The dorsal area of the anterior cingulate cortex (ACC) constructs the salience network associated with the anterior insular cortex. Conventional brain imaging studies, such as functional magnetic resonance imaging (fMRI), have demonstrated that relational memory formation occurs in the ACC. However, how such memory is encoded and retrieved remains unknown due to limited time resolution of conventional fMRI. This study aimed to investigate temporal dynamics of the dorsal ACC (dACC) during word-pair tasks based on a newly developed event-related deep brain activity (ER-DBA) method using occipital electroencephalogram (EEG) signal powers. The method assesses dACC activity at a temporal resolution of approximately 0.3 s beyond the conventional resolution limit. We found that transient deactivation of dACC during the presentation of the second word of each pair was essential for encoding success regardless of whether the words were related or unrelated. We also found that memory accuracy was not affected by the intervention of inter-trials until the recall trial. Taken together, these findings suggest that dACC deactivation for encoding success is accompanied with short-term potentiation essential for durability of memory. We further found that false memory formation associated with the presentation of word pairs was occasionally committed. In such cases, dACC exhibited a similar transient deactivation although false memory commission was independent of related or unrelated conditions. Our findings suggest that encoding and retrieval of associates are paralleled and that simultaneous production of associates seems to be an essential strategy for successful relational memory formation. The study was limited to the assessment of dACC activity and did not account for other regional brain activities or receptor regulation related to short-term potentiation. We detected fast behavior of dACC during relational memory formation using the novel ER-DBA method. Such temporal dynamics will be important for eliciting underlying mechanisms of memory dysfunctions.
Traditionally, memory functions were believed to be regulated by the hippocampus and the medial temporal lobe (MTL) [
The deactivation of MTL during encoding is counter-intuitive as the hippocampus plays a primary role in durable memory formation. The hippocampus may, therefore, be dissociable from the network related to MTL [
Clinical evidence demonstrating that semantic-dementia patients maintain intact episodic memory despite severe atrophy of the hippocampus contradicts theoretical frameworks relying on MTL functions [
A candidate novel framework could be based on the anterior cingulate cortex (ACC) that has been hypothesized to contribute to the consolidation of recent and remote memories associated with information transferred from the hippocampus [
We hypothesized that dACC is directly related to durable memory formation and that its temporal activity reflects encoding and recall processes during memory formation, assuming that the two memory processes are temporally dissociable. We tested this hypothesis by investigating dACC functions during durable memory formation. The activity of dACC was assessed with a noninvasive technique using occipital electroencephalogram (EEG) alpha-2 (10 - 13 Hz) power defined as a deep brain activity (DBA) index [
We used word-pair tasks in our experiment. Word-pair tasks are associated with relational memory [
Subjects were recruited from Kobe University. Twelve healthy volunteers (six males and six females) from the ages of 27 to 44 (mean = 32; standard deviation, SD = 5.3) with no historical records of hearing impairment and psychiatric diseases participated in the study. They provided written informed consent in accordance with the protocol approved by the ethical committee of Kobe University Graduate School of Health Sciences (No. 529). All subjects were therapists with similar higher-education levels.
We adopted two word-pair lists for the word-pair tasks. The lists included 30 commonly used and semantically related (i.e., lion versus tiger) or unrelated (i.e., snake versus bread) Japanese nouns. A total of 60 pairs were used in this study. The nouns were extracted from the standard verbal paired-associate learning test (S-PA) with permission of the Japan Society for Higher Brain Dysfunction [
The experimental procedure consisted of two sessions using the two word-pair lists (
In the encoding phase, the paired words were auditorily presented to the subjects by using digital data recorded with a voice recorder by a native speaker. The word pairs W1 and W2 were sequentially presented after the event markers S1 and S2, respectively. The two event markers were separated by 2 s. The interval between the onset of the word presentation and the event marker was approximately 500 ms. At the event markers, beep sounds with frequencies of 1000 Hz were presented to the subjects as prior stimulation to maintain attention. The word pairs (W1-W2) were presented only once. In the encoding phase, the subjects were asked to remember word pairs to induce a delayed recall.
