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Cerebral Cortex Advance Access published August 13, 2014
The Fault Lies on the Other Side: Altered Brain Functional Connectivity in PsychiatricDisorders is Mainly Caused by Counterpart Regions in the Opposite Hemisphere Jie Zhang1,2,†, Keith M. Kendrick3,†, Guangming Lu4,2 and Jianfeng Feng1,2,5 1Centre for Computational Systems Biology, Fudan University, Shanghai 200433, PR China, 2Fudan University – Jinling HospitalComputational Translational Medicine Center, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, PR China,3Key Laboratory for Neuro Information, University of Electronic Science and Technology of China, School of Life Science andTechnology, Chengdu 610054, PR China, 4Department of Medical Imaging, Jinling Hospital, Nanjing University School ofMedicine, Nanjing 210002, PR China and 5Department of Computer Science, University of Warwick, Coventry, UK Address correspondence to Email: [email protected] (J.F.); [email protected] (G.L.) †Jie Zhang and Keith M. Kendrick contributed equally to the work and are joint first authors.
Many psychiatric disorders are associated with abnormal resting- Other functional brain network state functional connectivity between pairs of brain regions, alterations have also been found, for example, dorsal attention although it remains unclear whether the fault resides within the pair and prefrontal-striatal networks of regions themselves or other regions connected to them. Identify- in ADHD, affective network in depres- ing the source of dysfunction is crucial for understanding the eti- ology of different disorders. Using pathway- and network-based and extensive dysconnectivity in schizophrenia ( techniques to analyze resting-state functional magnetic imaging ; ). There is also growing interest in data from a large population of patients with attention deficit hyper- establishing transdiagnostic approaches aiming to identify activity disorder (239 patients, 251 controls), major depression common molecular, neural, and behavioral phenotypes in (39 patients, 37 controls), and schizophrenia (69 patients, 62 con- mental disorders (; trols), we show for the first time that only network-based cross- correlation identifies significant functional connectivity changes in Functional connectivity is primarily measured by temporal all 3 disorders which survive correction. This demonstrates that the correlation of activities in pairs of brain regions and analyzed primary source of dysfunction resides not in the regional pairs them- using either cross-correlation (Pearson) ; selves but in their external connections. Combining pathway and ) or partial correlation network-based functional-connectivity analysis, we established that, , ; ) techniques. Despite the extensive in all 3 disorders, the counterparts of pairs of regions in the opposite research carried out on functional connectivity analysis in hemisphere contribute 60–76% to altered functional connectivity, mental disorders, it is still unclear whether the cause of the compared with only 17–21% from the regions themselves. Thus, a reported changes resides within the region pairs themselves, transdiagnostic feature is of abnormal functional connectivity or in other external regions connected to them in the brain between brain regions produced via their contralateral counterparts.
network. If we are going to be able to establish the optimal Our results demonstrate an important role for contralateral counter- targets for both diagnostic and therapeutic advances the part regions in contributing to altered regional connectivity in psychi- primary sources responsible for observed functional connect- atric disorders.
ivity changes need to be identified.
Cross-correlation analysis has the advantage that it takes Keywords: cross-correlation, functional connectivity alteration, mental into account contributions from all the different regions in a disorders, partial correlation, resting-state functional brain network distributed brain network to the correlation observed betweena specific pair of regions. However, while it may be a moreaccurate reflection of the brain as an interconnected network, cross-correlation techniques may be biased by detecting An increasing number of functional connectivity studies using contributions from third-party regions which are not actually resting-state or task-related functional magnetic resonance structurally connected ( imaging (fMRI) data from the brain have identified changes in This has led to the alternative use of partial- the strength of coupling between pairs of connected regions correlation techniques designed to consider functional links associated with many mental disorders, including Alzheimer's between pairs of regions in isolation, thereby removing contri- disease ; depres- butions from all other third-party regions in the brain network anxiety (schizophrenia ( This approach is more accurate in identifying functional connections between region pairs and attention deficit hyperactivity disorder (ADHD) which are also structurally connected because third-party influ- ences are excluded (However, the disad- functional connectivity alterations have been identified in vantage is that it may not identify changes occurring at a more these psychiatric disorders, most prominently in the Default complex network level.
Mode Network: ADHD ( In the current study, we have therefore used a combination of cross- (Pearson-) and partial-correlation analysis of resting- and schizophrenia ( state fMRI data in individuals with 3 different psychiatric The Author 2014. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected] disorders (ADHD, schizophrenia, and major depression) com- trauma. Healthy controls were also confirmed using DSM-IV criteria to pared with matched healthy controls. Our hypothesis was that be free of schizophrenia or other Axis 1 disorders and not to have a if functional connectivity alterations of patients in pairs of history of substance abuse or clinically significant head trauma. All pa-tients and healthy controls were right handed with the exception of 2 regions are primarily contributed to by changes within these patients who were left handed.
regions, then partial correlation, which removes third-party in- Details of drug treatments for patients in the 3 datasets are provided fluences and reflects direct interaction between a pair of in Relevant ethical permissions for experi- regions, should be the most sensitive in detecting the function- ments and subject individual consent forms were obtained for all 3 da- al connectivity alterations. If on the other hand such changes tasets (Dataset 1 can be found at are primarily contributed by third-party regions, then the ; Dataset 2 is depression data (andDataset 3 is schizophrenia data )).
