Neuropsychology and Behavioral Neurology

585 Pages·2008·16.166 MB·English

by  Michael J. Aminoff, François Boller, Dick F. Swaab, Georg Goldenberg and Bruce L. Miller (Eds.)

HandbookofClinicalNeurology,Vol.88(3rdseries)
Neuropsychologyandbehavioralneurology
G.Goldenberg,B.L.Miller,Editors
#2008ElsevierB.V.Allrightsreserved
Cha pter 1
Cholinergic components of frontal lobe function
and dysfunction
LAURA A. RABIN 1 *, PATIMA TANAPAT 2, AND NORMAN RELKIN 3
1Department of Psychology, Brooklyn College and the Graduate Center, City University of New York, Brooklyn, NY, USA
2Research Consultant, Princeton, NJ, USA
3Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA
1.1. Introduction Throughout the chapter, important findings related
to the brain cholinergic system will be presented and
Anatomically represented by cortical areas anterior to the directions for future research highlighted.
central sulcus, the frontal lobes are richly and recipro-
cally interconnected with widespread brain regions 1.2. Acetylcholine
through numerous pathways including the limbic
(motivational/mnemonic) system, reticular activating The synthesis of ACh is the resu lt of a chem ical reac tion
(arousal) system, posterior association cortex (percep- involving the acetyl ation of choline by acetyl CoA. This
tual/cognitive processes and knowledge base), and motor reaction is catalyzed by choline acetyl transfera se
(action) areas (Goldman-Rakic, 1987; Cummings, 1995). (ChAT), an enzyme that, becau se of its cent ral role in
This broad pattern of connectivity underlies the signifi- catalyzi ng this reaction, is widel y used as a marker of
cant control exerted over posterior cortical and subcorti- cholinergi c activit y. Altho ugh choline can be synthe-
cal systems by the frontal cortex. All areas of the frontal sized de novo in the brain, ACh is synthesized pri marily
cortex receive substantial cholinergic innervation. Con- from ingested choline, which is transpor ted to the brain
sequently, acetylcholine (ACh) plays a significant role by the blood either free or in phospho lipid form. Fo llow-
in various aspects of frontal lobe function, particularly ing its synthesis, ACh is then stored in synapti c vesi cles.
complex cognitive processes such as attention and mem- The level of ACh at any given time may be regul ated by
ory. In this chapter, we will first review cholinergic anat- either feedback inhi bition of ChAT, mass action, or the
omy, neurochemistry, and physiology related to frontal availabili ty of acetyl CoA and/or chol ine. Additiona lly,
lobe function. Next, the contribution of cholinergic dys- there is som e sugges tion that intrac ellular levels of ACh
function to Alzheimer’s disease (AD) and other disorders play a role in regulat ing its rate of synt hesis, thus li mit-
associated with cognitive deterioration, as well as the use ing the maxim um amo unt of the neuro transmitt er that
of drugs to enhance cholinergic activity under these can be achieved in the brain, even with the adm inistra-
conditions, will be discussed. Finally, imaging strategies tion of drug compounds ( Klei n et al., 1993 ). Upon depo-
such as functional MRI (fMRI) and positron emission larization of the cell membr ane, the vesicles fuse with
tomography (PET), which are playing an increasingly the cell membrane and ACh cont ained in presynapti-
important role in investigations of the human ACh sys- callylocalizedvesiclesisreleasedintothesynapticcleft
tem, will be reviewed. These techniques can be used to tointeractwithbothpostsynapticandpresynapticrecep-
investigate effects of cholinergic agonists and antagonists tors. Postsynaptically, ACh receptor activation may
on cognitive performance in healthy and compromised resultinanumberofeventsthatleadtochangesinmem-
individuals and can assist in disease detection and moni- brane potential of the postsynaptic cell whereaspresy-
toring of progression, treatment, and clinical outcome. napticreceptoractivationactstoinhibitfurtherrelease
*Correspondenceto: LauraA.Rabin, Ph.D. DepartmentofPsychology, Brooklyn College,CityUniversityofNew York, 2900
Bedford Avenue, Brooklyn, NY 11210, USA. E-mail: [email protected], Telþ: 1-718-951-5601, Fax: þ 1-718-951-4814.
2 L.A. RABIN ET AL.
of the neurotransmitter. Following its release into the
synapse, unbound ACh is hydrolyzed by acetylcho-
linesterase (AChE) and, to a much lesser extent, by
butyrylcholinesterase (BuChE). About 35–50% of the
liberatedcholineisthen transportedback tothepresy-
naptic terminal by a sodium-dependent, high-affinity
active transportsystem tobe re-utilizedinACh synth-
esis. The remaining fraction may be catabolized or
incorporatedintophospholipids,whichcanlaterbeused
asasourceofcholine.
AlthoughtheroleofBuChEhistoricallyhasreceived
muchlessattentionthanAChE,recentevidencesuggests
that BuChE may play an important role that is distinct
fromthatofAChE.IncontrasttoAChE,whichisloca-
lizedprimarilywithinneurons,BuChEtendstobeasso-
ciated not only with neurons, but also with glial and
endothelial cells (Darvesh et al., 2003). At low neuro-
transmitter concentrations, BuChE is relatively ineffi-
cient at hydrolyzing ACh. At high concentrations,
whichtendtoinhibittheactionsofAChE,BuChEisvery
efficient.Thissuggeststhatduringperiodsofhighbrain
activity, characterized by synaptic levels of ACh that
are likely to inhibit AChE, BuChE may be critically
responsibleformaintainingnormalcholinergicfunction.
