By applying TMS pulses at a range of stimulus onset asynchronies (SOAs), researchers could demonstrate that recurrent interactions between early visual cortex and higher-order regions are necessary for conscious perception not only of phosphenes, but also when regular visual stimuli were used (e.g., Ro et al., 2003). For example, Silvanto et al. (2005b) applied TMS pulses at different SOAs to early visual cortex or to hMT/V5, measuring conscious perception of motion stimuli. Chronometrically, first only early visual cortex TMS disrupted conscious perception of motion, then only TMS over hMT/V5 disrupted conscious perception, and subsequently only early visual cortex TMS again disrupted conscious perception of motion (see also Koivisto et al., 2010). Also for stationary stimuli, the necessity of recurrent projections from extrastriate cortex (this time lateral-occipital cortex) to early visual cortex was recently demonstrated (Koivisto et al., 2011b). A very interesting recent demonstration of how recurrent processing leads to conscious vision involved the TMS-masking of Kanizsa-type illusory stimuli. TMS pulses applied to early visual cortex *only* successfully masked such illusory percepts in SOAs *following* the SOAs in which extrastriate cortex was functionally relevant (Wokke et al., 2013).

Another interesting application of TMS in the masking paradigm involves what has been referred to as "TMS-induced blindsight" (Ro, 2010). TMS applied to early visual cortex can abolish vision, but this can be measured and evaluated in two ways: with direct subjective reports ["did you see the stimulus (feature)?"], or with (forced-choice) stimulus discrimination tasks. In contrast to blindsight patients, participants with fully intact brains have not had years of training and possible brain reorganization, so it would be useful to probe "blindsight" behavior in them. TMS has been used to this effect, and successfully demonstrated blindsight-like behavioral patterns across a range of stimuli and tasks. In trials without reported awareness of TMS-masked stimuli, "unseen" stimuli could still affect saccade responses (Ro et al., 2004), reaching movements (Christensen et al., 2008; Ro, 2008), emotion recognition (Jolij and Lamme, 2005), and even orientation and color discrimination (Boyer et al., 2005). The occurrence of such dissociations seems to depend on SOA (Koivisto et al., 2010; Jacobs et al., 2012b; Allen et al., 2014). Depending on stimuli and tasks, some have reported that TMS does affect subjective and objective measures, as well as priming measures, as a whole

across SOAs (Sack et al., 2009; Jacobs et al., 2012a). And it has been shown recently that the experimental paradigm and analysis can make quite a difference as well. Lloyd et al. (2013) showed that, in their experiments, obtained TMS-induced blindsight effects disappeared when performing signal detection theory analysis, suggesting that response criteria may play a large role and should be controlled for. New evidence on this exciting topic is continually added, such as a very clever study by Allen et al. (2014) who attempted to determine whether retinotectal and/or geniculate subcortical pathways underlie TMS-induced blindsight effects, by manipulating their stimuli such that the retinotectal (and magnocellular) pathways were bypassed. They found that blindsight-like performance still obtained for such stimuli.

#### **TMS OVER PARIETAL CORTEX**

Interestingly, we can make a smooth transition from TMS masking to TMS studies of the role of parietal cortex in conscious vision, because recent reports suggest that phosphenes can be elicited by TMS over parietal cortex as well (Marzi et al., 2009). And while one recent study did not obtain consistent visual suppression by TMS pulses over these parietal regions (Tapia et al., 2014), Koivisto et al. (2014) did report evidence for parietal (inferior parietal sulcus) TMS masking of specifically subjective conscious vision.

Quite a number of TMS studies have addressed the functional role of parietal cortex in conscious vision, even if the distinction between attention and consciousness was not always clear. In bistable vision paradigms, offline TMS-induced "virtual lesions" of parietal cortex affected the rate of perceptual switching (Carmel et al., 2010; Kanai et al., 2010, 2011), where the direction of effect (increased or decreased switch rates) was found to depend on the exact parietal region stimulated (Kanai et al., 2011). Effects of online parietal TMS on binocular rivalry have also been shown (Miller et al., 2000; Zaretskaya et al., 2010). Mechanisms in parietal cortex may thus play a role in the maintenance of conscious percepts, as also suggested by the finding that parietal TMS pulses can actually induce fading of a continuous peripheral stimulus from consciousness (Kanai et al., 2008). A more general role of resource allocation among competing percepts is suggested by the finding that decreasing excitability of right parietal cortex by continuous TBS (an inhibitory rTMS protocol) rather increased the durations of target disappearance in a motion-induced blindness paradigm (Nuruki et al., 2013). Parietal cortex has further been shown functionally relevant for visual awareness in TMS studies on change blindness (Beck et al., 2006; Tseng et al., 2010), attentional blink (Kihara et al., 2007), and conscious perception of an illusory gestalt (Zaretskaya et al., 2013).

One line of TMS research on the role of parietal cortex in visual awareness we find particularly intriguing, and it concerns TMSinduced extinction (Pascual-Leone et al., 1994). Patients with "neglect," and the symptom of "extinction," were described above. Using TMS over parietal cortex, extinction-like behavior could be replicated in healthy participants (Pascual-Leone et al., 1994), which may be attributable to a biasing of interhemispheric competition for attentional resource allocation.  Interestingly, and in keeping with the idea of interhemispheric competition, TMS delivered over both parietal cortices simultaneously actually abolishes this effect (Dambeck et al., 2006).

#### **TMS OVER FRONTAL CORTEX**

Parietal and frontal cortex are frequently mentioned together, as a "frontoparietal network," because they simply do often co-occur in neuroimaging studies in general, and NCC studies particularly. For some NCC paradigms, frontal regions have subsequently been shown to be functionally relevant. For example, we already saw how TMS pulses over FEF can improve visual target detection (Grosbras and Paus, 2003). In subsequent work, TMS applied over FEF concurrently with fMRI was shown to have BOLD effects in low-level visual cortices, compatible with observed effects on psychophysics (Ruff et al., 2006). We already saw that FEF pulses facilitated perception of moving phosphenes from hMT/V5 TMS (Silvanto et al., 2006), and Amassian et al. (2008) reported frontal TMS-induced facilitation of complex phosphenes elicited by early visual cortex pulses, as well as facilitated reporting of weakly illuminated letter stimuli.

For bistable vision paradigms, there is surprisingly little published research with frontal brain stimulation. Neuroimaging has often implicated both frontal and parietal activity in perceptual switching in bistable paradigms (see references above). For example, it was shown with fMRI that specifically frontal activity occurs earlier for spontaneous percept reversals than externally induced ("replay") reversals (Sterzer and Kleinschmidt, 2007), suggesting a causal role (Sterzer et al., 2009). On the other hand, there is recent evidence that if the gradual transition of percept reversals (Knapen et al., 2011) or percept reporting (Frässle et al., 2014) are controlled for, frontal activations conventionally obtained in bistable vision studies with fMRI may be reduced or no longer found. When it comes to NIBS, while parietal disruption leads to effects (see above), we are not aware of studies demonstrating functional relevance of frontal regions for spontaneous perceptual reversals in passive bistable vision so far. (Virtual) lesions of frontal cortex appeared to affect voluntarily induced reversal rates, though no such effect on passive viewing reversals was found (Windmann et al., 2006; de Graaf et al., 2011b). Yet the frontal lobe is large and null results remain fundamentally limited (de Graaf and Sack, 2011). It could be worthwhile to combine fMRI with neuronavigated brain stimulation in future studies to further elucidate the role of frontal regions in passive bistable vision. For the moment we dare not say whether, specifically in the context of bistable paradigms, frontal NCCs are neural consequences, prerequisites or substrates.

There does seem to be evidence for frontal involvement in visual awareness as a metacognitive process. TMS over dorsolateral prefrontal cortex (DLPFC) decreased detection of visual change (Turatto et al., 2004). FMRI research controlling for objective visual task performance found a specifically frontal activation corresponding to subjective visual report (Lau and Passingham, 2006), and in a group of frontal lesion patients, predominantly

subjective visual awareness in a masking paradigm was decreased (Del Cul et al., 2009). In line with this, a theta-burst TMS study in healthy volunteers inhibited bilateral DLPFC and investigated metacognitive sensitivity to visual stimuli. Concretely, a response-bias free measure was calculated, quantifying how well participants' subjective reports of visibility could discriminate their correct or incorrect responses to the same visual stimuli. Frontal TMS decreased this metacognitive sensitivity, and further analysis suggested that this was specifically due to decreased visibility on trials with correctly identified visual stimuli (Rounis et al., 2010).

## **ADVANCED NIBS PROTOCOLS AND THE STUDY OF CONSCIOUS VISION**

We have seen examples of inspiring TMS experiments that directly tested, and demonstrated, functional relevance of brain regions for conscious vision, as well as functional relevance of particular projections between brain regions for conscious vision. Evidence for the latter, while revealing, was generally indirect; for example with the inference of feedforward and feedback projections between early visual cortex and motion area hMT/V5 from the relative temporal patterns of TMS-induced perceptual disruptions (Silvanto et al., 2005b). But new paradigms of NIBS may more directly address the functional relevance of brain interactions, as we discuss below. Similarly, new protocols may widen the range of NCCs that can be tested for causal involvement in conscious perception.

#### **ENTRAINMENT AND PHASE COHERENCE**

Starting with the latter, TMS or tDCS entrainment protocols may be used to test the causal involvement of oscillatory NCCs. The power (Thut et al., 2006; van Dijk et al., 2008) and phase (Mathewson et al., 2009) of alpha oscillations in parietal–occipital cortex, for example, has been related to attention/perception, indexing the successful detection of visual targets (see also Busch et al., 2009; Mathewson et al., 2010, 2012; de Graaf et al., 2013) and see Jensen and Mazaheri (2010), Britz and Michel (2011), and Mathewson et al. (2011) for recent reviews. The relevance of these alpha oscillations had already been probed with TMS by demonstrating that their power (Romei et al., 2008) and phase (Dugué et al., 2011) at TMS pulse onset directly reflected visual cortex excitability as measured by phosphene perception. The hypothesis arose that rhythmic TMS might actually phase-lock and/or amplify such oscillations if the rhythm was of compatible frequency (Thut et al., 2011a). Thut et al. (2011b) could indeed demonstrate that alpha-frequency TMS amplifies alpha oscillations in the brain, and Romei et al. (2010) showed that such a TMS entrainment protocol had attentional/perceptual consequences. Specifically for alpha-frequency, and in a retinotopically specific location, visual performance was enhanced, directly demonstrating the causal relevance of these oscillatory patterns for conscious vision. Rhythmic TMS was recently used to confirm also the functional relevance of alpha phase for visual perception (Jaegle and Ro, 2014). Helfrich et al. (2014) recently demonstrated, using simultaneous EEG and tACS, that alpha oscillations can successfully be induced by tACS at the same frequency, moreover with perceptual consequences. The idea

of TMS (or tACS) entrainment to test functional relevance of endogenous oscillations has moreover been extended to other frequencies and paradigms (Romei et al., 2011, 2012; Neuling et al., 2012).

Another recent development in the field of NIBS is the use of tACS over different regions to bring interregional oscillations either in coherence, or out of phase. This method was pioneered by Polanía et al. (2012), who applied tACS over frontal and parietal cortex at theta-frequency (and control frequencies). Importantly, either the frontal and parietal oscillatory stimulation were at the same phase (0◦ phase-lag), or in anti-phase (180◦ phase lag). Matching prior correlational evidence from EEG, specifically the in-phase frontoparietal stimulation, at the appropriate frequency, led to enhanced task performance. Anti-phase stimulation actually resulted in a performance decrement. Thus, NIBS can now also be used to study the functional relevance of previously observed oscillations, *and* the relevance of interregional coherence of oscillations, implicated in conscious vision.

A very recent example successfully demonstrates this approach. Strüber et al. (2013) took advantage of the fact that a particular bistable visual stimulus, the "motion quartet," involves inter hemispheric communication in one perceptual interpretation (horizontal motion across the vertical meridian) but not in the other perceptual interpretation (vertical motion across the horizontal meridian). Perceptual switches in this paradigm had previously been linked to changes in the synchronization of gamma-band oscillations, so the authors applied 40 Hz (and 6 Hz as a control) tACS to bilateral occipital cortices, at either 0 degrees phase-lag or 180◦ phase-lag. Specifically for anti-phasic tACS at specifically 40 Hz, they observed both perceptual effects in the form of less perceived horizontal motion and effects on coherence in the gamma-band as measured by EEG.

