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Microstructural white matter alterations in borderline personality disorder: A minireview
Journal of Affective Disorders 264 (2020) 249–255
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Review article
Microstructural white matter alterations in borderline personality disorder: A minireview M. Grottarolia, G. Delvecchioa, C. Bressia,b, C. Moltrasiob, J.C. Soaresc, P. Brambillaa,b,
T
⁎
a
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy c Department of Psychiatry and Behavioural Sciences, UT Houston Medical School, Houston, TX, USA b
ARTICLE INFO
ABSTRACT
Keywords: Borderline personality disorder Diffusion tensor imaging White matter Connectivity
Background: Borderline personality disorder (BPD) affects 1–5% of the population and is characterized by a complex symptomatology and selective functional impairments. Although brain imaging studies have contributed to better characterizing the pathophysiological mechanisms underlying BPD, the white matter (WM) deficits associated with this disorder are still unclear. Therefore, the present review aims at providing an overview of the findings emerged from the available diffusion tensor imaging (DTI) studies on BPD. Methods: From a bibliographic research in PubMed until May 2019, we collected 12 studies that fulfilled our inclusion criteria, including a total sample of 291 BPD subjects and 293 healthy controls. Results: Overall, the DTI studies reviewed showed impairments in selective WM tracts that are part of the prefronto-limbic system, including frontal WM (short and long tracts), anterior cingulate cortex, corpus callosum, corona radiata, hippocampal fornix and thalamic radiation, in BPD patients compared to healthy controls. Limitations: Few DTI studies with heterogeneous findings. Conclusions: Overall these results reported that BPD is characterized by selective structural connectivity alterations in prefronto-limbic structures, further supporting the neurobiological model of BPD that suggests the presence of an abnormal modulation of frontal regions over limbic structures. Finally, the results also highlighted that the disrupted WM integrity in selective brain regions may also explain key-aspects of BPD symptomatology, including emotional dysregulation, ambivalence, contradictory behaviors and cognitive dysfunctions.
1. Background Borderline Personality Disorder (BPD) is a mental disorder, with a prevalence of 1–5% among the general population and 10-12% among psychiatric populations (Leichsenring et al., 2011; Ellinson et al., 2018). It is characterized by a pervasive pattern of persistent instability of emotions, mood and self-concept as well as by various maladaptive cognitive-affective processes, including mentalizing dysfunctions (Fonagy and Bateman, 2007) and abnormal emotion recognition abilities (Domes et al., 2009). Importantly, BPD patients often show symptoms of other psychiatric disorders, which may mask the underlying borderline psychopathology, thus possibly delaying its diagnosis and treatment. Therefore, due to the complexity of BPD, its etiology is not yet clearly understood, especially because the biological causes
underpinning the disorder have not yet been fully explored. Indeed, although a recent voxel-based meta-analysis consistently suggested that BPD is characterized by selective grey matter (GM) disruptions in brain regions that are part of two well-known brain networks, the frontolimbic network and the default mode network (Yang et al., 2016), evidence on how the regions within these systems interact are still far to be understood. Nonetheless, disruptions of these systems may ultimately explain the pathological emotional hyper-responsivity and the mood fluctuations (Rossi et al., 2015) as well as deficits in several cognitive processes, including self-referential thought (Winter et al., 2015; Gagnon et al., 2019) and the maintenance of a coherent sense of self (Wilkinson-Ryan and Westen, 2000; Janis et al., 2006; Qin et al., 2016), often observed in BPD patients. Therefore, the shift in focus from structural deficits within individual areas to connectivity with distributed regions is of paramount importance in order to increase our
⁎ Corresponding author. Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via F. Sforza 35, 20122 Milan, Italy. E-mail address: [email protected] (P. Brambilla).
https://doi.org/10.1016/j.jad.2019.12.033 Received 6 November 2019; Received in revised form 17 December 2019; Accepted 30 December 2019 Available online 31 December 2019 0165-0327/ © 2020 Elsevier B.V. All rights reserved.
Sample (age, mean ± S.D.)
BPD = 9 (34.1 ± 10.8) HC = 7 (32.8 ± 9.5)
BPD = 20 (28.0 ± 5.9) HC = 20 (27.2 ± 7.6)
BPD = 28 (25.5) HC = 25 (25.17)
BPD = 24 (14 adolescents; 10 adults; 32.0 ± 9.0) HC = 19 (28.6 ± 9.0)
BPD adolescents = 20 (16.7 ± 1.6) Patients with mixed psychiatric diagnoses (Clinical Control Group, CCG) = 20 (16.0 ± 1.3) HC = 20 (16.8 ± 1.2)
BPD = 26 (26.45 ± 7.04) HC = 26 (26.80 ± 6.58)
BPD = 20 (35.8 ± 8.61) HC = 18 (34.9 ± 9.
Study
Grant et al. (2007)
Rüsch et al. (2007)
Carrasco et al. (2012)
New et al. (2013)
Maier-Hein et al. (2014)
Lischke et al. (2015)
250
Whalley et al. (2015)
BPD = 17/3 HC = 14/4
BPD = 26/0 HC = 26/0
BPD adolescents = 20/0 CCG = 20/0 HC = 20/0
BPD = 5/19 HC = 6/12
BPD = 15/13 HC = 14/11
BPD = 20/0 HC = 20/0
BPD = 9/0 HC = 7/0
Gender F/M
12 with antipsychotic medications 15 with antidepressant medications
15 medication-free
9 BPD and 5 CCG were taking psychopharmacologic medication
All BPD adults free of medication 2 BPD adolescents free of medication
Free of medication
20 medication-free for at least 2 weeks prior to image acquisition
All of BPD were taking psychotropic medications
Psychotropic medications
Table. 1 Sociodemographic and clinical characteristic of patients in the original studies included.
3.0-tesla, 64 diffusion directions 3.0-tesla, 56 diffusion directions
3.0-tesla, 12 diffusion directions
3.0-tesla, 12 diffusion directions
1.5-tesla, not declared
3.0-tesla, 12 diffusion directions
1.5-tesla, 12 diffusion directions
MRI acquisition
TBSS- Whole brain approach ROI-based approach
ROI-based approach
TBSS- Whole brain approach ROI-based approach
TBSS- Whole brain approach
TBSS- Whole brain approach
ROI-based approach
ROI-based approach
Analysis method
(continued on next page)
- Decreased FA in inferior frontal WM in BPD with selfinjurious behavior compared to HC. -Posterior WM integrity correlated with perseverative and nonperseverative responses on the WCST. - Anterior WM integrity correlated with a component of verbal memory test performance. - No statistically significant differences between BPD and HC in terms of FA and MD in inferior frontal WM. - In BPD with comorbid major depression had reduced FA in left inferior frontal WM compared to BPD without a previous major depressive episode. - BPD with a current eating disorder had increased MD in inferior frontal WM compared to BPD without a current eating disorder - In BPD patients, increased MD in inferior frontal WM correlated with higher dysfunctional affect regulation, anger-hostility, dissociative symptoms and general psychopathology. - Decreased FA in the genu and rostral areas of CC and OFC WM in BPD compared to HC. - No significant correlations between WM tracts and sociodemographic and clinical measures. - No statistically significant differences in BPD adults compared to HC. - FA reduction in the ILF, UF and FOF in BPD adolescents compared to HC. - No significant correlations between WM tracts and clinical measures. - Lower FA in hippocampal fornix in BPD patients compared to CCG and HC. - Lower FA in superior FOF in BPD patients compared to CCG. - Increased RD in inferior FOF, internal capsule, SLF and superior FOF in BPD patients compared to CCG. - Increased AD in SLF in BPD patients compared to CCG. - Lower FA and higher RD in the UF in BPD compared to HC. - No significant correlations with clinical symptoms. - Decreased FA in the cingulum and hippocampal fornix in BPD compared to HC. - Negative correlation between FA in cingulum and clinical symptoms of anger. - Negative correlation between FA in hippocampal fornix and affective instability. - Positive correlation between FA in hippocampal fornix and symptoms of avoidance of abandonment.
