S. Laureys (Ed.)

Progress in Brain Research, Vol. 150

ISSN 0079-6123

Copyright r 2005 Elsevier B.V. All rights reserved

Chapter 11

From synchronous neuronal dischargesto subjective awareness?

E. Roy John1,2,�

1Brain Research Laboratories, NYU School of Medicine, New York, NY 10016, USA2Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA

Abstract: For practical clinical purposes, as well as because of their deep philosophical implications, itbecomes increasingly important to be aware of contemporary studies of the brain mechanisms that generatesubjective experiences. Current research has progressed to the point where plausible theoretical proposalscan be made about the neurophysiological and neurochemical processes which mediate perception andsustain subjective awareness. An adequate theory of consciousness must describe how information aboutthe environment is encoded by the exogenous system, how memories are stored in the endogenous systemand released appropriately for the present circumstances, how the exogenous and endogenous systemsinteract to produce perception, and explain how consciousness arises from that interaction. Evidenceassembled from a variety of neuroscience areas, together with the invariant reversible electrophysiologicalchanges observed with loss and return of consciousness in anesthesia as well as distinctive quantitativeelectroencephalographic profiles of various psychiatric disorders, provides an empirical foundation for thistheory of consciousness. This evidence suggests the need for a paradigm shift to explain how the brainaccomplishes the transformation from synchronous and distributed neuronal discharges to seamless globalsubjective awareness. This chapter undertakes to provide a detailed description and explanation of thesecomplex processes by experimental evidence marshaled from a wide variety of sources.

Introduction

Beliefs about the basis of subjective human expe-rience have slowly evolved, from mystical notionsof the soul and a disembodied mind to acceptanceof the proposal that consciousness must derivefrom neurobiological processes. After a long reluc-tance to confront the task, resulting first from theinfluence of religion and then from the dogmas ofbehaviorism, a widespread consensus that under-standing consciousness is the most important prob-lem of neuroscience is emerging. Not only

philosophical interest motivates this endeavor. Ad-equate anesthesia demands suppression of move-ment, pain, and awareness during surgery, whichanesthesiologists achieve by administering drugs toalter the interactions between brain regions. Amongthe millions who undergo general anesthesia everyyear, a substantial percentage manifest post-oper-ative cognitive deficit of unknown origin. Tens ofthousands of persons suffer traumatic head injuriesin vehicular accidents, and many remain with sig-nificant cognitive impoverishment or in long-lastingcoma. Psychoactive drugs are administered to mil-lions of patients every year by general practitionerscompared to those by psychiatrists. Many of thecognitive and functional disturbances in patientsthus medicated can be considered as disorders ofconsciousness, distorted in a manner which deviates

�Corresponding author. Brain Research Laboratories, Depart-

ment of Psychiatry, NYU School of Medicine, 550 First

Avenue, New York, NY 10016, USA. Tel.: +1212-263-6288;

Fax: +1212-263-6457; E-mail: johnr01@popmail.med.nyu.edu

DOI: 10.1016/S0079-6123(05)50011-6 143

consistently from a realistic interpretation of thepast and the present, in terms of the patient’s lifeexperience, leading to maladaptive behaviors. Thedeviations may originate from the individual’s ge-netic endowment or vulnerability, activation of ep-isodic memories of traumatic experiences in thepast, or some temporary neurochemical imbalanc-es. Regardless of the genesis, their manifestationrepresents a deviation from the regulatory processesthat enable the normal brain to achieve adaptivebehavior and a comfortable, tranquil state for theindividual.

A self-organizing system may define a ‘‘groundstate’’ of the brain. Homeostatic regulation of theground state is temporarily altered during generalanesthesia, may be perturbed persistently in coma,and is often disturbed in psychiatric patients. Re-turn of consciousness after general anesthesia isaccompanied by restoration of regulation. Suc-cessful treatment of comatose patients and thosewith neurological and psychiatric disorders may befacilitated by correction of underlying disturbanc-es of regulation. For these practical clinicalpurposes, as well as because of their deep philo-sophical implications, contemporary studies of thebrain mechanisms that generate subjective experi-ences are increasingly important. Plausible expla-nations can be made about the neurophysiologicaland neurochemical processes that mediate percep-tion, sustain subjective awareness, and create thephenomenon of consciousness. This chapter pro-vides an overview of contemporary studies pro-viding useful insights into these processes. It alsopresents a radical proposal to resolve the gap be-tween the discrete processes of neuronal interac-tion and the global experience of consciousness,which is speculative in that it is based on inferencesindirectly derived from the inadequacy of connec-tionist theories rather than upon direct evidence.The following overview provides a synopsis of themajor conclusions:

(i) Attributes of complex stimuli are fractionatedand projected by the thalamo-cortical relaysof the sensory specific ‘‘exogenous system’’ tothe basal dendrites of ensembles of pyramidalneurons throughout the cortex, and thus en-coded as time series of nonrandom synchro-

nization within dispersed cell assemblies rath-er than by discharges of dedicated cells. Thesefragments of sensations constitute islands oflocal negative entropy.

(ii) Collateral fibers from afferent sensory path-ways project to the ascending reticular ac-tivating system from which they aredistributed as time series of nonrandomlysynchronized volleys that are propagated tostructures in the limbic system, where theyare encoded as episodic memories. Thoserepresentations of previous experiencesmost similar to the momentary present in-put, which have been stored in the limbicsystem, are simultaneously activated byassociational mechanisms and readout as atime series of nonrandom discharges. This‘‘endogenous’’ readout is propagated viathe nonsensory specific nuclei of the diffuseprojection system to the apical dendrites ofthe cortical sheet of pyramidal neurons.

(iii) Coincidence detection between the converg-ing time series of inputs to basal somatic andapical dendritic synapses of dispersed pyram-idal neurons causes enhanced excitability,converting those assemblies that are current-ly encoding fragments of sensation into frag-ments of perception, which further increasesthe local negative entropy. This coincidenceintegrates encoded sensory information withoutput of systems encoding expectations,memories, planned actions, interoceptive, af-fective, and motivational states.

(iv) Integration of these fragments is required toyield a global percept. Modulation of mem-branes by local field potentials (LFPs) facil-itates discharge of excited cells as a coherentcortico-thalamic volley, followed by back-propagated high-frequency reverberatingoscillations. Coherent interactions of thesecortico-thalamo-limbic-cortical oscillationscause a state transition of the system intoresonance, binding these fragments into glo-bal negative entropy that creates conscious-ness, producing a unified perception.

(v) LFP oscillations are homeostatically regu-lated, controlling local synchrony, regionalinteractions, and periodic sampling, and

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defining a ‘‘ground state’’ with maximumentropy. Activity corresponding to thisground state is the most probable in a nor-mally functioning, healthy individual at restwith eyes closed but alert.

(vi) Perturbations of the homeostatic LFP reg-ulatory system alter the normal regulatedthresholds that define the ground state. Cy-clic fluctuations in these thresholds occurwith the diurnal rhythms of sleep. Devia-tions constituting negative entropy are con-sistently found during processing of sensorystimulation, cognitive activity, developmen-tal, neurological and psychiatric disorders,seizures, sleep, substance use, coma, andgeneral anesthesia. Shifts from the groundstate can be induced by chemicals such asanesthetics or addicting substances and ac-company many neurological and psychiatricdisorders. Restoration of the normal groundstate is accompanied by return of normalconsciousness and adaptive behavior.

This theory of consciousness proposes that ele-ments of consciousness are dispersed as negativeentropy, within many cell assemblies. Conscious-ness requires that this dispersed statistically non-random activity be transformed into a seamlesssubjective experience. Connectionistic concepts areinadequate to explain this conversion. The integra-tion of dispersed, local negative entropies into glo-bal negative entropy may produce consciousness,an inherent property of an electrical field resonat-ing in a critical mass of coherently coupled cells.

Fractionation or ‘‘local negative entropy’’ andconsciousness or ‘‘global negative entropy’’

Understanding perception is propadeutic to anunderstanding of consciousness, since it specifiesthe content of consciousness. Evidence indicatesthat perception is compounded of a multimodalrepresentation of momentary exteroceptive andinteroceptive stimuli contributed from an ‘‘exo-genous system’’ combined with a continuous con-textual rendering derived from readout ofrelevant episodic and short term or workingmemories and associated emotional coloration

contributed by an ‘‘endogenous system.’’ Consid-eration of this evidence has led some to the aptdescription of consciousness as perception of theremembered present (Edelman, 2001). The ‘‘ex-ogenous system’’ processes information abouteach sensory modality, continuously fractionatingincoming complex, multimodal signals into dis-tinct features that are processed separately. Fea-ture extractors or analyzers exist within multipleanatomically dispersed brain regions, each con-taining large neuronal networks relatively special-ized for extracting distinct attributes of complexstimuli or representing selective aspects of recentor episodic memories. These fragmented multimo-dal attributes are recombined and placed into thecontext of past experience to construct perceptionsthat are the momentary, dynamically changingcontent of consciousness. This dispersed local an-alytic information is constantly reintegrated glo-bally by dynamic interactions among regions. Forthis synthesis to achieve a reliable assessment ofreality, certain errors must be avoided. Neuronsare unreliable reporters. Neural activity represent-ing information useful for adaptive response to themomentary environment, or ‘‘signal,’’ must auto-matically be segregated from spontaneous neuralactivity, or ‘‘noise.’’ Failure of a ‘‘dedicated’’ cellin a feature detector to respond due to refractori-ness should not result in failure of the system todetect the corresponding attribute. Persistent aftereffects and self-sustained reverberatory activityshould be suppressed. Contributions from neuron-al assemblies that represent an attribute absentfrom the exogenous input must be excluded. Itsometimes might be advantageous to use a subsetof cues to complete the encoding of important butcomplex stimuli that have only partially been de-tected. It would be advantageous to automaticallyattach a valence to the encoded stimuli that re-flected their importance. Failure to avoid such er-rors may result in seizure activity, inappropriatebehavior, misperceptions, delusions, or other psy-chiatric symptoms. How the brain reassembles thefractionated sensory elements from dispersedpopulations into a global percept, while comply-ing with these requirements, constitutes the ‘‘bind-ing problem.’’ How this representation ofessentially statistical information is transformed

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into a personal subjective experience is the prob-lem of consciousness.

