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Restorative Neurology and Neuroscience 25 (2007) 435–443 Pharmacological modulation oflearning-induced plasticity in human auditorycortex Christiane M. Thiel∗Institute of Biology and Environmental Sciences, University of Oldenburg, 26111 Oldenburg, Germany Abstract. Purpose: Converging evidence from animals and humans indicate that the primary auditory cortex is continuously
reshaped in an experience-dependent way. Reorganisation in primary auditory cortex can be observed at the level of receptive
fields, topographic maps and brain activations measured with neuroimaging methods. Several neuromodulatory systems were
shown to contribute to such an experience-dependent reorganization.
Methods: This paper reviews evidence addressing the cholinergic, noradrenergic, dopaminergic and serotonergic modulation of
learning-, experience-, and injury-induced plasticity in the auditory cortex.
Results: Regarding learning-induced plasticity in the auditory cortex most studies have investigated the role of the cholinergic
system and shown that ACh is essential for this form of rapid plasticity. Nevertheless there is also evidence that the catecholamines
dopamine and noradrenaline might contribute to learning- and experience-induced changes in the auditory cortex.
Conclusions: I suggest, that the available experimental data on cholinergic and noradrenergic modulation of plasticity offers a
promising basis for potential pharmacological interventions to aid recovery of aural functions.
Keywords: Plasticity, psychopharmacology, auditory cortex, drug, experience rochemical modulation of plasticity outside the audito-ry cortex, assuming that similar neurochemical mech- Several studies have highlighted the importance of anisms may be responsible for promoting plasticity in neuromodulators, especially the cholinergic system, in other primary sensory and motor cortices.
regulating learning-induced plasticity in the auditory An important issue when addressing the pharmaco- cortex. This review will summarize research on phar- logical modulation of plasticity is its clinical appli- macological modulation of plasticity in humans and cation. The use of pharmacological interventions for animals. The main focus is on neurochemical mecha- promoting cognitive or motor functions after brain in- nisms of rapidly induced plasticity in associative learn- jury has recently received some attention (Parton et ing situations, but evidence from studies on training- al., 2005). One of the most promising approaches has induced plasticity as well as findings on recovery offunction after injury are also considered. Since the been the administration of amphetamines for recovery number of studies is small that specifically address of motor and language functions after stroke (Martins- pharmacological modulation of plasticity in the audi- son and Eksborg, 2004). Even though in the auditory tory cortex, I will also consider evidence showing neu- system, evidence from basic research in animals andhumans offers a promising basis for potential pharma-cological interventions, there are currently no clinical Address for correspondence: Institute of Biology and Environ- applications of this knowledge. One preliminary study mental Sciences, Faculty V, Carl von Ossietzky University of Olden-burg, 26111 Oldenburg, Germany. Tel.: +441 798 3641; Fax: +441 however suggests that amphetamine might be useful for 798 3848; E-mail: christiane.thiel@uni-oldenburg.de.
improving aural rehabilitation and increasing neural ac- 0922-6028/07/$17.00  2007 – IOS Press and the authors. All rights reserved C.M. Thiel / Pharmacological modulation of learning-induced plasticity in human auditory cortex tivity in the auditory cortex after cochlear implantation viously best frequency (Bakin and Weinberger, 1990; (Tobey et al., 2005).
see however Ohl and Scheich, 2005). The learning-induced changes are acquired rapidly after only a fewpairings of the tone and footshock and have an endur- 2. Plasticity in the auditory cortex
ing effect on the receptive fields of auditory corticalneurons (Weinberger et al., 1993; Edeline et al., 1993).
