The effect of self‐generated versus externally generated actions on timing, duration, and amplitude of blood oxygen level dependent response for visual feedback processing

It has been widely assumed that internal forward models use efference copies to create predictions about the sensory consequences of our own actions. While these predictions have frequently been associated with a reduced blood oxygen level dependent (BOLD) response in sensory cortices, the timing and duration of the hemodynamic response for the processing of video feedback of self-generated (active) versus externally generated (passive) movements is poorly understood. In the present study, we tested the hypothesis that predictive mechanisms for self-generated actions lead to early and shorter neural processing compared with externally generated movements. We investigated active and passive movements using a custom-made fMRI-compatible movement device. Visual video feedback of the active and passive movements was presented in real time or with variable delays. Participants had to judge whether the feedback was delayed. Timing and duration of BOLD impulse response was calculated using a first (temporal derivative [TD]) and second-order (dispersion derivative [DD]) Taylor approximation. Our reanalysis confirmed our previous finding of reduced BOLD response for active compared to passive movements. Moreover, we found positive effects of the TD and DD in the supplementary motor area, cerebellum, visual cortices, and subcortical structures, indicating earlier and shorter hemodynamic responses for active compared to passive movements. Furthermore, earlier activation in the putamen for active compared to passive conditions was associated with reduced delay detection performance. These findings indicate that efference copy-based predictive mechanisms enable earlier processing of action feedback, which might have reduced the ability to detect short delays between action and feedback

Anxiety and depression severity in neuropsychiatric SLE are associated with perfusion and functional connectivity changes of the frontolimbic neural circuit: a resting-state f(unctional) MRI study.

peer reviewed[en] OBJECTIVE: To examine the hypothesis that perfusion and functional connectivity disturbances in brain areas implicated in emotional processing are linked to emotion-related symptoms in neuropsychiatric SLE (NPSLE). METHODS: Resting-state fMRI (rs-fMRI) was performed and anxiety and/or depression symptoms were assessed in 32 patients with NPSLE and 18 healthy controls (HC). Whole-brain time-shift analysis (TSA) maps, voxel-wise global connectivity (assessed through intrinsic connectivity contrast (ICC)) and within-network connectivity were estimated and submitted to one-sample t-tests. Subgroup differences (high vs low anxiety and high vs low depression symptoms) were assessed using independent-samples t-tests. In the total group, associations between anxiety (controlling for depression) or depression symptoms (controlling for anxiety) and regional TSA or ICC metrics were also assessed. RESULTS: Elevated anxiety symptoms in patients with NPSLE were distinctly associated with relatively faster haemodynamic response (haemodynamic lead) in the right amygdala, relatively lower intrinsic connectivity of orbital dlPFC, and relatively lower bidirectional connectivity between dlPFC and vmPFC combined with relatively higher bidirectional connectivity between ACC and amygdala. Elevated depression symptoms in patients with NPSLE were distinctly associated with haemodynamic lead in vmPFC regions in both hemispheres (lateral and medial orbitofrontal cortex) combined with relatively lower intrinsic connectivity in the right medial orbitofrontal cortex. These measures failed to account for self-rated, milder depression symptoms in the HC group. CONCLUSION: By using rs-fMRI, altered perfusion dynamics and functional connectivity was found in limbic and prefrontal brain regions in patients with NPSLE with severe anxiety and depression symptoms. Although these changes could not be directly attributed to NPSLE pathology, results offer new insights on the pathophysiological substrate of psychoemotional symptomatology in patients with lupus, which may assist its clinical diagnosis and treatment

Converging evidence of impaired brain function in systemic lupus erythematosus: changes in perfusion dynamics and intrinsic functional connectivity.