This theory proposes that homeostatically reg-ulated thresholds exist in every neuronal popula-tion, defining the baseline levels of randomsynchronization of firing in the ensemble thatreflect transactions within the local neural networkand inputs from exteroceptors and other brain re-gions. A local ‘ground state’ of maximum entropycan be defined as the absence of information orperfect predictability. The regulated thresholds de-fine the range of fluctuation that is most probablein each brain region, within the normal distribu-tion of the resting power spectra of local field po-tentials and the cross-spectra of interactionsbetween regions. Such power spectra or cross-spectra are mathematical descriptions of the aver-age frequency composition of a time series ofvoltages, or synchronized deviations from therandomness in spatiotemporal discharge patterns.A temporal sequence of synchronized activation orinhibition of some significant proportion of thecells in any brain region, deviating from the meanvalues of the distributions that define the groundstate, is the neural activity of informational value.Complex, multimodal environmental inputs causenonrandom, temporal patterns of synchronizedactivity in extensive networks that deviate from theregulated thresholds, establishing spatially dis-persed states of local negative entropy. Evaluationof such spatially dispersed statistical representa-tions by any cell or set of cells so as to uniquelyidentify the complex inputs from the environmentcannot plausibly be envisaged, let alone the trans-formation of such statistical description intosubjective experience by processes restricted todiscrete synaptic transactions in dedicated cellularnetworks. The difficulty of accounting for thistransformation has been termed the ‘‘explanatorygap’’ (Levine, 1983). As a solution to this quan-dary, we have proposed that consciousness mayemerge from global negative entropy, integratedacross anatomically dispersed neuronal ensemblesthat are nonrandomly active and electrically co-herent in spite of spatial separation, and is a prop-erty of an electrical field of information resonatingin a critical mass of brain regions (John et al.,2001; John, 2002, 2003, 2004).

Local field potentials (LFPs) are the envelope ofthe time series of synchronization in ensembles

In parallel with the activity of neural elements,voltage oscillations of LFPs can be observed with-in the volume of the brain. Like the LFPs, theelectroencephalogram (EEG) is the time series ofsynchronized activity in huge neural ensembles inthe vicinity of the recording site. The voltagewaves and coherences arise from synchronized ex-citatory and inhibitory post-synaptic potentialsproduced by transactions between elements withina local region as well as from interactions amongregions, while neuronal discharge is determined byinfluences impinging upon a single element. Thesetwo aspects of brain activity, discrete unit dis-charges, and potential waves are intrinsic to theprinciples by which the brain operates. This articleproposes specific processes by which slow waveoscillations (1) contribute to the construction andidentification of meaningful stimulus attributesfrom non-random synchrony of neural dischargescaused by afferent inputs producing sensationsand (2) enable the brain to bind these fragmentsinto meaningful percepts which enter subjectiveawareness of the individual.

Since single neurons respond erratically, the dis-charge of an individual neuron does not providereliable or interpretable information. Then, a ques-tion arises: where is the information? Were neu-ronal activity in a brain region random, the unitdischarges would be distributed evenly throughouttime, and a macroelectrode recording would be es-sentially isopotential. A certain level of ‘‘self-or-ganizing’’ synchronization, or coherence, occursspontaneously among CNS neurons and has alsobeen observed to take place in stimulations of neu-ral tissue in which the elements are weakly coupled(Abeles et al., 1994). As a consequence, the voltageswhich are recorded from these large neural aggre-gates approach zero only in slabs of cortical tissuesurgically isolated from the rest of the brain (Burns,1968). Oscillations of LFPs or evoked potentials(EPs) reflect nonrandom neural activity (Fox andO’Brien, 1965). When brain voltages recorded fromsome brain region depart significantly from thebaseline, the local neuronal activity is synchronizedor ‘‘nonrandom,’’ indicating transactions among

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brain regions or regional involvement in processingexteroceptive or interoceptive information.

LFPs and multiple unit activity (MUA) areclosely related, with multiple unit activity increas-ing when LFPs are negative. Multiple unit activityand LFPs can be entrained by visual stimuli in thedelta, theta, alpha, beta, and gamma ranges(Rager and Singer, 1998). Synchronization is moreprecise with oscillatory modulation in the beta andgamma range (Herculano-Houzel et al., 1999).Synchronized neural activity in multiple ensem-bles, rather than the local discharge of dedicatedneurons, integrates dispersed fragments of sensa-tion and may be the basis of perception (Nicoleliset al., 1995). fMRI results suggest that recurrentloops across multiple brain areas lead to reso-nance, which is the neural correlate of consciousvision (Goebel et al. 2001).

Basis vectors of the brain, the ground state, andglobal negative entropy

Power Spectra

Striking regularities, which may reflect action of agenetically specified homeostatic system commonto all healthy human beings, have been found byquantitative analysis of the EEG (QEEG). Thepower spectrum of the QEEG from every corticalregion changes predictably as a function of age inhealthy, normally functioning individuals in aresting but alert state (Matousek and Petersen,1973; John et al., 1980, 1983, 1988). These highlypredictable values of the normative age-appropri-ate power spectra and spatio-temporal organiza-tion of EEG patterns define the baseline or‘‘ground state’’ of brain activity. Under restingconditions, EEG spectra remain within the vari-ance defined by their distributions in normal ref-erence groups. Normative values have beenestablished from age 1 to 95 in large normativestudies for numerous parameters, such as absoluteand relative power, power ratios (symmetry) andsynchrony (coherence) in different frequencybands, within every local region, and betweenpairs of regions within and across the hemispheres.The specificity and independence from ethnic fac-tors of these descriptors have been established in

cross-cultural replications in Barbados, China,Cuba, Germany, Hungary, Japan, Korea, Mexi-co, Netherlands, Sweden, USA and Venezuela(John and Prichep, 1993). Like the electrocardio-gram, these rhythms display extremely high test-retest reliability within the healthy individualacross intervals of hours, days, or even years (Ko-ndacs and Szabo, 1999) and have been demon-strated to be clinically sensitive (John and Prichep,1993; Hughes and John, 1999). This stability,specificity, and sensitivity of the EEG in all healthyhuman beings from any ethnic background is dueto dynamic regulation by complex homeostaticprocesses that we believe to reflect our commongenetic heritage.

Multivariate descriptors

Lawful patterns of covariance of QEEG variablesacross the whole brain as well as among sets ofbrain regions have been quantified as MahalanobisDistances (composite features with inter-correla-tions removed), which display similar stability andreplicability across the life span (John and Prichep,1993). These multivariate compressions display re-markable specificity and sensitivity to subtle braindysfunctions (Jonkman et al., 1985). High levels ofcommon mode resonance of the EEG exist overlong-range cortical-cortical distances (John et al.,1990).

Spatial principal components

Spatial principal component analysis (SPCA) hasbeen applied to EEGs from large groups of nor-mally functioning individuals, to quantify statisti-cally significant, independent spatiotemporalmodes of neuronal interaction across the entirecortex as well as to classify distinctive brain ac-tions of drugs (John et al., 1972). As few as fivespatial principal components account for 90% ofthe variance of the EEG and reveal a high degreeof true phase correlation. The complex electricalactivity of the brain reflects interactions amonga limited number of simultaneously active, well-regulated subsystems, each with its characteristicmode of oscillation and distinctive functional ne-uroanatomical organization (Duffy et al., 1992;John et al., 1997; Srinivasan, 1999).

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Microstates

A variety of evidence, presented below, indicatesthat information processing in the brain occurs indiscrete discontinuous microstates and samplingoccurs at a specific rate that is similarly well reg-ulated. Adaptive segmentation reveals that thereare a limited number of microstate topographiesand they correspond well to spatial principal com-ponent loadings (Koenig et al., 2002). Clearly, thisregulation requires control of neurotransmitters.

Departures from ground state

Recently developed clinical QEEG instruments re-liably monitor the depth of general anesthesiaduring surgery independent anesthesia. In individ-ual patients, such instruments provide an index ofthe level of consciousness by continuous quantifi-cation of multivariate deviations of brain electricalactivity from the ground state defined above inde-pendent particular anesthetics agents. The level ofconsciousness during anesthesia can be accuratelypredicted by the magnitude and direction of suchmultivariate deviations, independent of anestheticagents. When baseline values are restored, con-sciousness returns (Prichep et al., 2000; John et al.,2001). A wide variety of QEEG and EP monitorsof effects of anesthetics on brain activity confirmthe high sensitivity of these descriptors (John andPrichep, 2005).

Deficiencies or excesses of any neurotransmittershould produce marked departure from thehomeostatically regulated normative EEG spec-trum. In fact, consistent profiles of deviation fromvalues predicted by normative databases have beenreplicably found in large groups of psychiatricpatients in conditions such as attention deficit dis-order, dementia, head injury, mood disorders, ob-sessive compulsive disorder, schizophrenia, and anumber of other behavioral, developmental, andcognitive disorders (Prichep and John, 1992; Alperet al., 1993), as well as in groups of patients un-dergoing general anesthesia. The patterns of thesedeviant values are so distinctive that accurate,replicable statistical classification of patients intodifferent DSM IV diagnostic categories has beenaccomplished (Prichep and John, 1992; Alperet al., 1993; John and Prichep, 1993; Hughes and

John, 1999; John et al., 2001). Further, deviationsinduced in normally functioning individuals bydrugs that are clinically effective for a particulardisorder, are opposite from the distinctive devia-tions found in unmedicated patients with the cor-responding disorder, and successful treatment ofsuch patients restores the QEEG to normativevalues (Saletu et al., 2000). Such observations val-idate the conclusion that baseline LFP spectra andpatterns of covariance are functionally relevantand clinically useful manifestations of processesrelevant to consciousness and subjective experi-ence.

Global negative entropy

These normative baselines are considered to bebasis vectors describing genetically determinedmodes of brain electrical organization, or basic‘‘traits,’’ whose set points determine the origin of amultidimensional signal space. The brain is a self-organizing system that conforms to these geneticconstraints. The electrical ‘‘ground state’’ of thebrain is defined as a hypersphere around this or-igin, the surface of which is defined by the varianceof the normally functioning human population.Regions within this hypersphere represent a regionof maximum entropy in which the range of mag-nitudes of interactions among functional brainsystems can be predicted. Subjectively, we habit-uate to these states and, therefore, we treat suchactivity as if it contains no information. The stateof the brain can be represented as a ‘‘brain statevector’’ in this multivariate signal space. Excur-sions of the brain state vector that extend outsidethe boundaries of this hypersphere constitute neg-ative entropy. Phasic modulations of the funda-mental modes reflect the present, momentarysensory, cognitive, and motor states of the indi-vidual, as well as transient alterations of con-sciousness. Tonic or sustained departures fromthese modes can be considered as deviant orpathophysiological, abundant evidence for whichwas cited above. Overall momentary deviationsfrom these fundamental modes of synchronization,within and among brain regions, are how infor-mation is represented in the brain and are globalnegative entropy, the content of consciousness.