The processing of auditory information depends not Frequency receptive fields in primary auditory cortex only on the physical properties of stimuli but also on were also shown to be rapidly modified in other learning prior experience and learning. Response properties of paradigms such as habituation learning, instrumental single neurons and neuron populations are continuous- avoidance learning and frequency discrimination learn- ly reshaped in an experience-dependent way through- ing (Condon and Weinberger, 1991; Edeline and Wein- out life to meet changing behavioural needs.
berger, 1993; Bakin et al., 1996). A complementary ticity refers to such an experience-related structural approach is to study learning-induced plasticity by in- and/or functional neuronal reorganization. Different vestigating changes in cerebral metabolism (Gonzalez- techniques have been used to gauge plastic changes Lima and Scheich, 1986; Poremba et al., 1998) or tono- in animals and humans. These include the analysis topic maps (Rutkowski and Weinberger, 2005). These of receptive fields in single cells, topographic cortical studies provide evidence for an increased spatial repre- maps, brain activations measured in metabolic studies sentation of conditioned stimuli in the auditory cortex.
and lately brain activity measured with neuroimaging An elegant study by Rutkowski et al. (2005) further methods in humans (Bakin and Weinberger, 1990; Re- suggests that the extent of the area tuned to the CS fre- canzone et al., 1993; Thiel et al., 2002b).
quency is related to the behavioural importance of the Plasticity encompasses a variety of different con- cepts, ranging from plastic changes that are inducedrapidly up to modifications observed only at longer time 2.2. Learning-induced plasticity in humans scales. I will refer to rapidly induced plasticity in as-sociative learning situations as learning-induced plas- Several neuroimaging studies, using eye-blink and ticity. Plasticity observed in perceptual learning situ- aversive conditioning paradigms, have shown learning- ations, which involves repeated training over several induced changes in regional cerebral blood flow (rCBF) days and weeks will be referred to as training-induced or blood-oxygen-level dependent (BOLD) signal in the plasticity. Finally injury-induced plasticity relates to human auditory cortex (Molchan et al., 1994; Schreurs reorganization evident after damage to the periphery or et al., 1997; Morris et al., 1998; Thiel et al., 2002a; central nervous system.
Thiel et al., 2002b). Molchan et al. (1994) and Schreurset al. (1997) provided evidence for increased rCBF 2.1. Learning-induced plasticity in animals in primary auditory cortex when comparing the pairedpresentation of a tone and an air puff in an eye blink Learning-induced plasticity within the auditory cor- conditioning paradigm with explicitly unpaired presen- tex is often studied in aversive conditioning paradigms tations of the tone and air puff. This suggests increased (Edeline, 1999; Weinberger, 2004). In aversive con- neural activity in the auditory cortex during associa- ditioning a previously neutral stimulus, such as a tive learning. Using functional magnetic resonance tone (conditioned stimulus; CS), acquires significance imaging (fMRI) and a differential aversive conditioning through its prediction of a future aversive event, such paradigm we found evidence for an increase in BOLD as an electric shock (unconditioned stimulus; US).
signal in the auditory cortex for a tone which was paired Learning-induced plasticity in such associative learn- with an aversive event as compared to a tone, which ing paradigms has been documented with a variety of was not paired with the aversive event. That is, auditory different methods and species. Several studies have stimuli with an acquired relevance induce greater neu- demonstrated that frequency responsive receptive fields ral activity in the auditory cortex than stimuli without in the primary auditory cortex are retuned during aver- sive conditioning (Bakin and Weinberger, 1990; Wein- Overall, the findings demonstrate that blood-flow berger et al., 1993; Edeline et al., 1993). Most stud- based techniques such as positron emission tomogra- ies reported a shift of the receptive fields towards the phy (PET) or fMRI are able to gauge learning-induced frequency of the CS with reduced responses to the pre- changes in associative learning paradigms and provide C.M. Thiel / Pharmacological modulation of learning-induced plasticity in human auditory cortex valuable evidence regarding mechanisms of plastici- the cochlea. In humans, one neuroimaging study inves- ty in the human brain. It should be however empha- tigated the effects of high frequency hearing loss and sised that despite some striking similarities between was able to demonstrate cortical map reorganization in learning-induced receptive field or map plasticity in the auditory cortex (Dietrich et al., 2001). In contrast animals and plasticity seen with neuroimaging meth- to training-induced reorganization there is however on- ods in humans, there are differences in the underly- ly limited evidence for perceptual consequences of a ing techniques to measure plasticity (e.g. neuronal re- haemodynamic responses), and experi- mental protocols (i.e. animal studies mostly comparereceptive fields before and after conditioning has taken 3. Neurochemical modulation of plasticity in
place while neuroimaging studies often assess learning- induced changes during conditioning). Nevertheless,the fact that both measures of plasticity are sensitive to 3.1. The cholinergic system cholinergic manipulations (see below) suggests at leastsome commonality.
