- Email: [email protected]
Thalamocortical dysrhythmia II.
Thalamus & Related Systems 1 (2001) 245–254
Thalamocortical dysrhythmia II. Clinical and surgical aspects D. Jeanmonod a,∗ , M. Magnin a , A. Morel a , M. Siegemund a , A. Cancro b , M. Lanz c , R. Llinás d , U. Ribary d , E. Kronberg d , J. Schulman d , M. Zonenshayn d a
Neurochirurgische Klinik, Lab. for Functional Neurosurgery, Universitätsspital Zürich, Sternwartstrasse 6, 8091 Zürich, Switzerland b Department of Psychiatry, New York University School of Medicine, New York, NY, USA c Psychiatrie-Zentrum Hard, Zürich, Switzerland d Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY, USA Accepted 2 October 2001
Abstract The companion paper (Llinás et al., 2001) presents evidence, at both cellular and network levels, for the role of resonant oscillatory thalamocortical properties in normal and pathological brain function. Here we present confirmatory single cell electrophysiology from the thalami of thalamocortical dysrhythmia (TCD) patients and review our surgical approach towards the relief of this chronic disabling condition, in its many forms. The goal of surgery is a rebalancing of the abnormal thalamocortical oscillation responsible for TCD. Our approach uses small strategically placed pre-thalamic and medial thalamic lesions that serve to make subcritical the low frequency thalamocortical reentry network attractor via desinhibition and desamplification. The lesions address classical and new stereotactic targets that provide therapeutic efficiency coupled with the sparing of the specific thalamocortical loops. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Low threshold calcium spike bursts; Positive symptoms; Medial thalamotomy; Pallidothalamic tractotomy
1. Introduction The companion paper (Llinás et al., 2001) describes, at the experimental level, the cellular and network properties that we invoke as responsible for the thalamocortical resonant oscillations that underlie normal hemispheric brain functions. Based on such physiological evidence as well as on human thalamic unit recordings (Jeanmonod et al., 1996) and magneto-encephalography (Llinás et al., 1999), we proposed that a single global mechanism, involving the thalamocortical reentrance loop, is responsible for the generation of the five domains of positive/negative symptoms that characterize the so-called thalamocortical dysrhythmia (TCD). These domains comprise motor disorders (e.g. Parkinson’s disease), neurogenic pain (after central and peripheral lesions of the somatosensory system), tinnitus, neuropsychiatric disorders (including psychosis, obsessive compulsive disease and major depression) and epilepsy. A schematic description of the TCD mechanisms is given in Fig. 5 of the companion paper (Llinás et al., 2001). The primary factor for the generation of TCD is the presence of ∗ Corresponding author. Tel.: +41-1-255-3580; fax: +41-1-255-8946. E-mail address: [email protected] (D. Jeanmonod).
protracted neuronal hyperpolarization due to disfacilitation (Curro et al., 1992) or overinhibition of thalamic neurons, either from above (cortical lesion), from below (decrease of peripheral afferent inputs to the thalamus), from an alteration of basal ganglia or cerebellar inputs, or from thalamic lesions. Thalamic cells are thus, hyperpolarized and set in low threshold calcium spike (LTS) burst production mode, with a rhythmicity locked in the theta–delta range (Jeanmonod et al., 1996). This thalamic low frequency rhythmicity recruits, via resonant oscillatory thalamocortical interactions, the related cortical structures (Llinás et al., 1999, 2001). Divergent corticothalamic, corticoreticular and reticulothalamic projections provide the anatomical basis for a progressive march of these low frequencies to neighboring thalamocortical loops, as indicated by the increased coherence observed in MEG (Llinás et al., 1999, 2001). This phase is proposed to correlate with the appearance of deficits, or negative symptoms, in the same way as delta low frequencies correlate with unconsciousness in slow wave sleep. The last step of this TCD chain reaction is most likely cortical, through asymmetrical corticocortical inhibition: the low frequency cortical domain is viewed as providing reduced lateral inhibition resulting in a disinhibitory fringe of excitation that we have termed the “edge effect” (Llinás
1472-9288/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 1 4 7 2 - 9 2 8 8 ( 0 1 ) 0 0 0 2 6 - 7
246
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
et al., 1999). This edge effect correlates with the appearance of the positive symptomatology (Berrios, 1985), and is supported by a MEG power gain in theta and beta domains associated with an increase of coherence between the two (see Llinás et al., 2001). The location of the edge effect on the cortical mantle determines the type of positive symptoms. Negative and positive symptoms may arise in the context of all types of TCD. Consider as examples the association of tremor and akinesia in Parkinson’s disease, of pain and reversible hypoaesthesia in neurogenic pain, the presence of cognitive deficits in epilepsy as well as the coupling of negative and positive symptoms in schizophrenia. With these TCD mechanisms in mind, we developed a surgical strategy that would make sense of the extraordinarily rich but scattered and often forgotten classical surgical protocols. This review makes it clear that much of the positive and negative surgical outcomes of the past may be addressed within the TCD framework. Our own surgical direction, guided by classical surgical experience and the new knowledge of thalamocortical dynamics, has evolved to emphasize the reduction of TCD with the fundamental added requirement that all specific and all normally functioning nonspecific thalamocortical modules be left intact. Indeed sparing the thalamocortical connectivity is indispensable for the maintenance of sensory, motor and cognitive functions (see Llinás et al., 2001). The goal of surgery is, in this context, focused on the correction of the increased low frequency production via two approaches that involve interventions at the pre-thalamic and at the medial thalamic levels. These two approaches are geared to: (1) the reduction of thalamic inhibition (mainly from the pallidum); and (2) the reduction of the low frequency synchronization and amplification (mainly from the medial thalamus). This physiologically-based rationale provides, we feel, an efficient surgical strategy coupled with a sparing of neurological functions. The paper begins with a review of the evidence of the presence of LTS bursts in the human thalamus, followed by a description of our surgical results. We also address the dynamics of the post-operative restabilization, thalamocortical excitotoxicity as well as the importance of the mental factor in the pre- and post-surgical phase.
2. Low threshold calcium spike bursts in human thalamic neurons Although thalamic LTS bursts were already recorded in the 1970s in the human brain (Modesti and Waszak, 1975), for a long time they were not recognized as distinct entities and their significance to pathological conditions totally overlooked. More recently, these bursts were recorded, at single cell level, both in the specific somatosensory thalamus (ventral posterior nucleus) (Lenz et al., 1989) and in the medial thalamus (Jeanmonod et al., 1993) of patients suffering from neurogenic pain. More precisely, Lenz et al.
(1990) demonstrated that LTS bursts were localized in and around the region of the ventral posterior nucleus somatotopically related to the deafferented body area that also demonstrated neurogenic pain. By contrast, the LTS bursts identified in the medial thalamus by Jeanmonod et al. (1993) were more numerous and were spread diffusely throughout the posterior portion of the central lateral nucleus (CLP). This distribution was fully in accordance with the known morpho-functional organization of the lateral and medial thalamus (Steriade et al., 1997). In the field of movement disorders, Raeva et al. (1999) and Magnin et al. (2000) have provided clear evidence of LTS bursts in the ventral anterior and ventral lateral thalamic nuclei, in full accordance with experimental data in the Parkinsonian monkey thalamus (Kaneoke and Vitek, 1995). The pervasiveness of LTS bursts in diseases characterized by positive symptoms has been underscored by the evidence of their presence in the medial thalamus of patients suffering from tinnitus, epilepsy, Parkinson’s disease and neuropsychiatric disorders, building on the previous findings in patients with neurogenic pain (Jeanmonod et al., 1996). In all five disease groups, two striking patterns emerged as invariant components of the TCD: (1) in all patients, the recorded bursting activity demonstrated a statistically-consistent interburst discharge frequency (3.8 ± 0.7 Hz); and (2) in over 2000 single unit recordings, cells displayed consistent intraburst characteristics, including a mean spike frequency of 206±44 Hz, very much in accordance with the in vitro electrophysiological results originally describing the LTS burst characteristics (Jahnsen and Llinás, 1984). These human data, speaking for a common pathophysiology for a set of symptomatically diverse diseases, support the proposition of 19th century English neurology (reviewed in Berrios, 1985) that coined the term “positive symptoms” for these manifestations, and considered a “state of overfunction” or a “loss of equilibrium” as their basis. Notwithstanding the most important confirmatory evidence from MEG data (see Llinás et al., 2001), additional support for a common pathophysiology for all positive symptoms is provided by pharmacological, epidemiological and surgical domains: (1) some neurological or psychiatric medications are successful therapeutic agents against more than one symptom (e.g. the use of carbamazepine in epilepsy, neurogenic pain, neuropsychiatric disorders, some motor disorders and even in tinnitus); (2) more than one positive symptom can be found to coexist in individual patients (e.g. pain and tinnitus), suggesting a related physiological underpinning; (3) the CL thalamotomy (CLT) has been effective against several different positive symptoms (Jeanmonod et al., 1996), again suggesting a common mechanism; (4) we have noted families in which multiple members are affected by one or more positive symptoms (Jeanmonod et al., 1996), an observation consistent with epidemiological data positing genetic influences in Parkinson’s disease, epilepsy and neuropsychiatric disorders, in addition to some experimental observations (Seltzer et al., 1993).
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
247
Fig. 1. (A) Extracellular unit recording of a cell located in the central lateral nucleus in a Parkinsonian patient. Its activity is characterized by the clock-like generation of bursts of spikes at a frequency of 4.8 Hz. The two bursts presented at a shorter time scale illustrate the intrinsic characteristics which indicate that they originate from a low threshold calcium spike. First, one notes a progressive increase of the successive interspike intervals (ISIs). Second, the number of spikes within a burst is inversely correlated to the duration of its first ISI. Scale: spike = 200 V; time = 50 ms (upper trace) and 2 ms (lower trace). (B) Left histogram illustrates quantitatively the progressive increase of ISIs within the burst, for bursts with a different number of spikes; right histogram shows that the duration of the first ISI decreases when the number of spikes in the burst increases (fitting curve using a logarithmic function).