### **CONCLUSION**

A review of the literature suggests that researchers in the field of NCC are often aware of the conceptual limitations around neuroimaging-based, empirical NCCs, either implicitly or explicitly advising caution with regards to interpretations of functional roles. We believe that the explicit division of empirical NCCs into three possible functional roles, which are neural prerequisites, neural substrates, and neural consequences, remains a useful one. Review of the literature also demonstrates how valuable NIBS can be, and indeed has already been, for the enlightenment of these functional roles as a complement to neuroimaging research. The growing number of brain stimulation experiments, and the continuous development of new stimulation techniques and protocols, is a testament to the potential and value of brain stimulation. Hopefully, many more applications of NIBS in the context of NCC research can be expected. And hopefully, the framework of three NCCs will prove useful in this endeavor.

#### **ACKNOWLEDGMENTS**

Tom A. de Graaf is supported by the Netherlands Organization for Scientific Research (NWO 451-13-024). Alexander T. Sack is supported by European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 263472. We thank Dr. Juha Silvanto and Dr. Christianne Jacobs for reviewing earlier versions of the manuscript.

#### **REFERENCES**

Rees, G., Wojciulik, E., Clarke, K., Husain, M., and Frith, C. (2000). Unconscious activation of visual cortex in the damaged right hemisphere of a parietal patient with extinction. *Brain* 123(pt 8), 1624–1633. doi: 10.1093/brain/123.8.1624

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Received: 15 June 2014; accepted: 26 August 2014; published online: 23 September 2014.*

*Citation: de Graaf TA and Sack AT (2014) Using brain stimulation to disentangle neural correlates of conscious vision. Front. Psychol. 5:1019. doi: 10.3389/fpsyg.2014. 01019*

*This article was submitted to Consciousness Research, a section of the journal Frontiers in Psychology.*

*Copyright © 2014 de Graaf and Sack. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

## It is time to combine the two main traditions in the research on the neural correlates of consciousness: C L D **= ×**

## *Talis Bachmann1\* and Anthony G. Hudetz 2*

*1 University of Tartu, Tallinn, Estonia*

*2 Medical College of Wisconsin, Milwaukee, WI, USA*

#### *Edited by:*

*Anil K. Seth, University of Sussex, UK*

#### *Reviewed by:*

*George Mashour, University of Michigan Medical School, USA Jakob Hohwy, Monash University, Australia*

#### *\*Correspondence:*

*Talis Bachmann, University of Tartu, Kaarli Puiestee 3, 10119 Tallinn, Estonia e-mail<EMAIL_ADDRESS>
Research on neural correlates of consciousness has been conducted and carried out mostly from within two relatively autonomous paradigmatic traditions – studying the specific contents of conscious experience and their brain-process correlates and studying the level of consciousness. In the present paper we offer a theoretical integration suggesting that an emphasis has to be put on understanding the mechanisms of consciousness (and not a mere correlates) and in doing this, the two paradigmatic traditions must be combined. We argue that consciousness emerges as a result of interaction of brain mechanisms specialized for representing the specific contents of perception/cognition – the data – and mechanisms specialized for regulating the level of activity of whatever data the content-carrying specific mechanisms happen to represent. Each of these mechanisms are necessary because without the contents there is no conscious experience and without the required level of activity the processed contents remain unconscious.Together the two mechanisms, when activated up to a necessary degree each, provide conditions sufficient for conscious experience to emerge. This proposal is related to pertinent experimental evidence.

**Keywords: consciousness, neural correlates of consciousness, contents, level, state, visiual perception, thalamus, excitatory postsynaptic potentials**

### **INTRODUCTION**

Scientific research on consciousness has made a major leap forward after influential papers by Bernard Baars, Francis Crick, and Christof Koch outlining the logic and perspective directions of the contrastive analysis (Baars, 1989; Crick and Koch, 1990, 2003). To discover the neural correlates of consciousness (NCC), they suggested to compare brain-process recordings collected in the conditions when subject is conscious (C) with those when that subject is not conscious (U). The difference between these two conditions was operationalized as the NCC, the minimal necessary neural correlates expressed by specific signatures of brain processes differentiating these two conditions as NCC = C − U. There are two main traditions of research using this methodological approach: (1) studying the general states of consciousness versus unconsciousness for revealing NCC (Tradition-1) and (2) studying the correlates of the contents of consciousness in a conscious subject who in some of the experimental trials (or subconditions of trials) has subjective experience of the target stimulus and in some other conditions does not (Tradition-2). (See articles by Steriade, 1996; Laureys, 2005; Massimini et al., 2005; Seth et al., 2006; Rosanova et al., 2012; Sarasso et al., 2014 for an overview of typical tradition-1 studies and Del Cul et al., 2007; Aru and Bachmann, 2009a,b; Lamy et al., 2009; Hesselmann et al., 2011; Pitts and Britz, 2011; Aru et al., 2012a; Sekar et al., 2013 for typical tradition-2 studies.) Tradition (1) has made some progress in finding NCC for the *state* of consciousness while tradition (2) has found a lot of data on NCC in terms of its specific *content*. Ironically, an observer cannot infer the state of consciousness with certainty without testing the presence of some subjective content

in consciousness. In other words, there is no empty or contentless consciousness and even though a highly skillful meditation may perhaps reduce the contents to a minimal extreme (Hohwy, 2009), an experience of some unchanging "empty" state of mind will still have a felt emptiness or oneness as a content. Thus, states and contents seem to be unseparable in that as soon as the unconscious state changes to a conscious state, some content of consciousness inevitably appears. Nevertheless, the above mentioned two traditions of research have been developing in relative mutual isolation.

Recently, a methodological crisis in studying the NCC was spotted (Aru et al., 2012b; de Graaf et al., 2012). It appears that with standard contrastive analysis not only the NCC of the consciousness itself are extracted from brain recordings, but the observed neural signatures may also pertain to processes necessarily preceding those directly responsible for consciousness itself (correlates of the prerequisites of consciousness or NCCpr) and processes that are aftereffects or consequences of consciousness (NCCae). It appears that it is not at all easy to distinguish the NCCpr and NCCae from the processes directly equivalent to the neural processes minimally sufficient for the conscious experience itself (i.e., the NCC proper, or constituents of consciousness, to use the distinction made by Miller, 2001, 2007). We believe – together with Hohwy, 2009 – that the theoretical picture used to explain and understand the results of research on NCC is confused partly because the above mentioned two traditions, the study of conscious state vs. content, have progressed separately. "It seems then that neither the content nor the state-based approach taken in isolation from one another will help us discover the NCC" (Hohwy, 2009, p. 435). Thus, we argue that Tradition-1, by concentrating on the brain mechanisms necessary for the general state of consciousness, has been neglectful with regard to the systematic experimentation in the domain of finding the NCC for subjective contents and because of this, it has had difficulties in properly specifying the NCC. Neither the difference in the exact contents nor the difference in the exact timing of the subjective experience of these contents along the subsecond timescale have been studied. We also argue that Tradition-2, by concentrating on the brain processes that correlate with subjective awareness of specific target stimuli has tended to overlook the data and regularities obtained in the research on NCC of conscious states. In observing and analyzing brain-process signatures as candidates for NCC, no attempt has been made to clearly distinguish the contributions of the state and content systems to these signatures.

Aside from the issue of the exact timing of emergence of conscious contents and their NCC in terms of brain-imaging signatures, an attempt to bridge to state-content interrelationship is the former study by Owen, Laureys and colleagues capitalizing on the contrastive analysis of fMRI signals between vegetative state (VS) patients and normal alert controls (Owen et al., 2006). VS patients who were clinically defined as being unconscious were asked to imagine playing tennis while their pattern of fMRI activation was compared to that obtained in healthy control subjects reporting the corresponding phenomenal content. The two brain activation patterns were quite similar, which the authors used to suggest that VS patients have conscious contents. Hohwy (2009) criticizes this approach based on the grounds that what the investigators tested really was volition rather than qualia. In our opinion this critique is insufficient for several reasons: (1) the subjective experience of volition is also a kind of consciousness with its content, although possibly different in form from sensory experience fo qualia, (2) in order to express volition, patients had to first semantically process the command and be able to differentiate between the requested choices. Thus it seems that either we really have some residual form of consciousness in VS patients or the brains of VS patients are capable of surprisingly intricate and precise information processing without the concomitant subjective experience simply executing automatisms of processing sensory input up to cognitive and semantic stages (supporting the zombie mode of complex information processing). On the other hand, the so-called zombie modules seem to exist indeed if we accept data by Kotchubey (2005) and Owen et al. (2006) as evidence for complex perceptual-cognitive processing of stimulation contents by the unconscious brains. The serious shortcoming of this type of research consists in the lack of reliable independent measures clearly associated with phenomenal subjectivity. We do not know whether the specific contents processed by the brain in a specific state (e.g., VS or a locked-in state) are also reflected phenomenally in the first person perspective. Because verbal reports from subjects in states for which we cannot definitely say whether these are conscious or unconscious cannot be reliably obtained, we are left with the option to study *the effect of experimental manipulations of the brain's state systems only when these manipulations are applied when the human subject is in a state allowing subjective report*. When this type of research has developed well enough and the corresponding mechanisms of consciousness will have become more precisely specified, experiments with animal models can be then carried out in a more meaningful way with regard to the problem of NCC.

Although many of the clinical criteria for qualifying a state as a conscious, minimally conscious or unconscious state and as a state of sleep or behavioral arousal are objectively physiological (e.g., EEG) and behavioral (e.g., reflexes), at present we can rely on subjective reports and evaluations of the contents of mind as the only available method to assess presence of consciousness reliably. An important dimension which allows measurement of variable states from the point of view of subjectivity is the scale of the *levels of consciousness* expressed in terms of the clarity, vividness and fullness of subjective conscious experiences. Vague, barely noticeable, fragmented, poorly differentiated experiences stand at the one end of the scale and clear, vivid, differentiated and stable experiences at the other end. Sedated patients typically describe their experiences in terms of this kind of qualia continuum where the quality of contents changes along with the change of state from unconsciousness to hypnagogic experiences to vague experiences up to the full blown clear and vivid perception of the world and private thoughts (Newton et al., 1990; Andrade et al., 1994; Zacny et al., 1994; Hudetz and Pearce, 2010). Consciousness contents have different levels of expression that can vary vith invariant environmental stimuli input as a function of the varying state of the brain. Thus, operationally the effects of the state system on the content system should be possible to measure as the variations in the level of subjective experience as measured by the contents typical for the gradations of the level (Bachmann, 2012). Importantly, there are scalable attributes of the level common to different modalities and within-modality contents which makes these attributes universal.

We believe that by combining the two approaches within a theoretical synthesis some – but not all – of the controversies in NCC research can be solved. We suggest a theoretical synthesis where the activity of the mechanisms examined in each of the two traditions are the prerequisites (NCCpr) of consciousness, but together they form the combination jointly sufficient for consciousness (i.e., NCC proper). In a highly simplified form, we propose an expression for consciousness: C = L × D, where C stands for consciousness, L stands for the critical *level* of activity of neuromodulatory systems regulating the state of the brain, and D stands for the *data*, i.e., the contents of consciousness provided by the specific representational systems of the brain. In order to ease the abstractness of the concept, we give a few examples on what we mean here. In an experiment aimed to manipulate the state level L, for example, with an incremental dosing of anesthetics, a suitable task-response can be studied simultaneously at matched performance levels (accompanied with subject's scaling of the level and/or contents of his/her subjective experience) while doing fMRI, MEG, EEG or something else. In doing this, matching the task performance may be important to minimize the contribution of NCCae on the recorded neuronal signatures. One could also look at other changes in the brain, e.g., functional connectivity as candidates of NCC proper or its reliable signature. Similarly, EEG/ERP recordings can be used for comparing subjective reports under varying degrees and means of sedation by anesthetics, including measurements of possible NCCae (e.g., Veselis et al., 2009). Some additional examples will be given later on in this article. Obviously, in order to follow the strategy of the combined use of the L-system and D-system based approach, these systems should be known sufficiently well in terms of neuroanatomy and ways of functioning.

Before elaborating this concept further, let us have a closer look at the putative brain mechanisms and processes that have been proposed as necessary for consciousness both in terms of its content and state, and after having done so, we will return to the problem of NCC.

