Bipolar disorder (BD) is a severe mental disease characterized by recurrent depression and mania or hypomania (1). According to neuroimaging studies, BD patient’s cognition and emotion-related brain regions are abnormally activated during mood episodes and remission periods (2), although the unusual activation is discrepant during various periods; therefore, probing for shared and distinction of brain activities in different states is of great importance to acquire the trait and state-related characteristics of bipolar disorder, which may help to improve the precise diagnosis and treatment for this severe mental disorder.

Previous researches on BD found abnormal brain activity largely located in the prefronto-limbic system, especially in the amygdala-prefrontal circuit and prefronto-striatal circuit (3, 4). Vargas et al. (3) conducted a comprehensive review of eight studies, comparing the resting state fMRI of 241 BD patients and 278 healthy controls, and discovered prefronto-limbic cortex connectivity disruption in BD compared to healthy controls. And researches on bipolar depression and remission, found abnormal activation primarily involved in the prefrontal and limbic cortex as well (5). Most researchers applied the amygdala as a seed point to map the cortical-amygdala connectivity during tasks related with emotional processing, and discovered that in both states, the amygdala and the prefrontal cortex often emerged abnormal activation (6–9) and connectivity (10, 11). In addition, during tasks involved in rewarding processing, abnormal activation and functional connectivity were consistently observed in the prefronto-striatal circuit in bipolar depression or remission episode (12, 13). In summary, prior research has established that individuals with bipolar disorder exhibit comparable irregularities in the prefronto-limbic system during both depression and remission phases. However, there is a lack of direct comparison to identify shared and distinctive biomarkers between these states. Furthermore, prior investigations have primarily focused on the amygdala and striatum within the limbic system, neglecting the crucial role of the thalamus in the development of bipolar disorder.

The thalamus plays a vital role as an information transfer relay station that receives all sensory information, excluding those from the olfactory region. Afferent or efferent information after being transferred in the thalamus are then paralleled in projection to different brain regions; thus, the thalamus stands in the center of bottom-up transmission and top-down regulation of the brain, plays a vital role in emotion and cognition regulation (14). Thalamic dysfunction is a well-established characteristic of schizophrenia. Although, bipolar disorder is considered to be within the same spectrum as schizophrenia (15), the studies investigating thalamic abnormalities in bipolar disorder have been limited. Only a few studies have explored this area of research, including findings of abnormalities of Steullet (16) in the thalamic reticular nucleus in bipolar disorder patients. Hiber et al. (17) also reported reduced thalamic volume, but no significant difference between bipolar type I and type II. Furthermore, research based on functional analysis revealed hypoconnectivity between the thalamus and the prefrontal cortex (18), and hyperconnectivity between the sensorimotor cortex and thalamus (15).

Thus far, researchers have not extensively investigated thalamic abnormalities in different states of bipolar disorder, which makes it challenging to distinguish the state and trait characteristics of bipolar disorder. The limited comparative studies that have focused on bipolar depression and remission include comparison of the differences between the two states using the whole-brain functional connectivity method in a resting state by Lv et al. (11), and comparison of brain activation between the two groups using the Stroop task (12) by Kronhaus et al. (9). However, both studies have neglected to examine the thalamus.

The thalamus comprises several diverse nuclei that project to specific regions of the cortex. For instance, the dorsomedial nucleus (MD) projects to the prefrontal cortex, while the lateral geniculate nucleus projects to the occipital cortex (19). Therefore, by mapping the functional connectivity anomalies between the thalamus subregions and the cortex, may help us more accurately understand the shared and distinction of brain functions in the two states. In this study, we applied the thalamus subregions atlas from Human Brainnetome Atlas,¹ which parcellated the thalamus into eight subdivisions bilaterally based upon the current largest database of brain activation (20), and it has been used in our past studies as well (21).

In this study, a comparison of the connectivity discrepancy in the thalamo-cortical circuit across bipolar depression, remission, and healthy control was made, and it was found that dysconnectivity mainly existed in the prefronto-thalamo-cerebellar and sensorimotor-thalamic circuits. Compared to the healthy controls, the two patient groups showed significantly inferior connectivity in sensorimotor-thalamic; however, patients with depressive episodes not in remission showed significantly lower connectivity in the prefronto-thalamic circuit. In the intervening time, a significantly negative correlation was found between the BOLD signal of the prefronto-thalamic and the score of the HAMD scale.

