Chiaramente, ogni formato ha i propri vantaggi e svantaggi comprare amoxil senza ricetta per effettuare un acquisto, non è necessario fornire la prescrizione medica.

Doi:10.1016/s1074-7427(03)00076-5


Neurobiology of Learning and Memory 80 (2003) 234–244 Cholinergic modulation of learning and memory in the human brain as detected with functional neuroimaging Christiane M. Thiel* Institute of Medicine, Research Centre J€ ulich, 52425 J€ Received 5 May 2003; revised 10 July 2003; accepted 15 July 2003 The advent of neuroimaging methods such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) has provided investigators with a tool to study neuronal processes involved in cognitive functions in humans. Recent yearshave seen an increasing amount of studies which mapped higher cognitive functions to specific brain regions. These studies have hada great impact on our understanding of neuroanatomical correlates of learning and memory in the living human brain. Recently,advances were made to go beyond the use of fMRI as a pure cognitive brain mapping device. One of these advances includes the useof psychopharmacological approaches in conjunction with neuroimaging. The paper will introduce the combination of neuroi-maging and psychopharmacology as a tool to study neurochemical modulation of human brain function. A review of imagingstudies using cholinergic challenges in the context of explicit and implicit learning and memory paradigms is provided which showthat cholinergic neurotransmission modulates task-related activity in sensory and frontal cortical brain areas.
Ó 2003 Elsevier Inc. All rights reserved.
Keywords: Acetylcholine; Neuroimaging; Learning; Memory; Review; Drug; Psychopharmacology; fMRI; PET; Human Tsumoto, 1987). Experimental evidence further showsthat cholinergic modulation seems to be specific in its The clinical discovery that memory deficits in Alz- effect for behaviourally relevant stimuli rather than en- heimerÕs disease are concomitant with a loss of cholin- hancing neuronal responses globally (Ashe, McKenna, ergic markers (Perry et al., 1981) has sparked growing & Weinberger, 1989).
interest in the role that acetylcholine (ACh) plays in Cholinergic cell groups send widespread projections learning and memory. Psychopharmacological studies in to the entire cortex. Two groups of cholinergic projec- human and animal subjects have shown concordantly tion neurons are found: (i) the basal forebrain cholin- that systemic cholinergic blockade results in deficits of ergic neurons (including nucleus basalis, medial septum, attention, learning and memory (for review see Blok- and diagonal band of Broca) which innervate the cere- land, 1996 or Fibiger, 1991). Conversely, cholinesterase bral cortex and hippocampus and (ii) the brain stem inhibitors often effectively reverse lesion and pharma- cholinergic neurons (including laterodorsal and pedun- cologically induced deficits. The behavioural results in culopontine tegmental nuclei) which primarily innervate humans are complemented by animal data showing that the thalamus. Additionally there are cholinergic inter- basal forebrain ACh modulates the responsiveness of neurons in striatal areas (Cooper, Bloom, & Roth, cortical neurons (Krnjevic, Pumain, & Renaud, 1971; 1996). Intracerebral injections and neurochemical le- Kurosawa, Sato, & Sato, 1989), which is mediated by sions have enabled animal based research to manipulate muscarinic receptors (Farkas, Korodi, & Toldi, 1996; cholinergic neurotransmission in circumscribed brain Metherate, Cox, & Ashe, 1992; Sato, Hata, Masui, & regions. In vivo microdialysis, single unit recordings andother methods are available to study effects of such cholinergic manipulations locally. In contrast, in the Fax: +2461-61-2820.
human brain, localisation of memory impairing or 1074-7427/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S1074-7427(03)00076-5 C.M. Thiel / Neurobiology of Learning and Memory 80 (2003) 234–244 promoting effects of cholinergic challenges was not that the drugsÕ action was not present in, for example, achieved for many decades as human psychopharma- visual regions (Sperling et al., 2002; Thiel, Henson, cology was restricted to behavioural or electrophysio- Morris, Friston, & Dolan, 2001) thus arguing against global changes in blood flow or neurovascular coupling resolution (Knott, Harr, & Ilivitsky, 1997; Potter, with the respective drug. This does, however, not ex- Pickles, Roberts, & Rugg, 2000). With the advent of clude regionally specific vascular effects. In order to functional neuroimaging it became feasible to parallel minimise both global and regional vascular effects of a animal research and localise cholinergic modulation of drug, our paradigms always involve the analysis of dif- learning, memory, and related plastic changes in the ferential effects. Comparing different stimulus types or living human brain.
conditions with each other, as compared to approacheswhich subtract a resting or fixation baseline from anactivation condition, removes vascular confounds. Even 2. Neuroimaging and psychopharmacology if these are region specific or specific to activations per se(as shown for example for caffeine by Mulderink, Git- Imaging the human brain during cognitive tasks is elman, Mesulam, & Parrish, 2002), they should equally now possible using non-invasive methods. Most tech- influence both types of stimuli and thus subtract out in niques, such as PET and fMRI are indirect measures of the direct comparison.
