As a psychiatrist who treats patients with schizophrenia, I’ve long been struck by a fundamental puzzle: why do individuals with psychosis hold onto beliefs with such unwavering certainty, even when presented with compelling contradictory evidence? The answer, it turns out, may lie in a marble-sized brain region most people have never heard of—and the revelation comes from an entirely unexpected source.
When Tremor Treatment Accidentally Illuminates Psychosis
A groundbreaking study by Mackenzie et al. (2025, bioRxiv) has provided some of the strongest evidence yet for a circuit-level understanding of belief formation and revision. The researchers weren’t studying schizophrenia at all—they were investigating patients receiving focused ultrasound treatment for essential tremor. But when post-surgical brain swelling accidentally affected the mediodorsal (MD) thalamus, something remarkable happened: patients developed a specific pattern of overconfident decision-making that mirrors core features of delusional thinking.
Using a sophisticated behavioral task that probes how people balance exploiting known information versus exploring new possibilities, the researchers found that MD disruption led to a precise computational deficit: patients lost their capacity for adaptive doubt. They became overly confident in their existing beliefs and stopped seeking information that might challenge those beliefs—the very cognitive pattern we see in psychotic disorders.
The Neurobiology of Certainty Gone Wrong
This finding connects directly to my clinical experience treating patients with schizophrenia. In my practice, I’ve observed that the challenge isn’t simply that patients hold false beliefs—it’s that they hold beliefs with pathological certainty. The traditional psychiatric focus on the content of delusions may be missing the more fundamental issue: a breakdown in confidence calibration.
The MD thalamus appears to act as a critical “confidence regulator” in the brain’s decision-making networks. When functioning normally, it helps determine how much we should trust our own predictions versus remaining open to new information. This circuit-level understanding aligns with emerging theoretical frameworks about how the brain coordinates distributed computations for flexible cognition (Scott et al., 2024).
Consider the implications: if the thalamus normally helps us maintain appropriate uncertainty about our beliefs, then thalamic dysfunction could explain why patients with schizophrenia often exhibit such rigid certainty in their delusional beliefs. They haven’t simply acquired false information—they’ve lost the neural capacity to doubt what they think they know.
From Confidence to Delusions: A Circuit-Based Understanding
The Mackenzie study reveals something crucial about the computational nature of belief updating. When MD-prefrontal circuits were disrupted, patients didn’t simply become perseverative or confused. Instead, they showed a specific pattern:
- Increased reward sensitivity: Greater influence of learned values on choices
- Eliminated exploration bonus: Loss of information-seeking behavior
- Overexploitation: Excessive reliance on existing knowledge
- Reduced directed exploration: Failure to investigate uncertain but potentially informative options
This behavioral signature maps remarkably well onto what we observe clinically in psychotic disorders. Patients with delusions often show:
- Pathological certainty in false beliefs despite contradictory evidence
- Reduced information-seeking that might challenge their beliefs
- Overreliance on internal models rather than external feedback
- Failure to update beliefs when environmental contingencies change
The convergence is striking and suggests we may be looking at the same underlying computational dysfunction from different angles—one measured in the laboratory, the other observed in the clinic.
The Promise of Circuit-Based Psychiatry
This research opens exciting possibilities for precision approaches to treating schizophrenia. Rather than the broad neurochemical interventions we currently rely on, we might be able to target specific computational dysfunctions in thalamocortical circuits.
The study’s anatomical precision is particularly encouraging. The behavioral effects correlated specifically with disruption of the lateral (parvocellular) MD, which connects primarily to dorsolateral prefrontal cortex and frontal pole—regions critical for cognitive flexibility and belief updating. This anatomical specificity suggests that focused neuromodulation approaches could potentially restore more adaptive confidence calibration without affecting other brain functions.
Clinical Implications for Treatment
In my practice, I’ve been developing approaches that integrate computational insights with traditional psychiatric care. The MD thalamus findings suggest several potential therapeutic directions:
- Targeted Neuromodulation: Technologies like focused ultrasound or deep brain stimulation could potentially modulate MD activity to restore appropriate exploration-exploitation balance.
- Confidence Calibration Training: Cognitive interventions could be designed specifically to help patients develop more accurate metacognitive awareness of their own uncertainty.
