HYPOTHESIS AND THEORY ARTICLE published: 02 August 2012 INTEGRATIVE NEUROSCIENCE doi: 10.3389/fnint.2012.00053 Hypotheses relating to the function of the

John Smythies1*, Lawrence Edelstein 2 and Vilayanur Ramachandran1

1 Center for Brain and Cognition, University of California San Diego, La Jolla, CA, USA 2 Medimark Corporation, Del Mar, CA, USA

Edited by: This paper presents a new hypothesis as to the function of the claustrum. Our basic Warren H. Meck, Duke University, premise is that the claustrum functions as a detector and integrator of synchrony in the USA axonal trains in its afferent inputs. In the first place an unexpected stimulus sets up a Reviewed by: processed signal to the sensory cortex that initiates a focus of synchronized gamma Warren H. Meck, Duke University, USA oscillations therein. This focus may then interact with a general alerting signal conveyed Antonio Pereira, Federal University from the reticular formation via mechanisms, and with other salient activations of Rio Grande do Norte, Brazil set up by the stimulus in other sensory pathways that are relayed to the cortex. This *Correspondence: activity is relayed from the cortex to the claustrum, which then processes these several John Smythies, Center for Brain and inputs by means of multiple competitive intraclaustral synchronized oscillations at different Cognition, University of California San Diego, 9500 Gilman Drive, frequencies. Finally it modulates the synchronized outputs that the claustrum distributes La Jolla, CA 92039, USA. to most cortical and many subcortical structures, including the motor cortex. In this e-mail: [email protected] way, during multicenter perceptual and cognitive operations, reverberating claustro-cortical loops potentiate weak intracortical synchronizations by means of connected strong intraclaustral synchronizations. These may also occur without a salient stimulus. By this mechanism, the claustrum may play a strong role in the control of interactive processes in different parts of the brain, and in the control of voluntary behavior. These may include the neural correlates of consciousness. We also consider the role of GABAergic mechanisms and deafferentation plasticity.

Keywords: claustrum, binding, GABAergic interneurons, salience, consciousness, synchrony, oscillations

INTRODUCTION published evidence, based on experiments that employed injec- In 2005 Crick and Koch suggested that the claustrum might play tions of cholera toxin B (CTB), and biotinylated dextran amine a key role in information processing in the brain by correlat- tracers, application of antibodies to GABA and ing the separate activity in the different sensory cortices into one decarboxylase, and confocal and electron microscopy, that the coherent activity that “binds” separate sensations into the unitary two have reciprocal connections. They also noted that four times objects that we experience in consciousness. In a previous paper as many cells were labeled in the claustrum as compared to the (Smythies et al., 2012)weoutlinedanhypothesisastohowthis dorsal lateral geniculate nucleus following V1 CTB injections. “binding” process might be effected. This hypothesis, however, The auditory cortex may have somewhat different claustral proved to be unsatisfactory. The present paper presents a new connections than the visual and somatosensory cortices. Clarey hypothesis that includes not only an account of sensory binding and Irvine (1986) report than, in the cat, the input from the pri- but a number of other functions of the claustrum as well. mary auditory area to the claustrum is sparse and comes rather The claustrum is broadly divided into three compartments from higher auditory areas. Beneyto and Prieto (2001)studied [an anterior-dorsal connected with the somatosensory and motor the connections between the claustrum and the auditory cortex cortices, a posterior dorsal () and a ventral area by tracer injection methods. They report that all auditory areas (auditory cortex)] (LeVay and Sherk, 1981; Sherk and LeVay, have reciprocal connections with the ipsi- and contralateral claus- 1981; Sherk, 1986; Edelstein and Denaro, 2004; Crick and Koch, trum. They state, “These findings suggest that the intermediate 2005). The claustrum has reciprocal widely distributed anatom- region of the claustrum integrates inputs from all auditory cor- ical projections to almost all regions of the cortex, as well as tical areas, and then sends the result of such processing back to many subcortical structures. A recent high definition diffu- to every auditory cortical field.” By means of differential bidi- sion imaging study (Park et al., 2012) reports that the claustrum rectional tracer injection experiments in mouse somatosensory has connections with the frontal, premotor, ventral anterior cin- cortex Smith et al. (2012) failed to find any significant anatom- gulate, ventral temporal, visual, motor, somatosensory, olfactory ical projections from the primary somatosensory cortex S1 to cortices, and most strongly with the entorhinal cortex. It also the claustrum, whereas they detected dense projections from the has connections with some subcortical structures including the same part of the claustrum to both S1 and the motor cortex. , , and lateral . Until recently, They conclude that this shows that the claustrum, in rats, does however, the connections between the claustrum and V1 were the not function as an integrator of somesthetic and motor func- subject of some disagreement. Day-Brown et al. (2009)havenow tion. The experiments of Remedios et al. (2010), however, show

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 1 Smythies et al. Hypotheses relating to the function of the claustrum

that there is a rapid functional connection between the auditory (Churchland and Sejnowski, 1999), or non-linear dynamics system and the claustrum. Moreover, Zhang et al. (2001), using a (Freeman, 2011), or synchronized oscillations (Uhlhaas et al., similar technique, were able to demonstrate bidirectional connec- 2009). In this paper we will focus on the last. One task the tions between the claustrum, on the one hand, and both primary claustrum performs may be to provide the cortex with infor- and secondary visual, somatosensory, and auditory cortices on mation that allows the cortex to “bind” certain of its on-going the other. activities. In addition the claustrum may not involved solely in The claustrum has a well-marked retinotopically organized sensory “binding”, but it may also be concerned with synchrony map of the visual field, as well as an equivalent map of the detection and modulation in connection with salience processing somatosensory field (Olson and Graybiel, 1980; LeVay and Sherk, and a wide range of cognitive processes. 1981; Sherk and LeVay, 1981; Sherk, 1986). It has been claimed that areas of the claustrum in the cat sends “precisely recipro- OUR HYPOTHESIS cal” projections back to those area(s) of the cortex whence its Our basic hypothesis is that the claustrum functions as a syn- inputs derived (LeVay and Sherk, 1981; Sherk and LeVay, 1981; chrony detector, and modulator and integrator of synchronized Sherk, 1986). It has also been claimed that the projections to and oscillations (for background see König et al., 1996; Uhlhaas et al., from the claustrum are diffuse, but quite specific, in both direc- 2009). By “synchrony detector” we mean nothing more elabo- tions (one point to specific points) (Divac et al., 1978; Divac, rate than is implied in the application of two well established 1979; Sloniewski et al., 1986). Single cells in the claustrum have principles (1) that respond more robustly to synchro- been reported to send branched axons to several cortical areas. nized bursts then to random spikes, and (2) that neurons tend to Thesamecellsreceiveinputfromtheseareas(Rahman and reproduce in their efferent outputs the pattern of synchronization Baizer, 2007). However, there are marked species differences in contained in their afferent inputs. No elaborate timing devices, the anatomy of the claustrum and others claim that the cortico- such as those found in the aural mechanisms used to compute claustral projection is more diffuse. Crick and Koch summarize the location of auditory stimuli (Jeffress, 1948; Grothe, 2003), are their view of the situation thus, “Most regions of the cortex implied. send a projection to the claustrum, usually to many parts of it. When an incoming sensory volley reaches the brain, there Thus, their mappings are far from being a precise local mapping are two immediate tasks the brain must perform. The first and tend to be somewhat global (that is, all to all, though not (1) is to determine whether the information contained in the completely so).” volley matches the brain’s expectation of what that informa- The ventral claustrum is also connected to limbic structures, tion should be. The second (2) is to find out if the stimu- such as the amygdala, , and cingulate cortex. The claus- lus signals a state of affairs that is potentially threatening or trum also has a relatively uniform microanatomical structure that rewarding. The mechanism for (1) entails that, early in the would allow what Crick and Koch describe as “widespread intra- afferent inflow, the incoming down-up messages are matched claustral interactions.” These, they suggest, may be in the form against the up-down messages of what the brain expects the of waves of information involving dendrodendritic synapses and message to be. Grossberg and Versace (2008) have developed networks of gap junction linked neurons. They also suggest that a detailed model (SMART) that locates the matching site in a claustral neurons “could be especially sensitive to the timing of complex net that involves the LGN and midline non-specific the inputs.” But they do not suggest any precise mechanism to thalamic nuclei. In their model (hypothesis A) a match results perform these functions. Rahman and Baizer (2007) also suggest in increased synchrony in cerebral gamma oscillations that pro- that the claustrum mediates “integration across compartments motes spike-timing-dependent plasticity (STDP), and is related mediated by inhibitory interneurons (INNs).” On the afferent to the continued use by the brain of the software it is cur- side, previous reports stated that the majority (75%) of claus- rently using. If a mismatch occurs, the LGN activates the midline tral neurons are multisensory in that they respond to stimuli and intralaminar nuclei of the (MILN). This sets in in more than one sensory modality, whereas 25% are unimodal motion a process, which promotes beta synchronization, inhibits (Spector et al., 1969, 1970). The injection of three different STDP and generates modulation of software operations, such fluorescent tracers into the occipital, frontal, and cingulate cor- as giving “reset” and hypothesis testing instructions. They do tices results in double- and triple-labeled cells in the claustrum not, however, present experimental data that specifically supports (Li et al., 1986). In contrast, a recent investigation in awake pri- this hypothesis. Moreover, the hypothesis presents the follow- mates found that the great majority of claustral neurons are ing problem. To signal a mismatch the matching mechanism unimodal (Remedios et al., 2010). On the efferent side, using could either send continual matching signals that were inter- similar techniques Minciacchi et al. (1985)reportedthatsingle rupted when a mismatch occurred (hypothesis A): or it could claustral neurons project to both anterior and posterior cortex, remain quiescent until a mismatch occurred, and then send the some ipsilaterally and some contralaterally. This suggests that sin- signal (hypothesis B). The former is extravagant with comput- gle claustral cells project to more than one major cortical area. We ing time, whereas the latter is thrifty. Moreover, in human EEG will return to this point later. experiments, Kaiser (2003) reports that a bottom-up-driven audi- This paper considers what these “waves of information” might tory spatial “mismatch” detection elicits gamma-band activity be, and what type of timing-related, or other, computations and over the posterior parietal cortex, whereas an auditory pattern integrations they might perform. Neurocomputations may take “mismatch” report leads to gamma-band enhancements over various forms, for example, those based on fixed neural networks the anterior temporal and inferior frontal regions. For these

