- Email: [email protected]
Cortico-basal ganglia-cortical circuitry in Parkinson's disease reconsidered
Experimental Neurology 212 (2008) 226–229
Contents lists available at ScienceDirect
Experimental Neurology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y e x n r
Brief Communication
Cortico-basal ganglia-cortical circuitry in Parkinson's disease reconsidered Heiko Braak ⁎, Kelly Del Tredici Institute for Clinical Neuroanatomy, J.W. Goethe University, Frankfurt am Main, Germany
A R T I C L E
I N F O
Article history: Received 9 January 2008 Revised 14 March 2008 Accepted 1 April 2008 Available online 15 April 2008 Keywords: Basal ganglia Bradykinesia Cortico-basal ganglia-cortical circuit Deep brain stimulation Hypokinesia Parkinson's disease Pedunculopontine nucleus Striatum Spines Subthalamic nucleus
A B S T R A C T The classical model of the cortico-basal ganglia-cortical circuit, with its indirect and direct pathways, was developed to explain the phenomenon of hypokinesia in Parkinson's disease (PD). The model has undergone refinement, but the emphasis on the basal ganglia side of the equation (dopamine deficiency in the dorsal striatum) remains. Here, a revised version of the basic model incorporates key non-dopaminergic connectivities known to become affected in the course of PD and, thus, the cortico-basal ganglia-cortical circuit appears within the context of the larger pathological process. The central roles of the corticostriatal projection, corticosubthalamic projection, and lower brainstem nuclei are emphasized. © 2008 Elsevier Inc. All rights reserved.
The prefrontal cortex and additional extensive portions of the neocortex probably activate the dorsal striatum through excitatory glutamatergic projections. From there, impulses via the pallidum reach the anteroventral thalamic nuclei, which relay data back to the cerebral neocortex, thereby establishing the cortico-basal gangliacortical circuit (Albin et al., 1989; Alexander et al., 1990; Blandini et al., 2000; Chesselet and Delfs 1996; DeLong and Wichmann 2007; Parent and Cicchetti 1998; Parent and Hazrati 1995; Tepper et al., 2007; Wichmann and DeLong 1998, 2003; Fig. 1A). This basic model is essential for understanding motor dysfunctions that develop in the course of sporadic Parkinson's disease (PD) and it also serves as part of the theoretical basis for stereotactic surgical procedures (deep brain stimulation) (Benabid 2003; Kopell et al., 2006; Obeso et al., 1997; Stefani et al., 2007; Volkmann 2007). Dopamine depletion in the striatum probably induces postsynaptic changes in striatal projection neurons and produces an imbalance within both the direct pathway (insufficient activation) as well as the indirect pathway (insufficient inhibition). The net-effect of the inequilibrium probably is hyperactivity or disinhibition of the subthalamic nucleus. The resulting predominance of the internal pallidum leads, in turn, to inhibition of thalamo-cortical activity and, clinically, to hypokinesia (Blandini et al., 2000; DeLong and Wichmann 2007; Tepper et al., 2007; Wichmann and DeLong 2003). Equilibrium between the indirect and direct ⁎ Corresponding author. Institute for Clinical Neuroanatomy, J.W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. Fax: +49 69 6301 6425. E-mail address: [email protected] (H. Braak). 0014-4886/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2008.04.001
pathways can be restored, to an extent, by pharmacological alleviation of the striatal dopamine deficiency or by a surgically induced reduction of the hyperactivity in the subthalamic nucleus (Fig. 1A). But can this model be utilized to explain more than the consequences of the gradual loss of striatal dopamine for the motor system? Clinicians have pointed out that the symptoms associated with PD cannot be explained alone by dopamine deficiency in the striatum; rather, the synucleinopathy PD involves predisposed nerve cell types, multiple neurotransmitter types, and components of various functional systems throughout the entire human nervous system (Ahlskog 2007; DeLong and Wichmann 2007; Lang and Obeso 2004; Langston 2006; Tepper et al., 2007). In the brain, the intraneuronal inclusions (Lewy neurites/bodies) appear to begin in the lower brainstem and progress caudo-rostrally in six stages into hitherto uninvolved regions (Braak and Del Tredici, 2008; Braak et al., 2003; Del Tredici et al., 2002; Duda et al., 2007). The present text proposes an amended version of the basic model in that it includes nondopaminergic connectivities that become involved in PD and places these schematically, together with the cortico-basal ganglia-cortical circuitry, in relationship to the proposed neuropathological course of PD as characterized by the topographic and sequential distribution pattern of the intraneuronal inclusions. Even a rather minimalist view of the pathological process that underlies PD indicates that it is instructive to study the cortico-basal ganglia-cortical circuitry within the context of the larger disease process. Our analysis of motor structures within the central nervous system begins with preganglionic parasympathetic motor neurons as well as
Brief Communication
227
Fig. 1. A. Basic model of the direct and indirect pathways through the cortico-basal ganglia-cortical circuit. Terminal axons of midbrain nigral dopaminergic neurons activate substance P/GABAergic projection cells in the dorsal striatum while inhibiting enkephalin/GABAergic neurons. Striatal outflow reaches neocortical motor areas via relay nuclei of the ventral thalamus (VA/VLa). B. In the brain, the pathological process underlying Parkinson's disease (PD) commences in the medullary dorsal motor nucleus of the vagal nerve (neuropathological stage 1, black shading). Premotor and motor neurons of the spinal cord and brainstem, by contrast, remain uninvolved for the duration of the disorder. In stage 2, Lewy neurites/bodies appear within the lower raphe nuclei, magnocellular reticular nuclei, and coeruleus/subcoeruleus complex in the lower brainstem (dark gray shading). All of these nuclei send descending projections to somatomotor and visceromotor neurons and become affected prior to the substantia nigra, pars compacta. They are capable of limiting the conduction of incoming pain signals and placing the organism's motor neurons in a heightened state of preparedness for action, particularly in stress situations. Relay centers of the visceromotor system (central subnucleus of the amygdala) and nuclei influencing the somatomotor system (pedunculopontine tegmental nucleus, dopaminergic neurons of the substantia nigra) are drawn into the disease process at stage 3 (light gray shading). Both the pedunculopontine nucleus and the central nucleus of the amygdala send descending projections to lower brainstem centers mentioned above and project to all of the non-thalamic nuclei with diffuse cortical and subcortical efferents that likewise become involved at stage 3.