Pearson-correlation technique should be more sensitive. If thelatter proved to be the case, we could also combine these 2 ap- proaches to identify which third-party regions contribute mostto observe functional connectivity changes. Here, we adopted Image Acquisitions and Data Preprocessing a triplets-regions of interest (ROI)-based partial-correlation A strict criterion of head movement not greater than ±1.5 mm and±1.5° was used. For Dataset 1 (ADHD) resting-state functional imaging approach especially suited to identify the influences from each data were acquired from Peking University and New York University.
individual third-party mediator. Our work therefore is Peking University All functional imaging data and T1-weighted expected to provide new insights into the mechanisms of how images were acquired using a SIEMENS TRIO 3 T. A black screen with large-scale organization of functional networks changes in the a white fixation cross was displayed during the scan. Participants were disordered brain and therapeutic strategies.
asked to relax and keep still when functional imaging data were col-lected. A total of 232 volumes of echo planar images (EPI) were ob-tained axially (slices, 30; repetition time (TR), 2000 ms; echo time (TE),30 ms; slice thickness, 4.5 mm; flip angle 90°; field of view (FOV), Materials and Methods 220 × 220 mm2; matrix, 64 × 64). A high-resolution T1-weighted mag-netization prepared rapid acquisition gradient echo (mprage) image was obtained for all subjects, see for details.
Three resting-state datasets were used from ADHD, depression, and New York University Participants were asked to remain still, close schizophrenia patients and their respective healthy control groups.
their eyes and think of nothing systematically but not to fall Full demographic details of patients and healthy controls are given in asleep when functional imaging data were collected. A black screen The ADHD dataset (Database 1) was obtained was presented to them. Image data were acquired using Siemens from the ADHD-200 Consortium for the Global Competition Allegra 3.0 T scanner. A total of 172 volumes of EPI images were and includes a total of obtained axially (slices, 33; TR, 2000 ms; TE, 15 ms; slice thickness, 490 subjects (251healthy controls and 239 ADHD patients—55 patients 4 mm; flip angle, 90°; FOV, 240 × 240 mm2; matrix, 80 × 80). A high- are identified as medicated and 85 as unmedicated. For the remaining resolution T1-weighted mprage was obtained for each subject (slices, 99 patients no information is given). All ADHD patients and healthy 128; TR, 2530 ms; TE, 3.25 ms; inversion time, 1100 ms; slice thick- controls were evaluated using the Schedule of Affective disorders and ness, 1.33 mm; flip angle, 7°; FOV, 256 × 256; matrix, 256 × 256).
schizophrenia for Children—Present and Lifetime version (KSADS-PL) For Dataset 2 (depression), image data were acquired using a 1.5 T with one parent for the establishment of diagnosis. The ADHD Rating Siemens MRI scanner. Individuals were instructed to keep their eyes Scale (ADHD-RS) IV was employed to measure severity of ADHD closed but not go to sleep. A total of 180 volumes of EPI images were symptoms. All patients and healthy controls were either from China obtained axially (slices, 20; TR, 2000 ms; TE, 40 ms; thickness, 5 mm; or USA and (1) right handed, (2) no history of head trauma with loss of gap, 1 mm; flip angle, 90°; FOV, 240 × 240 mm2; resolution, 64 × 64).
consciousness (3) no history of neurological disease or diagnosis High-resolution whole-brain T1-weighted images were acquired sagit- of schizophrenia, affective disorder, pervasive development disorder, tally with a 3D spoiled gradient echo pulse sequence (TR, 12.1 ms; TE, or substance abuse (4) had a Weschler Intelligence Scale for Children 4.2 ms; flip angle, 151; FOV = 240 × 240 mm2; acquisition matrix, score of >80.
256 × 256; thickness, 1.8 mm; number of excitations, 2; 172 slices).
The major depression database (Database 2) includes 76 Chinese For Dataset 3 (schizophrenia), all subjects underwent a structural subjects (37 healthy controls and 39 depression patients—15 first and functional MRI scan in a single session using a 3T MR system (TIM episode depression who were unmedicated and 24 medicated, Trio, Siemens). Individuals were instructed to keep their eyes closed treatment-resistant depression) from Second Xiangya Hospital, Central but not go to sleep. A total of 180 volumes of EPI images were obtained South University in Changsha, Hunan Province, China and also re- axially, (slices, 34; TR, 2000 ms; TR, 24 ms; thickness, 3 mm; flip angle, ported in a previous paper ). All patients met the fol- 90°; FOV, 256 × 256 mm2; resolution, 64 × 64). A whole-brain high- lowing inclusion criteria: (1) current major depressive disorder attack resolution T1-weighted MR image was acquired using a magnetization as assessed by 2 experienced psychiatrists using the Structural Clinical prepared rapid gradient echo (MPRAGE) sequence in a coronal view Interview for DSM-IV; (2) 18–45 years of age; (3) right-handed Han (TR, 2000 ms; TE, 2.98 ms; inversion time, 900 ms; image matrix size, Chinese; (4) Hamilton Rating Scale for depression scores of at least 17; 192 × 256, spatial resolution, 1 × 1 mm2, FOV, 192 × 256 mm2; slice (5) treatment-naive adult patients with first episode major depression thickness, 1 mm).