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 2 Smythies et al. Hypotheses relating to the function of the claustrum

reasons hypothesis B might be preferable in the present state of olfactory one (“smell of tiger”). These oscillatory activities may knowledge. then interact in the internal P cell/IN syncytium, and a derived So we will first examine the situation where the claustrum is signal is then sent to the motor cortex (“run for it”). We will involved with gamma synchronization in response to a mismatch return to the possible detailed operations of this system later. (hypothesis B). The matching site could be a retinotopically We will now look at the alternative hypothesis (A) suggested identified location in the LGN. In which case, on detecting a mis- by Grossberg and Versace (2008). In this gamma synchroniza- match, this would send a signal of axonal spikes, synchronized tion is associated with a “match” signal, and beta synchronization at a gamma frequency, to the equivalent retinotopic site on the with a “mismatch” signal. Two points seem relevant. The first is visual map in the claustrum. This relays it promptly to the appro- that the gamma signal may not just convey the signal “match,” priate part X of the visual cortex where it sets up a short-lived but it may also carry information about what has been matched, excitation. The claustrum (at least in the tree shrew) projects four in which case a null signal would not be sufficient. Secondly, in times as many fibers to V1 than does the LGN (Day-Brown et al., the Remedios et al. (2010) experiment, the stimulus was a “famil- 2009). With an ever-changing retinal input, such small groups iar jungle scene.” Therefore, the animal was expecting it, and the of synchronized cells in the cortex may continually form and signal recorded by the experiments might have been a “match” reform in competition. Their fate depends on the degree of sub- signal. To elicit a “mismatch” signal highly salient stimuli such sequent attention, recruitment and reinforcement dictated by the as the picture of a tiger and the roar of a tiger might be more nature and details of the stimuli and of the task being performed. appropriate. The “mismatch” signal from the claustrum may then potentiate In hypothesis (B), the mechanism of action of the claustrum activity in one such group at retinotopic location X. An unex- would be the same as in hypothesis (A), but the “software” would pected stimulus also activates the reticular activating system with be different. In hypothesis (A), gamma oscillations are involved its widespread projection to the cortex from the of in using default software, whereas, in hypothesis (B) they are Meynert (Smythies, 1997, 1999). This system has no map and so involved in testing and changing the software program. Thus, in cannot signal where X is located. The claustrum may supply this hypothesis (A), a “match” signal from the claustrum to the cor- information. The claustral efferent activity might locally augment tex potentiates synchronized oscillations in one of the competing the cholinergic activation at X. The oscillations of these acti- small groups of cells. In hypothesis (B), the “mismatch” signal vated neurons might be synchronized at the gamma frequency of does this. In both this process may recruit other groups. These the signal from the claustrum. This synchronization would then oscillations are then potentiated and integrated by intraclaus- be transmitted, via cortico-claustral loops, to the packed densely tral oscillations, leading to an executive signal. In contrast, the connected cell bodies (P cells and INs; see Figure 1)intheclaus- processes of testing and changing software in hypothesis (A) are trum. We may suppose that these are in continual state of interact- affected by beta oscillations. ing synchronized oscillations at various frequencies in dynamic However, the following reports on the role of attention and competition. In a natural environment salient stimuli rarely affect other factors in synchronization suggest that the actual mecha- only one sensory channel. So, when the signal from visual X (e.g., nism may be more complicated. “sight of tiger”) reaches the interior of the claustrum, it may be accompanied by an auditory signal (“roar of tiger”) and an 1. Attention to a stimulus enhances frequency synchrony in visual areas (Buffalo et al., 2011). In the gamma range (40–60 Hz) this is largely confined to the superficial layers, whereas the deep layers showed maximum coherence at low frequencies (6–16 Hz). In the superficial layers of V2 and V4, gamma synchrony was increased by attention, whereas in the deep layers, alpha synchrony was reduced by attention. This indicates different roles for the same synchrony in different locations. 2. Cardin et al. (2009) report that light-driven activation of fast-spiking interneurons at varied frequencies (8–200 Hz) selectively amplifies gamma oscillations. In contrast, such stimulation of pyramidal neurons amplifies only lower fre- quency oscillations. They reported that the timing of a sen- sory input relative to a gamma cycle determines both the amplitude and the precision of evoked responses. Thus specificity for gamma oscillations may be dependent on the type of involved. 3. Chalk et al. (2010) measured the local field potential (LFP) FIGURE 1 | A diagram of the suggested relation between the cortex and V1 spiking activity in monkeys during an attention- and the claustrum. Oscillations between two distant cortical areas are demanding detection task. They reported that, if attention synchronized by long corticocortical projections. This synchronization is was directed at a visual stimulus in the receptive field of the augmented and developed by intraclaustral connections. recorded neurons, decreased LFP gamma power and gamma

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 3 Smythies et al. Hypotheses relating to the function of the claustrum

synchrony resulted. The authors suggested that this decrease effects. The former synchronize with fast gamma oscillations could be the result of an attention-mediated reduction of in the medial entorhinal cortex (an area that provides infor- surround inhibition. They further suggested that modula- mation about the animal’s current position) whereas the tion of synchrony in V1 could be a byproduct of reduced latter synchronize with slow gamma oscillations in the CA3 inhibitory drive, rather than a mechanism that directly area of the (an area necessary for memory involved perceptual processing. storage of such information). This report suggests a different mechanism altogether for 12. Fujioka et al. (2009) studied beta and gamma band activi- gamma oscillations. ties in the auditory cortex of humans during musical beat Thenextninereportsaddyetmorecomplexity. processing. The beta reaction peaked after each tone but 4. Dockstader et al. (2009) used time-frequency analyses showed no response after an omission. The gamma response, of human somatosensory oscillations with neuromagnetic in contrast, peaked after both tones and omissions. This recordings during stimulation of the median nerve in healthy suggests that the beta response, in auditory cortex under adults. They reported that selective attention modulated these circumstances does not signal “mismatch”; and that somatosensory oscillations in the alpha, beta, and gamma the gamma response is related to anticipation rather than a bands. These were either phase-locked or non-phase-locked “match” signal. to the stimulus. In the primary somatosensory cortex, if the subject’s attention was toward the somatosensory stimulus, In view of the many unanswered questions these reports raise, we this resulted in increased gamma band power (30–55 Hz) will confine our hypothesis to limited terms with respect to the that was phase-locked to stimulus onset. Such attention also functions and frequencies of the synchronizations involved. The produced an initial desynchronization, followed by increased claustrum may be involved in detecting, integrating, promoting, synchronization, in the beta range, that was not phase-locked and directing synchronized oscillations in a wide range of fre- to the stimulus. quencies and in a number of functional categories. The details 5. Tallon-Baudry (2009) suggests that “... gamma oscillations await further experimental investigations. are not related to a single cognitive function, and are prob- Claustral activation may not occur only in response to mis- ably better understood in terms of a population mechanism match signals. Take, for example, a condition where the subject taking advantage of the neuron’s fine temporal tuning: the is engaged in a complex task that involves coordination between 10–30 ms time precision imposed by gamma-band rhythms sight and touch. Frequent activations of selected visual and tactual could favor the selective transmission of synchronized infor- cortical neurons will result. On the principle that cells that work mation (attention) and foster synaptic plasticity (memory).” together oscillate together, the activated cells will start to synchro- 6. Palva and Palva (2007) propose that simultaneous alpha-, nize their oscillations. Both sets of cells will spontaneously start beta- (14–30 Hz) and gamma- (30–70 Hz) frequency band synchronized oscillations and will generate axon spikes that will oscillations are necessary for unified cognitive operations that have a timing determined by these oscillations. Each will initially mediate, the selection and maintenance of neuronal object oscillate at its own preferred frequency. This concomitant activ- representations during working memory, perception, and ity might tend to bind their frequencies of oscillation, and spike consciousness. timing patterns, into line. These cortical neurons project to the 7. In human EEG studies Haenschel et al. (2000)reportedthat claustrum via specific layer 6 pyramidal cells. The axons of these evoked (stimulus-locked) gamma oscillations preceded beta layer 6 cells synapse on the cell bodies and dendrites of claustral 1 oscillations in response to novel stimuli. pyramidal cells and will induce in them oscillations at the same 8. In 10 patients who underwent intracranial electrocorticog- frequency. raphy, somatosensory-related gamma augmentation involv- Evidence that this could occur is based on the following ing the post- and pre-central gyri evolved into beta and reports. Axons can carry multiple codes in the spatio-temporal alpha augmentation. This was later followed by beta and patterns of their spike trains (Kayser et al., 2009; Uhlhaas et al., alpha attenuation that involved the post- and pre-central gyri 2009). Codes based on temporal spike-train patterns and spa- (Fukuda et al., 2010). tial populations can nest additional information (codes) based 9. The prediction of a forthcoming stimulus by a warning cue on the relative phase of slow ongoing rhythms at which these stimulus was associated with an increase in gamma oscilla- (temporal or population) responses occur. Information carried by tions overlying occipital areas and a decrease in beta oscilla- spike trains can cross synapses and transmit to the post-synaptic tions overlying sensorimotor cortex before the stimulus was neuron. Kumar et al. (2010) state, “The brain is a highly modu- presented (Kilner et al., 2005). lar structure. To exploit modularity, it is necessary that spiking 10. Gregoriou et al. (2009) suggest that long-range excitatory activity can propagate from one module to another while pre- connections onto interneurons determine whether differ- serving the information it carries.” Masuda and Aihara (2002) ent pyramidal cell “assemblies” can synchronize at gamma put it thus, “If a real brain uses spike timing as a means of infor- frequencies, whereas excitatory connections onto pyramidal mation processing, other neurons receiving spatiotemporal spikes cells determine whether such assemblies can synchronize at from such sensory neurons must also be capable of treating infor- beta frequencies. mation included in deterministic interspike intervals.” Asai et al. 11. Colgin et al. (2009) report that fast and slow gamma syn- (2008) found that cortical regular-spiking neurons can propa- chronizations in the hippocampus CA1 area have differential gate filtered temporal information in a reliable way through the

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 4 Smythies et al. Hypotheses relating to the function of the claustrum

thalamo-cortical network, and with high temporal accuracy. This initial signal only switches on the cortico-claustral mechanism evidence supports the concept that a synchronized afferent input that does, if circumstances are favorable, effect “binding.” to the claustral cells can cause them to fire at the same frequency There is considerable debate on whether the projections of the and allow them to form reverberating cortico-claustral-cortico cortex onto claustral neurons are point-to-point or diffuse. There loops. are also considerable interspecies differences in the anatomy of The layer 6 cells in the cortex in the two groups (hearing and this system. In the cat this projection is described as “precisely vision) are far apart, and are directly connected only by cor- reciprocal” (Sherk, 1986).Littleisknownaboutthisanatomy ticocortical axons. The claustral cell bodies connected to them in the primate: there are indications that this projection may be are close together and are connected to each other by short more diffuse (Sherk, 1986). However, in this context, it is impor- axon collaterals. They are also embedded in a GABAergic syn- tant to note that the only requirement of our hypothesis is that cytium and are linked to each other via the GABAergic gap the activated claustral P cells should receive their input from junction-linked syncytium. This allows very fast communica- the cortex via local groups of neurons. This ensures that there tion. It may allow rapid movements of electrolytes and current is no ambiguity when they fire. Their efferent targets could be between them. Electrical synapses between interneurons have back to these neurons by direct return axons, or to other cortical been reported to contribute to synchronized firing and network neurons by branched axons. The projections of groups of sin- oscillations in the brain (Vervaeke et al., 2010). In the bushy gle cortical neurons to the claustrum may follow a bell-shaped cells of the cochlear nucleus Chanda and Xu-Friedman (2010) curve. That is, there are more connections with the closest claus- have shown that the activation of GABAergic receptors adjust tral neurons, and less with more distal ones: the more distant the function of these cells by suppressing the relaying of indi- the fewer the connections. Then the projection as a whole will vidual inputs and requiring the coincident activity of multiple consist of a series of partly reciprocal return projections with a inputs. Activation of such GABAergic systems strongly promotes degree of overlap. Each small group of claustral neurons may gamma synchronization. So co-temporal activity in the auditory project back to the small group of cortical neurons that gave and visual cortex, in this case, may result in a common frequency rise to the axons that connect the two groups in the statistical of oscillation throughout this simple net under the influence of manner just described. More widespread distribution of claustral possibly weak cortico-cortical interactions but strong intraclaus- impulses may also be mediated by the intraclaustral integrative tral interactions. This particular link up may persist while this system of multiple interacting synchronized oscillations that we particular audio-visual task is being conducted. When the task is have described. completed, the conjoined activity in the cortico-claustro-cortical system would die down, and will be replaced when a new task FURTHER DATA ON THE ROLE OF THE CLAUSTRUM IN is undertaken, when the whole process will be repeated again SYNCHRONIZED OSCILLATIONS elsewhere. In a magnetoencephalographic study, Emrich et al. (2006)exam- Thus, this model allows the claustrum to promote synchro- ined the effect on synchronous oscillations in the brain associated nized intermodal gamma oscillations in widely separated parts with object perception (shape-from-motion) in six normal vol- of the cortex. In our previous hypothesis (Smythies et al., 2012) unteers. The stimulus was a computer generated “object” seen it was thought that to do this the claustrum needed direct against background noise. Each lasted for 4 s. During the MOVE inputs to individual claustral cells from axons derived from the epoch, the object and background moved in counter phase, fol- two disparate cortices. The data recently obtained by Remedios lowed by one of two stationary epochs. In the first—STOP—the et al. (2010) suggest that these direct connections do not exist. motion stopped, and the object remained in the display along However, in our present model, such direct connections are not with the stationary background noise. In the second—VANISH— necessary, because the majority of the “binding” is done inside the motion stopped and the object was removed from the display, the claustrum. Furthermore, no complex spike codes are involved leaving only the stationary background noise. During the MOVE as in the previous model (Smythies et al., 2012). In non-sensory epoch synchronized gamma oscillations (35–45) appeared in “higher” cognitive processing operations, that require interac- the right insula, right claustrum, right superior temporal gyrus tion between any higher cortical areas, the same mechanism (RSTG), and right parahippocampal gyrus (RHG). During the may be involved. Weak cortico-cortical promotion of a common STOP epoch the gamma synchronization remained but changed oscillation frequency is promoted by a strong intraclaustral pro- to a higher frequency (55–72 Hz). The authors propose that claus- motion. The P cells in the claustrum, embedded in a GABAergic tral activity during the MOVE epoch may be related to conscious syncytium, may generate a complex, fluctuating, competitive, awareness of the object, and/or motion cues, and/or memory pro- and dynamic domain of shared and disparate oscillations. This cesses: and that claustral activity during the STOP epoch might is modulated by the ever-changing pattern of afferent spikes be related to awareness of the object only (since the object is not from the cortex, as well as by chemical neuromodulators such moving). as dopamine and input from subcortical structures. For exam- However, it could be objected that the absence of movement ple, positive reward leads to a widespread release of dopamine of a previously moving object carries information just as much as in the brain. Dopamine promotes gamma synchrony. Remedios the presence of movement does, and both are recorded in mem- et al. (2010) suggest that the short, sharp initial claustral signal ory processes. Therefore, this experiment may actually be relevant from the sense organ to the cortex involves salience and does not to the binding of form and movement, rather than, or in addition involve “binding.” We suggest the hypothesis that this short, sharp to, the “conscious awareness” of an object. Furthermore, in their

