Global Prefrontal and Fronto-Amygdala Dysconnectivity in Bipolar I Disorder with Psychosis History

Abstract

Background Pathophysiological models of bipolar disorder postulate that mood dysregulation arises from fronto-limbic dysfunction, marked by reduced prefrontal cortex (PFC) inhibitory control. This may occur both due to disruptions within PFC networks and abnormal inhibition over subcortical structures involved in emotional processing. However, no study has examined global PFC dysconnectivity in bipolar disorder and tested if regions with within-PFC dysconnectivity also exhibit fronto-limbic connectivity deficits. Further, no study has investigated whether such connectivity disruptions differ for bipolar patients with psychosis history, who may exhibit a more severe clinical course. Methods We collected resting-state fMRI at 3T in 68 remitted bipolar I patients (34 with psychosis history) and 51 demographically-matched healthy participants. We employed a recently developed Global Brain Connectivity method, restricted to PFC (rGBC). We also independently tested connectivity between anatomically-defined amygdala and PFC. Results Bipolar patients exhibited reduced medial PFC (mPFC) rGBC, increased amygdala-MPFC connectivity, and reduced connectivity between amygdala and dorso-lateral PFC. All effects were driven by psychosis history. Moreover, the magnitude of observed effects was significantly associated with lifetime psychotic symptom severity. Conclusions This convergence between rGBC, seed-based amygdala findings and symptom severity analyses highlights that mPFC, a core emotion regulation region, exhibits both within-PFC dysconnectivity and connectivity abnormalities with limbic structures in bipolar illness. Furthermore, lateral PFC dysconnectivity in patients with psychosis history converges with published work in schizophrenia, indicating possible shared risk factors. Observed dysconnectivity in remitted patients suggests a bipolar trait characteristic and may constitute a risk factor for phasic features of the disorder.

Save the Global: Global Signal Connectivity as a Tool for Studying Clinical Populations with Functional Magnetic Resonance Imaging

“…Studies focused on the prefrontal cortex found connectivity in this area to be aberrant using the GBC measure in schizophrenia (Cole et al, 2011;Yang et al, 2014) and bipolar disorder (Anticevic et al, 2013). Others found a reduction in global FC in a group of participants with autistic spectrum disorder in comparison to controls, and, therefore, did not regress the global signal from the data .…”

“…In addition, the GBC is also used to study clinical populations. For example, specific prefrontal cortex functional alternations in schizophrenia (Cole et al, 2011), bipolar disorder (Anticevic et al, 2013), and obsessive-compulsive disorder (Anticevic et al, 2014) were studied using this method. Recently, this measure was also used to study the relationship between spontaneous FC and schizophrenia-like symptoms in healthy participants (Driesen et al, 2013).…”

“…Next, we reveal a tight relationship between the GBC measure and voxel-wise FC of the global signal, using both theoretical and experimental methods. Since the GBC method is widely used to characterize neural pathologies (Anticevic et al, 2013(Anticevic et al, , 2014Cole et al, 2011), its high resemblance to global signal FC suggests that the global signal holds value as a research tool of various clinical conditions. Finally, these findings extend previous suggestions related to the perils of global signal regression from data of clinical populations (Gotts et al, 2013;Saad et al, 2012) to schizophrenia, in which resting-state data have been extensively used (Calhoun et al, 2009).…”

Ketamine Treatment and Global Brain Connectivity in Major Depression

“…Moreover, GBCr has been successfully used to identify alterations across major networks in clinical conditions. Reduced PFC GBCr was reported in bipolar, chronic schizophrenia, and obsessive-compulsive disorders; all of which harbor a strong component of chronic stress and were previously related to glutamate synaptic homeostasis (Anticevic et al, 2013;Anticevic et al, 2015a;Anticevic et al, 2014;Cole et al, 2011). Additionally, ketamine has been repeatedly shown to increase PFC GBCr during ketamine infusion in healthy volunteers (Anticevic et al, 2015a;Driesen et al, 2013a;Driesen et al, 2013b).…”

The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity

“…Acute effects of MDPV at low-to-moderate doses are likely to involve brain reward regions targeted by other stimulants, such as cocaine and METH (Baumann et al, 2012;Simmler et al, 2013), whereas higher doses have the potential to influence other brain networks (Penders and Gestring, 2011). Given the nature of the reported behavioral disturbances, it is possible that MDPV causes disruptions in the coherent interactions among brain regions that are necessary for normal cognition and affect, as reported in other neuropsychiatric conditions involving audiovisual hallucinations (Anticevic et al, 2013;Lui et al, 2009;Sommer et al, 2012;Wolf et al, 2011).…”