had not taken any medication before the MRI scan. Patients and For the 3 datasets prior to preprocessing, the first 10 volumes were healthy controls met the following exclusion criteria: (1) a history of discarded to allow for scanner stabilization and the subjects' adaptation neurological diseases or other serious physical diseases; (2) a history to the environment. fMRI data preprocessing was then conducted by of electroconvulsive therapy; (3) a history of substance abuse (4) SPM8 ) and a Data Processing Assist- comorbidities with other disorders (no evidence for schizoaffective ant for Resting-State fMRI (DPARSF). The remaining functional scans disorder or Axis II, personality disorders and mental retardation).
were first corrected for within-scan acquisition time differences The schizophrenia dataset (Database 3) includes 131 Taiwanese between slices and then realigned to the middle volume to correct for subjects (62 healthy controls and 69 medicated schizophrenia patients) interscan head motions. Subsequently, the functional scans were from National Taiwan University Hospital in Taiwan and reported in a spatially normalized to a standard template (Montreal Neurological In- previous paper (All patients were identified according stitute) and resampled to 3 × 3 × 3 mm3. After normalization, blood to DSM-IV diagnostic criteria by qualified psychiatrists and symptom oxygen level-dependent (BOLD) signal of each voxel was firstly de- severity assessed using the Positive and Negative Syndrome Scale trended to abandon linear trend and then passed through a band-pass (PANSS). Exclusion criteria included (1) the presence of other DSM-IV filter (0.01–0.08 Hz) to reduce low-frequency drift and high-frequency disorders; (2) history of substance abuse; (3) clinically significant head physiological noise. Finally, nuisance covariates including head 2 Altered Functional Connectivity Caused by Contralateral Regions • Zhang et al.
motion parameters, global mean signals, white matter signals, and It should be noted that there are 88 third-party mediators for each cerebrospinal signals were regressed out from the BOLD signals. After region pair i and j, thereby forming 88 triplets, each of which generates data preprocessing, the time series were extracted in each ROI by aver- a partial-correlation coefficient. We have chosen the smallest one (in aging the signals of all voxels within that region.
absolute value) as the final partial correlation between i and j, because For all 3 datasets, the automated anatomical labeling atlas the largest influence among all third-party regions is removed in this ) was used to parcellate the brain into 90 ROIs way. We call this third-party region that exerts the largest influence to (45 per hemisphere). The names of the ROIs and their corresponding the given pair i and j as the primary mediating region (denoted by K), abbreviations are listed in with its mediating strength being Pe − PaK. Similarly, if we choose thethird-party region that lead to the second smallest partial correlation(among all 88 partial correlations), then this third-party region is Functional Connectivity Analysis defined as the secondary mediating region, with the corresponding The BOLD signals of all voxels were obtained by a band-pass filter, ex- mediating strength being the secondary mediating strength. Finally, a tracting the low frequencies of interest (0.01–0.08 Hz). Regional BOLD positive mediation indicates that third-party region influences i and j in signals for each individual were obtained by averaging the time series the same direction, for example, excites (or inhibit) both of them.
of all the voxels in the region. For all subjects, both cross-correlation A negative mediation means the third-party region is affecting i and j (Pearson-correlation) and partial-correlation analysis were performed in different directions.
to measure whole-brain functional connectivity using regional BOLDtime series. We used a triplets-ROI-based partial-correlation approachto remove the mediation from third-party regions. For an arbitrary pair Support Vector Machine (SVM) Classifier of regions i and j, its partial correlation is calculated multiple times, The SVM is a learning machine for a 2-class classification problem each time with one third-party region k (k = 1, 2, … ,90, k ≠ i and k ≠ j) widely used because of its ability to handle very high-dimensional data being controlled (i.e., the mediation from region k is removed). We call and due to its accuracy in classification and prediction. In the current these 3 regions i, j, and k a triplet in this case. Since there are altogether study we used the same method (to calculate the pre- 90 brain regions, there will be 88 third-party mediators for i and j (i.e., diction accuracy for the altered functional connections identified by 88 triplets), and thus 88 partial-correlation coefficients will be obtained cross-correlation and also the contralateral mediating strength in the 3 for region pair i and j. We then pick the smallest one (in absolute different disorders. We used SVM toolkit libsvm ( value) as the partial-correlation coefficient between i and j , by Lin Chih-Jen of Taiwan University). A radial ; indicating that the largest influence among all basis function is selected as the kernel function (t = 2) and parameter C third-party mediators is removed. The corresponding third-party is fixed to 10 to trade-off learning and generalization while other para- region, which has the largest mediation effect and leads to the smallest meters are kept as default values. Statistical significance of the accuracy partial correlation (in absolute value), is called the primary mediating estimates was also calculated using a permutation analysis.
The reason why we used this triplets-based approach to estimate partial correlation is 2-fold: (1) the number of samples (length of BOLD signal) is small compared with the number of variables (brainregions) that traditional inverse covariance matrix approach may lead Functional Connectivity Changes in ADHD, depression, to poor estimate; our approach avoids this problem by performing afirst-order estimate, that is, removes the mediation from one third-party and schizophrenia region at a time, and then pick the smallest partial correlation (i.e., re- We first carried out a whole-brain functional-connectivity analysis moving the largest mediation); (2) Our approach allows evaluation of comparing patient groups and their respective healthy controls the mediating strength from each individual third-party region to a using both Pearson- and partial-correlation analysis. Results re- given functional pair (see below), therefore, we can spot the third- vealed that only Pearson-correlation identified significantly party mediator that exerts the largest influence. The goal of partialling altered pathways in all 3 disorders following standard FDR cor- out the influence from one third-party mediator at a time is not todiscard useful information, but to identify which region has the great- rection (see for abbreviations of brain est influence to a given pair of regions.
