Psychiatry

1. Neurobiology and
developmental perspective
of borderline personality
Presenter: Dr. Harshitha Handral
Chairperson: Dr. Madhusudan
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2. Outline
• Introduction
• Core psychopathology
• Neurobiology associated with core symptom domains
• Neurotransmitters
• Structural imaging
• Functional imaging
• Neuroendocrine system
• Neurophysiological findings
• Genetics
• Developmental perspective
• Limitations
• Recent advances
• Conclusion
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3. Introduction
• Personality: Dynamic organization of the psychobiological
systems by which a person shapes and adapts in a unique way to
a changing internal and external environment.
• Personality disorder: A Personality disorder is defined as an
“enduring pattern of inner experience and behaviour that
deviates markedly from the expectations of the individual’s
culture, is pervasive and inflexible, has an onset in adolescent or
early adulthood, is stable over time, and leads to distress or
impairment in social, occupational or other important areas of
functioning ”
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4. Borderline personality disorder
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5. Psychopathology
The psychopathology of
borderline personality disorder is
related to three core domains :
• Disturbed emotional processing
and emotional dysregulation
• Behavioural dysregulation and
impulsivity
• Interpersonal disturbances
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6. Disturbed Emotion Processing
• Majority of fMRI studies have shown hyperactivity of
the amygdala in response to negative stimuli in BPD
• They showed hyperactivity of the amygdala in
response to neutral stimuli as well.
• They showed prolonged activation of the amygdala.
• Failure to habituate during repeated presentation.
• One study revealed the presence of insular
hyperactivity along with amygdala hyperactivity.
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8. Disturbed emotion processing
Frontal hypoactivation :-
• Blunted response of bilateral DLPFC, ACC in response to emotionally
arousing stimuli (fearful faces).
• When patient were confronted with self reported traumatic memories,
they did not exhibit increased activity in ACC or OFC unlike healthy
controls.
• Reduced gray matter in DLPFC, ACC, VmPFC. Increased white
matter in ACC.
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9. Emotional dysregulation
• Deficient “top-down” frontal control mechanisms involved in
regulating activation in hyperactive “bottom-up” emotional generating
limbic structures.
• FDG –PET shows a decrease in regional glucose metabolism in areas
of right-left prefrontal cortex.
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10. Emotional dysregulation
• Mood stabilizers role:
1)Carbamazepine was found to be effective in improving depressive
symptoms in BPD.
2)Valproate was found to be effective in treatment of aggressive
behaviour in BPD.
3)Lithium reduced anger and suicidal symptoms.
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11. Dissociation
• Dissociation can be regarded as a regulatory strategy to cope with
overwhelming affective arousal during stressful situation (i.e opposite
to that in BPD without dissociation)
Stress
fight
flight freeze
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12. Dissociation
• EOS is involved in the modulation of sensory information process.
Alteration in the levels of endogenous opioids is involved in the
generation of dissociative states.
• k- receptor agonist ketocyclazocine and MR-2033 have led to
dissociative symptoms such as changes in perception,
depersonalization and derealization.
• Naltrexone reduced dissociative symptoms (k-opioid receptor-
blocking)
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13. Dissociation
• Serotonergic dysfunction was associated with dissociative symptoms.
• Fluoxetine reduced depersonalization.
• Dissociation seems to be associated with dampened amygdala
activation and increased activation in the frontal brain region
• Involment of frontolimbic structures is told.
• Neurobiology of dissociation is not yet completely understood.
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14. Self injury
• The incision resulted in decrease in tension and HR in BPD group
compared to control group.
• A resting fMRI study after incision pointed to decrease in amygdala
activity, together with normalised functional connectivity of amygdala
and superior frontal gyrus.
• Attention shift due to sensory stimulation.
• The stress reducing effects of tissue damage that affects subjective
experience, psychophysiological reactions and brain function in BPD.
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15. Self injury
• Dysfunction of the endogenous opioid system.
• The reduced EOS may underpin chronic dysphoria
• It is suggested that self-harm represents an unconscious drive to
increase EOS activity.
• PET studies: mu-receptor binding dysfunction, lower levels of
endogenous opiods in the CSF of individuals with BPD.
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16. Impulsivity
• Eg: Substance abuse, binge eating, high-risk behavior, aggressive
outbursts or sudden relationship breakups.
• FDG-PET studies showed cerebral blood flow during resting states
revealed blunted baseline metabolism in premotor and prefrontal brain
areas.
• Decoupling of the orbitofrontal-amygdala response.
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17. Impulsivity
• Imbalance between prefrontal and limbic responsivity may relate to
impaired serotonergic facilitation of top-down control.
