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. 2016 Sep 1;27(9):4339–4349. doi: 10.1093/cercor/bhw234

Age-Related Increases in Tip-of-the-tongue are Distinct from Decreases in Remembering Names: A Functional MRI Study

Willem Huijbers 1,2,3,*, Kathryn V Papp 1,2,4, Molly LaPoint 1,2,4, Sarah E Wigman 1,4, Alex Dagley 1,2, Trey Hedden 1,2, Dorene M Rentz 1,2,4, Aaron P Schultz 1,2, Reisa A Sperling 1,2,4
PMCID: PMC6074848  PMID: 27578492

Abstract

Tip-of-the-tongue (TOT) experiences increase with age and frequently heighten concerns about memory decline. We studied 73 clinically normal older adults participating in the Harvard Aging Brain Study. They completed a functional magnetic resonance imaging (fMRI) task that required remembering names associated with pictures of famous faces. Older age was associated with more self-reported TOT experiences and a decrease in the percentage of remembered names. However, the percentage of TOT experiences and the percentage of remembered names were not directly correlated. We mapped fMRI activity for recollection of famous names and TOT and examined activity in the hippocampal formation, retrosplenial cortex, and lateral prefrontal cortex. The hippocampal formation was similarly activated in recollection and TOT experiences. In contrast, the retrosplenial cortex was most active for recollection and lateral prefrontal cortex was most active for TOT experiences. Together, the results confirm that age-related increases in TOT experiences are not only solely the consequence of age-related decline in recollection, but also likely reflect functional alterations in the brain networks that support retrieval monitoring and cognitive control. These findings provide behavioral and neuroimaging evidence that age-related TOT experiences and memory failure are partially independent processes.

Keywords: aging, fMRI, Harvard aging brain study, memory, tip-of-the-tongue

Introduction

With advancing age the experience of tip-of-the-tongue (TOT) experiences become more frequent and can heighten concerns about memory decline (Brown 1991; Heine et al. 1999; Schwartz 2006; Schwartz and Brown 2014). TOT experiences consist of a strong feeling that information is present in memory, but that it cannot be successfully retrieved (Schwartz 2006). Meta-cognitive theories suggest that the monitoring of retrieved information is a key component of TOT experiences (Schwartz and Metcalfe 2011; Brown 2012; Schwartz and Brown 2014). TOT experiences are distinguishable from other types of retrieval failure, not only in the subjective experience, but also in that partial information is often retrieved (Rubin 1975; Maril et al. 2005; Gollan and Brown 2006). Salthouse and Mandell (2013) recently demonstrated that age-related increases in TOT experiences are relatively uncorrelated with age-related decreases in episodic memory performance. The age-related increase of TOT experiences might therefore be a consequence of changes in metacognition rather than decline in memory. In their behavioral study, Salthouse and Mandell (2013) did not examine brain activity and did not distinguish between the types of retrieval failure. Here, we extend previous findings using a memory test and a retrospective evaluation in combination with functional magnetic resonance imaging (fMRI) to examine the neural correlates of remembering names and TOT experiences in older adults.

Only a limited number of fMRI studies have examined TOT experiences in older adults (Shafto et al. 2007, 2010). Similar to what is observed in young adults (Kikyo et al. 2001; Maril et al. 2001, 2005), TOT experiences evoke fMRI activity in the lateral prefrontal cortex of older adults. These previous fMRI studies investigating TOT experiences did not report retrieval-related activity in the hippocampal formation, perhaps due to the verbal and semantic nature of the experimental questions. For example: “Another name of Vitamin C is…?”. Pictures of famous individuals tend to evoke fMRI activity in the hippocampal formation, when contrasted with fMRI activity evoked by pictures of non-famous individuals (Douville et al. 2005; Nielson et al. 2006, 2010; Sugarman et al. 2012; Seidenberg et al. 2013). Remembering names, guided by pictures of famous celebrities and politicians, has also been shown to elicit a particularly high frequency of TOT experiences (Beeson et al. 1997). Alternatively, it is possible that self-evaluation of the retrieval experience (meta-memory) changes retrieval-related brain activity and this accounts for the lack of hippocampal activity in previous fMRI studies on TOT experiences (Kikyo et al. 2001; Maril et al. 2001, 2005; Shafto et al. 2007, 2010). Therefore, we designed an fMRI paradigm, where older adults retrieved names associated with famous individuals, and subsequently rated their subjective experiences. Using this design in an elderly cohort, we mapped brain activity related to memory retrieval and retrospectively assessed TOT experiences.

Our first aim was to examine the relationship between memory for names, TOT experiences, and age. Our second aim was to map fMRI activity related to recognition of famous faces, memory for names, and TOT experiences. We predicted that images of famous faces would evoke fMRI activity in a relatively large heterogeneous set of brain regions, including the hippocampal formation, retrosplenial cortex, posterior cingulate cortex and precuneus, and lateral prefrontal cortex, consistent with previous studies on memory retrieval and famous faces (Bernard et al. 2004; Douville et al. 2005; Spaniol et al. 2009; Woodard et al. 2009; Huijbers et al. 2010; Kim 2015). We predicted that successful recollection of names would evoke fMRI activity in a subset of the regions related to recognition of famous faces, specifically in regions labeled the “recollection-network” (Rugg and Vilberg 2013), which include the hippocampal formation and retrosplenial cortex. Based on previous studies (Maril et al. 2001; Shafto et al. 2010), we predicted that TOT experiences would evoke fMRI activity in the lateral prefrontal cortex and anterior cingulate cortex. As an exploratory aim, we compared the level of brain activity related to self-report of whether a name was recollected, was on the TOT, evoked a feeling of knowing (FOK), or judged as unknown (UNK). Mapping fMRI activity evoked by remembering names, TOT experiences, and retrieval failure provides novel information on the question of whether age-related increases in TOT experiences are driven by memory decline.

