Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change

Abstract

Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129 non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesis-driven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in earlycourse patients, predictive of symptoms and diagnostic classification, but less evidence for "hypoconnectivity." At the whole-brain level, we observed "hyperconnectivity" around areas centered on the default system, with modest overlap with PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n ϭ 25), which also predicted immediate symptom improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may decrease longitudinally, could have prognostic and therapeutic implications.

Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade

“…[40][41][42] Moreover, recent functional MRI studies have indicated that functional connectivity in the prefrontal cortex increases with the severity of psychotic symptoms, especially in the early stage of schizophrenia. 43,44 As functional hyperconnectivity may be reflected in regional FA increases, [40][41][42] our findings of both positive and negative associations with positive symptoms in 2 closely linked anatomical structures (AF and SLF) support the idea that psychotic symptoms arise from regional irregularities in white matter rather than deficits per se.…”

Imaging human brain networks to improve the clinical efficacy of non-invasive brain stimulation

“…In line with these results, recent resting-state fMRI investigations have shown that symptoms of schizophrenia involve widespread hypo-connectivity between frontal areas and temporal, thalamic, and striatal regions Anticevic et al, 2015;Cocchi et al, 2014; van den Heuvel M a n u s c r i p t Sale et al,30 and Fornito, 2014). This hypoconnectivity has often been associated with an early dysregulation in the function of frontal circuitry (Anticevic et al, 2015). An excitatory tDCS paradigm targeting a highly interconnected hub in the lateral frontal cortex, such as the DLPFC, may provide a means to restore widespread patterns of connectivity associated with frontal areas.…”

“…Such deficits have been consistently associated with altered lateral prefrontal activity (Tan et al, 2005). In line with these results, recent resting-state fMRI investigations have shown that symptoms of schizophrenia involve widespread hypo-connectivity between frontal areas and temporal, thalamic, and striatal regions Anticevic et al, 2015;Cocchi et al, 2014; van den Heuvel M a n u s c r i p t Sale et al,30 and Fornito, 2014). This hypoconnectivity has often been associated with an early dysregulation in the function of frontal circuitry (Anticevic et al, 2015).…”

Ketamine Treatment and Global Brain Connectivity in Major Depression

“…In contrast, chronic stress is believed to precipitate glutamatergic dysregulation, leading to increased extracellular glutamate, and excitotoxicity, with subsequent synaptic dysconnectivity and reduced synaptic strength (Bessa et al, 2009;Kang et al, 2012;Yuen et al, 2012). Intriguingly, earlycourse schizophrenia patients were found to have increased PFC GBCr (Anticevic et al, 2015a;Anticevic et al, 2015b). However, following a long course of illness, chronic schizophrenia patients showed significant reduction in PFC GBCr (Anticevic et al, 2015a;Cole et al, 2011).…”

“…Details of GBCr methods were previously described (Anticevic et al, 2013;Anticevic et al, 2015a;Anticevic et al, 2014;Anticevic et al, 2015b;Cole et al, 2011;Cole et al, 2012;Driesen et al, 2013a;Driesen et al, 2013b) (see Supplementary Information). GBCr value for each voxel is the average of the correlation between the BOLD time series of a voxel and all other gray matter voxels in the brain.…”