regions. ADHD: 50 connections, depression: 18 connections, and After obtaining the whole-brain functional connectivity using both schizophrenia: 70 connections see Fig. and Pearson- and partial-correlation, we then performed 2-sample t-test Partial correlation failed to identify any changes that between patients and matched controls for each of the functional con- survived FDR correction. This failure of partial correlation there- nectivity. The difference across the 2 groups was only considered sig- fore showed that the significant functional connectivity changes nificant where they survived false discovery rate (FDR) (q < 0.025). Weused a stringent correction here to avoid type-I error in multiple com- found using Pearson-correlation must primarily have been con- parison. For schizophrenia data, we used a strict Bonferroni correction tributed to by third-party regions. This is further emphasized by as there would otherwise be too many functional connectivity changes the finding that partial correlation for the same functional connec- (by Pearson correlation) identified using a looser correction. Finally, to tions identified by Pearson as significantly altered in the 3 disor- evaluate the correlation between altered functional connectivity in pa- ders were considerably lower than those calculated using tients and corresponding symptom scores of various diseases, Pearson Pearson (see Fig. and correlation analysis is performed.
In ADHD significantly altered connections were found in a range of frontal, parietal, temporal, occipital, subcortical, andlimbic areas with the most affected regions being the orbito- Identifying Primary Mediating Regions and the Strengthof Their Influence frontal cortex, inferior and superior frontal gyrus, anterior and For a given pair of brain regions i and j, the above triplets-ROI-based posterior cingulate gyrus, calcarine cortex, and parahippocam- partial-correlation analysis allows us to evaluate the mediation, or con- pal gyrus. For depression changes were primarily in orbito- tributions from each individual third-party region. Pearson-correlation frontal cortex, posterior cingulate cortex, parietal and temporal between i and j (denoted by Pe) embraces simultaneously mediations cortices, hippocampus, amygdala, insula, caudate, putamen, from all third-party regions, while partial correlation with region k pallidum and thalamus. Schizophrenia patients showed the being the controlled variable (denoted by Pak) reflects functional con-nectivity between i and j after removing the mediation of region k.
most widespread changes involving all major cortical and Therefore, the mediation, or influence exerted by k to the functional subcortical subdivisions. However, the most affected regions connectivity between i and j can be defined as Pe − Pak.
were medial and superior frontal gyri, medial and posterior Figure 1. Regional links showing significantly altered functional connectivity identified by Pearson correlation in (a) ADHD, (b) depression and (c) schizophrenia. Corresponding alterationsin partial correlation are also given for each link although none of these are significant (for abbreviations see . "*" denotes that the altered connectivity isinterhemispheric. Where regions are underlined this indicates that their contralateral counterparts are first or second primary mediators of the corresponding altered link.
cingulate gyri, pre- and postcentral gyri, angular gyrus, fusi- were within brain hemispheres and half between them (within form and lingual gyri, thalamus, and caudate. In all 3 disorders vs. between hemispheres: ADHD = 24/26; depression = 10/8; approximately half of the altered functional connections schizophrenia: 34/36 links).
4 Altered Functional Connectivity Caused by Contralateral Regions • Zhang et al.
Which Third-party Regions are Responsible for Altered contralateral mediating strength (across control and patient Functional Connectivity? group) contributed 60–76% of the altered Pearson-correlation Since partial correlation between a pair of brain regions (which found in patients in individual regional pairs, whereas the removes mediations from third-party regions) is not sensitive change within the pairs themselves, that is, partial correlation, in finding significant functional-connectivity changes, while accounted for only 17.5–21% (Table This finding indicates Pearson-correlation (which contains third-party mediation) can that it is altered mediation by contralateral counterpart regions detect the changes, this suggests that the third-party mediation which is primarily responsible for the changes in functional con- is vital for the functional-connectivity alteration in patients. By nectivity observed in regional pairs in patients in all 3 disorders.
triplets-ROI-based partial-correlation analysis, we manage to Note here "change" means the difference between control and find which third-party region played the most significant role in patient groups.
contributing to altered functional connections between pairs of The proportion of the altered connections in the 3 disorders brain regions in ADHD, depression, and schizophrenia. This where a contralateral counterpart was either the first (primary) revealed that the main contributors were the 2 contralateral or second (secondary) strongest mediating region was also counterpart regions for many of these regional pairs exhibiting very high (ADHD—88%; depression—94.4%; schizophrenia— altered functional connectivity (Fig. and 80%—see Indeed, overall there . We defined contralateral mediating strength as the- was a significant positive correlation between altered function- larger one (in absolute value) contributed to by the 2 individual al connectivity in region pairs in all 3 disorders and altered counterpart regions. Overall, we found that the change in mediating strength from the most influential contralateral Figure 2. Schematic drawing of contralateral mediation for a specific functional connectivity. The top and bottom panel are for interhemispheric (a–c) and intrahemisphericconnectivity (d–f ), respectively. In the top panel, the functional connectivity between xR and y (black circles) is mediated by the contralateral symmetric region of xR, that is, xL(green circle). (a) shows a strong functional connectivity (dark red line) between xR and y calculated using Pearson correlation because it is contributed to by the direct interactionbetween xR and y ( partial correlation, pink line, which excludes contributions from xL, see b), and by contralateral mediation from region xL on both xR and y (red line, see c). This isthe same for the intrahemispheric connectivity in bottom panel, that is, the strong functional connectivity between xL and y calculated using Pearson correlation (in d) is contributedto by the direct interaction between xL and y ( partial correlation, which excludes contributions from xR, see e), and by contralateral mediation from region xR on both xL and y (seef). We found that for the altered functional connectivity of all 3 disorders, there is always motif-3 structure whereby both the right (xR) and left sides (xL) of the same region showedaltered functional connectivity with another region (y) such that for xR to y, xL is the primary mediator and for xL to y, xR is the primary mediator.

