- Email: [email protected]
The Darwinian plasticity hypothesis for tinnitus and pain
B. Langguth, G. Hajak, T. Kleinjung, A. Cacace & A.R. Møller (Eds.) Progress in Brain Research, Vol. 166 ISSN 0079-6123 Copyright r 2007 Elsevier B.V. All rights reserved
CHAPTER 5
The Darwinian plasticity hypothesis for tinnitus and pain Dirk De Ridder1, and Paul Van de Heyning2 1 Department of Neurosurgery, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium Department of Otorhinolaryngology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium
2
Abstract: We present the hypothesis that expression of neural plasticity is a form of adaptation based on natural selection, where cells or cell groups deprived of sensory input actively go and look for information in order to survive. The Darwinian model of brain plasticity can explain the symptomatology induced by deprivation of input which was not well explained by classical plasticity without contradicting pertinent data from the neurophysiological, neuroanatomical, functional neuroimaging, and clinical literature. Applying the concept of Darwinian plasticity to sensory plasticity that causes symptoms and signs of disease might lead to the development of new treatments for deprivation of input induced symptomatology. We will use results from the application of electrical and magnetic stimulation of the auditory and the somatosensory cortices for treatment of tinnitus and for alleviating some forms of pain in support of the Darwinian hypothesis about neural plasticity. We will also review the literature regarding physiological and anatomical, as well as imaging data that support the existence of this hypothetical form of plasticity. Keywords: Darwin; Darwinian plasticity; deafferentation; neurostimulation; phantom pain; tinnitus; auditory cortex; somatosensory cortex plasticity is a form of adaptation based on natural selection, where cells or cell groups deprived of sensory input actively go and look for information in order to survive. Explaining expression of neural plasticity by the concept of Darwinian development solves the clinical conundrum regarding the symptoms and signs of expression of cortical plasticity such as it is believed to occur in some forms of tinnitus and pain. The concept of Darwinian principles of survival of the fittest can explain why input-deprived neurons start processing information from adjacent neurons, namely in order to survive. This way of viewing neural plasticity provides a theoretical framework for developing new treatments for brain dysfunctions induced by
Introduction Neuropathic pain and tinnitus are both considered phantom perceptions sharing a similar pathophysiology and clinical symptoms. Both neuropathic pain and tinnitus are perceptions coming from the missing part of the body, and are considered the result of maladaptive plasticity, where cortex not deprived of sensory input expands into the vacated area. Clinically, however, this should result in pain or tinnitus representing lesion-edge characteristics, contradictory to what is noted in real life. We present the hypothesis that expression of neural Corresponding author. Tel.: +32 3 8213336; Fax: +32 3 8252428; E-mail: [email protected] DOI: 10.1016/S0079-6123(07)66005-1
55
56
Fig. 1. In classical plasticity the non-deprived lesion edge frequencies expand into the deprived area, in Darwinian plasticity the deprived frequencies will look for information in the adjacent area. Example of the differences in high frequency hearing loss (drawing by Jan Ost).
deprivation of input. Based on this hypothesis, treatments can be developed for disorders that are caused by deprivation of sensory input. The basic concept being that supplying the missing information directly to the deafferented area will suppress deafferentiation-induced symptoms, by preventing or reversing Darwinian plasticity. To test this hypothesis we have analyzed the results from treatment of patients with phantom sound ( ¼ tinnitus) and patients with phantom pain by electrical stimulation of the auditory cortex and the somatosensory cortex respectively (Chapter 36). In the following we review neurophysiological, neuroanatomical, and functional imaging data, and suggest that the generally accepted hypothesis that topographic map plasticity changes seen in reorganization are not only due to ingrowths of synapses into an area of deprived input, but that the opposite might also be occurring: input-deprived synapses could sprout to adjacent non-deprived
areas in an attempt to survive in long-term reorganization. Similarly, short-term reorganization could involve input-deprived neurons processing information from adjacent neurons by changing synaptic efficacy. Figure 1 shows how sprouting in the auditory cortex would occur within an area where neurons are tuned to similar frequencies. Darwinian hypothesis of plasticity suggest that sprouting occurs between areas where neurons are tuned to different frequencies, for example, from high frequency areas to areas where neurons are tuned to middle frequencies.
