7.2.2.2a Cortico-Limbic Connectivity

The study of cortico-limbic connectivity implies that investigators studied the relationship between cortical mood-regulating areas, for example, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and subcortical or limbic mood-generating areas such as the amygdala (AMYG) and ventral striatum (VS). This hypothesis is derived from the Jacksonian view of neural architecture, which models the brain in terms of hierarchical structures with the higher structures influencing the activity of the lower structures (79). The influence of mood-regulating regions on the mood-generating regions also harkens back to the Freudian model of the psyche in which the superego and ego control the expression of the instinctual drives of the id. It should be noted though that despite being a neurologist, Freud did not propose a neuroanatomical model for his model of the organization of the psyche (80). As BD involves impairments in inhibition of emotional responses and impulsive behavior, it is thought that cortico-limbic emotion regulatory mechanisms have become impaired in some way leading to unregulated mood symptomatology. As noted earlier, functional connectivity does not give any information regarding the effect of one region over the other but coherence of activity between brain regions has been thought to provide some information regarding whether two brain areas are working simultaneously or not. The findings of altered cortico-limbic functional connectivity in BD are summarized later.

Task-Related Cortico-Limbic Psychophysiological Interaction (PPI) Studies:

Using facial emotion identification/matching tasks, several studies have reported decreased connectivity between amygdala and areas of the frontal cortex such as the ventromedial prefrontal cortex (vmPFC) (9) and posterior anterior cingulate cortex (pACC) (81). On a verbal working memory task, euthymic BD subjects (BPE) exhibited decreased PPI right-sided cortico-amygdalar connectivity compared to HC (13). Other studies have reported increased cortico-limbic connectivity: increased PPI dlPFC-amygdalar connectivity in BPE versus HC using an emotional Stroop task (8) and during an emotion regulation task, PPI cortico-limbic connectivity has been reported to be less decreased in BPE I subjects compared to HC (7, 10). Still, other studies have reported both an increase and a decrease depending on the emotional task used: using a face processing task, increased pACC-amygdala connectivity during processing of sad faces versus decreased OFC-amygdala connectivity during processing of happy faces was reported in remitted/depressed BD subjects compared to HCs (12). During a reward-processing task, increased FC between VS and mPFC during reward receipt and decreased FC during reward omission in BD I subjects compared to controls(16), while in a reward anticipation task decreased FC between VS and anterior prefrontal cortex (aPFC) was seen (17).

In a study that investigated state-related differences, subjects who transitioned from BPM to BPD after treatment, BPM at baseline had increased frontal gyri (IFC)-amygdala correlation of activations during continuous performance task (CPT-END) while when they transition to a BPD state, this connectivity was decreased but right amygdala-insula connectivity increased(11). In another study in which BPE I and BPE II were directly compared in terms of PPI FC during an emotion regulation task, BPE I subjects exhibited a decreased inverse correlation between cortico-amygdalar connectivity while BP-II subjects exhibited increased inverse correlation suggesting a difference between the two subtypes (7).

In studies that investigated differences between BPD and MDD, the following cortico-limbic FC abnormalities have been reported: Redlich and colleagues using PPI during a card-guessing reward-processing task reported increased FC between the VS and ventral tegmental area (VTA) in the MDD group compared to HC, but no differences with BPD group were found compared to HC (18). In a study that investigated effective connectivity differences in amygdala-OFC connectivity in BD and MDD subjects, Almeida and colleagues reported top-down left-sided amygdala-OMPFC abnormality in MDD and right-sided bottom-up abnormality in BD (82).

Resting-State Reference ROI-Based Cortico-Limbic Connectivity Studies:

Anand and colleagues first reported decreased resting-state LFBFs correlation with perigenual ACC-limbic connectivity in medication-free subjects compared to HCs in both BPD and BPM groups compared to HCs (3). Since the first report, several studies have studied cortico-limbic, particularly cortico-amygdalar connectivity in BD and in general have reported decreased amygdala connectivity with dorsal PFC areas but increased amygdala and other limbic areas with the ventral PFC in BD. Chepenik and colleagues reported increased vPFC correlations with amygdala (28). Increased amygdala-mPFC but decreased amygdala-dlPFC connectivity was also reported in remitted BD patients with and without psychosis (25). Increased frontal-hippocampal and vlPFC-VS FC has also been reported in BD subjects compared to HCs (49). Studies that have specifically looked at differences between BPE and HC to identify trait-related abnormalities have reported hyperconnectivity between right amygdala and right vlPFC (29), decreased amygdala connectivity with supplementary more area (32), greater connectivity between mPFC and right amygdala compared to HS, which was also correlated with the duration of the disease (26), and increased amygdala connectivity to the subgenual ACC (23).

A number of cortico-limbic RSFC studies have looked at state-related differences between bipolar mood states. In general, both BPD and BPM have been found to share cortico-limbic connectivity abnormalities, but some differences were also found. Decreased pregenual ACC connectivity with the striatum and thalamus (3), decreased amygdala connectivity with inferior frontal orbital gyrus and lingual gyrus (30), decreased FC between the amygdala and left middle frontal cortex (27), and widespread common cortico-striatal connectivity abnormalities (52) have been reported in both states. Decreased FC between right OFC and amygdala in BPM compared to BPD and in a study comparing BPM with BPE subjects, decreased connectivity between amygdala and ACC in BPM has been reported (24). Conversely, increased connectivity between the amygdala and dorsal frontal cortical structures involved in emotion regulation has also been observed (24). Cortico-striatal connectivity has been reported to be different in BPM and BPD subjects. In a relatively large study comparing medication-free subjects, BPD showed increased connectivity of the dorsal caudal putamen with somatosensory areas such as the insula and temporal gyrus while BPM showed unique increased connectivity between left dorsal caudate and midbrain regions as well as increased connectivity between VS and thalamus (52). Another study reported similar findings in first episode manic patients regarding reduced connectivity in the dorsal and caudal cortico-striatal systems and increased connectivity in a circuit linking the VS with the medial orbitofrontal cortex, cerebellum, and thalamus when compared to HCs (50).

Studies with an aim to distinguish between BPD and MDD have reported significant differences in hippocampal and striatal FC. In an FDG PET study, Benson and colleagues (83) reported an increased correlation between hippocampus and prefrontal areas in MDD versus BPD. In resting-state LFBF studies also, hippocampal connectivity abnormalities have been found in both BPD and MDD with some differences. In BPD patients, increased FC of the bilateral anterior/posterior hippocampus with lingual gyrus and inferior frontal gyrus (IFG) relative to MDD patients was observed while in comparison to HCs, both groups had an increased FC between the right anterior hippocampus and lingual gyrus and a decreased FC between the right posterior hippocampus and right IFG (47). Increased FC between IFG and lingual gyrus with the hippocampus in BPD compared to MDD (48) was also observed. Increased FC of the striatum in BPD versus MDD has also been reported in a few studies. Increased positive metabolic correlations between prefrontal and ventral striatal areas(83), increased FC between VS and ACC (84), and increased dlPFC connectivity with the striatum in BPD compared to MDD in a PET cerebral blood flow study (51) have been reported.