Cross-Frequency Coupling as a Biomarker for Early Stroke Recovery.

BACKGROUND: The application of neuroimaging-based biomarkers in stroke has enriched our understanding of post-stroke recovery mechanisms, including alterations in functional connectivity based on synchronous oscillatory activity across various cortical regions. Phase-amplitude coupling, a type of cross-frequency coupling, may provide additional mechanistic insight. OBJECTIVE: To determine how the phase of prefrontal cortex delta (1-3 Hz) oscillatory activity mediates the amplitude of motor cortex beta (13-20 Hz) oscillations in individual's early post-stroke. METHODS: Participants admitted to an inpatient rehabilitation facility completed resting and task-based EEG recordings and motor assessments around the time of admission and discharge along with structural neuroimaging. Unimpaired controls completed EEG procedures during a single visit. Mixed-effects linear models were performed to assess within- and between-group differences in delta-beta prefrontomotor coupling. Associations between coupling and motor status and injury were also determined. RESULTS: Thirty individuals with stroke and 17 unimpaired controls participated. Coupling was greater during task versus rest conditions for all participants. Though coupling during affected extremity task performance decreased during hospitalization, coupling remained elevated at discharge compared to controls. Greater baseline coupling was associated with better motor status at admission and discharge and positively related to motor recovery. Coupling demonstrated both positive and negative associations with injury involving measures of lesion volume and overlap injury to anterior thalamic radiation, respectively. CONCLUSIONS: This work highlights the utility of prefrontomotor cross-frequency coupling as a potential motor status and recovery biomarker in stroke. The frequency- and region-specific neurocircuitry featured in this work may also facilitate novel treatment strategies in stroke.

Tissue-Resident Alveolar Macrophages Reduce Ozone-induced Inflammation via MerTK-mediated Efferocytosis.

Lung inflammation, caused by acute exposure to ozone (O3), one of the six criteria air pollutants, is a significant source of morbidity in susceptible individuals. Alveolar macrophages (AMØs) are the most abundant immune cells in the normal lung, and their number increases after O3 exposure. However, the role of AMØs in promoting or limiting O3-induced lung inflammation has not been clearly defined. In this study, we used a mouse model of acute O3 exposure, lineage tracing, genetic knockouts, and data from O3-exposed human volunteers to define the role and ontogeny of AMØs during acute O3 exposure. Lineage-tracing experiments showed that 12, 24, and 72 hours after exposure to O3 (2 ppm) for 3 hours, all AMØs were of tissue-resident origin. Similarly, in humans exposed to filtered air and O3 (200 ppb) for 135 minutes, we did not observe at ∼21 hours postexposure an increase in monocyte-derived AMØs by flow cytometry. Highlighting a role for tissue-resident AMØs, we demonstrate that depletion of tissue-resident AMØs with clodronate-loaded liposomes led to persistence of neutrophils in the alveolar space after O3 exposure, suggesting that impaired neutrophil clearance (i.e., efferocytosis) leads to prolonged lung inflammation. Moreover, depletion of tissue-resident AMØs demonstrated reduced clearance of intratracheally instilled apoptotic Jurkat cells, consistent with reduced efferocytosis. Genetic ablation of MerTK (MER proto-oncogene, tyrosine kinase), a key receptor involved in efferocytosis, also resulted in impaired clearance of apoptotic neutrophils after O3 exposure. Overall, these findings underscore the pivotal role of tissue-resident AMØs in resolving O3-induced inflammation via MerTK-mediated efferocytosis.

Corticomuscular Coherence in Children with Unilateral Cerebral Palsy: A Feasibility and Preliminary Protocol Study.