neuronal activity based upon changes in blood flow and Compared to the benchmark technique of PET, the blood oxygenation following neuronal activation. The development and increasing use of fMRI offers several coupling of neuronal activity to vascular changes is thus advantages in terms of higher temporal and spatial central to measurements in PET or fMRI. Neurovas- resolution and the feasibility of repeated testing within cular coupling has been investigated in detail and is re- the same subjects. The latter is particularly advanta- viewed elsewhere (e.g., Villringer & Dirnagl, 1995). In geous as it allows to use within-subject designs where the relation to psychopharmacological approaches it is im- volunteer acts as his or her own control. Further de- portant to note that a given drug might not only change velopments in fMRI, such as the use of event-related neuronal activity but also global blood flow, local blood designs, have brought additional advantages, especially flow and/or neurovascular coupling. Many researchers for the study of learning and memory. Such advantages are thus reluctant to use blood-flow based techniques to include: (i) the possibility of randomly intermixing dif- track drug effects—especially with fMRI, where the ratio ferent trial types, such as for example previously seen of deoxygenated and oxygenated haemoglobin provides and unseen stimuli in priming paradigms; (ii) investi- the basis for the BOLD (blood oxygenation level de- gating different stages of memory processes such as en- pendent) signal.
coding, maintenance, and retrieval; and (iii) sorting Concerning the cholinergic system, it has been argued events post hoc based on the subjects behaviour such as that pharmacological manipulations might influence whether an event was subsequently remembered or not neurovascular coupling (Tsukada et al., 1997). This ar- (Buckner et al., 1996; Josephs, Turner, & Friston, 1997; gument is however based on evidence in monkeys where Rosen, Buckner, & Dale, 1998; Wagner, Koutstaal, & doses of scopolamine were 10 times higher than those Schacter, 1999). Event-related designs thus provide a used in human psychopharmacology and of critical powerful context to investigate the role of cholinergic relevance is the fact that no effects on rCBF were found neurotransmission on different aspects of human learn- at a lower dose. Furthermore, experimental evidence ing and memory.
also suggests that psychopharmacological neuroimaging Combining neuroimaging with psychopharmacology is viable even if the pharmacological challenge bears basically involves the administration of a drug or re- vascular effects. Gollub et al. (1998) were able to dem- spective placebo before volunteers undergo a cognitive onstrate that BOLD signal change in human visual task in PET or fMRI (see Fig. 1). A comparison between cortex is unaffected by application of cocaine which in- drug and placebo then reveals the drugÕs action on task- duced a 14% decrease in global blood flow. Others have related brain activity. Note that the findings of such shown experimentally for specific drugs that the fMRI studies identify neurochemical modulation of brain ac- signal in primary sensory or motor areas is unaffected by tivity that is induced by a specific task rather than ex- drug challenge. For example, it was reported that acti- citation or inhibition of brain regions per se. The latter vations in visual cortex are unchanged by nicotine ad- approach is also possible and excellently reviewed in ministration (Jacobsen et al., 2002). If the drug had Salmeron and Stein (2002). In principle, designs of affected neurovascular coupling, changes should have psychopharmacological neuroimaging studies do not been evident in all activated areas, including visual differ from conventional imaging experiments. For the cortex. Indeed many cognitive neuroimaging studies above-mentioned reasons of vascular confounds it is, with a pharmacological challenge have either demon- however, important that stimuli or activation condi- strated region specific drug effects or explicitly shown tions, such as a memory task are compared to a C.M. Thiel / Neurobiology of Learning and Memory 80 (2003) 234–244 only. As any interaction, this can be due to differentreasons, and the plotted example illustrates that the re-duction in BOLD signal in area Z is specific to A andthus a blockade of conditioning-related activity underdrug. An absence of activations to both, A and B wouldalso yield a group by condition interaction but argue forunspecific drug effects. It is thus important to furtherexamine the BOLD signal in areas showing drug bycondition interactions.
3. Cholinergic modulation of learning and memory in thehuman brain Even though the combination of psychopharmacol- ogy and neuroimaging offers many possibilities previ-ously unavailable for human research, the approach isstill limited in comparison to work in animals. It shouldbe kept in mind when reading the following section, thatpharmacological challenges in humans are always sys-temic and will affect every brain region containing therespective receptors. It is only by modulation of task-induced activity, that a pharmacological action can be Fig. 1. Illustration of a drug fMRI paradigm and analysis. An event- localised. Note that areas identified by such group by related design with two different stimuli (A and B) is illustrated. Both condition interactions, do not necessarily represent pri- groups are presented randomly with the stimuli during fMRI mea- mary areas of drug binding. Changes in brain activity surements. Data evaluation involves analysis of differential effects only(i.e., A vs. B). The same applies to studies using block designs (with A may occur downstream from the initial site of pharma- and B as an experimental and control condition respectively). Under cological action by bottom up or top down modulation.
