Evidence of trace conditioning in comatose patients revealed by the reactivation of EEG responses to alerting sounds

Trace conditioning refers to a learning process occurring after repeated presentation of a neutral conditioned stimulus (CS+) and a salient unconditioned stimulus (UCS) separated by a temporal gap. Recent studies have reported that trace conditioning can occur in humans in reduced levels of consciousness by showing a transfer of the unconditioned autonomic response to the CS+ in healthy sleeping individuals and in vegetative state patients. However, no previous studies have investigated the neural underpinning of trace conditioning in the absence of consciousness in humans. In the present study, we recorded the EEG activity of 29 post-anoxic comatose patients while presenting a trace conditioning paradigm using neutral tones as CS+ and alerting sounds as UCS. Most patients received therapeutic hypothermia and all were deeply unconscious according to standardized clinical scales. After repeated presentation of the CS+ and UCS couple, learning was assessed by measuring the EEG activity during the period where the UCS is omitted after CS+ presentation. Specifically we assessed the 'reactivation' of the neural response to UCS omission by applying a decoding algorithm derived from the statistical model of the EEG activity in response to the UCS presentation. The same procedure was used in a group of 12 awake healthy controls. We found a reactivation of the UCS response in absence of stimulation in eight patients (five under therapeutic hypothermia) and four healthy controls. Additionally, the reactivation effect was temporally specific within trials since it manifested primarily at the specific latency of UCS presentation and significantly less before or after this period. Our results show for the first time that trace conditioning may manifest as a reactivation of the EEG activity related to the UCS and even in the absence of consciousness.

[1]  C. Koch,et al.  Working memory and fear conditioning , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  R. Oostenveld,et al.  Nonparametric statistical testing of EEG- and MEG-data , 2007, Journal of Neuroscience Methods.

[3]  Richard F. Thompson,et al.  Neural substrates of eyeblink conditioning: acquisition and retention. , 2003, Learning & memory.

[4]  J. Rohrbaugh,et al.  Endogenous potentials generated in the human hippocampal formation and amygdala by infrequent events. , 1980, Science.

[5]  Erich Schröger,et al.  I know what is missing here: electrophysiological prediction error signals elicited by omissions of predicted ”what” but not ”when” , 2013, Front. Hum. Neurosci..

[6]  Christo Pantev,et al.  Emotion-Associated Tones Attract Enhanced Attention at Early Auditory Processing: Magnetoencephalographic Correlates , 2011, The Journal of Neuroscience.

[7]  L. Pessoa.  To what extent are emotional visual stimuli processed without attention and awareness? , 2005, Current Opinion in Neurobiology.

[8]  Tom M. Mitchell,et al.  Machine learning classifiers and fMRI: A tutorial overview , 2009, NeuroImage.

[9]  Mingzhou Ding,et al.  Effects of emotional conditioning on early visual processing: Temporal dynamics revealed by ERP single‐trial analysis , 2012, Human brain mapping.

[10]  A. Hamm,et al.  Fear acquisition requires awareness in trace but not delay conditioning. , 2007, Psychophysiology.

[11]  M. Murray,et al.  A Tutorial Review of Electrical Neuroimaging From Group-Average to Single-Trial Event-Related Potentials , 2012, Developmental neuropsychology.

[12]  Jean-Marie Annoni,et al.  Experience-based Auditory Predictions Modulate Brain Activity to Silence as Do Real Sounds , 2015, Journal of Cognitive Neuroscience.

[13]  Karen Smith,et al.  Treatment of Comatose Survivors of Out-of-hospital Cardiac Arrest With Induced Hypothermia , 2003 .

[14]  Athina Tzovara,et al.  Prediction of awakening from hypothermic postanoxic coma based on auditory discrimination , 2016, Annals of neurology.

[15]  Dominique Morlet,et al.  Predictive value of sensory and cognitive evoked potentials for awakening from coma , 2004, Neurology.

[16]  Peter A. Bandettini,et al.  Neural substrates of explicit and implicit fear memory , 2009, NeuroImage.

[17]  A. Keil,et al.  Modulation of the C1 visual event-related component by conditioned stimuli: evidence for sensory plasticity in early affective perception. , 2006, Cerebral cortex.

[18]  D. M. Green,et al.  Signal detection theory and psychophysics , 1966 .

[19]  Han Na Kim,et al.  A Learning Set Up for Detecting Minimally Conscious State (MCS) , 2012, Annals of rehabilitation medicine.

[20]  Jonas Larsson,et al.  fMRI repetition suppression: neuronal adaptation or stimulus expectation? , 2012, Cerebral cortex.