Material and Methods

Seventy-three clinically normal older adults were recruited from the Harvard Aging Brain Study (Table 1), which is an ongoing longitudinal study designed to further our understanding of normal aging and preclinical Alzheimer's disease. All adults had normal, or corrected-to-normal vision and were highly educated (Table 1). Subjects were deemed clinically normal at baseline based on a global Clinical Dementia Rating (CDR) score of 0 (Morris 1993), normal Mini Mental State Exam (Folstein et al. 1975), and scores above age and education-adjusted cutoffs on the 30-Minute Delayed Recall of the Logical Memory Story IIa (Wechsler 1984). At the neuropsychological examination closest to the magnetic resonance imaging (MRI) visit, six of the 73 older adults were rated as a 0.5 on CDR (Table 1); however, none met criteria for Mild Cognitive Impairment according to ADNI criteria (http://www.adni-info.org/). The neuropsychological examination also included the AMNART to assess verbal intelligence (VIQ), and the Boston Naming Test (BNT; Table 1) to assess confrontation naming. None of the subjects had a history of alcoholism, drug abuse, head trauma, neurological disorder, or current serious medical/psychiatric illness. Informed consent was obtained from every participant prior to experimental procedures. The study was approved and conducted in accordance with the Partners Human Research Committee at the Brigham and Women Hospital and the Massachusetts General Hospital (Boston, MA). As part of the Harvard Aging Brain Study, neuropsychological and neuroimaging data from these participants have been previously published (e.g., Vannini et al. 2013; Hedden et al. 2016; Huijbers et al. 2014; Mormino et al. 2014; Schultz et al. 2014; Reijmer et al. 2015; Ward et al. 2015). However, the behavioral and functional MRI results presented in the current manuscript are novel and have not been published previously. More information on the Harvard Aging Brain Study can be found at http://www.nmr.mgh.harvard.edu/harvardagingbrain, including information on the public release of the data (Dagley et al. 2015).

Table 1.

Demograhics

Label
N 73
Age 63–90 ; 72.25 ± 0.79
Sex 51 females; 22 males
Years of education 16.11 ± 0.38
VIQ 123.4 ± 0.71
CDR 67 CDR 0; 6 CDR 0.5
MMSE 29.27 ± 0.12
BNT 27.71 ± 0.37
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Notes: N denotes the number of participants, Age includes the range, mean, and standard error of the mean (±). VIQ stands for the Verbal Intelligence Quotient estimate from the AMNART, CDR for the Clinical Dementia Rating, MMSE for the Mini Mental State Exam, and BNT for the Boston Naming Test.

Experimental Paradigm

The experimental paradigm consisted of an in-scanner phase and a post-scan phase. The paradigm was designed and generated using Java (NetBeans 7.3.1, Oracle, Redwood Shores, CA). Inside the MRI scanner (Fig. 1), participants observed 120 famous faces and 48 novel non-famous foils; all were color images on a black background. The 120 famous names are included as supplemental materials (Supplemental Table 1). Visual stimuli were projected on a screen positioned at the head of the magnet bore and seen via a mirror attached to the head coil. Responses were made with the right hand using an MRI-compatible button-box. Head motion was restrained with foam pads and scanner noise was minimized using earplugs and noise-reduction headphones.

Figure 1.

Figure 1.

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Experimental design. The experimental paradigm consisted of an in-scanner phase (upper box) and a post-scan phase (lower box). Inside the MRI scanner, participants reported by a yes/no button response if they remembered the names belonging to the famous faces or not. We instructed the participant to reject the name if they did not recognize the face and only report “yes” if they could hear themselves say the name in their mind. Post-scan, after the MRI, there was a retest of the famous faces. For each famous individual, participants indicated 1 out of 4 options: whether they successfully recollected the name (REC), or if they failed, if the name was on the tip-of-the-tongue (TOT), induced a feeling-of-knowing (FOK) or was unknown (UNK). Next, using multiple choice, the participant selected which 1 out of 4 names belonged to the famous face.

Inside the MRI scanner, the task was divided into 6 runs of 5 minutes each. In each run 20 famous and 8 novel faces were shown for 7500 milliseconds, with an inter-trial-interval between 500 and 12 500 milliseconds, during which a white fixation cross was presented at the center of the screen. The trial order and durations of the inter-trial-intervals were optimized using optseq2 (Dale 1999). The participant was instructed to indicate whether they knew and could produce the name associated with the face by responding “yes” with the pointer finger or “no” with the middle finger. The memory task was acquired after a MPRAGE and a resting-state scan.

Following the MRI, participants conducted the post-scan tests and re-evaluated the famous faces previously seen inside the scanner (Fig. 1). The participants were instructed to evaluate each famous item again, regardless of their previous response to the name while inside the scanner. They were asked to say the name aloud, if remembered, prior to responding on a button-box. Participants indicated via a button-box whether they recollected the name (REC). If they did not recollect the name, they were asked to indicate if the name was on the TOT, if the face induced a FOK, but the name could not be remembered, or if the face was UNK. After each judgment, the participant selected the name that belonged to the face from 4 options (1 correct and 3 incorrect from the same category, e.g., former presidents, in counter-balanced order). The subsequent face was presented after 500 milliseconds and 120 faces were shown consecutively in 3 sessions of 40 faces. In a second post-scan test, we also examined recognition for the non-famous faces. Because the analyses here focus on the famous faces only, the data from this post-scan recognition test is not included in the current manuscript.

