Human Cerebellum And Corticocerebellar Connections Involved in Emotional Memory Enhancement Part 2

Emotional information is better remembered than neutral information. Extensive evidence indicates that the amygdala and its interactions with other cerebral regions play an important role in the memory-enhancing effect of emotional arousal. While the cerebellum is involved in fear conditioning, its role in the emotional enhancement of episodic memory is less clear. To address this issue, we used a whole-brain functional MRI approach in 1,418 healthy participants. 

Emotion refers to human inner feelings and experiences and is an important part of human psychological activities. Memory is a basic intellectual ability of human beings. It is the process by which humans obtain information from past experiences, and preserve and review it. The two play important roles in human life activities, and there is a close relationship between them.

The relationship between emotional information and memory is very close. According to research, when people experience emotional experiences, they process the emotional information in more depth and detail, thereby improving the starting point and preservation strength of the information in memory storage. This means that the inner experience contained in emotional experience is easier to remember by the human brain and harder to forget.

Therefore, emotional information can also stimulate human enthusiasm for learning and creation. During emotional experiences, people are more sensitive and curious about the information they receive, thus promoting human learning and creativity. At the same time, emotional experience can also stimulate people's emotional expression and social skills, thereby improving the intimacy of human emotional relationships.

To sum up, the relationship between emotional information and memory is inseparable. Emotional experience can promote a deep understanding of information and memory storage, and memory storage can improve human emotional experience response and emotional expression capabilities. Therefore, we should pay more attention to our own emotional experiences and try to find more beauty and happiness in emotional communication to promote the improvement of our own emotions and memory. It can be seen that we need to improve our memory. Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, meat can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thus improving brain vitality and endurance.

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First, we identified clusters significantly activated during enhanced memory encoding of negative and positive emotional pictures. In addition to the well-known emotional memory–related cerebral regions, we identified a cluster in the cerebellum. We then used dynamic causal modeling and identified several cerebellar connections with increased connection strength corresponding to enhanced emotional memory, including one to a cluster covering the amygdala and hippocampus, and bidirectional connections with a cluster covering the anterior cingulate cortex. The present findings indicate that the cerebellum is an integral part of a network involved in the emotional enhancement of episodic memory.

Enhanced memory for emotionally arousing information is a well-recognized phenomenon that has adaptive value in evolutionary terms, as it is vital to remember both dangerous and favorable situations (1, 2). From studies in rodents, it is well established that emotional arousal leads to noradrenergic activation of the amygdala, which in turn activates the hippocampus and other brain regions to enhance memory consolidation of emotionally arousing information (3–5). 

Moreover, there is evidence from human studies that emotional arousal and noradrenergic activation already regulate memory processes during encoding (6–10) and that the connection strength from the amygdala to the hippocampus is rapidly increased during the encoding of emotionally arousing information compared to neutral information (11). Apart from the amygdala and hippocampus, two meta-analyses of human brain activation studies using functional MRI (fMRI) indicated the potential relevance of several additional brain regions for enhanced encoding of declarative memory by emotional arousal, including the middle occipital gyrus, middle frontal gyrus, fusiform gyrus, inferior frontal gyrus, supramarginal gyrus, orbitofrontal cortex, parietal cortex, claustrum, caudate, and the insula (12, 13). 

Even though the cerebellum has been occasionally listed in fMRI studies on emotional memory enhancement (14, 15), a meta-analysis including 15 studies did not list it (12). A more recent meta-analysis including 25 studies did find the cerebellum to be significantly activated, but after excluding three studies showing no behavioral enhancement effect, the significance vanished (13). Potential reasons for this ambiguity include that the cerebellum may have shown only subthreshold significance levels in individual studies or that the cerebellum has a priori not been included in the analysis (16).

The cerebellum is typically known for its important role in controlling motor functions (17). However, there is evidence that the outputs of the cerebellum target not only cortical motor areas but also several nonmotor cortical and subcortical regions that are involved in higher brain functions, including emotion and cognition (18–21), and that the cerebellum itself holds robust representations of multiple networks involved in these functions (22, 23). 