## **TWO MUTUALLY INTERACTING BRAIN SYSTEMS RELATED TO CONSCIOUSNESS**

To experience something subjectively, the brain has to be in the state of consciousness, but also capable of processing sensory data which constitute the contents of experience. In other words, the presence of specific sensory contents in conscious awareness is not automatically granted, but requires involvement of cerebral *interactive mechanisms* that aid the explication of preconsciously processed information. Neurobiological experimental data, deep brain stimulation data, and anesthesiological data converge in showing that modulations mediated by the thalamocortical "nonspecific" system targeted at the specific system of encoding the sensory-perceptual information are necessary for subjective contentful experience to emerge (Brooks and Jung, 1973; Bachmann, 1994; Purpura and Schiff, 1997; Llinás and Ribary, 2001; Ribary, 2005; John, 2005; Hudetz, 2006; Alkire et al., 2008; Hudetz and Alkire, 2011; Giacino et al., 2012; Liu et al., 2013). An important aspect of this dual functional architecture consists in the way these two systems interact at the cellular level. There is massive presynaptic targeting of the apical dendrites of the layer-5 pyramidal neurons in cortex originating from the non-specific system while the layer-5 pyramidal neurons are the prime part of the specific afferent system at the cortical level serving the function of encoding specific stimulation content. This specific afference arrives presynaptically at the more somatic parts of these nerve cells. It is suggested that this is the cellular level mechanism where nonspecific and contextual top-down modulatory influences interact with primary specific afferent input and that the extent or pattern of this interaction highly correlates with subjective states of consciousness (Brooks and Jung, 1973; Purpura and Schiff, 1997; Llinás and Ribary, 2001; Ribary, 2005; Alkire et al., 2008; Pillay et al., 2014). The layer-5 pyramidal neurons are naturally suitable to be a mechanism where perceptual contents are modulated up to consciousness, but at the same time this mechanism allows both pre-conscious and unconscious information processing. Although inputs to cell soma and dendrite tuft can perform their own functions autonomously (Berger et al., 2001; Larkum et al., 2004), these inputs are also capable of intense integrative interaction. Therefore, the same system can perform information processing in either the preconsious (non-interacting) or the conscious (interacting) domain. Membrane activity caused by somatically targeted sensory input is "available" for effective (i.e., hypothetically awareness-providing) modulation if it has sufficient frequency (Larkum et al., 1999a) and optimal timing with respect to the apical dendrite targeted

input (Larkum et al., 1999b; Larkum, 2013). The autonomous function of the two neuron compartments is possible also due to the fact that the level of membrane depolarization is progressively attenuated distally from soma, and also from the tuft, as well as for the very fact that an absence of temporal coincidence of somatic and distal-dendritic input dissociates the two subcellular activities and thus the potential to act as an integrative device remains unused (Berger et al., 2001; Larkum, 2013).

For conscious perception, it is *necessary that both systems* be active in concert – (i) the bottom-up, specific content-signaling data system D receiving afferents by the layer-5 pyramidal neurons' basal compartment, and (ii) the modulation system sending intracortical top-down associative signals and/or non-specific thalamo-cortical signals leading to up-states necessary for a sufficient consciousness level L (Bachmann, 1994; Ribary, 2005; Larkum, 2013). When only one of the two principal input streams to pyramidal neurons – somatic specific afferents and dendritic presynaptic nonspecific afferents – is active without the "partnering" effect of the other system, consciousness is expected to fade away. Formally: D(0) × L(z) = C(0); D(x) × L(0) = C(0). Only D(x) × L(z) = C(x), with x being the contents of the experienced subjective state.

It is likely that for the hypothetical dual-input consciousness mechanism to become ignited, both neuron compartments – somatic and apical dendritic – must receive enough presynaptic input in order to generate the wide excitatory postsynaptic potential (EPSP) plateau-waves carrying a burst of spikes representing an up-state. One good candidate for being the core cellular level mechanism in this system is the backpropagation activated calcium spike firing (BAC firing) mechanism described by Matthew Larkum and colleagues. For the layer-5 pyramidal neurons to generate plateau-wave-based spiking, the temporal coincidence of somatic sodium channel-related presynaptic input (i.e., data for the subsystem D) and calcium channel-related presynaptic input targeted at the apical compartment of the cell dendrite (i.e., modulation by the subsystem L) is necessary (Larkum et al., 1999b; Larkum, 2013). It is important to acknowledge that dendritic calcium spikes are a direct target of anesthetics (Potez and Larkum, 2008) and after release from the anesthetic effects, calcium electrogenesis in layer-5 pyramidal neurons dramatically increases (Murayama and Larkum, 2009). This supports the notion of the principal importance of the BAC firing mechanism for consciousness. Importantly, suprathreshold input to the neuron's body (responsible for the bottom-up inflow of sensory signals by D) produces fewer action potentials of the cell than triggering of the dendritic Ca2+ spikes. This once more substantiates the importance of modulatory brain processes in addition to the straightforward sensory afference and provides a convincing argument for the common effects of biased perception being under the contextual and arousal systems control. [See also works by E. Roy John (e.g., John, 2005) and Rodolfo Llinás (e.g., Llinás et al., 1998) on the putative significance of coincidence detection for the effectively working consciousness mechanism.]

In addition (or alternatively to) the thalamocortical resonance or interaction theory, the role of cortico-cortical interactions in the NCC should not be excluded or overlooked. For example, Mashour and coworkers (Lee et al., 2013) demonstrated the selective alterations in fronto-parietal interactions during general anesthesia with three different anesthetic agents. The use of different drugs in the same investigational setting is important in order to be able to identify an anesthetic-invariant mechanism of loss and return of state consciousness (John, 2001), removing agent-specific effects, and by the same token, at least some of the NCCpr or NCCae. A particularly interesting aspect of the work of Lee et al. (2013) is that fronto-parietal communication was preferentially suppressed by all three anesthetics in the feedback (top-down) direction. This important finding is consistent with what was proposed by Del Cul et al. (2007) and predicted by prior preclinical anesthesia studies by Imas et al. (2005a), suggesting that cortical long range connectivity, especially in its top-down aspect, may be critical for consciousness. On the other hand, based on the general knowledge that non-specific thalamocortical effects target more frontal and central than posterior areas it is possible that the typical effect on the top-down aspect of cortical effective connectivity reflects also (or first of all) the effect of the extended thalamo-cortical modulation system. Further, indirect support for the nonspecific brain systems regulating conscious thresholds for visual stimuli comes from a recent study by Park et al. (2014) who showed that the threshold varied with the phase of heartbeats. It is difficult to assume that heartbeats are directly associated with processing specific visual input, but it is easy to understand that and how heartbeats reflect activation levels of the non-specific systems involving the autonomic system contribution to arousal.

In some situations, specific input is processed by the brain and/or stored in its long term memory system but there is insufficient L-system modulation for conscious awareness of the sensory input or stored memory-information. Examples include subjects having fallen asleep, undergone fainting, or brought into anesthetic states. Brains of sleeping or anesthetized subjects receive localized specific input that comes from sensory receptors, but associative input and modulating arousal input from the reticulothalamic activation system is insufficient (Magoun, 1958; Hassler, 1978; Purpura and Schiff, 1997; John, 2005; Ribary, 2005; Hudetz et al., 2009; Hudetz and Alkire, 2011; Zhou et al., 2011). Information integration to consciousness is absent (Alkire et al., 2008). On the other hand, when the L-system is artificially stimulated, arousal and consciousness accompanied by sensing the contents of ambient stimulation can be brought about, cortical information-integration can be augmented, release from visual masking produced, or artificial sensations evoked (Smirnov et al., 1978; Tasker et al., 1980; Bachmann, 1994; Giacino et al., 2012; Pillay et al., 2014). Artificial stimulation of the intralaminar thalamic sites that are part of the nonspecific system augments visual evoked potentials in response to grating stimuli (Hunsperger and Roman, 1976). Visual, auditory and somatosensory research using recording of brain potentials has repeatedly shown that the level of expression and timing of the negative-polarity potential N1 (with post-stimulus latency equal to about 50–200 ms depending on the modality and stimulation characteristics) strongly correlates with conscious perception (Uttal and Cook, 1964; Wagman and Battersby, 1964; Hassler, 1979; Alter et al., 1990; Cauller and Kulics, 1991; Bachmann, 1994; Imas et al., 2006; Schubert et al., 2006; Schoenfeld et al., 2011; Auksztulewicz et al., 2012; Auksztulewicz and Blankenburg, 2013; Sinke et al., 2014; Pitts et al., submitted). For example, while early post-stimulus potential components are more or less invariant between sleep or sedation on the one hand and awake conditions on the other hand (or even increased in sedation – Imas et al., 2006), N1 is considerably suppressed in the unconscious state. Similarly, visual cortical neurons in anesthetized animals show early activity in response to light flashes similar to the unanesthtized state, but long-latency responses significantly decrease under sedation (Hudetz et al., 2009). Also, in the crowding effect when target information is left out of awareness, N1 is suppressed although P1 ERP component still reflects basic stimulus characteristics regardless of crowding (Chicherov et al., 2014). When similar monocular textures fuse into subjectively visible images, conspicuous occipitally recorded negative component is present, but absent when fusion into visibility is not achieved (Fahrenfort et al., 2012). Moreover, recently it was shown that whether subjective experience of a visual stimulus in hysterical blindness is present or not is reflected in the amplitude of N1 (Schoenfeld et al., 2011). Importantly, while N1 appeared as an authentic NCC, fMRI recording data could not differentiate between consciously seen vs unseen stimuli. For our purposes it is essential that the electrogenesis of negativity of the surface-recorded brain potentials considerably owes to the apical dendritic activity in the upper layers of the cortex (Larkum, 2013). The stimulus-evoked negativity can be easily explained as resulting from the excitatory synaptic input to the distal compartment of the apical dendrites of layer-5 pyramidal neurons. The fact that consciousness of a stimulus emerges with a relatively long delay after 100 ms (Bachmann, 1994, 2000) is strongly consistent with the fact that N1 is relatively slow compared to the timing of the early arrival of stimulus signals to cortex as indexed by the faster ERP components. This is despite the fact that the early ERP components with latencies under 100 ms can vary depending on whether the target stimulus presented in invariant physical conditions becomes consciously experienced or not (Aru and Bachmann, 2009b) suggesting that they are signatures of the NCCpr and not NCC proper. Furthermore, an ERP signature termed visual awareness negativity (VAN) most conspicuously present as recorded by lateral occipital electrodes also correlates with stimulus awareness (Railo et al., 2011). (However, see Bachmann, 2009, concerning the problem that VAN duration is too short compared to the duration of subjective experience when subjects hold target-stimulus in explicit immediate memory. This problem appears to find a solution in the correlation of slow negative potentials with conscious awareness as discussed later in this article.)

Thus, taking into account the experimental regularities reviewed above, let us operationally regard EEG potential negativity as a signature of the involvement of the L-system in modulating the neural activity of the D-system. This notion does not mean that modulation by the L-system *always* leads to conscious experience of the stimuli; it is likely that a certain level of the L-activity modulating D-activity is necessary. This in turn implies the existence of a threshold level and/or threshold duration of the processes producing ERP negativity, with sub-threshold levels of the measured negative cortical potential measurable in principle. Consistent with this, Intaité et al. (2014), demonstrated pre-reversal negativity as a signature of the change in conscious perceptual contents. Several hundred ms before subjective reversal of the perceptual contents of an invariant ambiguous stimulus, ERP negativity was enhanced when subsequently the conscious contents were changed.

Not only brief transient ERPs with negative polarity correlate with stimulus awareness timing, but also the slower negative deflections of the brain potentials such as, the contingent negative variation, slow cortical potential waves, or contralateral delay activity appear to be good candidates of a reliable and robust correlate of consciousness, especially as related to expectancy states and application of general-purpose brain-process resources for a specific task involving focused attention (Rösler et al., 1997; Birbaumer, 1999; Devrim et al., 1999; He and Raichle, 2009; Murayama and Larkum, 2009; Fischer et al., 2010; Murd et al., 2010; Stamm et al., 2011; Birbaumer et al., 2012; Pun et al., 2012; Jo et al., 2014; Li et al., 2014). Basically, the slow potential dynamics reflects changes in cortical excitability (He and Raichle, 2009; Raichle, 2011). This notion is substantiated by the known intimate relationship between the slow cortical potential and the thalamocortical neuromodulatory system (i.e., the system controlling L, according to our notation). This conceptualization is consistent with observations that trans-cranial magnetic stimulation (TMS) of the occipital cortex elicits state-dependent effects when performed in a state of increased arousal (brought about by caffeine administration) as compared to quiet wakefulness (placebo condition; Murd et al., 2010), or during NREM sleep compared to awake state (Stamm et al., 2011). When caffeine was applied or wakeful state was tested, TMS evoked a stronger early negative component (N1) and enhanced slow negativity in remote cortical areas compared to the placebo condition or NREM sleep condition. Because TMS is a task-irrelevant, nonspecific signal in terms of the contents of consciousness, these results speak in favor of the stance that (slow) negativity reflects nonspecific effects on cortical excitability. Provided that slow negativity correlates with (readiness for) long range effective connectivity, TMS is expected to facilitate cortical communication in conscious states in order to allow sufficient information integration. Studies by Tononi, Massimini and associates indeed show this (e.g., Massimini et al., 2009; Ferrarelli et al., 2010). They tested the state-dependence of the cortical propagation of a TMS-induced EEG signal and found that in the unconscious condition, either in slow wave sleep or anesthesia, long-range cortical communication was suppressed, and restricted to a local region surrounding the stimulation site. In terms of temporal dynamics, the late (sustained) component of TMS-evoked signal was also suppressed, in agreement with results obtained previously with the direct measurement of flashevoked unit activity in the visual cortex of rats (Hudetz et al., 2009).

