Mechanical pain sensitivity is associated with hippocampal structural integrity.

ABSTRACT: Rodents and human studies indicate that the hippocampus, a brain region necessary for memory processing, responds to noxious stimuli. However, the hippocampus has yet to be considered a key brain region directly involved in the human pain experience. One approach to answer this question is to perform quantitative sensory testing on patients with hippocampal damage-ie, medial temporal lobe epilepsy. Some case studies and case series have performed such tests in a handful of patients with various types of epilepsy and have reported mixed results. Here, we aimed to determine whether mechanical pain sensitivity was altered in patients diagnosed with temporal lobe epilepsy. We first investigated whether mechanical pain sensitivity in patients with temporal lobe epilepsy differs from that of healthy individuals. Next, in patients with temporal lobe epilepsy, we evaluated whether the degree of pain sensitivity is associated with the degree of hippocampal integrity. Structural integrity was based on hippocampal volume, and functional integrity was based on verbal and visuospatial memory scores. Our findings show that patients with temporal lobe epilepsy have lower mechanical pain sensitivity than healthy individuals. Only left hippocampal volume was positively associated with mechanical pain sensitivity-the greater the hippocampal damage, the lower the sensitivity to mechanical pain. Hippocampal measures of functional integrity were not significantly associated with mechanical pain sensitivity, suggesting that the mechanisms of hippocampal pain processing may be different than its memory functions. Future studies are necessary to determine the mechanisms of pain processing in the hippocampus.

High throughput functional profiling of genes at intraocular pressure loci reveals distinct networks for glaucoma.

INTRODUCTION: Primary open angle glaucoma (POAG) is a leading cause of blindness globally. Characterized by progressive retinal ganglion cell degeneration, the precise pathogenesis remains unknown. Genome-wide association studies (GWAS) have uncovered many genetic variants associated with elevated intraocular pressure (IOP), one of the key risk factors for POAG. We aimed to identify genetic and morphological variation that can be attributed to trabecular meshwork cell (TMC) dysfunction and raised IOP in POAG. METHODS: 62 genes across 55 loci were knocked-out in a primary human TMC line. Each knockout group, including five non-targeting control groups, underwent single-cell RNA-sequencing (scRNA-seq) for differentially-expressed gene (DEG) analysis. Multiplexed fluorescence coupled with CellProfiler image analysis allowed for single-cell morphological profiling. RESULTS: Many gene knockouts invoked DEGs relating to matrix metalloproteinases and interferon-induced proteins. We have prioritized genes at four loci of interest to identify gene knockouts that may contribute to the pathogenesis of POAG, including ANGPTL2, LMX1B, CAV1, and KREMEN1. Three genetic networks of gene knockouts with similar transcriptomic profiles were identified, suggesting a synergistic function in trabecular meshwork cell physiology. TEK knockout caused significant upregulation of nuclear granularity on morphological analysis, while knockout of TRIOBP, TMCO1 and PLEKHA7 increased granularity and intensity of actin and the cell-membrane. CONCLUSION: High-throughput analysis of cellular structure and function through multiplex fluorescent single-cell analysis and scRNA-seq assays enabled the direct study of genetic perturbations at the single-cell resolution. This work provides a framework for investigating the role of genes in the pathogenesis of glaucoma and heterogenous diseases with a strong genetic basis.

Hippocampal-cortical interactions during event boundaries support retention of complex narrative events.

According to most memory theories, encoding involves continuous communication between the hippocampus and neocortex, but recent work has shown that key moments at the end of an event, called event boundaries, may be especially critical for memory formation. We sought to determine how communication between the hippocampus and neocortical regions during the encoding of naturalistic events related to subsequent retrieval of those events and whether this was particularly important at event boundaries. Participants encoded and recalled two cartoon movies during fMRI scanning. Higher functional connectivity between the hippocampus and the posterior medial network (PMN) at an event's offset is related to the subsequent successful recall of that event. Furthermore, hippocampal-PMN offset connectivity also predicted the amount of detail retrieved after a 2-day delay. These data demonstrate that the relationship between memory encoding and hippocampal-neocortical interaction is dynamic and biased toward boundaries.