counterpart region (see Fig. ). A further analysis of the pro- influences were weakened (ADHD—42%; depression –55.6%; portion of altered functional connections where the mediating schizophrenia—45.7%) with only a small proportion being strength of contralateral counterpart regions was actually sig- strengthened (ADHD—18%; depression—5.6%; schizophrenia nificantly (P < 0.05) different between patients and controls showed this to be 35/44 (79.5%) in ADHD, 11/17 (64.7%) in A number of regions with altered functional links in the depression and 54/56 (96.4%) in schizophrenia with overall 3 disorders were also identified as significant mediators (see levels of significance being higher for changes in schizophre- A notable motif revealed by our nia. In all 3 disorders the majority of these mediation analysis is that in many cases a 3-region bilateral interactivenetwork is formed whereby if the right side of a region (xR)shows altered connectivity with another one (y) in patients,then the left side (xL) of the same region acts as the key mediat- ing structure (see Fig. , in which xL serves as the mediator The mean change (across controls and patients) in functional connectivity measured by partial for link xR to y). Additionally, the link between xL and y is also correlation, the contralateral mediating strength, and Pearson correlation for all the altered often altered, and in this case xR acts as the key mediating functional connections in ADHD (50 links), depression (18 links), and schizophrenia (70 links),respectively structure (see Fig. –e). This pattern whereby xR and xL bothact as mediators for their counterpart's altered link with y Pearson correlation occurs in a number of cases in all 3 disorders (see Fig. The most marked in ADHD is for the right and left medial orbito- (a) Using the original correlation value frontal cortices which have this motif with the right and left parahippocampal gyrus, right and left calcarine cortex, and left rectus gyrus (i.e., 14 altered links); in depression the right and (b) Using the square of the original correlation value left putamen, right and left pallidum, and right and left insula all have this motif in altered links with the right inferior orbito- frontal cortex (i.e., 6 altered links); in schizophrenia the right The change in Pearson correlation between a given pair of regions is contributed by change in and left thalamus had this motif with the left and right medial direct interaction (i.e., partial correlation) between this pair of regions and the change of mediation frontal gyrus, left and right postcentral gyrus, left and right from third-party regions (e.g., contralateral counterparts to the given pair of regions), thus that fusiform gyrus, right precentral gyrus, and left lingual gyrus contributed by the contralateral counterpart mediation (60–76%). Furthermore, when added (i.e., 18 altered links). Furthermore, the sign of the difference together Pearson correlation change can be deemed as overall change (i.e., 100%). It can be seenin Table (a) that the actual change in direct interaction (measured by partial correlation) is much between functional connectivity strengths in patients versus smaller (17.5–21%) than the 2 contributions from the functional link itself and its primary controls for xR to xL, xR to y, and xL to y is the same (i.e., contralateral mediator account for 81–95% of the total change measured by Pearson correlation.
always positive or always negative) in almost all cases, indicat- Table (b) is the same as Table (a), but is obtained using the square of the original correlation ing potential additive effects involving all 3 links. Overall func- value. Table (b) shows that the contribution from contralateral counterpart mediation is much tional connectivity strengths between bilateral counterpart larger than that from the direct interaction of a functional pair (0.0137/0.0016 = 8.6 times forADHD, 0.0253/0.0035 = 7.3 times for depression, and 0.0426/0.0033 = 12.9 times for regions (i.e., xR to xL) were always higher than for any other connections (see Figure 3. Significant positive correlations between the difference of the magnitude of altered functional connectivity (Pearson) across controls and patients and that of associatedcontralateral mediating strength for (a) ADHD (50 links), (b) depression (18 links) and (c) schizophrenia (70 links) patients. In all cases absolute values and the contralateralcounterpart region with the strongest mediating strength were used.
6 Altered Functional Connectivity Caused by Contralateral Regions • Zhang et al.
Figure 4. Functional connections and their associated mediating regions significantly correlated with symptom scores. (a) ADHD, (b) depression (only main altered connections areshown since there are no correlations with symptoms), (c) schizophrenia (positive-symptom-related connections), (d) schizophrenia (negative-symptom-related connections).
Functional connections (solid lines) and mediating links (dashed lines) are either reduced in strength in patients compared with healthy controls (blue) or increased (red).
Connections are either positively correlated with symptom severity (dark red/blue) or negatively correlated (light red/blue). In all cases the direction of the changes in functionalconnectivity and that of mediating strength is the same. Regions only associated with functional connectivity changes are denoted by large nodes (black) and where they are onlymediators as smaller nodes (green). Where regions are involved in both functional connectivity and mediating then a large node includes a smaller one inside it. In all cases themediation influence on a specific functional connection is on both regions involved and only the contralateral counterpart region with the strongest mediating influence is shown.
We also carried out a separate analysis to determine if the mediation rate is higher in medicated patients than unmedi- general pattern of weakened mediating effects by contralat- cated patients (which might be due to medication effect), in eral counterpart regions in the 3 disorders might have both cases there was still an overall reduction in mediating resulted from the medications used. Medicated and unmedi- strength (see Thus, it would cated ADHD or depression patients were compared separate- appear unlikely that our findings were influenced by non- ly with their respective control groups. While contralateral specific medication effects.