In accordance with the conceptualization presented above, Yasuda et al. (2011) showed that with the loss of consciousness at sleep onset, N1 decreased, P2 increased (!), and CNV was increasingly more positive. In sleep the CNV was absent.

We believe that a step forward in revealing the NCC would be achieved by the use of a combined strategy consisting in three key requirements: (i) *causal* mechanistic effects are used and studied instead of correlational ones in the objective domain of

research so that microelectrode stimulation, optical stimulation, TMS, psychopharmacological intervention, or other methods of purposeful manipulation of neural tissue in selected brain areas allow to study the resulting effects on brain processes by brainimaging or similar methods; (ii) the *relative involvement of the D- and L-systems* is specifically examined in the context of objective causal manipulations and measurements; (iii) psychophysical procedures are used in combination with (i) and (ii) allowing the *precise measurement of subjective contents* of *consciousness* as they emerge, unfold, and decay along the objective time axis. Correspondences between precise timing of the neural signatures and psychophysical phenomena pertaining to the domains of (i), (ii), and (iii) will hopefully make it possible to find causal relationships that are more likely to be indicative of the real constituents of consciousness in terms of the underlying neural processes. An important accompanying research agenda should be to use animal models with mammalian species, executing studies (i) and (ii) and by analogy, invoking and postulating the corresponding variability of the experienced contents (iii). In what follows, we will provide a few *ad hoc* interpretations of the published research suitable for differentiating the D- and L-system effects in the context of the problem of NCC. Thereafter, we will conclude by envisaging possible experimental approaches for future research in service of the view that C = L × D.

## **EMPIRICAL FACTS CONSISTENT WITH C = L × D**

There are surprisingly few research data on the NCC as based on experiments explicitly relating content- and state-related system effects within the same study that utlize the methodology of contrastive analysis. Measurements and discussions have been evolving around the specific D-system contributions with rarely – if at all – mentioning the L-system contribution. This conclusion is especially valid with regard to the real-time examination of the NCC as they unfold along the fine timescales of psychophysical experimental paradigms. Although a lot of psychophysical and cognitive neuroscience research has been published with results that can be *interpreted* according to our C = L × D "formula," this kind of research lacks the power of *direct evidence*. Nevertheless, here we discuss both – studies with experimental protocols and designs more directly combining the L-system and D-system variables as well as studies allowing indirect interpretations of their data in terms of L- and D-system interactive contributions. We do this, being well aware of the methodological weaknesses of the *ad hoc* type of argumentation about the second sub-variety of the pertinent research as mentioned above.

Alert patients regularly treated by chronically implanted microelectrodes in order to relieve the suffering from Parkinson's disease were used as volunteer subjects in a visual mutual masking experiment (Bachmann, 1994). They were asked to discriminate spatially overlapping brief stimuli presented successively with stimulus onset asynchrony (SOA, values less than 100 ms) leading to masking. Compared to the control condition without the pre-test microelectrode stimulation, awareness of the visual targets improved considerably in the main condition with a preliminary activating stimulation targeted at the thalamic nuclei which were the known part of the L-system (including the central medial intralaminar nucleus). Artificially activating the L-system produced improvement of perception of the specific contents represented by the D-system. The effect was obtained also with invariant physical conditions of the independent variables.

A very brief near-threshold Gabor patch was presented for orientation discrimination in the study by Li et al. (2014). MEG responses as an equivalent of slow cortical potential (SCP) were recorded in the conditions allowing comparison of trials with (i) strong and marginal awareness and unawareness, (ii) correct and incorrect behavioral responses, and (iii) subjective confidence in the correctness of response, all with invariant values of the principal independent variables. After the effects of objective performance and confidence were both removed from data, the SCPs were found to be a strong and reliable correlate of consciousness while the neural signatures correlating with veridicality of response and confidence were mostly related to transient brain activity. Because long-lasting EPSPs at the apical dendrites of the (mostly layer-5) pyramidal neurons are considered as the main contributors of surface-recorded SCPs and as the equivalent MEG contrasts between aware/unaware conditions stood for the expression of SCPs, we can conclude that modulation of the D-system (carrying the contents of Gabors) by the L-system (modulating the EPSPs of the content-carrying neurons of the D-system) may be an instance of the NCC. In light of these results, it is inviting to speculate about the possible reasons why LFP responses indicative of correct stimulus perception in the slower theta band preceded the single-neuron gamma band response by about 50- 100 ms in the experiment reported byRey et al. (2014). It is possible that the slower LFP activity in the theta band range represents the L-system activity and the gamma band single-cell responses correspond to the D-system activity. If so, the contextual and/or expectancy-related or arousal-related L-system activity may precede the bottom-up afferent signaling from the specific modal stimulus so that it enhances EPSPs by presynaptic signals targeting the apical dendrites, but not much the high-frequency firing which needs also a sufficient input to the somatic compartment of the D-system nerve cells in the temporal cortex. Only as soon as there is enough coincidence of the L-system and D-system input, firing commences and explicit recognition results. This conjecture is consistent with that of Larkum (2013) with respect to the BAC firing mechanism.

Thus, in spite of suggestions by several authors (Llinás, for example) it seems that a change in thalamocortical 40Hz gamma oscillations, at least in the local sense, may not be the critical factor in the involvement of the L-system for the NCC. Various data support this. In anesthesia with various select agents, the power of both spontaneous and sensory evoked gamma oscillations is *enhanced* (Imas et al., 2005b; Sellers et al., 2013), although preliminary findings suggest that high-frequency gamma (70- 140 Hz) may be suppressed (Hudetz et al., 2011). Nevertheless, the long-range cortical interactions at 40–50 Hz gamma frequencies do seem to be selectively altered in an opposite direction to what should have been expected from the traditional gamma band hypothesis (Imas et al., 2005a,b). All this is consistent with recent findings by Aru et al. (2012a) and Hermes et al. (2014) with respect to the lack of a band-specific gamma correlate of conscious perception. As suggested by several authors (e.g., He and Raichle, 2009; He, 2014; Miller et al., 2014), broadband and/or

scale-fee activity of neuronal populations seems to be associated with surface potentials, dendritic integration and very likely with awareness. It appears that BAC firing as a potential mechanism subserving the NCC are unlikely to be tightly coupled with the gamma band responses in implementing the C = L × D type of interaction.

The BAC firing mechanism as related to behavior of alert animals was involved also in the findings of Palmer et al. (2012a,b). They showed how contralateral sensory stimulation inhibited the firing of layer-5 pyramidal neurons in response to a sensory stimulus *in vivo* and that this inhibition acted on the apical dendrites. Somatic input to pyramidal neurons generates predominantly short-lived EPSPs and fragmented cortical neural activity but not a sustained "field of consciousness," unless substantial additional modulatory input to the apical parts of the dendrites arrives. On the other hand, only or predominantly non-specific modulation by the L-system targeting the superficial cortical layers in the absence of sufficient afferentation from sensory signals by the D-system (targeting the perisomatic compartment) should lead to fading or "contentless" conscious experience. For example, this happens with fading of retinally stabilized images (due to massive adaptation of the same sensory units), Ganzfeld effects featuring feelings of sensory emptiness (e.g., the coloring of the Ganzfeld disappears from subjective phenomenal experience), falling asleep in sensory isolation experiments, and with hypnotic effects of mononotonous and predictable stimuli (the responses to which are diminished by adaptation effects).

Whatever the normally functioning consciousness mechanism is, it must not represent mainly unreal or hallucinatory content in the awake state but perform adaptively sound *reality monitoring* (communicating actual environmental input to the subject by the D-system). This is obvious. Indeed, integrative computation by the BAC firing mechanism works mostly when the real presynaptic input via the D-system to the neuron's basal compartment is present (Larkum, 2013). Only when the cell is caused to fire by feedforward presynaptic D-input to the soma it becomes highly sensitive to the apical-dendritic modulation (Larkum, 2013). This means that the mechanism that brings contents to consciousness has its strong effect insofar as the actual input is present, meaning that in consciousness we clearly experience actual sensory input. Conversely, when subjects experience dreams or are engaged in daydreaming, the conscious contents that are hypothetically ignited by the presynaptic input to the dendrite tufts originating from more rostral, higher level cortical areas responsible for top-down effects (ignited by the L-system) cannot be as detailed and vivid as they are in the actual conscious perception of the real environment.

In the absence of top-down facilitation or selection by the L-system (which may be contolled by the brainstem-nonspecific thamocortical axis) the conscious contents are blurred or nonexistent. The necessary integration is missing. It can be presumed, that with increasing depth of anesthesia, from shallow sedation to deeper levels, the L-system and the D-system neural processes are changed in parallel: reduced state means reduced level of data input to the integrative system and vice versa. Even though strong inputs by the D-system may break through in the state of suboptimal L-system activity, they produce strong and focused

sensory activation but in a limited, modality-specific local area (e.g., Laureys et al., 2002; Liu et al., 2013). However, integration with context from higher, supramodal associative processing centers, that are now silent, does not take place. Moreover, there are specific conditions, for example under the influence of hallucinogens, when the normal interaction of the L and D systems can be clearly dissociated.

Many subjective psychophysical phenomena of perception have temporal resolution with time constants varying around 30– 300 ms (see Bachmann et al., 2011, for listing and characterizing the many pertinent phenomena.) Thus, for example metacontrast masking maxima occur typically at the target/mask delays of 30– 60 ms; apparent motion in the form of beta motion integrating two static inputs for perception is optimized with SOA set at about 40–100 ms; iconic (visual sensory) memory (i.e., visible persistence) spans about 100–200 ms; critical flicker fusion temporal values are also specified in the range of dozens of ms; attentional blink is maximized at about 250–350 ms; target stimulus that is backward-masked by a pattern mask or by an other, competing, subsequently presented target becomes fully consciously available when the mask-free time approaches about 150 ms, but is replaced by mask in visual awareness with shorter target/mask time intervals. This suggests that the neural processes fitting to allow effective inter-stimuli interactivity (caused by presynaptic input arriving from different sources in response to briefly inset stimuli) and also for sustained activity enabling inter-stimuli interaction should be unfolding in the range of intervals of about 30–350 ms. In the traditional integrate-and-fire neuronal models, the EPSP decay is usually too short for this. However, in the BAC firing model the plateau-wave time-course corresponds well to this temporal scale. Most significantly, the BAC firing model nicely corroborates the distinction between the L-system effects and D-system effects related, respectively, to the presynaptic input to the tuft dendrite compartment and the basal somatic compartment of the post-synaptic membrane of layer-5 pyramids. Several psychophysical phenomena can be explained by the hypothetical action of the BAC firing mechanism allowing to combine the L-system and D-system effects by a single cellular level mechanism of integration. We believe that this is exactly the locus where the two traditions of NCC research can be mutually harmonized.