Darwinian hypothesis of neural plasticity The human brain can be considered the result of a Darwinian evolutionary development (Calvin, 1987). A synapse can be seen as the analogue of a biological creature, replication and growth of
57
connections the analogue of organism reproduction, and in this view, competition for connections is the analogue of competition for food and mates, and which connections survive is based on its environment and the competition (Deacon, 1997). Neural connections that are fit for the environment survive and can be strengthened or weakened, much the same as individuals that fit the environment. Neurons that are fit follow the same rules (proliferation and apoptosis), analogous to whole species. This evolution-like process for building brains allows brains to become adapted to the bodies they inhabit within their own internal constraints, with a minimum of pre-planned design: brains are not genetically hardwired, but only the rules coding for self-organization via Darwinian competition are coded for (Deacon, 1997). This axonal competition for target territories furthermore results in development of topographic maps such as the visuotopic map, somatotopic map of the motor and sensory cortex and the tonotopic map of the auditory system. Plasticity refers to the capacity of the nervous system to modify its organization (see Chapter 2) (Bavelier and Neville, 2002). This is more pronounced in the developing brain but the mature auditory system still has the capacity for reorganization, adjusting itself to changes in the auditory environment. One form of neural plasticity regards the tonotopic maps of the auditory cortex. These maps are not rigid and may reorganize under influence of physiological (Gao and Suga, 1998) or pathological (Suga et al., 2000) sensory stimuli. Similar modification of tonotopic mapping in the entire auditory pathways may be artificially induced by focal electrical auditory cortex stimulation (Suga et al., 2000; Zhang and Suga, 2000; Suga and Ma, 2003). This adaptive plasticity can be both beneficial, such as in learning and repair or maladaptive, resulting for example in tinnitus. The same holds for the mature somatosensory system: any alteration of somatosensory input, whether physiological (Recanzone et al., 1992) or pathological (Kaas et al., 1983) can induce a topographical reorganization in the somatosensory cortex. Topographic reorganization has been demonstrated in humans by means of magnetic source
imaging (MSI) (Flor et al., 1995; Muhlnickel et al., 1998) and functional magnetic resonance imaging (fMRI) (Melcher et al., 2000; Maihofner et al., 2003). Furthermore there is a clear correlation between the amount of reorganization and the intensity of the phantom percept, associated with this sensory cortex reorganization, whether tinnitus or phantom pain (Flor et al., 1995; Muhlnickel et al., 1998). Successful treatment of the phantom perception reverses the reorganization electrophysiologically (Theuvenet et al., 1999; Maihofner et al., 2004). Cortical areas that have been reorganized, as visualized by fMRI are the targets for supplying the missing information, in attempts to normalize function. We have used non-invasive fMRI guided neuronavigated transcranial magnetic stimulation (TMS) (De Ridder et al., 2004, 2005b) for that purpose. If successful, the clinical suppression of the phantom perception can be perpetuated by implantation of an electrode in the same fMRI based neuronavigated way (see Chapter 36) (De Ridder et al., 2004, 2005a).
Basis for the Darwinian hypothesis Neurophysiology Kaas and Schwaber have used closely spaced microelectrode recordings to determine the receptive fields of cortical neurons in monkeys creating a detailed tonotopic map of the A1 cortical area. After inducing a high-frequency lesion by administering ototoxic antibiotics (kanamycin) combined with furosemide (Schwaber et al., 1993) that preferentially lesion high-frequency hair cells, they studied the concomitant changes in the tonotopic maps of the auditory cortex. Recording from neurons that normally responded to highfrequency tones, they found these neurons now responded to tones of lower frequencies (midfrequency). These findings were interpreted to show that synaptic connections had been established with neurons that previously responded to high frequencies. Similar studies in deafferentation pain by the same group yielded findings that were interpreted in a similar way (Kaas et al., 1983).
58
However, these results might also be interpreted from a Darwinian point of view to indicate that high-frequency neurons deprived of sensory input begin to process information from adjacent nondeprived areas by changes in synaptic strength (in short-term reorganization), or by sprouting of dendrites into the adjacent area that were not affected by the deprivation of input (in long-term reorganization). Such cells will respond to midfrequency tones as well. Thus electrophysiological data support both explanations of the alterations that are caused by deprivation of input. Thus anatomical and other data are necessary to distinguish between the two possible forms of plasticity. Neuroanatomy While plenty neurophysiological data exist characterizing topographic (re)organization of central maps, the underlying anatomical correlates have not been thoroughly investigated. That dendrites of neurons that are deprived of input can anatomically sprout into the adjacent areas in the auditory system has at least been demonstrated in the cricket (Hoy et al., 1985; Brodfuehrer and Hoy, 1988). For the somatosensory system, dendritic arbors are noted to expand distally reaching into non-deprived cortical areas (Churchill et al., 2004), suggesting that sprouting occurs from deprived toward non-deprived areas and not in the opposite direction. These anatomical observations favor the Darwinian hypothesis of neural plasticity. Clinical experience Both in the auditory system (Norena et al., 2002) and in the somatosensory system (Ramachandran and Hirstein, 1998), auditory phantom perceptions (tinnitus) and phantom pain are those coming from the missing part of the body. The tinnitus spectrum a patient perceives is found to occupy a wide frequency range corresponding largely to that at which hearing thresholds are abnormally elevated (Norena et al., 2002), and phantom pain is perceived in the missing body part. Darwinian plasticity also more accurately explains how tactile stimuli of the face demonstrate a hand representation in
individuals with an amputated arm (Ramachandran and Hirstein, 1998) than conventional hypotheses about neural plasticity. If cells that represent the hand in the somatosensory cortex have sprouted into the non-affected adjacent face area these cells that were deprived of their normal input will be activated by touching the face (Ramachandran and Hirstein, 1998; Ramachandran and RogersRamachandran, 2000). If on the other hand the dendrites of the neurons that receive normal input would have sprouted into the vacated arm area on the sensory cortex, hand perception as such would have disappeared altogether. Our clinical case with the abnormal perception of the location of the eye (Chapter 36) can be explained in a similar way, where the sensory-deprived supraorbital area is the one that is painful. The phantom eye perception may be explained in a similar way. If the neurons that receive normal input would have sprouted towards the neurons that receive input from the V1 (forehead) area that is deprived of input, it would have caused the phantom eye to be localized on the forehead. It was this clinical picture that inspired us to question the accepted pathophysiological hypothesis of reorganization through expression of neural plasticity in response to deprivation of input.
Functional imaging A further argument favoring the Darwinian hypothesis for plasticity comes from magnetoencephalographic (MEG) studies. Thus Muhlnickel (Muhlnickel et al., 1998) and Flor (Flor et al., 1995) using MSI explored the reorganization of the auditory cortex that occurred in patients with tinnitus. They found a shift of the cortical representation of the tinnitus frequency into an area adjacent to the tonotopic location of the frequency of the tinnitus. They also found a strong a strong positive correlation between the subjective strength of the tinnitus and the degree of cortical reorganization, similarly to what has been shown for the somatosensory system (Flor et al., 1995). The amount of phantom limb pain is highly correlated with degree of cortical reorganization of the primary somatosensory cortex (Flor et al., 1995).