The medial premotor thalamus comprises the ventral anterior nucleus (VA) and ventrolateral nucleus (VL), which project to the premotor cortices. Our study revealed that there was decreased connectivity between the medial premotor thalamus and the medial superior frontal cortex in patients with bipolar depression. Previous studies have primarily concentrated on the functional disruption of higher-order thalamic nuclei in bipolar disorder, such as the dorsomedial nucleus (15). However, our findings indicate that the first-order thalamic nucleus also plays a direct role in the cortical-thalamic circuit. The prefronto-thalamic circuit is widely considered as a cognitive-related circuit, playing a vital role in execution (24–26). Disrupting the circuit may cause damage to the regulation of emotion and cognition reactions. The medial superior frontal cortex showed abnormal connectivity in our study, which outputs signals to cortex and subcortical regions (27), such as the posterior cingulate, thalamus, amygdala, and hippocampus, function as top-down regulation on attention bias, behavior inhibition and working memory (28, 29). For bipolar depressive patients, weakened connectivity in the prefronto-thalamic subregions may associate with patients’ disruption in the working memory maintenance and social interaction (30, 31).

Numerous studies have demonstrated that individuals with depression exhibit impaired functional connectivity of prefronto-thalamic circuitry compared to healthy controls (32, 33). For instance, Zhang et al. (32) discovered that the group of patients with bipolar depression displayed significantly lower functional connectivity between the bilateral thalamus and frontal cortex during the resting state. In this study, a significant positive correlation was noted between the HAMD score and the BOLD signal of the prefronto-thalamus, which also demonstrated that enhancing prefronto-thalamus connectivity may help to relieve depression. The prefronto-thalamo hypoconnectivity was particularly evident in patients with depression but not in those in remission, suggesting that the distinct state characteristic between the two states is potentially located in the prefronto-thalamic circuitry.

Both patient groups showed significantly weakened connectivity between the posterior parietal thalamus, which primarily encompasses the anterior portion of the pulvinar, and the cerebellum. The pulvinar, which is the largest nucleus of the thalamus, is largely connected to the anterior cingulate and prefrontal areas (34). And the cerebellum is widely believed to be involved in motor function (35, 36), cerebellar lesion can lead to motor function impaired. In this study, both the patients groups showed hypoconnectivity between the thalamus and cerebellar, which may contribute to bipolar patients’ psychomotor abnormalities such as psychological retardation and impulsivity. Researches have also confirmed that abnormal psychomotor of mental disorder is associated with dysfunction of the cerebellum and thalamus (37). Furthermore, the cerebellum projects to several regions of the prefrontal cortex through the thalamus, including the medial, dorsal, and lateral areas of the prefrontal region (38). And one crucial study have confirmed that, the prefronto-thalamo-cerebellar circuitry is closely related to motor plan (39), persistent information expression of the frontal during motor planning is dependent on the cerebellum, therefore, the disruption of this circuitry may suggest abnormal psychomotor.

Besides, brain damage studies in mice have found that cerebellum damaged mice suffered from spatial and working memory disruption. For instance, Lalonde (40) observed that cerebellum damaged mice run a maze, and found that cerebellar lesions would cause cognitive deficits resulting in impaired completion of maze tasks. Therefore, it is likely that the diminished functional connectivity of the prefronto-thalamo-cerebellar circuitry may be linked to impairments in working memory, planning, and rule-based learning among patients.

Both patient groups exhibited hypoconnectivity in the sensorimotor-thalamic circuit, which includes the precuneus and lingual regions, consistent with prior research (33). Historically, the precuneus has received little scrutiny, possibly due to its concealed location and the lack of studies on focal lesions (41). However, recent studies have indicated that the precuneus is an integral component of the network of neural correlates of consciousness (42, 43), which may contribute to alterations in conscious states, such as sleep. Therefore, it is plausible that the weakened connectivity between the precuneus and thalamus could be associated with sleep disturbances in patients.

A few limitations should be noted in this study. First, medication may be a confounding factor. The majority of the recruited patients were on medications; most of them were consuming mood stabilizers and other medications such as antipsychotics, antidepressants, or benzodiazepines, depending upon the patient’s clinical performance. Additional studies in drug-naive BD patients are crucial to confirm the findings of this study. Second, the study is a cross-sectional design, which limits the assessment of the dynamic changes between depression and remission in BD patients; thus, future longitudinal studies with drug-naive patients are required to clarify the dynamic transformation.

In this study, both patient groups displayed abnormality in the prefronto-thalamic-cerebellar and sensorimotor-thalamic circuits, depressive patients specifically exhibited decreased connectivity in the prefronto-thalamic circuit, which perhaps was associated with their cognitive disruption and rumination thinking. And remission patients also exhibited weakened connectivity in the sensorimotor-thalamic circuit; however, they significantly increased the connectivity of prefronto-thalamic compared to the depressive group. The results showed that the irregularity of the sensorimotor-thalamic circuit possibly is the trait-related distinguishing factor of bipolar disorder, while the prefronto-thalamic circuit is the state-related characteristic feature.

The original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by ethics committee of Xiangya Second Hospital. The patients/participants provided their written informed consent to participate in this study.

CZ wrote the main manuscript text. SL edited language. WP designed the experiments. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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