[21]  Diego E. Shalom,et al.  Sea Slugs, Subliminal Pictures, and Vegetative State Patients: Boundaries of Consciousness in Classical Conditioning , 2011, Front. Psychology.

[22]  Dominique Morlet,et al.  MMN and Novelty P3 in Coma and Other Altered States of Consciousness: A Review , 2013, Brain Topography.

[23]  Michela Sarlo,et al.  Automatic Temporal Expectancy: A High-Density Event-Related Potential Study , 2013, PloS one.

[24]  M. Carrasco,et al.  Nonconscious fear is quickly acquired but swiftly forgotten , 2012, Current Biology.

[25]  Nirbhay N. Singh,et al.  Assessing learning as a possible sign of consciousness in post-coma persons with minimal responsiveness , 2014, Front. Hum. Neurosci..

[26]  George Tomlinson,et al.  Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. , 2004, JAMA.

[27]  D. Kumaran,et al.  An Unexpected Sequence of Events: Mismatch Detection in the Human Hippocampus , 2006, PLoS biology.

[28]  A. Tzovara,et al.  Neural detection of complex sound sequences in the absence of consciousness. , 2015, Brain : a journal of neurology.

[29]  U Dimberg,et al.  Nonconscious associative learning: Pavlovian conditioning of skin conductance responses to masked fear-relevant facial stimuli. , 1994, Psychophysiology.

[30]  Athina Tzovara,et al.  Robust discrimination between EEG responses to categories of environmental sounds in early coma , 2014, Front. Psychol..

[31]  Alan D. Lopez,et al.  Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. , 2002, The New England journal of medicine.

[32]  B. Jennett,et al.  Assessment of coma and impaired consciousness. A practical scale. , 1974, Lancet.

[33]  Lucas Spierer,et al.  Progression of auditory discrimination based on neural decoding predicts awakening from coma. , 2013, Brain : a journal of neurology.

[34]  R. Clark,et al.  Classical conditioning and brain systems: the role of awareness. , 1998, Science.

[35]  S. Dehaene,et al.  Neural signature of the conscious processing of auditory regularities , 2009, Proceedings of the National Academy of Sciences.

[36]  Sylvain Baillet,et al.  Rapid Amygdala Responses during Trace Fear Conditioning without Awareness , 2014, PloS one.

[37]  Leslie G. Ungerleider,et al.  Increased Activity in Human Visual Cortex during Directed Attention in the Absence of Visual Stimulation , 1999, Neuron.

[38]  Karl J. Friston,et al.  A Dual Role for Prediction Error in Associative Learning , 2008, Cerebral cortex.

[39]  E. Bernat,et al.  Event-related brain correlates of associative learning without awareness. , 2004, International journal of psychophysiology : official journal of the International Organization of Psychophysiology.

[40]  Ueli Rutishauser,et al.  Single-Trial Learning of Novel Stimuli by Individual Neurons of the Human Hippocampus-Amygdala Complex , 2006, Neuron.

[41]  M. Flaten,et al.  Fear potentiated startle at short intervals following conditioned stimulus onset during delay but not trace conditioning. , 2009, Psychophysiology.

[42]  A. Chesson,et al.  The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology, and Techinical Specifications , 2007 .

[43]  Andreas Keil,et al.  Acquired fears reflected in cortical sensory processing: a review of electrophysiological studies of human classical conditioning. , 2012, Psychophysiology.

[44]  Lars Hausfeld,et al.  Pattern analysis of EEG responses to speech and voice: Influence of feature grouping , 2012, NeuroImage.

[45]  S. Dehaene,et al.  Event related potentials elicited by violations of auditory regularities in patients with impaired consciousness , 2012, Neuropsychologia.

[46]  E. Schröger,et al.  Hearing Silences: Human Auditory Processing Relies on Preactivation of Sound-Specific Brain Activity Patterns , 2013, The Journal of Neuroscience.

[47]  Robyn L McClelland,et al.  Validation of a new coma scale: The FOUR score , 2005, Annals of neurology.

[48]  S. Dehaene,et al.  Neural detection of complex sound sequences or of statistical regularities in the absence of consciousness? , 2015, Brain : a journal of neurology.

[49]  S. Dehaene,et al.  Probing consciousness with event-related potentials in the vegetative state , 2011, Neurology.

[50]  Manuel Schabus,et al.  Spontaneous neural activity during human slow wave sleep , 2008, Proceedings of the National Academy of Sciences.