1.3. Neuroanatomy
Damage to the cholinergic system is characteristic
of a number of pathological conditions including
Alzheimer’s disease (AD), vascular dementia (VaD),
Parkinson’s disease (PD), dementia with Lewy bodies
(DLB), and Down syndrome (DS), all of which are
associated with substantial cognitive impairment
(Perry, 1999; Roman and Kalaria, 2005). As a result,
a great deal of attention has been focused upon under-
standing the cholinergic system’s influence on frontal
corticalregions. Thecholinergicsystem directly influ-
ences frontal cortex activity via projections from the
nucleus basalis of Meynert (NBM) in the basal fore-
brain, as well as indirectly via the thalamus, which
receives cholinergic input from NBM projections and
midbrain tegmental nuclei, and via the basal ganglia.
Inthefollowingsection,thepropertiesoftheseprojec-
tionswillbedescribedinthecontextoftheirrelevance
to clinical neuropathology. Fig. 1.1 presents primary
frontallobe cholinergicpathways.
Panel 1: Direct cholinergic innervation of the frontal lobe originating in the basal
forebrain: NCX, neocortex: NBM, nucleus basalis of Meynert
1.3.1. Directcholinergic regulation by the nucleus
Panel 2: Indirect cholinergic innervation of the frontal lobe originating in the
basalis ofMeynert (NBM)
podunculapontine and laterodorsal nuclei of the tegmentum: PF, prefrontal cortex;
TH, thalamus; PMT, pontomesencephalotegmental system (pedunculopontine
and laterodorsal tegmental nuclei)
The cells of the NBM provide the primary extrinsic
Panel 3: Cholinergic pathways influencing the frontal lobe that involve projections
cholinergic innervation of the frontal cortex. These of the basal ganglia: AC, anterior cingulate cortex OF, orbitofrontal cortex; TH, thalamus;
VS, ventral striatum; GP, globus pallidus (internal segment): SN, substantia
cells, which correspond to Ch4 cells as described by nigra (pars reticulata); VTA, ventral tegmental area
Mesulam and Geula (1988), can be divided into four Fig.1.1. Frontallobecholinergicpathways.
CHOLINERGIC COMPONENTS OFFRONTAL LOBEFUNCTION AND DYSFUNCTION 3
subregions based upon their location and target cells: this implies that damage to or degeneration of a small
(1) Ch4am (anteromedial) projects to cingulate cortex areamayimpactanumberofbehavioralfunctions.
and basolateral amygdala; (2) Ch4al (anterolateral) Like other cortical regions, the frontal cortex exhi-
projects to orbitofrontal cortex and opercular cortex; bits a rich density of cholinergic fibers. These fibers
(3)Ch4id(intermediate)projectstolateralfrontal,par- areforthemostpartunmyelinated,varicose,andform
ietal,peristriate,temporalcortex;and(4)Ch4p(poster- synapses on the perikarya, dendritic shafts, and spines
ior) projects to superior temporal and temporopolar of pyramidal and, to a lesser extent, non-pyramidal
cortex. In individuals exhibiting various neurode- neurons (Wainer et al., 1984; Frotscher and Leranth,
generative diseases, a significant loss of cells in the 1985). Cholinergic projections to the cortex are orga-
NBM is observed consistently. Although the reasons nizedintoamedialandlateralpathway,bothofwhich
underlying this damage are not yet fully understood, a provide innervation to frontal regions (Saper, 1984;
number of age-related pathological processes that Kittetal.,1994;Seldenetal.,1998).Thegreatestden-
may be responsible have been identified. These pro- sity of cholinergic fibers is exhibited in motor cortex
cessesincludedecreasesinthecalciumbindingprotein with lower but significant densities in premotor and
calbindin, deficits in neurotrophic factor protection, anterior cingulate cortex, as well as association areas
and the formation of amyloid plaques (Iacopino and ofprefrontalcortex.Atpresent,itisnotknownwhether
Christakos, 1990; Wu et al., 1997; Geula et al., 1998; theincreasingrostrocaudalgradientisfunctionallysig-
Chuetal.,2001;Wuetal.,2003).Inspiteofsignificant nificant,orwhetheritissimplytheresultofthegreater
disagreementsurroundingtheetiologyofthecognitive density of fiber projections present in the more caudal
deficitsassociatedwithvariousneurodegenerativecon- cortical regions. With regard to their laminar distribu-
ditions, it remains clear that deterioration of choliner- tion,cholinergicfiberstendtobeconcentratedinlayers
gic cells within the NBM is an important contributing I through upper III, as well as in layer V in agranular
factor. cortex, V and VI in motor and premotor regions, and
In general, the morphology, organization, and con- I and V-VI in prefrontal regions (Mesulam et al.,
nectivity of cholinergic cells in the NBM suggest that 1984; Lewis, 1991). Although the density of choliner-
they are well suited to integrating information from a gic fibers tends to vary significantly by region and
diversity of sources and transmitting that information laminar position, their widespread presence across all
diffusely throughout neocortical target regions. These cortical areas and layers may underlie the spectrum of
cholinergiccellstendtobecharacterizedbyextensive, symptoms associated with conditions of cholinergic
overlapping dendritic arbors that contact myelinated dysfunction.
