Schizophrenia is a serious mental disorder that, in addition to psychotic symptoms, causes long-lasting and difficult-to-treat cognitive deficits related to malfunctions between the prefrontal cortex (dlPFC) and the mediodorsal thalamus (MD). Researchers have found that this connection is crucial for executive functions such as decision-making and adaptation to change.
Schizophrenia is a relatively common and serious mental disorder that affects millions of people around the world. The disorder causes symptoms such as hallucinations, delusions, and profound cognitive deficits, such as difficulties with reasoning, memory, and concentration.
Although antipsychotic medications are widely used, about 30% of patients do not respond well to treatment, and almost all continue to experience cognitive deficits, which hinder their social and professional lives.
Therefore, finding new targets to treat these cognitive difficulties is an important research goal. Scientists have known for some time that these cognitive deficits in schizophrenia are linked to malfunctioning in a region of the brain called the prefrontal cortex (PFC), specifically the area known as the dorsolateral prefrontal cortex (dlPFC).
The dlPFC is essential for “executive function,” or the ability to process information and make decisions. It acts as a control center that processes complex information and coordinates appropriate responses.
This process is described as a “top-down” model, as it involves the prefrontal cortex directing other regions to adjust the operations that are taking place. However, understanding exactly how these cognitive processes go awry in schizophrenia has been a challenge.
Part of the complexity comes from the fact that the deficits are diverse, affecting multiple areas of cognition and with no clear pattern as to which part of the brain is responsible for each symptom. To move forward, scientists propose studying how certain mental processes, called “latent processes,” are related to executive functions and linking them to specific brain regions.
A key player in this process appears to be the thalamus, a brain structure that connects multiple areas of the brain and helps organize information. In particular, the portion of the thalamus called the mediodorsal (MD) thalamus plays a key role in coordinating the activities of the PFC.
While the thalamus is traditionally known for relaying sensory signals, recent research suggests that it is also crucial in controlling complex PFC functions, especially when we need to switch between different tasks or respond to change.
With this in mind, researchers at Vanderbilt University investigated how the connection between the MD thalamus and the dlPFC could help us understand and perhaps even treat the executive deficits of schizophrenia.
They began by developing a decision-making task to measure how people with schizophrenia react to stimulus uncertainty, that is when they have to make decisions based on unclear signals. They used a brain imaging technique called fMRI (functional magnetic resonance imaging) to analyze the activity of these areas during the task.
They recruited 42 participants; 18 healthy controls (HCs) and 24 people diagnosed with schizophrenia spectrum disorder.
They found that people with schizophrenia were more sensitive to signal uncertainty than the control group of people without the disorder. This difference was correlated with a change in connectivity between the right MD thalamus and the right dlPFC. In other words, the level of communication between these brain areas was linked to how they reacted in situations of uncertainty.
This suggests that schizophrenia may involve a “disconnect” in communications essential for executive function. The scientists then tested whether thalamic-dlPFC function could predict patients’ performance on tasks that require attentional control and distraction suppression.
They used data from an independent cohort of 172 individuals recruited as part of a previous study 55 that were used to investigate the generalizability of MD-dlPFC resting-state connectivity associations with cognition.
They found that in healthy individuals, MD thalamic activation was especially important in tasks that required mental flexibility, such as a task called “probabilistic rule reversal,” where one had to switch between different responses as rules changed.
These findings suggest that the network between the MD thalamus and the right dlPFC may be a critical pathway for understanding executive function deficits in schizophrenia. In other words, when this connection malfunctions, as appears to occur in schizophrenia, patients have a harder time dealing with uncertain situations or situations that require rapid task switching.
The finding is significant because it suggests potential new “biomarkers” for schizophrenia, which are observable features of the brain that can be used to monitor cognitive function in patients.
Thus, the study not only deepens our understanding of the mechanisms underlying executive deficits in schizophrenia but also paves the way for treatments that could focus on strengthening or correcting this network between the thalamus and the PFC.
The rMD-rdlPFC network is involved in strategy updating. (A) Single-trial timeline of the probabilistic Go/NoGo task. (B) Illustration of a learning block. In each block, 70% of trials in which one of the two tactile patterns was presented were assigned to “Go,” whereas 70% of trials in which the alternative tactile pattern was presented were assigned to “NoGo.” Within each block, the stimulus-response association was switched on a random trial basis. Trials immediately before a block transition were categorized as a steady state, and trials immediately after were categorized as a switch. (C) When contrasting the switch with the steady state, we found significant activity in the right MD. (D) rMD was used as the seed region for psychophysiological interaction (PPI) analysis. (E and F) PPI revealed significantly strengthened connectivity between rMD and right dlPFC immediately after a transition (switch > steady state). (G) Changes in rMD-rdlPFC PPI estimates (switch – steady state) were negatively correlated with speed to change decision strategy, suggesting that the more the connectivity between rMD and rdlPFC changed after reversals, the less time (trials) participants needed to adapt their behavioral strategy. Mediodorsal thalamus (MD), Dorsolateral prefrontal cortex (dlPFC). Rostral mediodorsal thalamus (rMD).
Patients with SZ show behavioral impairment that scales with cue uncertainty and correlates with lateralized MD-dlPFC resting-state functional connectivity. (A) Example performance of a subject with SZ showing smoothed performance (top) and correct (green) vs. incorrect (red) behavioral test rasters separated by uncertainty level (bottom). (B–C) (B) Group comparison of psychometric adjustments shows poorer performance of subjects with SZ specifically for tests with greater cue ambiguity (B–C). (D) There was a positive association between uncertainty thresholds and rMD-rdlPFC across all participants, regardless of group membership.
READ MORE:
A prefrontal thalamocortical readout for conflict-related executive dysfunction in schizophrenia
Anna S. Huang, Ralf D. Wimmer, Norman H. Lam, Bin A. Wang, Sahil Suresh, Maxwell J. Roeske, Burkhard Pleger, Michael M. Halassa and Neil D. Woodward
Cell Reports Medicine, Volume 0, Issue 0, 101802. November 7, 2024
DOI: 10.1016/j.xcrm.2024.101802
Abstract:
Executive dysfunction is a prominent feature of schizophrenia and may drive core symptoms. Dorsolateral prefrontal cortex (dlPFC) deficits have been linked to schizophrenia executive dysfunction, but mechanistic details critical for treatment development remain unclear. Here, capitalizing on recent animal circuit studies, we develop a task predicted to engage human dlPFC and its interactions with the mediodorsal thalamus (MD). We find that individuals with schizophrenia exhibit selective performance deficits when attention is guided by conflicting cues. Task performance correlates with lateralized MD-dlPFC functional connectivity, identifying a neural readout that predicts susceptibility to conflict during working memory in a larger independent schizophrenia cohort. In healthy subjects performing a probabilistic reversal task, this MD-dlPFC network predicts switching behavior. Overall, our three independent experiments introduce putative biomarkers for executive function in schizophrenia and highlight animal circuit studies as inspiration for the development of clinically relevant readouts.
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