- BPD patients failed to show increase in post-task amygdala resting state functional connectivity (rsFC) with mPFC, dlPFC, and vlPFC, but did show decrease in amygdala-PCC rsFC
   - Indicates that BPD have difficulty rationalizing a stimulus/situation that prompted an emotional reaction, increasing the time it takes for them to return to baseline
- Post-regulatory task, BPD patients should be better able to do this, but healthy controls had significant improvement over patients
   - extrapolation: impaired top-down cortical modulation of extreme emotion
   - Further identifies amygdala-PFC FC as critical for BPD FC


University of Minnesota - Twin Cities

- The typical areas that have been subject to study are the nuclei clusters comprising the amygdalae and the prefrontal cortex (PFC) as their functionality and activation is abnormal relative to healthy controls.
   - The amygdalae constitute part of the limbic system and play a role in the emotional response to a stimulus, most notably inducing physiological reactions to fear, anger, anxiety, and aggression.
      - Hyperarousal of the amygdalae give rise to the intense emotional responses that are characteristic of BPD.
   - The PFC is a major contributor to our executive control, influencing emotional and motivational behaviors.
      - Diminished efficacy of top-down cortical modulation—wherein the brain uses models, ideas, and expectations to interpret sensory information—is observed in BPD, as misinterpretation of events often invokes the onset of a crisis. 
- Both the amygdalae and the PFC are associated with different neural networks.
   - Within the SN, a network that detects and incorporates emotional and sensory stimuli, the amygdalae are considered a subcortical node.
   - Subsections of the PFC are classified as cortical nodes in the DFN, a network involved in various functions but guessed at being the primary determinant of the neurological basis for the self.
- Abnormal neuronal connectivity of the amygdalae and the PFC may be an underlying cause of the impaired communication between the aforementioned neural networks often reported in BPD.

Functional Connectivity in BPD

Baczkowski, B. M., van Zutphen, L., Siep, N., Jacob, G. A., Domes, G., Maier, S., Sprenger, A., Senft, A., Willenborg, B., Tüscher, O., Arntz, A., & van de Ven, V. (2017). Deficient amygdala-prefrontal intrinsic connectivity after effortful emotion regulation in borderline personality disorder. European Archives of Psychiatry and Clinical Neuroscience, 267, 551-565. https://doi.org/10.1007/s00406-016-0760-z

Deficient amygdala-prefrontal intrinsic connectivity after effortful emotion regulation in borderline personality disorder

- In BPD subjects, there was an increased size of largest connected component (LCC).
   - Increased size of LCC indicates a lower number of disconnected nodes in a functional network.
- In BPD subjects, there was increased small-worldness, clustering coefficients, and local efficiency.
   - Small-world systems have the ability for specialized processing to occur within densely interconnected groups of brain regions and also has the ability to combine specialized information from distributed brain regions.
   - Clustering coefficients are defined as the ratio of the number of existing links and the number of all possible links between the direct neighbors of the node.
   - Local efficiency measures how efficiently information is exchanged over the network.
- Increased clustering coefficients and local efficiency indicates greater network "cliquishness" (i.e., more clustered structure).
   - Increased cliquishness seen in limbic and paralimbic brain regions, including the amygdala.
     - Could explain vulnerability to the fast and extreme reaction to a negative stimulus, the emotion being difficult to regulate.
- BPD subjects suggest long-distance functional connections between regions associated with self-referential processes. 
- BPD subjects might also cause an increase in the number of connections to non-hub nodes and a decrease in the number of connections to hub nodes in functional brain networks.
   - An example of a hub node is the posterior cingulate cortex (PCC), acting as a literal hub that contributes connections to other networks. 

Differences in topological brain organization in BPD

- The salience network (SN) is anchored to the bilateral insula and anterior cingulate cortex (ACC).
   - Subtle alterations in functional connectivity (FC) at the local level observed in BPD subjects.
   - Intrinsic connectivity varies more widely across BPD patients.
- The default mode network (DMN) includes the posterior cingulate cortex (PCC), inferior parietal lobule, lateral temporal lobes, bilateral hippocampi, mPFC, and dlPFC.
   - BPD patients had modest reductions in intrinsic FC with uniform distribution across DMN.

Altered extrinsic connectivity of networks in BPD

- Healthy controls (HCs) had increased functional connectivity (FC) between precuneus and default mode network (DMN)-associated structures
- BPD patients had less intrinsic connectivity between DMN structures than HCs
   - extrapolation: BPD patients seemed more doubtful and unsure about the interpersonal content of the stimuli, which is in line with BPD symptomatology
- Also found decreased FC between anterior cingulate cortex (ACC) and ToM-associated regions in BPD patients
   - Pain activates the limbic system because the unpleasantness of pain is encoded in the ACC (ACC neurons have large, diffuse receptive fields); thus, this enables pain to be cognitive-emotional
      - i.e., assigns feelings/emotions to physical sensations
   - Reduced FC indicates lack of modulation of ToM network from regions involved in emotional processing


 Deficits in Theory of Mind (ToM) processing in BPD

Ineffective emotional regulation in BPD

- Neurofeedback (NF) training allows for changes in neural activity to be monitored in real-time and reported to a patient via a visual display.
   - NF can enhance self-control of brain regions by showing dysregulation and may improve behavioral impairment.
   - Training downregulation in BPD patients may help decrease amygdala hyperactivity; thus, improving emotion regulation.
- Resting-state fMRI (rsfMRI) scans can be obtained before NF training sessions for comparison of before and after.
- Amygdala NF during presentation of aversive pictures was associated with successful down-regulation of right dorsal amygdala activation in BPD patients.
   - extrapolation: limbic hyperreactivity and lPFC hypoactivity are considered neural correlates of emotion dysregulation in patients
- It was found that BPD patients had increased amygdala-dlPFC functional connectivity (FC) at rest, and decreased amygdala-other limbic regions FC at rest.

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