Superagers Resist Typical Age-Related White Matter Structural Changes.

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age, 81.9; 59% women) and 55 typical older adults (mean age, 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed the better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibers and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus, and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional aging pattern is in line with the last-in-first-out hypothesis.

Three-dimensional histology reveals dissociable human hippocampal long-axis gradients of Alzheimer's pathology.

INTRODUCTION: Three-dimensional (3D) histology analyses are essential to overcome sampling variability and understand pathological differences beyond the dissection axis. We present Path2MR, the first pipeline allowing 3D reconstruction of sparse human histology without a magnetic resonance imaging (MRI) reference. We implemented Path2MR with post-mortem hippocampal sections to explore pathology gradients in Alzheimer's disease. METHODS: Blockface photographs of brain hemisphere slices are used for 3D reconstruction, from which an MRI-like image is generated using machine learning. Histology sections are aligned to the reconstructed hemisphere and subsequently to an atlas in standard space. RESULTS: Path2MR successfully registered histological sections to their anatomic position along the hippocampal longitudinal axis. Combined with histopathology quantification, we found an expected peak of tau pathology at the anterior end of the hippocampus, whereas amyloid-beta (Aß) displayed a quadratic anterior-posterior distribution. CONCLUSION: Path2MR, which enables 3D histology using any brain bank data set, revealed significant differences along the hippocampus between tau and Aß. HIGHLIGHTS: Path2MR enables three-dimensional (3D) brain reconstruction from blockface dissection photographs. This pipeline does not require dense specimen sampling or a subject-specific magnetic resonance (MR) image. Anatomically consistent mapping of hippocampal sections was obtained with Path2MR. Our analyses revealed an anterior-posterior gradient of hippocampal tau pathology. In contrast, the peak of amyloid-beta (Aß) deposition was closer to the hippocampal body.

Hippocampal sclerosis of aging at post-mortem is evident on MRI more than a decade prior.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically-defined features is unknown. We investigated pre-mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia-associated pathologies. METHODS: We analyzed hippocampal volumes from magnetic resonance imaging (MRI) segmentations in 64 dementia patients with longitudinal MRI follow-up and post-mortem neuropathological evaluation, including HS assessment in the hippocampal head and body. RESULTS: Significant HS-associated hippocampal volume changes were observed throughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's disease (AD) neuropathology and were driven specifically by CA1 and subiculum atrophy. AD pathology, but not HS, was associated significantly with the rate of hippocampal atrophy. DISCUSSION: HS-associated volume changes are detectable on MRI earlier than 10 years before death. Based on these findings, volumetric cutoffs could be derived for in vivo differentiation between HS and AD. HIGHLIGHTS: Hippocampal atrophy was found in HS+ patients earlier than 10 years before death. These early pre-mortem changes were driven by reduced CA1 and subiculum volumes. Rates of hippocampus and subfield volume decline were independent of HS. In contrast, steeper atrophy rates were associated with AD pathology burden. Differentiation between AD and HS could be facilitated based on these MRI findings.

Brain structure and episodic learning rate in cognitively healthy ageing.

Memory normally declines with ageing and these age-related cognitive changes are associated with changes in brain structure. Episodic memory retrieval has been widely studied during ageing, whereas learning has received less attention. Here we examined the neural correlates of episodic learning rate in ageing. Our study sample consisted of 982 cognitively healthy female and male older participants from the Vallecas Project cohort, without a clinical diagnosis of mild cognitive impairment or dementia. The learning rate across the three consecutive recall trials of the verbal memory task (Free and Cued Selective Reminding Test) recall trials was used as a predictor of grey matter (GM) using voxel-based morphometry, and WM microstructure using tract-based spatial statistics on fractional anisotropy (FA) and mean diffusivity (MD) measures. Immediate Recall improved by 1.4 items per trial on average, and this episodic learning rate was faster in women and negatively associated with age. Structurally, hippocampal and anterior thalamic GM volume correlated positively with learning rate. Learning also correlated with the integrity of WM microstructure (high FA and low MD) in an extensive network of tracts including bilateral anterior thalamic radiation, fornix, and long-range tracts. These results suggest that episodic learning rate is associated with key anatomical structures for memory functioning, motivating further exploration of the differential diagnostic properties between episodic learning rate and retrieval in ageing.

