Scalp and hippocampal sleep correlates of memory function in drug-resistant temporal lobe epilepsy.

Seminal animal studies demonstrated the role of sleep oscillations such as cortical slow waves, thalamocortical spindles, and hippocampal ripples in memory consolidation. In humans, whether ripples are involved in sleep-related memory processes is less clear. Here, we explored the interactions between sleep oscillations (measured as traits) and general episodic memory abilities in 26 adults with drug-resistant temporal lobe epilepsy who performed scalp-intracranial electroencephalographic recordings and neuropsychological testing, including two analogous hippocampal-dependent verbal and nonverbal memory tasks. We explored the relationships between hemispheric scalp (spindles, slow waves) and hippocampal physiological and pathological oscillations (spindles, slow waves, ripples, and epileptic spikes) and material-specific memory function. To differentiate physiological from pathological ripples, we used multiple unbiased data-driven clustering approaches. At the individual level, we found material-specific cerebral lateralization effects (left-verbal memory, right-nonverbal memory) for all scalp spindles (rs > 0.51, ps < 0.01) and fast spindles (rs > 0.61, ps < 0.002). Hippocampal epileptic spikes and short pathological ripples, but not physiological oscillations, were negatively (rs > -0.59, ps < 0.01) associated with verbal learning and retention scores, with left lateralizing and antero-posterior effects. However, data-driven clustering failed to separate the ripple events into defined clusters. Correlation analyses with the resulting clusters revealed no meaningful or significant associations with the memory scores. Our results corroborate the role of scalp spindles in memory processes in patients with drug-resistant temporal lobe epilepsy. Yet, physiological and pathological ripples were not separable when using data-driven clustering, and thus our findings do not provide support for a role of sleep ripples as trait-like characteristics of general memory abilities in epilepsy.

Focal epilepsy disrupts spindle structure and function.

Sleep spindles are the hallmark of N2 sleep and are attributed a key role in cognition. Little is known about the impact of epilepsy on sleep oscillations underlying sleep-related functions. This study assessed changes in the global spindle rate in patients with epilepsy, analysed the distribution of spindles in relation to the epileptic focus, and performed correlations with neurocognitive function. Twenty-one patients with drug-resistant focal epilepsy (12 females; mean age 32.6 ± 10.7 years [mean ± SD]) and 12 healthy controls (3 females; 24.5 ± 3.3 years) underwent combined whole-night high-density electroencephalography and polysomnography. Global spindle rates during N2 were lower in epilepsy patients compared to controls (mean = 5.78/min ± 0.72 vs. 6.49/min ± 0.71, p = 0.02, d = - 0.70). Within epilepsy patients, spindle rates were lower in the region of the epileptic focus compared to the contralateral region (median = 4.77/min [range 2.53-6.18] vs. 5.26/min [2.53-6.56], p = 0.02, rank biserial correlation RC = - 0.57). This decrease was driven by fast spindles (12-16 Hz) (1.50/min [0.62-4.08] vs. 1.65/min [0.51-4.28], p = 0.002, RC = - 0.76). The focal reduction in spindles was negatively correlated with two scales of attention (r = - 0.54, p = 0.01; r = - 0.51, p = 0.025). Patients with focal epilepsy show a reduction in global and local spindle rates dependent on the region of the epileptic focus. This may play a role in impaired cognitive functioning. Future work will show if the local reduction in spindles can be used as potential marker of the epileptic focus.

Decomposing MRI phenotypic heterogeneity in epilepsy: a step towards personalized classification.

