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Static and dynamic network properties of the repetitive transcranial magnetic stimulation target predict changes in emotion regulation in obsessive-compulsive disorder
Corresponding author. Department of Anatomy & Neurosciences, O|2 building room 13W09, Amsterdam UMC, location VUmc, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands.
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy & Neurosciences, Amsterdam Neuroscience, De Boelelaan 1108, 1081 HZ, Amsterdam, the NetherlandsAthinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149 13th Street, Boston, MA 02129, USA
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy & Neurosciences, Amsterdam Neuroscience, De Boelelaan 1108, 1081 HZ, Amsterdam, the NetherlandsAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy & Neurosciences, Amsterdam Neuroscience, De Boelelaan 1108, 1081 HZ, Amsterdam, the NetherlandsAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy & Neurosciences, Amsterdam Neuroscience, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands
Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Anatomy & Neurosciences, Amsterdam Neuroscience, De Boelelaan 1108, 1081 HZ, Amsterdam, the NetherlandsAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands
Pre-treatment network topology of the target region predicts rTMS-response.
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Greater baseline local connectivity implied greater stimulation effects.
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Less temporal integration also predicted greater stimulation effects.
Abstract
Background
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique to treat psychiatric disorders, such as obsessive-compulsive disorder (OCD). However, the rTMS response varies across subjects.
Objective/hypothesis
We hypothesize that baseline network properties of the rTMS target may help understand this variation and predict response.
Methods
Excitatory rTMS to the dorsolateral prefrontal cortex (dlPFC) was applied in 19 unmedicated OCD patients, while inhibitory dlPFC-rTMS was applied in 17 healthy controls. The vertex was used as an active control target (19 patients, 18 controls). The rTMS response was operationalized as the individual change in state distress rating during an emotion regulation task. At baseline, subjects underwent resting-state functional MRI. The brain network was constructed by calculating wavelet coherence between regional activity of regions in the Brainnetome atlas. Local and integrative static connectivity and the dynamic network role of the target were calculated. Baseline target region network features were non-parametrically correlated to rTMS response.
Results
In the dlPFC-stimulated patients, greater local connectivity (Kendall’s Tau = −0.415, p = 0.013) and less promiscuous role of the target (Kendall’s Tau = 0.389, p = 0.025) at baseline were related to greater distress reduction after excitatory rTMS. There were no significant associations in healthy subjects nor in the active control stimulated patients.
Conclusions
Pre-treatment network topological indices predict rTMS-induced emotional response changes in OCD, such that greater baseline resting-state local connectivity and less temporal integration of the target region imply greater stimulation effects. These results may lead the way towards personalized neuromodulation in OCD.
], but remains an invasive and last-resort treatment.
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that utilizes repetitive, rapid magnetic field pulses to suppress (low-frequency stimulation) or stimulate (high-frequency stimulation) activity of specific brain circuits [
Decreased neural activity and neural connectivity while performing a set-shifting task after inhibiting repetitive transcranial magnetic stimulation on the left dorsal prefrontal cortex.
]. However, like in any treatment of OCD, there are large individual differences in rTMS treatment effects in terms of neural changes and behavioral response [
]. It is essential to find predictors of individual rTMS response to achieve personalized treatment, which is the main aim of the current work. In order to investigate such prognostic factors, we employ advanced imaging in combination with network theory.
Functional connectivity and network topological indices may offer advanced imaging-based predictors of individual response [
]. Functional connectivity refers to the statistical interdependencies between time series representing brain activity of different locations in the brain that are presumed to represent functional communication [
]. Functional connectivity based on resting-state functional MRI (rsfMRI) has previously been investigated as a biomarker for rTMS success. In OCD, higher baseline connectivity between a dorsal medial prefrontal cortex (dmPFC) rTMS target and the ventral striatum predicted greater subsequent symptom reduction [
]. However, measures of functional connectivity between two predefined brain regions are necessarily constrained by the topology of the entire brain network, which has not been taken into account [
A more complete and sensitive prediction of rTMS outcome may be achieved by concurrently analyzing all pairwise connectivities between brain regions through network or graph analysis [
]. In the field of functional network neuroscience, each brain region is seen as a node, and functional connectivity is represented by correlation weights between them in a connectivity matrix. Several whole-brain and nodal network properties may then be computed, such as measures of local segregation and global integration [
Frontal lobe connectivity and network community characteristics are associated with the outcome of subthalamic nucleus deep brain stimulation in patients with Parkinson’s disease.
Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.
]. Greater baseline local and/or segregated connectivity of the target region, for instance quantified with node strength or clustering, generally yields larger effects as opposed to more global or integrative connectivity, e.g. high betweenness centrality, of the target region [
The most recent insights in the field of network neuroscience relate to the dynamic nature of the brain network; while network topology averaged over an entire functional scan certainly relates to (alterations in) cognitive functioning, temporal fluctuations therein may even better explain cognitive variance [
]. The current study aims to expound the application of (dynamic) network analysis to predict response to excitatory dlPFC-rTMS on distress ratings during an emotional task paradigm in a relatively small sample of OCD patients that has been previously reported on [
]. Since the original experiment was designed to elucidate the neural basis of OCD, healthy controls received inhibitory rTMS to temporarily mimic OCD [
]. We hypothesize that individual response is predicted by baseline (dynamic) resting-state network topology of the target region and its associated subnetwork of connected brain regions. Participants with greater baseline local, segregated, connectivity of the target node and/or subnetwork are expected to show a greater behavioral change after rTMS compared to participants with more integratively connected target regions.
Material and methods
Participants
This study was approved by the VUmc Medical Ethics Committee and was executed in accordance with the Declaration of Helsinki on treatment of study participants. All participants gave written informed consent before participation.
Patients were recruited through outpatient clinics within The Netherlands OCD Association [
The Netherlands Obsessive Compulsive Disorder Association (NOCDA) study: design and rationale of a longitudinal naturalistic study of the course of OCD and clinical characteristics of the sample at baseline.
], the Academic Anxiety Center Altrecht (Utrecht, the Netherlands) and online advertisements. Healthy controls, group-level matched on age, sex and education, were recruited by local and online community advertisements. Our final sample consisted of 38 OCD patients and 35 healthy controls (HCs) randomly appointed to the verum dlPFC condition (OCD: n = 19, HC: n = 17) or active control vertex condition (OCD n = 19, HC n = 18). Since the HCs underwent inhibitory rTMS, while patients underwent excitatory rTMS, we report on this asymmetric control population only in the Supplementary materials.
All patients were screened for the presence of psychiatric disorders with the Structural Clinical Interview for DSM-IV [
]). The main inclusion criterion was a primary diagnosis of OCD without predominant hoarding, while psychiatric co-morbidity, such as major depressive disorder, was not an exclusion criterion. Patients were free of medication for at least four weeks. Further exclusion criteria were presence of current psychoactive medication use, current or past psychosis, a major physical or neurological illness (including current or previous severe traumatic head injuries and alcohol or drug dependence), MRI contraindications and excessive head movement during the resting-state scan session. Excessive motion was defined as a mean relative root mean squared displacement (RMS) > 0.2 mm, or >20 vol with frame-wise relative RMS displacement > 0.5 mm [
]. In short, participants visited Amsterdam UMC (location VUmc) for three measurements within the course of 1–4 weeks. Participants first underwent a psychiatric screening session and practiced the emotion regulation task (ERT) to be used during tfMRI. Participants then had a baseline fMRI scan session in which they first underwent rsfMRI and then tfMRI. During this ERT, participants viewed OCD-related or fearful pictures in two different instruction conditions: they were asked to either attend to the picture or regulate their emotions while viewing the pictures. During each block, three pictures were presented. After each picture the participants indicated their level of distress, using a visual analogue scale, which fed into our main behavioral outcome measure (see next section). For the current analyses we only used the fearful pictures.
In the verum condition, baseline tfMRI activations were used to derive the coordinates for rTMS stimulation or inhibition of the dlPFC in each individual participant, the so-called rTMS hotspot [
During the final visit, participants underwent rTMS and tfMRI directly after offline rTMS was applied using a hand-held statically cooled figure-of-eight TMS coil (Medtronic MagOption) under guided real-time neuronavigation (Visor v1.0, Eemagine GmbH, Germany). In the verum condition, patients received 10 Hz rTMS over the left dlPFC at 110% of their resting motor threshold during 20min in thirty pulse trains of 10sec with a 30sec inter-train-interval [
], which resulted in 3000 pulses in total. In the active control condition, the protocol was identical to the verum condition, apart from coil localization. Participants were naive to rTMS and blind to stimulation condition.
