Cerebellar Theta and Beta Noninvasive Stimulation Rhythms Differentially Influence Episodic Memory versus Semantic Prediction.

The human cerebellum is thought to interact with distributed brain networks to support cognitive abilities such as episodic memory and semantic prediction. Hippocampal and fronto-temporo-parietal networks that respectively support episodic memory versus semantic prediction have been associated with distinct endogenous oscillatory activity frequency bands: theta (∼3-8 Hz) versus beta (∼13-30 Hz) respectively. We sought to test whether it is possible to toggle cerebellar participation in episodic memory versus semantic prediction by noninvasively stimulating with theta versus beta rhythmic transcranial magnetic stimulation. In human subjects of both sexes, cerebellar theta stimulation improved episodic memory encoding but did not influence neural signals of semantic prediction, whereas beta stimulation of the same cerebellar location increased neural signals of semantic prediction but did not influence episodic memory encoding. This constitutes evidence for double dissociation of cerebellar contributions to semantic prediction versus episodic memory based on stimulation rhythm, supporting the hypothesis that the cerebellum can be biased to support these distinct cognitive abilities at the command of network-specific rhythmic activity.SIGNIFICANCE STATEMENT The cerebellum interacts with several distinct large-scale brain networks for cognitive function, but the factors governing selectivity of such interactions for particular functions are not fully understood. We tested the hypothesis that cerebellar contributions to cognition are guided by neural oscillations with function-specific frequency bands. We demonstrated that matching noninvasive stimulation to network-specific frequencies selectively enhanced episodic memory versus semantic prediction. These findings suggest that cerebellar contributions to cognitive networks are selected based on corresponding activity rhythms and could be used to develop cerebellar stimulation interventions for specific neurocognitive impairments.

Early Seizures Are Predictive of Worse Health-Related Quality of Life at Follow-Up After Intracerebral Hemorrhage.

OBJECTIVES: Early seizures are a common complication of intracerebral hemorrhage, occurring in ~10% of patients. However, the independent effect of early seizures on patient outcomes, particularly health-related quality of life, is unclear. Without a potential benefit to patient outcomes, the widespread use (~40%) of prophylactic seizure medications has no reasonable chance of improving patient outcomes. We tested the hypothesis that health-related quality of life at follow-up is different between patients with and without early seizures (and secondarily, with nonconvulsive status epilepticus) after intracerebral hemorrhage. DESIGN: Patients with intracerebral hemorrhage were enrolled in an observational cohort study that prospectively collected clinical data and health-related quality of life at follow-up. SETTING: Academic medical center. PATIENTS: One-hundred thirty-three patients whose health-related quality of life was assessed 3 months after intracerebral hemorrhage onset. MEASUREMENTS AND MAIN RESULTS: Health-related quality of life was obtained at 3 months after intracerebral hemorrhage onset. T Scores of health-related quality of life were modeled with multivariable linear models accounting for severity with the intracerebral hemorrhage Score and hematoma location. Health-related quality of life was measured with National Institutes of Health Patient Reported Outcomes Measurement Information System/Neuroquality of life, expressed in T Scores (U.S. normal 50 ± 10). The modified Rankin Scale (a global measure) was a secondary outcome. There were 12 patients (9%) with early seizures. T Scores of health-related quality of life at follow-up were lower (worse) in patients with early seizure compared with patients without an early seizure (44 [32.75-51.85] vs 30.25 [18.9-39.15]; p = 0.04); results for other domains of health-related quality of life were similar. The association persisted in multivariable models. There was no association between early seizures and prophylactic seizure medications (p = 0.4). Results for patients with nonconvulsive status epilepticus were similar. There was no association between early seizures and the modified Rankin Scale at 3 months. CONCLUSIONS: Early seizures and nonconvulsive status epilepticus were associated with lower health-related quality of life at follow-up in survivors of intracerebral hemorrhage.

Immunologic Treatments of Seizures and Status Epilepticus.