59
If the reorganization consisted of invasion from the non-deprived adjacent area into the deprived area, as has been generally accepted, there would be a shift in the magnetic source of the adjacent frequencies, and not the deprived frequencies as noted in both of the MEG studies mentioned above (Flor et al., 1995; Muhlnickel et al., 1998). It has been demonstrated that the BOLD effect on fMRI correlates with event-related synchronization in the gamma band (32–38 Hz), both in EEG (Foucher et al., 2003) and MEG (Brookes et al., 2005) studies. This suggests that fMRI (Smits et al., 2004) can visualize the gamma band synchronized activity associated with tinnitus and pain (Llinas et al., 2005).
Brain stimulation A last argument favoring the Darwinian hypothesis for neural plasticity comes from studies of electrical stimulation of sensory cortices (De Ridder et al., 2006, , 2007a, b). Low-frequency stimulation (o120 Hz) activate cells as demonstrated in the human subthalamic nucleus (Beurrier et al., 2001), whereas high-frequency stimulation inactivate cells in a ‘functional lesion’ (Benabid et al., 2005). Both tinnitus (Eggermont and Roberts, 2004) and neuropathic pain (Chudler et al., 1990) are associated with hyperactivity of their respective primary sensory cortices. Our stimulation parameters, consisting of (activating) low-frequency stimulation should worsen tinnitus and pain if the adjacent areas have sprouted into the deprived areas, as they would then be stimulated even more, based on the egocentric selection principle (Suga et al., 2000). On the contrary, in a Darwinian model of brain functioning, supplying low intensity electrical stimuli to synapses of cells that are deprived of input would prevent (or reverse) such cells to sprout (prevent the looking for information in order to survive), thereby clinically preventing (or reversing) the phantom perceptions. Electrical stimulation of sensory cortices may supply the missing input directly and high-intensity stimulation would be predicted to induce tinnitus and pain, as seen in our patients (De Ridder et al., 2006, 2007a, b).
Conclusion Neurophysiological and neuroanatomical data, functional imaging, and clinical experience support the Darwinian hypothesis for explaining symptomatology caused by deprivation of input, better than a classical reorganization model. Darwinian plasticity models can help in devising effective treatments for brain dysfunction caused by deprivation of input, such as some forms of tinnitus and neuropathic pain. Acknowledgments and financial disclosure No external funding was used for this study. The authors thank Jan Ost for the artwork. References Bavelier, D. and Neville, H. (2002) Developmental neuroplasticity. In: Ramachandran V. (Ed.), Encyclopedia of the Human Brain, Vol. 3. Academic Press, Amsterdam, pp. 561–578. Benabid, A.L., Wallace, B., Mitrofanis, J., Xia, C., Piallat, B., Fraix, V., Batir, A., Krack, P., Pollak, P. and Berger, F. (2005) Therapeutic electrical stimulation of the central nervous system. C. R. Biol., 328: 177–186. Beurrier, C., Bioulac, B., Audin, J. and Hammond, C. (2001) High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J. Neurophysiol., 85: 1351–1356. Brodfuehrer, P.D. and Hoy, R.R. (1988) Effect of auditory deafferentation on the synaptic connectivity of a pair of identified interneurons in adult field crickets. J. Neurobiol., 19: 17–38. Brookes, M.J., Gibson, A.M., Hall, S.D., Furlong, P.L., Barnes, G.R., Hillebrand, A., Singh, K.D., Holliday, I.E., Francis, S.T. and Morris, P.G. (2005) GLM-beamformer method demonstrates stationary field, alpha ERD and gamma ERS co-localisation with fMRI BOLD response in visual cortex. Neuroimage, 26: 302–308. Calvin, W.H. (1987) The brain as a Darwin machine. Nature, 330: 33–34. Chudler, E.H., Anton, F., Dubner, R. and Kenshalo Jr., D.R. (1990) Responses of nociceptive SI neurons in monkeys and pain sensation in humans elicited by noxious thermal stimulation: effect of interstimulus interval. J. Neurophysiol., 63: 559–569. Churchill, J.D., Tharp, J.A., Wellman, C.L., Sengelaub, D.R. and Garraghty, P.E. (2004) Morphological correlates of injury-induced reorganization in primate somatosensory cortex. BMC Neurosci., 5: 43.
