BD-II was used to consider as briefly a ‘softer’ pattern of BD-I, thus supposing that the identical neuropathological dysfunction underlying BD-I and BD-II. It's just that the degree of the dysfunctions can vary. Recently, this perspective has been challenged through clinical and neurobiological findings. Clinical researches presented that course and severity of symptoms in BD-II were at least as severe as in BD-I [27, 41]. The differences in resting state fMRI comparing BD-I with BD-II were insufficient, particularly in pediatric bipolar disorder (PBD). This research focused on the difference of the functional connectivity in resting state fMRI comparing PBD-I with PBD-II.
In general, Our findings were consistent with prior results of BD, with differences between BD-I and BD-II. PBD-I showed more abnormal functional connectivity within default mode network (DMN), fronto-parietal network (FPN), salience network (SN), and limbic system compared with PBD-II. According to meta-analysis[14, 42], abnormal functional connectivity of the intrinsic networks has been found in adult BD related to healthy control. Besides, we also found that functional connectivity in intrinsic networks were correlated with emotional symptoms and cognitive impairments.
Default mode network (DMN)
Our study found that functional connectivity of posterior cingulate gyrus and bilateral angular gyrus were enhanced, while functional connectivity of bilateral superior parietal cortex and bilateral precuneus were weakened when PBD-I compared with PBD-II. In PBD-I, the posterior cingulate cortex was positively associated with forward order digital recite, and the left angular gyrus was positively correlated with reverse order digital recite. In PBD-II, the posterior cingulate cortex was negatively associated with suicidal ideation, and the right precuneus was negatively associated with depression.
In the latest meta-analysis, the patients of BD exhibited changed functional connectivity in the DMN. The altered functional connectivity within the DMN presented the shortage of integration of inner activity, might show aberrant communication in external cognitive flexibility and internal self-monitoring function[22, 43]. Our previous fMRI research showed weakened functional connectivity of the DMN in the PBD.
Working memory and self-reflection processing task-fMRI research in BD-I showed abnormal activation and functional connectivity of the precuneus, which supported the precuneus could be the pathophysiologic mechanism of BD[45, 46]. Precuneus has been shown to involve self-referential processing and depressive rumination. This study exhibited difference of the precuneus connectivity comparing PBD-I with PBD-II, and which was correlated with depression only in PBD-II. This result indicated that PBD-I versus PBD-II had distinction in the functional connectivity of the precuneus.
Disrupted functional connectivity of the posterior cingulate cortex (PCC) was likely to support the evidence for working memory and cognitive function impairment in BD. Our study supported this theory and found that decreased functional connectivity in PCC when PBD-I compared with PBD-II. In PBD-I, PCC was positively associated with attention, and the left angular gyrus was positively correlated with working memory. PCC is also a key nodes of the DMN, the activity of which is involved in emotional processing, self-evaluation and suicidal ideation in bipolar disorder. Our study verified this theory and found that PCC connectivity was associated with the suicidal ideation of PBD-II. Overall, our result suggested that difference in DMN connectivity between PBD-I and PBD-II was obvious, which was associated with depressive symptoms, suicidal ideation and cognitive function.
Fronto-parietal network (FPN)
We found both hyper- (FPN seeds and regions of the right middle temporal cortex, right dorsolateral prefrontal gyrus and bilateral orbitofrontal cortex) and hypo-connectivity (FPN region of the right superior parietal gyrus, left dorsolateral prefrontal gyrus) within the FPN while PBD-I compared with PBD-II. The FPN was contributed to varied cognitive function, such as working memory, attention and response inhibition [23, 50–52]. In the correlation analysis of this study, FPN functional connectivity was associated with attention, working memory, cognitive flexibility and response inhibition in PBD-I and PBD-II respectively. Altered resting state-functional connectivity in the FPN are common findings in cognitive dysfunction of BD[23, 50–52]. Our finding presented further evidence for the connectivity difference comparing PBD-I with PBD-II in the FPN.
Salience network (SN)
Salience network (SN) is considered to a core hub in exploring salient stimuli, and modulate the attention and working memory resources for that[53, 54]. The crucial view is the SN mediate dynamic communication between other neural circuits referring to internally oriented attention and externally oriented cognition[53, 55]. This study showed both hyper- (SN seeds and regions of bilateral anterior insula and bilateral inferior frontal gyrus) and hypo-connectivity (SN seeds and region of bilateral anterior cingulate gyrus and middle cingulate gyrus) within the SN compared PBD-I with PBD-II.