Figs. 1 and 2 provide detailed visualization and characterization of the LTS bursts, and Fig. 3 a collection of examples of rhythmic bursting cells in the posterior medial thalamus of patients suffering from seven different positive symptoms.
3. Surgical treatment of the chronic therapy-resistant TCD Surgical intervention in TCD patients should only be considered when the following criteria are fulfilled: (i) chronicity of the disease, with a minimum of 1 year duration; (ii) resistance of the symptoms to pharmacological and other recognized conservative therapies; and (iii) major impact of the disease on the patient’s quality of life. It is difficult to obtain precise figures concerning suitable
candidates under this scheme, but it is doubtful that such criteria would be fulfilled by more than 10% of the patient populations for the diseases under consideration. Our surgical strategy is fully grounded on the physiological evidence, presented above and in the companion paper (Llinás et al., 2001), that the thalamocortical module is the anatomo-physiological substratum for the appearance of all sensory, motor and cognitive functions and dysfunctions. As there is evidence that the TCD is due to changes in the inputs to some thalamocortical modules, these should be rebalanced by regulating these inputs without destroying the affected modules themselves. 3.1. Surgical approaches Two surgical approaches fulfill these criteria and allow efficiency coupled with sparing of neurological functions.
248
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
Fig. 2. Comparison between the LTS bursts recorded in the lateral (upper histogram row) and medial (lower histogram row) thalamic nuclei in Parkinsonian patients. As a reference, data obtained from five cells recorded during sleep periods are plotted using filled squares. On the left, the quantification of the progressive increase in ISI duration and on the right, the logarithmic decrease of ISI duration in function of the spike number within the bursts. Note the tight similarity of intraburst characteristics for LTS bursts recorded either in medial or lateral nuclei and during sleep periods. A very large majority of LTS bursts recorded in the lateral thalamus were produced by cells located in pallidal recipient nuclei: the ventral anterior and the ventral lateral anterior nuclei. In the medial thalamus, LTS bursting cells were preferentially found in the central lateral nucleus.
They are displayed in Fig. 4, schematically on atlas planes (Morel et al., 1997) and as seen in magnetic resonance (MR) on the second post-operative day. The first approach is a reduction of the low frequency amplification/synchronization, which can be accomplished by a therapeutic lesion in the medial thalamus, known as the medial thalamotomy since the dawn of stereotactic neurosurgery (Hécaen et al., 1949). Indeed, such an effect is in full accordance with long standing physiological experimental studies (Morison and Dempsey, 1942) demonstrating the progressive spread of the recruiting response on the cortical surface during low frequency stimulation of the medial thalamus. We have taken advantage of the pathophysiological data mentioned above (Jeanmonod et al., 1993, 1994), allowing us to focus the medial thalamotomy target on the CLP, where more than 95% of the cells produce LTS bursts and/or are unresponsive to stimuli. We can thus spare all other medial thalamic subnuclei that function normally and to which, over time, the functions originally fulfilled by CLP have been transferred. This might explain why patients experience no detectable reduction in sensory, motor or cognitive domains after such an operation. The target coordinates for the CLT are anteroposteriorly 2 mm posterior to the posterior commissure, mediolaterally 6 mm lateral to the border of the third ventricle and dorsoventrally at the level of the
intercommissural plane. The target is reached using an anteroposterior angle of 60◦ and a mediolateral angle of 5–10◦ . The CLT lesion measures 3–4 mm diameter over 12–14 mm length. The second surgical possibility is a thalamic disinhibition allowing thalamic cell membrane hyperpolarization to be corrected. This may be accomplished by a therapeutic lesion placed on the inhibitory pallidothalamic and nigrothalamic pathways. The first target is on the pallidothalamic tract in the subthalamic fields H1 and H2 of Forel and was termed a pallidothalamic tractotomy (PTT) (Magnin et al., 2001a). This area was targeted by some surgeons over 30 years ago (Spiegel and Wycis, 1963), but often in an undifferentiated conjunction with other subthalamic areas and motor thalamic nuclei. We prefer the PTT to a pallidal approach on the basis of its superior efficiency, namely, the opportunity to impact a large portion (at least two-thirds) of the inhibitory pallidothalamic fibers as they join together before entering the thalamus with a small lesion in the fields of Forel. Our target is placed anteroposteriorly at the level of the midcommissural line, mediolaterally 7 mm lateral to the ventricular border and dorsoventrally 2 mm ventral to the intercommissural plane. It is reached with an anteroposterior angle of 65◦ and a mediolateral angle of 15◦ . The PTT lesion measures 3–4 mm diameter over 7–8 mm length. It also
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
249
Fig. 3. Examples of unit activities recorded in the medial thalamus (CL and SG/Li) in seven positive symptoms. This activity, analyzed by interspike interval (left) and auto-correlation histograms (right), is characterized by rhythmic bursts with frequencies between 3 and 5 Hz. The localization of each unit is shown on a sagittal section of our stereotactic atlas of the human thalamus, 7 mm from the medial thalamic border. The two crosses correspond to the positions of the anterior (right) and posterior (left) commissures. Horizontal and vertical scale bars for unit activities are 200 ms and 100 mV, respectively. CM, centre median nucleus, CLP, central lateral nucleus, LD, lateral dorsal nucleus, Po, posterior nucleus, PuM and PuO, medial and oral pulvinar nuclei, RT, reticular nucleus, SG/Li, suprageniculate-limitans complex, SN, substantia nigra, STh, subthalamic nucleus, VA, ventral anterior nucleus, VLPd,v, ventral lateral posterior nucleus, dorsal and ventral divisions, VM, ventromedial nucleus, VPM, ventral posterior medial nucleus, and ZI, zona incerta (from Jeanmonod et al., 1996).
250
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
Fig. 4. Sagittal atlas projections (left column) and 2 days post-operative T1-weighed MR images (right column) of CLT (A), PTT (B) and AMP (C) lesions. The coordinates of atlas sections are 7.2 mm (A and B) and 12 mm (C) lateral to the ventricular border, and crosses indicate the position of the posterior (A and B) and anterior (C) commissures. In both series, sections are oriented with posterior to the left and the intercommissural plane (represented by an interrupted line in left panels) horizontal. The lesions represented in atlas sections do not include the oedematic area seen on MR images. Stippled areas in the CL represent densocellular clusters. Abbreviations: ac, anterior commissure; AV, anteroventral nucleus; Cd, caudate nucleus; CL, central lateral nucleus; CM, centre median nucleus; LD, lateral dorsal nucleus; Li, limitans nucleus; GPi, e, internal and external pallidum; MDpc, mediodorsal nucleus, parvocellular division; Pf, parafascicular nucleus; PuM, medial pulvinar; PuT, putamen; R, reticular nucleus; RN; red nucleus; STh, subthalamic nucleus; VA, ventral anterior nucleus; VAmc, magnocellular division of VA; VLPd,v, ventral lateral posterior nucleus, dorsal and ventral divisions; VLa, ventral lateral anterior nucleus; VM, ventromedial nucleus; VPMpc, ventral posterior medial nucleus, parvocellular division; ZI, zona incerta. Scale bars: 2 mm in atlas and 10 mm in MRI.