fiber tracts in regions that contain corticofugal projec-
tions (Saper, 1984; Woolf, 1991). Cholinergic cells of 1.3.2.Indirectcholinergicregulationviaprojections
theNBMarethereforecapableofreceivinginformation tothe thalamus
derivingfrombothneighboringcellsandfromcortical
cellpopulations.Moreover,thesecellstendtobeorga- Inadditiontoreceivingdirectcholinergicinputfromthe
nizedintoclusters.Whiletheexactsignificanceofthis NBM,thefrontalcortexisindirectlyinfluencedbycho-
clusteringphenomenonisunclear,thistypeofintimate linergicprojectionstothethalamusthatderivefromtwo
intercellular association may provide the basis for an different pathways. The first of these pathways origi-
enhanced capacity for information processing (Bigl nates in the pedunculopontine and laterodorsal nuclei
etal.,1982).Indeed,ithasbeennotedthatphylogeneti- of the tegmentum and, together with the direct projec-
cally advanced animals possess larger aggregates of tionsfromtheNBM,isresponsibleforthevastmajority
cells, leading to the postulation that these aggregates of cholinergic innervation to the cortex. In contrast to
mayformaphysiologicalsubstrateforthetypeofinfor- thecholinergiccellsoftheNBM,however,cellsofthe
mationprocessingcharacteristicofmoreadvancedspe- pedunculopontineandlaterodorsalnucleiacttoinhibit
cies.Withregardtotheirconnectivity,cholinergiccells gamma-aminobutyric acid (GABA) cell populations
oftheNBMhavebeenshowntoextendaxonsthatare withinthemediodorsalthalamus,whichinturnprovide
organized into discrete bundles and project to highly theprimarysourceofascendingthalamicinputtopre-
restricted telencephalic regions (Selden et al., 1998). frontal cortical regions (Sillito and Kemp, 1983). The
In spite of the restrictive nature of their connectivity, second pathway by which the cortex receives indirect
however, cholinergic cells in the NBM projecting to cholinergic input derives from a small population of
very different areas areoftenobserved adjacent toone cellsintheNBMthatprojecttothenucleusreticularis,
another, indicating that the activation of a relatively a thalamic region known to play an important role in
smallareaintheNBMhasthepotentialtoaffectawide the synchronization of cortical activity (Hallanger
target area in the cortex (Bigl et al., 1982). Moreover, etal.,1987;Leveyetal.,1987;Steriadeetal.,1987).
4 L.A. RABIN ET AL.
1.3.3. Indirect cholinergic regulation viathe basal appropriatestimuli.Theadministrationofantimuscarinic
ganglia drugssuchasatropineandscopolamineappearstocom-
pletely block responsiveness to stimuli, inducing slow
AlthoughthecholinergicprojectionsfromtheNBMand waveEEGactivitycharacteristicofthedrowsyandsleep
tegmentalnucleihavebeentheprimaryfocusofefforts states. Likewise, surgical depletion of ACh originating
tocharacterizecholinergicmodulationofactivityinthe fromtheNBMpreventscorticalneuronsinthevisualcor-
frontalcortex, increasingattentionisbeingfocused on texfromrespondingappropriatelytoexcitatoryinputs,an
the role of the basal ganglia. This interest has been effectthatisreadilyreversiblebythemicroionophoretic
fueled, at least inpart, bythe observation that patients application of ACh (Sato et al., 1987). Despite the fact
with AD undergo a selective loss of cholinergic inter- thatthelatterstudydescribestheresponsivenessofcells
neurons in the ventral striatum (Nagai et al., 1983; inthevisualcortex,themechanismsdescribedarelikely
Steriadeetal.,1984;Lehericyetal.,1989).Comprised toberelevanttoNBMmodulationofthefrontalcortical
oftheventralportionsofthecaudatenucleus,putamen, regionsaswell.
nucleus accumbens, and olfactorytubercle, the ventral SimilartothedirectprojectionsfromtheNBMtothe
striatumreceivesinputfromtheventraltegmentalarea neocortex, cholinergic projections thatexert their influ-
andprojectstotheinternalsegmentoftheglobuspalli- enceviaconnectionstothethalamustendtohaveasome-
dus,theventralpallidum,andsubstantianigraparsreti- what diffuse effect on frontal cortical activity. The
culata.Thesethreenucleiareresponsibleforinputtothe pedunculopontine and dorsolateral nuclei influence
medial dorsal and ventral anterior thalamic nuclei, activity in the cortex by inhibiting cell populations
whichinturnprovideinformationtotheanteriorcingu- withinthedorsomedialthalamus,a regionthatprovides
lateandorbitofrontalcorticalregions.Inadditiontothe innervationtotheentireprefrontalcortex.Asaresult,the
ventral striatum, the substantia nigra pars compacta pedunculopontineanddorsolateralnucleiareessentially
(SNc)alsohasbeenafocusofattentionwithregardto responsible for modulating the activity of all prefrontal
itsrelationshiptothecholinergicsystem.Dopaminergic cortical regions. Likewise, the nucleus reticularis plays
cells of the SNc receive cholinergic input originating animportantroleinprocessesthataresomewhatgeneral-
from the reticular formation,anarea involved inarou- ized.Althoughthisnucleuswasoriginallybelievedtobe
sal,andthesecellsprovideinputtoareasofthefrontal important in activation-related cortical desynchroniza-
cortex.AlthoughtheSNcisthoughttoplayanimportant tion,subsequentworkhasrevealedthatthisregiondoes
role in the regulation of movement, results of primate notprojectdirectlytothecortex.Thenucleusreticularis,
physiological experiments suggest that the activity of however,doesappeartoplayaroleinneocorticalrhyth-
many of these neurons may be related to the salience micsynchronization(Steriadeetal.,1984;1985;1987),
ofstimuliratherthantomovementperse.Thishypoth- a phenomenon that is suppressed by cholinergic input
esis has credence given that the SNc receives projec- originating from the NBM (Buzsaki et al., 1988). This
tions not only from the reticular formation but also observation implies that the cholinergic system plays a
from the amygdala, which is involved in motivation majorroleinneocorticalactivationnotonlyviathedirect
andemotion. activationoftheneocortex,butalsothroughitsinhibitory
effectontheRT-thalamocorticalsynchronizingsystem.