MRI Data Acquisition

MRI data were collected on two matched Siemens TrioTim 3.0 Tesla scanners (Siemens Medical Systems, Erlangen, Germany), at the Athinoula A. Martinos Center for Biomedical Imaging. Both scanners were equipped with a 12-channel phased-array head coil. High-resolution T1-weighted anatomical images were acquired using an MPRAGE with the following parameters: 256 sagittal slices, repetition time (TR) = 2300 ms, echo time (TE) = 2.95 ms, inversion time (TI) = 900 ms, flip angle (FA) = 9°, FOV= 270 × 253 mm, matrix = 256 × 240, voxel size = 1.05 × 1.05 × 1.2 mm. Task-related blood oxygenation level-dependent data were acquired using a T2*-weighted gradient-echo planar (EPI) sequence. We acquired 6 runs of 180 volumes, (after excluding 4 dummies). Each volume consisted of 33 axial slices, 3.0 mm thickness, with a skip of 0.8 mm; TR = 2000 ms; TE = 30 ms; FA = 90°, FOV = 192 × 192 mm, matrix = 64 × 64, effective voxel size = 3.0 × 3.0 × 3.8 mm.

Data Analysis

Statistical analysis of the behavioral data employed t-tests (two-sided) and correlations which were quantified using a Pearson correlation. The descriptive statistics include the mean and standard error of the mean (±), unless otherwise indicated. We also used linear regression models, as implemented in R v3.0.1 (http://www.r-project.org/) and the companion to Applied Regression Toolbox (Fox and Weisberg 2011) to control for age.

The fMRI time series were preprocessed and analyzed using SPM8 (UCL, http://www.fil.ion.ucl.ac.uk/spm). The data were slice time-corrected, realigned, and normalized to the MNI EPI template, resampled to 3.0 × 3.0 × 3.0 mm voxels and smoothed with 8 mm full-width half-maximum Gaussian kernel. We used SPM8 together with in-house developed MATLAB scripts (GLM-Flex, Harvard Aging Brain Study, MartinosCenter, MGH, Boston, MA, http://mrtools.mgh.harvard.edu). At the subject-level, we used SPM8 called on via in-house developed batch scripts. The event-types in the SPM models were defined using the experimental design (famous/novel), and the remember response to the names inside the scanner (hit/miss for famous items or correct rejection/false alarm for novel items). We also used the post-scan judgments to further categorize the items into REC, TOT, FOK, and UNK. The novel items were separately included in the SPM models at the subject level by the subsequent memory test (encoding hit/miss), but these were not used separately in the contrast or any of group-level analyses. Similarly, omissions were included in the SPM model, but not used in any of the analyses. The onsets for these events were convolved with the canonical hemodynamic response function using the trial duration (7500 ms). The subject-level models also included regressors for the motion parameters, bad-volume regressors, and a high-pass filter (1/128 Hz). Scans were coded as bad-volumes when movement to the previous scans exceeded 0.75 mm or 1.5 degrees in one direction. Individual beta-maps were calculated by contrasting all task events versus fixation. Thus, task-induced activations and deactivations were identified regardless of the memory condition or task performance. The general linear model (GLM) scripts in GLM_FLEX allowed for flexible modeling of the within- and between-group effects using a single partitioned error model. Group fMRI analyses consisted of voxel-wise one-sample t-tests using the contrasts: (1) recognition of famous faces, as defined by famous > novel (2) recollection of famous names, as defined by both the experimental design and the behavioral responses: REC > (TOT + FOK + UNK) and (3) TOT experiences as defined by both the experimental design and the behavioral responses: TOT > (REC + FOK + UNK). We employed a threshold of P < 0.05, FDR-corrected with a minimum cluster size of 5 voxels (Fig. 3). Statistical group maps were projected to the cortical surface using FreeSurfer (v5.1) via a standard MNI to the FreeSurfer average template transformation or were resliced to 2.0 × 2.0 × 2.0 mm voxels and overlaid on the standard SPM8 individual T1-weighted volume. In addition, we extracted the beta estimates using a 5 mm radius sphere at 6 peaks of activity from the contrast famous > novel (Fig. 4) using GLM-Flex. At these peaks, we extracted the individual beta estimates for REC > Fixation, TOT > Fixation, FOK > Fixation, and UNK > Fixation. From the individual beta-estimates, we calculated the mean activity, standard error of the mean, and conducted paired t-tests.

Figure 3.

Figure 3.

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Whole brain maps of functional MRI activity. (A) The top row shows fMRI activity related to memory retrieval based on the contrast: famous > novel. (B) The middle row shows fMRI activity related to recollection based on the contrast: REC > (TOT + FOK + UNK). (C) The bottom row shows fMRI activity related to TOT based on the contrast: TOT > (REC + FOK + UNK). Brain activity is projected onto the cortical surface and shown at a threshold of P < 0.05 (FDR-corrected). On the right, coronal slices are shown to visualize activity in the hippocampal formation.

Figure 4.

Figure 4.

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Level of fMRI activity in regions of interest. The top row, for illustrative purposes, shows the whole brain maps of fMRI activity for famous faces > novel faces (see also Fig. 3A) used to define the regions of interest. The bottom row shows bar plots with the level of fMRI activity for the hippocampal formation (A), retrosplenial cortex (B), and lateral prefrontal cortex (C) separated by the categorical post-scan judgments: the name was recollected (REC), on the TOT, elicited a FOK, or was UNK.

