Petit-mal

ScienceDaily (here) reports research by Huguenard and others, ‘A new mode of corticothalamic transmission revealed in the Gria4-/- model of absence epilepsy’.

Absence or petit-mal seizures are a sudden loss of consciousness for a short period which may or may not be noticed by onlookers but is not noticed by the person having the seizure. “It’s like pushing a pause button.”

A bioengineered strain of mice, without the GluA4 receptor, is prone to these seizures and were used to investigate the cause of absence seizures. During seizures (human and mouse) there is an unusual, strong oscillation involving the cortex and thalamus. What causes this rhythm?

Normally:

To keep from being constantly bombarded by distracting sensory information from other parts of the body and from the outside world, the cortex flags its activity level by sending a steady stream of signals down to the thalamus, where nearly all sensory signals related to the outside world are processed for the last time before heading up to the cortex. In turn, the thalamus acts like an executive assistant, sifting through sensory inputs from the eyes, ears and skin, and translating their insistent patter into messages relayed up to the cortex. The thalamus carefully manages those messages in response to signals from the cortex.

These upward- and downward-bound signals are conveyed through two separate nerve tracts that each stimulate activity in the other tract. In a vacuum, this would soon lead to out-of-control mutual excitement, similar to a microphone being placed too close to a P.A. speaker. But there is a third component to the circuit: an inhibitory nerve tract that brain scientists refer to as the nRT. This tract monitors signals from both of the other two, and responds by damping activity. The overall result is a stable, self-modulating system that reliably delivers precise packets of relevant sensory information but neither veers into a chaotic state nor completely shuts itself down.

The bioengineered mice lack the GluA4 receptor which is critical to the stimulation of nRT cells.

This leaves nRT receiving signals from one tract, but not the other, which upsets the equilibrium usually maintained by the circuit. As a result, one of its components — the thalamocortical tract — is thrown into overdrive. Its constituent nerve cells begin firing en masse, rather than faithfully obeying the carefully orchestrated signals from the cortex. This in turn activates the nRT to an extraordinary degree, because its contact with the thalamocortical tract is not affected in these mice…. In the face of over-amped signaling from the thalamocortical tract, however, the fraction of excited nRT nerve cells rose much higher, perhaps as much as 50 percent — enough to effectively silence all signaling from the thalamus to the cortex — a key first step in a seizure….But the shutdown was transitory. A property of thalamic cells (like other nerve cells) is that when they’ve been inhibited they tend to overreact and respond even more strongly than if they had been left alone. After a burst of nRT firing, this tract’s overall inhibition of the thalamocortical tract all but halted activity there for about one-third of a second. Like boisterous schoolchildren who can shut up only until the librarian leaves the room, the thalamocortical cells resumed shouting in unison as soon as the inhibition stopped, and a strong volley of signaling activity headed for the cortex. Then the nRT’s inhibitory signaling recommenced, and the stream of signals from the thalamus to the cortex ceased once again. This three-Hertz cycle of oscillations consisting of alternating quiet and exuberant periods repeated over the course of 10 or 15 seconds was the electrophysiology of a seizure.

The group is now looking for triggers that could produce a similar malfunction in humans, that would allow the cortico-thalamo-cortical transmission system to escape the control of the nRT (reticular thalamic nucleus).

Here is the abstract:

Cortico-thalamo-cortical circuits mediate sensation and generate neural network oscillations associated with slow-wave sleep and various epilepsies. Cortical input to sensory thalamus is thought to mainly evoke feed-forward synaptic inhibition of thalamocortical (TC) cells via reticular thalamic nucleus (nRT) neurons, especially during oscillations. This relies on a stronger synaptic strength in the cortico-nRT pathway than in the cortico-TC pathway, allowing the feed-forward inhibition of TC cells to overcome direct cortico-TC excitation. We found a systemic and specific reduction in strength in GluA4-deficient (Gria4−/−) mice of one excitatory synapse of the rhythmogenic cortico-thalamo-cortical system, the cortico-nRT projection, and observed that the oscillations could still be initiated by cortical inputs via the cortico-TC-nRT-TC pathway. These results reveal a previously unknown mode of cortico-thalamo-cortical transmission, bypassing direct cortico-nRT excitation, and describe a mechanism for pathological oscillation generation. This mode could be active under other circumstances, representing a previously unknown channel of cortico-thalamo-cortical information processing.

I see this result somewhat differently. More from the bottom up then the to down. Consciousness is driven by waves of activity – waves from the brain stem up through the ascending reticular formation into the thalamus (the nRT part) and from the thalamus radiated to most of the cortex. It is the rhythm from below that drives the thalamus-cortex rhythm not vice versa. (Of course seizures are different and may be driven differently.) I do not have access to the original paper and so I am not sure whether the authors imply in it that the cortex controls the thalamus. I continue to view the close relationship between the thalamus and the cortex during consciousness as a partnership of equals. However it is closer to ‘the thalamus having the assistance of the cortex’ rather than ‘the thalamus acting as the executive assist to the cortex’ in my view. Perhaps further work on absence seizures will change my mind.

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