Lukas L. Imbach

Increased sleep need and daytime sleepiness 6 months after traumatic brain injury: a prospective controlled clinical trial.

Post-traumatic sleep-wake disturbances are common after acute traumatic brain injury. Increased sleep need per 24 h and excessive daytime sleepiness are among the most prevalent post-traumatic sleep disorders and impair quality of life of trauma patients. Nevertheless, the relation between traumatic brain injury and sleep outcome, but also the link between post-traumatic sleep problems and clinical measures in the acute phase after traumatic brain injury has so far not been addressed in a controlled and prospective approach. We therefore performed a prospective controlled clinical study to examine (i) sleep-wake outcome after traumatic brain injury; and (ii) to screen for clinical and laboratory predictors of poor sleep-wake outcome after acute traumatic brain injury. Forty-two of 60 included patients with first-ever traumatic brain injury were available for follow-up examinations. Six months after trauma, the average sleep need per 24 h as assessed by actigraphy was markedly increased in patients as compared to controls (8.3 ± 1.1 h versus 7.1 ± 0.8 h, P < 0.0001). Objective daytime sleepiness was found in 57% of trauma patients and 19% of healthy subjects, and the average sleep latency in patients was reduced to 8.7 ± 4.6 min (12.1 ± 4.7 min in controls, P = 0.0009). Patients, but not controls, markedly underestimated both excessive sleep need and excessive daytime sleepiness when assessed only by subjective means, emphasizing the unreliability of self-assessment of increased sleep propensity in traumatic brain injury patients. At polysomnography, slow wave sleep after traumatic brain injury was more consolidated. The most important risk factor for developing increased sleep need after traumatic brain injury was the presence of an intracranial haemorrhage. In conclusion, we provide controlled and objective evidence for a direct relation between sleep-wake disturbances and traumatic brain injury, and for clinically significant underestimation of post-traumatic sleep-wake disturbances by trauma patients.

Sleep-wake disorders persist 18 months after traumatic brain injury but remain underrecognized

Objective: This study is a prospective, controlled clinical and electrophysiologic trial examining the chronic course of posttraumatic sleep–wake disturbances (SWD). Methods: We screened 140 patients with acute, first-ever traumatic brain injury of any severity and included 60 patients for prospective follow-up examinations. Patients with prior brain trauma, other neurologic or systemic disease, drug abuse, or psychiatric comorbidities were excluded. Eighteen months after trauma, we performed detailed sleep assessment in 31 participants. As a control group, we enrolled healthy individuals without prior brain trauma matched for age, sex, and sleep satiation. Results: In the chronic state after traumatic brain injury, sleep need per 24 hours was persistently increased in trauma patients (8.1 ± 0.5 hours) as compared to healthy controls (7.1 ± 0.7 hours). The prevalence of chronic objective excessive daytime sleepiness was 67% in patients with brain trauma compared to 19% in controls. Patients significantly underestimated excessive daytime sleepiness and sleep need, emphasizing the unreliability of self-assessments on SWD in trauma patients. Conclusions: This study provides prospective, controlled, and objective evidence for chronic persistence of posttraumatic SWD, which remain underestimated by patients. These results have clinical and medicolegal implications given that SWD can exacerbate other outcomes of traumatic brain injury, impair quality of life, and are associated with public safety hazards.

Sleep deprivation before stroke is neuroprotective: A pre-ischemic conditioning related to sleep rebound