placebo higher activations to A as compared to B are seen in three This issue is amenable to further analysis by in vivo different brain regions (X, Y, and Z). Under drug, higher activations to imaging of receptor binding using PET and radiola- A as compared to B are seen in two regions only (X,Y). Differential belled drugs or studies of effective connectivity (Friston effects in region Z are absent under drug. In region Y differential effectsare numerically smaller under drug than under placebo. A group by et al., 1997).
condition interaction comparing differential effects under drug and A further constraint in human research is the re- placebo yields region Z. Note that activity in region Y is not signifi- stricted range of available drugs licensed for use in hu- cantly different under placebo and drug when compared statistically.
mans. With respect to blockade of cholinergic function The plots of percent signal change demonstrate the interaction ob- one is limited to the use of the muscarinic antagonist served in region Z and show that it is due to reduced activations tostimulus A under drug challenge.
scopolamine. The nicotinic antagonist mecamylaminewas applied in some studies, but is not available for respective control condition instead of a resting baseline.
experimental use in humans in several countries. Drugs Data analysis should include a within-group analysis to increase cholinergic neurotransmission on the other showing task-related brain activity under drug and hand are more abundant and involve a variety of cho- placebo, and finally a group by condition interaction linesterase inhibitors, such as physostigmine. Nicotine showing areas with significant differences in task-related which specifically stimulates nicotinic receptors is also activity between the groups. Plotting activity changes in easily available in different forms.
these areas will provide further information on the Despite these constraints, pharmacological neuroi- modulatory action of the drug on a given cognitive maging studies make an important contribution to our process. Imagine the design depicted in Fig. 1 was a understanding of cholinergic modulation of cognitive conditioning fMRI study which involved two stimuli, A function in humans. In the following, PET and fMRI (CS+) and B (CS)). Under normal conditions, which studies in healthy volunteers involving the acute appli- are reflected in the placebo group, conditioning-related cation of a cholinergic drug in the context of a learning activity is evident in three brain regions, X, Y, and Z.
or memory paradigm are reviewed. For reasons of With drug challenge, however, conditioning-related clarity the studies are classified into those using explicit brain activity is smaller in region Y and absent in region memory paradigms and those using implicit memory Z. A group by condition interaction looking for differ- paradigms. The terms explicit and implicit memory were ences in conditioning-related brain activity under drug originally introduced by Graf and Schacter (1985) and and placebo yields significant differences in region Z refer to the observation that memory retrieval can be C.M. Thiel / Neurobiology of Learning and Memory 80 (2003) 234–244 dependent (explicit) or independent (implicit) of explicit under physostigmine, indicating improved recognition.
recollection. It was shown that in amnesia implicit Memory-related brain activity was measured by com- memory functions involving classical conditioning, skill paring rCBF under task performance with a resting learning or priming are often preserved, suggesting baseline. The drug reduced memory-dependent activa- neuronally different processes or networks for implicit tions in right inferior temporal cortex which extended and explicit memory. The classification into explicit and into the cerebellum and right prefrontal cortex. The implicit memory is also interesting from a pharmaco- magnitude of rCBF reduction in prefrontal cortex cor- logical point of view. While cholinergic modulation of related with decreased reaction times. Cholinergic effects explicit memory has been shown behaviourally (Caine, were thus seen again in prefrontal cortex, the direction Weingartner, Ludlow, Cudahy, & Wehry, 1981; Curran, of these effects was however the same as that obtained Pooviboonsuk, Dalton, & Lader, 1991a; Frith, Rich- with cholinergic blockade. Authors interpreted this ardson, Samuel, Crow, & McKenna, 1984; Nissen, somewhat counterintuitive result as an effect of reduced Knopman, & Schacter, 1987; Rusted & Warburton, effort to perform the task under physostigmine. In- 1988), cholinergic effects on implicit learning are con- creases in task difficulty or cognitive load are indeed troversial and it has often been argued that implicit often associated with increased frontal activations (e.g., learning is not cholinergically modulated (Knopman, Bullmore et al., 2003). From a behavioural point of view, the explanation of reduced prefrontal activationswith reduced effort is thus reasonable. From a phar- 3.1. Explicit memory macological point of view such explanation wouldhowever imply, that frontal effects are neurochemically 3.1.1. Working memory unspecific since they should occur with any drug re- Brain mechanisms contributing to working memory ducing the effort needed to perform the task. Further- have received a great deal of interest in the neuroimag- more, such explanation does not hold for effects of ing literature. The frontal cortex has been found to scopolamine, which should increase task effort but re- consistently activate under working memory conditions duce frontal activations. Nor does it explain that a re- (see Fletcher & Henson, 2001 for review). Given the duction of load-related frontal activity was found with cholinergic contribution to explicit memory it is thus not scopolamine in a recent fMRI study (Bullmore et al., surprising that one of the first neuroimaging studies involving a cholinergic manipulation used a working Since PET studies are not able to investigate different memory paradigm (Grasby et al., 1995). Subjects re- stages of working memory such as encoding and re- ceived either 0.4 mg scopolamine (s.c.) or placebo and trieval related processes, authors subsequently per- were presented auditorily with short and long word lists formed an fMRI experiment to investigate different which they were asked to remember and immediately stages in the above working memory paradigm (Furey, recall. The difference between those two conditions was Pietrini, & Haxby, 2000). This fMRI experiment yielded the greater involvement of memory processes in the long activity increases to faces under physostigmine in several list condition. Memory-related brain activity was mea- extrastriate regions and the intraparietal sulcus which sured with PET and involved a comparison of rCBF in were bigger during encoding than retrieval. Again, re- the long list condition with the short list condition.
