Ventromedial Prefrontal Cortex Is Critical for the Regulation of Amygdala Activity in Humans

Abstract

Background Dysfunction in ventromedial prefrontal cortex (vmPFC) is believed to play a pivotal role in the pathogenesis of mood and anxiety disorders. Leading neurocircuitry models of these disorders propose that hypoactivity in vmPFC engenders disinhibited amygdala activity, and consequently, pathologically elevated levels of negative affect. This model predicts that a selective loss or diminution of vmPFC function would result in heightened amygdala activity. While this prediction has been borne out in rodent lesion and electrophysiological studies using fear conditioning and extinction paradigms, there has not yet been a definitive test of this prediction in humans. Methods In this study, we tested this prediction through a novel use of fMRI in n=4 neurosurgical patients with focal, bilateral vmPFC damage. Results Relative to neurologically healthy comparison subjects, the vmPFC lesion patients exhibited potentiated amygdala responses to aversive images as well as elevated rest-state amygdala functional connectivity. We observed no comparable group differences for activity in other brain regions. Conclusions These results provide unique evidence for the critical role of vmPFC in regulating amygdala activity in humans, and help elucidate the causal neural interactions that underlie mental illness.

The Neurobiology of Impulsive Aggression

“…Consistent with this view, some animal studies show that lesions of the vmPFC increase aggression (Izquierdo et al 2005), and human patients with vmPFC lesions are at increased risk for impulsive aggression (Grafman et al 1996). In addition, there has been a report that lesions of the vmPFC show increased amygdala responses to threatening stimuli relative to comparison individuals (Motzkin et al 2015), although other studies report that patients with vmPFC lesions show typical transient reactions to emotional stimuli (Gillihan et al 2011). Moreover, at first pass, the data from the studies of approaching threat also support the ''brakes'' view.…”

The Neuro-Environmental Loop of Plasticity: A Cross-Species Analysis of Parental Effects on Emotion Circuitry Development Following Typical and Adverse Caregiving

“…In addition, on a different emotion regulation task involving cognitive reappraisal of a negative event, the amygdala showed stronger coupling with the dlPFC, OFC, subgenual ACC, and dmPFC, with the extent of such coupling being positively associated with post-reappraisal attenuation of negative affect (Banks et al, 2007;Ochsner et al, 2002;Urry et al, 2006). Indeed, weak amygdala-mPFC connections result in pathological emotional overarousal (Milad et al, 2008(Milad et al, , 2009Motzkin et al, 2015). Hence, in adults, there is clear evidence for the role of prefrontal regions in emotion regulation and control of amygdala output.…”

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

“…The ventromedial prefrontal cortex (VMPFC) plays a critical role in regulation of amygdala activity (Blair, 2013;Motzkin et al, 2015). ASD subjects show increased neuronal activities in the VMPFC and amygdala in response to emotional stimuli and higher microglial activity in the VMPFC (Monk et al, 2010;Suzuki et al, 2013).…”