• Polymorphisms in the genes for 5-HT2 receptor, tryptophan
hydroxylase and serotonin transport promoter are found in BPD.
• Low CSF 5-HIAA: linked to impulsive aggression, suicidal behavior.
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18. Impulsivity
• Individuals who attempted suicide had the most robust cortisol
response to challenge tests than individuals without suicidal ideas.
• Reduced prolactin response to fenfluramine challenge than healthy
controls.
• Fluoxetine (20 to 60 mg) - SSRI is found to increase the metabolic rate
in OFC and significantly improve impulsive and aggressive
personality.
• Sertraline (50 to 200 mg) - SSRI is found to decrease aggression.
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19. Interpersonal disturbance
• Interpersonally hypersensitive, often distorting social cues, forming
extreme opinions of others and making negative attributions about
others’ actions and even facial expressions.
• These biases are linked to heightened amygdala responses to the
negative emotional stimuli eg: social rejection.
• Reduced CSF and serum oxytocin were found. Oxytocin dysregulation
may contribute to interpersonal dysfunction.
• Opioid system abnormality may underlie interpersonal dysfunction.
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20. Serotonin
• Functional impairment within the central serotonin system(5-HT)
(affective instability, impulsive aggression) were noted.
• It has been proposed that the imbalance between frontal and limbic
responsivity may relate to impaired serotonergic facilitation of top-down
control.
• PET studies indicate that there is reduced serotonin transporter availability
in prefrontal cortex in BPD.
• Reduced prolactin release in response to serotoninergic
agonist(fenfluramine) is associated with impulsivity, self harm and anger.
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21. Oxytocin
• A prosocial neuropeptide.
• It promotes empathy, trust and social reward.
• Evidence suggests that oxytocin may improve social cognition and human
social behavior.
• Oxytocin downregulates stress responses to social threat.
• Lower levels of baseline levels of oxytocin.
• This results in defective cognition of social stimuli leading to abnormal
behaviour, affective instability, unresolved attachment and emotional
dysregulation.
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22. Oxytocin
• There is some evidence to support the moderating role of alleles of the
oxytocin receptor (OXTR) coding gene in the development of BPD
symptoms.
• Environmental factors can lead to methylation of OXTR gene, reduces
transcription of OXTR protein, thereby diminishes the effect of
oxytocin.
• The carriers of OXTR rs53576 A allele are more likely to perceive
others negatively, experience loneliness, subjective symptoms of
psychological stress with high cortisol levels.
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23. Dopamine
• There is an emerging consensus that DA dysfunction contributes to the
affective, cognitive and behavioural traits seen in BPD.
• Negative affectivity and impulsivity are more likely related to
hypodopaminergic functioning.
• A meta-analysis concluded that dopamine antagonists were associated
with worsening symptom severity.
• However, there is some evidence supporting the reduction in symptom
severity in BPD with Olanzapine, Quetiapine and Aripiprazole
• Hypo or hyperfunctioning remain unresolved yet.
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24. Endogenous opioid system
• Alteration in the sensitivity of opioid receptors or the availability of
endogenous opioids.
• Anhedonia and feelings of emptiness may be an expression of reduced
activity of EOS.
• The self-destructive behavior may be explained by uncontrollable and
unconscious attempts to stimulate their EOS.
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25. Magnetic Resonance Spectroscopy
• MRS finding in amygdala have shown conflicting results, as both
higher and lower concentrations of total creatinine in the left
amygdala.
• Creatinine is associated with energy metabolism and that alteration
may occur due to cell death or brain trauma.
• Higher total NAA(N-Acetyl Aspartate) and glutamate concentrations
in the left ACC.
• Lower NAA in bilateral DLPFC.
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26. Positron emission tomography
• Lower resting-state metabolism in the medial OFC
• Few more findings that are not reproducible across studies:
1) Higher metabolism in ACC, Superior and Inferior frontal gyri
2) Lower metabolism in cuneus and hippocampus
3) Lower metabolism in bilateral frontal regions
4) Lower metabolism in temporal pole, fusiform gyrus, precuneus,
PCC.
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27. Volumetric Magnetic Resonance Imaging
• Female with BPD showed a smaller volume of frontal lobes.
• Less volume of amygdala and hippocampus bilaterally.
• A polymorphism in the 5-HTR1A promoter gene is associated with
smaller amygdala volume.
• Less grey matter in the cingulate cortex and medial PFC.
• Less cortical thickness in bilateral OFC
• Smaller parietal cortex(not replicated across study)
• Emerging finding: Patients with BPD have more gray matter volume
in the right basolateral nucleus of the amygdala and larger volume of
this are correlated with more severe BPD symptoms.