60 De Ridder, D., De Mulder, G., Verstraeten, E., Seidman, M., Elisevich, K., Sunaert, S., Kovacs, S., Van der Kelen, K., Van de Heyning, P., Møller, A. (2007a) Auditory cortex stimulation for intractable tinnitus. In: Sakas, D.E., Simpson, B., Krames, E.S., (Eds.), Operative Neuromodulation Vol. 1: Functional Neuroprosthetic Surgery. An introduction. Springer Verlag, Wien, Suppl. 97/1 (in press). De Ridder, D., De Mulder, G., Verstraeten, E., Smits, M., Kovacs, S., Sunaert, S., Verlooy, J., Van der Kelen, K., van de Heyning, P. and Møller, A. (2005a) Primary and secondary auditory cortex stimulation for intractable tinnitus. ORL (in press). De Ridder, D., De Mulder, G., Verstraeten, E., Sunaert, S., Møller, A. (2007b) Somatosensory cortex stimulation for deafferentation pain. In: Sakas, D.E., Simpson, B., Krames, E.S., (Eds.), Operative Neuromodulation Vol. 1: Functional Neuroprosthetic Surgery. An introduction. Springer Verlag, Wien, Suppl. 97/1 (in press). De Ridder, D., De Mulder, G., Verstraeten, E., Van der Kelen, K., Sunaert, S., Smits, M., Kovacs, S., Verlooy, J., Van de Heyning, P. and Møller, A.R. (2006) Primary and secondary auditory cortex stimulation for intractable tinnitus. ORL J. Otorhinolaryngol. Relat. Spec., 68: 48–54 discussion, 54–55. De Ridder, D., De Mulder, G., Walsh, V., Muggleton, N., Sunaert, S. and Møller, A. (2004) Magnetic and electrical stimulation of the auditory cortex for intractable tinnitus. Case report. J. Neurosurg., 100: 560–564. De Ridder, D., Verstraeten, E., Van der Kelen, K., De Mulder, G., Sunaert, S., Verlooy, J., Van de Heyning, P. and Møller, A. (2005b) Transcranial magnetic stimulation for tinnitus: influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Otol. Neurotol., 26: 616–619. Deacon, T. (1997) Evolution and intelligence: Beyond the argument from design. In: Scheibel A. and Schopf J. (Eds.), The Origin and Evolution of Intelligence. Jones and Bartlett, Boston, MA, pp. 103–136. Eggermont, J.J. and Roberts, L.E. (2004) The neuroscience of tinnitus. Trends Neurosci., 27: 676–682. Flor, H., Elbert, T., Knecht, S., Wienbruch, C., Pantev, C., Birbaumer, N., Larbig, W. and Taub, E. (1995) Phantomlimb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature, 375: 482–484. Foucher, J.R., Otzenberger, H. and Gounot, D. (2003) The BOLD response and the gamma oscillations respond differently than evoked potentials: an interleaved EEG-fMRI study. BMC Neurosci., 4: 22. Gao, E. and Suga, N. (1998) Experience-dependent corticofugal adjustment of midbrain frequency map in bat auditory system. Proc. Natl. Acad. Sci. U.S.A., 95: 12663–12670. Hoy, R.R., Nolen, T.G. and Casaday, G.C. (1985) Dendritic sprouting and compensatory synaptogenesis in an identified interneuron follow auditory deprivation in a cricket. Proc. Natl. Acad. Sci. U.S.A., 82: 7772–7776. Kaas, J.H., Merzenich, M.M. and Killackey, H.P. (1983) The reorganization of somatosensory cortex following peripheral
nerve damage in adult and developing mammals. Annu. Rev. Neurosci., 6: 325–356. Llinas, R., Urbano, F.J., Leznik, E., Ramirez, R.R. and van Marle, H.J. (2005) Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect. Trends Neurosci., 28: 325–333. Maihofner, C., Handwerker, H.O., Neundorfer, B. and Birklein, F. (2003) Patterns of cortical reorganization in complex regional pain syndrome. Neurology, 61: 1707–1715. Maihofner, C., Handwerker, H.O., Neundorfer, B. and Birklein, F. (2004) Cortical reorganization during recovery from complex regional pain syndrome. Neurology, 63: 693–701. Melcher, J.R., Sigalovsky, I.S., Guinan Jr., J.J. and Levine, R.A. (2000) Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J. Neurophysiol., 83: 1058–1072. Muhlnickel, W., Elbert, T., Taub, E. and Flor, H. (1998) Reorganization of auditory cortex in tinnitus. Proc. Natl. Acad. Sci. U.S.A., 95: 10340–10343. Norena, A., Micheyl, C., Chery-Croze, S. and Collet, L. (2002) Psychoacoustic characterization of the tinnitus spectrum: implications for the underlying mechanisms of tinnitus. Audiol. Neurootol., 7: 358–369. Ramachandran, V.S. and Hirstein, W. (1998) The perception of phantom limbs. The D. O. Hebb lecture. Brain, 121(Pt 9): 1603–1630. Ramachandran, V.S. and Rogers-Ramachandran, D. (2000) Phantom limbs and neural plasticity. Arch. Neurol., 57: 317–320. Recanzone, G.H., Merzenich, M.M., Jenkins, W.M., Grajski, K.A. and Dinse, H.R. (1992) Topographic reorganization of the hand representation in cortical area 3b owl monkeys trained in a frequency-discrimination task. J. Neurophysiol., 67: 1031–1056. Schwaber, M.K., Garraghty, P.E. and Kaas, J.H. (1993) Neuroplasticity of the adult primate auditory cortex following cochlear hearing loss. Am. J. Otol., 14: 252–258. Smits, M., Kovacs, S., De Ridder, D., Peeters, R., Van Hecke, P. and Sunaert, S. (2004) Lateralization of signal change in the auditory pathway in patients with lateralized tinnitus studied with functional magnetic resonance imaging (fMRI), radiology, 233(Suppl.) abstract 12-06. Suga, N., Gao, E., Zhang, Y., Ma, X. and Olsen, J.F. (2000) The corticofugal system for hearing: recent progress. Proc. Natl. Acad. Sci. U.S.A., 97: 11807–11814. Suga, N. and Ma, X. (2003) Multiparametric corticofugal modulation and plasticity in the auditory system. Nat. Rev. Neurosci., 4: 783–794. Theuvenet, P.J., Dunajski, Z., Peters, M.J. and van Ree, J.M. (1999) Responses to median and tibial nerve stimulation in patients with chronic neuropathic pain. Brain Topogr., 11: 305–313. Zhang, Y. and Suga, N. (2000) Modulation of responses and frequency tuning of thalamic and collicular neurons by cortical activation in mustached bats. J. Neurophysiol., 84: 325–333.
