Thalamo-cortical coupling during encoding and consolidation is linked to durable memory formation.

Memory formation transforms experiences into durable engrams. The stabilization critically depends on processes during and after learning, and involves hippocampal-medial prefrontal interactions that appear to be mediated by the nucleus reuniens of the thalamus in rodents, which corresponds to the human medioventral thalamus. How this region contributes to durable memory formation in humans is, however, unclear. Furthermore, the anterior-, lateral dorsal-, and mediodorsal nuclei appear to promote mnemonic function as well. We hypothesized that durable memory formation is associated with increases in thalamo-cortical interactions during encoding and consolidation. Thirty-three human subjects underwent fMRI while studying picture-location associations. To assess consolidation, resting-state brain activity was measured after study and was compared to a pre-study baseline. Memory was tested on the same day and 48 h later. While "weak" memories could only be remembered at the immediate test, "durable" memories persisted also after the delay. We found increased coupling of the medioventral-, adjacent anterior-, lateral dorsal-, and mediodorsal thalamus with the hippocampus and surrounding medial temporal lobe, as well as with anterior and posterior midline regions related to durable memory encoding. The medioventral and lateral dorsal thalamus showed increased connectivity with posterior medial and parietal cortex from baseline to post-encoding rest, positively scaling with the proportion of durable memories formed across subjects. Additionally, the lateral dorsal thalamus revealed consolidation-related coupling with the inferior temporal, retrosplenial, and medial prefrontal cortex. We suggest that thalamo-cortical cross-talk strengthens mnemonic representations at initial encoding, and that cortical coupling of specific thalamic subregions supports consolidation thereafter.

Eye-Movement Intervention Enhances Extinction via Amygdala Deactivation.

Improving extinction learning is essential to optimize psychotherapy for persistent fear-related disorders. In two independent studies (both n = 24), we found that goal-directed eye movements activate a dorsal frontoparietal network and transiently deactivate the amygdala (η p2 = 0.17). Connectivity analyses revealed that this downregulation potentially engages a ventromedial prefrontal pathway known to be involved in cognitive regulation of emotion. Critically, when eye movements followed memory reactivation during extinction learning, it reduced spontaneous fear recovery 24 h later (η p2 = 0.21). Stronger amygdala deactivation furthermore predicted a stronger reduction in subsequent fear recovery after reinstatement (r = 0.39). In conclusion, we show that extinction learning can be improved with a noninvasive eye-movement intervention that triggers a transient suppression of the amygdala. Our finding that another task which taxes working memory leads to a similar amygdala suppression furthermore indicates that this effect is likely not specific to eye movements, which is in line with a large body of behavioral studies. This study contributes to the understanding of a widely used treatment for traumatic symptoms by providing a parsimonious account for how working-memory tasks and goal-directed eye movements can enhance extinction-based psychotherapy, namely through neural circuits (e.g., amygdala deactivation) similar to those that support cognitive control of emotion.SIGNIFICANCE STATEMENT Fear-related disorders represent a significant burden on individual sufferers and society. There is a high need to optimize treatment, in particular via noninvasive means. One potentially effective intervention is execution of eye movements following trauma recall. However, a neurobiological understanding of how eye movements reduce traumatic symptoms is lacking. We demonstrate that goal-directed eye-movements, like working-memory tasks, deactivate the amygdala, the core neural substrate of fear learning. Effective connectivity analyses revealed amygdala deactivation potentially engaged dorsolateral and ventromedial prefrontal pathways. When applied during safety learning, this deactivation predicts a reduction in later fear recovery. These findings provide a parsimonious and mechanistic account of how behavioral manipulations taxing working memory and suppressing amygdala activity can alter retention of emotional memories.

The increase in medial prefrontal glutamate/glutamine concentration during memory encoding is associated with better memory performance and stronger functional connectivity in the human medial prefrontal-thalamus-hippocampus network.

