*Laboratory for Sleep, Cognition and Consciousness Research, Division of Physiological Psychology, University of Salzburg + Centre for Cognitive Neuroscience Salzburg, Salzburg, Austria Unser Gehirn - Von Bewusstsein, Lernen und Erkrankungen

- Behavioral assessment remains the gold standard to monitor level of consciousness in patients with DOC. - However, high rate of misdiagnosis for the vegetative state (VS) evident. MINIMALLY CONSCIOUS STATE AROUSAL AWARENESS VEGETATIVE STATE AROUSAL AWARENESS AROUSAL AWARENESS NORMAL CONSCIOUSNESS AROUSAL AWARENESS SLEEP

AWARENESSWAKEFULNESS - Neuroscientific Evidence for Consciousness and DOC

VEGETATIVE STATE COMA LOCKED-IN SYNDROME SLEEP GENERAL ANESTHESIA P P P P P P P P F F F F F F F F Pr MF C Baars, Ramsoy, Laureys Trends in Neurosiences 2003 F, prefrontal; MF, mesiofrontal; P, posterior parietal cortex; Pr, posterior cingulate/precuneus Regional decrements in frontoparietal association cortices.

-Behavioral assessment remains the gold standard to monitor level of consciousness in patients with DOC -Therefore, high rate of misdiagnosis (41%, Schnakers et al., 2009) for the vegetative state (VS). AUDITORY FUNCTION SCALE 4 - Consistent Movement to Command * 3 - Reproducible Movement to Command * 2 - Localization to Sound 1 - Auditory Startle 0 – None VISUAL FUNCTION SCALE 5 - Object Recognition * 4 - Object Localization: Reaching * 3 - Visual Pursuit * 2 - Fixation * 1 - Visual Startle 0 – None MOTOR FUNCTION SCALE 6 - Functional Object Use ! 5 - Automatic Motor Response * 4 - Object Manipulation * 3 - Localization to Noxious Stimulation * 2 - Flexion Withdrawal 1 - Abnormal Posturing 0 - None/Flaccid

Cooperation partners: Albert-Schweitzer-Klinik (OA Dr. Pichler, Graz) “Apalliker Care Unit” im Geratriezentrum am Wienerwald (Prim. Dr. Donis, Wien) Hospital Hermanos Ameheiras (Havana, Cuba) - Prof.Dr. Calixto Machado

Sleep spindles are related to fading of C but also learning Sleep architecture appears more complex in MCS than VS/UWS (Cologan, Schabus et al., 2010; Cologan et al., 2013) incl. spindles

132Ch Baby EEG

Attempt to develop individual and quantitative markers for diagnosis and prognosis. Advantage: Resting state EEG is independent of the patient‘s will to cooperate and does not rely on specific abilities! Fellinger,…& Schabus, (2011)

Lechinger,.. & Schabus (2013) Alpha / Theta ratio highly informative!

Spindle Activity (C3) Fast Spindles (>13 Hz) Control NightLearning Night Schabus, M. et al. (2006). Sleep spindle-related activity in the human EEG and its relation to general cognitive and learning abilities. European Journal of Neuroscience, 23(7), General Cognitive Ability („g“) measured with Raven‘s Advanced Progressive Matrices (APM ) High Medium Low APM Groups

Time (seconds) Response Amplitude (a.u.) Slow Spindles Fast Spindles D Spindles CONJUNCTION Time (seconds) Response Amplitude (a.u.) f E k g Time (seconds) h Time (seconds) a i l d e j B c A b Time (seconds) Response Amplitude (a.u.) Response Amplitude (a.u.) Time (seconds) Time (seconds) Time (seconds) z = 6 x = -6 x = -4 x = -36 z = 8 x = -10 x = -6 x = -36 z = 6 x = -10 x = -2 x = 34 Schabus, M., et al. (2007). Hemodynamic cerebral correlates of sleep spindles during human non-REM sleep. Proceedings of the National Academy of Sciences USA, 104(32),

Mesial Prefrontal Cortex Time (seconds) Response Amplitude (a.u.) Time (seconds) Response Amplitude (a.u.) Hippocampus Schabus et al., PNAS, 2007 Nishida & Walker, PLoS One, 2007

Lower spindle activity relates to lower memory performance in Alzheimer’s Disease (e.g., Schabus et al., 2006; Rauchs et al., 2008) !  Even ipsilateral deviations after hemispheric strokes (e.g., Gottselig et al., 2002)

Neuronal loops in corticothalamic networks that are implicated for spindle generation. (A) Spindles are generated within the thalamus, due to the interplay of reticular thalamic (RE), thalamocortical (Th-Cx), and cortical (Cx) neurons. (B) Two rhythms (7-14 Hz and Hz) of spindle oscillations in cortical EEG. (Modified from: Steriade, M. THE CORTICOTHALAMIC SYSTEM IN SLEEP. Frontiers in Bioscience 8, d , May 1, 2003) Synchronized high-frequency bursts of APs in thalamus evoke massive Ca 2+ entry into cortical pyradmidal cells  Biochemical cascades, leading to synaptic plasticity in target cortical neurons, as necessary for „memory“ (long-term changes) processes.