CHAPTER 5
The Darwinian plasticity hypothesis for tinnitus and pain Dirk De Ridder1, and Paul Van de Heyning2 1 Department of Neurosurgery, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium Department of Otorhinolaryngology, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium
2
Abstract: We present the hypothesis that expression of neural plasticity is a form of adaptation based on natural selection, where cells or cell groups deprived of sensory input actively go and look for information in order to survive. The Darwinian model of brain plasticity can explain the symptomatology induced by deprivation of input which was not well explained by classical plasticity without contradicting pertinent data from the neurophysiological, neuroanatomical, functional neuroimaging, and clinical literature. Applying the concept of Darwinian plasticity to sensory plasticity that causes symptoms and signs of disease might lead to the development of new treatments for deprivation of input induced symptomatology. We will use results from the application of electrical and magnetic stimulation of the auditory and the somatosensory cortices for treatment of tinnitus and for alleviating some forms of pain in support of the Darwinian hypothesis about neural plasticity. We will also review the literature regarding physiological and anatomical, as well as imaging data that support the existence of this hypothetical form of plasticity. Keywords: Darwin; Darwinian plasticity; deafferentation; neurostimulation; phantom pain; tinnitus; auditory cortex; somatosensory cortex plasticity is a form of adaptation based on natural selection, where cells or cell groups deprived of sensory input actively go and look for information in order to survive. Explaining expression of neural plasticity by the concept of Darwinian development solves the clinical conundrum regarding the symptoms and signs of expression of cortical plasticity such as it is believed to occur in some forms of tinnitus and pain. The concept of Darwinian principles of survival of the fittest can explain why input-deprived neurons start processing information from adjacent neurons, namely in order to survive. This way of viewing neural plasticity provides a theoretical framework for developing new treatments for brain dysfunctions induced by
Introduction Neuropathic pain and tinnitus are both considered phantom perceptions sharing a similar pathophysiology and clinical symptoms. Both neuropathic pain and tinnitus are perceptions coming from the missing part of the body, and are considered the result of maladaptive plasticity, where cortex not deprived of sensory input expands into the vacated area. Clinically, however, this should result in pain or tinnitus representing lesion-edge characteristics, contradictory to what is noted in real life. We present the hypothesis that expression of neural Corresponding author. Tel.: +32 3 8213336; Fax: +32 3 8252428; E-mail: [email protected] DOI: 10.1016/S0079-6123(07)66005-1
55
56
Fig. 1. In classical plasticity the non-deprived lesion edge frequencies expand into the deprived area, in Darwinian plasticity the deprived frequencies will look for information in the adjacent area. Example of the differences in high frequency hearing loss (drawing by Jan Ost).
deprivation of input. Based on this hypothesis, treatments can be developed for disorders that are caused by deprivation of sensory input. The basic concept being that supplying the missing information directly to the deafferented area will suppress deafferentiation-induced symptoms, by preventing or reversing Darwinian plasticity. To test this hypothesis we have analyzed the results from treatment of patients with phantom sound ( ¼ tinnitus) and patients with phantom pain by electrical stimulation of the auditory cortex and the somatosensory cortex respectively (Chapter 36). In the following we review neurophysiological, neuroanatomical, and functional imaging data, and suggest that the generally accepted hypothesis that topographic map plasticity changes seen in reorganization are not only due to ingrowths of synapses into an area of deprived input, but that the opposite might also be occurring: input-deprived synapses could sprout to adjacent non-deprived
areas in an attempt to survive in long-term reorganization. Similarly, short-term reorganization could involve input-deprived neurons processing information from adjacent neurons by changing synaptic efficacy. Figure 1 shows how sprouting in the auditory cortex would occur within an area where neurons are tuned to similar frequencies. Darwinian hypothesis of plasticity suggest that sprouting occurs between areas where neurons are tuned to different frequencies, for example, from high frequency areas to areas where neurons are tuned to middle frequencies.
Darwinian hypothesis of neural plasticity The human brain can be considered the result of a Darwinian evolutionary development (Calvin, 1987). A synapse can be seen as the analogue of a biological creature, replication and growth of
57
connections the analogue of organism reproduction, and in this view, competition for connections is the analogue of competition for food and mates, and which connections survive is based on its environment and the competition (Deacon, 1997). Neural connections that are fit for the environment survive and can be strengthened or weakened, much the same as individuals that fit the environment. Neurons that are fit follow the same rules (proliferation and apoptosis), analogous to whole species. This evolution-like process for building brains allows brains to become adapted to the bodies they inhabit within their own internal constraints, with a minimum of pre-planned design: brains are not genetically hardwired, but only the rules coding for self-organization via Darwinian competition are coded for (Deacon, 1997). This axonal competition for target territories furthermore results in development of topographic maps such as the visuotopic map, somatotopic map of the motor and sensory cortex and the tonotopic map of the auditory system. Plasticity refers to the capacity of the nervous system to modify its organization (see Chapter 2) (Bavelier and Neville, 2002). This is more pronounced in the developing brain but the mature auditory system still has the capacity for reorganization, adjusting itself to changes in the auditory environment. One form of neural plasticity regards the tonotopic maps of the auditory cortex. These maps are not rigid and may reorganize under influence of physiological (Gao and Suga, 1998) or pathological (Suga et al., 2000) sensory stimuli. Similar modification of tonotopic mapping in the entire auditory pathways may be artificially induced by focal electrical auditory cortex stimulation (Suga et al., 2000; Zhang and Suga, 2000; Suga and Ma, 2003). This adaptive plasticity can be both beneficial, such as in learning and repair or maladaptive, resulting for example in tinnitus. The same holds for the mature somatosensory system: any alteration of somatosensory input, whether physiological (Recanzone et al., 1992) or pathological (Kaas et al., 1983) can induce a topographical reorganization in the somatosensory cortex. Topographic reorganization has been demonstrated in humans by means of magnetic source
imaging (MSI) (Flor et al., 1995; Muhlnickel et al., 1998) and functional magnetic resonance imaging (fMRI) (Melcher et al., 2000; Maihofner et al., 2003). Furthermore there is a clear correlation between the amount of reorganization and the intensity of the phantom percept, associated with this sensory cortex reorganization, whether tinnitus or phantom pain (Flor et al., 1995; Muhlnickel et al., 1998). Successful treatment of the phantom perception reverses the reorganization electrophysiologically (Theuvenet et al., 1999; Maihofner et al., 2004). Cortical areas that have been reorganized, as visualized by fMRI are the targets for supplying the missing information, in attempts to normalize function. We have used non-invasive fMRI guided neuronavigated transcranial magnetic stimulation (TMS) (De Ridder et al., 2004, 2005b) for that purpose. If successful, the clinical suppression of the phantom perception can be perpetuated by implantation of an electrode in the same fMRI based neuronavigated way (see Chapter 36) (De Ridder et al., 2004, 2005a).