peer reviewed[en] PURPOSE: Τhe study examined changes in hemodynamics and functional connectivity in patients with systemic lupus erythematosus (SLE) with or without neuropsychiatric manifestations. METHODS: Participants were 44 patients with neuropsychiatric SLE (NPSLE), 20 SLE patients without such manifestations (non-NPSLE), and 35 healthy controls. Resting-state functional MRI (rs-fMRI) was used to obtain whole-brain maps of (a) perfusion dynamics derived through time shift analysis (TSA), (b) regional functional connectivity (intrinsic connectivity contrast (ICC) coefficients), and (c) hemodynamic-connectivity coupling. Group differences were assessed through independent samples t-tests, and correlations of rs-fMRI indices with clinical variables and neuropsychological test scores were, also, computed. RESULTS: Compared to HC, NPSLE patients demonstrated intrinsic hypoconnectivity of anterior Default Mode Network (DMN) and hyperconnectivity of posterior DMN components. These changes were paralleled by elevated hemodynamic lag. In NPSLE, cognitive performance was positively related to higher intrinsic connectivity in these regions, and to higher connectivity-hemodynamic coupling in posterior DMN components. Uncoupling between hemodynamics and connectivity in the posterior DMN was associated with worse task performance. Non-NPSLE patients displayed hyperconnectivity in posterior DMN and sensorimotor regions paralleled by relatively increased hemodynamic lag. CONCLUSION: Adaptation of regional brain function to hemodynamic changes in NPSLE may involve locally decreased or locally increased intrinsic connectivity (which can be beneficial for cognitive function). This process may also involve elevated coupling of hemodynamics with functional connectivity (beneficial for cognitive performance) or uncoupling, which may be detrimental for the cognitive skills of NPSLE patients

Chronic Mild Traumatic Brain Injury: Aberrant Static and Dynamic Connectomic Features Identified Through Machine Learning Model Fusion.

peer reviewedTraumatic Brain Injury (TBI) is a frequently occurring condition and approximately 90% of TBI cases are classified as mild (mTBI). However, conventional MRI has limited diagnostic and prognostic value, thus warranting the utilization of additional imaging modalities and analysis procedures. The functional connectomic approach using resting-state functional MRI (rs-fMRI) has shown great potential and promising diagnostic capabilities across multiple clinical scenarios, including mTBI. Additionally, there is increasing recognition of a fundamental role of brain dynamics in healthy and pathological cognition. Here, we undertake an in-depth investigation of mTBI-related connectomic disturbances and their emotional and cognitive correlates. We leveraged machine learning and graph theory to combine static and dynamic functional connectivity (FC) with regional entropy values, achieving classification accuracy up to 75% (77, 74 and 76% precision, sensitivity and specificity, respectively). As compared to healthy controls, the mTBI group displayed hypoconnectivity in the temporal poles, which correlated positively with semantic (r = 0.43, p < 0.008) and phonemic verbal fluency (r = 0.46, p < 0.004), while hypoconnectivity in the right dorsal posterior cingulate correlated positively with depression symptom severity (r = 0.54, p < 0.0006). These results highlight the importance of residual FC in these regions for preserved cognitive and emotional function in mTBI. Conversely, hyperconnectivity was observed in the right precentral and supramarginal gyri, which correlated negatively with semantic verbal fluency (r=-0.47, p < 0.003), indicating a potential ineffective compensatory mechanism. These novel results are promising toward understanding the pathophysiology of mTBI and explaining some of its most lingering emotional and cognitive symptoms

The effect of self-generated versus externally generated actions on timing, duration, and amplitude of blood oxygen level dependent response for visual feedback processing

It has been widely assumed that internal forward models use efference copies to cre-ate predictions about the sensory consequences of our own actions. While these pre-dictions have frequently been associated with a reduced blood oxygen leveldependent (BOLD) response in sensory cortices, the timing and duration of thehemodynamic response for the processing of video feedback of self-generated(active) versus externally generated (passive) movements is poorly understood. In thepresent study, we tested the hypothesis that predictive mechanisms for self-generated actions lead to early and shorter neural processing compared with exter-nally generated movements. We investigated active and passive movements using acustom-made fMRI-compatible movement device. Visual video feedback of theactive and passive movements was presented in real time or with variable delays.Participants had to judge whether the feedback was delayed. Timing and duration ofBOLD impulse response was calculated using a first (temporal derivative [TD]) andsecond-order (dispersion derivative [DD]) Taylor approximation. Our reanalysis con-firmed our previous finding of reduced BOLD response for active compared to pas-sive movements. Moreover, we found positive effects of the TD and DD in thesupplementary motor area, cerebellum, visual cortices, and subcortical structures,indicating earlier and shorter hemodynamic responses for active compared to passivemovements. Furthermore, earlier activation in the putamen for active compared topassive conditions was associated with reduced delay detection performance. Thesefindings indicate that efference copy-based predictive mechanisms enable earlierprocessing of action feedback, which might have reduced the ability to detect shortdelays between action and feedback