Associations between Functional Connectivity and (positive or negative) was the same for altered functional links Contralateral Mediation Changes and Symptom and altered contralateral region mediating strength.
The regions showing significantly altered functional connect- Functional connectivity (Pearson correlation) changes signifi- ivity and contralateral counterpart mediation associated with cantly associated with symptom severity in the 3 disorders are symptom severity in ADHD and for schizophrenia are shown in shown in Figure and For ADHD, Figure , It can be seen 7/50 functional pathways were associated with symptom sever- that for ADHD the main links are those involving the medial or- ity. These included the right medial orbitofrontal cortex connec- bitofrontal cortex and calcarine cortex. For schizophrenia, links tions with left middle orbitofrontal cortex and right inferior associated with positive symptoms include more frontal (orbito- frontal gyrus (triangular) (positive correlation) and the left frontal and medial frontal) and medial (medial cingulate, medial orbitofrontal cortex with the left and right calcarine caudate and thalamus) structures whereas for negative symp- cortex (negative correlation); the right and left inferior frontal toms medial (medial cingulate gyrus and pallidum) and poster- gyrus (triangular) connections to the left rectus gyrus and right ior ( posterior cingulate gyrus and lingual gyrus) structures are.
anterior cingulate gyrus, respectively (positive correlation) and For illness duration associations were also with medial and pos- left medial frontal gyrus connection with right inferior temporal terior structures (see gyrus (negative correlation, see Fig. ). For depression patients we did not find any significant correlations with Hamilton SVM Analysis of the Predictive Value of Functional scores, although these were mostly high and had a narrow range Connectivity Changes in our patient groups. Figure b shows the 11 out of 18 altered Classification accuracy revealed by support vector machine links showing contralateral mediation and including the 2 most (SVM) showed that pathways showing altered functional con- frequently involved regions, the medial orbitofrontal cortex nectivity identified by Pearson-correlation were effective for (8 links) and inferior parietal lobule (3 links). For schizophrenia distinguishing patients from healthy controls (leave-one-out 22/70 functional connections were found to correlate significant- accuracy: ADHD: 68.0%; depression: 85.5%; schizophrenia: ly with PANSS scores (13 with positive and 9 with negative 84.7%, respectively, all P < 0.001). A separate analysis of the ac- symptom severity, see Fig. ,d). For positive symptoms connec- curacy of altered mediating strength in contralateral counter- tions involved either thalamo-frontal (6 links—negative correl- part regions for discriminating patients and controls in the 3 ation) or thalamo-postcentral gyrus/rolandic operculum (3 links— disorders revealed similar results (ADHD: 64.7%; depression: positive correlation) links; medial cingulate gyrus to superior 72.4%, schizophrenia: 82.4%, all P < 0.001, see occipital gyrus (negative correlation); caudate to middle tem- for details. We did not use partial correlation in the poral pole (2 links—positive correlation) and right posterior cin- SVM analysis as it failed to identify any changes that survived gulate cortex to left medial frontal gyrus (negative correlation) FDR correction.
and left fusiform gyrus (positive correlation). For negative symp-toms connections involved either the posterior cingulate gyrus tofusiform and lingual gyri (5 links—positive correlation) and medial cingulate gyrus to pallidum and putamen (4 links—nega-tive correlation). In addition, 13/70 functional pathways were Overall we have provided the first systematic investigation of significantly associated with illness duration in schizophrenia.
what contributes to altered functional coupling between These had a large overlap (6/13 links) with functional connec- region pairs in the disordered brain through a combined use of tions associated with negative symptom severity and included cross-correlation and partial-correlation techniques. It is note- medial cingulate gyrus to putamen, pallidum, and amygdala worthy that the goal of partialling out third-party mediation (in (6 links—negative correlation) and posterior cingulate gyrus to our triplets-ROI-based partial-correlation analysis) is not to lingual gyrus (3 links—positive correlation). Other links asso- discard information arbitrarily but, on the contrary, to evaluate ciated with illness duration included left lingual gyrus to bilateral the third-party mediation and, to identify the mediator exerting amygdala (positive correlation), left to right pallidum (negative the greatest mediation to a given pair of regions. This revealed correlation) and left angular gyrus to left superior occipital gyrus that significant changes observed in patients are not due pri- (positive correlation) (see .
marily to the specific region pairs themselves but to altered me- A further correlation analysis between strengths of the 2 diation influences via third-party structures. In 80–94% of links contralateral mediating regions influencing each of the altered in ADHD, depression and schizophrenia patients the first or functional pathways and symptom severity revealed that in the second most influential mediator of altered functional connect- majority of cases they were also significantly correlated with ivity was one of the 2 contralateral counterpart regions, and in symptom severity (ADHD: 8 and 7 links, see a high proportion of these the change in mediating strength in schizophrenia—positive symptoms: 15 and 20 patients was also significant, most notably in schizophrenia(93%). The overall contribution from these counterpart regions links, see negative symptoms: accounted for 60–76% of the functional-connectivity change 9 and 10 links—see . In schizo- between region pairs in patients compared with controls, phrenia both contralateral counterpart mediating regions were whereas changes restricted to the region pairs themselves only often correlated with symptom severity (5 links for positive accounted for 17.5–21%. Furthermore, associations between symptoms and 5 for negative symptoms). For illness duration in symptom severity and illness duration and altered functional schizophrenia there was a similar pattern with 10/13 of the links connectivity found in region pairs were reflected in most cases showing significant associations between the altered mediating by similar alterations in the mediating strength from their strength from either of the 2 contralateral regions (see contralateral counterparts. A SVM analysis showed good . In all cases the direction of the correlation discrimination of patients and healthy controls either using 8 Altered Functional Connectivity Caused by Contralateral Regions • Zhang et al.
