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Thalamocortical dysrhythmia I.
Thalamus & Related Systems 1 (2001) 237–244
Thalamocortical dysrhythmia I. Functional and imaging aspects R. Llinás a,∗ , U. Ribary a , D. Jeanmonod c , R. Cancro b , E. Kronberg a , J. Schulman a , M. Zonenshayn a , M. Magnin c , A. Morel c , M. Siegmund c a
Department of Physiology and Neuroscience, New York University School of Medicine, 550 First Avenue MSB-442, New York, NY 10016, USA b Department of Psychiatry, New York University School of Medicine, New York, NY, USA c Neurochirurgische Klinik, Universitatsspital Zurich, Zurich, Switzerland Accepted 2 October 2001
Abstract Thalamic and cortical neurons are richly and reciprocally interconnected and support recurrent functional loops in the intact brain, but the role of this circuitry is still poorly understood. Here, we present evidence—from cellular and from functional neuroimaging in control and clinical domains—that thalamocortical resonance is not only a prerequisite for normal cognition, but that its perturbation, in a dynamic sense (e.g. a dysrhythmia) can underlie a variety of neurological and psychiatric disorders. © 2001 Published by Elsevier Science Ltd. Keywords: Corticothalamic re-entry; Intrinsic properties; Burst firing; MEG; Edge effect
1. Introduction It is at present well documented that thalamic and cortical areas are mutually and robustly interconnected and that corticothalamic (CT) connections clearly outnumber their reciprocal thalamocortical (TC) counterparts (Steriade et al., 1990). Moreover, the thalamic dendritic arbor, a site known to generate calcium-dependent gamma-band sub-threshold oscillations (Pedroarena and Llinás, 1997), has most of its synaptic input arising from the overlaying cortex (Liu et al., 1995). Nevertheless, the functional role of the CT system has not been unambiguously elucidated. The temporal and spatial patterns of activity in cortical and thalamic areas demonstrate wide variability across different functional states, suggesting that such a “reverberating circuit” (Lorente de No, 1932) or re-entry function (Hebb, 1949; Edelman, 1992) could support a wide range of dynamic interactions (Llinás et al., 1998). Diverse anatomical and physiological evidence indicate that CT connectivity is excitatory and glutamatergic (Baughman and Gilbert, 1981; Giuffrida et al., 1988; Deschenes ∗ Corresponding author. Tel.: +1-212-263-5415; fax: +1-212-689-9060. E-mail address: [email protected] (R. Llin´as).
1472-9288/01/$ – see front matter © 2001 Published by Elsevier Science Ltd. PII: S 1 4 7 2 - 9 2 8 8 ( 0 1 ) 0 0 0 2 3 - 1
and Hu, 1990; McCormick and von Krosigk, 1992; Kao and Coulter, 1997; Golshani et al., 1998; Turner and Salt, 1998). When activated through repetitive stimulation of the CT pathway, thalamic projection neurons exhibit frequency facilitation in both in vivo (Deschenes and Hu, 1990; Lindstrom and Wrobel, 1990) and in vitro studies (Pedroarena and Llinás, 1997; Turner and Salt, 1998; von Krosigk et al., 1999) and can modulate the dynamics of the synaptic input though dendritic oscillation (Pedroarena and Llinás, 2001), indicating that the weight of this input is modified according to the cortical and thalamic states of activity. However, since thalamocortical neurons (TN) exhibit a set of intrinsic voltage- and time-dependent ionic conductances (Llinás and Jahnsen, 1982; Jahnsen and Llinás, 1984a,b; Coulter et al., 1989; McCormick and Pape, 1990; Huguenard, 1996; Pedroarena and Llinás, 1997; Parri and Crunelli, 1998) that determine variable responsiveness according to the set of ionic conductances activated, it is likely that different responsive states of the TNs result in variable patterns of activity of the TC loop. This combination of distinct ionic conductances and firing modes in the context of the TC system has been suggested to form the basis for normal sensory binding in the awake and dreaming states (Llinás and Pare, 1991; Llinás et al., 1998).
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Furthermore, aberrations in these dynamics may also serve as the basis for a class of neurological and neuropsychiatric disorders (Llinás et al., 1999).
2. Normal cellular and thalamocortical dynamics 2.1. High-frequency thalamic neuron oscillation and thalamocortical resonance Cellular recordings in vivo and in vitro have demonstrated that the intrinsic oscillatory properties of thalamic and cortical neurons are well-suited to a system which facilitates coherence among its interconnected elements. The ionic mechanisms for gamma-band (30–50 Hz) sub-threshold oscillations have been uncovered in both cortical interneurons (Llinás and Pare, 1991) and at least a sub-population of pyramidal cells (Brumberg et al., 2000) and at thalamic neuron level (Pedroarena and Llinás, 1997), though the particular mechanisms underlying this mode of firing are specific to the neuron type. Thus, the high-frequency oscillations of sparsely spiny inhibitory cortical layer IV interneurons depend upon a persistent sodium conductance, while the fast oscillations of thalamocortical cells are based upon the activation of voltage-dependent calcium conductances. In the latter case, this calcium current—which is mostly supported by P channels—is preferentially located in dendrites, indicating that active oscillations occur in the dendritic compartment (Fig. 1) (Pedroarena and Llinás, 1997). At a circuit level, the recordings of thalamic gammarhythms suggest that high-frequency thalamic oscillations are supported in part by the intrinsic properties of thalamic neurons. The collective significance of these active dendritic oscillations lies in the fact that returning corticothalamic synapses terminate on the distal dendrites of thalamic cells (Landry et al., 1984; Liu et al., 1995; Steriade et al., 1998), providing a substrate for the interaction of rhythmic synaptic inputs with intrinsic dendritic oscillations (Pedroarena and Llinás, 2001). Thus, during waking and rapid-eye-movement (REM) sleep, thalamic depolarization, coupled with the geometry of synaptic inputs, provides an effective mechanism for TC coherence. Evidence consistent with this conception includes the observation that thalamic EPSPs evoked by pair-pulse stimulation of corticothalamic afferents demonstrate maximum facilitation at 25–30 ms (30–40 Hz) intervals (Pedroarena and Llinás, 1997; von Krosigk et al., 1999). The question of coherent electrical activity in the cortex and its relation to cognitive binding has been addressed by several authors in recent years (von der Malsburg, 1981; Eckhorn et al., 1988; Gray and Singer, 1989; Gray et al., 1989; Crick and Koch, 1990; Llinás, 1990; Llinás and Pare, 1991; Llinás and Ribary, 1993; Singer, 1993;). While it has been suggested by some that coherent events occur at the cortical level and that such cortical events are the primary binding substrate (Crick and Koch, 1990; Singer, 1993), others have proposed that the binding event must not be cortical, but
Fig. 1. Oscillatory properties of thalamic neurons and corticothalamic EPSPs: (A) direct activation of a thalamic cell evoked repetitive firing from +Vm to −60 mV when depolarized up to −37 mV, while a burst of spikes was triggered by the activation of a low threshold calcium spike from −Vm to −65 mV; (B) high-frequency sub-threshold oscillations were evoked by depolarizing the membrane potential (−46 and −43 mV) by protracted outward dc injection. The autocorrelogram in the inset corresponds to the −43 mV trace; (C) in a different neuron EPSPs were evoked by identical stimulation of the corticothalamic pathway at two different membrane potentials. Each trace is an average to 10 single stimulus. Note the increase in EPSPs amplitude when the membrane was −46 mV compared to control at −57 mV ((A) and (B) adapted from Pedroarena and Llin´as, 1997).