GiventheroleofAChinenhancingthecorticalresponse
1.4. Physiology
to stimuli, it seems logical that interference with choli-
1.4.1. Cholinergic regulation ofactivityin the nergicinputwouldhaveimportantconsequencesforpro-
frontalcortex cesses requiring experiential input. Indeed, available
evidenceindicatesthatcholinergicinputfromthebasal
The ascending cholinergic system originating in the forebrain is critically involved in activity-dependent
NBM is responsible for maintaining a desynchronized synaptic modifications in the visual, somatosensory,
pattern of cortical activity that is thought to enhance and auditory cortices (Gu, 2002). Likewise, for indivi-
neuronal responsiveness to stimuli. Consistent with duals withlesions tothe NBM, the inability to respond
thisassertion,singleunitrecordingstudieshavedemon- appropriately to stimuli also prevents the formation of
stratedthatundernormalconditions,increasedcholiner- stimulus–rewardassociations(Robertsetal.,1990).
gicactivityintheNBMcorrelateswithbothneocortical
desynchronization as well as behavioral activation 1.4.2. Cholinergicreceptors
(Buzsaki et al., 1988). Studies also have shown that
pharmacological interference with cholinergic activity, Acetylcholine exerts its effects via nicotinic and mus-
which presumably prevents cortical desynchronization, carinic receptor subtypes, each of which is associated
negatively impacts an animal’s ability to respond to withabroadspectrumofdownstreamevents.Through
CHOLINERGIC COMPONENTS OFFRONTAL LOBEFUNCTION AND DYSFUNCTION 5
these downstream events, ACh appears to facilitate contain either the a b subunits or the a subunit. The
4 2 7
ratherthaninitiatechangesinmembranepotential.Stu- a b receptors bind nicotine with very high affinity
4 2
dies using immunohistochemical techniques, in situ anddemonstraterelativelyslowratesofdesensitization
hybridization, and receptor binding assays have found (Fenster et al., 1997). The a receptors, on the other
7
that the frontal cortical regions express both the mus- hand, bind nicotine with a somewhat lower affinity,
carinic,andtoalesserextentnicotinic,subtypesofcho- are effectively blocked by a-bungarotoxin, exhibit
linergic receptor. Muscarinic receptors are slow rapid desensitization, and are highly permeable to
response time (100–250ms) G-protein coupled recep- Ca2þ(Couturieretal.,1990;Seguelaetal.,1993;Zhang
torsthatacteitherdirectlyonionchannelsorarelinked etal.,1994;CastroandAlbuquerque,1995).Boththea
7
to a second messenger system. At least five different andnon-a typenicotinicreceptorsmaybeeitherpresy-
7
subtypeshavebeendesignated(M -M ).Activationof napticallyorpostsynapticallylocated.Activationofthe
1 5
the M -like receptors (M , M , and M ) stimulates the presynapticreceptorsresultsinchangesinintracellular
1 1 3 5
phosphoinositol pathway, which results in the closing Ca2þconcentrations,which arethencapableofaffect-
of Kþ channels, opening of Ca2þ channels, and cell ing neurotransmitter release. In contrast, postsynaptic
depolarization (Caulfield and Birdsall, 1998; Lucas- receptorsarecapableofinducingafastcationicinward
Meunier et al., 2003). These receptors are generally current (Lucas-Meunier et al., 2003). Although there
post-synaptic, acting to facilitate cholinergic transmis- seemstobearelativelylowexpressionofa b receptors
4 2
sion.TheM subtypeofreceptors,whichareexpressed inneocortex,thea subtypeappearstobesignificantly
1 7
onlymodestlyintheperiphery,existingreatabundance expressedinanumberofareas thatinclude thefrontal
in the brain. They are found in all major neocortical regions (Geerts, 2005). Over the past few years,
areas, including frontal regions, and it is believed that researchershavebeguntoexplorethefunctionaldiffer-
the major effect of ACh in these areas, i.e., rendering ences between the a b and the a receptor subtypes.
4 2 7
cortical neurons more responsive to other excitatory Results of these efforts indicate that the a receptors
7
input, is mediated by the activation of M receptors arespecificallyvulnerabletoeffectsofabetapeptides.
1
(Coxet al.,1994).TheM receptorsalsoare observed Giventheputativeroleofa activationincellsurvival
3 7
inthebrain;however,theyareexpressedatarelatively (Geerts, 2005), this observation suggests a possible
lowlevelandextant studies have been unsuccessful at mechanism by which abeta may contribute to cell
assigning them a clear phenotype (Bymaster et al., degeneration.
2003).AlthoughtheM receptorshavebeenidentified Although various neurodegenerative conditions
5
in cerebral blood vessels, they represent only approxi- have been directly linked to cholinergic dysfunction
mately two percent of the muscarinic receptors in the within the frontal lobe, the relationship between these
brain, and they have not been observed in neocortical disorders and changes in cholinergic activity at the
regions (Elhusseiny et al., 1999; Phillips et al., 1997; receptor level has yet to be fully elucidated. Broadly
Yasuda et al., 1993). In contrast to activation of the speaking, pathological conditions associated with cho-
M -like receptors, activation of the M -like receptors linergicdysfunctiontendtobecharacterizedbysimilar
1 2
(M and M ) inhibits adenylate cyclase, causing the changes in receptor pharmacology. In patients with
2 4
inhibition of voltage-gated Ca2þ channels, and cell AD, PD, and DLB, no changes in antagonist binding
hyperpolarization (Egan and North, 1986). These of M receptors have been observed, indicating that
1
receptors are pre-synaptic autoreceptors that decrease the expression of the receptor protein is unchanged
cholinergic activity. Although not as abundant as the (Aubert et al., 1992). However, the ability of the M
1
M receptors, a significant level of M receptors receptortoformahighaffinityagonist-receptor-Gpro-
1 2
is expressed in the frontal cortex (Li et al., 1991). tein complex, and therefore its overall ability to bind
Knockout studies indicate that the release of ACh in ACh,maybecompromisedinpatientswithAD(Flynn
neocorticalareasismediatedprimarilybytheM auto- and Mash, 1993). This observation is significant as it
2
receptors(Zhangetal.,2002).M autoreceptors,onthe implies that therapeutic compounds targeting M
4 1
otherhand,appeartobeprimarilyinvolvedinmediating receptor activation should take into consideration
AChreleaseinthestriatum. alterations in affinity in order to restore normal func-
Nicotinicreceptorsarefastactingpentamericligand- tion.Withregardtothemuscarinicautoreceptors,sev-
gatedcationchannelsthatmaybecomposedofacombi- eral studies have identified an overall decrease in
nationofaandbsubunits,orasubunitsalone.Although antagonist binding and immunoreactivity of the M
2
othersubunitsexist,theyarenotexpressedbyneuronal receptor in AD and DLB patients (Flynn et al., 1995)
celltypes.Atleastnineasubunitsandthreebsubunits butan increase in these parameters with M receptors.