the premotor and motor neurons of the spinal cord and brainstem (Fig. 1B). Briefly, parasympathetic preganglionic projection neurons in the dorsal motor nucleus of the vagal nerve become involved in PD in neuropathological stage 1. In stage 2, the disease process proceeds further into the lower brainstem and lesions appear in the lower raphe nuclei, magnocellular portions of the reticular formation (e.g., gigantocellular nucleus), and coeruleus/subcoeruleus complex (Braak and Del Tredici, 2008; Braak et al., 2003; Del Tredici et al., 2002; Duda et al., 2007). This group of nuclei serves as a motor control system, whose descending projections influence both somatomotor and visceromotor neurons (Holstege et al., 2004; Fig. 1B). Basal portions of the mid- and forebrain become involved at neuropathological stage 3, including relay centers (e.g., central subnucleus of the amygdala) of the visceromotor system and centers (pedunculopontine tegmental nu-
cleus, substantia nigra pars compacta) that exert influence on the somatomotor system (Figs.1B, 2). Affection of the anterior and posterior thalamic intralaminar nuclei (excluding the centrum medianum and parafascicular nucleus) that project to the striatum and cerebral cortex occurs in stage 4 (Groenewegen and Berendse 1994; Rüb et al., 2002). In stages 5–6, extended neocortical association areas and the premotor areas are drawn into the disease process (Braak et al., 2003; Fig. 2). The amended version of the basic model of the cortico-basal ganglia-cortical circuit (Fig. 2) assigns a position to the pedunculopontine tegmental nucleus, which does not appear in the classical scheme (Fig. 1A). This nucleus receives afferents from the internal pallidum and subthalamic nucleus, and sends efferents not only to nigral dopaminergic nerve cells but also to lower brainstem and spinal cord (DeLong and Wichmann 2007; Lee et al., 2000; Mena-Segovia
228
Brief Communication
Fig. 2. Amended version of the cortico-basal ganglia-cortical circuit. This model encompasses motor areas from the spinal cord to the neocortex and incorporates not only the consequences of dopamine depletion in the dorsal striatum but also additional non-dopaminergic somatomotor centers that become consecutively and severely impaired in PD. Cortical pathology most probably impairs the corticostriatal projection, whereas the corticosubthalamic connection remains intact. This model encourages recognition of the broader somatomotor dysfunctions within cortico-basal ganglia-circuitry in relationship to the caudo-rostral progress of the disease process. Neuropathological stages are indicated by various degrees of shading.
et al., 2004; Pahapill and Lozano 2000; Winn 2006). Descending projections from the pedunculopontine nucleus probably establish an outflow pathway from the otherwise nearly closed cortico-basal ganglia-cortical circuit that directs part of the data stream via nuclei of the lower brainstem to premotor and motor neurons of the somatomotor system. Connectivities between the reticulate portion of the substantia nigra and the superior colliculus may provide another outflow with descending projections. In light of its influence on somatomotor activity, the pedunculopontine nucleus is analogous to the amygdalar central subnucleus that primarily influences visceromotor activity, and both nuclei send efferents to all of the nonthalamic nuclei that have diffuse cortical as well as subcortical projections, i.e. the locus coeruleus, upper raphe nuclei, magnocellular nuclei of the basal forebrain (including the basal nucleus of Meynert), and the hypothalamic tuberomamillary nucleus (Fig. 1B). Intraneuronal inclusions in the pedunculopontine nucleus and central subnucleus of the amygdala appear in most autopsy cases during neuropathological stage 3 accompanied by the occurrence of initial inclusions in the substantia nigra pars compacta (Fig. 2). The severity of the Lewy body pathology at all three sites increases between stages 4–6 (Braak and Del Tredici, 2008; Braak et al., 2003). The sequel to the pathological changes in the substantia nigra is depletion of striatal dopamine, and this deficit produces hyperactivity on the part of striatal projection neurons belonging to the indirect pathway because corticostriatal glutamatergic influence is no longer sufficiently curbed. Reduction of striatal glutamate receptors or even a loss of spines would both be suitable mechanisms for limiting cortical excitatory input. Loss of spines along dendrites of striatal projection cells has been described in PD (Day et al., 2006; Deutch 2006; Gerfen
