Movatterモバイル変換

[0]ホーム
URL:

Skip to main content
NCBI home page
Search in PMCSearch
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.
Learn more:PMC Disclaimer | PMC Copyright Notice
NIHPA Author Manuscripts logo
. Author manuscript; available in PMC: 2021 Jul 1.

Contingency awareness, aging, and the parietal lobe

Dominic T Chenga,b,*,Alyssa M Katzenelsona,Monica L Faulknera,John F Disterhoftc,John M Powerd,John E Desmonda
aDepartment of Neurology, Johns Hopkins University School ofMedicine, Baltimore, MD, USA
bDepartment of Psychology, Auburn University, Auburn, AL,USA
cDepartment of Physiology, Northwestern University FeinbergSchool of Medicine, Chicago, IL, USA
dDepartment of Physiology, University of New South Wales,Sydney, NSW, Australia

CRediT authorship contribution statement

Dominic T. Cheng: Conceptualization, Methodology, Formalanalysis, Investigation, Writing - original draft, Project administration,Funding acquisition.Alyssa M. Katzenelson: Investigation,Writing - review & editing.Monica L. Faulkner:Investigation, Writing - review & editing.John F.Disterhoft: Writing - review & editing, Supervision.John M. Power: Software, Writing - review & editing.John E. Desmond: Conceptualization, Methodology, Software,Formal analysis, Writing - original draft, Supervision, Projectadministration, Funding acquisition.

*

Corresponding author at: Department of Psychology,Auburn University, 226 Thach Hall, Auburn, AL 36849, USA. Tel.: 334-844-6489;fax: 344-844-4447.dominic.cheng@gmail.com (D.T.Cheng).

Issue date 2020 Jul.

PMCID: PMC7953809  NIHMSID: NIHMS1574216  PMID:32241582
The publisher's version of this article is available atNeurobiol Aging

Abstract

Contingency awareness is thought to rely on an intact medial temporallobe and also appears to be a function of age, as older subjects tend to be lessaware. The current investigation used functional magnetic resonance imaging,transcranial direct current stimulation, and eyeblink classical conditioning tostudy brain processes related to contingency awareness as a function of age.Older adults were significantly less aware of the relationship between thetone-airpuff pairings than younger adults. Greater right parietal functionalmagnetic resonance imaging activation was associated with higher levels ofcontingency awareness for younger and older subjects. Cathodal transcranialdirect current stimulation over the right parietal lobe led to lower levels ofawareness in younger subjects without disrupting conditioned responses. Olderadults exhibited hyperactivations in the parietal and medial temporal lobes,despite showing no conditioning deficits. These findings strongly support theidea that the parietal cortex serves as a substrate for contingency awarenessand that age-related disruption of this region is sufficient to impairawareness, which may be a manifestation of some form of naturally occurringage-related neglect.

Keywords: Classical conditioning, Consciousness, fMRI, Memory, tDCS

1. Introduction

Conscious awareness has been extensively discussed by scholars ranging fromphilosophers to scientists. Modern neuroscience continues to address the biologicalnature of human awareness, but the neuroanatomy supporting general awareness can bedifficult to identify because awareness itself is a broad construct and consists ofmultiple psychological processes. However, one form of awareness, contingencyawareness, specifically refers to the explicit knowledge of the temporalrelationship between 2 events (Lovibond and Shanks,2002).

One simple and elegant paradigm that has been used to investigate contingencyawareness is classical conditioning. It is a well-characterized model system, inwhich a neutral conditioned stimulus (CS) and a biologically meaningfulunconditioned stimulus (US) are temporally paired and has highly predictablebehavioral outcomes. After multiple paired CS–US presentations, the CS aloneelicits a conditioned response (CR) in anticipation of the US, indiacating that anassociation between the CS and US has been formed.Delay and trace conditioning are 2different procedures that vary in timing. In delay conditioning, the CS and UScoterminate, whereas in trace conditioning, a stimulus-free period (called the traceinterval) elapses between offset of the CS and onset of the US. Interestingly, thisminor manipulation has strong implications on what neural mechanisms are recruited.Human functional magnetic resonance imaging (fMRI) studies have shown thatsuccessful trace conditioning uniquely engages supplementary neural structures suchas the medial temporal lobes (MTLs), hippocampus, parietal lobe, and middle frontalgyrus (Buchel et al., 1999;Cheng et al., 2008;Haritha et al., 2013;Knight et al.,2004).

One form of classical conditioning, eyeblink classical conditioning, is oneof the most studied forms of mammalian learning, and consequently, the neurosciencecommunity largely agrees that the cerebellum is critically important (Christian and Thompson, 2003). However, thereis less agreement on the role of contingency awareness during human eyeblinkconditioning as it has been extensively debated (LaBar and Disterhoft, 1998;Lovibond andShanks, 2002;Manns et al., 2002).Clark and Squire (1998) argued that thehippocampus and awareness are necessary for trace conditioning, as temporal lobeamnesics, who could not accurately and explicitly report CS-US relationships, wereimpaired at trace but not delay conditioning. In addition, only healthy subjectsclassified as aware were able to demonstrate trace conditioning, whereas both awareand unaware subjects were capable of showing intact delay conditioning. This generalclaim that trace, but not delay, conditioning requires contingency awareness hasbeen supported by subsequent studies using several variants of these procedures(Manns et al., 2001,2000a,b,2002;Smith etal., 2005).

Others have reported contradictory findings and argued that awareness isnecessary for both trace and delay conditioning. Lovibond et al have publishedseveral studies that used the same methodology asClark and Squire (1998) (Lovibond etal., 2011), masking procedures (Weidemannet al., 2013), the Perruchet effect (Weidemann and Lovibond, 2016), and verbal instructions (Weidemann et al., 2016) to manipulate awareness and allconclude that awareness was needed for both trace and delay conditioning.Furthermore, in a series of experiments examining the effects of aging and awarenesson eyeblink conditioning,Knuttinen et al.(2001) andBellebaum and Daum(2004) support the claim that awareness plays an important role for delayconditioning. Functional MRI studies using fear conditioning as a model showed thatawareness of the CS-US relationship is associated with activations in thehippocampus, parahippocampus, middle frontal gyrus, and ventral striatum (Baeuchl et al., 2019;Cacciaglia et al., 2015;Carter et al., 2006;Klucken et al.,2009;Knight et al., 2009;Tabbert et al., 2006,2011).

The debate over the role of awareness during classical conditioning may berelated to why some subjects fail to achieve contingency awareness. There may beseveral reasons for why contingency awareness eluded some older subjects. Onepossible explanation is that the ability to form accurate judgments for temporalrelationships between 2 stimuli worsens as one ages (Bedard and Barnett-Cowan, 2016;Poliakoff et al., 2006). Importantly, this impairment was not due to ageneral sensory processing deficit as older adults performed comparably to youngeradults during short time intervals (70 ms) (Setti etal., 2011). Another factor potentially contributing to a lack ofawareness is that bottom-up forms of spatial attention necessary for consciousperception/awareness rely on fronto-parietal networks, which have been shown to bedamaged in older populations (Chica and Bartolomeo,2012;Hoffman and Morcom, 2018).Furthermore, it is also possible the CS and US are superficially processed and tosome degree, neglected, and hence, this information fails to reach consciousness.Contingency awareness also appears to be a function of age, as older subjects tendto be less aware (Knuttinen et al., 2001) andhave poorer trace conditioning relative to younger subjects (Finkbiner and Woodruff-Pak, 1991). To date, no fMRIstudies have addressed the interaction between aging and contingency awareness usingeyeblink conditioning as a model system. In 2 separate studies, we used fMRI andtranscranial direct current stimulation (tDCS) to examine key brain structures,including the parietal lobe, a crucial area in neglect patients (Donaldson et al., 2015;Vuilleumier, 2013), as they relate to awareness in older and youngeradults. If a lack of contingency awareness is partially mediated by neglect of theCS and US, greater parietal activation should be measured in those who were awarerelative to unaware subjects. Because both awareness and the hippocampus aretypically relied on during trace, but not delay conditioning, we predict that MTLactivation would be greater for subjects who were aware relative to unawaresubjects. Furthermore, because older subjects tend to demonstrate poorer awarenessand trace conditioning in comparison to younger subjects, we predict that oldersubjects would be less aware than younger subjects and awareness would be correlatedwith levels of trace, but not delay conditioning. Our results provide partialsupport for these predictions and reveal that the neural substrates of CS-UScontingency awareness likely involve the parietal region.