Results

Behavioral Results

The percentage of recollected names (i.e., “yes, I remember the name”) was 55.2% ± 3.4 for the famous faces shown inside the scanner. In contrast, 96.7% ± 0.4 of the 48 novel foils (non-famous faces) were correctly rejected (i.e., “no, I do not remember the name”). In the post-scan test, the famous faces were judged again but rather than responding: yes/no, the participants indicated: REC, TOT, FOK, or UNK. On average, 53.8% ± 2.2 were judged as REC, 15.0% ± 1.4 as TOT, 16.0% ± 1.2 as FOK, and 15.1% ± 1.4 as UNK. Figure 2A shows that 84.8% ± 1.4 of items judged REC were similarly remembered inside the scanner (“yes, I remember the name”), 44.7% ± 3.0 for TOT, 11.0% ± 1.9 for FOK, and 1.5% ± 0.5 for UNK. Paired t-tests confirmed that the percentage of remembered names was highest for REC (REC > TOT; t = 14.98, P < 0.001) followed by TOT (TOT > FOK, t = 13.28, P < 0.001). FOK was higher compared with UNK (FOK > UNK, t = 5.24, P < 0.001). The percentage of in-scanner remembered names was correlated with the post-scan percentage REC (r = 0.83, t = 12.32, P < 0.001, see Supplemental Figure S1). We calculated the mean Kappa coefficient (k = 0.65 ± 0.016) by using the percentage of in-scanner remembered names (“yes, I remember the name” vs. “no, I do not remember the name”) and post-scan percentage of REC responses (REC vs. TOT/FOK/UNK). The coefficient indicates that both in- and post-scan judgments are in good agreement. On the multiple choice question, the percentage of names correctly selected was 94.1% ± 0.6 for REC, 94.2% ± 1.0 for TOT, 87.4% ± 1.3 for FOK, and 73.5% ± 2.3 for UNK (Fig. 2B). This indicates that participants largely knew the names associated with the famous faces they previously endorsed as TOT. Moreover, even for famous faces judged as FOK or UNK, participants frequently endorsed the correct name on multiple choice. In the supplementary materials, we plotted the relationship between the in-scanner and post-scan responses (Supplemental Figure S1). These analyses confirm that across participants, the post- and in-scanner judgments were consistent, except for the number of TOT items, as these were relatively independent from the number of names remembered inside the MRI.

Figure 2.

Figure 2.

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Behavioral results. (A) The bar chart on the top left shows the percentage of remembered names when inside the MRI. Green represents the percentage remembered and red is the percentage not remembered. On the x-axis are the categorical post-scan judgments, whether: the name was REC, on the TOT, elicited a FOK or was UNK. (B) The top-middle bar chart shows the percentage correct on a 4-option multiple-choice post-scan evaluation. Green represents the percentage correct and red is the percentage incorrect. On the x-axis are the categorical post-scan judgments: REC, TOT, FOK and UNK. (C) The bar chart on the top right shows the in-scanner response times in milliseconds. On the x-axis are the categorical post-scan judgments: REC, TOT, FOK, and UNK. (D) The scatterplot on the bottom left shows age on the x-axis and the percentage of in-scanner remembered names on the y-axis. The line represents a linear regression (R = −0.269, P = 0.021). (E) The scatterplot on the bottom middle shows age on the x-axis and the percentage of post-scan TOT on the y-axis. The line represents a linear correlation (R = 0.235, P = 0.045). (F) The scatterplot on the bottom right shows the percentage of in-scanner remembered names on the x-axis and the percentage of TOT on the y-axis. The line represents a linear correlation (R = −0.149, P = 0.21).

To verify the occurrence of TOT experiences inside the MRI, we examined the response times for the judgment inside the scanner (i.e., “yes, I remember the name”). On average, REC items were judged in 2897 ± 85 milliseconds, TOT-items in 4186 ± 127 milliseconds, FOK items in 3614 ± 117 milliseconds, and UNK items in 2722 ± 90 milliseconds (Fig. 2C.) Paired t-tests indicated that the response times for TOT items were significantly longer than any of the other judgments (TOT > REC; t = 13.43, P < 0.001; TOT > FOK; t = 5.62, P < 0.001; TOT > UNK, t = 12.27, P < 0.001) which is consistent with previous fMRI studies on TOT (Maril et al. 2001; Shafto et al. 2010).

Next, we examined the relationship between age, name memory, and TOT. Name memory was quantified by the percentage of “yes” responses inside the MRI, and TOT was quantified by the percentage of TOT responses in the post-scan test. Pearson correlations indicated that increasing age was associated with both a decrease in the percentage of recollected names (r = −0.269, t = −2.36, P = 0.021, Fig. 2D), and an increase in percentage of TOT responses (r = 0.235, t = 2.04, P = 0.045, Fig. 2E). We found no significant correlation between the percentage of names remembered and the percentage TOT experiences (r = −0.149, t = −1.27, P = 0.21, Fig. 2F). Using a linear regression model (multiple r = 0.283), we examined the relationship between the percentage of recollected names and the percentage of TOT endorsements while controlling for age. Similarly, this model was not indicative of a relationship between the percentage of recollected names and percentage of TOT (t = −0.77, P = 0.44), while confirming the relationship between age and the percentage recollected names (t = −2.10, P = 0.039). Together, these regression analyses indicate that the percentage of names recollected and of TOT endorsements are relatively independent, although both are related to age.