In the *visual backward masking by pattern*, a brief target stimulus (e.g., with 40 ms duration) is immediately followed by a masking pattern and as a result, target is not consciously perceived while the masking pattern is explicitly experienced (Bachmann, 1994; Breitmeyer and Ö˘gmen, 2006). Recall that the theoretically necessary condition for sensory input to be integrated up to the level of conscious experience requires that input from feedforward D-channels targeted at the somatic compartment of the neurons that represent the stimulus content and associative (modulating) input targeted at the distal dendritic compartment that modulate content-specific activity up to the necessary level for consciousness must simultaneously coincide in time. Target signals feed synaptic receiving membrane compartment close to cell soma with a short delay (say, 30–50 ms) generating few somatic Na+ spikes. However, because this delay is too short for any associative input to arrive to the tuft region of the dendrite in

response to the target-evoked perturbation, initially there is no target experience. Processing is pre-conscious. After some more time has lapsed, this associative, tuft-area directed presynaptic input arrives (say, with about 100 ms post-target delay), but it coincides with the mask-stimulus evoked Na+ spikes produced by the neurons that encode mask features. Because certain features of target and mask are shared by the target-responsive and maskresponsive cells (e.g., spatial location, some blob- or line-defining features, etc.), mask-responsive cells receive also the associative presynaptic Ca2+activity initiating input to the dendrite's upper compartment (this was evoked by the preceding target) and as this input is coincident with Na+ spikes, a plateau wave is produced primarily for the neurons representing the mask features instead of the neurons representing exclusively the target features. We must remember here that the modulating input through the L-system in response to a perturbation by a stimulus has a longer delay to reach the apical compartments of the dendrites of the neurons compared to the delay it takes for the initial basal input throught the D-system to arrive to the cell. This basic fact is the crucial precondition for BAC firing based binding of the later presented stimulus with conscious representation instead of the first presented, briefly offset stimulus. Thus, the target-evoked dendritic Ca2+ mediated EPSP appears after a delay, is spread also to the dendrites of other cells (e.g., mask-related neurons), and coincides with the fast Na+ based somatic EPSP/spiking process of the mask-related cells. It is exatly then and there when and where the coincidence detection device sets in, but as a result, masking stimulus is emphasized for awareness. Bachmann (1994, 1997) in his model of modulated EPSPs as the explanatory mechanism of masking contends that temporal dynamics of the target-evoked N1 may be a signature of the L-system effects as they unfold in real time and are applied onto the D-system neural nodes.

In the *mutual masking of the spatially overlapping two successive targets* subjects are asked to report both successive stimuli, S1 and S2 (Bachmann and Allik, 1976; Bachmann, 1994). With very short SOAs (e.g., 0–20 ms) the results typically show neither the perfect identification of both the S1 and S2 nor the perfect masking of S1 and S2. The BAC firing mechanism based explanation is as follows. Because the SOA is so short, the L-system presynaptic input to the dendrites tuft-region compartment arrives with a considerable delay and "finds" S1 and S2 related neurons producing some residual somatically ignited Na+ spikes in response to the presynaptic D-system afferents. As a result, a plateau wave with enhanced spiking in the form of a burst is produced and both stimuli become bound together as an integrated pseudo-object in visual awareness. With intermediate SOAs (e.g., 40–90 ms) usually the following stimulus (S2) is well perceived, but the preceding stimulus (S1) is not perceived or not so well perceived. BAC firing mechanism based explanation of this psychophysical result is essentially the same as was used for explaining pattern masking above. When the time interval between onsets of S1 and S2 (SOA) exceeds about 100–150 ms, S1 becomes well visible also. The strongest dominance of S2 over S1 is typically found with SOAs around 40–60 ms. The BAC-based scenario for explaining this is as follows. Somatic presynaptic inputs from S1 carrying the contents of S1 arrive at the layer-5 neurons that represent S1 features, creating Na+ EPSPs'spiking response, but because there is no dendritic calcium response as yet (this response cannot be produced unless more time-consuming L-system mediated signaling originating from the nonspecific reticulo-thalamic influence on apical dendrites is present), plateau/burst wave is not produced for the neurons carrying S1 sensory contents in this early time window. When this delayed presynaptic input arrives at the distal parts of the apical dendrites, EPSPs of the S1-neurons are somewhat decayed, firing frequency is decreased, and probability of the conspicuos plateau-wave is low. S1 is not explicitly perceived so well as the following S2 which altogether suppresses S1 in conscious perception. This is because the somatic-compartment response of the following stimulus related neuron (S2 neuron) is maximized at the moment temporally coinciding with the slower (S1-induced) calcium wave and because due to the spatial-location and some partial featural similarity between S1 and S2, apical dendrites of the S2 neurons are also targeted and the plateau wave is distinctive and strong for the S2-related neurons. As a result, S2 is consciously perceived and S1 perception suppressed. (It is likely that some additional assumptions with regard to the mechanisms involved are needed. For example, the role of NMDA receptors and finely localized sub-cellular membrane mechanisms of competitive inhibition could be postulated to explain why S2 so robustly overpowers S1. See Larkum et al. (2009), for premises of this kind of mechanisms. Also, more precise understanding of the workings of GABAa and GABAb mediated inhibitory mechanisms may be needed in order to precisely describe the ways the L-system and D-system interact on the basis of the layer-5 pyramidal neurons.)

*Metacontrast masking* can be explained similarly by the L-system and D-system interaction taking place at the basal and apical-dendritic membrane of the cortical neurons representing the contents of stimulation. In this phenomenon, S1 (the target stimulus) is spatially non-overlapping with S2 (the masking stimulus), but is closely spatially adjacent. Typically, when contrasts and durations of S1 and S2 are compatible, with very short SOAs S1 and S2 are both perceived as if they form a single, composite object. The BAC firing based L/D interaction explanation is similar to what was used for mutual masking with shortest SOAs as described above. Simply because in metacontrast S1 and S2 are not spatially superimposed, the common formed perceptual image allows good discrimination of mask and target features spatially. It is easy to envisage a small neural network where the distinct spatial location cues dictate that modulations executed by the associative presynaptic input to the apical dendritic compartment is bifurcated to different neurons in parallel due to the difference in the receptive fields which is an important feature of stimulation. With intermediate SOAs (e.g., 40–70 ms) S1 is again strongly masked while S2 is well perceived – metacontrast masking is effective. The theoretical explanation is similar to the one presented when explaining pattern- and mutual masking. Moreover, as the shapes of S1 perimeter and S2 internal part surrounding S1 shape are identical or very similar in most of the metacontrast stimuli setups, surface quality of S2 (i.e., the metacontrast mask such as a ring for example) becomes preceptually represented combined with S1 shape which lacks its surface quality and therefore is shown as being"emptied"from this quale.

Explaining masking based on L-system and D-system interaction is not a recent "invention." For example, Bachmann (1984, 1997) in his perceptual retouch theory interpreted masking as a result of L-system-mediated modulation of mask-specific signals up to the level of conscious experience by simultaneously depriving the target-specific signals of a sufficient level of this kind of modulation. Because L-system effecs at the cortical level of the D-system nodes are delayed compared to the initial Dsystem effects, the boost of L-system modulation ignited by target presentation is maximized exactly when the freshly ariving D-system signals carrying mask content arrive cortical neurons dedicated to encode contents. As the signal-to-noise ratio of the mask-related specific afferent activity is higher than the specific target-related activity when the boost of L-modulation arrives, mask-related net activity combining the presynaptic D-input and L-input effects wins over the target-related net activity (targetrelated neural activity has decayed already when L-input arrives, but mask-related activity is maximized at that moment). Modulated post-synaptic EPSPs (Bachmann, 1994, 1997) and N1 components of ERPs (Bachmann, 1984) were used to illustrate the hypothetical D-system and L-system interactive effects producing psychophysical effects of visual awareness. Results of more recent studies with directly measuring ERPs and spectral EEG perturbations and using contrastive analysis with invariant physical stimulation conditions also show that NCC in masking includes a relatively late brain activity (Aru and Bachmann, 2009a,b).

A psychophysical paradigm called *perceptual latency priming* (PLP) has helped to demonstrate that there is a relative latency advantage (i.e., earlier perception) of a visual stimulus that is preceded by another, masked stimulus at its location (Bachmann, 1989; Neumann and Scharlau, 2007; Scharlau, 2007). The first stimulus accelerates perception of the second stimulus even if the first stimulus is backward-masked by the second one up to a total invisibility for direct awareness. In the control condition S2 is presented alone and the temporal delay of its perception is measured psychophysically (e.g., temporal order judgment against a reference stimulus). In the main condition, S2 is preceded by a priming stimulus S1 (spatially adjacent or overlapping with S2). As a result of priming, subjective delay is shortened compared to the control condition without priming. (The effect is obtained also when the prime remains unconscious and is masked.) L- and D-systems interaction-based explanation capitalizing on BAC firing neuronal mechanism assumes that S1 induces the processes consisting in presynaptic somatic input to the neurons encoding its features and a temporally delayed associative (collateral and/or cortico-thalamic) presynaptic input to apical tufts of the neurons that represent attributes of the stimuli associated with the prime in an associative network (including S2 related neurons). Spatial location and approximate size are among the important attributes shared by the prime (S1) and the target (S2). This delayed apical presynaptic input sent via the L-system appears to be temporally coincident with S2 related early somatic-compartment activity in the neurons representing S2 (this being brought about via the Dsystem). As a result, a plateau wave with a burst of spiking will be an associative medium for temporal binding of S1-evoked late activity and S2-evoked early activity. Because the apical-compartment input for the S2-representing neurons is unusually early (due to

the preceding S1-evoked associative activity), already the very first somatic presynaptic input to the S2 neurons finds unusually early coincidence with the apical calcium spikes, which means that S2 is consciously perceived unusually fast.

*Object substitution masking* (OSM) can be explained in a similar vein. In OSM, if a backward mask does not cover the target in space and is spatially and form-wise sparse (e.g., four dots surrounding a target image such as a landolt C), the masking effect is absent. However, when the same target and mask are presented among the spatially distributed distractor objects (with the subject not knowing beforehand where the target is located), with the mask specifying which object is the target and when mask offset is considerably delayed after target offset (a simultaneous onset, asynchronous offset display), strong masking occurs (Enns and Di Lollo, 1997; Di Lollo et al., 2000). In OSM, traditionally weak masks have strong effects when attention is not focused on the target before its presentation. The BAC firing mechanism could be used to suggest a similar explanation to what was presented for backward masking and mutual masking. However, it is necessary to explain why masking is absent in the condition without distractors and occurs when distractors are presented. It is natural to expect that the temporally delayed associative top-down modulation targeting presynaptically the layer-5 neurons' dendrites and igniting the BAC firing mechanism is susceptible to the lateral inhibitory influences mediated by the inhibitory synaptic effects in the dendrites' tuft compartment. If the early-onset OSM display contains many competing stimuli presented simultaneously from the several spatially separated locations, the subsequent delayed associative modulation of the target-related neurons will be inhibited by the lateral afferents from the formerly activated neurons representing the spatially remote competing stimuli. Basically, OSM results from the main share of the L-system-mediated modulation being used by the mask D-system representation instead of the target D-system representation.

In the*motion-induced blindness* displays a few static yellow disks otherwise clearly perceptible become extinguished from awareness from time to time, provided that they are viewed on the background of a moving texture or a set of moving random dots (Bonneh et al., 2001). The BAC firing mechanism-based explanation: two higher level representations – static disks versus moving set of small items – compete for being "serviced" by the top-down modulation by the L-system targeted at the tuft compartment of their respective neurons. Although somatic D-system responses to presynaptic input are preserved all the time for both types of stimuli, dendritic apical compartment afference through the L-system is unstable and fails at times. As a result, discs temporarily fade out of awareness. Competition at the higher level between two classes of neurons representing two different actual perceptual events (one showing static objects and the other a dynamic background) does not allow to send sufficiently steady and efficient top-down signals simultaneously to the dendrites of the lower level neurons that represent local cues of these two types of events.

*Ganzfeld effects*. When a subject stares at an empty field with homogeneous coloring (no brightness gradients and contours in it) for a long time, sooner or later an experience of "fading out" or "emptiness" of the visual sense occurs (Avant, 1965; Wackermann et al., 2008). Colorful visual experience disappears. The explanation founded on the L/D systems' interaction implemented by the BAC firing mechanism assumes this: without almost any specific input that would "recruit" layer-5 pyramidal neurons by somatic-compartment presynaptic input (there is simply not enough sensory input) being available, apical-compartment directed modulation by the L-system becomes without its necessary somatic counterpart of presynaptic input and as a result, any sufficient amount of the plateau-waves is absent. Awareness "gets visually empty." This interpretation invites another assumption. The top-down modulating signals from the higher level are generated insofar as there is a certain minumum amount of objectand feature-specific variability in the perceived environment.

(Hypnotic states resulting from sensory input monotony and lack of variability are also a common reality. Conversely, hallucinatory experiences so common to Ganzfeld experiments suggest a dominance of the top-down or associative input mediated by the dendritic calcium sub-mechanism in predetermining the contents of consciousness in comparison with the input from the actual sensory environment.) How exactly this principle is implemented in the brain remains only a matter of speculation for now.