Notably, it is known from animal and human studies that the cerebellum plays an important role in fear conditioning (19, 24–27), which is traditionally categorized as an unconscious or nondeclarative form of learning with a strong emotional component (5, 28). It is less clear, however, whether the cerebellum is also involved in the enhancing effect of emotional arousal on episodic memory, a declarative form of memory that requires conscious memory encoding and enables the conscious recollection of information along with its context (5, 29, 30). 

Animal and human lesion studies and human neuroimaging studies indicate that fear conditioning and emotional enhancement of episodic memory partly depend on the same neural underpinnings, such as the amygdala (5, 12, 31, 32). Therefore, the cerebellum may be involved not only in fear conditioning but also in the emotional enhancement of episodic memory. In the present study, we investigated whether the cerebellum and cerebellar–cerebral connections are involved in the phenomenon of superior episodic memory for emotionally arousing visual information.

We used an fMRI sample of 1,418 healthy human participants who performed a picture encoding task containing positive and negative emotional and neutral pictures, followed by a free recall test, which assesses episodic memory (29, 30), 20 min after the end of encoding. While emotional arousal rather than valence has been identified as driving the memory-enhancing effect of salient information on episodic memory (5, 33, 34), valence-related differences have also been identified (35).
Here, we focused on the identification of emotional arousal effects common to positive and negative valence. The large sample size allowed us to divide the sample into a discovery (n = 945 participants) and a replication sample (n = 473 participants; see Materials and Methods). To measure the neural correlates of superior memory for emotional information during encoding, we used the subsequent emotional memory paradigm (12). This paradigm assesses the difference between the encoding activity of later successfully recalled emotional items versus that of nonrecalled emotional items, compared to recalled neutral items vs. nonrecalled neutral items (termed “enhanced emotional memory encoding”). At first, we identified voxels with significantly increased activity during enhanced emotional memory encoding in the discovery sample. We performed this analysis for the entire brain, including the cerebellum. 

From the voxels that showed increased activity during enhanced emotional memory encoding, we defined regions of interest (ROIs). We defined ROIs functionally, rather than anatomically, as the sensitivity of detecting the presence of connections can be increased by using ROIs that match actual functional boundaries (36). Specifically, we combined voxels with a similar response profile to create spatially coherent and temporal homogeneous ROIs by using a clustering approach (37). We then tested whether the identified ROIs showed increased activity during enhanced emotional memory encoding in the replication sample.

With the replicated ROIs (i.e., one cerebellar ROI, 25 cerebral ROIs) we finally explored the directed effective connectivity between the cerebellar ROI and the cerebral ROIs using dynamic causal modeling (DCM) (38, 39) in both samples. Whereas DCM was originally developed to test specific hypotheses concerning the presence, direction, and modulators of effective connectivity between a set of predefined brain regions, it can be also applied in an exploratory manner involving a large number of brain regions and models ([40]; see Materials and Methods). 

Here we applied DCM to explore the directed effective connectivity between the cerebellar ROI and the cerebral ROIs involved in emotional memory enhancement. DCM allowed us to determine 1) whether the strength of those connections was increased during successful emotional memory encoding, and 2) the direction of effective connectivity to learn whether the input from the cerebellum causally drives a cerebral ROI implicated in emotional memory enhancement or if the direction of influence is the other way around.

Results

Behavioral data: Emotional memory enhancement. The behavioral results in both the discovery and replication samples indicated that participants freely recalled more emotional (positive and negative) pictures than neutral pictures (discovery sample, mean difference: 4.50 ± 2.76 [mean ± SD], T = 50.01, P = 7.53 x 10-268, n = 945; replication sample, mean difference: 4.65 ± 2.60 [mean ± SD], T = 38.82, P = 7.03 x 10-149, n = 473). For a detailed description of the behavioral data, see reference (11). This emotional memory enhancement was not significantly associated with age or sex (P > 0.05; 2-sided).

Activity related to enhanced emotional memory encoding.

