Christopher T. Anderson

Explaining how brain stimulation can evoke memories

An unexplained phenomenon in neuroscience is the discovery that electrical stimulation in temporal neocortex can cause neurosurgical patients to spontaneously experience memory retrieval. Here we provide the first detailed examination of the neural basis of stimulation-induced memory retrieval by probing brain activity in a patient who reliably recalled memories of his high school (HS) after stimulation at a site in his left temporal lobe. After stimulation, this patient performed a customized memory task in which he was prompted to retrieve information from HS and non-HS topics. At the one site where stimulation evoked HS memories, remembering HS information caused a distinctive pattern of neural activity compared with retrieving non-HS information. Together, these findings suggest that the patient had a cluster of neurons in his temporal lobe that help represent the “high school-ness” of the current cognitive state. We believe that stimulation here evoked HS memories because it altered local neural activity in a way that partially mimicked the normal brain state for HS memories. More broadly, our findings suggest that brain stimulation can evoke memories by recreating neural patterns from normal cognition.

Decoding the memorization of individual stimuli with direct human brain recordings

Through decades of research, neuroscientists and clinicians have identified an array of brain areas that each activate when a person views a certain category of stimuli. However, we do not have a detailed understanding of how the brain represents individual stimuli within a category. Here we used direct human brain recordings and machine-learning algorithms to characterize the distributed patterns that distinguish specific cognitive states. Epilepsy patients with surgically implanted electrodes performed a working-memory task and we used machine-learning algorithms to predict the identity of each viewed stimulus. We found that the brains representation of stimulus-specific information is distributed across neural activity at multiple frequencies, electrodes, and timepoints. Stimulus-specific neuronal activity was most prominent in the high-gamma (65-128 Hz) and theta/alpha (4-16 Hz) bands, but the properties of these signals differed significantly between individuals and for novel stimuli compared to common ones. Our findings are helpful for understanding the neural basis of memory and developing brain-computer interfaces by showing that the brain distinguishes specific cognitive states by diverse spatiotemporal patterns of neuronal.

Day-Night Patterns of Epileptiform Activity in 65 Patients With Long-Term Ambulatory Electrocorticography.

Purpose: To characterize cyclic day–night patterns of electrocorticographic epileptiform activity (EA) in patients with focal onset seizures. Methods: Epileptiform events as defined by the physician (also termed more generally as “epileptiform activity” or EA) were recorded in 65 patients with partial onset (also referred to as “focal onset”) seizures using the RNS System, which includes a cranially implanted neurostimulator connected to 1 or two 4-contact leads placed at the seizure focus. The neurostimulator is programmed to detect specific patterns of electrocorticographic activity and to provide responsive stimulation. The 24-hour periodicity of detections of EA was analyzed for individual patients and for subgroups of patients according to the type of EA, laterality, lobe of onset, and whether the onset was neocortical or hippocampal. The time of day when peaks in EA occurred was also analyzed. Results: There were robust circadian patterns of detections of EA in most patients, with a primary peak in detections at night and a secondary peak in the late afternoon in some cases. Subset analyses were performed by lobe, region of the brain, and type of cortex (neocortical vs. hippocampal); significant circadian rhythmicity was present in all subsets. Conclusions: This is the first report of circadian cycles of EA as assessed through chronic ambulatory electrocorticographic recordings in adults with focal onset seizures. Epileptiform activity displayed circadian patterns in the majority of these patients. These findings suggest that epilepsy therapies might be optimized by adjusting the timing of therapy according to each patients unique circadian pattern of EA.

The TARC/sICAM5 Ratio in Patient Plasma is a Candidate Biomarker for Drug Resistant Epilepsy