Main DTI findings
M. Grottaroli, et al.
Journal of Affective Disorders 264 (2020) 249–255
BPD = 43 (31.55 ± 7.32) HC = 43 (32.40 ± 11.8)
BPD = 21 (26.21 ± 6.12) HC = 20 (26.81 ± 4.89)
Salvador et al. (2016)
Lischke et al. (2017)
BPD = 35 (23.3 ± 1.2) HC = 50 (25.8 ± 7.4)
BPD = 30 (22.10 ± 1.31) HC = 31 (22.38 ± 1.62)
Gan et al. (2016)
Ninomiya et al. (2018)
Sample (age, mean ± S.D.)
Study
Table. 1 (continued)
BPD = 11/24 HC = 17/33
BPD = 21/0 HC = 20/0
BPD = 43/0 HC = 43/0
BPD patients = 14/16 HC = 17/14
Gender F/M
35 medication-free
BPD taking typical antipsychotic medication were excluded
Patients were allowed to take pharmacologic treatment
30 medication-free
Psychotropic medications
251 3.0-tesla, 12 diffusion directions
3.0-tesla, 64 diffusion directions
1.5-tesla, 12 diffusion directions
3.0-tesla, diffusion directions
MRI acquisition
TBSS- Whole brain approach
ROI-based approach
TBSS- Whole brain approach
TBSS-Whole brain approach
Analysis method
(continued on next page)
- Lower FA in the genu and body of CC, corona radiata and hippocampal fornix in BPD compared to HC. - Higher RD in the left anterior thalamic radiation in BPD compared to HC. -Negative correlations between FA in the genu/ body of the CC and impulsivity. - Negative correlations between FA in hippocampal fornix and impulsivity and negative affect. - Negative correlation between RD in anterior thalamic radiation and attention impulsivity. - Positive correlation between FA in the fornix and positive intensity and motor Ellinson et al., 2018; Leichsenring et al., 2011 impulsivity. - Decreased FA in external capsule, genu and body of the CC, UF, corona radiata, and inferior FOF in BPD compared to HC. -Higher MD in anterior brain regions (lateral and orbitofrontal structures, insulae, precental and postcentral cortices, anterior part of temporal lobe and ACC) in BPD compared to HC. - In BPD, higher MD in anterior brain regions - although at trend level (p˂ 0.1) - were positively correlated with BPD clinical severity. -Lower FA in the splenium and lower FA and MD in the genu of CC in BPD compared to HC. - Number of suicide attempts correlated with FA and MD in splenium and with FA in the genu of CC - Suicidal BPD patient had lower FA and higher MD (trend level) in splenium compared to HC. - No differences in any DTI measures between non-suicidal BPD patients and HC. - Decreased AD in cingulum, ILF, and in inferior FOF in BPD compared to HC. Correlations in BPD - AD in cingulum correlated negatively with POMS scale (depression). - AD in inferior FOF correlated positively with DACS measures (future denial). Correlations in HC - AD in inferior FOF correlated negatively with CTQ measures (physical neglect). Correlations in the combined sample (HC +BPD) - AD in inferior FOF correlated negatively with CTQ measures (emotional abuse and physical neglect) - AD in cingulum and inferior FOF correlated negatively with STAI measures (trait anxiety and state anxiety [only for the inferior FOF]. - AD in cingulum correlated negatively with BDI and DACS (future denial, threat prediction, self-denial, past denial) scales. - AD in inferior FOF correlated positively with DACS scales (self-denial and interpersonal threat)
Main DTI findings
M. Grottaroli, et al.
Journal of Affective Disorders 264 (2020) 249–255
Journal of Affective Disorders 264 (2020) 249–255
ACC: Anterior Cingulate Cortex; AD: Axial Diffusivity; BPD: Borderline Personality Disorder; CC: Corpus Callosum; CCG: Clinical Control Group; CTQ: Childhood Trauma Questionnaire; DACS: Depression and Anxiety Cognition Scale; DTI: Diffusion Tensor Imaging; F: Female; FA: Fractional Anisotropy; FOF: Fronto-Occipital Fasciculus; HC: Healthy Control; ILF: Inferior Longitudinal Fasciculus; M: Male; MD: Mean Diffusivity; MRI: Magnetic Resonance Imaging; OFC: Orbitofrontal cortex; POMS: Profile of Mood State; RD: Radial Diffusivity; ROI: Region of Interest; S.D.: Standard Deviation; SLF: Superior Longitudinal Fasciculus; STAI: State-Trait Anxiety Inventory; TBSS: Tract-Based Spatial Statistics; UF: Uncinate Fasciculus; WCST: Wisconsin Card Sorting Test; WM: White Matter.
- Decreased FA in right hemisphere within the splenium of CC, SLF, inferior FOF, ILF, internal capsule, posterior corona radiata and posterior thalamic radiation in BPD compared to HC. -Higher RD in anterior and posterior brain areas (whole CC, posterior thalamic radiation, internal capsule, SLF, corona radiata, inferior FOF and ILF, bilaterally) in BPD compared to HC. - Positive association between higher RD in genu and body of the CC and anxiety dimension of the STAI scale. TBSS- Whole brain approach 1.5-tesla, 6 diffusion directions BPD = 15 (37.3 ± 8.9) HC = 14 (35.6 ± 7.2) Quattrini et al. (2019)
BPD = 7/8 HC = 4/10
12 BPD patients were taking psychopharmacologic medication
Analysis method Sample (age, mean ± S.D.) Study
Table. 1 (continued)
Gender F/M
Psychotropic medications
MRI acquisition
Main DTI findings
M. Grottaroli, et al.
understanding on the pathophysiology of mental illnesses, including BPD. Indeed, although a growing body of evidence supports the hypothesis that the altered neural connectivity between regions, rather than deficits within specific brain areas, may better characterize the clinical symptoms of psychiatric diseases (Konrad and Eickhoff, 2010; Fitzsimmons et al., 2013; Ueltzhöffer et al., 2019), little is still known about brain connectivity deficits in BPD patients. In this context, this review aimed at summarizing the evidence reported by the available diffusion tensor imaging (DTI) studies that quantitatively investigated the white matter (WM) integrity in BPD patients with the final goal of providing a clearer neurobiological model of this disorder. 2. Methods A systematic Medline research was performed using the key words “white matter”, “WM”, “myelin”, “myelination”, “connectivity”, “Diffusion Tensor Imaging”, “DTI”, “myelin”, “myelination” each individually combined with “borderline”, “borderline personality”, “borderline personality disorder”, “BPD”. Only DTI studies investigating WM dysfunctions in BPD patients, with or without pharmacological treatments, were included. Exclusion criteria were (a) a comorbid diagnosis of schizophrenia or bipolar disorder, (b) employment of Magnetic Resonance Imaging (MRI) methods other than DTI. A total of 12 studies matched our inclusion criteria, with a total sample of 291 BPD subjects and 293 healthy controls (HC). Please refer to Table 1 for the summary of the methods and results of all the studies included in this review. 3. Results The majority of the identified studies found significant WM deficits in selective brain regions, especially within prefrontal and callosal areas, as well as in specific WM tracts within the limbic system, including the corona radiata, hippocampal fornix, thalamus and cingulate cortex. Furthermore, regarding long-rage WM tracts, alterations in uncinate fasciculus (UF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF) and inferior fronto-occipital fasciculus (FOF), were observed. Interestingly, (Quattrini et al., 2019) also reported a “systemic” pattern of decreased fractional anisotropy (FA) in right posterior hemisphere and higher bilateral radial diffusivity (RD) in anterior and posterior brain areas in BPD patients compared to HC. In contrast, two DTI studies employing a sample of adolescents BPD (New et al., 2013; Maier-Hein et al., 2014) reported WM deficits in selective long-rage WM projections in BPD adolescents compared to either HC or to a clinical control group of subjects with different psychiatric diagnoses (only for Maier-Hein et al., 2014). With regards to frontal WM deficits, Grant et al. (2007) found WM microstructure deficits in inferior frontal regions whereas Carrasco et al. (2012) reported reduced FA in orbito-frontal cortex (OFC), in BPD patients, also with self-injurious behavior (Grant et al. (2007)), versus HC. Interestingly, Grant et al. (2007) also reported significant associations between WM integrity and cognition, with anterior and posterior WM integrity correlating with verbal memory and measures of executive functions respectively. Similarly, Salvador et al. (2016) showed higher mean diffusivity (MD) in anterior brain regions, from lateral OFC to insula bilaterally and up to the precentral and postcentral cortices, which were also correlated, as a trend level, with BPD clinical severity. Interestingly, Rüsch et al. (2007) found that BPD patients with comorbid ADHD, comorbid major depression or eating disorder had impaired inferior frontal WM integrity, which correlated with higher levels of dysfunctional affect regulation, anger-hostility, dissociative symptoms and general psychopathology (Rüsch et al., 2007). With regards to long-range frontal WM connections, two DTI studies showed reduced FA in UF, a major WM tract connecting (para-)limbic areas to prefrontal brain regions (New et al., 2013; Lischke et al., 2015) 252