4
have been identified thus far (Martin-Ruiz et al., Given the decrease in cholinergic synaptic activity
2003).Thevastmajorityofneuronalnicotinicreceptors that results from depletion of the cholinergic cell
6 L.A. RABIN ET AL.
population,thedecreaseinthedensityofinhibitoryM patientsandfacilities,andmakingthetechnologymore
2
autoreceptors is notsurprising.Thesignificance ofthe widely available (Zhang et al., 2003). Initial results in
upregulation of the M receptors, however, remains primateandratstudieshaveshownencouragingcharac-
4
unclear.Severalstudiesemployingvariousantagonists teristics for a novel compound (N-[18F]fluoroethyl-4-
havereportedchangesinnicotinicreceptorpharmacol- piperidinyl acetate), suggesting its future utility as a
ogy as well. Specifically, these studies report a PET radiotracer for measuring brain AChE activity
decrease in the binding of presynaptic nicotinic recep- (Kikuchietal.,2005;Shaoetal.,2005).
tors in the frontal cortex of patients with AD, PD, and
DLB (Rinne et al., 1991; Perry et al., 1995; Court 1.5.2.Functionalimagingincognitivelyhealthyand
et al., 2000; Pimlott et al., 2004) that is likely due to compromisedhumans
adecreaseinthenumberofcellsexpressingtherecep-
tor(Schroderetal.,1991;1995).Atleastinthecaseof Researchers are using functional magnetic resonance
AD,thedecreaseinreceptordensitydoesnotappearto imaging (fMRI) and PET with increasing frequency to
beassociatedwithachangeinbindingaffinity(Aubert investigate the impact of pharmacologically induced
et al., 1992). neurochemicalchangesonhumanbrainnetworks.These
methods have elucidated the role of major neurotrans-
mitter systems in cognitive function and the effects of
1.5. Neuroimaging
neurotransmitter depletion or overexpression on brain
1.5.1. PET imaging ofAChE function and behavior (Honey and Bullmore, 2004;
Goekoopetal.,2006).Thecholinergicsystemhasbeen
Positron emission tomography (PET) can be used to a focus study due to its innervation of key cortical and
measure AChE activity in vivo by imaging the human subcortical regions involved in cognition, particularly
brain using 11C-labeled radiotracers such as N-[11C] memory processes, in addition to its association with
methyl-4-piperidinyl acetate (AMP or MP4A) and variousneurologicalconditions.Inmostcases,adminis-
N-[11C]methyl-4-piperidinyl propionate (PMP or tration of a drug or placebo occurs before participants
MP4P).TheseestersserveasAChEsubstratesandare undergo a cognitive task. A comparison between drug
hydrolyzed to a hydrophilic product that is unable to and placebo then reveals the drug’s action on task-
cross the blood–brain barrier, and which therefore relatedbrainactivity.Thesubsequentreviewofneuroi-
remains in the brain according to the distribution of magingresearchincludesafairlyheterogeneousbodyof
AChEenzymeactivity(Irieetal.,1994;Kikuchietal., work withregardto imagingmodality (PET vs. fMRI),
2005; Shao et al., 2005). Subsequently, a quantitative drug (cholinergic agonist vs. antagonist), dosing (acute
estimateofregionalAChEactivityisprovidedthrough vs. prolonged), participants (healthy vs. cognitively
kinetic analysis of this radioactivity trapping. Statisti- compromised), targeted memory systems or subpro-
callysignificantlocalizeddecreasesincorticalhydroly- cesses(explicitvs.implicit,encoding,retrieval,orwork-
sisrateof[11C]AMPor[11C]PMPcanbeobservedin ing memory), experimental design (within vs. between
certain clinical populations (i.e., AD, PD, DLB) (Iyo subjects)andtask(e.g.,blockedvs.event-related,visual
et al., 1997; Kuhl et al., 1999; Shinotoh et al., 1999; vs. verbal modality). Table 1.1 outlines human neuroi-
2003). Additionally, studies applying cross-sectional magingstudiesfocusedonthecholinergicsystemalong
and longitudinal designs with healthy individuals can with a summary of key findings. Studies chosen for
beusedtoinvestigatechangesinAChEactivityincorti- inclusionallcontainresultswithsignificantinvolvement
cal regions associated with the aging process (Namba offrontalbrainregions.
et al., 2002). [11C]PMP also has been used to quantify
AChE inhibitionandtodemonstrate theutilityofPET 1.5.3. Impact ofcholinergic manipulation on
radiotracersforAChEactivityinevaluatingtheefficacy learning incognitively healthysubjects
ofcholinergicdrugsandoptimizingdrugdosagesche-
dules (Kilbourn et al., 1999; Kuhl et al., 2000; Shao Research has demonstrated an attenuation of learning-
etal.,2005).Currentresearchisfocusedondeveloping related activity in healthy volunteers under scopola-
and assessing the utility of F-labeled PMP analogs, mine,apotentantagonistofmuscarinicM AChrecep-
2
which may permit longer imaging times, better image tors.Sperlingetal.(2002)examinedalterationsinbrain
quality, and allow the use of radiotracers with slower activation associated with scopolamine induced mem-
pharmacokinetics. Additionally, the longer half-life of oryimpairmentusingaface–nameassociativelearning
18F is convenient for long-time storage and transport, paradigm in the context of a repeated-measures design.