Basal forebrain cholinergic neurons send projections to the entire cortical mantle, including the primary au- 2.3. Training- and injury-induced plasticity ditory cortex (Kamke et al., 2005). A considerableamount of data indicate the importance of the cholin- Changes in the cortical representation of auditory ergic basal forebrain in modulating responses of corti- stimuli have also been found with behavioural train- cal neurons. Evidence for long lasting changes in neu- ing or after injury (Irvine et al., 2001). In the audi- ronal reactivity due to iontophoretical application of tory cortex of owl monkeys Recanzone et al. (1993) acetylcholine (ACh) was shown by Krnjevic and Phillis have shown a reorganization of frequency representa- (1963a) in anaesthetised animals. Several other animal tion following several weeks of frequency discrimina- studies confirmed this modulatory role of basal fore- tion training which correlated with performance. How- brain ACh upon responses to visual (Sato et al., 1987), ever, in cats improvements in frequency discrimination auditory (Metherate and Ashe, 1991) or somatosenso- were not accompanied by changes in tonotopic maps ry (Tremblay et al., 1990) stimulation. The choliner- (Brown et al., 2004). Several studies in human volun- gic modulation of neuronal responsiveness in auditory teers have reported plastic changes in auditory cortex and visual cortex is blocked by the administration of activity after successful frequency discrimination train- atropine, suggesting an effect mediated through mus- ing or a pitch memory task (Cansino and Williamson, carinic cholinergic receptors (Sato et al., 1987; Mether- 1997; Menning et al., 2000; Jancke et al., 2001; Gaab et ate and Ashe, 1991). While the majority of respons- al., 2006). Note, that both, decreases and increases in es are facilitated by ACh, a suppression of firing rate the measured signal were found and it has been shown has also been found (Sato et al., 1987; Tremblay et al., that depending on the training task used, an increased 1990; Metherate and Ashe, 1991). The direction of or reduced representation is found in the auditory cor- cortical response modulation can vary depending, for tex (Guenther et al., 2004). Several other studies, not example, on the strength of basal forebrain stimulation, mentioned in further detail here, have investigated con- the cortical layer of ACh application or the type of neu- sequences of auditory experience in relation to learning ron investigated (Metherate and Ashe, 1991; Xiang et speech sounds (e.g. Callan et al., 2003) or plasticity al., 1998; Kimura et al., 1999).
in musicians (Pantev et al., 2003). However, in con- It is widely reported that increases in cortical ACh trast to learning-induced plasticity observed in associa- release occur when animals are presented with be- tive learning situations, auditory experiences associated haviourally relevant, aversive stimuli (Acquas et al., with behavioural training require at least several hours 1996; Thiel et al., 2000). With regard to learning- of practice to develop and tonotopic reorganizations are induced plasticity, a striking observation is that audito- not always observed.
ry cortex receptive field and map plasticity can not on- Similar changes in tonotopic representations in pri- ly be induced by pairing a tone with an aversive event mary auditory cortex are also seen after restricted but also by pairing the tone with electrical stimulation cochlear lesions in animals (see Irvine et al., 2000).
of the nucleus basalis (Hars et al., 1993; Bakin and The changes are evident as expanded representations of Weinberger, 1996; Kilgard and Merzenich, 1998; Mi- frequencies represented at loci in the unaffected part of asnikov et al., 2001) or an iontophoretic administration



C.M. Thiel / Pharmacological modulation of learning-induced plasticity in human auditory cortex Fig. 1. Schematic illustration of the aversive conditioning approach used in the fMRI studies.
