Longitudinal Changes In Functional Connectivity Research Articles

Early effect of onabotulinumtoxinA on EEG-based functional connectivity in patients with chronic migraine: A pilot study.

In this pilot prospective cohort study, we aimed to evaluate, using high-density electroencephalography (HD-EEG), the longitudinal changes in functional connectivity (FC) in patients with chronic migraine (CM) treated with onabotulinumtoxinA (OBTA). OBTA is a treatment for CM. Several studies have shown the modulatory action of OBTA on the central nervous system; however, research on migraine is limited. This study was conducted at the Neurology Unit of "Policlinico Tor Vergata," Rome, Italy, and included 12 adult patients with CM treated with OBTA and 15 healthy controls (HC). Patients underwent clinical scales at enrollment (T0) and 3 months (T1) from the start of treatment. HD-EEG was recorded using a 64-channel system in patients with CM at T0 and T1. A source reconstruction method was used to identify brain activity. FC in δ-θ-α-β-low-γ bands was analyzed using the weighted phase-lag index. FC changes between HCs and CM at T0 and T1 were assessed using cross-validation methods to estimate the results' reliability. Compared to HCs at T0, patients with CM showed hyperconnected networks in δ (p = 0.046, area under the receiver operating characteristic curve [AUC: 0.76-0.98], Cohen's κ [0.65-0.93]) and β (p = 0.031, AUC [0.68-0.95], Cohen's κ [0.51-0.84]), mainly involving orbitofrontal, occipital, temporal pole and orbitofrontal, superior temporal, occipital, cingulate areas, and hypoconnected networks in α band (p = 0.029, AUC [0.80-0.99], Cohen's κ [0.42-0.77]), predominantly involving cingulate, temporal pole, and precuneus. Patients with CM at T1, compared to T0, showed hypoconnected networks in δ band (p = 0.032, AUC [0.73-0.99], Cohen's κ [0.53-0.90]) and hyperconnected networks in α band (p = 0.048, AUC [0.58-0.93], Cohen's κ [0.37-0.78]), involving the sensorimotor, orbitofrontal, cingulate, and temporal cortex. These preliminary results showed that patients with CM presented disrupted EEG-FC compared to controls restored by a single session of OBTA treatment, suggesting a primary central modulatory action of OBTA.

Correlation transfer function analysis as a biomarker for Alzheimer brain plasticity using longitudinal resting-state fMRI data

Neural plasticity is the ability of the brain to alter itself functionally and structurally as a result of its experience. However, longitudinal changes in functional connectivity of the brain are still unrevealed in Alzheimer’s disease (AD). This study aims to discover the significant connections (SCs) between brain regions for AD stages longitudinally using correlation transfer function (CorrTF) as a new biomarker for the disease progression. The dataset consists of: 29 normal controls (NC), and 23, 24, and 23 for early, late mild cognitive impairments (EMCI, LMCI), and ADs, respectively, along three distant visits. The brain was divided into 116 regions using the automated anatomical labeling atlas, where the intensity time series is calculated, and the CorrTF connections are extracted for each region. Finally, the standard t-test and ANOVA test were employed to investigate the SCs for each subject’s visit. No SCs, along three visits, were found For NC subjects. The most SCs were mainly directed from cerebellum in case of EMCI and LMCI. Furthermore, the hippocampus connectivity increased in LMCI compared to EMCI whereas missed in AD. Additionally, the patterns of longitudinal changes among the different AD stages compared to Pearson Correlation were similar, for SMC, VC, DMN, and Cereb networks, while differed for EAN and SN networks. Our findings define how brain changes over time, which could help detect functional changes linked to each AD stage and better understand the disease behavior.

Neural Changes in Children With Residual Speech Sound Disorder After Ultrasound Biofeedback Speech Therapy.