Epilepsy is a common affliction that involves inflammatory processes. There are currently no definitive chemical diagnostic biomarkers in the blood, so diagnosis is based on a sometimes expensive synthesis of clinical observation, radiology, neuro-psychological testing, and interictal and ictal EEG studies. Soluble ICAM5 (sICAM5), also known as telencephalin, is an anti-inflammatory protein of strictly central nervous system tissue origin that is also found in blood. Here we have tested the hypothesis that plasma concentrations of select inflammatory cytokines, including sICAM5, might serve as biomarkers for epilepsy diagnosis. To test this hypothesis, we developed a highly sensitive and accurate electrochemiluminescent ELISA assay to measure sICAM5 levels, and measured levels of sICAM5 and 18 other inflammatory mediators in epilepsy patient plasma and controls. Patient samples were drawn from in-patients undergoing video-EEG monitoring, without regard to timing of seizures. Differences were defined by t-test, and Receiver Operating Condition (ROC) curves determined the ability of these tests to distinguish between the two populations. In epilepsy patient plasmas, we found that concentrations of anti-inflammatory sICAM5 are reduced (p = 0.002) and pro-inflammatory IL-1β, IL-2, and IL-8 are elevated. TARC (thymus and activation regulated chemokine, CCL17) concentrations trend high. In contrast, levels of BDNF and a variety of other pro-inflammatory mediators are not altered. Based on p-value and ROC analysis, we find that the ratio of TARC/sICAM5 discriminates accurately between patients and controls, with an ROC Area Under the Curve (AUC) of 1.0 (p = 0.034). In conclusion, we find that the ratio of TARC to sICAM5 accurately distinguishes between the two populations and provides a statistically and mechanistically compelling candidate blood biomarker for drug resistant epilepsy.

Epilepsy Surgery: Factors That Affect Patient Decision-Making in Choosing or Deferring a Procedure

Surgical resection for well-selected patients with refractory epilepsy provides seizure freedom approximately two-thirds of the time. Despite this, many good candidates for surgery, after a presurgical workup, ultimately do not consent to a procedure. The reasons why patients decline potentially effective surgery are not completely understood. We explored the socio cultural, medical, personal, and psychological differences between candidates who chose (n = 23) and those who declined surgical intervention (n = 9). We created a novel questionnaire addressing a range of possible factors important in patient decision making. We found that patients who declined surgery were less bothered by their epilepsy (despite comparable severity), more anxious about surgery, and less likely to listen to their doctors (and others) and had more comorbid psychiatric disease. Patients who chose surgery were more embarrassed by their seizures, more interested in being “seizure-free”, and less anxious about specific aspects of surgery. Patient attitudes, beliefs, and anxiety serve as barriers to ideal care. These results can provide opportunities for education, treatment, and intervention. Additionally, patients who fit a profile of someone who is likely to defer surgery may not be appropriate for risky and expensive presurgical testing.

Sleep structure following status epilepticus

OBJECTIVES To determine the effect of status epilepticus (SE) on sleep. BACKGROUND SE has a high incidence of morbidity and mortality. The study of sleep structure following SE may have implications for recovery in these patients. METHODS Twenty-four hour polysomnography was recorded in a 52-year-old patient following generalized convulsive SE not complicated by other medical or neurologic conditions. Another patient with no known history of seizures was recorded under similar conditions. RESULTS The first day following SE was associated with markedly abnormal sleep structure, consisting largely of stage 1 with minimal slow wave or REM sleep. Over 4 days, slow wave and REM returned to normal values and no rebound was seen. The control patient demonstrated normal sleep parameters for their age, demonstrating that sleep disruption was not due to recording conditions alone. CONCLUSIONS This case demonstrates that sleep structure is markedly abnormal following generalized convulsive SE. As sleep may serve a restorative function, improving sleep postictally may hasten or improve recovery. Larger studies will be required to determine whether this is a common finding in such patients, and whether outcome is associated with improved sleep quality.

Utilization of care among drug resistant epilepsy patients with symptoms of anxiety and depression

PURPOSE Epilepsy patients have a significantly higher rate of anxiety and depression than the general population, and psychiatric disease is particularly prevalent among drug resistant epilepsy patients. Symptoms of anxiety and depression might serve as a barrier to appropriate epilepsy care. The aim of this study was to determine if drug resistant epilepsy patients with symptoms of anxiety and/or depression receive different epilepsy management than controls. METHOD We identified 83 patients with drug resistant focal epilepsy seen at the Penn Epilepsy Center. Upon enrollment, all patients completed 3 self-report scales and a neuropsychiatric inventory and were grouped into those with symptoms of anxiety and/or depression and controls. Each patients medical records were retrospectively reviewed for 1-2 years, and objective measures of outpatient and inpatient epilepsy management were assessed. RESULTS At baseline, 53% (n=43) of patients screened positive for symptoms of anxiety and/or depression. The remaining 47% (n=38) served as controls. Patients with anxiety and/or depression symptoms had more missed outpatient visits per year compared to controls (median 0.84 vs. 0.48, p=0.02). Patients with symptoms of both anxiety and depression were more likely to undergo an inpatient admission or procedure (56% vs. 24%, p=0.02). CONCLUSION For most measures of epilepsy management, symptoms of anxiety and/or depression do not alter epilepsy care; however, drug resistant epilepsy patients with anxiety and/or depression symptoms may be more likely to miss outpatient appointments, and those with the highest burden of psychiatric symptoms may be admitted more frequently for inpatient services compared to controls.