An autoimmune etiology for seizures, epilepsy, and status epilepticus is becoming increasingly recognized. The role of autoimmunity in epilepsy has been highlighted in the literature and the International League Against Epilepsy now recognizes autoimmune epilepsy as a distinct entity. An appropriate and thorough work-up of all new-onset seizures and status epilepticus is paramount in determining the likely efficacy of immunotherapeutic agents in treating seizures and status epilepticus. Criteria for the clinical diagnosis of autoimmune mediated epilepsy and encephalitis have been published by expert consensus and validated models to predict response to immunotherapy exist. These guidelines should guide clinicians about when to promptly start immunotherapy. Immunotherapy has been shown to improve outcomes and may reduce relapse rates in autoimmune encephalitis. Treatment algorithms with immunotherapeutic agents have been established by expert opinion and multiple observational retrospective trials in the past 10 years. However, future prospective randomized controlled trials are still needed to better understand the optimal regimen, dosing schedule, and duration of treatment with immunotherapeutic agents.

Frequency-specific noninvasive modulation of memory retrieval and its relationship with hippocampal network connectivity.

Episodic memory is thought to rely on interactions of the hippocampus with other regions of the distributed hippocampal-cortical network (HCN) via interregional activity synchrony in the theta frequency band. We sought to causally test this hypothesis using network-targeted transcranial magnetic stimulation. Healthy human participants completed four experimental sessions, each involving a different stimulation pattern delivered to the same individualized parietal cortex location of the HCN for all sessions. There were three active stimulation conditions, including continuous theta-burst stimulation, intermittent theta-burst stimulation, and beta-frequency (20-Hz) repetitive stimulation, and one sham condition. Resting-state fMRI and episodic memory testing were used to assess the impact of stimulation on hippocampal fMRI connectivity related to retrieval success. We hypothesized that theta-burst stimulation conditions would most strongly influence hippocampal-HCN fMRI connectivity and retrieval, given the hypothesized relevance of theta-band activity for HCN memory function. Continuous theta-burst stimulation improved item retrieval success relative to sham and relative to beta-frequency stimulation, whereas intermittent theta-burst stimulation led to numerical but nonsignificant item retrieval improvement. Mean hippocampal fMRI connectivity did not vary for any stimulation conditions, whereas individual differences in retrieval improvements due to continuous theta-burst stimulation were associated with corresponding increases in fMRI connectivity between the hippocampus and other HCN locations. No such memory-related connectivity effects were identified for the other stimulation conditions, indicating that only continuous theta-burst stimulation affected memory-related hippocampal-HCN connectivity. Furthermore, these effects were specific to the targeted HCN, with no significant memory-related fMRI connectivity effects for two distinct control brain networks. These findings support a causal role for fMRI connectivity of the hippocampus with the HCN in episodic memory retrieval and indicate that contributions of this network to retrieval are particularly sensitive to continuous theta-burst noninvasive stimulation.

Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy.

Glutamic acid decarboxylase (GAD) antibody-associated encephalitis causes both acute seizures and chronic epilepsy with predominantly temporal lobe onset. This condition is challenging in diagnosis and management, and the incidence of GAD antibody (Ab)-related epilepsy could be much higher than commonly believed. Imaging and CSF evidence of inflammation along with typical clinical presentations, such as adult onset temporal lobe epilepsy (TLE) with unexplained etiology, should prompt testing for the diagnostic antibodies. High serum GAD Ab titer (≥2000U/mL or ≥20nmol/L) and evidence of intrathecal anti-GAD Ab synthesis support the diagnosis. Unlike other immune-mediated epilepsies, antiglutamic acid decarboxylase 65 (GAD65) antibody-mediated epilepsy is often poorly responsive to antiepileptic drugs (AEDs) and only moderately responsive to immune therapy with steroids, intravenous immunoglobulin (IVIG), or plasma exchange (PLEX). Long-term treatment with more aggressive immunosuppressants such as rituximab (RTX) and/or cyclophosphamide is often necessary and may be more effective than current immunosuppressive approaches. The aim of this review is to review the physiology, pathology, clinical presentation, related ancillary tests, and management of GAD Ab-associated autoimmune epilepsy by searching the keywords and to promote the recognition and the initiation of proper therapy for this condition.