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28. Functional MRI – Emotion Perception
• Patients with BPD had greater activity in the left amygdala when
viewing neutral, sad and fearful faces.
• Higher activity in the insular cortex: Reflects the degree of
subjectively perceived negative-emotion intensity compared to
controls.
• Less activation in DLPFC and Subgenual ACC: Reflects diminished
recruitment of brain regions involved in the regulation of emotion.
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29. Functional MRI – Emotional Regulation
• Cognitive reappraisal – an emotion regulation strategy: Which
involves thinking about satiation in a different way to reduce
emotional impact.
• fMRI studies of cognitive reappraisal less activation than controls in
brain regions involved in cognitive control, especially the dorsal ACC,
inferior frontal gyrus and inferior parietal sulcus, less deactivation than
controls in the amygdala.
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31. Baseline Neuroendocrine Assay
• A study showed that patients with BPD, especially women have shown to
have a higher cortisol response upon awakening from sleep and throughout
the day while awake.
• Lower peripheral levels of BDNF (role in stress response, especially by its
influences on neurons in the hippocampus).
• Higher baseline concentration of serum prolactin (A hormone that increases
to social stress)
• Lower level of oxytocin(A hormone involved in social relationship)
• Higher levels of endocannabinoid related neuromodulatory fatty acids(these
compounds may be associated with stress related responses and pain
sensation in BPD)
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32. Neurophysiological studies
A meta-analysis published in 2005 showed that patient with BPD had
lower performance on the neurocognitive testing in:-
• Attention
• Cognitive flexibility
• Learning and memory
• Planning
• Speed processing
• Visuospatial abilities.
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34. Family studies
• Risk for affective instability and impulsivity was greater in the
relatives of individuals diagnosed with BPD than in relatives of
individuals with other personality disorders
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36. Twin studies
• The concordance rate for BPD was 38% among monozygotic twins
and 11% among dizygotic twins.
• A multivariate twin study on 2794 young twins showed the heritability
of 55%
• One more twin study chromosome 9p22 genomic region has the
highest likelihood of being co-transmitted with BPD.
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37. Association studies
• THP1 polymorphism is associated with suicidal behaviour.
• THP heterozygotes have the highest risk for BPD.
• Serotonin 2A receptor (HTR 2A) gene is considered as a candidate gene for
BPD. It is associated with suicide, impulsivity and emotional lability.
• Serotonin transporter gene (5-HTT) polymorphism is associated with
suicide, impulsivity and emotional lability, addiction.
• Polymorphisms within the gene encoding for MAOA, which is involved in
the degradation of serotonin and norepinephrine have been associated with
impulsivity and aggression.
• Dopamine transporter gene DAT1 associated with BPD.
• Other genes with inconsistent association across studies: BDNF gene,
arginine vasopressin receptor 1A (AVPR1A gene)
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38. Few more findings
• In BPD, there are alterations in the connections between default mode
network, salience network and medial temporal lobe network.
• Connectivity is also heightened between the amygdala and
parahippocampus, ventral ACC and insula.
• Increased levels of vasopressin consistently co-relate with a higher
level of aggression.
• Magnetic seizure therapy is found to be a safe and effective brain
stimulation technique in localised areas of prefrontal cortex used in
depression and suicidal ideations in BPD.
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40. Frontolimbic gray matter abnormalities
A meta-analysis done in 2016 showed :-
• Increased gray matter in bilateral supplementary motor area extending
to right PCC and bilateral primary motor cortex, right middle frontal
gyrus and bilateral precuneus extending to bilateral PCC.
• Decreased gray matter in bilateral middle temporal gyri, right inferior
frontal gyrus extending to left medial OFC.
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42. Developmental perspective
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43. Biosocial developmental model
Proposed by Dr. Marsha Linehan, genetic vulnerability interacts with a
chronically invalidating environment to produce constellation of BPD
disorder.
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44. heightened emotional
regulation
Increased risk of
psychopathology
Inherited impulse control deficits are met with environmental reinforcement of
emotional lability
Transient emotional states
Longer lasting traits
BPD diagnosis
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45. Biological vulnerabilities
• Genetic influences (5-HTT s/s polymorphism, TPH gene, 5-HT
receptor genes, DAT-1)
• Abnormalities of brain systems (5-HT, DA, HPA axis)
• Frontolimbic dysfunction
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46. Caregiver contribution
• Invalidation of child emotions
• Inadequate coaching of emotion
• Negative reinforcement of aversive emotional expression
• Ineffective parenting due to insufficient family resources (time, money,
social support)
• Maternal separation
• Poor maternal attachment
• Parental substance abuse, Serious parental psychopathology
• Physical abuse
• Emotional abuse
• Sexual abuse
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47. Mentalising model
Proposed by Peter Fonagy and Anthony Bateman
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48. Mentalising model
• Mentalizing is a capacity to understand accurately the intentions of
oneself and others.