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 5 Smythies et al. Hypotheses relating to the function of the claustrum

analysis, the action of the claustrum during the MOVE epoch The involvement of the claustrum in perception may involve involves binding of form and movement, but, during the STOP other processes besides, or even instead of, “binding.” The three epoch, there is no binding, since the only input to the claustrum, different visual parameters—color, shape, and movement—are in their analysis, involves form only. initially processed by separate cortical mechanisms. Feed-forward Using an fMRI technique (that provides evidence of activation over-lapping projections from these areas to the higher visual but not synchronization) Kavounoudias et al. (2008)demon- cortex synapse on single neurons. These can thus react to stim- strated that, in the case of integrating intramodal proprioceptive uli from all three lower centers. One neuron may receive inputs and tactile information, which resulted in kinesthetic illusions of from say a lower “red” reactive cell, a “round” receptive cell, and a a clockwise rotation of the right hand, activation of the supe- “moving to the left” sensitive cell. So it has the necessary informa- rior temporal gyrus, the inferior parietal lobe and the claustrum tion for “binding” this input into “a red, round object is moving resulted. They suggest that this involved detection of spatial left.” However, these cells have progressively wider receptive fields coherence by the inferior parietal lobule and detection of tem- the higher in the cortex one goes. Thus these nets may possess poral coincidence by the insula structure “usually linked to the the necessary information for binding, but they have poor, or relative synchrony of different stimuli.” In an fMRI investigation no, information as to where in the visual field these bindings are of color synesthesia activation of the color area V4 resulted (Nunn located. Perhaps this information is supplied by the claustrum, et al., 2002). whose projection to the visual cortex is retinotopically ordered. So How does our hypothesis explain these findings? Firstly we perhaps the claustral projections to layer IV neurons in the higher can note that Emrich et al. (2006) found that the effect they visual cortex might provide a type of retinotopically ordered report does not involve the whole cortex, but only the RSTG “template” to which the multidomain cells in the higher visual and the RHG. This suggests that these two loci have a special cortex can “refer” in some way. This “referral” might be medi- importance for object recognition of the type examined in this ated in some way by interaction of some sort between the binding experiment. The STG contains both auditory and polysensory information carried by each system. The claustral input to the areas (Cappe and Barone, 2005; Smiley and Falchier, 2009). In cortex will reactivate the neurons that started the cycle, so the particular, it contains visual neurons sensitive to both form and re-entry cycle will continue. These cycles may form the NCCs of the direction of movement (Oram and Perrett, 1996)andpro- consciousness and presumably activate the decision-making cen- jections to the frontal eye fields (Scalaidhe et al., 1997). The ters in the brain so that the appropriate behavior results. We will RHG contains a higher visual area that processes topographic take up this matter again later. scenes. The insula has multiple involvements in interoceptive awareness, emotions, and salience. We suggest that the claus- THE RELEVANCE OF INFORMATION FROM CORTICAL trum is involved in tying this inter-center activity together by DEAFFERENTATION EXPERIMENTS synchronizing the oscillations in their respective neuronal pop- Itusedtobethoughtthattheneuralcorrelateofaconscious ulations. event was activity in a neuron in a specific place in the brain. For Cappe et al. (2012) have suggested a similar mechanism example, in the case of vision the place was some location in the whereby the thalamus, rather than the claustrum acted an inte- defined optic cortex. We now know that the modality of a given grator of synchronized oscillations. They say, “Some restricted sensory neuron is determined, not by where it is, but where its thalamic territories send divergent projections to cortical areas afferent neurons originate. For example, in experiments in blind and thus could afford different sensory and/or motor inputs subjects skilled in Braille, Ptito et al. (2008) showed that mag- which can be mixed simultaneously. This could support a tem- netic transcranial stimulation of neurons in the optic cortex can poral coincidence mechanism as a synchronizer between remote result in a somatosensory, and not a visual, experience in these cortical areas, allowing a higher perceptual saliency of multimodal subjects. In these cases, neurons in somatosensory cortex take stimuli.” over the deafferented “visual” cells, and the latter start to process somatic information instead. This activity results in somatosen- CLINICAL EVIDENCE FOR BINDING sory sensations in consciousness (sensations that the fingers are We know from the work of Schilder and others (Schilder, 1942) being touched) instead of the normal visual sensations. These on the manner in which sight returns following injury to the authors conclude “Our data show that the qualitative character occipital lobe, that the visual field in consciousness is constructed of the subject’s experience is not determined by the area of cortex by a tripartite mechanism. After such an injury, the first aspect of that is active (cortical dominance), but by the source of input to sight to recover is movement perception. In this the subject sees it (cortical deference).” pure motion, usually rotary, without any shape or color. Then At a functional level a deafferented cortex (e.g., the visual “space” or “film” colors appear floating about in visual space cortex in the blind) can take over functions of another sensory unattached to any objects. Next, the subjects starts seeing parts modality (e.g., hearing) in a number of ways, as reported by of objects, say the handle of a teacup. Lastly these parts join up Lomber et al. (2010), and Heron et al. (2012). If the sensory inflow to form complete objects into which the space colors enter. So of one system is diverted to the cortex of another system (e.g., reti- activity in the visual field in consciousness can be driven solely nal axons to the auditory thalamus) shortly after birth, this can by one of these parameters. Their binding into one complete col- result in profound changes on different components of cortical ored, moving object comes later as the cortical areas concerned circuitry, both at the anatomical and functional levels (Roe et al., recover from the injury. 1992; Gao and Pallas, 1999; Pallas et al., 1999; Sharma et al., 2000;

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 6 Smythies et al. Hypotheses relating to the function of the claustrum

Linden and Schreiner, 2003; Chowdhury and DeAngelis, 2008). listed above in the postsynaptic neuron by a similar mechanism. These changes must be a function of some signaling system in the Alternatively, or additionally, these changes could be induced afferent axons. The nature of this system is not currently known. by second messenger signaling systems unique to each sensory The efferent outflow to the claustrum from that part of the modality. deafferented visual cortex, that now performs somatosensory pro- cessing (as in the case of the blind subjects skilled in Braille), must TWO BINDING SYSTEMS? enter the claustrum via its medial optic compartment. Here, in We now know that, not only higher cortex, but also probably most spite of being in the “optic” pathway, it is “recognized,” by the of the primary sensory cortex, is polysensory (Falchier et al., 2002; claustrum as carrying, in this case, somatosensory information. Rockland and Ojima, 2003; Clavagnier et al., 2004; Budinger et al., How could the claustrum do this? There seem to be two possible 2006; Driver and Noesselt, 2008; Ptito et al., 2008; Collignon answers. The first answer is that the claustrum has a mechanism et al., 2009). Ghazanfar and Schroeder (2006) conclude that, “The to recognize the unknown modular specific code carried by the nature of most, possibly all, of the forces us to abandon afferent axon. The second answer is simpler. The claustral effer- the notion that the senses ever operate independently during real- ents, or at least some of them, return to the same neuron (or world cognition.” Thus, the computations necessary for binding neuronal group) that gave rise to the afferent axon. This neu- mightbealldone“inhouse”withinthecortex,inwhichcasewe ron (or group) is now processing somatosensory information and need to explain the need for a second claustral binding mecha- belongs to the somatosensory system. So the sensation in con- nism. To approach this question we will first consider the visual sciousness that results from this neural cortico-claustral cycling system. There is evidence that the claustrum may have two differ- will be a touch on the face, and not a visual sensation. We men- ent operative visual systems. The “lower” visual cortex (LVC) (i.e., tioned earlier that our hypothesis requires only that the efferent those areas that receive direct projections from the lateral genic- outflow from a claustral P cell (or a small group of functionally ulate body) connects with the dorso-lateral claustrum, whereas related P cells) should project in part to the cortical neurons that those “higher” visual areas that lack a direct input from the lat- activated those claustral cells. This is clearly what is happening in eral geniculate body connect with the ventral claustrum (Sherk, the case of the blind subjects skilled in Braille. 1986). These “higher” visual areas include areas 20a, 21a, 21b, We will now return to the question of how the claustrum and the PMLS and PLLS areas of the suprasylvian gyrus, as well and the cortex might exchange information. How is this signal- as the precuneus (area 7)—a multisensory area with visual and ing organized and what information might these signals carry? somatosensory inputs. Moreover, the precuneus itself has a topo- We have suggested that binding is effected mainly by intraclaus- graphically organized visual field map, as does its projection to tral synchrony alignments. The data from cortical deafferentation the claustrum. Therefore the claustrum appears to have two visual experiments that we have presented suggests other factors that field maps, one connected to the LVC and the other to some need to be considered. We brought forward evidence to show parts of the “higher” visual cortex (HVC) (Sherk, 1986). It is pos- that the modality of a neuron is determined by the modality sible that circuits between “unbound” unisensory LVC and the of its afferent axon. The most likely vehicle that could carry claustrum may have a different function than circuits connect- such a modality code is the spatio-temporal pattern of spikes ing “bound” polysensory HVC and the claustrum. The former in the afferent axon. The only study in this area that we have may have more to do with “binding,” and the latter with pro- been able to find reports differences in the character of the viding the information where particular objects are located. In spike trains in three different cortical areas “... neuronal spik- polysensory cortex the “binding” would be performed by multi- ing patterns are regular in motor areas, random in the visual modal feed-forward nerve nets. In the LVC (neurons with small areas, and bursts in the prefrontal area” (Shinomoto et al., 2009). receptive fields) the sensory data is unbound, whereas in the mul- However, these modality codes would primarily affect the syn- tisensory HVC (neurons with large receptive fields) the sensory chronypatternintheirowndomains.Itmightnotaffectthe data is already bound intracortically by multiple crossing feed- fact that these individual synchrony bind into one overall pat- forward connections. So the cortico-claustral circuits in the LVC tern. Further data in this area is urgently required. In particular may co-operate in the binding, whereas, in the HVC case, they information is needed if a claustral P cell responds to only may be more concerned with providing information as to the spa- one visual submode (e.g., color), or whether an individual cell tial location of the stimuli as described earlier. In general, these responds to any visual submode (i.e., color, shape, and move- same considerations may apply to the difference between primary ment). The mechanism by which modal and sub-modal codes “unbound” “lower” sensory cortex and “higher” bound sensory produce the reported major effects in the post-synaptic neurons cortex. that they impinge on is currently unknown. However, it may be noteworthy that electrical fields produced by the synchronized THE ROLE OF GABAergic INTERNEURONS oscillation of microtubules play a role in morphogenesis dur- Our hypothesis suggests that the key to the action of the ing mitosis and meiosis (Kuceraˇ and Havelka, 2012; Zhao and claustrum lies in its densely packed and tightly interconnected Zhan, 2012). This involves alterations in the cell’s microstructure. neurons—pyramidal cells and GABAergic INs. The former cite “in the press” reports of resonant interactions In the cortex and the lateral geniculate nucleus GABAergic of microtubules with external oscillating electric fields. Therefore interneurons have been found to form extensive polysynaptic it is possible that the electrical fields produced by synchronized bidirectional networks linked by electrical junctions (Fukuda oscillations in afferent nerves might induce the structural changes et al., 2006). These authors suggest that these networks support