Paraneoplastic epilepsy.

Epilepsy can be a manifestation of paraneoplastic syndromes which are the consequence of an immune reaction to neuronal elements driven by an underlying malignancy affecting other organs and tissues. The antibodies commonly found in paraneoplastic encephalitis can be divided into two main groups depending on the target antigen: 1) antibodies against neuronal cell surface antigens, such as against neurotransmitter (N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), gamma-aminobutyric acid (GABA)) receptors, ion channels (voltage-gated potassium channel (VGKC)), and channel-complex proteins (leucine rich, glioma inactivated-1 glycoprotein (LGI1) and contactin-associated protein-2 (CASPR2)) and 2) antibodies against intracellular neuronal antigens (Hu/antineuronal nuclear antibody-1 (ANNA-1), Ma2/Ta, glutamate decarboxylase 65 (GAD65), less frequently to CV2/collapsin response mediator protein 5 (CRMP5)). In this review, we provide a comprehensive survey of the current literature on paraneoplastic epilepsy indexed by the associated onconeuronal antibodies. While a range of seizure types can be seen with paraneoplastic syndromes, temporal lobe epilepsy is the most common because of the association with limbic encephalitis. Early treatment of the paraneoplastic syndrome with immune modulation/suppression may prevent the more serious potential consequences of paraneoplastic epilepsy.

Counseling by epileptologists affects contraceptive choices of women with epilepsy.

INTRODUCTION: There are several important interactions between antiepileptic drugs (AEDs) and hormonal contraception that need to be carefully considered by women with epilepsy (WWE) and their practitioners. Many AEDs induce hepatic enzymes and decrease the efficacy of hormonal contraception. In addition, estrogen-containing hormonal contraception can increase the metabolism of lamotrigine, the most commonly prescribed AED in women of childbearing age. The intrauterine device (IUD) is a highly effective form of reversible contraception without AED drug interactions that is considered by many to be the contraceptive of choice for WWE. Women with epilepsy not planning pregnancy require effective contraceptive counseling that should include discussion of an IUD. There are no guidelines, however, on who should deliver these recommendations. The objective of this study was to explore the hypothesis that contraceptive counseling by a neurologist can influence the contraceptive choices of WWE. In particular, we explored the relationship between contraceptive counseling in the epilepsy clinic and the likelihood that patients would obtain an IUD. METHODS: We conducted a retrospective chart review of female patients age 18-45 seen at our institution for an initial visit between 2010 and 2014 to ascertain the type of contraceptive counseling each patient received as well as AED use and contraceptive methods. Patients who were pregnant or planning pregnancy at the first visit were excluded from further analyses as were patients with surgical sterilization. We also examined a subgroup of 95 patients with at least 4 follow-up visits to evaluate the efficacy of epileptologists' counseling. Specifically, we looked at the likelihood a patient obtained an IUD based on the type of counseling she had received. Fisher exact tests assessed associations between counseling type and whether patients had obtained an IUD. RESULTS: Three hundred and ninety-seven women met criteria for inclusion. Only 35% of female patients were counseled about contraception at the first visit. If women were not counseled at the first visit, they were unlikely to be counseled at subsequent visits; only 37% had ever received counseling by their fourth visit. Of the 95 patients who completed 4 visits, 28.4% were counseled about an IUD as an optimal contraceptive choice, 38.9% were generally counseled about contraceptive interactions, and 32.6% were not counseled about contraception. Women with epilepsy who received IUD-specific counseling were significantly more likely to switch to an IUD (44.4%) compared with women who received no contraceptive counseling (6.5%; p=0.0009). Women with epilepsy who received IUD-specific counseling also tended to switch to an IUD more often than those women receiving general counseling about AEDs and contraceptive interactions (18.9%; p=0.027). There was no significant difference in the likelihood of acquiring an IUD between the general counseling and no counseling groups. CONCLUSIONS: Contraceptive counseling by epileptologists and specific mention of an IUD is significantly associated with patient selection of an IUD as a contraceptive method. This suggests that neurologists can play an important role in patients' contraceptive choices.

