Longitudinal fMRI Research Articles

Task-independent effects are potential confounders in longitudinal imaging studies of learning in schizophrenia.

Learning impairment is a core deficit in schizophrenia that impacts on real-world functioning and yet, elucidating its underlying neural basis remains a challenge. A key issue when interpreting learning-task experiments is that task-independent changes may confound interpretation of task-related signal changes in neuroimaging studies. The nature of these task-independent changes in schizophrenia is unknown. Therefore, we examined task-independent “time effects” in a group of participants with schizophrenia contrasted with healthy participants in a longitudinal fMRI learning-experiment designed to allow for examination of non-specific effects of time. Flanking the learning portions of the experiment with a task-of-no-interest allowed us to extract task-independent BOLD changes. Task-independent effects occurred in both groups, but were more robust in the schizophrenia group. There was a significant interaction effect between group and time in a distributed activity pattern that included inferior and superior temporal regions, frontal areas (left anterior insula and superior medial gyri), and parietal areas (posterior cingulate cortices and precuneus). This pattern showed task-independent linear decrease in BOLD amplitude over the two scanning sessions for the schizophrenia group, but showed either opposite effect or no activity changes for the control group. There was a trend towards a correlation between task-independent effects and the presence of more negative symptoms in the schizophrenia group.The strong interaction between group and time suggests that both the scanning experience as a whole and the transition between task-types evokes a different response in persons with schizophrenia and may confound interpretation of learning-related longitudinal imaging experiments if not explicitly considered.

Dopaminergic genetic variation moderates effect of nicotine on cigarette reward self-report

Aims: Youth with a family history of substance use disorders (SUD) oftenhave particular emotional andbehavioral traits that are early predictors of later problem substance use. There is substantial evidence for a gender difference in risk trajectories such that females tend toward negative affectivity and males tend toward impulsivity. Gender differences in substance use are also evident during adolescence, concurrent with the appearance of genderbased developmental differences in the brain, indicating theremay also be gender-specific neural predictors in those at-risk for developing SUD. Methods: Longitudinal fMRI was conducted in males (n=18) and females (n=18) with a family history of SUD starting at ages 8–13 yrs. Participants performed an emotional arousal word task during fMRI at 1to 2-yr intervals (3–4 scans/participant), covering the age range of 8–17.5 yrs. Emotional words were positive, negative, or neutral, and participants were required to press a button indicating they understood the word when it appeared on the screen. A voxel-by-voxel analysis was conducted in SPM8 using a multiple regression model, designed to represent mixed linear effects and identify age-related changes between groups. Results: For performance measures, females demonstrated a significant reduction in reaction time to negative, positive, and neutral words across age, while males showed no change. Significant age-related differences were found between groups in the right premotor cortex (BA6) and right amygdala for the negative vs. neutral contrast, where males showed a significant decrease in activation with age (premotor: p= .006; amygdala: p= .001) and females non-significantly increased in activation (premotor: p= .111; amygdala: p= .351). Conclusions: These results reveal developmental differences in brain functional responses in emotional arousal between males and females at-risk for SUD. These differencesmay underlie gender differences in behavioral risk trajectories for SUD. Financial support:R01DA027261, R01AA12217, R01AA07065, T32 DA007267-19, and T32 DA7268-22.

Gender differences in the development of emotion circuitry in youth at risk for substance abuse: A longitudinal FMRI study

Gender differences in the development of emotion circuitry in youth at risk for substance abuse: A longitudinal FMRI study

CHANGES IN REGIONAL BRAIN ACTIVATION RELATED TO DEPRESSIVE STATE: A 2-YEAR LONGITUDINAL FUNCTIONAL MRI STUDY.