In drug-resistant temporal lobe epilepsy, precise predictions of drug response, surgical outcome and cognitive dysfunction at an individual level remain challenging. A possible explanation may lie in the dominant 'one-size-fits-all' group-level analytical approaches that does not allow parsing interindividual variations along the disease spectrum. Conversely, analysing inter-patient heterogeneity is increasingly recognized as a step towards person-centred care. Here, we used unsupervised machine learning to estimate latent relations (or disease factors) from 3 T multimodal MRI features [cortical thickness, hippocampal volume, fluid-attenuated inversion recovery (FLAIR), T1/FLAIR, diffusion parameters] representing whole-brain patterns of structural pathology in 82 patients with temporal lobe epilepsy. We assessed the specificity of our approach against age- and sex-matched healthy individuals and a cohort of frontal lobe epilepsy patients with histologically verified focal cortical dysplasia. We identified four latent disease factors variably co-expressed within each patient and characterized by ipsilateral hippocampal microstructural alterations, loss of myelin and atrophy (Factor 1), bilateral paralimbic and hippocampal gliosis (Factor 2), bilateral neocortical atrophy (Factor 3) and bilateral white matter microstructural alterations (Factor 4). Bootstrap analysis and parameter variations supported high stability and robustness of these factors. Moreover, they were not expressed in healthy controls and only negligibly in disease controls, supporting specificity. Supervised classifiers trained on latent disease factors could predict patient-specific drug response in 76 ± 3% and postsurgical seizure outcome in 88 ± 2%, outperforming classifiers that did not operate on latent factor information. Latent factor models predicted inter-patient variability in cognitive dysfunction (verbal IQ: r = 0.40 ± 0.03; memory: r = 0.35 ± 0.03; sequential motor tapping: r = 0.36 ± 0.04), again outperforming baseline learners. Data-driven analysis of disease factors provides a novel appraisal of the continuum of interindividual variability, which is probably determined by multiple interacting pathological processes. Incorporating interindividual variability is likely to improve clinical prognostics.

Feasibility of remote neurocognitive assessment: pandemic adaptations for a clinical trial, the Cognition and Obstructive Sleep Apnea in Parkinson's Disease, Effect of Positive Airway Pressure Therapy (COPE-PAP) study.

BACKGROUND: The COVID-19 pandemic poses challenges for timely outcome assessment in randomized clinical trials (RCT). Our aim was to describe our remote neurocognitive testing (NCT) protocol administered by telephone in patients with Parkinson's disease (PD) and obstructive sleep apnea (OSA). METHODS: We studied PD patients with OSA and Montreal Cognitive Assessment (MoCA) score ≤ 27 participating in a RCT assessing OSA treatment impact on cognition. Trial outcomes included change in MoCA and specific cognitive domains from baseline to 3 and 6 months. With COVID19 pandemic-related restrictions, 3-month visits were converted from in-person to telephone administration with materials mailed to participants for compatible tests and retrieved by courier the same day. In exploratory analyses, we compared baseline vs. 3-month results in the control arm, which were not expected to change significantly (test-re-test), using a paired t-test and assessed agreement with the intraclass correlation coefficient (ICC). RESULTS: Seven participants were approached and agreed to remote NCT at 3-month follow-up. Compared to the in-person NCT control arm group, they were younger (60.6 versus 70.6 years) and had a shorter disease course (3.9 versus 9.2 years). Remote NCT data were complete. The mean test-retest difference in MoCA was similar for in-person and remote NCT control-arm groups (between group difference - 0.69; 95%CI - 3.67, 2.29). Agreement was good for MOCA and varied for specific neurocognitive tests. CONCLUSION: Telephone administration of the MoCA and a modified neurocognitive battery is feasible in patients with PD and OSA. Further validation will require a larger sample size.

Atypical functional connectome hierarchy impacts cognition in temporal lobe epilepsy.

OBJECTIVE: Drug-resistant temporal lobe epilepsy (TLE) is typically associated with hippocampal pathology. However, widespread network alterations are increasingly recognized and suggested to perturb cognitive function in multiple domains. Here we tested (1) whether TLE shows atypical cortical hierarchical organization, differentiating sensory and higher order systems; and (2) whether atypical hierarchy predicts cognitive impairment. METHODS: We studied 72 well-characterized drug-resistant TLE patients and 41 healthy controls, statistically matched for age and sex, using multimodal magnetic resonance imaging analysis and cognitive testing. To model cortical hierarchical organization in vivo, we used a bidirectional stepwise functional connectivity analysis tapping into the differentiation between sensory/unimodal and paralimbic/transmodal cortices. Linear models compared patients to controls. Finally, we assessed associations of functional anomalies to cortical atrophy and microstructural anomalies, as well as clinical and cognitive parameters. RESULTS: Compared to controls, TLE presented with bidirectional disruptions of sensory-paralimbic functional organization. Stepwise connectivity remained segregated within paralimbic and salience networks at the top of the hierarchy, and sensorimotor and dorsal attention at the bottom. Whereas paralimbic segregation was associated with atypical cortical myeloarchitecture and hippocampal atrophy, dysconnectivity of sensorimotor cortices reflected diffuse cortical thinning. The degree of abnormal hierarchical organization in sensory-petal streams covaried, with broad cognitive impairments spanning sensorimotor, attention, fluency, and visuoconstructional ability and memory, and was more marked in patients with longer disease duration and Engel I outcome. SIGNIFICANCE: Our findings show atypical functional integration between paralimbic/transmodal and sensory/unimodal systems in TLE. Differential associations with paralimbic microstructure and sensorimotor atrophy suggest that system-level imbalance likely reflects complementary structural processes, but ultimately accounts for a broad spectrum of cognitive impairments. Hierarchical contextualization of cognitive deficits promises to open new avenues for personalized counseling in TLE.

