Thalamus

&
ELSEVIER Thalamus & Related Systems 1 (2001) 237-244
Related Systems
www.elsevier.com/locate/tharel

Thalamocortical dysrhythmia I.
Functional and imaging aspects
R. Llinas a'*, U. Ribarya, D. Jeanmonodc, R. Cancro b , E. Kronberga, J. Schulmana,
M. Zonenshayna, M. Magninc, A. Morel c , M. Siegmundc
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 cor-
ticothalamic (CT) connections clearly outnumber their re-
ciprocal 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 Llinas, 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 spa-
tial patterns of activity in cortical and thalamic areas demon-
strate wide variability across different functional states, sug-
gesting 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 (Llinas
et al., 1998).
Diverse anatomical and physiological evidence indicate
that CT connectivity is excitatory and glutamatergic (Baugh-
man and Gilbert, 1981; Giuffrida et al., 1988; Deschenes
•Corresponding author. Tel.: +1-212-263-5415; fax: +1-212-689-9060.
E-mail address: Ilinar01@popmail.med.nyu.edu (R. Llinas).
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; Lind-
strom and Wrobel, 1990) and in vitro studies (Pedroarena
and Llinas, 1997; Turner and Salt, 1998; von Krosigk et al.,
1999) and can modulate the dynamics of the synaptic input
though dendritic oscillation (Pedroarena and Lima's, 2001),
indicating that the weight of this input is modified accord-
ing to the cortical and thalamic states of activity. However,
since thalamocortical neurons (TN) exhibit a set of intrin-
sic voltage- and time-dependent ionic conductances (Lima's
and Jahnsen, 1982; Jahnsen and Llinas, 1984a,b; Coulter
et al., 1989; McCormick and Pape, 1990; Huguenard, 1996;
Pedroarena and Llinas, 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 (Llinas and Pare, 1991; Llinas et al., 1998).

