This study aimed at characterizing functional connectivity of RSNs in patients with BPD. Two main findings emerged. First, functional connectivity differences were detected in the DMN and in a right frontoparietal network, whereas 2 other a priori RSNs and 2 “control” networks did not exhibit between-group differences. Second, regions of abnormal connectivity within the DMN (i.e., cuneus, insula and FPC) were related to BPD symptoms, as indicated by scores of dissociation, impulsivity and measures of overall BPD psychopathology.
Converging functional imaging evidence supports the notion that the DMN is involved in a wide range of higher-order cognitive and affective functions, whereas the monitoring of self-referential activity has been suggested to be subserved by the DMN to a higher degree than processing of external stimuli.14
Possible functions of the DMN include internal mentalizing detached from external stimuli; processing of autobiographic memory traces; and monitoring of cognitive, affective and somatosensory states.14,15,37
Our data suggest that abnormal DMN connectivity in patients with BPD is restricted to a circumscribed set of brain regions, most notably the left FPC and the insula. Contributions of the FPC have been implicated in a variety of social–cognitive functions, most notably in the processing of intentional thoughts,38
self-referential information and interpersonal interactions,39
in good accordance with processes subserved by the DMN.15
In line with this notion, recent neuroimaging data indicate that the left FPC exhibits abnormal levels of activation in patients with BPD during the experience of social exclusion.40
The finding of abnormally increased left FPC connectivity during resting-state conditions, however, is also suggestive of a task-independent neural signature of BPD. This view receives further support from the positive relation between left FPC connectivity and BPD symptoms, as assessed by the BSL-23. In addition, left FPC connectivity was also found to correlate with symptoms of impulsivity, supporting a role of the FPC in the expression of clinically relevant symptom clusters. This brain–behaviour relation is in line with previous findings of abnormal prefrontal physiology in patients with BPD and other personality disorders with core symptoms of impulsivity and aggression.5,6,8
Moreover, several neuroimaging studies have specifically implicated the FPC as a part of the neural network subserving inhibitory control, where the FPC substantially contributes to efficient cognitive inhibition41
and affective regulation.42
In addition, it is possible that the left FPC dysfunction might contribute to several symptom dimensions of BPD, such as poor inhibitory control and impaired social cognition, a hypothesis that could be further tested by combined investigations of resting-state and task-based fMRI.
Interestingly, patients with BPD also exhibited increased resting-state connectivity of the insula. Abnormal activation of the insula has been frequently reported in patients with BPD, suggesting an involvement of this region in emotional regulation, pain sensitivity and processing during dissociative states.11,12
Perhaps most relevant to BPD, many studies have found insular contributions to the processing of noxious somatosensory, cognitive and affective states, such as acute or chronic pain.37,43
The insula has been associated with sensory intensity encoding44
and affective dimensions of noxious states,45
thus subserving multiple associative processes related to salient intero- and exteroceptive stimuli. More generally, functions of the insula have been related to the perception and monitoring of internal states, including both the somatosensory and the affective domain.45
The positive correlation between insula connectivity and measures of dissociation, as evidenced in our study, further supports the notion of insular involvement during dissociative states.12,46
Furthermore, increased activation of the insula has been previously linked to symptoms of dissociation along with reduced pain sensitivity in patients with BPD, suggesting a possible neural mechanism related to self-injurious behaviour.12
It is noteworthy, however, that unlike other studies reporting insula activation in patients with BPD, we specifically found increased insular connectivity during resting-state conditions. Thus, this region might contribute to symptoms of dissociation, and possibly also pain insensitivity, even in the absence of external conditions, suggesting a possible trait marker of BPD. Apart from the insula, however, a relation between indices of functional connectivity and dissociative symptoms was also found in the cuneus. A previous neuroimaging study reported a pattern of increased covariation between the ventrolateral thalamus and the right cuneus associated with dissociative responses in patients with PTSD.46
However, the precise contributions of the cuneus to dissociative symptoms or other symptom clusters of patients with BPD are unclear at present. Possible functions of the cuneus in the context of dissociation may include modulations of mental imagery47
or reactions to affectively relevant events48
that might be associated with an ongoing dissociative experience. However, the finding of lower cuneus connectivity argues against the occurrence of a vivid mental image or an increased vigilance response, thus discarding the possibility of spontaneous dissociation under scanning conditions. Alternatively, the finding of lower cuneus connectivity might suggest a decreased neural capacity for establishing and maintaining an attentional set,49
possibly conveying proneness to dissociation. Nevertheless, whereas this speculation might appear plausible in the context of dissociative symptoms, the specific functions of the cuneus in patients with BPD cannot be fully elucidated by the present data set.