Whole Brain Functional MRI Results

We identified brain regions associated with recognition of famous faces, recollection, and TOT experiences (Fig. 3). First, we examined the contrast in fMRI activity evoked by famous faces compared with novel (non-famous) faces (P < 0.05, FDR-corrected), regardless of the participant's behavioral response. A large set of brain regions, including the left lateral prefrontal cortex, retrosplenial cortex, posterior cingulate cortex and precuneus, the inferior parietal cortex, and the bilateral hippocampal formation showed greater fMRI activity during exposure to famous as compared with novel faces (Fig. 3A). Secondly, we identified brain regions associated with successful recollection of famous names (P < 0.05, FDR-corrected). The retrosplenial cortex, posterior cingulate cortex and precuneus, inferior parietal cortex, and bilateral hippocampal formation showed greater fMRI activity when names were judged as successfully recollected in the post-scan test (Fig. 3B). Third, we identified brain regions associated with TOT experiences (P < 0.05, FDR-corrected). The lateral prefrontal cortex, anterior insular cortex, and supplemental motor area, including the anterior cingulate cortex showed greater fMRI activity when names were judged as TOT in the post-scan test (Fig. 3C). Together these fMRI analyses indicate that successfully remembering names of famous individuals activates brain regions associated with recollection. In contrast, another set of brain regions, including the lateral prefrontal cortex and anterior cingulate cortex/supplemental motor area, is activated when names remain on the TOT.

Follow-up Analysis: Level of fMRI Activity

To further clarify the role of brain regions in successful recollection and failure to retrieve names, we extracted average fMRI activity for REC, TOT, FOK, and UNK versus fixation from the hippocampal formation, retrosplenial cortex, and lateral prefrontal cortex in the left hemisphere. The left hippocampal formation (Fig. 4A; MNI = −18, −19, −16; Tmax = 8.15) showed no difference in fMRI activity for REC and TOT (t = 1.43, P = 0.16), as indicated by paired t-tests. At the same time, activity was greater for REC compared with FOK (t = 6.76, P < 0.001) and UNK (t = 4.41, P < 0.001) and similarly for TOT compared with FOK (t = 4.48, P < 0.001) and UNK (t = 2.98, P = 0.004). UNK items showed slightly more fMRI activity compared with FOK (t = 2.45, P = 0.017). The retrosplenial cortex (Fig. 4B; MNI = −3, −55, 23; Tmax = 10.04) showed the greatest level of fMRI activity for REC compared with TOT (t = 3.68, P < 0.001), FOK (t = 5.28, P < 0.001), and UNK (t = 5.42, P < 0.001). TOT also showed greater activity compared with FOK (t = 2.17, P = 0.039) and a trend compared with UNK (t = 1.83, P = 0.071), while FOK and UNK showed no difference in fMRI activity (t = 0.11, P = 0.91). The lateral prefrontal cortex (Fig. 4C; MNI = −42,23,−7; Tmax = 12.70) exhibited the greatest level of fMRI activity for TOT compared with REC (t = 2.35, P = 0.021), FOK (t = 5.87, P < 0.001), and UNK (t = 6.50, P < 0.001). REC also exhibited greater activity compared with FOK (t = 5.50, P < 0.001) and UNK (t = 6.50, P < 0.001), while FOK and UNK showed no difference in fMRI activity (t = 0.35, P = 0.72).

To further clarify the influence of the in-scanner memory responses in relation to post-scan judgments of TOT, we examined whether fMRI activity in the hippocampus, retrosplenial cortex, and left PFC, was distinct for TOT-items judged remembered or not remembered inside the MRI (Supplemental Materials). Using paired t-tests in the previously defined regions of interest, we found no significant difference in the hippocampus (P = 0.401) and left PFC (P = 0.116), and a trend for greater activity in the retrosplenial cortex- when TOT items were judged as “remembered” inside the MRI (P = 0.064). This trend suggests that previously remembered TOT-items evoke activity levels more similar to REC responses, which also evoke greater activity in the retrosplenial cortex (Supplemental Figure S2), while TOT-items not remembered inside the scanner show activity levels more similar to FOK responses.

Discussion

We found both behavioral and functional imaging evidence that age-related increases in TOT experiences are distinguishable from age-related decline in memory for names, which is consistent with previous behavioural (Heine et al. 1999; Cleary 2006; Schwartz and Metcalfe 2011; Schwartz and Brown 2014; Cleary and Claxton 2015) and neuroimaging studies (Maril et al. 2001, 2005; Shafto et al. 2007; Galdo-Alvarez et al. 2009). A heterogeneous set of brain regions was engaged during retrieval of famous face-name associations and these regions where divided into those related to successful recollection, resembling the “recollection network” (Rugg and Vilberg 2013), and those associated with TOT, resembling the “cognitive control network” (Aron et al. 2007; Cole and Schneider 2007; Pochon et al. 2008). We found that the hippocampal formation was similarly activated in recollection and TOT experiences. The subsequent recognition of the correct name on multiple choice was quite high for TOT stimuli, providing support that indeed information could have been partially recollected by the hippocampal formation, even if the name was not explicitly retrieved. Thus, this information was not accessible, or at least did not support immediate recollection of the name. This finding is in line with the notion that during TOT experiences, partial information is often retrieved (Rubin 1975; Maril et al. 2005). We also found that the activity in retrosplenial cortex, in contrast with the hippocampal formation, distinguished between successful recollection and TOT experiences. This suggests that the retrosplenial cortex might plays a pivotal role in the recollection network. Below we discuss these findings in greater detail including the limitations and interpretation of these findings.

