Borderline personality disorder is a heritable brain disease

The prevailing view among many psy­chiatrists and mental health profession­als is that borderline personality disorder (BPD) is a “psychological” condition. BPD often is conceptualized as a behav­ioral consequence of childhood trauma; treatment approaches have emphasized intensive psychotherapeutic modali­ties, less so biologic interventions. You might not be aware that a large body of research over the past decade provides strong evidence that BPD is a neuro­biological illness—a finding that would drastically alter how the disorder should be conceptualized and managed.

Neuropathology underpins the personality disorder
Foremost, BPD must be regarded as a serious, disabling brain disorder, not simply an aberration of personality. In DSM-5, symptoms of BPD are listed as: feelings of abandonment; unstable and intense interpersonal relationships; un­stable sense of self; impulsivity; suicidal or self-mutilating behavior; affective in­stability (dysphoria, irritability, anxiety); chronic feelings of emptiness; intense anger episodes; and transient paranoid or dissociative symptoms. Clearly, these clusters of psychopathological and be­havioral symptoms reflect a pervasive brain disorder associated with abnormal neurobiology and neural circuitry that might, at times, stubbornly defy thera­peutic intervention.

No wonder that 42 published stud­ies report that, compared with healthy controls, people who have BPD display extensive cortical and subcortical abnor­malities in brain structure and function.¹ These anomalous patterns have been detected across all 4 available neuroim­aging techniques.

Magnetic resonance imaging. MRI studies have revealed the following abnormalities in BPD:
   • hypoplasia of the hippocampus, caudate, and dorsolateral prefrontal cortex
   • variations in the CA1 region of the hippocampus and subiculum
   • smaller-than-normal orbitofrontal cortex (by 24%, compared with healthy controls) and the mid-temporal and left cingulate gyrii (by 26%)
   • larger-than-normal volume of the right inferior parietal cortex and the right parahippocampal gyrus
   • loss of gray matter in the frontal, temporal, and parietal cortices
   • an enlarged third cerebral ventricle
   • in women, reduced size of the me­dial temporal lobe and amygdala
   • in men, a decreased concentra­tion of gray matter in the anterior cingulate
   • reversal of normal right-greater-than-left asymmetry of the orbitofron­tal cortex gray matter, reflecting loss of gray matter on the right side
   • a lower concentration of gray mat­ter in the rostral/subgenual anterior cin­gulate cortex
   • a  smaller frontal lobe.

In an analysis of MRI studies,2 cor­relation was found between structural brain abnormalities and specific symp­toms of BPD, such as impulsivity, sui­cidality, and aggression. These findings might someday guide personalized in­terventions—for example, using neuro­stimulation techniques such as repetitive transcranial magnetic stimulation and deep brain stimulation—to modulate the activity of a given region of the brain (depending on which symptom is most prominent or disabling).
 

Magnetic resonance spectroscopy. In BPD, MRS studies reveal:
   • compared with controls, a higher glutamate level in the anterior cingulate cortex
   • reduced levels of N-acetyl aspar­tate (NAA; found in neurons) and cre­atinine in the left amygdala
   • a reduction (on average, 19%) in the NAA concentration in the dorsolat­eral prefrontal cortex.

Functional magnetic resonance im­aging. From fMRI studies, there is evi­dence in BPD of:
   • greater activation of the amygdala and prolonged return to baseline
   • increased functional connectiv­ity in the left frontopolar cortex and left insula
   • decreased connectivity in the left cuneus and left inferior parietal and the right middle temporal lobes
   • marked frontal hypometabolism
   • hypermetabolism in the motor cor­tex, medial and anterior cingulate, and occipital and temporal poles
   • lower connectivity between the amygdala during a neutral stimulus
   • higher connectivity between the amygdala during fear stimulus
   • higher connectivity between the amygdala during fear stimulus
   • deactivation of the opioid system in the left nucleus accumbens, hypothal­amus, and hippocampus
   • hyperactivation of the left medial prefrontal cortex during social exclusion
   • more mistakes made in differenti­ating an emotional and a neutral facial expression.
 

Diffusion tensor imaging. DTI white-matter integrity studies of BPD show:
   • a bilateral decrease in fractional an­isotropy (FA) in frontal, uncinated, and occipitalfrontal fasciculi
   • a decrease in FA in the genu and rostrum of the corpus callosum
   • a decrease in inter-hemispheric connectivity between right and left ante­rior cigulate cortices.