ductions in prefrontal activity were found with physo- Behaviourally, the drug reduced the number of words stigmine. But these were restricted to anterior dorsal recalled from the long list. Neuronally, it was found that prefrontal regions and not specifically related to indi- blockade of cholinergic function with scopolamine at- vidual subcomponents of working memory. The authors tenuated memory-related rCBF in left and right pre- stress the cholinergic modulation of extrastriate regions frontal cortex and anterior cingulate cortex, suggesting and suggest that improved working memory under that the memory-impairing action of scopolamine might physostigmine is due to increased perceptual processing be due to disturbed activity in these frontal brain re- of task-relevant stimuli.
gions. Authors were however not able to differentiate While increasing cholinergic neurotransmission with between encoding and retrieval due to the poor tempo- physostigmine will act on both nicotinic and muscarinic ral resolution of PET rCBF imaging.
receptors, nicotine selectively binds to the former. The Effects of increased cholinergic neurotransmission on role of nicotinic neurotransmission on working memory working memory have been studied in several experi- in smokers and ex-smokers was examined by Ernst et al.
ments by Furey and colleagues using physostigmine (2001). A two back working memory task with visually (constant infusion 1 mg/h). In a first PET study (Furey presented letters was used and subjects received either et al., 1997) participants performed a visually presented 4 mg nicotine gum or placebo. rCBF was measured with working memory task for faces. They had to indicate by PET and involved a comparison of the working memory key press which of two test faces matched a previously condition (not dissociating encoding and retrieval) with presented face. Reaction times improved over scans a sensorimotor control task. Several differences were C.M. Thiel / Neurobiology of Learning and Memory 80 (2003) 234–244 found between smokers and ex-smokers. Compared to hippocampus. Since these latter regions are the key areas placebo, smokers showed reductions of brain activity that induce profound deficits of explicit memory when under nicotine during task performance while ex- lesioned, further studies should focus on paradigms smokers showed increases in prefrontal cortex and bi- which specifically activate medial temporal regions.
lateral inferior parietal areas. The only effect common toboth groups was a reduction of memory-related anterior 3.1.3. Summary explicit memory cingulate cortex activity under nicotine. Since behavio- Cholinergic modulation of explicit learning and ural effects of nicotine were only evident in smokers it is memory occurs on two levels. First, modulation was not clear whether the drugsÕ differential effects in these evident in ‘‘stimulus processing'' brain areas, such as the two groups of subjects are due to altered sensitivity of fusiform cortex or other extrastriate areas. Second, ef- cholinergic receptors in smokers and/or to the different fects were also found in a more ‘‘learning related'' net- behavioural outcome of nicotine administration. Nev- work including the prefrontal cortex and hippocampus.
ertheless, the possibility of differential modulation of Cholinergic effects on frontal cortical brain activity memory-related brain activity in smokers and non- suggest that intact cholinergic neurotransmission in this smokers should be taken into account when using drugs brain region might critically contribute to memory affecting nicotinic cholinergic receptors.
performance. The exact mechanism of such modulationis however not easily explained by the available data 3.1.2. Other explicit memory paradigms since activity reductions were observed with both cho- A slightly different approach to localising the am- linergic stimulation and cholinergic blockade. Further nestic effects of cholinergic blockade was taken by work is needed to resolve these discrepancies. The pat- Rosier et al. (1999). Subjects had to perform an abstract tern of cholinergic modulation in extrastriate regions on object recognition task where encoding and retrieval the other hand nicely demonstrates activity decreases were separated by three days. Scopolamine (0.8 mg or- with cholinergic blockade (scopolamine) and activity ally) was administered during encoding whereas PET increases with cholinergic stimulation (physostigmine).