Magnetoencephalography in the Preoperative Evaluation for Epilepsy Surgery

People with pharmacoresistant epilepsy are often candidates for resective epilepsy surgery. The presurgical evaluation for epilepsy aims to localize the epileptic network that initiates seizures (which should be disrupted or removed) and determine its spatial relationship to eloquent cortex (which should be preserved). Noninvasive functional imaging techniques play an increasingly important role in planning epilepsy surgery and assessing the feasibility, risks, and benefits of surgery. Magnetoencephalography (MEG) can be a very useful part of a comprehensive presurgical evaluation as it can model the sources of epileptiform activity and localize eloquent cortices within the same study. This review is designed to assist anyone in the field of neurology or related disciplines understand some methods and terminology relevant to clinical MEG. Every effort is made to present the information in nontechnical, approachable ways so that readers will come away with a basic understanding of how to interpret MEG findings when the reported data on one of their patients are presented to them.

Rescue Therapies for Seizures

Most medical therapies for epilepsy consist of daily (or multiple-daily) dose, fixed-schedule, pharmacologic oral agents. Despite adherence, many patients continue to experience seizures. Various products have been discovered, designed, and marketed to serve as seizure-abortant therapies. These agents can be administered rapidly, as a “rescue” therapy, once a clinical seizure or cluster of seizures starts. Rescue medications are given as needed in an attempt to disrupt progression of a given seizure, and forestall what would otherwise be a more prolonged or more severe clinical event. Seizure-abortants also serve to aid in the management of seizure emergencies, such as prolonged, repetitive seizures, or status epilepticus. These compounds are not appropriate for all patients. Nevertheless, they do provide therapeutic benefit to several groups of patients: 1) those who perceive the onset of their seizures and have time to perform a self-intervention, 2) patients’ caregivers who administer the therapy when they witness the onset of an ictal event, and 3) patients who are in the midst of an out-of-the-hospital seizure emergency (a seizure cluster or status epilepticus). In this article we will review currently available and future rescue therapies for seizures: US Food and Drug Administration (FDA) approved and FDA nonapproved drugs, nonpharmacologic behavioral treatments, the vagus nerve stimulator and the NeuroPace RNS® System (Mountain View, CA).

Outcomes Following Clinical Complete Response to Neoadjuvant Chemotherapy for Muscle-invasive Urothelial Carcinoma of the Bladder in Patients Refusing Radical Cystectomy

OBJECTIVE To investigate survival outcomes of patients with muscle-invasive bladder cancer (MIBC) that demonstrate complete clinical response (cT0) to neoadjuvant chemotherapy (NAC) and then reject subsequent radical cystectomy (RC). METHODS A retrospective chart review identified patients with MIBC who were cT0 after platinum-based NAC. cT0 was defined as negative cytology, cystoscopy with transurethral resection of bladder tumor, and imaging. cT0 patients refusing for RC were followed up with cytology, cystoscopy with biopsy, and cross-sectional imaging. RESULTS Forty-eight patients were identified with MIBC that were cT0 after NAC. Seven patients underwent immediate RC, whereas 41 elected bladder preservation with close surveillance. Of those remaining 41 patients, mean age was 68 ± 11 years with median follow-up of 35 months. NAC regimens were 46% methotrexate/vinblastine/doxorubicin/cisplatin, 39% gemcitabine/cisplatin, and 15% other platinum-based therapies. Five-year cancer-specific survival was 87%, disease-free survival was 58%, and cystectomy-free survival was 79%. A total of 19 patients (46%) relapsed with 5.4-month median recurrence time. CONCLUSION Bladder preservation may be a reasonable option in a highly select subset of patients with MIBC who are complete clinical responders after NAC. For those patients that were cT0 after NAC and refused or were ineligible for RC, 5-year disease-free survival was nearly 60% and cancer-specific survival was nearly 90%. Future studies should focus on identifying clinical and molecular factors associated with a durable pathologic complete response after NAC.