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Origins and functional relevance of rhythmic EEGoscillations

EEG activity has conventionally been described interms of a set of wide frequency bands, usuallydefined as delta (1.5–3.5Hz), theta (3.5–7.5Hz),alpha (7.5–12.5Hz), beta (12.5–25Hz), and gamma(25–50Hz). Factor analysis EEG power spectrahas found a similar factor structure, suggesting thatdifferent functional systems produce theserhythms. The observed predictability of the EEGpower spectrum arises from regulation by anatom-ically complex homeostatic systems involvingbrainstem, thalamus, and cortex and utilizing allneurotransmitters (Llinas, 1988; Steriade et al.,1990; McCormick, 1992; McCormick, 2002).‘‘Pacemaker neurons’’ throughout the thalamusinteract with the cortex and nucleus reticularis tooscillate synchronously in the alpha frequencyrange. Efferent projections of these oscillationsmodulate waves also generated by a dipole layer inwidely distributed cortical centers, producing thedominant alpha rhythm. The nucleus reticulariscan hyperpolarize the cell membranes of thalamicneurons, slowing this rhythm into the theta range,and diminishing sensory throughput to the cortex.Theta activity is also generated in the limbic systemby pacemakers in the septal nuclei, which can beinhibited by entorhinal and hippocampal influences(Buzsaki, 2002). Delta activity is believed to orig-inate in neurons in deep cortical layers and in thethalamus, normally inhibited by input from theascending reticular activating system (ARAS) andnucleus basalis of Meynert. Delta activity may re-flect hyperpolarization and inhibition of corticalneurons, resulting in dedifferentiation of neuralactivity. Activity in the beta band reflects cortico-cortical and thalamo-cortical transactions relatedto specific information processing. Gamma activityreflects cortico-thalamo-cortical and cortical-corti-cal reverberatory circuits, which may play an im-portant role in perception (also see Ribary, thisvolume). This activity is the topic of intense con-temporary investigation, some of which will bediscussed below. Sleep-wake cycles depend on in-teractions involving the pontine and mesencephalicreticular formation, locus ceruleus, the raphe nu-clei, thalamic nuclei, and the nucleus of Meynert.

As an oversimplification, the neurons of thethalamus manifest two intrinsic states: Whenhyperpolarized to a certain level, they enter abursting mode in which they do not relay infor-mation to the cortex and other brain regions, andsleep ensues. When in this state, the EEG manifestslarge delta waves, perhaps reflecting the release ofcortical neurons mentioned above, normally inhib-ited by the influences of the ARAS. For wakeful-ness to take place, the thalamo-cortical neuronsmust be restored to a state in which throughput ofafferent sensory information to the cortex is againpossible. This occurs by cholinergic influences ofthe ARAS and the nucleus of Meynert, a processthat is described below in further detail.

EEG regulation depends upon this extensiveneuroanatomical homeostatic system. Structuresin this system play an important role in a widevariety of behavioral functions. Thus, behavioralimplications are inherent in any detailed evalua-tion of disturbances from this homeostatic regula-tion, whether transient as in anesthesia, persistentas in coma, or tonic as in developmental and psy-chiatric disorders. Major elements of this system,neurotransmitters mediating their interactions andtheir putative behavioral contributions, are sche-matized below in Fig. 1.

The following explanation is an oversimplifica-tion for heuristic purposes. Assume that a subject isdrowsy, with an EEG dominated by slow waves,perhaps in the theta frequency range, indicating de-differentiation and increased synchrony of corticalneurons disengaged from information processing.This slowing of the alpha rhythm arises fromhyperpolarization of the alpha pacemakers, reflect-ing GABAergic inhibition of thalamic pacemakersby the nucleus reticularis that can be initiated byglutaminergic influences from the cortex.

Activation of the mesencephalic reticular forma-tion by altered environmental stimuli results in in-hibition of the nucleus reticularis by cholinergic andserotonergic mediation via the ARAS. This inhibi-tion by the ARAS releases the thalamic cells frominhibition by the nucleus reticularis, and flow ofinformation through the thalamus to the cortex isfacilitated. The dominant activity of the EEG be-comes more rapid, with return of alpha and higherfrequency beta activity, reflecting differentiation of

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cortical neurons and resumption of cortical-corticalinteractions. However, as an alternative result ofcortical influences, dopaminergic striatal projec-tions can inhibit the mesencephalic reticular for-mation, enabling differential inhibition of thalamicneurons by the nucleus reticularis to occur. Theseinteractions between the ARAS, nucleus reticularis,and the thalamo-cortical relay neurons provide amechanism whereby the brain dynamically filtersand selects permissible stimuli to reach cortical

centers. The flux of activity through these pathwaysconstitutes a temporal pattern of synchronized in-put from the exogenous system to the axosomaticsynapses of cortical pyramidal neurons in lowerlayers of the cortex.

In parallel, collateral pathways from the mesen-cephalic reticular formation enter the limbic sys-tem, which is intimately involved in the storageand retrieval of memories and contributes hedonicvalence and emotional tone to the momentary

Fig. 1. Oversimplified scheme of the neuroanatomical structures and neurotransmitters comprising the homeostatic system that

regulates the electrical rhythms of the brain. The diagram assigns putative roles in the generation of EEG oscillations in the delta,

theta, alpha, beta, and gamma frequency ranges and to components of event related potentials. Elements of the exogenous system

processing sensory specific inputs are encoded as blue, elements performing nonsensory specific processing are encoded as gold,

inhibitory influences are encoded as red, and endogenous processing of readout from the memory system is encoded as green. The

behavioral functions that various regions are believed to contribute to are tentatively indicated for some of these brain structures (see

text for details). See Plate 11.1 in Colour Plate Section.

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brain state. Influences from the limbic system im-pinge upon the cortex via nonsensory specificpathways, and are the major input from the en-dogenous system to the apical dendrites of corticalsheet of pyramidal neurons, in upper layers of thecortex. An entorhinal–hippocampal–septal circuitis involved in the storage of episodic memories.Affective valences are attached to these episodicmemories by associative linkages with other limbicregions. Septal–hippocampal interactions modu-late the activity of circuits that generate EEGrhythms in the theta band projected to the cortexvia the cingulate gyrus and the medialis dorsalisnucleus of the thalamus. When this circuit is ac-tivated, gamma oscillations arise in the hippocam-pus, become phase locked to the theta activity, andare projected to the cortex. Thus, cortical thetamay reflect either underactivation of the ARAS oractivation of affective states, memories, or relatedcognitive processes.

These reciprocal cortical–subcortical interactionscan diminish, modulate, or actually block the flowof sensory information to the cortex and, togetherwith the contribution from the limbic system ofretrieved memories most relevant to the currentenvironment, play an important role in focusingattention and can have a decisive influence on se-lective perception. This continuous interaction be-tween the exogenous and endogenous systemsconstructs the ‘‘remembered present.’’ In view ofthe dependence of both systems upon the delicatebalance and relative abundance of multiple neuro-transmitters, the relevance of these interactions topsychiatric disorders becomes self-evident.

The ‘‘microstate’’ — temporal parsing of brain fields

Although subjective time is experienced as contin-uous, ‘‘brain time’’ is in fact discontinuous, parsedinto successive ‘‘perceptual frames’’ that define a‘‘traveling moment of perception’’ (Allport, 1968;Efron, 1970). Sequential events within this brieftime interval will be perceived as simultaneous, butare perceived as sequential if separated by a longertime. The duration of the perceptual frame in dif-ferent sensory modalities is about 75–100ms. Themost familiar example of discontinuous sampling isthe apparent stability of a movie viewed at about 64

frames per second. Examination of the momentaryvoltage maps on the scalp reveals a kaleidoscopewith positive and negative areas on a field or‘‘microstate,’’ which persists briefly and changescontinuously (Lehmann, 1971). Computerized clas-sification of sequences of microstates in 500 normalsubjects, aged 6–80 years, yielded the same topo-graphic patterns in every individual, with 4–5 basicfields accounting for about 85% of the total spa-tiotemporal variance of the EEG with approxi-mately equal prevalence. The mean microstateduration slowly decreased during childhood, stabi-lizing for healthy young adults at about 8274ms(Koenig et al., 2002). The stability of these micro-state topographies and their mean duration acrossmuch of the human life span, and their independ-ence from ethnic factors, supports the suggestion ofgenetic regulation. The topographies of these mo-mentary fields closely resemble those of the com-puted modes described in the spatial principalcomponent studies cited above, indicating that thespatial principal component loadings are not acomputational artifact. While these normativemodes of regional interaction are statistically inde-pendent, they may overlap in time with differentweightings. Different microstates seem to correlatewith distinctive modes of ideation (Lehmann et al.,1998). The transition probabilities from one micro-state to another are apparently altered during cog-nitive tasks (Pascual-Marqui et al., 1995) and inschizophrenia (Streletz et al., 2003).

The correspondence between the experimentallyobtained durations of each subjective episode andthe mean duration of microstates suggest that amicrostate may reflect a ‘‘perceptual frame.’’ Recentfunctional brain-imaging evidence has led to similarproposals that consciousness is discontinuous and isparsed into sequential episodes by synchronousthalamo-cortical activity (Llinas and Ribary, 1993;see Ribary, this volume). Asynchronous, multimo-dal (Zeki, 2000) sensory information may therebybe integrated into a global instant of conscious, ap-parently simultaneous multimodal experience.

Introspection reveals fading, but persistent rec-ollection of the recent past that coexists in subjec-tive continuity with the momentary present. Adegree of constancy must persist across a sequenceof perceptual frames, analogous to a moving

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window of time much longer than the momentarypersistence of a microstate. Conversely, humanscan make temporal discriminations much fasterthan these estimates of perceptual frame duration.The brain’s sampling algorithm must somehowreconcile the 80ms microstate duration with mil-lisecond discriminations as well as persistent recentmemories. This implies that afferent input in anymodality is mediated in parallel by many multi-plexed channels. Sequential events within a singlesuch channel are combined into a correspondingperceptual frame. Subsets of channels must be in-tegrated in receiving areas as a ‘‘standing spatio-temporal wave’’ of synchronized activity, like aninterference pattern persisting through the inte-gration period across serial microstates. Adaptivebehavior requires that information in the immedi-ate perceptual frame be continuously evaluated inthe context of recent and episodic memories aswell as evaluation of emotional and motivationalvalence relevant to the immediately precedingframe. Coincidence detectors of the differences inlocal non-randomness across successive micro-states might provide a priority interrupt signalthat serves to close the integration period arbi-trarily, abruptly resetting the timing and opening anew frame.

The sustained persistence of microstates, as wellas many behavioral measures, is difficult to rec-oncile with the brevity of neural transactions.Some reentrant or reverberatory brain processmust sustain cortical transactions as a ‘‘smoothed’’steady state, independent of the activity of indi-vidual neurons. Temporal extension of neural ac-tivity has been considered critical for binding, andNMDA has been proposed to play an essentialrole in this regard (Flohr, 1998). It may be relevantthat EPSP–IPSP sequences ranging from 80 to200ms are omnipresent in mammalian forebrainneurons (Purpura, 1972), comparable to the long-persistent, post-synaptic depolarization displayedby NMDA receptors.

A comparator constructs perceptions fromsensations

Not only is brain processing of information dis-continuous, parsed into successive frames that are

subjectively continuous, but the content of eachframe appears to be constructed from interactionof two separate systems. The phenomenon of‘‘backward masking’’ or metacontrast, the abilityof a later sensory input to block perception of aprior event (Alpern, 1952), suggests that two dif-ferent processes representing independent inputsto a comparator are required for conscious per-ception. This interaction is constantly ongoingand, like any good computer operating system, istransparent to the user, the self.

