The Mallah Lab

For many people with TBI, cognitive dysfunction persists or worsens over the months and years following injury, with no approved therapies to prevent or halt its progression. This chronic phase remains poorly understood, leaving a critical gap in care for TBI survivors living with lasting cognitive impairment.

The complement system has emerged as a central driver of this process, sustaining neuroinflammation and synaptic loss long after the acute injury has resolved. We have previously shown that complement activation drives synaptic degeneration and progressive cognitive decline specifically in the chronic phase after TBI (Mallah et al., 2021, Acta Neuropathologica Communications), and that persistent complement signaling, rather than transient acute activation alone, is a primary driver of this chronic pathology.

This project extends that work using high-dimensional immune profiling and high-resolution immunofluorescence imaging to characterize how complement-mediated neuroinflammation evolves across several TBI models and brain regions at extended timepoints, with the goal of defining therapeutic windows that reach into the chronic post-injury period.

Depression and anxiety are among the most common and disabling long-term consequences of TBI, often persisting well after physical recovery.

TBI substantially increases the risk of both. A large-scale study of over 500,000 individuals confirmed elevated depression risk following TBI (Mantyla et al., 2026, Journal of Affective Disorders), and a meta-analysis of over 700,000 individuals found that TBI patients are nearly twice as likely to develop anxiety as non-TBI controls (Dehbozorgi et al., 2024, BMC Neurology).

Despite this well-established epidemiological link, the biological mechanisms by which TBI gives rise to these neuropsychiatric conditions remain poorly understood.

Our lab investigates how injury-driven neuroimmune activity, including complement pathway activation, alters pathology in brain regions implicated in these disorders. This project combines behavioral paradigms with molecular profiling of affected brain regions and analysis of post-mortem human TBI tissue to define the immune-mediated mechanisms driving the development of depression and anxiety after TBI, with the goal of identifying mechanistic targets for prevention.