rather thalamocortical (Llinás, 1990; Llinás and Pare, 1991; Llinás and Ribary, 1993). Thus, results from studies using non-invasive magneto-encephalography (MEG) in humans (Ribary et al., 1991) and extra- and intracellular recordings in cats in vivo (Steriade and Amzica, 1996) indicate that gamma-band activity is not only present at the cortical level, but that such activity is supported by resonance between thalamic and cortical structures at gamma-band frequencies (20–50 Hz, often centered near 40 Hz) as initially proposed in relation to cognition (Llinás, 1990; Llinás and Pare, 1991). These results favor the hypothesis that cognitive events depend on activity involving thalamocortical resonant columns. 2.2. Low-frequency thalamic neuron oscillation and the LTS Other intrinsic electrical properties also play a crucial role in thalamocortical dynamics. Thus, hyperpolarization of thalamic neurons has been shown (Deschenes et al., 1982; Llinás and Jahnsen, 1982) to produce rebound firing known as low threshold spikes (LTS). These spikes
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are supported by the de-inactivation of rapidly inactivating calcium channels (T channels, IT ). The activation of these channels results in inward calcium current which leads to bursts of LTS; these, in turn, activate sodium-dependent action potentials (Llinás and Jahnsen, 1982; Jahnsen and Llinás, 1984a,b; McCormick and Pape, 1990; Pedroarena and Llinás, 1997; Parri and Crunelli, 1998). The specific mechanism for LTS has been studied in detail, and in particular, the significance of the various cation conductances has been demonstrated. Indeed McCormick and coworkers (McCormick and Pape, 1990; Bal and McCormick, 1996; Luthi and McCormick, 1999) have demonstrated the role of the Ih currents in rhythmogenesis. This rhythmicity has been also characterized in vivo with intracellular recordings in cats (Curro Dossi et al., 1992). The electrophysiological description of the range of cortical rhythms has been proposed to be directly related to different states of consciousness since the work of Berger (1929).
3. MEG imaging of thalamocortical activity in the human brain The modes of TC activation derived from in vitro and in vivo recordings described above, if correct and global in the mammalian brain, should have a correlate in human brain activity. Given the context of thalamocortical dysrhythmia (TCD) as the source for various neurological and psychiatric conditions, it is important to relate the electrophysiology described above in animals with single cell and macroscopic recordings in normal and in relevant patient populations. Such a possibility has been addressed with high temporal resolution MEG recording described here, and with single cell recordings as described in our companion paper (Jeanmonod et al., 2001). From an MEG perspective, it has been shown that the waking state and REM sleep state are electrically similar, with one crucial difference: while gamma-oscillations are reset by sensory input in awake subjects, sensory stimulation does not reset gamma-activity during REM sleep (Llinás and Ribary, 1993). This distinction suggests that the central difference between wakefulness and dreaming is that the former is a state molded by TC sensory input, while the latter is generated by intrinsic activity in the absence of sensory input. This issue is crucial in discussing TCD patients. We underline the fact that in the dreaming state, intrinsic electrical activity, grossly indistinguishable from the waking state, can generate true cognition. That is, that feelings and all other sensory images generated are, to the dreaming subject, as real as those generated in the awake state from the outside world. This is significant when considering events such as phantom limbs, which appear real even in the fully awake condition. Thus, it is important to develop a plausible set of hypotheses linking the waking state with dreaming and with the abnormal conditions represented by intrinsically
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generated sensations or by intrinsically generated motor activity. 3.1. MEG recording from normal controls Magneto-encephalographic data from normal controls indicate that cognitive binding is a non-continuous process whose content is provided by synchronous activity in the TC system (Ribary et al., 1991; Joliot et al., 1994). Furthermore, as stated above, such binding appears to involve the temporal conjunction of the specific and non-specific thalamic systems—particularly, the intralaminar complex (Llinás and Pare, 1991; Llinás and Ribary, 1993). Neurons in this medial thalamus complex project in a spatially-continuous manner to superficial layers of all cortical areas. Single intralaminar neurons have been shown to burst at 30–40 Hz (Steriade et al., 1993) (particularly, during REM sleep), and it has long been known that damage to the intralaminar system results in lethargy or coma (Facon et al., 1958; Castaigne et al., 1962). In order to convey a general idea of the type of information that can be obtained with such measurements examples of the global brain rhythmicity determined by MEG in normal individuals are shown in Fig. 2. Two aspects of these recordings are illustrated. In the first, a general quantification of the power components for the different frequencies recorded are plotted as a frequency spectrum. This plot describes the total power profile recorded from the 148 coils that sample magnetic activity over the head of the recorded individual. The plot shows that the normal profile of frequencies are characterized by an alpha-rhythm peak at close to 10 Hz with a power spectrum that diminishes in amplitude with respect to frequency from that maximum. The gamma-band frequency represents, at any time, a vital, but small component of the total power output of the brain, especially when taken as the total sum of power over a protracted time period. Indeed, gamma-activity as such is continuously varying and is restricted to rather small cortical patches (Ribary et al., 1991; Contreras et