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playing a key role in memory (Sato et al., 2012), language (Papagno, 2011) and social functioning (Coad et al., 2017), in BPD patients compared to HC. Similarly, Quattrini et al. (2019) also reported reduced FA and increased RD in selective long-rage WM projections, including SLF, inferior FOF, ILF and internal capsule, in BPD patients compared HC. Similarly, two DTI studies also found decreased FA (Salvador et al., 2016) and local axial diffusivity (AD) (Ninomiya et al., 2018) in overlapping regions, including inferior FOF (Salvador et al., 2016; Ninomiya et al., 2018) and ILF (Ninomiya et al., 2018; New et al., 2013), which was also found positively associated with future denial (Ninomiya et al., 2018), in BPD patients compared to HC. Notably, Maier-Hein et al. (2014) also reported decreased FA in superior FOF, increased RD in inferior FOF, SLF and superior FOF, and increased AD in SLF in BPD adolescents compared to both HC and a clinical control group. Furthermore, several studies observed WM deficits in CC in BPD patients. Specifically, Carrasco et al. (2012) reported that BPD patients showed decreased FA in the knee and anterior part of CC, while Salvador et al. (2016) found lower FA values in the genu, the body, as well as the rostral regions of the CC, compared to HC. In the study of Gan et al., (2016), the BPD group displayed lower FA values in the genu and body of the CC, which were also correlated with impulsivity. Similarly, two studies found altered FA (Lischke et al., 2017; Quattrini et al., 2019) and MD (Lischke et al., 2017) in the splenium, which was also found, together with the genu of CC (Lischke et al., 2017), to be functionally associated with suicidal behavior (Lischke et al., 2017). Interestingly, Quattrini et al. (2019) also reported a positive association between RD in genu and body of CC and anxiety levels. Finally, some DTI studies reported selective WM deficits in brain regions that are part of the limbic system. Specifically, decreased FA (Whalley et al., 2015), increased MD (Salvador et al., 2016) and lower AD (Ninomiya et al., 2018) were observed in the cingulate cortex in BPD patients compared to HC. Interestingly, some studies also reported significant correlations between cingulate cortex WM deficits and symptoms of depression (Ninomiya et al., 2018) or anger intensity (Whalley et al., 2015). Moreover, within the cortico-subcortical pathways, the corona radiata, a sheet of both ascending and descending sensory-motor fibers, was found to have significantly lower FA in BPD patients compared to HC (Salvador et al., 2016; Quattrini et al., 2019). Specifically, Salvador et al. (2016) reported decreased FA in the portion of external capsule, a WM sheath surrounding the basal nuclei and functionally implicated in limbic reward's mechanisms (Xu et al., 2012), whereas Quattrini et al. (2019) and Maier-Hein et al. (2014) found micro alterations in the internal capsule, in BPD patients compared to HC. Some DTI studies also found that BPD patients displayed significant lower FA and decreased WM integrity in hippocampal fornix (Whalley et al., 2015; Gan et al., 2016; Maier-Hein et al., 2014), which was also associated with motor impulsivity (Gan et al., 2016), affective instability and symptoms of avoidance and abandonment (Whalley et al., 2015). Finally, two DTI studies found that BPD patients had reduced FA (Quattrini et al., 2019) and higher RD (Gan et al., 2016) in the thalamic radiation, which is part of the so-called “thalamic filter”, the organ that allows the selection of relevant stimuli from innocuous stimuli, in a context-dependent manner (Schmahl et al., 2006), in BPD patients compared to HC.
long-rage WM tracts and cortico-subcortical pathways. Notably, one of the major and more replicated findings reported by the reviewed studies is the altered WM integrity in prefrontal regions and frontal long WM tracts. This is not surprising especially because prefrontal regions play a key role in cognitive control of behavior, impulsivity and emotion regulation, all domains found altered in BPD patients. Indeed, the prefrontal cortex exert an inhibitory control over the amygdala and other limbic structures, and the model of altered prefronto–limbic connectivity seems to provide an explanation of a neural pathway subtending impulsive-aggressive behaviors in BPD (Ruocco et al., 2013; Krause-Utz et al., 2014; Schulze et al., 2016). Moreover, besides this complex network, from the abovementioned studies emerged that BPD is characterized by connectivity deficits in other frontal long WM tracts, including FOF and ILF, which are important bidirectional connections between the occipital cortex and the temporal lobe that are involved in semantic processing (Martino et al., 2010) and in visually guided decisions and behaviors (Herbet et al., 2018), possibly influencing the ability to discriminate facial emotional expressions (Unger et al., 2016). Furthermore, WM disruptions in regions within the limbic system might explain the behavioral and emotional hyper-responsivity as well as cognitive deficits often observed in BPD patients (Pessoa, 2017). Indeed, connectivity deficits observed in the corona radiata, which is part of the limbic-thalamo-cortical circuitry where three long-range association fibre tracts (inferior FOF, UF, thalamic radiation) converge, has been found to be notoriously associated with the top-down emotion regulation systems (Jenkins et al., 2016; van Velzen et al., 2019). Similarly, the hippocampal fornix, a portion of hippocampal structure that carries WM fibers that connect the hippocampus to the upper and lower regions, has been found altered in BPD patients. This is not surprising especially because this structure is involved in emotion and memory processing (Douet and Chang, 2014). Therefore, since deficits in hippocampal fornix have been found to interfere with memory (Raslau et al., 2015), the high degree of self-criticism and the worse view of themselves often found in BPD patients might be associated with an altered hippocampal fornix transmission of self-referential memories, ultimately causing the predominance of negative memories that may be not adequately filtered by the thalamus (Fama and Sullivan, 2015). Furthermore, WM alterations in the cingulate cortex have also been found to characterize BPD patients. This structure has been reported to be involved in the reciprocal influence of cognition and affective state (Kennerley et al., 2006), encoding of the emotionally salient stimuli (Haas et al., 2006) and promoting selective attention (Stave et al., 2017) and goal-related behaviors (Heilbronner and Hayden, 2016), core areas of difficulty in BPD. Interestingly, two DTI studies also reported the presence of microstructural deficits in UF in BPD patients compared to HC. However, although the UF is a main tract of the prefronto-limbic pathway that connects amygdala to the prefrontal cortex, its role in BPD is still under examined. This is particularly surprising since structural alterations in this structure have been observed in several psychiatric disorders, including bipolar (Versace et al., 2008) and anxiety (Phan et al., 2009; Fani et al., 2012) disorders, which share similar clinical profiles with BPD. Importantly, overall the above-mentioned evidence points towards the hypothesis that BPD is a complex disorder whose symptomatology is associated with extensive WM microstructural deficits within WM structures and interconnecting WM tracts that are part, but also go beyond, the prefronto-limbic pathway. Indeed, the fibre tracts identified to be altered in BPD were observed in cortico-cortical (e.g., SLF, UF), cortico-thalamic and cortico-striatal bundles (e.g., internal and external capsule, corona radiata), all tracts that seem to be involved in emotional and behavioral regulation as well as in cognition (Catani and Thiebaut de Schotten, 2008). Furthermore, it is important to highlight that the engagement of WM tracts that are key connectors of frontal and limbic regions and consistently found involved in emotion regulation and memory (Catani and Thiebaut de Schotten, 2008), such as the UF,
4. Discussion In the present review, we provided an overview of the current findings on WM connectivity deficits in BPD with the final aim of identifying the putative neurobiological model of this disorder, which may ultimately support the choice of a treatment path. The abovementioned results showed that BPD had extensive connectivity deficits in cortical and subcortical regions, which are part of the so-called prefronto-limbic circuit (Lichter and Cummings, 2001), as well as in 253