Abnormal brain activations during processing of emotional facial expressions in depressed patients have been demonstrated. We investigated the natural course of brain activation in response to emotional faces in depression, indexed by functional magnetic resonance imaging (fMRI) scans preceding and following change in depressive state. We hypothesized a decrease in activation in the amygdala, anterior cingulate cortex (ACC), and insula with a decrease in depressive pathology. A 2-year longitudinal fMRI study was conducted as part of the Netherlands Study of Depression and Anxiety. We included 32 healthy controls and 49 depressed patients. During the second scan, 27 patients were in remission (remitters), the other 22 were not (nonremitters). All participants viewed faces with emotional expressions during scanning. Rostral ACC activation during processing of happy faces was predictive of a decrease in depressive state (PFWE = .003). In addition, remitters showed decreased activation of the insula over time (PFWE = .016), specifically during happy faces. Nonremitters displayed increased abnormalities in emotion recognition circuitry during the second scan compared to the first. No effect of selective serotonin reuptake inhibitor use was observed. Our results demonstrate that rostral ACC activation may predict changes in depressive state even at 2-year outcome. The association between change in depressed state and change in insula activation provides further evidence for the role of the insula in a network maintaining emotional and motivational states.

Quantitative assessment of visual cortex function with fMRI at 7 Tesla-test-retest variability.

fMRI-based retinotopic mapping was used to assess systematic variations in activated cortical surface area, amplitude, and coherence across sessions. Seven healthy subjects were scanned at 7 T in three separate sessions with intervals of 51.4 ± 5.4 days (Sessions 1 and 2) and 167.9 ± 24.4 days (Sessions 2 and 3). We found a reduction between Sessions 1 and 2 for activated cortical surface area, between Sessions 1 and 3 for amplitude, and between Sessions 1 and 2/3 for coherence. The results do not support head motion as a major cause of the observed effect seen in Session 1, suggesting that cognitive effects were the underlying cause of change. The phase correlations for both eccentricity and polar angle mapping were highly correlated between sessions, demonstrating the stability of the maps. Furthermore, the sensitivity in determining inter-session changes of cortical surface area, response amplitude, and coherence were, at a 5% significance level, estimated to be 1.5, 6, and 5%, respectively. Any future longitudinal fMRI study should carefully evaluate activation across sessions to determine the eligibility of inclusion of all time points. This experimental design provides guidance in methodological issues of clinical longitudinal fMRI-studies, specifically regarding effects of subject experience.

Buffering effect of positive parent–child relationships on adolescent risk taking: A longitudinal neuroimaging investigation

Adolescence is marked by a steep increase in risk-taking behavior. The serious consequences of such heightened risk taking raise the importance of identifying protective factors. Despite its dynamic change during adolescence, family relationships remain a key source of influence for teenagers. Using a longitudinal fMRI approach, we scanned 23 adolescents twice across a 1.5-year period to examine how changes in parent–child relationships contribute to changes in adolescent risk taking over time via changes in adolescents’ neural reactivity to rewards. Results indicate that although parent–child relationships are not associated with adolescent risk taking concurrently, increases in positive parent–child relationships contribute to declines in adolescent risk taking. This process is mediated by longitudinal decreases in ventral striatum activation to rewards during risk taking. Findings highlight the neural pathways through which improvements in positive parent–child relationships serve to buffer longitudinal increases in adolescent risk taking.

Longitudinal Changes in Prefrontal Cortex Activation Underlie Declines in Adolescent Risk Taking.

Adolescence is a developmental period marked by steep increases in risk-taking behavior coupled with dramatic brain changes. Although theories propose that the prefrontal cortex (PFC) may influence adolescent risk taking, the specific ways in which it functions remain unclear. We report the first longitudinal functional magnetic resonance imaging study to examine how neural activation during risk taking changes over time and contributes to adolescents' real-life risk-taking behavior. We find that longitudinal declines in activation of the ventrolateral PFC are linked to declines in adolescent risk taking, whereas the medial PFC influences adolescent risk taking via its functional neural coupling with reward-related regions. This is the first study to identify the mechanism by which different regions of the PFC disparately contribute to declines in risk taking.

