Recovery from disorders of consciousness: Lesions and GABAergic modulation in a biologically inspired spiking neural...

The effects of positive allosteric modulators (PAMs) of the GABA_A receptor in disorders of consciousness (DoC)-such as the hypnotic zolpidem in coma-are frequently reported but remain poorly understood. Although several hypotheses have been proposed to explain their paradoxical effect, biologically plausible computational models that test why only a subset of patients with DoC respond to inhibitory-enhancing medications may clarify this phenomenon and guide therapeutic strategies. We extended a spiking neural network model to mechanistically investigate inhibitory neuron enhancement in DoC. The model featured biologically inspired elements, including a ratio of 80:20 excitatory-to-inhibitory neurons and 12 Hz of spontaneous intrinsic activity. Neurons were spatially organized, and the network performed a trace conditioning task to investigate conscious access. We implemented localized and diffuse lesions affecting excitatory and inhibitory neuron populations, individually and in combination. The positive allosteric modulation of GABA_A receptors was simulated by increasing inhibitory synaptic weights. Experiments revealed distinct recovery patterns depending on damage type and lesion distribution. Spontaneous recovery was more impaired by excitatory than inhibitory lesions, with local lesions generally affecting performance more than diffuse ones. Inhibitory postsynaptic potentiation produced dose-dependent recovery after inhibitory lesions, with therapeutic windows varying by lesion type. Our findings suggest that the paradoxical effect of GABA_A receptor PAMs arises from the restoration of excitatory-inhibitory balance when inhibitory networks are moderately disrupted. This computational framework offers a testable account in which insufficient inhibitory regulation represents a common pathway underlying DoC cases responsive to GABA_A receptor PAMs across diverse etiologies.