Kolja Jahnke

Automatic sleep staging using fMRI functional connectivity data

Recent EEG-fMRI studies have shown that different stages of sleep are associated with changes in both brain activity and functional connectivity. These results raise the concern that lack of vigilance measures in resting state experiments may introduce confounds and contamination due to subjects falling asleep inside the scanner. In this study we present a method to perform automatic sleep staging using only fMRI functional connectivity data, thus providing vigilance information while circumventing the technical demands of simultaneous recording of EEG, the gold standard for sleep scoring. The features to classify are the linear correlation values between 20 cortical regions identified using independent component analysis and two regions in the bilateral thalamus. The method is based on the construction of binary support vector machine classifiers discriminating between all pairs of sleep stages and the subsequent combination of them into multiclass classifiers. Different multiclass schemes and kernels are explored. After parameter optimization through 5-fold cross validation we achieve accuracies over 0.8 in the binary problem with functional connectivities obtained for epochs as short as 60s. The multiclass classifier generalizes well to two independent datasets (accuracies over 0.8 in both sets) and can be efficiently applied to any dataset using a sliding window procedure. Modeling vigilance states in resting state analysis will avoid confounded inferences and facilitate the study of vigilance states themselves. We thus consider the method introduced in this study a novel and practical contribution for monitoring vigilance levels inside an MRI scanner without the need of extra recordings other than fMRI BOLD signals.

Breakdown of long-range temporal dependence in default mode and attention networks during deep sleep

The integration of segregated brain functional modules is a prerequisite for conscious awareness during wakeful rest. Here, we test the hypothesis that temporal integration, measured as long-term memory in the history of neural activity, is another important quality underlying conscious awareness. For this aim, we study the temporal memory of blood oxygen level-dependent signals across the human nonrapid eye movement sleep cycle. Results reveal that this property gradually decreases from wakefulness to deep nonrapid eye movement sleep and that such decreases affect areas identified with default mode and attention networks. Although blood oxygen level-dependent spontaneous fluctuations exhibit nontrivial spatial organization, even during deep sleep, they also display a decreased temporal complexity in specific brain regions. Conversely, this result suggests that long-range temporal dependence might be an attribute of the spontaneous conscious mentation performed during wakeful rest.

To wake or not to wake? The two-sided nature of the human K-complex

Sleep fosters performance but likewise renders creatures insensitive to environmental threat. The brain balances between sleep promotion and protection during light sleep. One associated electrophysiological hallmark is the K-complex (KC), the sleep promoting versus arousal inducing role of which is under debate. We examined 37 subjects using EEG-combined fMRI and found KC-associated positive BOLD signal changes in subcortical (brainstem, thalamus), sensory and motor, midline and regions which form part of the default mode network, and negative changes in the anterior insula. Connectivity analysis revealed the primary auditory cortex as the first region to be influenced during the KC and that midline regions activated successively from front to back in association with the sleep protecting part of the KC. Our findings support thalamic involvement in KC mediation and an association of KCs with subcortical arousal mechanisms: activations in sensory areas suggest the existence of low level information processing during KC limited by anterior insula disengagement suggesting a two-sided nature of the KC: it embodies an arousal with subsequent sleep-guarding counteraction that might on the one hand serve periodical monitoring of the environment with basic information processing and on the other hand protect the continuity of sleep and thus its restoring effect.

Large-scale brain functional modularity is reflected in slow electroencephalographic rhythms across the human non-rapid eye movement sleep cycle

Large-scale brain functional networks (measured with functional magnetic resonance imaging, fMRI) are organized into separated but interacting modules, an architecture supporting the integration of distinct dynamical processes. In this work we study how the aforementioned modular architecture changes with the progressive loss of vigilance occurring in the descent to deep sleep and we examine the relationship between the ensuing slow electroencephalographic rhythms and large-scale network modularity as measured with fMRI. Graph theoretical methods are used to analyze functional connectivity graphs obtained from fifty-five participants at wakefulness, light and deep sleep. Network modularity (a measure of functional segregation) was found to increase during deeper sleep stages but not in light sleep. By endowing functional networks with dynamical properties, we found a direct link between increased electroencephalographic (EEG) delta power (1-4 Hz) and a breakdown of inter-modular connectivity. Both EEG slowing and increased network modularity were found to quickly decrease during awakenings from deep sleep to wakefulness, in a highly coordinated fashion. Studying the modular structure itself by means of a permutation test, we revealed different module memberships when deep sleep was compared to wakefulness. Analysis of node roles in the modular structure revealed an increase in the number of locally well-connected nodes and a decrease in the number of globally well-connected hubs, which hinders interactions between separated functional modules. Our results reveal a well-defined sequence of changes in brain modular organization occurring during the descent to sleep and establish a close parallel between modularity alterations in large-scale functional networks (accessible through whole brain fMRI recordings) and the slowing of scalp oscillations (visible on EEG). The observed re-arrangement of connectivity might play an important role in the processes underlying loss of vigilance and sensory awareness during deep sleep.

Costs and cost-driving factors for acute treatment of adults with status epilepticus: A multicenter cohort study from Germany

To provide first data on inpatient costs and cost‐driving factors due to nonrefractory status epilepticus (NSE), refractory status epilepticus (RSE), and super‐refractory status epilepticus (SRSE).