Myelin content changes in probable Alzheimer's disease and mild cognitive impairment

AbstractBackground. White matter (WM) changes, including myelin breakdown, have been reported in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) and both conditions are associated with increased comorbidity with late-life depression. The nature of NAWM changes associated with normal aging, dementia, depression and/or MCI has not been systematically investigated using measures particularly sensitive to regional myelin integrity. Multiexponential T2 (MET2) imaging calculates short T2 and myelin water fraction (MWF) values, strongly correlated with histological measures of myelin. In the present study a multi-echo, spin-echo (MESE) sequence was utilized to examine myelin content as a function of age and severity of neuropsychiatric impairment in patients diagnosed with AD or MCI and cognitively intact elders. Methods. Measurements of Short T2, Long T2 and MWF values were obtained within 12 NAWM areas in patients and controls, involving periventricular and deep frontal, parietal, temporal and occipital WM, separately in each hemisphere, as well as the genu and splenium of the Corpus Callosum (CC) in patients diagnosed with probable AD (n=25) or MCI (n=43) and cognitively intact elderly controls (n=33). All participants received a comprehensive neuropsychological and neuropsychiatric assessment.Results. AD patients displayed higher age-adjusted long and short T2 values and reduced MWF values in left temporal/parietal and bilateral periventricular NAWM than controls and MCI patients. Preliminary analyses revealed significantly increased Long and Short T2 values with age in the majority of ROIs in the NI and MCI groups. With few exceptions, corresponding reductions in MWF values were also found. Age-related effects in the Dementia group were restricted to the left temporal (Long T2) and periventricular NAWM (Short T2).Short T2/MWF values in temporal, frontal, and periventricular NAWM of controls and/or MCI patients were significantly associated with episodic and semantic memory performance and depressive symptomatology. In addition, the impact of age on memory performance was significantly mediated by age-related changes in short T2 and MWF values in these regions. Discussion. To our knowledge, this is the first study utilizing the Multi-echo T2 relaxation time technique to improve specificity in detecting myelin degradation, predominantly in left hemisphere temporal, parietal and periventricular NAWM, even in mild dementia. WM and myelin changes have been documented in age-related neurodegenerative disorders, such as AD and MCI, and potentially precede amyloid and tau pathology. Moreover, age-related demyelination was associated with reduced memory function and increased depression symptom severity in an anatomically specific manner. This effect was more pronounced for episodic memory function in prodromal dementia states (MCI). These changes suggest an important role of WM integrity in clinical and neuropsychiatric manifestations of these patientsΑντικείμενο της Μελέτης. Μεταβολές στην λευκή ουσία έχουν αναφερθεί