Altered communication dynamics reflect cognitive deficits in temporal lobe epilepsy.

OBJECTIVE: Although temporal lobe epilepsy (TLE) is recognized as a system-level disorder, little work has investigated pathoconnectomics from a dynamic perspective. By leveraging computational simulations that quantify patterns of information flow across the connectome, we tested the hypothesis that network communication is abnormal in this condition, studied the interplay between hippocampal- and network-level disease effects, and assessed associations with cognition. METHODS: We simulated signal spreading via a linear threshold model that temporally evolves on a structural graph derived from diffusion-weighted magnetic resonance imaging (MRI), comparing a homogeneous group of 31 patients with histologically proven hippocampal sclerosis to 31 age- and sex-matched healthy controls. We evaluated the modulatory effects of structural alterations of the neocortex and hippocampus on network dynamics. Furthermore, multivariate statistics addressed the relationship with cognitive parameters. RESULTS: We observed a slowing of in- and out-spreading times across multiple areas bilaterally, indexing delayed information flow, with the strongest effects in ipsilateral frontotemporal regions, thalamus, and hippocampus. Effects were markedly reduced when controlling for hippocampal volume but not cortical thickness, underscoring the central role of the hippocampus in whole-brain disease expression. Multivariate analysis associated slower spreading time in frontoparietal, limbic, default mode, and subcortical networks with impairment across tasks tapping into sensorimotor, executive, memory, and verbal abilities. SIGNIFICANCE: Moving beyond descriptions of static topology toward the formulation of brain dynamics, our work provides novel insight into structurally mediated network dysfunction and demonstrates that altered whole-brain communication dynamics contribute to common cognitive difficulties in TLE.

A connectome-based mechanistic model of focal cortical dysplasia.

Neuroimaging studies have consistently shown distributed brain anomalies in epilepsy syndromes associated with a focal structural lesion, particularly mesiotemporal sclerosis. Conversely, a system-level approach to focal cortical dysplasia has been rarely considered, likely due to methodological difficulties in addressing variable location and topography. Given the known heterogeneity in focal cortical dysplasia histopathology, we hypothesized that lesional connectivity consists of subtypes with distinct structural signatures. Furthermore, in light of mounting evidence for focal anomalies impacting whole-brain systems, we postulated that patterns of focal cortical dysplasia connectivity may exert differential downstream effects on global network topology. We studied a cohort of patients with histologically verified focal cortical dysplasia type II (n = 27), and age- and sex-matched healthy controls (n = 34). We subdivided each lesion into similarly sized parcels and computed their connectivity to large-scale canonical functional networks (or communities). We then dichotomized connectivity profiles of lesional parcels into those belonging to the same functional community as the focal cortical dysplasia (intra-community) and those adhering to other communities (inter-community). Applying hierarchical clustering to community-reconfigured connectome profiles identified three lesional classes with distinct patterns of functional connectivity: decreased intra- and inter-community connectivity, a selective decrease in intra-community connectivity, and increased intra- as well as inter-community connectivity. Hypo-connectivity classes were mainly composed of focal cortical dysplasia type IIB, while the hyperconnected lesions were type IIA. With respect to whole-brain networks, patients with hypoconnected focal cortical dysplasia and marked structural damage showed only mild imbalances, while those with hyperconnected subtle lesions had more pronounced topological alterations. Correcting for interictal epileptic discharges did not impact connectivity patterns. Multivariate structural equation analysis provided a mechanistic model of such complex, diverging interactions, whereby the focal cortical dysplasia structural makeup shapes its functional connectivity, which in turn modulates whole-brain network topology.

