Changes in Intermuscular Coherence as a Function of Age and Phase of Speech Production During an Overt Reading Task.

PURPOSE: The authors evaluated changes in intermuscular coherence (IMC) of orofacial and speech breathing muscles across phase of speech production in healthy younger and older adults. METHOD: Sixty adults (30 younger = M: 26.97 year; 30 older = M: 66.37 year) read aloud a list of 40 words. IMC was evaluated across phase: preparation (300 ms before speech onset), initiation (300 ms after onset), and total execution (entire word). RESULTS: Orofacial IMC was lowest in the initiation, higher in preparation, and highest for the total execution phase. Chest wall IMC was lowest for the preparation and initiation and highest for the total execution phase. Despite age-related differences in accuracy, neuromuscular modulation for phase was similar between groups. CONCLUSION: These results expand our knowledge of speech motor control by demonstrating that IMC is sensitive to phase of speech planning and production.

Thiamine deficiency results in release of soluble factors that disrupt mitochondrial membrane potential and downregulate the glutamate transporter splice-variant GLT-1b in cultured astrocytes.

Loss of astrocytic glutamate transporters is a major feature of both thiamine deficiency (TD) and Wernicke's encephalopathy. However, the underlying basis of this process is not well understood. In the present study we have investigated the possibility of release of astrocytic soluble factors that might be involved in the regulation of the glutamate transporter GLT-1b in these cells. Treatment of naïve astrocytes with conditioned media from astrocytes exposed to TD conditions resulted in a progressive decrease in glutamate uptake over 24 h. Immunoblotting and flow cytometry measurements indicated this was accompanied by a 20-40% loss of GLT-1b. Astrocytes exposed to either TD or TD conditioned media showed increased disruption of mitochondrial membrane potential compared to control cells, and treatment of astrocytes with TD resulted in an increase in the pro-inflammatory cytokine TNF-α and elevated levels of phospho-IκB fragment, indicative of increased activation of NF-κB. Inhibition of TNF-α activity with the use of a neutralizing antibody blocked the increased NF-κB activation, while inhibition of NF-κB ameliorated the decrease in GLT-1b and reversed the decrease in glutamate uptake occurring with TD treatment. Together, these findings indicate that astrocytes exposed to TD conditions show responses suggesting that soluble factors released by these cells under conditions of TD play a regulatory role in terms of glutamate transport function and mitochondrial integrity.

Loss of the glutamate transporter splice-variant GLT-1b in inferior colliculus and its prevention by ceftriaxone in thiamine deficiency.

Downregulation of astrocytic glutamate transporters is a feature of thiamine deficiency (TD), the underlying cause of Wernicke's encephalopathy, and plays a major role in its pathophysiology. Recent investigations suggest that ceftriaxone, a ß-lactam antibiotic, stimulates GLT-1 expression and confers neuroprotection against ischemic and motor neuron degeneration. Thus, ceftriaxone treatment may be a protective strategy against excitotoxic conditions. In the present study, we examined the effects of ceftriaxone on the glutamate transporter splice-variant GLT-1b in rats with TD and in cultured astrocytes under TD conditions. Our results indicate that ceftriaxone protects against loss of GLT-1b levels in the inferior colliculus during TD, but with no significant effect in the thalamus and frontal cortex by immunoblotting and immunohistochemistry. Ceftriaxone also normalized the loss of GLT-1b in astrocyte cultures under conditions of TD. These results suggest that ceftriaxone has the ability to increase GLT-1b levels in astrocytes during TD, and may be an important pharmacological strategy for the treatment of excitotoxicity in this disorder.

Modeling neurodegenerative disease pathophysiology in thiamine deficiency: consequences of impaired oxidative metabolism.

Emerging evidence suggests that thiamine deficiency (TD), the cause of Wernicke's encephalopathy, produces alterations in brain function and structural damage that closely model a number of maladies in which neurodegeneration is a characteristic feature, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, along with alcoholic brain disease, stroke, and traumatic brain injury. Impaired oxidative metabolism in TD due to decreased activity of thiamine-dependent enzymes leads to a multifactorial cascade of events in the brain that include focal decreases in energy status, oxidative stress, lactic acidosis, blood-brain barrier disruption, astrocyte dysfunction, glutamate-mediated excitotoxicity, amyloid deposition, decreased glucose utilization, immediate-early gene induction, and inflammation. This review describes our current understanding of the basis of these abnormal processes in TD, their interrelationships, and why this disorder can be useful for our understanding of how decreased cerebral energy metabolism can give rise to cell death in different neurodegenerative disease states.