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The present study aimed to describe the cortical connectivity of a sector located in the ventral bank of the superior temporal sulcus in the macaque (intermediate area TEa and TEm [TEa/m]), which appears to represent the major source of output of the ventral visual stream outside the temporal lobe. The retrograde tracer wheat germ agglutinin was injected in the intermediate TEa/m in four macaque monkeys. The results showed that 58-78% of labeled cells were located within ventral visual stream areas other than the TE complex. Outside the ventral visual stream, there were connections with the memory-related medial temporal area 36 and the parahippocampal cortex, orbitofrontal areas involved in encoding subjective values of stimuli for action selection, and eye- or hand-movement related parietal (LIP, AIP, and SII), prefrontal (12r, 45A, and 45B) areas, and a hand-related dysgranular insula field. Altogether these data provide a solid substrate for the engagement of the ventral visual stream in large scale cortical networks for skeletomotor or oculomotor control. Accordingly, the role of the ventral visual stream could go beyond pure perceptual processes and could be also finalized to the neural mechanisms underlying the control of voluntary motor behavior.

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BACKGROUND: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. METHODS: BioFINDER-2 participants with memory impairment, abnormal amyloid-ß and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-ß-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. RESULTS: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. CONCLUSIONS: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies.

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The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

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The psychological states of hunger and satiety play an important role in regulating human food intake. Several lines of evidence suggest that these states rely upon declarative learning and memory processes, which are based primarily in the medial temporal lobes (MTL). The MTL, and particularly the hippocampus, is unusual in that it is especially vulnerable to insult. Consequently, we examine here the impact on hunger and satiety of conditions that: (1) are central to ingestive behaviour and where there is evidence of MTL pathology (i.e., habitual consumption of a Western-style diet, obesity, and anorexia nervosa); and (2) where there is overwhelming evidence of MTL pathology, but where ingestive behaviour is not thought central (i.e., temporal lobe epilepsy and post-traumatic stress disorder). While for some of these conditions the evidence base is currently limited, the general conclusion is that MTL impairment is linked, sometimes strongly, to dysfunctional hunger and satiety. This focus on the MTL, and declarative learning and memory processes, has implications for the development of alternative treatment approaches for the regulation of appetite.

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The human auditory system includes discrete cortical patches and selective regions for processing voice information, including emotional prosody. Although behavioral evidence indicates individuals with autism spectrum disorder (ASD) have difficulties in recognizing emotional prosody, it remains understudied whether and how localized voice patches (VPs) and other voice-sensitive regions are functionally altered in processing prosody. This fMRI study investigated neural responses to prosodic voices in 25 adult males with ASD and 33 controls using voices of anger, sadness, and happiness with varying degrees of emotion. We used a functional region-of-interest analysis with an independent voice localizer to identify multiple VPs from combined ASD and control data. We observed a general response reduction to prosodic voices in specific VPs of left posterior temporal VP (TVP) and right middle TVP. Reduced cortical responses in right middle TVP were consistently correlated with the severity of autistic symptoms for all examined emotional prosodies. Moreover, representation similarity analysis revealed the reduced effect of emotional intensity in multivoxel activation patterns in left anterior superior temporal cortex only for sad prosody. These results indicate reduced response magnitudes to voice prosodies in specific TVPs and altered emotion intensity-dependent multivoxel activation patterns in adult ASDs, potentially underlying their socio-communicative difficulties.

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Our brains create new memories by capturing the 'who/what', 'where' and 'when' of everyday experiences. On a neuronal level, mechanisms facilitating a successful transfer into episodic memory are still unclear. We investigated this by measuring single neuron activity in the human medial temporal lobe during encoding of item-location associations. While previous research has found predictive effects in population activity in human MTL structures, we could attribute such effects to two specialized sub-groups of neurons: concept cells in the hippocampus, amygdala and entorhinal cortex (EC), and a second group of parahippocampal location-selective neurons. In both item- and location-selective populations, firing rates were significantly higher during successfully encoded trials. These findings are in line with theories of hippocampal indexing, since selective index neurons may act as pointers to neocortical representations. Overall, activation of distinct populations of neurons could directly support the connection of the 'what' and 'where' of episodic memory.

