Changes in the brain regions after treatments

The results of the psychological and drug analysis were combined and it was found that after treatments, the increased activation of brain regions where the treatments produced focused on MeFG, ACC, IFG, amygdala, LG, AG, insula and claustrum, accompanied with decreased activation of PCC.

Studies have shown that the ventral lateral prefrontal cortex (VLPFC), medial prefrontal cortex (mPFC), ACC, insula, and amygdala constitute a network of adaptive emotion regulation in healthy participants. IFG is part of VLPFC, which is related to emotional response inhibition and reassessment of negative emotions (Phillips, Ladouceur, & Drevets, Reference Phillips, Ladouceur and Drevets2008). The frontal cortex (including IFG) has an important impact on emotion regulation, impulsiveness, self-consciousness, and self-monitoring of BD (Morgan et al., Reference Morgan, Dazzan, Morgan, Lappin, Hutchinson, Suckling and David2010). IFG is identified as a brain region for regulating and integrating emotional intensity and information (Foland-Ross et al., Reference Foland-Ross, Bookheimer, Lieberman, Sugar, Townsend, Fischer and Altshuler2012). Increased activation of IFG may indicate that treatments help BD to sort out emotional information, revaluate negative emotions, and balance its over-processing of negative emotions. Normalisation of hyperactivity and hypoactivity in frontal cortex of BD after treatment (Drevets, Savitz, & Trimble, Reference Drevets, Savitz and Trimble2008), is consistent with our results. It is considered that mPFC integrates information during emotional and cognitive processes (Simpson, Snyder, Gusnard, & Raichle, Reference Simpson, Snyder, Gusnard and Raichle2001). In other studies of BD, dysfunctional deficits such as decreased metabolism have also been demonstrated in mPFC (Brooks et al., Reference Brooks, Wang, Bonner, Rosen, Hoblyn, Hill and Ketter2009). The frontal lobe is dominant in the outcome of the treatment, indicating that the treatment had a great regulatory effect on the frontal lobe. ACC is involved in working memory, attention and executive function in BD (Stevens, Hurley, & Taber, Reference Stevens, Hurley and Taber2011; Zimmerman, DelBello, Getz, Shear, & Strakowski, Reference Zimmerman, DelBello, Getz, Shear and Strakowski2006). And ACC can be regarded as a marker to predict the therapeutic response of BD (Lipsman et al., Reference Lipsman, McIntyre, Giacobbe, Torres, Kennedy and Lozano2010). Thus, it seems that ACC is a vital target brain region in BD after treatment. Amygdala and insula transport signals of sensory information (Phillips, Drevets, Rauch, & Lane, Reference Phillips, Drevets, Rauch and Lane2003), while VLPFC, mPFC and ACC integrate this information depending on situational requirements (Cabeza & Nyberg, Reference Cabeza and Nyberg2000; Ghashghaei, Hilgetag, & Barbas, Reference Ghashghaei, Hilgetag and Barbas2007). However, recent studies have found that emotional impairment in BD may be due to the imbalance between the prefrontal brain and limbic networks. Hyperactivation of limbic regions involved in emotional perception and recognition, and hypoactivation of prefrontal regions, including ACC, IFG, which are responsible for executive function, attention, and emotional regulation (Phillips et al., Reference Phillips, Ladouceur and Drevets2008; Strakowski et al., Reference Strakowski, Delbello and Adler2005, Reference Strakowski, Adler, Almeida, Altshuler, Blumberg, Chang and Townsend2012). Neuroimaging studies of BD unanimously agree that low activation of bilateral VLPFC and overactivation of limbic regions under emotional processing (Foland-Ross et al., Reference Foland-Ross, Bookheimer, Lieberman, Sugar, Townsend, Fischer and Altshuler2012; Morris, Sparks, Mitchell, Weickert, & Green, Reference Morris, Sparks, Mitchell, Weickert and Green2012). These areas in the present study showed changes in brain activity after treatment.