Pearson correlation (68–86%) or contralateral mediating connectivity with region y. In other words, the above findings strength (65–82%). Our results illustrate both that more atten- are not simply the result of the strong functional connectivity tion should be paid in future towards the contribution of these between bilateral regions xR and xL; they only occur when xR contralateral mediating regions rather than specific altered influences, or mediates both xL and y in a significant way. Fur- links in psychiatric and other mental disorders and that a thermore, it is just the changes in this contralateral region me- common motif in the disordered brain may be altered interhe- diation that lead to the significantly altered functional connectivity in patient group, see How do Contralateral Counterpart Regions Influence The Importance of Altered Interhemispheric Altered Functional Connectivity? Communication in Mental Disorders The influence of contralateral mediating structures could be There is considerable evidence for altered functional and/or both direct and indirect via other third-party regions. It is pos- sible that the altered mediation is via the direct connections number of mental disorders including Alzheimer's and mild with contralateral counterparts since, as discussed above, al- cognitive impairment depression ( though these do not exhibit significant changes in functional ), anxiety (), bipolar disorder connectivity themselves in the disorders they are the strongest functional connections. Thus even very small changes in their mediation influence might produce large effects. On the other Tourette's (), autism ( hand, we have shown that in many cases there is a 3-motif rela- borderline personality disorder (), and disor- tionship whereby both the right (xR) and left sides (xL) of the ders of consciousness ). Reduced same region showed altered functional connectivity with interhemispheric communication resulting from congenital another region (y), such that for xR to y, xL is the mediator and agenesis or sectioning of the corpus callosum has also been as- for xL to y, xR is the mediator (see Fig. ). Thus, xR and xL may sociated with impaired cognitive and emotional functioning also exert their mediation effects indirectly via y. With the methodology used in the current paper, we cannot distinguish Around 50% of altered functional connections in each of between these 2 potential routes of mediation effects.
the 3 disorders in the current study involved different regions Finally, it should be noted that the term "mediation", or "in- in the 2 hemispheres, and this together with the high propor- fluence" is from a triplets-based partial-correlation point of tion of altered links with significantly altered mediation via view, that is, if the functional connectivity between a pair of their contralateral counterparts indicates that there is a contri- regions is significantly changed by partialling out a third-party bution from both hemispheres to dysfunction in 120 out of 138 region, we believe that this third-party region will have a medi- links (87%). Further, in 100 out of these 120 links there are ation effect influencing a given pair. In this case Granger Caus- significantly altered mediating strength from a contralateral ality Analysis needs to be conducted in the future to clarify the counterpart region and which mainly reflects a weakened causal relation among these triplets ROIs (xR and xL and y), and identify the possible mediation pathways.
In support of previous studies (we found that functional connectivity between counterpart regions inthe 2 hemispheres is generally very strong and reflects exten- What are the Main Functional Connectivity Changes sive fiber links between bilateral structures involving the in ADHD, depression, and Schizophrenia? corpus callosum or commissures ( Although we found 50 altered functional connections in ). As we used a rather stringent correction for mul- ADHD, 18 in depression, and 70 in schizophrenia we will tiple comparison, alteration of functional connectivity between focus our discussion mainly on groups of connections where bilateral regions themselves in the 2 hemispheres is not very right and left regions of some key structures play reciprocal significant (only 1/138 altered links was bilateral). However, roles as mediators and are interconnected with a widespread using the same dataset we have shown recently that in both network. The relevance of these particular altered circuits is schizophrenia and depression there is a general overall reduc- also underlined by the fact that they account for the majority of tion in functional connectivity involving them links associated with symptom severity in both ADHD and Furthermore, although changes in functional connectiv- ity between bilateral pairs of regions did not achieve signifi- In ADHD the most notable altered links exhibiting the cance the absolute magnitude of the differences between above criteria involved the medial orbitofrontal cortex and its controls and patients was often similar or even larger than that functional connections with the calcarine cortex, although observed in other less strongly connected links which did many altered functional connections with other frontal regions achieve significance. Thus it is possible that the very high and (middle orbitofrontal cortex, inferior frontal gyrus, rectus more variable functional correlation strengths found between gyrus, and anterior cingulate gyrus) were found. There is in- bilateral structures may have contributed to observed changes creasing evidence for altered resting-state and task-related con- failing to achieve significance.