interrupts at least a portion of the nigrothalamic tract as it courses through this location on its way to the thalamus. For neuropsychiatric TCD, thalamic disinhibition must be targeted to the path between the paralimbic or mesocortical (anterior) internal pallidum and the limbic thalamus. This operation, first reported in this publication, is based on recent anatomical work on the human basal ganglia (Morel et al., 2002) and will be denominated anteromedial pallidotomy (AMP). Its coordinates are anteroposteriorly 4 mm
posterior to the anterior commissure, mediolaterally 12 mm lateral to the ventricular border, and dorsoventrally 2 mm ventral to the intercommissural plane. It is reached using an anteroposterior angle of 55◦ and a mediolateral one of 20◦ . The AMP lesion measures 3–4 mm diameter over 5–6 mm length. To choose the different target combinations for the different symptoms (Table 1), we have used the following arguments: (1) CLT is to be used primarily but not exclu-
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254 Table 1 Target strategy in different positive symptoms
CLT PTT AMP
Neurogenic Tinnitus pain
Neuropsychiatry
+ +
+
+ +
+
Parkinson
Epilepsy
+
+ + +
sively against phasic TCD phenomena; (2) the desinhibition brought by PTT covers primarily the sensorimotor division of the pallidothalamic path, the one related to the AMP its paralimbic or mesocortical division (Parent and Hazrati, 1995); and (3) anatomo-physiological evidence (Clarey and Irvine, 1986; Yeterian and Pandya, 1998) support a role in audition for the putamen, thus, making the auditory TCD (tinnitus) amenable to a pallidothalamic desinhibition. A yet unexplored role for PTT in the neuropsychiatric field may be envisaged on the basis of the presence in the fields of Forel of projections from the associative pallidum (Baron et al., 2001). 3.2. Surgical outcomes 3.2.1. Neurogenic pain Our experience of over 12 years with 96 patients suffering from chronic neurogenic pain and treated with the CLT was described recently (Jeanmonod et al., 2001). Mean pain duration was 7.5 years, and the mean follow-up was 4 years. Global pain relief of 50–100% was obtained in 53% of the patients, and pain relief was complete in 19%. The relief of pain attacks was significantly higher (66%) than for continuous pain (20%), a fact fully in accordance with the role, discussed above, of the medial thalamus in the phasic synchronization of low frequencies. Four patients suffering from continuous neurogenic pain and proprioceptive allodynia were treated with PTT alone in three and in association with CLT in one. The mean pain duration before surgery was 4 years, the mean post-operative follow-up 12 months and the mean pain relief 68%. The mean visual analogue scale value (for minimal and maximal pain) was 55/100 before and 24/100 after the operation. One patient presented a slight post-operative chorea which fully regressed over a few months. It was due to an incomplete lesion of the pallidothalamic tract associated with a significant encroachment onto the subthalamic nucleus. A sufficient lesion of this tract protects fully against the appearance of such dyskinesias (see Magnin et al., 2001a). 3.2.2. Parkinson’s disease Our experience with PTT for 21 patients is described by Magnin et al. (2001a), with a mean disease duration of 11 years and a mean follow-up of 14 months. The improvement of the UPDRS in the medicated state was 65%. The improvement of tremor was 78%, of on-chorea 92%, rigidity 82%, distal hypobradykinesia 73%, axial hypobradykinesia
251
64%, gait 58%, postural reflexes 66%, but voice was not significantly improved. There was a 52% reduction of l-dopa intake, and 33% of the patients terminated pharmacotherapy successfully. We relate limited symptom control and focal post-operative symptom increase mainly (1) to pre-operative thalamocortical damages due to the Parkinsonian disease mechanisms but also to thalamocortical excitotoxicity; and (2) to mental factors. 3.2.3. Tinnitus The CLT brought 50–100% relief to three out of six patients (Jeanmonod et al., 1996). Following PTT, one patient showed an initial complete tinnitus relief, stabilized at 60% at the 5 month post-operative follow-up. Another patient received an extended medial thalamotomy (CLT plus centre median and posterior complex), resulting in a suppression of the tone component of his tinnitus. There was a 50% reduction of the noise component according to visual analogue scale determinations and a 30% tinnitus reduction according to audiometric tinnitus masking. 3.2.4. Neuropsychiatric disorders The coupling of CLT and AMP was recommended to a patient suffering from a chronic (14 years) severely disabling and fully therapy-resistant neuropsychiatric syndrome characterized by the coupling of an obsessive compulsive disorder (OCD) with major depression. Five years post-surgery, in spite of a strong reduction of her drug treatment, the patient enjoys complete relief of her OCD and has redeveloped a social and professional life, to a degree inconceivable before surgery. There were no reductions, to the contrary only improvements, in her neuropsychological sphere after surgery. She still experiences moderate to strong episodes of reactive depression, controllable with psychotherapy and antidepressant treatment. Three additional OCD patients have also demonstrated promising outcomes: one patient with complete and another with 75% relief (follow-ups 1.3 year and 4 months, respectively), and a third patient with complete symptom relief over a shorter duration only, but with the appearance of outspoken reactive factors in the context of a very difficult personal and familial situation (father and sister also affected, more than 20 years disease duration). One patient with a 20 year history of therapy-resistant schizoaffective disorder showed for a year a complete relief from delusional, hallucinatory, and bipolar manifestations, in spite of a reduction of his drug treatment. MEG recordings (refer Fig. 4 in Llinás et al., 2001) before surgery showed high levels of coherence and increased power in the theta range with a dominant peak at 8.2 Hz. Following surgery, the clinical improvement was mirrored by the MEG findings which showed a strong reduction of power in the theta domain, the reappearance of a normal alpha peak at 11 Hz and a distinct decrease in the level of coherence among frequencies. A year post-operatively, a difficult phase developed, characterized by an outspoken anxiety state, based on internal stressors and related to personal and interac-
252
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
tive family factors, with activation of powerful guilt and self-insufficiency feelings. Another patient with a 10 year history of a disabling therapy-resistant complex neuropsychiatric syndrome including schizoaffective, anxiety, obsessive-compulsive and impulse control disorders, was operated on the left side on the basis of the discovery of a small vascular, probably developmental abnormality in his left mediodorsal thalamic nucleus. At a follow-up of 6 months, he enjoys a drastic improvement of all symptoms, with as only problem a recent short depressive episode due to the cumulation of at least three very significant stressors. The pre- and post-operative MEG recordings demonstrate similar changes as described for the patient above. 3.2.5. Epilepsy We have already published (Jeanmonod et al., 1996) the results of CLT in frontal and parietal focal epilepsies, with a 50–100% relief for three of six patients. Short term results in one patient suffering from a post-traumatic epilepsy of mixed temporal and frontal types and treated with the coupling of CLT and AMP demonstrate a reduction of mean fit frequency from 3 to 1 per month, with a much appreciated subjective conceptual–emotional improvement. A second session with PTT and contralateral CLT (because of bilateral traumatic frontal lesions) is being planned. 3.3. Radiofrequency lesion versus chronic stimulation An issue of current interest in the neurosurgical community is the choice of therapeutic radiofrequency lesions versus chronic electrical stimulation. Both methods provide symptom relief by reducing the state of thalamic inhibition which is at the base of the occurrence of the TCD. The critical point for a coupling of efficiency and sparing of brain function by surgery is an adequate choice of the target on the basis of a sound understanding of the disease mechanisms, i.e. the resonant oscillatory network must be touched at proper locations to be efficiently and sparingly rebalanced. The most significant difference between lesioning and stimulation is the question of reversibility. This factor relates very much to technical safety, i.e. the precision of the targeting procedure. A sufficient accuracy (Bourgeois et al., 1999; Magnin et al., 2001b) is crucial as it assures a reduction of complications due to coincidental lesioning of surrounding (untargeted) structures. The option of reversibility may be questioned if the three following factors are present: (1) the patient expects a definitive and complete removal of his/her symptoms; (2) a satisfactory stereotactic precision is at disposition; and (3) the disease mechanisms to be controlled are understood. Deep brain stimulation is a more forgiving procedure than lesioning, as it is reversible and allows an increased stimulation intensity to compensate for an imprecise targeting. It is on the other side labor intensive and expensive, requiring an elaborate and long term attention, with significant loads on
patient, family, supporting team and insurer. The lesioning procedure requires a much simpler and shorter post-surgical attention, with more autonomy and less expenses. However, being irreversible, it has high precision requirements for targeting. The continuous presence and activity of a deep brain stimulation device may be at the source of a significant and long term placebo effect, which is not to be expected longer than a few weeks after a radiofrequency lesion.
4. Dynamics of the post-operative restabilization phase Considering the complex resonant thalamocortical networks generating TCD, it can be expected that the correction of low frequency production and the reduction of thalamic inhibition would arouse dynamic restabilization events of variable duration after surgery. Clinical observations confirm this prediction, showing that improvements may take place over many months following surgery. In our experience, tremor regresses in waves over days to months following a PTT. Similarly, after a CLT, pain attacks often recede over a few months, and our first patient with tinnitus described a 75% reduction of his symptoms overnight during the sixth post-operative night. Supporting this are data from PTTs performed by Jinnai and Mukawa (1987) which produced progressive improvements of the EEG, still present between 1 and 3 years after the operation. There is evidence that at least two factors can explain the variable length of this restabilization phase, i.e. the intensity of the pre-operative physiopathology and the completeness of the surgical control of the TCD.
5. Thalamocortical excitotoxicity Evidence of progressive cortical atrophy has been shown to occur in a percentage of patients suffering from neuropsychiatric disorders (DeLisi, 1999; Corvit et al., 2001), Parkinson’s disease (Schneider et al., 1979) and epilepsy (Pacia et al., 1996). One mechanism which may explain this phenomenon, which effectively leads to a self-destruction of the system harboring the TCD, is that a persistent increase of calcium entry into the thalamic cells generating LTS bursts could cause long-term deleterious effects (including via Ca++ activated second-messenger systems) which, over time, may result in extensive neuronal damage. Furthermore, the continual activation of high frequency cortical areas through the “edge effect” provides a framework for the development of excitotoxicity of cortical cells. Under these conditions, the system may fall into a self-reduction mode, a sort of “slow burn” with loss of neuronal substrate. Paradoxically, this process actually serves to reinforce the TCD as the level of corticothalamic and thalamocortical activation decreases and exposes thalamic cells to more hyperpolarization and, consequently, to more LTS burst generation.