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inferior FOF and ILF, suggest that these fibers might explain some of the core symptoms of BPD, including emotion sensitivity and dysregulation, by interfering with the correct communication/coupling between prefrontal cortex and amygdala. Finally, several studies also reported WM microstructural alterations within the CC in BPD. The CC is the major commissure integrating functional homologous regions of the two hemispheres that is involved in finalistic coordination of cognition, affect, behavior and impulse control. It contains hundreds of millions of fibers, which are anteriorly to posteriorly organized in the rostrum, the genu, the body and the splenium. Given that CC main function is to integrate and to transfer information from both cerebral hemispheres to process sensory, motor and high-level cognitive signals (Goldstein et al., 2019), this structure has been investigated in many psychiatric disorders, including bipolar (Bellani et al., 2009) and anxiety (Lu et al., 2018) disorders. Specifically for BPD, the microanatomical deficits in CC observed in this disorder may alter the interhemispheric transmission and biofeedback, ultimately interfering with the emergence of approach-related behaviors (Schutter and Harmon-Jones, 2013) and therefore underpinning some BPD symptoms, including incoherence of action and difficulty in maintaining stable relationships and work. Importantly, although FA is the most common reported measure in DTI investigations, the abovementioned studies also identified deficits in other DTI indices, including MD, RD and AD, which add further insight on the mechanisms underpinning WM alterations. Briefly, FA measures the anisotropy of water diffusion in a specific voxel, which is related to fibers directionality. MD quantifies the magnitude of water molecules diffusion, whereas AD and RD measure diffusivity along the principal axis or perpendicular to axonal fibers respectively (Squarcina et al., 2017), which seem to be related to axons myelin sheats integrity, providing key information on myelin degeneration (Song et al., 2002). Therefore, altogether the available DTI studies on BPD, although still limited, provide a comprehensive understanding of brain diffusion in this disorder, ultimately suggesting the key role of WM alterations in the pathogenesis of BPD. Nevertheless, overall, the results reported by the original studies reviewed are far from being conclusive, especially because they suffer from some limitations. First, the complex and heterogeneous nature of BPD may limit the generalizability of the findings. Second, many BPD patients have psychiatric comorbidities, such as depression and substance disorders, which may exacerbate their clinical phenotype and may explain the lack of consistency of the results. Third, many DTI studies included BPD patients receiving different psychotropic medications that, as a continuative treatment, could have biased the results. Therefore, future studies on drug-naïve patients are warranted. Finally, methodological differences (e.g., scanner and DTI acquisition parameters) may also have contributed to the heterogeneity of the findings. In conclusion, overall these results suggested that BPD is characterized by extensive structural connectivity alterations in selective WM tracts, including UF, interior FOF and ILF, that are mainly part of the prefronto-limbic pathway, further supporting the neurobiological model of BPD that suggests the presence of an abnormal modulation of prefrontal regions over the emotional limbic structures. Moreover, the associations between key BPD symptoms and WM disruptions, consistently observed in the original DTI studies, further support the need of identifying specific WM biomarkers for BPD that may allow clinicians to better understand the etiopathogenesis of emotional and behavioral dysregulations as well as of cognitive deficits characterizing BPD. However, larger and more homogenous samples are needed to further corroborate these DTI findings.
approved the final manuscript. Role of the funding source PB was partially supported by a grant from the Italian Ministry of Health(RF-2016-02364582) CRediT authorship contribution statement M. Grottaroli: Writing - original draft. G. Delvecchio: Writing review & editing, Supervision. C. Bressi: Writing - review & editing. C. Moltrasio: Writing - review & editing. J.C. Soares: Writing - review & editing. P. Brambilla: Writing - review & editing, Supervision. Declaration of Competing Interest None. Acknowledgements None. References Bellani, M., Yeh, P.H., Tansella, M., Balestrieri, M., Soares, J.C., Brambilla, P., 2009. DTI studies of corpus callosum in bipolar disorder. Biochem. Soc. Trans. 37 (Pt 5), 1096–1098. Carrasco, J.L., Tajima-Pozo, K., Díaz-Marsá, M., Casado, A., López-Ibor, J.J., Arrazola, J., Yus, M., 2012. Microstructural white matter damage at orbitofrontal areas in borderline personality disorder. J. Affect. Disord. 139 (2), 149–153. Catani, M., Thiebaut de Schotten, M., 2008. A diffusion tensor imaging tractography atlas for virtual in vivo dissections. Cortex 44 (8), 1105–1132. Coad, B.M., Postans, M., Hodgetts, C.J., Muhlert, N., Graham, K.S., Lawrence, A.D., 2017. Structural connections support emotional connections: uncinate fasciculus microstructure is related to the ability to decode facial emotion expressions. Neuropsychologia Nov 6. pii: S0028-3932(17)30420-7. Domes, G., Schulze, L., Herpertz, S.C., 2009. Emotion recognition in borderline personality disorder - a review of the literature. J. Pers. Disord. 23 (1), 6–19. Douet, V., Chang, L., 2014. Fornix as an imaging marker for episodic memory deficits in healthy aging and in various neurological disorders. Front. Aging Neurosci. 6, 343. Ellinson, W.D., Rosenstein, L.K., Morgan, T.A., Zimmerman, M., 2018. Community and clinical epidemiology of borderline personality disorder. Psychiatr. Clin. North Am. 41 (4), 561–573. Fama, R., Sullivan, E.V., 2015. Thalamic structures and associated cognitive functions: relations with age and aging. Neurosci. Biobehav. Rev. 54, 29–37. Fani, N., King, T.Z., Jovanovic, T., Glover, E.M., Bradley, B., Choi, K., Ely, T., Gutman, D.A., Ressler, K.J., 2012. White matter integrity in highly traumatized adults with and without post-traumatic stress disorder. Neuropsychopharmacology 37, 2740–2746. Fitzsimmons, J., Kubicki, M., Shenton, M.E., 2013. Review of functional and anatomical brain connectivity findings in schizophrenia. Curr. Opin. Psychiatry 26 (2), 172–187. Fonagy, P., Bateman, A.W., 2007. Mentalizing and borderline personality disorder. J. Men. Health. 16 (1), 83–101. Gagnon, J., Aldebert, J., Saleh, G., Kim, W.S., 2019. The modulating role of self-referential stimuli and processes in the effect of stress and negative emotion on inhibition processes in borderline personality disorder: proposition of a model to integrate the self-concept and inhibition processes. Brain Sci. 9 (4) Mar 30. Gan, J., Yi, J., Zhong, M., Cao, X., Jin, X., Liu, W., Zhu, X., 2016. Abnormal white matter structural connectivity in treatment-naıve young adults with borderline personality disorder. Acta. Psychiatr. Scand. 134 (6), 494–503 Dec. Goldstein, A., Covington, B.P., Mesfin, F.B., 2019. Neuroanatomy. Corpus Callosum. StatPearls Publishing. Grant, J.E., Correia, S., Brennan-Krohn, T., Malloy, P.F., Laidlaw, D.H., Schulz, S.C., 2007. Frontal white matter integrity in borderline personality disorder with self-injurious behavior. J Neuropsychiatry Clin. Neurosci. 19 (4), 383–390. Haas, B.W., Omura, K., Constable, R.T., Canli, T., 2006. Interference produced by emotional conflict associated with anterior cingulate activation. Cogn. Affect. Behav. Neurosci. 2, 152–156 6. Heilbronner, S.R., Hayden, B.Y., 2016. Dorsal anterior cingulate cortex: a bottom-up view. Annu. Rev. Neurosci. 39, 149–170 Jul 8. Herbet, G., Zemmoura, I., Duffau, H., 2018. Functional anatomy of the inferior longitudinal fasciculus: from historical reports to current hypotheses. Front. Neuroanat. 12, 77. Janis, I.B., Veague, H.B., Driver-Linn, E., 2006. Possible selves and borderline personality disorder. J. Clin. Psychol. 62 (3), 387–394 Mar. Jenkins, L.M., Barba, A., Campbell, M., Lamar, M., Shankman, S.A., Leow, A.D., Ajilore, O., Langenecke, S.A., 2016. Shared white matter alterations across emotional disorders: a voxel-based meta-analysis of fractional anisotropy. NeuroImage 12,
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Review article
Microstructural white matter alterations in borderline personality disorder: A minireview M. Grottarolia, G. Delvecchioa, C. Bressia,b, C. Moltrasiob, J.C. Soaresc, P. Brambillaa,b,
T
⁎
a
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy c Department of Psychiatry and Behavioural Sciences, UT Houston Medical School, Houston, TX, USA b
ARTICLE INFO
ABSTRACT
Keywords: Borderline personality disorder Diffusion tensor imaging White matter Connectivity
Background: Borderline personality disorder (BPD) affects 1–5% of the population and is characterized by a complex symptomatology and selective functional impairments. Although brain imaging studies have contributed to better characterizing the pathophysiological mechanisms underlying BPD, the white matter (WM) deficits associated with this disorder are still unclear. Therefore, the present review aims at providing an overview of the findings emerged from the available diffusion tensor imaging (DTI) studies on BPD. Methods: From a bibliographic research in PubMed until May 2019, we collected 12 studies that fulfilled our inclusion criteria, including a total sample of 291 BPD subjects and 293 healthy controls. Results: Overall, the DTI studies reviewed showed impairments in selective WM tracts that are part of the prefronto-limbic system, including frontal WM (short and long tracts), anterior cingulate cortex, corpus callosum, corona radiata, hippocampal fornix and thalamic radiation, in BPD patients compared to healthy controls. Limitations: Few DTI studies with heterogeneous findings. Conclusions: Overall these results reported that BPD is characterized by selective structural connectivity alterations in prefronto-limbic structures, further supporting the neurobiological model of BPD that suggests the presence of an abnormal modulation of frontal regions over limbic structures. Finally, the results also highlighted that the disrupted WM integrity in selective brain regions may also explain key-aspects of BPD symptomatology, including emotional dysregulation, ambivalence, contradictory behaviors and cognitive dysfunctions.