Noninvasive tongue stimulation combined with intensive cognitive and physical rehabilitation induces neuroplastic changes in patients with multiple sclerosis: A multimodal neuroimaging study.

BACKGROUND: Multiple sclerosis (MS) patients have central nervous system (CNS) lesions that may impede cognitive and sensorimotor function. Few rehabilitative therapies are available. OBJECTIVES: The objective of this paper is to study effects of noninvasive tongue stimulation using the Portable Neuromodulation Stimulator (PoNS™) combined with intensive cognitive and physical rehabilitation on working memory, gait, balance and concomitant changes in the brain. METHODS: Fourteen MS patients, seven each in an active and a sham stimulation group, participated. Participants received intensive physical therapy and working memory training for 14 weeks. Functional magnetic resonance imaging (fMRI) using motor imagery and working-memory tasks were completed prior to and following therapy, as were sensory organization tests (SOT), motor performance measures, and neuropsychological assessment. RESULTS: On the SOT, the active group showed significant improvement from baseline. fMRI revealed significant blood oxygen level-dependent signal changes in the left primary motor cortex for the Active Group, while the sham group had increased activity in bilateral premotor cortices. All individuals improved on working-memory tasks, but only the active group showed increased dorsolateral prefrontal cortex activity. CONCLUSIONS: In this cohort of MS patients, the results suggest that PoNS stimulation can enhance motor performance and working memory while also driving neuroplasticity. Further studies are warranted to explore these findings.

A pilot study of training and compensation interventions for mild cognitive impairment.

BACKGROUND: This pilot clinical trial sought to estimate the feasibility and efficacy of two interventions aimed at improving memory performance in geriatric clinic patients with mild cognitive impairment. METHODS: Fifteen participants were randomized to either a memory training group or a memory compensation group. RESULTS: Recruitment rates were low, whereas adherence and retention rates were acceptable. The memory training group improved in self-reported memory abilities and satisfaction with memory. The memory compensation group improved on one objective memory test but showed no consistent changes on any other outcomes. CONCLUSION: Effect size estimates will inform the design of larger clinical trials.

Bilingual brain organization: a functional magnetic resonance adaptation study.

We used functional magnetic resonance adaptation (fMRA) to examine whether intra-voxel functional specificity may be present for first (L1)- and second (L2)-language processing. We examined within- and across-language adaptation for spoken words in English-French bilinguals who had acquired their L2 after the age of 4 years. Subjects listened to words presented binaurally through earphones. In two control conditions (one for each language), six identical words were presented to obtain maximal adaptation. The remaining six conditions each consisted of five words that were identical followed by a sixth word that differed. There were thus a total of eight experimental conditions: no-change (sixth word identical to first five); a change in meaning (different final word in L1); a change in language (final item translated into L2); a change in meaning and language (different final word in L2). The same four conditions were presented in L2. The study also included a silent baseline. At the neural level, within- and across-language word changes resulted in release from adaptation. This was true for separate analyses of L1 and L2. We saw no evidence for greater recovery from adaptation in across-language relative to within-language conditions. While many brain regions were common to L1 and L2, we did observe differences in adaptation for forward translation (L1 to L2) as compared to backward translation (L2 to L1). The results support the idea that, at the lexical level, the neural substrates for L1 and L2 in bilinguals are shared, but with some populations of neurons within these shared regions showing language-specific responses.

What went where? Impaired object-location learning in patients with right hippocampal lesions.

The role of the right medial temporal-lobe structures in memory for object location was investigated in three studies. In the first two studies, 118 patients with selective amygdalo-hippocampectomy or with anterior temporal lobectomy (either invading or largely sparing the hippocampal region) and 33 healthy participants were tested on array learning. Groups with extensive right hippocampal lesions were impaired on immediate and delayed recall and on learning to criterion. In the third study, magnetic resonance imaging (MRI) was used in 75 of these patients to measure the extent of tissue remaining in the various medial temporal-lobe structures. The extent of right hippocampus remaining was found to be the best predictor of array-learning performance, underlining its critical role in building a representation of objects in space.