Behavioral Dissociation in Cognitively Normal Older Adults

Older adults commonly report increased difficulty when freely recalling proper names, as well as more frequent TOT experiences. The lack of a direct association between name memory inside the MRI, and post-scan self-report of TOT is consistent with a recent study by Salthouse and Mandell (2013), which also reported a partial dissociation between age-related increases in TOT and age-related memory decline. However, the exact relationship with age depends on the definition of the TOT rate. We defined the TOT-rate as a function of total number of items observed, while some other studies have divided by the number of recollected versus not recollected names depending on the research question (Gollan and Brown 2006). In the Supplemental Materials, we included comparisons between these alternative definitions of the TOT-rate, name memory, and age (Supplemental Figure S3). These supplemental analyses demonstrate that TOT experiences increase with age, but only relative to items judged as recollected post-scan, and not relative to the number of not recollected items. Thus, the age-related increase in the TOT-rate depends on the assumption that TOT experiences are not part of successful recollection. In general, these different definitions for the TOT-rate confirm that TOT and naming can be dissociated.

We found an age-related increase in TOT experiences in older adults (age > 60). We did not include young adults, as many the famous faces would not have been known to younger. Using a correlational approach within a cohort of older adults only, we can draw limited conclusions about TOT experiences across the lifespan. Rather, we interpret the findings in the context of healthy aging versus occult pre-clinical neurodegeneration. However, TOT experiences also occur in children and young adults (Brown 2012), when age-related memory decline is by definition absent, further suggesting that TOT experiences in older adults may not be solely a function of more general memory decline. Salthouse and Mandell (2013) examined healthy adults across the lifespan (age > 30) and their findings were largely driven by older adults (age > 60), similar to age-range of the Harvard Aging Brain Study. This previous study, combined with our behavioral findings, support the notion that increases in TOT may reflect age-related difficulties in retrieval monitoring rather than frank declines, or deficits, in either semantic or episodic memory.

Brain Regions Activated by Famous Faces

By contrasting brain activity evoked by famous faces and novel faces, we identified a set of brain regions often associated with memory retrieval (Spaniol et al. 2009; Kim 2015). Using the post-scan test, we also identified a relatively large set of brain regions associated with successful recollection and a relatively small set associated with TOT (Fig. 3). The regions associated with recollection are a key subset of the default-network (Raichle et al. 2001), including the retrosplenial cortex and hippocampal formation, and likely represent the set of regions recently dubbed the “recollection network” (Rugg and Vilberg 2013). The task-evoked activity in this set of brain regions, including the hippocampal formation, provide support for the notion that recollection of famous names is not purely semantic, but benefits from episodic and/or autobiographical memory (Westmacott and Moscovitch 2003; Douville et al. 2005; Denkova et al. 2006; St-Laurent et al. 2011). Our task may particularly engage these memory systems because participants are asked to recall the name associated with a specific picture of a famous individual, which can require a series of retrieval processes to match the specific stored representations of the well-known individual and further retrieval of stored information about the person, including their name. In contrast to the “recollection network”, TOT experiences evoke activity in a distinct set of brain regions, including the lateral prefrontal cortex, consistent with previous studies on TOT (Kikyo et al. 2001; Maril et al. 2001, 2005; Shafto et al. 2007, 2010). These TOT related brain regions do not seem to align within a single intrinsic network, for example, the salience network or frontoparietal control network (Seeley et al. 2007; Vincent et al. 2008; Cole and Petersen 2014). Instead, they resemble a set of regions that has been dubbed the “cognitive control network” (Aron et al. 2007; Cole and Schneider 2007; Pochon et al. 2008) that spans both salience network and frontoparietal control network regions.

The Hippocampal Formation is Similarly Activated in Recollection and TOT

To clarify the role of individual brain regions in recollection and retrieval failure, we plotted activity in the left hippocampal formation, retrosplenial cortex, and lateral prefrontal cortex. The hippocampal formation was similarly activated during recollection and TOT (Fig. 4A). This findings support the idea that TOT experiences are distinguishable from other types of retrieval failure, not only in the subjective experience but also in that partial information is often retrieved (Rubin 1975; Maril et al. 2005). The retrieval of partial, contextual information during TOT experiences is also likely to evoke activity in the hippocampal formation. This finding is consistent with the observation that fMRI activity in the hippocampal formation can distinguish previously seen versus novel information independent of the subjective experience (Henke et al. 2003; Daselaar 2006). Alternatively, the similar level of hippocampal activity in recollection versus TOT could also directly reflect the strong sense of familiarity that coincides with TOT experiences (Wais 2010).

The Retrosplenial Cortex is Strongly Activated in Recollection

The retrosplenial cortex showed the greatest activity for recollection and incrementally reduced activity in retrieval failure (Fig. 4B). This is consistent with studies that implicate the retrosplenial cortex in the integration and evaluation of information from memory (Johnson et al. 2009; Summerfield et al. 2009; Miller et al. 2014). When successfully remembering names of famous individuals, information from both episodic and semantic memory might be integrated into a coherent representation (Westmacott and Moscovitch 2003; Denkova et al. 2006). In TOT experiences, only partial information or incorrect information, is being retrieved, and is not integrated in a coherent representation. The lack of integration could explain the difference in fMRI activity between the hippocampal formation and retrosplenial cortex. This interpretation is also consistent with studies that have associated the retrosplenial cortex to “knowing that you know” (Chua et al. 2006; Vannini et al. 2010). More generally, these findings suggest a central role of the retrosplenial cortex within the recollection network, as integration of information likely requires communication with multiple brain regions (Rugg and Vilberg 2013).