The existence of this combinatory process wasinitially inferred from the results of animal exper-iments, in which electrical activity was recordedfrom electrodes that were chronically implantedinto multiple brain regions while the animalslearned discriminative behaviors. These electrodeswere implanted in pairs with closely spaced tipsseparated by 1mm, enabling ‘‘bipolar’’ recordingsfrom well-localized ensembles. The differentialcues were ‘‘tracer-conditioned stimuli’’ consistingof auditory or visual stimuli presented at two dif-ferent specified repetition rates. Appearance ofEEG activity at the tracer-conditioned stimuli fre-quency in bipolar recordings in any region wasinterpreted as ‘‘labeled response,’’ indicating localparticipation in processing the tracer-conditionedstimuli and in mediating the behavior. When catslearned to discriminate among several visual andauditory differential-conditioned stimuli, markedchanges were observed during training in the an-atomical distributions of labeled activity. Initially,labeled activity appeared in only a few regions, butas learning progressed, labeled responses began toappear in wider regions of the brain. Anatomicalspread of labeled activity gave direct insight intothe establishment of extensive brain networks dur-ing learning. More unexpected was the observa-tion that when errors were performed, labeledresponses in some brain regions corresponded notto the physically presented tracer-conditionedstimuli, but rather to the frequency of the cue ap-propriate for the behavior that was actually per-formed. These results showed that the brain couldstore a distinctive temporal pattern of synchro-nized discharges in a representational system andrelease that pattern from memory on a subsequentoccasion, when cues were misperceived.

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Further experiments examined averaged event-related potential (ERP) waveshapes elicited by thetracer-conditioned stimuli. Initially, ERPs dis-played only a primary positive component at ear-ly latencies. As the conditioned response wassuccessfully established, a later primarily positivecomponent appeared, implying that a second set ofinputs was reaching those regions, but was mani-fested only in those trials in which appropriate be-havior ensued. When differentiated behavioralresponses became firmly established, requiring dis-crimination between visual or auditory tracer-con-ditioned stimuli at two different repetition rates, theERP waveshapes elicited by the two tracer-condi-tioned stimuli developed distinctively different latecomponents. Waveshapes acquired distinctive mor-phology to different cues and became similar inbipolar recordings from multiple nonsensory- andsensory-specific regions. It was proposed that per-ception, i.e., accurate interpretation of inputs fromthe environment, required coincidence detectionbetween activity in sensory-specific and sensory-nonspecific systems (John, 1968).

Evidence of contributions to the comparator by atime series released from the hippocampus

A series of experiments were performed in such dif-ferentially conditioned cats, recording from multiplemovable arrays of closely spaced microelectrodeschronically implanted in different brain regions, inaddition to 24 fixed electrodes usually arranged inbipolar pairs sampling 12 other neuroanatomicalstructures that varied from animal to animal. Post-stimulus histograms were examined, showing theaverage temporal firing patterns of single and mul-tiple units as well as LFPs and ERPs simultaneouslyelicited by different tracer-conditioned stimuli wereexamined. Recording simultaneously from all bipo-lar electrode pairs and moving the microelectrodes0.1mm every week, extensive brain regions weresurveyed as different behaviors were performed torandomized presentations of the two tracer-condi-tioned stimuli. These experiments yielded some sa-lient findings: (1) Although single tracer-conditionedstimuli presentations from several neurons in thesame neighborhood elicited firing patterns that werehighly variable and very different for each cell, after

several hundred presentations almost identical post-stimulus histograms were obtained from every cell;(2) The post-stimulus histograms of single neuronsduring large numbers of tracer-conditioned stimulipresentations slowly converged to the post-stimulushistograms of multiple unit activity from the localneural ensemble that was rapidly elicited during asmall number of presentations; (3) The ERPs re-corded from any region were the envelope of thepost-stimulus histograms from multiple units in thatregion, and remained very similar as the microelec-trodes traversed through extensive intracerebral dis-tances (3–4mm); (4) Different distinctive ERPwaveshapes and post-stimulus histograms contourswere elicited by different behavioral cues, but thetime series of nonrandom synchronization of neu-ronal firing was very similar in different brain re-gions; (5) The ERPs and post-stimulus histogramsthroughout such extensive traverses of the sensory-specific lateral geniculate body (a thalamo-corticalrelay nucleus) and in the contralateral non-sensory-specific dorsal hippocampus displayed very similarpost-stimulus histograms and ERP waveshapes; (6)The distinctive time series of neuronal dischargeswere present in the thalamo-cortical relay nucleus,but absent from hippocampus when correct re-sponses failed to occur, and the thalamo-corticalrelay nucleus and hippocampus displayed very dis-parate waveshapes in response to novel stimuli; and(7) Similar ERP waveshapes were recorded simul-taneously from bipolar electrode derivations inmany other brain regions (John and Morgades,1969a, b; John, 1972).

These results and those of subsequent studies sug-gested that activity of an individual element was in-formational only insofar as it contributed to thepopulation statistics. The time series of voltagescomprising an EEG or ERP waveshape recordedfrom a brain region closely corresponded to thetemporal pattern of synchronized firing among theneurons in the local ensemble. Storage of an episodicmemory appeared to establish a system that dis-played distinctive temporal patterns of nonrandomactivity synchronized across widely dispersed regionsof the sensory cortex appropriate to the modality ofthe cue, the corresponding thalamo-cortical relaynucleus, the intralaminar nuclei, the mesencephalicreticular formation, and the hippocampus. When

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novel stimuli at an intermediate rate midway be-tween the two tracer frequencies were randomly in-terspersed into a series containing the two tracer-conditioned stimuli, ‘‘differential generalization’’ oc-curred and the animal performed one or more dif-ferentiated, conditioned responses. When differentialgeneralization occurred, both the ERP waveshapesand post-stimulus histograms firing patterns elicitedby the neutral cue corresponded to those distinctivefor the tracer-conditioned stimuli appropriate for thebehavior that was subsequently performed. The re-trieval of a particular episodic memory seemed to berelated to the readout of the corresponding distinc-tive time series of synchronized discharges from anendogenous system, concordant with a similar timeseries of synchronized discharges in the exogenouspathways. When ERP waveshapes recorded duringbehavioral errors of omission were subtracted fromERP waveshapes when behavioral response was cor-rect, the resulting ‘‘difference waveshape’’ was es-sentially identical, with simultaneous peak latencies,in cortex, intralaminar nuclei, mesencephalic re-ticular formation, and hippocampus, but substan-tially delayed in the thalamo-cortical relay nucleus.The ‘‘difference waveshape’’ was interpreted to bethe time series of the ‘‘readouts’’ released when aneutral stimulus elicited differential generalization.The delay in the corresponding thalamo-cortical re-lay nucleus (lateral geniculate body) was interpretedto mean that a memory system imposed a selectivefilter on the sensory nucleus processing incomingvisual information (John et al., 1969, 1972, 1973;Ramos et al., 1976). Readout waveshapes in sensory-specific brain regions could be released by tracerstimuli of several sensory modalities; during differ-ential generalization, the same cue distinctive ERPwaveshapes were elicited in the medial geniculatebody (a supposedly specific ‘‘auditory thalamo-cor-tical relay’’ nucleus) by novel visual as well as au-ditory tracer-conditioned stimuli (Thatcher andJohn, 1977).

These results led to an hypothesis that informa-tion was encoded statistically by the time series ofnonrandomly synchronized neural activity withinneuronal ensembles in various brain regions, ratherthan by synaptic changes in specific neurons in ded-icated pathways. This idea was tested experimentallyusing electrical stimulation of brain regions to ar-

tificially produce nonrandom neuronal discharges.Independent of the region, it was shown that brainstimulation could achieve complete differential be-havioral control, parametrically proportional to theamount of current delivered. Efficacy depended up-on current strength rather than locus of stimulation,and regions differed only with respect to the amountof current required to achieve behavioral control(Kleinman and John, 1975). When two patternedpulse trains were delivered out of phase to arbitrar-ily selected pairs of brain regions, behaviors appro-priate to the global temporal sum of the twoelectrical patterns were performed; simultaneous re-cordings suggested that integration between the twopulse trains took place in the intralaminar nuclei.Synchronized activation in arbitrarily selected pairsof brain regions was integrated and incorporated bythe brain into a single cue that could guide adaptivebehavior. Such arbitrarily placed pulses of electriccurrent cannot be presumed to activate dedicatedbrain circuits selective for different behaviors.

Different geometric forms elicited different ERPwaveshapes in humans, which displayed ‘‘size in-variance;’’ the same basic waveshape was elicited bya geometric form independent of its size (John et al.,1967). When a series of numbers or letters werepresented to human subjects, a vertical line elicitedmarkedly different ERPs on the parietal cortex,when perceived as the letter ‘‘i’’ imbedded in a lettersequence or as the number ‘‘1’’ in a number se-quence. However, ERPs from the visual cortex wereidentical under the two different conditions(Thatcher and John, 1977). Such findings suggestthat information about a complex stimulus is rep-resented by a distinctive spatiotemporal pattern ofdischarges coherent across a dispersed set of re-gions, which is encoded by a limbic memory mech-anism that can reproduce the specific time seriesand propagate it effectively to other brain regions.

The chronometry of consciousness

Psychophysiological research has established thatlatencies of ERP components are correlated withinformation processing, and successive peaks cor-respond to (a) sensory activation, (b) detection ofsensation, (c) perceptual identification of the infor-mation, (d) cognitive interpretation of the meaning

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of the input, (e) linguistic encoding of that concept,and (f) organization of adaptive reactions.

Sensory activation

In a cognitive auditory task, evoked gamma oscil-lations (40–45Hz) phase-locked between vertexand posterior temporal scalp regions have beendetected as early as 45ms (Gurtubay et al., 2004).In recordings restricted to lower frequencies, theearliest components of scalp-recorded ERPs ap-pear as a surface negativity (N1) at about 60–80msand a positivity (P1) at about 100ms. These com-ponents have been localized by imaging methods tothe primary cortical sensory receiving areas of thecorresponding modalities. The later peaks are task-dependent and localization of their sources is still asubject of investigation (Gazzaniga et al., 2002).

Detection of sensation

In an attempt to establish the minimum durationof a stimulus for it to be detected, Libet (1973,1982, 1985) studied the experiential consequencesof series of electrical stimuli delivered directly intothe brain of conscious human subjects, as well asother stimuli of varying duration. A debate stillrages about the interpretations of those experi-ments, indicated by a special issue of a leadingjournal recently devoted to this topic (Baars et al.,2002). In brief, evidence suggests that although aperson may not yet be aware of a stimulus, it hasalready been detected by the brain by about80–100ms. Intracerebral recordings from multiplesites suggest that initial visual processing may oc-cur exclusively in the visual association cortexfrom approximately 90 to 130ms (Halgren et al.,2002), an estimate concordant with the observedaverage duration of a microstate discussed above.