Interleukin 6: at the interface of human health and disease.

Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes, blood brain barrier permeability, synovial inflammation, hematopoiesis, and embryonic development. This cytokine empowers the transition between innate and adaptive immune responses and helps recruit macrophages and lymphocytes to the sites of injury or infection. Given that IL-6 is involved both in the immune homeostasis and pathogenesis of several autoimmune diseases, research into therapeutic modulation of IL-6 axis resulted in the approval of a number of effective treatments for several autoimmune disorders like neuromyelitis optica spectrum disorder (NMOSD), rheumatoid arthritis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis (GCA), and cytokine release syndrome, associated with SARS-CoV2 pneumonia. This review discusses downstream inflammatory pathways of IL-6 expression and therapeutic applications of IL-6 blockade, currently investigated for the treatment of several other autoimmune conditions such as autoimmune encephalitis, autoimmune epilepsy, as well as myelin oligodendrocyte glycoprotein associated demyelination (MOGAD). This review further highlights the need for clinical trials to evaluate IL-6 blockade in disorders such neuropsychiatric lupus erythematosus (SLE), sarcoidosis and Behcet's.

Case report: Use of granulocyte-colony stimulating factor as an immunomodulatory therapy in a patient with neuromyelitis optica spectrum disorder and comorbid immunodeficiency.

Background: Autoimmune diseases can coexist with immunodeficiency. We describe a treatment approach in which granulocyte-colony stimulating factor (G-CSF) is used to restore immune competence without worsening autoimmunity. G-CSF is a polyfunctional cytokine that influences survival, proliferation, and differentiation of hematopoietic stem cells, and has immunomodulatory effects on the innate and adaptive immune systems. Objective: To report a case of neuromyelitis optica spectrum disorder (NMOSD) with comorbid immunodeficiency and frequent infections. Methods: Case report and review of literature. Results: A 23 years-old man presented with a focal onset seizure with impaired awareness at age 12. At age 18, he developed headaches, recurrent multifocal seizures, and non-convulsive status epilepticus. Brain magnetic resonance imaging (MRI) showed extensive T2 hyperintense and gadolinium-enhancing periventricular and corpus callosum lesions. Serum aquaporin 4 antibody was positive 1:10,000 (normal value <1.5 titer), hence he was diagnosed with NMOSD. As a complication, patient developed mucormycotic pneumonia with cavitation, requiring thoracotomy precluding use of immunosuppressants. Gene testing demonstrated a mutation in MT-ND4 gene encoding for NADH dehydrogenase 4 in mitochondrial complex 1. Eventually, he began a treatment with filgrastim, a G-CSF analog, in addition to intravenous immunoglobulins and prednisone. Patient's NMOSD has been in remission without relapses, or coexistent infections ever since. Conclusion: G-CSF is a polyfunctional cytokine with important immunomodulatory effects, which makes it an interesting therapeutic option when autoimmunity coexists with immunodeficiency and was used successfully in this case.

Stimulation of distinct parietal locations differentiates frontal versus hippocampal network involvement in memory formation.

Adjacent regions of parietal cortex are thought to affiliate with distinct large-scale networks and thereby make different contributions to memory formation. We directly tested this putative functional segregation within parietal cortex by perturbing activity of anterior versus posterior parietal areas. We applied noninvasive theta-burst transcranial magnetic stimulation to these locations immediately before a semantic encoding task, and subsequently tested recollection memory. Consistent with previous findings, fMRI activity in left inferior frontal gyrus during semantic encoding correlated with subsequent high memory accuracy and strong subjective recollection. Stimulation of the posterior parietal cortex decoupled its network - the hippocampal-cortical network - from left inferior frontal gyrus. Furthermore, posterior parietal stimulation reduced highly accurate subjective recollection. Critically, both of these changes occurred relative to stimulation of the anterior parietal cortex. Stimulating anterior versus posterior parietal cortex therefore differentiated hippocampal network involvement in episodic memory. This provides direct evidence that distinct territories within close proximity of each other in parietal cortex make functionally distinct contributions to memory formation. Further, noninvasive stimulation has the spatial resolution required to differentially modulate the interaction of these adjacent parietal locations with distributed large-scale brain networks.