al., 1996) at any given moment. A totally different picture is obtained if one examines frequencies below the alpha-band (e.g. at theta-band frequencies (4–8 Hz)). Such frequencies also contribute low power under normal circumstances, but may be present during particular tasks such as memory trials (Sasaki et al., 1994). However, such rhythmicity is not constantly present in the frequency spectrum of normal individuals. In order to further clarify these measurements, we present a plot of the power spectrum for the eyes-open and eyes-closed conditions for a normal individual, together with an illustration of the difference between the two traces (Fig. 2). Similarly, if the frequency spectrum is plotted against itself, a measure of coherence between frequencies is obtained. In normal controls, such correlation plots yield a well-defined image indicating that low and high frequencies are not temporally coherent. This is expected as, indeed, low frequencies in the power spectrum represent low frequencies of thalamocortical rhythmicity, corresponding to
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Fig. 2. (A) Power frequency spectrum and coherence plot from a control subject. A results illustrate power spectra in conditions where eyes were closed (blue) compared to open (red). The difference between the two conditions (upper left panel) demonstrates, as expected, the classical increase in the power of the spectrum at alpha-band frequency. (B) A coherence plot demonstrating the lack of coherence across frequencies, for eyes-open and eyes-closed conditions in a healthy individual.
the low-frequency oscillatory activity observed in thalamic neurons during membrane hyperpolarization due either to inhibition or to disfacilitation (Curro Dossi et al., 1992). In contrast, thalamic depolarization due to synaptic input from the external world as it happens in the visual system when one opens one’s eyes, is accompanied by a diminution of alpha-rhythm and its substitution by gamma-band activity. Thus, low- and high-frequencies are normally not coherent as they represent different thalamocortical functional states. Such comparison in made between coherence profiles for eye-open and eye-closed conditions in Fig. 2. 3.2. MEG recording in TCD patients Following the reasoning presented above, it is reasonable to expect that if a portion of the thalamus were to be continuously hyperpolarized there would ensue in these patients protracted rhythmic LTS burst activity. Such continuous activity should recruit cortical feedback firing that should generate an abnormal low-frequency oscillatory attractor. Such abnormal and continuous re-entry should lead to the generation of large, complex, and almost invariant oscillatory states possibly correlated with abnormal brain
function. One possible example of this continuous rhythmic activation is the tremor of Parkinsonian patients (Llinás and Jahnsen, 1982; Llinás and Pare, 1991). Indeed, using MEG, Volkmann et al. (1996) confirmed this assumption in Parkinson’s disease. Independently from this effort, our clinical colleagues had been asking similar questions regarding Parkinson’s and neurological and psychiatric conditions. Indeed, it was found that the intraoperatively-obtained single cell recordings, described in the companion paper (Jeanmonod et al., 2001), related very nicely to the theta- and delta-domains, an observation consistent with refractory periods seen after the generation of LTS bursts. We considered the possible functional phenotypes that might be generated if such TCD (as we have termed this low-frequency thalamocortical resonance activity) were to occur in circuits other than the motor thalamocortical system responsible for Parkinson’s tremor. Employing advanced spectral analysis methods for accurate calculation of power, recordings from a cohort of subjects with a variety of symptoms demonstrated an increase of MEG power at the theta–delta interface and an associated increase of coherence both within this domain and between it and the beta-range (13–40 Hz) (Llinás et al.,
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Fig. 3. Power spectra and coherence plots for a set of TCD patients suffering from different aspects of this condition: (A) each power spectral plot represents a typical example for one of the six different pathological conditions described in each panel. In each case the same control plot (blue) is utilized as a reference; (B) comparison of the average power spectral plot for 26 patients and eight controls. Note the leftward frequency shift towards theta-rhythm in all six pathological cases, and in the average of all patients (n = 32) (red) when compared with the average from normal controls (n = 8) (blue); (C) a set of coherence plots for the same conditions illustrated in (A); and (D) a comparison of the average for a control population.
1999). Further MEG recordings in a larger subject population continue to support these initial results. Examples from several types of neurological and psychiatric conditions are illustrated as power spectrum plots and as coherence plots in Fig. 3A and B. The types of patients studied to this point are illustrated in Fig. 3. Quite possibly, this list does not cover all TCD phenotypes, and quite possibly, some patients of the described phenotypes may not generate the phenotype via TCD. Thus, far, our experience includes three of four neurogenic pain patients, patients with tinnitus (n = 4 out of 4)
neuropsychiatric diseases patients (n = 11 out of 11), including obsessive-compulsive disorder (OCD, n = 6), major depression (n = 2), and psychosis patients (n = 3), and a set of Parkinson’s patients (n = 5 out of 5). All these patients showed increased coherence between low frequencies and the beta-range. Careful analysis of one subject illustrates the dynamic variation which may be interpreted to underlie the transformation from normal to pathological activity. We shall discuss in detail (Jeanmonod et al., 2001) some of the intraoperative recordings and the surgical treatment of some of the patients suffering from TCD.