Mismatch negativity

A series of experiments (Naatanen et al., 1987,1993, 2004) have established that as soon as astimulus registers in the brain, a memory trace ap-pears to be established that compares subsequentevents to a representation of the previous event.This dynamic ‘‘echoic trace’’ appears to last forabout 10 s (Sams et al., 1993). When the second

element of a pair of sensory stimuli differs from thefirst, an enhancement of the ERP excursion fromthe second negativity (N2) to the second positivity(P2) takes place. The amplitude N2P2 is consideredto be a measure of attention, referred to as mis-match-negativity (MMN). This process appears tobe ‘‘preconscious.’’ A critical set of experiments isrelevant here (Libet et al., 1979). Essentially, acomplex set of observations was interpreted toshow that conscious awareness of a neural event isdelayed approximately 500ms after the onset of thestimulating event, but this awareness is referredbackward in time relative to that onset. Cotterill(1997) proposed a neural circuit to account for this‘‘backward referral’’ namely, the ‘‘vital triangle,’’which was further elaborated by Gehring andKnight (2000) in a study of human-error correc-tion. These authors propose that a model of theoriginal event is stored in the dorsolateral prefron-tal cortex and is compared to the subsequent event.The existence of MMN suggests that a model ofthe recent past is continuously compared with thepresent and, together with other evidence, has ledEdelman (2001) to refer to consciousness as ‘‘theremembered present.’’

Perceptual awareness

Numerous reports from intracerebral as well asscalp recordings from conscious human subjects in-dicate that a burst of phase-locked activity appearsbetween the parietal and prefrontal cortex fromabout 180–230ms after presentation of a stimulusto a subject engaged in performing a cognitive task(Desmedt and Tomberg, 1994; Tallon-Baudry et al.,1997; Tallon-Baudry, 2000; Varela, 2000). In pos-terior temporal regions, phase-locked as well asnon-phase-locked gamma oscillations at about200723ms at 43Hz have been observed byGurtubay et al. (2004). Results in studies alreadycited above, in which intracerebral recordings wereobtained from multiple implanted electrodes in oc-cipital, parietal, Rolandic, and prefrontal sites dur-ing working memory tasks, suggested that theresults of initial perceptual processing from approx-imately 90 to 130ms after stimulus presentationwere projected from the visual association cortex toprefrontal–parietal areas from approximately 130 to

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280ms (Halgren et al., 2002). On the basis of suchfindings, and from results cited in the next section,we propose that the neurophysiological processesthat generate the second positive component of theERP, P2, at about 200ms represent the neural cor-relates of awareness.

Cognitive interpretation

The most studied electrophysiological correlate ofhuman cognitive processes, the so-called P300(Sutton et al., 1965; Donchin et al., 1986), hasbeen investigated in thousands of experimentalstudies since first reported. This process is actuallycomposed of an early event, referred to as P3A,that appears over anterior brain regions at about225–250ms and a later component, or P3B, thatappears more prominently over posterior brainregions at about 300–350ms, after an unexpected‘‘oddball’’ or ‘‘target’’ event occurs in a series ofcommon events. Intracerebral recordings have es-tablished that target-evoked P3-like componentswere most frequently recorded from medial tem-poral and prefrontal sites (Clarke et al., 1999). Inan auditory oddball task, 33–45Hz oscillationsphase-locked between midline and frontal, central,and parietal regions in the 250–400ms latency do-main were found only after the target stimuli(Gurtubay et al., 2004).

Haig (2001) studied gamma synchrony in schiz-ophrenic patients and normal controls using anoddball paradigm. This author found early- andlate-gamma band phase synchrony (37–41Hz) as-sociated with the components N1 and P3 compo-nents elicited by the ‘‘target’’ stimuli. He proposedthat gamma synchrony served to index the activityof integrative cognitive networks and suggested animpairment of brain integrative activity in schizo-phrenic illness. Spencer et al. (2003) have furtherstudied neural synchronization in schizophrenic pa-tients and matched normal controls discriminatingbetween illusory square and control stimuli. Theseauthors hypothesized that illusory square stimulipresumably synchronize neural mechanisms thatsupport visual feature binding. They reported thatcompared to the matched controls, using complexwavelet analysis of the EEG, responses of the schiz-ophrenic patients relative to the stimulus onset

demonstrated (1) absence of the posterior compo-nent of the early visual gamma (30–100Hz) re-sponse to the Gestalt stimuli, (2) abnormalities inthe topography, latency, and frequency of the an-terior component, (3) delayed onset of phase coher-ence changes, and (4) a pattern of interhemisphericcoherence decreases in patients that replaced thepattern of anterior–posterior coherence increasesdisplayed in the responses of control subjects. In arelated subsequent study using a similar experimen-tal paradigm, both healthy controls and schizo-phrenic patients displayed a gamma oscillation thatwas phase locked to the reaction time, presumed toreflect conscious perception of the stimulus (Spenceret al., 2004). Reaction time was slower in the pa-tients, and further, the frequency of this oscillationwas lower in patients than in the controls. This wasinterpreted to reflect a lower capacity of schizo-phrenic brains to support high-frequency oscilla-tions. The degree of phase locking was correlatedwith visual hallucinations, thought disorder, anddisorganization in the patients, as assessed by theirperformance on the positive and negative syndromescale and separate scales for the assessment of pos-itive and of negative symptoms. They interpretedtheir findings as an evidence that although theschizophrenics could perform the task, the interac-tions within the neuronal networks engaged in de-tection of the target were poorly organized andproceeded at a slower rate.

Semantic encoding

Evidence has accumulated confirming that a latenegative component of ERPs, termed the N450, iscorrelated with the operations performed duringsemantic encoding (Kutas and Hillyard, 1980;Hillyard et al., 1985; Donchin et al., 1986; Hillyardand Mangun, 1987). This finding is mentionedhere only for the sake of completeness, but doesnot directly pertain to the model being proposed.

In summary, this body of data suggests thatshort latency contributions to the ERP appear toarise from inherent sensory encoding processes,while later contributions to the ERP appear toarise from working memory and an experientiallydependent memory system, and further suggeststhat perception requires the interaction between

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two systems, the exogenous sensory-specific systemand the endogenous nonsensory-specific system.

Coincidence detection between exogenous andendogenous activity

Direct electrical stimulation, phase-locked to a pe-ripheral stimulus to block the primary componentof the ERP in cortical sensory receiving areas, hadlittle effect on behavioral accuracy in trained cats,but greatly decreased performance when delayed toblock the secondary nonsensory-specific compo-nent. Such results led to the proposal that coinci-dence at the cortical level between exogenous inputof information about the environment and endog-enous readout of relevant memories, detected by aneuronal comparator at the cortical level, identifiedthe informational significance of the stimulus andwas critical for perception (John, 1968). Similarhypotheses were proposed by other investigators(Sokolov, 1963). Subsequently, in awake neurosur-gical patients, Libet (1973) stimulated the cortexelectrically to coincide with the time of arrival ofthe nonsensory-specific, secondary component ofthe EP waveshape, usually present in the responseof the somatosensory cortex that was evoked by amild electrical shock to the wrist, and found thatsuch time-locked brain stimulation could blocksubjective awareness of the wrist shock. Similarfindings during brain surgery were reported shortlythereafter by Hassler (1979) who recorded the cor-tical evoked responses to mild wrist shock, andelectrical shock to the sensory-specific ventrobasalnucleus and the non-sensory-specific nucleus cen-tralis lateralis. The waveshape of the cortical re-sponse evoked by wrist shock consisted of an earlycomponent like the response to the ventrobasalnucleus alone and a later component like that tothe nucleus centralis lateralis alone. Hassler thenshowed that the perception of wrist shocks by apatient could be blocked by later stimulation of thenucleus centralis lateralis in the thalamus, appro-priately delayed to disrupt the late cortical re-sponse. In comatose patients, presence of early butnot late components of multisensory evoked po-tentials has been used to stage severity of traumaticbrain injury (Greenberg et al., 1981) (see Guerit

this volume). The return of late evoked potentialcomponents is predictive of recovery from coma(Alter et al., 1990). Such data indicate that a com-parator between exogenous sensory-specific andendogenous non-sensory-specific systems is essen-tial for sensations to be perceived and is reflected inlate ERP components.

Recent research has described a priming mecha-nism, whereby top-down influences have a primingeffect on bottom-up signals. The electrical activity ofthe major output neurons of the cortex is stronglyinfluenced by the laminar distributions of synapticactivity. Vertically aligned sheets of pyramidal neu-rons have basal axosomatic synapses in layers 4–5 inthe neocortex, which receive exogenous inputs aboutcomplex environmental stimuli from sensory-specif-ic afferent pathways. Apical axodendritic synapsesof these pyramidal cells are in layer 1, and receiveendogenous input via the non-sensory-specificprojection system of the thalamus. Using directelectrical stimulation of pyramidal neurons with mi-cropipettes, it has been demonstrated that pyrami-dal neurons act as comparators, detecting temporalcoincidence of inputs to apical and basal synapses(Larkum, 1999). Direct stimulation of either apicalor basal synaptic regions alone caused a sparse ax-onal discharge of the pyramidal neuron. However,concurrent stimuli delivered to both apical and basalregions within a brief interval elicited clearly en-hanced firing of the neuron, with a back-propagateddischarge in the gamma frequency range (�50Hz).Thus, ‘‘top-down’’ axodendritic signals may modu-late the saliency of a ‘‘bottom-up’’ axosomatic sig-nal, changing the neuronal output from one or a fewspikes into a burst (Siegel et al., 2000). It has beensuggested that local rhythmic oscillations may causesubthreshold membrane fluctuations that play apossible contributory role in this process (Engel andSinger, 2000). The somadendrite interactions seemto depend critically upon frequencies of back-prop-agation between 20 and about 70Hz, which is thebeta and gamma range.

A more recent experiment extended this observa-tion in a very important way, using voltage-sensitivedyes to achieve visualization of cellular activation inbrain slices oriented so as to include regions of thethalamus and their projections to the cortex. Directelectrical stimulation by micropipettes placed upon a

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specific thalamic relay nucleus (ventrobasal thalamicnucleus) caused a visible moderate activation in lay-er 5 of the corresponding sensory cortex. Directstimulation of a nonspecific nucleus of the diffuseprojection system (nucleus centralis lateralis) causeda visible moderate activation in cortical layer 1.When the ventrobasal, nuclei and centralis lateraliswere stimulated concurrently (i.e., when the simu-lated inputs from the exogenous and endogenoussystems were coincident), cortico-thalamic activitywas markedly enhanced, with a synchronized strongdischarge back to the thalamic regions from wherethe stimuli had originated. Most important from thetheoretical viewpoint advanced, when both regionswere subjected to a train of pulses at 50Hz, therewas markedly stronger and more widely spread ac-tivation of the cortical regions containing Layers 1and 5. A volley of cortico-thalamic activity at gam-ma frequency was transmitted to the thalamic re-gions where the stimulating pulses had been initiallydelivered, that was back-propagated to the corticalregions where coincidence had occurred. Thus, a re-verberating cortico-thalamo-cortical loop was estab-lished (Llinas et al., 2002).