Behavioral outcome measure
We used the mean distress ratings of both attend and regulate conditions for the fearful pictures. Since we were mostly interested in the change in distress after rTMS, a relative difference score was calculated for distress using the following formula:
A constant (c) of 1 was added to the denominator to avoid dividing by zero. This relative change in distress was used as the outcome measure of rTMS effect.
Image acquisition
Imaging was performed on a GE Signa HDxt 3T magnet (General Electric, USA) with an 8-channel headcoil. Structural scanning entailed a sagittal 3-dimensional gradient-echo T1-weighted sequence (256 × 256 matrix; voxel size = 1 × 0.977 × 0.977 mm; 172 sections). In the current study, only baseline rsfMRI was utilized, during which participants were instructed to remain awake with their eyes closed. Whole-brain functional images were acquired with a gradient echo-planar imaging sequence (TR = 1800 ms; TE = 30 ms; 64 × 64 matrix; field of view = 24 cm; flip angle = 80°; 200 vol; total duration 6min) with 40 ascending slices per volume (3.75 × 3.75 mm in-plane resolution; slice thickness = 2.8 mm; inter-slice gap = 0.2 mm).
Image analysis
Nodes in the cortical brain network were defined using the Brainnetome atlas [
]. Because we focused on the baseline network role of the rTMS target region, we determined the target node by calculating the overlap of a sphere (5 mm radius) centered around the MNI coordinates used for individual TMS coil localization with all regions in the atlas. The atlas region with highest percentage overlap with the rTMS target was selected as the primary node used for network analysis.
The rsfMRI preprocessing steps included: (a) extraction of brain tissue using BET [
], (b) coregistration of rsfMRI to the structural scan using FLIRT and FNIRT in order to warp atlas regions to individual functional images, (c) application of several preprocessing steps through MELODIC [
], and a high pass filter of 100 s cut-off, (d) regression of time series from voxels in the white matter and cerebrospinal fluid, (e) exclusion of atlas regions containing <4 active voxels in any participant, which yielded a total of 200 regions common to all datasets. We then extracted time series from each of these 200 nodes in each participant. In order to mitigate the effect of movement, we scrubbed time points with >0.3 mm relative frame-wise displacement.
Static network analysis
Fig. 1 schematically depicts the network analysis pipeline. Statically, we focused on node strength, representing the total sum of the connection weights of a (subnetwork of) node(s), as a measure of local network connectivity of both the target node (primary predictor) and the average of the target subnetwork (secondary predictor; see Fig. 1B). As measures of more integrative connectivity, we calculated both betweenness centrality, which refers to the weighted fraction of all shortest paths that pass through a (subnetwork of) node(s), and the participation coefficient, which assesses the weighted diversity of connections a (subnetwork of) node(s) has with other subnetworks.
Fig. 1Schematic overview of (dynamic) network analysis. (A) depicts how the target node and target subnetwork were defined on both the connectivity matrix (top left) and the brain (top right). Static and dynamic network analysis was subsequently performed on this decomposition into target node and subnetwork. The top row of (B) shows an exemplar toy network of a subject with high average node strength of the target subnetwork: the target subnetwork has an average strength of: 3 (target node in magenta) + 2 (target subnetwork node 1 in purple) + 3 (target subnetwork node 2 in purple))/3 = 2.7. Conversely, the bottom row subject has low average node strength of the target subnetwork, namely (2 + 1 + 1)/3 = 1.3. In (C), the dynamic network analysis is schematically indicated. While the line surrounding each node still indicates target node, target subnetwork or non-target node, the fill of each node indicates the module to which it belongs in each particular window of data (windows 1 to 3 displayed in rows). The subject depicted in the left column has low promiscuity of the target region: the magenta node consistently belongs to the white module. However, the subject depicted in the right column has high promiscuity of the target region, as it belongs to the white, black, and gray modules consecutively.