Children with residual speech sound disorders (RSSD) have shown differences in neural function for speech production, as compared to their typical peers; however, information about how these differences may change over time and relative to speech therapy is needed. To address this gap, we used functional magnetic resonance imaging (fMRI) to examine functional activation and connectivity on adaptations of the syllable repetition task (SRT-Early Sounds and SRT-Late Sounds) in children with RSSD before and after a speech therapy program. Sixteen children with RSSD completed an fMRI experiment before (Time 1) and after (Time 2) a speech therapy program with ultrasound visual feedback for /ɹ/ misarticulation. Progress in therapy was measured via perceptual ratings of productions of untreated /ɹ/ word probes. To control for practice effects and developmental change in patterns of activation and connectivity, 17 children with typical speech development (TD) completed the fMRI at Time 1 and Time 2. Functional activation was analyzed using a region-of-interest approach and functional connectivity was analyzed using a seed-to-voxel approach. Children with RSSD showed a range of responses to therapy. After correcting for multiple comparisons, we did not observe any statistically significant cross-sectional differences or longitudinal changes in functional activation. A negative relationship between therapy effect size and functional activation in the left visual association cortex was on the SRT-Late Sounds after therapy, but it did not survive correction for multiple comparisons. Significant longitudinal changes in functional connectivity were observed for the RSSD group on SRT-Early Sounds and SRT-Late Sounds, as well as for the TD group on the SRT-Early Sounds. RSSD and TD groups showed connectivity differences near the left insula on the SRT-Late Sounds at Time 2. RSSD and treatment with ultrasound visual feedback may thus be associated with neural differences in speech motor and visual association processes recruited for speech production.

Impact of multidomain preventive strategies on functional brain connectivity in older adults with cognitive complaint: Subset from the Montpellier center of the ancillary MAPT-MRI study.

The impact of multi-domain preventive interventions on older adults, in particular on those with higher risk to develop Alzheimer's disease (AD), could be beneficial, as it may delay cognitive decline. However, the precise mechanism of such positive impact is not fully understood and may involve brain reserve and adaptability of brain functional connectivity (FC). To determine the effect of multidomain interventions (involving physical activity, cognitive training, nutritional counseling alone or in combination with omega-3 fatty acid supplementation and vs. a placebo) on the brain, longitudinal FC changes were assessed after 36 months of intervention on 100 older adults (above 70 year-old) with subjective cognitive complaints. No global change in FC was detected after uni or multidomain preventive interventions. However, an effect of omega-3 fatty acid supplementation dependent on cognitive decline status was underlined for frontoparietal, salience, visual and sensorimotor networks FC. These findings were independent of the cortical thickness and vascular burden. These results emphasize the importance of patient stratification, based on risk factors, for preventive interventions.

Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab

BackgroundMigraine involves central and peripheral nervous system mechanisms. Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody with little central nervous system penetrance, is effective for migraine prevention. The objective of this study was to determine if response to erenumab is associated with alterations in brain functional connectivity and pain-induced brain activations.MethodsAdults with 6–25 migraine days per month during a 4-week headache diary run-in phase underwent pre-treatment brain functional MRI (fMRI) that included resting-state functional connectivity and BOLD measurements in response to moderately painful heat stimulation to the forearm. This was followed by two treatments with 140 mg erenumab, at baseline and 4 weeks later. Post-treatment fMRI was performed 2 weeks and 8 weeks following the first erenumab treatment. A longitudinal Sandwich estimator analysis was used to identify pre- to post-treatment changes in resting-state functional connectivity and brain activations in response to thermal pain. fMRI findings were compared between erenumab treatment-responders vs. erenumab non-responders.ResultsPre- and post-treatment longitudinal imaging data were available from 32 participants. Average age was 40.3 (+/− 13) years and 29 were female. Pre-treatment average migraine day frequency was 13.8 (+/− 4.7) / 28 days and average headache day frequency was 15.8 (+/− 4.4) / 28 days. Eighteen of 32 (56%) were erenumab responders. Compared to erenumab non-responders, erenumab responders had post-treatment differences in 1) network functional connectivity amongst pain-processing regions, including higher global efficiency, clustering coefficient, node degree, regional efficiency, and modularity, 2) region-to-region functional connectivity between several regions including temporal pole, supramarginal gyrus, and hypothalamus, and 3) pain-induced activations in the middle cingulate, posterior cingulate, and periaqueductal gray matter.ConclusionsReductions in migraine day frequency accompanying erenumab treatment are associated with changes in resting state functional connectivity and central processing of extracranial painful stimuli that differ from erenumab non-responders.Trial registrationclinicaltrials.gov(NCT03773562).

