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04-10-2008, 07:23 PM | #1 | |||
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I was telling my aunt the other day that's it's all about the rhythms being off kilter, so I supply my own rhythms.
"In this study we show that in the parkinsonian off state the low-beta rhythm in the human STN harmonically distorts the high-beta rhythm; the distortion disappears after dopaminergic medication." ‘the normal dopaminergic system supports segregation of the functional subcircuits of the basal ganglia, and that a breakdown of this independent processing is a hallmark of Parkinson's disease’ 'Intriguingly, the disruption of non-linear correlations between different LFP rhythms in the human STN could be critical not only for improving the clinical efficacy of dopaminergic medication, but also for understanding the mechanisms responsible for the action of deep brain stimulation.' The Journal of Physiology Volume 571 Issue 3 Page 579-591, March 2006 To cite this article: S. Marceglia, G. Foffani, A. M. Bianchi, G. Baselli, F. Tamma, M. Egidi, A. Priori (2006) Dopamine-dependent non-linear correlation between subthalamic rhythms in Parkinson's disease The Journal of Physiology 571 (3) , 579–591 doi:10.1113/jphysiol.2005.100271 ABSTRACT: The basic information architecture in the basal ganglia circuit is under debate. Whereas anatomical studies quantify extensive convergence/divergence patterns in the circuit, suggesting an information sharing scheme, neurophysiological studies report an absence of linear correlation between single neurones in normal animals, suggesting a segregated parallel processing scheme. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and in parkinsonian patients single neurones become linearly correlated, thus leading to a loss of segregation between neurones. Here we propose a possible integrative solution to this debate, by extending the concept of functional segregation from the cellular level to the network level. To this end, we recorded local field potentials (LFPs) from electrodes implanted for deep brain stimulation (DBS) in the subthalamic nucleus (STN) of parkinsonian patients. By applying bispectral analysis, we found that in the absence of dopamine stimulation STN LFP rhythms became non-linearly correlated, thus leading to a loss of segregation between rhythms. Non-linear correlation was particularly consistent between the low-beta rhythm (13–20 Hz) and the high-beta rhythm (20–35 Hz). Levodopa administration significantly decreased these non-linear correlations, therefore increasing segregation between rhythms. These results suggest that the extensive convergence/divergence in the basal ganglia circuit is physiologically necessary to sustain LFP rhythms distributed in large ensembles of neurones, but is not sufficient to induce correlated firing between neurone pairs. Conversely, loss of dopamine generates pathological linear correlation between neurone pairs, alters the patterns within LFP rhythms, and induces non-linear correlation between LFP rhythms operating at different frequencies. The pathophysiology of information processing in the human basal ganglia therefore involves not only activities of individual rhythms, but also interactions between rhythms. INTRO: In the classic view of basal ganglia processing, single neurones represent the elementary channels of thalamo-cortico-basal ganglia communication (Albin et al. 1995; Wichmann & Delong, 1996; Wichmann & Delong, 2003). Under physiological conditions in animals, the firing activity between nearby neurones is virtually independent, suggesting that these channels are functionally segregated (Hoover & Strick, 1993; Nini et al. 1995; Bar-Gad et al. 2003) to maximize information transmission (Bar-Gad & Bergman, 2001). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated monkeys (Bergman et al. 1994; Nini et al. 1995; Raz et al. 2000, 2001; Heimer et al. 2002) and in parkinsonian patients (Levy et al. 2000, 2002a), the firing activity between neurones becomes linearly correlated, suggesting that the lack of dopamine results in a loss of segregation between communication channels (Bergman et al. 1998). Recent studies with local field potential (LFP) recordings from electrodes implanted for deep brain stimulation (DBS) in patients with Parkinson's disease are providing a new complementary scenario of information processing in the human basal ganglia (Brown & Williams, 2005). In this scenario, the elementary channels of thalamo-cortico-basal ganglia communication are defined at the network level by LFP rhythms operating at various frequencies (Brown et al. 2001; Marsden et al. 2001; Levy et al. 2002b; Priori et al. 2002, 2004; Cassidy et al. 2002; Williams et al. 2002, 2003, 2005; Silberstein et al. 2003; Kühn et al. 2004, 2005; Foffani et al. 2003, 2004, 2005a,b,c,d; Doyle et al. 2005; Alegre et