enablingpreparationofradiotracerbatchesformultiple Participantswerescannedonfourconsecutiveoccasions,
Table1.1
Humanpharmacologicalneuroimagingstudiesofthecholinergicsystem
Reference/drug/participants Studydesignandgoals Mainfindingsandconclusions C
H
O
Fureyetal.(2000b)/physostigmineor Investigatedtheeffectofphysostigmineoncognitionusinga Physostigmineincreasedactivationofextrastriatevisual L
I
placebo(saline)/healthy,young visualWMtaskforfacesthatalternatedwithsensorimotor cortexandinferiorfrontalregions,particularlyduringthe N
adults(n¼7). controlitems(blockdesign).Thestudyutilizedwasa early,stimulus-encodingphaseofeachtrial,withreduced ER
double-blind,placebo-controlled,cross-overdesignwith activationindorsalanteriorprefrontalcortex. G
I
twofMRIsessions—oneduringsteady-stateinfusionof Neurophysiologicaleffectswereassociatedwith C
C
physostigmineandtheotherwithsaline. performanceimprovements.EnhancementoftheACh O
systemmayincreaseperceptualprocessingoftask-relevant M
P
stimuli,reducingtheneedforprefrontalparticipation. O
Thieletal.(2001)/scopolamine*or Investigatedpharmacologicalmodulationofrepetition Relativetoplacebo,scopolamineattenuatedthebehavioral N
E
placebo/healthyadultsdrug(n¼12) primingusinganevent-related,between-groupsdesignwith expressionofpriming.Repetitionwasassociatedwitha N
placebo(n¼13). aword-stemcompletiontask(bothblockdesigns).The decreasedneuronalresponseinleftextrastriate,leftmiddle TS
*Additionalparticipantsreceivedlorazepam behavioralindexofprimingwasthenumberofstems frontal,andleftinferiorfrontalcorticesintheplacebo O
F
insteadofscopolamine. completedwithwordsfromapreviouslypresentedlist group.Scopolamineabolishedthe‘repetitionsuppression’
F
((cid:2)40minbetweenpresentationandscan).Participants effectsinthesebrainregions,providingevidencefor R
O
wererandomlyassignedtoplacebooracutescopolamine cholinergicmodulationofrepetitioneffects. N
treatment,received(cid:2)80minbeforethescan. T
A
Romboutsetal.(2002)/rivastigmineor Investigatedtheeffectofacuterivastigminetreatmenton Forthefaceencodingtask,increasesinbrainactivationduring L
placebo/olderadultswithmildAD. brainactivationinmildADduringfaceencodinganda treatmentoccurredinthefusiformgyrus,bilaterallywithno L
O
faceencodingtask(n¼7) visual2-backWMtask.Participantswerestudiedontwo decreases.Forthe2-backtask,signalincreaseswere B
2-backtask(n¼5ofthe7) occasions,withaseven-dayperiodinbetween.Halfwere observedintheleftmiddleandsuperiorfrontalgyriduring E
F
drug-freeatthefirstsessionandreceiveddrugthreehours simpleWM(1-backcondition),withnosignaldecreases; U
beforescanningforthesecondsession;theotherhalf bothincreasesanddecreasesoccurredwithincreasedWM N
C
receivedtreatmentinthereverseorder. loadinthefrontalcortexontreatment.Findingssuggested T
I
enhancedprocessinginthefrontalcortexduringWMinAD O
N
afterrivastigmine.
A
Parryetal.(2003)/rivastigmineor Investigatedtheeffectofrivastigmineondisease-associated Despitesimilartaskperformance,MSpatientsinitially N
placebo*/adultswithMS(n¼5)or brainactivationpatternsinMSpatientsandhealthy showedgreateractivationprimarilyinleftmiddlefrontal D
healthyadultcontrols(n¼4). controls,duringavisualcountingStrooptask(block gyrus/leftsuperiorfrontalsulcusandbilateralsuperior D
Y
*Initialdeterminationoftask-related design).Participantswerestudiedontwooccasionsand frontalgyurs.Controlsshowedgreateractivationinthe S
F
activationpatternsutilizedalarger receivedoralrivastigmineorplacebo(cid:2)150minbefore rightinferiorfrontalcortex.ForMSpatients,rivastigmine U
groupofparticipants(n¼21). scanninginapseudo-randomized,double-blinddesign. ledtonormalizationofabnormalpatternsofbrain NC
activation.Findingssuggestedthatthefunctionalchanges T
I
observedinMSpatientsaremodulatedbythecholinergic O
N
agonism.
(Continued)
7
8
Table1.1
(Continued)
Reference/drug/participants Studydesignandgoals Mainfindingsandconclusions
Sperlingetal.(2002)/scopolamineor Investigatedeffectsofscopolamineonencoding-related Resultsindicatedadecreaseintheextentandmagnitudeof
placebo*/healthy,youngadultmales activityinadouble-blindusingablockdesign,face-name activationininferiorprefrontalcortex,hippocampus,and
(n¼10). associativelearningtask.Participantswerescannedonfour fuisformgyruswithscopolamineascomparedtoplacebo.
*Participantsreceivedscopolamineduring separateoccasions(twoweeksapart);theyreceived Performancewasimpairedonpostscanmemorymeasures
onesessionandlorazepamduringanother placeboduringthefirsttwosessionsanddrugthereafter suggestingthatmedicationsthatimpairmemoryalso
(cross-overdesign). ((cid:2)60minpriortoscanning).Encoding-relatedbrain diminishactivationincriticalbrainregionssubserving
activitywasisolatedbycomparingface-nameassociation memoryprocesses.
learningwithvisualfixation.