The possible combinations of the D-system and L-system neurons' post-synaptic activity in response to the strength and synchronicity of their presynaptic inputs are schematically illustrated in **Figure 1**. The psychophysical phenomena of variable consciousness can be explained on the basis of the variants of D/L interaction. Variant (i) characterizes conditions for an absence of contentful conscious experience when the D-system input is insufficient or asynchronous with the L-system despite a strong contribution from the latter. Variant (ii) shows how conscious experience is absent when the L-system contribution is sub-par and/or asynchronous despite the normal contribution of the Dsystem. Variant (iii) illustrates the emergence of the interactivity between D- and L systems sufficient for conscious awareness as a result of strong enough and synchronized input.

#### **CONCLUSION**

In this article, we presented a theoretical perspective, supported by variable empirical data, integrating the two traditions of NCC research which have been developing in relative mutual isolation. Tradition-1 has been examining consciousness state systems with their central role in regulating the level of consciousness, but largely ignoring or overlooking, or being unable to study in detail the functioning and expression of the system of specific contents. Tradition-2, on the other hand, has produced a vast amount of information about the system of processing contents of consciousness and its activity signatures, but has largely ignored the involvement of the state/level system. Importantly, there is enough scientific knowledge about the build and expression of function of the neural mechanisms subservig each of these two functions but unfortunately, there has been insufficient research simultaneously investigating the contributions of the mechanisms serving the two functions within the same experiment in the context of contrastive analysis. We suggest an integration of these two paradigmatic perspectives whereby the objective measurements of the processes of the two neural systems – the state/level system and the contents system – are carried out in experiments where the confounds from stimulus variability are avoided and the problems emerging from the need to distinguish NCCpr, NCC, and NCCae are minimized.

We describe the two neural systems – the data-representng D-system and the level-modulating L-system – and characterize their working parameters and regularities. We suggest a heuristic "formula" C = L × D enabling to combine the two necessary subsystems for consciousness jointly sufficient for producing the subjectve experience with its specific content and varyig in the level of expression of this content, spanning from unconscious to fully conscious and stable phenomenal representation. Importantly, several measurable neurobiological, temporal, and spatial

parameters of functioning of the two systems allow us to explain many experimental facts as a result of interaction of the Land D-systems in real time. Our conceptualization is consistent with several well known approaches and accepted principles in consciousness studes such as the importance of top-down, backpropagating information flow in the brain for consciousness, the temporally delayed nature of phenomenal experience compared to unconscious specific information processing and the importance of the long-range connectivity and global integration of information for consciousness. Among other aspects of the present theoretical view, it must be emphasized that because the L-systembased modulation targets superficial cortical layers and thus largely contributes to negativity and because long-range connectivity which is principally significant for the information integration theory of Tononi and associates also implies apical presynaptic input, the SCP/negativity hypothesis, info-integration theory, and Larkum's BAC firing mechanism seem highly mutually consistent. We also think that our approach has merit because the neural subcellular level, cellular-level, local field potential level, local-circuit level and global-connectivity level aspects seem to be harmonized within the same conceptual framework, which at the same time, does not necessarily remain merely speculative but can be tested and falsified by specific experiments combining brain imaging and psychophysical experiments. We believe that C = L × D helps better specify the NCC, especially by objectively measuring and differentiating the relative contribution of the mechanistically distinguishable subcomponents of the brain involved in producing the astonishingly rich and often hearthbreakingly beautiful phenomenal view of the world.

#### **ACKNOWLEDGMENTS**

The research leading to this publication was partly supported by the Estonian Science Agency, institutional financing IUT20-40 (TSHPH14140I) and by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R01-GM103894. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

#### **REFERENCES**

Hudetz, A. G., and Alkire, M. T. (2011). "Thalamocortical system and anestheticinduced unconsciousness," in *Neuroscientific Foundations of Anesthesiology*, eds G. A. Mashour and R. Lydic (New York: Oxford University Press), 45–61.

activation of functionally diverse neuronal populations. *Neuroimage* 85, 711–720. doi: 10.1016/j.neuroimage.2013.08.070

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Received: 16 June 2014; accepted: 06 August 2014; published online: 22 August 2014. Citation: Bachmann T and Hudetz AG (2014) It is time to combine the two main traditions in the research on the neural correlates of consciousness: C* = *L* × *D. Front. Psychol. 5:940. doi: 10.3389/fpsyg.2014.00940*

*This article was submitted to Consciousness Research, a section of the journal Frontiers in Psychology.*

*Copyright © 2014 Bachmann and Hudetz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

## Closing in on the constitution of consciousness

## **Steven M. Miller 1,2\***

1 Monash Alfred Psychiatry Research Centre, Monash University Central Clinical School and The Alfred Hospital, Melbourne, VIC, Australia 2 School of Psychological Sciences, Monash University, Melbourne, VIC, Australia

#### **Edited by:**

Talis Bachmann, University of Tartu, Estonia

#### **Reviewed by:**

Alexander Maier, Vanderbilt University, USA Jaan Aru, University of Tartu, Estonia

**\*Correspondence:**

Steven M. Miller, Monash Alfred Psychiatry Research Centre, Level 4, 607 St Kilda Road, Melbourne, VIC 3004, Australia e-mail<EMAIL_ADDRESS>The science of consciousness is a nascent and thriving field of research that is founded on identifying the minimally sufficient neural correlates of consciousness. However, I have argued that it is the neural constitution of consciousness that science seeks to understand and that there are no evident strategies for distinguishing the correlates and constitution of (phenomenal) consciousness. Here I review this correlation/constitution distinction problem and challenge the existing foundations of consciousness science. I present the main analyses from a longer paper in press on this issue, focusing on recording, inhibition, stimulation, and combined inhibition/stimulation strategies, including proposal of the Jenga analogy to illustrate why identifying the minimally sufficient neural correlates of consciousness should not be considered the ultimate target of consciousness science. Thereafter I suggest that while combined inhibition and stimulation strategies might identify some constitutive neural activities—indeed minimally sufficient constitutive neural activities—such strategies fail to identify the whole neural constitution of consciousness and thus the correlation/constitution distinction problem is not fully solved. Various clarifications, potential objections and related scientific and philosophical issues are also discussed and I conclude by proposing new foundational claims for consciousness science.

**Keywords: consciousness, neural correlates, constitution, binocular rivalry, philosophy of mind, mechanistic explanation, foundations, philosophy of science**

## **HISTORICAL CONTEXT OF THE PROBLEM**

The science of consciousness is founded on searching for the neural correlates of consciousness (Crick and Koch, 1990, 1998; Crick, 1994; usually referred to as "NCC" but here as "NCrC," unless quoting directly). Specifically, consciousness science seeks to identify the *minimally sufficient* NCrC. Chalmers (2000) provided a foundational work concerning this notion, in a paper entitled, "What is a neural correlate of consciousness?" His paper is widely cited, as is his definition of the NCrC (p. 31):

An NCC is a minimal neural system N such that there is a mapping from states of N to states of consciousness, where a given state of N is sufficient, under conditions C, for the corresponding state of consciousness.

Also widely cited is the shorter definition by Koch (2004, p. 16) in which the NCrC is considered to be the "minimal set of neuronal events and mechanisms jointly sufficient for a specific conscious percept." Although there has been some discussion of Chalmers' definitions and claims, and the methodological assumptions on which they are based (e.g., Noë and Thompson, 2004; Bayne, 2007; Hohwy, 2007, 2009; Neisser, 2012; Bayne and Hohwy, 2013), there has been less scrutiny than might be expected for a foundational work in a nascent scientific discipline.

A few years ago, two groups of scientists (Aru et al., 2012; de Graaf et al., 2012) independently parsed NCrCs into "NCrC substrate" or "NCrC proper" on the one hand (the construct of interest for consciousness science) and "NCrC precursors/prerequisites" and "NCrC consequences" on the other (constructs of lesser interest). Their partition was aimed at developing strategies to distinguish these various NCrCs and this is of course, the topic of this special issue. In proposing this terminology, however, these authors were unaware that the problem of identifying which, from among many, NCrCs1 are most directly relevant to consciousness had been appreciated, named and analyzed a decade prior.

Both Revonsuo (2000, 2001, 2006, in press) and myself (Miller, 2001, 2007, 2013a, in press-a,b) have been explicitly concerned with just how science will distinguish the neural *correlates* and the neural *constitution* of consciousness (NCnC). This is particularly problematic for *phenomenal* consciousness—the subjective or qualitative nature of our conscious states (Nagel, 1974). Revonsuo's (2000, 2001) concern was that current scientific methodologies—brain recording techniques in particular—are not capable of targeting the right level of organization in the brain (which he termed, "the phenomenal level"). Revonsuo (2006, in press) also developed a highly detailed level-based biological framework for a consciousness research program that seeks to discover the *constitutive mechanisms* of consciousness.

1Note that the plural "NCrCs" indicates the many individual neural activities that correlate with a specific state of consciousness. This is different to "the NCrC" which is a collective term commonly used to denote the set of all NCrCs for such a state. More points of clarification and definition are detailed below.

Although I have a great deal of affinity with Revonsuo's concerns and his framework, my development of the issue has been different. I noted (Miller, 2001) that although the problem of identifying the constitution of consciousness had been *alluded to* by investigators in the science of consciousness, such as Francis Crick, Christof Koch, and Nikos Logothetis (Crick, 1994; Crick and Koch, 1998; Logothetis, 1998) 2 , it required much more than such passing reference. I therefore sought to name and examine the *correlation/constitution distinction problem* (herewith, Cr/Cn distinction problem) so that it might be addressed *explicitly*, with a view to its solution or dissolution, or indeed to its acceptance as an ultimate epistemic limit.

I explicated the Cr/Cn distinction problem utilizing the phenomenon of binocular rivalry (Miller, 2001). Unlike Revonsuo, my initial analysis led me to be concerned that perhaps even future scientific methodologies, including those targeting the right level of organization in the brain, might fail to solve the problem. I suggested there were no obvious corollaries regarding the NCnC from studies of the NCrC and yet it was the NCnC that a science of consciousness should ultimately wish to identify. I therefore proposed that consciousness science might require entirely new scientific strategies if it is to move from mere correlation to actual constitution. My initial concerns were re-stated and developed in a subsequent paper (Miller, 2007), in which I noted (p. 161, italics in original):

If we imagine that through the employment of all current and future neuroscientific methods (in all contexts, under all conditions and with all methodological constraints overcome), we were able to obtain a complete, real-time and multimodal description of all the NCC and all observable properties of such, would we be satisfied that we had obtained a comprehensive understanding of the neuroscience of consciousness? I assert not, because *not every neural correlate of a conscious state is necessarily constitutive of that state.*

In both my 2001 and 2007 papers, I discussed how NCrC recording, inhibition (disablement), and stimulation techniques—either alone or in combination—failed to distinguish correlated but non-constitutive neural activities that are *upstream* or *downstream* from correlated constitutive neural activities (Miller, 2001, 2007). (This upstream/downstream terminology is equivalent to the precursors/consequences terminology and is also used by others; e.g., Chalmers, 2000; Hohwy and Bayne, in press.)3 I considered therefore, that these empirical approaches failed to yield conclusions regarding the NCnC, that entirely new approaches might be needed and that the Cr/Cn distinction problem might need to join other well-known hard problems of consciousness. I also made it clear, however, that there were no grounds, as yet, to proclaim the problem intractable (Miller, 2007).

#### **CURRENT STATUS OF THE PROBLEM**

Discussion of the Cr/Cn distinction problem has since gained momentum, evidenced by this special issue and by a two-volume project in which scientists and philosophers discuss the problem and the conceptual, empirical, and philosophical territory within which it is situated. In the first volume (Miller, 2013a), scientific groundwork was laid with papers on the brain and visual system's constituents, organization and processes, on the current status of binocular rivalry research from multiple empirical perspectives and on current neuroscientific investigative techniques (including various invasive and non-invasive recording, inhibition, and stimulation techniques).

The second volume (Miller, in press-a) addresses scientific and philosophic perspectives on consciousness science and its methods and foundational constructs, the Cr/Cn distinction problem, the philosophical territory of phenomenal consciousness, hard problems of consciousness, the notion of explanation in consciousness science, the relation between brain and mind, and in particular, notions of correlation, constitution, identity, causation, supervenience, emergence, and realization. My paper in that second volume (Miller, in press-b) closely examines Chalmers' (2000) foundational notion of the minimally sufficient NCrC and through that analysis suggests new foundational claims for consciousness science.

In the present paper—given the topic of this special issue— I outline the specifically *methodological* aspects from Miller (in press-b). I start by providing brief reference to foundational issues in consciousness science and then discuss neural inhibition approaches that challenge those issues. Thereafter I discuss neural stimulation and the combined inhibition/stimulation approach, suggesting that although the latter may provide the best evidence for identifying at least some constitutive neural activities, it fails to fully solve the Cr/Cn distinction problem. Various points of clarification are then discussed and six objections to the presented arguments are listed, with three discussed in detail. A brief presentation of related scientific and philosophic issues is then provided and I conclude with the proposed new foundational claims for consciousness science.

