Shashank A. Anand

BACKGROUND: Loss of hand control is a major source of poststroke disability, particularly when infarcts involve subcortical white matter. Yet, most preclinical models target the cortex and infer recovery from task performance without quantifying whether improvements reflect restoration or adaptation. To address this, we developed a novel nonhuman primate model of focal internal capsule infarct. This study is exploratory and hypothesis-testing, including prespecified hypotheses regarding motor impairment and adaptation. METHODS: Three adult male rhesus macaques ( Macaca mulatta , 5–10 years) received stereotactically guided ET-1 (endothelin-1) injections (0.5 µg/µL; 9–10 µL total) into the left posterior limb of the internal capsule in a within-subject pre-infarct versus post-infarct design. Infarcts were characterized by magnetic resonance imaging and postmortem histology. Motor function was tested with a center-out joystick task and a Klüver board task using standard behavioral metrics; hand posture was additionally scored by blinded raters to quantify adaptation. Pre-infarct versus post-infarct comparisons used generalized linear mixed models with per-session random effects; adaptation covariates were evaluated using likelihood-ratio tests. RESULTS: Magnetic resonance imaging and histology confirmed focal infarcts centered on the posterior limb of the internal capsule, with variable volumes. All animals significantly reduced contralesional hand use post-infarct (Fisher exact test; all P P P =0.0015). Pooled generalized linear mixed models showed significant post-infarct increases in retrieval time (estimate=0.73 s; P P P <0.0001). CONCLUSIONS: This model recapitulates key features of human subcortical stroke, including persistent distal motor deficits, shifts in hand preference, systematic motor adaptation, and interindividual variability, establishing a translationally oriented platform for studying stroke mechanisms and evaluating recovery-promoting interventions.

Loss of distal hand and finger control is among the most disabling consequences of stroke. Functional outcomes are typically worse when infarcts involve subcortical white matter tracts, particularly the internal capsule, yet most preclinical stroke models target cortical regions. To address this gap, we developed a non-human primate model of internal capsule infarct using stereotactically guided endothelin-1 injections to disrupt descending fibers from the primary motor cortex hand area. Serial structural and diffusion MRI, along with histology, confirmed subcortical infarcts centered on the targeted white matter region with no apparent cortical involvement. Motor function was assessed pre- and post-infarct using a joystick-based center-out task (proximal forelimb control) and a Klüver board task (distal forelimb control). Animals exhibited variable impairments in proximal function and consistent post-infarct deficits in distal function, including reduced contralesional hand use, longer retrieval time, and increased in-well digit flexions. One animal showed mild post-infarct impairment and the smallest lesion, highlighting that this model reflects inter-individual differences in infarct size and functional outcome as seen in human subcortical stroke. In contrast, the other two animals developed a compensatory wrist-extended posture on the Klüver board task by 4 weeks post-infarct, which stabilized the hand and enabled improved digit flexion. Incorporating this behavioral adaptation into statistical models improved prediction of motor performance. The observed adaptation may have drawn on spared corticospinal output pathways, allowing animals to re-engage pre-existing motor routines to perform the retrieval. While future studies may benefit from ethologically relevant tasks to further elucidate such adaptations, findings from this study recapitulate key features of human subcortical stroke, including persistent distal motor deficits and emergence of adaptive motor strategies. By combining precise lesioning, longitudinal imaging, and detailed behavioral analysis, this model provides a translationally oriented platform for studying white matter stroke mechanisms and evaluating interventions that promote functional recovery.

Arousal states are thought to influence many aspects of cognition and behavior by broadly modulating neural activity. Many studies have observed arousal-related modulations of alpha (~8 to 15 Hz) and gamma (~30 to 50 Hz) power and coherence in local field potentials across relatively small groups of brain regions. However, the global pattern of arousal-related oscillatory modulation in local field potentials is yet to be fully elucidated. We simultaneously recorded local field potentials in numerous cortical and subcortical regions in the primate brain and assessed oscillatory activity and inter-regional coherence associated with arousal state. In high arousal states, we found a uniquely strong and coherent gamma oscillation between the amygdala and basal forebrain. In low arousal rest-like states, a relative increase in coherence at alpha frequencies was present across sampled brain regions, with the notable exception of the medial temporal lobe. We consider how these patterns of activity may index arousal-related brain states that support the processing of incoming sensory stimuli during high arousal states and memory-related functions during rest.

Motor action after auditory stimulus elicits high gamma responses in sensory-motor and auditory cortex, respectively. We show that high gamma coherence reliably and greatly increased during motor response, but not after auditory stimulus. Underlying high gamma power could not explain high gamma coherence. Our results indicate that high gamma coherence is a physiologically distinct sensory-motor phenomenon that may serve as an indicator of increased synaptic communication on short timescales (∼1 s).