The classical model of the declarative memory system describes the hippocampus and its interactions with representational brain areas in posterior neocortex as being essential for the formation of long-term episodic memories. However, new evidence suggests an extension of this classical model by assigning the medial prefrontal cortex (mPFC) a specific, yet not fully defined role in episodic memory. In this study, we utilized 1H magnetic resonance spectroscopy (MRS) and psychophysiological interaction (PPI) analysis to lend further support for the idea of a mnemonic role of the mPFC in humans. By using MRS, we measured mPFC γ-aminobutyric acid (GABA) and glutamate/glutamine (GLx) concentrations before and after volunteers memorized face-name association. We demonstrate that mPFC GLx but not GABA levels increased during the memory task, which appeared to be related to memory performance. Regarding functional connectivity, we used the subsequent memory paradigm and found that the GLx increase was associated with stronger mPFC connectivity to thalamus and hippocampus for associations subsequently recognized with high confidence as opposed to subsequently recognized with low confidence/forgotten. Taken together, we provide new evidence for an mPFC involvement in episodic memory by showing a memory-related increase in mPFC excitatory neurotransmitter levels that was associated with better memory and stronger memory-related functional connectivity in a medial prefrontal-thalamus-hippocampus network.

The Yin and Yang of Memory Consolidation: Hippocampal and Neocortical.

While hippocampal and cortical mechanisms of memory consolidation have long been studied, their interaction is poorly understood. We sought to investigate potential interactions with respect to trace dominance, strengthening, and interference associated with postencoding novelty or sleep. A learning procedure was scheduled in a watermaze that placed the impact of novelty and sleep in opposition. Distinct behavioural manipulations-context preexposure or interference during memory retrieval-differentially affected trace dominance and trace survival, respectively. Analysis of immediate early gene expression revealed parallel up-regulation in the hippocampus and cortex, sustained in the hippocampus in association with novelty but in the cortex in association with sleep. These findings shed light on dynamically interacting mechanisms mediating the stabilization of hippocampal and neocortical memory traces. Hippocampal memory traces followed by novelty were more dominant by default but liable to interference, whereas sleep engaged a lasting stabilization of cortical traces and consequent trace dominance after preexposure.

Non-symbolic and symbolic notations in simple arithmetic differentially involve intraparietal sulcus and angular gyrus activity.

Addition problems can be solved by mentally manipulating quantities for which the bilateral intraparietal sulcus (IPS) is likely recruited, or by retrieving the answer directly from fact memory in which the left angular gyrus (AG) and perisylvian areas may play a role. Mental addition is usually studied with problems presented in the Arabic notation (4+2), and less so with number words (four+two) or dots (:: +·.). In the present study, we investigated how the notation of numbers influences processing during simple mental arithmetic. Twenty-five highly educated participants performed simple arithmetic while their brain activity was recorded with functional magnetic resonance imaging. To reveal the effect of number notation, arithmetic problems were presented in a non-symbolic (Dots) or symbolic (Arabic; Words) notation. Furthermore, we asked whether IPS processing during mental arithmetic is magnitude specific or of a more general, visuospatial nature. To this end, we included perception and manipulation of non-magnitude formats (Colors; unfamiliar Japanese Characters). Increased IPS activity was observed, suggesting magnitude calculations during addition of non-symbolic numbers. In contrast, there was greater activity in the AG and perisylvian areas for symbolic compared to non-symbolic addition, suggesting increased verbal fact retrieval. Furthermore, IPS activity was not specific to processing of numerical magnitude but also present for non-magnitude stimuli that required mental visuospatial processing (Color-mixing; Character-memory measured by a delayed match-to-sample task). Together, our data suggest that simple non-symbolic sums are calculated using visual imagery, whereas answers for simple symbolic sums are retrieved from verbal memory.

Reinstatement of associative memories in early visual cortex is signaled by the hippocampus.

The cortical reinstatement hypothesis of memory retrieval posits that content-specific cortical activity at encoding is reinstated at retrieval. Evidence for cortical reinstatement was found in higher-order sensory regions, reflecting reactivation of complex object-based information. However, it remains unclear whether the same detailed sensory, feature-based information perceived during encoding is subsequently reinstated in early sensory cortex and what the role of the hippocampus is in this process. In this study, we used a combination of visual psychophysics, functional neuroimaging, multivoxel pattern analysis, and a well controlled cued recall paradigm to address this issue. We found that the visual information human participants were retrieving could be predicted by the activation patterns in early visual cortex. Importantly, this reinstatement resembled the neural pattern elicited when participants viewed the visual stimuli passively, indicating shared representations between stimulus-driven activity and memory. Furthermore, hippocampal activity covaried with the strength of stimulus-specific cortical reinstatement on a trial-by-trial level during cued recall. These findings provide evidence for reinstatement of unique associative memories in early visual cortex and suggest that the hippocampus modulates the mnemonic strength of this reinstatement.