• Mentalizing capacity is considered to develop in the context of
attachment relationships.
• Psychological trauma  attachment disruption  disruption in
mentalising capacity  poor integration of cognitive and affective
aspects of mentalisation.
• Mentalization based therapy is a psychodynamic insight-oriented
psychotherapy that focuses on distorted perceptions of oneself and
other persons.
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49. Theory by Otto Kernberg
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50. Theory by Otto Kernberg
• Kernberg hypothesized that the infant experiences the maternal figure
in a dichotomous framework
1) The loving and nurturing mother who provides for the child.
2) The punishing hateful mother who deprives the child.
• This contradiction causes intense anxiety and, if not integrated into a
more unitary concept, ultimately leads to the development of
“splitting”, i.e at any given time, the other person is viewed as entirely
good or entirely bad.
• This inability to view others as having both positive and negative leads
to interpersonal impairment in BPD.
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51. Object relations theory
• Disturbance in the object-world representation.
• That is the merging of cognition relating to self and others and the
affects attached to those representations.
• Accounts for interpersonal problems experienced by BPD individuals.
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52. Limitation
• Mixed findings in a few aspects across studies. (Due to differences in
sample-specific characteristics, research methodology, a co-morbid
condition that could feasibly affect CNS)
• Animal studies are difficult to do, as an exact state of BPD cannot be
induced.
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53. Recent advances
• BPD is characterized by a preponderance of comorbid circadian
rhythm, sleep-wake disorders, phase delayed and misaligned rest-
activity patterns.
• Such symptoms may exacerbate symptom severity.
• Amelioration in this circadian phenotype may confer substantial
clinical benefit.
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55. Conclusion
Research on BPD implicates dysfunction affecting multiple
neurobiological system-interconnection among harmones,
neuropeptides, brain metabolites, neurotransmitters, white and gray
matter volumes connecting with emotions, cognition and sense of self.
Major interaction with genetic and environmental influences important
advances in the development of BPD
• Role in Identifying disorder early in its course.
• Role of intervention intervening sooner, to prevent its fullest
development (suicidality).
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56. • https://youtu.be/RuIfIzgHkjI
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57. Future directions
• To develop biomarkers for each core symptom dimension.
• To develop scales to assess the risk factors in adolescence
predisposing to the development of BPD in adult life.
• To link more neurobiological findings to track and predict the
effectiveness of psychological and pharmacological treatment.
• Plasticity model with positive and negative experiences need to
improve to come to any conclusion or to plan therapy.
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58. References
• Ruocco AC, Carone D. A neurobiological Model of Borderline
Personality Disorder: Systemic and Integrative Review . Vol24,
Harvard Review of Psychiatry. Ovid Technologies; 2016
• Christian G, Thomas H. Neurobiological Correlates of Borderline
Personality Disorder
• Amad A, Ramoz N, Thomas P. Genetics of borderline personality
disorder: systematic review and proposal of an integrative model.
Neurosci Biobehav Rev. 2014 Mar; 40:6-19.
• McGown, NM, Saunders, K.E.A. The Emerging Circadian Phenotype
of Borderline Personality Disorder: Mechanisms, Oppurtunities and
Future Directions. Curr Psychiatry Rep 23, 30;2021
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59. References
• Yang, X et al. Default mode network and frontolimbic gray matter
abnormalities in patients with borderline personality disorder: A voxel-
based meta analysis; doi: 10.1038/srep3427(2016)
• Rucco AC, Rodrigo AH, McMain SF. Predicting treatment outcomes
from prefrontal cortex activation for self-harming patients with
borderline personality disorder: a preliminary study.2016
• Crowell SE, Beauchaine TP, Linehan MM. A biosocial development
model of borderline personality:Elaborating and extending linhan’s
theory. Vol 135, Psychological Bulletin. American Psychological
Association;2009
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60. References
• Annegret Krause, Inga Niedtfeld, Julia Knauber. Neurobiology of
borderline personality disorder. In: Barbara Stanley, Antonia New
(Eds). Borderline Personality Disorder. USA: Oxford University
Press; 2018. p83-111.
• Kate E. A Saunders, Steve Pearce. Basic mechanisms of, and treatment
planning/targets for personality disorders. In: John R Geddes, Nancy C
Andersen, Guy M Goodwin (Eds). New Oxford textbook of
Psychiatry. 3rd ed. UK: Oxford University Press; 2020.p1211-1217.
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61. THANK YOU
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