Fig. 2. Plots of percent signal change (mean and S.E.M.) of two voxels in the auditory cortex illustrating cholinergic modulation of learning-inducedBOLD activity (for full data see [68; 69]) a. Effects of cholinergic blockade with scopolamine in a right auditory cortex voxel showing asignificant group by conditioning interaction (x = 57, y = 15, z = 6) b. Effects of cholinergic enhancement with physostigmine. Activityin a left auditory cortex voxel showing a group by conditioning interaction in the follow up study (x = 63, y = 18, z = 9). Note thatin comparison with placebo, scopolamine reduced activations to the CS+ whereas physostigmine increased activations to the CS. Reprintedfrom Neurobiology of Learning and Memory, 80, Thiel, Cholinergic modulation of learning and memory in the human brain as detected withfunctional neuroimaging, 234–244, Copyright (2003), with permission from Elsevier".
of ACh (Metherate and Weinberger, 1989). A study a shock (CS). A partial reinforcement schedule was by McLin et al. (2002) further underlines that stimula- used in which only one half of the CS+ stimuli were tion of the cholinergic basal forebrain not only induces paired with the aversive event (CS+ paired) and the frequency specific neuronal plasticity but also elicits other half were not (CS+ unpaired). This enabled the cardiac and respiratory responses to the frequency of comparison of BOLD activity to the CS+ in the absence the tone, indicating the induction of behavioural asso- of the shock with activations to the CS(see Fig. 1).
ciative memory. The plasticity induced by pairing nu- In other words, two auditory stimuli are compared, one cleus basalis stimulation with a tone is blocked by sys- with acquired significance and one without. Learning- temic or cortical atropine which suggests that activa- induced plasticity in this context is defined as a higher tion of muscarinic ACh receptors is crucial to this form BOLD signal to the unpaired CS+ as compared to the of learning-induced plasticity (Bakin and Weinberger, 1996; Miasnikov et al., 2001).
In our first study subjects were given in a between In order to investigate the role of the cholinergic sys- group design either placebo or 0.4 mg of the muscarinic tem in learning-induced plasticity in humans we per- antagonist scopolamine intravenously to block cholin- formed two fMRI studies involving a cholinergic drug ergic function (Thiel et al., 2002b). A reaction time challenge (Thiel et al., 2002a; Thiel et al., 2002b).
measure indicated behavioural learning in the place- Learning-induced auditory plasticity was studied in a bo but not the scopolamine group.
differential conditioning paradigm. We used two tones group, learning-induced enhancement of the BOLD re- of different frequency as CS (400 Hz or 1600 Hz). One sponse in the auditory cortex was evident to the CS+ of these tones was paired with an electric shock to the but not to the respective CS. Under scopolamine, left leg (CS+) whereas the other was never paired with the enhancement of BOLD activity to the CS+ was C.M. Thiel / Pharmacological modulation of learning-induced plasticity in human auditory cortex blocked, suggesting that cholinergic muscarinic recep- ry cortex (Juliano et al., 1991). These findings are in tors are involved in these learning-induced responses contrast with recent evidence by Kamke et al. (2005) in (see Fig. 2a). The findings provide in vivo evidence that the auditory cortex that suggests that cholinergic input learning-induced plasticity in human auditory cortex is is not required for lesion-induced plasticity. It is cur- attenuated by blockade of cholinergic neurotransmis- rently open whether the observed discrepancies are due to difference between cortical systems or rather differ- Since a cholinergic blockade was found to impair ences in experimental design between the studies (see learning-induced plasticity we aimed to further investi- Kilgard, 2005 for further discussion).
gate the clinically more relevant question whether an in-crease in cholinergic function would increase plasticity.