In-house scripts for MATLAB R2017a (The MathWorks, Inc, Natick, MA, USA) were used. Static connectivity matrices were calculated by correlating the 200 time series using the wavelet transform in the 0.06–0.12 Hz frequency band, conforming to previous studies [
]. Since negative correlations may occur, but have no known biological substrate as of yet, we absolutized correlations. Subsequent network analysis took place on 200 × 200 weighted matrices using the Brain Connectivity Toolbox (BCT), with all formulas described in Ref. [
Although we took care to localize the target node, it is expected that the (predictive) effect of rTMS is not limited to a single node; this is why we included both the target node and its subnetwork as predictors. In order to obtain the subnetwork encompassing the target region, the global modular structure of each subject was determined using the Louvain modularity algorithm (see Fig. 1A, in which the module containing the magenta target node is depicted in purple). A gamma of 1.08 was used to create on average seven (range 5–9) subnetworks per participant in line with previous work [
Finally, based on this target subnetwork analysis, a control node was chosen that was least frequently present in the target subnetworks across all subjects. This node was located in the right occipital lobe and therefore unlikely to be affected by dlPFC-rTMS.
Dynamic network analysis
We also investigated dynamic or temporal segregation versus integration through the measure of promiscuity [
], which represents the fraction of all subnetworks in which the target node participated at least once across different windows of the entire scan (see Fig. 1C). Higher promiscuity indicates greater spatial diversity in a node’s modular allegiance over time.
Dynamic network analysis was performed identically to the static analysis, with the exception that connectivity was established over a constant range of timepoints from the entire scan using a sliding window approach. Based on the literature, window length was 25 TRs (45sec) with 1 TR shift (1.8sec [
Statistical analyses were carried out in R (R Foundation for Statistical Computing, 2017, Vienna, Austria) and SPSS Statistics 22 (IBM Corp., Armonk, NY, USA). ANOVA and Mann-Whitney U tests were used to compare group demographic and behavioral characteristics. As the behavioral and network measures were not normally distributed, Wilcoxon signed rank tests were used to compare baseline measurements between the four groups of participants.
In order to test our hypotheses, Kendall’s Tau correlations between baseline static and dynamic network properties and relative change in distress were calculated with bootstrapped 95% confidence intervals. Due to the high level of interdependence between network measures and the exploratory nature of this study, these analyses were not corrected for multiple comparisons. Significance was set at an alpha level of 0.05.
Results
Participants, baseline characteristics and behavioral outcomes
The mean age of the sample was 38.9 ± 10.5 years; about 50% of participants were men (see Table 1); the four groups were well matched in terms of age, sex and education.
Table 1Baseline participant characteristics.
OCD patients
Healthy controls
Statistic (df)
p
verum n = 19
control n = 19
verum n = 17
control n = 18
Number/% of males
9/47
9/47
9/53
8/44
χ(3) = 0.263
0.966
Age
39.1 ± 9.56
39.4 ± 11.03
38.4 ± 11.16
38.7 ± 11.14
F(3,69) = 0.029
0.993
Education (years)
12.7 ± 3.21
12.9 ± 2.86
13.2 ± 3.15
13.1 ± 2.92
F(3,69) = 0.069
0.976
YBOCS total
20.0 ± 7.19
22.5 ± 5.41
NA
NA
F(1,36) = 1.498
0.229
YBOCS obsession
9.2 ± 3.69
11.1 ± 3.46
NA
NA
F(1,36) = 2.664
0.111
YBOCS compulsion
10.8 ± 4.12
11.4 ± 2.50
NA
NA
F(1,36) = 0.327
0.571
Legend. Cells indicate mean ± standard deviation unless otherwise specified.
]. In short, state distress was higher in patients compared with HCs at baseline (Mann-Whitney U = 350, p < 0.001) and post-treatment (U = 362.5, p < 0.001). In patients, distress was generally lower post-treatment as compared to baseline (Fig. 2), but paired Wilcoxon signed rank tests were not significant (verum patients Z = −1.953, p = 0.051; active control patients Z = −1.729, p = 0.084).
Fig. 2Distress ratings within each group at baseline and after treatment. Dot and box plots are shown to visualize the distress ratings during the Emotion Regulation Task at baseline and after rTMS in OCD patients. The ‘spaghetti’ lines show the change in distress ratings from baseline to after rTMS. The distress ratings represent the subject’s appraisal of both the attend and regulate conditions combined.
