Electrophysiological Evidence for Alternative Motor Networks in REM Sleep Behavior Disorder.

Patients with Parkinson's disease (PD) and REM sleep behavior disorder (RBD) show mostly unimpaired motor behavior during REM sleep, which contrasts strongly to coexistent nocturnal bradykinesia. The reason for this sudden amelioration of motor control in REM sleep is unknown, however. We set out to determine whether movements during REM sleep are processed by different motor networks than movements in the waking state. We recorded local field potentials in the subthalamic nucleus (STN) and scalp EEG (modified 10/20 montage) during sleep in humans with PD and RBD. Time-locked event-related ß band oscillations were calculated during movements in REM sleep compared with movements in the waking state and during NREM sleep. Spectral analysis of STN local field potentials revealed elevated ß power during REM sleep compared with NREM sleep and ß power in REM sleep reached levels similar as in the waking state. Event-related analysis showed time-locked ß desynchronization during WAKE movements. In contrast, we found significantly elevated ß activity before and during movements in REM sleep and NREM sleep. Corticosubthalamic coherence was reduced during REM and NREM movements. We conclude that sleep-related movements are not processed by the same corticobasal ganglia network as movements in the waking state. Therefore, the well-known seemingly normal motor performance during RBD in PD patients might be generated by activating alternative motor networks for movement initiation. These findings support the hypothesis that pathological movement-inhibiting basal ganglia networks in PD patients are bypassed during sleep. SIGNIFICANCE STATEMENT: This study provides evidence that nocturnal movements during REM sleep in Parkinson's disease (PD) patients are not processed by the same corticobasal ganglia network as movements in the waking state. This implicates the existence of an alternative motor network that does not depend directly on the availability of l-Dopa in the basal ganglia. These findings further indicate that some PD patients are able to perform movements in the dopamine depleted state, possibly by bypassing the pathological basal ganglia network. The existence and direct activation of such alternative motor networks might finally have potential therapeutic effects for PD patients.

Aggregatibacter aphrophilus ventriculitis following C1-C2 transarticular screw fixation.

OBJECTIVE: Central nervous system (CNS) infections after cervical spine surgery are a rare but serious complication and may be caused by uncommon pathogens. We report the case of a 57-year-old male who developed slowly progressive mental confusion with headaches, increased daytime sleepiness and mild gait disturbance within the last 3 weeks. Six weeks prior to admission to our department, he underwent an atlantoaxial fusion by C1-C2 transarticular screw fixation for rheumatoid arthritis related C1-C2 multidirectional instability. METHODS: We analyzed clinical and neuroradiological findings. RESULTS: The findings were consistent with communicating hydrocephalus secondary to ventriculitis and the left C1-C2 screw was found to be misplaced with perforation of the dura. The situation was interpreted as implant related surgical site infection of the cerebrospinal fluid followed by ventriculitis and hydrocephalus. Bacterial broad range 16S rRNA gene PCR from the cerebrospinal fluid (CSF) followed by sequencing identified Aggregatibacter aphrophilus as the causative agent, while conventional cultures remained negative due to its fastidious growth. The patient was successfully treated with a lumbar drain and intravenous ceftriaxone. CONCLUSIONS: To our knowledge, this is the first report of Aggregatibacter aphrophilus ventriculitis following C1-C2 transarticular screw fixation.

Stimulation sites in the subthalamic nucleus projected onto a mean 3-D atlas of the thalamus and basal ganglia.

BACKGROUND: In patients with severe forms of Parkinson's disease (PD), deep brain stimulation (DBS) commonly targets the subthalamic nucleus (STN). Recently, the mean 3-D Morel-Atlas of the basal ganglia and the thalamus was introduced. It combines information contained in histological data from ten post-mortem brains. We were interested whether the Morel-Atlas is applicable for the visualization of stimulation sites. METHODS: In a consecutive PD patient series, we documented preoperative MRI planning, intraoperative target adjustment based on electrophysiological and neurological testing, and perioperative CT target reconstruction. The localization of the DBS electrodes and the optimal stimulation sites were projected onto the Morel-Atlas. RESULTS: We included 20 patients (median age 62 years). The active contact had mean coordinates Xlat = ±12.1 mm, Yap = -1.8 mm, Zvert = -3.2 mm. There was a significant difference between the initially planned site and the coordinates of the postoperative active contact site (median 2.2 mm). The stimulation site was, on average, more anterior and more dorsal. The electrode contact used for optimal stimulation was found within the STN of the atlas in 38/40 (95 %) of implantations. CONCLUSIONS: The cluster of stimulation sites in individual patients-as deduced from preoperative MR, intraoperative electrophysiology and neurological testing-showed a high degree of congruence with the atlas. The mean 3D Morel Atlas is thus a useful tool for postoperative target visualization. This represents the first clinical evaluation of the recently created atlas.