2. Materials and methods

2.1. Subjects

Subjects were recruited from the greater Baltimore area through theinternet (Craigslist), flyers, and local TV advertisements. 49 healthy,right-handed volunteers (19 males) participated in the fMRI study: 28 youngeradults (24.6 ± 0.6 years) and 21 older adults (63.7 ± 0.8 years).16 healthy, right-handed volunteers (5 males; 24.3 ± 0.7 years)participated in the tDCS study. Selection was based on the following exclusioncriteria: (1) disturbed consciousness; (2) other neurological or systemicdisorders that can cause dementia or cognitive dysfunction; (3) prior history ofa major psychiatric disorder; (4) history of definite stroke; (5) focal lesionon MRI examination; (6) use of anxiolytic, antidepressant, neuroleptic, orsedative medication. General cognitive abilities were assessed with theMini-Mental State Examination (Folstein et al.,1975); a simple reaction time task; the Alzheimer’s DiseaseAssessment Scale (ADAS: Recall and Recognition) (Rosen et al., 1984); subtests of the Wechsler Adult IntelligenceScale–III (Matrix Reasoning, Digit Span, Digit Symbol, and Vocabulary)(Wechsler, 1987); and the NationalAdult Reading Test (Nelson, 1982). Scoresfrom the Wechsler Adult Intelligence Scale–III were age-adjusted for eachparticipant’s age. Each subject received an audiogram at 3 frequencies(500, 1000, and 1500 Hz) in each ear to determine their minimum auditorythreshold. All subjects were compensated $20/h, and all procedures were approvedby the institutional review boards for human subject research at the JohnsHopkins University School of Medicine.

2.2. Magnetic resonance imaging

Whole-brain imaging was performed on a Philips 3-tesla MRI scanner.Functional images were collected using a T2*-weighted gradient echo planarimaging pulse sequence. 6-mm axial slices (TR, 1000 ms; TE, 30 ms; FOV, 24 cm;flip angle, 61°) were collected in a series of 1090 sequential images.Structural images were collected using a T1-weighted magnetization-preparedrapid acquisition gradient echo pulse sequence.

2.3. Transcranial direct current stimulation

tDCS (2 mA) was delivered with 0.9% saline-soaked sponges (25cm2) over the right parietal lobe on the participant’sscalp with the reference electrode on the left mandible. Cathodal stimulationlasted 20 minutes and sham stimulation lasted 30 seconds. Localization was basedon peak activation coordinates (x, y, z) in the fMRI study. Scalp location overthis coordinate was determined on one participant whose structural MRI wascoregistered to head land-marks using Brainsight (Rogue Industries, Canada). Fornormalization purposes, this location was defined as a percentage of theanterior-posterior (nasion to inion) and left-right (preauricular points) axes.The normalized scalp location (39.5% of the distance between the nasion-inion asmeasured from the inion and 22.6% of the distance between the left-rightpreauricular points as measured from the right preauricular point) was thenapplied to individual subjects.

2.4. Eyeblink conditioning

A laptop computer interfaced to DT9834 data acquisition module (DataTranslations) running custom software developed under LabView version 7.1(National Instruments) was used for presenting stimuli (tones and airpuffs) andrecording eyeblinks. Auditory stimuli were delivered with MRI-compatiblepneumatic head-phones (MRA, Inc). Custom modifications to standard laboratorysafety glasses accommodated the end of a polyethylene tube for airpuff deliveryand an MRI-compatible infrared sensor for recording eyeblinks (Cheng et al., 2008). A fiber-optic probe (RoMack,Inc) measured the reflectance of infrared light from the left eye (Miller et al., 2005), and airpuff deliverywas controlled by a solenoid valve (Asco).

2.5. Stimuli

A 1000-Hz tone served as the delay and trace CS. The delay CS lasted1350 ms and coterminated with a 100 ms left corneal airpuff (5 psi). The traceCS lasted 250 ms and was followed by a 1000 ms trace period (stimulus free)before airpuff presentation (Fig. 1A). Forthe MRI study, 120 delay or trace CS-US presentations were delivered with anaverage intertrial interval of 18 seconds (range of 15–21 seconds). Forthe tDCS study, 30 delay CS-US presentations were delivered with an averageintertrial interval of 18 seconds (range of 15–21 seconds). CS and USwere paired at 100% for both studies.

Fig. 1.

Fig. 1.

Experimental design and behavioral data. (A) Participants receivedeither delay CSs (coterminates with the US) or trace CSs (stimulus-free periodbetween CS offset and US onset). Dotted lines indicate the time window (500 ms)in which eyeblinks were considered conditioned responses. (B) Learning duringthe early stages of the experiment. (C) No significant differences in overallconditioning levels (120 trials) were measured between the 4 groups ofparticipants. (D) The left panel shows that older adults were less likely to beaware of the CS-US relationship as compared with younger adults. The right panelshows that older adults scored significantly lower than younger adults on theirpostexperimental questionnaire. Abbreviations: CR, conditioned response; CS,conditioned stimulus; US, unconditioned stimulus.

2.6. Procedures

2.6.1. MRI study

Subjects were randomly assigned to receive delay or traceconditioning trials. They were informed that this study investigated theeffects of distracting tones and airpuffs have on their ability to rememberdetails about a silent movie (Charlie Chaplin’sThe GoldRush). They were told that their movie knowledge would betested after the experiment. After being fitted with the safety glasses,they were placed in the magnet with instructions to watch and pay attentionto the movie while distracting tones and airpuffs were presented. Afterconditioning, a movie quiz and postexperimental questionnaire assessingawareness of the CS-US contingencies were administered (seeAppendix 1).

2.6.2. tDCS study

Subjects were randomly assigned to receive cathodal or shamstimulation. They were informed that this study investigated the effects ofbrain stimulation, distracting tones, and airpuffs have on their ability toremember details about the silent movie. A line bisection test wasadministered before stimulation. Once scalp localization was determined oneach participant, sponges and safety glasses were applied. Stimulation begansimultaneously with the start of the movie and conditioning. Afterstimulation, a movie quiz, postexperimental questionnaire assessingawareness of the CS-US contingencies (seeAppendix 1), and a second-linebisection test was administered.

2.7. Analyses

2.7.1. Behavioral data

CRs were defined using the following criteria: the differencebetween the maximum and minimum responses in a 500 ms pre-US time windowmust exceed 4 times the standard deviation of the mean of the baselineperiod (250 ms pre-CS presentation). The 500 ms pre-US time window wasselected to minimize the inclusion of voluntary and alpha responses as CRs(Spence and Ross, 1959).Performance was expressed as %CR and examined in an age (younger and older)by trial type (delay and trace) analysis of variance (ANOVA). To evaluateearly learning, the frequency at which subjects produced a CR during thefirst 4 trials was evaluated using a nonparametric Cochran’s Qtest.