measurements were performed during recognition test- Such effects indicate that cholinergic neurotransmission ing three days later and involved a comparison between might increase the efficacy of processing task relevant recognition and fixation. Scopolamine induced impair- stimuli in explicit learning paradigms. Further studies ments in object recognition and decreased activity in left will need to determine whether these extrastriate effects fusiform gyrus, which correlated with behavioural per- contribute to cholinergic modulation of frontal cortical formance. Increases in activity were found in the thal- activity or whether frontal cortical activations are in- dependent of extrastriate drug effects.
performance dependent decrease of fusiform cortex ac-tivity suggests that scopolamine exerts its main effect in 3.2. Implicit memory an area that deals with processing and recognition ofabstract objects. Even though the authors were not able Pharmacological neuroimaging studies are often de- to investigate scopolamineÕs effects on encoding, the signed from a behavioural point of view and intend to advantage of their approach is to measure drug-related localise amnesic or memory-promoting effects of phar- deficits without the presence of the drug during macological agents (e.g., Furey et al., 2000; Grasby et al., 1995; Sperling et al., 2002). The paradigms used during The effects of scopolamine on encoding-related ac- imaging are thus sensitive to drug induced behavioural tivity were investigated by Sperling et al. (2002) using impairments but might induce widespread brain acti- fMRI and a face-name associative learning task. Prior vations, especially when compared to baseline, which to scanning, subjects received 0.4 mg scopolamine or are not necessarily truly memory-related. Our approach placebo i.v. Scopolamine impaired face recognition therefore uses relatively simple paradigms, such as postscanning. Encoding-related brain activity was iso- priming and conditioning where learning has reliable lated by comparing face–name association learning with neuronal correlates which are well described by prior fixation. Attenuation of encoding-related activity was neuroimaging work and restricted to specific brain ar- evident in inferior prefrontal cortex, fusiform cortex, eas. Implicit learning paradigms such as conditioning and hippocampus. The activation decreases in fusiform also bear the advantage that they can be implemented in cortex are in accordance with the findings of Rosier et al.
animal experiments and thus provide the possibility for (1999) showing that one of the effects of scopolamine complementary research in animals and humans.
consists of attenuation of brain activity in areas associ-ated with processing of task specific stimuli during en- 3.2.1. Repetition priming coding and retrieval. Apart from those ‘‘stimulus Priming describes a behavioural phenomenon where processing areas,'' effects of cholinergic blockade were prior exposure to a stimulus facilitates or biases its also evident in medial temporal regions such as subsequent processing. One potential neuronal signature C.M. Thiel / Neurobiology of Learning and Memory 80 (2003) 234–244 for this form of learning was established in monkey and interaction. In the placebo group, repetition-related termed ‘‘response suppression,'' a decrement in response decreases were evident in several brain areas, including to repeated stimuli in neurons that fire to initial pre- left extrastriate cortex, left inferior frontal cortex, and sentation (Desimone, 1996). In humans, analogous de- left middle frontal cortex, regions previously shown to creases in haemodynamic response following stimulus manifest Ôrepetition suppressionÕ effects (e.g., Buckner repetition (i.e., ‘‘repetition suppression'') in brain areas et al., 2000). The comparison of repetition-related effects such as extrastriate and frontal cortices have been re- under placebo and drug revealed a significant interac- peatedly demonstrated with neuroimaging methods tion in these same regions including left extrastriate, left (Buckner, Koutstaal, Schacter, & Rosen, 2000; Henson, middle frontal, and to a lesser extent, left inferior frontal Shallice, & Dolan, 2000; Schacter & Buckner, 1998). It cortex. In other words, Ôrepetition suppressionÕ was im- has been suggested that decreased BOLD activity with paired in the presence of scopolamine. This drug-by- stimulus repetition is due to a sharpening of cortical repetition interaction reflected an absence of Ôrepetition representations leading to faster behavioural responses suppressionÕ following scopolamine which is shown for (Wiggs & Martin, 1998). Even though the link between left extrastriate cortex in Fig. 2A (see Thiel et al., 2001 behavioural, neuronal, and BOLD responses is probably for further discussion).
more complex (see Henson & Rugg, 2003 for further Very similar results for scopolamine were obtained in discussion), the important point for our purposes was the face priming paradigm (Thiel et al., 2002c). Volun- that repetition suppression is reliably observed in ex- teers were presented in a study phase outside the scanner trastriate cortices and concurrent with the behavioural with a subset of famous and unfamous faces and asked phenomenon of priming. Repetition suppression thus to make fame judgments. This was followed by a test provides a useful platform from which pharmacological phase inside the scanner where subjects were presented modulation of implicit learning can be studied with with the whole set of faces, containing randomly inter- mixed famous and unfamous faces that were either Using event-related fMRI, we investigated choliner- presented in the study phase or were not. Participants gic modulation of neuronal and behavioural indices of were asked to make fame judgements. The mean correct priming with two tasks, a word stem completion and a reaction times for first versus second presentation of face repetition paradigm (Thiel, Henson, & Dolan, famous and unfamous faces provided the behavioural 2002c; Thiel et al., 2001). In both task, volunteers were index of repetition priming in this paradigm. Scopol- given either placebo or scopolamine (0.4 mg i.v.) prior to amine impaired priming of famous faces (see Fig. 2B, study. The experimental question of interest was whe- left graph). The placebo group showed repetition sup- ther scopolamine would modulate Ôrepetition suppres- pression to famous faces in right fusiform cortex. Sco- sionÕ in extrastriate and frontal regions.