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Across the animal kingdom, neural responses in the auditory cortex are suppressed during vocalization, and humans are no exception. A common hypothesis is that suppression increases sensitivity to auditory feedback, enabling the detection of vocalization errors. This hypothesis has been previously confirmed in non-human primates, however a direct link between auditory suppression and sensitivity in human speech monitoring remains elusive. To address this issue, we obtained intracranial electroencephalography (iEEG) recordings from 35 neurosurgical participants during speech production. We first characterized the detailed topography of auditory suppression, which varied across superior temporal gyrus (STG). Next, we performed a delayed auditory feedback (DAF) task to determine whether the suppressed sites were also sensitive to auditory feedback alterations. Indeed, overlapping sites showed enhanced responses to feedback, indicating sensitivity. Importantly, there was a strong correlation between the degree of auditory suppression and feedback sensitivity, suggesting suppression might be a key mechanism that underlies speech monitoring. Further, we found that when participants produced speech with simultaneous auditory feedback, posterior STG was selectively activated if participants were engaged in a DAF paradigm, suggesting that increased attentional load can modulate auditory feedback sensitivity.

The brain lowers its response to inputs we generate ourselves, such as moving or speaking. Essentially, our brain 'knows' what will happen next when we carry out these actions, and therefore does not need to react as strongly as it would to unexpected events. This is why we cannot tickle ourselves, and why the brain does not react as much to our own voice as it does to someone else's. Quieting down the brain's response also allows us to focus on things that are new or important without getting distracted by our own movements or sounds. Studies in non-human primates showed that neurons in the auditory cortex (the region of the brain responsible for processing sound) displayed suppressed levels of activity when the animals made sounds. Interestingly, when the primates heard an altered version of their own voice, many of these same neurons became more active. But it was unclear whether this also happens in humans. To investigate, Ozker et al. used a technique called electrocorticography to record neural activity in different regions of the human brain while participants spoke. The results showed that most areas of the brain involved in auditory processing showed suppressed activity when individuals were speaking. However, when people heard an altered version of their own voice which had an unexpected delay, those same areas displayed increased activity. In addition, Ozker et al. found that the higher the level of suppression in the auditory cortex, the more sensitive these areas were to changes in a person's speech. These findings suggest that suppressing the brain's response to self-generated speech may help in detecting errors during speech production. Speech deficits are common in various neurological disorders, such as stuttering, Parkinson's disease, and aphasia. Ozker et al. hypothesize that these deficits may arise because individuals fail to suppress activity in auditory regions of the brain, causing a struggle when detecting and correcting errors in their own speech. However, further experiments are needed to test this theory.

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Understanding the neurobiology of semantic knowledge is a major goal of cognitive neuroscience. Taxonomic and thematic semantic knowledge are represented differently within the brain's conceptual networks, but the specific neural mechanisms remain unclear. Some neurobiological models propose that the anterior temporal lobe is an important hub for taxonomic knowledge, whereas the TPJ is especially involved in the representation of thematic knowledge. However, recent studies have provided divergent evidence. In this context, we investigated the neural correlates of taxonomic and thematic confrontation naming errors in 79 people with aphasia. We used three complementary lesion-symptom mapping (LSM) methods to investigate how structure and function in both spared and impaired brain regions relate to taxonomic and thematic naming errors. Voxel-based LSM mapped brain damage, activation-based LSM mapped BOLD signal in surviving tissue, and network-based LSM mapped white matter subnetwork integrity to error type. Voxel- and network-based lesion symptom mapping provided converging evidence that damage/disruption of the left mid-to-anterior temporal lobe was associated with a greater proportion of thematic naming errors. Activation-based lesion symptom mapping revealed that higher BOLD signal in the left anterior temporal lobe during an in-house naming task was associated with a greater proportion of taxonomic errors on the Philadelphia Naming Test administered outside of the scanner. A lower BOLD signal in the bilateral angular gyrus, precuneus, and right inferior frontal cortex was associated with a greater proportion of taxonomic errors. These findings provide novel evidence that damage to the anterior temporal lobe is especially related to thematic naming errors.

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The visual word form area in the occipitotemporal sulcus (here OTS-words) is crucial for reading and shows a preference for text stimuli. We hypothesized that this text preference may be driven by lexical processing. Hence, we performed three fMRI experiments (n = 15), systematically varying participants' task and stimulus, and separately evaluated middle mOTS-words and posterior pOTS-words. Experiment 1 contrasted text with other visual stimuli to identify both OTS-words subregions. Experiment 2 utilized an fMRI adaptation paradigm, presenting compound words as texts or emojis. In experiment 3, participants performed a lexical or color judgment task on compound words in text or emoji format. In experiment 2, pOTS-words, but not mOTS-words, showed fMRI adaptation for compound words in both formats. In experiment 3, both subregions showed higher responses to compound words in emoji format. Moreover, mOTS-words showed higher responses during the lexical judgment task and a task-stimulus interaction. Multivariate analyses revealed that distributed responses in pOTS-words encode stimulus and distributed responses in mOTS-words encode stimulus and task. Together, our findings suggest that the function of the OTS-words subregions goes beyond the specific visual processing of text and that these regions are flexibly recruited whenever semantic meaning needs to be assigned to visual input.