2006; Lach et al., 1992; McNeill et al., 1988; Neely et al., 2007; Stephens et al., 2005; Zaja-Milatovic et al., 2005). Whether the elimination of dendritic spines by striatal projection neurons is a plastic or a protective response to dampen excessive cortical drive and to ensure their own survival is currently a matter of debate (Deutch 2006). Levodopa therapy does not appear to reverse the process. The loss of spines could be attributable to the Lewy pathology that develops in corticostriatal projections. In any event, the loss of spines implies a disconnection or impairment of the glutamatergic corticostriatal input (Braak et al., 2007). The pathological process in stage 5 cases extends into neocortical areas, and inclusion-bearing pyramidal cells are seen predominantly in the deep layers V–VI where the neuronal somata of the corticostriatal projection are also located. The most plausible explanation for both findings (spine loss by striatal projection cells and occurrence of PD-related inclusions in cortical layer V and VI pyramidal cells) is that the neurons that generate the corticostriatal projection become affected late in the pathological process (Braak et al., 2007). The majority of synapses in the striatum belong to the corticostriatal projection. Thus, impairment of this major input can be anticipated to interrupt the data stream directly at the “front door,” as it were, of the cortico-basal ganglia-cortical circuit (Fig. 2). The observation that patients eventually become refractory to the therapeutic benefits of levodopa can possibly and partly be explained by the progressive impairment of the corticostriatal pathway, which gains in significance the longer the duration of the motor phase in PD. The hyperactivity that develops in the subthalamic nucleus during PD also appears in a somewhat different light in the amended model: Subthalamic disinhibition most probably does not result exclusively from the influence of the external pallidum as suggested by the basic
Brief Communication
model (Blandini et al., 2000; Fig. 1A). The hyperactivity might also result from the excitatory influence of “hyperdirect” corticosubthalamic connectivities, which originate chiefly from the primary motor area (Aron and Poldrack 2006; Hamani et al., 2004; Smith et al., 1998). In PD, the primary motor field remains intact, and, as such, its input into the “hyperdirect” corticosubthalamic tract is fully functional even in the end phase of the disorder (Frank et al., 2007). By contrast, if, as proposed above, the corticostriatal projection forfeits its excitatory input, the subthalamic nucleus would be subjected all the more to the excitatory influence of the primary motor cortex. This interpretation not only accounts for the hyperactivity of the subthalamic nucleus but also assigns the nucleus a more independent and central role than previously in the organization of the striatal circuit. The consequences and implications of the disease process in nondopaminergic neurons have received too little attention to date and await fuller integration into future models of the cortico-basal gangliacortical circuitry, perhaps facilitated by the amended version of the basic model proposed here. Acknowledgment Funding for this research was provided by the German Research Council (Deutsche Forschungsgemeinschaft). The authors also wish to thank Ms. Inge Szasz-Jacobi for technical assistance (graphics). References Ahlskog, J.E., 2007. Beating a dead horse: dopamine and Parkinson's disease. Neurology 69, 1701–1711. Albin, R.L., Young, A.B., Peney, J.B., 1989. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375. Alexander, G.E., Crutcher, M.D., DeLong, M.R., 1990. Basal ganglia-thalamocortical circuits: Parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Progr. Brain Res. 85, 119–146. Aron, A.R., Poldrack, R.A., 2006. Cortical and subcortical contributions to stop signal response inhibition: role of the subthalamic nucleus. J. Neurosci. 26, 2424–2433. Benabid, A.L., 2003. Deep brain stimulation for Parkinson's disease. Curr. Opin. Neurobiol. 13, 696–706. Blandini, F., Nappi, G., Tassorelli, C., Martignioni, E., 2000. Functional changes of the basal ganglia circuitry in Parkinson's disease. Progr. Neurobiol. 62, 63–88. Braak, H., Del Tredici, K., 2008. Nervous system pathology in sporadic Parkinson's disease. Neurology 70, 1916–1925. Braak, H., Del Tredici, K., Rüb, U., de Vos, R.A.I., Jansen Steur, E.N.H., Braak, E., 2003. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211. Braak, H., Sastre, M., Del Tredici, K., 2007. Development of a-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson's disease. Acta Neuropathol. 114, 231–241. Chesselet, M.F., Delfs, J.M., 1996. Basal ganglia and movement disorders: an update. Trends Neurosci. 19, 417–422. Day, M., Wang, Z., Ding, J., An, X., Ingham, C., Shering, A.F., Wokosin, D., Ilijic, E., Sun, Z., Sampson, A.R., Mugnaini, E., Deutch, A.Y., Sesack, S.R., Arbuthnott, G.W., Surmeier, D.J., 2006. Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nature Neurosci. 9, 251–259. DeLong, M.R., Wichmann, T., 2007. Circuits and circuit disorders of the basal ganglia. Arch. Neurol. 64, 20–24. Del Tredici, K., Rüb, U., de Vos, R.A.I., Bohl, J.R.E., Braak, H., 2002. Where does Parkinson disease pathology begin in the brain? J. Neuropathol. Exp. Neurol. 61, 413–426. Deutch, A.Y., 2006. Striatal plasticity in parkinsonism: dystrophic changes in medium spiny neurons and progression in Parkinson's disease. J. Neural Transm. 70, 67–70 (Suppl). Duda, J.E., Noorigian, J.V., Petrovitch, H., White, L.R., Ross, G.W., 2007. Pattern of Lewy pathology progression suggested by Braak staging system is supported by analysis
