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Pilots are most likely to experience motion sickness while flying through thick clouds due to a phenomenon known as spatial disorientation. When flying in overcast conditions, pilots can lose visual references to the horizon and the ground. This loss of orientation can create confusion about the aircraft's movement, leading to a disconnect between what the inner ear senses (the body's perception of motion) and what the eyes see (or do not see in this case).

When the visual system cannot provide adequate information to confirm or resolve the sensations of movement, such as during abrupt changes in the aircraft's position or turbulence, the result can be symptoms of motion sickness. The stimulation of the vestibular system, combined with the inability to visually ascertain movement, can lead to nausea, dizziness, and other symptoms associated with motion sickness.

In contrast, flying in clear weather or over flat terrain typically provides pilots with sufficient visual cues to maintain orientation, minimizing the risk of experiencing motion sickness, while high altitudes also generally do not induce symptoms unless combined with other factors like hypoxia or turbulence.