Deep brain stimulation of the central thalamus restores arousal and motivation in a zolpidem-responsive patient with akinetic mutism after severe brain injury

Abstract

After severe brain injury, zolpidem is known to cause spectacular, often short-lived, restorations of brain functions in a small subgroup of patients. Previously, we showed that these zolpidem-induced neurological recoveries can be paralleled by significant changes in functional connectivity throughout the brain. Deep brain stimulation (DBS) is a neurosurgical intervention known to modulate functional connectivity in a wide variety of neurological disorders. In this study, we used DBS to restore arousal and motivation in a zolpidem-responsive patient with severe brain injury and a concomitant disorder of diminished motivation, more than 10 years after surviving hypoxic ischemia. We found that DBS of the central thalamus, targeted at the centromedian-parafascicular complex, immediately restored arousal and was able to transition the patient from a state of deep sleep to full wakefulness. Moreover, DBS was associated with temporary restoration of communication and ability to walk and eat in an otherwise wheelchair-bound and mute patient. With the use of magnetoencephalography (MEG), we revealed that DBS was generally associated with a marked decrease in aberrantly high levels of functional connectivity throughout the brain, mimicking the effects of zolpidem. These results imply that 'pathological hyperconnectivity' after severe brain injury can be associated with reduced arousal and behavioral performance and that DBS is able to modulate connectivity towards a 'healthier baseline' with lower synchronization, and, can restore functional brain networks long after severe brain injury. The presence of hyperconnectivity after brain injury may be a possible future marker for a patient's responsiveness for restorative interventions, such as DBS, and suggests that lower degrees of overall brain synchronization may be conducive to cognition and behavioral responsiveness.

Figure 1

Postoperative lead localization of the right DBS electrode projected in a T1-weighted MRI, showing active contact points in the centromedian-parafascicular complex with its effective electrical field size visualized (bottom right) by calculating the volume of tissue activated in Brainlab’s Guide-XT software module (Brainlab AG, Munich, Germany, version 3.2.0.281). Monopolar settings were used with the lowest contact point as cathode and pulse generator as anode.

Figure 2

Spectral analysis of four different conditions and healthy controls (grand average over all regions). Green: pre-DBS/zolpidem, purple: after zolpidem administration, red: DBS off condition, blue: DBS effect, yellow: healthy controls (HC).

Figure 3

Regional functional connectivity of four different conditions and healthy controls. Green: pre-DBS/zolpidem, purple: after zolpidem administration, red: DBS off condition, blue: DBS effect, yellow: healthy controls. For definition of AAL regions: see Supplementary Table 1. Note: error bars depict ‘confidence intervals’ based on the standard deviation of each computed metric (measured within epochs/time) in each condition.

Figure 4

Regional differences in functional connectivity of four different conditions compared to healthy controls (darker red = regions with high levels of functional connectivity, light-yellow = regions with lower levels of functional connectivity).

Figure 5

Neural variablity for four different conditions and healthy controls. Blue: DBS off condition, red: DBS effect, yellow: healthy controls, purple: after zolpidem administration, green: before DBS/zolpidem (baseline condition). For definition of AAL regions: see Supplementary Table 1. Note: error bars depict ‘confidence intervals’ based on the standard deviation of each computed metric (measured within epochs/time) in each condition.