229
of a population-based cohort of patients. The Movement Disorders Society's 11th International Congress Late Breaking Abstracts A3. Frank, M.J., Samanta, J., Moustafa, A.A., Sherman, S.J., 2007. Hold your horses: impulsivity, deep brain stimulation, and medication in Parkinsonism. Science 318, 1309–1312. Gerfen, C.R., 2006. Indirect-pathway neurons lose their spines in Parkinson's disease. Nature Neurosci. 9, 157–158. Groenewegen, H.J., Berendse, H.W., 1994. The specificity of the ‘nonspecific’ midline and intralaminar thalamic nuclei. Trends Neurosci. 17, 52–57. Hamani, C., Saint-Cyr, J.A., Fraser, J., Kaplitt, M., Lozano, A.M., 2004. The subthalamic nucleus in the context of movement disorders. Brain 127, 4–20. Holstege, G., Mouton, L.J., Gerrits, N.M., 2004. Emotional motor system, In: Paxinos, G., Mai, J.K. (Eds.), The Human Nervous System, 2nd edition. Elsevier, San Diego and London, pp. 1306–1325. Kopell, B.H., Rezai, A.R., Chang, J.W., Vitek, J.L., 2006. Anatomy and physiology of the basal ganglia: implications for deep brain stimulation for Parkinson's disease. Mov. Disord. 21 (suppl 14), 238–246. Lach, B., Grimes, D., Benoit, B., Minkiewicz-Janda, A., 1992. Caudate nucleus pathology in Parkinson's disease: ultrastructural and biochemical findings in biopsy material. Acta Neuropathol. 83, 352–360. Lang, A.E., Obeso, J.A., 2004. Current challenges in Parkinson's disease: restoring the nigrostriatal dopamine system is not enough. Lancet Neurology 3, 309–316. Langston, J.W., 2006. The Parkinson's complex: Parkinsonism is just the tip of the iceberg. Ann. Neurol. 59, 591–596. Lee, M.S., Rinne, J.O., Marsden, C.D., 2000. The pedunculopontine nucleus: its role in the genesis of movement disorders. Yonsei Med. J. 41, 167–184. McNeill, T.H., Brown, S.A., Rafols, J.A., Shoulson, I., 1988. Atrophy of medium spiny striatal dendrites in advanced Parkinson's disease. Brain Res. 455, 148–152. Mena-Segovia, J., Bolam, J.P., Magill, P.J., 2004. Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same familiy? Trends Neurosci. 27, 585–588. Neely, M.D., Schmidt, D.E., Deutch, A.Y., 2007. Cortical regulation of dopamine depletioninduced dendritic spine loss in striatal medium spiny neurons. Neuroscience 149, 457–464. Obeso, J.A., Guridi, J., DeLong, M.R., 1997. Surgery for Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 62, 2–8. Pahapill, P.A., Lozano, A.M., 2000. The pedunculopontine nucleus and Parkinson's disease. Brain 123, 1767–1783. Parent, A., Hazrati, L.N., 1995. Functional anatomy of the basal ganglia. I. The corticobasal ganglia-thalamo-cortical loop. Brain Res. Rev. 20, 91–127. Parent, A., Cicchetti, F., 1998. The current model of basal ganglia organization under scrutiny. Mov. Disord. 13, 199–202. Rüb, U., Del Tredici, K., Schultz, C., Ghebremedhin, E., de Vos, R.A., Jansen Steur, E., Braak, H., 2002. Parkinson's disease: the thalamic components of the limbic loop are severely impaired by a-synuclein immunopositive inclusion body pathology. Neurobiol. Aging 23, 245–254. Smith, Y., Shink, E., Sidibé, M., 1998. Neuronal circuitry and synaptic connectivity of the basal ganglia. Neurosurg. Clin. N. Am. 9, 203–222. Stefani, A., Lozano, A.M., Peppe, A., Stanzione, P., Galati, S., Tropepi, D., Pierantozzi, M., Scarnati, E., Mazzone, P., 2007. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain 130, 1596–1607. Stephens, B., Mueller, A.J., Shering, A.F., Hood, S.H., Taggart, P., Arbuthnott, G.W., Bell, J.E., Kilford, L., Kingsbury, A.E., Daniel, S.E., Ingham, C.A., 2005. Evidence of a breakdown of corticostriatal connections in Parkinson's disease. Neuroscience 132, 741–754. Tepper, J.M., Abercrombie, E.D., Bolam, J.P., 2007. Basal ganglia macrocircuits. Progr. Brain Res. 160, 3–7. Volkmann, J., 2007. Update on surgery for Parkinson's disease. Curr. Opin. Neurol. 20, 465–469. Wichmann, T., DeLong, M.R., 1998. Models of basal ganglia function and pathophysiology of movement disorders. Neurosurg. Clin. N. Am. 9, 223–236. Wichmann, T., DeLong, M.R., 2003. Functional neuroanatomy of the basal ganglia in Parkinson's disease. Adv. Neurol. 91, 9–18. Winn, P., 2006. How best to consider the structure and function of the pedunculopontine tegmental nucleus: evidence from animal studies. J. Neurol. Sci. 248, 234–250. Zaja-Milatovic, S., Milatovic, D., Schantz, A.M., Zhang, J., Montine, K.S., Samii, A., Deutch, A.Y., Montine, T.J., 2005. Dendritic degeneration in neostriatal medium spiny neurons in Parkinson's disease. Neurology 64, 545–547.