We then continued to test our hypotheses whether baseline static network properties were associated with post-treatment relative change in state distress. All statistical information can be found in Supplementary Table 1. Baseline betweenness and participation of the target node or subnetwork were not associated with relative change in distress. In the verum stimulated patients, average node strength of the target subnetwork was negatively associated with relative change in distress (Kendall’s Tau = −0.415, 95% CI [-0.753, −0.006], p = 0.013; Fig. 3A), indicating that higher strength of the target subnetwork related to greater reduction in task-induced state distress after stimulatory dlPFC-rTMS. This was not the case in the active control patient group (Kendall’s Tau = −0.246 [-0.572, 0.120], p = 0.141). There was also no significant association with strength of the target node in patients (Supplementary Table 1).
Fig. 3Significant association between change in distress and baseline network properties. In (A), the association between mean strength of the target subnetwork at baseline and the subsequent change in distress is shown for OCD patients undergoing verum rTMS to the dorsolateral prefrontal cortex (dlPFC, purple circles) or active control rTMS to the vertex (cyan triangles). In the verum condition, there was a significant association (Kendall’s Tau = −0.415, 95% CI [-0.753, −0.006], p = 0.013), which was not present in the active control condition (Kendall’s Tau = −0.246 [-0.572, 0.120], p = 0.141). In (B), the association between promiscuity of the target node at baseline and the subsequent change in distress is shown for the same groups, showing significant results in the verum condition (Kendall’s Tau = 0.389 [0.088, 0.695], p = 0.025), but not in the vertex group (Kendall’s Tau = 0.313 [-0.134, 0.663], p = 0.071). Note that a linear correlation line is drawn in these figures, but that this association was tested non-parametrically.
We similarly tested our hypotheses on dynamic network properties. Promiscuity of the target node was positively associated with change in fear distress ratings in verum stimulated patients (Kendall’s Tau = 0.389 [0.088, 0.695], p = 0.025; Fig. 3B). Thus, patients with less baseline promiscuity of the target node showed greater reductions in task-induced distress. Node promiscuity of two exemplar patients is illustrated in Fig. 4.
Fig. 4Target node promiscuity in two exemplar OCD patients. In order to illustrate the target node allegiance with different modules over all windows of data, we selected subject A with very low promiscuity and subject B with very high promiscuity. Each color indicates a module. It is evident that subject A had more stable modular allegiance and thus lower promiscuity than subject B.
To check whether the association between promiscuity of the target node and distress change was spatially specific, we also correlated promiscuity of the control node with change in state distress. This yielded non-significant results (Supplementary Table 1).
Finally, we tested the relationship between node strength of the target subnetwork and promiscuity of the target node, since both were related to relative change in distress in the OCD patients. However, these two network characteristics were not significantly correlated in patients (Kendall’s Tau = −0.278 [-0.566, 0.047], p = 0.110).
Discussion
The aim of the present study was to explore whether baseline static and dynamic networks predict dlPFC-rTMS response in OCD patients. Confirming our hypothesis, OCD patients with strong local connectivity (high subnetwork strength) and low dynamic integration (low promiscuity) at the target location were more sensitive to rTMS-induced behavioral effects.
We found an association between baseline average strength of the target subnetwork and post-treatment reduction in task-induced distress in OCD patients, indicating that greater pre-treatment resting-state strength of local connections in the subnetwork of the target region facilitates the excitatory effects of rTMS. Although we did not test whether this association in the verum group was significantly different from the correlation coefficient found in the active control group, the latter did not show a significant relationship between network topology and change in distress. These results are in line with earlier rsfMRI studies that show greater effectiveness of rTMS when stimulated regions are more strongly connected pre-treatment [
]. It has already been suggested that local, but not integrative, connectivity during the resting-state may be of particular relevance for subsequent intervention effects [
]. In the current study, we did not find an association between integrative connectivity of the target region and treatment effect. Speculatively, our results may suggest that local spatial segregation may potentiate the excitatory effect of rTMS.
We also report the value of innovative dynamic network properties in predicting rTMS outcome in the verum OCD patient group. Again, we did not test whether the verum association was greater than the correlation in the active control group, although dynamic network topology did not significantly relate to change in distress in the active control condition. Whereas static network measures may assess predominantly spatial segregation and integration, dynamic network measures are tailored to pick up temporal signs of segregation and integration. Promiscuity is a dynamic network measure that is based on the notion that the brain network operates in modules or subnetworks [
]. The composition of these subnetworks is dynamic over time, resulting in nodes that participate in several subnetworks and, assumedly, different neural processes to a lesser or greater extent [
]. Our current results suggest that patients with target regions that dynamically participate in fewer subnetworks (i.e. show lower promiscuity) at baseline show greater reduction in task-induced distress after excitatory rTMS. Analogous to the spatial interpretation offered for static network results, we speculate that target nodes with high promiscuity participate in many different processes, thereby diffusing rTMS-induced excitation and decreasing its behavioral impact. Furthermore, our results suggest that both spatial and temporal measures of segregation are predictive of dlPFC-rTMS effects in OCD patients, while there was no significant association between the two measures.