MRI compatible optrodes for simultaneous LFP and optogenetic fMRI investigation of seizure-like afterdischarges

In preclinical studies, implanted electrodes can cause severe degradation of MRI images and hence are seldom used for chronic studies employing functional magnetic resonance imaging. In this study, we developed carbon fiber optrodes (optical fiber and electrode hybrid devices), which can be utilised in chronic longitudinal studies aiming to take advantage of emerging optogenetic technologies, and compared them with the more widely used tungsten optrodes. We find that optrodes constructed using small diameter (~130 μm) carbon fiber electrodes cause significantly reduced artifact on functional MRI images compared to those made with 50 μm diameter tungsten wire and at the same time the carbon electrodes have lower impedance, which leads to higher quality LFP recordings. In order to validate this approach, we use these devices to study optogenetically-induced seizure-like afterdischarges in rats sedated with dexmedetomidine and compare these to sub (seizure) threshold stimulations in the same animals. The results indicate that seizure-like afterdischarges involve several extrahippocampal brain regions that are not recruited by subthreshold optogenetic stimulation of the hippocampus at 20 Hz. Subthreshold stimulation led to activation of the entire ipsilateral hippocampus and septum, whereas afterdischarges additionally produced activations in the contralateral hippocampal formation, neocortex, cerebellum, nucleus accumbens, and thalamus. Although we demonstrate just one application, given the ease of fabrication, we anticipate that carbon fiber optrodes could be utilised in a variety of studies that could benefit from longitudinal optogenetic functional magnetic resonance imaging.

Alteration of brain regional homogeneity of monkeys with spinal cord injury: A longitudinal resting-state functional magnetic resonance imaging study

PurposeTo investigate the longitudinal brain regional homogeneity (ReHo) changes in nonhuman primate after spinal cord injury (SCI) by resting-state functional magnetic resonance imaging (fMRI). MethodsThree adult female rhesus monkeys underwent unilateral thoracic cord injury. A resting-state fMRI examination was performed in the healthy stage and 4, 8, and 12weeks after the injury. The ReHo value of each voxel in the monkey brain was calculated and compared between pre- and post-SCI monkeys with paired t test. The regions of interest (ROIs) in the significantly changed ReHo regions were set. The correlations between the ReHo change and the time after injury were also determined. ResultsCompared with those in healthy period, the ReHo values of the left premotor cortex and the anterior cingulate cortex (ACC) in post-SCI rhesus monkeys significantly increased in 4-week follow-up examinations. The ReHo values of posterior cingulate cortex, left precuneus, left temporal parietooccipital area, and bilateral superior parietal lobules decreased at 8-week follow-up examinations. In 12-week follow-up examinations, the ReHo values of the left postcentral gyrus, right caudate nucleus, and superior temporal gyrus increased. Correlation analysis showed positive correlations between left ACC and the postoperative time. ConclusionSCI can change the regional synchronism of brain activity in sensorimotor system and the default mode network. These findings may help us to understand the potential pathophysiological changes in the central nervous system after SCI.

Emotion Reactivity Is Increased 4-6 Weeks Postpartum in Healthy Women: A Longitudinal fMRI Study.

Marked endocrine alterations occur after delivery. Most women cope well with these changes, but the postpartum period is associated with an increased risk of depressive episodes. Previous studies of emotion processing have focused on maternal–infant bonding or postpartum depression (PPD), and longitudinal studies of the neural correlates of emotion processing throughout the postpartum period in healthy women are lacking. In this study, 13 women, without signs of post partum depression, underwent fMRI with an emotional face matching task and completed the MADRS-S, STAI-S, and EPDS within 48 h (early postpartum) and 4–6 weeks after delivery (late postpartum). Also, data from a previous study including 15 naturally cycling controls assessed in the luteal and follicular phase of the menstrual cycle was used. Women had lower reactivity in insula, middle frontal gyrus (MFG), and inferior frontal gyrus (IFG) in the early as compared to the late postpartum assessment. Insular reactivity was positively correlated with anxiety in the early postpartum period and with depressive symptoms late postpartum. Reactivity in insula and IFG were greater in postpartum women than in non-pregnant control subjects. Brain reactivity was not correlated with serum estradiol or progesterone levels. Increased reactivity in the insula, IFG, and MFG may reflect normal postpartum adaptation, but correlation with self-rated symptoms of depression and anxiety in these otherwise healthy postpartum women, may also suggest that these changes place susceptible women at increased risk of PPD. These findings contribute to our understanding of the neurobiological aspects of the postpartum period, which might shed light on the mechanisms underlying affective puerperal disorders, such as PPD.

