Special Topic Section: Borderline Personality Disorder
Editors: J.F. Clarkin, M.I. Posner
Overview
Psychopathology 2005;38:56–63
DOI: 10.1159/000084812
Defining the Mechanisms of Borderline
Personality Disorder
John F. Clarkin Michael Posner
Weill Cornell Medical Center, New York, N.Y., USA
Key Words
Personality disorder W Borderline personality disorder W
Temperament W Psychotherapy of borderline personality
disorder
Abstract
Understanding the biological connections to mental pro-
cesses was one of the original goals of psychoanalysis,
and the development of cognitive and affective neurosci-
ence and its methods might contribute to actualizing this
goal. Personality disorders provide an opportunity to
examine the complex mental structures of individuals
experiencing extreme difficulties in interacting with their
social environment. We provide initial information on a
collaboration exploring an approach to one of the most
serious personality disorders, borderline personality dis-
order, based upon the study of normal attention, individ-
ual differences in temperament, self definition and at-
tachment organization, with the potential to illuminate
the psychology and psychobiology of the disorder and to
contribute to psychotherapeutic intervention. This devel-
oping model of borderline personality disorder can re-
late the symptoms to more enduring temperamental
aspects of the patients. The goal is to understand the
development of neural networks that underlie the abnor-
malities of adults, and eventually work out the interac-
tion between temperament, genes, and experience that
produce the disorder, and potentially inform interven-
tion.
Copyright © 2005 S. Karger AG, Basel
© 2005 S. Karger AG, Basel
ABC 0254–4962/05/0381–0056$22.00/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/psp
Received: February 13, 2003
Accepted: May 26, 2003
Published online: March 31, 2005
Introduction
Borderline personality disorder (BPD) constitutes one
of the most important sources of long-term impairment in
both treated and untreated populations [1]. Approximate-
ly 11% of psychiatric outpatients and 19% of inpatients
meet criteria for BPD [2], the majority of whom are wom-
en. A population prevalence of 0.3% for diagnosed defi-
nite or probable BPD was found in a nonclinical popula-
tion using a conservative diagnostic interview [3], and a
similar figure (0.7%) was found subsequently in a Norwe-
gian population-based study using a somewhat less con-
servative interview [4]. Suicidal [5, 6] and self-injurious
behavior are particularly prevalent with BPD patients.
BPD is substantially comorbid with other personality dis-
orders [7, 8] and with Axis I disorders [9]. BPD negatively
affects the treatment efficacy for a number of Axis I disor-
ders [10] and is less responsive to pharmacotherapy [11].
This prevalent, chronic, and debilitating syndrome is
associated with high rates of medical and psychiatric utili-
zation of services [12].
Personality disorders represent an opportunity to ex-
amine the complex mental structures of people experienc-
ing extreme difficulties in interacting with their social
environment. Because of its behavioral complexity and
lack of clear organic markers, BPD poses one of the great-
est challenges to understanding the psychobiology of its
development. BPD is a defined mental health problem
that has been identified and studied by psychoanalytic
[13] as well as behaviorally oriented therapists [14]. Un-
Dr. John F. Clarkin
Weill Cornell Medical Center, Westchester Division
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Psychology Department, White Plains
New York, NY 10605 (USA)
Tel. +1 914 997 5911, Fax +1 914 682 6964, E-Mail jclarkin@med.cornell.edu
Univ. of California Davis
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derstanding the biological connections to mental pro-
cesses was one of the original goals of psychoanalysis, and
the rapid development of cognitive and affective neuro-
science built on brain imaging methods might help actual-
ize this goal [15, 16a, b]. A unique aspect of our work is
the collaboration of a team of researchers with different
areas of expertise. With funding from the Borderline Per-
sonality Disorder Research Foundation, we assembled a
team of neurocognitive scientists (M. P., David Silber-
sweig), a leading psychoanalyst (Otto Kernberg), experts
on attachment style (Kenneth Levy), and psychotherapy
researchers (J. C.).