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
6. The mental factor In the term “mental”, we include conceptual, emotional, mnestic and attentional functions, which are supported by the distributed activity in the association and mesocortical (or paralimbic) domains (Mesulam, 1985). Within these widespread and strongly interconnected networks, the lateral/medial or specific/nonspecific thalamocortical duality remains: although the association/mesocortical network displays no or a much reduced topology, its specific thalamus (mediodorsal and medial pulvinar nuclei) nevertheless keeps more focal cortical projections than medial nonspecific nuclei (Macchi, 1997). Accumulating evidence from EEG and MEG studies underscores the fact that conceptual and mnestic (Sasaki et al., 1994; Klimesch, 1999; von Stein and Sarnthein, 2000) as well as emotional (Machleidt et al., 1989) activity in humans increases low frequency activity in associative and mesocortical areas. This finding provides a substratum for the well-recognized role of mental functions in the modulation of all positive symptoms. TCD may thus, arise either on the basis of a disease-related abnormal input to the thalamus, or via a “top–down” mechanism, driven by mental activity and generating low frequencies on a “reactive” basis. In this sense, the loss of control which may occur during strong stimulus-bound transitory emotional reactions may be seen as a short-lived and controllable TCD phenomenon. Additionally, an explanation for psychogenic disorders may be found here, as the maintenance of chronic low frequencies in the associative and mesocortical domains of patients suffering from somatoform pain, psychogenic abnormal movements, psychogenic pseudoepileptic fits, psychogenic tinnitus and neurotic disorders. Support for such a view is provided by a PET study (Mountz et al., 1998) of patients with fibromyalgia, a disease in which no causal peripheral lesion for the development of pain is found and for which central limbic mechanisms are increasingly considered: the thalamus of these patients displayed extreme and bilateral hypometabolism, fully compatible with a TCD syndrome. Our clinical observations have shown that the surgical strategy that we apply provides a reduction of the disease-related TCD but does not reduce, as wished and expected, the mental reactions of the patient to his/her new post-operative situation. Fear, expectations, despair and frustration may even increase for a time following surgery and necessitate psychotherapy. These powerful mental sources for TCD production may, as long as they stay active, entertain an abnormal neurological state which keeps elements of the long lasting disease-related TCD. A closer look at these patients demonstrates, however, a focalization on domains with strong limbic input (e.g. the voice in Parkinson’s disease) and/or typical psychogenic characteristics (symptom extension beyond primarily affected body area, clinical inconsistencies with highly selective disabilities, outspoken variations along time and according to situations). The development of such a mentally-based TCD is readily
253
observed after chronic suffering, does not fit most of the time in any specific psychiatric diagnosis, and requires an early and intensive psychotherapeutic support. Resistant TCD of that sort strongly correlate, in our experience, with frustration and non-acceptance of the disease-related health impairment. 7. Conclusion Clearly, much remains to be considered and developed regarding the most effective control of TCD. As neuroscience expands the understanding of the molecular mechanisms that control the TCD syndrome, a more refined approach will hopefully ultimately appear, with highly specific tools targeting the neurones that originate and support it. Acknowledgements This work was supported by the University of Zürich, the University Hospital of Zürich and the Swiss National Science Foundation (Grants 31-36330.92, 31-47238.96 and 31-54179.98). We thank Dr. P.M. Ott for collaboration on tinnitus patients, P. Roth and A. Roth for photographic work, V. Streit for histological work, C. Lebzelter for psychotherapeutic support to the patients, J. Dodd for instrumentation and V. Bügler for secretarial help. References Baron, M.S., Sidibé, M., DeLong, M.R., Smith, Y., 2001. Course of motor and associative pallidothalamic projections in monkeys. J. Comp. Neurol. 429, 490–501. Berrios, G.E., 1985. Positive and negative symptoms and Jackson: a conceptual history. Arch. Gen. Psychiatr. 42, 95–97. Bourgeois G., Magnin M., Morel A., Sartoretti S., Huisman T., Tuncdogan E. et al., 1999. Accuracy of MRI-guided stereotactic thalamic functional neurosurgery. Neuroradiology 41, 636–645. Clarey, J.C., Irvine, D.R., 1986. Auditory response properties of neurons in the claustrum and putamen of the cat. Exp. Brain Res. 61, 432–437. Corvit, A., Wolf, O.T., de Leone, M.J., Patalinjug, M., Kandil, E., Caraos, C., et al., 2001. Volumetric analysis of the prefrontal regions: Findings in aging and schizophrenia. Psychiat. Res. 107, 61–73. Curro Dossi, R., Nunez, A., Steriade, M., 1992. Electrophysiology of a slow (0.5–4 Hz) intrinsic oscillation of cat thalamocortical neurones in vivo. J. Physiol. 447, 215–234. DeLisi, L.E., 1999. Defining the course of brain structural change and plasticity in schizophrenia. Psychiatr. Res. 92, 1–9. Hécaen, H., Talairach, T., David, M., Dell, M.B., 1949. Coagulations limitées du thalamus dans les algies du syndrome thalamique. Rev. Neurol. 81, 917–931. Jahnsen, H., Llinás, R., 1984. Electrophysiological properties of guinea-pig thalamic neurones: an in vitro study. J. Physiol. (Lond.) 349, 205–226. Jeanmonod, D., Magnin, M., Morel, A., 1993. Thalamus and neurogenic pain: physiological, anatomical and clinical data. Neuroreport 4, 475– 478. Jeanmonod D., Magnin M., Morel A., 1994. A thalamic concept of neurogenic pain. In: Gebhart G.F., Hammond D.L., Jensen T.S. (Eds.), Progress in Pain Research and Management. IASP Press, Seattle, pp. 767–787.
254
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
Jeanmonod, D., Magnin, M., Morel, A., 1996. Low-threshold calcium spike bursts in the human thalamus: common physiopathology for sensory, motor and limbic positive symptoms. Brain 119, 363–375. Jeanmonod, D., Magnin, M., Morel, A., Siegemund, M., 2001. Surgical control of the human thalamocortical dysrhythmia. Part I. Central lateral thalamotomy in neurogenic pain. Thalamus Related Syst. 1, 71–79. Jinnai D., Mukawa J., 1987. Clinical observation in man: Forel-H-tomy and its place in epilepsy. In: Fromm G.H., Faingold C.L., Browning R.A., Burnham V.M. (Eds.), Epilepsy and the Reticular Formation: the Role of the Reticular Core in Convulsive Seizures. Alan R. Liss, New York, pp. 163–191. Kaneoke, Y., Vitek, J.L., 1995. The motor thalamus in the Parkinsonian primate: enhanced bursts and oscillatory activities. Soc. Neurosci. Abstr. 21, 1428. Klimesch, W., 1999. EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis. Brain Res. Rev. 29, 169–195. Lenz, F.A., Kwan, H.C., Dostrovsky, J.O., Tasker, R.R., 1989. Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain. Brain Res. 496, 357–360. Lenz, F.A., Kwan, H.C., Martin, R., Tasker, R.R., Dostrovsky, J.O., 1990. Characteristics of spontaneous neuronal activity at different locations in ventrocaudal thalamus of patients with central pain following spinal cord transection. Pain Suppl. 5, 493. Llinás, R.R., Ribary, U., Jeanmonod, D., Kronberg, E., Mitra, P.P., 1999. Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc. Natl. Acad. Sci. U.S.A. 96, 15222–15227. Llinás, R., Ribary, U., Jeanmonod, D., Cancro, K., Kronberg, E., Schulman, J., Zonenshayn, M., Magnin, M., Morel, A., Siegemund, M., 2001. Thalamocortical dysrhythmia I. Functional and imaging aspects. Thalamus 1, 237–244. Macchi G., 1997. Thalamic functions as interpreted from human lesions. In: Steriade M., Jones E.G., McCormick D.A. (Eds.), Thalamus, Vol. II. Elsevier, Amsterdam, pp. 543–615. Machleidt W., Gutjahr L., Mügge A., 1989. Grundgefühle: Phänomenologie, Psychodynamik. EEG-Spektralanalytik, Springer Verlag, Berlin. Magnin, M., Morel, A., Jeanmonod, D., 2000. Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in Parkinsonian patients. Neuroscience 96, 549–564. Magnin, M., Jeanmonod, D., Morel, A., Siegemund, M., 2001a. Surgical control of the human thalamocortical dysrhythmia. Part II. Pallidothalamic tractotomy in Parkinson’s disease. Thalamus Related Syst. 1, 81–89. Magnin, M., Jetzer, U., Morel, A., Jeanmonod, D., 2001b. Microelectrode recording and macrostimulation in thalamic and subthalamic MRI guided stereotactic surgery. Neurophysiol. Clin. 31, 230–238.
Mesulam M.M., 1985. Principles of Behavioral Neurology. F.A. Davis Company, Philadelphia. Modesti, L.M., Waszak, M., 1975. Firing pattern of cells in human thalamus during dorsal column stimulation. Appl. Neurophysiol. 38, 251–258. Morel A., Magnin M., Jeanmonod D., 1997. Multiarchitectonic and stereotactic atlas of the human thalamus. J. Comp. Neurol. 387, 588–630 (erratum, J. Comp. Neurol. 391, 545). Morel, A.., Loup, F., Magnin, M., Jeanmonod, D., 2002. Neurochemical organization of the human basal ganglia: anatomo-functional territories defined by the distributions of calcium-binding proteins and SMI-32. J. Comp. Neurol. (in press). Morison, R., Dempsey, E., 1942. A study of thalamocortical relations. Am. J. Physiol. 135, 281–292. Mountz, J.M., Bradley, L.A., Alarcon, G.S., 1998. Abnormal functional activity of the central nervous system in fibromyalgia syndrome. Am. J. Med. Sci. 315, 385–396. Pacia S.V., Devinsky O., Perrine K., Ravdin L., Luciano D., Vazquez B. et al., 1996. Clinical features of neocortical temporal lobe epilepsy. Ann. Neurol. 40, 724–730. Parent, A., Hazrati, L.N., 1995. Functional anatomy of the basal ganglia. Part I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res. Rev. 20, 91–127. Raeva, S.N., Vainberg, N.A., Dubinin, V., 1999. Analysis of spontaneous activity patterns of human thalamic ventrolateral neurons and their modifications due to functional brain changes. Neuroscience 88, 365– 376. Sasaki, K., Tsujimoto, T., Nambu, A., Matsuzaki, R., Kyuhou, S., 1994. Dynamic activities of the frontal association cortex in calculating and thinking. Neurosci. Res. 19, 229–233. Schneider, E., Becker, H., Fischer, P.A., Grau, H., Jacobi, P., Brinkmann, R., 1979. The course of brain atrophy in Parkinson’s disease. Arch. Psychiatr. Nervenkr. 227, 89–95. Seltzer Z., Attal U., Devor M., Levi Z., Neuman S., Shavit Y., 1993. Neuropathic pain-related behaviour and epileptogenesis are co-inherited in rats. In: Proceedings of the 7th World Conference on Pain. IASP Publications, Seattle, p. 513. Spiegel, E.A., Wycis, H., 1963. Campotomy in various extrapyramidal disorders. J. Neurosurg. 20, 871–884. Steriade M., Jones E.G., McCormick D.A., 1997. Thalamus, Vol. I. Elsevier, Amsterdam. von Stein, A., Sarnthein, J., 2000. Different frequencies for different scales of cortical integration: from local gamma to long range alpha/theta synchronization. Int. J. Psychophysiol. 38, 301–313. Yeterian, E.H., Pandya, D.N., 1998. Corticostriatal connections of the superior temporal region in rhesus monkeys. J. Comp. Neurol. 399, 384–402.
