Dissociation and Alterations in Brain Function and Structure: Implications for Borderline Personality Disorder

Up to now, the precise neural/neurobiological underpinnings of dissociation remain elusive. Yet, a growing number of neuroimaging studies in DDD, DID, and D-PTSD have implicated dissociative symptoms in altered brain structure and function.

Over the past decades, neuroimaging has become one of the most important tools in clinical neurobiology. Techniques such as magnetic resonance imaging (MRI), MR spectroscopy (MRS), positron emission tomography (PET), and diffusion tensor imaging (DTI) are used to study abnormalities in the brain. By detecting changes in blood-oxygen-level-dependent (BOLD) signal (hemodynamic response), functional MRI (fMRI) provides a measure of brain activity and coactivity (functional connectivity) during experimental tasks or resting state, i.e., in the absence of experimental stimulation. PET (e.g., in combination with pharmacologic challenge) can be used to detect changes in glucose metabolism and neurotransmitter systems. MRS assesses concentrations of neurochemical metabolites like glutamate, N-acetylaspartate (NAA), lactate, or choline in the brain. Structural MRI and DTI measure anatomical abnormalities, e.g., in gray or white matter volume.

Several neuroimaging studies have related their findings to higher scores on psychometric scales like the dissociative experiences scale (DES), measuring trait dissociation with the subscales depersonalization/derealization, amnesia, and absorption [51], or the dissociation stress scale (DSS), a measure of state dissociation, including items on psychological and somatic dissociation and one item on aversive inner tension [52‐54]. As an attempt to mimic dissociative experiences in everyday-life situations, some studies used script-driven imagery to experimentally induce dissociation [55‐59, 60•]: a narrative of an autobiographical situation involving dissociative experiences (“dissociation script,” as compared to an emotionally neutral script) is created together with each participant and presented in an experimental setting (e.g., during fMRI). Participants are instructed to recall the specific situation as vividly as possible. Other studies used pharmacological challenge (e.g., NMDA antagonists and cannabinoids) to induce dissociative symptoms (see [61]). In the following section, neurobiological models of dissociation, primarily based on research in DDD, DID, and D-PTSD, are discussed.

Already in 1998, Sierra and Berrios proposed that symptoms of depersonalization may be associated with a “disconnection” of a cortico-limbic brain system, involving the amygdala, anterior cingulate cortex (ACC), and prefrontal structures. In this model, depersonalization is more broadly conceptualized as a state of subjective detachment, involving emotional numbing, emptiness of thoughts, analgesia, and hypervigilance [62]. It is assumed that these symptoms are associated with increased activity in the medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (dlPFC), and ACC [63], brain areas implicated in attention, cognitive control, and arousal modulation. Increased recruitment of the PFC may (both directly and indirectly via the ACC) lead to dampened activity in the amygdala and a marked attenuation of automatic responses, comparable to “shutting down the affective system” [62, 64‐66]. The amygdala is fundamentally involved in salience detection and emotion processing such as the initiation of stress and fear responses [63, 67‐69]. States of detachment (e.g., numbing) may thus be associated with reduced reactivity in this area [70].

Using fMRI, Phillips and colleagues (2001) investigated brain activity during the presentation of aversive versus neutral images in patients with chronic depersonalization disorder, patients with obsessive-compulsive disorder (OCD), and healthy controls (HC) [69]. In response to aversive images, depersonalization disorder patients reported less arousal and showed diminished activity in the occipito-temporal cortex, ACC, and insula compared to OCD and HCs [69]. The insula plays an important role in attention modulation, encoding of negative emotions, interoceptive awareness, and pain perception [71‐75]. Diminished activity in this area may therefore reflect reduced interoceptive/emotional awareness [69, 76•]—an assumption that is supported by a more recent study in chronic depersonalization patients [77•]. In this study by Lemche and colleagues, altered anterior insula and dorsal ACC reactivity to sad emotional expressions was associated with traits of alexithymia, i.e., difficulties in identifying and describing feelings. In another study of this group [78•], a stronger coupling of the dorsomedial PFC (Brodmann area (BA) 9) and posterior cingulate cortex (PCC; BA31) was found in depersonalization disorder patients [78•]. The PCC is a critical node of the default mode network (DMN), a brain network that has been implicated in “inward-directed” (self-referential) processes, such as episodic memory encoding/retrieval, self-monitoring, daydreaming, planning, rumination, and pain processing [79‐81]. Further evidence for altered self-referential processing in depersonalization disorder patients stems from an fMRI study in which DDD patients were exposed to either their own photographs or a stranger’s face [82•]. While viewing their own photographs, patients showed stronger activity in areas implicated in self-referential processing, e.g., mPFC, which was positively correlated with depersonalization severity [82•].