The inferior frontal cortex, anterior insula, and anterior cingulate cortex are significant node of a "salience network" which helps extract the most relevant information in the stimuli to regulate behavior. Taken together, the observed hyper-functional connectivity in anterior insula and inferior frontal gyrus between the PBD-I and PBD-II might show the imbalanced communication between cognitive and affective network. This study also exhibited hypo-connectivity within the anterior cingulate cortex and bilateral middle cingulate cortex comparing PBD-I with PBD-II. Anterior cingulate gyrus involves in conducting salience, which present disrupted coordination with neural circuits involved in internal oriented thought and external goal-oriented control. This study provided a further explanation for more dysfunction of the cognitive function and emotion regulation in contrast PBD-I with PBD-II[57, 58].
It is worth emphasizing that anterior insula is crucial in the regulating negative emotion. This study supported this perspective, and we found functional connectivity of the left anterior insula was related to depression in PBD-II. Besides, anterior insula, as a core node of SN, plays an important effect in high-level cognitive and attentional process. In this research, the functional connectivity of the anterior insula was correlated with attention in both PBD-I and PBD-II. Additionally, the left inferior frontal gyrus was correlated with attention and visual memory, and the middle cingulate gyrus was correlated with attention and processing speed in PBD-II. In general, PBD-I versus PBD-II were found to differ in functional connectivity of the salience network, and which was associated with mood and cognitive dysfunction.
A meta-analysis study found that prefrontal-limbic system dysfunction was an important pathological mechanism of PBD. This study exhibited that PBD-I had different functional connectivity of the limbic system compared with PBD-II (enhanced functional connectivity in the left postcentral cortex, left middle orbitofrontal cortex, right inferior orbitofrontal cortex, and bilateral parahippocampal gyrus; weakened functional connectivity in the bilateral olfactory cortices and bilateral rectus gyrus). In previous comparative studies of BD-I and BD-II, distinction were reported in the structure,functional connectivity and anatomical connectivity of the limbic system. Our study confirmed that PBD-I versus PBD-II had altered functional connectivity in the limbic system as those in adult patients . It could be seen that limbic systems had significant differences based on functional connectivity comparing PBD-I with PBD-II.
Additionally, we found an association between functional connectivity of the left postcentral cortex and sleep quality in PBD-I; and the functional connectivity of the bilateral parahippocampal gyrus of PBD-II was correlated with sleep quality. It has been proposed that the postcentral gyrus and parahippocampal gyrus in the limbic system participate in the regulation of sleep in adolescents. Clinical observation has proved that children with severe insomnia due to brain surgery injury to the limbic system. Therefore, abnormal functional connectivity of the limbic system in PBD may be the mechanism of the common sleep problems in PBD patients.
Besides, the functional connectivity in the left middle orbitofrontal gyrus, right inferior orbitofrontal cortex and bilateral rectus cortex were correlated with manic symptoms. Manic symptoms are the core emotional symptoms of PBD-I and the key difference between PBD-I and PBD-II (only hypomanic episodes occur in PBD-II). The orbitofrontal gyrus in the frontal-limbic system is known to be referred to emotional processing. The fact that the symptoms of mania was correlated with the functional connectivity in the orbitofrontal gyrus suggested that the possible mechanism underlying the difference in manic mood comparing PBD-I with PBD-II.
In the correlation of cognitive function and functional connectivity, PBD-I found that the right parahippocampal gyrus was correlated with visual memory and working memory; and the left orbitofrontal gyrus was correlated with cognitive flexibility, working memory and attention. PBD-II only found that the left parahippocampal gyrus was associated with response inhibition. The parahippocampal gyrus and the orbitofrontal gyrus in the limbic system is involved in memory processing, and the damage of which structure can cause the abnormality of emotion and memory. Our result suggested that differences in the functional connectivity of the limbic system between PBD-I and PBD-II are associated with cognitive impairment, especially memory dysfunction. The difference of functional connectivity in the limbic system may provide new evidence for the pathological mechanism that PBD-I has more disorganized cognitive function and emotion than PBD-II.
Some limitation of our research should be noticed. Firstly, our sample size was not large. If verified in greater PBD sample, this result could propose as the biomarker for the differential diagnosis of PBD-I and PBD-II. Secondly, major PBD subjects were using medication. Prior researches have presented that medication neutralized the aberrant functional connectivity of BD. Although this research showed changed functional connectivity in PBD-I compared with PBD-II, it still needed to be detected how psychoactive medication impacted the functional connectivity of PBD-I and PBD-II.
In summary, this study showed that abnormal functional connectivity in the DMN, FPN, salience network and limbic system when PBD-I compared with PBD-II. Besides, associations between clinical features, cognitive function and changed functional connectivity in the intrinsic networks were presented in PBD subtypes. This study, from the first finding to explore difference of functional connectivity comparing PBD-I with PBD-II, proposed the possibility that altered functional connectivity in the DMN, FPN, salience network and limbic system could exhibit a different neural mechanism between PBD-I and PBD-II.