Genetic Studies
There is substantial scientific evidence that BPD is highly heritable—a finding that suggests that brain abnormalities of this disorder are a consequence of genes involved in brain development (similar to what is known about schizophrenia, bipolar disorder, and autism).

A systematic review of the heritabil­ity of BPD examined 59 published stud­ies that were categorized into 12 family studies, 18 twin studies, 24 association studies, and 5 gene-environment inter­action studies.3 The authors concluded that BPD has a strong genetic compo­nent, although there also is evidence of gene-environment (G.E) interactions (ie, how nature and nurture influence each other).

The G.E interaction model appears to be consistent with the theory that ex­pression of plasticity genes is modified by childhood experiences and environ­ment, such as physical or sexual abuse. Some studies have found evidence of hypermethylation in BPD, which can ex­ert epigenetic effects. Childhood abuse might, therefore, disrupt certain neuro­plasticity genes, culminating in morpho­logical, neurochemical, metabolic, and white-matter aberrations—leading to pathological behavioral patterns identi­fied as BPD.
 

The neuropsychiatric basis of BPD must guide treatment
There is no such thing as a purely psycho­logical disorder: Invariably, it is an abnor­mality of brain circuits that disrupts normal development of emotions, thought, behavior, and social cognition. BPD is an exemplar of such neuropsychiatric illness, and treat­ment should support psychotherapeutic ap­proaches to mend the mind at the same time it moves aggressively to repair the brain.

The prevailing view among many psy­chiatrists and mental health profession­als is that borderline personality disorder (BPD) is a “psychological” condition. BPD often is conceptualized as a behav­ioral consequence of childhood trauma; treatment approaches have emphasized intensive psychotherapeutic modali­ties, less so biologic interventions. You might not be aware that a large body of research over the past decade provides strong evidence that BPD is a neuro­biological illness—a finding that would drastically alter how the disorder should be conceptualized and managed.

Neuropathology underpins the personality disorder
Foremost, BPD must be regarded as a serious, disabling brain disorder, not simply an aberration of personality. In DSM-5, symptoms of BPD are listed as: feelings of abandonment; unstable and intense interpersonal relationships; un­stable sense of self; impulsivity; suicidal or self-mutilating behavior; affective in­stability (dysphoria, irritability, anxiety); chronic feelings of emptiness; intense anger episodes; and transient paranoid or dissociative symptoms. Clearly, these clusters of psychopathological and be­havioral symptoms reflect a pervasive brain disorder associated with abnormal neurobiology and neural circuitry that might, at times, stubbornly defy thera­peutic intervention.

No wonder that 42 published stud­ies report that, compared with healthy controls, people who have BPD display extensive cortical and subcortical abnor­malities in brain structure and function.¹ These anomalous patterns have been detected across all 4 available neuroim­aging techniques.

Magnetic resonance imaging. MRI studies have revealed the following abnormalities in BPD:
   • hypoplasia of the hippocampus, caudate, and dorsolateral prefrontal cortex
   • variations in the CA1 region of the hippocampus and subiculum
   • smaller-than-normal orbitofrontal cortex (by 24%, compared with healthy controls) and the mid-temporal and left cingulate gyrii (by 26%)
   • larger-than-normal volume of the right inferior parietal cortex and the right parahippocampal gyrus
   • loss of gray matter in the frontal, temporal, and parietal cortices
   • an enlarged third cerebral ventricle
   • in women, reduced size of the me­dial temporal lobe and amygdala
   • in men, a decreased concentra­tion of gray matter in the anterior cingulate
   • reversal of normal right-greater-than-left asymmetry of the orbitofron­tal cortex gray matter, reflecting loss of gray matter on the right side
   • a lower concentration of gray mat­ter in the rostral/subgenual anterior cin­gulate cortex
   • a  smaller frontal lobe.

In an analysis of MRI studies,2 cor­relation was found between structural brain abnormalities and specific symp­toms of BPD, such as impulsivity, sui­cidality, and aggression. These findings might someday guide personalized in­terventions—for example, using neuro­stimulation techniques such as repetitive transcranial magnetic stimulation and deep brain stimulation—to modulate the activity of a given region of the brain (depending on which symptom is most prominent or disabling).
 