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 7 Smythies et al. Hypotheses relating to the function of the claustrum

“...the precise synchronization of neuronal populations with dif- connectivity patterns.” It has yet to be determined if this applies fering feature preferences thereby providing a temporal frame for to the claustrum. the generation of distributed representations.” Such gap junction The cortico-claustral-cortico system may be an example of a linked networks can either promote network synchronization, strong feed forward inhibitory circuit (FFI) (Bruno, 2011). An or trigger rapid network desynchronization, depending on the FFI is composed of a group of pre-synaptic neurons that directly synaptic input (Vervaeke et al., 2010). This network may promote excite both glutamatergic excitatory (P cells) and GABAergic complex oscillatory interactions of the whole system. INNs, and provide greater synaptic input to the latter. The post- The GABAergic system is also complicated by the presence synaptic neurons are interconnected. Circuits that lack inhibition of a number of different types of GABAergic cell. Rahman simply relay pre-synaptic activity to post-synaptic neurons. In and Baizer (2007) analyzed the patterns of immunoreactivity to contrast, post-synaptic neurons in an FFI are highly sensitive calcium-binding proteins, GAD, serotonin, nNOS, and the glu- to the relative timing of action potentials, and this the syn- tamate transporter EAAC1 in the cat claustrum. They found chrony, transmitted by the pre-synaptic neurons (Bruno, 2011). multiple neurochemically defined cell types, suggesting multi- Neuromodulators and feedback connections may modulate the ple classes of projection neurons and interneurons. Each class temporal sensitivity of such circuits and gate the propagation of was found throughout the entire claustrum, in all functionally synchrony into other layers and cortical areas. The prevalence of defined subdivisions. Kowianski et al. (2009) report the follow- strong FFI throughout the central nervous system suggests that ing co-localizations of neuropeptides in the interneurons of the synchrony codes and timing-sensitive circuits may be widespread, claustrum in rat brain: occurring well beyond sensory thalamus and cortex (Bruno, 2011).However,theevidenceiscurrentlylackingastowhether • cortico-claustral axons provide the needed greater synaptic input neuropeptide Y with calbindin D28k, calretinin, or parvalbu- to the inhibitory neurons than to the excitatory neurons needed min for a strong FFI system. • somatostatin with calbindin D28k • vasoactive intestinal polypeptide with calretinin KAPPA OPIOID RECEPTORS An interesting clue may be provided by recent findings con- A further subdivision of GABAergic interneurons into five cerning the psychoactive drug salvinorin A. This is a specific types (in the lateral amygdala) using electronic and electroge- agonist at kappa opioid receptors. Psychologically it induces an netic parameters has been described by Sosulina et al. (2010). intense sensory synesthesia in which subjects claim that they If the same, or similar, subdivisions are found in the claus- see sounds and hear sights (Babu et al., 2008;andseeHubbard trum, this might offer scope for further neurocomputational and Ramachandran, 2005 and Baron-Cohen, 2008). This may be mechanisms. This detailed arrangement suggested to Rahman interpreted as an inhibition of sensory binding. In our present and Baizer (2007) that many claustral neurons make extensive context it is interesting that activation of the kappa opioid recep- inter cell type and intraclaustral connections. These connections tor has been shown to inhibit the release of GABA in the bed between the GABAergic network and the INs in the CDNN may nucleus of the by a pre-synaptic mechanism (Li serve to allow many modulatory functions as to the fine tuning et al., 2012a). If the same holds in the claustrum, this would of the CDNN by neuromodulators, such as and provide direct evidence that the GABAergic system in the claus- others (Doucette et al., 2001). trum may be related to sensory binding. The claustrum contains In a combined light- and electron-microscopic study Hinova- particularly high levels of mRNA for the kappa receptor (Meng Palova et al. (2007) showed that the calcium-binding protein et al., 1993; Mansour et al., 1994). The binding of kappa-1 parvalbumin is distributed widely and evenly across the cat’s opioid-stimulated [35S] GTPgammaS (a marker of the kappa opi- claustrum. It occurred in dendritic spines and both spiny and oid receptor) is also particularly high in the ventral claustrum aspiny dendrites. It was also found in boutons at both excitatory (Sim-Selley et al., 1999). (asymmetric) and inhibitory (symmetric) synapses. The authors noted the lack of intrinsic, and possibly functional, heterogene- THE RELEVANCE OF ILLUSORY CONJUNCTIONS AND ity, as evidenced by the uniform distribution of PV throughout ATTENTION the cat claustrum. This suggested that the influence of the claus- Attention plays a prominent role in binding. Vohn et al. (2007) trum on diverse multisensory mechanisms may have more to do have shown that the right claustrum is involved both in within- with its afferent than efferent relationships. It also indicated its modal and cross-modal (auditory and visual) divided attention importance in the sensory hierarchy. performance as part of a circuit that includes the prefrontal cor- In mouse frontal cortex Fino and Yuste (2011)report tex and the inferior parietal cortex. Also relevant to the binding dense connectivity of GABAergic somatostatin-positive INs. They problem is the question of “illusory conjunctions” (Treisman and found that every IN was connected to every pyramidal cell within Schmidt, 1982; Crick and Koch, 2003). If separate features of the range of its axonal tree. They say, “In fact, the complete con- an object (e.g., “red square”/“moving left”) are processed in dif- nectivity that we observe appears in some cases deterministic, ferent brain areas (i.e., the color area V4 and the motion area as if the circuit has been built to ensure that every interneu- MT), which results in the loss of their topographic location label, ron is connected to every single local PC cell ... in this way and if two objects are simultaneously presented—e.g., a red one neighboring neurons would have overlapping but not identical moving left and a green one moving right, then how does the

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 8 Smythies et al. Hypotheses relating to the function of the claustrum

brain compute which color goes with which motion? One pos- patterns, have shown this phenomenon, where the perception of sibility is that Crick’s “searchlight” of attention is directed toward an improbable input is suppressed by the brain, and replaced with different portions of the visual scene at an early stage of pro- the perception of what it computes to be a more probable one (see cessing when topographical information is still present (e.g., area Ramachandran and Anstis, 1983). 17 of the primary visual cortex, or the claustrum). If the spot- light permits “red” and “left” to go through, then they will be THE ROLE OF THE CLAUSTRUM IN COGNITIVE PROCESSING bound. This explains why, if a red triangle and green square are So far we have focused upon the original Crick-Koch hypothesis briefly presented and masked, subjects see illusory conjunctions that is based on the idea that the claustrum is involved in binding in 50% of trials. This is because there has been enough time features of the sensory stimulus. We have suggested that a spike to process the features separately, but not enough time for (in burst synchrony detecting, modulating, and transmitting mech- our scheme) claustro-striate iterations to ensure correct binding anism may be involved. However, it is clear that the claustrum through attention. Crick and Treisman suggested that that the is involved in many other processes besides sensory binding. The nucleus reticularis thalami is involved. We would argue, from the claustrum has bidirectional connections with non-sensory limbic, current evidence, that ascending brainstem efferents to the claus- temporal, and frontal cortices, as much as with the sensory-motor trum interacting iteratively with topographically organized area cortex. The claustrum also has a massive input from all the major 17 may constitute the searchlight (see also Smythies, 1997). neuromodulator circuits (Lackovic´ et al., 1990; Meador-Woodruff Some difference in the motor and sensory functions of the et al., 1991; Sutoo et al., 1994; Baizer, 2001; Edelstein and Denaro, claustrum may be suggested by the observations that the claustral 2004; Gill et al., 2006; Eggan and Lewis, 2007; Das, 2010). The neurons projecting to the contralateral motor cortex are predom- ventral claustrum has extensive connections with limbic areas inantly pyramidal in shape, whereas the predominant claustral such as the anterior cingulate gyrus, amygdala, hippocampus, neurons projecting to the somatosensory, visual, and auditory and others. Why would this information, relating largely to emo- cortices are mainly oval on shape (Sadowski et al., 1997). tions, reinforcement, and motivation, be required by a system Naghavi et al. (2007) have reported that, whereas the claus- concerned with sensory binding? One answer might be that the tum/insula area (CIA) was activated by attentionally-focused claustrum is composed of synchrony modulators involved in congruent stimuli (e.g., sight of a cat’s face and hearing a meow) binding between limbic operations (emotions, etc.) and the sen- it failed to be activated by attentionally-focused non-congruent sory and motor systems. The dorsal claustrum has connections stimuli from the same location in external space e.g., the visual mainly with sensory and motor cortices, the ventral claustrum stimulus of a cat’s face with the contemporaneous auditory stim- has connections mainly with limbic cortex and subcortical struc- ulus of a dog’s bark. They suggest that this indicates that the tures, and the rostral claustrum mainly with frontal cortex (LeVay CIA must be involved in the “analysis of the content of stim- and Sherk, 1981; Sherk and LeVay, 1981; Sherk, 1986). The ante- uli.” However, it must be noted that the CIA did not react at rior dorsal, posterior dorsal, and part of the ventral subdivisions all to the cat’s face/dog’s bark. So it can hardly be said to have could be concerned with sensory-motor binding in the manner extracted the information “cat” from its visual input, and “dog” we described earlier. The anterior and another part of the ventral from its auditory input, compared the two, computed that they subdivisions could be concerned with reinforcement and other are incongruent and rejected them from its binding operation. limbic functions. Thus, the claustrum could cooperate with the Furthermore, we suggest that the CIA simply does not have the sensory cortex for sensory binding, with the limbic system for computational capacity to decipher all the immense flow of infor- emotional coordination to allow modulation of behavior by com- mation that passes through it. The decision that “cat” and “bark” plex patterns of reinforcement, and with the decision-making do not go together must have been made in the higher cortex mechanisms in the to coordinate “higher brain” before it activates the CIA. functions (in response in each case to specific inputs from these So we would suggest is that the CIA does not react in this different loci). experiment to “cat/bark” and “dog/meow” because these improb- Our hypothesis suggests that, in these cognitive and limbic able signals have been suppressed upstream. This would be an processes, the role of the claustrum may be put as follows. The example of the same sort of mechanism that operates in the exper- claustrum may become activated whenever a computational pro- iment reported by Kovács et al. (1996). In this experiment they cess involves more than one brain area. If two such areas are took two photographs, one of a monkey’s face and the second of involved, for example, the synchronized activities in each are a leafy tropical jungle. They converted these into two pastiches coordinated by the claustrum in the manner we have described— each composed of portions of each photo, so that in the loca- scattered weak intercortical synchronizations are potentiated and tion where one photo showed part of the monkey’s face the other processed by strong intraclaustral synchronizations. We can call showed leafy jungle. Then each pastiche was shown separately this “cognitive binding.” to each retina, so that retinal rivalry occurred. Under these cir- Recent research suggests what some of these “higher brain cumstances, the subject did not see what was actually there—that functions” may be. Volz et al. (2010) carried out fMRI stud- is the two pastiches alternating—but rather a complete monkey ies of retrieval fluency in normal subjects. This is defined as face alternating with a complete leafy jungle. Clearly the brain how long it takes to retrieve a trace from long-term memory. had suppressed the improbable mixed pastiche in favor of what Ifoneoftwoobjectsisretrievedmorequicklythisindicates it was familiar with (and thus computed to be more probable). that that one has a higher value than the other. This measure Many other experiments, based on stimuli such as moving plaid was accompanied by another that assessed the emotional feeling