Saykinetal.(2004)/donepezilorno Investigatedeffectsofdonepezilhydrochlorideoncognition Atbaseline,patientsshowedreducedactivationof
medication/olderadultswithMCI brainactivityinpatientswithMCIusingablockdesign frontoparietalregionsrelativetocontrols.After
(n¼9)healthyolderadultcontrols auditory2-backWMtask.Patientswerescannedbefore stabilizationondonepezil,patientsshowedincreased
(n¼9). initiatingdrugtreatmentandafterstabilization(approx frontalactivityrelativetounmedicatedcontrols,whichwas
L
11weeks);unmedicatedcontrolparticipantswerescanned positivelycorrelatedwithimprovementintask .A
atsimilartimeintervals. performance.Short-termtreatmentwithdonepezilappeared .
R
toenhanceactivityoffrontalcircuitryinMCIandthis A
B
increasewasrelatedtoimprovedcognition. I
N
Goekoopetal.(2004)/acute Investigatedcholinergicsystemreactivitytopharmacological Significantincreasesinbrainactivationfrombaselinewere
E
galantamineorprolonged challengewithgalantamineinMCIusingface-encoding observedafterprolongedexposure.Forfaceencoding, T
galantamineornomedication/older andvisual2-backWMtasks(blockdesign).Scansoccurred increasesoccurredinleftprefrontalareas,anterior A
L
adultswithMCI(n¼28). atbaselineandfollowingsingle-doseandprolonged cingulategyrus,leftoccipitalareas,andleftposterior .
exposure(5days)todrug.Baseline,acute,andprolonged hippocampus.ForWM,increasedactivationoccurredin
regimeswererandomizedacrossscanningsessions,and rightprecuneusandrightmiddlefrontalgyrus,coinciding
washoutperiodsseparatedacuteandprolongedregimes. withincreasedaccuracyaftertreatment.Cholinergic
treatmentproducedalterationsinbrainactivationpatterns
inMCIrelatedtoimprovedcognition.
Goekoopetal.(2006)/acute Investigateddifferentialresponsetocholinergicstimulation InMCI,acutegalantaminechallengeenhancedbrain
galantamineorprolonged withgalantamineinMCIandADusinganevent-related activationinareasinprefrontalandotherdistributed
galantamineornomedication/older face-recognitiontask.fMRIwasperformedatbaselineand corticalandsubcorticalregions.Prolongedexposure
adultswithMCI(n¼28) followingsingle-doseandprolongedexposure(5days)to decreasedactivationinsimilarfrontalandotherbrain
andAD(n¼18). galantamine.Baseline,acute,andprolongedregimeswere regions.InAD,acutegalantamineintakeincreasedbrain
randomizedacrossscanningsessions,andwashoutperiods activationinregionsotherthanfrontalcortex(mainly
separatedacuteandprolongedregimes. medialtemporal)andprolongedexposuredecreased
activationintheseareas.Findingsalsosuggesteda
preferentialtargetingofmemoryretrievalratherthan
encodingprocessesbygalantamine.
Grasby et al. (1995) /scopolamine or Repeated measures of regional rCBF were made during Behaviorally, scopolamine reduced the number of words
placebo (saline)/ healthy adult males. auditory verbal memory tasks (with alternating short vs. recalled from the long list. Neuronally, the drug attenuated
Drug ( n ¼ 6) or placebo ( n ¼ 6). long word lists). Memory-related brain activity involved a memory-related rCBF in bilateral prefrontal cortex
comparison of rCBF in the long vs. short condition. (predominantly middle frontal gyri) and right anterior
C
Participants underwent 6 scans, with no drug during scans cingulate, suggesting that the memory-impairing action H
O
1–2 and drug or saline (with tasks) during scans 3–6. may be due to disturbed activity in these frontal brain
L
regions. IN
Furey et al. (1997)/ physostigmine or Participants performed a visual WM task for faces. Memory- Physostigmine improved WM efficiency (as indicated by E
R
placebo (saline) /healthy adults. Drug related brain activity was measured by comparing rCBF faster RTs) and reduced task-related activity in anterior and G
( n ¼ 13) or Placebo (n ¼ 8). under task performance compared with a resting baseline. posterior regions of the right midfrontal gyrus. The IC
Participants underwent 10 scans, with saline administered magnitude of drug-induced RT change correlated with C
O
during scans 1–2 and drug or saline (with tasks) during rCBF reduction in a task-specific right prefrontal region. M
scans 3–10. Enhancement of cholinergic function may improve P
O
processing efficiency and reduce effort required to perform N
a WM task. E
N
Furey et al. (2000a)/ physostigmine or Participants performed a visual WM task for faces. Memory- Cholinergically induced improvements in WM were related to T
S
placebo (saline)/ healthy adults. Drug related brain activity was measured by comparing rCBF alterations in neural activity in multiple cortical regions.
O
( n ¼ 13) or placebo ( n ¼ 13). under task performance with a resting baseline. Used a data Increased activity occurred in regions associated with early F
F
set similar to that reported by Furey et al. (1997) (see perceptual processing (medical occipital visual cortex) R
above), with the additional goal of examining correlations while decreases occurred in regions associated with O
N
between physostigmine-related changes in rCBF in all brain attention, encoding, and memory maintenance (right frontal T
A
areas (not just right prefrontal cortex) and changes in RT. cortex, left temporal cortex, anterior cingulate, and left
L
hippocampus). Cholinergic potentiation may improve L
cognition by enhancing perceptual processing in early O
B
visual areas or by improving signal-to-noise in memory E
processing at different sites (i.e., making relevant stimuli F
U
moresalientbyreducingbackgroundnoise). N
C
T
Note: rCBF ¼ regional cerebral blood flow; AD ¼ Alzheimer’s disease; fMRI ¼ functional magnetic resonance imaging; MCI ¼ mild cognitive impairment; MS ¼ multiple sclerosis; RT ¼ reaction IO
time; WM ¼ working memory. Studies included both male and female participants unless otherwise noted. With the exception of Goekoop et al. (2004, 2006) and Rombouts et al. (2002), participants in N
A
allstudieswerenotedtoberight-handed.