This Special Section provides some initial information
on a collaboration exploring an approach to BPD based
upon the study of normal attention [17, 18], individual
differences in temperament and personality [19, 20] and
brain imaging [21, 22], with the potential to illuminate the
psychobiology of the disorder and contribute to interven-
tion strategies. In the first section of this overview, we
present a discussion of the symptoms of the disorder and
the centrality of temperamental aspects of negative affect
and poor self-control. We discuss the relationship of these
variables to the conception of self and others, and the
nature of attachment to others in the environment. We
then provide an outline of our research plan and summa-
rize the findings we have obtained so far from borderline
patients and appropriate controls prior to their undergo-
ing a year of therapy. This summary places the papers in
the Special Section in their context.
BPD Symptomatology
BPD is diagnosed if the individual has any 5 or more of
a set of 9 criteria in DSM-IV, Axis II [23], including items
relating to identity diffusion, impulsivity, and affect dys-
regulation. That BPD symptomatology is characterized
by several major dimensions of psychopathology has long
been established. The empirical clusters or primary di-
mensions of BPD have been discussed by researchers [24]
and clinicians since the seminal multivariate work by
Grinker [25]. A burgeoning literature has suggested that
impulsivity and negative affectivity/emotional dysregula-
tion are the two core personality traits that characterize
much of the phenotypic variation seen in BPD [26–29].
Theoretical literature has only recently begun to ad-
dress the manner in which these dimensions are linked to
major underlying personality or temperamental pro-
cesses. It is not clear how these processes yield BPD
through unspecified interactions among the processes
Defining the Mechanisms of Borderline
Personality Disorder
themselves and environmental and developmental in-
puts. We consider briefly the two major domains of tem-
perament and personality processes with respect to the
development of BPD.
Symptomatology and phenomenology of the disorder
are a first attempt to isolate individuals with a common
condition. In order to understand the nature of BPD,
there are many reasons why research must go beyond the
symptom level. Symptoms change over time, and have
been found to be unstable [30]. This is not surprising,
because the criteria set is composed of behaviors, symp-
toms, traits, and attitudes. Symptoms do not reveal mech-
anisms of action. Even the motivational level of human
behavior is not approached in the symptom/criteria set.
In addition, the criteria set does not include many aspects
of human functioning that are crucial to an understanding
of personality disorder.
Temperament and Personality Organization
The constructs emerging from the field of tempera-
ment research may have considerable utility in articulat-
ing the causes and emergence of personality disorders,
particularly BPD. Within academic psychology and par-
ticularly within developmental laboratories, extensive re-
search on temperament and its relationship to biological
systems has matured into a rich and powerful corpus.
Derived principally from the study of children, the con-
temporary framework for temperament provides an im-
portant organizing scheme for the investigation of the
development of personality disorders. In one view, tem-
perament refers to individual differences in motor and
emotional reactivity and self-regulation [31]. Tempera-
ment arises from genetic endowment [32], but tempera-
mental systems are clearly influenced by the environment
and follow a developmental course [33, 34]. The interac-
tion of temperament and environment appears to be cen-
tral to the development of self-control, emotional control,
empathy, and social behavior [31], and one of its out-
comes is adult personality and personality pathology. For
example, research work using the children’s version of
these temperament scales has found that empathy and the
development of conscience are related to strong, effortful
control mechanisms [35, 36].
Our research on BPD has been guided by a model of
temperament as it relates to negative affect, evolving self-
control, the internal sense of self and others, and related
impact on social behavior. Each of these aspects deserves
individual consideration.
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 Negative Affect and Defective Self-Regulation
Negative affect, especially hostility and aggression, and
a paucity of positive affect is an essential aspect in under-
standing the individual with BPD [37, 38]. Negative
affect invades the information processing of the individu-
al [39] and the organization of the individual’s interper-
sonal and personal experience.
A second central feature of borderline pathology is
poor self-regulation. This relative inability to self-regulate
is manifested in impulsive behaviors, including impulsive
self-destructive behaviors, and difficulties in modulating
affective experience. Impulsivity and/or impulsive ag-
gression are considered to be underlying dimensions in
BPD [28, 40, 41].
Impulsivity best predicts the persistence of borderline
psychopathology across time [41]. Impulsivity combined
with other factors has been related to suicidal behavior in
BPD patients. For example, impulsive actions, comorbid
antisocial personality disorder and depression are related
to a history of suicidal behavior in BPD patients [42] and
other mixed personality disorder groups [43].