- Precision Diagnostics: Computational tasks like the restless bandit could help identify specific cognitive profiles and guide personalized treatment approaches.
- Early Intervention: Understanding confidence miscalibration as a core deficit could lead to earlier detection and intervention before full psychotic episodes develop.
Beyond Schizophrenia: A New Framework for Mental Health
The implications extend beyond schizophrenia to other conditions where belief updating goes awry:
- Depression: May involve underconfidence leading to learned helplessness
- Anxiety disorders: Could reflect miscalibrated threat assessments
- Substance use disorders: Might involve overconfidence in drug-related beliefs
- Obsessive-compulsive disorder: May reflect inability to achieve confidence in safety
This represents a fundamental shift from thinking about psychiatric symptoms as categorical disease states toward understanding them as specific computational dysfunctions in learning and decision-making algorithms.
The Clinical Reality: From Lab to Bedside
As someone who treats patients with schizophrenia daily, I’m acutely aware of the challenges in translating neuroscience findings into clinical practice. However, this study is particularly compelling because it provides causal evidence in humans—not just correlational findings from neuroimaging studies.
The patients in the Mackenzie study didn’t lose their ability to learn or make decisions entirely. They maintained overall task performance while showing specific deficits in belief updating and uncertainty management. This selectivity suggests that interventions targeting MD-prefrontal circuits might improve cognitive flexibility without causing global cognitive impairment.
Looking Forward: A Personal Perspective
For me, this research represents something I’ve been working toward throughout my career: a true bridge between basic neuroscience and clinical psychiatry. The fact that these insights emerged from a completely different clinical context—tremor treatment—underscores how interconnected our understanding of brain function really is.
In my clinical work, I’ve seen how traditional approaches to schizophrenia, while helpful, often fall short of fully restoring cognitive flexibility and adaptive functioning. Understanding the neural basis of confidence calibration offers hope for more targeted, effective interventions.
The convergence between this human lesion study and years of animal research on thalamic function (including work from our lab and others) gives me confidence that we’re identifying fundamental principles of brain organization rather than isolated curiosities. When different methodologies and species point toward the same underlying mechanisms, it usually means we’re onto something important.
The Road Ahead
Several critical questions remain:
- Reversibility: Can confidence calibration deficits be restored through targeted interventions?
- Early detection: Could computational tasks identify at-risk individuals before psychotic episodes?
- Personalized medicine: How can we match specific circuit dysfunctions to optimal treatments?
- Combination approaches: How might neuromodulation combine with cognitive and pharmacological interventions?
As we move forward, the goal isn’t to replace current treatments but to enhance them with circuit-based insights. The patients I treat deserve approaches grounded in rigorous understanding of how their brains actually work, not just symptomatic management.
Conclusion: When Certainty Becomes the Enemy
The patients in the Mackenzie study teach us something profound about the nature of adaptive cognition: the capacity to doubt ourselves, when doubt is warranted, may be one of our most important mental faculties. When that capacity is lost—whether through thalamic dysfunction, psychiatric illness, or other causes—we become trapped by our own certainty.
This has broader implications beyond psychiatry. In an era of polarization and “alternative facts,” understanding the neural basis of belief formation and revision is more important than ever. The same circuits that go awry in schizophrenia may also be involved in more everyday forms of rigid thinking and confirmation bias.
For my patients with schizophrenia, this research offers something precious: hope for treatments based on understanding rather than trial and error. Instead of simply suppressing symptoms with broad-acting medications, we may soon be able to restore the specific cognitive functions—like appropriate confidence calibration—that enable adaptive functioning in a complex, uncertain world.
The brain’s confidence problem is solvable. And that gives me confidence that better treatments are within reach.
This research builds on extensive work linking thalamic circuits to cognitive flexibility and psychiatric disorders, offering new insights into the computational basis of belief updating and its therapeutic implications.
References:
- Mackenzie, G., et al. (2025). Focused ultrasound neuromodulation of mediodorsal thalamus disrupts decision flexibility during reward learning. bioRxiv.
- Scott, D.N., Mukherjee, A., Nassar, M.R., & Halassa, M.M. (2024). Thalamocortical architectures for flexible cognition and efficient learning. Trends in Cognitive Sciences, 28(7), 639-652.