Objective This study assessed the feasibility of corticomuscular coherence measurement during a goal-directed task in children with unilateral cerebral palsy while establishing optimal experimental parameters. Methods Participants (Manual Ability Classification System levels I-III) completed a submaximal isometric goal-directed grip task during simultaneous electroencephalography and electromyography (EMG) acquisition. Results All participants (n = 11, 6 females, mean age 11.3 ±2.4 years) completed corticomuscular coherence procedures. Of the 40 trials obtained per extremity, an average of 29 (n = 9) and 27 (n = 10) trials were retained from the more- and less-affected extremities, respectively. Obtaining measurement stability required an average of 28 trials per extremity. Conclusion Findings from this work support the feasibility of corticomuscular coherence measurement in children with unilateral cerebral palsy. Acquiring 28 to 40 corticomuscular coherence trials per extremity is ideal. The experimental parameters established in this work will inform future corticomuscular coherence application in pediatric unilateral cerebral palsy.

Aerobic exercise and action observation priming modulate functional connectivity.

Aerobic exercise and action observation are two clinic-ready modes of neural priming that have the potential to enhance subsequent motor learning. Prior work using transcranial magnetic stimulation to assess priming effects have shown changes in corticospinal excitability involving intra- and interhemispheric circuitry. The objective of this study was to determine outcomes exclusive to priming- how aerobic exercise and action observation priming influence functional connectivity within a sensorimotor neural network using electroencephalography. We hypothesized that both action observation and aerobic exercise priming would alter resting-state coherence measures between dominant primary motor cortex and motor-related areas in alpha (7-12 Hz) and beta (13-30 Hz) frequency bands with effects most apparent in the high beta (20-30 Hz) band. Nine unimpaired individuals (24.8 ± 3 years) completed a repeated-measures cross-over study where they received a single five-minute bout of action observation or moderate-intensity aerobic exercise priming in random order with a one-week washout period. Serial resting-state electroencephalography recordings acquired from 0 to 30 minutes following aerobic and action observation priming revealed increased alpha and beta coherence between leads overlying dominant primary motor cortex and supplementary motor area relative to pre- and immediate post-priming timepoints. Aerobic exercise priming also resulted in enhanced high beta coherence between leads overlying dominant primary motor and parietal cortices. These findings indicate that a brief bout of aerobic- or action observation-based priming modulates functional connectivity with effects most pronounced with aerobic priming. The gradual increases in coherence observed over a 10 to 30-minute post-priming window may guide the pairing of aerobic- or action observation-based priming with subsequent training to optimize learning-related outcomes.

Functional connectivity drives stroke recovery: shifting the paradigm from correlation to causation.

Stroke is a leading cause of disability, with deficits encompassing multiple functional domains. The heterogeneity underlying stroke poses significant challenges in the prediction of post-stroke recovery, prompting the development of neuroimaging-based biomarkers. Structural neuroimaging measurements, particularly those reflecting corticospinal tract injury, are well-documented in the literature as potential biomarker candidates of post-stroke motor recovery. Consistent with the view of stroke as a 'circuitopathy', functional neuroimaging measures probing functional connectivity may also prove informative in post-stroke recovery. An important step in the development of biomarkers based on functional neural network connectivity is the establishment of causality between connectivity and post-stroke recovery. Current evidence predominantly involves statistical correlations between connectivity measures and post-stroke behavioural status, either cross-sectionally or serially over time. However, the advancement of functional connectivity application in stroke depends on devising experiments that infer causality. In 1965, Sir Austin Bradford Hill introduced nine viewpoints to consider when determining the causality of an association: (i) strength; (ii) consistency; (iii) specificity; (iv) temporality; (v) biological gradient; (vi) plausibility; (vii) coherence; (viii) experiment; and (ix) analogy. Collectively referred to as the Bradford Hill Criteria, these points have been widely adopted in epidemiology. In this review, we assert the value of implementing Bradford Hill's framework to stroke rehabilitation and neuroimaging. We focus on the role of neural network connectivity measurements acquired from task-oriented and resting-state functional MRI, EEG, magnetoencephalography and functional near-infrared spectroscopy in describing and predicting post-stroke behavioural status and recovery. We also identify research opportunities within each Bradford Hill tenet to shift the experimental paradigm from correlation to causation.