There is evidence of the link between impulsivity and
underlying biological systems. Both impulsive aggression
and affective instability show a stronger familial relation-
ship than the diagnosis of BPD itself [44]. In twins, impul-
sivity and affective instability are heritable [45, 46]. Bio-
logical, neuroendocrine and imaging studies provide evi-
dence for the involvement of serotonergic activity in
impulsive aggression [26, 47, 48].
Affect dysregulation or emotional instability has been
described as involving unpredictable responses to stimuli,
increased baseline lability, unusual intensity of responses
and unusual responses [49], all characteristics of a poorly
constrained biobehavioral regulatory system [50]. Pa-
tients with affective disorders have dysregulation of posi-
tive affectivity [51, 52] whereas BPD patients have dys-
regulation of negative affect [49].
The evolution of self-regulation in the developing
child – the antidote to aggression, impulsivity, and affect
dysregulation – is a central issue in understanding both
the development of normal personality and its organiza-
tion and personality pathology [31]. Studies suggest that
effortful control has a developmental course in which
some children by age 3 are capable of efficiently making
choices in conflict situations, especially those involving
the suppression of dominant response modes.
Identity Diffusion
There is a general recognition that the developing indi-
vidual evolves a sense of self that, in turn, influences
58 Psychopathology 2005;38:56–63
information processing and reactions to the environment.
Influenced by temperamental disposition and environ-
mental events (sometimes traumatic), a secondary level of
intrapsychic organization takes place that determines the
clinical syndrome of identity diffusion [13] reflected in
the DSM-IV diagnostic criteria for BPD. Identity diffu-
sion is characterized by a lack of integration of the con-
cept of self and significant others. These poorly integrated
conceptions of self and others are derived from an exces-
sive dissociation between positive and negative affective
investment of self and other representations, leading to
chronic deficiency in the assessment of self and self-moti-
vations. The clinical characteristics of BPD show chronic,
severe pathology of object relations and immaturity in
judgments of emotional relationships, difficulties in the
commitment to work or to a profession, difficulties in the
commitment to intimate relations and disturbances in
sexual and love life. Imaging results have proved an ana-
tomical connection between mechanisms of self-regula-
tion and self-referential processes in the midfrontal cortex
[53].
Attachment
Recently, clinical researchers and theorists have under-
stood fundamental aspects of BPD such as unstable,
intense interpersonal relationships, feelings of emptiness,
bursts of rage, chronic fears of abandonment and intoler-
ance for aloneness, as stemming from impairments in the
underlying attachment organization [54–56].
The dependent and vulnerable infant’s experience of
the relationship with the caregiver has been hypothesized
to lead to the development of representations of self and
others [57–59]. This experience between infant and care-
giver is potentially influenced by many factors, including
the temperament of the child and the nature of the care-
giver’s attention and nurturing. Samples of borderline
patients show high incidence of early abuse [60], pro-
longed separations from caregivers during childhood [61]
and neglect [62]. These experiences would make the
development of insecure internal working models of at-
tachments in borderline patients quite plausible.
Representations of self and others and strategies for
processing attachment-related thoughts and feelings can
predispose the individual to psychopathologies such as
that found in BPD. An expectation of caregiver rejection
or undependability could lead to a conceptualization of
self as bad and unlovable, and conceptualization of others
as rejecting. Infants who develop internal working models
of insecure attachments to others may minimize or max-
imize attachment needs [63]. Borderline patients are
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characterized by insecure attachments, but this can take
the form of dismissive or preoccupied states of mind [55].
Patients rated as preoccupied on the Adult Attachment
Interview (AAI) were less likely to show significant change
after one year of psychotherapy and had a higher drop-out
rate than patients rated as dismissing. In addition, border-
line patients with relatively higher reflective functioning
(an ability to evoke feelings, beliefs, intentions and other
psychological states in their account of relationship expe-
riences) as measured from the AAI [64] narratives fare
better in treatment than those with low reflective func-
tioning.
A Working Model of Borderline Personality Disorder
Our working model of BPD, therefore, posits a dy-
namic interaction of temperament, especially a prepon-
derance of negative affect over positive affect, low effort-
ful control, and an absence of a coherent sense of self and
others, in the context of a non-secure, anxious attachment
style [65a]. Our working model has many similarities to
those of others [65b, 66]. What is unique about our work
is the measurement of temperament, related investigation
of neurocognitive mechanisms of attention, orienting,
and conflict resolution, and measurement of identity dif-
fusion and attachment style. These concepts are becoming
increasingly connected to particular brain circuits and
thus allow us to predict changes in brain imaging studies
that might occur with various forms of therapy.