After the encoding session, a recall test started within a few minutes. Such prompt recall test was promoted to distinct encoding failure from exponential decrease of memory accuracy. In the recall phase, the subjects were given the first word (W1) and then asked to orally state the target word (W2) upon presentation of the speech cue (S2). The interval between S1 and S2 was 2 s. The subjects were prevented from ignoring the speech cue in silence (i.e., they were asked to say “Forget” if they had forgotten the target word). The subjects’ responses were recorded on a voice recorder for behavioral analyses. The order of the word pairs varied among the task phases but did not change among subjects.
Scalp EEG signals were recorded from Ag/AgCl electrodes aligned in accordance with the international 10 - 20 system. The recording was conducted under the eye-open condition using a digital EEG recorder with a sampling frequency of 512 Hz and 24-bit analogue-to-digital converters grounded at the AFZ site of the 10 - 10 system. The montage data were generated with references from the mastoid electrodes.
Performance on the word-pair tests was assessed using the subjects’ responses measured on the voice recorder in the recall phase. The performance assessment was repeated for each trial and all trial responses were grouped into three response groups: high memory accuracy (HA), medium memory accuracy (MA), and low memory accuracy (LA). HA responses were defined as accurately remembering the target word, whereas LA responses were defined as forgetting the target word. HA responses were identified by verifying whether the generated words corresponded with the targets. LA responses were detected by self-assessment by stating “Forget”. MA was a discordant response defined as stating a word that differed from the target word. MA was not numerically assessed due to the lack of clear measures for quantitatively evaluating semantic distance between the correct (target) and incorrect (falsely generated) words. Semantic similarity between the false word and target was assessed with multiple experimenters to control for inter-judge reliability. When the false word was similar to the first word of the pair (W1), the false trial was labeled as MA (W1). We similarly defined MA (W2) for the incorrect word similar to W2. Inadequate responses in the recall phase such as missing speech cues, regarded as commission error (CE), were excluded from performance analyses.
In our word-pair tasks, words were sequentially presented according to the trial-by-trial design that presented word pairs separated by only 2 s (
We developed an ER-DBA method with a time resolution of approximately 300 ms to investigate task-oriented activities of deep brain structures for cognitive studies, including dACC and upper brainstem [
Behavioral responses were grouped into performance categories for all subjects. To investigate the effects of lexical similarity on relational memory formation, paired t-tests were performed to detect differences in memory accuracy and CE incidence between related and unrelated pairs. To determine whether the false W1 and W2 responses were similar, paired t-tests were performed between the
two MA groups. We further investigated how the presented words affected memory accuracy. Statistical analyses using paired t-tests were performed between the MA (W1) and MA (W2) groups.
The baseline of the ER-DBA was used to assess whether dACC was activated or deactivated. Statistical significance for the assessment was numerically evaluated with the standard error of the mean (SE). The statistical evaluation was conducted for every trace accompanied by a shaded area corresponding to 1.96 SE to show significant activation or deactivation at a significance level of 0.05. Deactivations regarded as dips in ER-DBA traces were characterized by depth and duration. Depth was assessed by the bottom of the traces. Width was numerically evaluated using the full width at half maximum (FWHM).