For the contrast representing enhanced emotional memory encoding, 7,708 voxels with increased activity were identified in the discovery sample at a whole-brain level, corrected for multiple comparisons using the family-wise error (FWE) rate procedure (n = 944, Pwhole-brain-FWE-corrected < 0.05; SI Appendix, Fig. S2 and Table S3). We did not observe significant positive or negative associations between activity and the effects of sex, age, changes in scanner software, or changes in gradient coils (Pwhole-brain-FWE-corrected > 0.05). 

Voxels related to enhanced emotional memory encoding were parcellated into 30 clusters (i.e., ROIs) to reduce the dimensionality of the data (Fig. 1 and SI Appendix, Figs. S3–S7, see Materials and Methods for details on the parcellation method). One cluster (ROI 11) contained isolated voxels and small clusters of voxels that were not spatially coherent and were therefore removed from further analysis.

Out of the 29 remaining ROIs, 28 were located in neocortical and subcortical regions of the cerebrum and one was in the cerebellum (Fig. 1; see SI Appendix, Table S5 for details on the number of voxels as well as the anatomical correspondence per cluster). According to a probabilistic magnetic resonance (MR) atlas of the human cerebellum (41), the cerebellar cluster in the discovery sample mapped mainly onto the vermis of the cerebellum (local maximum by 76% in lobule IX, and by 22% in the replication sample). 

Out of the 29 ROIs identified in the discovery sample, 26 ROIs (including the cerebellum) were also significantly activated during enhanced emotional memory encoding in the replication sample (significance threshold for ROI maxima: T = 4.41, P < 0.05, one-sided, Bonferroni-corrected for all significant voxels of the 29 ROIs identified in the discovery sample). Maxima for ROIs 7, 13, and 25 did not reach significance in the replication sample and therefore, these ROIs were not considered for the DCM analysis. 

In summary, the replicated 26 ROIs mapped onto the occipital, temporal, parietal, and frontal cortex and the amygdala/hippocampus, cingulate, thalamus, brainstem, and cerebellum (Fig. 1; SI Appendix, Table S5).

Notably, activity related to successful memory encoding did not significantly differ between the positive and negative pictures in the cerebellar ROI in both the discovery and the replication samples (Pwhole-brain-FWE-corrected > 0.05, Psmall-volume-corrected > 0.001).

DCM: Connection strength during enhanced emotional memory encoding.

The replicated 26 ROIs related to enhanced emotional memory encoding entered the DCM analysis. To investigate changes in connection strength during enhanced emotional memory encoding between the cerebellar ROI and the remaining 25 cerebral ROIs, we used a series of 2-node (cerebellum to all others) DCMs to explore all pairwise (bidirectional) connections (note that a large number of model parameters precluded the inclusion of all 26 ROIs into a single DCM model).

Within the discovery sample, 25 connections (out of the 50 possible unidirectional connections) showed increased strength during enhanced emotional memory encoding (posterior probability > 0.99). Considering the number of tests, we applied a conservative probability threshold of 0.99 and replicated the results in an independent sample using the same threshold (38, 42, 43). Fifteen out of the 25 connections also had increased strength in the replication sample (posterior probability > 0.99) (Fig. 2 and SI Appendix, Figs. S8–S10). Out of those 15 replicated connections, 11 connections showed increased connection strength from the cerebellum to the cerebral regions. 

Of particular interest is the strong connection from the cerebellar ROI to ROI 26 that includes voxels from the amygdala and hippocampus (Fig. 2). Four connections showed increased connection strength from the cerebral regions to the cerebellum (Fig. 2). The connections between the cerebellar ROI and ROI 22 that includes voxels from the rostral anterior cingulate ROI and between the cerebellar ROI and ROI 9 that contains voxels from the precentral cortex showed increased strength in both directions.

Discussion

The present study aimed to investigate whether the cerebellum and cerebellar–cerebral connections are involved in the phenomenon of superior episodic memory for emotionally arousing visual information. In the first step, we identified clusters showing increased activity during enhanced encoding of emotional pictures. The cerebral clusters mapped onto the occipital, temporal, parietal, and frontal cortex and the amygdala/hippocampus, cingulate, and thalamus. These brain activation results are largely in line with the findings of two meta-analyses of enhanced emotional memory encoding in humans (12, 13) and extensive experimental work in animals (4, 32, 44). 