[51]  Noël Staeren,et al.  Sound Categories Are Represented as Distributed Patterns in the Human Auditory Cortex , 2009, Current Biology.

[52]  A. Rossetti,et al.  Early Multimodal Outcome Prediction After Cardiac Arrest in Patients Treated With Hypothermia* , 2014, Critical care medicine.

[53]  Diego E. Shalom,et al.  Classical conditioning in the vegetative and minimally conscious state , 2009, Nature Neuroscience.

[54]  H. Eichenbaum,et al.  Critical role of the hippocampus in memory for sequences of events , 2002, Nature Neuroscience.

[55]  Dominique Morlet,et al.  Mismatch Negativity and N100 in Comatose Patients , 2000, Audiology and Neurotology.

[56]  Christoph M. Michel,et al.  Decoding stimulus-related information from single-trial EEG responses based on voltage topographies , 2012, Pattern Recognit..

[57]  Joseph E LeDoux,et al.  Contributions of the Amygdala to Emotion Processing: From Animal Models to Human Behavior , 2005, Neuron.

[58]  P. Kaplan,et al.  Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest , 2010, Critical care.

[59]  N. Sobel,et al.  Humans can learn new information during sleep , 2012, Nature Neuroscience.

[60]  W. Walter,et al.  Contingent Negative Variation : An Electric Sign of Sensori-Motor Association and Expectancy in the Human Brain , 1964, Nature.

[61]  S. Clarke,et al.  Prediction of cognitive outcome based on the progression of auditory discrimination during coma. , 2016, Resuscitation.

[62]  H. T. Blair,et al.  Placing prediction into the fear circuit , 2011, Trends in Neurosciences.

[63]  J. R. King,et al.  Single-trial decoding of auditory novelty responses facilitates the detection of residual consciousness , 2013, NeuroImage.

[64]  Vanessa M. Johnen,et al.  Human Scalp Electroencephalography Reveals that Repetition Suppression Varies with Expectation , 2011, Front. Hum. Neurosci..

[65]  S. Bernard,et al.  Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. , 2002, The New England journal of medicine.

[66]  J. Desmond,et al.  Neural substrates underlying human delay and trace eyeblink conditioning , 2008, Proceedings of the National Academy of Sciences.

[67]  Thomas Koenig,et al.  A Method to Determine the Presence of Averaged Event-Related Fields Using Randomization Tests , 2010, Brain Topography.

[68]  Peter Boesiger,et al.  Implicit Associative Learning Engages the Hippocampus and Interacts with Explicit Associative Learning , 2005, Neuron.

[69]  B. Kotchoubey,et al.  Predicting coma and other low responsive patients outcome using event-related brain potentials: A meta-analysis , 2007, Clinical Neurophysiology.

[70]  Michael Holzer,et al.  Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest , 2002 .

[71]  D. Shanks,et al.  The role of awareness in Pavlovian conditioning: empirical evidence and theoretical implications. , 2002, Journal of experimental psychology. Animal behavior processes.

[72]  A. Tzovara,et al.  Reply: Neural detection of complex sound sequences or of statistical regularities in the absence of consciousness? , 2015, Brain : a journal of neurology.

[73]  F. Angeleri,et al.  Eliciting P300 in comatose patients , 1995, The Lancet.

[74]  A. Godbolt,et al.  Disorders of consciousness: Preliminary data supports added value of extended behavioural assessment , 2012, Brain injury.

[75]  Mauro Oddo,et al.  Prognostication after cardiac arrest and hypothermia: A prospective study , 2010, Annals of neurology.

[76]  Karl J. Friston,et al.  A theory of cortical responses , 2005, Philosophical Transactions of the Royal Society B: Biological Sciences.

[77]  Itzhak Fried,et al.  Large-Scale Microelectrode Recordings of High-Frequency Gamma Oscillations in Human Cortex during Sleep , 2010, The Journal of Neuroscience.

[78]  H. T. Nguyen,et al.  Expression of conditional fear with and without awareness , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Lars Muckli,et al.  Dissociation of Prediction from Conscious Perception , 2014, Perception.

[80]  M. Boly,et al.  Diagnostic accuracy of the vegetative and minimally conscious state: Clinical consensus versus standardized neurobehavioral assessment , 2009, BMC neurology.

[81]  John-Dylan Haynes,et al.  Disentangling neural representations of value and salience in the human brain , 2014, Proceedings of the National Academy of Sciences.

[82]  N. Birbaumer,et al.  Information processing in severe disorders of consciousness: Vegetative state and minimally conscious state , 2005, Clinical Neurophysiology.