Summary: A new Emory University study reveals a biological connection between inflammation and reduced motivation in people with schizophrenia, pointing to a potential treatment target for negative symptoms that current antipsychotic medications do not reliably improve. Elevated levels of the inflammatory marker high-sensitivity C-reactive protein (hsCRP) were linked to lower activity and reduced connectivity in reward-related brain regions, including the ventral striatum and ventromedial prefrontal cortex (vmPFC).
These brain changes were specifically associated with negative symptoms related to motivation—such as avolition, difficulties finding or keeping work, and social withdrawal—rather than with positive symptoms like hallucinations or delusions. The findings support a precision medicine approach that targets inflammation in the subgroup of patients with schizophrenia who show elevated inflammatory markers and prominent motivational deficits.
Key Facts:
- Inflammation linked to motivation: Higher hsCRP correlates with greater motivational deficits.
- Reward circuitry affected: Inflammation associates with reduced activity and connectivity in the ventral striatum and ventromedial prefrontal cortex.
- Targeted clinical trial: The anti-inflammatory drug infliximab is being evaluated for patients with both elevated inflammation and negative symptoms of schizophrenia.
Source: Emory University
Study overview
Published in Neuropsychopharmacology, this study examined the relationship among systemic inflammation, brain reward circuitry, and negative symptoms in people diagnosed with schizophrenia. Researchers measured levels of hsCRP, a liver-produced blood biomarker of low-grade inflammation, and evaluated resting-state functional connectivity (rsFC) between key reward regions—the inferior ventral striatum (iVS) and vmPFC—alongside detailed clinical assessments of negative symptoms.
The investigators found that higher hsCRP was significantly associated with greater scores on the motivation and pleasure dimension of the Brief Negative Symptom Scale (BNSS), especially on measures of avolition and asociality. In contrast, hsCRP did not relate to expressive negative symptoms such as blunted affect or alogia, nor to positive symptoms like hallucinations and delusions.
On the neuroimaging side, elevated hsCRP correlated with decreased resting-state functional connectivity between the right inferior ventral striatum and the vmPFC. Importantly, reduced corticostriatal connectivity was linked to increased avolition among the subgroup with higher inflammation (hsCRP > 2 mg/L), suggesting a potential mechanism by which inflammation impairs motivation in these individuals.
These results are noteworthy because current antipsychotic medications typically address positive symptoms but have limited and inconsistent effects on negative symptoms. In some cases, they may even exacerbate motivational impairments. Identifying an inflammatory mechanism connected to reward-circuit dysfunction helps explain why certain negative symptoms are resistant to standard treatments and points to new therapeutic directions.
The study underpins a precision medicine strategy: anti-inflammatory treatments may benefit only a subset of patients with schizophrenia—those who have both elevated inflammatory markers and clinically meaningful motivational deficits. Prior clinical trials of anti-inflammatory drugs in schizophrenia may have failed in part because they did not stratify participants by inflammation status.
Building on this work, Emory researchers have initiated an experimental medicine trial testing the anti-TNF agent infliximab—commonly used for rheumatoid arthritis and inflammatory bowel disease—in people with schizophrenia who show high inflammation and pronounced negative, motivational symptoms. This trial aims to determine whether reducing inflammation can causally improve corticostriatal connectivity and alleviate avolition.
“There is an urgent need for treatments that address the negative symptoms of schizophrenia, which remain one of the field’s greatest unmet needs,” said David Goldsmith, MD, an associate professor in Emory’s Department of Psychiatry and Behavioral Sciences. “By identifying a biological mechanism that links inflammation to reward-circuit dysfunction and motivation loss, we move closer to targeted therapies that could improve recovery and real-world functioning.”
Funding: This research was supported by the National Institutes of Mental Health via a K23 Career Development Award (K23MH114037) totaling $957,420 over five years, as well as KL2TR002381 and UL1TR002378. Mentors included Andrew Miller, MD (primary mentor), Michael Treadway, PhD, and Elaine Walker, PhD.
About this inflammation and schizophrenia research news
Author: Jennifer Johnson McEwen
Source: Emory University
Contact: Jennifer Johnson McEwen – Emory University
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Inflammation is associated with avolition and reduced resting state functional connectivity in corticostriatal reward circuitry in patients with schizophrenia” by David Goldsmith et al., Neuropsychopharmacology.
Abstract
Inflammation is associated with avolition and reduced resting state functional connectivity in corticostriatal reward circuitry in patients with schizophrenia
Low-grade systemic inflammation has previously been linked to negative symptoms in schizophrenia, with motivational deficits—particularly avolition—among the most disabling. Research in depression has shown that inflammation can disrupt corticostriatal reward circuitry, involving the inferior ventral striatum (iVS) and ventromedial prefrontal cortex (vmPFC). This study examined relationships among inflammation, negative symptom dimensions, and rsFC within this reward circuit in patients with schizophrenia.
Fifty-seven individuals with schizophrenia had assessments of negative symptoms and hsCRP, and 43 of these participants underwent resting-state fMRI to measure rsFC between iVS and vmPFC. Statistical models controlled for age, sex, race, smoking status, body mass index, depression, and antipsychotic dose equivalents.
Higher hsCRP was significantly associated with greater impairment on the BNSS motivation and pleasure (MAP) dimension (β = 0.34, p_corr = 0.022), specifically in avolition and asociality domains, but not with the BNSS expressivity (EXP) dimension. Elevated hsCRP also correlated with reduced rsFC from right iVS to vmPFC (β = −0.37, p_corr = 0.029). Reduced corticostriatal connectivity was linked to greater avolition in participants with higher inflammation (hsCRP > 2 mg/L), whereas this association was not present in those with lower inflammation.
These findings indicate that increased inflammation relates to both motivational deficits and impaired corticostriatal connectivity in a subset of patients with schizophrenia, supporting further research into targeted anti-inflammatory interventions for this group.