2.7.2. Awareness data

A postexperimental questionnaire consisting of 7 true/falsestatements (Manns et al., 2000a) wasgiven to subjects to probe their awareness of the CS-US relationship.Subjects were classified as aware if they answered 6 or more questionscorrectly and unaware if they answered fewer than 6 questions correctly.This threshold was based on the probability of obtaining 6 correct responsesof 7 from a binomial distribution that is set top = 0.05.Chi-square analyses were performed on awareness level (aware or unaware) inyounger and older subjects.

2.7.3. Imaging data

Statistical Parametric Mapping (SPM2 and SPM8) software (WellcomeDepartment of Cognitive Neurology, London, UK) was used to performstructural and functional imaging preprocessing and statistical analyses.Preprocessing included motion correction, slice timing correction,structural data coregistration, normalization, and smoothing. Echo planarimaging functional images were realigned and resliced correcting for minormotion artifacts, and structural images were coregistered to the meanmotion-corrected functional image for each participant. Functional andstructural images were transformed into standard stereotaxic space (2× 2 × 2) according to the Montreal Neurological Instituteprotocol, and the functional images were smoothed with a Gaussian filter(full-width half-maximum 5 mm). Cerebellar data were treated separately byisolation and normalization (1 × 1 × 1) into standardstereotaxic space using the spatially unbiased atlas template of the humancerebellum and brainstem (Diedrichsen,2006). First-level analyses adopted an event-related approach inwhich the general linear model was used to estimate individual subjectactivations based on all 120 trials. Reference waveforms were created basedon CS onset times and were convolved with individually estimated hemodynamicresponse functions to account for aging effects on the hemodynamic response.These hemodynamic response functions were generated using a standard fingertapping task.

In a whole brain, voxel-wise analysis, between-group contrasts wereperformed to assess the effects of conditioning (delay and trace), awareness(aware vs. unaware), and aging (older vs. younger) (Tables 2–4). Additional whole-brain, voxel-wise analyses includedcontrasts between aware and unaware participants and regression analysesusing individual awareness scores as predictors of interest. Second,structural regions of interest (ROI) analyses based on probabilistic maps ofMTL structures (Amunts et al., 2005)and a priori ROI analyses using parietal lobe coordinates that overlapped inlesions in neglect patients (Mort et al.,2003) were performed. These coordinates served as the center of a3D sphere (10 mm radius) that was created to individually sample theparietal region most affected in neglect patients. For voxelwise analyses, ap < 0.001 significant threshold with a minimumcluster threshold of 10 voxels was set. For each ROI analysis, mean betavalues were extracted from individual participants so that statisticalanalyses could be performed using SPSS software. Finally, a correlationanalysis between participant’s awareness scores and their parietalactivity was performed.

Table 2.

Significant BOLD changes related to delay and trace conditioning

Brain structure (neocortex,p < 0.00001)xyzSPM{Z}Voxels
L Superiortemporal gyrus (BA 41, 22)−55−20585135
R Superior temporal gyrus (BA 13, 41, 22)54−27685976
 R insula (BA 13)38−2648
L precentral gyrus (BA 6)−39−11404.8110
R precentral gyrus (BA 4)41−15415.6232
R postcentral gyrus (BA 2)32−22335.544
R cingulate gyrus (BA 24)27325.7773
 R medial frontal gyrus (BA 6)23505.4
R insula (BA 13)312076.2354
L insula (BA 13)−322166.3332
R lingual gyrus (BA 18)19−5636.21853
 L lingual gyrus (BA 18)−11−6956.1
 R thalamus8−26−35.7
 R cuneus (BA 18)13−77225.9
 L posterior cingulate (BA 30)−20−6675.7
Brainstructure (cerebellum,p < 0.001)xyzSPM{Z}Voxels
L cerebellum(lobule HVI)−34−56−323.211
L cerebellum (lobule HVIII)−28−66−524.367
L cerebellum (lobule HVI)−26−62−263.419
L cerebellum (lobule HVIII)−18−68−403.314
R cerebellum (lobule HVI)8−68−20457
R cerebellum (lobule HVIII)20−70−543.969

MNI (cerebellar) and Talairach (noncerebellar) coordinates ofactivation maxima (Schmahmann et al.,2000;Talairach and Tournoux,1988) as a function of delay and trace trials.

Key: BOLD, blood oxygenation level dependent; MNI, MontrealNeurological Institute.

Table 4.

Significant BOLD differences between older and younger adults

Older > younger
Brain structure(neocortex,p < 0.001)xyzSPM{Z}Voxels
L superiortemporal gyrus (BA 38)−2820−304.473
L precuneus (BA 7)−13−64303.525
L cingulate gyrus (BA 23)1−1724430
R cingulate gyrus (BA 24)44253.633
R parahippocampal gyrus (BA 35)16−25−93.329
R parahippocampal gyrus (BA 34)16−6−163.849
R middle frontal gyrus (BA 9)3240363.520
R middle frontal gyrus (BA 46)4033133.8104
R superior parietal lobule (BA 7)43−61503.637
R superior temporal gyrus (BA 38)426−203.621
R middle temporal gyrus (BA 21)62−21−93.9118
Younger > older
Brain structure (neocortex,p< 0.001)xyzSPM{Z}Voxels
None

Talairach coordinates of activation maxima (Talairach and Tournoux, 1988) as a function ofage.

Key: BOLD, blood oxygenation level dependent; EBC, eyeblinkclassical conditioning.

3. Results

3.1. Behavioral results

To investigate awareness and possible instances of neglect duringeyeblink classical conditioning, younger and older adults were randomly assignedto receive delay or trace conditioning during fMRI (Fig. 1A). Subject breakdown was 14 younger delay (24.4± 0.9 years), 14 younger trace (24.9 ± 0.8 years), 11 older delay(64.6 ± 0.8 years), and 10 older trace (62.7 ± 0.9 years).Eyeblinks were considered CRs if they occurred 500 ms before presentation of thecorneal airpuff to exclude alpha, voluntary responses (Spence and Ross, 1959). Postexperimentalquestionnaires were administered after training, and each subject was labeledaware or unaware based on their answers.

Significant age-related differences in cognitive testing were seen inADAS Recall (younger: 2.07 ± 0.29, older: 3.05 ± 0.27) MatrixReasoning (younger: 13.32 ± 0.49, older: 11.43 ± 0.79), DigitSymbol (younger: 12.25 ± 0.69, older: 9.60 ± 0.77), and NationalAdult Reading Test (younger: 32.54 ± 1.11, older: 38.15 ± 1.63)(allp’s < 0.05). No significant changes wereseen in Mini-Mental State Examination, reaction time, Digit Span, and Vocabulary(allp’s > 0.05). A trend (p =0.051) was detected for ADAS recognition (younger: 0.82 ± 0.17, older1.55 ± 0.35). SeeTable 1.

Table 1.