Nucleus Accumbens Stimulation Modulates Inhibitory Control by Right Prefrontal Cortex Activation in Obsessive-Compulsive Disorder.

Inhibitory control is considered a compromised cognitive function in obsessive-compulsive (OCD) patients and likely linked to corticostriatal circuitry disturbances. Here, 9 refractory OCD patients treated with deep brain stimulation (DBS) were evaluated to address the dynamic modulations of large-scale cortical network activity involved in inhibitory control after nucleus accumbens (NAc) stimulation and their relationship with cortical thickness. A comparison of DBS "On/Off" states showed that patients committed fewer errors and exhibited increased intraindividual reaction time variability, resulting in improved goal maintenance abilities and proactive inhibitory control. Visual P3 event-related potentials showed increased amplitudes during Go/NoGo performance. Go and NoGo responses increased cortical activation mainly over the right inferior frontal gyrus and medial frontal gyrus, respectively. Moreover, increased cortical activation in these areas was equally associated with a higher cortical thickness within the prefrontal cortex. These results highlight the critical role of NAc DBS for preferentially modulating the neuronal activity underlying sustained speed responses and inhibitory control in OCD patients and show that it is triggered by reorganizing brain functions to the right prefrontal regions, which may depend on the underlying cortical thinning. Our findings provide updated structural and functional evidence that supports critical dopaminergic-mediated frontal-striatal network interactions in OCD.

Functional organization of the hippocampal longitudinal axis.

The precise functional role of the hippocampus remains a topic of much debate. The dominant view is that the dorsal (or posterior) hippocampus is implicated in memory and spatial navigation and the ventral (or anterior) hippocampus mediates anxiety-related behaviours. However, this 'dichotomy view' may need revision. Gene expression studies demonstrate multiple functional domains along the hippocampal long axis, which often exhibit sharply demarcated borders. By contrast, anatomical studies and electrophysiological recordings in rodents suggest that the long axis is organized along a gradient. Together, these observations suggest a model in which functional long-axis gradients are superimposed on discrete functional domains. This model provides a potential framework to explain and test the multiple functions ascribed to the hippocampus.

Static Magnetic Field Stimulation over Parietal Cortex Enhances Somatosensory Detection in Humans.

The role of neuronal oscillations in human somatosensory perception is currently unclear. To address this, here we use noninvasive brain stimulation to artificially modulate cortical network dynamics in the context of neurophysiological and behavioral recordings. We demonstrate that transcranial static magnetic field stimulation (tSMS) over the somatosensory parietal cortex increases oscillatory power specifically in the alpha range, without significantly affecting bottom-up thalamocortical inputs indexed by the early cortical component of somatosensory evoked potentials. Critically, we next show that parietal tSMS enhances the detection of near-threshold somatosensory stimuli. Interestingly, this behavioral improvement reflects a decrease of habituation to somatosensation. Our data therefore provide causal evidence that somatosensory perception depends on parietal alpha activity.SIGNIFICANCE STATEMENT Artificially increasing alpha power by placing a powerful magnetic field over the somatosensory cortex overcomes the natural decline in detection probability of a repeated near-threshold sensory stimulus.

Transcranial static magnetic field stimulation (tSMS) of the visual cortex decreases experimental photophobia.

Background Transcranial static magnetic field stimulation (tSMS) reduces cortical excitability in humans. Methods The objective of this study was to determine whether tSMS over the occipital cortex is effective in reducing experimental photophobia. In a sham-controlled double-blind crossover study, tSMS (or sham) was applied for 10 minutes with a cylindrical magnet on the occiput of 20 healthy subjects. We assessed subjective discomfort induced by low-intensity and high-intensity visual stimuli presented in a dark room before, during and after tSMS (or sham). Results Compared to sham, tSMS significantly reduced the discomfort induced by high-intensity light stimuli. Conclusions The visual cortex may contribute to visual discomfort in experimental photophobia, providing a rationale for investigating tSMS as a possible treatment for photophobia in migraine.

Static Magnetic Field Stimulation over the Visual Cortex Increases Alpha Oscillations and Slows Visual Search in Humans.