Common and distinct neural effects of risperidone and olanzapine during procedural learning in schizophrenia: a randomised longitudinal fMRI study.

RationaleMost cognitive domains show only minimal improvement following typical or atypical antipsychotic treatments in schizophrenia, and some may even worsen. One domain that may worsen is procedural learning, an implicit memory function relying mainly on the integrity of the fronto-striatal system.ObjectivesWe investigated whether switching to atypical antipsychotics would improve procedural learning and task-related neural activation in patients on typical antipsychotics. Furthermore, we explored the differential effects of the atypical antipsychotics risperidone and olanzapine.MethodsThirty schizophrenia patients underwent functional magnetic resonance imaging during a 5-min procedural (sequence) learning task on two occasions: at baseline and 7–8 weeks later. Of 30 patients, 10 remained on typical antipsychotics, and 20 were switched randomly in equal numbers to receive either olanzapine (10–20 mg) or risperidone (4–8 mg) for 7–8 weeks.ResultsAt baseline, patients (all on typical antipsychotics) showed no procedural learning. At follow-up, patients who remained on typical antipsychotics continued to show a lack of procedural learning, whereas those switched to atypical antipsychotics displayed significant procedural learning (p = 0.001) and increased activation in the superior-middle frontal gyrus, anterior cingulate and striatum (cluster-corrected p < 0.05). These neural effects were present as a linear increase over five successive 30-s blocks of sequenced trials. A switch to either risperidone or olanzapine resulted in comparable performance but with both overlapping and distinct task-related activations.ConclusionsAtypical antipsychotics restore procedural learning deficits and associated neural activity in schizophrenia. Furthermore, different atypical antipsychotics produce idiosyncratic task-related neural activations, and this specificity may contribute to their differential long-term clinical profiles.

Concussion in Women

INTRODUCTION: Since the enactment of Title IX (1972), rates of female participation in sports have grown exponentially. However, despite these growing numbers, women are infrequently asked about risk factors for and consequences of concussion in the ambulatory care setting or during well-woman visits. As well, concussion in women and men usually are not differentiated when considering presentation and adverse outcomes. Data are emerging that suggest concussion not only has long-term health implications but also that the effect of this injury in women compared with men is related to physical differences, cognitive differences (particularly in the verbal, quantitative, and visuospatial domains) and differences in the hormonal milieu. METHODS: A review of the literature on concussion in the female athlete on PubMed was conducted, with attention to both clinical studies and diagnostic studies. RESULTS: Data suggest that sex and gender contribute to concussion prevalence and severity, presenting symptoms, and recovery. For example, women may present with more drowsiness and sensitivity to noise after concussion than men. As well, increased surveillance appears to be warranted despite obvious behavioral recovery. Results of a longitudinal functional magnetic resonance imaging study in athletes with concussion suggest that neural recovery lags behind behaviorally assessed recovery, and alterations in white matter fiber tracts over the 2 months after injury have been demonstrated. Screening templates are available, and consideration of incorporation of relevant questionnaires into the electronic health record as well as the potential role of imaging will be discussed. CONCLUSION/IMPLICATION: Inquiry about concussion should be considered a part of the well-woman visit for all patients, especially those engaged in at-risk contact sports. The gynecologic visit and examination should include questions about head injury from sports involvement and a prior diagnosis of concussion.

Second language lexical development and cognitive control: A longitudinal fMRI study

In this paper we report a longitudinal functional magnetic resonance imaging (fMRI) study that tested contrasting predictions about the time course of cognitive control in second language (L2) acquisition. We examined the neural correlates of lexical processing in L2 learners twice over the course of one academic year. Specifically, while in the scanner, participants were asked to judge the language membership of unambiguous first and second language words, as well as interlingual homographs. Our ROI and connectivity analyses reveal that with increased exposure to the L2, overall activation in control areas such as the anterior cingulate cortex decrease while connectivity with semantic processing regions such as the middle temporal gyrus increase. These results suggest that cognitive control is more important initially in L2 acquisition, and have significant implications for understanding developmental and neurocognitive models of second language lexical processing.