Memory performance was evaluated using recorded speech data and represented by task scores across subjects (
Numerical analyses on behavioral performance data revealed that related word pairs had much higher HA response incidence than unrelated pairs (p < 0.01;
Subjects | Responsea (%) | Trialb | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
ID | Age | Sex | HA | LA | MA | CE | HA | LA | MA | CE | ||||
(W1) | (W2) | (W1) | (W2) | |||||||||||
1 | 38 | F | 23 | 6 | 1 | 0 | 0 | 1 - 5, 7 - 18, | 6, 19, 20, | 28 | − | − | ||
(76.7) | (20.0) | (3.3) | 21 - 23, 25 - 27 | 24, 29, 30 | ||||||||||
2 | 39 | M | 24 | 3 | 1 | 1 | 1 | 1 - 3, 5, 6, 8 - 16, | 4, 17, 21 | 7 | 20 | 23 | ||
(80.0) | (10.0) | (3.3) | (3.3) | 18, 19, 22, 24 - 30 | ||||||||||
3 | 29 | F | 18 | 9 | 2 | 1 | 0 | 1 - 7, 10 - 13, | 8, 14, | 9, 26 | 15 | − | ||
(60.0) | (30.0) | (6.7) | (3.3) | 16 - 18, 23 - 25, 27 | 19 - 22, 28 - 30 | |||||||||
4 | 29 | M | 24 | 4 | 1 | 0 | 1 | 1 - 3, 5 - 15, | 16, 21, | 4 | − | 23 | ||
(80.0) | (13.3) | (3.3) | 17 - 20, 22, 24 - 28 | 29, 30 | ||||||||||
5 | 30 | F | 22 | 6 | 2 | 0 | 0 | 1 - 6, 8, 10 - 13, 15, | 7, 14, 16, | 9, 17 | − | − | ||
(73.3) | (20.0) | (6.7) | 18 - 21, 23, 25 - 27, 29, 30 | 22, 24, 28 | ||||||||||
6 | 30 | M | 27 | 2 | 1 | 0 | 0 | 1 - 20, 22 - 28 | 29, 30 | 21 | − | − | ||
(90.0) | (6.7) | (3.3) | ||||||||||||
7 | 28 | F | 21 | 6 | 2 | 1 | 0 | 1 - 8, 11 - 18, | 9, 10, 19, | 22, 28 | 25 | − | ||
(70.0) | (20.0) | (6.7) | (3.3) | 20, 23, 24, 26, 27 | 21, 29, 30 | |||||||||
8 | 27 | F | 25 | 2 | 2 | 1 | 0 | 1 - 7, 9, 10, 12 - 15, | 21, 29 | 11, 16 | 8 | − | ||
(83.3) | (6.7) | (6.7) | (3.3) | 17 - 20, 22 - 28, 30 | ||||||||||
9 | 44 | F | 23 | 7 | 0 | 0 | 0 | 1 - 8, 10, 12 - 21, | 9, 11, 22, | − | − | − | ||
(76.7) | (23.3) | 23, 24, 26, 27 | 25, 28 - 30 | |||||||||||
10 | 28 | M | 28 | 2 | 0 | 0 | 0 | 1, 3 - 28, 30 | 2, 29 | − | − | − | ||
(93.3) | (6.7) | |||||||||||||
11 | 32 | M | 25 | 4 | 1 | 0 | 0 | 1, 3 - 13, 15 - 26, 30 | 2, 14, | 27 | − | − | ||
(83.3) | (13.3) | (3.3) | 28, 29 | |||||||||||
12 | 33 | M | 27 | 2 | 0 | 0 | 1 | 1 - 22, 24 - 27, 30 | 28, 29 | − | − | 23 | ||
(90.0) | (6.7) |
Subjects | Responsea (%) | Trialb | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
ID | Age | Sex | HA | LA | MA | CE | HA | LA | MA | CE | ||||
(W1) | (W2) | (W1) | (W2) | |||||||||||
1 | 38 | F | 18 | 10 | 1 | 1 | 0 | 1 - 5, 7, 9, 11, 12, | 6, 8, 14, 15, | 13 | 10 | − | ||
(60.0) | (33.0) | (3.3) | (3.3) | 16 - 18, 21 - 25, 30 | 19, 20, 26 - 29 | |||||||||
2 | 39 | M | 19 | 8 | 2 | 1 | 0 | 1 - 3, 5, 9 - 12, 14, 16, 17, | 4, 6 - 8, 15, | 13, 25 | 26 | − | ||