polamine impaired this repetition suppression (see Word stem completion tasks are used in several Fig. 2B, right graph). Consequently, both paradigms priming studies. They involve the presentation of a list underline a role of ACh in repetition priming. Cholin- of words with an incidental learning instruction. After a ergic modulation is expressed as an attenuation of short interval, a list of three letter word stems is pro- Ôrepetition suppressionÕ in the same brain areas associ- vided and subjects are asked to complete each stem with ated with repetition effects in the placebo group and in the first word that comes to mind. The measure of previous studies using the respective paradigm (Buckner priming is the number of stems completed with words et al., 2000; Henson et al., 2000).
from the previously presented list. In our experiment, Our neuroimaging evidence is in contrast to most of volunteers studied the word list prior to scanning. This the prior behavioural (Knopman, 1991) or animal elec- was followed by a test phase inside the scanner where trophysiological (Miller & Desimone, 1993) data which subjects were presented with a completion task for the could not find evidence for cholinergic modulation of stems of the words presented in the study phase (‘‘old repetition effects. Two potential differences between our word stems'') randomly intermixed with stems of non- and prior studies might explain the discrepant findings.
presented words (‘‘new word stems''). Scopolamine re- First, we would like to suggest that cholinergic deficits in duced behavioural measures of priming (see Fig. 2A, left priming paradigms are only found with higher doses of graph). Since scopolamine impaired the behavioural scopolamine. The only other study showing an impair- expression of repetition priming, we next asked whether ment of priming (Vitiello et al., 1997) used a similar dose these effects are expressed in modulatory influences on of scopolamine as we did (i.e., 0.5 mg i.v.) while other the neuronal index of priming, i.e., repetition suppres- studies (e.g., Knopman, 1991; Schifano & Curran, 1994) sion. We therefore identified brain regions showing used effectively lower doses (between. 0.3 and 0.6 mg significant repetition suppression under placebo and i.m.). Note that Schifano and Curran (1994), who used drug. Second, we compared the magnitude of these re- two doses of scopolamine found a tendency towards ductions by contrasting the placebo and drug group, i.e., attenuated repetition priming at the higher drug dose.
we tested for a group (placebo and drug) by repetition Another critical difference between priming studies C.M. Thiel / Neurobiology of Learning and Memory 80 (2003) 234–244 Fig. 2. Effects of scopolamine on repetition priming. (A) Word stem completion priming. Left graph: Behavioural performance. Mean and standarderrors of word stems completed with target words from the previously presented list (old word stems) and words from previously non-presented list(new word stems ¼ chance completion). Priming is evident as above chance (dotted line) use of previously presented words, both under placebo andscopolamine. Scopolamine treated subjects use less words from the previously presented list as compared to placebo subjects, i.e., show a reduction ofpriming. Right graph: Repetition suppression. A left extrastriate region is plotted ()36, )75, )6) showing repetition suppression under placebo butnot scopolamine. The plots of percent signal change (mean and standard error) demonstrate the Ôrepetition suppressionÕ to old word stems underplacebo. In scopolamine subjects there is an absence of repetition suppression; activations to old word stems are even higher than activations to newword stems. For repetition effects in other brain regions see (Thiel et al., 2001). (B) Face repetition priming. Left graph: Behavioural performance.
Mean and standard errors of reaction times to famous faces. Priming is evident as reduced reaction times to previously seen (old) famous faces underplacebo but not under scopolamine. Right graph: Repetition suppression. A right fusiform region (30, )45, )30) showing repetition suppressionunder placebo is plotted. Under scopolamine, repetition suppression is reduced. Only data for famous faces are shown since priming was not evidentfor unfamous faces, for full data see (Thiel et al., 2002c).
pertains to the delay between study and test phase which tended to other implicit learning situations. Aversive was 40 min in our studies. Since repetition suppression conditioning is a form of associative learning in which a can be sensitive to lag (Henson et al., 2000) it may be previously neutral stimulus, such as a tone (conditioned that weaker repetition suppression with longer lags is stimulus, CS), acquires significance through its predic- more sensitive to drug influences. Indeed, Nissen et al.