τόσο σε ασθενείς με πιθανή ν. Alzheimer (ΝΑ), όσο και σε άτομα με Ηπια Γνωστική Διαταραχή (ΗΓΔ) και σχετίζονται με αυξημένη συννοσηρότητα με κατάθλιψη. H φύση των αλλαγών στην λευκή ουσία, που σχετίζονται με φυσιολογική γήρανση, άνοια, κατάθλιψη και ήπια γνωστική διαταραχή, δεν εχει μελετηθεί με την χρήση μεθόδων ευαίσθητων στο βαθμό ακεραιότητας της μυελίνης. Η νεότερη πολυεκθετική τεχνική Τ2 χρόνου μαγνητικής αποκαταστάσης επιτρέπει τη διάκριση των σημάτων από μόρια νερού που βρίσκονται σε διάφορετικά περιβάλλοντα στον εγκέφαλο. Ιδιαιτέρως το κλάσμα νερού/μυελίνης (MWF) σχετίζεται στενά με την περιεκτικότητα του ιστού σε μυελίνη. Στην παρούσα μελέτη χρησιμοποιήσαμε την πολυεκθετική ακολουθία MESE για να εξετάσουμε την περιεκτικότητα σε μυελίνη και την συσχέτιση της με ηλικία και με νευροψυχιατρικές παραμέτρους σε ασθενείς με ν. Alzheimer, ΗΓΝ και υγιείς μάρτυρες. Μέθοδοι. Μετρήθηκαν οι συνιστώσες του σήματος Τ2 και ο δείκτης MWF σε 12 περιοχές ενδιαφέροντος (περικοιλιακή λευκή ουσία και την εν τω βάθη λευκή ουσία των τεσσάρων λοβών, και το μεσολόβιο) σε 25 ασθενείς με ΝΑ, 43 ασθενείς με ΗΝΔ, και 33 φυσιολογικόυς ηλικιωμένους. Ολοι οι συμμετέχοντες υποβλήθηκαν σε νευροψυχολογική και νευροψυχιατρική αξιολόγηση. Αποτελέσματα. Οι προσαρμοσμένες για την ηλικία τιμές τόσο της βραχείας όσο και της μακράς συνιστώσας του σήματος Τ2 βρέθηκαν σημαντικά αυξημένες (και αντιστοίχως μειωμένες οι τιμές του κλάσματος νερού/μυελίνης) στους ασθενείς με ΝΑ στη λευκή ουσία του αριστερού κροταφικού και βρεγματικού λοβού και στην περικοιλιακή λευκή ουσία αμφοτερόπλευρα σε σύγκριση με τους φυσιολογικούς μάρτυρες και τους ασθενείς με ήπια γνωστική διαταραχή. Παρατηρήθηκε επίσης αύξηση των τιμών Τ2 και αντίστοιχη μείωση των τιμών του κλάσματος νερού/μυελίνης με την ηλικία στην πλειοψηφία των περιοχών που μετρήθηκαν. Σημειώθηκαν επίσης σημαντικές συσχετίσεις μεταξύ των τιμών της βραχείας συνιστώσας του σήματος Τ2 και του κλάσματος νερού/μυελίνης στην κροταφική και μετωπιαία λευκή ουσία καθώς και στην περικοιλιακή λευκή ουσία με νευροψυχιατρικές μετρήσεις (επεισοδιακή και σημασιολογική μνήμη και συμπτώματα κατάθλιψης) στους φυσιολογικούς μάρτυρες και στους ασθενείς με ΗΝΔ. Συζήτηση. Η παρούσα μελέτη εκμεταλεύεται την αυξημένη ειδικότητα της πολυεκθετικής τεχνικής Τ2 χρόνου μαγνητικής αποκαταστάσης για να εντοπίσει το βαθμό αλλοίωσης της μυελίνης ακόμα και σε ήπιες μορφές ΝΑ, ιδιάιτερα στον αριστερό κροταφικό και βρεγματικό λοβό καθώς και στην περικοιλιακή φυσιολογικά απεικονιζόμενη λευκή ουσία. Αλλαγές στην λευκή ουσία, και κατα συνέπεια και στην μυελίνη, έχουν καταγραφεί σε σχετιζόμενες με την ηλικία νευροεκφυλιστικές ασθένειες και ενδεχομένως να προηγούνται της παθολογικής εναπόθεσης β αμυλοειδούς και πρωτείνης tau. Αξιοσημείωτο είναι ότι ο αυξημένος ρυθμός απομυελίνωσης με την ηλικία στους ασθενείς με ΗΝΔ σχετίζονταν με τη βαρύτητα των ατομικών δυσκολιών στη μνήμη επεισοδίων καθώς και αυξημένα συμπτώματα κατάθλιψης.Το γεγονός ότι οι παραπάνω συσχετίσεις ανιχνεύτηκαν σε περιοχές με σημαίνοντα ρόλο στα παραπάνω νευροψυχιατρικά προβλήματα υποστηρίζουν την εγκυρότητα της μεθόδου στην κλινική αξιολόγηση νευροεκφυλιστικών νόσων