#### **A BRIEF SCAN OF THE FOUNDATIONS**

The Cr/Cn distinction problem is neatly exposed when considering NCrCs during binocular rivalry. This visual phenomenon in which *dynamic* perceptual alternations are induced by *static* presentation of a different image to each eye—provides several advantages for the scientific study of consciousness (reviewed in Miller, 2013b). In particular, binocular rivalry allows for dissociation between neural activity correlated with a subject's perceptual alternations and neural activity correlated with image presentation. Thus, *perception-dependent* neural activity is rightly considered a neural correlate of visual consciousness during rivalry. However, the perception-dependent data for rivalry from electrophysiological and brain-imaging *recording* studies (reviewed in many chapters in Miller, 2013a) yield a wide array of such NCrCs. This *makes evident* the Cr/Cn distinction problem. That is, because not every NCrC is necessarily constitutive of that conscious state, we can ask *which* NCrCs from this array are actually constitutive. Moreover, we can ask what methodologies science

2 I expect the problem to have been alluded to by many other authors as well, as I continue to discover (e.g., Bachmann, 2000, p. 125; Frith et al., 1999, p. 109). 3 It should also be noted that in addition to correlated non-constitutive activities upstream and downstream from correlated constitutive activities, there can be correlated non-constitutive activities that are *parallel* to correlated constitutive activities. For simplicity, in the arguments that follow I do not consider the parallel category further.

might employ to experimentally examine various hypotheses in this regard.

In Chalmers' (2000) examination of the NCrC notion, he discusses the range of cases over which a correlation should be expected to hold. Those discussed include the normal brain, unusual input (such as binocular rivalry), lesion studies, and stimulation studies. Chalmers' analysis is predominantly conceptual rather than a detailed methodological approach to identifying the NCrC, but he does discuss the lesion case in some depth. He notes that such studies should be regarded very cautiously and perhaps abandoned altogether in searching for the NCrC, due to the altered brain architecture they induce (thus suggesting that an NCrC should be architecture-dependent not architecture-independent)4 . Chalmers discusses in far less detail, the methodological NCrC approach to the normal brain, unusual input, and brain stimulation. He notes nonetheless that there are interpretive complexities with unusual input and brain stimulation too, but he considers these cases and the normal brain case to be those over which an NCrC should be required to hold (with perhaps some "good" lesion approaches also being admitted). The present analyses aim to address in detail, inhibition and stimulation empirical strategies—and their interpretive complexities—that surround the notion of the minimally sufficient NCrC.

There are several other aspects to Chalmers' (2000) formulation of the NCrC construct that are worth mentioning. First, his definition is intended to constrain the discussion to "correlation" terminology, as he considers this to be theoretically neutral rather than theoretically loaded. Second, he notes his definition is constructed in a way that provides a tractable methodology for NCrC identification, and thus a way forward for consciousness science. Third, he accepts that even if the thus-defined NCrC was identified, this would not necessarily *explain* consciousness and may not even be the key to understanding processes underlying consciousness. However, he does not *explicitly* consider the potential for a Cr/Cn distinction problem, perhaps because of his reluctance to shift the discussion beyond notions of correlation. Moreover, although his formulation of the minimally sufficient NCrC construct acknowledges the empirical potential it provides, it does not adequately examine the empirical entailment of the "minimally sufficient" qualifier or the methodological details of such entailment.

As outlined in greater detail in Miller (in press-b), despite the valuable contribution provided by Chalmers' conceptual proposals, there are several problems with accepting his formulation as unchallenged foundations for consciousness science. Indeed, Chalmers himself considered his work to be "conceptual spadework" that would require refinement. If my contention above is accurate—that consciousness science wishes to ultimately identify the NCnC—then it is noteworthy that this construct is nowhere to be seen in Chalmers' analysis. It is a construct that can be conveyed using a wide range of terms such as the neural "basis," "mechanism," or "substrate" of consciousness (see Miller, 2007 for more terms), so concerns over the entailed philosophical commitments of "constitution" terminology should not be reason to avoid such a construct, or something like it5 . Moreover, once we admit talk of such notions, questions arise regarding: (i) whether by minimally sufficient NCrC, we mean the very same thing as the neural basis, mechanism, substrate, or constitution of consciousness; (ii) whether these constructs pick out the same or different neural activity sets; and (iii) if they could pick out *different* neural activity sets, which should be considered the ultimate empirical target for consciousness science.

### **STEPWISE INHIBITION**

The notion of the minimally sufficient NCrC was created to distinguish it from the *merely* sufficient NCrC (with a *necessity* criterion being considered altogether too strong; Chalmers, 2000). However, the distinction between the merely and minimally sufficient NCrC *entails* an empirical strategy. If we are to arrive at identification of the minimally sufficient NCrC, we will presumably need to *remove* NCrCs one by one to assess whether each has minimally sufficient status. It is critical here to note that when I refer to an NCrC being minimally sufficient, or having minimally sufficient status, I mean to say that it is a *part* of the whole minimally sufficient neural activity set. Similarly, when I refer to an NCrC being constitutive, or having constitutive status, I mean to say that it is a *part* of the whole NCnC. Returning to the empirical approach to reducing the merely sufficient NCrC to the minimally sufficient NCrC, the most obvious means of doing this is by *stepwise inhibition* (disablement) of neurons, neuron types6 ,

4Although Chalmers expresses caution over the lesion analysis case, no one would deny that modern understanding of the brain and its functional specialization owes a great debt to such neuropsychological analysis.  Hence, by "NCnC" I mean to equally imply the neural "basis," "mechanism," or "substrate" of consciousness. At times I will state these terms in full to remind the reader of this point and indeed, on this broad construal, one could even "define" the NCnC as the neural basis, mechanism, or substrate of consciousness. However, although the Cr/Cn distinction problem is able to be appreciated and analyzed using any of these broadly synonymous terms, use of "constitution" terminology becomes relevant and informative later, as a specific relation within philosophy of mind (with additional implications for science thereafter). It is because of the relational complexities in the philosophical domain that I resist any further simple definition of the NCnC. For example, a definition could be proposed that states the NCnC is the neural activity that simply *is* the conscious state in question, but any such definition then invites debate about contrasting the "is of identity" with the "is of constitution" (see Miller, 2007, and various papers in Miller, in press-a).

6On the issue of neuron types, Koch (2004, p. 282) refers to perceptiondependent neural activity high in the visual processing pathway (inferior temporal cortex, IT, and superior temporal sulcus, STS) during binocular rivalry as follows:

It is implausible that all of the storied IT and STS neurons that follow the percept express its phenomenological attributes directly. Some must be involved in the underlying winner-take-all operations; others must relay the winner's identity to the motor centers to initiate behavior or to short-term memory for future recall; some must carry a transient signal indicative of

local or distributed neural circuits, specific brain regions or sets of NCrCs.

Chalmers' definitions would seem to imply something like a stepwise inhibition empirical strategy when he comments (2000, p. 25), "In this way, we pare down any potential NCC to its core: Any irrelevant material will be whittled away, and an NCC will be required to contain only the core processes that suffice for the conscious state in question." There is some conflict in Chalmers' view here, given his willingness to whittle away but not to lesion. We therefore need to qualify the *type* of inhibition to be employed in identifying the minimally sufficient NCrC, and select methods that do not induce gross lesions and consequent architectural disruption (such as that induced by stroke, tumor, injury, or surgery). Although current methods such as inhibitory transcranial magnetic stimulation could be employed—and indeed this method provides striking and immediate perceptual disruption during binocular rivalry (Miller et al., 2000; see also Ngo et al., 2013)—for conceptual clarity we might postulate future highly specific molecular knockout techniques in which this or that NCrC can be selectively and reversibly inhibited. Such techniques were predicted by Crick and Koch (1998; see also the quote further below from Fenno et al., 2011) and are *currently* being developed and refined, with stunning progress, in the field of optogenetics (as detailed further below; Fenno et al., 2011; see also Klink et al., 2013). Although harmless application of such techniques in humans remains a very long way off, we can nonetheless begin to think through how such highly selective inhibitory techniques could, *in principle*, assist with identification of the NCnC.

As I have previously noted (Miller, 2001, 2007), if we inhibit an NCrC and consciousness disappears (or degrades), this might suggest the inhibited NCrC *is* constitutive in the normal case but does not actually prove its constitutive status. This is because such an NCrC might simply be *necessary and supportive* for consciousness without being constitutive of it. Conversely, if we inhibit an NCrC and consciousness does not disappear (or degrade), this might suggest the inhibited NCrC is *non*-constitutive in the normal case but does not prove such non-constitutive status. This is because such an NCrC might simply be *redundantly* constitutive. Because of these uncertainties, I have claimed that stepwise inhibition does not lead to conclusions regarding the NCnC. However, it certainly *does* lead to conclusions regarding the minimally sufficient NCrC.

#### **THE JENGA ANALOGY**

To illustrate how the minimally sufficient NCrC and the NCnC are constructs that can pick out different neural activity sets, and to schematize the stepwise inhibition approach described above, I have proposed the Jenga analogy (Miller, in press-b). This analogy is from the popular game in which blocks are removed from a tower structure, one by one, until eventually a *critical point* is reached and the tower falls. An upright tower in this analogy (**Figure 1**) represents a *specific* conscious state or content being present while the fallen tower represents the absence (or degradation) of that conscious state or content. Each block in the tower represents an NCrC that correlates with that specific conscious state or content. This follows the distinction by Koch (2004) between "specific factors" and "enabling factors," with the former dealing with particular conscious states or content and the latter with the overall state of being conscious. Although this distinction is itself the subject of considerable conceptual and methodological controversy (see Noë and Thompson, 2004; Bayne, 2007; Hohwy, 2007, 2009; Neisser, 2012; Bayne and Hohwy, 2013; Hohwy and Bayne, in press), I sidestep this debate and constrain the ensuing discussion to just specific factors7 .

As the case of binocular rivalry illustrates (**Figure 2A**; see Miller, 2013a, in press-b), there are many (specific factor) NCrCs for a given conscious state and these can include specific brain regions or specific neural populations within brain regions. In the Jenga analogy, each NCrC block can thus be considered representative of a specific factor NCrC at either local, distributed or regional levels8 . The first step in the stepwise inhibition strategy is to use recording techniques to create an NCrC specific factor map for a specific (target) conscious state. Several further stipulations for the Jenga analogy are required. First, the entire tower is considered to be the outcome of previous strategies to "screen off " irrelevant *neural* activities (Hohwy, 2009; Hohwy and Bayne, in press). Hence, on this analogy, already screened off would be (i) neural activities that do *not* correlate with specific conscious states or content; (ii) neural activities that correlate with specific conscious states or content, but do so only in a *loose* fashion, in which the correlation can be broken one way or another9 ; (iii) neural activities that correlate with specific conscious states or content but whose precise *timing* provides clear ascription of either upstream or downstream, rather than constitutive, status (see Miller, in press-b for details;

a perceptual switch; and still others might represent the same information but in a delayed manner.

When considering the temporal profile of cellular responses in these areas, I am struck by their extreme heterogeneity. An entire menagerie of distinct patterns can be observed. Some cells fire in a transient manner whereas others respond in a more sustained fashion. Some fire in bursts, some show a pronounced, rhythmic discharge in the 4–6 Hz range, while others peak early before settling down to a more sedate and sustained pace of firing. Do these reflect discrete cell types with discrete functions and connectivity patterns? This will be important to know.

7Bayne and Hohwy (2013; see also Hohwy and Bayne, in press) refer to *differentiating* NCrCs, which are considered neural states that are selectively implicated in particular kinds of conscious states in an already conscious creature.

8As neurophysiological understanding develops, so too will the notion of what an NCrC block could be taken to be in this analogy—that is, what appropriate "units" of neurophysiological signaling will turn out to be. For now, however, each block represents individual NCrCs such as those being identified at various levels of constituents, organization and processes in studies of binocular rivalry.