Basis for the Darwinian hypothesis Neurophysiology Kaas and Schwaber have used closely spaced microelectrode recordings to determine the receptive fields of cortical neurons in monkeys creating a detailed tonotopic map of the A1 cortical area. After inducing a high-frequency lesion by administering ototoxic antibiotics (kanamycin) combined with furosemide (Schwaber et al., 1993) that preferentially lesion high-frequency hair cells, they studied the concomitant changes in the tonotopic maps of the auditory cortex. Recording from neurons that normally responded to highfrequency tones, they found these neurons now responded to tones of lower frequencies (midfrequency). These findings were interpreted to show that synaptic connections had been established with neurons that previously responded to high frequencies. Similar studies in deafferentation pain by the same group yielded findings that were interpreted in a similar way (Kaas et al., 1983).
58
However, these results might also be interpreted from a Darwinian point of view to indicate that high-frequency neurons deprived of sensory input begin to process information from adjacent nondeprived areas by changes in synaptic strength (in short-term reorganization), or by sprouting of dendrites into the adjacent area that were not affected by the deprivation of input (in long-term reorganization). Such cells will respond to midfrequency tones as well. Thus electrophysiological data support both explanations of the alterations that are caused by deprivation of input. Thus anatomical and other data are necessary to distinguish between the two possible forms of plasticity. Neuroanatomy While plenty neurophysiological data exist characterizing topographic (re)organization of central maps, the underlying anatomical correlates have not been thoroughly investigated. That dendrites of neurons that are deprived of input can anatomically sprout into the adjacent areas in the auditory system has at least been demonstrated in the cricket (Hoy et al., 1985; Brodfuehrer and Hoy, 1988). For the somatosensory system, dendritic arbors are noted to expand distally reaching into non-deprived cortical areas (Churchill et al., 2004), suggesting that sprouting occurs from deprived toward non-deprived areas and not in the opposite direction. These anatomical observations favor the Darwinian hypothesis of neural plasticity. Clinical experience Both in the auditory system (Norena et al., 2002) and in the somatosensory system (Ramachandran and Hirstein, 1998), auditory phantom perceptions (tinnitus) and phantom pain are those coming from the missing part of the body. The tinnitus spectrum a patient perceives is found to occupy a wide frequency range corresponding largely to that at which hearing thresholds are abnormally elevated (Norena et al., 2002), and phantom pain is perceived in the missing body part. Darwinian plasticity also more accurately explains how tactile stimuli of the face demonstrate a hand representation in
individuals with an amputated arm (Ramachandran and Hirstein, 1998) than conventional hypotheses about neural plasticity. If cells that represent the hand in the somatosensory cortex have sprouted into the non-affected adjacent face area these cells that were deprived of their normal input will be activated by touching the face (Ramachandran and Hirstein, 1998; Ramachandran and RogersRamachandran, 2000). If on the other hand the dendrites of the neurons that receive normal input would have sprouted into the vacated arm area on the sensory cortex, hand perception as such would have disappeared altogether. Our clinical case with the abnormal perception of the location of the eye (Chapter 36) can be explained in a similar way, where the sensory-deprived supraorbital area is the one that is painful. The phantom eye perception may be explained in a similar way. If the neurons that receive normal input would have sprouted towards the neurons that receive input from the V1 (forehead) area that is deprived of input, it would have caused the phantom eye to be localized on the forehead. It was this clinical picture that inspired us to question the accepted pathophysiological hypothesis of reorganization through expression of neural plasticity in response to deprivation of input.
Functional imaging A further argument favoring the Darwinian hypothesis for plasticity comes from magnetoencephalographic (MEG) studies. Thus Muhlnickel (Muhlnickel et al., 1998) and Flor (Flor et al., 1995) using MSI explored the reorganization of the auditory cortex that occurred in patients with tinnitus. They found a shift of the cortical representation of the tinnitus frequency into an area adjacent to the tonotopic location of the frequency of the tinnitus. They also found a strong a strong positive correlation between the subjective strength of the tinnitus and the degree of cortical reorganization, similarly to what has been shown for the somatosensory system (Flor et al., 1995). The amount of phantom limb pain is highly correlated with degree of cortical reorganization of the primary somatosensory cortex (Flor et al., 1995).
