Abstract
AbstractReports of the beneficial effects of the hypnotic imidazopyridine, zolpidem, described in persistent vegetative state^1, 2^ have been replicated recently in brain-injured and cognitively impaired patients^3-7^. Previous single photon emission computed tomography (SPECT) studies have suggested that sub-sedative doses of zolpidem increased regional cerebral perfusion in affected areas^5, 8^, implying enhanced neuronal metabolic activity; which has led to speculation that zolpidem 'reawakens' functionally dormant cortex. However, a neuronal mechanism by which this hypnotic drug affords benefits to brain injured patients has yet to be demonstrated. Here, we report the action of sub-sedative doses of zolpidem on neuronal network oscillatory activity in human brain, measured using pharmaco-magnetoencephalography (pharmaco-MEG). Study participant JP suffered a stroke in 1996, causing major damage to the left hemisphere that impaired aspects of both motor and cognitive function. Pharmaco-MEG analyses revealed robust and persistent pathological theta (4-10Hz) and beta (15-30Hz) oscillations within the lesion penumbra and surrounding cortex. Administration of zolpidem (5mg) reduced the power of pathological theta and beta oscillations in all regions of the lesioned hemisphere. This desynchronizing effect correlated well with zolpidem uptake (occurring approximately 40 minutes after acute administration) and was coincident with marked improvements in cognitive and motor function. Control experiments revealed no effect of placebo, while a structurally unrelated hypnotic, zopiclone, administered at a comparable dose (3.5mg) elicited widespread increases in cortical oscillatory power in the beta (15-30Hz) band without functional improvement. These results suggest that in JP, specific motor and cognitive impairments are related to increased low-frequency oscillatory neuronal network activity. Zolpidem is unique amongst hypnotic drugs in its ability to desynchronize such pathological low-frequency activity, thereby restoring cognitive function.
Highlights
Previous single photon emission computed tomography (SPECT) studies have suggested that there is reduced regional blood perfusion in the affected brain area, with respect to the contralateral hemisphere, suggestive of diminished neuronal activity
We addressed the question of how focal desynchronization was related to cognitive and sensorimotor function in JP through MEG measures of language and motor function
We found a strong spatial and frequency domain correspondence between the zolpidem-induced (Fig. 3a & b) and functional desynchronization events (Fig. 3i-k), suggesting that zolpidem administration had direct functional consequences within modalities in which JP is compromised
Summary
Summary Our participant, JP, presented with sensorimotor and language deficits following major stroke, which were reported to improve following single daily administration of zolpidem. Voxels were identified with the left temporal lesion, the lesion penumbra and comparative location contralateral to the lesion These three voxels were examined using MRS and MEG to identify the chemical composition and power spectra respectively. MEG data were coregistered with JP’s anatomical MRI12 and analysis was performed using a SAM beamforming method[13, 14] to identify peaks of synchronous power change in response to each of the drugs administered. In order to establish the exact nature of JP’s cognitive impairments and improvements following zolpidem, a comprehensive psychometric evaluation was performed using the WAIS-III. These were undertaken firstly with zolpidem and 6 months later without zolpidem, to account for potential practice effects
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