Contents lists available at ScienceDirect
Experimental Neurology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y e x n r
Brief Communication
Cortico-basal ganglia-cortical circuitry in Parkinson's disease reconsidered Heiko Braak ⁎, Kelly Del Tredici Institute for Clinical Neuroanatomy, J.W. Goethe University, Frankfurt am Main, Germany
A R T I C L E
I N F O
Article history: Received 9 January 2008 Revised 14 March 2008 Accepted 1 April 2008 Available online 15 April 2008 Keywords: Basal ganglia Bradykinesia Cortico-basal ganglia-cortical circuit Deep brain stimulation Hypokinesia Parkinson's disease Pedunculopontine nucleus Striatum Spines Subthalamic nucleus
A B S T R A C T The classical model of the cortico-basal ganglia-cortical circuit, with its indirect and direct pathways, was developed to explain the phenomenon of hypokinesia in Parkinson's disease (PD). The model has undergone refinement, but the emphasis on the basal ganglia side of the equation (dopamine deficiency in the dorsal striatum) remains. Here, a revised version of the basic model incorporates key non-dopaminergic connectivities known to become affected in the course of PD and, thus, the cortico-basal ganglia-cortical circuit appears within the context of the larger pathological process. The central roles of the corticostriatal projection, corticosubthalamic projection, and lower brainstem nuclei are emphasized. © 2008 Elsevier Inc. All rights reserved.
The prefrontal cortex and additional extensive portions of the neocortex probably activate the dorsal striatum through excitatory glutamatergic projections. From there, impulses via the pallidum reach the anteroventral thalamic nuclei, which relay data back to the cerebral neocortex, thereby establishing the cortico-basal gangliacortical circuit (Albin et al., 1989; Alexander et al., 1990; Blandini et al., 2000; Chesselet and Delfs 1996; DeLong and Wichmann 2007; Parent and Cicchetti 1998; Parent and Hazrati 1995; Tepper et al., 2007; Wichmann and DeLong 1998, 2003; Fig. 1A). This basic model is essential for understanding motor dysfunctions that develop in the course of sporadic Parkinson's disease (PD) and it also serves as part of the theoretical basis for stereotactic surgical procedures (deep brain stimulation) (Benabid 2003; Kopell et al., 2006; Obeso et al., 1997; Stefani et al., 2007; Volkmann 2007). Dopamine depletion in the striatum probably induces postsynaptic changes in striatal projection neurons and produces an imbalance within both the direct pathway (insufficient activation) as well as the indirect pathway (insufficient inhibition). The net-effect of the inequilibrium probably is hyperactivity or disinhibition of the subthalamic nucleus. The resulting predominance of the internal pallidum leads, in turn, to inhibition of thalamo-cortical activity and, clinically, to hypokinesia (Blandini et al., 2000; DeLong and Wichmann 2007; Tepper et al., 2007; Wichmann and DeLong 2003). Equilibrium between the indirect and direct ⁎ Corresponding author. Institute for Clinical Neuroanatomy, J.W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. Fax: +49 69 6301 6425. E-mail address: [email protected] (H. Braak). 0014-4886/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2008.04.001
pathways can be restored, to an extent, by pharmacological alleviation of the striatal dopamine deficiency or by a surgically induced reduction of the hyperactivity in the subthalamic nucleus (Fig. 1A). But can this model be utilized to explain more than the consequences of the gradual loss of striatal dopamine for the motor system? Clinicians have pointed out that the symptoms associated with PD cannot be explained alone by dopamine deficiency in the striatum; rather, the synucleinopathy PD involves predisposed nerve cell types, multiple neurotransmitter types, and components of various functional systems throughout the entire human nervous system (Ahlskog 2007; DeLong and Wichmann 2007; Lang and Obeso 2004; Langston 2006; Tepper et al., 2007). In the brain, the intraneuronal inclusions (Lewy neurites/bodies) appear to begin in the lower brainstem and progress caudo-rostrally in six stages into hitherto uninvolved regions (Braak and Del Tredici, 2008; Braak et al., 2003; Del Tredici et al., 2002; Duda et al., 2007). The present text proposes an amended version of the basic model in that it includes nondopaminergic connectivities that become involved in PD and places these schematically, together with the cortico-basal ganglia-cortical circuitry, in relationship to the proposed neuropathological course of PD as characterized by the topographic and sequential distribution pattern of the intraneuronal inclusions. Even a rather minimalist view of the pathological process that underlies PD indicates that it is instructive to study the cortico-basal ganglia-cortical circuitry within the context of the larger disease process. Our analysis of motor structures within the central nervous system begins with preganglionic parasympathetic motor neurons as well as
Brief Communication
227
Fig. 1. A. Basic model of the direct and indirect pathways through the cortico-basal ganglia-cortical circuit. Terminal axons of midbrain nigral dopaminergic neurons activate substance P/GABAergic projection cells in the dorsal striatum while inhibiting enkephalin/GABAergic neurons. Striatal outflow reaches neocortical motor areas via relay nuclei of the ventral thalamus (VA/VLa). B. In the brain, the pathological process underlying Parkinson's disease (PD) commences in the medullary dorsal motor nucleus of the vagal nerve (neuropathological stage 1, black shading). Premotor and motor neurons of the spinal cord and brainstem, by contrast, remain uninvolved for the duration of the disorder. In stage 2, Lewy neurites/bodies appear within the lower raphe nuclei, magnocellular reticular nuclei, and coeruleus/subcoeruleus complex in the lower brainstem (dark gray shading). All of these nuclei send descending projections to somatomotor and visceromotor neurons and become affected prior to the substantia nigra, pars compacta. They are capable of limiting the conduction of incoming pain signals and placing the organism's motor neurons in a heightened state of preparedness for action, particularly in stress situations. Relay centers of the visceromotor system (central subnucleus of the amygdala) and nuclei influencing the somatomotor system (pedunculopontine tegmental nucleus, dopaminergic neurons of the substantia nigra) are drawn into the disease process at stage 3 (light gray shading). Both the pedunculopontine nucleus and the central nucleus of the amygdala send descending projections to lower brainstem centers mentioned above and project to all of the non-thalamic nuclei with diffuse cortical and subcortical efferents that likewise become involved at stage 3.