Several limitations apply to the current work. First, the small sample size limits the power of statistical analyses and may inflate our results [
]. Moreover, the small sample size in combination with relative change in behavioral results led to a non-normal distribution of the dependent variable, thereby limiting our statistics to non-parametric analyses. Comorbidity in the patient population may also have impacted the variation in rTMS response, but could not be controlled for in this small sample. Second, our healthy controls received a different type of rTMS than the OCD patients, limiting interpretation of the specificity of our results for OCD patients: it could be that healthy subjects show the same vulnerability to excitatory TMS depending on their prestimulation network topology. Third, due to excessive movement during tfMRI in our cohort, only resting-state scans were analyzed in the current work, even though the contrast in network organization between emotional states may explain more behavioral variance [
]. Nevertheless, most variation in regional network characteristics remains stable across states (rest versus task) and conditions (time of day), but instead largely depends on inter-individual differences [
]. Taken together, combining rest and task conditions may add predictive power of rTMS response and should be investigated in future studies. Fourth, we applied a commonly used sliding window approach to assess dynamic network properties, but the chosen window length may have influenced our results [
A wavelet-based estimator of the degrees of freedom in denoised fMRI time series for probabilistic testing of functional connectivity and brain graphs.
]. Future studies may explore whether these hypothetically more sensitive approaches may yield greater predictive power in the context of rTMS. Fourth, we consider our current work preliminary evidence for the potential relevance of (dynamic) network properties as biomarkers for rTMS effects. However, since correlational studies do not allow statistical inferences at the level of individual patients, future studies are necessary to develop this potential.
In conclusion, we show that baseline resting-state network properties of the rTMS target region relate to post-treatment change in task-induced distress, such that dlPFC targets with strong local connections and low promiscuity are most susceptible to the effects of rTMS. As emotion regulation is disturbed in OCD patients, these results may have implications for the application of rTMS in OCD treatment by improving the choice of a stimulation target or selecting the optimal individualized treatment.
Financial disclosures
Dr. Douw was sponsored by NWO (NWO-ZonMw Veni 016.146.086) and Society in Science (Branco Weiss Fellowship). Prof. van den Heuvel received an NIMH grant (R01MH113250-01) and an NWO-ZonMW grant (BEO-60-63600-98-326). Dr. Vriend received grants from the Brain Foundation Netherlands (HA-2017-00227), Amsterdam Neuroscience and the Dutch Parkinson Patient Association. Ms. Quaak, Ms. Fitzsimmons, Dr. de Wit and Prof. van der Werf reported no biomedical financial interests or potential conflicts of interest.
Acknowledgements
We thank Dr. Niels J.H.M. Gerrits and Dr. Froukje E. de Vries for their help in acquiring and analyzing these data. This study was funded by the Netherlands Organisation for Scientific Research (NWO-ZonMw Veni 916.86.036 and Vidi 917.17.306 for OAvdH), the Brain & Behavior Research Foundation (NARSAD Young Investigators Award 2009 for OAvdH), the Netherlands Brain Foundation (2010(1)-50), and the Amsterdam Brain Imaging Platform. These funding bodies did not have any involvement in the design, data collection, analysis and interpretation of this study.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Decreased neural activity and neural connectivity while performing a set-shifting task after inhibiting repetitive transcranial magnetic stimulation on the left dorsal prefrontal cortex.
Frontal lobe connectivity and network community characteristics are associated with the outcome of subthalamic nucleus deep brain stimulation in patients with Parkinson’s disease.
Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.
The Netherlands Obsessive Compulsive Disorder Association (NOCDA) study: design and rationale of a longitudinal naturalistic study of the course of OCD and clinical characteristics of the sample at baseline.
A wavelet-based estimator of the degrees of freedom in denoised fMRI time series for probabilistic testing of functional connectivity and brain graphs.
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