N
D
D
Y
S
F
U
N
C
T
I
O
N
9
10 L.A. RABIN ET AL.
with a two-week interval between sessions. Results recruitment of prefrontal cortical tissue due to more
revealed decreases in extent and magnitude of activa- efficientprocessingelsewhere.1
tionininferiorprefrontalcortex,hippocampus,andfusi- Overall,thebodyofcholinergicimagingworkutiliz-
formgyruswithscopolaminerelativetoplaceboduring inglearningandmemoryparadigmswithhealthyindivi-
encoding as compared to visual fixation. Activation duals reveals several notable findings. First, across
within all regions of interest was consistent across the experiments,cholinergicmodulationoccurredinfrontal
two placebo scans during encoding. Additionally, per- areastypicallyactivatedinlearningandmemorypara-
formancewasimpairedonpost-scanmemorymeasures digms,suggestingthatmemoryimpairingorpromoting
suggesting that medications that impair memory also effectsofcholinergicdrugsmaybelinkedtomodulation
diminishactivation incriticalbrainregionssubserving offrontalcorticalactivity.Theexactmechanismofsuch
memory. Other researchers have identified activity modulation, however, is not readily apparent because
reductionsinfrontalbrainregionsduringbothimplicit reduced activity was observed with both cholinergic
(repetitionpriming)andexplicit(wordrecall)memory blockade and stimulation. Further work is required to
paradigmswithscopolamine(Grasbyetal.,1995;Thiel clarify and extend current findings. Results also sug-
etal.,2001).Takentogether,thesefindingssuggestthat gestedthatcholinergicneurotransmissionismodulated
intact cholinergic neurotransmission in frontal brain byactivityinregions involvedinprocessing taskrele-
regionsmaybecrucialforsuccessfulfunctioningacross vantstimuli(e.g.,fusiformcortex,extrastriateregions,
memoryprocesses. auditorycortex),suggestingacholinergicroleinstimu-
Researchalsohasinvestigatedthecerebralcorrelates lus processing and attentional function (Rosier et al.,
ofimprovedstimulusprocessinginhealthy participants 1999; Furey et al., 2000a; Sperling et al., 2002; Thiel
usingaclassofdrugknownasacetylcholinesteraseinhi- etal.,2002). Furtherresearchwillberequiredtodeter-
bitors (AChEIs), which serve to enhance synaptic con- mine whether these extrastriate effects contribute to
centrations of ACh. Furey et al. (1997) examined cholinergic modulation of frontal activity or whether
changes in regional cerebral blood flow (rCBF) and frontalcorticalactivationsareindependentofextrastri-
behavioral performance associated with cholinergic sti- atedrugeffects.2Experimentaldesignsthatdonotcon-
mulation during a working memory (WM) task for foundlearningandstimulusprocessingwillberequired.
faces. Experimental participants received a saline infu-
sionforthefirst2of10PETscans,followedbyacon-
1Physostigmine may improve behavioral performance by
tinuous infusion of physostigmine; control participants
increasing visual attention mediated by cholinergic projec-
receivedsaline.Resultsindicatedthatthedrugimproved tionsfrom NBM towidespread corticalregions.This would
WM efficiency (as indicated by faster reaction times, account for the observed correlation between RT reductions
RTs) and reduced WM task-related activity in anterior and rCBF increases in medial occipital visual cortex, and is
and posterior regions of the right midfrontal gyrus, consistent with work suggesting that cholinergic enhance-
a region associated with WM. The magnitude of this ment facilitates visual attention by increasing activity in
RT change correlated with right midfrontal rCBF. extrastriate cortex (Furey et al., 2000a; Bentley et al.,
2004). Another possibility is that the drug exerts a more
Reduction in prefrontal rCBF was interpreted as
directeffectonWMcircuitryviatheseptohippocampalcho-
enhancedefficiencyofWMprocessesondrug(i.e.,less
linergicsystembyfacilitatingtheinhibitoryeffectofAChon
effortrequiredtoperformthetaskledtoareducedneed
the hippocampus. As septal cholinergic fibers projecting to
torecruitprefrontalcortex).InasubsequentfMRIstudy,
thehippocampusareinhibitory,physostigminemaydecrease
Furey et al. (2000b) investigated effects of physostig-
neuronal activity in this region while enhancing signal (i.e.,
mine,againusingaWMtaskforfacesinadouble-blind, improving signal-to-noise ratio and making relevant stimuli
placebo-controlled,cross-overdesign.Resultsindicated more salient). This would account for the observed relation
that physostigmine increased activation of extrastriate between RT reductions and rCBF reductions in the hippo-
visual cortex and inferior frontal regions, particularly campus(Fureyetal.,2000a).
during the early, stimulus-encoding phase of each trial, 2SeeThiel(2003)foradditionalstudiesrelatedtomodulation
withreducedactivationindorsalanteriorprefrontalcor- of learning and memory in cognitively intact humans. Of
note,Bentleyetal.(2003a;2003b)usedfMRItoinvestigate
tex. These neurophysiological effects again were asso-
cholinergic modulation of responses to emotional stimuli,
ciated with performance improvements. Enhancement
with the goal of mapping inputs to the frontoparietal cortex
of the ACh system was interpreted as augmenting per-
thatinfluenceallocationofattentiontoandprimingofemo-
ceptualprocessingoftask-relevantstimuliduringencod-
tional information. Additionally, Ernst et al. (2001) used
ing, resulting in reduced processing demands for
PET to study effects of nicotine gum (which binds exclu-
‘executive’ anterior prefrontal regions. Together these sively to nicotinic receptors) on differences in cholinergic
and other findings (e.g., Furey et al., 2000a) suggest modulation of memory-related brain activity in smokers vs.
that cholinergic enhancement of WM serves to reduce non-smokers.