Deficits in fronto-limbic circuits may be responsible for difficulties in emotion regulation in BD (Miola et al., Reference Miola, Cattarinussi, Antiga, Caiolo, Solmi and Sambataro2022). The results of these studies show that the activity of BD in several neural regions associated with mood regulation, including the prefrontal cortex, amygdala, insula, thalamus, and hippocampus in patients with BD, insula, thalamus, and hippocampus, is significantly increased and decreased compared to healthy adults. The results of the study found that the function of the fronto-limbic network (MeFG, ACC and amygdala) improved after treatment. This further suggests that the treatment may change these abnormal brain neural circuits in BD.

In conclusion, it is suggested that the treatment effect can be achieved by regulating the activity of network of adaptive emotion regulation and fronto-limbic circuit. Specifically, normalising the brain regions with hyperactivity or hypoactivity will alleviate the symptoms of these diseases and achieve the therapeutic effect.

Distinct brain areas activated by psychotherapy and drug therapy

The results of psychotherapy and drug therapy were analysed separately and it was found that after treatments, only IFG was activated after both psychotherapy and drug therapy, that maybe because a limited number of psychological studies or it could also be due to IFG is an important regulatory brain region in both psychotherapy and drug therapy. These results demonstrate that the activated brain areas of the two therapies are mostly different. There are more brain areas in which the activation changes after drug therapy than after psychotherapy. The differences between the two treatments are possible because these two therapies may work through different neural mechanisms.

Psychotherapy is thought to have top-down effects on the limbic system (Mayberg et al., Reference Mayberg, Liotti, Brannan, McGinnis, Mahurin, Jerabek and Fox1999). It first regulates cortical activation and then influences limbic regions. Psychotherapy can improve symptoms more broadly and for longer after treatment (Petersen, Reference Petersen2006). In our study, psychotherapy increased activation of IFG and STG, suggesting that psychotherapy may work in the frontal and temporal lobes. Untreated patients with BD had lower activation of frontal lobe and they also observed differences in the brain activation of STG between the BD patients and the healthy control group, in BD patients, the STG is potently hyperactive (Kupferschmidt & Zakzanis, Reference Kupferschmidt and Zakzanis2011). And STG has been found to be associated with emotional processing deficits and other symptoms (Malhi et al., Reference Malhi, Lagopoulos, Sachdev, Ivanovski, Shnier and Ketter2007; Osuch et al., Reference Osuch, Ketter, Kimbrell, George, Benson, Willis and Post2000; Takahashi et al., Reference Takahashi, Malhi, Wood, Yücel, Walterfang, Kawasaki and Pantelis2010). In our analysis, the activation of STG is found to be greater that may because of different tasks used or because BD mood state differs from the subjects used in previous study.

In studies of drug therapy in depression, changes in the activation of the prefrontal cortex were uniformly reported, and drug therapy normalised the activation of the frontal cortex (Kennedy et al., Reference Kennedy, Evans, Krüger, Mayberg, Meyer, McCann and Vaccarino2001, Reference Kennedy, Konarski, Segal, Lau, Bieling, McIntyre and Mayberg2007; Mayberg et al., Reference Mayberg, Brannan, Tekell, Silva, Mahurin, McGinnis and Jerabek2000). Changes in activity also occur in the limbic and subcortical areas, including amygdala, hippocampus, PCC, and insula (Anand et al., Reference Anand, Li, Wang, Wu, Gao, Bukhari and Lowe2005; Goldapple et al., Reference Goldapple, Segal, Garson, Lau, Bieling, Kennedy and Mayberg2004). The PCC is an important part of the DMN; it plays a crucial role in memory and self-reference processing and hyperactivity of PCC is linked to depression (Leech, Kamourieh, Beckmann, & Sharp, Reference Leech, Kamourieh, Beckmann and Sharp2011; Szaflarski et al., Reference Szaflarski, Allendorfer, Goodman, Byington, Philip, Correia and LaFrance2022). Hypoactivity of PCC in our analysis may infer the effect of drug therapy.

Low activation of specific sub-regions in a cognitive control network located in the MeFG has been described in BD (Welander-Vatn et al., Reference Welander-Vatn, Jensen, Otnaess, Agartz, Server, Melle and Andreassen2013). Drug therapy increased the activity in the MeFG, which may indicate that patients with BD can more effectively regulate their more emotions regulation after undergoing therapy.

