Our examination of RSFC in youths with pediatric BD has three main findings. First, our primary analysis revealed a significant between-group difference in RSFC between the left DLPFC and right STG. In particular, pediatric BD participants had significantly greater negative RSFC between the left DLPFC and the right STG vs. controls. Subsequent iterative analyses showed that pediatric BD participants had significantly decreased RSFC between the right STG and bilateral PFC (BA 9), left thalamus/caudate, and increased RSFC between the right STG and the right parahippocampal gyrus. Second, PCC analysis showed that, when relationships with the other ROIs were taken into account, BD and control youths had opposite phase relationships between spontaneous BOLD fluctuations in the left DLPFC and right STG—i.e., whereas RSFC was in-phase for controls, it was 180 degrees out of phase (anti-correlated) for BD youths. Third, MAR analyses identified significantly different relationships among patterns of spontaneous fluctuation between BD and control youth in our circuits of interest, but caution is urged in interpreting these MAR analyses given potential contributions of physiological variables, such as regional differences in the hemodynamic response, to the relationships observed (32
The results from our primary analyses, showing that BD youths have altered RSFC between the DLPFC and STG, and iteratively, between the STG and frontal, striatal, and parahippocampal areas, align with prior studies implicating working memory in BD (34
). For example, BD youths have impaired working memory vs. controls (36
). Working memory deficits in BD youths have been associated with increased PFC and temporal fMRI activation (39
). Similar fronto-temporal alterations have been shown in BD youths using emotionally-valenced picture and face tasks (10
Our results align with the small connectivity literature in BD. The only task-independent RSFC study in BD involved BD adults (n=11), showing decreased RSFC between the pregenual ACC and bilateral amygdala and thalamus (40
). Using task-dependent data from a face processing paradigm, BD youths have decreased functional connectivity between the left amygdala and the right posterior cingulate/precuneus and fusiform/parahippocampal gyri (41
). Therefore, our work is an important first step towards understanding how some of this fronto-temporal dysfunction may be intrinsic to pediatric BD, rather than contingent upon a particular cognitive task or process.
Our data also suggests the importance of development in the pathophysiology of pediatric BD. Specifically, top-down control of cognitive processes, including declarative memory, requires interplay between the frontal cortex, especially DLPFC, and the striatum and temporal cortex (42
). Longitudinal neuroimaging studies have shown that typical development involves the progressive maturation of phylogenetically older brain areas, like the temporal cortex and striatum, prior to newer ones, like the DLPFC (45
). Some posit that typical adolescent characteristics, including identity formation and risk-taking, depend on the dynamic balance between the earlier maturing striatum and amygdala responsible for bottom-up reward processing, and the later maturing PFC responsible for top-down cognitive control (46
Three studies have robustly demonstrated developmental maturation effects on RSFC, showing that healthy adults have stronger, more focused within-network RSFC vs. children or adolescents (47
). Our data show that BD and control participants have the opposite correlation between age and RSFC between the right STG and parahippocampal gyrus. Given power issues, such post-hoc comparisons should be interpreted with caution. Future longitudinal neuroimaging studies will be required to ascertain the developmental trajectories of spontaneous neural activity in pediatric BD, with sufficient power to address issues inherent in BD research, including potential neuromodulatory effects of medications and comorbidity.
Regarding the functional significance of negative (anti-phase, anti-correlated) DLPFC/STG RSFC in BD participants, and positive RSFC in controls, we note the continuing controversy in the RSFC literature surrounding negative connectivity (50
). Authors agree that negative correlations can and do exist in the brain (51
), but recent work has suggested that procedures—e.g., GSC—may exaggerate them by shifting “zero” correlations into negative ones (53
). However, re-processing and re-analyzing our data without GSC confirmed that incorporating GSC reduced inter-subject variability, thus enhancing our ability to detect between-group differences, rather than either altering negative correlations or disproportionately affecting one group vs. another. This aligns with both mathematical and empirical investigations of GSC’s effect on RSFC, showing that GSC resulted in improved ability to detect system-specific correlations in RSFC and improved the correspondence between RSFC and anatomy (51
). We conclude that our data indicate that pediatric BD involves a greater degree of segregation between the DLPFC and STG than was observed in controls.
Three issues related to our ROI approach bear further comment. First, both structural (55
) and functional (58
) ROIs have been used to guide RSFC analyses. In our current study, we chose to follow up on structural ROIs identified by our prior work, but functional ROIs would be equally important for future studies. Second, our failure to fully replicate our prior VBM results does not diminish the relevance of our ROIs because they have been consistently implicated by other pediatric BD neuroimaging studies (17
). Moreover, we note several important methodological differences between our original study and our current post-hoc VBM analyses, including: (1) greater power to detect gray matter volume differences in our original study (20 vs. 15 participants per group), (2) lack of gender matching as in our original study, (3) different MRI manufacturers and field strengths (original=GE 1.5 Tesla vs. current=Siemens 3 Tesla), (4) different structural scan sequences (original=SPGR [TRepetition
=5.0ms, slices=124]; current=MPRAGE [TRepetition
=2.98ms, slices=160]), (5) different statistical software (SPM vs. FSL). Third, while our post-hoc analyses using an anatomic left amygdala ROI confirmed our lack of amygdala findings from our primary analysis, larger samples are necessary to evaluate RSFC alterations in other ROIs among BD youths.
Our study has several additional limitations, including psychotropic medications, comorbidity, and sample size. First, our post-hoc analyses suggest that medications do not confound our current results. However, all BD participants were taking their usual psychotropic medications with the exception of psychostimulants, which were withheld for a minimum of five drug half-lives. The rationale was that psychostimulants are commonly held for drug holidays—e.g., school vacations—in clinical care, and they affect the BOLD signal (61
), whereas it would be unethical to withhold anti-manic, anti-depressant, or anti–anxiety medications for research purposes alone, and brief discontinuations would be ineffective given their longer half-lives. Recent BD research suggests that such medications may not influence BOLD signal in fMRI studies such as ours (63
). Nevertheless, future work, perhaps with non-human primates is warranted to evaluate the effect of pharmacologic treatment on fronto-temporal RSFC during development.
Secondly, our BD participants had rates of comorbid psychopathology corresponding to other pediatric and adult BD studies. Yet, future studies are needed to deterimine the specificity of these RSFC alterations, including comparisons to those with primary ADHD or anxiety (20
). Third, while our BD and control samples are on par with the current literature in pediatric BD, we note the need for even larger studies with sufficient power to meaningfully explore the potential effects of age, sex, puberty, and treatment.