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Temporal lobe epilepsy (TLE) is the most common form of drug-resistant epilepsy. A major focus of human and animal studies on TLE network has been the limbic circuit. However, there is also evidence suggesting an active role of the basal ganglia in the propagation and control of temporal lobe seizures. Here, we characterize the involvement of the substantia nigra (SN) and somatosensory cortex (SI) during temporal lobe (TL) seizures induced by penicillin injection in the hippocampus (HPC) of two nonhuman primates. The seizure onset and offset patterns were manually classified and spectral power and coherence were calculated. We then compared the 3-second segments recorded in pre-ictal, onset, offset and post-ictal periods based on the seizure onset and offset patterns. Our results demonstrated an involvement of the SN and SI dependent on the seizure onset and offset pattern. We found that low amplitude fast activity (LAF) and high amplitude slow activity (HAS) onset patterns were associated with an increase in activity of the SN while the change in activity was limited to LAF seizures in the SI. However, the increase in HPC/SN coherence was specific to the farther-spreading LAF onset pattern. As for the role of the SN in seizure cessation, we observed that the coherence between the HPC/SN was reduced during burst suppression (BS) compared to other termination phases. Additionally, we found that this coherence returned to normal levels after the seizure ended, with no significant difference in post-ictal periods among the three types of seizure offsets. This study constitutes the first demonstration of TL seizures entraining the SN in the primate brain. Moreover, these findings provide evidence that this entrainment is dependent on the onset and offset pattern and support the hypothesis that the SN might play a role in the maintenance and termination of some specific temporal lobe seizure.

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The language network of the human brain has core components in the inferior frontal cortex and superior/middle temporal cortex, with left-hemisphere dominance in most people. Functional specialization and interconnectivity of these neocortical regions is likely to be reflected in their molecular and cellular profiles. Excitatory connections between cortical regions arise and innervate according to layer-specific patterns. Here, we generated a gene expression dataset from human postmortem cortical tissue samples from core language network regions, using spatial transcriptomics to discriminate gene expression across cortical layers. Integration of these data with existing single-cell expression data identified 56 genes that showed differences in laminar expression profiles between the frontal and temporal language cortex together with upregulation in layer II/III and/or layer V/VI excitatory neurons. Based on data from large-scale genome-wide screening in the population, DNA variants within these 56 genes showed set-level associations with interindividual variation in structural connectivity between the left-hemisphere frontal and temporal language cortex, and with the brain-related disorders dyslexia and schizophrenia which often involve affected language. These findings identify region-specific patterns of laminar gene expression as a feature of the brain's language network.

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Episodic memory in older adults is varied and perceived to rely on numbers of synapses or dendritic spines. We analyzed 2157 neurons among 128 older individuals from the Religious Orders Study and Rush Memory and Aging Project. Analysis of 55,521 individual dendritic spines by least absolute shrinkage and selection operator regression and nested model cross-validation revealed that the dendritic spine head diameter in the temporal cortex, but not the premotor cortex, improved the prediction of episodic memory performance in models containing ß amyloid plaque scores, neurofibrillary tangle pathology, and sex. These findings support the emerging hypothesis that, in the temporal cortex, synapse strength is more critical than quantity for memory in old age.

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The functional importance of the anterior temporal lobes (ATLs) has come to prominence in two active, albeit unconnected literatures-(i) face recognition and (ii) semantic memory. To generate a unified account of the ATLs, we tested the predictions from each literature and examined the effects of bilateral versus unilateral ATL damage on face recognition, person knowledge, and semantic memory. Sixteen people with bilateral ATL atrophy from semantic dementia (SD), 17 people with unilateral ATL resection for temporal lobe epilepsy (TLE; left = 10, right = 7), and 14 controls completed tasks assessing perceptual face matching, person knowledge and general semantic memory. People with SD were impaired across all semantic tasks, including person knowledge. Despite commensurate total ATL damage, unilateral resection generated mild impairments, with minimal differences between left- and right-ATL resection. Face matching performance was largely preserved but slightly reduced in SD and right TLE. All groups displayed the familiarity effect in face matching; however, it was reduced in SD and right TLE and was aligned with the level of item-specific semantic knowledge in all participants. We propose a neurocognitive framework whereby the ATLs underpin a resilient bilateral representation system that supports semantic memory, person knowledge and face recognition.