the premotor and motor neurons of the spinal cord and brainstem (Fig. 1B). Briefly, parasympathetic preganglionic projection neurons in the dorsal motor nucleus of the vagal nerve become involved in PD in neuropathological stage 1. In stage 2, the disease process proceeds further into the lower brainstem and lesions appear in the lower raphe nuclei, magnocellular portions of the reticular formation (e.g., gigantocellular nucleus), and coeruleus/subcoeruleus complex (Braak and Del Tredici, 2008; Braak et al., 2003; Del Tredici et al., 2002; Duda et al., 2007). This group of nuclei serves as a motor control system, whose descending projections influence both somatomotor and visceromotor neurons (Holstege et al., 2004; Fig. 1B). Basal portions of the mid- and forebrain become involved at neuropathological stage 3, including relay centers (e.g., central subnucleus of the amygdala) of the visceromotor system and centers (pedunculopontine tegmental nu-
cleus, substantia nigra pars compacta) that exert influence on the somatomotor system (Figs.1B, 2). Affection of the anterior and posterior thalamic intralaminar nuclei (excluding the centrum medianum and parafascicular nucleus) that project to the striatum and cerebral cortex occurs in stage 4 (Groenewegen and Berendse 1994; Rüb et al., 2002). In stages 5–6, extended neocortical association areas and the premotor areas are drawn into the disease process (Braak et al., 2003; Fig. 2). The amended version of the basic model of the cortico-basal ganglia-cortical circuit (Fig. 2) assigns a position to the pedunculopontine tegmental nucleus, which does not appear in the classical scheme (Fig. 1A). This nucleus receives afferents from the internal pallidum and subthalamic nucleus, and sends efferents not only to nigral dopaminergic nerve cells but also to lower brainstem and spinal cord (DeLong and Wichmann 2007; Lee et al., 2000; Mena-Segovia
228
Brief Communication
Fig. 2. Amended version of the cortico-basal ganglia-cortical circuit. This model encompasses motor areas from the spinal cord to the neocortex and incorporates not only the consequences of dopamine depletion in the dorsal striatum but also additional non-dopaminergic somatomotor centers that become consecutively and severely impaired in PD. Cortical pathology most probably impairs the corticostriatal projection, whereas the corticosubthalamic connection remains intact. This model encourages recognition of the broader somatomotor dysfunctions within cortico-basal ganglia-circuitry in relationship to the caudo-rostral progress of the disease process. Neuropathological stages are indicated by various degrees of shading.
et al., 2004; Pahapill and Lozano 2000; Winn 2006). Descending projections from the pedunculopontine nucleus probably establish an outflow pathway from the otherwise nearly closed cortico-basal ganglia-cortical circuit that directs part of the data stream via nuclei of the lower brainstem to premotor and motor neurons of the somatomotor system. Connectivities between the reticulate portion of the substantia nigra and the superior colliculus may provide another outflow with descending projections. In light of its influence on somatomotor activity, the pedunculopontine nucleus is analogous to the amygdalar central subnucleus that primarily influences visceromotor activity, and both nuclei send efferents to all of the nonthalamic nuclei that have diffuse cortical as well as subcortical projections, i.e. the locus coeruleus, upper raphe nuclei, magnocellular nuclei of the basal forebrain (including the basal nucleus of Meynert), and the hypothalamic tuberomamillary nucleus (Fig. 1B). Intraneuronal inclusions in the pedunculopontine nucleus and central subnucleus of the amygdala appear in most autopsy cases during neuropathological stage 3 accompanied by the occurrence of initial inclusions in the substantia nigra pars compacta (Fig. 2). The severity of the Lewy body pathology at all three sites increases between stages 4–6 (Braak and Del Tredici, 2008; Braak et al., 2003). The sequel to the pathological changes in the substantia nigra is depletion of striatal dopamine, and this deficit produces hyperactivity on the part of striatal projection neurons belonging to the indirect pathway because corticostriatal glutamatergic influence is no longer sufficiently curbed. Reduction of striatal glutamate receptors or even a loss of spines would both be suitable mechanisms for limiting cortical excitatory input. Loss of spines along dendrites of striatal projection cells has been described in PD (Day et al., 2006; Deutch 2006; Gerfen