9 In my view, and without wishing to undermine or dismiss these important conceptual and methodological efforts, I consider the strategies so far proposed to distinguish NCrC precursors/prerequisites, NCrC proper/substrate, and NCrC consequences by de Graaf and Sack (in press) and Aru et al. (in press) generally fall into this category, appealing to ever more refined means of identifying loosely from tightly correlated neural activities. This refinement certainly helps to close in on the constitution of consciousness but the Jenga analogy begins only *after* application of such strategies.

see also Aru et al., in press; de Graaf and Sack, in press; Hohwy and Bayne, in press; Revonsuo, in press) 10; and (iv) neural activities that correlate with specific conscious states or content but whose known mechanistic functions provide grounds for clear ascription as non-constitutive11. What remains after such a screening off process therefore, is a tower of neural activities that *tightly* correlate with a specific conscious state or content and whose precise timing or known mechanistic functions cannot be used to accurately ascribe upstream, downstream, or constitutive status12 .

Second, NCrC blocks in the lower third of the tower (colored yellow) represent tightly correlated non-constitutive upstream activities (tightly correlated NCrC precursors or NCrC prerequisites), those in the upper third (colored blue) represent tightly correlated non-constitutive downstream activities (tightly correlated NCrC consequences), and those in the middle third (colored red) represent tightly correlated *constitutive* NCrCs (the NCnC). Third, the upright tower at the critical point beyond which any further block removal will result in its collapse and the disappearance (or degradation) of the target conscious state represents the minimally sufficient NCrC.

Consider now that each of the thus-defined tightly correlated neural activity blocks in the Jenga tower can be described by only *one* of the following conjunctions:

Consider further, the following two possibilities (P), each of which is to be considered in isolation (because complexities arise when they are considered together):

Possibility 1 (P1): Considering all individual NCrCs that have survived the screening off process, the possibility of nonconstitutive minimally sufficient NCrCs means that the minimally sufficient NCrC could be a *larger* set of neural activities than the neural basis, mechanism, substrate, or constitution of consciousness.

Possibility 2 (P2): Imagining just the neural basis, mechanism, substrate, or constitution of consciousness, the possibility of redundancy (the possibility of constitutive non-minimally sufficient NCrCs) means that the minimally sufficient NCrC could be a *smaller* set of neural activities than the neural basis, mechanism, substrate, or constitution of consciousness.

Suppose now, that the first five correlated non-constitutive upstream activity blocks are removed but the conscious state remains and the tower stays upright. Those NCrCs are therefore *non*-minimally sufficient. Further suppose, however, that removal of the sixth correlated non-constitutive upstream activity block does lead to the disappearance (or degradation) of the conscious state and to falling of the tower. That sixth NCrC *is* minimally sufficient. But the Jenga analogy shows that an NCrC can be minimally sufficient *without* necessarily being constitutive. In this way, the minimally sufficient NCrC could be a larger set of neural activities than the NCnC (**Figure 1**). The downstream case is a little more complex (see Aru et al., in press; de Graaf and Sack, in press; Hohwy and Bayne, in press; van Boxtel and Tsuchiya, in press), and it is not always clear what should be regarded as an upstream activity and what a downstream activity, particularly given the unclear neurophysiological role of feedback. However, the difference between upstream and downstream cases is not particularly important for the point I am making and P1 is illustrated clearly with reference to just the upstream case.

Next imagine the set of neural activities that is the NCnC and consider that due to the possibility of redundancy in this neural activity set, five NCrC blocks could be removed without the disappearance (or degradation) of the conscious state and with the tower remaining upright. Those five neural activities are therefore *non*-minimally sufficient despite being actually constitutive. Removal of the sixth correlated constitutive neural activity block, however, takes the tower passed its critical point and the conscious state disappears (or degrades) and the tower falls. This sixth NCrC block then is *both* constitutive and minimally sufficient. In this way, the minimally sufficient NCrC within this (imagined) constitutive neural activity set could be a smaller set of neural activities than the NCnC (**Figure 1**).

The issue of claiming larger versus smaller sets is complicated when conceiving of P1 and P2 *together*, but the key message here is not about the overall size of the different neural activity sets, but rather that the minimally sufficient NCrC and the NCnC *can be different sets of neural activities*. Other important complexities include combinatorial and order complexities (i.e., whether the critical block removal would be critical *whenever* it is removed, or only when removed *after* removal of the previous five blocks, or only after removal of the previous five blocks in *that* specific order). Despite these complexities, what is important here is that while the empirical strategy of stepwise inhibition can identify an NCrC's minimally sufficient status, it cannot identify its constitutive status. As the Jenga analogy shows, and as depicted in **Figure 2** using the case of binocular rivalry, while stepwise inhibition achieves identification of the minimally sufficient NCrC, it cannot identify (i) which of the *remaining* blocks are constitutive of the conscious state and which are not; or (ii) which of the

10With such a brief treatment here, I do not wish to downplay the importance and complexity of timing in the brain with respect to correlations between neural and phenomenal states. This issue is itself likely to be a source of interpretive difficulty and hence there will be many cases in which such "clear ascription" will not be possible. Indeed, this fact underscores the problems being discussed in the present paper. Nonetheless, in cases for which clear ascription appears possible, timing can be used to screen off candidates for constitutive neural activity. For a detailed source on the issue of timing and phenomenal consciousness, see Bachmann (2000) and for a more recent example of timing studies, see Liu et al. (2009).

11I provided an example of this fourth category in my first explication of the Cr/Cn distinction problem (Miller, 2001) in terms of the expected correlated neural activity that would be found in subcortical nuclei controlling eye movement tracking (optokinetic nystagmus) during rivalry with drifting gratings. Despite being correlated with consciousness during such rivalry, the known mechanistic function of eye movement nuclei suggests a nonconstitutive role for this individual NCrC.

12Herewith, I combine points (ii), (iii), and (iv) such that when I refer to *tightly* correlated NCrCs, I mean to also include the precise timing and mechanistic function issues.

**FIGURE 1 | The Jenga analogy schematizes the stepwise inhibition strategy inherent in distinguishing the merely sufficient from the minimally sufficient NCrC and shows how the minimally sufficient NCrC can differ from the NCnC.** In all panels, the upright tower represents the presence of a specific conscious state (or content) while in panels (**A,B**) the fallen tower (rubble) represents the loss (or degradation) of that state. Each block represents a perception-dependent NCrC that correlates with the specific conscious state (i.e., a specific factor NCrC). The whole tower is what remains after a process of screening off non-correlated neural activities and NCrCs that are only loosely correlated with consciousness or whose precise timing or known mechanistic function indicates they are not candidates for the NCnC. Panels **(A,C)** depict real-world situations, while panels **(B,D,E)** depict colored subdivisions that could only be identified if the Cr/Cn distinction problem is solvable. In **(B,D,E)**, yellow blocks represent tightly correlated non-constitutive upstream activities (NCrC precursors/ prerequisites), blue blocks represent tightly correlated non-constitutive downstream activities (NCrC consequences) and red blocks represent correlated constitutive activities (the NCnC). The right tower in **(B)** represents a more distributed depiction of the colored subdivisions than the left tower in **(B)**. In **(C,D)**, the upright tower with NCrC blocks removed is at the critical point beyond which any further block removal will result in the disappearance (or degradation) of the conscious state and collapse of the tower. The upright tower in **(C,D)** thus represents the minimally sufficient NCrC. Blocks in this critical point tower have minimally sufficient status, while those removed from it do not. In P1 (see main text), the possibility of non-constitutive minimally sufficient NCrCs (remaining yellow and blue blocks in **D**) means that

*removed* blocks are constitutive of the conscious state and which are not13 .

13It is important to note that the Jenga analogy is just that—an analogy. It *schematizes* the stepwise inhibition approach to illustrate the points I am making. There is certainly no implied direct equivalence between removing a block from a tower of mechanically related blocks on the one hand, and inhibiting a neuron, neural circuit or set of neural circuits within an exquisitely complex, dynamic and inter-related neural system with the capacity for functional and structural reorganization, on the other. Aside from differences in complexity between a Jenga tower and a neural system, there are further the minimally sufficient NCrC could be a larger set of neural activities than the neural basis, mechanism, substrate, or constitution of consciousness (i.e., the tower in **D** is a larger set of blocks than the red middle third of the left tower in **B**). In P2 (see main text), the possibility of redundancy in the NCnC (i.e., the possibility of constitutive non-minimally sufficient NCrCs; removed red blocks in **E**) means that the minimally sufficient NCrC could be a smaller set of neural activities than the neural basis, mechanism, substrate, or constitution of consciousness (i.e., the red remaining blocks in the tower in **E** is a smaller set of blocks than the red middle third of the left tower in **B**; note P1 and P2 are not meant to be considered together—see main text). The stepwise inhibition strategy can therefore be used to assign minimally sufficient status to each block in the Jenga tower in **(A)** (thus the real-world situation of getting from **A** to **C**). However, the Cr/Cn distinction problem claims that there are no evident strategies to readily assign color status (constitutive red versus non-constitutive yellow/blue) to each of the NCrC blocks (thus it is not clear how to get from **A** to **B**). The analogy shows that although we might get from **(A)** to **(C)** using the stepwise inhibition approach, this will not satisfy consciousness science because we still cannot assign color status to either the remaining or removed blocks in **(C)** (we cannot get from **C** to **D**). Through this analogy it is claimed that the ultimate target of consciousness science is not to identify the minimally sufficient NCrC, but rather to distinguish constitutive (red) NCrCs from non-constitutive (yellow/blue) NCrCs. That is, it is ultimately the neural basis, mechanism, substrate, or constitution of consciousness that we seek to understand and this construct can pick out a different neural activity set from that of the minimally sufficient NCrC. Figure and caption reprinted with permission from Miller (in press-b).

This is not to say that identifying the minimally sufficient NCrC through stepwise inhibition would be an insignificant

points of difference such as the effect that inhibiting a neuron has on the neuron's milieu and on non-neural structures like nearby glia and vasculature (Logothetis, 2010). Because of these issues, problems of interpretation can arise with respect to whether it is the neural inhibition that is (or is not) changing consciousness or it is the secondary physiological effects of that inhibition. The same interpretive problems arise regarding neural stimulation (discussed in the next section, where further caveats are raised).

**FIGURE 2 | The Cr/Cn distinction problem is clearly illustrated with reference to the phenomenon of binocular rivalry. (A)** Research using electrophysiological (single-unit and local field potential), brain-imaging and brain stimulation (and inhibition) approaches has identified a wide array of NCrCs during binocular rivalry and related phenomena such as flash suppression (for details, see Miller, 2013a, in press-b; for even further electrophysiological NCrCs during rivalry and related phenomena, see Figure 6 in Boly et al., 2013). The existence of multiple NCrCs during rivalry raises the issue of which activities can be said to constitute a specific conscious state rather than being merely correlated with it. There are multiple hypotheses possible for which NCrCs are upstream from (i.e., precursors or prerequisites), which are downstream from (i.e., consequences), and which are constitutive of, consciousness. These competing hypotheses are indicated by the color-coding alternatives in the smaller panels (**B–G**, which follow the color coding of the Jenga analogy in **Figure 1**). While this NCrC array could be subjected to the stepwise inhibition strategy underlying the notion of the minimally sufficient NCrC,

the problem of assigning the appropriate color-coding to each NCrC cannot be solved with the same strategy because of the Cr/Cn distinction problem. There are several caveats to interpreting this figure, including issues such as: not all neurons in each area will exhibit perception-dependent firing (e.g., V1/V2, V4, middle temporal area, MT); even when perceptiondependent in V4 and MT, this includes a proportion of neurons with the opposite expected firing pattern (i.e., lower firing rates when their preferred stimulus is perceived and higher firing rates when their preferred stimulus is suppressed); some of the regions correlate with transitions between rivaling states (or with reporting of such states) rather than with the visual states themselves; some regions are targets of rivalry temporal parameter modulation rather than consciousness modulation per se; regions engaged in attentional selection and top-down modulation could be considered either upstream or downstream activities; and there may be important binding mechanisms that physiologically link individual NCrCs (see main text). Figure reprinted and caption adapted with permission from Miller (in press-b).

achievement for consciousness science. On the contrary, it would be a *major* achievement. However, the problem remains of just how science will experimentally distinguish the neural activity sets of the minimally sufficient NCrC and the NCnC (or if these are in fact the very same sets, how this can be shown to be the case). In my view then, the minimally sufficient NCrC construct should not be considered the ultimate empirical target for consciousness science because it could *include* neural activities that are *not* part of the neural basis, mechanism, substrate, or constitution of consciousness (P1) and it could *exclude* neural activities that *are* (P2). The minimally sufficient NCrC notion, for all its worth, subtly shifts the target of consciousness science to an empirically tractable one, while the real target remains elusive due to the Cr/Cn distinction problem.

## **STEPWISE STIMULATION AND COMBINED INHIBITION/STIMULATION**