1. Background Borderline Personality Disorder (BPD) is a mental disorder, with a prevalence of 1–5% among the general population and 10-12% among psychiatric populations (Leichsenring et al., 2011; Ellinson et al., 2018). It is characterized by a pervasive pattern of persistent instability of emotions, mood and self-concept as well as by various maladaptive cognitive-affective processes, including mentalizing dysfunctions (Fonagy and Bateman, 2007) and abnormal emotion recognition abilities (Domes et al., 2009). Importantly, BPD patients often show symptoms of other psychiatric disorders, which may mask the underlying borderline psychopathology, thus possibly delaying its diagnosis and treatment. Therefore, due to the complexity of BPD, its etiology is not yet clearly understood, especially because the biological causes
underpinning the disorder have not yet been fully explored. Indeed, although a recent voxel-based meta-analysis consistently suggested that BPD is characterized by selective grey matter (GM) disruptions in brain regions that are part of two well-known brain networks, the frontolimbic network and the default mode network (Yang et al., 2016), evidence on how the regions within these systems interact are still far to be understood. Nonetheless, disruptions of these systems may ultimately explain the pathological emotional hyper-responsivity and the mood fluctuations (Rossi et al., 2015) as well as deficits in several cognitive processes, including self-referential thought (Winter et al., 2015; Gagnon et al., 2019) and the maintenance of a coherent sense of self (Wilkinson-Ryan and Westen, 2000; Janis et al., 2006; Qin et al., 2016), often observed in BPD patients. Therefore, the shift in focus from structural deficits within individual areas to connectivity with distributed regions is of paramount importance in order to increase our
⁎ Corresponding author. Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via F. Sforza 35, 20122 Milan, Italy. E-mail address: [email protected] (P. Brambilla).
https://doi.org/10.1016/j.jad.2019.12.033 Received 6 November 2019; Received in revised form 17 December 2019; Accepted 30 December 2019 Available online 31 December 2019 0165-0327/ © 2020 Elsevier B.V. All rights reserved.
Sample (age, mean ± S.D.)
BPD = 9 (34.1 ± 10.8) HC = 7 (32.8 ± 9.5)
BPD = 20 (28.0 ± 5.9) HC = 20 (27.2 ± 7.6)
BPD = 28 (25.5) HC = 25 (25.17)
BPD = 24 (14 adolescents; 10 adults; 32.0 ± 9.0) HC = 19 (28.6 ± 9.0)
BPD adolescents = 20 (16.7 ± 1.6) Patients with mixed psychiatric diagnoses (Clinical Control Group, CCG) = 20 (16.0 ± 1.3) HC = 20 (16.8 ± 1.2)
BPD = 26 (26.45 ± 7.04) HC = 26 (26.80 ± 6.58)
BPD = 20 (35.8 ± 8.61) HC = 18 (34.9 ± 9.
Study
Grant et al. (2007)
Rüsch et al. (2007)
Carrasco et al. (2012)
New et al. (2013)
Maier-Hein et al. (2014)
Lischke et al. (2015)
250
Whalley et al. (2015)
BPD = 17/3 HC = 14/4
BPD = 26/0 HC = 26/0
BPD adolescents = 20/0 CCG = 20/0 HC = 20/0
BPD = 5/19 HC = 6/12
BPD = 15/13 HC = 14/11
BPD = 20/0 HC = 20/0
BPD = 9/0 HC = 7/0
Gender F/M
12 with antipsychotic medications 15 with antidepressant medications
15 medication-free
9 BPD and 5 CCG were taking psychopharmacologic medication
All BPD adults free of medication 2 BPD adolescents free of medication
Free of medication
20 medication-free for at least 2 weeks prior to image acquisition
All of BPD were taking psychotropic medications
Psychotropic medications
Table. 1 Sociodemographic and clinical characteristic of patients in the original studies included.
3.0-tesla, 64 diffusion directions 3.0-tesla, 56 diffusion directions
3.0-tesla, 12 diffusion directions
3.0-tesla, 12 diffusion directions
1.5-tesla, not declared
3.0-tesla, 12 diffusion directions
1.5-tesla, 12 diffusion directions
MRI acquisition
TBSS- Whole brain approach ROI-based approach
ROI-based approach
TBSS- Whole brain approach ROI-based approach
TBSS- Whole brain approach
TBSS- Whole brain approach
ROI-based approach
ROI-based approach
Analysis method
(continued on next page)
- Decreased FA in inferior frontal WM in BPD with selfinjurious behavior compared to HC. -Posterior WM integrity correlated with perseverative and nonperseverative responses on the WCST. - Anterior WM integrity correlated with a component of verbal memory test performance. - No statistically significant differences between BPD and HC in terms of FA and MD in inferior frontal WM. - In BPD with comorbid major depression had reduced FA in left inferior frontal WM compared to BPD without a previous major depressive episode. - BPD with a current eating disorder had increased MD in inferior frontal WM compared to BPD without a current eating disorder - In BPD patients, increased MD in inferior frontal WM correlated with higher dysfunctional affect regulation, anger-hostility, dissociative symptoms and general psychopathology. - Decreased FA in the genu and rostral areas of CC and OFC WM in BPD compared to HC. - No significant correlations between WM tracts and sociodemographic and clinical measures. - No statistically significant differences in BPD adults compared to HC. - FA reduction in the ILF, UF and FOF in BPD adolescents compared to HC. - No significant correlations between WM tracts and clinical measures. - Lower FA in hippocampal fornix in BPD patients compared to CCG and HC. - Lower FA in superior FOF in BPD patients compared to CCG. - Increased RD in inferior FOF, internal capsule, SLF and superior FOF in BPD patients compared to CCG. - Increased AD in SLF in BPD patients compared to CCG. - Lower FA and higher RD in the UF in BPD compared to HC. - No significant correlations with clinical symptoms. - Decreased FA in the cingulum and hippocampal fornix in BPD compared to HC. - Negative correlation between FA in cingulum and clinical symptoms of anger. - Negative correlation between FA in hippocampal fornix and affective instability. - Positive correlation between FA in hippocampal fornix and symptoms of avoidance of abandonment.