3.2. The noradrenergic system We used the same differential conditioning paradigmand between group design as above but the choli- Noradrenergic neurons are located in the pontine and neesterase inhibitor physostigmine to boost choliner- medullary reticular formation. The main source of the gic function (Thiel et al., 2002a). Data in the placebo central noradrenergic innervation is the locus ceruleus, group showed again an enhanced BOLD response to which provides widespread projections to the entire the CS+ as compared to the CSin the auditory cor- brain (Drouin and Tassin, 2002). With regard to plas- tex, indicating learning-induced changes. In contrast ticity in the auditory system, the work of Edeline and to our hypothesis however, the physostigmine group colleagues suggests that the iontophoretic application did not show any differential activation to the CS+ of noradrenaline primarily decreases evoked responses vs. CS. This absence of learning-induced plastic in the auditory cortex of anaesthetised rats (Manunta changes was however different from that seen previ- and Edeline, 1997; Manunta and Edeline, 1998). Fur- ously with scopolamine. While scopolamine prevent- ther, pairing a particular tone frequency with a nora- ed the increased neural activation to the CS+ but did drenaline application changed frequency tuning curves not interfere with activity to the CS, physostigmine in the auditory cortex, suggesting that noradrenaline increased activations to the CSwithout interfering modulates learning-induced plasticity. The effect was with the CS+ (see Fig. 2b). We therefore suggest that dependent on alpha noradrenergic receptors and was in healthy human volunteers, cholinergic blockade re- in most cases evident as a response decrease (Manunta duces neuronal processing of relevant stimuli, where- and Edeline, 2004).
as cholinergic stimulation increases processing of ir- There is ample evidence for a noradrenergic role in relevant stimuli. Both mechanisms reduce learning- training-induced and injury-dependent plasticity in the induced plasticity in the auditory cortex. The effects motor system. In healthy humans it has been shown of physostigmine could reflect that cholinergic stimu- that amphetamine can facilitate plasticity induced by lation in healthy volunteers may overstimulate an oth- motor training (Butefisch et al., 2002; Tegenthoff et al., erwise perfectly balanced cholinergic system.
2004) and language learning (Breitenstein et al., 2004).
The influence of the cholinergic system on training- Further, a single dose of the noradrenaline reuptake induced auditory plasticity has not been investigat- inhibitor reboxetine improves motor skill acquisition Training-induced plasticity has however often and excitability in the motor cortex of healthy volun- been studied in the motor system, where it has been teers (Plewnia et al., 2004). These findings underline shown that changes in functional topography are ob- the importance of noradrenergic neurotransmission for served after training voluntary movements (Nudo et training-induced plasticity, at least in the motor cortex.
al., 1996). Two studies support a cholinergic role in Regarding potential clinical applications, the com- training-induced motor plasticity. First, the muscarinic bination of amphetamines with behavioural training is antagonist scopolamine is able to attenuate training- currently one of the most promising pharmacological induced motor plasticity in humans (Sawaki et al., approaches in stroke recovery (Boyeson and Feeney, Second, animal evidence suggests that le- 1990).1 Amphetamine acts on a variety of neurotrans- sions of the cholinergic basal forebrain abolish training- mitter systems including the dopaminergic, noradren- induced map expansions in the primary motor cortex ergic and serotonergic system but it has been suggested (Conner et al., 2005).
With regard to injury-induced plasticity, nucleus 1Note, however, that due to the small number of studies and open basalis lesions were found to block topographic reor- safety-issues the routine use of amphetamines is currently not indi- ganizations after peripheral injury in the somatosenso- cated for the treatment of stroke.
C.M. Thiel / Pharmacological modulation of learning-induced plasticity in human auditory cortex that the noradrenergic action is crucial for the recovery- al., 2001). Even though l-dopa is the precursor of both, promoting effects after injury (Boyeson and Feeney, dopamine and noradrenaline, only a small fraction of 1990; see however Breitenstein et al., 2006). In ani- l-dopa is converted into noradrenaline, suggesting that mals it was shown that a single dose of amphetamine recovery-promoting effects of l-dopa may primarily be can promote motor recovery after motor cortex ablation due to the dopaminergic action of the drug (Breitenstein (Feeney et al., 1982). Recovery-promoting effects of et al., 2006).