Magnetic resonance spectroscopy. In BPD, MRS studies reveal:
   • compared with controls, a higher glutamate level in the anterior cingulate cortex
   • reduced levels of N-acetyl aspar­tate (NAA; found in neurons) and cre­atinine in the left amygdala
   • a reduction (on average, 19%) in the NAA concentration in the dorsolat­eral prefrontal cortex.

Functional magnetic resonance im­aging. From fMRI studies, there is evi­dence in BPD of:
   • greater activation of the amygdala and prolonged return to baseline
   • increased functional connectiv­ity in the left frontopolar cortex and left insula
   • decreased connectivity in the left cuneus and left inferior parietal and the right middle temporal lobes
   • marked frontal hypometabolism
   • hypermetabolism in the motor cor­tex, medial and anterior cingulate, and occipital and temporal poles
   • lower connectivity between the amygdala during a neutral stimulus
   • higher connectivity between the amygdala during fear stimulus
   • higher connectivity between the amygdala during fear stimulus
   • deactivation of the opioid system in the left nucleus accumbens, hypothal­amus, and hippocampus
   • hyperactivation of the left medial prefrontal cortex during social exclusion
   • more mistakes made in differenti­ating an emotional and a neutral facial expression.
 

Diffusion tensor imaging. DTI white-matter integrity studies of BPD show:
   • a bilateral decrease in fractional an­isotropy (FA) in frontal, uncinated, and occipitalfrontal fasciculi
   • a decrease in FA in the genu and rostrum of the corpus callosum
   • a decrease in inter-hemispheric connectivity between right and left ante­rior cigulate cortices.

Genetic Studies
There is substantial scientific evidence that BPD is highly heritable—a finding that suggests that brain abnormalities of this disorder are a consequence of genes involved in brain development (similar to what is known about schizophrenia, bipolar disorder, and autism).

A systematic review of the heritabil­ity of BPD examined 59 published stud­ies that were categorized into 12 family studies, 18 twin studies, 24 association studies, and 5 gene-environment inter­action studies.3 The authors concluded that BPD has a strong genetic compo­nent, although there also is evidence of gene-environment (G.E) interactions (ie, how nature and nurture influence each other).

The G.E interaction model appears to be consistent with the theory that ex­pression of plasticity genes is modified by childhood experiences and environ­ment, such as physical or sexual abuse. Some studies have found evidence of hypermethylation in BPD, which can ex­ert epigenetic effects. Childhood abuse might, therefore, disrupt certain neuro­plasticity genes, culminating in morpho­logical, neurochemical, metabolic, and white-matter aberrations—leading to pathological behavioral patterns identi­fied as BPD.
 

The neuropsychiatric basis of BPD must guide treatment
There is no such thing as a purely psycho­logical disorder: Invariably, it is an abnor­mality of brain circuits that disrupts normal development of emotions, thought, behavior, and social cognition. BPD is an exemplar of such neuropsychiatric illness, and treat­ment should support psychotherapeutic ap­proaches to mend the mind at the same time it moves aggressively to repair the brain.

The prevailing view among many psy­chiatrists and mental health profession­als is that borderline personality disorder (BPD) is a “psychological” condition. BPD often is conceptualized as a behav­ioral consequence of childhood trauma; treatment approaches have emphasized intensive psychotherapeutic modali­ties, less so biologic interventions. You might not be aware that a large body of research over the past decade provides strong evidence that BPD is a neuro­biological illness—a finding that would drastically alter how the disorder should be conceptualized and managed.

Neuropathology underpins the personality disorder
Foremost, BPD must be regarded as a serious, disabling brain disorder, not simply an aberration of personality. In DSM-5, symptoms of BPD are listed as: feelings of abandonment; unstable and intense interpersonal relationships; un­stable sense of self; impulsivity; suicidal or self-mutilating behavior; affective in­stability (dysphoria, irritability, anxiety); chronic feelings of emptiness; intense anger episodes; and transient paranoid or dissociative symptoms. Clearly, these clusters of psychopathological and be­havioral symptoms reflect a pervasive brain disorder associated with abnormal neurobiology and neural circuitry that might, at times, stubbornly defy thera­peutic intervention.

No wonder that 42 published stud­ies report that, compared with healthy controls, people who have BPD display extensive cortical and subcortical abnor­malities in brain structure and function.¹ These anomalous patterns have been detected across all 4 available neuroim­aging techniques.