Nucleolin promotes angiogenesis and endothelial metabolism along the oncofetal axis in the human brain vasculature.

Glioblastomas are among the deadliest human cancers and are highly vascularized. Angiogenesis is dynamic during brain development, almost quiescent in the adult brain but reactivated in vascular-dependent CNS pathologies, including brain tumors. The oncofetal axis describes the reactivation of fetal programs in tumors, but its relevance in endothelial and perivascular cells of the human brain vasculature in glial brain tumors is unexplored. Nucleolin is a regulator of cell proliferation and angiogenesis, but its roles in the brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit in human fetal brains, adult brains, and human gliomas in vivo as well as its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression correlated with glioma malignancy in vivo. In culture, siRNA-mediated Nucleolin knockdown reduced human brain endothelial cell (HCMEC) and HUVEC sprouting angiogenesis, proliferation, filopodia extension, and glucose metabolism. Furthermore, inhibition of Nucleolin with the aptamer AS1411 decreased brain endothelial cell proliferation in vitro. Mechanistically, Nucleolin knockdown in HCMECs and HUVECs uncovered regulation of angiogenesis involving VEGFR2 and of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that promotes sprouting angiogenesis and endothelial metabolism, characterizing Nucleolin as an oncofetal protein. Our findings have potential implications in the therapeutic targeting of glioma.

Selective deep brain stimulation in the substantia nigra reduces myoclonus in progressive myoclonic epilepsy: a novel observation and short review of the literature.

We report the case of a patient suffering from pharmacotherapy-resistant bilateral progressive myoclonic epilepsy (PME) showing a beneficial response upon selective deep brain stimulation (DBS) of the substantia nigra pars reticulata. As an individual experimental therapeutic approach, we implanted DBS electrodes in the transitional zone between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). Electrode placement allowed for a selective stimulation of either the STN, SNr, or both targets. Postoperatively, we observed a moderate subjective and objective improvement in positive and negative myoclonus by high-frequency DBS of the STN/SNr transitional zone. However, a systematic exploration of different stimulation settings revealed that monopolar stimulation of the substantia nigra alone was more effective than high-frequency monopolar DBS of either the motor STN (monopolar) or stimulation of both targets (STN/SNr). This observation confirms earlier findings showing that patients with PME benefit from high-frequency DBS. However, in contrast to previous reports stimulating the STN/SNr transitional zone, our patient showed the most significant effect upon selective stimulation of the SNr. We propose that in patients undergoing DBS for myoclonus, at least one electrode contact should be placed in the SNr allowing for selective monopolar stimulation of this target.

Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex.

Cerebral cavernous malformations (CCM) are prevalent cerebrovascular lesions predisposing to chronic headaches, epilepsy, and hemorrhagic stroke. Using a combination of direct sequencing and MLPA analyses, we identified 15 novel and eight previously published CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) mutations. The mutation detection rate was >90% for familial cases and >60% for isolated cases with multiple malformations. Splice site mutations constituted almost 20% of all CCM mutations identified. One of these proved to be a de novo mutation of the most 3' acceptor splice site of the CCM1 gene resulting in retention of intron 19. A further mutation affected the 3' splice site of CCM2 intron 2 leading to cryptic splice site utilization in both CCM2 and its transcript variant lacking exon 2. With the exception of one in-frame deletion of CCM2 exon 2, which corresponds to the naturally occurring splice variant of CCM2 on the RNA level and is predicted to result in the omission of 58 amino acids (CCM2:p.P11_K68del), all mutations lead to the introduction of premature stop codons. To gain insight into the likely mechanisms underlying the only known CCM2 in-frame deletion, we analyzed the functional consequences of loss of CCM2 exon 2. The CCM2:p.P11_K68del protein could be expressed in cell culture and complexed with CCM3. However, its ability to interact with CCM1 and to form a CCM1/CCM2/CCM3 complex was lost. These data are in agreement with a loss-of-function mechanism for CCM mutations, uncover an N-terminal CCM2 domain required for CCM1 binding, and demonstrate full-length CCM2 as the essential core protein in the CCM1/CCM2/CCM3 complex.

Cavernoma of the trochlear nerve.

Here we present the case of a 53-year old man with progressive double vision due to isolated left trochlear nerve palsy. Cranial magnetic resonance imaging (MRI) showed a small tumor within the left quadrigeminal cistern that did not increase in size after several months. Explorative neurosurgical intervention revealed a left trochlear nerve cavernoma. The lesion was microsurgically excised followed by end-to-end anastomosis of the trochlear nerve. After a one-year follow up, double vision totally disappeared and cranial MRI showed no recurrence. Cerebral cavernous malformations usually become symptomatic in seizures or focal neurological deficits after intracerebral hemorrhage. Rarely, cavernomas arise from cranial nerves. To the authors' knowledge, this is the first report on a symptomatic cavernous malformation arising from the trochlear nerve and on its successful surgical management.