amphetamine were also observed after lesions of thevisual and sensorimotor cortices (Feeney and Hovda, 3.4. The serotonergic system 1985; Schmanke and Barth, 1997). These findingsindicate that pharmacological interventions may show The serotonergic innervation of the cortex originates similar effects in different sensory and motor cortices from the brain stems raphe nuclei (Azmitia and Segal, and that beneficial effects of amphetamine might also 1978). Iontophoretic application of serotonin (5-HT) be seen after damage to the auditory cortex. Indeed, a was shown to induce both, inhibition and excitation of preliminary study by Tobey et al. (2005) in eight pa- cortical neurons (Krnjevic and Phillis, 1963b). With re- tients with cochlear implants provides first evidence gard to learning-induced plasticity in the auditory cor- that the additional use of d-amphetamine in aural re- tex in vivo microdialysis data suggest however that 5- habilitation facilitates speech tracking scores and neu- HT is rather related to the stress induced by the aversive ral activity in the auditory cortex in adult cochlear im- stimulus in conditioning paradigms than to associative plant users. The study therefore suggests that a nora- learning (Stark and Scheich, 1997). Even though this drenergic/dopaminergic intervention may be useful for would speak against a critical role of 5-HT in learning- promoting recovery of function in the auditory system.
induced plasticity, there is at least evidence for a sero-tonergic modulation of training-dependent plasticity in 3.3. The dopaminergic system the motor cortex (Pleger et al., 2004). This findingin healthy volunteers is in line with clinical evidence The dopaminergic input to the cortex originates in showing that stimulation of serotonergic function in- the ventral tegmental area (Moore and Bloom, 1978).
creases functional recovery from motor deficits after Iontophoretic application of dopamine to cells in the stroke (Pariente et al., 2001). Further research is need- cerebral cortex results mostly in a depression of neu- ed to investigate in more detail the potential role of ronal activity (Krnjevic and Phillis, 1963b). With re- serotonin in plasticity in the auditory cortex.
gard to learning-induced plasticity, in vivo microdial-ysis provides evidence for increased dopaminergic ac-tivity in the primary auditory cortex during learning of tone-shock associations (Stark and Scheich, 1997).
Further, it has been shown that pairing a particular I have summarised evidence that drugs targeting dif- tone frequency with stimulation of the ventral tegmen- ferent neurotransmitter systems are able to modulate tal area shifts frequency response curves and increases learning- and experience-induced plasticity and recov- the spatial representation of the respective frequency ery of function. Regarding learning-induced plasticity area in the primary auditory cortex. Since the effects in the auditory cortex most studies have investigated the were blocked by D1 and D2 receptor antagonists, the role of the cholinergic system and shown that ACh is findings suggest that the neurotransmitter dopamine en- essential for this form of rapid plasticity. Nevertheless ables learning-induced plasticity in the auditory cortex there is also evidence that the catecholamines dopamine (Kisley and Gerstein, 2001; Bao et al., 2001).
and noradrenaline might contribute to learning- and Even though most of the evidence on recovery- experience-induced changes in the auditory cortex and promoting actions of amphetamine suggests that the to aural rehabilitation after cochlear implantation.
main action is dependent on noradrenergic neurotrans- Several questions however deserve further attention: mission, some data also speaks in favour of a dopamin- It is currently unknown, whether different neuromodu- ergic role. First, the recovery-promoting actions of am- latory systems subserve similar, overlapping functions phetamine can be blocked by the dopaminergic antag- in promoting plasticity or whether their action can be onist haloperidol (Feeney et al., 1982). Second, there differentiated. For example, even though pairing a tone is evidence in humans for increased recovery of motor with electrical stimulation of brain areas containing ei- functions after l-dopa administration (Scheidtmann et ther cholinergic or dopaminergic neurons both increase C.M. Thiel / Pharmacological modulation of learning-induced plasticity in human auditory cortex the spatial representation of the respective tone in the Azmitia, E. C., & Segal, M. (1978). An autoradiographic analysis of primary auditory cortex, other measures, such as the the differential ascending projections of the dorsal and median representation of adjacent frequencies or the effects in raphe nuclei in the rat. J Comp Neurol, 179, 641-667.
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Lara et al, Cancerología 1 (2006): 283-295 Manejo del Paciente Terminal Argelia Lara Solares, Antonio C. Tamayo Valenzuela, Sandra P. Gaspar Carrillo Unidad de Medicina del Dolor y Paliativa. Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" A Terminal disease is by definition, an advanced progressive and not curable il ness that does not respond to a specific