Evidence from theta-burst stimulation that age-related de-differentiation of the hippocampal network is functional for episodic memory.

Episodic memory is supported by hippocampal interactions with a distributed network. Aging is associated with memory decline and network de-differentiation. However, the role of de-differentiation in memory decline has not been directly tested. We reasoned that hippocampal network-targeted stimulation could test these theories, as age-related changes in the network response to stimulation would indicate network reorganization, and corresponding changes in memory would suggest that this reorganization is functional. We compared effects of stimulation on fMRI connectivity and memory in younger versus older adults. Theta-burst network-targeted stimulation of left lateral parietal cortex selectively increased hippocampal network connectivity and modulated memory in younger adults. In contrast, stimulation in older adults increased connectivity throughout the brain, without network selectivity, and did not influence memory. These findings provide evidence that network responses to stimulation are de-differentiated in aging and suggest that age-related de-differentiation is relevant for memory. This manuscript is part of the Special Issue entitled "Cognitive Neuroscience of Healthy and Pathological Aging" edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

Multiple sclerosis: BAFF and CXCL13 in cerebrospinal fluid.

BACKGROUND: There is increasing evidence of B-cell involvement in the pathogenesis of multiple sclerosis (MS). B-cell activating factor (BAFF) has an essential role in B-cell homeostasis. The chemokine CXCL13 has an important role in the formation and maintenance of B-cell follicles. OBJECTIVE: To measure BAFF and CXCL13 levels in the cerebrospinal fluid (CSF) of patients with MS compared to patients with other neurological diseases. METHODS: Cytokine/chemokine levels were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: In MS patients, BAFF levels were highest in patients with secondary progressive disease, and were higher during relapse in patients with relapsing-remitting and secondary progressive disease. CXCL13 levels were also higher during relapse. There was a positive correlation between CXCL13 and the IgG index, and an inverse correlation between BAFF and the IgG index. The implications of this finding are discussed. CONCLUSION: During relapse, we found various positive correlations between BAFF, CXCL13 and the cytokines IL-6 and IL-10. These findings show that molecules that are essential for B-cell recruitment, survival, maturation and function may be working in concert to affect B-cell homeostasis in MS and contribute to the pathophysiology of the disease.

Rapid coordination of effective learning by the human hippocampus.

Although the human hippocampus is necessary for long-term memory, controversial findings suggest that it may also support short-term memory in the service of guiding effective behaviors during learning. We tested the counterintuitive theory that the hippocampus contributes to long-term memory through remarkably short-term processing, as reflected in eye movements during scene encoding. While viewing scenes for the first time, short-term retrieval operative within the episode over only hundreds of milliseconds was indicated by a specific eye-movement pattern, which was effective in that it enhanced spatiotemporal memory formation. This viewing pattern was predicted by hippocampal theta oscillations recorded from depth electrodes and by shifts toward top-down influence of hippocampal theta on activity within visual perception and attention networks. The hippocampus thus supports short-term memory processing that coordinates behavior in the service of effective spatiotemporal learning.

Paraclinical serum markers as aids in the diagnosis of autoimmune encephalitis.