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4. Discussion 4.1. Cognition and its relation to thalamocortical dysrhythmia (TCD) Considering the generation of TCD, a hypothesis that can serve as the basis for such dysfunction is a variance of that proposed for the generation of cognition in the normal brain. That is, that the specific thalamocortical system works in temporal conjunction with the “non-specific” thalamic system, particularly, the intralaminar complex, and that as a result of such coincidence, a recurrent gamma-band activation of this loop is generated (Llinás and Pare, 1991; Llinás and Ribary, 1993). In this model, gamma-oscillations in neurons of the specific thalamic nuclei establish cortical resonance through direct activation of pyramidal cells and feed-forward inhibition through activation of 40 Hz inhibitory interneurons in layer IV (Llinás et al., 1991). These oscillations re-enter the thalamus via layer VI pyramidal cell axon collaterals, producing thalamic feedback inhibition via the reticular nucleus (Steriade et al., 1990). In the second system, the non-specific thalamic nuclei project to cortical layers I and VI and to the reticular nucleus. Layer V pyramidal cells would serve to return oscillatory activity to the intralaminar nuclei. Indeed, cells in this complex have been shown to oscillate at gamma-band frequency (Steriade et al., 1993) and to be capable of recursive activation. In this scheme (Llinás and Ribary, 1993; Llinás and Pare, 1991), cortical sites “peaking” at gamma-band frequency via specific thalamic activity would represent the different components of the cognitive world that have reached optimal activity at that time. The problem of the conjunction of such a fractured description into a single cognitive event, the binding function, could come about by the concurrent
summation of specific and non-specific 40 Hz activity along the radial dendritic axis of given cortical elements, that is, by coincidence detection via temporal coherence. In this fashion, the time-coherent activity of the specific and non-specific oscillatory inputs, by summing distal and proximal activity in given dendritic elements, would enhance de facto 40 Hz cortical coherence by their multimodal character, and in this way would provide one mechanism for global binding. The “specific” system would, thus, provide the content that relates to the external world and the non-specific system would give rise to the temporal conjunction, or the context (on the basis of a more interoceptive context concerned with alertness) (Llinás et al., 1994) that would together generate a single cognitive experience. In this context, then, TCD also involves a binding issue. The abnormal continuous activation of the specific thalamus must function in conjunction with the non-specific counterpart to generate a robust thalamocortical resonance a prerequisite in our hypothesis for the generation of the edge effect. In the companion paper, a second component relating to the role of the emotional realm and its relation to mesocortex will be addressed in detail. 4.2. Conflict in the cortex: the edge effect Concerning the mechanism for the generation of neurological and psychiatric conditions described above one crucial organizing feature of the cortex is its system of reciprocal corticocortical inhibition-mediated by GABAergic interneurons. Thus, it has been proposed (Llinás et al., 1999) that this lateral inhibitory component of the cortical circuit is crucial in the genesis of the so-called positive symptoms (see accompanying paper). The mechanism proposed for the generation of positive symptoms, the asymmetric neuronal activity generated at functional boundaries between
Fig. 4. MEG recordings from a psychotic patient before and after stereotaxic surgery: (A) comparison of power frequency spectrum before (red) and after (blue) surgery as described in the companion paper; (B) the coherence plots for the same two conditions as in (A).
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cortical modules continuously functioning at low-frequency and those functioning at high-frequency allow disinhibition of neighboring high-frequency regions (see Figs. 4 and 5). Evidence for such a phenomenon is provided by the increased interfrequency coherence seen between low- and high-frequencies on recordings of neuromagnetic activity in subjects with positive symptoms. Thus, as described in the accompanying paper, it has been proposed that dysrhythmia of particular cortical regions underlies the generation of corresponding positive symptoms. Thus, neurogenic pain may reflect aberrant activation of the insula, secondary somatosensory and cingulate cortices, and possibly also the posterior parietal and primary somatosensory cortices. Similarly, tremor may result from dysfunction of lateral motor and premotor cortex, while the anterior supplementary motor area (SMA) is likely to be dysrhythmic in Parkinsonian akinesia, and dysrhythmia in broad lateral and medial (SMA) sections of area six could produce dystonia. Tinnitus would follow improper activation of meso- and neo-cortical auditory and associative temporal areas, and prefrontal medial, orbitofrontal, and temporopolar meso- and neo-cortical areas could be dysrhythmic in major depression, obsessive-compulsive disorder and psychosis. Fig. 5. Diagram of the thalamocortical circuits that support the positive symptoms hypothesis. Two thalamocortical systems are shown, the specific pathway (yellow) to layer IV of the cortex, that activates layer VI cortical neurons and feed-forward inhibition via inhibitory cortical interneurons (red). Collaterals of these projections produce thalamic feedback inhibition via the reticular nucleus (red at thalamic level). The return pathway (circular arrow on the right) re-enters this oscillation to specificand reticularis-thalamic nuclei via layer VI pyramidal cells (blue). The second loop shows non-specific nuclei (green) projecting to the most superficial layer of the cortex and giving collaterals to the reticular nucleus. The conjunction of the specific and non-specific loops is proposed to generate temporal coherence (left panel). Protracted thalamic cell hyperpolarization by altered synaptic input triggers low-frequency neuronal oscillation (left panel). Either disfacilitation, as occurs after de-afferentation (as in neurogenic pain or tinnitus), or excess inhibition due to pallidal over-activity (as in Parkinson’s disease) hyperpolarize the cells sufficiently to de-inactivate of T-type calcium channels resulting in thalamic oscillation at theta-range. Such oscillation can entrain corticothalamic loops (left panel) generating increase coherence as observed in this study. At cortical level, low-frequency activation of corticocortical inhibitory interneurons, by reducing lateral inhibitory drive (dysinhibition) can result in high-frequency coherent activation of neighboring cortical modules, the “edge effect” (right panel) (adapted from Llin´as et al., 1999).