Such an evidence shows that influences from in-puts to the upper levels can dominate the effects offeedforward sensory input arriving at basal levels.The precise effect of these interactions upon the fir-ing patterns of the pyramidal neurons depends uponthe duration and timing of the inputs to the differentlevels. The spatio-temporal configuration of cortico-fugal and cortico-cortical projections from this co-incidence detection system may be strongly depend-ent upon the concordance between the two timeseries converging thereupon from the exogenousand endogenous systems. The critical time intervalwithin which such interaction can occur probablyvaries as a function of the level of arousal, but thepresent results provide an initial approximation forthe pertinent time intervals. While this neural en-hancement process has thus far only been shown tooperate at intervals on the order of tens of millisec-onds, some findings (Flohr, 1998) suggest that de-lays on the order of a 100ms or more involving theNMDA receptor may serve as a local bindingmechanism for a combination of specific and non-specific inputs. It must be emphasized that this syn-thesis of percepts from the interaction between the

past and the present is mediated by a wide variety ofneurotransmitters. Adaptive brain functions arecritically dependent upon the availability of thesesubstances and the processes that control their syn-thesis and metabolism, a topic beyond the scope ofthis article.

The evidence suggests the existence of a distrib-uted coincidence detection system that is dispersedthroughout the cortex. This system serves as acomparator between present multimodal, ex-ogenous input from the environment and inputfrom a ‘‘hedonic system,’’ which integrates endog-enous activity reflecting present state, workingmemory, relevant episodic experience, motivation,and idiosyncratic individual values. The readoutfrom the value system could arise from mecha-nisms generating experiential associations activat-ed by collateral inputs from the just previouscomplex sensory stimuli. In a sense, this can beenvisaged as a process enabling the past to ‘‘leap-frog’’ into the future. The hypothesized system ofcoincidence detectors might act as a filter, segre-gating random neural ‘‘noise’’ or unimportant el-ements of the complex stimuli from enhancedneural discharges that are thereby recognized as‘‘signal’’ of informational value.

Contribution to perception of endogenous readoutfrom memory

According to the model herein proposed, activity ina spatially dispersed sheet of neurons encoding at-tributes representing fragmented sensations wouldbe enhanced, by coincidence between exogenousand endogenous inputs, to become fragments ofperception. Outputs from this multimodal compa-rator converge as ongoing synchronous cortico-thalamo-cortical loops engaging regions of thala-mus and cortex in coherent reverberation in thefrequency range of the gamma rhythm (25–50Hz),binding the distributed fragments into a unifiedpercept. Such reverberation has been proposed bysome to play an essential role in perception(Ribrary et al., 1991; Llinas and Ribary, 1993;Rodriguez et al., 1999; Varela, 2000; Lachauxet al., 2000; John et al., 2001; Llinas et al., 2002)and is hypothesized to be reflected by the induced

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long-distance synchronization of gamma oscilla-tions (Pantev, 1995; Rodriguez et al., 1999; Varela,2000). These ideas are consonant with the exper-imental evidence and theoretical proposals byBasar and his colleagues that oscillatory systemsat various frequencies, but particularly in the gam-ma range, act as resonant communication systemsthrough large populations of neurons (Basaret al., 2000).

Perception is an active process, modulatedstrongly by endogenous influences representingreadout of the relevant recent and episodic pastand present states, which place the immediate en-vironmental input into context and enable the in-dividual to generate predictions and expectationsabout future stimuli. This process is envisaged tooccur continuously in multiplexed channels, suchthat the past and the present are inseparablymerged in every update of the microstate or per-ceptual frame. An ERP can be conceptualized asan approximation of one cycle of the constructionof a frame, extracted from one channel by repet-itive phase-locked sampling of the continuouslyongoing process.

The sequential steps in this process of construc-tion of perception can be inferred from ERP re-search and is based upon our knowledge of ‘‘mentalchronometry’’ summarized above. In Fig. 1, theendogenous retrieval system was schematized bythe green arrows indicating interactions betweenparticular brain regions. The exogenous–endog-enous interactions that comprise this process areschematized in Fig. 2, and are hypothetically con-ceptualized to operate in the following manner:

f(t0). Inputs from multimodal sensory receptorsactivated by a complex environmental scene areencoded as time series, f(t0), of nonrandomly syn-chronized discharges in multiplexed parallel chan-nels of afferent pathways, projecting to sensory-specific thalamo-cortical relay nuclei of every sen-sory modality.

f(t). At time t, volleys of synchronized outputsfrom multimodal sensory-specific thalamo-corticalrelay nuclei reencode f(t0), and are propagated as amodified time series, f(t), of non-randomly synchro-nized exogenous inputs to the lower layers of thesheet of pyramidal neurons dispersed throughoutcortical ensembles of feature detectors. Activation

of basal synapses of pyramidal neurons in corticalLayer 5 causes the positive ERP component P1 withlatency about 50ms, reflecting initial registration offragments of sensation. Corresponding synchro-nized volleys from the thalamo-cortical relay nuclei,and collateral pathways transmit the modified timeseries, f(t), to the reticular formation in the brain-stem where it is further modulated to reflect thearousal level.

f ðtþ 1Þ: At time tþ 1; efferent volleys fromsensory cortical regions instruct nucleus reticularisto modulate the thalamo-cortical relay neurons tofocus attention by raising the threshold of thosepathways that do not significantly contribute tothe ascending volley of synchronous activity re-ceived at time t. These corticofugal volleys causethe ERP component N1 at about 130ms. At thesame time, the ARAS sends the time series f ðtþ 1Þto the non-sensory-specific intralaminar anddorsomedial nuclei of the thalamus and to theraphe nucleus and structures of the limbic system.

f ðtþ 2Þ: At time tþ 2; the intralaminar nucleisend the nonrandomly synchronized time seriesf ðtþ 2Þ modified by the ARAS to the apicalsynapses of cortical Layer 1, enhancing the ex-citability of pyramidal neurons in which coinci-dence detection occurs, thereby transformingfragments of sensation into islands of local neg-ative entropy. This coincidence causes vigorousdischarge causing the ERP component P2 atabout 210ms, accompanied by back-propagationof reverberatory cortico-thalamo-cortical gammaactivity. The time series f ðtþ 2Þ is rapidly trans-mitted from posterior cortical regions and con-verges with f ðtþ 2Þ from the dorsomedialthalamic nucleus upon the prefrontal cortex,which in turn relays f ðtþ 2Þ to Layer 1 of theentorhinal cortex. Activity then propagates fromarea CA3 to CA1, hence to the amygdala, nucleusaccumbens, septum, and hypothalamus. Memo-ries originally encoded as time series of nonran-dom synchrony and stored in the neural networksof this system are activated by associationalprocesses modulated by emotions, providing thevalence most relevant to the sensory pattern in-itially encoded by the exogenous system.

f ðtþ 3Þ: At time tþ 3; the circuit of the timeseries f ðtþ 2Þ through the memory storage

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networks of the limbic system is completed. Thereadout of the activated memory is transmitted asthe time series f ðtþ 3Þ via a hippocampus-ent-orhinal-fornix circuit to the reticular formationand thalamus, and via the anterior cingulate gyrusto the prefrontal cortex, where coincidence detec-tors compare the time series f ðtþ 3Þ with time se-ries previously received from posterior sensoryregions and the thalamus. If the cortical coinci-dence detection indicates a discrepancy betweentime series from these two sources, a dischargeproduces the ERP component P3 at about 300ms.The timing of the sequential perceptual framesmay be reset whenever a discrepancy is noted.

The process just described must be envisaged as asliding window of successive microstates, continu-ously matching the representation of the present inposterior regions of the cortex with representation ofthe recent past in the prefrontal cortex, together withepisodic memories retrieved from the limbic system.As subsets of neurons in the coincidence detectornetwork of the prefrontal cortex match the two timeseries, sustained gamma reverberations link posteriorand prefrontal cortex together with cingulate-limbicand thalamus a resonant field that establishes globalnegative entropy, i.e., the content of consciousness.

Relevance of local field potentials to extraction ofinformation

The central issue is how coherent, informationalneuronal activity in multiple cortical areas is weldedinto a seamless unity that becomes aware of itself.We postulate that the ground state of local syn-chronization within neuronal ensembles, spontane-ous interactions among cells in different brainregions, and periodic integration intervals isregulated intracerebrally by the same geneticallyspecified homeostatic system that regulates theEEG. While the power spectrum of an artifact-freesample of resting EEG from a given scalp electrodereaches a stable and reproducible composition(stationarity) in as little as 8 s in the alert restingperson, the power spectrum of LFPs around an in-tracerebral electrode in the cat can be consideredstationary on the scale of 1 s (Bernasconi and Konig,2001). Numerous reports in the literature documentthe relationship between amplitude and polarity ofLFP in a domain and the probability of neural dis-charge from local ensembles (Fox and O’Brien,1965; John and Morgades, 1969b; Ramos et al.,1976). The evidence of homeostatic regulation of theEEG and the ambient extracellular electrical field

Fig. 2. Simplified scheme of the neurophysiological transactions resulting in the automatic readout of relevant memories from

neuroanatomical structures of the endogenous memory storage and retrieval system, and their relation to major components of the

event related potentials (see text for details).

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clearly implies homeostatic regulation of the prob-ability of synchronized neural activity in the regionsof the brain. Single and multiple unit recordings inbrain slices in vitro and in anesthetized and una-nesthetized, unrestrained animals reveal coherentdischarges in diffusely distributed ensembles (Johnet al., 1990; Roelfsema et al., 1997; Brecht et al.,1998). Some of this coherence must be anatomically‘‘hard-wired,’’ while some reflects transient func-tional interactions and coupling.

Fast spontaneous oscillations in intrathalamicand thalamo-cortical networks may play a decisiverole in binding. Synchronization of fast rhythmsmay be subserved by intralaminar neurons that firerhythmic spike bursts in the gamma frequencyrange and have diffuse cortical projections(Steriade et al., 1991, 1993). Sensory stimula-tion increases synchrony (Castelo-Branco andNeuenschwander, 1998), and synchronized dis-charges of neurons in different brain regions maybind spatially dispersed representations of a mul-timodal stimulus into an integrated percept (Llinas,1988; Gray et al., 1989; Kreiter and Singer, 1996;Llinas and Ribary, 1998). Functionally coherentcell assemblies may represent the constellation offeatures defining a particular perceptual object,with transient synchrony dependent upon statevariables related to the EEG. Such coherence hasbeen proposed as crucial for awareness and con-scious processing, including attentional focusing,perceptual integration, and establishment of work-ing memory (Singer, 2001; Engel and Singer, 2001).The signal to noise ratio for several multimodalattributes of a complex attended stimulus may beenhanced by higher order convergence upon a par-ticular neuronal neighborhood (Sheinberg and Lo-gothetio, 1997). Gamma oscillations facilitatecoherence of neural activity within and betweenregions, and have been suggested as a necessarycondition for the occurrence awareness stimuli(Llinas and Ribary, 1998; Engel and Singer, 2000).LFP fluctuations predicted response latency to vis-ual stimuli, with negative LFPs associated withearlier responses and positive LFPs with later re-sponses (Fries et al., 2001).