Expert opinion suggests the presence ANA and thyroid antibodies may be helpful to diagnosis autoimmune encephalitis (AE). This study investigates the sensitivity of these serum markers in a cohort of 26 patients with AE. TPO-Ab, TG-Ab and ANA (titer ≥1:320) were present in 45%, 35% and 32% of patients tested, respectively. The prevalence of TPO-Ab (11.3%), TG-Ab (10.4%) and ANA ≥1:320 (3.3%) has been previously reported in disease-free populations. Although these antibodies represent non-specific markers of autoimmunity, this study demonstrated that TPO-Ab, TG-Ab and ANA were significantly elevated in AE compared to disease-free populations (p < .001, p = .003, p < .001, respectively).

Noninvasive Brain Stimulation in Epilepsy.

Neurostimulation in epilepsy is a long standing established concept, and through experimental and clinical uses, our understanding of neurostimulation and neuromodulation has grown substantially. Noninvasive brain stimulation techniques use electromagnetic principles to noninvasively modulate brain activity in a spatiotemporally targeted manner. This review focused on the two predominant forms of noninvasive neurostimulation: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, and their current applications in the diagnosis and management of epilepsy. A number of small randomized sham-controlled studies suggest that both TMS and transcranial direct current stimulation may have a beneficial effect in decreasing seizure frequency in patients with medically refractory epilepsy, without significant side effects. Small pilot studies also suggest that TMS in combination with EEG may be used to develop quantitative biomarkers of cortical hyperexcitability in patients with epilepsy. Furthermore, TMS is already Food and Drug Administration-cleared for presurgical mapping of eloquent cortex, and preliminary studies suggest that navigated TMS represents a highly valuable clinical supplement for preoperative functional planning. Transcranial magnetic stimulation and transcranial direct current stimulation have shown great potential benefit for patients with epilepsy; however, further large multicenter randomized sham-controlled studies are needed to better optimize stimulation settings and protocols, define mechanisms of action, assess long-term effects, and clearly define roles and determine efficacy.

Hippocampal theta coordinates memory processing during visual exploration.

The hippocampus supports memory encoding and retrieval, which may occur at distinct phases of the theta cycle. These processes dynamically interact over rapid timescales, especially when sensory information conflicts with memory. The ability to link hippocampal dynamics to memory-guided behaviors has been limited by experiments that lack the temporal resolution to segregate encoding and retrieval. Here, we simultaneously tracked eye movements and hippocampal field potentials while neurosurgical patients performed a spatial memory task. Phase-locking at the peak of theta preceded fixations to retrieved locations, indicating that the hippocampus coordinates memory-guided eye movements. In contrast, phase-locking at the trough of theta followed fixations to novel object-locations and predicted intact memory of the original location. Theta-gamma phase amplitude coupling increased during fixations to conflicting visual content, but predicted memory updating. Hippocampal theta thus supports learning through two interleaved processes: strengthening encoding of novel information and guiding exploration based on prior experience.

Epilepsy Emergencies: Status Epilepticus, Acute Repetitive Seizures, and Autoimmune Encephalitis.

PURPOSE OF REVIEW: This article reviews epilepsy emergencies, including status epilepticus, acute repetitive seizures, autoimmune encephalitis, and the current perspective on their diagnosis and treatment. RECENT FINDINGS: Recent guidelines on the treatment of status epilepticus from the Neurocritical Care Society in 2012 and the American Epilepsy Society in 2016 highlight areas of consensus in the treatment of status epilepticus as well as areas of uncertainty. The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) trial is the first prospective randomized clinical trial to evaluate the efficacy of IV antiseizure medications in controlling nonconvulsive seizures on continuous EEG. It demonstrated that IV lacosamide is noninferior to fosphenytoin in this setting. Autoimmune encephalitis is an increasingly recognized cause of new-onset seizures or status epilepticus. Recently described scoring systems, the Antibody Prevalence in Epilepsy score and the Response to Immunotherapy in Epilepsy score, can help in the assessment of autoimmune encephalitis. SUMMARY: Status epilepticus, acute repetitive seizures, and autoimmune encephalitis are neurologic emergencies. For all these conditions, rapid and appropriate treatment may influence patient prognosis and mitigate neuronal injury. For convulsive status epilepticus, there is reasonable consensus on the initial steps that need to be taken. There is less agreement about the management of acute repetitive seizures and nonconvulsive status epilepticus. An increasingly recognized etiology of status epilepticus is autoimmune encephalitis, which may not be as rare as previously thought.