Transcranial static magnetic field stimulation (tSMS) was recently introduced as a promising tool to modulate human cerebral excitability in a noninvasive and portable way. However, a demonstration that static magnetic fields can influence human brain activity and behavior is currently lacking, despite evidence that static magnetic fields interfere with neuronal function in animals. Here we show that transcranial application of a static magnetic field (120-200 mT at 2-3 cm from the magnet surface) over the human occiput produces a focal increase in the power of alpha oscillations in underlying cortex. Critically, this neurophysiological effect of tSMS is paralleled by slowed performance in a visual search task, selectively for the most difficult target detection trials. The typical relationship between prestimulus alpha power over posterior cortical areas and reaction time (RT) to targets during tSMS is altered such that tSMS-dependent increases in alpha power are associated with longer RTs for difficult, but not easy, target detection trials. Our results directly demonstrate that a powerful magnet placed on the scalp modulates normal brain activity and induces behavioral changes in humans.

Bidirectional synaptic plasticity can explain bidirectional retrograde effects of emotion on memory.

Emotional events can either impair or enhance memory for immediately preceding items. The GANE model explains this bidirectional effect as a glutamate "priority" signal that modulates noradrenaline release depending on arousal state. We argue for an alternative explanation: that priority itself evokes phasic noradrenaline release. Thus, contrasting E-1 memory effects are explained by a mechanism based on the Bienenstock-Cooper-Munro theory.

Neuronal population representation of human emotional memory.

Understanding how emotional processing modulates learning and memory is crucial for the treatment of neuropsychiatric disorders characterized by emotional memory dysfunction. We investigate how human medial temporal lobe (MTL) neurons support emotional memory by recording spiking activity from the hippocampus, amygdala, and entorhinal cortex during encoding and recognition sessions of an emotional memory task in patients with pharmaco-resistant epilepsy. Our findings reveal distinct representations for both remembered compared to forgotten and emotional compared to neutral scenes in single units and MTL population spiking activity. Additionally, we demonstrate that a distributed network of human MTL neurons exhibiting mixed selectivity on a single-unit level collectively processes emotion and memory as a network, with a small percentage of neurons responding conjointly to emotion and memory. Analyzing spiking activity enables a detailed understanding of the neurophysiological mechanisms underlying emotional memory and could provide insights into how emotion alters memory during healthy and maladaptive learning.

Voxel-based dysconnectomic brain morphometry with computed tomography in Down syndrome.

OBJECTIVE: Alzheimer's disease (AD) is a major health concern for aging adults with Down syndrome (DS), but conventional diagnostic techniques are less reliable in those with severe baseline disability. Likewise, acquisition of magnetic resonance imaging to evaluate cerebral atrophy is not straightforward, as prolonged scanning times are less tolerated in this population. Computed tomography (CT) scans can be obtained faster, but poor contrast resolution limits its function for morphometric analysis. We implemented an automated analysis of CT scans to characterize differences across dementia stages in a cross-sectional study of an adult DS cohort. METHODS: CT scans of 98 individuals were analyzed using an automatic algorithm. Voxel-based correlations with clinical dementia stages and AD plasma biomarkers (phosphorylated tau-181 and neurofilament light chain) were identified, and their dysconnectomic patterns delineated. RESULTS: Dementia severity was negatively correlated with gray (GM) and white matter (WM) volumes in temporal lobe regions, including parahippocampal gyri. Dysconnectome analysis revealed an association between WM loss and temporal lobe GM volume reduction. AD biomarkers were negatively associated with GM volume in hippocampal and cingulate gyri. INTERPRETATION: Our automated algorithm and novel dysconnectomic analysis of CT scans successfully described brain morphometric differences related to AD in adults with DS, providing a new avenue for neuroimaging analysis in populations for whom magnetic resonance imaging is difficult to obtain.

Aphasic seizures in patients with temporopolar and anterior temporobasal lesions: a video-EEG study.

Studies of patients with temporal lobe epilepsy provide few descriptions of seizures that arise in the temporopolar and the anterior temporobasal brain region. Based on connectivity, it might be assumed that the semiology of these seizures is similar to that of medial temporal lobe epilepsy. However, accumulating evidence suggests that the anterior temporobasal cortex may play an important role in the language system, which could account for particular features of seizures arising here. We studied the electroclinical features of seizures in patients with circumscribed temporopolar and temporobasal lesions in order to identify specific features that might differentiate them from seizures that originate in other temporal areas. Among 172 patients with temporal lobe seizures registered in our epilepsy unit in the last 15 years, 15 (8.7%) patients had seizures caused by temporopolar or anterior temporobasal lesions (11 left-sided lesions). The main finding in our study is that patients with left-sided lesions had aphasia during their seizures as the most prominent feature. In addition, while all patients showed normal to high intellectual functioning in standard neuropsychological testing, semantic impairment was found in a subset of 9 patients with left-sided lesions. This case series demonstrates that aphasic seizures without impairment of consciousness can result from small, circumscribed left anterior temporobasal and temporopolar lesions. Thus, the presence of speech manifestation during seizures should prompt detailed assessment of the structural integrity of the basal surface of the temporal lobe in addition to the evaluation of primary language areas.