What might be the role of these ubiquitous po-tential oscillations? The neuronal population in anybrain region displays a range of excitability at any

moment, depending upon the recency and numberof synaptic inputs that have affected their membranepotentials. A small fraction of cells are depolarizedalmost to the threshold for firing spontaneously anda small proportion are refractory after recent firing.The central limit theorem leads us to expect anoverall gaussian distribution of excitability in thepopulation of neurons as a whole. We hypothesizethat a weak rhythmic modulation of membrane po-tentials, insufficient in itself to produce axonal dis-charges and perhaps arising from and distributedsynchronously by the diffuse projection nuclei of thethalamus, is superimposed upon the neuronsthroughout the brain. As the oscillatory influencesimpinge, neurons should discharge whose state ofmembrane depolarization, and the modulatory de-polarization exceeds the local firing threshold. Atthe other end of the excitability distribution, thoseneurons in a relatively refractory state while theirnormal resting membrane potential is being restoredafter a recent discharge should be further inhibitedby the subsequent hyperpolarizing phase of the os-cillations. The mean excitability of the ensembleshould fluctuate at the frequency of the modulatoryrhythm to an extent proportional to the depth ofmodulation. On the basis of a review of evidencerelevant to the possibility of non-synaptic modula-tion of neuronal membranes by extracellular fields,Jefferys (1995) concluded that ‘‘In general, electricalfield effects can mediate neuronal synchronizationon a millisecond time scale.’’ Weaver et al. (1998)computed the theoretical threshold for such effectsas requiring a gradient of the order of 100mV/mm.We have observed gradients of 100–200mV/mm inintracerebral recordings from human patients.

The effect of this hypothetical rhythmic fluctu-ation of excitability should be to enhance the syn-chronization of neural firing within any local brainregion. To the extent that if the same modulatoryinfluence is imposed across the cortex, it shouldincrease the level of coherence of non-randomoutput across distant brain regions. If cell assem-blies of feature detectors are dispersed throughoutthe cortex such that some subset of them encodedspecific attributes of the afferent stimulus complexas ‘‘fragments of sensation,’’ and if the hypothe-sized comparator network had achieved coinci-dence between exogenous and endogenous inputs

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to certain patches of cells thereby to identify‘‘fragments of perception’’ and selectively increasetheir excitability, then the consequence of thisrhythmic modulatory influence would be to facil-itate a coherent corticofugal discharge convergingupon the thalamus from many dispersed corticaldetectors. These coherent cortico-thalamic volleysare proposed as the integrative process, which en-ables the brain to bind the spatially dispersedmultimodal attributes into an integrated percept.

Abundant evidence has been presented, which es-tablishes that there are distinctive power spectra forany cortical region, with a wide range of frequencies.These cortical rhythms reflect thalamo-cortical andcortico-cortical interactions, which may exert com-plex modulating influences upon local ensembles. Ithas been proposed that lower the frequency, themore remote the brain region from which the influ-ence arises (von Stein and Sarnththeim, 2000;Bressler and Kelso, 2001). The observation thatabout 65% of the EEG is coherent across the cortex(John, 1990) suggests that the hypothesized bindingprocess is actually mediated by a resonance or com-mon mode interference pattern shared among anumber of systems generating these rhythms. Thisproposal is reminiscent of the scansion mechanismsuggested half a century ago (Pitts and McCulloch,1947). It must also be considered that although theLFPs converge rapidly to a predictable power spec-trum, on the short term these potentials can be con-sidered as a random ambient noise. Recent studieshave shown that the effect of ambient noise on aweakly interconnected network of weakly responsiveelements is to synchronize them by stochastic reso-nance, a process that functions best at high frequen-cies (Allingham et al., 2004; Torok and Kish, 2004).

Zero-phase synchronization

It is possible (Engel and Singer, 2000) that zerophase lag plays a critical role in binding dispersedfragments of sensation into a coherent whole (Koniget al., 1995; Engel et al., 1997). Phase-locking of40Hz oscillations, with zero delay between theprefrontal and parietal human cortex, has beenobserved in scalp recordings during focused atten-tion and conscious perception of recognized audi-tory or visual events. Using intracranial as well as

scalp recordings in humans, the amplitude, longdistance, and local synchronization of gamma ac-tivity have been studied during auditory, visual, andsomatosensory stimulation and during cognitive orperceptual tasks (Desmedt and Tomberg, 1994;Tallon-Baudry et al., 1997; Tallon-Baudry, 2000;Varela, 2000). In each modality, a transient burst ofphase-locked gamma (of varying frequencies) oc-curs, most prominently in the primary sensory cor-tex, about 100ms after stimulus onset. About230ms after stimulus onset, there is a pattern ofgamma oscillations synchronized between frontaland parietal cortical regions. The latency of 230mscorresponds approximately to the latency of the so-called cognitive potential, P3A, prominently dis-played in anterior regions of the human scalp. Thisgamma activity is induced by but not synchronizedwith stimulus onset, occurs only in trials when afigure or a word is perceived, and has been proposedas ‘‘the correlate of perception itself’’ (Pantev, 1995;Rodriguez et al., 1999). Such phase-locked sync-hrony between distant brain regions has been ad-duced as support for proposals that perceptioninvolves integration of many distinct, functionallyspecialized areas (Tallon-Baudry, 2000), and thatthe ‘‘self’’ may be a transient dynamic signature of adistributed array of many brain regions integratedby such coherence (Varela, 2000). This inducedlong-distance synchrony seems to be the equivalentin humans of the late component in animal EPs,described above, when stimuli acquire meaning(Galambos and Sheatz, 1962; John, 1972). The longdistance between regions synchronized with zero-lagrules out volume conduction, which decays rapidlywith distance between electrodes. It is possible thatthe apparent zero-lag arises from a common sourceof thalamo-cortical reverberations, but the alterna-tive that it is evidence for a resonating field mustalso be considered.

Critical neuroanatomy of consciousness

Various strategies have been used to find anatom-ical structures or brain processes critical for con-sciousness, including lesioning, imaging, andpharmacological techniques. Recent proposals haveincluded an extended reticulo-thalamo-corticaldistributed network, the intralaminar nuclei of the

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thalamus, nucleus reticularis, anterior cingulatecortex, or hippocampus. Prolonged activity in someset of unique ‘‘awareness cells’’ sparsely distributedover many regions, or a pattern of activity amongregions rather than within a particular brain region,have been proposed as the neural correlate of con-sciousness (Koch, 1998). A ‘‘Dynamic Core Hy-pothesis’’ has been proposed, constituting a set ofspatially distributed and meta-stable thalamo-cor-tical elements, sustaining interactions that maintainunity in spite of constantly changing composition(Tononi and Edelman, 2000).

One approach to identify such a system is todetermine whether a particular set of brain regionschanges its state with the loss of consciousness dueto the action of anesthetics. Using 18F-fluor-odeoxyglucose positron emission tomography(FDG-PET), cerebral metabolism was studied dur-ing propofol anesthesia (Alkire et al., 1998). At lossof consciousness, mean cerebral metabolic rate wasglobally reduced throughout the brain by 38%,relatively more in cortex than subcortex. Similarglobal quantitative results were found with isoflu-rane. In sedation, very similar but lesser global re-duction was observed. It was initially concludedthat loss of consciousness was not caused bychanges within a specific circuit, but rather by auniform reduction below a critical level in a dis-tributed neural system. In a more recent study us-ing H2

15O-PET to measure dose-related changes inregional cerebral blood flow (rCBF) during seda-tion with midazolam, a similar global reduction ofabout 12% was found (Veselis et al., 2000). In ad-dition, however, a discrete set of brain regions dis-played a significantly more extreme reduction incerebral blood flow. These regions included multi-ple areas in the prefrontal cortex, the superiorfrontal gyrus, anterior cingulate gyrus, parietal as-sociation areas, insula, and the thalamus (see Fiset,this volume; Alkire, this volume; for an extensivereview of functional imaging in general anesthesia).

Routine surgical anesthesia offers a naturalisticenvironment where loss and return of conscious-ness can be studied in a systematic manner. Inmany such studies of anesthetic effects, quantita-tive features have been extracted from EEG powerspectra (QEEG) and bispectra. Such variableshave been repeatedly shown to be related to clin-

ical signs or anesthetic endpoints (Sebel et al.,1997; Rampil, 1998; Veselis et al., 2000). Changesin the level of consciousness cause distinctive shiftsfrom the EEG ground state. Using quantitativeanalysis of continuous EEG recordings collectedduring several hundred surgical procedures, wesought invariant reversible changes in brain elec-trical activity with loss and return of conscious-ness. Details of these studies are given elsewhere(Prichep et al., 2000; John et al., 2001). Two kindsof changes in brain activity were found, independ-ent of anesthetic agents used: (1) At loss of con-sciousness, in all EEG frequency bands dramaticchanges took place in coherence within and be-tween the cerebral hemispheres. Rostral brain re-gions abruptly became functionally disconnectedfrom posterior regions and the two hemisphereswere functionally uncoupled (i.e., incoherent). On-ly in the beta and gamma bands is coherence re-stored upon return of consciousness. (2) At loss ofconsciousness, EEG power on each hemispherebecame dominated by low frequencies and strong-ly anteriorized. Normal posterior power domi-nance was restored at return of consciousness.These changes were used to construct a multivari-ate algorithm to provide a quantitative index ofthe level of consciousness. This algorithm has beenimplemented in a clinical monitor of the depth ofanesthesia (PSA 4000, Physiometrix, Inc., N. Bill-erica, MA). Three-dimensional source localizationrevealed that regions of the mesial orbital anddorsolateral prefrontal and frontal cortex, para-central gyrus, anterior cingulate gyrus, amygdala,and basal ganglia invariably displayed profoundreversible inhibition with loss and return of con-sciousness, independent of the anesthetic agents(Prichep et al., 2000; John et al., 2001). An over-view of recent electrophysiological and brain im-aging studies has provided the basis for a recentlypublished comprehensive theory of anesthesia(John and Prichep, 2005).

An integrative theory of consciousness

This theory is largely based upon experimentalevidence from many levels of neuroscientific in-quiry, some cited but much not explicitly men-tioned. However, I must concede that much of this

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formulation represents my speculations of ‘‘howthings must be,’’ in order for the brain to generatethe sense of self that we all share and the abnormalbehaviors we observe in clinical surroundings. As-sertions that are considered as basic propositionsof this theory are summarized below.