Thalamocortical dysrhythmia II. Clinical and surgical aspects D. Jeanmonod a,∗ , M. Magnin a , A. Morel a , M. Siegemund a , A. Cancro b , M. Lanz c , R. Llinás d , U. Ribary d , E. Kronberg d , J. Schulman d , M. Zonenshayn d a
Neurochirurgische Klinik, Lab. for Functional Neurosurgery, Universitätsspital Zürich, Sternwartstrasse 6, 8091 Zürich, Switzerland b Department of Psychiatry, New York University School of Medicine, New York, NY, USA c Psychiatrie-Zentrum Hard, Zürich, Switzerland d Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY, USA Accepted 2 October 2001
Abstract The companion paper (Llinás et al., 2001) presents evidence, at both cellular and network levels, for the role of resonant oscillatory thalamocortical properties in normal and pathological brain function. Here we present confirmatory single cell electrophysiology from the thalami of thalamocortical dysrhythmia (TCD) patients and review our surgical approach towards the relief of this chronic disabling condition, in its many forms. The goal of surgery is a rebalancing of the abnormal thalamocortical oscillation responsible for TCD. Our approach uses small strategically placed pre-thalamic and medial thalamic lesions that serve to make subcritical the low frequency thalamocortical reentry network attractor via desinhibition and desamplification. The lesions address classical and new stereotactic targets that provide therapeutic efficiency coupled with the sparing of the specific thalamocortical loops. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Low threshold calcium spike bursts; Positive symptoms; Medial thalamotomy; Pallidothalamic tractotomy
1. Introduction The companion paper (Llinás et al., 2001) describes, at the experimental level, the cellular and network properties that we invoke as responsible for the thalamocortical resonant oscillations that underlie normal hemispheric brain functions. Based on such physiological evidence as well as on human thalamic unit recordings (Jeanmonod et al., 1996) and magneto-encephalography (Llinás et al., 1999), we proposed that a single global mechanism, involving the thalamocortical reentrance loop, is responsible for the generation of the five domains of positive/negative symptoms that characterize the so-called thalamocortical dysrhythmia (TCD). These domains comprise motor disorders (e.g. Parkinson’s disease), neurogenic pain (after central and peripheral lesions of the somatosensory system), tinnitus, neuropsychiatric disorders (including psychosis, obsessive compulsive disease and major depression) and epilepsy. A schematic description of the TCD mechanisms is given in Fig. 5 of the companion paper (Llinás et al., 2001). The primary factor for the generation of TCD is the presence of ∗ Corresponding author. Tel.: +41-1-255-3580; fax: +41-1-255-8946. E-mail address: [email protected] (D. Jeanmonod).
protracted neuronal hyperpolarization due to disfacilitation (Curro et al., 1992) or overinhibition of thalamic neurons, either from above (cortical lesion), from below (decrease of peripheral afferent inputs to the thalamus), from an alteration of basal ganglia or cerebellar inputs, or from thalamic lesions. Thalamic cells are thus, hyperpolarized and set in low threshold calcium spike (LTS) burst production mode, with a rhythmicity locked in the theta–delta range (Jeanmonod et al., 1996). This thalamic low frequency rhythmicity recruits, via resonant oscillatory thalamocortical interactions, the related cortical structures (Llinás et al., 1999, 2001). Divergent corticothalamic, corticoreticular and reticulothalamic projections provide the anatomical basis for a progressive march of these low frequencies to neighboring thalamocortical loops, as indicated by the increased coherence observed in MEG (Llinás et al., 1999, 2001). This phase is proposed to correlate with the appearance of deficits, or negative symptoms, in the same way as delta low frequencies correlate with unconsciousness in slow wave sleep. The last step of this TCD chain reaction is most likely cortical, through asymmetrical corticocortical inhibition: the low frequency cortical domain is viewed as providing reduced lateral inhibition resulting in a disinhibitory fringe of excitation that we have termed the “edge effect” (Llinás
1472-9288/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 1 4 7 2 - 9 2 8 8 ( 0 1 ) 0 0 0 2 6 - 7
246
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
et al., 1999). This edge effect correlates with the appearance of the positive symptomatology (Berrios, 1985), and is supported by a MEG power gain in theta and beta domains associated with an increase of coherence between the two (see Llinás et al., 2001). The location of the edge effect on the cortical mantle determines the type of positive symptoms. Negative and positive symptoms may arise in the context of all types of TCD. Consider as examples the association of tremor and akinesia in Parkinson’s disease, of pain and reversible hypoaesthesia in neurogenic pain, the presence of cognitive deficits in epilepsy as well as the coupling of negative and positive symptoms in schizophrenia. With these TCD mechanisms in mind, we developed a surgical strategy that would make sense of the extraordinarily rich but scattered and often forgotten classical surgical protocols. This review makes it clear that much of the positive and negative surgical outcomes of the past may be addressed within the TCD framework. Our own surgical direction, guided by classical surgical experience and the new knowledge of thalamocortical dynamics, has evolved to emphasize the reduction of TCD with the fundamental added requirement that all specific and all normally functioning nonspecific thalamocortical modules be left intact. Indeed sparing the thalamocortical connectivity is indispensable for the maintenance of sensory, motor and cognitive functions (see Llinás et al., 2001). The goal of surgery is, in this context, focused on the correction of the increased low frequency production via two approaches that involve interventions at the pre-thalamic and at the medial thalamic levels. These two approaches are geared to: (1) the reduction of thalamic inhibition (mainly from the pallidum); and (2) the reduction of the low frequency synchronization and amplification (mainly from the medial thalamus). This physiologically-based rationale provides, we feel, an efficient surgical strategy coupled with a sparing of neurological functions. The paper begins with a review of the evidence of the presence of LTS bursts in the human thalamus, followed by a description of our surgical results. We also address the dynamics of the post-operative restabilization, thalamocortical excitotoxicity as well as the importance of the mental factor in the pre- and post-surgical phase.
2. Low threshold calcium spike bursts in human thalamic neurons Although thalamic LTS bursts were already recorded in the 1970s in the human brain (Modesti and Waszak, 1975), for a long time they were not recognized as distinct entities and their significance to pathological conditions totally overlooked. More recently, these bursts were recorded, at single cell level, both in the specific somatosensory thalamus (ventral posterior nucleus) (Lenz et al., 1989) and in the medial thalamus (Jeanmonod et al., 1993) of patients suffering from neurogenic pain. More precisely, Lenz et al.
(1990) demonstrated that LTS bursts were localized in and around the region of the ventral posterior nucleus somatotopically related to the deafferented body area that also demonstrated neurogenic pain. By contrast, the LTS bursts identified in the medial thalamus by Jeanmonod et al. (1993) were more numerous and were spread diffusely throughout the posterior portion of the central lateral nucleus (CLP). This distribution was fully in accordance with the known morpho-functional organization of the lateral and medial thalamus (Steriade et al., 1997). In the field of movement disorders, Raeva et al. (1999) and Magnin et al. (2000) have provided clear evidence of LTS bursts in the ventral anterior and ventral lateral thalamic nuclei, in full accordance with experimental data in the Parkinsonian monkey thalamus (Kaneoke and Vitek, 1995). The pervasiveness of LTS bursts in diseases characterized by positive symptoms has been underscored by the evidence of their presence in the medial thalamus of patients suffering from tinnitus, epilepsy, Parkinson’s disease and neuropsychiatric disorders, building on the previous findings in patients with neurogenic pain (Jeanmonod et al., 1996). In all five disease groups, two striking patterns emerged as invariant components of the TCD: (1) in all patients, the recorded bursting activity demonstrated a statistically-consistent interburst discharge frequency (3.8 ± 0.7 Hz); and (2) in over 2000 single unit recordings, cells displayed consistent intraburst characteristics, including a mean spike frequency of 206±44 Hz, very much in accordance with the in vitro electrophysiological results originally describing the LTS burst characteristics (Jahnsen and Llinás, 1984). These human data, speaking for a common pathophysiology for a set of symptomatically diverse diseases, support the proposition of 19th century English neurology (reviewed in Berrios, 1985) that coined the term “positive symptoms” for these manifestations, and considered a “state of overfunction” or a “loss of equilibrium” as their basis. Notwithstanding the most important confirmatory evidence from MEG data (see Llinás et al., 2001), additional support for a common pathophysiology for all positive symptoms is provided by pharmacological, epidemiological and surgical domains: (1) some neurological or psychiatric medications are successful therapeutic agents against more than one symptom (e.g. the use of carbamazepine in epilepsy, neurogenic pain, neuropsychiatric disorders, some motor disorders and even in tinnitus); (2) more than one positive symptom can be found to coexist in individual patients (e.g. pain and tinnitus), suggesting a related physiological underpinning; (3) the CL thalamotomy (CLT) has been effective against several different positive symptoms (Jeanmonod et al., 1996), again suggesting a common mechanism; (4) we have noted families in which multiple members are affected by one or more positive symptoms (Jeanmonod et al., 1996), an observation consistent with epidemiological data positing genetic influences in Parkinson’s disease, epilepsy and neuropsychiatric disorders, in addition to some experimental observations (Seltzer et al., 1993).
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
247
Fig. 1. (A) Extracellular unit recording of a cell located in the central lateral nucleus in a Parkinsonian patient. Its activity is characterized by the clock-like generation of bursts of spikes at a frequency of 4.8 Hz. The two bursts presented at a shorter time scale illustrate the intrinsic characteristics which indicate that they originate from a low threshold calcium spike. First, one notes a progressive increase of the successive interspike intervals (ISIs). Second, the number of spikes within a burst is inversely correlated to the duration of its first ISI. Scale: spike = 200 V; time = 50 ms (upper trace) and 2 ms (lower trace). (B) Left histogram illustrates quantitatively the progressive increase of ISIs within the burst, for bursts with a different number of spikes; right histogram shows that the duration of the first ISI decreases when the number of spikes in the burst increases (fitting curve using a logarithmic function).