In this process of developing a model, we are attempt-
ing to use these key concepts in active challenges to the
BPD patient in order to understand how they function in
the immediate present. An information processing system
that is actively influenced by negative affect, faulty and
ineffective conflict resolution, and expectations of attach-
ment to others in an anxious, ambivalent way specifies
the BPD experience, but also makes the issue of treatment
foci and treatment development more specific and attain-
able. This suggests that interventions focused on the infor-
mation-processing system, especially in the social inter-
personal sphere, will have the most impact on the patient,
and is a necessary target of change if symptom improve-
ment is to be maintained across time.
We think that adverse environmental events, such as
sexual abuse, physical abuse and neglect, should be seen
in the context of the basic information processing of the
individual. It is plausible that these traumatic events add
further stress to an already vulnerable individual. We do
not assume that a temperamental disposition of negative
affect and poor effortful control will, of necessity, result in
BPD. Rather, it is assumed that if these temperamental
Defining the Mechanisms of Borderline
Personality Disorder
dispositions meet with an environment involving early
separations as well as physical and/or sexual abuse, paren-
tal neglect can lead to identity diffusion and impulsive,
self-destructive behavior. We note that other neurobehav-
ioral systems could also interact with the basic high nega-
tive affect/low control (constraint) to potentiate the ex-
pression of a BPD-prone temperament.
It is possible that attentional training accomplished at
the time of development of the executive system might
help a broad range of children to overcome the deficits
involved in development with this inadequate self-regula-
tion. Although the chances that this will be effective in
overcoming the dramatic deficits of BPD do not seem
very great, it is important that our understanding of the
nature of the disorder and its development leads to a con-
sideration of that possibility.
Research Plan and Subsequent Findings
Temperament
Our research plan flows from the hypothesized concep-
tualization of the nature of BPD, enunciated above. Since
the symptoms of BPD include dysregulation of negative
emotions particularly in interpersonal relations, we hy-
pothesized that borderline patients would be high in nega-
tive affect and low in effortful control as measured by
common temperament and personality scales. The Adult
Temperament Questionnaire (ATQ) [32] was utilized be-
cause it has scales for negative affect and effortful control,
and because it was based upon measures that had been
widely used for young children. A temperament high in
negative emotionality, including anger, and low in effort-
ful control would appear to provide the basis for poor
interpersonal relations, thus producing another of the cen-
tral difficulties in BPD.
The data we have reported [67a] suggest that patients
with BPD are higher than normal persons in their self-
described negative affect and lower in their self-described
ability to control emotions and behavior (effortful con-
trol). As expected, the patients showed quite high levels of
negative affect, well above the average, and were also
somewhat lower than normal on effortful control. Their
scores in these temperamental dimensions did not differ
depending on their medication status.
We screened over 1,000 university students who were
administered the ATQ. Of primary interest were the fac-
tors of negative affect and of effortful control. We selected
two groups of controls. The temperamentally matched
control group was selected to show a similar temperamen-
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tal profile to the borderline patients, i.e., high negative
affect and low effortful control. We also selected average
controls whose scores on negative affect and effortful con-
trol were close to the middle scale score of 4 on both of
these variables. All control subjects were screened for per-
sonality disorders and did not meet criteria for BPD.
While the majority of temperamentally matched controls
did not have a personality disorder, in our efforts to
recruit them for experimental and brain imaging sessions
we noted the difficulty in working with some members of
this population due to frequent changes of address and
phone number, unreliability in keeping appointments,
and/or their heightened anxiety and paranoia regarding
experimental procedures. Our general perception was that
these were rather difficult people whose behavior seemed
to show evidence of dysregulation, even though they were
functioning in an academic setting and did not meet crite-
rion for BPD. As described in the paper by Hoermann et
al. [67b], we examined the clusters of borderline patients
formed by a consideration of varying degrees of effortful
control. Once the patients were empirically grouped by
the effortful-control construct, we examined hypothesized
differences between the groups in terms of symptoms,
interpersonal behavior, and self-conception or identity
diffusion. These findings may have implications for
which treatment an individual should receive, and/or how
the treatment must be delivered to result in clinical
response.