Drug therapy involves changes in activation of the limbic area, whereas psychotherapy does not. Drug therapy is more classically seen as ‘bottom-up’ (or a combination of bottom-up and top-down) (Mayberg et al., Reference Mayberg, Liotti, Brannan, McGinnis, Mahurin, Jerabek and Fox1999). First the subcortical level is regulated, followed by an effect on the higher cortical levels. Drug therapy can quickly relieve symptoms. From the results, we can see activation in both higher brain regions, which perform cognitive control, and limbic regions. One review described the effects of drug therapy on BD, finding that drug therapy can affect the activation of the prefrontal lobes of the brain in emotional processing and cognitive tasks (Laidi & Houenou, Reference Laidi and Houenou2016). This is consistent with the activation of the frontal lobe region in our results. The insula was activated after drug therapy in BD, possibly indicating that this region plays a broader regulatory role in antidepressant response and remission (McGrath et al., Reference McGrath, Kelley, Holtzheimer, Dunlop, Craighead, Franco and Mayberg2013). Additionally, we found changes in activation of CG in BD after medication. Abnormal activation of the CG can be used as a potential diagnostic marker and neurofeedback target for depression (Mel'nikov et al., Reference Mel'nikov, Petrovskii, Bezmaternykh, Kozlova, Shtark, Savelov and Natarova2018), while the activation of the CG changed after medication in our study. These findings indicate that these brain regions may be important in determining treatment outcomes.

It can be speculated that both treatments work by regulating the activity of relevant brain regions, possibly ‘normalising’ brain abnormalities in specific ways. Combined with the conclusions of previous research on the brain effects of drugs and psychotherapy and the meta-analysis results of this study (Boccia, Piccardi, & Guariglia, Reference Boccia, Piccardi and Guariglia2016), this study proposed theoretical models of psychotherapy and drug therapy based on the emotional circuits (Fig. 5). Psychotherapy changes the activation of amygdala, ACC and PCC by increasing the activation of the frontal and temporal lobe regions to produce a top-down effect. And drug therapy by reducing the activation of limbic region to produce a ‘bottom-up’ effect, or a top-down effect by increasing cortical activity at the same time, and make the activation of ACC, MeFG and IFG increased. These two therapies, in their own way, affect the patient's emotional circuit, ‘normalising’ the activation of the corresponding brain region and thereby reducing symptoms.

Fig. 5. Hypothetical model of psychotherapy and drug therapy. Psychotherapy changes the activation of amygdala, ACC and PCC by increasing the activation (red part) of the frontal and temporal lobe regions to produce a top-down effect. And drug therapy changes the activation of IFG, MeFG and STG by reducing the activation (blue part) of limbic region to produce a ‘bottom-up’ effect, or a top-down effect by increasing cortical activity at the same time.

Brain areas activated during different imaging states

Most treatments focus on the emotional and cognitive processes of BD to improve their adaptation and achieve functional recovery (Bernhard et al., Reference Bernhard, Schaub, Kümmler, Dittmann, Severus, Seemüller and Grunze2006; Honig, Hofman, Rozendaal, & Dingemans, Reference Honig, Hofman, Rozendaal and Dingemans1997). It was found that the activated brain regions are various under different imaging conditions. Under the emotional tasks, the activation of ACC and IFG increased, and activation of CG decreased. While under cognitive tasks, the activation of STG increased, and precuneus and MeFG decreased. However, no similar findings were observed in amygdala. In our meta-analysis, there were no differences in the activation of amygdala before and after treatment. This may suggest that the lack of activation of amygdala may be due to the habituation of the amygdala response after repeated reception of emotional stimuli (Breiter et al., Reference Breiter, Etcoff, Whalen, Kennedy, Rauch, Buckner and Rosen1996).