Menstrual cycle-related changes in amygdala morphology are associated with changes in stress sensitivity.

Premenstrual increases in negative mood are thought to arise from changes in gonadal hormone levels, presumably by influencing mood regulation and stress sensitivity. The amygdala plays a major role in this context, and animal studies suggest that gonadal hormones influence its morphology. Here, we investigated whether amygdala morphology changes over the menstrual cycle and whether this change explains differences in stress sensitivity. Twenty-eight young healthy women were investigated once during the premenstrual phase and once during the late follicular phase. T1-weighted anatomical images of the brain were acquired using magnetic resonance imaging and analyzed with optimized voxel-based morphometry. To measure mood regulation and stress sensitivity, negative affect was assessed after viewing strongly aversive as well as neutral movie clips. Our results show increased gray matter volume in the dorsal part of the left amygdala during the premenstrual phase when compared with the late follicular phase. This volume increase was positively correlated with the premenstrual increase in stress-induced negative affect. This is the first study showing structural plasticity of the amygdala in humans at the macroscopic level that is associated with both endogenous gonadal hormone fluctuations and stress sensitivity. These results correspond with animal findings of gonadal hormone-mediated neural plasticity in the amygdala and have implications for understanding the pathogenesis of specific mood disorders associated with hormonal fluctuations.

Age-effects on associative object-location memory.

Aging is accompanied by an impairment of associative memory. The medial temporal lobe and fronto-striatal network, both involved in associative memory, are known to decline functionally and structurally with age, leading to the so-called associative binding deficit and the resource deficit. Because the MTL and fronto-striatal network interact, they might also be able to support each other. We therefore employed an episodic memory task probing memory for sequences of object-location associations, where the demand on self-initiated processing was manipulated during encoding: either all the objects were visible simultaneously (rich environmental support) or every object became visible transiently (poor environmental support). Following the concept of resource deficit, we hypothesised that the elderly probably have difficulty using their declarative memory system when demands on self-initiated processing are high (poor environmental support). Our behavioural study showed that only the young use the rich environmental support in a systematic way, by placing the objects next to each other. With the task adapted for fMRI, we found that elderly showed stronger activity than young subjects during retrieval of environmentally richly encoded information in the basal ganglia, thalamus, left middle temporal/fusiform gyrus and right medial temporal lobe (MTL). These results indicate that rich environmental support leads to recruitment of the declarative memory system in addition to the fronto-striatal network in elderly, while the young use more posterior brain regions likely related to imagery. We propose that elderly try to solve the task by additional recruitment of stimulus-response associations, which might partly compensate their limited attentional resources.

Substrate reduction therapy in the infantile form of Tay-Sachs disease.

Substrate reduction therapy (SRT) with miglustat has been proposed for treatment of some lysosomal storage disorders. Based on the positive experience in Gaucher disease and experimental data in Tay-Sachs (TSD) and Sandhoff animal models, the authors investigated the clinical efficacy of SRT in two patients with infantile TSD. SRT could not arrest the patients' neurologic deterioration. However, a significant drug concentration in CSF as well as macrocephaly prevention were observed.

Covariation of spectral and nonlinear EEG measures with alpha biofeedback.

This study investigated how different spectral and nonlinear EEG measures covaried with alpha power during auditory alpha biofeedback training, performed by 13 healthy subjects. We found a significant positive correlation of alpha power with the largest Lyapunov-exponent, pointing to an increased dynamical instability of the EEG accompanying alpha enhancement. Alpha power amplification, moreover, was significantly correlated with a decrease of spectral entropy within the alpha range. This outcome reflects a sharpening of the alpha peak during biofeedback training. The fact that the sharpening effect clearly preceded the increase of alpha amplitude could be exploited in future biofeedback settings.