Cortico-Striatal-Thalamic Loop Circuits of the Salience Network: A Central Pathway in Psychiatric Disease and Treatment.

Sarah K Peters,Katharine Dunlop,Jonathan Downar

doi:10.3389/fnsys.2016.00104

Sarah K Peters, Katharine Dunlop + Show 1 more

Open Access

https://doi.org/10.3389/fnsys.2016.00104

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Abstract

The salience network (SN) plays a central role in cognitive control by integrating sensory input to guide attention, attend to motivationally salient stimuli and recruit appropriate functional brain-behavior networks to modulate behavior. Mounting evidence suggests that disturbances in SN function underlie abnormalities in cognitive control and may be a common etiology underlying many psychiatric disorders. Such functional and anatomical abnormalities have been recently apparent in studies and meta-analyses of psychiatric illness using functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM). Of particular importance, abnormal structure and function in major cortical nodes of the SN, the dorsal anterior cingulate cortex (dACC) and anterior insula (AI), have been observed as a common neurobiological substrate across a broad spectrum of psychiatric disorders. In addition to cortical nodes of the SN, the network’s associated subcortical structures, including the dorsal striatum, mediodorsal thalamus and dopaminergic brainstem nuclei, comprise a discrete regulatory loop circuit. The SN’s cortico-striato-thalamo-cortical loop increasingly appears to be central to mechanisms of cognitive control, as well as to a broad spectrum of psychiatric illnesses and their available treatments. Functional imbalances within the SN loop appear to impair cognitive control, and specifically may impair self-regulation of cognition, behavior and emotion, thereby leading to symptoms of psychiatric illness. Furthermore, treating such psychiatric illnesses using invasive or non-invasive brain stimulation techniques appears to modulate SN cortical-subcortical loop integrity, and these effects may be central to the therapeutic mechanisms of brain stimulation treatments in many psychiatric illnesses. Here, we review clinical and experimental evidence for abnormalities in SN cortico-striatal-thalamic loop circuits in major depression, substance use disorders (SUD), anxiety disorders, schizophrenia and eating disorders (ED). We also review emergent therapeutic evidence that novel invasive and non-invasive brain stimulation treatments may exert therapeutic effects by normalizing abnormalities in the SN loop, thereby restoring the capacity for cognitive control. Finally, we consider a series of promising directions for future investigations on the role of SN cortico-striatal-thalamic loop circuits in the pathophysiology and treatment of psychiatric disorders.

Highlights

Psychiatric illnesses are among the leading causes of disability and disease burden worldwide in the 21st century
The finding of dACC CSTC functional connectivity as both a predictor and correlate of clinical improvement was replicated in a follow-up study in ED patients undergoing dmPFC-Repetitive Transcranial Magnetic Stimulation (rTMS) for binge and purge behaviors (Dunlop et al, 2015a). In another follow-up study in patients with OCD (Dunlop et al, 2016), connectivity from the dACC to the head of the caudate nucleus and the MD thalamus was a predictor and a correlate of clinical improvement; reductions rather than increases in connectivity within this CSTC loop were required for clinical improvement, paralleling the findings of Figee et al (2014) in OCD patients undergoing Deep Brain Stimulation (DBS). These findings suggest that the therapeutic effects of rTMS in major depressive disorder (MDD), ED and OCD may be mediated by changes in the integrity of the SN-CSTC circuit
A recent study using magnetic resonance spectroscopy (MRS) has for the first time directly demonstrated that active but not sham dlPFC-Transcranial Direct Current Stimulation (tDCS) increases levels of glutamate and glutamine in the striatum as well as N-acetylaspartate in the dlPFC itself (Hone-Blanchet et al, 2015). These findings suggest that tDCS can modulate both neurotransmission and network connectivity patterns in the subcortical as well as the cortical components of CSTC loops when targeting the SN

Summary

INTRODUCTION

Psychiatric illnesses are among the leading causes of disability and disease burden worldwide in the 21st century. The dlPFC primarily projects to the dorsolateral caudate to serve cognitive control and executive functioning (Furman et al, 2011), while the thalamic MDN supports cortico-striatal-cortical information transfer and modulates cortical activity through extensive connections with the PFC and midbrain dopaminergic regions (Mitchell, 2015). On resting-state fMRI, reduced dorsal caudate-anterior thalamus functional connectivity was associated with symptomatic improvement following fluoxetine (Anticevic et al, 2014) Such findings highlight the importance of SN-CSTC dysfunction in the pathophysiology of OCD. With regards to abnormalities throughout CSTC loops, individuals with PTSD have been shown to have reduced thalamic functional connectivity with a variety of brain regions including the rostral ACC and mPFC (Duarte et al, 2011; Yin et al, 2011), and it has been suggested that flashback symptoms occur in part due to dysfunctional corticothalamic activity (Liberzon et al, 1996/1997). The dorsal neural system supporting such regulatory capacity—which includes functions of inhibition, emotion regulation, and goal-directed behavior—includes the dorsal caudate, dACC and insula, among other SN regions (Wierenga et al, 2014)

Summary

CONCLUSION