Brain function in depersonalization disorder may also be altered in the absence of experimental stimulation: in a PET study by Simeon and colleagues (2000), patients with chronic depersonalization disorder demonstrated significantly lower metabolic activity in the right middle/superior temporal gyrus (BA21/22) and higher metabolism in the parietal and occipital areas (BA7, 39, and 19)—metabolic activity in area 7B was positively correlated with clinical depersonalization scores [83]. Altered glucose metabolism in tempo-parietal regions may play a role in “feeling unreal” [83], e.g., altered consciousness, sensory integration, body schema, and memory, as suggested by observations in patients with temporal lobe epilepsy [84] and research on the role of the temporal lobe in memory processing [32].

In sum, there is evidence for altered activity in brain regions associated with emotional and self-referential processing in patients with chronic depersonalization disorder.

Based on an earlier research in PTSD, Krystal and colleagues (1995) proposed that the thalamus plays an important role in dissociative-like states of altered consciousness. One of the functions of the thalamus is that of a sensory gate or filter, receiving direct and indirect input from sub-cortical areas (e.g., raphe nuclei and locus coeruleus), limbic regions (e.g., amygdala), and frontal areas (e.g., ACC and prefrontal cortices) [85]. Within this network, the thalamus may both directly and indirectly modulate responses to environmental stimuli, facilitating or impeding the flow of information [34, 61, 85].

Furthermore, the hippocampus and parahippocampal regions may be critical to the understanding of altered memory processing during dissociative states [31‐33, 61].

Based on more recent neuroimaging findings in PTSD [10], Lanius and colleagues (2010) proposed a neurobiological model that distinguishes between two types of responses to traumatic reminders or other stressors: patients with a dissociative response type (D-PTSD) are thought to “over-modulate” their emotions, as opposed to patients who primarily suffer from re-experiencing symptoms, including (affective) hyperarousal, intense feelings of shame and guilt, and difficulties in emotion downregulation (re-experiencing response type). Emotion over-modulation (dissociative response type) is thought to primarily activate frontal regions implicated in cognitive control and emotion downregulation (e.g., dorsal/rostral ACC and mPFC), associated with dampened activity in amygdala and insula. The reversed pattern—diminished frontal recruitment (ACC and mPFC) and hyperactivity in amygdala and insula—is assumed to underlie emotion under-modulation (re-experience response type) [10].

Central to the development of this model [10] was a script-driven imagery fMRI study [57], in which PTSD patients were exposed to autobiographical narratives of traumatic events. The majority of patients (∼70%) reported marked re-experiencing symptoms and showed a substantial increase in heart rate during the script. In a smaller patient group (∼30%), however, this heart rate increase was not observed—instead, these patients showed stronger activity in the medial frontal gyrus, anterior and medial cingulate, middle temporal gyri (BA38), precuneus, occipital areas, and inferior frontal gyrus (IFG), compared to a control group of traumatized persons who had not developed PTSD [57].

In another fMRI study [86], patients with D-PTSD showed increased activity in the amygdala, insula, and thalamus while fearful versus neutral facial expressions were presented nonconsciously. Interestingly, these limbic(-related) areas were not significantly activated when images were presented consciously. In the latter case, dissociative patients showed increased activity in ventral PFC and diminished activity in the dorsomedial PFC, suggesting a conscious over-modulation of emotions and suppression of self-referential processing [86].

For PTSD patients who showed dissociative responses to autobiographical trauma scripts (compared to patients with a flashback response and healthy controls), there is also evidence for altered functional connectivity (FC), i.e., coactivation in areas implicated in sensory processing, consciousness, memory, and emotion regulation [56]: compared to controls, dissociative patients showed stronger FC of the left ventrolateral thalamus (VLT) with right insula, middle frontal gyrus, superior temporal gyrus, cuneus, and with left parietal lobe, but reduced VLT-FC with the left superior frontal gyrus, right parahippocampal gyrus, and right superior occipital gyrus. Compared to patients with a flashback response, dissociative patients showed increased FC between right cingulate gyrus and left IFG [56].