Severe meningoencephalomyelitis due to CNS-Toxocarosis

CNS-Toxocarosis is a rare clinical manifestation of Toxocara canis or Toxocara catis infection. Commonly, blood or CSF-eosinophilia directs investigations towards a parasitic origin of the syndrome. We describe a patient with severe eosinophilic meningoencephalomyelitis due to a Toxocara infection. A 44-year-old woman (dog owner) was admitted to a hospital due to a probable epileptic seizure and increasing headache. CSF-analysis revealed mild lymphomonocytic pleocytosis (86 leucocytes/ll), elevated protein levels (1,410 mg/l) and mildly elevated CSF-lactate (2.94 mmol/ l). The patient was treated with ceftriaxone, ampicillin and aciclovir (until negative HSV-PCR testing was confirmed). Six days later, she developed fever (41 C) and signs of myelopathy with paraparesis, sensory loss below TH4 and urinary retention. She was transferred to our hospital as psychomotorically slowed, with intermittent disturbances of consciousness, slight meningism and paraplegia of the legs without pyramidal signs, normal muscle tendon reflexes, diminished anal sphincter tonus and severe sensory loss below TH6. Spinal MRI revealed signs of myelitis (Fig. 1) while cerebral MRI was normal except for a slight leptomeningeal enhancement. CSF-analysis 2 weeks after symptom onset showed lymphomonocytic pleocytosis (51/ ll) and 10% eosinophilic granulocytes. Lactate was 4.72 mmol/l, protein (935 mg/l) and serum/CSF-albumin ratio were elevated (19.2, normal \7), CSF-glucose concentration was 55% of serum-glucose. CSF-IgM index was 1.1 (normal \0.2), IgA and IgG indices were normal. No eosinophilia was found in peripheral blood. Extensive microbiological workup was negative for all herpesviridiae, HIV, FSME, HHV6, LCMV, HTLV1, poliomyelitis, neurosyphilis, neuroborreliosis, neurotuberculosis, brucellosis, toxoplasmosis, listeriosis, ascaridosis, cysticercosis, filariosis or infections with chlamydia or mycoplasma-species. Vasculitis and sarcoidosis screening was unremarkable. An oncologic disorder was ruled out by whole-body PET/CT. Toxocara IgG-ELISA (sensitivity 91–95%, specificity 86–93%) and Western blot were positive in peripheral blood (35 antibody units) and CSF (65 antibody units) [1]. Treatment with dexamethasone (3 9 8 mg/day) led to marked improvement with the patient being fully oriented, awake, and remission of the paraplegia to a MRC 2–3 paraparesis. Tapering of dexamethasone to 2 mg/day worsened the paraparesis resolving again under high-dose methylprednisolone (1 g/day for 5 days), thereafter continued with 1 mg/kg body weight/day for several weeks. O. C. Singer (&) K. Jahnke H. Steinmetz Department of Neurology, Goethe-University, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany e-mail: o.singer@em.uni-frankfurt.de

Addition of Anti-Angiogenetic Therapy with Bevacizumab to Chemo- and Radiotherapy for Leptomeningeal Metastases in Primary Brain Tumors

Leptomeningeal dissemination of a primary brain tumor is a condition which is challenging to treat, as it often occurs in rather late disease stages in highly pretreated patients. Its prognosis is dismal and there is still no accepted standard of care. We report here a good clinical effect with a partial response in three out of nine patients and a stable disease with improvement on symptoms in two more patients following systemic anti-angiogenic treatment with bevacizumab (BEV) alone or in combination with chemo- and/or radiotherapy in a series of patients with leptomeningeal dissemination from primary brain tumors (diffuse astrocytoma WHO°II, anaplastic astrocytoma WHO°III, anaplastic oligodendroglioma WHO°III, primitive neuroectodermal tumor and glioblastoma, both WHO°IV). This translated into effective symptom control in five out of nine patients, but only moderate progression-free and overall survival times were reached. Partial responses as assessed by RANO criteria were observed in three patients (each one with anaplastic oligodendroglioma, primitive neuroectodermal tumor and glioblastoma). In these patients progression-free survival (PFS) intervals of 17, 10 and 20 weeks were achieved. In three patients (each one with diffuse astrocytoma, anaplastic astrocytoma and primitive neuroectodermal tumor) stable disease was observed with PFS of 13, 30 and 8 weeks. Another three patients (all with glioblastoma) were primary non-responders and deteriorated rapidly with PFS of 3 to 4 weeks. No severe adverse events were seen. These experiences suggest that the combination of BEV with more conventional therapy schemes with chemo- and/or radiotherapy may be a palliative treatment option for patients with leptomeningeal dissemination of brain tumors.

Corrigendum to “Automatic sleep staging using fMRI functional connectivity data” [Neuroimage 63/1 (2012) 63–72]

The authors regret that an accidental mislabelling of four subwith and without noise regression should read: [0.86/0.86,0.12/ jects in the two sleep + wake datasets of Fig. 3 resulted in a 0.12,0.01/0.01,0.00/0.00; 0.59/0.60,0.36/0.34,0.04/0.05,0.00/0.00; 0.48/ computation error of the results reported for the testing set #1. 0.49,0.06/0.06,0.42/0.43,0.02/0.02; 0.01/0.01,0.00/0.00,0.00/0.00,0.99/ Accuracy using a 2 minute window for this dataset is 75%/74%, 0.99]. with and without noise regression respectively. Confusion matrices The authors would like to apologise for any inconvenience caused. NeuroImage 81 (2013) 506