Anxiety and depression severity in neuropsychiatric SLE are associated with perfusion and functional connectivity changes of the frontolimbic neural circuit: a resting-state f(unctional) MRI study

Objective To examine the hypothesis that perfusion and functional connectivity disturbances in brain areas implicated in emotional processing are linked to emotion-related symptoms in neuropsychiatric SLE (NPSLE).Methods Resting-state fMRI (rs-fMRI) was performed and anxiety and/or depression symptoms were assessed in 32 patients with NPSLE and 18 healthy controls (HC). Whole-brain time-shift analysis (TSA) maps, voxel-wise global connectivity (assessed through intrinsic connectivity contrast (ICC)) and within-network connectivity were estimated and submitted to one-sample t-tests. Subgroup differences (high vs low anxiety and high vs low depression symptoms) were assessed using independent-samples t-tests. In the total group, associations between anxiety (controlling for depression) or depression symptoms (controlling for anxiety) and regional TSA or ICC metrics were also assessed.Results Elevated anxiety symptoms in patients with NPSLE were distinctly associated with relatively faster haemodynamic response (haemodynamic lead) in the right amygdala, relatively lower intrinsic connectivity of orbital dlPFC, and relatively lower bidirectional connectivity between dlPFC and vmPFC combined with relatively higher bidirectional connectivity between ACC and amygdala. Elevated depression symptoms in patients with NPSLE were distinctly associated with haemodynamic lead in vmPFC regions in both hemispheres (lateral and medial orbitofrontal cortex) combined with relatively lower intrinsic connectivity in the right medial orbitofrontal cortex. These measures failed to account for self-rated, milder depression symptoms in the HC group.Conclusion By using rs-fMRI, altered perfusion dynamics and functional connectivity was found in limbic and prefrontal brain regions in patients with NPSLE with severe anxiety and depression symptoms. Although these changes could not be directly attributed to NPSLE pathology, results offer new insights on the pathophysiological substrate of psychoemotional symptomatology in patients with lupus, which may assist its clinical diagnosis and treatment

Evidence of Age-Related Hemodynamic and Functional Connectivity Impairment: A Resting State fMRI Study.

peer reviewedPurpose: To assess age-related changes in intrinsic functional brain connectivity and hemodynamics during adulthood in the context of the retrogenesis hypothesis, which states that the rate of age-related changes is higher in late-myelinating (prefrontal, lateral-posterior temporal) cerebrocortical areas as compared to early myelinating (parietal, occipital) regions. In addition, to examine the dependence of age-related changes upon concurrent subclinical depression symptoms which are common even in healthy aging. Methods: Sixty-four healthy adults (28 men) aged 23-79 years (mean 45.0, SD = 18.8 years) were examined. Resting-state functional MRI (rs-fMRI) time series were used to compute voxel-wise intrinsic connectivity contrast (ICC) maps reflecting the strength of functional connectivity between each voxel and the rest of the brain. We further used Time Shift Analysis (TSA) to estimate voxel-wise hemodynamic lead or lag for each of 22 ROIs from the automated anatomical atlas (AAL). Results: Adjusted for depression symptoms, gender and education level, reduced ICC with age was found primarily in frontal, temporal regions, and putamen, whereas the opposite trend was noted in inferior occipital cortices (p < 0.002). With the same covariates, increased hemodynamic lead with advancing age was found in superior frontal cortex and thalamus, with the opposite trend in inferior occipital cortex (p < 0.002). There was also evidence of reduced coupling between voxel-wise intrinsic connectivity and hemodynamics in the inferior parietal cortex. Conclusion: Age-related intrinsic connectivity reductions and hemodynamic changes were demonstrated in several regions-most of them part of DMN and salience networks-while impaired neurovascular coupling was, also, found in parietal regions. Age-related reductions in intrinsic connectivity were greater in anterior as compared to posterior cortices, in line with implications derived from the retrogenesis hypothesis. These effects were affected by self-reported depression symptoms, which also increased with age

