Neurological Diseases Part II

Neurological Diseases and Seizures

• Seizures are brief, spontaneous neurological events caused by excessive and synchronized brain activity.
• Types of seizures include typical absence seizures, focal impaired awareness seizures (FIAS), and tonic-clonic seizures, each activating different brain circuits.

Typical Absence Seizures

• Engages widespread regions across both cerebral hemispheres rapidly, reflecting immediate cortical activation.
• Functional imaging techniques (fMRI, MEG, high-density EEG) show that these seizures primarily involve the thalamus, frontal, and parietal cortices.
• In animal models, they activate specific cortical and thalamic areas, including the somatosensory barrel cortex and thalamic nuclei (nRT and VPM).

Cortico-Thalamo-Cortical (CTC) Circuitry

• CTC circuitry has three significant features promoting oscillations:
  • Excitatory VPM neurons project to inhibitory GABAergic neurons in nRT, which inhibit VPM, creating feedback.
  • VPM shows two firing modes: tonic and bursting.
  • High interconnectivity exists between VPM and nRT neurons within and across thalamic nuclei.

Absence Seizure Mechanisms

• In non-epileptic individuals, VPM burst-mode firing contributes to delta activity during deep sleep and high-frequency sleep spindles.
• Research identifies conditions that lead this oscillating circuit to produce pathological spike-wave discharges (SWDs) during absence seizures.
• In CAE animal models, SWD spikes originate in the somatosensory cortex and rapidly spread to the thalamus.

GABA and Seizure Phenomena

• Inhibition of somatosensory cortex GABA receptors can induce SWDs, while action potential blockade in this region abolishes bilateral SWDs.
• Increased GABA inhibition in nRT reduces or eliminates SWDs, whereas bilateral GABA antagonists promote them.
• Tonic hyperpolarization in VPM increases SWDs, but synaptic GABA signaling facilitation does not affect them.

Genetic Factors in Seizures

• Typical absence seizures commonly occur in patients with idiopathic generalized epilepsy (IGE), which lack gross anatomical lesions.
• IGE syndromes are often monogenic, involving familial or de novo mutations in synaptic protein genes impacting neurotransmitter receptors and ion channels.
• Specific gene mutations associated with absence seizures include:
  • GABRA1, GABRB3, and GARRG2 for childhood absence epilepsy (CAE).
  • SCN1A mutations linked to Dravet syndrome.
• GABA receptors, primarily chloride-selective ion channels responsible for CNS inhibition, are heteropentamers composed mainly of two alpha subunits among various combinations of receptor subunits.