Inflammation, sleep-circadian disruption, and neuropsychiatric recovery after stroke: Mechanisms and integrated interventions for post-stroke depression and anxiety

Table 1 Assessment domains for post-stroke mood-sleep-circadian-inflammatory dysregulation

Domain	Suggested assessments	Clinical value	Important cautions
Mood symptoms	PHQ-9, HDRS, HADS, GAD-7, clinical interview	Identify depression, anxiety, comorbidity, and symptom severity	Somatic items may overlap with fatigue, aphasia, cognitive impairment, and neurological deficits
Sleep disturbance	PSQI, ISI, ESS, sleep diary, snoring/apnea screening	Identify insomnia, daytime sleepiness, sleep-disordered breathing, and fragmented sleep	Subjective sleep complaints may be influenced by mood and cognition
Circadian rhythm	Sleep timing, nap pattern, light exposure, activity rhythm, actigraphy	Identify irregular sleep-wake rhythm, low daytime activity, and weak day-night contrast	Actigraphy is useful but not always available in routine care
Inflammatory status	CRP, IL-6, TNF-α, IL-1β, NLR	Characterize inflammatory risk and biological vulnerability	Markers are nonspecific and affected by infection, stroke severity, metabolic disease, and medications
Rehabilitation context	Activity level, therapy participation, ward environment, pain, nocturia	Identify modifiable barriers to recovery	Requires multidisciplinary observation and repeated assessment

PHQ-9: Patient Health Questionnaire-9; HDRS: Hamilton Depression Rating Scale; HADS: Hospital Anxiety and Depression Scale; Generalized Anxiety Disorder-7; PSQI: Pittsburgh Sleep Quality Index; ISI: Insomnia Severity Index; ESS: Epworth Sleepiness Scale; CRP: C-reactive protein; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; NLR: Neutrophil-to-lymphocyte ratio.

Table 2 Phenotype-based integrated intervention strategies for post-stroke mood-sleep-circadian dysregulation

Dominant phenotype	Clinical clues	Immediate clinical priority	Integrated management
Insomnia-dominant	Difficulty initiating or maintaining sleep, early awakening	Exclude pain, nocturia, medication effects, and major environmental disruption	Sleep hygiene, stroke-adapted CBT-I, pain/nocturia control, nighttime environment optimization
Sleep-disordered breathing phenotype	Snoring, witnessed apnea, daytime sleepiness, resistant fatigue	Confirm respiratory risk and arrange formal sleep evaluation	Sleep medicine referral, CPAP if appropriate, vascular risk management
Circadian-disruption phenotype	Excessive daytime napping, nighttime wakefulness, low daytime activity	Restore daytime light exposure and regular activity timing	Morning light exposure, regular wake time, structured rehabilitation schedule, reduce evening light
Anxiety-hyperarousal phenotype	Fear of recurrence, bodily vigilance, panic-like symptoms, nocturnal worry	Assess symptom severity and stabilize nocturnal hyperarousal	Psychoeducation, relaxation training, graded return to activity, sleep stabilization
Inflammatory-risk phenotype	High CRP/IL-6, infection, pain, obesity, diabetes, poor sleep	Identify infection or uncontrolled medical comorbidity	Treat infection/pain, metabolic control, activity promotion, mood and sleep treatment
Fatigue-dominant phenotype	Low energy, reduced participation, daytime sleepiness	Distinguish sleepiness, mood symptoms, and physical deconditioning	Activity pacing, rehabilitation adjustment, sleep/circadian care, mood management

CBT-I: Cognitive behavioral therapy for insomnia; CPAP: Continuous positive airway pressure; CRP: C-reactive protein; IL-6: Interleukin-6.