The Lateral Prefrontal and Anterior Cingulate Cortex are Strongly Activated in TOT

The lateral prefrontal and anterior cingulate cortex exhibited the greatest activity during TOT experiences, even in comparison with successful recollection or other types of retrieval failure (Fig. 4C). This is consistent with previous fMRI studies (Maril et al. 2001, 2005). To clarify whether brain activity was specific to TOT experiences or driven by recollection (REC) as compared with failure, we conducted a follow-up analysis using the items that elicited a feeling-of-knowing (FOK). The follow-up analysis, using a whole brain comparison between TOT and FOK items only, demonstrated that lateral prefrontal cortex and anterior cingulate cortex/supplemental motor area show greater activity for TOT experiences compared with FOK (Supplemental Figure S4), as well as REC (Fig. 3). Together, these whole brain analyses clarify what regions are especially active during TOT experiences. TOT, related activity in the prefrontal cortex, has often been interpreted in terms of cognitive control processes that occur when information cannot be retrieved (Maril et al. 2001; Shafto et al. 2010). The lateral prefrontal cortex is often linked to monitoring and awareness of errors (Wheeler et al. 2008; Neta et al. 2015). Thus, one interpretation is that activity in the lateral prefrontal cortex reflects cognitive control processes related to conflict between the feeling that information is present in memory and a failure to successfully access this information. Similarly, the anterior cingulate cortex has been linked to monitoring and awareness of errors (Botvinick et al. 2004). Thus, the increase in TOT experiences in older adults might be partially driven by a failure in monitoring of errors that can result in persistent attempts to retrieve information from memory. This interpretation of TOT activation is consistent with the view that age-related changes in the prefrontal cortex underlie age-related decline in retrieval monitoring (McDonough et al. 2013). Supporting this interpretation, the activity pattern related to TOT we observed strongly resembled the pattern previously linked to both monitoring of retrieval (Shafto et al. 2010; McDonough et al. 2013; Wang et al. 2016) and cognitive control (Aron et al. 2007; Cole and Schneider 2007; Cohen et al. 2008). This also suggests that TOT may be not by detrimental, but rather can be compensatory, by suggesting the possibility that retrieval failure may be overcome by encouraging additional retrieval search (Schwartz and Metcalfe 2011; Schwartz and Brown 2014).

Considerations for Interpretation

One limitation of our study is that we used self-reports to quantify TOT experiences. Inside the MRI scanner, we were unable to assess vocal utterances as speech induces motion that distorts the MRI signal. Thus, we rely on self-report as do most other comparable neuroimaging studies (Maril et al. 2001, 2005; Shafto et al. 2010). Self-report drives the interpretation towards meta-cognitive theories of TOT, rather than psycholinguistic theories (Schwartz and Metcalfe 2011; Brown 2012; Schwartz and Brown 2014). In line with meta-cognitive theories, we define tip-of-tongue as the strong feeling that information is present in memory, but cannot be successfully retrieved (Schwartz 2006) and discuss TOT related brain activity in the context of the control network. Nonetheless, the left lateral PFC has also been labeled a “higher order” language region (Fedorenko and Thompson-Schill 2014). Moreover, both the lateral PFC and the anterior cingulate cortex are activated during retrieval of phonological or semantic information (Davachi et al. 2001; Kan and Thompson-Schill 2004). Psycholinguistic models of TOT can also explain the patterns of fMRI activity and typically emphasize two components of retrieval. More specifically, similar levels of hippocampal activity can be explained by successful retrieval of partial information from memory, while differences in activity in the lateral PFC can be explained by the failure to retrieve phonological information. Thus, although our methods are more consistent with meta-cognitive theories, the findings are also compatible with a psycholinguistic interpretation and do not provide strong evidence in favor for one theory or another. Thus, although our methods are more consistent with meta-cognitive theories, the findings are also compatible with a psycholinguistic interpretation and do not provide strong evidence in favor for one theory or another.

A second limitation is that we used a post-scan evaluation to retrospectively isolate TOT related brain activity in order not to influence the naming inside the scanner by meta-judgments. This post-scan evaluation was motivated by a behavioral study that demonstrated that TOT experiences are likely to recur when items are presented for a second time (Warriner and Humphreys 2008). However, behavioral research has also shown that TOT experiences can occur at time one, but not time two, or vise versa. The first presentation could induce “incubation”, whereby more names are remembered later and TOT experiences decrease (Choi and Smith 2005; Schwartz 2010). Incubation might therefore result in an underestimation of the number of TOT experiences inside the MRI. Then again, post-scan participants were instructed to speak the names out loud before making a rating. This explicit vocal utterance might have induced more TOT experiences and resulted in an overestimation of TOT (Schwartz and Brown 2014). Overall, the in-scanner judgments (yes/no) were consistent with the post-scan ratings (REC/TOT/FOK and UNK). The REC items were typically remembered (84.8% yes) and UNK items almost always rejected (98.5% no). Interestingly, TOT-items were equally likely to have been remembered (45.7%) or not (55.3%). This is at odds with “incubation” and suggests that explicit vocal utterances might have increased the number of TOT experiences. One alternative interpretation is that a strong feeling of familiarity encouraged participants to reply, “Yes, I remember the name”, while in fact they would not have been able to produce name in the scanner or in subsequent questioning. Regardless of whether the TOT experiences decreased or increased in the post-scan evaluation, we only gather indirect information on the TOT experiences inside the MRI. An additional limitation of the post-scan rating is that REC/TOT/FOK/UNK are collectively exhaustive categories. Therefore, the post-scan rating might have been influenced by the relative difficulty of retrieval decision. Indirect evidence for TOT experiences comes from response times for the yes/no judgments inside the MRI. These were longest for items judged TOT (see Fig. 2). This suggests that the judgments inside the MRI were most difficult for items judged TOT post-scan. This is consistent with a meta-cognitive definition of TOT experiences. Finally, the neuroimaging results are very consistent with previous fMRI studies on TOT (Maril et al. 2001,2005; Shafto et al. 2010). This suggests that the post-scan evaluation captures TOT experiences. However, based on behavioral studies (Choi and Smith 2005; Warriner and Humphreys 2008; Schwartz 2010), it is possible that the retrospective evaluation of TOT experiences captures the relative difficulty of the mnemonic decisions and it is still the mnemonic decision that drives fMRI activity in our study, as well as other fMRI studies on TOT (Maril et al. 2001, 2005; Shafto et al. 2007; Galdo-Alvarez et al. 2009).