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238 R. Llinds et al./Thalamus & Related Systems 1 (2001) 237-244
Furthermore, aberrations in these dynamics may also serve
as the basis for a class of neurological and neuropsychiatric
disorders (Llinds 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 cor-
tical 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 os-
cillations have been uncovered in both cortical intemeurons
(Llinds and Pare, 1991) and at least a sub-population of pyra-
midal cells (Brumberg et al., 2000) and at thalamic neuron
level (Pedroarena and Llinds, 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 intemeurons de-
pend upon a persistent sodium conductance, while the fast
oscillations of thalamocortical cells are based upon the ac-
tivation of voltage-dependent calcium conductances. In the
latter case, this calcium current—which is mostly supported
by P channels—is preferentially located in dendrites, indi-
cating that active oscillations occur in the dendritic compart-
ment (Fig. 1) (Pedroarena and Llinds, 1997).
At a circuit level, the recordings of thalamic gamma-
rhythms 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
Llinds, 2001). Thus, during waking and rapid-eye-movement
(REM) sleep, thalamic depolarization, coupled with the ge-
ometry of synaptic inputs, provides an effective mechanism
for TC coherence. Evidence consistent with this concep-
tion includes the observation that thalamic EPSPs evoked by
pair-pulse stimulation of corticothalamic afferents demon-
strate maximum facilitation at 25-30 ms (30-40 Hz) inter-
vals (Pedroarena and Llinds, 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; Eck-
horn et al., 1988; Gray and Singer, 1989; Gray et al., 1989;
Crick and Koch, 1990; Llinds, 1990; Llinds and Pare, 1991;
Llinds 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
(A)
20 mV
-66mV;
OnA • iinA
20 ms
37.5 Hz
(B)
. 50 msr
- 4 3 mV v V W l A W J \ M ^ s / ^ ^ ^
-46 mV ^^«Av»*y<*vw^<<*^^/W*^^
-66 mV 10 mV
200 ms
(C) Corticothalamic EPSPS
- 4 6 mV 4mV
-57 mV-
20 ms
Fig. 1. Oscillatory properties of thalamic neurons and corticothalamic
EPSPs: (A) direct activation of a thalamic cell evoked repetitive firing
from +V m 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 - 4 3 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 Llinas, 1997).
rather thalamocortical (Llinds, 1990; Llinds and Pare, 1991;
Llinds and Ribary, 1993). Thus, results from studies using
non-invasive magneto-encephalography (MEG) in humans
(Ribary et al., 1991) and extra- and intracellular record-
ings 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 be-
tween thalamic and cortical structures at gamma-band fre-
quencies (20-50 Hz, often centered near 40 Hz) as initially
proposed in relation to cognition (Llinas, 1990; Llinas and
Pare, 1991). These results favor the hypothesis that cogni-
tive events depend on activity involving thalamocortical res-
onant 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; Llinds and Jahnsen, 1982) to produce rebound fir-
ing known as low threshold spikes (LTS). These spikes
 R. Hinds et al./Thalamus & Related Systems 1 (2001) 237-244
are supported by the de-inactivation of rapidly inactivating
calcium channels (T channels, h). The activation of these
channels results in inward calcium current which leads to
bursts of LTS; these, in turn, activate sodium-dependent
action potentials (Llinds and Jahnsen, 1982; Jahnsen and
Llinds, 1984a,b; McCormick and Pape, 1990; Pedroarena
and Llinds, 1997; Parri and Crunelli, 1998). The specific
mechanism for LTS has been studied in detail, and in par-
ticular, 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 /h 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 cor-
tical 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 hu-
man brain activity. Given the context of thalamocortical
dysrhythmia (TCD) as the source for various neurologi-
cal 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 stimu-
lation does not reset gamma-activity during REM sleep
(Lima's 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 sen-
sory 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 sub-
ject, 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
239
generated sensations or by intrinsically generated motor
activity.
3.1. MEG recording from normal controls
Magneto-encephalographic data from normal controls in-
dicate 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 tem-
poral conjunction of the specific and non-specific thalamic
systems—particularly, the intralaminar complex (Lima's and
Pare, 1991; Llin&s and Ribary, 1993). Neurons in this medial
thalamus complex project in a spatially-continuous manner
to superficial layers of all cortical areas. Single intralami-
nar 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 record-
ings 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 compo-
nent of the total power output of the brain, especially when
taken as the total sum of power over a protracted time pe-
riod. Indeed, gamma-activity as such is continuously vary-
ing 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 fre-
quencies (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 con-
ditions 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 it-
self, a measure of coherence between frequencies is ob-
tained. 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 fre-
quencies of thalamocortical rhythmicity, corresponding to
240 R. Llinds et al./Thalamus & Related Systems 1 (2001) 237-244
Eyes Closed & Eyes Open
10 20
(A) Frequency, [Hz]
Eyes Closed
10 20 30
(B) Frequency, [Hz]
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 contin-
uously hyperpolarized there would ensue in these patients
protracted rhythmic LTS burst activity. Such continuous ac-
tivity should recruit cortical feedback firing that should gen-
erate an abnormal low-frequency oscillatory attractor.
Such abnormal and continuous re-entry should lead to
the generation of large, complex, and almost invariant os-
cillatory states possibly correlated with abnormal brain
Average Open / Average Closed
0.7
a
0
^0.3
Q)
W
0
Qo.1
-0.1
30 10 20 30
Frequency, [Hz]
Eyes Open
10 20 30
Frequency, [Hz]
function. One possible example of this continuous rhythmic
activation is the tremor of Parkinsonian patients (Llinds
and Jahnsen, 1982; Llinas and Pare, 1991). Indeed, using
MEG, Volkmann et al. (1996) confirmed this assumption in
Parkinson's disease. Independently from this effort, our clin-
ical colleagues had been asking similar questions regarding
Parkinson's and neurological and psychiatric conditions. In-
deed, it was found that the intraoperatively-obtained single
cell recordings, described in the companion paper (Jean-
monod et al., 2001), related very nicely to the theta- and
delta-domains, an observation consistent with refractory pe-
riods 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 tha-
lamocortical resonance activity) were to occur in circuits
other than the motor thalamocortical system responsible for
Parkinson's tremor.
Employing advanced spectral analysis methods for ac-
curate calculation of power, recordings from a cohort of
subjects with a variety of symptoms demonstrated an in-
crease 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) (Llinas et al.,
 R. Llinds et al./Thalamus & Related Systems 1 (2001) 237-244 241

Obsessive-Compulsive Neurogenic Pain Parkinson's Disease Controls and TCD

10 20 30 40 10 20 20 3O 4O
Frequency, [Hz]
Frequency, [Hz]
Psychosis Tinnitus Depression
Average TCD / Average controls

10

10 20 30
10 20 30 40
Frequency, [Hz]