Main DTI findings
M. Grottaroli, et al.
Journal of Affective Disorders 264 (2020) 249–255
BPD = 43 (31.55 ± 7.32) HC = 43 (32.40 ± 11.8)
BPD = 21 (26.21 ± 6.12) HC = 20 (26.81 ± 4.89)
Salvador et al. (2016)
Lischke et al. (2017)
BPD = 35 (23.3 ± 1.2) HC = 50 (25.8 ± 7.4)
BPD = 30 (22.10 ± 1.31) HC = 31 (22.38 ± 1.62)
Gan et al. (2016)
Ninomiya et al. (2018)
Sample (age, mean ± S.D.)
Study
Table. 1 (continued)
BPD = 11/24 HC = 17/33
BPD = 21/0 HC = 20/0
BPD = 43/0 HC = 43/0
BPD patients = 14/16 HC = 17/14
Gender F/M
35 medication-free
BPD taking typical antipsychotic medication were excluded
Patients were allowed to take pharmacologic treatment
30 medication-free
Psychotropic medications
251 3.0-tesla, 12 diffusion directions
3.0-tesla, 64 diffusion directions
1.5-tesla, 12 diffusion directions
3.0-tesla, diffusion directions
MRI acquisition
TBSS- Whole brain approach
ROI-based approach
TBSS- Whole brain approach
TBSS-Whole brain approach
Analysis method
(continued on next page)
- Lower FA in the genu and body of CC, corona radiata and hippocampal fornix in BPD compared to HC. - Higher RD in the left anterior thalamic radiation in BPD compared to HC. -Negative correlations between FA in the genu/ body of the CC and impulsivity. - Negative correlations between FA in hippocampal fornix and impulsivity and negative affect. - Negative correlation between RD in anterior thalamic radiation and attention impulsivity. - Positive correlation between FA in the fornix and positive intensity and motor Ellinson et al., 2018; Leichsenring et al., 2011 impulsivity. - Decreased FA in external capsule, genu and body of the CC, UF, corona radiata, and inferior FOF in BPD compared to HC. -Higher MD in anterior brain regions (lateral and orbitofrontal structures, insulae, precental and postcentral cortices, anterior part of temporal lobe and ACC) in BPD compared to HC. - In BPD, higher MD in anterior brain regions - although at trend level (p˂ 0.1) - were positively correlated with BPD clinical severity. -Lower FA in the splenium and lower FA and MD in the genu of CC in BPD compared to HC. - Number of suicide attempts correlated with FA and MD in splenium and with FA in the genu of CC - Suicidal BPD patient had lower FA and higher MD (trend level) in splenium compared to HC. - No differences in any DTI measures between non-suicidal BPD patients and HC. - Decreased AD in cingulum, ILF, and in inferior FOF in BPD compared to HC. Correlations in BPD - AD in cingulum correlated negatively with POMS scale (depression). - AD in inferior FOF correlated positively with DACS measures (future denial). Correlations in HC - AD in inferior FOF correlated negatively with CTQ measures (physical neglect). Correlations in the combined sample (HC +BPD) - AD in inferior FOF correlated negatively with CTQ measures (emotional abuse and physical neglect) - AD in cingulum and inferior FOF correlated negatively with STAI measures (trait anxiety and state anxiety [only for the inferior FOF]. - AD in cingulum correlated negatively with BDI and DACS (future denial, threat prediction, self-denial, past denial) scales. - AD in inferior FOF correlated positively with DACS scales (self-denial and interpersonal threat)
Main DTI findings
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ACC: Anterior Cingulate Cortex; AD: Axial Diffusivity; BPD: Borderline Personality Disorder; CC: Corpus Callosum; CCG: Clinical Control Group; CTQ: Childhood Trauma Questionnaire; DACS: Depression and Anxiety Cognition Scale; DTI: Diffusion Tensor Imaging; F: Female; FA: Fractional Anisotropy; FOF: Fronto-Occipital Fasciculus; HC: Healthy Control; ILF: Inferior Longitudinal Fasciculus; M: Male; MD: Mean Diffusivity; MRI: Magnetic Resonance Imaging; OFC: Orbitofrontal cortex; POMS: Profile of Mood State; RD: Radial Diffusivity; ROI: Region of Interest; S.D.: Standard Deviation; SLF: Superior Longitudinal Fasciculus; STAI: State-Trait Anxiety Inventory; TBSS: Tract-Based Spatial Statistics; UF: Uncinate Fasciculus; WCST: Wisconsin Card Sorting Test; WM: White Matter.
- Decreased FA in right hemisphere within the splenium of CC, SLF, inferior FOF, ILF, internal capsule, posterior corona radiata and posterior thalamic radiation in BPD compared to HC. -Higher RD in anterior and posterior brain areas (whole CC, posterior thalamic radiation, internal capsule, SLF, corona radiata, inferior FOF and ILF, bilaterally) in BPD compared to HC. - Positive association between higher RD in genu and body of the CC and anxiety dimension of the STAI scale. TBSS- Whole brain approach 1.5-tesla, 6 diffusion directions BPD = 15 (37.3 ± 8.9) HC = 14 (35.6 ± 7.2) Quattrini et al. (2019)
BPD = 7/8 HC = 4/10
12 BPD patients were taking psychopharmacologic medication
Analysis method Sample (age, mean ± S.D.) Study
Table. 1 (continued)
Gender F/M
Psychotropic medications
MRI acquisition
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understanding on the pathophysiology of mental illnesses, including BPD. Indeed, although a growing body of evidence supports the hypothesis that the altered neural connectivity between regions, rather than deficits within specific brain areas, may better characterize the clinical symptoms of psychiatric diseases (Konrad and Eickhoff, 2010; Fitzsimmons et al., 2013; Ueltzhöffer et al., 2019), little is still known about brain connectivity deficits in BPD patients. In this context, this review aimed at summarizing the evidence reported by the available diffusion tensor imaging (DTI) studies that quantitatively investigated the white matter (WM) integrity in BPD patients with the final goal of providing a clearer neurobiological model of this disorder. 2. Methods A systematic Medline research was performed using the key words “white matter”, “WM”, “myelin”, “myelination”, “connectivity”, “Diffusion Tensor Imaging”, “DTI”, “myelin”, “myelination” each individually combined with “borderline”, “borderline personality”, “borderline personality disorder”, “BPD”. Only DTI studies investigating WM dysfunctions in BPD patients, with or without pharmacological treatments, were included. Exclusion criteria were (a) a comorbid diagnosis of schizophrenia or bipolar disorder, (b) employment of Magnetic Resonance Imaging (MRI) methods other than DTI. A total of 12 studies matched our inclusion criteria, with a total sample of 291 BPD subjects and 293 healthy controls (HC). Please refer to Table 1 for the summary of the methods and results of all the studies included in this review. 3. Results The majority of the identified studies found significant WM deficits in selective brain regions, especially within prefrontal and callosal areas, as well as in specific WM tracts within the limbic system, including the corona radiata, hippocampal fornix, thalamus and cingulate cortex. Furthermore, regarding long-rage WM tracts, alterations in uncinate fasciculus (UF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF) and inferior fronto-occipital fasciculus (FOF), were observed. Interestingly, (Quattrini et al., 2019) also reported a “systemic” pattern of decreased fractional anisotropy (FA) in right posterior hemisphere and higher bilateral radial diffusivity (RD) in anterior and posterior brain areas in BPD patients compared to HC. In contrast, two DTI studies employing a sample of adolescents BPD (New et al., 2013; Maier-Hein et al., 2014) reported WM deficits in selective long-rage WM projections in BPD adolescents compared to either HC or to a clinical control group of subjects with different psychiatric diagnoses (only for Maier-Hein et al., 2014). With regards to frontal WM deficits, Grant et al. (2007) found WM microstructure deficits in inferior frontal regions whereas Carrasco et al. (2012) reported reduced FA in orbito-frontal cortex (OFC), in BPD patients, also with self-injurious behavior (Grant et al. (2007)), versus HC. Interestingly, Grant et al. (2007) also reported significant associations between WM integrity and cognition, with anterior and posterior WM integrity correlating with verbal memory and measures of executive functions respectively. Similarly, Salvador et al. (2016) showed higher mean diffusivity (MD) in anterior brain regions, from lateral OFC to insula bilaterally and up to the precentral and postcentral cortices, which were also correlated, as a trend level, with BPD clinical severity. Interestingly, Rüsch et al. (2007) found that BPD patients with comorbid ADHD, comorbid major depression or eating disorder had impaired inferior frontal WM integrity, which correlated with higher levels of dysfunctional affect regulation, anger-hostility, dissociative symptoms and general psychopathology (Rüsch et al., 2007). With regards to long-range frontal WM connections, two DTI studies showed reduced FA in UF, a major WM tract connecting (para-)limbic areas to prefrontal brain regions (New et al., 2013; Lischke et al., 2015) 252