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 9 Smythies et al. Hypotheses relating to the function of the claustrum

in the subject of the “rightness” of that memory (a feeling- act as a salience detector. They note that inputs from the early of-knowing judgment). The authors suggest that a number of cortices and/or thalamic nuclei are rapidly fed to the claustrum, brain processes could contribute to these measures including and are rapidly directed from there widespread to the higher “... theeasewithwhichsuchmemoriesareboundtogether.” cortex. Their results were that these procedures were associated with We agree with the hypothesis that one function of the claus- activation of the dorsal claustrum, but not the ventromedial pre- trum may be saliency detection. However, as we have seen, it is frontal cortex. The authors suggest that their findings indicate not necessary for Crick and Koch type binding that each claus- that the claustrum may also bind semantic and emotional infor- tral cell should to receive axons from both cortical areas whose mation in addition to sensory information. Tian et al. (2011) functions are to be bound. This binding may be effected inside have investigated another possible function in which the claus- the claustrum in the manner we have suggested. Also, even if the trum may play a role—the mental preparation of successful input to claustral cells is unimodal, the output axons from claus- insight problem solving (that is the “Aha” experience as exem- tral P cells commonly bifurcate and project to more than one plified by Archimedes). Using fMRI they showed that successful modal type of cortex (Divac et al., 1978; Divac, 1979; Sloniewski preparation coding was associated with activation of a circuit et al., 1986; Rahman and Baizer, 2007). The experiments reported that included the parts of the frontal and temporal cortices, the by Remedios et al. (2010) only produce strong evidence that the cerebellum and the bilateral claustrum. Our postulated claustral input to individual claustral P cells in not intermodal. However, synchrony detection and augmenting mechanism may be plugged this evidence is not relevant to the possibility of intraclaustral into a number of different neural circuits engaged in different binding operations, nor to the question of whether the output of distributed computations. The claustrum is also engaged in the single claustral P cells projects to more than one cortical modality. rapid interhemispheric dissemination of information needed for Moreover, in support of the saliency hypothesis, spike-timing the bilateral coordination of movement regulation (Smith and (synchrony) codes may carry information in addition to that Alloway, 2010). The mechanism we propose might effect this by relating to the properties of the stimulus. Doucette et al. (2001) “binding” information from two inputs, one from each ipsilateral suggest another account of what information synchronized spikes motor system. may be carrying. This leads to a wider concept of what the The mechanism described in our hypothesis may underlie the function of the postulated spike burst synchrony detection mech- proposed mechanisms of timing and time perception that rely anism of the claustrum might be. Doucette et al. (2001)studied on “beat-frequency” patterns generated by cortical oscillations spike-timing codes in the olfactory system and came up with a (see Matell and Meck, 2004; Buhusi and Meck, 2005; Allman and challenging result. They report that the number of synchronous Meck, 2012). spikes (SS) fired by pairs of olfactory bulbar neurons signals, not stimulus properties, but the salient information of whether THE SALIENCY DETECTION HYPOTHESIS the odor is associated with reward or not. The SS fall below the Remedios et al. (2010) have suggested that the function of the spontaneous activity level for unrewarded odors, and rise above claustrum is related to salience and salience detection. This was it in the case of rewarded odors. The authors suggest that this based on their own experiments conducted on awake primates. is an easily understood and implemented population temporal The stimuli were naturalistic video recordings, naturalistic audi- code, the decoding of which simply requires downstream coin- tory recordings, and both presented together. Recordings were cidence detectors, connected to decision-making networks, that taken from individual neurons in various parts of the claus- take input from both members of the neuron pair. Doucette et al. trum. Their results confirmed the fact that visual neurons and (2001) then found that the SS rate is modulated by noradren- auditory neurons are located in different loci of the claustrum ergic input to the bulb. In this way the SS code can signal the (ventral and dorso-central, respectively). However, they reported reinforcement significance of the stimulus. Katz and Maier (2011) that the neurons reacted to visual or auditory stimuli, but not comment in the same issue of Neuron “It is also unclear whether, both. They added some other interesting details. In all cases the when coherently firing neurons are studied in larger ensembles, response latencies were short and the responses were brief and the observable patterns will become more complicated.” Katz and stereotyped—a short strong transient followed by a diminished Maier conclude, “Thus, these are important, novel data added to a sustained response. Even the responses of claustral neurons to growing corpus suggesting that “sensory” coding is as much about long naturalistic sounds were in the form of brief transients. This the stimulus in context as what the stimulus physically is.” That is was in contrast to what the same group, using the same stimuli, to say that the reinforcement significance of most stimuli will be had found in higher sensory cortex, where considerable fractions affected by other events happening in the environment. For exam- of integrating or bimodal neurons were found in the auditory cor- ple, the last meal chosen and eaten by a condemned prisoner will tex (Kayser et al., 2008) and the superior temporal cortex (Dahl not carry the same reinforcement value that it should. et al., 2010). Furthermore, Remedios et al. (2010)testedformul- Perhaps, then, the claustrum could be functioning, in some tisensory integration in the claustrum by looking for instances locations, as such a reinforcement related “downstream coinci- where the response to one stimulus is modulated by a stimulus dence detector” on a global scale in larger assemblies? In some in a different modality. No such modulations were found. These areas (such as the anterior and part of the ventral claustrum) workers suggested that previous reports of multimodal neurons the spikes impinging on the coincidence (synchrony) detectors in the claustrum were probably contaminated by influences from in the claustrum may carry salient information relating to the the insula. They concluded that the claustrum is most likely to reinforcement value of the stimulus rather than to the sensory

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 10 Smythies et al. Hypotheses relating to the function of the claustrum

properties of the stimulus. The function of this might be to mechanism for this effect is suggested by Kuznetsova and Deth provide a metastable network that enables the brain to com- (2008). They found that dopamine, acting on D4 receptors, pute the significance of a stimulus in its complex global context. promotes synchronization of oscillations in cortical pyramidal That is, a stimulus can be signaling reward, or the opposite, cell—interneuron networks. This is mediated by modulation of depending on its contextual environment—on what surrounds phospholipid methylation that alters the kinetics of potassium it. In other words the brain must have a global mechanism that channels. P cell-interneuron networks are prominent in the claus- needs input from other sensory systems to evaluate the reinforce- trum. Perhaps the claustrum is involved in this type of salient ment significance of a single stimulus presented in a complex activity? environment. For an example from another system, anxiety is reported to It is possible, therefore, that the claustrum might perform both be associated with theta-frequency synchronization between the functions described above—computing binding and computing ventral hippocampus and the mPFC (Adhikari et al., 2010). These global reinforcement—in different locations. The brain contains authors suggest that such synchronization is a general mecha- several systems involved in salience detection—for example the nism by which the hippocampus communicates with downstream mesolimbic dopamine system (Enomoto et al., 2011; Friston structures of behavioral relevance. Other structures besides the et al., 2012). Another salience network includes the dorsal ante- hippocampus may do the same. rior cingulate cortex, middle and inferior temporal cortex and Therefore we fully agree with the conclusion by Remedios et al. the fronto-insular cortex (Cauda et al., 2011; Yuan et al., 2012). (2010)andRemedios (2012) that the claustrum is involved in a Day-Brown et al. (2010) report the existence of a direct projec- variety of higher cognitive processes, including saliency relevant tion from the superior colliculus to the amygdala in the tree shrew ones. that they suggest alerts the animal to the presence of danger, i.e., carries negative salience. There is at least one system involved ADVANTAGES OF OUR HYPOTHESIS in salience and executive control of which the claustrum is an The advantages of our hypothesis seem to us to be: integral part, and that is the rubral network based on the red nucleus. This consists, in addition to the red nucleus, the cerebel- • Its simplicity of action. It does not need any complex mech- lum, mesencephalon, , , pallidum, anisms, such as axonal spike time pattern analysis. The thalamus, insula, claustrum, posterior hippocampus, precuneus, claustrum simply detects synchrony, processes intraclaustral and occipital, prefrontal, and fronto-opercular cortices (Nioche synchronies, and promotes intermodal synchrony in function- et al., 2009). Little is known about the functions of this circuit. ally connected cortical and subcortical areas. It is therefore necessary to distinguish between several types of • Its low neurocomputational cost. The claustrum is not con- “salience.” “Salience” can involve the process by which new and cerned with the informational content of the spike trains fed possibly important stimuli are identified and evaluated. In this into it, only with their degree of synchrony. form of salience detection, the direct sensory input from the sense • It accounts for how one mechanism can exert functions that organ is compared with feedback from the higher cortex that pre- affects many “higher” brain functions. dicts what the input should be. It can also mean the process by • It gives a key role to the GABAergic interneuron system in which information about the reinforcement history of stimuli is claustral function. processed. We also need to enquire further how reinforcing and salient If we ask “What makes the claustrum special?” we would stimuli could affect this system. The cortex receives widespread reply that it reproduces in a small volume activity from all over projections from dopamine neurons in the ventral tegmental the much larger volume of the rest of the brain. This promotes area (VTA) that are activated when a stimulus with more than the development of multiple, fluctuating, and differential syn- expected reward is received. Representations of sensory stimuli in chronous oscillations essential to the claustrum’s postulated role. the cerebral cortex can undergo progressive and extensive remod- No other brain structure has this property. eling according to the behavioral importance of the stimuli (Bao The differences between our previous hypothesis (H1) and our et al., 2001). There are several reports that dopamine promotes present hypotheses (H2) are as follows. (1) The essential feature in neuronal oscillations. At the microcircuit level, during striatal H1 was a series of pyramidal cells that acted as [AND gates] which network activity, the selective activation of either D1 or D2 recep- detected synchronous axonal spikes, and reported back to the part tors results in an increase of neuronal synchronization (Carrillo- of the cortex whence these spikes originated. (2) The function of Reid et al., 2011). In bullfrog retinal ganglion cells dopamine the GABAergic INs was allotted merely to noise reduction. (3) promotes synchronization (Li et al., 2012b). Dopaminergic stim- In H1 a bimodal innervation of claustral P cells was required. ulation can either promote, modulate or inhibit oscillatory activ- In H2: (1) the P cells and INs act as units that detect synchro- ity depending on the structure innervated, and the frequency nized oscillations in the afferent inflow, and then integrate these of the oscillation (Lee et al., 2004). For example, Cassidy et al. by its competitive intraclaustral oscillatory system. The claustrum (2002) studied human patients following surgery for Parkinson’s then projects executive signals based on this integration to the disease. Without medication coherent oscillations were appar- motor cortex and limbic system. (2) Noise reduction has been ent between the and the globus pallidus eliminated. (3) Bimodal innervation is not required. interna at <30 Hz. After exogenous dopamine stimulation the We feel that we should mention that we have carried an exten- coherence frequency increased to 70–85 Hz. A neurochemical sive exploration of other possible hypotheses, in relation to the

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 11 Smythies et al. Hypotheses relating to the function of the claustrum