Cognitive testing results for younger and older adults

Cognitive testingYounger (n = 28)Older (n = 21)t
Mini-Mental State Exam (MMSE)29.36 (0.14)29.43 (0.16)0.34
Reaction time281.19 (4.78)292.66 (6.68)1.44
Alzheimer’s Disease Assessment
 Scale (ADAS)
 Recall2.07 (0.29)3.05 (0.27)2.38a
 Recognition0.82 (0.17)1.55 (0.35)2.00
Wechsler Adult Intelligence
 Scale-III (WAIS-III)
 Matrix Reasoning13.32 (0.49)11.43 (0.79)2.14a
 Digit Span11.14 (0.46)12.00 (0.67)1.09
 Digit Symbol12.25 (0.69)9.60 (0.77)2.51a
 Vocabulary12.81 (0.48)12.48 (0.36)0.52
National Adult Reading Test (NART)32.54 (1.11)38.15 (1.63)2.92a
a

p < 0.05 Values are mean (SEM).

A Cochran’s Q test indicated a significant difference between thenumber of subjects producing a CR during early trials (trials 1–4)(χ2 (3, N = 49) = 4.98,p = 0.046).Pairwise comparisons showed that significantly more subjects produced a CR ontrials 2, 3, and 4 relative to trial 1 (p ≤ 0.05) (Fig. 1B). However, when we assessed CRincidence (%CRs) on overall conditioning levels (120 trials), there were nosignificant main effects of age (F(1,41) = 0.418,p= 0.52), trial type (F(1,41) = 0.008,p = 0.93), and awareness (F(1,41) = 0.018,p = 0.90), or interactions (allp’s> 0.70) (Fig. 1C). A signicantassociation between age and awareness was calculated, χ2 (1, N= 49) 4.98,p < 0.05. Despite comparable CR production,older adults were less likely to be classified as aware as younger adults (leftFig. 1D). Consistent with thisclassification measure, older adults also scored significantly(t(47) = 2.36,p = 0.02) lower thanyounger adults when raw awareness scores were compared (rightFig. 1D). Average auditory CS thresholds,unconditioned responses amplitudes, and number of correctly answered moviequestions were compared and showed no significant differences between age groups(allp’s > 0.05). The behavioral difference inawareness scores guided subsequent imaging analyses.

3.2. Imaging results

3.2.1. Voxelwise analyses

3.2.1.1. Conditioning effects.

Conditioning effects, defined as significant whole-brainactivations as a function of both delay and trace conditioning trialpresentations, are summarized inTable2. Large clusters of activation found in bilateral superiortemporal gyri/auditory cortices (left: −55, −20, 5; right:54, −27, 6) indicate that these regions play a role in processingthe delay or trace tone CS, whereas greater activation in the rightpostcentral gyrus (32, −22, 33) may represent sensory informationfrom the corneal airpuff as the left eye was trained. Greater activationin the bilateral precentral gyri (left: −39, −11, 40;right: 41, −15, 41) suggests these regions may reflect bilateralmotor eyeblink responses (Campolattaroand Freeman, 2009), but we did not measure responses from theuntrained eye in the present study. Finally, significant activations inthe cerebellum, including key regions for eyeblink conditioning, such asleft lobule VI (2 clusters in the left hemisphere: −26,−62, −26; −34, −56, −32) was measuredduring the 2 trial types, further supporting the position that thisstructure is important for eyeblink conditioning.

Comparisons between delay and trace conditioning trials showedgreater delay-related activity in the bilateral superior temporal gyri(left: −38, −30, 6, 512 voxels; right: 38, −29, 8,331 voxels) and left claustrum (−34, −14,11, 19 voxels) inall subjects. No significant trace-related activations wereobserved.

3.2.1.2. Awareness effects.

Table 3 lists significantregions of activation after between-group comparisons of awareness(aware vs. unaware). Subjects classified as aware showed greateractivation in the right parietal lobe (48, −46, 35) relative tosubjects classified as unaware (Table3 andFig. 2A). Thisawareness effect did not seem to be affected by age as older aware andyounger aware subjects also showed greater right parietal activity(older: 48, −44, 33; younger: 47, −46, 35) relative toolder unaware and younger unaware subjects. Additional independentanalyses included regression models that used individual awarenessscores as covariates and showed that greater awareness of the CS-USrelationship predicted greater right parietal activity in all subjects(Fig. 2B), further suggestingthat neural processing in this region supported greater awareness of thestimulus contingencies. Correlation analyses between individualawareness scores and parietal activity showed a significant positiverelationship (r = +0.38,p = 0.007)(Fig. 2C).Fig. 2 further divides aware and unawareparticipants based on their age (older vs. younger), and one limitationof doing so is that it resulted in a reduction in sample sizes, leadingto a decrease in power, and so these data should be interpreted withthis consideration.

Table 3.

Significant BOLD differences between aware and unaware subjects

Aware > unaware (allsubjects)Aware < unaware (allsubjects)
Brain structure(neocortex,p < 0.001)xyzSPM{Z}VoxelsBrain structure(neocortex,p < 0.001)xyzSPM{Z}Voxels
L superiortemporal gyrus (BA 42)−64−29174.169L PrecentralGyrus (BA 6)−22−16513.622
L superior temporal gyrus (BA 22)−59−48153.850L Medial Frontal Gyrus (BA 11)−132−134.242
L superior temporal gyrus (BA 13)−50−43193.413
L Insula (BA 13)−45−333.761
L lentiform nucleus/globus pallidus−25−152436
L lentiform nucleus/putamen−25063.984
L superior frontal gyrus (BA 6)−13−3603.515
R medial frontal gyrus (BA 32)67474.6114
R medial frontal gyrus (BA 6)133533.614
R lentiform nucleus/putamen25434.9157
R precentral gyrus (BA 6)41−10453.565
R middle temporal gyrus (BA 22)49−4513.532
R inferior parietal lobe (BA 40)48−46354.3241
R superior temporal gyrus (BA 42)54−33113.320
Aware > unaware (older subjects)Aware < unaware (older subjects)
Brain structure (neocortex,p< 0.001)xyzSPM{Z}VoxelsBrain structure (neocortex,p< 0.001)xyzSPM{Z}Voxels
L superiortemporal gyrus (BA 22)−59−44153.787none
L middle temporal gyrus (BA 21)−57−6054.246
L parahippocampal gyrus (BA 27)−27−29−33.625Aware > unaware(younger subjects)
L lingual gyrus−23−7114.384Brain structure (neocortex,p < 0.001)xyzSPM{Z}Voxels
L parahippocampal gyrus (BA 34)−14−11−153.711R lentiform nucleus/putamen27403.415
L medial frontal gyrus (BA 6)−9−5613.723R parietal lobe (BA 40)47−46353.8128
L medial frontal gyrus (BA 6)−9−1533.525
R medial frontal gyrus (BA 32)45465.393Aware < unaware(younger subjects)
R lingual gyrus (BA 18)3−76−53.725Brain structure (neocortex,p < 0.001)xyzSPM{Z}Voxels
R medial frontal gyrus (BA 6)172574.5133L superior temporal gyrus (BA 38)−3011−333.926
R lingual gyrus (BA 18)15−69−43.754L medial frontal gyrus (BA 9)−944324.133
R thalamus21−12113.715
R parahippocampal gyrus (BA 19)23−56−23.717
R parietal lobe (BA 40)48−44333.325
R superior temporal gyrus (BA 22)58−33114.1214
R middle temporal gyrus (BA 21)51−4943.758
R parietal lobe (BA 40)58−44323.315

Talairach coordinates of activation maxima (Talairach and Tournoux, 1988) as a function ofawareness and age.

Key: BOLD, blood oxygenation level dependent.

Fig. 2.

Fig. 2.