Longitudinal changes in functional connectivity in speech motor networks in apraxia of speech after stroke.

The cerebral substrates of apraxia of speech (AOS) recovery remain unclear. Resting state fMRI post stroke can inform on altered functional connectivity (FC) within cortical language networks. Some initial studies report reduced FC between bilateral premotor cortices in patients with AOS, with lowest FC in patients with the most severe AOS. However, longitudinal FC studies in stroke are lacking. The aims of the present longitudinal study in early post stroke patients with AOS were (i) to compare connectivity strength in AOS patients to that in left hemisphere (LH) lesioned stroke patients without a speech-language impairment, (ii) to investigate the relation between FC and severity of AOS, aphasia and non-verbal oral apraxia (NVOA) and (iii) to investigate longitudinal changes in FC, from the subacute phase to the chronic phase to identify predictors of AOS recovery. Functional connectivity measures and comprehensive speech-language assessments were obtained at 4 weeks and 6 months after stroke in nine patients with AOS after a LH stroke and in six LH lesioned stroke patients without speech-language impairment. Functional connectivity was investigated in a network for speech production: inferior frontal gyrus (IFG), anterior insula (aINS), and ventral premotor cortex (vPMC), all bilaterally to investigate signs of adaptive or maladaptive changes in both hemispheres. Interhemispheric vPMC connectivity was significantly reduced in patients with AOS compared to LH lesioned patients without speech-language impairment. At 6 months, the AOS severity was associated with interhemispheric aINS and vPMC connectivity. Longitudinal changes in FC were found in individuals, whereas no significant longitudinal change in FC was found at the group level. Degree of longitudinal AOS recovery was strongly associated with interhemispheric IFG connectivity strength at 4 weeks. Early interhemispheric IFG connectivity may be a strong predictor of AOS recovery. The results support the importance of interhemispheric vPMC connection in speech motor planning and severity of AOS and suggest that also bilateral aINS connectivity may have an impact on AOS severity. These findings need to be validated in larger cohorts.

Default-Mode Network Connectivity Changes During the Progression Toward Alzheimer's Dementia: A Longitudinal Functional Magnetic Resonance Imaging Study.

Background/Purpose: Brain function changes with Alzheimer's disease (AD) progression. Evaluating those changes longitudinally is important to understand the complex relationships between brain pathologies and cognition. We aimed (1) to identify longitudinal changes in functional connectivity in patients with mild cognitive impairment (MCI) characterized for amyloid-β (Aβ) status and (2) to relate these functional changes to clinical progression. Methods: Forty-four patients with MCI were followed using serial functional magnetic resonance imaging (fMRI) over 1.2 years (three sessions) and cognitive testing over 3.1 years (five sessions). Intra and inter-network connectivities were computed to assess changes in brain connectivity using a network atlas adapted for late adulthood. Sixteen low-Aβ clinically normal older adults underwent a single fMRI session for group comparisons at baseline. Linear mixed-effects models with random intercept and slope were used to predict changes in connectivity based on Aβ status and progression to dementia. Results: At baseline, intra and inter-network resting-state fMRI connectivities did not differ by baseline clinical diagnosis, Aβ status, or clinical progression to dementia. At the final imaging session, progressive MCI had significantly higher connectivity compared with stable MCI, specifically within the default-mode network (DMN). Longitudinally, progressive MCI had increasing intra-DMN connectivity over time compared with stable MCI, and the rate of changes in connectivity was significantly associated with the rate of cognitive decline. Conclusions: Intra-DMN connectivity increases in MCI patients progressing toward dementia, suggesting aberrant synchronization in the symptomatic stages of AD. Impact statement Changes in functional connectivity occur in the course of Alzheimer's disease. We observed a progressive increase over time in resting-state functional connectivity within the default-mode network in patients with mild cognitive impairment who progressed to dementia. The rate of connectivity increase was significantly associated with the rate of cognitive decline. The observation of increased functional connectivity during the progression to dementia, and not only in the pre-clinical stage, is interpreted as an aberrant synchronization rather than a compensation mechanism.