tion of a future aversive event, such as an electric shock (1987) found that word fragment completion was im- (unconditioned stimulus, US). Brain systems involved in paired by scopolamine when there was a 60 min delay aversive conditioning are well described (LeDoux, between study and test phase but not when the delay 1995). Conditioning paradigms thus provide a compel- was 5 min as usually used in word stem completion ling model to study mechanisms of learning-related paradigms (although the authors attributed these lag plasticity. In the context of a neuroimaging experiment, effects to an influence of explicit memory). We would we operationally define plasticity in a broad sense as thus like to suggest that cholinergic modulation of im- experience-dependent changes in haemodynamic re- plicit learning in priming paradigms is only seen with sponses to relevant sensory stimuli. Prior neuroimaging longer lags between study and test phase.
studies, using eye-blink and aversive conditioning par-adigms, have provided evidence that learning-related 3.2.2. Conditioning plasticity occurs in human auditory cortices (Molchan, Since ACh seemed to modulate neuronal correlates of Sunderland, McIntosh, Herscovitch, & Schreurs, 1994; priming we asked whether these findings could be ex- Morris, Friston, & Dolan, 1998; Schreurs et al., 1997).
C.M. Thiel / Neurobiology of Learning and Memory 80 (2003) 234–244 Animal data suggest that cholinergic cortical projections changes, a critical experiment to conduct from a clinical are important for modulating such learning-related point of view would be one aiming to increase learning- plasticity (Weinberger, 1997). We thus designed a psy- related plasticity. Indeed, there is behavioural evidence chopharmacological event-related fMRI study to ad- showing recovery promoting actions of cholinergic dress cholinergic modulation of experience dependent treatment in aphasia (Berthier, Hinojosa, Martin Md, & changes in the human brain which was very much based Fernandez, 2003). We therefore conducted a follow-up on animal experiments. We used a differential condi- study using the same differential conditioning paradigm tioning paradigm with partial reinforcement where as above but a physostigmine infusion to enhance ACh BOLD activity to an unpaired CS+ can be contrasted and possibly conditioning-related activity (Thiel et al., with activations to a CS). Since both stimuli are phys- 2002a). Data in the placebo group showed again en- ically identical, differential activity to the CS+ must be hanced BOLD response to the CS+ in auditory cortex, due to its acquired significance during conditioning.
indicating learning-related changes (Fig. 3, right graph).
Conditioned stimuli were high (1600 Hz) and low tones In contrast to our expectations however, the physostig- (400 Hz), one of which was paired with an electrical mine group did not show any differential activation to shock (Thiel, Friston, & Dolan, 2002b). Prior to scan- CS+ vs. CS). This absence of conditioning-related ac- ning, subjects were given either placebo or 0.4 mg i.v.
tivations was however different from that seen previ- ously with scopolamine (see left graph) and due to an haemodynamic responses to the CS+ but not the re- increase of activations to the CS). Note that activations spective CS) was evident in the placebo group. Under to the CS+ were not different between drug and placebo, scopolamine, the enhancement of BOLD activity to the i.e., there was also an increase of activation to the CS+ CS+ was blocked, suggesting that cholinergic receptors under physostigmine (but this was similar to the increase are involved in these conditioning-related responses observed with the irrelevant CS)).
(Fig. 3, left graph). The findings provide in vivo evidence It has been shown that pairing a tone with direct that conditioning-related plasticity in human auditory iontophoretic application of ACh in place of the US cortex is attenuated by blockade of cholinergic (mus- produces conditioning specific changes in receptive fields carinic) neurotransmission. They are supported by a in auditory cortex which can be blocked with atropine wealth of animal literature and nicely illustrate that (see Weinberger, 1995 for review). Even though the re- psychopharmacological approaches in neuroimaging are lationship between receptive field analysis in animals able to extend findings based on animal research to the and BOLD signal change in humans has not been es- human brain.
tablished, we would like to use this evidence from ani- Studying modulatory effects of drugs on learning-re- mal data to speculate on the neuronal mechanisms of lated plasticity in humans is also of significance for the cholinergic modulation observed with neuroimaging in study of mechanisms of recovery and treatment effects in our conditioning experiments. Imagine that under nor- patients with neurological damage. But rather than mal conditions the pairing of the CS+ with a shock showing a cholinergic blockade of learning-related would induce a release of ACh which would contribute Fig. 3. Effects of scopolamine and physostigmine on auditory cortex during conditioning. Plots of percent signal change (mean and SEM) of twovoxels in auditory cortex illustrating cholinergic modulation of conditioning-related activity under scopolamine, physostigmine, and their respectiveplacebo control (for full data see Thiel, Bentley, & Dolan, 2002a and 2002b). Left graph: Effects of cholinergic blockade with scopolamine in a rightauditory cortex voxel showing significant group by conditioning effects (x ¼ 57; y ¼ 15; z ¼ 6). Right graph: Effects of cholinergic enhancementwith physostigmine. Activity in a left auditory cortex voxel showing a group by conditioning interaction in the follow up study(x ¼ 63; y ¼ 18; z ¼ 9). Note that in comparison with placebo, scopolamine reduced activations to the CS+ whereas physostigmine increasedactivations to the CS). CS, conditioned stimulus.