Longitudinal alterations to brain function, structure, and cognitive performance in healthy older adults: A fMRI-DTI study

Cross-sectional research has shown that older adults tend to have different frontal cortex activation patterns, poorer brain structure, and lower task performance than younger adults. However, relationships between longitudinal changes in brain function, brain structure, and cognitive performance in older adults are less well understood. Here we present the results of a longitudinal, combined fMRI-DTI study in cognitive normal (CN) older adults. A two time-point study was conducted in which participants completed a task switching paradigm while fMRI data was collected and underwent the identical scanning protocol an average of 3.3 years later (SD=2 months). We observed longitudinal fMRI activation increases in bilateral regions of lateral frontal cortex at time point 2. These fMRI activation increases were associated with longitudinal declines in WM microstructure in a portion of the corpus callosum connecting the increasingly recruited frontal regions. In addition, the fMRI activation increase in the left VLPFC was associated with longitudinal increases in response latencies. Taken together, our results suggest that local frontal activation increases in CN older adults may in part reflect a response to reduced inter-hemispheric signaling mechanisms.

The effect of estrogen synthesis inhibition on hippocampal memory

17-Beta-estradiol (E2) facilitates long term-potentiation (LTP) and increases spine synapse density in hippocampal neurons of ovariectomized rodents. Consistent with these beneficial effects on the cellular level, E2 improves hippocampus-dependent memory. A prominent approach to study E2 effects in rodents is the inhibition of its synthesis by letrozole, which reduces LTPs and spine synapse density. In the current longitudinal functional magnetic resonance imaging (fMRI) study, we translated this approach to humans and compared the impact of E2 synthesis inhibition on memory performance and hippocampal activity in post-menopausal women taking letrozole (n = 21) to controls (n = 24). In particular, we employed various behavioral memory paradigms that allow the disentanglement of hippocampus-dependent and -independent memory. Consistent with the literature on rodents, E2 synthesis inhibition specifically impaired hippocampus-dependent memory, however, this did not apply to the same degree to all of the employed paradigms. On the neuronal level, E2 depletion tended to decrease hippocampal activity during encoding, whereas it increased activity in the anterior cingulate and the dorsolateral prefrontal cortex. We thus infer that the inhibition of E2 synthesis specifically impairs hippocampal functioning in humans, whereas the increased prefrontal activity presumably reflects a compensatory mechanism, which is already known from studies on cognitive aging and Alzheimer's disease.

Progesterone mediates brain functional connectivity changes during the menstrual cycle—a pilot resting state MRI study

The growing interest in intrinsic brain organization has sparked various innovative approaches to generating comprehensive connectivity-based maps of the human brain. Prior reports point to a sexual dimorphism of the structural and functional human connectome. However, it is uncertain whether subtle changes in sex hormones, as occur during the monthly menstrual cycle, substantially impact the functional architecture of the female brain. Here, we performed eigenvector centrality (EC) mapping in 32 longitudinal resting state fMRI scans of a single healthy subject without oral contraceptive use, across four menstrual cycles, and assessed estrogen and progesterone levels. To investigate associations between cycle-dependent hormones and brain connectivity, we performed correlation analyses between the EC maps and the respective hormone levels. On the whole brain level, we found a significant positive correlation between progesterone and EC in the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral sensorimotor cortex. In a secondary region-of-interest analysis, we detected a progesterone-modulated increase in functional connectivity of both bilateral DLPFC and bilateral sensorimotor cortex with the hippocampus. Our results suggest that the menstrual cycle substantially impacts intrinsic functional connectivity, particularly in brain areas associated with contextual memory-regulation, such as the hippocampus. These findings are the first to link the subtle hormonal fluctuations that occur during the menstrual cycle, to significant changes in regional functional connectivity in the hippocampus in a longitudinal design, given the limitation of data acquisition in a single subject. Our study demonstrates the feasibility of such a longitudinal Resting-state functional Magnetic Resonance Imaging (rs-fMRI) design and illustrates a means of creating a personalized map of the human brain by integrating potential mediators of brain states, such as menstrual cycle phase.