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playing a key role in memory (Sato et al., 2012), language (Papagno, 2011) and social functioning (Coad et al., 2017), in BPD patients compared to HC. Similarly, Quattrini et al. (2019) also reported reduced FA and increased RD in selective long-rage WM projections, including SLF, inferior FOF, ILF and internal capsule, in BPD patients compared HC. Similarly, two DTI studies also found decreased FA (Salvador et al., 2016) and local axial diffusivity (AD) (Ninomiya et al., 2018) in overlapping regions, including inferior FOF (Salvador et al., 2016; Ninomiya et al., 2018) and ILF (Ninomiya et al., 2018; New et al., 2013), which was also found positively associated with future denial (Ninomiya et al., 2018), in BPD patients compared to HC. Notably, Maier-Hein et al. (2014) also reported decreased FA in superior FOF, increased RD in inferior FOF, SLF and superior FOF, and increased AD in SLF in BPD adolescents compared to both HC and a clinical control group. Furthermore, several studies observed WM deficits in CC in BPD patients. Specifically, Carrasco et al. (2012) reported that BPD patients showed decreased FA in the knee and anterior part of CC, while Salvador et al. (2016) found lower FA values in the genu, the body, as well as the rostral regions of the CC, compared to HC. In the study of Gan et al., (2016), the BPD group displayed lower FA values in the genu and body of the CC, which were also correlated with impulsivity. Similarly, two studies found altered FA (Lischke et al., 2017; Quattrini et al., 2019) and MD (Lischke et al., 2017) in the splenium, which was also found, together with the genu of CC (Lischke et al., 2017), to be functionally associated with suicidal behavior (Lischke et al., 2017). Interestingly, Quattrini et al. (2019) also reported a positive association between RD in genu and body of CC and anxiety levels. Finally, some DTI studies reported selective WM deficits in brain regions that are part of the limbic system. Specifically, decreased FA (Whalley et al., 2015), increased MD (Salvador et al., 2016) and lower AD (Ninomiya et al., 2018) were observed in the cingulate cortex in BPD patients compared to HC. Interestingly, some studies also reported significant correlations between cingulate cortex WM deficits and symptoms of depression (Ninomiya et al., 2018) or anger intensity (Whalley et al., 2015). Moreover, within the cortico-subcortical pathways, the corona radiata, a sheet of both ascending and descending sensory-motor fibers, was found to have significantly lower FA in BPD patients compared to HC (Salvador et al., 2016; Quattrini et al., 2019). Specifically, Salvador et al. (2016) reported decreased FA in the portion of external capsule, a WM sheath surrounding the basal nuclei and functionally implicated in limbic reward's mechanisms (Xu et al., 2012), whereas Quattrini et al. (2019) and Maier-Hein et al. (2014) found micro alterations in the internal capsule, in BPD patients compared to HC. Some DTI studies also found that BPD patients displayed significant lower FA and decreased WM integrity in hippocampal fornix (Whalley et al., 2015; Gan et al., 2016; Maier-Hein et al., 2014), which was also associated with motor impulsivity (Gan et al., 2016), affective instability and symptoms of avoidance and abandonment (Whalley et al., 2015). Finally, two DTI studies found that BPD patients had reduced FA (Quattrini et al., 2019) and higher RD (Gan et al., 2016) in the thalamic radiation, which is part of the so-called “thalamic filter”, the organ that allows the selection of relevant stimuli from innocuous stimuli, in a context-dependent manner (Schmahl et al., 2006), in BPD patients compared to HC.
long-rage WM tracts and cortico-subcortical pathways. Notably, one of the major and more replicated findings reported by the reviewed studies is the altered WM integrity in prefrontal regions and frontal long WM tracts. This is not surprising especially because prefrontal regions play a key role in cognitive control of behavior, impulsivity and emotion regulation, all domains found altered in BPD patients. Indeed, the prefrontal cortex exert an inhibitory control over the amygdala and other limbic structures, and the model of altered prefronto–limbic connectivity seems to provide an explanation of a neural pathway subtending impulsive-aggressive behaviors in BPD (Ruocco et al., 2013; Krause-Utz et al., 2014; Schulze et al., 2016). Moreover, besides this complex network, from the abovementioned studies emerged that BPD is characterized by connectivity deficits in other frontal long WM tracts, including FOF and ILF, which are important bidirectional connections between the occipital cortex and the temporal lobe that are involved in semantic processing (Martino et al., 2010) and in visually guided decisions and behaviors (Herbet et al., 2018), possibly influencing the ability to discriminate facial emotional expressions (Unger et al., 2016). Furthermore, WM disruptions in regions within the limbic system might explain the behavioral and emotional hyper-responsivity as well as cognitive deficits often observed in BPD patients (Pessoa, 2017). Indeed, connectivity deficits observed in the corona radiata, which is part of the limbic-thalamo-cortical circuitry where three long-range association fibre tracts (inferior FOF, UF, thalamic radiation) converge, has been found to be notoriously associated with the top-down emotion regulation systems (Jenkins et al., 2016; van Velzen et al., 2019). Similarly, the hippocampal fornix, a portion of hippocampal structure that carries WM fibers that connect the hippocampus to the upper and lower regions, has been found altered in BPD patients. This is not surprising especially because this structure is involved in emotion and memory processing (Douet and Chang, 2014). Therefore, since deficits in hippocampal fornix have been found to interfere with memory (Raslau et al., 2015), the high degree of self-criticism and the worse view of themselves often found in BPD patients might be associated with an altered hippocampal fornix transmission of self-referential memories, ultimately causing the predominance of negative memories that may be not adequately filtered by the thalamus (Fama and Sullivan, 2015). Furthermore, WM alterations in the cingulate cortex have also been found to characterize BPD patients. This structure has been reported to be involved in the reciprocal influence of cognition and affective state (Kennerley et al., 2006), encoding of the emotionally salient stimuli (Haas et al., 2006) and promoting selective attention (Stave et al., 2017) and goal-related behaviors (Heilbronner and Hayden, 2016), core areas of difficulty in BPD. Interestingly, two DTI studies also reported the presence of microstructural deficits in UF in BPD patients compared to HC. However, although the UF is a main tract of the prefronto-limbic pathway that connects amygdala to the prefrontal cortex, its role in BPD is still under examined. This is particularly surprising since structural alterations in this structure have been observed in several psychiatric disorders, including bipolar (Versace et al., 2008) and anxiety (Phan et al., 2009; Fani et al., 2012) disorders, which share similar clinical profiles with BPD. Importantly, overall the above-mentioned evidence points towards the hypothesis that BPD is a complex disorder whose symptomatology is associated with extensive WM microstructural deficits within WM structures and interconnecting WM tracts that are part, but also go beyond, the prefronto-limbic pathway. Indeed, the fibre tracts identified to be altered in BPD were observed in cortico-cortical (e.g., SLF, UF), cortico-thalamic and cortico-striatal bundles (e.g., internal and external capsule, corona radiata), all tracts that seem to be involved in emotional and behavioral regulation as well as in cognition (Catani and Thiebaut de Schotten, 2008). Furthermore, it is important to highlight that the engagement of WM tracts that are key connectors of frontal and limbic regions and consistently found involved in emotion regulation and memory (Catani and Thiebaut de Schotten, 2008), such as the UF,
4. Discussion In the present review, we provided an overview of the current findings on WM connectivity deficits in BPD with the final aim of identifying the putative neurobiological model of this disorder, which may ultimately support the choice of a treatment path. The abovementioned results showed that BPD had extensive connectivity deficits in cortical and subcortical regions, which are part of the so-called prefronto-limbic circuit (Lichter and Cummings, 2001), as well as in 253