Figs. 1 and 2 provide detailed visualization and characterization of the LTS bursts, and Fig. 3 a collection of examples of rhythmic bursting cells in the posterior medial thalamus of patients suffering from seven different positive symptoms.
3. Surgical treatment of the chronic therapy-resistant TCD Surgical intervention in TCD patients should only be considered when the following criteria are fulfilled: (i) chronicity of the disease, with a minimum of 1 year duration; (ii) resistance of the symptoms to pharmacological and other recognized conservative therapies; and (iii) major impact of the disease on the patient’s quality of life. It is difficult to obtain precise figures concerning suitable
candidates under this scheme, but it is doubtful that such criteria would be fulfilled by more than 10% of the patient populations for the diseases under consideration. Our surgical strategy is fully grounded on the physiological evidence, presented above and in the companion paper (Llinás et al., 2001), that the thalamocortical module is the anatomo-physiological substratum for the appearance of all sensory, motor and cognitive functions and dysfunctions. As there is evidence that the TCD is due to changes in the inputs to some thalamocortical modules, these should be rebalanced by regulating these inputs without destroying the affected modules themselves. 3.1. Surgical approaches Two surgical approaches fulfill these criteria and allow efficiency coupled with sparing of neurological functions.
248
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
Fig. 2. Comparison between the LTS bursts recorded in the lateral (upper histogram row) and medial (lower histogram row) thalamic nuclei in Parkinsonian patients. As a reference, data obtained from five cells recorded during sleep periods are plotted using filled squares. On the left, the quantification of the progressive increase in ISI duration and on the right, the logarithmic decrease of ISI duration in function of the spike number within the bursts. Note the tight similarity of intraburst characteristics for LTS bursts recorded either in medial or lateral nuclei and during sleep periods. A very large majority of LTS bursts recorded in the lateral thalamus were produced by cells located in pallidal recipient nuclei: the ventral anterior and the ventral lateral anterior nuclei. In the medial thalamus, LTS bursting cells were preferentially found in the central lateral nucleus.
They are displayed in Fig. 4, schematically on atlas planes (Morel et al., 1997) and as seen in magnetic resonance (MR) on the second post-operative day. The first approach is a reduction of the low frequency amplification/synchronization, which can be accomplished by a therapeutic lesion in the medial thalamus, known as the medial thalamotomy since the dawn of stereotactic neurosurgery (Hécaen et al., 1949). Indeed, such an effect is in full accordance with long standing physiological experimental studies (Morison and Dempsey, 1942) demonstrating the progressive spread of the recruiting response on the cortical surface during low frequency stimulation of the medial thalamus. We have taken advantage of the pathophysiological data mentioned above (Jeanmonod et al., 1993, 1994), allowing us to focus the medial thalamotomy target on the CLP, where more than 95% of the cells produce LTS bursts and/or are unresponsive to stimuli. We can thus spare all other medial thalamic subnuclei that function normally and to which, over time, the functions originally fulfilled by CLP have been transferred. This might explain why patients experience no detectable reduction in sensory, motor or cognitive domains after such an operation. The target coordinates for the CLT are anteroposteriorly 2 mm posterior to the posterior commissure, mediolaterally 6 mm lateral to the border of the third ventricle and dorsoventrally at the level of the
intercommissural plane. The target is reached using an anteroposterior angle of 60◦ and a mediolateral angle of 5–10◦ . The CLT lesion measures 3–4 mm diameter over 12–14 mm length. The second surgical possibility is a thalamic disinhibition allowing thalamic cell membrane hyperpolarization to be corrected. This may be accomplished by a therapeutic lesion placed on the inhibitory pallidothalamic and nigrothalamic pathways. The first target is on the pallidothalamic tract in the subthalamic fields H1 and H2 of Forel and was termed a pallidothalamic tractotomy (PTT) (Magnin et al., 2001a). This area was targeted by some surgeons over 30 years ago (Spiegel and Wycis, 1963), but often in an undifferentiated conjunction with other subthalamic areas and motor thalamic nuclei. We prefer the PTT to a pallidal approach on the basis of its superior efficiency, namely, the opportunity to impact a large portion (at least two-thirds) of the inhibitory pallidothalamic fibers as they join together before entering the thalamus with a small lesion in the fields of Forel. Our target is placed anteroposteriorly at the level of the midcommissural line, mediolaterally 7 mm lateral to the ventricular border and dorsoventrally 2 mm ventral to the intercommissural plane. It is reached with an anteroposterior angle of 65◦ and a mediolateral angle of 15◦ . The PTT lesion measures 3–4 mm diameter over 7–8 mm length. It also
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
249
Fig. 3. Examples of unit activities recorded in the medial thalamus (CL and SG/Li) in seven positive symptoms. This activity, analyzed by interspike interval (left) and auto-correlation histograms (right), is characterized by rhythmic bursts with frequencies between 3 and 5 Hz. The localization of each unit is shown on a sagittal section of our stereotactic atlas of the human thalamus, 7 mm from the medial thalamic border. The two crosses correspond to the positions of the anterior (right) and posterior (left) commissures. Horizontal and vertical scale bars for unit activities are 200 ms and 100 mV, respectively. CM, centre median nucleus, CLP, central lateral nucleus, LD, lateral dorsal nucleus, Po, posterior nucleus, PuM and PuO, medial and oral pulvinar nuclei, RT, reticular nucleus, SG/Li, suprageniculate-limitans complex, SN, substantia nigra, STh, subthalamic nucleus, VA, ventral anterior nucleus, VLPd,v, ventral lateral posterior nucleus, dorsal and ventral divisions, VM, ventromedial nucleus, VPM, ventral posterior medial nucleus, and ZI, zona incerta (from Jeanmonod et al., 1996).
250
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
Fig. 4. Sagittal atlas projections (left column) and 2 days post-operative T1-weighed MR images (right column) of CLT (A), PTT (B) and AMP (C) lesions. The coordinates of atlas sections are 7.2 mm (A and B) and 12 mm (C) lateral to the ventricular border, and crosses indicate the position of the posterior (A and B) and anterior (C) commissures. In both series, sections are oriented with posterior to the left and the intercommissural plane (represented by an interrupted line in left panels) horizontal. The lesions represented in atlas sections do not include the oedematic area seen on MR images. Stippled areas in the CL represent densocellular clusters. Abbreviations: ac, anterior commissure; AV, anteroventral nucleus; Cd, caudate nucleus; CL, central lateral nucleus; CM, centre median nucleus; LD, lateral dorsal nucleus; Li, limitans nucleus; GPi, e, internal and external pallidum; MDpc, mediodorsal nucleus, parvocellular division; Pf, parafascicular nucleus; PuM, medial pulvinar; PuT, putamen; R, reticular nucleus; RN; red nucleus; STh, subthalamic nucleus; VA, ventral anterior nucleus; VAmc, magnocellular division of VA; VLPd,v, ventral lateral posterior nucleus, dorsal and ventral divisions; VLa, ventral lateral anterior nucleus; VM, ventromedial nucleus; VPMpc, ventral posterior medial nucleus, parvocellular division; ZI, zona incerta. Scale bars: 2 mm in atlas and 10 mm in MRI.