Ambient air pollution and functional brain network development in adolescence

Air pollution is linked to neurodevelopmental delays, but its association with brain network development has yet to be investigated utilizing a longitudinal cohort. We aimed to characterize the relationship between PM2.5, O3, and NO2 exposure at ages 9-10 years and 2-year longitudinal changes in functional connectivity (FC) in regions important for emotional and cognitive functioning, namely the salience, frontoparietal, and default-mode brain networks as well as the amygdala and hippocampus. 7719 participants from the Adolescent Brain Cognitive Development (ABCD) Study® were included. Annual averages of pollutants were assigned to the child’s primary residential address using an ensemble-based exposure modeling approach. Resting-state functional MRI was collected on 3T MRI scanners at baseline and follow-up visits. Single- and multi-pollutant mixed-effect linear models, with subject and study site as random effects, were constructed to examine the putative exposure effect on intra-network, inter-network, and subcortical-to-network FC change, by testing age-by-pollutant interactions and adjusting for sex, race/ethnicity, household income, parental education, handedness, scanner type, and motion during scanning. After Bonferroni correction, single- and multi-pollutant models revealed inter-network FC increased with age for individuals with higher PM2.5 exposure but decreased with age for those with higher NO2 exposure. Similarly, subcortical-to-network FC increased with age for those with higher PM2.5 exposure but decreased with age for individuals with higher O3 exposure. There were no significant intra-network associations with pollutant-by-age interactions. PM2.5 and O3 were negatively correlated (r=-0.18, p<2.2e-16); PM2.5 and NO2 were positively correlated (r=0.20, p<2.2e-16); no correlation existed between O3 and NO2 (r=-0.02, p=0.15). In normative development, inter-network segregation is expected. Our findings indicate that higher levels of exposure to PM2.5 in childhood relate to distinct changes in age-related patterns of network segregation, suggesting functional network immaturity. However, functional network segregation does not seem to be hindered by increased exposure to NO2 and O3.

Compounding Vulnerability in the Neurocircuitry of Addiction: Longitudinal Functional Connectivity Changes in Alcohol Use Disorder.

The addiction neurocircuitry model describes the role of several brain circuits (drug reward, negative emotionality and craving/executive control) in alcohol use and subsequent development of alcohol use disorder (AUD). Human studies examining longitudinal change using resting-state functional magnetic resonance imaging (rs-fMRI) are needed to understand how functional changes to these circuits are caused by or contribute to continued AUD. In order to characterize how intrinsic functional connectivity changes with sustained AUD, we analyzed rs-fMRI data from individuals with (n = 18; treatment seeking and non-treatment seeking) and without (n = 21) AUD collected on multiple visits as part of various research studies at the NIAAA intramural program from 2012 to 2020. Results of the seed correlation analysis showed that individuals with AUD had an increase in functional connectivity over time between emotionality and craving neurocircuits, and a decrease between executive control and reward networks. Post hoc investigations of AUD severity and alcohol consumption between scans revealed an additive effect of these AUD features in many of the circuits, such that more alcohol consumption or more severe AUD was associated with more pronounced changes to synchronicity. These findings suggest an increased concordance of networks underlying emotionality and compulsions toward drinking while also a reduction in control network connectivity, consistent with the addiction neurocircuitry model. Further, they suggest a compounding effect of continued heavy drinking on these vulnerabilities in neurocircuitry. More longitudinal research is necessary to understand the trajectories of individuals with AUD not adequately represented in this study, as well as whether this can inform effective harm reduction strategies.