Controls, average
Obsessive-Compulsive Neurogenic Pain Parkinson's Disease
40 ^ ^ ^ ^ ^ ^ ^ M 401

.0.5
10.4
10 20 30
0 10 20 30 40 10 20 30 40 0 10 20 30 40 10.3 Frequency, [Hz]
Frequency, [Hz]
10.2
Patients, average

Psychosis Tinnitus Depression 10.1

•o

10 20 30
10 20 30 40 0 10 20 30 40 Frequency, [Hz]

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 popula-
tion 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 de-
scribed phenotypes may not generate the phenotype via
TCD. Thus, far, our experience includes three of four neu-
rogenic 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 frequen-
cies and the beta-range. Careful analysis of one subject
illustrates the dynamic variation which may be interpreted
to underlie the transformation from normal to pathologi-
cal 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.
242 R. Llinds et al./Thalamus & Related Systems 1 (2001) 237-244
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 sys-
tem, particularly, the intralaminar complex, and that as a re-
sult of such coincidence, a recurrent gamma-band activation
of this loop is generated (Llinds and Pare, 1991; Llinds and
Ribary, 1993).
In this model, gamma-oscillations in neurons of the spe-
cific thalamic nuclei establish cortical resonance through
direct activation of pyramidal cells and feed-forward inhi-
bition through activation of 40 Hz inhibitory interneurons
in layer IV (Llinds 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 (Llinds and Ribary, 1993; Llinds 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 opti-
mal 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
101 20
10
Frequency, [Hz]
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).
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 prox-
imal activity in given dendritic elements, would enhance de
facto 40 Hz cortical coherence by their multimodal char-
acter, and in this way would provide one mechanism for
global binding. The "specific" system would, thus, pro-
vide the content that relates to the external world and the
non-specific system would give rise to the temporal con-
junction, or the context (on the basis of a more interoceptive
context concerned with alertness) (Llinds 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 counter-
part to generate a robust thalamocortical resonance a prereq-
uisite 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 neu-
rological and psychiatric conditions described above one
crucial organizing feature of the cortex is its system of re-
ciprocal corticocortical inhibition-mediated by GABAergic
interneurons. Thus, it has been proposed (Llinds 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 neu-
ronal activity generated at functional boundaries between
Psychosis Pre-surgery
10 20 30 40
Psychosis Pre-surgery
30
10 20 30 40
Frequency, [Hz]
 R. Llinds et al./Thalamus & Related Systems 1 (2001) 237-244
- SYMPTOMS + SYMPTOMS
LOW FREQUENCY HIGH FREQUENCY
OSCILLATION "EDGE EFFECT"
Fig. 5. Diagram of the thalamocortical circuits that support the positive
symptoms hypothesis. Two thalamocortical systems are shown, the spe-
cific pathway (yellow) to layer IV of the cortex, that activates layer VI
cortical neurons and feed-forward inhibition via inhibitory cortical in-
terneurons (red). Collaterals of these projections produce thalamic feed-
back inhibition via the reticular nucleus (red at thalamic level). The return
pathway (circular arrow on the right) re-enters this oscillation to specific-
and reticularis-thalamic nuclei via layer VI pyramidal cells (blue). The
second loop shows non-specific nuclei (green) projecting to the most su-
perficial 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 hyper-
polarization by altered synaptic input triggers low-frequency neuronal os-
cillation (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 oscil-
lation 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 in-
terneurons, by reducing lateral inhibitory drive (dysinhibition) can result
in high-frequency coherent activation of neighboring cortical modules,
the "edge effect" (right panel) (adapted from Llinas 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 limu-
lus 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 be-
tween retinal ommatidia less illuminated and those more
illuminated. This was accompanied by a reduction of ac-
tivity 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-
243
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 in-
creased 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 un-
derlies 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 somatosen-
sory cortices. Similarly, tremor may result from dysfunc-
tion of lateral motor and premotor cortex, while the ante-
rior supplementary motor area (SMA) is likely to be dys-
rhythmic in Parkinsonian akinesia, and dysrhythmia in broad
lateral and medial (SMA) sections of area six could pro-
duce dystonia. Tinnitus would follow improper activation of
meso- and neo-cortical auditory and associative temporal ar-
eas, and prefrontal medial, orbitofrontal, and temporopolar
meso- and neo-cortical areas could be dysrhythmic in major
depression, obsessive-compulsive disorder and psychosis.
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