“binding” function of the claustrum, based on other fixed nerve as a synchrony detector that detects and reacts to the degree net systems, spike train spatio-temporal codes, and non-linear of synchrony contained in spike bursts in their selective input dynamics, but failed to develop any promising candidates in those axons. This synchrony is facilitated by intraclaustral synchroniz- fields. ing interactions between the P cells, and GABAergic IN cells, and is maintained in dynamic cortico-claustral-cortical reverberating PROBLEMS WITH THE HYPOTHESIS? circuits. These cycles may function as the neural correlates of con- Duffau et al. (2007) conducted total unilateral excision of the sciousness. In the case of the ventral claustrum this system may claustrum and insula for glioma in 42 patients. They could relate to the reinforcement (salience) value of stimuli and other not detect any neurological or psychological abnormalities post- higher brain functions of the claustrum in some cases. We also operatively in any of the cases, who all returned to their normal discuss a complementary hypothesis related to salience detection professional lives, except for three who suffered a stroke due to and estimation. vascular complications. The authors concluded that the system Thus our position is very close to the hypothesis proposed by must have an effective compensatory system, but do not venture Crick and Koch (2005). They describe “widespread intraclaustral an opinion as to what this might be. We suggest that the answer interactions,” that may be in the form of “waves of information may lie in the fact that the claustrum has extensive connections {that} can travel within the claustrum.” This may involve, they with the contralateral cortex, at least in the cat (Sherk, 1986). She suggest further, dendrodendritic synapses and networks of gap states— junction linked neurons. They also suggest that claustral neurons “Norita (1977) found that all areas of cortex tested received “could be especially sensitive to the timing of the inputs.” We feel input from two roughly corresponding regions in the two claus- that we have merely supplied some details of this process. We also tra, though the projection from the contralateral side was always support the hypothesis presented by Remedios et al. (2010)ifthis considerably weaker. These findings have been confirmed by is stated that one function of the claustrum is related to salience others, chiefly Macchi et al. (1981).” processing. In a study of sparse and dense codes in the brain during expo- EXPERIMENTS TO TEST OUR HYPOTHESIS sure to language passages and music Lloyd (2011)foundthat Central to our hypothesis is the question of how does a neu- the resulting fMRI activity has properties more similar to music ron react if its input consists of two trains of spikes produced by than to language. Crick and Koch (2005) famously likened the two groups of afferent neurons oscillating at different frequencies. claustrum to the conductor of the orchestra. We agree that the evi- Gielen et al. (2010) have conducted a theoretical and computer dence points to this role for the claustrum, as the conductor of an simulation study, and have come to the conclusion that the target orchestra that plays a symphony woven out of a continual shim- neuron(s) fired in a pattern that was highly phase-locked with the mering interplay of information-laden harmonies built out of larger of the two afferent signals. The question then arises what synchronized potentials oscillating at many different frequencies. is the result if they are of equal size. However, different types of pyramidal cell react in different ways, and there is currently no POSTSCRIPT information as to which type the claustral pyramidal cells belong THE FUNCTION OF THE CLAUSTRUM IN A NUTSHELL: THE (Gielen, personal communication). An extended answer to this BRAIN’S WAR ROOM problem might produce essential evidence as to the possible role Any large organization, composed of many modules that process of such a mechanism in the claustrum. Interesting basic data on incoming information, and has an output in the form of intel- the synchronization properties of pyramidal neurons are pro- ligent behavior, will have a problem with internal information vided by Di Garbo et al. (2007). Relevant information might be flow. Each module is busy processing its own input and provid- obtained by experiments that fed axonal bursts synchronized at ing an output, but how does one module know what another different frequencies into the claustrum, and recorded what form is doing, and how does the organism as a whole know what is of synchronized bursts appeared in the relevant outputs from the going on, and what best to do next? Intercommunication between claustrum. the modules soon leads to overload. Direct intermodular connec- In particular, the problem to be solved might be put in the fol- tions, however extensive, and non-linear dynamics can only go lowing form. The claustrum consists of a fairly uniform tangled so far. array of pyramidal cells and a wide variety of GABAergic INNs, For example, in an army, one unit can make judgments about all densely interconnected by axon collaterals of the P cells, axons, what to do next by observing what other units beside it in the line and dendrites of the INNs, and the gap junction linked syncytium are doing, and making rational decisions. These may be right in formed by the INNs. This complex system receives afferent axons the local context, but wrong in the context of the overall war plan. from most brain areas. So what is the likely form of interaction In the Napoleonic wars this is what generals in charge of brigades between all the different synchronized oscillations, both of intrin- had to do during the time it took a galloping horse to get from sic and extrinsic origin, set up by this system, and how would this Paris to Madrid. Another example is the battle of New Orleans, affect the output patterns of the P cells? which was fought after the War of 1812 had ended. The advent of wireless telegraphy changed the situation. During WW2 Churchill CONCLUSION set up a control room in the basement of 10 Downing Street. This This paper presents a specific hypothesis on the mechanism of was equipped with a large map in the center of the room, where action of the claustrum. It suggests that the claustrum functions small models of the planes, ships, tanks, etc. involved could be

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 12 Smythies et al. Hypotheses relating to the function of the claustrum

moved about in response to telegraphed reports from the front. Our hypothesis suggests that sensory—and much cognitive— The generals could review the whole situation at a glance, and discrimination and integration (leading to an executive order) make instant decisions about what orders to send back. is effected by competitive synchronous gamma oscillations. This We suggest that the claustrum, with its own internal maps, is mechanism operates at a weak level within the cortex (via cor- doing the same thing. It not only “binds” sensory information, as ticocortical synchronizations), and at a stronger level within the Crick and Koch proposed, but it is receives edited incoming infor- claustrum (via intraclaustral synchronizations), the connection mation (evaluated for novelty and salience) from five different between the two maintained by cortico-claustrocortical loops. channels (via cortico-claustral and thalamoclaustral afferents). It In the case of the lesioned rat “stuck” at the center of the then calls in further reports and analyses, when needed, from maze, we suggest that this has nothing to do with behavioral areas of cortex it activates (by means of a web of synchronized or emotional “freezing,” but that it is a case of the “donkey oscillations and axon bursts). Lastly the claustral circuits integrate caught between two identical bales of hay” syndrome. The loss all this activity (via intraclaustral synchronized oscillations), to of the claustrum results in the subject losing its ability to choose come up with a series of executive orders transmitted to the motor between what are very similar arms of the maze. The weak signals, cortex. In other words, the claustrum may do for its brain what produced by the now isolated cortical system, are insufficient to Churchill’s War Room did for the Allied armies. trigger the executive order necessary for the rat to enter an arm of We do not imply that this model requires the infamous lit- the maze. In effect, the lesioned animal can no longer make up its tle green man in the War Room reading all this incoming data mind. Likewise, the running lesioned animal, by the operation of and making decisions based on it. The evaluation of the data and a similar mechanism, cannot decide when to stop. the decisions are both functions of the competitively interacting In addition, with the use of BOLD fMRI in these saporin- rhythms. lesioned rats, Remedios reported increased widespread positive correlations across the various sensory cortical areas, as well as NOTE ADDED IN PROOF increased activity in the prefrontal cortex (PFC). Our hypothesis This note added in proof details how our hypothesis explains also explains this finding, premised on the well-known principle the new experimental data reported by Ryan Remedios in his that, when one mechanism in the brain is inactivated, it imme- invited lecture entitled “The Claustrum and the Orchestra of diately tries to activate some other mechanism(s) to compensate Cognitive Control,” presented at the First Annual Francis Crick for the loss. In this case, the loss of the integrating activity of the Memorial Conference: Consciousness in Human and Non-human claustrum leads to an expected compensatory increase in activ- Animals, held at Churchill College, Cambridge on July 7th, 2012 ity in the corticocortical system. In this regard, we also wish to (Remedios, 2012)1. note that our hypothesis serves to explain the multiple cognitive At the Conference (which was live-streamed over the internet), effects of claustral activity, as detailed in this paper. It is unclear Remedios presented the results of a series of experiments he had to us how an “interhemispheric bidirectional PFC-claustrum net- conducted in rats using a molecular lesioning technique involving work,” as detailed by Remedios in his lecture (without specifics saporin (a ribosome-inactivating protein), to effectively eliminate offered as to what its function might be), would accomplish this. most if not all of the claustrum. When these “aclaustral” animals Lastly, we have already commented in this paper on the point were placed on the center platform of an elevated eight-arm radial raised by Christof Koch during the Q&A session, which imme- maze, they did not explore the maze as did the control subjects, diately followed the Remedios lecture, referring to the lack of but, in the speaker’s words, remained “frozen” at its center, with salience in the stimuli used in his monkey claustrum unit phys- infrequent short forays into one of the arms. Likewise, rats placed iology study (Remedios et al., 2010), which was also presented in a running situation on a Rotarod continued running far longer during his talk. We agree with his point that, in order to test a than did the control subjects. salience hypothesis, it is necessary to use salient stimuli, which, in the case of the monkey claustrum study (Remedios et al., 2010), 1http://fcmconference.org/#talks would be a multisensory/multimodal task.

REFERENCES receptors and legal highs: Salvia endopiriform nucleus in the cat. Buhusi, C. V., and Meck, W. H. (2005). Adhikari, A., Topiwala, M. A., and divinorum and Kratom. Clin. Brain Res. Bull. 15, 485–498. Whatmakesustick?Functional Gordon, J. A. (2010). Synchronized Toxicol. (Phila.) 46, 146–152. Bruno, R. (2011). Synchrony in sen- and neural mechanisms of inter- activity between the ventral hip- Baizer, J. S. (2001). Serotonergic inner- sation. Curr. Opin. Neurobiol. 21, val timing. Nat. Rev. Neurosci. 6, pocampus and the medial PFC. vation of the primate claustrum. 701–708. 755–765. Neuron 65, 257–269. Brain Res. Bull. 55, 431–434. Budinger, E., Heil, P., Hess, A., and Clavagnier, S., Falchier, A., and Allman, M. J., and Meck, W. H. Bao, S., Chan, V. T., and Merzenich, Scheich, P. (2006). Multisensory Kennedy, H. (2004). Long-distance (2012). Pathophysiological distor- M. M. (2001). Cortical remodel- processing via early cortical stages: feedback projections to area V1, tions in time perception and timed ing induced by activity of ven- connections of the primary auditory implications for multisensory performance. Brain 135, 656–677. tral tegmental dopamine neurons. cortical field with other sensory sys- integration, spatial aware- Asai, Y., Guha, A., and Villa, A. Nature 412, 79–83. tems. Neuroscience 143, 1063–1083. ness, and visual consciousness. E. (2008). Deterministic neural Baron-Cohen, S. (2008) Autism and the Buffalo, E. A., Fries, P., Landman, R., Cogn.Affect.Behav.Neurosci.4, dynamics transmitted through Asperger Syndrome. New York, NY: Buschman, T. J., and Desimione, 117–126. neural networks. Neural Netw. 21, Oxford University Press. R. (2011). Laminar differences in Cappe, C., and Barone, P. (2005). 799–809. Beneyto, M., and Prieto, J. J. (2001). gamma and alpha coherence in the Heteromodal connections support- Babu,K.M.,McCurdy,C.R.,and Connections of the auditory cor- ventral stream. Proc. Natl. Acad. Sci. ing multisensory integration at Boyer, E. W. (2008). Opioid tex with the claustrum and the U.S.A. 108, 11262–11261. low levels of cortical processing in

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 13 Smythies et al. Hypotheses relating to the function of the claustrum