In the absence of experimental tasks, altered resting-state functional connectivity (RSFC) in the DMN was found in patients with D-PTSD [87•], including altered synchrony between the DMN (which is usually activated during rest) and the “central executive network” (commonly activated during cognitive tasks, as reflected in strong anticorrelations [75, 88]). Findings of altered intra-network resting-state connectivity (in DMN) and altered inter-network connectivity were significantly associated with depersonalization and derealization severity [87•].

In another RS-fMRI study [89•], patients with D-PTSD (compared to PTSD patients without the dissociative subtype and HC) demonstrated increased FC of the amygdala with prefrontal and parietal regions, including dorsal PCC and precuneus, which may further support the assumption of a distinct “neurobiological profile” of D-PTSD [89•].

There is some evidence that the aforementioned neurobiological alterations may not be specific to a specific disorder but rather represent a trans-diagnostic phenomenon related to dissociation. Recent findings in DID [90•, 91•] resemble findings for D-PTSD, albeit intra-individual differences (instead of inter-individual differences) were observed: neurobiological responses significantly differed depending on whether DID patients were in a “hyper-aroused traumatic identity state” (with voluntary access to traumatic memories) or in their “normal dissociative identity state” (characterized by dissociative amnesia) [90•, 91•]. In the two studies by Reinders and colleagues (2006, 2014), DID patients showed elevated cardiovascular responses (heart rate and blood pressure) and stronger amygdala and insula activity, along with lower activity in cingulate gyrus, parietal cortex, and parahippocampus when exposed to a trauma script (versus neutral script) while being in their “hyper-aroused traumatic identity state” than in their neutral “hypo-aroused identity state” [90•, 91•]. In another study, DID patients exhibited increased perfusion in bilateral thalamus while being in their (apparently) “normal” state of identity compared to an (apparently) “emotional” identity state [92•]. More research is needed to clarify whether brain activity patterns may differ dependent on states (in the same individuals) or represent stable inter-individual differences, which may allow for a discrimination between diagnostic subgroups/categories [10].

In sum, theoretical assumptions and research in depersonalization/DDD, DID, and D-PTSD suggest a link between dissociative symptoms and alterations in brain regions associated with emotion processing and memory (amygdala, hippocampus, parahippocampal gyrus, and middle/superior temporal gyrus), attention and interoceptive awareness (insula), filtering of sensory input (thalamus), self-referential processes (PCC, precuneus, and mPFC), cognitive control, and arousal modulation (IFG, ACC, and lateral prefrontal cortices). As many studies did not include clinical control groups or groups of traumatized individuals who did not develop a disorder, it remains unclear whether the aforementioned results are related to a specific disorder or a trans-diagnostic feature, possibly associated with high dissociation. Findings that are based on correlations (e.g., between brain structure/function and psychometric scores) do not allow causal conclusions, i.e., whether they represent a predisposition for or a result of frequent dissociative experiences (see below).

The second aim of our article is to review neuroimaging studies in BPD that investigated links to dissociative symptoms. We searched databases (PubMed, PsychInfo, Web of Science, and Science Direct) for different combinations of “Borderline Personality Disorder,” “Dissociation,” and the following keywords: brain, brain alterations, functional magnetic resonance imaging, magnetic resonance imaging, neurobiological, neuroimaging, neurophysiological, positron emission tomography, and structural magnetic resonance imaging.

In the next section, we first describe clinical expressions of dissociation in BPD, providing a background for the subsequent discussion of neuroimaging research.

Lange and colleagues used 18fluoro-2-deoxyglucose (FDG-)PET to investigate glucose metabolism in 17 BPD patients (with a history of childhood sexual/physical abuse, mixed gender, partly medicated; see Table 1) and 9 healthy controls (HCs) [131]. BPD patients displayed reduced FDG uptake in the right temporal pole, anterior fusiform gyrus, and left precuneus and PCC. Impaired memory performance among patients was correlated with metabolic activity in ventromedial and lateral temporal cortices (implicated in episodic memory consolidation and retrieval), while no correlations with trait dissociation (DES) were reported. The finding of decreased temporo-parietal metabolism was discussed as possible neural underpinning of altered memory processes that may also play a role in the context of dissociation [131]. However, sample sizes were relatively small, and findings may not be specific to BPD due to comorbidities (depersonalization disorder, DID, and PTSD).