BACKGROUND AND AIM We have previously shown in a rat model of focal cerebral ischemia that sleep deprivation after stroke onset aggravates brain damage. Others reported that sleep deprivation prior to stroke is neuroprotective. The main aim of this study was to test the hypothesis that the neuroprotection may be related to an increase in sleep (sleep rebound) during the acute phase of stroke. METHODS Male Sprague Dawley rats (n=36) were subjected to continuous polygraphic recordings for baseline, total sleep deprivation (TSD), and 24h after ischemia. TSD for 6h was performed by gentle handling and immediately followed by ischemia. Focal cerebral ischemia was induced by permanent occlusion of distal branches of the middle cerebral artery. Control experiments included ischemia without SD (nSD) and sham surgery with TSD (n=6/group). RESULTS Shortly after stroke, the amount of slow wave sleep (SWS) and paradoxical sleep (PS) increased significantly (p<0.05) in the TSD/ischemia, resulting in an increase in the total sleep time by 30% compared to baseline, or by 20% compared with the nSD/ischemia group. The infarct volume decreased significantly by 50% in the TSD/ischemia compared to nSD group (p<0.02). Removal of sleep rebound by allowing TSD-rats sleep for 24h before ischemia eliminated the reduction in the infarct size. CONCLUSION PRESTROKE Sleep deprivation results in sleep rebound and reduces brain damage. Sleep rebound may be causally related to the neuroprotection.

Interleaving deep brain stimulation for a patient with both Parkinson's disease and essential tremor†‡

Parkinson’s disease (PD) and essential tremor (ET) sometimes appear in the same patient, but the nature of this coexistence is a matter of ongoing debate. Although deep brain stimulation (DBS) is effective for both disorders, the targeted brain regions differ: the subthalamic nucleus (STN) or pars interna of the globus pallidus is preferred in PD patients and the nucleus ventralis intermedius of the thalamus (Vim) for ET patients. In addition, stimulation of the caudal zona incerta has been suggested for tremor control. In 1 reported patient with ET and PD, DBS in the STN improved both disorders. We present the case of a 50-year-old man who has suffered from ET since he was 5 years old. His mother and brother also suffered from ET. The Whiget Tremor Rating Scale score was 34 points (left, 14; right, 20) and improved to 16 (8/8) points after alcohol intake. Furthermore, he showed progressive signs of PD, which started 2 years ago. Both ET and PD were more dominant on the right side. Apart from the rest tremor, PD signs responded well to levodopa (motor part of the Unified Parkinson’s Disease Rating Scale score: 32 points off, 17 points on levodopa). Pharmacological treatment was difficult; treatment for ET was either insufficient (gabapentin, topiramate, alprazolam) or not well tolerated (primidone, propranolol). Dopaminergic drugs (pramipexole, ropinirole, levodopa) caused severe sleepiness. After careful evaluation, we recommended DBS. Although at this point the patient was still more affected by ET, PD symptoms were already significantly limiting the patient’s daily activities. Based on the above-mentioned case report, we selected as a target structure the medial STN, neighboring the caudal zona incerta in T2-weighted MRI (Suppl. Fig.; mid-commissural point [MCP]–based coordinates as x/y/z in millimeters: L, 10.72/ 5.75/ 4.08; R, 10.15/ 5.0/ 4.08). However, we aimed for an electrode trajectory that allowed the most dorsal poles of the quadripolar electrodes (Medtronic model 3389) to be located as close as possible to the Vim. After 5 microelectrode recordings and intraoperative macrostimulation, and after weighing benefits versus side effects, we implanted the electrodes in the anterior (left side) and lateral (right side) trajectory passing the thalamus and ending down in the STN, but not in proximity of the zona incerta. Fusion of intraoperative stereotactic computed tomography images with preoperative MRI revealed the following MCPbased positions (Suppl. Fig.): c0, 11.18/ 2.85/ 3.50; c8, 11.21/ 2.97/ 4.24; c3, 13.17/ 0.50/1.70; c11, 14.01/ 0.70/ 0.56. Projection of the electrodes on a 3-D atlas confirmed the localization of the most ventral poles (c0/c8) in the STN and the most dorsal poles (c3/c11) in the ventrolateral anterior thalamus (Fig. 1 and Suppl. Fig.). After bilateral electrode implantation, we first stimulated the left STN to alleviate right-sided symptoms of both PD and ET. However, this did not improve ET (unipolar stimulation of the most ventral pole; amplitude up to 3.5 V; impulse width, 60 ls; frequency, 130 Hz). Conversely, unipolar stimulation of the most dorsal pole (up to 4.2 V/60 ls/ 130 Hz) only improved ET. Thereafter, we programmed simultaneous unipolar stimulation at both extreme poles (up to 4.2 V/60 ls/130 Hz), but this strategy improved neither PD nor ET. Finally, we employed an interleaving stimulation of the same extreme poles (ventral: 3.3 V, dorsal: 4.3 V, both 60 ls/125 Hz). For the first time, symptoms of both PD and ET were significantly improved (Video). In contrast to an earlier case report, stimulation of the STN alone was not beneficial for ET in this patient. And simultaneous unipolar stimulation at both extreme poles was not efficacious for any symptom. However, an interleaving stimulation strategy, that is, alternating unipolar impulses with different amplitudes for the extreme poles in the STN and the ventrolateral anterior thalamic region near the Vim was successful in improving both PD and ET. The importance of pulse timing (simultaneous vs interleaving) may be related to temporal integration in the receiving brain areas.

Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson's disease.

&NA; Subthalamic deep brain stimulation is superior to best medication for improvement of Parkinson’s‐related pain. This treatment effect can be predicted by pre‐operative l‐dopa challenge tests. &NA; Pain is a frequently observed non‐motor symptom of patients with Parkinson’s disease. In some patients, Parkinson’s‐related pain responds to dopaminergic treatment. In the present study, we aimed to elucidate whether subthalamic deep brain stimulation has a similar beneficial effect on pain in Parkinson’s disease, and whether this effect can be predicted by a pre‐operative l‐dopa challenge test assessing pain severity. We prospectively analyzed 14 consecutive Parkinson’s patients with severe pain who underwent subthalamic deep brain stimulation. In 8 of these patients, pain severity decreased markedly with high doses of l‐dopa, irrespective of the type and localization of the pain symptoms. In these patients, subthalamic deep brain stimulation provided an even higher reduction of pain severity than did dopaminergic treatment, and the majority of this group was pain‐free after surgery. This effect lasted for up to 41 months. In the remaining 6 patients, pain was not improved by dopaminergic treatment nor by deep brain stimulation. Thus, we conclude that pain relief following subthalamic deep brain stimulation is superior to that following dopaminergic treatment, and that the response of pain symptoms to deep brain stimulation can be predicted by l‐dopa challenge tests assessing pain severity. This diagnostic procedure could contribute to the decision on whether or not a Parkinson’s patient with severe pain should undergo deep brain stimulation for potential pain relief.

Sleep Modulation Alleviates Axonal Damage and Cognitive Decline after Rodent Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It produces diffuse axonal injury (DAI), which contributes to cognitive impairment, but effective disease-modifying treatment strategies are missing. We have recently developed a rat model of closed skull TBI that reproduces human TBI consequences, including DAI and clinical sequelae such as memory impairment. Here, we investigated whether sleep modulation after trauma has an impact on DAI and memory outcome. We assessed cognition with the novel object recognition test and stained for amyloid precursor protein, a DAI marker. We found that both sleep induction and restriction acutely after TBI enhanced encephalographic slow-wave activity, markedly reduced diffuse axonal damage in the cortex and hippocampus, and improved memory impairment 2 weeks after trauma. These results suggest that enhancing slow-wave sleep acutely after trauma may have a beneficial disease-modifying effect in subjects with acute TBI. SIGNIFICANCE STATEMENT Traumatic brain injury (TBI) is a clinically important entity. Cognitive deficits belong to the most prevalent chronic posttraumatic symptoms, most likely due to diffuse axonal injury (DAI). A growing body of evidence suggests a role of sleep in the clearance of waste products in the brain, possibly including amyloid precursor protein (APP), a marker of DAI. In this study, we provide evidence that enhancement of slow-wave oscillatory activity in the delta-frequency range decreases the APP-immunoreactivity and preserves cognitive abilities after trauma, potentially offering novel, noninvasive treatment options for traumatic injury.

Inter-hemispheric oscillations in human sleep.