interrupts at least a portion of the nigrothalamic tract as it courses through this location on its way to the thalamus. For neuropsychiatric TCD, thalamic disinhibition must be targeted to the path between the paralimbic or mesocortical (anterior) internal pallidum and the limbic thalamus. This operation, first reported in this publication, is based on recent anatomical work on the human basal ganglia (Morel et al., 2002) and will be denominated anteromedial pallidotomy (AMP). Its coordinates are anteroposteriorly 4 mm
posterior to the anterior commissure, mediolaterally 12 mm lateral to the ventricular border, and dorsoventrally 2 mm ventral to the intercommissural plane. It is reached using an anteroposterior angle of 55◦ and a mediolateral one of 20◦ . The AMP lesion measures 3–4 mm diameter over 5–6 mm length. To choose the different target combinations for the different symptoms (Table 1), we have used the following arguments: (1) CLT is to be used primarily but not exclu-
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254 Table 1 Target strategy in different positive symptoms
CLT PTT AMP
Neurogenic Tinnitus pain
Neuropsychiatry
+ +
+
+ +
+
Parkinson
Epilepsy
+
+ + +
sively against phasic TCD phenomena; (2) the desinhibition brought by PTT covers primarily the sensorimotor division of the pallidothalamic path, the one related to the AMP its paralimbic or mesocortical division (Parent and Hazrati, 1995); and (3) anatomo-physiological evidence (Clarey and Irvine, 1986; Yeterian and Pandya, 1998) support a role in audition for the putamen, thus, making the auditory TCD (tinnitus) amenable to a pallidothalamic desinhibition. A yet unexplored role for PTT in the neuropsychiatric field may be envisaged on the basis of the presence in the fields of Forel of projections from the associative pallidum (Baron et al., 2001). 3.2. Surgical outcomes 3.2.1. Neurogenic pain Our experience of over 12 years with 96 patients suffering from chronic neurogenic pain and treated with the CLT was described recently (Jeanmonod et al., 2001). Mean pain duration was 7.5 years, and the mean follow-up was 4 years. Global pain relief of 50–100% was obtained in 53% of the patients, and pain relief was complete in 19%. The relief of pain attacks was significantly higher (66%) than for continuous pain (20%), a fact fully in accordance with the role, discussed above, of the medial thalamus in the phasic synchronization of low frequencies. Four patients suffering from continuous neurogenic pain and proprioceptive allodynia were treated with PTT alone in three and in association with CLT in one. The mean pain duration before surgery was 4 years, the mean post-operative follow-up 12 months and the mean pain relief 68%. The mean visual analogue scale value (for minimal and maximal pain) was 55/100 before and 24/100 after the operation. One patient presented a slight post-operative chorea which fully regressed over a few months. It was due to an incomplete lesion of the pallidothalamic tract associated with a significant encroachment onto the subthalamic nucleus. A sufficient lesion of this tract protects fully against the appearance of such dyskinesias (see Magnin et al., 2001a). 3.2.2. Parkinson’s disease Our experience with PTT for 21 patients is described by Magnin et al. (2001a), with a mean disease duration of 11 years and a mean follow-up of 14 months. The improvement of the UPDRS in the medicated state was 65%. The improvement of tremor was 78%, of on-chorea 92%, rigidity 82%, distal hypobradykinesia 73%, axial hypobradykinesia
251
64%, gait 58%, postural reflexes 66%, but voice was not significantly improved. There was a 52% reduction of l-dopa intake, and 33% of the patients terminated pharmacotherapy successfully. We relate limited symptom control and focal post-operative symptom increase mainly (1) to pre-operative thalamocortical damages due to the Parkinsonian disease mechanisms but also to thalamocortical excitotoxicity; and (2) to mental factors. 3.2.3. Tinnitus The CLT brought 50–100% relief to three out of six patients (Jeanmonod et al., 1996). Following PTT, one patient showed an initial complete tinnitus relief, stabilized at 60% at the 5 month post-operative follow-up. Another patient received an extended medial thalamotomy (CLT plus centre median and posterior complex), resulting in a suppression of the tone component of his tinnitus. There was a 50% reduction of the noise component according to visual analogue scale determinations and a 30% tinnitus reduction according to audiometric tinnitus masking. 3.2.4. Neuropsychiatric disorders The coupling of CLT and AMP was recommended to a patient suffering from a chronic (14 years) severely disabling and fully therapy-resistant neuropsychiatric syndrome characterized by the coupling of an obsessive compulsive disorder (OCD) with major depression. Five years post-surgery, in spite of a strong reduction of her drug treatment, the patient enjoys complete relief of her OCD and has redeveloped a social and professional life, to a degree inconceivable before surgery. There were no reductions, to the contrary only improvements, in her neuropsychological sphere after surgery. She still experiences moderate to strong episodes of reactive depression, controllable with psychotherapy and antidepressant treatment. Three additional OCD patients have also demonstrated promising outcomes: one patient with complete and another with 75% relief (follow-ups 1.3 year and 4 months, respectively), and a third patient with complete symptom relief over a shorter duration only, but with the appearance of outspoken reactive factors in the context of a very difficult personal and familial situation (father and sister also affected, more than 20 years disease duration). One patient with a 20 year history of therapy-resistant schizoaffective disorder showed for a year a complete relief from delusional, hallucinatory, and bipolar manifestations, in spite of a reduction of his drug treatment. MEG recordings (refer Fig. 4 in Llinás et al., 2001) before surgery showed high levels of coherence and increased power in the theta range with a dominant peak at 8.2 Hz. Following surgery, the clinical improvement was mirrored by the MEG findings which showed a strong reduction of power in the theta domain, the reappearance of a normal alpha peak at 11 Hz and a distinct decrease in the level of coherence among frequencies. A year post-operatively, a difficult phase developed, characterized by an outspoken anxiety state, based on internal stressors and related to personal and interac-
252
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
tive family factors, with activation of powerful guilt and self-insufficiency feelings. Another patient with a 10 year history of a disabling therapy-resistant complex neuropsychiatric syndrome including schizoaffective, anxiety, obsessive-compulsive and impulse control disorders, was operated on the left side on the basis of the discovery of a small vascular, probably developmental abnormality in his left mediodorsal thalamic nucleus. At a follow-up of 6 months, he enjoys a drastic improvement of all symptoms, with as only problem a recent short depressive episode due to the cumulation of at least three very significant stressors. The pre- and post-operative MEG recordings demonstrate similar changes as described for the patient above. 3.2.5. Epilepsy We have already published (Jeanmonod et al., 1996) the results of CLT in frontal and parietal focal epilepsies, with a 50–100% relief for three of six patients. Short term results in one patient suffering from a post-traumatic epilepsy of mixed temporal and frontal types and treated with the coupling of CLT and AMP demonstrate a reduction of mean fit frequency from 3 to 1 per month, with a much appreciated subjective conceptual–emotional improvement. A second session with PTT and contralateral CLT (because of bilateral traumatic frontal lesions) is being planned. 3.3. Radiofrequency lesion versus chronic stimulation An issue of current interest in the neurosurgical community is the choice of therapeutic radiofrequency lesions versus chronic electrical stimulation. Both methods provide symptom relief by reducing the state of thalamic inhibition which is at the base of the occurrence of the TCD. The critical point for a coupling of efficiency and sparing of brain function by surgery is an adequate choice of the target on the basis of a sound understanding of the disease mechanisms, i.e. the resonant oscillatory network must be touched at proper locations to be efficiently and sparingly rebalanced. The most significant difference between lesioning and stimulation is the question of reversibility. This factor relates very much to technical safety, i.e. the precision of the targeting procedure. A sufficient accuracy (Bourgeois et al., 1999; Magnin et al., 2001b) is crucial as it assures a reduction of complications due to coincidental lesioning of surrounding (untargeted) structures. The option of reversibility may be questioned if the three following factors are present: (1) the patient expects a definitive and complete removal of his/her symptoms; (2) a satisfactory stereotactic precision is at disposition; and (3) the disease mechanisms to be controlled are understood. Deep brain stimulation is a more forgiving procedure than lesioning, as it is reversible and allows an increased stimulation intensity to compensate for an imprecise targeting. It is on the other side labor intensive and expensive, requiring an elaborate and long term attention, with significant loads on
patient, family, supporting team and insurer. The lesioning procedure requires a much simpler and shorter post-surgical attention, with more autonomy and less expenses. However, being irreversible, it has high precision requirements for targeting. The continuous presence and activity of a deep brain stimulation device may be at the source of a significant and long term placebo effect, which is not to be expected longer than a few weeks after a radiofrequency lesion.
4. Dynamics of the post-operative restabilization phase Considering the complex resonant thalamocortical networks generating TCD, it can be expected that the correction of low frequency production and the reduction of thalamic inhibition would arouse dynamic restabilization events of variable duration after surgery. Clinical observations confirm this prediction, showing that improvements may take place over many months following surgery. In our experience, tremor regresses in waves over days to months following a PTT. Similarly, after a CLT, pain attacks often recede over a few months, and our first patient with tinnitus described a 75% reduction of his symptoms overnight during the sixth post-operative night. Supporting this are data from PTTs performed by Jinnai and Mukawa (1987) which produced progressive improvements of the EEG, still present between 1 and 3 years after the operation. There is evidence that at least two factors can explain the variable length of this restabilization phase, i.e. the intensity of the pre-operative physiopathology and the completeness of the surgical control of the TCD.
5. Thalamocortical excitotoxicity Evidence of progressive cortical atrophy has been shown to occur in a percentage of patients suffering from neuropsychiatric disorders (DeLisi, 1999; Corvit et al., 2001), Parkinson’s disease (Schneider et al., 1979) and epilepsy (Pacia et al., 1996). One mechanism which may explain this phenomenon, which effectively leads to a self-destruction of the system harboring the TCD, is that a persistent increase of calcium entry into the thalamic cells generating LTS bursts could cause long-term deleterious effects (including via Ca++ activated second-messenger systems) which, over time, may result in extensive neuronal damage. Furthermore, the continual activation of high frequency cortical areas through the “edge effect” provides a framework for the development of excitotoxicity of cortical cells. Under these conditions, the system may fall into a self-reduction mode, a sort of “slow burn” with loss of neuronal substrate. Paradoxically, this process actually serves to reinforce the TCD as the level of corticothalamic and thalamocortical activation decreases and exposes thalamic cells to more hyperpolarization and, consequently, to more LTS burst generation.