Reactive astrocytes prevent maladaptive plasticity after ischemic stroke.

Restoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAP-/-Vim-/-). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted magnetic resonance imaging (MRI) and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAP-/-Vim-/- mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes modulate recovery-promoting plasticity responses after ischemic stroke.

No evidence for motor-recovery-related cortical connectivity changes after stroke using resting-state fMRI

It has been proposed that a form of cortical reorganization (changes in functional connectivity between brain areas) can be assessed with resting-state (rs) functional MRI (fMRI). Here, we report a longitudinal data set collected from 19 patients with subcortical stroke and 11 controls. Patients were imaged up to five times over 1 year. We found no evidence, using rs-fMRI, for longitudinal poststroke cortical connectivity changes despite substantial behavioral recovery. These results could be construed as questioning the value of resting-state imaging. Here, we argue instead that they are consistent with other emerging reasons to challenge the idea of motor-recovery-related cortical reorganization poststroke when conceived of as changes in connectivity between cortical areas.NEW & NOTEWORTHY We investigated longitudinal changes in functional connectivity after stroke. Despite substantial motor recovery, we found no differences in functional connectivity patterns between patients and controls, nor any changes over time. Assuming that rs-fMRI is an adequate method to capture connectivity changes between cortical regions after brain injury, these results provide reason to doubt that changes in cortico-cortical connectivity are the relevant mechanism for promoting motor recovery.

Orbitofrontal cortex and dorsal striatum functional connectivity predicts incubation of opioid craving after voluntary abstinence

We recently introduced a rat model of incubation of opioid craving after voluntary abstinence induced by negative consequences of drug seeking. Here, we used resting-state functional MRI to determine whether longitudinal functional connectivity changes in orbitofrontal cortex (OFC) circuits predict incubation of opioid craving after voluntary abstinence. We trained rats to self-administer for 14 d either intravenous oxycodone or palatable food. After 3 d, we introduced an electric barrier for 12 d that caused cessation of reward self-administration. We tested the rats for oxycodone or food seeking under extinction conditions immediately after self-administration training (early abstinence) and after electric barrier exposure (late abstinence). We imaged their brains before self-administration and during early and late abstinence. We analyzed changes in OFC functional connectivity induced by reward self-administration and electric barrier-induced abstinence. Oxycodone seeking was greater during late than early abstinence (incubation of oxycodone craving). Oxycodone self-administration experience increased OFC functional connectivity with dorsal striatum and related circuits that was positively correlated with incubated oxycodone seeking. In contrast, electric barrier-induced abstinence decreased OFC functional connectivity with dorsal striatum and related circuits that was negatively correlated with incubated oxycodone seeking. Food seeking was greater during early than late abstinence (abatement of food craving). Food self-administration experience and electric barrier-induced abstinence decreased or maintained functional connectivity in these circuits that were not correlated with abated food seeking. Opposing functional connectivity changes in OFC with dorsal striatum and related circuits induced by opioid self-administration versus voluntary abstinence predicted individual differences in incubation of opioid craving.

Functional connectivity in multiple sclerosis modelled as connectome stability: A 5-year follow-up study