59
If the reorganization consisted of invasion from the non-deprived adjacent area into the deprived area, as has been generally accepted, there would be a shift in the magnetic source of the adjacent frequencies, and not the deprived frequencies as noted in both of the MEG studies mentioned above (Flor et al., 1995; Muhlnickel et al., 1998). It has been demonstrated that the BOLD effect on fMRI correlates with event-related synchronization in the gamma band (32–38 Hz), both in EEG (Foucher et al., 2003) and MEG (Brookes et al., 2005) studies. This suggests that fMRI (Smits et al., 2004) can visualize the gamma band synchronized activity associated with tinnitus and pain (Llinas et al., 2005).
Brain stimulation A last argument favoring the Darwinian hypothesis for neural plasticity comes from studies of electrical stimulation of sensory cortices (De Ridder et al., 2006, , 2007a, b). Low-frequency stimulation (o120 Hz) activate cells as demonstrated in the human subthalamic nucleus (Beurrier et al., 2001), whereas high-frequency stimulation inactivate cells in a ‘functional lesion’ (Benabid et al., 2005). Both tinnitus (Eggermont and Roberts, 2004) and neuropathic pain (Chudler et al., 1990) are associated with hyperactivity of their respective primary sensory cortices. Our stimulation parameters, consisting of (activating) low-frequency stimulation should worsen tinnitus and pain if the adjacent areas have sprouted into the deprived areas, as they would then be stimulated even more, based on the egocentric selection principle (Suga et al., 2000). On the contrary, in a Darwinian model of brain functioning, supplying low intensity electrical stimuli to synapses of cells that are deprived of input would prevent (or reverse) such cells to sprout (prevent the looking for information in order to survive), thereby clinically preventing (or reversing) the phantom perceptions. Electrical stimulation of sensory cortices may supply the missing input directly and high-intensity stimulation would be predicted to induce tinnitus and pain, as seen in our patients (De Ridder et al., 2006, 2007a, b).
Conclusion Neurophysiological and neuroanatomical data, functional imaging, and clinical experience support the Darwinian hypothesis for explaining symptomatology caused by deprivation of input, better than a classical reorganization model. Darwinian plasticity models can help in devising effective treatments for brain dysfunction caused by deprivation of input, such as some forms of tinnitus and neuropathic pain. Acknowledgments and financial disclosure No external funding was used for this study. The authors thank Jan Ost for the artwork. References Bavelier, D. and Neville, H. (2002) Developmental neuroplasticity. In: Ramachandran V. (Ed.), Encyclopedia of the Human Brain, Vol. 3. Academic Press, Amsterdam, pp. 561–578. Benabid, A.L., Wallace, B., Mitrofanis, J., Xia, C., Piallat, B., Fraix, V., Batir, A., Krack, P., Pollak, P. and Berger, F. (2005) Therapeutic electrical stimulation of the central nervous system. C. R. Biol., 328: 177–186. Beurrier, C., Bioulac, B., Audin, J. and Hammond, C. (2001) High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J. Neurophysiol., 85: 1351–1356. Brodfuehrer, P.D. and Hoy, R.R. (1988) Effect of auditory deafferentation on the synaptic connectivity of a pair of identified interneurons in adult field crickets. J. Neurobiol., 19: 17–38. Brookes, M.J., Gibson, A.M., Hall, S.D., Furlong, P.L., Barnes, G.R., Hillebrand, A., Singh, K.D., Holliday, I.E., Francis, S.T. and Morris, P.G. (2005) GLM-beamformer method demonstrates stationary field, alpha ERD and gamma ERS co-localisation with fMRI BOLD response in visual cortex. Neuroimage, 26: 302–308. Calvin, W.H. (1987) The brain as a Darwin machine. Nature, 330: 33–34. Chudler, E.H., Anton, F., Dubner, R. and Kenshalo Jr., D.R. (1990) Responses of nociceptive SI neurons in monkeys and pain sensation in humans elicited by noxious thermal stimulation: effect of interstimulus interval. J. Neurophysiol., 63: 559–569. Churchill, J.D., Tharp, J.A., Wellman, C.L., Sengelaub, D.R. and Garraghty, P.E. (2004) Morphological correlates of injury-induced reorganization in primate somatosensory cortex. BMC Neurosci., 5: 43.
