Cortical spreading depression (CSD) is a fundamental neurophysiological event in the brain, representing a massive wave of electrical and chemical change that moves slowly across the cerebral cortex. This phenomenon was first described in 1944 by the Brazilian neurophysiologist Aristides Leão, who initially observed a wave of suppressed electrical activity in the brains of rabbits. CSD is a unique form of neural signaling that temporarily disrupts normal brain function and underlies several neurological conditions. It is recognized as a key process in understanding the mechanisms behind both relatively benign and highly pathological neurological events.
Defining the Spreading Wave
Cortical spreading depression is a self-propagating wave that moves slowly across the gray matter of the brain, fundamentally different from the rapid electrical transmission of a normal seizure. This wave of depolarization travels at a speed of approximately 2 to 5 millimeters per minute. It is not a typical electrical signal, but rather a profound breakdown of the electrochemical gradients that maintain the brain’s resting state.
CSD is characterized by two distinct phases that move together across the cortex. The initial phase is a massive wave of electrical excitation, where neurons and glial cells in the affected area undergo a sudden depolarization. This instantaneous hyperactivity is followed almost immediately by the second, more prolonged phase: a period of functional silence or profound electrical depression. This “depression” phase temporarily renders the local neural network unable to fire action potentials or process information normally.
The wave effectively stuns the local brain tissue as it passes, silencing the spontaneous electrical activity of the neurons. The entire event, from the initial depolarization to the full recovery of normal electrical activity, can last for several minutes. This slow, spreading wave is the macroscopic signature of CSD.
The Cellular Mechanism of Propagation
The propagation of the CSD wave is driven by a catastrophic imbalance of ions across cell membranes. When CSD is initiated, neurons and glial cells undergo depolarization, which causes a massive efflux of potassium ions (\(\text{K}^+\)) from inside the cells into the extracellular space. Simultaneously, there is a large influx of sodium (\(\text{Na}^+\)) and calcium (\(\text{Ca}^{2+}\)) ions into the cells, leading to severe swelling.
This dramatic shift in ion concentrations triggers the release of excitatory neurotransmitters, most notably glutamate, into the space between cells. Glutamate then diffuses outward, activating receptors on adjacent neurons and glial cells, causing them to depolarize and release their own ions and neurotransmitters. This self-sustaining cycle of ion flux and neurotransmitter release is what allows the wave to propagate slowly across the cortex.
The brain must work intensely to restore the normal ionic balance from this electrochemical collapse. Cell membrane pumps, particularly the \(\text{Na}^+/\text{K}^+\)-ATPase, must hyperactivate to push the excess \(\text{Na}^+\) out and pull \(\text{K}^+\) back in against their concentration gradients. This process requires a tremendous amount of energy, leading to a surge in metabolic demand, sometimes increasing local glucose consumption by as much as 250 percent.
Relationship to Migraine Aura
Cortical spreading depression is widely accepted as the underlying physiological cause of the migraine aura phase. The aura, typically experienced as transient visual or sensory disturbances, manifests as the CSD wave moves across specific functional areas of the cortex. The most common form is the visual aura, which usually appears as a shimmering, geometric pattern known as a scintillating scotoma.
This visual display corresponds to the wave of initial electrical hyperactivity as it traverses the visual cortex, located in the occipital lobe. As the wave front of depolarization moves, the area it leaves enters the prolonged phase of electrical depression. This depressed area corresponds to a temporary loss of vision, or a blind spot, which is the “scotoma” part of the visual disturbance.
The slow propagation speed of the CSD wave, approximately 3 millimeters per minute, aligns closely with the time course of a typical aura, which usually lasts between 30 and 60 minutes. If the wave spreads to the somatosensory or motor cortex, the person may experience transient symptoms like numbness, tingling, or temporary weakness. While the CSD itself is thought to cause the aura, the subsequent period of electrical depression and the associated changes in blood flow are hypothesized to contribute to the subsequent headache phase.
Role in Acute Brain Injury
While CSD is relatively benign in a healthy brain experiencing a migraine aura, it becomes harmful following acute brain injuries. In compromised tissue, such as after an ischemic stroke, traumatic brain injury (TBI), or subarachnoid hemorrhage, the event is often referred to as spreading depolarization. It occurs frequently in these patients and is a powerful factor that can expand the area of damage.
In an injured brain, the tissue surrounding the primary lesion often has insufficient oxygen and blood flow, a state known as the penumbra in stroke. When a CSD wave sweeps through this energy-starved tissue, the massive metabolic demand required for ionic recovery cannot be met. The cells are unable to restore their ion gradients, leading to a sustained depolarization and failure of the membrane pumps.
This failure results in permanent cell damage and death, causing the core injury area to expand. Spreading depolarizations are considered a mechanism of secondary injury, worsening the patient’s neurological outcome in critical care settings. Monitoring and potentially treating these spreading depolarizations is a growing area of clinical focus due to their detrimental effect on tissue survival.