Is the image guidance of ultrasonography beneficial for neurosurgical routine?

BACKGROUND: Intraoperative US has been widely used in neurosurgical procedures. However, images are often difficult to read. In the present study, we evaluate whether the image guidance of ultrasonography is helpful for the interpretation of US scans. METHODS: Twenty-nine patients with tumor were operated on with the aid of intraoperative US from January to June 2005. Image-guided sonography was used in 13 cases and nonnavigated US technology in the remaining cases. We compared the 2 technologies retrospectively. RESULTS: Although image quality was good in most cases, orientation remained difficult in 8 of the 16 patients where conventional sonography was used. With the aid of image fusion for navigated sonography, the orientation was judged superior to nonnavigated US. CONCLUSION: In our experience, integration of the US into the navigation system facilitates anatomical understanding. Thus, we feel that this technology is beneficial for neurosurgical routine.

Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve.

We show here that recombinant endostatin protein has a biphasic effect on the inhibition of endothelial cell migration in vitro. In tumor-bearing animals, there is a similar biphasic effect on the inhibition of tumor growth and on circulating endothelial cells after once-daily s.c. injections. This biphasic effect is revealed as a U-shaped curve in which efficacy is optimal between very low and very high doses depending on the tumor type. This result may be applicable to other inhibitors of endothelial growth and to angiogenesis. Furthermore, these results have important implications for clinicians who administer angiogenesis inhibitors for cancer or other angiogenesis-dependent diseases. When these results are taken together with two previous reports of angiogenesis inhibitors with a U-shaped dose-response, they suggest that other regulators of endothelial growth may display a similar pattern.

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.

Adaptive grip force is modulated by subthalamic beta activity in Parkinson's disease patients.

INTRODUCTION: Healthy subjects scale grip force to match the load defined by physical object properties such as weight, or dynamic properties such as inertia. Patients with Parkinson's disease (PD) show an elevated grip force in dynamic object handling, but temporal aspects of anticipatory grip force control are relatively preserved. In PD patients, beta frequency oscillatory activity in the basal ganglia is suppressed prior to externally paced movements. However, the role of the subthalamic nucleus (STN) in anticipatory grip force control is not known. METHODS: After implantation of deep brain stimulation (DBS) electrodes in the STN, PD patients performed adaptive and voluntary grip force tasks, while we recorded subthalamic local field potentials (LFP) and scalp EEG. RESULTS: During adaptive grip force control (Shake), we found event related desynchronization (ERD) in the beta frequency band, which was time-locked to the grip force. In contrast, during voluntary grip force control (Press) we recorded a biphasic ERD, corresponding to peak grip force and grip force release. Beta synchronization between STN and cortical EEG was reduced during adaptive grip force control. CONCLUSION: The time-locked suppression of beta oscillatory activity in the STN is in line with previous reports of beta ERD prior to voluntary movements. Our results show that the STN is involved in anticipatory grip force control in PD patients. The difference in the phasic beta ERD between the two tasks and the reduction of cortico-subthalamic synchronization suggests that qualitatively different neuronal network states are involved in different grip force control tasks.

Development of a short sleeper phenotype after third ventriculostomy in a patient with ependymal cysts.

A naturally short sleeper phenotype with a sleep need of less than 6 hours without negative impact on health or performance is rare. We present a case of an acquired short sleeper phenotype after third ventriculostomy. A 59-year-old patient suffering from chronic hydrocephalus reported an average of 7-8 h of nocturnal sleep. After surgical intervention, the patient noted a strikingly reduced sleep need of 4-5 h without consequent fatigue or excessive daytime sleepiness, but with good daytime performance and well-balanced mood. Short sleep per 24 hours was confirmed by actigraphy. Postoperative imaging revealed decreased pressure around the anterior third ventricle. The temporal link between development of a short sleeper phenotype and third ventriculostomy is striking. This might suggest that individual short sleep need is not only determined by genetics but can be also be induced by external factors.

A critical reflection on the technological development of deep brain stimulation (DBS).