Attention Network Task
The next step was to examine whether consistent pat-
terns of performance on psychological tests would
emerge both from the diagnosed population and from the
temperamentally matched group, while a different pat-
tern would emerge from the average controls. Experi-
mental procedures known to tap effortful control were
used. It would also be important to study the interaction
of attentional control and negative emotionality in a task
designed to assess the ability to control responses in the
face of negative input. If patients differed from both con-
trol groups, we would expect the functions on which they
differed to provide a basis for hypotheses about the
pathophysiology of the disorder. If the patients and the
temperamentally matched controls showed a similar pat-
tern but those two groups differed from average controls,
we would posit that borderline personality disorder arises
from socialization of a particular type of temperamental
pattern.
Subjects were given the Attention Network Test (ANT)
[68a] to provide an evaluation of the efficiency in three
60 Psychopathology 2005;38:56–63
aspects of attention: alerting, orienting and conflict reso-
lution. The network scores have proven reliable and show
considerable independence across subjects. The ANT is
described in the paper by Fertuck et al. [68b].
We found that patients differed from the average and
temperamentally matched controls in the conflict net-
work, but not in any other attentional network, nor in
overall reaction time or error rate [67]. In subsequent
analyses, patients differed from average controls but not
from temperamentally matched controls. The direction of
the differences is for temperamentally matched control
subjects to have a larger conflict score than the average
controls; however, they did not show significant differ-
ences from either the average controls nor from the
patients. We evaluated whether the difference between
patients and controls could be explained by differences in
age, medication, or temperament, and we concluded that
the difference between patients and average controls
could not be explained by age or medication.
As described by Fertuck et al. in this Special Section,
we have found that when borderline patients are exam-
ined not in contrast to controls but as compared to each
other, borderline patients differ not only on the ANT task
but also in selected neurocognitive tasks that assess execu-
tive control.
These results indicate two important findings about
the BPD patients. First, there is a particular abnormality
in the functioning of the attentional network specifically
involved in control of conflict. The other two components
of the attentional system (alerting and orienting) do not
seem to be impaired in these patients relative to controls.
Second, the abnormality is present in BPD patients but
not in the temperamental controls. Although the tempera-
mental controls also show elevated conflict scores, they do
not differ significantly from average controls. We con-
clude that temperament may play a role in the disorder,
possibly in predisposing individuals to develop BPD, but
some other factors must be involved, such as the forma-
tion of identity diffusion and severe environmental stres-
sors.
Conceptualization of Interpersonal Relations
In yet another attempt to understand the heterogeneity
of BPD pathology, especially as it relates to interpersonal
behavior and interpersonal connectedness, Levy et al.
[68c] describe the BPD patients in terms of their attach-
ment styles. In the developmental literature, there is evi-
dence that the infant learns effortful control through the
attachment and attention of a caregiver who models
soothing and self-control in high-affect-laden situations.
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We have, therefore, provided a measure of the borderline
patients’ internal working model of attachments. This
attachment style may relate to effortful control, and to the
nature of the interaction between patient and therapist in
treatment.
Treatment
Psychotherapy is the recommended primary technique
for treating BPD patients [69] and is the most widely
practiced approach to their treatment. A recent meta-
analysis [70] suggests that psychotherapy is an effective
treatment and may be associated with up to a sevenfold
faster rate of recovery in comparison with the natural his-
tory of the personality disorders. While these findings are
encouraging, few controlled studies have actually exam-
ined the efficacy of particular treatments for BPD pa-
tients.
In contrast to the extensive use of psychotherapy, only
two treatments – psychodynamic treatment and dialec-
tical-behavioral therapy (DBT) – have shown acute effica-
cy for treating BPD [71, 72]. The Linehan [72] study
examined outpatient psychotherapy for BPD patients,
but only for the subgroup that exhibited suicidal behavior.
Compared to the treatment usually given in the commu-
nity, DBT led to a reduction in the number and severity of
suicide attempts and a decrease in the length of inpatient
admissions.
Among several other common and promising treat-
ment approaches to BPD is the object relations approach
based on Kernberg’s clinical theorizing [37]. Kernberg et
al. [73] call this treatment Transference-Focused Psycho-
therapy (TFP) because it relies principally on the tech-
niques of clarification, confrontation and interpretation
within the evolving transference relationship between the
patient and the therapist. Although Kernberg’s techniques
are widely practiced in treating BPD, there has been little
research concerning the effectiveness and efficacy of these
techniques.