In addition to these cerebral regions, we found robust evidence for a cluster located mainly within the vermis of the cerebellum showing increased activity during enhanced emotional memory encoding in two large samples. Interestingly, the midline cerebellum is activated during the recall of emotional personal life episodes, indicating a role of this region in emotional memory retrieval (21).

There is accumulating evidence that the cerebellum, in particular the cerebellar vermis, is crucially involved in fear conditioning (19, 24, 26, 27). In rodents, it has been shown that lesions of the vermis abolish heart rate conditioning (45) and that the vermis is necessary for intact fear conditioning (46). In humans, it has been reported that patients with lesions of the cerebellar vermis show impaired acquisition of fearconditioned bradycardia (47). Moreover, an fMRI study in healthy participants found the vermis to be involved in eye-blink classical conditioning (48). 

The vermis has efferent projections to limbic regions, including the amygdala and hippocampus, structures involved in delay conditioning and trace conditioning, respectively (49). The connection of the vermis with the amygdala and hippocampus would also allow an influence of the vermis on the enhancement of episodic memories by emotional arousal, which depends on both structures (5). The findings of the present study indeed indicate that the vermis is not only involved in fear conditioning but is also involved in the phenomenon of superior episodic memory of emotionally arousing visual information.

The subsequent DCM connectivity analysis indicated that several cerebellar–cerebral connections showed increased strength during enhanced emotional memory encoding (Fig. 2), suggesting that the cerebellum is an integral component of the network involved in emotional memory enhancement. Specifically, we found 11 connections with increased connection strength from the cerebellum to the cerebral regions. In the context of enhanced emotional memory encoding, the connection to the ROI that includes voxels from the amygdala and hippocampus (ROI 26) seems of special interest. It has been shown that the cerebellum and the amygdala are functionally interconnected during fear conditioning (50, 51). 

Moreover, studies in rats and cats showed that electrical stimulation of the vermis (outside of a learning context) modulates (i.e., some units are facilitated and others are inhibited) amygdala and hippocampus activity (52, 53), indicating that the vermis is functionally connected with these limbic regions. These findings fit with the direction found in the current DCM analysis, indicating an influence of the vermis on ROI 26. There is ample evidence that the amygdala and hippocampus, as well as their interactions, are crucially involved in the enhancing effect of emotional arousal on episodic memory (4, 5, 11, 54).

We also found evidence for the involvement of bidirectional connections of the cerebellum with the ROI, which included voxels from the anterior cingulate cortex (ROI 22), in emotional memory enhancement. A resting-state functional connectivity MRI study in healthy humans has shown that the cingulate is functionally connected with the cerebellum (23). Furthermore, the anterior cingulate has been related to emotion, reward valuation, and value representations (55). It has been postulated that the anterior cingulate cortex, in addition to the amygdala and the insula, is a fundamental part of a large-scale salience network that functions to segregate the most relevant among internal and extrapersonal stimuli to guide behavior (56, 57). 

Moreover, the salience network has been reported to be activated by noradrenergic activation (58), a neurotransmitter system crucially involved not only in arousal and attentional processes but also in emotional memory enhancement (59). Interestingly, the locus coeruleus, the principal site for brain synthesis of norepinephrine, also projects to areas throughout the cerebellum (60). Whether the cerebellum gets activated directly by the locus coeruleus or indirectly by the salience network has yet to be determined. 

Furthermore, we found a bidirectional connection of the cerebellum with the ROI in the frontal cortex (mainly precentral) that may be related to the regulation of motor functions (61), possibly motor learning, in the context of emotional memory enhancement. Finally, we found connections with increased connection strength from two cerebral ROIs to the cerebellum (i.e., ROI 10, including voxels from the lingual and peri calcarine gyrus, and ROI 23, including voxels from the lateral occipital cortex).

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