Sleep is generally categorized into discrete stages based on characteristic electroencephalogram (EEG) patterns. This traditional approach represents sleep architecture in a static way, but it cannot reflect variations in sleep across time and across the cortex. To investigate these dynamic aspects of sleep, we analyzed sleep recordings in 14 healthy volunteers with a novel, frequency-based EEG analysis. This approach enabled comparison of sleep patterns with low inter-individual variability. We then implemented a new probability dependent, automatic classification of sleep states that agreed closely with conventional manual scoring during consolidated sleep. Furthermore, this analysis revealed a previously unrecognized, interhemispheric oscillation during rapid eye movement (REM) sleep. This quantitative approach provides a new way of examining the dynamic aspects of sleep, shedding new light on the physiology of human sleep.

The impact of subthalamic deep brain stimulation on sleep-wake behavior: A prospective electrophysiological study in 50 Parkinson patients

Study Objectives This prospective observational study was designed to systematically examine the effect of subthalamic deep brain stimulation (DBS) on subjective and objective sleep-wake parameters in Parkinson patients. Methods In 50 consecutive Parkinson patients undergoing subthalamic DBS, we assessed motor symptoms, medication, the position of DBS electrodes within the subthalamic nucleus (STN), subjective sleep-wake parameters, 2-week actigraphy, video-polysomnography studies, and sleep electroencepahalogram frequency and dynamics analyses before and 6 months after surgery. Results Subthalamic DBS improved not only motor symptoms and reduced daily intake of dopaminergic agents but also enhanced subjective sleep quality and reduced sleepiness (Epworth Sleepiness Scale: -2.1 ± 3.8, p < .001). Actigraphy recordings revealed longer bedtimes (+1:06 ± 0:51 hours, p < .001) without shifting of circadian timing. Upon polysomnography, we observed an increase in sleep efficiency (+5.2 ± 17.6%, p = .005) and deep sleep (+11.2 ± 32.2 min, p = .017) and increased accumulation of slow-wave activity over the night (+41.0 ± 80.0%, p = .005). Rapid eye movement sleep features were refractory to subthalamic DBS, and the dynamics of sleep as assessed by state space analyses did not normalize. Increased sleep efficiency was associated with active electrode contact localization more distant from the ventral margin of the left subthalamic nucleus. Conclusion Subthalamic DBS deepens and consolidates nocturnal sleep and improves daytime wakefulness in Parkinson patients, but several outcomes suggest that it does not normalize sleep. It remains elusive whether modulated activity in the STN directly contributes to changes in sleep-wake behavior, but dorsal positioning of electrodes within the STN is linked to improved sleep-wake outcomes.

Bradysomnia in Parkinson’s disease

OBJECTIVE Polysomnography studies in Parkinsons disease (PD) patients show altered sleep microstructure with decreased level of arousability, indicating impaired sleep-wake dynamics in PD. The aim of this study was to investigate dynamical aspects of sleep EEG in PD as compared to healthy controls. METHODS In this retrospective, controlled study, we applied a previously established mathematical model of sleep EEG analysis (state space model) to PD patients and age- and gender-matched healthy volunteers (N=64). Dynamical aspects of sleep were quantified by measuring the spectral variability of the sleep EEG (by means of state space velocity). RESULTS State space analysis revealed preserved global sleep-wake architecture in PD patients, but the velocity of sleep stage transitions was significantly reduced as compared to healthy controls. Correlation analysis revealed a strong association of state space velocity with arousal scores and daily dopamine agonist intake. CONCLUSIONS Quantitative analysis of spectral sleep EEG variability (state space velocity) revealed reduced sleep-wake dynamics in PD patients as compared to control subjects. SIGNIFICANCE We propose state space velocity as an objective and quantitative measure for altered sleep microstructure and as a potential biomarker of sleep alterations in PD, not accessible by conventional sleep analysis.

Diminished event-related cortical arousals and altered heart rate response in Parkinson's disease

In Parkinsons disease (PD), partial neuronal loss occurs in several arousal‐promoting structures, but the effects on arousability have not yet been studied.