Magnetic resonance imaging. MRI studies have revealed the following abnormalities in BPD:
   • hypoplasia of the hippocampus, caudate, and dorsolateral prefrontal cortex
   • variations in the CA1 region of the hippocampus and subiculum
   • smaller-than-normal orbitofrontal cortex (by 24%, compared with healthy controls) and the mid-temporal and left cingulate gyrii (by 26%)
   • larger-than-normal volume of the right inferior parietal cortex and the right parahippocampal gyrus
   • loss of gray matter in the frontal, temporal, and parietal cortices
   • an enlarged third cerebral ventricle
   • in women, reduced size of the me­dial temporal lobe and amygdala
   • in men, a decreased concentra­tion of gray matter in the anterior cingulate
   • reversal of normal right-greater-than-left asymmetry of the orbitofron­tal cortex gray matter, reflecting loss of gray matter on the right side
   • a lower concentration of gray mat­ter in the rostral/subgenual anterior cin­gulate cortex
   • a  smaller frontal lobe.

In an analysis of MRI studies,2 cor­relation was found between structural brain abnormalities and specific symp­toms of BPD, such as impulsivity, sui­cidality, and aggression. These findings might someday guide personalized in­terventions—for example, using neuro­stimulation techniques such as repetitive transcranial magnetic stimulation and deep brain stimulation—to modulate the activity of a given region of the brain (depending on which symptom is most prominent or disabling).
 

Magnetic resonance spectroscopy. In BPD, MRS studies reveal:
   • compared with controls, a higher glutamate level in the anterior cingulate cortex
   • reduced levels of N-acetyl aspar­tate (NAA; found in neurons) and cre­atinine in the left amygdala
   • a reduction (on average, 19%) in the NAA concentration in the dorsolat­eral prefrontal cortex.

Functional magnetic resonance im­aging. From fMRI studies, there is evi­dence in BPD of:
   • greater activation of the amygdala and prolonged return to baseline
   • increased functional connectiv­ity in the left frontopolar cortex and left insula
   • decreased connectivity in the left cuneus and left inferior parietal and the right middle temporal lobes
   • marked frontal hypometabolism
   • hypermetabolism in the motor cor­tex, medial and anterior cingulate, and occipital and temporal poles
   • lower connectivity between the amygdala during a neutral stimulus
   • higher connectivity between the amygdala during fear stimulus
   • higher connectivity between the amygdala during fear stimulus
   • deactivation of the opioid system in the left nucleus accumbens, hypothal­amus, and hippocampus
   • hyperactivation of the left medial prefrontal cortex during social exclusion
   • more mistakes made in differenti­ating an emotional and a neutral facial expression.
 

Diffusion tensor imaging. DTI white-matter integrity studies of BPD show:
   • a bilateral decrease in fractional an­isotropy (FA) in frontal, uncinated, and occipitalfrontal fasciculi
   • a decrease in FA in the genu and rostrum of the corpus callosum
   • a decrease in inter-hemispheric connectivity between right and left ante­rior cigulate cortices.

Genetic Studies
There is substantial scientific evidence that BPD is highly heritable—a finding that suggests that brain abnormalities of this disorder are a consequence of genes involved in brain development (similar to what is known about schizophrenia, bipolar disorder, and autism).

A systematic review of the heritabil­ity of BPD examined 59 published stud­ies that were categorized into 12 family studies, 18 twin studies, 24 association studies, and 5 gene-environment inter­action studies.3 The authors concluded that BPD has a strong genetic compo­nent, although there also is evidence of gene-environment (G.E) interactions (ie, how nature and nurture influence each other).

The G.E interaction model appears to be consistent with the theory that ex­pression of plasticity genes is modified by childhood experiences and environ­ment, such as physical or sexual abuse. Some studies have found evidence of hypermethylation in BPD, which can ex­ert epigenetic effects. Childhood abuse might, therefore, disrupt certain neuro­plasticity genes, culminating in morpho­logical, neurochemical, metabolic, and white-matter aberrations—leading to pathological behavioral patterns identi­fied as BPD.
 

The neuropsychiatric basis of BPD must guide treatment
There is no such thing as a purely psycho­logical disorder: Invariably, it is an abnor­mality of brain circuits that disrupts normal development of emotions, thought, behavior, and social cognition. BPD is an exemplar of such neuropsychiatric illness, and treat­ment should support psychotherapeutic ap­proaches to mend the mind at the same time it moves aggressively to repair the brain.