Post-Stroke Neuropsychiatric Complications: Types, Pathogenesis, and Therapeutic Intervention

Abstract

Almost all stroke survivors suffer physical disabilities and neuropsychiatric disturbances, which can be briefly divided into post-stroke neurological diseases and post-stroke psychiatric disorders. The former type mainly includes post-stroke pain, post-stroke epilepsy, and post-stroke dementia while the latter one includes post-stroke depression, post-stroke anxiety, post-stroke apathy and post-stroke fatigue. Multiple risk factors are related to these post-stroke neuropsychiatric complications, such as age, gender, lifestyle, stroke type, medication, lesion location, and comorbidities. Recent studies have revealed several critical mechanisms underlying these complications, namely inflammatory response, dysregulation of the hypothalamic pituitary adrenal axis, cholinergic dysfunction, reduced level of 5-hydroxytryptamine, glutamate-mediated excitotoxicity and mitochondrial dysfunction. Moreover, clinical efforts have successfully given birth to many practical pharmaceutic strategies, such as anti-inflammatory medications, acetylcholinesterase inhibitors, and selective serotonin reuptake inhibitors, as well as diverse rehabilitative modalities to help patients physically and mentally. However, the efficacy of these interventions is still under debate. Further investigations into these post-stroke neuropsychiatric complications, from both basic and clinical perspectives, are urgent for the development of effective treatment strategies.

Figure 1.

The prevalence, risk factors and potential risk of different post-stroke neuropsychiatric complications.

Figure 2.

Schematic overview of mechanisms underlying post-stroke neuropsychiatric complications. In the acute phase, stroke as a stressor initiates the activation of the hypothalamic-pituitary-adrenal (HPA) axis and simultaneously stimulates the secretion of pro-inflammatory cytokines from immune cells, e.g., TNF-α, IL-1 and IL-6. The burst of systematic inflammation after stroke attenuates the inhibitory feedback of glucocorticoids (GCs) on hypothalamus and thus prolongs HPA axis activation. Moreover, stroke cascades affect diverse neurotransmitter pathways resulting in the reduced level of 5-HT and cholinergic dysfunction. Stroke also leads to the impaired release and reuptake of glutamate, as well as the overload of intracellular Ca²⁺ that promotes the rapid rise of glutamate levels in the cerebrospinal fluid. The activation of NMDA and AMPA GluR further induces glutamate toxicity. Excess ROS and Ca²⁺ accumulation induce mitochondrial dysfunction that leads to oxidative stress and lipid peroxidation. The MPTP open, followed by cytochrome C releasing from mitochondria into the cytoplasm. These dysregulations contribute to PSNCs, e.g., cognitive impairment, pain, epilepsy, depression, apathy and anxiety. However, the key brain areas responsible for serotoninergic and cholinergic dysfunction are still murky. Moreover, although microglia-mediate neuroinflammation has long been believed to play an essential role in stroke, the changes of microglia (like polarization, synapse pruning and synapse stripping) have not been dynamically observed in vivo in the context of PSNCs. Furthermore, the interplay between these pathological events awaits further study.

Figure 3.

The perspective of future research in post-stroke neuropsychiatric complications. (1) Progress in basic research: a. Establish reliable and practical experimental models for PSNCs and b. Employ advanced pharmacological technologies. (2) Develop novel tools for rapid diagnoses. (3) Conduct cooperative, high-quality randomized and community-based clinical trials. (4) Combine multiple therapeutic strategies.