Apperception defines content of consciousness

A major hypothesis underlying this theory is thatthe content of consciousness is dominated by ap-perception. By apperception, we mean integrationof momentary perception of the external and in-ternal environment with the working and episodicmemories activated by associative reactions to thatperception. I contend that the conscious organism,and particularly the human being, is continuouslyinterpreting awareness of the present in the contextof both the recent and the remote past, to attribute‘‘meaning’’ to the present events. A further majorhypothesis of this theory is that information in thebrain is not encoded by the firing of dedicatedneurons in particular brain regions that representsspecific stimulus attributes or features, but ratherby distinctive temporal patterns of synchronizedfiring dispersed among many brain regions. Indi-vidual neurons can participate in numerous suchtemporal patterns.

Information is nonrandomness

Information establishes local negative entropyconsisting of spatially distributed time series ofsynchronized activity in multimodal, sensory-spe-cific systems (the ‘‘exogenous system’’). Energyreaching the receptor surfaces of multiple sensorysystems activates a barrage of neural activity thatpropagates through successive levels of afferentpathways to widely dispersed ensembles of cellsresponsive to particular aspects of the complex,multimodal environmental stimuli. In each brainregion, this barrage impinges on populations ofneurons with a range of excitability, with mem-brane potentials varying from hyperpolarization,refractory just after discharge, to relatively depo-larization, just on the verge of discharge. Circu-lation of the input throughout local networkscauses some responsive subsets of neurons dis-tributed in these many brain regions to respond

with a distinctive temporal pattern, producing atime series of synchronized neural discharges. In-trinsic excitability cycles modulate the reactivityof cell ensembles at frequencies in the range ofgamma oscillations (35–50Hz), selecting particu-lar subsets of neurons in the receiving system thatcan discharge synchronously with this distinctivetemporal pattern. This distributed, improbablesynchrony constitutes fragments of sensation,which represent islands of local negative entropy,relative to a regulated ground state. These ex-ogenous inputs are encoded as time series of syn-chronized firing in parallel, multiplexed channelswithin each sensory pathway, offset by 25ms andsampled every 80ms. The cyclic modulation ofexcitability produces multiplexed, parallel chan-nels encoding the same information. However,this information is phase-shifted so that the tem-poral patterns of synchronized activity encodinginformation in the multiplexed channels are asyn-chronous, offset by some temporal delay on theorder of 20ms. Within each such channel, thelength of the representational time series appearsto be 80–100ms.

Perception is discontinuous, parsed into momentary

episodes or ‘‘perceptual frames’’

This discontinuity has been demonstrated in everysensory modality using a variety of experimentalpsychophysical procedures. These include the so-called ‘‘backward masking’’ and ‘‘perceptualframe’’ phenomena. The experimentally deter-mined duration of such episodes appears to be ofthe order of 80ms, during which a representationaltime series unfolds. This ‘‘experiential chunk’’ maycorrespond to the episodic synchronization thathas been shown by Freeman (2004) to occuramong remote cortical regions every 80ms, and tothe ‘‘microstates’’ of stable field topographyshown to have a mean duration of 8072ms acrossthe age range from 6 to 90 years; as described byKoenig and colleagues (2002).

‘‘Hyperneuron’’ de-multiplexes afferent input

Circulating updated, multiplexed channels main-tain the stable representation of environment as aspatiotemporal steady state in an anatomically

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dispersed hyperneuron. No single neuron or ded-icated set of neurons can maintain the distinctivepattern of times series of synchronization acrosssuccessive perceptual frames to mediate the ap-parent continuity of subjective experience or‘‘awareness.’’ Rather, the multiplexed parallelchannels converge successively upon the sensoryreceiving ensembles. Interactions caused by thecirculation of temporal patterns of asynchronousactivity in neural networks within spatially exten-sive, dispersed populations of neurons establish aspatiotemporal interference pattern in each regionthat remains stable for extended periods of time,like a standing wave of covariance. This sustainedspatiotemporal distribution of nonrandom syn-chronization, independent of the firing of any par-ticular neurons, constitutes a ‘‘hyperneuron.’’ Ahyperneuron is a sustained, improbable spatio-temporal pattern of negative entropy.

‘‘Endogenous system’’

Episodic memories are stored in non-sensory-spe-cific brain regions that encode distinctive time se-ries of incoming activity and constitute an‘‘Endogenous system.’’ Collaterals from the mul-tiplexed afferent sensory pathways enter the pon-tine and mesencephalic reticular formation, andthe encoded representational time series of syn-chronized activation from the brainstem and po-lysensory cortical areas are distributed via theparahippocampal and entorhinal cortex into thelimbic system. When such nonrandom activationby successive inputs persists for a sustained butbrief period, associational or ‘‘contiguity’’ mech-anisms link together a network of neurons dis-tributed throughout regions including portions ofthe neocortex together with the amygdala, nucle-us accumbens, hippocampus, hypothalamus, andseptum, establishing a representational assemblythat is sensitive or ‘‘tuned’’ to that distinctivespatiotemporal pattern of input. This tuning inthe endogenous system is consolidated over abrief period into a molecular structure, perhapsprotein specified via RNA within the neurons inthe network, so that it will be preserved by syn-thetic mechanisms that renew that capability by

replication that preserves the tuning even after theinitial structure is replaced.

Readout of relevant memory – ‘‘context’’

At any later time, if a sufficient portion of theactivity of sensory exteroceptors and/or interocep-tors in the exogenous system becomes nonran-domly synchronized, the tuned representationalnetwork in the endogenous system with most sim-ilar temporal pattern becomes activated and dis-charges a synchronized time series from theparticipating limbic regions, providing a contextof emotional tone and motivational valence to theretrieved episodic memory. The readout from thissystem is a time series of synchronized discharges,reflected by oscillations in the gamma frequencyrange that become phase locked to waves recurringabout every 200ms, or in the theta frequencyrange, with essentially zero phase lag among cor-tical regions. Owing to the multiplexed nature ofsustained exogenous inputs and the duration of thestored representational time series, patterns of re-trieved outputs from this endogenous system per-sist for a sustained period, producing aninterference pattern similar to that of the hyper-neuron.

Coincidence detection by pyramidal neurons

When input from the exogenous system of a non-randomly synchronous temporal pattern to thebasal dendrites of the cortical sheet of pyramidalneurons coincides with a nonrandomly synchro-nous input from the endogenous system to theapical dendrites with the same temporal pattern,the excitability of a spatially dispersed network ofpyramidal neurons is significantly enhanced. Thisprocess converts fragments of sensation into frag-ments of perception, increasing the level of localnegative entropy.

‘‘Ground state’’ of the brain is defined and regulated

by a homeostatic system

A genetically determined homeostatic system reg-ulates normal brain electrical activity, controllinginteractions among brain regions as well as excit-ability within local regions. Due to this regulation,

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the mixture of frequencies in rhythmic oscillationsin each brain region, the spatiotemporal principalcomponents of the cross-spectra (which quantifythe relationships among all brain regions acrossfrequencies), and the parsing of these spatiotem-poral patterns into discrete epochs of time can allbe precisely defined, describing the basic processesmaintaining the system in stable resting equilibri-um. These homeostatically regulated baselines ofinter- and intra-regional oscillatory brain electricalactivity define the normative, hence most proba-ble, spatiotemporal distribution of variances andcovariances in brain electrical activity, the‘‘ground state’’ of maximum entropy, that con-tains zero information.

Brain state vector

If the electrical activity of the brain is conceptu-alized as a ‘‘signal space,’’ the complete set ofnormative QEEG data define the ground state as a‘‘hypersphere,’’ a region around the origin of anN-dimensional signal space that encompasses thevariance of the normative descriptors of brainelectrical activity. The measurements from any in-dividual, after appropriate rescaling, can be de-scribed as a multidimensional Z-vector or ‘‘brainstate vector’’ in that signal space; each dimensionis scaled in standard deviations (SD) of the distri-bution of the corresponding variable. The brainstate vector of a resting, healthy individual will liewithin the hypersphere of radius Zo 3.2 SD alongall dimensions around the origin of the multidi-mensional signal space. The brain state vector ofany individual in any state can be depicted as apoint somewhere in the signal space thus defined.The content of consciousness in the resting state(eyes closed) is fleeting ideas and thoughts causingtransient fluctuations of the brain state vector thatremain within the normative hypersphere.

Local field potentials acting on pyramidal neurons

can produce coherent reverberations

In the short term, LFPs can be considered as ran-dom noise that has been shown to synchronizeactivity among weakly interconnected networks ofweakly responsive elements. This effect of LFPsmakes coherent the cortico-thalamic discharge of

the distributed pyramidal neurons whose excita-bility has been enhanced by coincidence betweenexogenous and endogenous inputs. The synchro-nous discharge from these spatially distributedislands of local negative entropy results in acoherent reverberation of cortico-thalamo-corticalgamma activity. Findings of zero or near-zerophase lag between prefrontal and parietal cortexmay be the snapshots of momentary cross-sectionalglimpses of these synchronized time series.

Global negative entropy is the content of

consciousness

Sustained reverberations of multiple cortico-tha-lamo-cortical circuits become coherent and phase-locking between them, perhaps facilitated by trans-mission across gap junctions, leads to resonance inthe coherent network. This phenomenon can beconsidered as a ‘‘phase transition,’’ reflecting anintegrative process whereby dispersed fragments ofperception are bound into a unified global percept,which is global negative entropy. The resonantnetwork includes the prefrontal, parietal, andcingulate cortex as well as regions of the basalganglia, limbic system, thalamus, and brain stemidentified in the discussion of Fig. 2. These brainregions correspond well to those shown to be un-coupled in conditions associated with an absence ofconsciousness in studies of anesthesia (Alkire et al.,1998; Fiset et al., 1999; Veselis et al., 2000), (Fiset,this volume; Alkire, this volume) deep sleep (Portaset al., 2000) and coma (Laureys et al., 2000, 2002)as well as ‘‘absence’’ seizures (Pavone andNiedermeyer, 2000; Blumenfeld, this volume). Thisresonant field corresponds in many respects to theparietal-prefrontal system that some have proposedmay be the residence of the ‘‘observing self’’ (Baarset al., 2003; Baars, this volume). I believe this the-ory supports and extends that suggestion. The glo-bal negative entropy of the brain encompasses allof the momentary information content of the entiresystem, as an ‘‘information field’’ that subsumesthe parallel processing circuits that are simultane-ously activated at a nonrandom level in the brain,and comprises the content of consciousness. Forthe purpose of this theoretical formulation, theglobal negative entropy of a resting healthy

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individual whose brain electrical activity is at theprecise origin of the ground state is proposed to beat a maximum. In this hypothetical state, the braincontains no information so that consciousness isvoid of content. One might speculate that this statecorresponds to what Buddhists term ‘‘Nirvana.’’

Acknowledgements

I acknowledge the constructive contributions of Dr.Leslie S. Prichep to this theory and the InternationalBrain Research Foundation and Dr Philip De Finafor support received to conduct this research.

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