Four independent analyses characterizing the neural correlatesunderlying CS-US awareness. (A) Magnitude of correlation betweenlearning-related activations and level of awareness for all, younger, and olderadults. Higher awareness scores predicted increased activation in the rightparietal lobe. (B) A group comparison between aware and unaware participants(based on post-experimental questionnaires) also revealed greater activation inthe parietal lobe by aware participants. (C) Scatterplot shows a positiverelationship between parietal lobe activity and individual awareness scores. (D)A priori structural ROI analyses using parietal lobe coordinates that mostcommonly overlapped in lesions in neglect patients (Mort et al., 2003) showed greater activation in thisregion for all, younger, and older adults. *p < 0.05.Abbreviations: CS, conditioned stimulus; ROI, region of interest; US,unconditioned stimulus.

3.2.1.3. Age effects.

Table 4 lists significantregions of activation after between-group comparisons of age (older vs.younger). Older subjects showed greater activation in multipleneocortical structures, including the right parietal lobe (43,−6, 50) (Fig. 3A), whereasyounger subjects failed to show significantly greater activity in anyregion. Younger and older subjects showed a comparable number ofbehavioral CRs (t(47) = 0.96,p =0.34), suggesting that brain activation differences between the 2 groupswere not due to a motor performance effect.

Fig. 3.

Fig. 3.

Effects of age during eyeblink classical conditioning in the parietaland medial temporal lobes. (A) Older adults demonstrated greater activation inthe parietal lobe relative to younger adults during learning. (B) A prioristructural ROIs based on probabilistic maps of the MTL region (Amunts et al., 2005) were used to show that themedial temporal lobe and subregions were more active in older adults relative toyounger adults during conditioning. Abbreviations: CA, cornu ammonis; EC,entorhinal cortex; FD, fascia dentata; MTL, medial temporal lobe; PRh,perirhinal cortex; SUB, subiculum.

3.2.1.4. Interaction between awareness, age, and trial type.

Because older adults demonstrated less awareness than youngeradults (t(47) = 2.36,p = 0.02;Fig. 1D), fMRI analyses designed tobetter understand the interaction between awareness and age wereperformed. These analyses revealed main effects of age and awareness inthe right parietal region. In addition, a triple interaction (aware× age × trial type) was observed in the rightparahippocampus (p < 0.001), characterized byhigh levels of activation in older, aware adults receiving traceconditioning (Fig. 4A).Furthermore, an age × awareness interaction was observed in theleft parahippocampus, right hippocampus, and left superior temporalgyrus, revealing high levels of activation in older, aware subjectsreceiving either delay or trace trial types (p <0.001;Fig. 4B–D).

Fig. 4.

Fig. 4.

Neural correlates of CS-US awareness as a function of age. (A) Onlyolder, aware adults receiving trace conditioning showed greater activation inthe right parahippocampus (p < 0.001). (BeD) Only olderadults who were aware of the CS-US relationship showed greater activity in theleft paraphippocampus, right hippocampus, and left superior temporal gyrus. (E)Activation maps showing main effects of awareness (red;p< 0.001) and age (green;p < 0.001). Yellowcolors indicate areas of overlap between awareness and age. Abbreviations: CS,conditioned stimulus; US, unconditioned stimulus.

3.2.2. Regions of interest analyses

3.2.2.1. Age and awareness effects.

To further examine the role of the parietal cortex in neglectand contingency awareness, the structural ROI analysis based oncoordinates of overlapping lesions in neglect patients (Mort et al., 2003) was used to sampleindividual subject activations. This analysis further corroborated theparietal/awareness effect by revealing greater fMRI parietal activity inaware subjects relative to unaware subjects in both older and youngersubjects (Fig. 2D). Using a prioristructural ROIs based on probabilistic maps of the MTL region (Amunts et al., 2005), analysesshowed that older subjects showed greater activation in the MTLs andvarious subregions (Fig. 3B).

3.3. Results from tDCS study

To corroborate the fMRI findings and to further investigate the role ofthe parietal lobe as it relates to contingency awareness, we applied tDCS tothis region during eyeblink conditioning. The timeline of procedures is shown inFig. 5A. Sixteen naïve subjects(24.3 ± 0.7 years) were randomly assigned to receive cathodal or shamtDCS. Localization was based on fMRI activations (Fig. 5B), and electrodes were applied over these coordinates whilesubjects received delay eyeblink conditioning trials (seeSection 2). After concurrent stimulation andconditioning, subjects’ awareness was assessed using postexperimentalquestionnaires. Although no significant group differences in CR production weremeasured (t(14) = 0.13,p = 0.90), thecathodal group reported being less aware of the CS-US relationship in comparisonto the sham group (t(14) = 2.57,p = 0.02;Fig. 5C). Critically, there were nosignificant differences in correctly answered movie question(t(14) = 1.53,p = 0.15), suggesting that thestimulation did not produce a general learning impairment. These findingscomplement the fMRI results and strongly suggest that the parietal region ishighly involved in the conscious processing of CS-US relationships.

Fig. 5.

Fig. 5.

Effects of cathodal transcranial direct current stimulation (tDCS) overthe right parietal lobe on CS-US awareness during delay conditioning. (A)Timeline of events during the tDCS experiment. Participants received a linebisection test before conditioning and received either cathodal or shamstimulation during conditioning. After conditioning and tDCS, a questionnaireprobing their awareness of the CS-US relationship and movie content wasadministered, which was followed by a poststimulation line bisection test. (B)Placement of the center of a 5 × 5 cm tDCS sponge (red circle) was basedon fMRI activations (shown in yellow;Fig.2A) and normalized to each participant’s scalp. (C) Nodifferences in eyeblink CRs were found between the cathodal and sham group (leftgraph). However, participants receiving cathodal stimulation over the rightparietal lobe demonstrated less awareness of the CS-US relationship than thosereceiving sham stimulation (right graph). Abbreviations: CR, conditionedresponse; CS, conditioned stimulus; US, unconditioned stimulus.

4. Discussion

This investigation sought to characterize brain activity mediating theinteractions of contingency awareness, aging, and delay and trace conditioning usingfMRI and tDCS. Major findings include the following: (1) older adults weresignificantly less aware of the relationship between the CS and US than youngeradults, and this result was not attributable to differences in sensitivity to the CSor US, or to general learning deficits, as evidenced by the lack of groupdifferences for correct answers about the movie. (2) Greater right parietal fMRIactivation was associated with higher levels of contingency awareness for allsubjects receiving either delay or trace conditioning. (3) Cathodal tDCS over theright parietal lobe led to lower levels of awareness in younger subjects withoutdisrupting CRs. (4) Older adults exhibited hyperactivations in the parietal andMTLs, despite showing no conditioning deficits. (5) MTL regions were differentiallyrecruited based on awareness, age, and conditioning trial type.

Prior studies have indicated a link between contingency awareness and traceconditioning and between trace conditioning and MTL structures (Cheng et al., 2008;Clarkand Squire, 1998). Because of these associations, and because aging hasbeen shown to impair MTL functions (Daselaar et al.,2006;Dennis et al., 2008), onemight expect that age-related decreases in awareness would manifest neuronally asabnormal MTL activations and would preferentially affect only trace conditioning.Our results, however, indicated that age-related decrements in awareness areobserved for delay as well as trace conditioning and that right parietal cortex isinvolved in the brain circuitry for contingency awareness (Fig. 2). Main effects of both awareness and age wereobserved in the right parietal cortex, but no interaction of either of thesevariables with conditioning type was seen. These present findings suggest thatcontingency awareness, as supported by the parietal cortex, may not be uniquelyrequired for trace conditioning, which is a position supported by multiple delayconditioning behavioral investigations using a variety of procedures includingdifferential conditioning (Knuttinen et al.,2001), conditional discrimination (Bellebaum and Daum, 2004), and directed-attention (Weidemann et al., 2016). This also suggests a model inwhich the parietal cortex serves as a substrate for contingency awareness and thatage-related disruption of this region is sufficient to impair awareness in oldersubjects regardless of conditioning type. Consistent with this model, we found thatartificially disrupting the right parietal cortex with cathodal tDCS was able toimpair awareness in healthy young subjects performing delay conditioning, a protocolthat does not depend on MTL function.