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inferior FOF and ILF, suggest that these fibers might explain some of the core symptoms of BPD, including emotion sensitivity and dysregulation, by interfering with the correct communication/coupling between prefrontal cortex and amygdala. Finally, several studies also reported WM microstructural alterations within the CC in BPD. The CC is the major commissure integrating functional homologous regions of the two hemispheres that is involved in finalistic coordination of cognition, affect, behavior and impulse control. It contains hundreds of millions of fibers, which are anteriorly to posteriorly organized in the rostrum, the genu, the body and the splenium. Given that CC main function is to integrate and to transfer information from both cerebral hemispheres to process sensory, motor and high-level cognitive signals (Goldstein et al., 2019), this structure has been investigated in many psychiatric disorders, including bipolar (Bellani et al., 2009) and anxiety (Lu et al., 2018) disorders. Specifically for BPD, the microanatomical deficits in CC observed in this disorder may alter the interhemispheric transmission and biofeedback, ultimately interfering with the emergence of approach-related behaviors (Schutter and Harmon-Jones, 2013) and therefore underpinning some BPD symptoms, including incoherence of action and difficulty in maintaining stable relationships and work. Importantly, although FA is the most common reported measure in DTI investigations, the abovementioned studies also identified deficits in other DTI indices, including MD, RD and AD, which add further insight on the mechanisms underpinning WM alterations. Briefly, FA measures the anisotropy of water diffusion in a specific voxel, which is related to fibers directionality. MD quantifies the magnitude of water molecules diffusion, whereas AD and RD measure diffusivity along the principal axis or perpendicular to axonal fibers respectively (Squarcina et al., 2017), which seem to be related to axons myelin sheats integrity, providing key information on myelin degeneration (Song et al., 2002). Therefore, altogether the available DTI studies on BPD, although still limited, provide a comprehensive understanding of brain diffusion in this disorder, ultimately suggesting the key role of WM alterations in the pathogenesis of BPD. Nevertheless, overall, the results reported by the original studies reviewed are far from being conclusive, especially because they suffer from some limitations. First, the complex and heterogeneous nature of BPD may limit the generalizability of the findings. Second, many BPD patients have psychiatric comorbidities, such as depression and substance disorders, which may exacerbate their clinical phenotype and may explain the lack of consistency of the results. Third, many DTI studies included BPD patients receiving different psychotropic medications that, as a continuative treatment, could have biased the results. Therefore, future studies on drug-naïve patients are warranted. Finally, methodological differences (e.g., scanner and DTI acquisition parameters) may also have contributed to the heterogeneity of the findings. In conclusion, overall these results suggested that BPD is characterized by extensive structural connectivity alterations in selective WM tracts, including UF, interior FOF and ILF, that are mainly part of the prefronto-limbic pathway, further supporting the neurobiological model of BPD that suggests the presence of an abnormal modulation of prefrontal regions over the emotional limbic structures. Moreover, the associations between key BPD symptoms and WM disruptions, consistently observed in the original DTI studies, further support the need of identifying specific WM biomarkers for BPD that may allow clinicians to better understand the etiopathogenesis of emotional and behavioral dysregulations as well as of cognitive deficits characterizing BPD. However, larger and more homogenous samples are needed to further corroborate these DTI findings.
approved the final manuscript. Role of the funding source PB was partially supported by a grant from the Italian Ministry of Health(RF-2016-02364582) CRediT authorship contribution statement M. Grottaroli: Writing - original draft. G. Delvecchio: Writing review & editing, Supervision. C. Bressi: Writing - review & editing. C. Moltrasio: Writing - review & editing. J.C. Soares: Writing - review & editing. P. Brambilla: Writing - review & editing, Supervision. Declaration of Competing Interest None. Acknowledgements None. References Bellani, M., Yeh, P.H., Tansella, M., Balestrieri, M., Soares, J.C., Brambilla, P., 2009. DTI studies of corpus callosum in bipolar disorder. Biochem. Soc. Trans. 37 (Pt 5), 1096–1098. Carrasco, J.L., Tajima-Pozo, K., Díaz-Marsá, M., Casado, A., López-Ibor, J.J., Arrazola, J., Yus, M., 2012. Microstructural white matter damage at orbitofrontal areas in borderline personality disorder. J. Affect. Disord. 139 (2), 149–153. Catani, M., Thiebaut de Schotten, M., 2008. A diffusion tensor imaging tractography atlas for virtual in vivo dissections. Cortex 44 (8), 1105–1132. Coad, B.M., Postans, M., Hodgetts, C.J., Muhlert, N., Graham, K.S., Lawrence, A.D., 2017. Structural connections support emotional connections: uncinate fasciculus microstructure is related to the ability to decode facial emotion expressions. Neuropsychologia Nov 6. pii: S0028-3932(17)30420-7. Domes, G., Schulze, L., Herpertz, S.C., 2009. Emotion recognition in borderline personality disorder - a review of the literature. J. Pers. Disord. 23 (1), 6–19. Douet, V., Chang, L., 2014. Fornix as an imaging marker for episodic memory deficits in healthy aging and in various neurological disorders. Front. Aging Neurosci. 6, 343. Ellinson, W.D., Rosenstein, L.K., Morgan, T.A., Zimmerman, M., 2018. Community and clinical epidemiology of borderline personality disorder. Psychiatr. Clin. North Am. 41 (4), 561–573. Fama, R., Sullivan, E.V., 2015. Thalamic structures and associated cognitive functions: relations with age and aging. Neurosci. Biobehav. Rev. 54, 29–37. Fani, N., King, T.Z., Jovanovic, T., Glover, E.M., Bradley, B., Choi, K., Ely, T., Gutman, D.A., Ressler, K.J., 2012. White matter integrity in highly traumatized adults with and without post-traumatic stress disorder. Neuropsychopharmacology 37, 2740–2746. Fitzsimmons, J., Kubicki, M., Shenton, M.E., 2013. Review of functional and anatomical brain connectivity findings in schizophrenia. Curr. Opin. Psychiatry 26 (2), 172–187. Fonagy, P., Bateman, A.W., 2007. Mentalizing and borderline personality disorder. J. Men. Health. 16 (1), 83–101. Gagnon, J., Aldebert, J., Saleh, G., Kim, W.S., 2019. The modulating role of self-referential stimuli and processes in the effect of stress and negative emotion on inhibition processes in borderline personality disorder: proposition of a model to integrate the self-concept and inhibition processes. Brain Sci. 9 (4) Mar 30. Gan, J., Yi, J., Zhong, M., Cao, X., Jin, X., Liu, W., Zhu, X., 2016. Abnormal white matter structural connectivity in treatment-naıve young adults with borderline personality disorder. Acta. Psychiatr. Scand. 134 (6), 494–503 Dec. Goldstein, A., Covington, B.P., Mesfin, F.B., 2019. Neuroanatomy. Corpus Callosum. StatPearls Publishing. Grant, J.E., Correia, S., Brennan-Krohn, T., Malloy, P.F., Laidlaw, D.H., Schulz, S.C., 2007. Frontal white matter integrity in borderline personality disorder with self-injurious behavior. J Neuropsychiatry Clin. Neurosci. 19 (4), 383–390. Haas, B.W., Omura, K., Constable, R.T., Canli, T., 2006. Interference produced by emotional conflict associated with anterior cingulate activation. Cogn. Affect. Behav. Neurosci. 2, 152–156 6. Heilbronner, S.R., Hayden, B.Y., 2016. Dorsal anterior cingulate cortex: a bottom-up view. Annu. Rev. Neurosci. 39, 149–170 Jul 8. Herbet, G., Zemmoura, I., Duffau, H., 2018. Functional anatomy of the inferior longitudinal fasciculus: from historical reports to current hypotheses. Front. Neuroanat. 12, 77. Janis, I.B., Veague, H.B., Driver-Linn, E., 2006. Possible selves and borderline personality disorder. J. Clin. Psychol. 62 (3), 387–394 Mar. Jenkins, L.M., Barba, A., Campbell, M., Lamar, M., Shankman, S.A., Leow, A.D., Ajilore, O., Langenecke, S.A., 2016. Shared white matter alterations across emotional disorders: a voxel-based meta-analysis of fractional anisotropy. NeuroImage 12,
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