A third limitation is that by probing retrieval of famous names, presumably stored in long-term memory, we have limited control over when these faces and names were initially encoded and how frequently they have been reinforced. To address the concern that participants might never have known a famous face, we included a multiple-choice question with 1 target and 3 alternate names (Fig. 1). On the multiple-choice, participants correctly identified most of the names. Even for items judged unknown, they were correct more than 73.5% of the time. The multiple choice design of the recognition paradigm likely inflated the accuracy rate, as subjects might have been able to reason through their responses via a process of elimination (“aka it is not Nixon”), rather than relying on explicit memory. Therefore, the multiple-choice is likely to have overestimated the percentage of famous names known to the participants. Nonetheless, our results continue to suggest that most of the names were known, and if not recalled explicitly, could be identified by eliminating alternatives. Therefore, individual differences in familiarity with the famous faces and names are unlikely to fully account for the observed behavior or neuroimaging results.

Relevance of TOT for Understanding Aging

TOT experiences in older adults increase worry about decline in memory and in particular, fear of developing Alzheimer's disease (Brown 1991; Schwartz 2006). The dissociation between age-related increases in TOT and decline of memory suggest that this fear is not universally justified. TOT experiences are related to increased activity in the prefrontal cortex, which is often interpreted as a sign of compensation (Cabeza 2002; Davis et al. 2008). One possibility is that TOT experiences are especially prevalent in older adults who are trying to compensate for memory decline. In that case, TOT experiences might be a sign of compensation (Stern 2012). A second possibility is that TOT experiences increase with age because of a growing vocabulary across the lifespan (Dahlgren 1998). This alternative explanation for age-related increases in TOT experiences does not require memory decline and can also explain the dissociation. Nevertheless, both compensation and the growth of one's vocabulary are consistent with the view that TOT experiences are not merely a consequence of age-related decline of memory.

A recent longitudinal study demonstrated that cognitively normal older adults at high genetic risk for Alzheimer's disease show aberrant fMRI activation in the posteromedial cortex—including retrosplenial cortex—during recognition of famous faces and these at-risk adults declined faster on episodic memory (Rao et al. 2015). Our group has also shown that cognitively normal older adults with high levels of amyloid show aberrant activity in posterior brain regions during memory encoding and retrieval (Vannini et al. 2013). Thus, it is possible that memory decline is more closely linked to age-related changes in posterior brain regions and TOT experiences are driven by age-related changes in prefrontal regions. A dissociation between age-related changes in episodic memory and TOT is compatible with the emerging view that age-related decline in memory and executive function are driven by multiple, yet distinct, pathological processes that often co-occur (Hedden et al. 2012; Jagust 2013).

The current results could suggest that TOT experiences emerge as a consequence of age-related alterations that impact cognitive control, and are relatively independent of age-related alterations that drive memory decline. More specifically, it is possible that cerebrovascular pathology affecting frontal white matter tracts preferentially increases TOT experiences, whereas emerging amyloid and tau pathology will be associated with failure of episodic memory. Regardless of the underlying pathology, the behavioral and neuroimaging results suggest that TOT experiences are not solely the consequence of age-related decline of the recollection network, but are likely the consequence of age-related changes in brain regions that support cognitive control. More generally, these findings demonstrate that TOT experiences represent a distinct cognitive phenomenon that might prove useful to further dissociate cognitive aging from occult age-related neurodegenerative disease.

Supplementary Material

Supplementary material can be found at: http://www.cercor.oxfordjournals.org/.

Supplementary Material

Supplementary Data
Click here for additional data file. (1.3MB, docx)

Notes

Information on the Harvard Aging Brain Study can be found at: http://www.nmr.mgh.harvard.edu/harvardagingbrain. Conflict of Interest: None declared.

Funding

National Institute on Aging (grants P01 AG036694, P50 AG005134 to (R.S.), K01 AG040197 to T.H.); T32 Translational Research in Aging (5T32AG023480-08 to K.P.); Charles King Trust Postdoctoral Fellowship (K.P.); the European Molecular Biology Organization (ALTF 318-2011 to W.H.); a philanthropic gift to Foundation for Neurologic Diseases (W.H./R.S.); the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies (P41EB015896); a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health; NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, (grant numbers S10 RR023401, S10 RR023043); National Institute on Aging or the National Institutes of Health.

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