C.M. Thiel / Neurobiology of Learning and Memory 80 (2003) 234–244 to development of conditioning-related plasticity. This changes. The aim to enhance experience-dependent re- experience-dependent enhancement of responses re- sponses with administration of physostigmine failed, quires a temporal coincidence between neuronal depo- which could reflect that cholinergic stimulation in heal- larisation produced by ACh and neuronal excitation thy volunteers effectively overstimulates an otherwise produced by the sensory stimulus (Hars, Maho, Edeline, perfectly balanced cholinergic system. It needs to be & Hennevin, 1993). With scopolamine, any release of investigated in future studies, whether effects of cholin- ACh upon stimulation is ineffective due to blockade of ergic stimulation are beneficial in states of reduced muscarinic ACh receptors resulting in a lack of condi- cholinergic activity, such as AlzheimerÕs disease. Indeed tioning-related response increase. This is reflected in there is in vitro evidence for differential effects of cho- similar activations to the CS) and CS+ in our first study linesterase inhibitors on ACh release in normal brains (Thiel et al., 2002b). The pharmacological action of and brains of Alzheimer patients (Nordberg, Nilsson- physostigmine on the other hand is an increase in am- Hakansson, Adem, Lai, & Winblad, 1989).
bient ACh levels, and a prolongation of cholinergic ac-tion upon stimulation. Such mechanism could bebeneficial in increasing the action of ACh when released 4. Summary and future perspectives in response to a CS+; but it might also interfere with theprecise timing necessary for conditioning-related plas- I have presented several studies which tried to localise ticity and result in a temporal overlap of still increased cholinergic modulation of learning-related brain activ- cholinergic activity with a following irrelevant stimulus ity. The results obtained are diverse and depend on the (i.e., CS)). Temporal coincidence of the CS) with a still paradigm used. Nevertheless, if one has to come to an elevated cholinergic activity might then result in similar integration of cholinergic neuroimaging studies two enhancements of neuronal activation to both the CS) common findings should be stressed. First, in several and CS+ which was observed in this follow-up study experiments, cholinergic modulation was seen in frontal (Thiel et al., 2002a). We therefore suggest, that cholin- cortical areas, which are known to activate in neuroi- ergic blockade reduces activations to relevant stimuli maging studies of learning and memory, suggesting that while cholinergic stimulation with physostigmine results memory impairing or promoting effects of cholinergic in inordinate activations to irrelevant stimuli. Both drugs in these paradigms are be closely linked to mod- mechanisms interfere with learning-related plasticity, ulation of frontal cortical activity. Second, in several one by decreasing the ‘‘signal'' and the other by paradigms cholinergic modulation was also demon- strated in areas that are involved in processing the task The idea that physostigmine might increase irrelevant relevant stimuli such as fusiform cortex, extrastriate signals in healthy volunteers seems in contrast to data by regions or auditory cortex. The finding that cholinergic Furey et al. (2000) who suggest that cholinergic stimu- neurotransmission modulates activity in such areas lation improves stimulus processing. First note, that the would suggest a cholinergic role in stimulus processing study by Furey et al. (2000) did not employ task-irrrel- and attentional function which is also supported by evant stimuli so that no conclusions can be drawn about behavioural and neurochemical evidence in animals possible increases of processing of irrelevant stimuli with (Blokland, 1996; Sarter & Bruno, 1997). Such finding cholinergic stimulation. Second, the beneficial effect of does not preclude a cholinergic role in learning and physostigmine on task-relevant stimuli in the Furey memory, it just underlines that experimental designs are study, which we could not find in our experiment might needed were learning and stimulus processing are un- be linked to the fact that their task was cognitively more demanding (working memory for faces vs. key press to a It is still early days for pharmacological neuroimag- tone) and that cholinergic stimulation may be especially ing studies and more experiments are clearly required to beneficial in such situations.
obtain further information on the role of ACh in cog-nitive function. Such experiments should compare: (i) 3.2.3. Summary implicit memory the effects of the same drug in different paradigms (es- This section on implicit memory presented four of pecially those of learning and memory vs. attention) and our own studies on cholinergic modulation of implicit (ii) the effects of different cholinergic drugs within one learning. In both learning paradigms neuronal correlates paradigm. Further insights into the role of ACh on in- are well defined and involve differential experience-de- tegrated activity in the human brain during learning and pendent effects to otherwise similar stimuli. Repetition- memory are expected from new approaches, which in- related changes were evident as experience-dependent vestigate interactions between brain regions, rather than response decreases whereas conditioning-related chan- activity within one region (Buchel & Friston, 2001).
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