Changes in resting-state functional connectivity in neuropsychiatric lupus: A dynamic approach based on recurrence quantification analysis

peer reviewedThere is growing interest in dynamic approaches to functional brain connectivity (FC), and their potential applications in understanding atypical brain function. In this study, we assess the relative sensitivity of cross recurrence quantification analysis CRQA) to identify aberrant FC in patients with neuropsychiatric systemic lupus erythematosus (NPSLE) in comparison with conventional static and dynamic bivariate FC measures, as well as univariate (nodal) RQA. This technique was applied to resting-state fMRI data obtained from 45 NPSLE patients and 35 healthy volunteers (HC). Cross recurrence plots were computed for all pairs of 16 frontoparietal brain regions known to be critically involved in visuomotor control and suspected to show hemodynamic disturbance in NPSLE. Multivariate group comparisons revealed that the combination of six CRQA measures differentiated the two groups with large effect sizes (.214>η2>.061) in 40 out of the 120 region pairs. The majority of brain regions forming these pairs also showed group differences on nodal RQA indices (.146>η2>.09) Overall, larger values were found in NPSLE patients vs. HC with the exception of FC formed by the paracentral lobule. Determinism within five pairs of right-hemisphere sensorimotor regions (paracentral lobule, primary somatosensory, primary motor, and supplementary motor areas), correlated positively with visuomotor performance among NPSLE patients (pη2>.061), none of which correlated significantly with visuomotor performance. Indices derived from dynamic, temporal-based FC analyses displayed large effect sizes in 11/120 region pairs (.11>η2>.063). These findings further support the importance of feature-based dFC in advancing current knowledge on correlates of cognitive dysfunction in a clinically challenging disorder, such as NPSLE

Distinct hemodynamic and functional connectivity features of fatigue in clinically isolated syndrome and multiple sclerosis: accounting for the confounding effect of concurrent depression symptoms.

peer reviewedPURPOSE: This study aims to identify common and distinct hemodynamic and functional connectivity (FC) features for self-rated fatigue and depression symptoms in patients with clinically isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RR-MS). METHODS: Twenty-four CIS, 29 RR-MS patients, and 39 healthy volunteers were examined using resting-state fMRI (rs-fMRI) to obtain whole-brain maps of (i) hemodynamic response patterns (through time shift analysis), (ii) FC (via intrinsic connectivity contrast maps), and (iii) coupling between hemodynamic response patterns and FC. Each regional map was correlated with fatigue scores, controlling for depression, and with depression scores, controlling for fatigue. RESULTS: In CIS patients, the severity of fatigue was associated with accelerated hemodynamic response in the insula, hyperconnectivity of the superior frontal gyrus, and evidence of reduced hemodynamics-FC coupling in the left amygdala. In contrast, depression severity was associated with accelerated hemodynamic response in the right limbic temporal pole, hypoconnectivity of the anterior cingulate gyrus, and increased hemodynamics-FC coupling in the left amygdala. In RR-MS patients, fatigue was associated with accelerated hemodynamic response in the insula and medial superior frontal cortex, increased functional role of the left amygdala, and hypoconnectivity of the dorsal orbitofrontal cortex, while depression symptom severity was linked to delayed hemodynamic response in the medial superior frontal gyrus; hypoconnectivity of the insula, ventromedial thalamus, dorsolateral prefrontal cortex, and posterior cingulate; and decreased hemodynamics-FC coupling of the medial orbitofrontal cortex. CONCLUSION: There are distinct FC and hemodynamic responses, as well as different magnitude and topography of hemodynamic connectivity coupling, associated with fatigue and depression in early and later stages of MS