Table 3 Clinical applicability, advantages, limitations, and current evidence status of interventions for post-stroke mood-sleep-circadian dysregulation

Intervention	Main target population or indication	Main advantages	Major limitations and implementation issues	Current evidence and clinical status
Basic sleep and circadian care	Stroke patients receiving acute or inpatient rehabilitation care, particularly those with environmental sleep disruption or a weakened day-night rhythm	Low risk, inexpensive, and feasible within routine multidisciplinary care	Effects on mood and functional recovery are difficult to isolate; implementation depends on ward organization and staff coordination	Routine supportive care consistent with rehabilitation guidelines, although direct intervention evidence for mood outcomes remains limited[32,33]
Stroke-adapted CBT-I	Medically stable patients with an insomnia-dominant phenotype; caregiver support may be required when communication or cognitive limitations are present	First-line nonpharmacological treatment for chronic insomnia; avoids sedative adverse effects and addresses behavioral factors that maintain insomnia	Requires trained personnel and adaptation for aphasia, cognitive impairment, or severe fatigue; treatment engagement may be difficult	Established for chronic insomnia in adults; clinically reasonable after stroke, but stroke-specific evidence remains limited[34]
Continuous positive airway pressure	Patients with confirmed sleep apnea, particularly those with snoring, witnessed apnea, or persistent daytime sleepiness	Directly treats airway obstruction and intermittent hypoxia; may support vascular and neurological recovery	Adherence and mask tolerance remain major barriers; cognitive or physical impairment may complicate treatment; direct effects on mood remain uncertain	Established treatment for confirmed sleep apnea; evidence for post-stroke recovery is supportive but heterogeneous[35]
Morning bright light and circadian scheduling	Patients with circadian disruption, excessive daytime napping, low daytime activity, or irregular sleep-wake timing	Low pharmacological burden and directly strengthens environmental timing cues; feasible during rehabilitation	Optimal light intensity, timing, and treatment duration remain uncertain; response may vary among patients	Promising but still exploratory as a stroke-specific intervention; evidence is based on a limited number of clinical trials[36]
Exercise and structured daytime activity	Medically stable patients with reduced activity, physical deconditioning, fatigue, or depressive symptoms	Already forms part of routine rehabilitation and may support mood, sleep, and functional recovery	Intensity must be adapted to neurological and cardiovascular status; intervention protocols remain heterogeneous	Routine rehabilitation component with supportive evidence for reducing depressive symptoms[39]
Antidepressant medication and structured psychotherapy	Patients with clinically significant or persistent post-stroke depression or anxiety	Directly targets emotional symptoms and can be integrated with rehabilitation and sleep-focused care	Medication adverse effects and interactions require monitoring; psychotherapy may be limited by aphasia, cognitive impairment, or access to trained professionals	Established components of post-stroke depression care; evidence is stronger for depression than for post-stroke anxiety[37]
Repetitive transcranial magnetic stimulation	Selected medically stable patients with persistent post-stroke depression, particularly when standard treatment is insufficient or poorly tolerated	Nonpharmacological neuromodulation with potential antidepressant effects	Requires specialized equipment and trained personnel; treatment protocols remain heterogeneous; accessibility and cost may limit use	Specialized adjunct rather than routine first-line treatment; supported by meta-analytic evidence but requiring further protocol standardization[38]
Anti-inflammatory pharmacotherapy	No established routine indication for post-stroke depression or anxiety; currently relevant mainly to research settings	Biologically plausible and may target pathways implicated in the proposed network	Clinical efficacy, appropriate patient selection, and safety remain uncertain; inflammatory biomarkers are nonspecific	Exploratory; anti-inflammatory medication cannot currently be recommended specifically for post-stroke depression or anxiety outside clinical research
Melatonin and other chronobiotic strategies	Selected patients with circadian misalignment or persistent sleep-timing disturbance	May support circadian timing with a relatively low treatment burden	Stroke-specific efficacy and optimal timing remain uncertain; medication interactions and individual tolerability require consideration	Exploratory in post-stroke care and not yet supported for routine phenotype-based use
Sedative or hypnotic medication	Selected patients with severe short-term sleep disturbance when nonpharmacological measures are insufficient	May provide short-term symptom relief	Sedation, falls, cognitive adverse effects, respiratory suppression, and daytime impairment are important concerns after stroke	Selective and cautious use only; not preferred as the sole or first-line long-term strategy

CBT-I: Cognitive behavioral therapy for insomnia.