Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency.

Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.

The conceptual framework for the investigation of emotions.

The experimental study of the emotions as pursued by LeDoux and Damasio is argued to be flawed as a consequence of the inadequate conceptual framework inherited from the work of William James. This paper clarifies the conceptual structures necessary for any discussion of the emotions. Emotions are distinguished from appetites and other non-emotional feelings, as well as from agitations and moods. Emotional perturbations are distinguished from emotional attitudes and motives. The causes of an emotion are differentiated from the objects of an emotion, and the objects of an emotion are distinguished into formal and material ones. The links between emotions and reasons for the emotion, for associated beliefs and for action are explored, as well as the connection between emotion and care or concern, and between emotion and fantasy. The behavioural criteria for the ascription of an emotion are clarified. In the light of this conceptual network, Damasio's theory of the emotions is subjected to critical scrutiny and found wanting.