60 De Ridder, D., De Mulder, G., Verstraeten, E., Seidman, M., Elisevich, K., Sunaert, S., Kovacs, S., Van der Kelen, K., Van de Heyning, P., Møller, A. (2007a) Auditory cortex stimulation for intractable tinnitus. In: Sakas, D.E., Simpson, B., Krames, E.S., (Eds.), Operative Neuromodulation Vol. 1: Functional Neuroprosthetic Surgery. An introduction. Springer Verlag, Wien, Suppl. 97/1 (in press). De Ridder, D., De Mulder, G., Verstraeten, E., Smits, M., Kovacs, S., Sunaert, S., Verlooy, J., Van der Kelen, K., van de Heyning, P. and Møller, A. (2005a) Primary and secondary auditory cortex stimulation for intractable tinnitus. ORL (in press). De Ridder, D., De Mulder, G., Verstraeten, E., Sunaert, S., Møller, A. (2007b) Somatosensory cortex stimulation for deafferentation pain. In: Sakas, D.E., Simpson, B., Krames, E.S., (Eds.), Operative Neuromodulation Vol. 1: Functional Neuroprosthetic Surgery. An introduction. Springer Verlag, Wien, Suppl. 97/1 (in press). De Ridder, D., De Mulder, G., Verstraeten, E., Van der Kelen, K., Sunaert, S., Smits, M., Kovacs, S., Verlooy, J., Van de Heyning, P. and Møller, A.R. (2006) Primary and secondary auditory cortex stimulation for intractable tinnitus. ORL J. Otorhinolaryngol. Relat. Spec., 68: 48–54 discussion, 54–55. De Ridder, D., De Mulder, G., Walsh, V., Muggleton, N., Sunaert, S. and Møller, A. (2004) Magnetic and electrical stimulation of the auditory cortex for intractable tinnitus. Case report. J. Neurosurg., 100: 560–564. De Ridder, D., Verstraeten, E., Van der Kelen, K., De Mulder, G., Sunaert, S., Verlooy, J., Van de Heyning, P. and Møller, A. (2005b) Transcranial magnetic stimulation for tinnitus: influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Otol. Neurotol., 26: 616–619. Deacon, T. (1997) Evolution and intelligence: Beyond the argument from design. In: Scheibel A. and Schopf J. (Eds.), The Origin and Evolution of Intelligence. Jones and Bartlett, Boston, MA, pp. 103–136. Eggermont, J.J. and Roberts, L.E. (2004) The neuroscience of tinnitus. Trends Neurosci., 27: 676–682. Flor, H., Elbert, T., Knecht, S., Wienbruch, C., Pantev, C., Birbaumer, N., Larbig, W. and Taub, E. (1995) Phantomlimb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature, 375: 482–484. Foucher, J.R., Otzenberger, H. and Gounot, D. (2003) The BOLD response and the gamma oscillations respond differently than evoked potentials: an interleaved EEG-fMRI study. BMC Neurosci., 4: 22. Gao, E. and Suga, N. (1998) Experience-dependent corticofugal adjustment of midbrain frequency map in bat auditory system. Proc. Natl. Acad. Sci. U.S.A., 95: 12663–12670. Hoy, R.R., Nolen, T.G. and Casaday, G.C. (1985) Dendritic sprouting and compensatory synaptogenesis in an identified interneuron follow auditory deprivation in a cricket. Proc. Natl. Acad. Sci. U.S.A., 82: 7772–7776. Kaas, J.H., Merzenich, M.M. and Killackey, H.P. (1983) The reorganization of somatosensory cortex following peripheral
nerve damage in adult and developing mammals. Annu. Rev. Neurosci., 6: 325–356. Llinas, R., Urbano, F.J., Leznik, E., Ramirez, R.R. and van Marle, H.J. (2005) Rhythmic and dysrhythmic thalamocortical dynamics: GABA systems and the edge effect. Trends Neurosci., 28: 325–333. Maihofner, C., Handwerker, H.O., Neundorfer, B. and Birklein, F. (2003) Patterns of cortical reorganization in complex regional pain syndrome. Neurology, 61: 1707–1715. Maihofner, C., Handwerker, H.O., Neundorfer, B. and Birklein, F. (2004) Cortical reorganization during recovery from complex regional pain syndrome. Neurology, 63: 693–701. Melcher, J.R., Sigalovsky, I.S., Guinan Jr., J.J. and Levine, R.A. (2000) Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J. Neurophysiol., 83: 1058–1072. Muhlnickel, W., Elbert, T., Taub, E. and Flor, H. (1998) Reorganization of auditory cortex in tinnitus. Proc. Natl. Acad. Sci. U.S.A., 95: 10340–10343. Norena, A., Micheyl, C., Chery-Croze, S. and Collet, L. (2002) Psychoacoustic characterization of the tinnitus spectrum: implications for the underlying mechanisms of tinnitus. Audiol. Neurootol., 7: 358–369. Ramachandran, V.S. and Hirstein, W. (1998) The perception of phantom limbs. The D. O. Hebb lecture. Brain, 121(Pt 9): 1603–1630. Ramachandran, V.S. and Rogers-Ramachandran, D. (2000) Phantom limbs and neural plasticity. Arch. Neurol., 57: 317–320. Recanzone, G.H., Merzenich, M.M., Jenkins, W.M., Grajski, K.A. and Dinse, H.R. (1992) Topographic reorganization of the hand representation in cortical area 3b owl monkeys trained in a frequency-discrimination task. J. Neurophysiol., 67: 1031–1056. Schwaber, M.K., Garraghty, P.E. and Kaas, J.H. (1993) Neuroplasticity of the adult primate auditory cortex following cochlear hearing loss. Am. J. Otol., 14: 252–258. Smits, M., Kovacs, S., De Ridder, D., Peeters, R., Van Hecke, P. and Sunaert, S. (2004) Lateralization of signal change in the auditory pathway in patients with lateralized tinnitus studied with functional magnetic resonance imaging (fMRI), radiology, 233(Suppl.) abstract 12-06. Suga, N., Gao, E., Zhang, Y., Ma, X. and Olsen, J.F. (2000) The corticofugal system for hearing: recent progress. Proc. Natl. Acad. Sci. U.S.A., 97: 11807–11814. Suga, N. and Ma, X. (2003) Multiparametric corticofugal modulation and plasticity in the auditory system. Nat. Rev. Neurosci., 4: 783–794. Theuvenet, P.J., Dunajski, Z., Peters, M.J. and van Ree, J.M. (1999) Responses to median and tibial nerve stimulation in patients with chronic neuropathic pain. Brain Topogr., 11: 305–313. Zhang, Y. and Suga, N. (2000) Modulation of responses and frequency tuning of thalamic and collicular neurons by cortical activation in mustached bats. J. Neurophysiol., 84: 325–333.