Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival.

The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.

Tracking Your Mind's Eye during Recollection: Decoding the Long-Term Recall of Short Audiovisual Clips.

Unlike familiarity, recollection involves the ability to reconstruct mentally previous events that results in a strong sense of reliving. According to the reinstatement hypothesis, this specific feature emerges from the reactivation of cortical patterns involved during information exposure. Over time, the retrieval of specific details becomes more difficult, and memories become increasingly supported by familiarity judgments. The multiple trace theory (MTT) explains the gradual loss of episodic details by a transformation in the memory representation, a view that is not shared by the standard consolidation model. In this study, we tested the MTT in light of the reinstatement hypothesis. The temporal dynamics of mental imagery from long-term memory were investigated and tracked over the passage of time. Participant EEG activity was recorded during the recall of short audiovisual clips that had been watched 3 weeks, 1 day, or a few hours beforehand. The recall of the audiovisual clips was assessed using a Remember/Know/New procedure, and snapshots of clips were used as recall cues. The decoding matrices obtained from the multivariate pattern analyses revealed sustained patterns that occurred at long latencies (>500 msec poststimulus onset) that faded away over the retention intervals and that emerged from the same neural processes. Overall, our data provide further evidence toward the MTT and give new insights into the exploration of our "mind's eye."

Refining understanding of working memory buffers through the construct of binding: Evidence from a single case informs theory and clinical practise.

Binding operations carried out in working memory enable the integration of information from different sources during online performance. While available evidence suggests that working memory may involve distinct binding functions, whether or not they all involve the episodic buffer as a cognitive substrate remains unclear. Similarly, knowledge about the neural underpinnings of working memory buffers is limited, more specifically regarding the involvement of medial temporal lobe structures. In the present study, we report on the case of patient KA, with developmental amnesia and selective damage to the whole hippocampal system. We found that KA was unable to hold shape-colours associations (relational binding) in working memory. In contrast, he could hold integrated coloured shapes (conjunctive binding) in two different tasks. Otherwise, and as expected, KA was impaired on three relational memory tasks thought to depend on the hippocampus that are widely used in the early detection of Alzheimer's disease. Our results emphasize a dissociation between two binding processes within working memory, suggesting that the visuo-spatial sketchpad could support conjunctive binding, and may rely upon a large cortical network including sub-hippocampal structures. By contrast, we found evidence for a selective impairment of relational binding in working memory when the hippocampal system is compromised, suggesting that the long-term memory deficit observed in amnesic patients may be related to impaired short-term relational binding at encoding. Finally, these findings may inform research on the early detection of Alzheimer's disease as the preservation of conjunctive binding in KA is in sharp contrast with the impaired performance demonstrated very early in this disease.

Extremely long-term memory and familiarity after 12 years.

In 2006 Mitchell demonstrated that implicit memory was robust to decay. He showed that the ability to identify fragments of pictures seen 17 years before was significantly higher than for new stimuli. Is this true only for implicit memory? In this study, we tested whether explicit memory was still possible for drawings (n = 144) that had been presented once or three times, two seconds each time on average, approximately 12 years earlier. Surprisingly, our data reveal that our participants were able to recognize pictures above chance level. Preserved memory was mainly observed in the youngest subjects, for stimuli seen three times. Despite the fact that confidence judgments were low, reports suggest that recognition could be based on a strong sense of familiarity. These data extend Mitchell's findings and show that familiarity can also be robust to decay.

Waking Up Buried Memories of Old TV Programs.

Although it has been demonstrated that visual and auditory stimuli can be recalled decades after the initial exposure, previous studies have generally not ruled out the possibility that the material may have been seen or heard during the intervening period. Evidence shows that reactivations of a long-term memory trace play a role in its update and maintenance. In the case of remote or very long-term memories, it is most likely that these reactivations are triggered by the actual re-exposure to the stimulus. In this study we decided to explore whether it is possible to recall stimuli that could not have been re-experienced in the intervening period. We tested the ability of French participants (N = 34, 31 female) to recall 50 TV programs broadcast on average for the last time 44 years ago (from the 60's and early 70's). Potential recall was elicited by the presentation of short audiovisual excerpts of these TV programs. The absence of potential re-exposure to the material was strictly controlled by selecting TV programs that have never been rebroadcast and were not available in the public domain. Our results show that six TV programs were particularly well identified on average across the 34 participants with a median percentage of 71.7% (SD = 13.6, range: 48.5-87.9%). We also obtained 50 single case reports with associated information about the viewing of 23 TV programs including the 6 previous ones. More strikingly, for two cases, retrieval of the title was made spontaneously without the need of a four-proposition choice. These results suggest that re-exposures to the stimuli are not necessary to maintain a memory for a lifetime. These new findings raise fundamental questions about the underlying mechanisms used by the brain to store these very old sensory memories.

The effect of striatal pre-enkephalin overexpression in the basal ganglia of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

The midbrain dopamine (DA) cell death underlying Parkinson's disease (PD) is associated with upregulation of pre-enkephalin (pENK) in striatopallidal neurons. Our previous results obtained with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys suggest that increased striatal expression of pENK mRNA is a compensatory mechanism to alleviate PD-related motor symptoms. In this study, we tested the hypothesis that increased pENK expression in the striatum protects against the neurotoxic insults of MPTP in mice. To this end, recombinant adeno-associated virus serotype 2 also containing green fluorescent protein was used to overexpress pENK prior to DA depletion. Our results showed that overexpression of pENK in the striatum of MPTP mice induced: (i) increased levels of the opioid peptide enkephalin (ENK) in the striatum; (ii) higher densities of ENK-positive fibers in both the globus pallidus (GP) and the substantia nigra; (iii) higher locomotor activity; and (iv) a higher density of striatal tyrosine hydroxylase-positive fibers in the striatum. In addition, striatal overexpression of pENK in MPTP -treated mice led to 52 and 43% higher DA concentrations and DA turnover, respectively, in the GP compared to sham-treated MPTP mice. These observations are in agreement with the idea that increased expression of pENK at an early stage of disease can improve PD symptoms.