A Novel Orthoplastic Reconstruction of Relapsed Clubfoot With Total Ankle Arthroplasty.

Congenital clubfoot is addressed in infancy and rarely persists into adulthood. Ankle arthroplasty is an increasingly popular surgical intervention for patients with ankle arthritis since it allows a natural ankle range of motion and completely replaces a degenerative hindfoot. Here, we describe the first successful total ankle arthroplasty (TAA) for a patient with previously treated congenital clubfoot that reverted later in life. To address the patient's poor soft-tissue integument and reduce the likelihood of post-surgical complications, a perioperative latissimus muscle-free flap was performed. This two-staged, novel orthoplastic intervention addressed our patient's ankle issues and appears to be a viable option for clubfoot patients.

Leveraging the resting brain to predict memory decline after temporal lobectomy.

OBJECTIVE: Predicting memory morbidity after temporal lobectomy in patients with temporal lobe epilepsy (TLE) relies on indices of preoperative temporal lobe structural and functional integrity. However, epilepsy is increasingly considered a network disorder, and memory a network phenomenon. We assessed the utility of functional network measures to predict postoperative memory changes. METHODS: Seventy-two adults with TLE (37 left/35 right) underwent preoperative resting-state functional magnetic resonance imaging and pre- and postoperative neuropsychological assessment. We compared functional connectivity throughout the memory network of each patient to a healthy control template (n = 19) to identify differences in global organization. A second metric indicated the degree of integration of the to-be-resected temporal lobe with the rest of the memory network. We included these measures in a linear regression model alongside standard clinical variables as predictors of memory change after surgery. RESULTS: Left TLE patients with more atypical memory networks, and with greater functional integration of the to-be-resected region with the rest of the memory network preoperatively, experienced the greatest decline in verbal memory after surgery. Together, these two measures explained 44% of variance in verbal memory change, outperforming standard clinical and demographic variables. None of the variables examined was associated with visuospatial memory change in patients with right TLE. SIGNIFICANCE: Resting-state connectivity provides valuable information concerning both the integrity of to-be-resected tissue and functional reserve across memory-relevant regions outside of the to-be-resected tissue. Intrinsic functional connectivity has the potential to be useful for clinical decision-making regarding memory outcomes in left TLE, and more work is needed to identify the factors responsible for differences seen in right TLE.

Long-term, multi-event surprise correlates with enhanced autobiographical memory.

Neurobiological and psychological models of learning emphasize the importance of prediction errors (surprises) for memory formation. This relationship has been shown for individual momentary surprising events; however, it is less clear whether surprise that unfolds across multiple events and timescales is also linked with better memory of those events. We asked basketball fans about their most positive and negative autobiographical memories of individual plays, games and seasons, allowing surprise measurements spanning seconds, hours and months. We used advanced analytics on National Basketball Association play-by-play data and betting odds spanning 17 seasons, more than 22,000 games and more than 5.6 million plays to compute and align the estimated surprise value of each memory. We found that surprising events were associated with better recall of positive memories on the scale of seconds and months and negative memories across all three timescales. Game and season memories could not be explained by surprise at shorter timescales, suggesting that long-term, multi-event surprise correlates with memory. These results expand notions of surprise in models of learning and reinforce its relevance in real-world domains.

The effects of acute dopamine depletion on resting-state functional connectivity in healthy humans.