2006; Lach et al., 1992; McNeill et al., 1988; Neely et al., 2007; Stephens et al., 2005; Zaja-Milatovic et al., 2005). Whether the elimination of dendritic spines by striatal projection neurons is a plastic or a protective response to dampen excessive cortical drive and to ensure their own survival is currently a matter of debate (Deutch 2006). Levodopa therapy does not appear to reverse the process. The loss of spines could be attributable to the Lewy pathology that develops in corticostriatal projections. In any event, the loss of spines implies a disconnection or impairment of the glutamatergic corticostriatal input (Braak et al., 2007). The pathological process in stage 5 cases extends into neocortical areas, and inclusion-bearing pyramidal cells are seen predominantly in the deep layers V–VI where the neuronal somata of the corticostriatal projection are also located. The most plausible explanation for both findings (spine loss by striatal projection cells and occurrence of PD-related inclusions in cortical layer V and VI pyramidal cells) is that the neurons that generate the corticostriatal projection become affected late in the pathological process (Braak et al., 2007). The majority of synapses in the striatum belong to the corticostriatal projection. Thus, impairment of this major input can be anticipated to interrupt the data stream directly at the “front door,” as it were, of the cortico-basal ganglia-cortical circuit (Fig. 2). The observation that patients eventually become refractory to the therapeutic benefits of levodopa can possibly and partly be explained by the progressive impairment of the corticostriatal pathway, which gains in significance the longer the duration of the motor phase in PD. The hyperactivity that develops in the subthalamic nucleus during PD also appears in a somewhat different light in the amended model: Subthalamic disinhibition most probably does not result exclusively from the influence of the external pallidum as suggested by the basic
Brief Communication
model (Blandini et al., 2000; Fig. 1A). The hyperactivity might also result from the excitatory influence of “hyperdirect” corticosubthalamic connectivities, which originate chiefly from the primary motor area (Aron and Poldrack 2006; Hamani et al., 2004; Smith et al., 1998). In PD, the primary motor field remains intact, and, as such, its input into the “hyperdirect” corticosubthalamic tract is fully functional even in the end phase of the disorder (Frank et al., 2007). By contrast, if, as proposed above, the corticostriatal projection forfeits its excitatory input, the subthalamic nucleus would be subjected all the more to the excitatory influence of the primary motor cortex. This interpretation not only accounts for the hyperactivity of the subthalamic nucleus but also assigns the nucleus a more independent and central role than previously in the organization of the striatal circuit. The consequences and implications of the disease process in nondopaminergic neurons have received too little attention to date and await fuller integration into future models of the cortico-basal gangliacortical circuitry, perhaps facilitated by the amended version of the basic model proposed here. Acknowledgment Funding for this research was provided by the German Research Council (Deutsche Forschungsgemeinschaft). The authors also wish to thank Ms. Inge Szasz-Jacobi for technical assistance (graphics). References Ahlskog, J.E., 2007. Beating a dead horse: dopamine and Parkinson's disease. Neurology 69, 1701–1711. Albin, R.L., Young, A.B., Peney, J.B., 1989. The functional anatomy of basal ganglia disorders. Trends Neurosci. 12, 366–375. Alexander, G.E., Crutcher, M.D., DeLong, M.R., 1990. Basal ganglia-thalamocortical circuits: Parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Progr. Brain Res. 85, 119–146. Aron, A.R., Poldrack, R.A., 2006. Cortical and subcortical contributions to stop signal response inhibition: role of the subthalamic nucleus. J. Neurosci. 26, 2424–2433. Benabid, A.L., 2003. Deep brain stimulation for Parkinson's disease. Curr. Opin. Neurobiol. 13, 696–706. Blandini, F., Nappi, G., Tassorelli, C., Martignioni, E., 2000. Functional changes of the basal ganglia circuitry in Parkinson's disease. Progr. Neurobiol. 62, 63–88. Braak, H., Del Tredici, K., 2008. Nervous system pathology in sporadic Parkinson's disease. Neurology 70, 1916–1925. Braak, H., Del Tredici, K., Rüb, U., de Vos, R.A.I., Jansen Steur, E.N.H., Braak, E., 2003. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211. Braak, H., Sastre, M., Del Tredici, K., 2007. Development of a-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson's disease. Acta Neuropathol. 114, 231–241. Chesselet, M.F., Delfs, J.M., 1996. Basal ganglia and movement disorders: an update. Trends Neurosci. 19, 417–422. Day, M., Wang, Z., Ding, J., An, X., Ingham, C., Shering, A.F., Wokosin, D., Ilijic, E., Sun, Z., Sampson, A.R., Mugnaini, E., Deutch, A.Y., Sesack, S.R., Arbuthnott, G.W., Surmeier, D.J., 2006. Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nature Neurosci. 9, 251–259. DeLong, M.R., Wichmann, T., 2007. Circuits and circuit disorders of the basal ganglia. Arch. Neurol. 64, 20–24. Del Tredici, K., Rüb, U., de Vos, R.A.I., Bohl, J.R.E., Braak, H., 2002. Where does Parkinson disease pathology begin in the brain? J. Neuropathol. Exp. Neurol. 61, 413–426. Deutch, A.Y., 2006. Striatal plasticity in parkinsonism: dystrophic changes in medium spiny neurons and progression in Parkinson's disease. J. Neural Transm. 70, 67–70 (Suppl). Duda, J.E., Noorigian, J.V., Petrovitch, H., White, L.R., Ross, G.W., 2007. Pattern of Lewy pathology progression suggested by Braak staging system is supported by analysis