The emotional neural circuit is generally considered to consist of the PFC, amygdala, ACC, thalamus and limbic system (Dalgleish, Reference Dalgleish2004). Radaelli et al. (Reference Radaelli, Poletti, Dallaspezia, Colombo, Smeraldi and Benedetti2012) used a face matching paradigm (Radaelli et al., Reference Radaelli, Poletti, Dallaspezia, Colombo, Smeraldi and Benedetti2012). Their results showed that the activation of the right ACC and hippocampus increased in patients with BD, and the activation of the DLPFC decreased. In the present study, most of the emotional tasks were related to emotional face recognition and the relevant brain areas were activated, including the ACC and IFG, which can also be activated under normal conditions. It was also found that ACC were activated in the BD patients. Moreover, the brain regions mentioned above are all related to this emotional circuit. Therefore, it can be speculated that this emotional circuit can be activated during emotional tasks, and treatments allow the emotional circuits to work properly in BD patients. In addition, activation of right VLPFC may contribute to the successful implementation of emotion-regulation strategies, like cognitive reappraisal. This kind of strategy also reduce activation of negative stimuli in the amygdala (Lieberman et al., Reference Lieberman, Eisenberger, Crockett, Tom, Pfeifer and Way2007; Wager, Davidson, Hughes, Lindquist, & Ochsner, Reference Wager, Davidson, Hughes, Lindquist and Ochsner2008). That could also explain why our results showed lack of activation of amygdala.

It has been proved that MeFG plays a role in cognitive control (Ridderinkhof, Ullsperger, Crone, & Nieuwenhuis, Reference Ridderinkhof, Ullsperger, Crone and Nieuwenhuis2004). However, it was found decreased activation in MeFG. This may be because, before treatment, BD patients want to inhibit the processing of negative information, so they use more cognitive control resources. Therefore, the symptoms of negative information processing can be effectively alleviated and activation decreased after treatment. In patients with BD, there is a deficit in working memory and recollection memory, and decreased activation of the lateral prefrontal cortex is often shown during working memory (Kurtz & Gerraty, Reference Kurtz and Gerraty2009; Townsend, Bookheimer, Foland-Ross, Sugar, & Altshuler, Reference Townsend, Bookheimer, Foland-Ross, Sugar and Altshuler2010). Precuneus is part of DMN, and it is involved in a lot of cognitive control functions such as visual representation, episodic memory and self-directed processes. It seems to play a crucial part in the integration of mental processing (Aryutova et al., Reference Aryutova, Paunova, Kandilarova, Stoyanova, Maes and Stoyanov2021; Raichle, Reference Raichle2015). However, its activation would be decreased when people confront with external attention-capturing stimuli. During cognitive tasks, we found decreased activation in precuneus after treatment. It may indicate that BD pays more attention to external stimulation after treatment since BD patients interfere with the integration of attention, memory and other resources (Zhang et al., Reference Zhang, Liu, Shi, Tan, Suo, Dai and Liu2022).

There is a problem in the present analysis that and the effects of tasks may be confounded by treatments and also effects of treatments may be confounded by tasks. Because of the paucity of studies, like psychotherapeutic intervention with emotional task (n = 3), and psychotherapeutic intervention with cognitive task (n = 4), and pharmacological intervention with cognitive task (n = 5) were too few to be included in separate ALE meta-analyses. Paediatric bipolar disorders have more complex phenomenology and less related researches (Pavuluri, Birmaher, & Naylor, Reference Pavuluri, Birmaher and Naylor2005), in order to include more literatures, we expanded to include all BD types without adding age criteria. As more studies are published in the future, we can separate adult and paediatric studies to get more pure effect.

Limitations

Several limitations should be acknowledged in the study. First, this study was included a limited number of studies involving BD interventions using fMRI scans. Second, we included only one imaging method: fMRI. It can be considered including other neuroimaging methods such as positron emission tomography and single-photon emission computed tomography for future analysis. Third, the present study was only included two types of treatment: psychotherapy and drug therapy. In the future, we can include non-invasive brain stimulation therapies and explore the effect and mechanism of that kind of treatment. In addition, the imaging tasks were only divided into emotional and cognitive categories, and the results may also be affected by the specific task type. If there are more articles, it is hoped to analyse more similar task types. And we only analysed the effect of kind of treatment and imaging task, and there may be other factors that influence the brain region activation results. Only one condition could be controlled at a time when analysing the consistency of brain activation under different conditions due to limited number of studies. This may be influenced by the interaction of other regulatory factors such as age and gender. As more studies are included in the future, we can consider the influence of other factors on activated brain regions.