Sar et al. [132] used single-photon emission computed tomography (SPECT) with Tc99m-hexamethylpropylenamine (HMPAO) as a tracer to investigate regional cerebral blood flow (rCBF) in an unmedicated sample of DID patients (n = 21), 15 of whom met criteria for comorbid BPD, and 9 HCs. Compared to HCs, patients showed decreased rCBF ratio in bilateral medial OFC and increased rCBF in medial/superior frontal regions and occipital regions bilaterally [63]. No significant correlation with dissociation was reported.

Wolf and colleagues (2012) used continuous arterial spin labeling MRI to measure alterations in blood flow in 16 female BPD patients without comorbid PTSD (partly medicated but on a stable medication) and 16 HCs [133]. Compared to HCs, patients exhibited decreased blow flow in the medial OFC, while increased blood flow was found in the lateral OFC bilaterally. Like in the study by Sar and colleagues [132], no significant correlation with self-reported dissociation (DSS) was observed. Instead, medial and lateral OFC blood flow was positively correlated with impulsivity, as measured with the Barratt impulsiveness scale (BIS; [142])—suggesting an association with impulsivity rather than with dissociation.

In 17 female BPD patients without PTSD and 17 HCs (same sample as in [133]), Wolf and colleagues (2011) investigated changes in RSFC using RS-fMRI [134]. Within the DMN, patients showed increased RSFC in the left frontopolar cortex and insula, while showing decreased RSFC in the left cuneus. Within a fronto-parietal network, patients exhibited decreased RSFC in the left inferior parietal lobule and the right middle temporal cortex compared to HCs. No significant group differences were observed in two other networks comprising lateral prefrontal and cingulate regions. In the BPD group, state dissociation (DSS) positively predicted RSFC in the insula and precuneus [134]—as previously mentioned, these regions play a role in interoceptive awareness and self- referential processes [74].

In another RS-fMRI study, Krause-Utz et al. (2014) investigated the changes in RSFC of the three fronto-limbic core regions that are of specific relevance to BPD: bilateral amygdala (medial temporal lobe network), bilateral dorsal ACC (salience network), and bilateral ventral ACC (default mode network) [130•]. The DES was used to predict RSFC with these seed regions. The sample comprised 20 unmedicated female BPD patients (all with a history of interpersonal trauma) and 17 HCs. There was a trend for increased amygdala RSFC with right dorsal insula, lateral OFC, and putamen in patients compared to HCs. BPD patients further exhibited diminished negative RSFC between the dorsal ACC and the left PCC and increased negative RSFC of the left ventral ACC with occipital cortex, lingual gyrus, and cuneus. In the patient group, DES scores positively predicted amygdala RSFC with the right dlPFC. Furthermore, patients, who reported higher trait dissociation showed a reduced coupling of the amygdala with right fusiform gyrus. A subgroup comparison of BPD patients with (n = 9) versus without comorbid PTSD (n = 11) yielded similar findings.

The two RS-fMRI studies described above [130•, 134] provide primary evidence for a possible role of dissociation in altered RSFC in BPD. As pointed out before, no causal conclusions can be drawn from correlational findings. In order to gain more insight into the impact of dissociation on RSFC of large-scale brain networks in BPD, future studies may acquire resting-state scans before and after experimentally inducing dissociation (e.g., via script-driven imagery) and before and after therapeutic interventions aimed at a reduction of dissociative symptoms.

Again, interpretation of findings, summarized so far, is complicated by methodical differences (e.g., comorbidities with depersonalization disorder [131], DID [131, 132], and PTSD [130•]), trauma history [130•, 131], psychotropic medication [131, 133, 134], and relatively small sample sizes.

To our knowledge, one MRS study in BPD investigated links between trait dissociation (DES) and glutamate levels in the ACC within a sample of unmedicated female BPD patients (n = 30) and HCs (n = 30) [143]. Significantly higher levels of glutamate in the ACC were found in BPD as compared with HCs. In BPD, glutamate concentrations in the ACC were positively correlated not only to DES scores, but also to BIS scores. Associations between ACC glutamate levels and impulsivity (BIS scores) could be replicated in a more recent study [144], suggesting a link with impulsivity rather than with dissociation.