Brain structure and phenotypic profile of superagers compared with age-matched older adults: a longitudinal analysis from the Vallecas Project.

BACKGROUND: Cognitive abilities, particularly memory, normally decline with age. However, some individuals, often designated as superagers, can reach late life with the memory function of individuals 30 years younger. We aimed to characterise the brain structure of superagers and identify demographic, lifestyle, and clinical factors associated with this phenotype. METHODS: We selected cognitively healthy participants from the Vallecas Project longitudinal cohort recruited between Oct 10, 2011, and Jan 14, 2014, aged 79·5 years or older, on the basis of their delayed verbal episodic memory score. Participants were assessed with the Free and Cued Selective Reminding Test and with three non-memory tests (the 15-item version of the Boston Naming Test, the Digit Symbol Substitution Test, and the Animal Fluency Test). Participants were classified as superagers if they scored at or above the mean values for a 50-56-year-old in the Free and Cued Selective Reminding Test and within one standard deviation of the mean or above for their age and education level in the three non-memory tests, or as typical older adults if they scored within one standard deviation of the mean for their age and education level in the Free and Cued Selective Reminding Test. Data acquired as per protocol from up to six yearly follow-ups were used for longitudinal analyses. FINDINGS: We included 64 superagers (mean age 81·9 years; 38 [59%] women and 26 [41%] men) and 55 typical older adults (82·4 years; 35 [64%] women and 20 [36%] men). The median number of follow-up visits was 5·0 (IQR 5·0-6·0) for superagers and 5·0 (4·5-6·0) for typical older adults. Superagers exhibited higher grey matter volume cross-sectionally in the medial temporal lobe, cholinergic forebrain, and motor thalamus. Longitudinally, superagers also showed slower total grey matter atrophy, particularly within the medial temporal lobe, than did typical older adults. A machine learning classification including 89 demographic, lifestyle, and clinical predictors showed that faster movement speed (despite no group differences in exercise frequency) and better mental health were the most differentiating factors for superagers. Similar concentrations of dementia blood biomarkers in superager and typical older adult groups suggest that group differences reflect inherent superager resistance to typical age-related memory loss. INTERPRETATION: Factors associated with dementia prevention are also relevant for resistance to age-related memory decline and brain atrophy, and the association between superageing and movement speed could provide potential novel insights into how to preserve memory function into the ninth decade. FUNDING: Queen Sofia Foundation, CIEN Foundation, Spanish Ministry of Science and Innovation, Alzheimer's Association, European Research Council, MAPFRE Foundation, Carl Zeiss Foundation, and the EU Comission for Horizon 2020. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Three-dimensional histology reveals dissociable human hippocampal long axis gradients of Alzheimer's pathology.

INTRODUCTION: Three-dimensional (3D) histology analyses are essential to overcome sampling variability and understand pathological differences beyond the dissection axis. We present Path2MR, the first pipeline allowing 3D reconstruction of sparse human histology without an MRI reference. We implemented Path2MR with post-mortem hippocampal sections to explore pathology gradients in Alzheimer's Disease. METHODS: Blockface photographs of brain hemisphere slices are used for 3D reconstruction, from which an MRI-like image is generated using machine learning. Histology sections are aligned to the reconstructed hemisphere and subsequently to an atlas in standard space. RESULTS: Path2MR successfully registered histological sections to their anatomical position along the hippocampal longitudinal axis. Combined with histopathology quantification, we found an expected peak of tau pathology at the anterior end of the hippocampus, while amyloid-ß displayed a quadratic anterior-posterior distribution. CONCLUSION: Path2MR, which enables 3D histology using any brain bank dataset, revealed significant differences along the hippocampus between tau and amyloid-ß.

Deep-brain stimulation of the human nucleus accumbens-medial septum enhances memory formation.