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
6. The mental factor In the term “mental”, we include conceptual, emotional, mnestic and attentional functions, which are supported by the distributed activity in the association and mesocortical (or paralimbic) domains (Mesulam, 1985). Within these widespread and strongly interconnected networks, the lateral/medial or specific/nonspecific thalamocortical duality remains: although the association/mesocortical network displays no or a much reduced topology, its specific thalamus (mediodorsal and medial pulvinar nuclei) nevertheless keeps more focal cortical projections than medial nonspecific nuclei (Macchi, 1997). Accumulating evidence from EEG and MEG studies underscores the fact that conceptual and mnestic (Sasaki et al., 1994; Klimesch, 1999; von Stein and Sarnthein, 2000) as well as emotional (Machleidt et al., 1989) activity in humans increases low frequency activity in associative and mesocortical areas. This finding provides a substratum for the well-recognized role of mental functions in the modulation of all positive symptoms. TCD may thus, arise either on the basis of a disease-related abnormal input to the thalamus, or via a “top–down” mechanism, driven by mental activity and generating low frequencies on a “reactive” basis. In this sense, the loss of control which may occur during strong stimulus-bound transitory emotional reactions may be seen as a short-lived and controllable TCD phenomenon. Additionally, an explanation for psychogenic disorders may be found here, as the maintenance of chronic low frequencies in the associative and mesocortical domains of patients suffering from somatoform pain, psychogenic abnormal movements, psychogenic pseudoepileptic fits, psychogenic tinnitus and neurotic disorders. Support for such a view is provided by a PET study (Mountz et al., 1998) of patients with fibromyalgia, a disease in which no causal peripheral lesion for the development of pain is found and for which central limbic mechanisms are increasingly considered: the thalamus of these patients displayed extreme and bilateral hypometabolism, fully compatible with a TCD syndrome. Our clinical observations have shown that the surgical strategy that we apply provides a reduction of the disease-related TCD but does not reduce, as wished and expected, the mental reactions of the patient to his/her new post-operative situation. Fear, expectations, despair and frustration may even increase for a time following surgery and necessitate psychotherapy. These powerful mental sources for TCD production may, as long as they stay active, entertain an abnormal neurological state which keeps elements of the long lasting disease-related TCD. A closer look at these patients demonstrates, however, a focalization on domains with strong limbic input (e.g. the voice in Parkinson’s disease) and/or typical psychogenic characteristics (symptom extension beyond primarily affected body area, clinical inconsistencies with highly selective disabilities, outspoken variations along time and according to situations). The development of such a mentally-based TCD is readily
253
observed after chronic suffering, does not fit most of the time in any specific psychiatric diagnosis, and requires an early and intensive psychotherapeutic support. Resistant TCD of that sort strongly correlate, in our experience, with frustration and non-acceptance of the disease-related health impairment. 7. Conclusion Clearly, much remains to be considered and developed regarding the most effective control of TCD. As neuroscience expands the understanding of the molecular mechanisms that control the TCD syndrome, a more refined approach will hopefully ultimately appear, with highly specific tools targeting the neurones that originate and support it. Acknowledgements This work was supported by the University of Zürich, the University Hospital of Zürich and the Swiss National Science Foundation (Grants 31-36330.92, 31-47238.96 and 31-54179.98). We thank Dr. P.M. Ott for collaboration on tinnitus patients, P. Roth and A. Roth for photographic work, V. Streit for histological work, C. Lebzelter for psychotherapeutic support to the patients, J. Dodd for instrumentation and V. Bügler for secretarial help. References Baron, M.S., Sidibé, M., DeLong, M.R., Smith, Y., 2001. Course of motor and associative pallidothalamic projections in monkeys. J. Comp. Neurol. 429, 490–501. Berrios, G.E., 1985. Positive and negative symptoms and Jackson: a conceptual history. Arch. Gen. Psychiatr. 42, 95–97. Bourgeois G., Magnin M., Morel A., Sartoretti S., Huisman T., Tuncdogan E. et al., 1999. Accuracy of MRI-guided stereotactic thalamic functional neurosurgery. Neuroradiology 41, 636–645. Clarey, J.C., Irvine, D.R., 1986. Auditory response properties of neurons in the claustrum and putamen of the cat. Exp. Brain Res. 61, 432–437. Corvit, A., Wolf, O.T., de Leone, M.J., Patalinjug, M., Kandil, E., Caraos, C., et al., 2001. Volumetric analysis of the prefrontal regions: Findings in aging and schizophrenia. Psychiat. Res. 107, 61–73. Curro Dossi, R., Nunez, A., Steriade, M., 1992. Electrophysiology of a slow (0.5–4 Hz) intrinsic oscillation of cat thalamocortical neurones in vivo. J. Physiol. 447, 215–234. DeLisi, L.E., 1999. Defining the course of brain structural change and plasticity in schizophrenia. Psychiatr. Res. 92, 1–9. Hécaen, H., Talairach, T., David, M., Dell, M.B., 1949. Coagulations limitées du thalamus dans les algies du syndrome thalamique. Rev. Neurol. 81, 917–931. Jahnsen, H., Llinás, R., 1984. Electrophysiological properties of guinea-pig thalamic neurones: an in vitro study. J. Physiol. (Lond.) 349, 205–226. Jeanmonod, D., Magnin, M., Morel, A., 1993. Thalamus and neurogenic pain: physiological, anatomical and clinical data. Neuroreport 4, 475– 478. Jeanmonod D., Magnin M., Morel A., 1994. A thalamic concept of neurogenic pain. In: Gebhart G.F., Hammond D.L., Jensen T.S. (Eds.), Progress in Pain Research and Management. IASP Press, Seattle, pp. 767–787.
254
D. Jeanmonod et al. / Thalamus & Related Systems 1 (2001) 245–254
Jeanmonod, D., Magnin, M., Morel, A., 1996. Low-threshold calcium spike bursts in the human thalamus: common physiopathology for sensory, motor and limbic positive symptoms. Brain 119, 363–375. Jeanmonod, D., Magnin, M., Morel, A., Siegemund, M., 2001. Surgical control of the human thalamocortical dysrhythmia. Part I. Central lateral thalamotomy in neurogenic pain. Thalamus Related Syst. 1, 71–79. Jinnai D., Mukawa J., 1987. Clinical observation in man: Forel-H-tomy and its place in epilepsy. In: Fromm G.H., Faingold C.L., Browning R.A., Burnham V.M. (Eds.), Epilepsy and the Reticular Formation: the Role of the Reticular Core in Convulsive Seizures. Alan R. Liss, New York, pp. 163–191. Kaneoke, Y., Vitek, J.L., 1995. The motor thalamus in the Parkinsonian primate: enhanced bursts and oscillatory activities. Soc. Neurosci. Abstr. 21, 1428. Klimesch, W., 1999. EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis. Brain Res. Rev. 29, 169–195. Lenz, F.A., Kwan, H.C., Dostrovsky, J.O., Tasker, R.R., 1989. Characteristics of the bursting pattern of action potentials that occurs in the thalamus of patients with central pain. Brain Res. 496, 357–360. Lenz, F.A., Kwan, H.C., Martin, R., Tasker, R.R., Dostrovsky, J.O., 1990. Characteristics of spontaneous neuronal activity at different locations in ventrocaudal thalamus of patients with central pain following spinal cord transection. Pain Suppl. 5, 493. Llinás, R.R., Ribary, U., Jeanmonod, D., Kronberg, E., Mitra, P.P., 1999. Thalamocortical dysrhythmia: a neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc. Natl. Acad. Sci. U.S.A. 96, 15222–15227. Llinás, R., Ribary, U., Jeanmonod, D., Cancro, K., Kronberg, E., Schulman, J., Zonenshayn, M., Magnin, M., Morel, A., Siegemund, M., 2001. Thalamocortical dysrhythmia I. Functional and imaging aspects. Thalamus 1, 237–244. Macchi G., 1997. Thalamic functions as interpreted from human lesions. In: Steriade M., Jones E.G., McCormick D.A. (Eds.), Thalamus, Vol. II. Elsevier, Amsterdam, pp. 543–615. Machleidt W., Gutjahr L., Mügge A., 1989. Grundgefühle: Phänomenologie, Psychodynamik. EEG-Spektralanalytik, Springer Verlag, Berlin. Magnin, M., Morel, A., Jeanmonod, D., 2000. Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in Parkinsonian patients. Neuroscience 96, 549–564. Magnin, M., Jeanmonod, D., Morel, A., Siegemund, M., 2001a. Surgical control of the human thalamocortical dysrhythmia. Part II. Pallidothalamic tractotomy in Parkinson’s disease. Thalamus Related Syst. 1, 81–89. Magnin, M., Jetzer, U., Morel, A., Jeanmonod, D., 2001b. Microelectrode recording and macrostimulation in thalamic and subthalamic MRI guided stereotactic surgery. Neurophysiol. Clin. 31, 230–238.
Mesulam M.M., 1985. Principles of Behavioral Neurology. F.A. Davis Company, Philadelphia. Modesti, L.M., Waszak, M., 1975. Firing pattern of cells in human thalamus during dorsal column stimulation. Appl. Neurophysiol. 38, 251–258. Morel A., Magnin M., Jeanmonod D., 1997. Multiarchitectonic and stereotactic atlas of the human thalamus. J. Comp. Neurol. 387, 588–630 (erratum, J. Comp. Neurol. 391, 545). Morel, A.., Loup, F., Magnin, M., Jeanmonod, D., 2002. Neurochemical organization of the human basal ganglia: anatomo-functional territories defined by the distributions of calcium-binding proteins and SMI-32. J. Comp. Neurol. (in press). Morison, R., Dempsey, E., 1942. A study of thalamocortical relations. Am. J. Physiol. 135, 281–292. Mountz, J.M., Bradley, L.A., Alarcon, G.S., 1998. Abnormal functional activity of the central nervous system in fibromyalgia syndrome. Am. J. Med. Sci. 315, 385–396. Pacia S.V., Devinsky O., Perrine K., Ravdin L., Luciano D., Vazquez B. et al., 1996. Clinical features of neocortical temporal lobe epilepsy. Ann. Neurol. 40, 724–730. Parent, A., Hazrati, L.N., 1995. Functional anatomy of the basal ganglia. Part I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res. Rev. 20, 91–127. Raeva, S.N., Vainberg, N.A., Dubinin, V., 1999. Analysis of spontaneous activity patterns of human thalamic ventrolateral neurons and their modifications due to functional brain changes. Neuroscience 88, 365– 376. Sasaki, K., Tsujimoto, T., Nambu, A., Matsuzaki, R., Kyuhou, S., 1994. Dynamic activities of the frontal association cortex in calculating and thinking. Neurosci. Res. 19, 229–233. Schneider, E., Becker, H., Fischer, P.A., Grau, H., Jacobi, P., Brinkmann, R., 1979. The course of brain atrophy in Parkinson’s disease. Arch. Psychiatr. Nervenkr. 227, 89–95. Seltzer Z., Attal U., Devor M., Levi Z., Neuman S., Shavit Y., 1993. Neuropathic pain-related behaviour and epileptogenesis are co-inherited in rats. In: Proceedings of the 7th World Conference on Pain. IASP Publications, Seattle, p. 513. Spiegel, E.A., Wycis, H., 1963. Campotomy in various extrapyramidal disorders. J. Neurosurg. 20, 871–884. Steriade M., Jones E.G., McCormick D.A., 1997. Thalamus, Vol. I. Elsevier, Amsterdam. von Stein, A., Sarnthein, J., 2000. Different frequencies for different scales of cortical integration: from local gamma to long range alpha/theta synchronization. Int. J. Psychophysiol. 38, 301–313. Yeterian, E.H., Pandya, D.N., 1998. Corticostriatal connections of the superior temporal region in rhesus monkeys. J. Comp. Neurol. 399, 384–402.