Alpha-methyl-para-tyrosine (AMPT), a competitive inhibitor of tyrosine hydroxylase, can be used to deplete endogenous dopamine in humans. We examined how AMPT-induced dopamine depletion alters resting-state functional connectivity of the basal ganglia, and canonical resting-state networks, in healthy humans. Fourteen healthy participants (8 females; age [mean ± SD] = 27.93 ± 9.86) completed the study. Following dopamine depletion, the caudate showed reduced connectivity with the medial prefrontal cortex (mPFC) (Cohen's d = 1.89, p<.0001). Moreover, the caudate, putamen, globus pallidus, and midbrain all showed reduced connectivity with the occipital cortex (Cohen's d = 1.48-1.90; p<.0001-0.001). Notably, the dorsal caudate showed increased connectivity with the sensorimotor network (Cohen's d = 2.03, p=.002). AMPT significantly decreased self-reported motivation (t(13)=4.19, p=.001) and increased fatigue (t(13)=4.79, p=.0004). A greater increase in fatigue was associated with a greater reduction in connectivity between the substantia nigra and the mPFC (Cohen's d = 3.02, p<.00001), while decreased motivation was correlated with decreased connectivity between the VTA and left sensorimotor cortex (Cohen's d = 2.03, p=.00004). These findings help us to better understand the role of dopamine in basal ganglia function and may help us better understand neuropsychiatric diseases where abnormal dopamine levels are observed.

The hippocampus constructs narrative memories across distant events.

Life's events are scattered throughout time, yet we often recall different events in the context of an integrated narrative. Prior research suggests that the hippocampus, which supports memory for past events, can support the integration of overlapping associations or separate events in memory. However, the conditions that lead to hippocampus-dependent memory integration are unclear. We used functional brain imaging to test whether the opportunity to form a larger narrative (narrative coherence) drives hippocampal memory integration. During encoding of fictional stories, patterns of hippocampal activity, including activity at boundaries between events, were more similar between distant events that formed one coherent narrative, compared with overlapping events taken from unrelated narratives. One day later, the hippocampus preferentially supported detailed recall of coherent narrative events, through reinstatement of hippocampal activity patterns from encoding. These findings demonstrate a key function of the hippocampus: the integration of events into a narrative structure for memory.

Baseline resting-state functional connectivity determines subsequent pain ratings to a tonic ecologically valid experimental model of orofacial pain.

ABSTRACT: Pain is a subjective experience with significant individual differences. Laboratory studies investigating pain thresholds and experimental acute pain have identified structural and functional neural correlates. However, these types of pain stimuli have limited ecological validity to real-life pain experiences. Here, we use an orthodontic procedure-the insertion of an elastomeric separator between teeth-which typically induces mild to moderate pain that peaks within 2 days and lasts several days. We aimed to determine whether the baseline structure and resting-state functional connectivity of key regions along the trigeminal nociceptive and pain modulatory pathways correlate with subsequent peak pain ratings. Twenty-six healthy individuals underwent structural and resting-state functional MRI scanning before the placement of a separator between the first molar and second premolar, which was kept in place for 5 days. Participants recorded pain ratings 3 times daily on a 100-mm visual analogue scale. Peak pain was not significantly correlated with diffusion metrics of the trigeminal nerve or gray matter volume of any brain region. Peak pain did, however, positively correlate with baseline resting-state functional connectivity between the thalamus contralateral to the separator and bilateral insula, and negatively correlated with connectivity between the periaqueductal gray (PAG) and core nodes of the default mode network (medial prefrontal and posterior cingulate cortices). The ascending (thalamic) nociceptive and the descending (PAG) pain modulatory pathways at baseline each explained unique variation in peak pain intensity ratings. In sum, preinterventional functional neural architecture of both systems determined the individual pain experience to a subsequent ecologically valid pain stimulus.

Intrinsic connectivity reveals functionally distinct cortico-hippocampal networks in the human brain.

Episodic memory depends on interactions between the hippocampus and interconnected neocortical regions. Here, using data-driven analyses of resting-state functional magnetic resonance imaging (fMRI) data, we identified the networks that interact with the hippocampus-the default mode network (DMN) and a "medial temporal network" (MTN) that included regions in the medial temporal lobe (MTL) and precuneus. We observed that the MTN plays a critical role in connecting the visual network to the DMN and hippocampus. The DMN could be further divided into 3 subnetworks: a "posterior medial" (PM) subnetwork comprised of posterior cingulate and lateral parietal cortices; an "anterior temporal" (AT) subnetwork comprised of regions in the temporopolar and dorsomedial prefrontal cortex; and a "medial prefrontal" (MP) subnetwork comprised of regions primarily in the medial prefrontal cortex (mPFC). These networks vary in their functional connectivity (FC) along the hippocampal long axis and represent different kinds of information during memory-guided decision-making. Finally, a Neurosynth meta-analysis of fMRI studies suggests new hypotheses regarding the functions of the MTN and DMN subnetworks, providing a framework to guide future research on the neural architecture of episodic memory.