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Accurate and scalable quantification of amyloid-ß (Aß) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aß deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aß deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aß deposit types in GM and WM, and (3) investigate correlates of Aß deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts' evaluations. We provide comprehensive insights into the quantification and distribution of Aß deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aß load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research.

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Suicide is the second leading cause of death in youth, and depression is a strong proximal predictor of adolescent suicide. It is important to identify psychological factors that may protect against suicide ideation in depressed adolescents. Self-compassion may be such a factor. Converging evidence indicates the inverse association between self-compassion and suicide ideation, but the neural mechanisms underlying their link remain unknown. Because self-referential caudate activity is associated with both self-compassion and suicide ideation, its functional connectivity might explain their relationship. In this study, we examined the relationship between self-compassion and caudate functional connectivity during self-appraisals, a typical self-referential paradigm, and their associations with suicide ideation in both depressed and healthy youth. In the scanner, 79 depressed youth and 36 healthy controls evaluated, from various perspectives, whether phrases they heard were self-descriptive. Self-compassion and suicide ideation were rated with self-report and interview-based measures. We found that self-compassion was associated with stronger left caudate functional connectivity with bilateral posterior superior temporal sulcus/temporoparietal junction, the left middle temporal gyrus (MTG), and the left middle occipital gyrus during positive versus negative self-appraisals. Stronger left caudate connectivity with the left MTG explained the association between higher self-compassion and lower suicide ideation, even controlling for non-suicide ideation depression severity, anxiety severity, and non-suicidal self-injurious behavior. The findings suggest that the left caudate to MTG connectivity during positive versus negative self-referential processing could be a biomarker to be targeted by neural stimulation interventions for reducing suicide ideation in depressed youth, combined with self-compassion interventions.

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BACKGROUND: Research in functional asymmetry of Major Depressive Disorder (MDD) under different tasks is crucial for clinical diagnose. METHODS: Fifty individuals with MDD and twenty healthy controls (HCS) were recruited for hemodynamic data collection under four fNIRS tasks (Emotional picture, Verbal fluency, Fingering and Negative emotional picture description task). Integral values and functional connectivity strength were employed to probe neural activation and functional connectivity in frontal and temporal lobes in MDD. Following, asymmetry characteristic of the frontal cortex between MDD and HCS under four tasks were carefully analyzed and compared. RESULTS: Individuals with MDD demonstrated heightened connectivity between the frontal and right temporal lobes and reduced connectivity between the frontal and left temporal lobes compared to HCS in all tasks. Additionally, MDD exhibited attenuated activation in the left frontal lobes and exaggerated activation in the right frontal lobes, diverging from HCS. Furthermore, the disparities in left-right asymmetry characteristic of frontal cortex activation between MDD and HCS were more pronounced during the combined task. LIMITATIONS: Further research is required to grasp the neurophysiological mechanisms governing left-right asymmetry across various tasks and the influence of task-induced brain fatigue on cerebral cortex hemodynamics in MDD. CONCLUSION: The left-right asymmetry feature provides valuable neurophysiological insights for diagnosing MDD clinically. Variations in activation patterns and functional connectivity features between MDD and HCS are closely tied to the task chosen. Thus, in clinical practice, carefully selecting appropriate fNIRS tasks and relevant features can significantly improve the diagnostic accuracy of MDD.

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OBJECTIVES: Radiotherapy is the primary treatment for nasopharyngeal carcinoma, but it frequently leads to radiotherapy-induced temporal lobe injury (RTLI). Magnetic resonance imaging (MRI) is the main diagnostic method for RTLI after radiotherapy for nasopharyngeal carcinoma, but it is prone to missed diagnoses. This study aims to investigate the causes of missed diagnoses of RTLI in nasopharyngeal carcinoma patients undergoing MRI after radiotherapy. METHODS: Clinical and MRI data from nasopharyngeal carcinoma patients diagnosed and treated with radiotherapy at Xiangya Hospital of Central South University, from January 2010 to April 2021, were collected. Two radiologists reviewed all head and neck MRIs (including nasopharyngeal and brain MRIs) before and after radiotherapy of identify cases of late delayed response-type RTLI for the first time. If the original diagnosis of the initial RTLI in nasopharyngeal carcinoma patients did not report temporal lobe lesions, it was defined as a missed diagnosis. The first diagnosis of RTLI cases was divided into a missed diagnosis group and a non-missed diagnosis group. Clinical and imaging data were compared between the 2 groups, and multivariate logistic regression analysis was used to identify independent risk factors for MRI missed diagnoses of initial RTLI. RESULTS: A total of 187 nasopharyngeal carcinoma with post-radiotherapy RTLI were included. The original diagnostic reports missed 120 cases and accurately diagnosed 67 cases, with an initial RTLI diagnosis accuracy rate of 35.8% and a missed diagnosis rate of 64.2%. There were statistically significant differences between the missed diagnosis group and the non-missed diagnosis group in terms of lesion size, location, presence of contralateral temporal lobe lesions, white matter high signal, cystic degeneration, hemorrhage, fluid attenuated inversion recovery (FLAIR), and examination site (all P<0.05). Multivariate logistic regression analysis showed that lesions ≤25 mm, non-enhancing lesions, lesions without cystic degeneration or hemorrhage, lesions located only in the medial temporal lobe, and MRI examination only of the nasopharynx were independent risk factors for missed MRI diagnosis of initial RTLI (all P<0.05). CONCLUSIONS: The missed diagnosis of initial RTLI on MRI is mainly related to lesion size and location, imaging characteristics, and MRI examination site.

