Sahib Khalsa Profile picture
Feb 2, 2022 22 tweets 8 min read Read on X
Ever wonder how physical sensations such as a racing heart give rise to fear? Using an adrenaline-like challenge during brain imaging we found that abnormal heart-brain communication contributes to increased fear in women with generalized anxiety disorder…ja.ma/3GmzcSH
First, women with GAD showed a peripheral hypersensitivity to stimulation across all doses indicating that it took less adrenaline to make their hearts race than unaffected individuals… (2/n)
Second, the racing heart rates were accompanied by increased heartbeat sensations. But this difference happened only during a low level of stimulation… (3/n)
Suggesting that an interaction between the peripheral and central nervous systems must have selectively driven the differences in experience reported by the GAD patients… (4/n)
Using fMRI, we localized the source of this difference in ‘interoceptive awareness’ to a specific region of the brain. But it wasn’t the first area you would immediately think of… (5/n)
While we found that the paradigm focally activated the insular cortex in a dose-dependent manner… (6/n)
It was the ventromedial prefrontal cortex (vmPFC) that showed group differences in activation. Specifically, a blunted response occurred only at the lower level of stimulation, suggesting this brain region played a key role in the interoceptive differences seen earlier... (7/n)
Consistent with this interpretation, vmPFC hypoactivation was associated with heart rate responses, as well as heartbeat and breathing sensations… (8/n)
But not anxiety, despite the fact the drug increased anxiety to a greater extent in the patients at all levels of stimulation… (9/n)
So…what does this all mean? (10/n)
We think that in GAD, a lack of ‘top-down’ regulation in the presence of heightened ‘bottom-up’ sympathetic nervous system stimulation elicits an internal state that promotes anxiety… (11/n)
The lack of vmPFC associations with anxiety suggest that a more broadly distributed neurocircuitry is important for generating the experience of anxiousness in GAD… (12/n)
Maybe dysregulation within vmPFC-to-insula circuitry entails a failure to constrain sympathetic arousal resulting in downstream consequences such as worry, rumination, & anxiety. Some supporting evidence here: biorxiv.org/content/10.110… (13/n)
Our findings are consistent with recent conceptualizations of anxiety @theamygdaloid highlighting the role of higher-order circuits in subjectively experienced fear that is triggered by defensive bodily reactions… nature.com/articles/s4138… (14/n)
As well as a robust literature detailing the role of the vmPFC in discerning safety from threat... @DeanMobbs (14/n)
doi.org/10.1016/j.tics…
To our knowledge, this is the first functional neuroimaging study to examine how the direct modulation of interoceptive signals influences fear-related (ie, vmPFC) neurocircuitry in individuals with clinical anxiety… (15/n)
Potential clinical applications include pharmacological or neuromodulation targeting of vmPFC responses to determine their effect on anxious rumination in GAD. Real-time fMRI neurofeedback or transcranial focused ultrasound (tFUS) are methods that come to mind… (16/n)
Overall, this experimental medicine study provides novel mechanistic evidence that the autonomic and central nervous systems both contribute to the interoceptive pathophysiology of GAD. #interoception… (17/n)
So, the next time someone says that anxiety is “all in your head” you can correct them: it’s driven by your brain and body. And sometimes, it’s the interaction between them that may be the deciding fear factor… (18/n)
Huge thanks to intrepid first author Adam Teed, @mpwpaulus,@wesstat,@RachelcLapidus,@FloatResearch, Maria Puhl, Valerie Upshaw, Rayus Kuplicki, Walt Kaye, Olu Ajijola, Jerzy Bodurka, LIBR volunteers/staff who assisted the study & our funders @NIMH @NIGMS The WKW Foundation (19/n)
Adam is currently on the job market, with interests in #digitaltherapeutics #digitalpsychiatry #psychedelicmedicine. Find him here:
linkedin.com/in/adam-teed-b… (20/n)
Postscript: there’s much more in the paper and Supplement, including a Bayesian longitudinal time series analysis, ROI analyses of other limbic regions (e.g. amygdala), and evaluation of interoceptive accuracy. Thanks for reading to the end! (End)

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More from @KhalsaLab

Mar 13, 2022
Has anxiety ever taken your breath away? Wondered how your brain caused that to happen?
A brief🧵
In this review/theory paper led by Justin Feinstein @FloatResearch in a special issue on respiration in Biological Psychology, we highlight an interoceptive role for the amygdala in apnea-induced anxiety & inhibition of CO2-related fear doi.org/10.1016/j.biop…
2/
First, we review neurosurgical evidence showing that human amygdala stimulation reliably induces apnea without awareness. In other words, amygdala activation can literally "take one’s breath away" and the individual won’t even know it! 3/
Read 13 tweets

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