Several eyeblink conditioning studies have investigated the relationshipsbetween awareness, the MTL, and trace conditioning (Clark and Squire, 1998;Manns et al.,2001,2000a,b;Smith et al.,2005). In the first of these studies,Clark and Squire (1998) reported that MTL amnesics failed to acquiretrace conditioning. This was attributed to an inability to access awareness afterdamage to the hippocampus, as healthy controls showed intact trace conditioning onlyif they were aware. They extended these findings by showing that awareness developedconcurrently with trace CRs and was also necessary for both differential and singlecue trace conditioning but not delay conditioning (Manns et al., 2000b,2001;Smith et al., 2005). Our previous study (Cheng et al., 2008) has shown increasedactivation in the right MTL in trace compared with delay conditioning, and asobserved inFig. 4A, we observed a region inthe right MTL that exhibited enhanced activation for trace conditioning in olderaware subjects. Importantly, the awareness and trace conditioning relationshipproposed by Squire et al were also collected from older participants (mid to late60s) (Clark and Squire, 1998;Manns et al., 2000a,b). Thus, the development of trace conditioning may also uniquely relyon MTL activation and be accom-panied by contingency awareness, and we hypothesizethat this awareness information is supplied by the parietal cortex.

The main debate on the role of awareness and conditioning focused on itsnecessity during delay conditioning, with both positions agreeing that it isnecessary for trace conditioning. Hence, the lack of an awareness effect onbehavioral measures of trace conditioning in the present study was surprising.Interestingly, several studies suggest that trace conditioning can occur outsideconsciousness and awareness. Patients with varying levels of consciousness(vegetative and comatose patients) and healthy sleeping individuals coulddemonstrate successful trace conditioning (Arzi etal., 2012;Bekinschtein et al.,2009;Juan et al., 2016).Furthermore, awake individuals showed rapid amygdala responding during traceconditioning to unperceived faces, suggesting that trace conditioning is possiblewithout awareness (Balderston et al.,2014).

The locations of the awareness-related right parietal (Fig. 2A) and right parahippocampal (Fig. 4A) activations found in the present study arestrikingly similar to the regions that have been found to result in neglectsyndromes in middle cerebral artery and posterior cerebral artery stroke patients,respectively (Mort et al., 2003). Theinteraction of these 2 regions with each other may be particularly important, asThimm et al. (2008) found that functionalactivation increases in the right parietal cortex, and decreases in the rightparahippocampus were associated with recovery in neglect patients. These patientstypically present with a lack of awareness for stimuli presented to thecontralesional side of space. A pattern of greater parietal and lower MTL activitywas exhibited by our younger subjects (who demonstrated greater awareness), whereashyperactivation in both regions was measured in our older subjects (who demonstratedlower awareness), suggesting that hyperactivation in these 2 structures may bedetrimental to contingency awareness. Furthermore, subjects showing decreasedparietal lobe activity demonstrated a lack of contingency awareness. Consistent withthis finding, subjects receiving cathodal tDCS over this region were less aware thanthose receiving sham stimulation, and decrements in awareness were found tocorrelate (r = –0.54,p < 0.05) with the degree ofrightward shift in a line bisection test, a test commonly used to assess neglect.This raises an interesting question as to whether the age-dependent reduction ofCS-US awareness is a manifestation of some form of naturally occurring age-relatedneglect. Consistent with this notion, 2 studies have found that older subjectsexhibit abnormal (right shifted) line bisection test results compared with youngersubjects (Benwell et al., 2014;Fujii et al., 1995). If reduced CS-US awarenessis an indicator of underlying neglect, the parietal and parahippocampalhyperactivations found in our older subjects could provide a biomarker fordysfunction in these regions.

Neuromodulation methods have been used in both healthy and patientpopulations to study the phenomenon of neglect. In healthy subjects, parietaltranscranial magnetic stimulation can induce extinction of contralateral visualstimuli during a simultaneous double stimulus presentation (Pascual-Leone et al., 1994) and produced a significantrightward bias in symmetry judgments of pre-bisected lines as compared with basaland sham repetitive transcranial magnetic stimulation conditions (Fierro et al., 2000). In the tactile modality, rightparietal transcranial magnetic stimulation after cutaneous stimulation has produceddeficits in detecting either ipsilateral or contralateral stimulation (Oliveri et al., 1999). Two studies have shownthat anodal tDCS over the right parietal cortex can reduce visual neglect symptomsin patients with right parietal stroke and contralateral neglect (Ko et al., 2008;Sparinget al., 2009).Sparing et al.(2009) showed that in normal subjects, tDCS could enhance or impairperformance depending on stimulation parameters (anodal vs cathodal) and stimulatedhemisphere. Finally, simultaneous cathodal and anodal tDCS over the right and leftparietal lobes produced stronger and earlier neglect-like effects compared withcathodal stimulation alone (Giglia et al.,2011). These studies indicate that neuromodulation can not only replicatedeficits seen in right parietal neglect but can also be used to improve performance.In the present study, cathodal tDCS was seen to produce a decrement in CS-UScontingency awareness in young subjects that was correlated with neglect-likeeffects (line bisection). Future studies can address whether anodal tDCS stimulationis capable of enhancing awareness in older subjects and altering parietal andparahippocampal activation patterns to more closely resemble those seen in youngerindividuals.

One methodological consideration in the present study is the manner in whichawareness was assessed. We used a questionnaire designed to probe subject’sknowledge of the CS-US relationship after the conditioning session. This techniquehas been used in prior studies (Cheng et al.,2008;Clark and Squire, 1998,1999;Manns et al., 2000a) but is not without disadvantages, as it may notaccurately reflect participants’ awareness of the contingencies duringconditioning (due to forgetting). An alternative procedure is to requireparticipants to provide an online US expectancy rating on a trial by trial basisduring conditioning. One disadvantage of this technique is that it directsparticipants’ attention to the US, which may have an unintentional effect onawareness and conditioning levels. Another consideration in the present study isthat delay and trace conditioning trials varied in terms of stimulus durations (1350ms for delay and 250 ms for trace) and collapsing across these 2 trial types may nothave accounted for CS saliency effects. However, these trials were matched forinterstimulus intervals (1250 ms) and elicited comparable conditioning, suggestingsaliency did not differ between the trial types.

In summary, this is the first investigation to use fMRI and tDCS to identifythe neural circuitry related to contingency awareness as a function of age. Thefindings support that the parietal cortex serves as a substrate for contingencyawareness and that age-related disruption of this region is sufficient to impairawareness. It is speculated that a naturally occurring mild neglect could manifestas one ages, resulting in lower contingency awareness by our older subjects.Finally, contingency awareness and processing in the parietal region can bemodulated by tDCS, which represents a first step in developing a treatment fordisorders resulting from parietal damage.