nectivity between frontal cortex and primary visual cortex in Finally, it is important to note that our findings that region xR being identified in many cases as the primary mediating medial orbitofrontal cortex receives inputs from the ventral region for functional connectivity between xL and y is not visual processing stream involved in object recognition, and simply due to the generally high correlation between homolo- plays important roles in control of impulsivity and reward gous pair of regions xR and xL. In order for the above findings Impaired impulsivity is a key symptom in ADHD to hold, region xR must simultaneously have strong functional ) and is also associated with orbitofrontal cortex volume changes ; fusiform gyrus), gustatory (rolandic operculum), and somatic ). Thus, reduced functional connectivity between medial (postcentral gyrus) orbitofrontal and visual cortices suggests a reduced ability of Negative-symptom severity was negatively correlated with visual cues from social or other stimuli to elicit appropriate medial cingulate functional connectivity to the pallidum and impulse control or reward. Previous studies have also empha- putamen, which may contribute to altered cognitive, volition, sized fronto-striatal disconnection in ADHD ( and reward functions in schizophrenia ( ). Functional connectivity between the thalamus ). Posterior cingulate cortex connectivity with visual and putamen showed significantly increased connectivity in areas (lingual gyrus and fusiform gyrus) was positively corre- patients but this had no association with symptom severity.
lated with negative-symptom severity and may reflect compen- This supports previous findings in ADHD relating changes in sation for both cognitive and visual processing deficits ( this functional link to impaired spatial working memory cap- ). Illness duration correlated with many (6/13) of same functional links associated with negative-symptom sever- In depression, the right inferior orbitofrontal cortex is in- ity, but none of those associated with positive ones, perhaps volved in 8/18 altered functional connections including reflecting the progressive worsening of negative symptoms reduced connectivity with the bilateral putamen, insula, and pallidum and left hippocampus and thalamus. While the leftinferior orbitofrontal cortex has no altered functional links it exhibits significantly reduced mediating strength in relation to Implications of Altered Contralateral Mediation right orbitofrontal cortex functional connections with the bilat- as a Potential Transdiagnostic Feature eral pallidum and left insula. Our previous studies have also The presence of altered contralateral mediation found in all found evidence for both reduced gray matter volume ( 3 psychiatric disorders argues for it being a key common motif ) and either increased or decreased functional in a wide range of psychiatric and other mental disorders and therefore an important potential transdiagnostic feature.
involving the orbitofrontal cortex in major depression which Overall, SVM analysis showed a good discrimination accuracy may reflect altered responses to rewarding stimuli and anhedo- of this feature for schizophrenia (82.4%) and slightly less for nia ().Our finding of reduced func- depression (72.4%) and ADHD (64.7%) although importantly tional connectivity with the pallidum and putamen further discrimination accuracy was very similar to that using only the supports their reported association with anhedonia and Pearson correlation change between functional links (schizo- reduced responsivity to rewards in depression phrenia: 84.7%; depression: 85.5%; ADHD: 68%). A recent, ; Changes involving the right orbi- large genetic study of mental illnesses suggested that 5 major tofrontal cortex, putamen, and insula may result in altered re- disorders (schizophrenia, bipolar disorder, autism, major sponses to negative emotional stimuli in depression and depression, and ADHD) share some common genetic variants support our previous evidence suggesting altered neural pro- and it is possible that common cessing of "hate" (insula and putamen) ( gene variants might contribute to reduced contralateral hemi- sphere mediation in mental disorders.
In schizophrenia, the largest and most extensive functional In terms of identifying key molecular targets involved in the connectivity changes were found, supporting growing evi- control of contralateral mediation, obvious candidate genes dence that this disorder is associated with wide-ranging func- would be those both associated with agenesis of the corpus tional dysconnection in the brain ; callosum and multiple psychiatric disorders. One potential The most extensive circuit affected included the candidate is the disrupted in schizophrenia gene 1 (DISC1).
bilateral thalamus, postcentral gyrus, medial frontal gyrus and DISC1 was originally mainly associated with schizophrenia, fusiform gyrus and right dorsal superior frontal gyrus, right but intriguingly has recently shown to be associated with callo- putamen and right posterior cingulate gyrus and 18 altered sal agenesis as well as depression, bipolar links show a pattern of reciprocal contralateral mediation.
disorder, and ADHD ; Here, the right and left thalamus are particularly prominent Indeed, in mouse models of schizophre- suggesting that reduced sensory and motor inputs to and inte- nia where the DISC1 gene is targeted, one of the effects ob- gration with the cortex. Indeed, there is now extensive evi- served is agenesis of the corpus callosum ).
dence that thalamic damage and altered connectivity with the Thus, while different patterns of functional-connectivity cortex in schizophrenia are responsible for cognitive and sen- changes and symptoms occur across different disorders, there sorimotor processing dysfunction ( may well be common genetic or other factors which lead to altered contralateral mediation by disrupting interhemispheric ). Interestingly, altered links primarily in the medial and communication via the corpus callosum, or other fiber tracts frontal regions were associated with positive-symptom sever- such as the anterior commissure. Furthermore, therapeutic ity, with the strength of thalamo-frontal connections being strategies involving either transcranial magnetic stimulation, or negatively correlated. A similar association was found for func- deep brain stimulation, or voluntary control of brain activity tional connections between the right posterior cingulate cortex using feedback techniques may benefit from focusing on and left medial frontal cortex. On the other hand thalamic links promoting increased structural and functional connectivity with motor control regions (postcentral gyrus and rolandic between the hemispheres. Importantly, our findings show that operculum) and the right posterior cortex link to the left fusi- the primary target for such stimulation approaches will often form gyrus showed positive correlations with positive-symptom be in the opposite hemisphere to that identified as having severity. These regions are associated with hallucinations altered functional connectivity in patients. This is verified by a involving different sensory modalities, visual/auditory (left recent study showing that endogenous coupling between 10 Altered Functional Connectivity Caused by Contralateral Regions • Zhang et al.
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12 Altered Functional Connectivity Caused by Contralateral Regions • Zhang et al.

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