Parcellation of the Hippocampus Using Resting Functional Connectivity in Temporal Lobe Epilepsy.

We have previously shown that the connectivity of the hippocampus to other regions of the default mode network (DMN) is a strong indicator of memory ability in people with temporal lobe epilepsy (TLE). Recent work in the cognitive neuroscience literature has suggested that the anterior and posterior aspects of the hippocampus have distinct connections to the rest of the DMN and may support different memory operations. Further, structural analysis of epileptogenic hippocampi has found greater atrophy, characterized by mesial temporal sclerosis, in the anterior region of the hippocampus. Here, we used resting state FMRI data to parcellate the hippocampus according to its functional connectivity to the rest of the brain in people with left lateralized TLE (LTLE) and right lateralized TLE (RTLE), and in a group of neurologically healthy controls. We found similar anterior and posterior compartments in all groups. However, there was weaker connectivity of the epileptogenic hippocampus to multiple regions of the DMN. Both TLE groups showed reduced connectivity of the posterior hippocampus to key hubs of the DMN, the posterior cingulate cortex (PCC) and the medial pre-frontal cortex (mPFC). In the LTLE group, the anterior hippocampus also showed reduced connectivity to the DMN, and this effect was influenced by the presence of mesial temporal sclerosis. When we explored brain-behavior relationships, we found that reduced connectivity of the left anterior hippocampus to the DMN hubs related to poorer verbal memory ability in people with LTLE, and reduced connectivity of the right posterior hippocampus to the PCC related to poorer visual memory ability in those with RTLE. These findings may inform models regarding functional distinctions of the hippocampal anteroposterior axis.

A multivariate neuroimaging biomarker of individual outcome to transcranial magnetic stimulation in depression.

The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5-8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level-dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre-treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85-95% accuracy. Reduction in symptoms was predicted to within a mean error of ±16% (r = .68, p < .001). These preliminary findings suggest that therapeutic outcome to DLPFC-rTMS could be predicted at a clinically meaningful level using only a small number of core neurobiological features of MDD, warranting prospective testing to ascertain generalizability. This provides a novel, transparent and physiologically plausible multivariate approach for classification of individual response to what has become the most commonly employed rTMS treatment worldwide. This study utilizes data from a larger clinical study (Australian New Zealand Clinical Trials Registry: Investigating Predictors of Response to Transcranial Magnetic Stimulation for the Treatment of Depression; ACTRN12610001071011; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336262).

Increased Cortical Thickness in Attentional Networks in Parkinson's Disease with Minor Hallucinations.

Hallucinations are common in Parkinson's disease (PD). Based on functional brain MRI data, hallucinations are proposed to result from alterations in the dorsal attention network (DAN), ventral attention network (VAN), and default mode network. Using structural MRI data from Parkinson's Progression Markers Initiative (PPMI), we examined cortical thickness in these networks in PD patients with (n=30) and without (n=30) minor hallucinations who were matched on multiple clinical characteristics (e.g., age, sex, education, cognitive diagnosis, MoCA score, medication, disease duration, and severity) as well as healthy controls (n=30) matched on demographic variables. Multivariate analyses revealed mild hallucinations to be associated with thicker cortex in the DAN and VAN, and these effects were driven by the left superior precentral sulcus and postcentral sulcus for the DAN and by the right insular gyrus for the VAN. While these findings may seem at odds with prior work showing grey matter reductions, our patients are in earlier stages of the disease than those in other studies. This is consistent with an inverted U-shape pattern of cortical thickness alterations in other neurodegenerative diseases and warrants further investigations in longitudinal studies tracking brain correlates of PD psychosis progression.