cells clusters related to each other via lateral inhibition, was termed the “edge effect”. This lateral inhibition-mediated phenomenon, originally discovered in the retina of limulus eye by Hartline (1949) and Hartline et al. (1956) was found to generate an artificial border, an edge of increased neuronal activity due to reduction of lateral inhibition between retinal ommatidia less illuminated and those more illuminated. This was accompanied by a reduction of activity at the opposite side of the edge. As in it happens physiologically at the retina, asymmetrical inhibition at the corticocortical level is proposed to generate a dysfunctional interface wherein decreased lateral inhibition from thalamo-
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Thalamocortical dysrhythmia I. Functional and imaging aspects R. Llinás a,∗ , U. Ribary a , D. Jeanmonod c , R. Cancro b , E. Kronberg a , J. Schulman a , M. Zonenshayn a , M. Magnin c , A. Morel c , M. Siegmund c a
Department of Physiology and Neuroscience, New York University School of Medicine, 550 First Avenue MSB-442, New York, NY 10016, USA b Department of Psychiatry, New York University School of Medicine, New York, NY, USA c Neurochirurgische Klinik, Universitatsspital Zurich, Zurich, Switzerland Accepted 2 October 2001
Abstract Thalamic and cortical neurons are richly and reciprocally interconnected and support recurrent functional loops in the intact brain, but the role of this circuitry is still poorly understood. Here, we present evidence—from cellular and from functional neuroimaging in control and clinical domains—that thalamocortical resonance is not only a prerequisite for normal cognition, but that its perturbation, in a dynamic sense (e.g. a dysrhythmia) can underlie a variety of neurological and psychiatric disorders. © 2001 Published by Elsevier Science Ltd. Keywords: Corticothalamic re-entry; Intrinsic properties; Burst firing; MEG; Edge effect
1. Introduction It is at present well documented that thalamic and cortical areas are mutually and robustly interconnected and that corticothalamic (CT) connections clearly outnumber their reciprocal thalamocortical (TC) counterparts (Steriade et al., 1990). Moreover, the thalamic dendritic arbor, a site known to generate calcium-dependent gamma-band sub-threshold oscillations (Pedroarena and Llinás, 1997), has most of its synaptic input arising from the overlaying cortex (Liu et al., 1995). Nevertheless, the functional role of the CT system has not been unambiguously elucidated. The temporal and spatial patterns of activity in cortical and thalamic areas demonstrate wide variability across different functional states, suggesting that such a “reverberating circuit” (Lorente de No, 1932) or re-entry function (Hebb, 1949; Edelman, 1992) could support a wide range of dynamic interactions (Llinás et al., 1998). Diverse anatomical and physiological evidence indicate that CT connectivity is excitatory and glutamatergic (Baughman and Gilbert, 1981; Giuffrida et al., 1988; Deschenes ∗ Corresponding author. Tel.: +1-212-263-5415; fax: +1-212-689-9060. E-mail address: [email protected] (R. Llin´as).
1472-9288/01/$ – see front matter © 2001 Published by Elsevier Science Ltd. PII: S 1 4 7 2 - 9 2 8 8 ( 0 1 ) 0 0 0 2 3 - 1
and Hu, 1990; McCormick and von Krosigk, 1992; Kao and Coulter, 1997; Golshani et al., 1998; Turner and Salt, 1998). When activated through repetitive stimulation of the CT pathway, thalamic projection neurons exhibit frequency facilitation in both in vivo (Deschenes and Hu, 1990; Lindstrom and Wrobel, 1990) and in vitro studies (Pedroarena and Llinás, 1997; Turner and Salt, 1998; von Krosigk et al., 1999) and can modulate the dynamics of the synaptic input though dendritic oscillation (Pedroarena and Llinás, 2001), indicating that the weight of this input is modified according to the cortical and thalamic states of activity. However, since thalamocortical neurons (TN) exhibit a set of intrinsic voltage- and time-dependent ionic conductances (Llinás and Jahnsen, 1982; Jahnsen and Llinás, 1984a,b; Coulter et al., 1989; McCormick and Pape, 1990; Huguenard, 1996; Pedroarena and Llinás, 1997; Parri and Crunelli, 1998) that determine variable responsiveness according to the set of ionic conductances activated, it is likely that different responsive states of the TNs result in variable patterns of activity of the TC loop. This combination of distinct ionic conductances and firing modes in the context of the TC system has been suggested to form the basis for normal sensory binding in the awake and dreaming states (Llinás and Pare, 1991; Llinás et al., 1998).
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Furthermore, aberrations in these dynamics may also serve as the basis for a class of neurological and neuropsychiatric disorders (Llinás et al., 1999).
2. Normal cellular and thalamocortical dynamics 2.1. High-frequency thalamic neuron oscillation and thalamocortical resonance Cellular recordings in vivo and in vitro have demonstrated that the intrinsic oscillatory properties of thalamic and cortical neurons are well-suited to a system which facilitates coherence among its interconnected elements. The ionic mechanisms for gamma-band (30–50 Hz) sub-threshold oscillations have been uncovered in both cortical interneurons (Llinás and Pare, 1991) and at least a sub-population of pyramidal cells (Brumberg et al., 2000) and at thalamic neuron level (Pedroarena and Llinás, 1997), though the particular mechanisms underlying this mode of firing are specific to the neuron type. Thus, the high-frequency oscillations of sparsely spiny inhibitory cortical layer IV interneurons depend upon a persistent sodium conductance, while the fast oscillations of thalamocortical cells are based upon the activation of voltage-dependent calcium conductances. In the latter case, this calcium current—which is mostly supported by P channels—is preferentially located in dendrites, indicating that active oscillations occur in the dendritic compartment (Fig. 1) (Pedroarena and Llinás, 1997). At a circuit level, the recordings of thalamic gammarhythms suggest that high-frequency thalamic oscillations are supported in part by the intrinsic properties of thalamic neurons. The collective significance of these active dendritic oscillations lies in the fact that returning corticothalamic synapses terminate on the distal dendrites of thalamic cells (Landry et al., 1984; Liu et al., 1995; Steriade et al., 1998), providing a substrate for the interaction of rhythmic synaptic inputs with intrinsic dendritic oscillations (Pedroarena and Llinás, 2001). Thus, during waking and rapid-eye-movement (REM) sleep, thalamic depolarization, coupled with the geometry of synaptic inputs, provides an effective mechanism for TC coherence. Evidence consistent with this conception includes the observation that thalamic EPSPs evoked by pair-pulse stimulation of corticothalamic afferents demonstrate maximum facilitation at 25–30 ms (30–40 Hz) intervals (Pedroarena and Llinás, 1997; von Krosigk et al., 1999). The question of coherent electrical activity in the cortex and its relation to cognitive binding has been addressed by several authors in recent years (von der Malsburg, 1981; Eckhorn et al., 1988; Gray and Singer, 1989; Gray et al., 1989; Crick and Koch, 1990; Llinás, 1990; Llinás and Pare, 1991; Llinás and Ribary, 1993; Singer, 1993;). While it has been suggested by some that coherent events occur at the cortical level and that such cortical events are the primary binding substrate (Crick and Koch, 1990; Singer, 1993), others have proposed that the binding event must not be cortical, but
Fig. 1. Oscillatory properties of thalamic neurons and corticothalamic EPSPs: (A) direct activation of a thalamic cell evoked repetitive firing from +Vm to −60 mV when depolarized up to −37 mV, while a burst of spikes was triggered by the activation of a low threshold calcium spike from −Vm to −65 mV; (B) high-frequency sub-threshold oscillations were evoked by depolarizing the membrane potential (−46 and −43 mV) by protracted outward dc injection. The autocorrelogram in the inset corresponds to the −43 mV trace; (C) in a different neuron EPSPs were evoked by identical stimulation of the corticothalamic pathway at two different membrane potentials. Each trace is an average to 10 single stimulus. Note the increase in EPSPs amplitude when the membrane was −46 mV compared to control at −57 mV ((A) and (B) adapted from Pedroarena and Llin´as, 1997).