Apart from the DMN, connectivity differences in patients with BPD were also found in a right frontoparietal RSN, where patients with BPD showed less functional connectivity in left inferior parietal and right middle temporal regions. Abnormal function of temporoparietal regions in patients with BPD has been previously reported by several behavioural and functional imaging studies. For instance, some studies have shown decreased resting-state blood flow in right temporal regions6
and decreased activation of the temporal cortex during response inhibition.50
In contrast, increased activation of middle and inferior temporal areas has been described during tasks requiring emotional processing.51
With regard to parietal regions, neuropsychologic studies have suggested visuospatial processing and learning deficits in patients with BPD,52
possibly linked to an impaired engagement of prefrontal and posterior parietal attentional systems. Moreover, abnormal posterior and right hemisphere γ synchrony has been discussed as suggestive of a lack of sensory integration and attentional control in patients with BPD.53
Our data may lend some support to this hypothesis. For instance, a right lateralized ventral attentional system comprising middle and inferior prefrontal and posterior parietal regions has been described by numerous functional neuroimaging studies of attention, including studies of intrinsic and phasic alertness54
and attentional control.55
Moreover, several rs-fMRI studies have consistently reported a right frontoparietal network similar to the RSN identified in our study, possibly reflecting baseline properties of a network subserving attentional processes that persist in the absence of external events.17,37
In conjunction with findings of abnormal DMN connectivity, we speculate that decreased temporoparietal connectivity within an attention network in patients with BPD could indicate a decreased attentional capacity for relevant somatosensory stimuli or self-representational control. However, since the precise functions of the right frontoparietal network cannot be fully inferred by its resting-state characteristics, the preliminary conclusions drawn from the present resting-state findings clearly need further support from multimodal neuropsychologic, task-based and rs-fMRI studies. Moreover, unlike the regions within the DMN, the temporoparietal loci of dysfunction were not related to BPD symptoms. Thus, a direct relation to circumscribed symptom clusters cannot be established by these findings.
Similarly, although we expected to find connectivity differences in networks associated with cognitive control, our study did not find evidence for altered resting-state connectivity within the executive control RSN or the left frontoparietal RSN. The executive control network, as identified by our study, has been previously referred to as corresponding to cognition paradigms of inhibitory control, affective processing and pain, whereas the left frontoparietal RSN has been implicated in language processes.17
The negative findings of our study do not necessarily imply intact executive, inhibitory or linguistic pathways in patients with BPD, or intact function of the anterior cingulate and ventro- and dorsolateral prefrontal cortices. The latter regions have been addressed by numerous neuroimaging studies in patients with BPD,2,3
although mostly within the context of cognitive, affective and somatosensory stimulation. Since a range of clinical features of BPD might especially occur in reaction to (mostly negative) experiences,56
networks subserving cognitive control functions as a response to environmental demands might appear intact when studied under resting-state conditions. Thus, further research is needed to dissociate alterations of brain network connectivity during experimentally induced conditions and their interactions with baseline connectivity during the resting state.
From a clinical perspective, the question of whether the findings of the present study can be seen as specific for patients with BPD must remain open at this stage of research. Neuroimaging evidence from other clinical populations, such as patients with bipolar disorder, suggests left FPC (BA 10) dysfunction during tasks of response inhibition and working memory, regardless of the clinical status (i.e., in patients with acute mania,57
and nonpsychotic first-degree relatives).59
These studies at least suggest a more general link between deficient inhibitory control, abnormal left FPC activation and clinical populations characterized by mood instability. Similarly, aberrant neural responses of the insula and the cuneus have been shown in patients with PTSD and dissociative responses.46
When considering these results, however, it is important to note that most of these findings have been derived from task-based protocols, where stimulus-related interactions with brain activation have to be taken into account. Moreover, when considering extant bipolar or PTSD samples with available resting-state data, baseline connectivity differences have been reported in DMN regions distinct from those found in our BPD sample.60,61
More recently, a study investigating multiple RSNs in medication-free patients with major depression20
reported a pattern of dysfunction different from the pattern of dysconnectivity observed in our BPD sample. However, definite conclusions about the specificity of the present findings to BPD can only be drawn by rs-fMRI studies of 2 or more clinical groups.
Several potential limitations of this study have to be considered. First, our results should be cautiously interpreted given the potential influence of other comorbid axis I disorders on these findings. However, the question of whether patients with BPD with psychiatric comorbidities should be excluded to homogenize clinical sample characteristics remains controversial.2
Most patients with BPD have an additional axis I disorder, such as depression, even in very early samples,62
and thus, fully excluding participants with other co-ocurrent axis I disorders may reduce the generalizability of findings to the larger BPD population. Although our patient subgroup analyses did not reveal differences between patients with and without symptoms of major depression, future studies using appropriate clinical comparison groups are necessary to determine the specificity of RSN abnormalities in patients with BPD with respect to additional psychiatric comorbidities. Second, given reports of neural differences between patients with BPD with and without comorbid symptoms of PTSD,3
we chose to investigate only those patients without PTSD as a first attempt to homogenize our patient sample. However, we acknowledge that this approach could also constrain our findings to this patient subgroup, whereas patients with BPD with symptoms of PTSD might exhibit differential patterns of RSN dysfunction. Third, we excluded patients with an unstable physical condition before scanning and patients who presented with acute suicidal ideation, which might restrict our findings to clinically more stable patients. Fourth, all of our patients were medicated, and it is unclear at present if and which RSNs are selectively modulated by specific psychotropic agents. Nevertheless, since at least antipsychotic drugs have been reported to modulate DMN function and low-frequency fluctuations of BOLD signals,33,63
we can neither rule out nor specify potential effects of psychotropic treatment in the present BPD sample.