Concomitantly, fampridine and amantadine patients showed increased insular RS FC in dopamine-related and noradrenaline-related networks (p < 0.001, uncorrected). Amantadine patients also showed increased RS FC of anterior cingulate cortex in dopamine-related and noradrenaline-related networks (p < 0.001, uncorrected). Placebo patients showed increased precuneus/middle cingulate RS FC in the noradrenaline-related network (p < 0.001, uncorrected). In fampridine and placebo patients, just tendencies towards correlations between RS FC and fatigue modifications were found. In MS patients, specific RS FC modifications in PET-guided monoaminergic networks were observed, concomitantly with fatigue improvements following treatment. EudraCT 2010-023678-38.

Directed connectivity in Parkinson's disease patients during over-ground and treadmill walking

Treadmill walking is considered a useful therapeutic tool for improving gait in Parkinson's disease (PD) patients. The study investigated the role of top-down, frontal-parietal versus bottom-up parietal-frontal networks, during over-ground and treadmill walking in PD and control subjects, using functional connectivity. To this end, EEG was recorded simultaneously, during a ten-minute period of continuous walking either over-ground or on a treadmill, in thirteen PD patients and thirteen age-matched controls. We evaluated EEG directed connectivity, using phase transfer entropy in three frequency bands: theta, alpha and beta. PD patients showed increased top-down connectivity during over-ground compared with treadmill walking, in the beta frequency range. Control subjects showed no significant differences in connectivity between the two walking conditions. Our results suggest that in PD patients, OG walking was associated with increased allocation of attentional resources, compared with that on the TL. These functional connectivity modulations may shed further light on the mechanisms underlying treadmill versus overground walking in PD.

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).

Transcranial focused ultrasound selectively increases perfusion and modulates functional connectivity of deep brain regions in humans.

Low intensity, transcranial focused ultrasound (tFUS) is a re-emerging brain stimulation technique with the unique capability of reaching deep brain structures non-invasively. We sought to demonstrate that tFUS can selectively and accurately target and modulate deep brain structures in humans important for emotional functioning as well as learning and memory. We hypothesized that tFUS would result in significant longitudinal changes in perfusion in the targeted brain region as well as selective modulation of BOLD activity and BOLD-based functional connectivity of the target region. In this study, we collected MRI before, simultaneously during, and after tFUS of two deep brain structures on different days in sixteen healthy adults each serving as their own control. Using longitudinal arterial spin labeling (ASL) MRI and simultaneous blood oxygen level dependent (BOLD) functional MRI, we found changes in cerebral perfusion, regional brain activity and functional connectivity specific to the targeted regions of the amygdala and entorhinal cortex (ErC). tFUS selectively increased perfusion in the targeted brain region and not in the contralateral homolog or either bilateral control region. Additionally, tFUS directly affected BOLD activity in a target specific fashion without engaging auditory cortex in any analysis. Finally, tFUS resulted in selective modulation of the targeted functional network connectivity. We demonstrate that tFUS can selectively modulate perfusion, neural activity and connectivity in deep brain structures and connected networks. Lack of auditory cortex findings suggests that the mechanism of tFUS action is not due to auditory or acoustic startle response but rather a direct neuromodulatory process. Our findings suggest that tFUS has the potential for future application as a novel therapy in a wide range of neurological and psychiatric disorders associated with subcortical pathology.

Engaging in word recognition elicits highly specific modulations in visual cortex

A person's cognitive state determines how their brain responds to visual stimuli. The most common such effect is a response enhancement when stimuli are task relevant and attended rather than ignored. In this fMRI study, we report a surprising twist on such attention effects in the visual word form area (VWFA), a region that plays a key role in reading. We presented participants with strings of letters and visually similar shapes, which were either relevant for a specific task (lexical decision or gap localization) or ignored (during a fixation dot color task). In the VWFA, the enhancement of responses to attended stimuli occurred only for letter strings, whereas non-letter shapes evoked smaller responses when attended than when ignored. The enhancement of VWFA activity was accompanied by strengthened functional connectivity with higher-level language regions. These task-dependent modulations of response magnitude and functional connectivity were specific to the VWFA and absent in the rest of visual cortex. We suggest that language regions send targeted excitatory feedback into the VWFA only when the observer is trying to read. This feedback enables the discrimination of familiar and nonsense words and is distinct from generic effects of visual attention.