rather thalamocortical (Llinás, 1990; Llinás and Pare, 1991; Llinás and Ribary, 1993). Thus, results from studies using non-invasive magneto-encephalography (MEG) in humans (Ribary et al., 1991) and extra- and intracellular recordings in cats in vivo (Steriade and Amzica, 1996) indicate that gamma-band activity is not only present at the cortical level, but that such activity is supported by resonance between thalamic and cortical structures at gamma-band frequencies (20–50 Hz, often centered near 40 Hz) as initially proposed in relation to cognition (Llinás, 1990; Llinás and Pare, 1991). These results favor the hypothesis that cognitive events depend on activity involving thalamocortical resonant columns. 2.2. Low-frequency thalamic neuron oscillation and the LTS Other intrinsic electrical properties also play a crucial role in thalamocortical dynamics. Thus, hyperpolarization of thalamic neurons has been shown (Deschenes et al., 1982; Llinás and Jahnsen, 1982) to produce rebound firing known as low threshold spikes (LTS). These spikes
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are supported by the de-inactivation of rapidly inactivating calcium channels (T channels, IT ). The activation of these channels results in inward calcium current which leads to bursts of LTS; these, in turn, activate sodium-dependent action potentials (Llinás and Jahnsen, 1982; Jahnsen and Llinás, 1984a,b; McCormick and Pape, 1990; Pedroarena and Llinás, 1997; Parri and Crunelli, 1998). The specific mechanism for LTS has been studied in detail, and in particular, the significance of the various cation conductances has been demonstrated. Indeed McCormick and coworkers (McCormick and Pape, 1990; Bal and McCormick, 1996; Luthi and McCormick, 1999) have demonstrated the role of the Ih currents in rhythmogenesis. This rhythmicity has been also characterized in vivo with intracellular recordings in cats (Curro Dossi et al., 1992). The electrophysiological description of the range of cortical rhythms has been proposed to be directly related to different states of consciousness since the work of Berger (1929).
3. MEG imaging of thalamocortical activity in the human brain The modes of TC activation derived from in vitro and in vivo recordings described above, if correct and global in the mammalian brain, should have a correlate in human brain activity. Given the context of thalamocortical dysrhythmia (TCD) as the source for various neurological and psychiatric conditions, it is important to relate the electrophysiology described above in animals with single cell and macroscopic recordings in normal and in relevant patient populations. Such a possibility has been addressed with high temporal resolution MEG recording described here, and with single cell recordings as described in our companion paper (Jeanmonod et al., 2001). From an MEG perspective, it has been shown that the waking state and REM sleep state are electrically similar, with one crucial difference: while gamma-oscillations are reset by sensory input in awake subjects, sensory stimulation does not reset gamma-activity during REM sleep (Llinás and Ribary, 1993). This distinction suggests that the central difference between wakefulness and dreaming is that the former is a state molded by TC sensory input, while the latter is generated by intrinsic activity in the absence of sensory input. This issue is crucial in discussing TCD patients. We underline the fact that in the dreaming state, intrinsic electrical activity, grossly indistinguishable from the waking state, can generate true cognition. That is, that feelings and all other sensory images generated are, to the dreaming subject, as real as those generated in the awake state from the outside world. This is significant when considering events such as phantom limbs, which appear real even in the fully awake condition. Thus, it is important to develop a plausible set of hypotheses linking the waking state with dreaming and with the abnormal conditions represented by intrinsically
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generated sensations or by intrinsically generated motor activity. 3.1. MEG recording from normal controls Magneto-encephalographic data from normal controls indicate that cognitive binding is a non-continuous process whose content is provided by synchronous activity in the TC system (Ribary et al., 1991; Joliot et al., 1994). Furthermore, as stated above, such binding appears to involve the temporal conjunction of the specific and non-specific thalamic systems—particularly, the intralaminar complex (Llinás and Pare, 1991; Llinás and Ribary, 1993). Neurons in this medial thalamus complex project in a spatially-continuous manner to superficial layers of all cortical areas. Single intralaminar neurons have been shown to burst at 30–40 Hz (Steriade et al., 1993) (particularly, during REM sleep), and it has long been known that damage to the intralaminar system results in lethargy or coma (Facon et al., 1958; Castaigne et al., 1962). In order to convey a general idea of the type of information that can be obtained with such measurements examples of the global brain rhythmicity determined by MEG in normal individuals are shown in Fig. 2. Two aspects of these recordings are illustrated. In the first, a general quantification of the power components for the different frequencies recorded are plotted as a frequency spectrum. This plot describes the total power profile recorded from the 148 coils that sample magnetic activity over the head of the recorded individual. The plot shows that the normal profile of frequencies are characterized by an alpha-rhythm peak at close to 10 Hz with a power spectrum that diminishes in amplitude with respect to frequency from that maximum. The gamma-band frequency represents, at any time, a vital, but small component of the total power output of the brain, especially when taken as the total sum of power over a protracted time period. Indeed, gamma-activity as such is continuously varying and is restricted to rather small cortical patches (Ribary et al., 1991; Contreras et