A couple of fMRI studies in BPD examined links between changes in BOLD response during experimental tasks (e.g., viewing aversive images, pain stimulation, and cognitive tasks) and self-reported dissociation (e.g., DSS and DES).

Kraus and colleagues (2009) investigated amygdala activity in relation to pain processing (heat stimulation) and state dissociation (DSS) in an unmedicated sample of female BPD patients with (n = 12) and without comorbid PTSD (n = 17) [137]. No significant group differences in pain sensitivity were observed. A deactivation of the amygdala during pain processing was found to be more pronounced in BPD patients with comorbid PTSD than in those without PTSD, while this was not significantly correlated with DSS scores.

In a more recent study, pain processing and dissociation (DES and DSS before/after scanning) were investigated in relation to FC changes in an unmedicated female sample of BPD patients (n = 25, all with a history of self-harm) and 23 HCs [136]. Kluetsch and colleagues [136] used psychophysiological interaction (PPI) analysis [136] and independent component analysis to analyze changes in FC. Compared to controls, patients showed a reduced integration of the left retrosplenial cortex and left superior frontal gyrus into the DMN. During pain versus neutral temperature stimulation, patients further exhibited less FC between the PCC (seed region) and left dlPFC. Higher trait dissociation (DES) was associated with an attenuated signal decrease of the DMN in response to painful stimulation. Since only patients with a history of self-harm and no clinical control group were included, future studies should clarify whether these findings can be replicated in BPD patients without self-injurious behavior and whether they may underlie altered pain processing (e.g., analgesia) during dissociation.

Wingenfeld and colleagues (2009) applied an individualized emotional stroop task (EST, with neutral, general negative, and individual negative words) to investigate changes in BOLD signal during emotional interference in 20 BPD patients (partly medicated, mixed gender; see Table 1) and 20 HCs [140]. State dissociation (DSS) was assessed before and after scanning. Patients displayed overall slower reaction times than HCs, while no increase of reaction times after emotional interference was observed. Controls, but not BPD patients, showed a significant recruitment of the ACC and frontal areas for generally negative versus neutral and for individual negative versus neutral words, respectively. No significant correlations between DSS and behavioral measures or neural activity were reported.

Hazlett and colleagues (2012) investigated potentiated amygdala responses to repeatedly presented emotional pictures in an unmedicated sample of BPD patients (n = 33), schizotypal personality disorder (SPD) patients (n = 28), and 32 HCs (mixed gender; see Table 1) [135]. Participants underwent event-related fMRI scanning while viewing repeated (versus novel) neutral, pleasant, and unpleasant pictures. BPD patients demonstrated increased amygdala reactivity to repeated emotional, but not neutral pictures, and a prolonged return to baseline of amygdala activity across all conditions. Despite amygdala overactivation, BPD patients showed blunted arousal ratings of emotional, but not neutral pictures. A significant negative correlation between self-reported dissociation and amygdala activity was found in BPD and also in the SPD group: higher self-reported dissociation (DES) was associated with lower emotion-challenged amygdala reactivity. This latter finding is in line with the assumption that dissociation may serve as a defensive mechanism for unpleasant stimuli (see above).

The influence of dissociation on brain activity and FC during emotional distraction in the context of a working memory task was investigated in two fMRI studies by Krause-Utz and colleagues [139, 145•]. Twenty-two unmedicated female BPD patients (all with a history of interpersonal trauma) and 22 HCs performed a modified Sternberg item-recognition task (emotional working memory task, EWMT, with neutral versus negative interpersonal pictures versus no distractors presented during the delay interval between encoding and retrieval). Immediately before and after the EWMT, state dissociation (DSS) was measured. Patients showed significantly increased amygdala activation and impaired task performance during distraction by negative and neutral interpersonal pictures but not in the control condition without distractors, suggesting increased susceptibility to social cues in BPD [139]. Patients who reported a stronger increase of state dissociation (DSS) showed significantly lower amygdala reactivity to negative distractors [139], in line with aforementioned findings by Hazlett and colleagues [135] and theoretical models [10]. No significant differences were observed between BPD patients with (n = 9) versus without comorbid PTSD.