(63.3) | (26.7) | (6.7) | (3.3) | 19 - 21, 23, 24, 27, 29, 30 | 18, 22, 28 | |||||||||
3 | 29 | F | 16 | 13 | 0 | 1 | 0 | 2, 5, 7, 8, 10, 11, | 1, 4, 6, 9, 12, 13, | − | 3 | − | ||
(53.3) | (43.3) | (3.3) | 14 - 18, 21, 22, 27, 29, 30 | 19, 20, 23 - 26, 28 | ||||||||||
4 | 29 | M | 8 | 17 | 1 | 4 | 0 | 1, 6, 7, 11, 16, 18, 20, 29 | 2 - 5, 8 - 10, 13, 15, 19, | 25 | 12, 14, | − | ||
(26.7) | (56.7) | (3.3) | (13.3) | 21, 22, 24, 26 - 28, 30 | 17, 23 | |||||||||
5 | 30 | F | 18 | 7 | 0 | 4 | 1 | 2, 3, 5, 7, 10 - 15, 17, | 1, 4, 6, 9, 16, 23, 24 | − | 8, 20, | 19 | ||
(60.0) | (23.3) | (13.3) | 18, 22, 25, 26, 28 - 30 | 21, 27 | ||||||||||
6 | 30 | M | 13 | 14 | 0 | 3 | 0 | 1, 2, 7, 9, 11, 17, 19, | 3 - 6, 8, 10, 12 - 15, | − | 16, | − | ||
(43.3) | (46.7) | (10.0) | 21 - 24, 29, 30 | 18, 20, 27, 28 | 25, 26 | |||||||||
7 | 28 | F | 6 | 19 | 1 | 4 | 0 | 2, 5, 7, 13, 17, 26 | 1, 3, 4, 6, 8 - 12, 14 - 16, | 18 | 23, 24, | − | ||
(20.0) | (63.3) | (3.3) | (13.3) | 19 - 22, 25, 27, 30 | 28, 29 | |||||||||
8 | 27 | F | 8 | 22 | 0 | 0 | 0 | 4, 7, 16, 21, | 1 - 3, 5, 6, 8 - 15, | − | − | − | ||
(26.7) | (73.3) | 23, 24, 25, 26 | 17 - 20, 22, 27 - 30 | |||||||||||
9 | 44 | F | 8 | 19 | 0 | 2 | 1 | 1, 4, 7, 17, | 2, 5, 6, 8, 9, 11 - 16, | − | 3, 22 | 10 | ||
(26.7) | (63.3) | (6.7) | 20, 21, 24, 30 | 18, 19, 23, 25 - 29 | ||||||||||
10 | 28 | M | 13 | 16 | 1 | 0 | 0 | 1, 3, 7, 8, 11, 12, 14, | 2, 4 - 6, 9, 10, 16, | 13 | − | − | ||
(43.3) | (53.3) | (3.3) | 15, 17, 21, 25, 26, 30 | 18 - 20, 22 - 24, 27 - 29 | ||||||||||
11 | 32 | M | 12 | 14 | 2 | 1 | 1 | 1, 2, 5 - 7, 15, | 3, 4, 8 - 11, 14, 16, | 13, 18 | 12 | 27 | ||
(40.0) | (46.7) | (6.7) | (3.3) | 17, 21, 22, 25, 29, 30 | 19, 20, 23, 24, 26, 28 | |||||||||
12 | 33 | M | 11 | 17 | 1 | 1 | 0 | 2, 7, 11, 14, 18, | 1, 3 - 6, 8 - 10, 12, 15, | 13 | 17 | − | ||
(36.7) | (56.7) | (3.3) | (3.3) | 21, 23, 25, 26, 29, 30 | 16, 19, 20, 22, 24, 27, 28 |
aNumbers for each response represent the number of times that response was given by the subject out of a total of 30 trials per session. HA: high memory accuracy response; LA: low memory accuracy response; MA: medium memory accuracy response stating false words; MA (W1/W2): medium-accuracy response stating false words similar to either W1 or W2; CE: commission error. bNumbers indicate the nth word-pair that categorized HA, LA, or MA for the related session and HA, LA, MA (W1), or MA (W2) for the unrelated session.
False words that differed from the target word were regarded as discordant responses denoted by MA (medium memory accuracy). We obtained 17 MA responses for the related condition and 31 for the unrelated condition among the 12 subjects.