Deep-brain stimulation (DBS) is a potential novel treatment for memory dysfunction. Current attempts to enhance memory focus on stimulating human hippocampus or entorhinal cortex. However, an alternative strategy is to stimulate brain areas providing modulatory inputs to medial temporal memory-related structures, such as the nucleus accumbens (NAc), which is implicated in enhancing episodic memory encoding. Here, we show that NAc-DBS improves episodic and spatial memory in psychiatric patients. During stimulation, NAc-DBS increased the probability that infrequent (oddball) pictures would be subsequently recollected, relative to periods off stimulation. In a second experiment, NAc-DBS improved performance in a virtual path-integration task. An optimal electrode localization analysis revealed a locus spanning postero-medio-dorsal NAc and medial septum predictive of memory improvement across both tasks. Patient structural connectivity analyses, as well as NAc-DBS-evoked hemodynamic responses in a rat model, converge on a central role for NAc in a hippocampal-mesolimbic circuit regulating encoding into long-term memory. Thus, short-lived, phasic NAc electrical stimulation dynamically improved memory, establishing a critical on-line role for human NAc in episodic memory and providing an empirical basis for considering NAc-DBS in patients with loss of memory function.

Prefrontal-occipitoparietal coupling underlies late latency human neuronal responses to emotion.

Enhanced late positive potentials (LPPs) evoked by highly arousing unpleasant and pleasant stimuli have been consistently observed in event-related potential experiments in humans. Although the psychological factors modulating the LPP have been studied in detail, the neurobiological underpinnings of this response remain poorly understood. Current models suggest that the LPP is a product of both an automatic facilitation of perceptual activity, as well as postperceptual processing under cognitive control. Here we applied magnetoencephalography (MEG) and beamformer analysis combined with Granger causality measures to provide a mechanistic account for LPP generation that reconciles these two models. We demonstrate that the magnetic homolog of the LPP, mLPP, is localized within bilateral occipitoparietal and right prefrontal cortex. Critically, directed functional connectivity analysis between these brain regions, indexed by Granger causality, demonstrates stronger bidirectional influences between frontal and occipitoparietal cortex for high arousing emotional relative to low arousing neutral pictures. Thus, both bottom-up and top-down accounts of the late latency response to emotion derived from psychological studies can be explained by a reciprocal codependency between activity in prefrontal and occipitoparietal cortex.

Connecting to the long axis.

New study reveals how various regions of the human cortex connect to the hippocampus along its longer anterior-posterior axis, shedding light on the way this structure is functionally organized.

Static magnetic field stimulation over motor cortex modulates resting functional connectivity in humans.

Focal application of transcranial static magnetic field stimulation (tSMS) over the human motor cortex induces local changes in cortical excitability. Whether tSMS can also induce distant network effects, and how these local and distant effects may vary over time, is currently unknown. In this study, we applied 10 min tSMS over the left motor cortex of healthy subjects using a real/sham parallel design. To measure tSMS effects at the sensori-motor network level, we used resting-state fMRI. Real tSMS, but not sham, reduced functional connectivity within the stimulated sensori-motor network. This effect of tSMS showed time-dependency, returning to sham levels after the first 5 min of fMRI scanning. With 10 min real tSMS over the motor cortex we did not observe effects in other functional networks examined (default mode and visual system networks). In conclusion, 10 min of tSMS over a location within the sensori-motor network reduces functional connectivity within the same functional network.

Aversive memory formation in humans involves an amygdala-hippocampus phase code.

Memory for aversive events is central to survival but can become maladaptive in psychiatric disorders. Memory enhancement for emotional events is thought to depend on amygdala modulation of hippocampal activity. However, the neural dynamics of amygdala-hippocampal communication during emotional memory encoding remain unknown. Using simultaneous intracranial recordings from both structures in human patients, here we show that successful emotional memory encoding depends on the amygdala theta phase to which hippocampal gamma activity and neuronal firing couple. The phase difference between subsequently remembered vs. not-remembered emotional stimuli translates to a time period that enables lagged coherence between amygdala and downstream hippocampal gamma. These results reveal a mechanism whereby amygdala theta phase coordinates transient amygdala -hippocampal gamma coherence to facilitate aversive memory encoding. Pacing of lagged gamma coherence via amygdala theta phase may represent a general mechanism through which the amygdala relays emotional content to distant brain regions to modulate other aspects of cognition, such as attention and decision-making.