Supplementary Material

1

Acknowledgements

This work was supported by grants from the NIH/National Institute on AgingR01 AG021501 (JED) and NIH/ National Institute on Alcohol Abuse and Alcoholism K01AA020873 (DTC). The MRI equipment in this study was funded by NIH grant 1S10OD021648.

Footnotes

Disclosure statement

The authors declare no competing financial interests.

Appendix A. Supplementary data

Supplementary data to this article can be found online athttps://doi.org/10.1016/j.neurobiolaging.2020.02.024.

References

  1. Amunts K, Kedo O, Kindler M, Pieperhoff P, Mohlberg H, Shah NJ, Habel U, Schneider F, Zilles K, 2005. Cytoarchitectonic mapping of thehuman amygdala, hippocampal region and entorhinal cortex: intersubjectvariability and probability maps. Anat. Embryol. (Berl.)210,343–352. [DOI] [PubMed] [Google Scholar]
  2. Arzi A, Shedlesky L, Ben-Shaul M, Nasser K, Oksenberg A, Hairston IS, Sobel N, 2012. Humans can learn new informationduring sleep. Nat. Neurosci15,1460–1465. [DOI] [PubMed] [Google Scholar]
  3. Baeuchl C, Hoppstadter M, Meyer P, Flor H, 2019. Contingency awareness as aprerequisite for differential contextual fear conditioning.Cogn. Affect. Behav. Neurosci19,811–828. [DOI] [PubMed] [Google Scholar]
  4. Balderston NL, Schultz DH, Baillet S, Helmstetter FJ, 2014. Rapid amygdala responses during tracefear conditioning without awareness. PLoS One9, e96803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bedard G, Barnett-Cowan M, 2016. Impaired timing of audiovisual eventsin the elderly. Exp. Brain Res234,331–340. [DOI] [PubMed] [Google Scholar]
  6. Bekinschtein TA, Shalom DE, Forcato C, Herrera M, Coleman MR, Manes FF, Sigman M, 2009. Classical conditioning in thevegetative and minimally conscious state. Nat. Neurosci12,1343–1349. [DOI] [PubMed] [Google Scholar]
  7. Bellebaum C, Daum I, 2004. Effects of age and awareness oneyeblink conditional discrimination learning. Behav. Neurosci118,1157–1165. [DOI] [PubMed] [Google Scholar]
  8. Benwell CSY, Thut G, Grant A, Harvey M, 2014. A rightward shift in the visuospatialattention vector with healthy aging. Front. Aging Neurosci6, 113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buchel C, Dolan RJ, Armony JL, Friston KJ, 1999. Amygdala-hippocampal involvement inhuman aversive trace conditioning revealed through event-related functionalmagnetic resonance imaging. J. Neurosci19,10869–10876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cacciaglia R, Pohlack ST, Flor H, Nees F, 2015. Dissociable roles for hippocampal andamygdalar volume in human fear conditioning. Brain Struct. Funct220,2575–2586. [DOI] [PubMed] [Google Scholar]
  11. Campolattaro MM, Freeman JH, 2009. Examination of bilateral eyeblinkconditioning in rats. Behav. Neurosci123,1346–1352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Carter RM, O’Doherty JP, Seymour B, Koch C, Dolan RJ, 2006. Contingency awareness in humanaversive conditioning involves the middle frontal gyrus.Neuroimage29,1007–1012. [DOI] [PubMed] [Google Scholar]
  13. Cheng DT, Disterhoft JF, Power JM, Ellis DA, Desmond JE, 2008. Neural substrates underlying humandelay and trace eyeblink conditioning. Proc. Natl. Acad. Sci. U S A105,8108–8113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chica AB, Bartolomeo P, 2012. Attentional routes to consciousperception. Front. Psychol3, 1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Christian KM, Thompson RF, 2003. Neural substrates of eyeblinkconditioning: acquisition and retention. Learn. Mem10,427–455. [DOI] [PubMed] [Google Scholar]
  16. Clark RE, Squire LR, 1998. Classical conditioning and brainsystems: the role of awareness. Science280,77–81. [DOI] [PubMed] [Google Scholar]
  17. Clark RE, Squire LR, 1999. Human eyeblink classicalconditioning: effects of manipulating awareness of the stimuluscontingencies. Psychol. Sci10,14–18. [Google Scholar]
  18. Daselaar SM, Fleck MS, Dobbins IG, Madden DJ, Cabeza R, 2006. Effects of healthy aging onhippocampal and rhinal memory functions: an event-related fMRIstudy. Cereb. Cortex16,1771–1782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Dennis NA, Kim H, Cabeza R, 2008. Age-related differences in brainactivity during true and false memory retrieval. J. Cogn. Neurosci20,1390–1402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Diedrichsen J, 2006. A spatially unbiased atlas templateof the human cerebellum. Neuroimage33,127–138. [DOI] [PubMed] [Google Scholar]
  21. Donaldson PH, Rinehart NJ, Enticott PG, 2015. Noninvasive stimulation of thetemporoparietal junction: a systematic review.Neurosci. Biobehav. Rev55,547–572. [DOI] [PubMed] [Google Scholar]
  22. Fierro B, Brighina F, Oliveri M, Piazza A, La Bua V, Buffa D, Bisiach E, 2000. Contralateral neglect induced byright posterior parietal rTMS in healthy subjects.Neuroreport11,1519–1521. [PubMed] [Google Scholar]
  23. Finkbiner RG, Woodruff-Pak DS, 1991. Classical eyeblink conditioning inadulthood: effects of age and interstimulus interval on acquisition in thetrace paradigm. Psychol. Aging6,109–117. [DOI] [PubMed] [Google Scholar]
  24. Folstein MF, Folstein SE, McHugh PR, 1975. “Mini-mental state”. Apractical method for grading the cognitive state of patients for theclinician. J. Psychiatr. Res12,189–198. [DOI] [PubMed] [Google Scholar]
  25. Fujii T, Fukatsu R, Yamadori A, Kimura I, 1995. Effect of age on the line bisectiontest. J. Clin. Exp. Neuropsychol17,941–944. [DOI] [PubMed] [Google Scholar]
  26. Giglia G, Mattaliano P, Puma A, Rizzo S, Fierro B, Brighina F, 2011. Neglect-like effects induced by tDCSmodulation of posterior parietal cortices in healthysubjects. Brain Stimul. 4,294–299. [DOI] [PubMed] [Google Scholar]
  27. Haritha AT, Wood KH, Ver Hoef LW, Knight DC, 2013. Human trace fear conditioning:right-lateralized cortical activity supports trace-intervalprocesses. Cogn. Affect. Behav. Neurosci13,225–237. [DOI] [PubMed] [Google Scholar]
  28. Hoffman P, Morcom AM, 2018. Age-related changes in the neuralnetworks supporting semantic cognition: a meta-analysis of 47 functionalneuroimaging studies. Neurosci. Biobehav. Rev84,134–150. [DOI] [PubMed] [Google Scholar]
  29. Juan E, Nguepnjo Nguissi NA, Tzovara A, Viceic D, Rusca M, Oddo M, Rossetti AO, De Lucia M, 2016. Evidence of trace conditioning incomatose patients revealed by the reactivation of EEG responses to alertingsounds. Neuroimage141,530–541. [DOI] [PubMed] [Google Scholar]