To ascertain the robustness of the initial encoded memory, we examined the HA response (remembered) rate versus the number of inter-trials (∆N) involved in the retention period until later recall (
Related word pair―MA | |||
---|---|---|---|
W1 | W2 | False answer | Assessment |
Ju-do | Sumo | Kendo (2) | W1 |
Railroad | Station | Train (1) | W1 |
Rice | Miso-soup | Dish (1) | W1 |
Shower | Bath | Towel (1) | W1 |
Yukata | Paper fan | Belt (1) | W1 |
Soy-sauce | Sauce | Salt (1) | W1 |
Chest | Closet | Drawer (1) | W1 |
Marathon | Relay race | Relay (1) | W1 |
Boots | Umbrella | Rain (1) | W1 |
Salt | Sugar | Pepper (1) | W1 |
Sea | Mountain | Ship (1) | W1 |
Sea | Mountain | River (1) | W1 |
Sun | Moon | Cloud (1) | W2 |
Kendo | Karate | Ju-do (1) | W2 |
Hospital | Pharmacy | Medicine (1) | W2 |
Lion | Tiger | Zebra (1) | W2 |
Unrelated word pair―MA | |||
W1 | W2 | False answer | Assessment |
Lip | Can | Skin (5) | W1 |
Pimple | Rubber band | Cream (2) | W1 |
Teacher | Dragonfly | Music (1) | W1 |
Teacher | Dragonfly | Mike (1) | W1 |
Fountain | Saw | Cutter knife (2) | W2 |
Trumpet | Turtle | Frog (2) | W2 |
Glass | Newspaper | Paper (2) | W2 |
Ham | Sword | Cutter knife (1) | W2 |
Ham | Sword | Saw (1) | W2 |
Seaweed | Earthworm | Mouse (1) | W2 |
Seaweed | Earthworm | Snake (1) | W2 |
Hairdryer | Thunder | Cutter knife (1) | W2 |
Goldfish | Ladder | Cutter knife (1) | W2 |
Sardine | Sunflower | Sun (1) | W2 |
Gargle | Rainbow | Sun (1) | W2 |
Beach | Stew | Soup (1) | W2 |
Hammer | Cherry Blossoms | Fountain (1) | W2 |
Pimple | Rubber band | Rubber (1) | W2 |
Police car | Tuna | Whale (1) | W2 |
Clown | Fan | Hairdryer (1) | W2 |
Frog | Scoop | Cutting board (1) | W2 |
Violin | Cutter knife | Saw (1) | W2 |
Autumn | Pearl | Heart (1) | W2 |
no significant correlation was detected for the related (r = 0.095, p = 0.61) and unrelated (r = 0.0021, p = 0.99) pairs. This result indicated that HA (remembered) responses reflected the initial encoding success, without any intervention of inter-trials from encoding until later recall (
deactivation during the first (W1) and second (W2) word presentations. In contrast, we found that HA responses including 102 samples provided significant (p < 0.05) DBA deactivation only during the second word presentation. MA responses, regarded as encoding success in spite of imperfect memory formation accompanied with discordant responses stating incorrect words, were found to be significantly (p < 0.05) deactivated for the related and unrelated pairs, whereas they provided small sample sizes of N = 7 and 19, respectively. LA responses did not show any significant deactivation or activation on the ER-DBA traces.
As shown in each inset panels, these dips were characterized by depth and duration, while the depth was assessed by the bottom of the traces during the W2 presentation. The width was numerically evaluated by using FWHM.
an interval of around 500 ms. The speech cue (S2) was delay by 2 s from the onset signal (S1). When the speech cue arrived, the subjects randomly spoke, but they provided right answers or the forgetting sign. The traces exhibited significant deactivation during probe word (W1) presentation for almost all performances including HA (related: p < 0.05), HA (unrelated: p < 0.05), MA (related: p < 0.05), and MA (unrelated: p < 0.05). LA (unrelated) also provided significant deactivation (p < 0.05), whereas only LA (related) showed no significance.
We further characterized deactivations (dips) on ER-DBA traces for HA and MA responses during encoding and recall phases. We found that the widths and depths were narrower and deeper, respectively, for MA than those for HA responses. As shown in
This study aimed to investigate the temporal dynamics of dACC during word-pair tasks. Using a novel ER-DBA method with high temporal resolution compared with conventional imaging methods, we identified mechanisms underpinning relational memory formation.