229
of a population-based cohort of patients. The Movement Disorders Society's 11th International Congress Late Breaking Abstracts A3. Frank, M.J., Samanta, J., Moustafa, A.A., Sherman, S.J., 2007. Hold your horses: impulsivity, deep brain stimulation, and medication in Parkinsonism. Science 318, 1309–1312. Gerfen, C.R., 2006. Indirect-pathway neurons lose their spines in Parkinson's disease. Nature Neurosci. 9, 157–158. Groenewegen, H.J., Berendse, H.W., 1994. The specificity of the ‘nonspecific’ midline and intralaminar thalamic nuclei. Trends Neurosci. 17, 52–57. Hamani, C., Saint-Cyr, J.A., Fraser, J., Kaplitt, M., Lozano, A.M., 2004. The subthalamic nucleus in the context of movement disorders. Brain 127, 4–20. Holstege, G., Mouton, L.J., Gerrits, N.M., 2004. Emotional motor system, In: Paxinos, G., Mai, J.K. (Eds.), The Human Nervous System, 2nd edition. Elsevier, San Diego and London, pp. 1306–1325. Kopell, B.H., Rezai, A.R., Chang, J.W., Vitek, J.L., 2006. Anatomy and physiology of the basal ganglia: implications for deep brain stimulation for Parkinson's disease. Mov. Disord. 21 (suppl 14), 238–246. Lach, B., Grimes, D., Benoit, B., Minkiewicz-Janda, A., 1992. Caudate nucleus pathology in Parkinson's disease: ultrastructural and biochemical findings in biopsy material. Acta Neuropathol. 83, 352–360. Lang, A.E., Obeso, J.A., 2004. Current challenges in Parkinson's disease: restoring the nigrostriatal dopamine system is not enough. Lancet Neurology 3, 309–316. Langston, J.W., 2006. The Parkinson's complex: Parkinsonism is just the tip of the iceberg. Ann. Neurol. 59, 591–596. Lee, M.S., Rinne, J.O., Marsden, C.D., 2000. The pedunculopontine nucleus: its role in the genesis of movement disorders. Yonsei Med. J. 41, 167–184. McNeill, T.H., Brown, S.A., Rafols, J.A., Shoulson, I., 1988. Atrophy of medium spiny striatal dendrites in advanced Parkinson's disease. Brain Res. 455, 148–152. Mena-Segovia, J., Bolam, J.P., Magill, P.J., 2004. Pedunculopontine nucleus and basal ganglia: distant relatives or part of the same familiy? Trends Neurosci. 27, 585–588. Neely, M.D., Schmidt, D.E., Deutch, A.Y., 2007. Cortical regulation of dopamine depletioninduced dendritic spine loss in striatal medium spiny neurons. Neuroscience 149, 457–464. Obeso, J.A., Guridi, J., DeLong, M.R., 1997. Surgery for Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 62, 2–8. Pahapill, P.A., Lozano, A.M., 2000. The pedunculopontine nucleus and Parkinson's disease. Brain 123, 1767–1783. Parent, A., Hazrati, L.N., 1995. Functional anatomy of the basal ganglia. I. The corticobasal ganglia-thalamo-cortical loop. Brain Res. Rev. 20, 91–127. Parent, A., Cicchetti, F., 1998. The current model of basal ganglia organization under scrutiny. Mov. Disord. 13, 199–202. Rüb, U., Del Tredici, K., Schultz, C., Ghebremedhin, E., de Vos, R.A., Jansen Steur, E., Braak, H., 2002. Parkinson's disease: the thalamic components of the limbic loop are severely impaired by a-synuclein immunopositive inclusion body pathology. Neurobiol. Aging 23, 245–254. Smith, Y., Shink, E., Sidibé, M., 1998. Neuronal circuitry and synaptic connectivity of the basal ganglia. Neurosurg. Clin. N. Am. 9, 203–222. Stefani, A., Lozano, A.M., Peppe, A., Stanzione, P., Galati, S., Tropepi, D., Pierantozzi, M., Scarnati, E., Mazzone, P., 2007. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease. Brain 130, 1596–1607. Stephens, B., Mueller, A.J., Shering, A.F., Hood, S.H., Taggart, P., Arbuthnott, G.W., Bell, J.E., Kilford, L., Kingsbury, A.E., Daniel, S.E., Ingham, C.A., 2005. Evidence of a breakdown of corticostriatal connections in Parkinson's disease. Neuroscience 132, 741–754. Tepper, J.M., Abercrombie, E.D., Bolam, J.P., 2007. Basal ganglia macrocircuits. Progr. Brain Res. 160, 3–7. Volkmann, J., 2007. Update on surgery for Parkinson's disease. Curr. Opin. Neurol. 20, 465–469. Wichmann, T., DeLong, M.R., 1998. Models of basal ganglia function and pathophysiology of movement disorders. Neurosurg. Clin. N. Am. 9, 223–236. Wichmann, T., DeLong, M.R., 2003. Functional neuroanatomy of the basal ganglia in Parkinson's disease. Adv. Neurol. 91, 9–18. Winn, P., 2006. How best to consider the structure and function of the pedunculopontine tegmental nucleus: evidence from animal studies. J. Neurol. Sci. 248, 234–250. Zaja-Milatovic, S., Milatovic, D., Schantz, A.M., Zhang, J., Montine, K.S., Samii, A., Deutch, A.Y., Montine, T.J., 2005. Dendritic degeneration in neostriatal medium spiny neurons in Parkinson's disease. Neurology 64, 545–547.