Volumetry of temporopolar, perirhinal, entorhinal and parahippocampal cortex from high-resolution MR images: considering the variability of the collateral sulcus.

Researchers in clinical and basic neuroscience frequently target structures of the human medial temporal lobe (MTL) for volumetric analysis with magnetic resonance imaging (MRI). In neurodegenerative diseases, a precise volumetric analysis of MTL structures can assist in differential diagnosis and can be used in guiding early treatment. Also, in functional neuroimaging, exact localization is crucial for the correct interpretation of focal MTL activations with respect to specific memory functions. In presently available protocols, precise and consistent volumetric analysis of MTL structures is compromised in numerous ways. Most importantly, in order to cover all structures of the MTL, the researcher is presently forced to combine independently developed segmentation protocols for different structures from different laboratories. This approach limits anatomical precision because these protocols are based on different anatomical guidelines and descriptions that cannot easily be integrated. The segmentation approach presented in this paper was designed to address this issue by presenting segmentation guidelines for all major structures of the parahippocampal gyrus (PHG). It was developed directly to complement a volumetric protocol for hippocampus and amygdala (Pruessner et al., 2000, Cereb Cortex 10:433-442), thus allowing volumetric assessment of all major MTL structures in an integrated and consistent manner. Furthermore, it takes into consideration the neuroanatomical appearance of the collateral sulcus by presenting a method to correct the volumes of the surrounding cortices for the variability of this sulcus. The protocol was validated using MR images of 40 healthy normal control subjects (20 men and 20 women, age range 18-42 years). Intra- and interrater coefficients are presented, together with mean values for the volumes of all PHG structures, correlations with age and sex, and tests for hemispheric differences.

Do I know you? Face perception and memory in patients with selective amygdalo-hippocampectomy.

In 1968, Milner (Neuropsychologia 6 (1968) 191) demonstrated a face-memory impairment in patients with right, but not left, temporal-lobe excisions. Because all the removals included lateral and inferior temporal neocortex together with amygdala, parahippocampal gyrus and varying amounts of hippocampus, a combined-lesion effect could not be ruled out. We therefore examined the contribution of right temporal structures to recognition of previously unfamiliar faces by repeating Milner's original study, testing patients who had undergone selective amygdalo-hippocampectomy (AH), in addition to those with anterior temporal-lobectomy (TL). The paradigm involved selecting 12 previously studied faces from an array of 25 photographs. The Mooney Closure Faces Test was also administered. Subjects included 29 AH patients (14 left (LAH) and 15 right (RAH)) and 59 TL patients (30 L and 29 R) who were categorized further based on extensive (18 LTH and 21 RTH) or minimal (12 LTh and 8 RTh) hippocampal encroachment. Twenty age- and education-matched normal control subjects (NC) were also tested. For the face-memory task, one-way ANOVA revealed a strong group effect (P<0.001), and post-hoc tests confirmed that both the RTH and RAH groups recognized fewer faces than the NC and LAH groups; the RAH group also differed from the LTh, LTH and RTh groups. No group differences were found for the closure test. Our findings suggest that right medial temporal-lobe structures are critically involved in the retention, but probably not in the perception, of new faces.

Differential contributions of the parahippocampal place area and the anterior hippocampus to human memory for scenes.

Past neuroimaging research has identified a parahippocampal place area (PPA) in the posterior medial temporal lobe (MTL), which responds preferentially to visual scenes and plays a role in episodic memory for this class of stimuli. In the present positron emission tomography study, we examined to what extent the functional characteristics of the PPA resemble those of other, more anterior MTL regions across various learning and recognition-memory tasks. We also determined whether the involvement of the PPA in recognition of previously studied scenes is specific to a particular type of scene information. We found that, like the PPA, anterior hippocampal regions showed a novelty response (higher activation for novel than repeated scenes) and a stimulus-related response (higher activation for scenes than objects) during learning, indicating that MTL structures other than the PPA contribute to the encoding of novel stimulus relationships in scenes. However, these anterior hippocampal regions showed no involvement during recognition of either spatial or nonspatial information contained in scenes. The PPA, by contrast, was consistently involved in recognition of all types of scene details, presumably through interactions with co-activated parietal and occipitotemporal cortices. We suggest that MTL contributions from the PPA are sufficient to support recognition of scenes when the task can be based on a perceptually based familiarity process.