Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness

Abstract

Corticostriatal circuits through the orbitofrontal cortex (OFC) play key roles in complex human behaviors such as evaluation, affect regulation and reward-based decision-making. Importantly, the medial and lateral OFC (mOFC and lOFC) circuits have functionally and anatomically distinct connectivity profiles which differentially contribute to the various aspects of goal-directed behavior. OFC corticostriatal circuits have been consistently implicated across a wide range of psychiatric disorders, including major depressive disorder (MDD), obsessive compulsive disorder (OCD), and substance use disorders (SUDs). Furthermore, psychiatric disorders related to OFC corticostriatal dysfunction can be addressed via conventional and novel neurostimulatory techniques, including deep brain stimulation (DBS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Such techniques elicit changes in OFC corticostriatal activity, resulting in changes in clinical symptomatology. Here we review the available literature regarding how disturbances in mOFC and lOFC corticostriatal functioning may lead to psychiatric symptomatology in the aforementioned disorders, and how psychiatric treatments may exert their therapeutic effect by rectifying abnormal OFC corticostriatal activity. First, we review the role of OFC corticostriatal circuits in reward-guided learning, decision-making, affect regulation and reappraisal. Second, we discuss the role of OFC corticostriatal circuit dysfunction across a wide range of psychiatric disorders. Third, we review available evidence that the therapeutic mechanisms of various neuromodulation techniques may directly involve rectifying abnormal activity in mOFC and lOFC corticostriatal circuits. Finally, we examine the potential of future applications of therapeutic brain stimulation targeted at OFC circuitry; specifically, the role of OFC brain stimulation in the growing field of individually-tailored therapies and personalized medicine in psychiatry.

Keywords: brain stimulation; corticostriatal circuits; orbitofrontal cortex (OFC); psychiatric disease; research domain criteria (RDoC).

Figure 1

Structure of the cortico-striatal loops stemming from the orbitofrontal cortex (OFC) subregions. (A) Schematic showing the entire medial OFC (mOFC) cortico-striatal loop, originating from the mOFC shown in red. (B) Schematic showing the entire lateral OFC (lOFC) cortico-striatal loop, originating from the lOFC shown in blue. mOFC, medial orbitofrontal cortex; VM Caudate, ventromedial caudate; NAcc, nucleus accumbens; GPi, globus pallidus interna; SN, substantia nigra; DM Thalamus, dorsomedial thalamic nuclei; VA Thalamus, ventroanterior thalamic nuclei; VL Thalamus, ventrolaterial thalamic nuclei.

Figure 2

Functional profiles of the mOFC and lOFC subregions. (A) A connectivity-based parcellation of the OFC from resting-state functional magnetic resonance imaging (fMRI) revealed distinct medial and lateral subdivisions based on a K = 2 cluster solution using K-means clustering. Adapted from Kahnt et al. (2012). (B) Functional connectivity of the mOFC and lOFC subregions using meta-analytic connectivity modeling (MACM). The mOFC was found to primarily coactivate with regions of the default mode network (DMN), including the ventromedial prefrontal cortex (VMPFC) and the posterior cingulate cortex (PCC). The lOFC coactivated with cognitive control regions including the dorsomedial and dorsolateral prefrontal cortices (DMPFC and DLPFC, respectively), as well regions of the salience network including the bilateral anterior insula and rostral anterior cingulate cortex (rACC). Adapted from Zald et al. (2014). (C) Functional connectivity of the mOFC and lOFC subregions using resting-state functional connectivity (rsFC) analyses. As with the findings of the MACM technique described above, the mOFC was functionally connected with regions of the DMN, while the lOFC was functionally connected to cognitive control regions. Adapted from Kahnt et al. (2012).

Figure 3

Functional roles of the mOFC and lOFC subregions. (A) The lOFC is selectively activated during reversal learning, when a behavioral switch was required. Schematic adapted from Kringelbach and Rolls (2004). (B) The critical role of the right lOFC and the mOFC for probabilistic and reversal learning, as determined using voxel-based lesion-symptom mapping in patients with focal lesions of the OFC. Adapted from Tsuchida et al. (2010). (C) The mOFC encodes prediction error, calculating the difference between the actual and expected reward outcome. Schematic adapted from Boorman et al. (2009). (D) The lOFC encodes fictive error, computing the evidence for switching behavior based on reward value of previously unchosen actions. Schematic adapted from Boorman et al. (2009). (E) When a stimulus (eating chocolate) is rated as being highly pleasurable prior to satiety, the mOFC is recruited. Courtesy of Small et al. (2001). (F) As participants continued to eat the chocolate beyond satiety, the lOFC becomes preferentially activated. Courtesy of Small et al. (2001). (G) Successful emotional reappraisal is correlated with activation of the lOFC. Adapted from Wager et al. (2008). (H) During successful emotional reappraisal, the right lOFC is mediated by the amygdala. Adapted from Wager et al. (2008).

Figure 4

Modulations of OFC activity associated with non-invasive brain stimulation paradigms. (A) Following inhibitory OFC-repetitive transcranial magnetic stimulation (rTMS), obsessive compulsive disorder (OCD) symptom improvement was associated with a reduction in activity of the right lOFC, as shown in (i) and visualized in (ii). Adapted from Nauczyciel et al. (2014). (B) Inhibiting the mOFC with rTMS in cocaine addicted subjects led to an attenuation of craving that was associated with decreases in activation of the lOFC and the mOFC. Courtesy of Hanlon et al. (2015). (C) Acute administration of electroconvulsive therapy (ECT) reveals increases in regional cerebral blood flow in the lOFC and associated striatal components including anterior striatum, amygdala, globus pallidus, and thalamus. Yellow indicates areas with a greater increase in regional cerebral blood flow; red indicates areas with a lower increase in regional cerebral blood flow. Schematic adapted from Takano et al. (2007). (D) Depressive symptom improvement following ECT is correlated with reductions in activity of the bilateral OFC and the frontal pole. Schematic adapted from Henry et al. (2001).