al., 1996) at any given moment. A totally different picture is obtained if one examines frequencies below the alpha-band (e.g. at theta-band frequencies (4–8 Hz)). Such frequencies also contribute low power under normal circumstances, but may be present during particular tasks such as memory trials (Sasaki et al., 1994). However, such rhythmicity is not constantly present in the frequency spectrum of normal individuals. In order to further clarify these measurements, we present a plot of the power spectrum for the eyes-open and eyes-closed conditions for a normal individual, together with an illustration of the difference between the two traces (Fig. 2). Similarly, if the frequency spectrum is plotted against itself, a measure of coherence between frequencies is obtained. In normal controls, such correlation plots yield a well-defined image indicating that low and high frequencies are not temporally coherent. This is expected as, indeed, low frequencies in the power spectrum represent low frequencies of thalamocortical rhythmicity, corresponding to
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Fig. 2. (A) Power frequency spectrum and coherence plot from a control subject. A results illustrate power spectra in conditions where eyes were closed (blue) compared to open (red). The difference between the two conditions (upper left panel) demonstrates, as expected, the classical increase in the power of the spectrum at alpha-band frequency. (B) A coherence plot demonstrating the lack of coherence across frequencies, for eyes-open and eyes-closed conditions in a healthy individual.
the low-frequency oscillatory activity observed in thalamic neurons during membrane hyperpolarization due either to inhibition or to disfacilitation (Curro Dossi et al., 1992). In contrast, thalamic depolarization due to synaptic input from the external world as it happens in the visual system when one opens one’s eyes, is accompanied by a diminution of alpha-rhythm and its substitution by gamma-band activity. Thus, low- and high-frequencies are normally not coherent as they represent different thalamocortical functional states. Such comparison in made between coherence profiles for eye-open and eye-closed conditions in Fig. 2. 3.2. MEG recording in TCD patients Following the reasoning presented above, it is reasonable to expect that if a portion of the thalamus were to be continuously hyperpolarized there would ensue in these patients protracted rhythmic LTS burst activity. Such continuous activity should recruit cortical feedback firing that should generate an abnormal low-frequency oscillatory attractor. Such abnormal and continuous re-entry should lead to the generation of large, complex, and almost invariant oscillatory states possibly correlated with abnormal brain
function. One possible example of this continuous rhythmic activation is the tremor of Parkinsonian patients (Llinás and Jahnsen, 1982; Llinás and Pare, 1991). Indeed, using MEG, Volkmann et al. (1996) confirmed this assumption in Parkinson’s disease. Independently from this effort, our clinical colleagues had been asking similar questions regarding Parkinson’s and neurological and psychiatric conditions. Indeed, it was found that the intraoperatively-obtained single cell recordings, described in the companion paper (Jeanmonod et al., 2001), related very nicely to the theta- and delta-domains, an observation consistent with refractory periods seen after the generation of LTS bursts. We considered the possible functional phenotypes that might be generated if such TCD (as we have termed this low-frequency thalamocortical resonance activity) were to occur in circuits other than the motor thalamocortical system responsible for Parkinson’s tremor. Employing advanced spectral analysis methods for accurate calculation of power, recordings from a cohort of subjects with a variety of symptoms demonstrated an increase of MEG power at the theta–delta interface and an associated increase of coherence both within this domain and between it and the beta-range (13–40 Hz) (Llinás et al.,
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Fig. 3. Power spectra and coherence plots for a set of TCD patients suffering from different aspects of this condition: (A) each power spectral plot represents a typical example for one of the six different pathological conditions described in each panel. In each case the same control plot (blue) is utilized as a reference; (B) comparison of the average power spectral plot for 26 patients and eight controls. Note the leftward frequency shift towards theta-rhythm in all six pathological cases, and in the average of all patients (n = 32) (red) when compared with the average from normal controls (n = 8) (blue); (C) a set of coherence plots for the same conditions illustrated in (A); and (D) a comparison of the average for a control population.
1999). Further MEG recordings in a larger subject population continue to support these initial results. Examples from several types of neurological and psychiatric conditions are illustrated as power spectrum plots and as coherence plots in Fig. 3A and B. The types of patients studied to this point are illustrated in Fig. 3. Quite possibly, this list does not cover all TCD phenotypes, and quite possibly, some patients of the described phenotypes may not generate the phenotype via TCD. Thus, far, our experience includes three of four neurogenic pain patients, patients with tinnitus (n = 4 out of 4)
neuropsychiatric diseases patients (n = 11 out of 11), including obsessive-compulsive disorder (OCD, n = 6), major depression (n = 2), and psychosis patients (n = 3), and a set of Parkinson’s patients (n = 5 out of 5). All these patients showed increased coherence between low frequencies and the beta-range. Careful analysis of one subject illustrates the dynamic variation which may be interpreted to underlie the transformation from normal to pathological activity. We shall discuss in detail (Jeanmonod et al., 2001) some of the intraoperative recordings and the surgical treatment of some of the patients suffering from TCD.