al. 2005; Fogelson et al. 2005, 2006). LFPs reflect the synchronous presynaptic and postsynaptic activity of large neuronal populations and can detect focal network rhythms that are not necessarily observable in single neurones or neurone pairs (Creutzfeldt et al. 1966; Frost, 1968; Murthy & Fetz, 1992, 1996a,b; Baker et al. 1997; Donoghue et al. 1998; Magill et al. 2004; Goldberg et al. 2004). The presence of multiple LFP rhythms suggests ‘the existence at the network level of multiple functionally independent – but not necessarily spatially separated – subsystems operating at different frequencies’ (Priori et al. 2004). Hence ‘tuning to distinct frequencies may provide a means of marking and segregating related processing, over and above any anatomical segregation of processing streams’ (Fogelson et al. 2006). Little information is available on the segregation between LFP rhythms at different frequencies. This issue is critical for clarifying whether the segregation concept is pathophysiologically relevant for human basal ganglia information processing at the network level. In the same way as a loss of segregation at the cellular level induces linear correlation between neurones (i.e. linearly correlates neural signals oscillating at the same frequency), a loss of segregation at the network level presumably induces non-linear synchronization between LFP rhythms (i.e. non-linearly correlates neural signals oscillating at different frequencies). We therefore hypothesized that Parkinson's disease produces non-linear correlations between subthalamic LFP rhythms oscillating at different frequencies and that these non-linear correlations are reversed by dopaminergic medication. A useful approach for studying non-linear correlations is bispectral analysis, a procedure widely used in scalp EEG studies (Dumermuth et al. 1971; Barnett et al. 1971; Kearse et al. 1994a,b, 1998; Sebel et al. 1995, 1997; Glass et al. 1997; Pfurtsheller et al. 1997; Pfurtsheller & Lopes da Silva, 1999; Bannister et al. 2001) and already applied to investigate non-linear cortico-cortical correlations between LFP rhythms in mammals (Schanze & Eckhorn, 1997; Villa et al. 2000). We therefore tested our hypothesis by applying bispectral analysis to LFPs recorded from DBS electrodes implanted in the STN of patients with Parkinson's disease, searching for non-linear correlation between subthalamic rhythms before and after administration of levodopa. DISCUSSION: Our main finding is that Parkinson's disease produces non-linear correlations between subthalamic LFP rhythms oscillating at different frequencies. After levodopa administration these non-linear correlations decrease. The most marked non-linear correlation was found between the low-beta rhythm (13–20 Hz) and the high-beta rhythm (20–35 Hz). More precisely, we provide evidence that in the off state the high-beta rhythm is distorted by a harmonic of the low-beta rhythm and that this distortion is virtually eliminated by levodopa administration. When patients were in the off state, non-linear correlations were also observed between the low-beta rhythm and other rhythms at very-low frequencies (2–7 Hz) or in the alpha range (8–12 Hz). After levodopa administration non-linear correlation within very-low frequencies increased, but non-linear correlations between rhythms all decreased or remained unchanged. These results support the hypothesis that the lack of dopamine determines a loss of segregation between rhythms operating at different frequencies in the basal ganglia circuit in patients with Parkinson's disease. This dopamine-dependent segregation between STN rhythms opens a new level of pathophysiological information processing in the human basal ganglia. Methodological considerations The concept of non-linear correlation as used in this paper refers to non-linear phase coupling between LFP rhythms operating at different frequencies, as detected by applying higher-order spectral analysis – bicoherence and bispectrum – to single LFP signals. In parallel, we have employed the expression linear correlation to refer to the linear coupling between neural rhythms operating at the same frequency, frequently described in the literature by applying second-order spectral analysis – cross-correlation function and coherence – to pairs of neural signals. It is worth mentioning that the coupling between neural rhythms, either linear or non-linear, is often described in terms of synchronization (Varela et al. 2001; Gross et al. 2004; Schnitzler & Gross, 2005; Foffani et al. 2005b). However, the word synchronization is used in neuroscience literature with a variety of slightly different meanings (Salinas & Sejnowski, 2001). We have therefore preferred the term ‘correlation’, interpreted in its more rigorous and general sense, as absence of statistical independence between communication channels (Schneidman et al. 2003; Latham & Nirenberg, 2005; Narayanan et al. 2005). Patterns of non-linear correlation between LFP rhythms in our patients showed variability. Possible reasons for variability within and between studies using LFP recordings in humans include the time elapsed from electrode implant, the clinical features of the patients and possible biases in the localization of electrodes within the STN (Foffani et al. 2003, 2005c; Priori et al. 2004). In relation to the clinical conditions of the patients, even though the Parkinsonism substantially worsened after overnight withdrawal of levodopa and no patient was on long-acting agonists at the time of surgery, our experimental design leaves open the possibility that long-term drug effects influenced LFP activity. Nevertheless if they did we would probably have underestimated the non-linear correlations between LFP rhythms in the off state and the segregating effects of levodopa, variables that both yielded statistically significant results. More important, studies on polarity reversals, amplitude gradients between adjacent electrode contacts and topographical synchronization between LFP oscillations and single-neurone activity supported the hypothesis that LFP oscillations in the alpha and beta range originate in the subthalamic nucleus (Brown et al. 2001; Levy et al. 2002a; Kühn et al. 2004; Doyle et al. 2005; Fogelson et al. 2006), whereas the origin of LFP oscillations at very-low frequencies is still not well defined. The non-linear correlations we observed between the alpha, low-beta and high-beta LFP rhythms probably therefore reflect non-linear interactions within the subthalamic nucleus, whereas the strong correlations we observed at low frequencies might have been more broadly distributed in nearby brainstem regions. Another possibility we cannot exclude is that the correlation between LFP rhythms at least in part reflected the non-linear behaviour of a single oscillator. Nevertheless, the presence of non-linear correlation between LFP rhythms should be carefully considered to interpret correctly the results obtained with traditional spectral analysis. Finally, even though our results strongly suggest that independence between LFP rhythms is physiologically relevant, studies based on LFP recordings from DBS electrodes have been conducted exclusively in patients with movement disorders. Caution is therefore needed in extending these findings to physiological conditions..... Multiple rhythms in the human subthalamic nucleus In this study we show that in the parkinsonian off state the low-beta rhythm in the human STN harmonically distorts the high-beta rhythm; the distortion disappears after dopaminergic medication. This distortion is probably responsible for the small power decreases already observed in the high-beta rhythm after dopaminergic medication (Priori et al. 2004), for the correlation between the two beta rhythms in their dopamine-dependent power-changes (Priori et al. 2004) and for at least part of the subthalamo-pallido-cortical coherence overlapping from the low-beta band to the high-beta band (Brown et al. 2001; Williams et al. 2002; Foffani et al. 2005b; Fogelson et al. 2006). Previous studies of human subthalamic activity showed that LFP beta oscillations (frequency range 13–35 Hz) are tightly related to local single-unit activity (Levy et al. 2002a; Kühn et al. 2005), are coherent across multiple structures in the cortico-basal ganglia loop (Brown et al. 2001; Cassidy et al. 2002; Williams et al. 2002; Foffani et al. 2005b; Fogelson et al. 2006), and are typically decreased by dopaminergic medication (Brown et al. 2001; Levy et al. 2002a; Priori et al. 2004; Foffani et al. 2005a) and movement execution (Priori et al. 2002; Cassidy et al. 2002; Levy et al. 2002a; Foffani et al. 2002, 2004, 2005d; Kühn et al. 2004; Williams et al. 2005; Doyle et al. 2005). These observations implied that beta oscillations could be essentially ‘antikinetic’, directly contributing to the bradykinetic parkinsonian symptomatology (Brown, 2003). This pathological interpretation nevertheless seemingly contrasts with the widespread modulation of beta activity observed in the striatum of normal primates (Courtemanche et al. 2003), with the remarkably small differences observed in the movement-related amplitude modulation of beta activity in the human STN during the off and on states (Priori et al. 2002; Doyle et al. 2005; Foffani et al. 2005d; Alegre et al. 2005), and with the presence of (probably physiological) movement-related beta modulations in the external pallidum of patients with epilepsy (Sochurkova & Rektor, 2003). By separating the subthalamic beta activity into two rhythms – low-beta and high-beta (Priori et al. 2002, 2004; Foffani et al. 2004, 2005a,d; Fogelson et al. 2006) – our study may help to solve the discrepancy. Overall, our results suggest that the previously postulated pathological ‘antikinetic’ role of beta activity in the human STN (Brown, 2003) could be more specifically played by the low-beta rhythm, whereas the high-beta rhythm could be essentially physiological. The significant decrease in non-linear correlation between the high-beta rhythm and rhythms at lower frequencies in the on state supports the idea that under physiological conditions multiple rhythms operate independently in the human STN (Priori et al. 2004; Foffani et al. 2005d; Fogelson et al. 2006). Pathophysiological implications The presence of multiple physiological LFP rhythms is in agreement with the idea that LFP rhythms not only reflect pathological linear correlation between single neurone pairs but also represent independent physiological channels of information. This duality in the pathophysiological interpretation of LFP rhythms (i.e. pathological or physiological) could shed new light on an old debate about information processing in the basal ganglia circuit: information sharing versus segregated parallel processing (Alexander & Crutcher, 1990; Percheron & Filion, 1991; Parent & Hazrati, 1993; Joel & Weiner, 1994; Bergman et al. 1998). The information sharing view (i.e. great overlap in incoming information to different cells at the basal ganglia output) is supported by the bulk of anatomical studies describing the convergence/divergence from the input to the output of the basal ganglia (Yelnik et al. 1984; Percheron et al. 1984; Parent & Hazrati, 1993; Kita & Kitai, 1994). The segregated parallel processing view is supported by neurophysiological studies showing the absence of linear correlation between neurones at the basal ganglia output in normal animals (DeLong et al. 1985; Hoover & Strick, 1993; Yoshida et al. 1993; Bergman et al. 1994; Nini et al. 1995; Bar-Gad et al. 2003). How can our results reconcile these conflicting views? The wide convergence/divergence in the basal ganglia anatomical pathways could be necessary to sustain ‘normal’ LFP rhythms distributed in large ensembles of neurones (e.g. the ‘physiological’ high-beta rhythm), but not sufficient to induce correlated firing between pairs of neurones. The loss of dopamine in Parkinson's disease alters this equilibrium, generating pathological linear correlation between pairs of neurones (Bergman et al. 1994; Nini et al. 1995; Levy et al. 2000, 2002a; Raz et al. 2000, 2001; Heimer et al. 2002), inducing important alterations in the patterns of LFP rhythms (e.g. the pathological increase in the low-beta rhythm) and provoking the appearance of non-linear correlations between different LFP rhythms (e.g. the harmonic distortion of the low-beta rhythm onto the high-beta rhythm). In other words, our results suggest that Parkinson's disease determines a loss of segregation not only between different neurones, but also between different LFP rhythms. The present study therefore confirms and extends to the LFP level the idea that ‘the normal dopaminergic system supports segregation of the functional subcircuits of the basal ganglia, and that a breakdown of this independent processing is a hallmark of Parkinson's disease’ (Bergman et al. 1998). Intriguingly, the disruption of non-linear correlations between different LFP rhythms in the human STN could be critical not only for improving the clinical efficacy of dopaminergic medication, but also for understanding the mechanisms responsible for the action of deep brain stimulation. In conclusion, the dopamine-dependent non-linear correlations between LFP rhythms in the human STN open a non-linear dimension for rhythm-based pathophysiological models of basal ganglia processing, pointing out the importance of interactions between rhythms. http://www.blackwell-synergy.com/doi...ol.2005.100271 |
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04-10-2008, 09:19 PM | #2 | |||
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In Remembrance
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"the center cannot hold...."
I'm going to have to read that one a few more times, but it seems obvious that there is something going on in us that language such as "loss of rhythm" or "disharmony" or "desynchronous" or "disordered" or a dozen similar phrasings try to get a handle on.
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Born in 1953, 1st symptoms and misdiagnosed as essential tremor in 1992. Dx with PD in 2000. Currently (2011) taking 200/50 Sinemet CR 8 times a day + 10/100 Sinemet 3 times a day. Functional 90% of waking day but fragile. Failure at exercise but still trying. Constantly experimenting. Beta blocker and ACE inhibitor at present. Currently (01/2013) taking ldopa/carbadopa 200/50 CR six times a day + 10/100 form 3 times daily. Functional 90% of day. Update 04/2013: L/C 200/50 8x; Beta Blocker; ACE Inhib; Ginger; Turmeric; Creatine; Magnesium; Potassium. Doing well. |
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