The medial temporal lobe in nociception: a meta-analytic and functional connectivity study.

Recent neuroimaging studies implicate the medial temporal lobe (MTL) in nociception and pain modulation. Here, we aim to identify which subregions of the MTL are involved in human pain and to test its connectivity in a cohort of chronic low-back pain patients (CBP). We conducted 2 coordinate-based meta-analyses to determine which regions within the MTL showed consistent spatial patterns of functional activation (1) in response to experimental pain in healthy participants and (2) in chronic pain compared with healthy participants. We followed PRISMA guidelines and performed activation likelihood estimate (ALE) meta-analyses. The first meta-analysis revealed consistent activation in the right anterior hippocampus (right antHC), parahippocampal gyrus, and amygdala. The second meta-analysis revealed consistently less activation in patients' right antHC, compared with healthy participants. We then conducted a seed-to-voxel resting state functional connectivity of the right antHC seed with the rest of the brain in 77 CBP and 79 age-matched healthy participants. We found that CBP had significantly weaker antHC functional connectivity to the medial prefrontal cortex compared with healthy participants. Taken together, these data indicate that the antHC has abnormally lower activity in chronic pain and reduced connectivity to the medial prefrontal cortex in CBP. Future studies should investigate the specific role of the antHC in the development and management of chronic pain.

Language network measures at rest indicate individual differences in naming decline after anterior temporal lobe resection.

While anterior temporal lobe (ATL) resection is an effective treatment for temporal lobe epilepsy, surgery on the dominant hemisphere is associated with variable decline in confrontation naming. Accurate prediction of naming impairment is critical to inform clinical decision making, and while there has been some degree of success using task-based functional MRI (fMRI) paradigms, there remains a growing interest in the predictive utility of resting-state connectivity as it allows for relatively shorter scans with low task demands. Our objective was to assess the relationship between measures of preoperative resting-state connectivity and postoperative naming change in patients following left ATL resection. We compared the resting language network connectivity of each patient to a normative healthy control template using a novel measure called "matrix similarity," and found that patients with more abnormal global language-network connectivity-particularly of regions spared from surgery-showed greater postoperative naming decline than those with normative patterns of connectivity. When we interrogated the degree centrality of to-be-resected regions in a more targeted approach of the pathological temporal lobe, we found that greater functional integration of those regions with the rest of the language network at rest was related to greater decline in naming following surgery. Finally, we found that matrix similarity was a better predictor of postoperative outcome than degree within to-be-resected regions, network clustering, modularity, and language task fMRI laterality. We provide some of the first evidence that using this novel measure, a relatively short preoperative resting scan can be exploited to inform naming ability following ATL resection.

Applications of Resting-State Functional MR Imaging to Epilepsy.

We discuss the value of resting-state functional MR imaging (rsfMR imaging) as an emerging technique to address questions about memory and language that are central in surgery for temporal-lobe epilepsy, namely the identification and characterization of eloquent cortex to avoid surgical morbidity. The emergence of a robust set of data using rsfMR imaging has opened new avenues for exploring more direct relationships between neural networks and current cognitive function and prediction of postoperative change. These techniques are also being explored for their potential to characterize epilepsy subtypes, identify epileptic foci, and monitor treatment effects.

Distinct hippocampal functional networks revealed by tractography-based parcellation.

Recent research suggests the anterior and posterior hippocampus form part of two distinct functional neural networks. Here we investigate the structural underpinnings of this functional connectivity difference using diffusion-weighted imaging-based parcellation. Using this technique, we substantiated that the hippocampus can be parcellated into distinct anterior and posterior segments. These structurally defined segments did indeed show different patterns of resting state functional connectivity, in that the anterior segment showed greater connectivity with temporal and orbitofrontal cortex, whereas the posterior segment was more highly connected to medial and lateral parietal cortex. Furthermore, we showed that the posterior hippocampal connectivity to memory processing regions, including the dorsolateral prefrontal cortex, parahippocampal, inferior temporal and fusiform gyri and the precuneus, predicted interindividual relational memory performance. These findings provide important support for the integration of structural and functional connectivity in understanding the brain networks underlying episodic memory.