From the ER-DBA results in the encoding phase (
responses marked as HA were associated with significant deactivation of dACC during presentation of the second word (W2) as target in late recall independently of the task condition (related or unrelated). In contrast, incorrect responses marked as LA did not show any significant deactivation. Responses stating false words and marked as MA showed dACC deactivation patterns similar to those of correct responses. These results suggest that successful relational memory formation including imperfect memory (MA) is predicted by deactivation of dACC in the encoding phase. We also found from the behavior performance results that memory was stable at least in the experimental period, avoiding any influence of inter-trial intervention from encoding until recall (
Previous studies have revealed the role of the ACC in forming immediate, recent, and remote memories. For recent and remote memories, the N-methyl-D-aspartate receptor (NMDAR) is considered to be essential for memory durability accompanied with synaptic plasticity because activated NMDARs contribute to memory stabilization by increasing the number of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors [
Synaptic plasticity can occur even in the formation of short-term memory and the ACC is associated with this process regarded as short-term potentiation (STP) [
From the results associated with MA responses stating false words semantically associated with the target in the late recall session (
Various types of parallel information processes in memory formation have been reported, including integration of dissociable functional processes based on compartmentalization [
Importantly, it was suggested that a series of cognitive processes associated with relational memory formation was completed in a short time window corresponding to the narrow FWHM duration of dACC deactivation of <1 s. Our recent study found that dACC deactivation was correlated with upper brainstem activity associated with the monoaminergic neural systems at the ventral tegmental area [
activities of the deep brain neural structures (e.g., dACC and upper brainstem) and conducted in a short time window of approximately <1 s. Such a short time window may not impede time-limited (<2 s) enhancement of STP by dopaminergic neural activity in reward systems [
We further examined differences on the ER-DBA traces between related and unrelated pairs in encoding. dACC was deactivated during the presentation of the first word (W1) for related pairs while no deactivation was observed for unrelated pairs. Deactivation for the related condition cannot be explained by the model with parallel retrieval benefits (
We elicited that the deactivation of dACC, associated with hyperpolarization for generating giant depolarizing potentials, was essential for encoding success in relational memory formation. According to our recent study [
Another factor is the age-related impairment [
For both cases, an insufficient deactivation of dACC is considered to be effective neurophysiological markers for detecting memory dysfunction in various diseases with memory dysfunction.
To discuss memory dysfunction, we also have to mention excessive deactivation of dACC. As shown in
The ER-DBA method is limited to dACC and reports no information on other brain areas, including the hippocampus and posterior cingulate cortex that are associated with the Papez circuit. These areas are thought to contribute to memory formation based on neural plasticity similar to that occurring in STP. However, relationships between dACC and other Papez-associated areas remain unclear. Future studies should conduct simultaneous EEG and fMRI measurements to explore the mechanisms underpinning relational memory formation.
This study was also limited to an electrophysiological investigation so direct measurement of NMDA effects using positron-emission tomography tracers [
The findings of obtained in this study will contribute in eliciting neural mechanisms involved in memory impairment in various diseases typically including dementia, which has become a world-wide issue owing to its incredibly increasing prevalence in the last few decades [
We investigated dynamic behaviors of dACC during word-pair tasks using a novel event-related deep brain activity (ER-DBA) method to uncover underlying mechanisms of relational memory formation. Our findings suggest that temporal deactivation of dACC is essential for successful encoding and recall of relational memory. Although retention from encoding until later recall was very short, initially encoded memories were robust, independent of intervention of other trials. This suggests that encoding was supported by short-term neural plasticity in a short time window of a few 100 ms provided by the deactivation dip. Such dACC dynamics in relational memory formation, which was detected for the first time by event-related deep brain activity method beyond the temporal limitation of conventional event-related fMRI methods, will be expected to not only contribute to eliciting whole mechanisms of durable memories but also provide novel neurophysiological markers for detecting memory dysfunctions.
This study was partially supported by JSPS KAKENHI Grant Number JP16K01307.
Araki, A., Imai, E. and Katagiri, Y. (2018) Role of the Dorsal Anterior Cingulate Cortex in Relational Memory Formation: A Deep Brain Activity Index Study. Journal of Behavioral and Brain Science, 8, 269-293. https://doi.org/10.4236/jbbs.2018.85017