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

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.

Keywords: anxiety disorders; brain stimulation; corticostriatal; depression; repetitive transcranial magnetic stimulation; salience network; substance use disorders.

Figure 1

Meta-analytic co-activation of salience network (SN) nodes for response selection and inhibition. Neurosynth meta-analytic results following key word searches for “response inhibition”, “response selection” and “SN”. Considerable overlap exists in the dorsal anterior cingulate cortex (dACC) region (A) and lateral parietal cortex (B).

Figure 2

Cortical and subcortical nodes of the SN from meta-analyses of functional magnetic resonance imaging (fMRI) studies of task-based activation during cognitive control. Subcortical components of SN processing are apparent across a variety of executive functioning tasks, including Stroop task, set shifting task, Go-No Go task and Flanker interference task, as shown through meta-analytic functional imaging data.

Figure 3

SN cortico-striatal-thalamo-cortical circuit engagement during therapeutic brain stimulation. (A) In healthy controls, 10 Hz repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (dlPFC) results in increased dopamine transmission in the ipsilateral caudate nucleus and thalamus. (B) In depressed individuals, clinical improvement following 10 Hz dmPFC-rTMS was correlated with increased connectivity between the dACC and the thalamus. (C,D) In obsessive-compulsive disorder (OCD) patients, clinical improvement following 10 Hz dmPFC-rTMS was correlated with decreased functional connectivity between the dACC and the caudate nucleus, thalamus, putamen and midbrain. Adapted from (A) Strafella et al. (2001); (B) Salomons et al. (2014); (C,D) Dunlop et al. (2016).