Structural Thalamofrontal Hypoconnectivity Is Related to Oculomotor Corollary Discharge Dysfunction in Schizophrenia

Abstract

By predicting sensory consequences of actions, humans can distinguish self-generated sensory inputs from those that are elicited externally. This is one mechanism by which we achieve a subjective sense of agency over our actions. Corollary discharge (CD) signals-"copies" of motor signals sent to sensory areas-permit such predictions, and CD abnormalities are a hypothesized mechanism for the agency disruptions in schizophrenia that characterize a subset of symptoms. Indeed, behavioral evidence of altered CD, including in the oculomotor system, has been observed in schizophrenia patients. A pathway projecting from the superior colliculus to the frontal eye fields (FEFs) via the mediodorsal thalamus (MD) conveys oculomotor CD associated with saccadic eye movements in nonhuman primates. This animal work provides a promising translational framework in which to investigate CD abnormalities in clinical populations. In the current study, we examined whether structural connectivity of this MD-FEF pathway relates to oculomotor CD functioning in schizophrenia. Twenty-two schizophrenia patients and 24 healthy control participants of both sexes underwent diffusion tensor imaging, and a large subset performed a trans-saccadic perceptual task that yields measures of CD. Using probabilistic tractography, we identified anatomical connections between FEF and MD and extracted indices of microstructural integrity. Patients exhibited compromised microstructural integrity in the MD-FEF pathway, which was correlated with greater oculomotor CD abnormalities and more severe psychotic symptoms. These data reinforce the role of the MD-FEF pathway in transmitting oculomotor CD signals and suggest that disturbances in this pathway may relate to psychotic symptom manifestation in patients.

Organization of Corollary Discharge Neurons in Monkey Medial Dorsal Thalamus

“…This should provide the critical information for locating these neurons in future studies. In addition, our results provide the necessary information for comparing the location of CD neurons in the monkey with the recent identification in humans of a lateral area of MD with connections to the FEF using diffusion tensor imaging (Yao et al, 2019). In both monkey and humans, the area is at the lateral edge of MD, although it is somewhat lower on the lateral edge in our monkeys than in the human.…”

“…In the present experiments, we made a systematic series of penetrations covering the relevant regions of lateral MD. This meticulous localization of the CD pathway to FEF allows a better comparison to the same pathway recently demonstrated in humans using diffusion tensor imaging (Yao et al, 2019). This monkey-to-human comparison has additional significance given the recently recognized similarity between the behavior of monkeys with inactivations of the CD in MD (Sommer and Wurtz, 2008) and difficulty of schizophrenic patients in identifying the origin of their actions (Thakkar et al, 2017;Bansal et al, 2018), comparisons that are considered in the discussion.…”

“…Similar behavioral studies were then conducted in normal humans and in schizophrenic patients (for review, see Thakkar et al, 2017;Bansal et al, 2018), and deficits with similarities to those found in monkeys were found in these patients. In addition, the pathway between MD and FEF was found to be compromised in schizophrenic patients compared with human control subjects (Yao et al, 2019).…”

Altered thalamocortical structural connectivity in persons with schizophrenia and healthy siblings

“…The study was approved by the Medical Ethical Committee of the University Medical Center, Utrecht, The Netherlands. MRI data from a subset of current participants have been reported in previous studies ( Yao et al, 2019 , Thakkar et al, 2016 , Thakkar et al, 2017 , Asscheman et al, 2016 ).…”

Organization of primate amygdalar–thalamic pathways for emotions

“…The interactions of pathways that underlie the complex processes for decision and action are disrupted in psychosis (reviewed in [61]) and in anxiety disorders that affect emotional processing through the amygdala (e.g., [5]). Considerable evidence suggests disruption of corollary discharge mechanisms in schizophrenia, affecting the sense of agency and attribution of thoughts, desires, and actions to external sources (e.g., [62][63][64][65][66][67][68][69][70]). The thalamocortical motif that links the thalamus with high-order association prefrontal cortices is likely vulnerable to disruption along multiple dimensions, including the known deficits in eye movements in schizophrenia, as shown in computational studies [71].…”