  30. Klucken T, Tabbert K, Schweckendiek J, Merz CJ, Kagerer S, Vaitl D, Stark R, 2009. Contingency learning in human fearconditioning involves the ventral striatum. Hum. Brain Mapp30,3636–3644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Knight DC, Cheng DT, Smith CN, Stein EA, Helmstetter FJ, 2004. Neural substrates mediating humandelay and trace fear conditioning. J. Neurosci24,218–228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Knight DC, Waters NS, Bandettini PA, 2009. Neural substrates of explicit andimplicit fear memory. Neuroimage45,208–214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Knuttinen MG, Power JM, Preston AR, Disterhoft JF, 2001. Awareness in classical differentialeyeblink conditioning in young and aging humans.Behav. Neurosci115,747–757. [DOI] [PubMed] [Google Scholar]
  34. Ko MH, Han SH, Park SH, Seo JH, Kim YH, 2008. Improvement of visual scanning afterDC brain polarization of parietal cortex in stroke patients with spatialneglect. Neurosci. Lett448,171–174. [DOI] [PubMed] [Google Scholar]
  35. LaBar KS, Disterhoft JF, 1998. Conditioning, awareness, and thehippocampus. Hippocampus8,620–626. [DOI] [PubMed] [Google Scholar]
  36. Lovibond PF, Liu JC, Weidemann G, Mitchell CJ, 2011. Awareness is necessary fordifferential trace and delay eyeblink conditioning inhumans. Biol. Psychol87,393–400. [DOI] [PubMed] [Google Scholar]
  37. Lovibond PF, Shanks DR, 2002. The role of awareness in Pavlovianconditioning: empirical evidence and theoreticalimplications. J. Exp. Psychol. Anim. Behav. Process28, 3–26. [PubMed] [Google Scholar]
  38. Manns JR, Clark RE, Squire L, 2001. Single-cue delay eyeblinkconditioning is unrelated to awareness. Cogn. Affect. Behav. Neurosci1,192–198. [DOI] [PubMed] [Google Scholar]
  39. Manns JR, Clark RE, Squire LR, 2000a. Awareness predicts the magnitude ofsingle-cue trace eyeblink conditioning.Hippocampus10,181–186. [DOI] [PubMed] [Google Scholar]
  40. Manns JR, Clark RE, Squire LR, 2000b. Parallel acquisition of awarenessand trace eyeblink classical conditioning. Learn. Mem7,267–272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Manns JR, Clark RE, Squire LR, 2002. Standard delay eyeblink classicalconditioning is independent of awareness. J. Exp. Psychol. Anim. Behav. Process28,32–37. [PubMed] [Google Scholar]
  42. Miller MJ, Li L, Weiss C, Disterhoft JF, Wyrwicz AM, 2005. A fiber optic-based system forbehavioral eyeblink measurement in a MRI environment.J. Neurosci. Methods141,83–87. [DOI] [PubMed] [Google Scholar]
  43. Mort DJ, Malhotra P, Mannan SK, Rorden C, Pambakian A, Kennard C, Husain M, 2003. The anatomy of visualneglect. Brain126 (Pt 9),1986–1997. [DOI] [PubMed] [Google Scholar]
  44. Nelson HE, 1982. National Adult Reading Test (NART) Test ManualNFER-NELSON Publishing Company, Ltd,Windsor, Berkshire, England. [Google Scholar]
  45. Oliveri M, Rossini PM, Pasqualetti P, Traversa R, Cicinelli P, Palmieri MG, Tomaiuolo F, Caltagirone C, 1999. Interhemispheric asymmetries in theperception of unimanual and bimanual cutaneous stimuli. A study usingtranscranial magnetic stimulation. Brain122 (Pt 9),1721–1729. [DOI] [PubMed] [Google Scholar]
  46. Pascual-Leone A, Gomez-Tortosa E, Grafman J, Alway D, Nichelli P, Hallett M, 1994. Induction of visual extinction byrapid-rate transcranial magnetic stimulation of parietallobe. Neurology44 (3 Pt 1),494–498. [DOI] [PubMed] [Google Scholar]
  47. Poliakoff E, Shore DI, Lowe C, Spence C, 2006. Visuotactile temporal order judgmentsin ageing. Neurosci. Lett396,207–211. [DOI] [PubMed] [Google Scholar]
  48. Rosen WG, Mohs RC, Davis KL, 1984. A new rating scale forAlzheimer’s disease. Am. J. Psychiatry141,1356–1364. [DOI] [PubMed] [Google Scholar]
  49. Schmahmann JD, Doyon J, Toga A, Petrides M, Evans A, 2000. MRI Atlas of the Human Cerebellum.Academic Press, San Diego,CA. [DOI] [PubMed] [Google Scholar]
  50. Setti A, Finnigan S, Sobolewski R, McLaren L, Robertson IH, Reilly RB, Kenny RA, Newell FN, 2011. Audiovisual temporal discriminationis less efficient with aging: an event-related potentialstudy. Neuroreport22,554–558. [DOI] [PubMed] [Google Scholar]
  51. Smith CN, Clark RE, Manns JR, Squire LR, 2005. Acquisition of differential delayeyeblink classical conditioning is independent of awareness.Behav. Neurosci119,78–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sparing R, Thimm M, Hesse MD, Kust J, Karbe H, Fink GR, 2009. Bidirectional alterations ofinterhemispheric parietal balance by non-invasive corticalstimulation. Brain132 (Pt 11),3011–3020. [DOI] [PubMed] [Google Scholar]
  53. Spence KW, Ross LE, 1959. A methodological study of the formand latency of eyelid responses in conditioning. J. Exp. Psychol58,376–381. [DOI] [PubMed] [Google Scholar]
  54. Tabbert K, Merz CJ, Klucken T, Schweckendiek J, Vaitl D, Wolf OT, Stark R, 2011. Influence of contingency awareness onneural, electrodermal and evaluative responses during fearconditioning. Soc. Cogn. Affect. Neurosci6,495–506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Tabbert K, Stark R, Kirsch P, Vaitl D, 2006. Dissociation of neural responses andskin conductance reactions during fear conditioning with and withoutawareness of stimulus contingencies.Neuroimage32,761–770. [DOI] [PubMed] [Google Scholar]
  56. Talairach J, Tournoux P, 1988. Co-planar Stereotaxic Atlas of the Human Brain: 3-Dimensional Proportional System: An Approach to Cerebral Imaging. Thieme,New York. [Google Scholar]
  57. Thimm M, Fink GR, Sturm W, 2008. Neural correlates of recovery fromacute hemispatial neglect. Restor. Neurol. Neurosci26,481–492. [PubMed] [Google Scholar]
  58. Vuilleumier P, 2013. Mapping the functional neuroanatomyof spatial neglect and human parietal lobe functions: progress andchallenges. Ann. N. Y Acad. Sci. U. S. A1296,50–74. [DOI] [PubMed] [Google Scholar]
  59. Wechsler D, 1987. Wechsler Memory Scale-Revised Manual. The PsychologicalCorporation, SanAntonio. [Google Scholar]
  60. Weidemann G, Best E, Lee JC, Lovibond PF, 2013. The role of contingency awareness insingle-cue human eyeblink conditioning. Learn. Mem20,363–366. [DOI] [PubMed] [Google Scholar]
  61. Weidemann G, Lovibond PF, 2016. The role of US recency in thePerruchet effect in eyeblink conditioning. Biol. Psychol119,1–10. [DOI] [PubMed] [Google Scholar]
  62. Weidemann G, Satkunarajah M, Lovibond PF, 2016. I think, therefore eyeblink: theimportance of contingency awareness in conditioning.Psychol. Sci27,467–475. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1

ACTIONS

RESOURCES

[8]ページ先頭
©2009-2025 Movatter.jp