Symbolic transfer entropy (STE) in consciousness (A), anaesthesia (B) and disorders of consciousness (C + D; modified from Jordan et al., accepted). While MCS (C) looks more similar to conscious wakefulness (A), VS looks similar to propofol induced unconsciousness.

Wyatt et al. (1999) Bekinschtein et al. (2009)

 Lichtstimulation &  Melatonin Gabe zur Schlaf Normalisierung  Identifizierung von „Arousal Windows“

Licht Melatonin Akustische Reize

Sequences of 8 equiprobable first names: the own name and 7 non-familiar first names SimonPatrick Hector Helmut Manuel Perrin, Schnakers, Schabus et al, Arch Neurol, 2006

12 controls (CO) 13 minimally conscious patients (MC) 8 vegetative state patients (VS) Event-related theta synchronisation to counted own vs. other names even in VS patients, yet delayed!! n.s. p <.001 p<.021 Fellinger,…& Schabus (2011)

In DOC: In healthy SLEEP: Stimulus-Material: Emotional-relevante Eigennamen bzw. Kinderreime In Newborns:

Schabus et al. (2011)

 MCS- Patienten verlieren sprachliche “Vorhersage- Funktionen” ? Schabus et al. (2011)

Results: Topographic ERS/ERD distribution during video observation ( ms) Lechinger et al. (2012) Lower alpha (8-10Hz) SMR (12-15Hz)

(a)Theta band (4-7Hz) activation. Note the strong evoked response in the early time window (0-500ms after video onset) not only in control subjects, but also MCS patients. (b)Lower alpha band (8-10Hz) desynchronization is strongest in controls in the second time window (mirror). Again a similar, yet weaker, response in MCS patients can be observed (c)While SMR (12-15Hz) frequency desynchronizes in control subjects, MCS patients synchronize. Results: Task design: Topographic ERS/ERD distribution during video observation ( ms) Lechinger et al. (2012) Lower alpha (8-10Hz) SMR (12-15Hz)

Theta band (video onset) L-Alpha band (video observation) L-Alpha band (imagination period)

EEG (MRI compatible): – 62 channels – ECG and EOG fMRI: EPI sequence (T2*, BOLD) TR 2460 ms TE 40 ms Max volumes 32 slices / volume Truly continuous

Schabus et al., Frontiers Neurol., 2012

Tones / present SPINDLES Dang-Vu, Bonjean, Schabus et al., PNAS, 2011 Y=-30 X=8 Z=2 A1 (red circles), thalamus (red dotted circles), brainstem (purple circles), cerebellum (purple dotted circle), posterior cingulate gyrus (green circles) and precuneus (green dotted circle). Parahippocampal gyrus (blue circles) and brainstem (purple circle). No Thalamus or A1 activations! Parahippocampal gyrus (blue circles) and brainstem (purple circle). No Thalamus or A1 activations! X=30 Y=-36 Z=-28

 Bekannter Reim und vor allem die vertraute Mutterstimme scheinen besondere Relevanz zu besitzen!

 Kritischer Blick auf das „Bewusstsein“ Schlaf-Wach bei Gesunden Störungen des Bewusstseins „nicht-sprachlichen“ Individuen  „Wachkoma“ und deren Diagnose/Prognose besser verstehen Eventuell sensiblere Detektion von „minimalen Bewusstseinszeichen“ …Am Ende geht es einfach darum den Kern dessen besser zu verstehen der uns „menschlich“ macht…

Bewusstsein

Appendix o

Can we „boost“ sleep using Neurofeedback ? o Instrumental conditioning: If the production of a particular oscillation pattern is rewarded, that information acts as a ‘reward‘ and the likelihood of recurrence of that activity will be increased.

Facilitating the waking „spindle“ rhythm (SMR) in order to o Increase sleep spindles during the night o enhance learning or memory consolidation during sleep (Gais et al., 2002; Schabus et al., 2004, 2006) & o produce „longer epochs of undisturbed sleep“ (Sterman, Howe, & MacDonald, 1970; Hauri, 1981; Hauri et al., 1982) – (Berner*, Schabus* et al. 2006; Cortoos et al., 2010)

…Success in healthy & sub-clinical populations Hoedlmoser, K.,.., & Schabus, M., SLEEP, 2008 No effects in clinical primary insomnia!

DSM-IV Primary Insomnia Criteria o Sleep onset or continuity problem or non-restorative sleep o At least present (3x a week) for 1 month o Clinical significant complaint affecting social, occupational or other important areas of functioning Very high prevalence!  Non-pharmacological alternatives rarely used!

NFT effects on insomnia Decrease of NOA, (ii) a trend for decreased Sleep Onset Latency, and (iii) Enhancements of N3 min following the NFT blocks. Schabus et al., 2014

…but Placebo Effect Physical quality of life ( WHOQOL: energy, fatigue, sleep & rest, work capacity ) was enhanced over time.  yet, unrelated to NFT / PFT training ! ! Social quality of life ( WHOQOL ) shows a trend towards improved social relationships and social support after the NFT blocks only. For post-hoc comparison we adopted a combination of Cohen’s d and p-values. **, Cohen’s d > 0.5 and p 0.5.