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Studies have revealed that somatization symptoms are associated with emotional memory in adolescents with depressive disorders. This study investigated somatization symptoms and emotional memory among adolescents with depressive disorders using low-frequency amplitude fluctuations (ALFF). Participants were categorized into the somatization symptoms (FSS) group, non-FSS group and healthy control group (HC). The correctness of negative picture re-recognition was higher in the FFS and HC group than in the non-FSS group. The right superior occipital gyrus and right inferior temporal gyrus were significantly larger in the FSS group than those in the non-FSS and HC groups. Additionally, the ALFF in the superior occipital and inferior temporal gyrus were positively correlated with CSI score. Furthermore, the ALFF values in the temporal region positively correlated with correct negative image re-recognition. The negative image re-recognition rate was positively correlated with the ALFF in the left and right middle occipital gyri. These findings indicated that somatization symptoms in adolescent depression are associated with the superior occipital gyrus and inferior temporal gyrus. Notably, somatization symptoms play a role in memory bias within depressive disorders, with middle occipital and inferior temporal gyri potentially serving as significant brain regions.

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Congruent visual speech improves speech perception accuracy, particularly in noisy environments. Conversely, mismatched visual speech can alter what is heard, leading to an illusory percept that differs from the auditory and visual components, known as the McGurk effect. While prior transcranial magnetic stimulation (TMS) and neuroimaging studies have identified the left posterior superior temporal sulcus (pSTS) as a causal region involved in the generation of the McGurk effect, it remains unclear whether this region is critical only for this illusion or also for the more general benefits of congruent visual speech (e.g., increased accuracy and faster reaction times). Indeed, recent correlative research suggests that the benefits of congruent visual speech and the McGurk effect rely on largely independent mechanisms. To better understand how these different features of audiovisual integration are causally generated by the left pSTS, we used single-pulse TMS to temporarily disrupt processing within this region while subjects were presented with either congruent or incongruent (McGurk) audiovisual combinations. Consistent with past research, we observed that TMS to the left pSTS reduced the strength of the McGurk effect. Importantly, however, left pSTS stimulation had no effect on the positive benefits of congruent audiovisual speech (increased accuracy and faster reaction times), demonstrating a causal dissociation between the two processes. Our results are consistent with models proposing that the pSTS is but one of multiple critical areas supporting audiovisual speech interactions. Moreover, these data add to a growing body of evidence suggesting that the McGurk effect is an imperfect surrogate measure for more general and ecologically valid audiovisual speech behaviors.

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Humans have the remarkable cognitive capacity to rapidly adapt to changing environments. Central to this capacity is the ability to form high-level, abstract representations that take advantage of regularities in the world to support generalization1. However, little is known about how these representations are encoded in populations of neurons, how they emerge through learning and how they relate to behaviour2,3. Here we characterized the representational geometry of populations of neurons (single units) recorded in the hippocampus, amygdala, medial frontal cortex and ventral temporal cortex of neurosurgical patients performing an inferential reasoning task. We found that only the neural representations formed in the hippocampus simultaneously encode several task variables in an abstract, or disentangled, format. This representational geometry is uniquely observed after patients learn to perform inference, and consists of disentangled directly observable and discovered latent task variables. Learning to perform inference by trial and error or through verbal instructions led to the formation of hippocampal representations with similar geometric properties. The observed relation between representational format and inference behaviour suggests that abstract and disentangled representational geometries are important for complex cognition.

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