3. Functional MRI in the diagnosis and prognosis of multiple sclerosis

Whereas morphological MR imaging provides clear evidence of white and gray matter lesions reflecting multiple sclerosis (MS) pathology, functional MRI (fMRI) studies of the motor, visual and cognitive networks in MS patients have provided evidence of more diffuse cortical changes. Compared with healthy subjects, fMRI changes are characterized by expansion within physiological task-related networks, such as more prominent participation of higher-level areas or recruitment of additional areas, as well as differences in resting state networks and disrupted within-network connectivity. Longitudinal fMRI studies have demonstrated that the observed abnormalities vary over the course of the disease, even in patients in disease remission (i.e., outside of relapses). Treatment interventions, such as treatment of leg spasticity with intramuscular botulinum toxin, may cause notable, even if transient, normalization of task-related networks. Functional MRI changes in MS reflect morphological MRI abnormalities, especially when more sensitive techniques are applied to detect normal-appearing white and gray matter of the brain and spinal cord. This phenomenon fits in the more widely described mechanism of increased recruitment within functional networks to at least partially compensate for structural damage in brain diseases as diverse as stroke and amyotrophic lateral sclerosis ( Weiller et al., 2006 ). While notable progress has been made to improve prognosis of the clinical course of MS using sophisticated morphological markers, e.g., ( Kalincik et al., 2012 , Zivadinov et al., 2013 ), functional MRI might also contribute to improve disease monitoring prognosis. Finally, functional MRI may be used to study the effects of different therapies on central nervous system engagement ( Filippi and Rocca, 2013 ).

21. Longitudinal fMRI assessment in chronic spinal cord injury treated by intrathecal baclofen – Pilot data

Introduction Spasticity is a frequent disabling sign of upper motor neuron lesion in chronic spinal cord injury (SCI). In severe cases intrathecal baclofen (ITB) is recommended as a choice of effective treatment. Baclofen, being as a strong GABAB agonist, modulates cortical and spinal inhibitory circuits. The aim of this study was to assess longitudinal changes in brain activation after continuous ITB delivery during simple motor tasks performed by functional magnetic resonance imaging (fMRI). Material and Methods Two subjects (27 and 35 years-old males, 5.5 years after SCI) with chronic posttraumatic cervical spinal cord injury at C4–5 level underwent ITB pump implantation (Synchromed II, 20 ml, Medtronic). Spasticity was assessed by Modified Ashworth Scale (MAS, 0–4). Both subjects were studied by 1.5T fMRI with three tasks employed: (i) finger-tapping and mental movement simulating, (ii) finger taping and (iii) foot flexion. Tasks were performed before, 12 weeks and one year after ITB pump implantation. Analysis was processed in SPM8 using the FWE corrected threshold (p Results Both patients were classified as AIS-A and they presented no active movements of lower limbs. In both subjects, MAS score declined in the lower extremities from 4 to 1 before and after ITB implantation, respectively. Before-ITB pump implantation fMRI showed weak activations in all tasks. Post-ITB tasks extensively raised activation in the motor system network, namely the primary sensorimotor cortex and supplementary motor area. In one year follow-up, the activation in foot-flexion mental tasks were detectable only in one of the subjects, with slightly increased volume. One of the most important factors, influencing all the results, is subject motion. Conclusions Continuous ITB administration relieving spasticity in SCI patients was associated with increased activation of sensorimotor cortex. ITB treatment may cause distant functional reorganization of sensorimotor network probably by increased GABAB-mediated inhibitory activity at cortical level. Supported by Research Projects PRVOUK P34, UNCE 204010/2012 and IGA NT12282.

Developmental Trajectories for Visuo-Spatial Attention are Altered by Prenatal Alcohol Exposure: A Longitudinal FMRI Study

Developmental Trajectories for Visuo-Spatial Attention are Altered by Prenatal Alcohol Exposure: A Longitudinal FMRI Study

Neural correlates of longitudinal recovery of naming in stroke

Neural correlates of longitudinal recovery of naming in stroke