Functional and structural correlates of memory in patients with mesial temporal lobe epilepsy.

Individuals with medial temporal lobe epilepsy (mTLE) often show material-specific memory impairment (verbal for left, visuospatial for right hemisphere), which can be exacerbated following surgery aimed at the epileptogenic regions of medial and anterolateral temporal cortex. There is a growing body of evidence suggesting that characterization of structural and functional integrity of these regions using MRI can aid in prediction of post-surgical risk of further memory decline. We investigated the nature of the relationship between structural and functional indices of hippocampal integrity with pre-operative memory performance in a group of 26 patients with unilateral mTLE. Structural integrity was assessed using hippocampal volumes, while functional integrity was assessed using hippocampal activation during the encoding of novel scenes. We quantified structural and functional integrity in terms of asymmetry, calculated as (L - R)/(L + R). Factor scores for verbal and visual memory were calculated from a clinical database and an asymmetry score (verbal - visual) was used to characterize memory performance. We found, as expected, a significant difference between left and right mTLE (RTLE) groups for hippocampal volume asymmetry, with each group showing an asymmetry favoring the unaffected temporal lobe. Encoding activation asymmetry showed a similar pattern, with left mTLE patients showing activation preferential to the right hemisphere and RTLE patients showing the reverse. Finally, we demonstrated that functional integrity mediated the relationship between structural integrity and memory performance for memory asymmetry, suggesting that even if structural changes are evident, ultimately it is the functional integrity of the tissue that most closely explains behavioral performance.

Social inference deficits in temporal lobe epilepsy and lobectomy: risk factors and neural substrates.

In temporal lobe epilepsy and lobectomy, deficits in emotion identification have been found consistently, but there is limited evidence for complex social inference skills such as theory of mind. Furthermore, risk factors and the specific neural underpinnings of these deficits in this population are unclear. We investigated these issues using a comprehensive range of social inference tasks (emotion identification and comprehension of sincere, deceitful and sarcastic social exchanges) in individuals with temporal lobe epilepsy or lobectomy (n = 87). We observed deficits across patient groups which were partly related to the presence of mesial temporal lobe sclerosis, early age of seizure onset and left lobectomy. A voxel-based morphometry analysis conducted in the pre-operative group confirmed the importance of the temporal lobe by showing a relationship between left hippocampal atrophy and overall social inference abilities, and between left anterior neocortex atrophy and sarcasm comprehension. These findings are in keeping with theoretical proposals that the hippocampus is critical for binding diverse elements in cognitive domains beyond canonical episodic memory operations, and that the anterior temporal cortex is a convergence zone of higher-order perceptual and emotional processes, and of stored representations. As impairments were frequent, we require further investigation of this behavioural domain and its impact on the lives of people with epilepsy.

The human hippocampus is sensitive to the durations of events and intervals within a sequence.

Temporal details are an important facet of our memories for events. Consistent with this, it has been demonstrated that the hippocampus, a key structure in learning and memory, is sensitive to the temporal aspects of event sequences, including temporal order, context, recency and distance. One unexplored issue is whether the hippocampus also responds to the temporal duration characteristics of an event sequence, for example, how long each event lasted for or how much time elapsed between events. To address this, we used a temporal match-mismatch detection paradigm across two functional neuroimaging studies to explore whether the human hippocampus is sensitive to the durations of events and intervals that comprise a sequence lasting on the order of seconds. On each trial participants were shown a series of four scenes during an encoding and a test phase, and had to determine whether the durations of the intervals or events were altered. We observed hippocampal sensitivity to temporal durations within event sequences. Activity was significantly greater when participants detected repeating, in comparison to novel, durations. Moreover, greater functional connectivity was observed between hippocampus and brain regions previously implicated in second and millisecond timing when durations were novel, suggesting that the hippocampus may receive duration information from these areas for use within a mnemonic context rather than generate an independent timing signal. Our novel findings suggest that the hippocampus may integrate temporal duration information when binding event sequences.