the monkey. Eur. J. Neurosci. 22, plasticity for the spatial processing Functional compensation of the beta- and alpha-augmentation pre- 2886–2902. of sounds in visually deprived claustrum: lessons from low-grade cedes alpha- and beta-attenuation Cappe, C., Rouiller, E. M., and Barone, subjects. Exp. Brain Res. 192, glioma surgery. J. Neurooncol. 81, in humans. Clin. Neurophysiol. 121, P. (2012). “Cortical and thalamic 343–358. 327–329. 366–375. pathways for multisensory and sen- Crick, F. C., and Koch, C. (2003). A Edelstein, L. R., and Denaro, F. J. Gao, W. J., and Pallas, S. L. (1999). sorimotor interplay,” in The Neural framework for consciousness. Nat. (2004). The claustrum: a histori- Cross-modal reorganization of Bases of Multisensory Processes, eds Neurosci. 6, 119–126. cal review of its anatomy, physiol- horizontal connectivity in audi- M. M. Murray and W. T. Wallace Crick, F. C., and Koch, C. (2005). What ogy, cytochemistry and functional tory cortex without altering (Boca Raton, FL: CRC Press), is the function of the claustrum? significance. Cell. Mol. Biol. 50, thalamocortical projections. J. 15–30. Philos. Trans. R. Soc. Lond. B Biol. 675–702. Neurosci. 19, 7940–7950. Cardin,J.A.,Carién,M.,Meletis,K., Sci. 360, 1271–1279. Eggan, S. M., and Lewis, D. A. (2007). Ghazanfar, A. A., and Schroeder, C. E. Knoblich, U., Zhang, F., Deisseroth, Dahl, C. D., Logothetis, N. K., and Immunocytochemical distribution (2006). Is the neocortex essentially K., Tsai, L. H., and Moore, C. L. Kayser, C. (2010). Modulation of of the cannabinoid CB1 receptor in multisensory? Trends Cogn. Sci. 10, (2009). Driving fast-spiking cells visual responses in the superior the primate neocortex: a regional 278–285. induces gamma rhythm and con- temporal sulcus by audio-visual and laminar analysis. Cereb. Cortex Gielen, S., Krupa, M., and Zeitler, M. trols sensory responses. Nature 459, congruency. Front. Integr. Neurosci. 17, 175–191. (2010). Gamma oscillations as a 663–667. 4:10. doi: 10.3389/fnint.2010.00010 Emrich, S. M., Ferber, S., Klug, A., mechanism for selective informa- Carrillo-Reid, L., Hernández-López, S., Das, U. N. (2010). Metabolic Syndrome and Ross, B. (2006). “Examining tion transmission. Biol. Cybern. 103, Tapia, D., Galarraga, E., and Bargas, Pathophysiology: The Role of changes in synchronous oscillations 151–165. J. (2011). Dopaminergic modula- Essential Fatty Acids. New York, NY: associated with the segregation Gill, S. K., Ishak, M., Dobransky, tion of the striatal microcircuit: Wiley. and persistence of forms using T., Haroutunian, V., Davis, K. L., receptor-specific configuration of Day-Brown, D., Wei, H., Petry, H. magnetoencephalgraphy (MEG),” and Rylett, R. J. (2006). 82-kDa cell assemblies. J. Neurosci. 31, M., and Bickford, M., E. (2009). in Poster Cognitive Neuroscience choline acetyltransferase is in nuclei 14972–14983. “Characterization of claustrum-V1 Society Meeting,(SanFrancisco, of cholinergic neurons in human Cassidy,M.,Mazzone,P.,Olivero,A., connections,” in Poster 848.11/T15, CA). CNS and altered in aging and Insola, A., Tonali, P., Di Lazzaro, V., Society for Neuroscience Meeting, Enomoto, K., Matsumoto, N., Nakai, Alzheimer disease. Neurobiol. Aging and Brown, P. (2002). Movement- (Chicago, IL). S., Satoh, T., Sato, T. K., Ueda, 28, 1028–1040. related changes in synchronization Day-Brown,J.D.,Wei,H.,Chomsung, Y.,Inokawa,H.,Haruno,M.,and Gregoriou, G. G., Gotts, S. J., Zhou, in the human . Brain R. D., Petry, H. M., and Bickford, Kimura, M. (2011). Dopamine neu- H., and Desimone, R. (2009). 125, 1235–1246. M. E. (2010). Pulvinar projections rons learn to encode the long-term High-frequency, long-range cou- Cauda, F., D’Agata, F., Sacco, K., Duca, to the and amygdala in the value of multiple future rewards. pling between prefrontal and visual S., Geminiani, G., and Vercelli, A. tree shrew. Front. Neuroanat. 4:143. Proc. Natl. Acad. Sci. U.S.A. 108, cortex during attention. Science 324, (2011). Functional connectivity of doi: 10.3389/fnana.2010.00143 15462–15461. 1207–1210. the insula in the resting brain. Di Garbo, A., Berbi, M., and Chillemi, Falchier, A., Clavagnier, S., Barone, Grossberg, S., and Versace, M. (2008). Neuroimage 55, 8–23. S. (2007). The synchroniza- P., and Kennedy, H. (2002). Spikes, synchrony and attentive Chalk, M., Herrero, J. L., Gieselmann, tion properties of a network of Anatomical evidence of multi- learning by laminar thalamocor- M. A., Delicato, L. S., Gotthardt, inhibitory interneurons depend on modal ontegration in primate tical circuits. Brain Res. 1218, S., and Thiele, A. (2010). Attention the biophysical model. BioSystems striate cortex. J. Neurosci. 22, 278–313. reduces stimulus-driven gamma 88, 216–227. 5749–5759. Grothe, B. (2003). New roles for synap- frequency oscillations and spike Divac, I. (1979). Patterns of subcortico- Fino, E., and Yuste, R. (2011). Dense tic inhibition in sound localization. field coherence in V1. Neuron 66, cortical projections as revealed inhibitory connectivity in neocor- Nat. Rev. Neurosci. 4, 540–550. 114–125. by somatopetal horseradish per- tex. Neuron 69, 1188–1203. Haenschel, C., Baldeweg, T., Croft, R. Chanda, S., and Xu-Friedman, M. A. oxidase tracing. Neuroscience 4, Freeman, W. J. (2011) How Brains Make J., Whittington, M., and Gruzelier, (2010). by GABA 455–461. Up Their Minds. New York, NY: J. (2000). Gamma and beta fre- converts a relay into a coinci- Divac, I., Kosmal, A., Bjorklund, A., Columbia University Press. quency oscillations in response to dence detector. J. Neurophysiol. 104, and Lindvall, O. (1978). Subcortical Friston, K. J., Shiner, T., Fitzgerald, T., novel auditory stimuli: a compar- 2063–2974. projections to the prefrontal cor- Galea, J. M., Adams, R., Brown, ison of human electroencephalo- Chowdhury, S. A., and DeAngelis, tex in the rat revealed by the H.,Dolan,R.J.,Moran,R., gram (EEG) data with in vitro G. C. (2008). Fine discrimina- horseradish peroxidase technique. Stephan, K. E., and Bestman, models. Proc. Natl. Acad. Sci. U.S.A. tion training alters the causal con- Neuroscience 3, 785–796. S. (2012). Dopamine, affor- 97, 7645–7650. tribution of Macaque area MT Dockstader, C., Cheyne, D., and dance, and active inference. Heron, J., Roach, N. W., Hanson, J. V., to depths perception. Neuron 60, Tannock, R. (2009). Cortical PLoS Comput. Biol. 8:e100. doi: McGraw, P. V., and Whittaker, D. 367–377. dynamics of selective attention to 10.1371/journal.pcbi.1002327 (2012). Audiovisual time perception Churchland, P. S., and Sejnowski, T. somatosensory events. Neuroimage Fujioka,T.,Trainro,L.J.,Large,E. is spatially specific. Exp. Brain Res. J. (1999) The Computational Brain. 49, 1777–1785. W., and Ross, B. (2009). Beta and 218, 477–485. Cambridge, MA: MIT Press. Doucette, W., Gire, D. H., Whitesell, gamma rhythms in human audi- Hinova-Palova, D. V., Edelstein, L. Clarey, J. C., and Irvine, D. R. F. J., Carmean, V., Lucero, M. T., tory cortex during musical beat pro- R.,Paloff,A.M.,Hristov,S., (1986). Auditory response prop- and Restrepo, D. (2001). Associative cessing. Ann. N.Y. Acad. Sci. 1169, Papantchev,V.G.,andOvtscharoff, erties of neurons in the claus- cortex features in the first olfac- 89–92. W. A. (2007). Parvalbumin in the trum of the cat. Exp. Brain Res. 2, tory brain relay station. Neuron 69, Fukuda, T., Kosaka, T., Singer, W., cat claustrum: ultrastructure, distri- 432–437. 1176–1187. and Galuske, R. A. (2006). Gap bution and functional implications. Colgin, L. L., Denninger, T., Fyhn, M., Driver, J., and Noesselt, T. (2008). junctions among dendrites of cor- Acta Histochem. 109, 61–77. Hafting, P., Bonnevie, T., Jensen, O., Multisensory interplay reveals tical GABAergic neurons establish Hubbard, R. S., and Ramachandran, and Moser, E. I. (2009). Frequency crossmodal influences on ‘sensory- a dense and widespread inter- V. S. (2005). Neurocognitive mech- of gamma oscillations routes flow specific’ brain regions, neural columnar network. J. Neurosci. 26, anisms of synesthesia. Neuron 48, of information in the hippocampus. responses and judgments. Neuron 8595–8604. 509–520. Nature 462, 353–357. 57, 11–23. Fukuda, M., Juhász, C., Hoechstetter, Jeffress, A. (1948). A place theory of Collignon, O., Voss, P., Lassonde, M., Duffau, H., Mandonnet, E., Gatignol, K., Sood, S., and Asano, E. (2010). sound localization. J. Comp. Physiol. and Lepore, F. (2009). Cross-modal P., and Capelle, L. (2007). Somatosensory-related gamma-, Psychol. 41, 35–39.

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 14 Smythies et al. Hypotheses relating to the function of the claustrum