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4. Discussion 4.1. Cognition and its relation to thalamocortical dysrhythmia (TCD) Considering the generation of TCD, a hypothesis that can serve as the basis for such dysfunction is a variance of that proposed for the generation of cognition in the normal brain. That is, that the specific thalamocortical system works in temporal conjunction with the “non-specific” thalamic system, particularly, the intralaminar complex, and that as a result of such coincidence, a recurrent gamma-band activation of this loop is generated (Llinás and Pare, 1991; Llinás and Ribary, 1993). In this model, gamma-oscillations in neurons of the specific thalamic nuclei establish cortical resonance through direct activation of pyramidal cells and feed-forward inhibition through activation of 40 Hz inhibitory interneurons in layer IV (Llinás et al., 1991). These oscillations re-enter the thalamus via layer VI pyramidal cell axon collaterals, producing thalamic feedback inhibition via the reticular nucleus (Steriade et al., 1990). In the second system, the non-specific thalamic nuclei project to cortical layers I and VI and to the reticular nucleus. Layer V pyramidal cells would serve to return oscillatory activity to the intralaminar nuclei. Indeed, cells in this complex have been shown to oscillate at gamma-band frequency (Steriade et al., 1993) and to be capable of recursive activation. In this scheme (Llinás and Ribary, 1993; Llinás and Pare, 1991), cortical sites “peaking” at gamma-band frequency via specific thalamic activity would represent the different components of the cognitive world that have reached optimal activity at that time. The problem of the conjunction of such a fractured description into a single cognitive event, the binding function, could come about by the concurrent
summation of specific and non-specific 40 Hz activity along the radial dendritic axis of given cortical elements, that is, by coincidence detection via temporal coherence. In this fashion, the time-coherent activity of the specific and non-specific oscillatory inputs, by summing distal and proximal activity in given dendritic elements, would enhance de facto 40 Hz cortical coherence by their multimodal character, and in this way would provide one mechanism for global binding. The “specific” system would, thus, provide the content that relates to the external world and the non-specific system would give rise to the temporal conjunction, or the context (on the basis of a more interoceptive context concerned with alertness) (Llinás et al., 1994) that would together generate a single cognitive experience. In this context, then, TCD also involves a binding issue. The abnormal continuous activation of the specific thalamus must function in conjunction with the non-specific counterpart to generate a robust thalamocortical resonance a prerequisite in our hypothesis for the generation of the edge effect. In the companion paper, a second component relating to the role of the emotional realm and its relation to mesocortex will be addressed in detail. 4.2. Conflict in the cortex: the edge effect Concerning the mechanism for the generation of neurological and psychiatric conditions described above one crucial organizing feature of the cortex is its system of reciprocal corticocortical inhibition-mediated by GABAergic interneurons. Thus, it has been proposed (Llinás et al., 1999) that this lateral inhibitory component of the cortical circuit is crucial in the genesis of the so-called positive symptoms (see accompanying paper). The mechanism proposed for the generation of positive symptoms, the asymmetric neuronal activity generated at functional boundaries between
Fig. 4. MEG recordings from a psychotic patient before and after stereotaxic surgery: (A) comparison of power frequency spectrum before (red) and after (blue) surgery as described in the companion paper; (B) the coherence plots for the same two conditions as in (A).
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cortical modules continuously functioning at low-frequency and those functioning at high-frequency allow disinhibition of neighboring high-frequency regions (see Figs. 4 and 5). Evidence for such a phenomenon is provided by the increased interfrequency coherence seen between low- and high-frequencies on recordings of neuromagnetic activity in subjects with positive symptoms. Thus, as described in the accompanying paper, it has been proposed that dysrhythmia of particular cortical regions underlies the generation of corresponding positive symptoms. Thus, neurogenic pain may reflect aberrant activation of the insula, secondary somatosensory and cingulate cortices, and possibly also the posterior parietal and primary somatosensory cortices. Similarly, tremor may result from dysfunction of lateral motor and premotor cortex, while the anterior supplementary motor area (SMA) is likely to be dysrhythmic in Parkinsonian akinesia, and dysrhythmia in broad lateral and medial (SMA) sections of area six could produce dystonia. Tinnitus would follow improper activation of meso- and neo-cortical auditory and associative temporal areas, and prefrontal medial, orbitofrontal, and temporopolar meso- and neo-cortical areas could be dysrhythmic in major depression, obsessive-compulsive disorder and psychosis. Fig. 5. Diagram of the thalamocortical circuits that support the positive symptoms hypothesis. Two thalamocortical systems are shown, the specific pathway (yellow) to layer IV of the cortex, that activates layer VI cortical neurons and feed-forward inhibition via inhibitory cortical interneurons (red). Collaterals of these projections produce thalamic feedback inhibition via the reticular nucleus (red at thalamic level). The return pathway (circular arrow on the right) re-enters this oscillation to specificand reticularis-thalamic nuclei via layer VI pyramidal cells (blue). The second loop shows non-specific nuclei (green) projecting to the most superficial layer of the cortex and giving collaterals to the reticular nucleus. The conjunction of the specific and non-specific loops is proposed to generate temporal coherence (left panel). Protracted thalamic cell hyperpolarization by altered synaptic input triggers low-frequency neuronal oscillation (left panel). Either disfacilitation, as occurs after de-afferentation (as in neurogenic pain or tinnitus), or excess inhibition due to pallidal over-activity (as in Parkinson’s disease) hyperpolarize the cells sufficiently to de-inactivate of T-type calcium channels resulting in thalamic oscillation at theta-range. Such oscillation can entrain corticothalamic loops (left panel) generating increase coherence as observed in this study. At cortical level, low-frequency activation of corticocortical inhibitory interneurons, by reducing lateral inhibitory drive (dysinhibition) can result in high-frequency coherent activation of neighboring cortical modules, the “edge effect” (right panel) (adapted from Llin´as et al., 1999).
cells clusters related to each other via lateral inhibition, was termed the “edge effect”. This lateral inhibition-mediated phenomenon, originally discovered in the retina of limulus eye by Hartline (1949) and Hartline et al. (1956) was found to generate an artificial border, an edge of increased neuronal activity due to reduction of lateral inhibition between retinal ommatidia less illuminated and those more illuminated. This was accompanied by a reduction of activity at the opposite side of the edge. As in it happens physiologically at the retina, asymmetrical inhibition at the corticocortical level is proposed to generate a dysfunctional interface wherein decreased lateral inhibition from thalamo-
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