I would like to highlight a new paper that we published in collaboration with Neil Woodward’s lab at Vanderbilt, co-lead by research professors Anna Huang (Vanderbilt) and Ralf Wimmer (Tufts), with contributions from postdoctoral fellow Norman Lam and MSTP student Sahil Suresh from our group. This is the first serious effort in translating our animal work into translational human research—something I have really aspired to do given my other (less known) identity as a psychiatrist.
Schizophrenia is a complex mental health condition characterized by disruptions in thought processes, perception, and behavior. Among its myriad symptoms, executive dysfunction—challenges in making decisions and adapting to new information—is particularly debilitating and poorly understood. The newly published paper, in the relatively new journalCell Reports Medicine, sheds light on this issue, uncovering a crucial neural biomarker that links the mediodorsal (MD) thalamus and prefrontal cortex (PFC) to difficulties in processing conflicting information.
The Challenge of Cognitive Rigidity
Executive function allows us to navigate uncertainty and make decisions based on incomplete or conflicting information. For most people, this ability is seamless, like choosing to revisit a favorite restaurant despite one bad experience. However, for individuals with schizophrenia, this cognitive flexibility often breaks down, leading to inflexible and maladaptive decision-making.
Our research aimed to uncover the biological underpinnings of this rigidity. We hypothesized that disruptions in communication between the dorsolateral prefrontal cortex (dlPFC) and the MD thalamus—a network critical for integrating and resolving conflicting information based on our previous animal work—might be responsible.
Translating Insights from Animals to Humans
Building on a previous study led by postdocs Arghya Mukherjee and Norman Lam, where they developed a decision making task for allocating attention based on ambiguous cues, we developed an analogous human task which we could correlate with neuroimaging readouts. Anna and Neil recruited 40 participants, both neurotypical individuals and patients with schizophrenia, to perform tasks that required selecting between a visual and auditory target based on ambiguous cues on single trials. Healthy participants maintained high performance even in challenging scenarios, but those with schizophrenia struggled as ambiguity increased, revealing an elevated susceptibility to sensory noise. This was qualitatively similar to what we had observed in mice with optogenetic suppression of the MD thalamus!
A Novel Biomarker for Schizophrenia
In a subset of patients, resting state functional MRI data was available, so we were able to examine functional connectivity (the pearson correlation of BOLD signals across time) in various brain networks and examine if any correlated with the behavioral measures we observed. Remarkably we found that a network involving the right MD and dlPFC showed a significant correlation with the behavioral ambiguity threshold derived from the aforementioned task. This correlation generalized to an entirely new dataset involving the ability of patients to perform a working memory task in the presence of a conflicting input. All told, we think that this neural readout may represent a potential biomarker for conflict-related executive dysfunction in schizophrenia. Optimistically, it provides a measurement that may track certain forms of cognitive flexibility, paving the way for precision diagnostics and targeted interventions.
Toward Better Treatments
One of the most exciting implications of this study is its potential for patient stratification and the prediction of treatment efficacy. By combining the data from these types of measurements with other phenotyping efforts in the field, we might be able to identify subtypes of schizophrenia spectrum disorder that responds to certain antipsychotics, cognitive remediation or non-invasive neurostimulation. This aligns with our broader goal of bridging neuroscience research and clinical application to better serve patients.
Looking Ahead
Our next steps include validating these results in a larger and more diverse cohort. Additionally, we aim to expand the scope of our tasks to include more hierarchical decision-making scenarios that mirror everyday challenges. This will further refine our understanding of how thalamocortical disruptions impact real-world cognition in schizophrenia.
This study was a true collaborative effort between our two groups—a remarkable interdisciplinary effort among people who come from diverse intellectual backgrounds yet share similar goals of making a difference for science and humanity. I am extremely grateful to play a small part in this remarkable scientific story.