In a reanalysis of this data set, Krause-Utz, Elzinga, and colleagues (2014) further examined how activity in the bilateral amygdala (seed region) was correlated to activity in other regions across the brain [145•] using PPI [146]. In the BPD group, a stronger coupling of the amygdala with hippocampus and dorsomedial PFC was observed for negative versus no distractors, suggesting an increased coactivation (information exchange) of regions involved in emotional and self-referential processing, e.g., retrieval of autobiographical memories [145•]. During negative distractors, patients with higher state dissociation (DSS4) showed stronger bilateral amygdala FC with right thalamus, right ACC, left insula, and left precentral gyrus—regions implicated in arousal modulation, body movements, attention, and filtering of sensory information [145•].

In another fMRI study, Krause-Utz, Mauchnik, and colleagues [138] investigated the neural correlates of classical fear conditioning (using a differential delay aversive conditioning paradigm with an electric shock as unconditioned stimulus and two neutral pictures as CS− and CS+) in 27 unmedicated female BPD patients and 26 HCs. Controls but not BPD patients showed amygdala habituation during acquisition of CS+^paired (CS+ in temporal contingency with the aversive event). No significant effect of trait or state dissociation (DSS) was observed, neither on skin conductance response (SCR) nor on brain activity. In contrast to this, an earlier study by Ebner-Priemer and colleagues (2009) found diminished fear conditioning in terms of SCR and subjective ratings in BPD patients with high (compared to those with low) pre-experimental dissociation [7]. These discrepancies may be related to methodological differences (e.g., assessment of skin conductance during fMRI versus in the laboratory and different sample characteristics: patients in the study by Krause-Utz et al. [106] reported relatively low naturally occurring state dissociation).

To our knowledge, three fMRI studies in BPD so far have used script-driven imagery to experimentally induce dissociative states [55, 59, 60•].

In a pilot fMRI study, Ludascher and colleagues [120] investigated dissociation and pain sensitivity in unmedicated female BPD patients with (n = 10) and without comorbid PTSD (n = 5) [59]. During fMRI, patients were exposed to an autographical dissociation script versus a neutral script. After the dissociation script, DSS scores were significantly increased, indicating a successful experimental manipulation, and pain sensitivity was lower than after the neutral script. During the dissociation script, patients further showed increased activation in the left IFG (BA9). Scores on the DSS positively predicted activation in the left superior frontal gyrus (BA6) and negatively predicted activation in the right middle temporal gyrus (BA21) and inferior temporal gyrus (BA20). In the subgroup of patients with BPD+PTSD (n = 10), increased activity in the left cingulate gyrus (BA32) was observed during the dissociation script. Further, DSS scores were positively correlated to the bilateral insula activity (BA13) and negatively correlated with the right parahippocampal gyrus (BA35) activity. However, the sample size was relatively small and no control group was included.

In a subsequent study, Winter and colleagues (2015) investigated the impact of dissociation on cognitive control of emotional material, by combining script-driven imagery with an EST (with negative, neutral, and positive words), a free word recall task, and a recognition task for EST words [60•]. Dissociation was induced in 19 unmediated female BPD patients (BPDd), while 18 BPD patients (BPDn) and 19 HCs were exposed to a neutral script. Script-driven imagery again successfully increased dissociation (DSS) in the BPDd group. During the EST, BPDd patients showed overall cognitive impairments (more errors and slower reaction times) and prolonged reaction times in response to negative versus neutral words compared with the other groups. In the subsequent memory task, the BPDd group recalled fewer EST words and needed more time to recognize words than BPDn. Further, BPDd demonstrated increased activity in left IFG and dlPFC during negative versus neutral words, possibly reflecting increased attempts to inhibit (emotional) material during dissociation.

Recently, Krause-Utz and colleagues (submitted) combined script-driven imagery with the EWMT to study the effect of dissociation on amygdala activity and FC during emotional distraction [55]. Within an unmedicated female sample of 29 BPD patients, dissociation was induced in 17 patients (BPDd), while 12 patients (BPDn) and 18 HC were exposed to a neutral script. Script-driven imagery again successfully increased dissociation (DSS) and aversive pictures within the EWMT evoked significant changes in amygdala activity. Overall, the BPDd patients showed significantly more working memory impairments (incorrect responses and misses, suggesting disturbed memory encoding/retrieval), and reduced activity in bilateral amygdala. Amygdala hyperactivity to emotional pictures (relative to HCs) could only be observed in BPDn. During negative distractors (versus no distractors), BPDd patients further showed lower activity in left cuneus, lingual gyrus, and PCC than BPDn and increased left IFG activity than HC. Increased left IFG activity in BPDd resembles findings of previous studies [59, 60•], albeit it was also found in the BPDn group [55]. The PPI revealed a significantly stronger coupling of amygdala with the left inferior parietal lobule, right superior/middle temporal gyrus, right middle occipital gyrus, and left claustrum during negative distractors in the BPDd group compared to the other groups [55]. More studies, including clinical control groups and larger samples, are needed to gain a deeper insight into the impact of dissociation on neural processes during affective–cognitive processing.