Background: Brain functional connectivity (FC) in multiple sclerosis (MS) is abnormal compared to healthy controls (HCs). More longitudinal studies in MS are needed to evaluate whether FC stability is clinically relevant. Objective: To compare functional magnetic resonance imaging (fMRI)-based FC between MS and HC, and to determine the relationship between longitudinal FC changes and structural brain damage, cognitive performance and physical disability. Methods: T1-weighted MPRAGE and resting-state fMRI (1.5T) were acquired from 70 relapsing-remitting MS patients and 94 matched HC at baseline (mean months since diagnosis 14.0 ± 11) and from 60 MS patients after 5 years. Independent component analysis and network modelling were used to measure longitudinal FC stability and cross-sectional comparisons with HC. Linear mixed models, adjusted for age and sex, were used to calculate correlations. Results: At baseline, patients with MS showed FC abnormalities both within networks and in single connections compared to HC. Longitudinal analyses revealed functional stability and no significant relationships with clinical disability, cognitive performance, lesion or brain volume. Conclusion: FC abnormalities occur already at the first decade of MS, yet we found no relevant clinical correlations for these network deviations. Future large-scale longitudinal fMRI studies across a range of MS subtypes and outcomes are required.

Functional Connectivity in Antipsychotic-Treated and Antipsychotic-Naive Patients With First-Episode Psychosis and Low Risk of Self-harm or Aggression

Altered functional connectivity (FC) is a common finding in resting-state functional magnetic resonance imaging (rs-fMRI) studies of people with psychosis, yet how FC disturbances evolve in the early stages of illness, and how antipsychotic treatment influences these disturbances, remains unknown. To investigate longitudinal FC changes in antipsychotic-naive and antipsychotic-treated patients with first-episode psychosis (FEP). This secondary analysis of a triple-blind, randomized clinical trial was conducted over a 5-year recruitment period between April 2008 and December 2016 with 59 antipsychotic-naive patients with FEP receiving either a second-generation antipsychotic or a placebo pill over a treatment period of 6 months. Participants were required to have low suicidality and aggression, to have a duration of untreated psychosis of less than 6 months, and to be living in stable accommodations with social support. Both FEP groups received intensive psychosocial therapy. A healthy control group was also recruited. Participants completed rs-fMRI scans at baseline, 3 months, and 12 months. Data were analyzed from May 2019 to August 2020. Resting-state functional MRI was used to probe brain FC. Patients received either a second-generation antipsychotic or a matched placebo tablet. Both patient groups received a manualized psychosocial intervention. The primary outcomes of this analysis were to investigate (1) FC differences between patients and controls at baseline; (2) FC changes in medicated and unmedicated patients between baseline and 3 months; and (3) associations between longitudinal FC changes and clinical outcomes. An additional aim was to investigate long-term FC changes at 12 months after baseline. These outcomes were not preregistered. Data were analyzed for 59 patients (antipsychotic medication plus psychosocial treatment: 28 [47.5%]; mean [SD] age, 19.5 [3.0] years; 15 men [53.6%]; placebo plus psychosocial treatment: 31 [52.5%]; mean [SD] age, 18.8 [2.7]; 16 men [51.6%]) and 27 control individuals (mean [SD] age, 21.9 [1.9] years). At baseline, patients showed widespread functional dysconnectivity compared with controls, with reductions predominantly affecting interactions between the default mode network, limbic systems, and the rest of the brain. From baseline to 3 months, patients receiving placebo showed increased FC principally within the same systems; some of these changes correlated with improved clinical outcomes (canonical correlation analysis R = 0.901; familywise error-corrected P = .005). Antipsychotic exposure was associated with increased FC primarily between the thalamus and the rest of the brain. In this secondary analysis of a clinical trial, antipsychotic-naive patients with FEP showed widespread functional dysconnectivity at baseline, followed by an early normalization of default mode network and cortical limbic dysfunction in patients receiving placebo and psychosocial intervention. Antipsychotic exposure was associated with FC changes concentrated on thalamocortical networks. ACTRN12607000608460.

Increased Within-Network Functional Connectivity May Predict NEDA Status in Fingolimod-Treated MS Patients.