Network-targeted stimulation engages neurobehavioral hallmarks of age-related memory decline.

OBJECTIVE: To test whether targeting hippocampal-cortical brain networks with high-frequency transcranial magnetic stimulation in older adults influences behavioral and neural measures characteristic of age-related memory impairment. METHODS: Fifteen adults aged 64 to 80 years (mean = 72 years) completed a single-blind, sham-controlled experiment. Stimulation targets in parietal cortex were determined based on fMRI connectivity with the hippocampus. Recollection and recognition memory were assessed after 5 consecutive daily sessions of full-intensity stimulation vs low-intensity sham stimulation using a within-subjects crossover design. Neural correlates of recollection and recognition memory formation were obtained via fMRI, measured within the targeted hippocampal-cortical network vs a control frontal-parietal network. These outcomes were measured approximately 24 hours after the final stimulation session. RESULTS: Recollection was specifically impaired in older adults compared to a young-adult control sample at baseline. Relative to sham, stimulation improved recollection to a greater extent than recognition. Stimulation increased recollection fMRI signals throughout the hippocampal-cortical network, including at the targeted location of the hippocampus. Effects of stimulation on fMRI recollection signals were greater than those for recognition and were greater in the targeted network compared to the control network. CONCLUSIONS: Age-related recollection impairments were causally related to hippocampal-cortical network function in older adults. Stimulation selectively modified neural and behavioral hallmarks of age-related memory impairment, indicating effective engagement of memory intervention targets in older adults.

The effect of seizure spread to the amygdala on respiration and onset of ictal central apnea.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death for patients with refractory epilepsy, and there is increasing evidence for a centrally mediated respiratory depression as a pathophysiological mechanism. The brain regions responsible for a seizure's inducing respiratory depression are unclear-the respiratory nuclei in the brainstem are thought to be involved, but involvement of forebrain structures is not yet understood. The aim of this study was to analyze intracranial EEGs in combination with the results of respiratory monitoring to investigate the relationship between seizure spread to specific mesial temporal brain regions and the onset of respiratory dysfunction and apnea. METHODS: The authors reviewed all invasive electroencephalographic studies performed at Northwestern Memorial Hospital (Chicago) since 2010 to identify those cases in which 1) multiple mesial temporal electrodes (amygdala and hippocampal) were placed, 2) seizures were captured, and 3) patients' respiration was monitored. They identified 8 investigations meeting these criteria in patients with temporal lobe epilepsy, and these investigations yielded data on a total of 22 seizures for analysis. RESULTS: The onset of ictal apnea associated with each seizure was highly correlated with seizure spread to the amygdala. Onset of apnea occurred 2.7 ± 0.4 (mean ± SEM) seconds after the spread of the seizure to the amygdala, which was significantly earlier than after spread to the hippocampus (10.2 ± 0.7 seconds; p < 0.01). CONCLUSIONS: The findings suggest that activation of amygdalar networks is correlated with central apnea during seizures. This study builds on the authors' prior work that demonstrates a role for the amygdala in voluntary respiratory control and suggests a further role in dysfunctional breathing states seen during seizures, with implications for SUDEP pathophysiology.

Neuropsychological assessment as an objective tool to monitor treatment response in anti-N-methyl-D-aspartate receptor encephalitis.

We report a 1-year follow-up of a young woman with anti-N-methyl-D-aspartate receptor encephalitis. Management of autoimmune encephalitis remains challenging as objective and clinically relevant biomarkers are sought, which allow for the monitoring of treatment response. While further investigation is required, we believe that this case highlights the importance of following a comprehensive neuropsychological profile as a clinically relevant biomarker to guide therapeutic decision-making. By relying on the neuropsychological assessment of the patient, treatment with more toxic medications was avoided and her antiepileptic drug regimen was simplified.