Treatment planning, either for clinical research or clin-
ical practice, cannot be done solely on the basis of the
DSM-IV criteria that constitute the diagnosis. It is becom-
ing clear that these criteria and diagnostic membership
change with time. The characteristics of these patients
such as temperament, effortful control, attachment style,
and neurocognitive functioning, will either affect the
treatment or be targets for treatment. The following are
specific ways these variables might influence treatment.
Process of Interaction between Patient and Therapist.
The interaction between the patient and therapist can be
seen as a secondary element which must be managed so
Defining the Mechanisms of Borderline
Personality Disorder
that the patient learns skills, or it can be seen as a primary
vehicle for change in interpersonal behavior by the pa-
tient. All treatments are aware of the interaction between
patient and therapist, but different therapy orientations
put varying degrees of emphasis on the role of the interac-
tion and thus varying degrees of training of therapists. We
think future studies of therapy process between patient
and therapist will reveal differences between borderline
patients and between therapy types in terms of that pro-
cess, whether it is used for therapeutic leverage, and to
what extent the therapy process changes over time. The
current issue and its data provide some interesting hy-
potheses that could be examined in process studies.
Neurocognitive Impediments to Treatment. Neurocog-
nitive processes, both those involving affect and those
without affect (conflict resolution on the ANT) can be
seen as targets for intervention or as deficits to which the
treatment must be adapted for the patient to improve.
Emotion Processing. The borderline patient is charac-
terized by labile moods, expression of negative affect (es-
pecially aggression), and experiences affect storms either
in isolation or in interaction with others. The information
presented here in terms of assessment of negative affect
and poor effortful control are questionnaire methods of
assessing affect dysregulation. Treatment would have as
one of its goals the enhancement of emotional regulation,
with more modulation and control of anger and other neg-
ative affects.
Sense of Self and Others. The patients’ sense of self and
others is central to their interaction with others in the
environment and central to their interaction with the
therapist in the treatment itself. The treatment situation is
an opportunity to examine in detail the interaction of the
patient with others that is so central to the deficits in
social and work relations which brought the patient to
treatment initially. If the sense of self and others is infused
with hostility, defective and out of congruence with how
others perceive the patient, the therapy relationship is an
opportunity for corrective perception.
In the treatment study currently being conducted by
our research group, borderline patients are randomly
assigned to one of three treatment groups in a double-
blind design. One group receives a manualized psychoan-
alytically oriented treatment [73]. A second group re-
ceives a cognitive behavioral treatment [14] and a third
group receives the pharmacological and counseling treat-
ments common in the community. Changes that might
take place in self-reported temperamental dimensions of
negative affect and effortful control will be examined fol-
lowing therapy. Since these assays involve reports of
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recent experiences, it is possible that these will be in-
fluenced by the therapies. The brain scans to be carried
out after the therapy will show if the stronger activation of
the amygdala found in patients compared to average con-
trols prior to therapy will be reduced with therapy.
It will also be important to see if executive attention is
influenced by the therapeutic interventions. If amygdala
activation is reduced in patients, it will also seem likely
that control systems related to emotion would be affected.
However, since the ANT does not involve any emotional
system, it will be interesting to see if therapy generalizes to
this form of cognitive control.
A preliminary analysis after 4 months of therapy was
made in all patients who had reached this point, but with-
out breaking the code describing which therapy was
involved. It was apparent that there was significant symp-
tom improvement. The degree of improvement was in-
fluenced by the initial severity but also by the strength of
effortful control as reported by the patients prior to enter-
ing therapy.
In summary, we are developing a model of BPD that
can relate the symptoms to more enduring temperamental
aspects of the patients. We hope to understand the devel-
opment of the neural networks that underlie the abnor-
malities found in adults and eventually work out the inter-
action between temperament, genes and experience that
produce the disorder. This special section provides our
latest findings on effortful control in borderlines, corre-
lates of the attention network difficulties in these patients,
and further information on the attachment style patterns
in borderlines. We are hopeful that as the model is refined
with further data collection, it will indicate important
areas of borderline patient heterogeneity and direct future
treatment development.

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