Only a few studies have evaluated the brain functional changes associated with disease-modifying therapies (DMTs) in multiple sclerosis (MS), though none used a composite measure of clinical and MRI outcomes to evaluate DMT-related brain functional connectivity (FC) measures predictive of short-term outcome. Therefore, we investigated the following: (1) baseline FC differences between patients who showed evidence of disease activity after a specific DMT and those who did not; (2) DMT-related effects on FC, and; (3) possible relationships between DMT-related FC changes and changes in performance. We used a previously analyzed dataset of 30 relapsing MS patients who underwent fingolimod treatment for 6 months and applied the “no evidence of disease activity” (NEDA-3) status as a clinical response indicator of treatment efficacy. Resting-state fMRI data were analyzed to obtain within- and between-network FC measures. After therapy, 14 patients achieved NEDA-3 status (hereinafter NEDA), while 16 did not (EDA). The two groups significantly differed at baseline, with the NEDA group having higher within-network FC in the anterior and posterior default mode, auditory, orbitofrontal, and right frontoparietal networks than the EDA. After therapy, NEDA showed significantly reduced within-network FC in the posterior default mode and left frontoparietal networks and increased between-network FC in the posterior default mode/orbitofrontal networks; they also showed PASAT improvement, which was correlated with greater within-network FC decrease in the posterior default mode network and with greater between-network FC increase. No significant longitudinal FC changes were found in the EDA. Taken together, these findings suggest that NEDA status after fingolimod is related to higher within-network FC at baseline and to a consistent functional reorganization after therapy.

Vascular risk factors are associated with a decline in resting-state functional connectivity in cognitively unimpaired individuals at risk for Alzheimer's disease: Vascular risk factors and functional connectivity changes

Resting-state functional connectivity is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. However, evidence is lacking regarding longitudinal changes in functional connectivity. This study includes 247 cognitively unimpaired individuals with a family history of sporadic AD (185 women/ 62 men; mean [SD] age of 63 [5.3] years). Plasma total-, HDL-, and LDL-cholesterol and systolic and diastolic blood pressure were measured at baseline. Global (whole-brain) brain functional connectivity and connectivity from canonical functional networks were computed from resting-state functional MRI obtained at baseline and ~3.5 years of annual follow-ups, using a predefined functional parcellation. A subsample underwent Aβ- and tau-PET (n=91). Linear mixed-effects models demonstrated that global functional connectivity increased over time across the entire sample. In contrast, higher total-cholesterol and LDL-cholesterol levels were associated with greater reduction of functional connectivity in the default-mode network over time. In addition, higher diastolic blood pressure was associated with global functional connectivity reduction. The associations were similar when the analyses were repeated using two other functional brain parcellations. Aβ and tau deposition in the brain were not associated with changes in functional connectivity over time in the subsample. These findings provide evidence that vascular burden is associated with a decrease in functional connectivity over time in older adults with elevated risk for AD. Future studies are needed to determine if the impact of vascular risk factors on functional brain changes precede the impact of AD pathology on functional brain changes.

Longitudinal brain connectivity changes and clinical evolution in Parkinson's disease.

Longitudinal connectivity studies might guide our understanding of the underlying neurodegenerative processes. We report the results of a longitudinal study in patients at different stages of Parkinson's disease (PD), who performed motor and non-motor evaluations and serial resting state (RS) functional MRI (fMRI). Cluster analysis was applied to demographic and clinical data of 146 PD patients to define disease subtypes. Brain network functional alterations were assessed at baseline in PD relative to 60 healthy controls and every year for a maximum of 4 years in PD groups. Progression of brain network changes were compared between patient clusters using RS fMRI. The contribution of network changes in predicting clinical deterioration was explored. Two main PD clusters were identified: mild PD (86 patients) and moderate-to-severe PD (60 patients), with the latter group being older and having earlier onset, longer PD duration, more severe motor, non-motor and cognitive deficits. Within the mild patient cluster, two clinical subtypes were further identified: mild motor-predominant (43) and mild-diffuse (43), with the latter being older and having more frequent non-motor symptoms. Longitudinal functional connectivity changes vary across patients in different disease stages with the coexistence of hypo- and hyper-connectivity in all subtypes. RS fMRI changes were associated with motor, cognitive and non-motor evolution in PD patients. Baseline RS fMRI presaged clinical and cognitive evolution. Our network perspective was able to define trajectories of functional architecture changes according to PD stages and prognosis. RS fMRI may be an early biomarker of PD motor and non-motor progression.

Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson’s disease

BackgroundResting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson’s disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time. ObjectivesTo examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. MethodsWe assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11C-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. ResultsAt baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen. ConclusionsOur findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression.

Functional reorganization during the recovery of contralesional target selection deficits after prefrontal cortex lesions in macaque monkeys

Visual extinction has been characterized by the failure to respond to a visual stimulus in the contralesional hemifield when presented simultaneously with an ipsilesional stimulus (Corbetta and Shulman, 2011). Unilateral damage to the macaque frontoparietal cortex commonly leads to deficits in contralesional target selection that resemble visual extinction. Recently, we showed that macaque monkeys with unilateral lesions in the caudal prefrontal cortex (PFC) exhibited contralesional target selection deficits that recovered over 2–4 months (Adam et al., 2019). Here, we investigated the longitudinal changes in functional connectivity (FC) of the frontoparietal network after a small or large right caudal PFC lesion in four macaque monkeys. We collected ultra-high field resting-state fMRI at 7-T before the lesion and at weeks 1–16 post-lesion and compared the functional data with behavioural performance on a free-choice saccade task. We found that the pattern of frontoparietal network FC changes depended on lesion size, such that the recovery of contralesional extinction was associated with an initial increase in network FC that returned to baseline in the two small lesion monkeys, whereas FC continued to increase throughout recovery in the two monkeys with a larger lesion. We also found that the FC between contralesional dorsolateral PFC and ipsilesional parietal cortex correlated with behavioural recovery and that the contralesional dorsolateral PFC showed increasing degree centrality with the frontoparietal network. These findings suggest that both the contralesional and ipsilesional hemispheres play an important role in the recovery of function. Importantly, optimal compensation after large PFC lesions may require greater recruitment of distant and intact areas of the frontoparietal network, whereas recovery from smaller lesions was supported by a normalization of the functional network.

Longitudinal Changes in Functional Connectivity of the Caudate Is Associated With Recovery From Bell's Palsy.

Several studies have demonstrated through resting-state functional magnetic resonance imaging (fMRI) that functional connectivity changes are important in the recovery from Bell’s palsy (BP); however, these studies have only focused on the cortico-cortical connectivity. It is unclear how corticostriatal connectivity relates to the recovery process of patients with BP. In the present study, we evaluated the relationship between longitudinal changes of caudate-based functional connectivity and longitudinal changes of facial performance in patients with intractable BP. Twenty-one patients with intractable BP underwent resting-state fMRI as well as facial behavioral assessments prior to treatment (PT) and at the middle stage of treatment (MT); and 21 age- and sex-matched healthy controls (HC) were recruited and received the same protocol. The caudate was divided into dorsal and ventral sub-regions and separate functional connectivity was calculated. Compared with HC, patients with intractable BP at the PT stage showed decreased functional connectivity of both the dorsal and ventral caudate mainly distributed in the somatosensory network, including the bilateral precentral gyrus (MI), left postcentral gyrus, media frontal gyrus, and superior temporal gyrus (STG). Alternatively, patients in the MT stage showed decreased functional connectivity primarily distributed in the executive network and somatosensory network, including the bilateral cingulate cortex (CC), left anterior cingulate cortex (LACC), inferior prefrontal gyrus (IFG), MI, STG, and paracentral lobe. The longitudinal changes in functional connectivity of both the dorsal and ventral caudate were mainly observed in the executive network, including the right ACC, left CC, and IFG. Functional connectivity changes in the right ACC and left IFG were significantly correlated with changes in facial behavioral performance. These findings indicated that corticostriatal connectivity changes are associated with recovery from BP.