Katz, D. B., and Maier, J. X. (2011). long-lasting diabetes mellitus on Matell, M. S., and Meck, W. H. (2004). Park,S.,Tyszka,J.M.,andAllman, : odor signals put into rat and monoamines. Corticostriatal circuits and inter- J. M. (2012). The claustrum and context. Neuron 69, 1041–1042. J. Neurochem. 54, 143–147. val timing: coincidence-detection of insula in Microcebus murinus:a Kavounoudias, A., Roll, J. P., Anton, J. Lee, K. M., Ahn, T. B., Jeon, B. S., oscillatory processes. Cogn. Brain high resolution diffusion imaging L., Nazarian, B., Roth, M., and Roll, and Kim, D. G. (2004). Change Res. 21, 139–170. study. Front. Neuroanat. 6:21. doi: J. P. (2008). Proprio-tactile integra- in phase synchronization of local Meador-Woodruff, J. H., Mansour, 10.3389/fnana.2012.00021 tion for kinesthetic perception: an field potentials in anesthetized A., Civelli, O., and Watson, S. Palva, S., and Palva, J. M. (2007). New fMRI study. Neuropsychologia 46, rats after chronic dopamine J. (1991). Distribution of D2 vistas for alpha-frequency band 567–575. depletion. Neurosci. Res. 49, dopamine receptor mRNA in the oscillations. Trends Neurosci. 30, Kaiser, J. (2003). Induced gamma-band 179–184. primate brain. Prog. Neuropsycho- 475–484. activity and human brain function. LeVay, S., and Sherk, H. (1981). The pharmacol. Biol. Psychiatry 15, Ptito, M., Fumal, A., de Noordhout, Neuroscientist 9, 475–484. visual claustrum of the cat. II. The 885–893. A. M., Schoenen, J., Gjedde, A., Kayser, C., Petkov, C. L., and visual field map. J. Neurosci. 1, Meng,F.,Xie,G.X.,Thompson,R.G., and Kupers, R. (2008). TMS of Logothetis, N. K. (2008). Visual 981–992. Mansour, A., Goldstein, A., Watson, the occipital cortex induces tactile modulation of neurons in auditory Li, C., Pleil, K. E., Stamatakis, A. S. J., and Akil, H. (1993). Cloning sensations in the fingers of blind cortex. Cereb. Cortex 18, 1560–1574. M., Busan, S., Vong, L., Lowell, B. and pharmacological characteriza- Braille readers. Exp. Brain Res. 184, Kayser, C., Montemurro, N. K., B.,Stuber,G.D.,andKash,T.L. tion of a rat kappa opioid recep- 193–200. Logothetis, N. K., and Panzeri, (2012a). Presynaptic inhibition of tor. Proc. Natl. Acad. Sci. U.S.A. 90, Rahman, F. E., and Baizer, J. S. (2007). S. (2009). Spike-phase coding gamma-aminobutyric acid release 9954–9958. Neurochemically defined cell types boosts and stabilizes information in the bed nucleus of the stria Minciacchi, D., Molinari, M., in the claustrum of the cat. Brain carried by spatial and tempo- terminalis by kappa opioid recep- Bentivoglio, G., and Macchi, G. Res. 1159, 94–111. ral spike patterns. Neuron 61, tor signaling. Biol. Psychiatry 71, (1985). The organization of the Ramachandran, V. S., and Anstis, S. 4597–4608. 725–732. ipsi- and contralateral claustro- M. (1983). Perceptual organization Kilner, J., Bott, L., and Posada, A. Li, H., Liu, W. Z., and Liang, P. cortical system in rat with notes in moving patterns. Nature 304, (2005). Modulations in the degree J. (2012b). Adaptation-dependent on the bilateral claustrocortical 529–31. of synchronization during ongo- synchronous activity contributes to projections in cat. Neuroscience 16, Remedios, R. (2012). “The claustrum ing oscillatory activity in the receptive field size change of bull- 557–576. and the orchestra of cogni- human brain. Eur. J. Neurosci. 21, frog retinal ganglion cell. PLoS Naghavi, H. R., Eriksson, J., Larsson, tive control,” in Francis Crick 2547–2554. ONE 7:e34336. doi: 10.1371/jour- A., and Nyberg, L. (2007). The Memorial Conference, (Cambridge, König, P., Engel, A. K., and Singer, W. nal.pone.0034336 claustrum/insula region inte- UK). Available online at: http:// (1996). Integrator or co-incidence Li,Z.K.,Takada,M.,andHattori, grates conceptually related sounds fcmconference.org/#program detector? The role of the cortical T. (1986). Topographic organization and pictures. Neurosci. Lett. 422, Remedios, R., Logothetis, N. K., neuron revisited. Trends Neurosci. and collateralization of claustrocor- 77–80. and Kayser, C. (2010). Unimodal 19, 130–137. tical projections in the rat. Brain Nioche, C., Cabanis, E. A., and Habas, responses prevail within the multi- Kovács, I., Papathomas, T. V., Yang, Res. Bull. 17, 529–532. C. (2009). Functional connectiv- sensory claustrum. J. Neurosci. 30, M., and Fehér, A. (1996). When the Linden,J.F.,andSchreiner,C.E. ity of the human red nucleus in 12902–12907. brain changes its mind: interocu- (2003). Columnar transformations the brain resting state at 3T. Am. Rockland, K. S., and Ojima, H. (2003). lar grouping during retinal rivalry. in auditory cortex? A comparison to J. Neuroradiol. 30, 396–403. Multisensory convergence in cal- Proc. Natl. Acad. Sci. U.S.A. 1004, visual and somatosensory cortices. Norita, M. (1977). Demonstration of carine visual areas in macaque 289–296. Cereb. Cortex 13, 83–88. bilateral claustro-cortical connec- monkey. Int. J. Psychophysiol. 50, Kowianski, P., Dziewiatkowski, J., Lloyd, D. (2011). Mind as music. tions in the cat with the method 19–26. Morys, J. M., Majak, K., Wojcik, S., Front. Psychol. 2:63. doi: of retrograde axonal transport of Roe, A. W., Pallas, S. L., Kwon, Y. Edelstein, L. R., Lietzau, G., and 10.3389/fpsyg.2011.00063 horseradish peroxidase. Arch. Histol. H., and Sur, M. (1992). Visual Morys, J. (2009). Colocalization Lomber, S. G., Meredith, M. A., and Jpn. 40, 1–10. projections routed to the auditory of neuropeptides with calcium- Kral, A. (2010). Cross-modal plas- Nunn, J. A., Gregory, L. J., Brammer, pathway in ferrets: receptive fields binding proteins in the claustral ticity in specific auditory cortices M., Williams, S. C., Parslow, D. of visual neurons in the primary interneurons during postnatal underlies visual compensations M., Morgan, M. J., Morris, R. G., auditory cortex. J. Neurosci. 12, development of the rat. Br.Res.Bull. in the deaf. Nat. Neurosci. 13, Bullmore, E. T., Baron-Cohen, S., 3651–3664. 80, 100–106. 1412–1418. and Gray, J. A. (2002). Functional Sadowski, M., Morys, J., Jakubowska- Kucera,ˇ O., and Havelka, D. (2012). Macchi, G., Bentivoglio, M., magnetic resonance imaging of Sadowska, K., and Narkiewicz, O. Mechano-electrical vibrations of Minciacchi, D., and Molinari, synesthesia: activation of V4/V8 (1997). Some claustral neurons microtubules-Link to subcellu- M. (1981). The organization of by spoken words. Nat. Neurosci. 5, projecting to various neocortical lar morphology. BioSystems.doi: the claustroneocortical projec- 371–375. areas show morphological differ- 10.1016/j.biosystems.2012.04.009. tions in the cat studied by means Olson, C. R., and Graybiel, A. M. ences. Folia Morphol. (Warsz.) 56, [Epub ahead of print]. of the HRP retrograde axonal (1980). Sensory maps in the 65–76. Kumar, A., Rotter, S., and Aertsen, A. transport. J. Comp. Neurol. 195, claustrum of the cat. Nature 288, Scalaidhe, S. P., Rodman, H. R., (2010). Spiking activity propaga- 681–695. 479–481. Albright, T. D., and Gross, C. G. tion in neuronal networks: recon- Mansour, A., Fox, C. A., Burke, S., Oram, M. W., and Perrett, D. I. (1996). (1997). The effects of combined ciling different perspectives on neu- Meng, F., Thompson, R. C., Akil, Integration of form and motion superior temporal polysensory area ral coding. Nat. Rev. Neurosci. 11, H., and Watson, S. J. (1994). Mu, in the anterior superior tempo- and frontal eye field lesions on 615–627. delta and kappa opioid recep- ral polysensory area (STPa) of the eye movements in the macaque Kuznetsova, A. Y., and Deth, R. C. tor mRNA expression in the macaque monkey. J. Neurophysiol. monkey. Behav. Brain Res. 84, (2008). A mode for modulation rat CNS: an in situ hydridiza- 76, 109–129. 31–46. of neural synchronization by D4 tion study. J. Comp. Neurol. 350, Pallas, S. L., Littman, T., and Moore, Schilder, P. (1942) Mind. Perception receptor-mediated phospholipid 412–438. D. R. (1999). Cross-modal reor- and Thought in their Constructive methylation. J. Comput. Neurosci. Masuda, N., and Aihara, K. (2002). ganization of callosal connectiv- Aspects. New York, NY: Columbia 24, 14–29. Spatiotemporal spike encoding of a ity without altering thalamocortical University Press. Lackovic,´ Z., Salkovic,´ M., Kuci, Z., continuous external signal. Neural projections. Proc. Natl. Acad. Sci. Sharma, J., Angelucci, A., and Sur, and Relja, M. (1990). Effect of Comput. 14, 1599–1628. U.S.A. 96, 8751–8756. M. (2000). Induction of visual

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 15 Smythies et al. Hypotheses relating to the function of the claustrum

orientation modules in auditory connections in the rat: interhemi- Tallon-Baudry, C. (2009). The roles of Thesaliencenetworkcontributes cortex. Nature 404, 841–847. spheric communication between gamma-band oscillatory synchrony to an individual’s fluid reasoning Sherk, H. (1986) “The claustrum and specific parts of motor cortex. in human visual cognition. Front. capacity. Behav. Brain Res. 229, the cerebral cortex,” in Cerebral J. Neurosci. 30, 16832–16844. Biosci. 14, 321–332. 384–390. Cortex Vol. 5. Sensory-Motor Areas Smith, J. B., Radhakrishnan, H., and Tian,F.,Tu,S.,Qiu,J.,Lv,J.Y.,Wei, Zhang, X., Hannesson, D. K., Saucier, and Aspects of Cortical Connectivity, Alloway, K. D. (2012). Rat claus- D.T.,Su,Y.H.,andZhang,Q.L. D. M., Wallace, A. E., Howland, eds E. G. Jones and A. Peters (New trum coordinates but does not inte- (2011). Neural correlates of men- J., and Corcoran, M. E. (2001). York, NY: Plenum Press), 467–499. grate somatosensory and motor cor- tal preparation for successful insight Susceptibility to kindling and neu- Sherk, H., and LeVay, S. (1981). tical information. J. Neurosci. 32, problem solving. Behav. Brain Res. ronal connections of the ante- The visual claustrum of the cat: 8583–8588. 216, 626–630. rior claustrum. J. Neurosci. 21, III. Receptive field properties. J. Smythies, J. (1997). The functional Treisman, A., and Schmidt, H. (1982). 3674–3368. Neurosci. 1, 993–1002. neuroanatomy of awareness. Illusory conjunctions in the percep- Zhao, Y., and Zhan, Q. (2012). Electric Shinomoto, S., Kim. H., Shimokawa, T., Conscious. Cogn. 6, 455–481. tion of objects. Cogn. Psychol. 14, fields generated by synchronized Matsuno, N., Funahashi, S., Shima, Smythies, J. (1999). ‘Reality’ and ‘vir- 107–141. oscillations of microtubules, K., Fujita, I., Tamura, H., Doi, T., tual reality’ mechanisms in the brain Uhlhaas, P. J., Pipa, G., Lima, B., centrosomes and chromosomes Kawano, K., Inaba, N., Fukushima, and their significance. J. Conscious. Melloni, I., Neuenschwander, S., regulate the dynamics of mitosis K.,Kurkin,S.,Kurata,K.,Tiara,M., Stud. 16, 69–80. Nikolic,´ D., and Singer, W. (2009). and meiosis. Theor. Biol. Med. Tsuysui, K., Komatsu, H., Ogawa, Smythies, J., Edelstein, L., and Neural synchrony in cortical Model. 9, 26. T., Koida, K., Tanji, J., and Toyama, Ramachandran, V. (2012). The networks: history, concept and cur- K. (2009). Relating neuronal fir- functional anatomy of the claus- rent status. Front. Integr. Neurosci. Conflict of Interest Statement: The ing patterns to functional differ- trum: the net that binds. WMC 3:17. doi: 10.3389/neuro.07.017. authors declare that the research entiation of cerebral cortex. PLoS Neurosci. 3, WMC003182. 2009 was conducted in the absence of any Biol. 5:e1000433. doi: 10.1371/jour- Sosulina, L., Graebenitz, S., and Vervaeke, K., Lorincz, A., Gleeson, P., commercial or financial relationships nal.pcbi.1000433 Pape, H. C. (2010). GABAergic Farinella, M., Nusser, Z., and Silver, that could be construed as a potential Sim-Selley, L. J., Daunais, J. B., Porrino, interneurons in the mouse lateral R. A. (2010). Rapid desynchro- conflict of interest. L. J., and Childers, S. R. (1999). amygdala: a classification study. J. nization of an electrically coupled Mu and kappa1 opioid-stimulated Neurophysiol. 104, 617–626. interneuron network with sparse [35S]guanylyl-5’-O-(gamma-thio)- Spector, I., Albe-Fessard, D., excitatory synaptic input. Neuron Received: 26 April 2012; accepted: 12 July triphosphate binding in cynomol- and Hassmannova, J. (1969). 67, 17435–17451. 2012; published online: 02 August 2012. gus monkey brain. Neuroscience 94, Macroelectrode and microelectrode Vohn, R., Fimm, B., Weber, J., Citation: Smythies J, Edelstein L and 651–662. exploration of cat’s claustrum. Boll. Schnitker, R., Thron, A., Spijkers, Ramachandran V (2012) Hypotheses Sloniewski, P., Usunoff, K. G., and Soc. Ital. Biol. Sper. 45, 148. W.,Willmes,K.,andSturm,W. relating to the function of the claus- Pilgrim, C. (1986). Retrograde Spector, I., Albe-Fessard, D., and (2007). Management of attentional trum. Front. Integr. Neurosci. 6:53. doi: transport of fluorescent tracers Hassmannova, J. (1970). Sensory resources in within-modal and 10.3389/fnint.2012.00053 reveals extensive ipsi- and contralat- properties of single neurons in cross-modal attention tasks: an Copyright © 2012 Smythies, Edelstein eral claustrocortical connections the cat’s claustrum. Brain Res. 66, fMRI study. Hum. Brain Mapp. 28, and Ramachandran. This is an open- in the rat. J. Comp. Neurol. 246, 39–65. 1267–1275. access article distributed under the terms 467–477. Sutoo, D., Akiyama, K., Yabe, K., and Volz, K. G., Schooler, L. J., and Yves of the Creative Commons Attribution Smiley, J. F., and Falchier, A. (2009). Kohno, K. (1994). Quantitative von Gramon, D. (2010). It just felt License, which permits use, distribution Multisensory connections of mon- analysis of immunohistochemical right: the neural correlates of the and reproduction in other forums, pro- key auditory cerebral cortex. Hear. distributions of cholinergic and fluency heuristic. Conscious. Cogn. vided the original authors and source Res. 258, 37–46. catecholaminergic systems in the 19, 829–837. are credited and subject to any copy- Smith, J. B., and Alloway, K. D. (2010). human brain. Neuroscience 58, Yuan,Z.,Qin,W.,Wang,D.,Jiang, right notices concerning any third-party Functional specificity of claustrum 227–234. T., Zhang, Y., and Yu, C. (2012). graphics etc.

Frontiers in Integrative Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 53 | 16