Since the translational research findings of Benabid and colleagues which partly led to their seminal paper regarding the treatment of mainly tremor-dominant Parkinson patients through thalamic high-frequency-stimulation (HFS) in 1987, we still struggle with identifying a satisfactory mechanistic explanation of the underlying principles of deep brain stimulation (DBS). Furthermore, the technological advance of DBS devices (electrodes and implantable pulse generators, IPG's) has shown a distinct lack of dynamic progression. In light of this we argue that it is time to leave the paleolithic age and enter hellenistic times: the device-manufacturing industry and the medical community together should put more emphasis on advancing the technology rather than resting on their laurels.

Human intracranial high frequency oscillations (HFOs) detected by automatic time-frequency analysis.

OBJECTIVES: High frequency oscillations (HFOs) have been proposed as a new biomarker for epileptogenic tissue. The exact characteristics of clinically relevant HFOs and their detection are still to be defined. METHODS: We propose a new method for HFO detection, which we have applied to six patient iEEGs. In a first stage, events of interest (EoIs) in the iEEG were defined by thresholds of energy and duration. To recognize HFOs among the EoIs, in a second stage the iEEG was Stockwell-transformed into the time-frequency domain, and the instantaneous power spectrum was parameterized. The parameters were optimized for HFO detection in patient 1 and tested in patients 2-5. Channels were ranked by HFO rate and those with rate above half maximum constituted the HFO area. The seizure onset zone (SOZ) served as gold standard. RESULTS: The detector distinguished HFOs from artifacts and other EEG activity such as interictal epileptiform spikes. Computation took few minutes. We found HFOs with relevant power at frequencies also below the 80-500 Hz band, which is conventionally associated with HFOs. The HFO area overlapped with the SOZ with good specificity > 90% for five patients and one patient was re-operated. The performance of the detector was compared to two well-known detectors. CONCLUSIONS: Compared to methods detecting energy changes in filtered signals, our second stage - analysis in the time-frequency domain - discards spurious detections caused by artifacts or sharp epileptic activity and improves the detection of HFOs. The fast computation and reasonable accuracy hold promise for the diagnostic value of the detector.

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

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.

Neurosurgical venous considerations for tumors of the pineal region resected using the infratentorial supracerebellar approach.

The authors present a microsurgical technique for the resection of a heterogeneous group of pineal-region tumors and discuss the key points for successfully performing this surgery. Twenty-six consecutive patients with pineal-region tumors were resected by the senior author (H.B.) and analyzed retrospectively. For all 26 patients, the operation was conducted using the infratentorial supracerebellar (ITSC) approach in the sitting (23 patients) or Concorde (three patients) positions. Twenty-five patients had symptomatic obstructive hydrocephalus and were treated with ventricular drainage, a previously inserted ventriculoperitoneal shunt, or an endoscopic third ventriculostomy before undergoing resection of the pineal-region tumor. The gross total removal of the tumor was achieved in 23 patients and subtotal removal was achieved in three patients. The tumors were pathologically diagnosed mainly as pineocytomas (10), pilocytic astrocytomas (6), or pineal cysts (4). Twenty-five of the patients clinically improved after surgery, and there was no mortality. Two patients experienced transient postoperative neurological deterioration: one patient developed Parinaud syndrome, and one patient developed intermittent diplopia. Successful surgery and patient outcome when treating tumors of the pineal region using the ITSC approach requires: (i) preservation of the venous flow of the Galenic draining system; (ii) preservation of the thick bridging veins of the tentorial surface of the cerebellum, especially the hemispheric bridging veins; and (iii) minimizing retraction of the cerebellum during surgery to avoid adverse effects caused by both direct cerebellar compression and disturbance of the venous circulation.

CCM1 gene deletion identified by MLPA in cerebral cavernous malformation.

Familial cerebral cavernous malformations (CCMs) occur with a frequency of 1 in 2000 and may cause recurrent headaches, seizures, and hemorrhagic stroke. Exon-scanning-based methods have identified intragenic mutations in three genes, CCM1, CCM2, and CCM3, in about 70% of familial CCM. To date, only two large CCM2 and a single large CCM3 deletion have been published. In addition to direct sequencing of all three CCM genes, we applied a newly developed multiplex ligation-dependent probe amplification gene dosage assay (MLPA) designed to detect genomic CCM1-3 deletions/duplications. Direct sequencing did not reveal a mutation in the index case who presented with multiple CCMs that had caused a generalized tonic-clonic seizure with Todd's paralysis and headaches at the age of 5. In contrast, MLPA analyses detected a large deletion involving the entire CCM1 coding region in the proband and further affected members of this German CCM family. The MLPA results were corroborated by analyses of single nucleotide polymorphisms (SNPs) within the CCM1 gene. Thus, we here present the first report on a CCM1 gene deletion. Our results confirm a loss-of-function mutation mechanism for CCM1 and demonstrate that the use of MLPA enables a higher CCM mutation detection rate which is crucial for predictive testing of at-risk relatives.