Paret and colleagues [141•] used real-time fMRI to investigate the effects of a neurofeedback training task on amygdala activity and amygdala-PFC FC. In four training sessions, female BPD patients (n = 8) were instructed to downregulate emotional responses to aversive images based on feedback from a thermometer display, showing amygdala BOLD signals [141•]. The DSS was applied at the end of each training run. Amygdala-PFC FC was altered across the four sessions, with increased amygdala-vlPFC FC for regulating versus passively viewing aversive pictures. Interestingly, self-reported “lack of emotional awareness” (difficulties in emotion regulation scale [147]) and also state dissociation (DSS) decreased with training [148].

To sum up at this point, structural studies on dissociation in BPD are still relatively rare and heterogeneous. Task-related fMRI studies suggest a role of dissociation in brain regions that play an important role in emotion processing/regulation, pain processing, and impulse control, including the amygdala, medial temporal lobe, insula, fusiform gyrus, precuneus, IFG, ACC, and cortical structures (e,g., dlPFC) [110•, 111•, 112•]. These brain regions and (part of) their functions are summarized in Fig. 1.

As previously mentioned, the amygdala is fundamentally involved in emotion processing and the initiation of stress and fear responses [63, 67‐69] and activity in this area might be dampened during dissociation [10, 62]. Three studies in BPD [55, 135, 139] found lower activity in this region in patients reporting higher dissociation, while other studies did not [60•, 137, 138]. These discrepancies may partly be related to differences in study design: studies observing negative correlations studied amygdala reactivity to highly aversive (trauma-related) pictures [55, 135, 139], while Kraus and colleagues [137] studied amygdala activation during pain stimulation and Winter et al. [60•] used emotional words, which might have been less distressing than aversive pictures (not evoking significant changes in amygdala activity). Naturally occurring dissociative states (DSS4 ratings: mean ± standard deviation (M ± SD)) were relatively low ([137]: BPD 1.16 ± 0.28; [138] 2.14 ± 1.67) as compared to script-driven imagery studies inducing dissociation (e.g., [55]: BPDd 6.85 ± 2.03; 9-point Likert scale, 9 indicating extreme symptoms). More research is needed to examine whether effects of dissociation on “affective brain regions” (e.g., amygdala) may become particularly evident in highly stressful situations and during high state dissociation in BPD. This may have implications for neurobiological conceptualizations of the disorder, as amygdala hyperreactivity to emotional stimuli is assumed to be a key feature of BPD [110•, 111•]. Assuming that dissociation dampens amygdala reactivity to emotional stimuli, the presence of dissociative symptoms may partly (aside from other factors such as medication status [111•]) explain why some previous studies did not replicate amygdala hyperreactivity in BPD [110•].

Apart from the amygdala, the left IFG, which has been implicated in interference inhibition and suppression of impulses [104], may be implicated in dissociative states in BPD. Three script-driven imagery studies consistently found increased activity in this area in patients listening to a dissociation script [59] and performing affective–cognitive tasks after dissociation induction [55, 60•]. As no clinical control groups were included in these studies and a high percentage of patients [59, 60•] or all patients [55] respectively reported a history of trauma, it remains unclear whether these findings are specific to BPD. Increased activity in the IFG [10] and stronger IFG FC with right cingulate gyrus [131] was also observed in D-PTSD exposed to autobiographical trauma scripts [57].

In addition, there is primary evidence for an association between trait dissociation and alterations in regions of the DMN (subsystems) such as the PCC, precuneus, hippocampus, and dorsal PFC in BPD. As previously mentioned, the DMN has been associated with “inward-directed” (self-referential) processes [79‐81]. Again, it remains unclear whether these alterations in FC are specific to BPD or rather a trans-diagnostic phenomenon, as alterations in DMN (regions) were also found in depersonalization disorder [78•] and D-PTSD [87•].