Faculty Bibliography

There are no functional imaging based biomarkers for pharmacological treatment response in temporal lobe epilepsy (TLE). In this study, we investigated whether there is an association between resting state functional brain connectivity (RsFC) and seizure control in TLE. We screened a large database containing resting state functional magnetic resonance imaging (Rs-fMRI) data from 286 epilepsy patients. Patient medical records were screened for seizure characterization, EEG reports for lateralization and location of seizure foci to establish uniformity of seizure localization within patient groups. Rs-fMRI data from patients with well-controlled left TLE, patients with treatment-resistant left TLE, and healthy controls were analyzed. Healthy controls and cTLE showed similar functional connectivity patterns, whereas trTLE exhibited a significant bilateral decrease in thalamo-hippocampal functional connectivity. This work is the first to demonstrate differences in neural network connectivity between well-controlled and treatment-resistant TLE. These differences are spatially highly focused and suggest sites for the etiology and possibly treatment of TLE. Altered thalamo-hippocampal RsFC thus is a potential new biomarker for TLE treatment resistance.

Slow-oscillations and spindle activity during non-REM sleep have been implicated in memory consolidation. Closed-loop acoustic stimulation has previously been shown to enhance slow oscillations and spindle activity during sleep and improve verbal associative memory. We assessed the effect of closed-loop acoustic stimulation during a daytime nap on a virtual reality spatial navigation task in 12 healthy human subjects in a randomized within-subject crossover design. We show robust enhancement of slow-spindle activity during sleep. However, no effects on behavioral performance were observed when comparing real versus sham stimulation. To explore whether memory enhancement effects were task-specific and dependent on nocturnal sleep, in a second experiment with 19 healthy subjects, we aimed to replicate a previous study which used closed-loop acoustic stimulation to enhance memory for word pairs. Methods were as close as possible to the original study, except we used a double-blind protocol, in which both subject and experimenter were unaware of the test condition. Again, we successfully enhanced slow-spindle power, but again did not strengthen associative memory performance with stimulation. We conclude that enhancement of slow-spindle oscillations may be insufficient to enhance memory performance in spatial navigation or verbal association tasks, and provide possible explanations for lack of behavioral replication.SIGNIFICANCE STATEMENT Prior studies have demonstrated that a closed-loop acoustic pulse paradigm during sleep can enhance verbal memory performance. This technique has widespread scientific and clinical appeal due to its non-invasive nature and ease of application. We tested with a rigorous double-blind design whether this technique could enhance key sleep rhythms associated sleep-dependent memory performance. We discovered that we could reliably enhance slow and spindle rhythms, but did not improve memory performance in the stimulation condition compared to sham condition. Our findings suggest that enhancing slow-spindle rhythms is insufficient to enhance sleep-dependent learning.

Mutations of the TRIM8 gene coding for a tripartite motif protein have been reported in a patient with epileptic encephalopathy by Sakai and colleagues. We present here two additional patients with TRIM8 mutations: an eight year old girl with pharmacoresistant epileptic encephalo-pathy associated with stereotypies and glomerular protei-nuria, and further clinical details of a patient reported by the Epi4K consortium. Exome sequencing revealed de novo truncating mutations of TRIM8 in our patient as well as the patient from the trio sequenced by the Epi4K consortium. The de novo mutations were confirmed by Sanger sequencing. Our case presented nephrotic syndrome not reported in the patient of Sakai and colleagues and the Epi4K consortium case. The clinical presentation of these patients overlaps with Galloway-Mowat syndrome, but mutations in the WDR73 gene were absent suggesting a Galloway-Mowat-like phenotype in our cases. Moreover, Galloway-Mowat syndrome seems to result in earlier death than in our cases. These observations suggest that phenotypic variability is observed in patients with TRIM8 mutations and genetic testing of TRIM8 should be expanded to patients with EE associated with dysmorphic features or nephrotic syndrome

Cingulate epilepsy manifests with a broad range of semiologic features and seizure types. Key clinical features may elucidate ictal involvement of certain subregions of the cingulate gyrus. Ictal and interictal electroencephalogram findings in cingulate epilepsy vary and are often poorly localized, adding to the diagnostic challenge of identifying the seizure onset zone for presurgical cases, particularly in the absence of a lesion on imaging. Recent advances in multimodal imaging techniques may contribute to ictal localization and further our understanding of neural and epileptic pathways involving the cingulate gyrus. Beyond medication and surgical resection, new techniques including stereotactic laser ablation, responsive neurostimulation, and deep brain stimulation offer additional approaches for the treatment of cingulate epilepsy.

Introduction: Peri-ictal breathing dysfunction was proposed as a potential mechanism for SUDEP. We examined the incidence and risk factors for both ictal (ICA) and post-convulsive central apnea (PCCA) and their relationship with potential seizure severity biomarkers (i. e., post-ictal generalized EEG suppression (PGES) and recurrence. Methods: Prospective, multi-center seizure monitoring study of autonomic, and breathing biomarkers of SUDEP in adults with intractable epilepsy and monitored seizures. Video EEG, thoraco-abdominal excursions, capillary oxygen saturation, and electrocardiography were analyzed. A subgroup analysis determined the incidences of recurrent ICA and PCCA in patients with ≥2 recorded seizures. We excluded status epilepticus and obscured/unavailable video. Central apnea (absence of thoracic-abdominal breathing movements) was defined as ≥1 missed breath, and ≥5 s. ICA referred to apnea preceding or occurring along with non-convulsive seizures (NCS) or apnea before generalized convulsive seizures (GCS). Results: We analyzed 558 seizures in 218 patients (130 female); 321 seizures were NCS and 237 were GCS. ICA occurred in 180/487 (36.9%) seizures in 83/192 (43.2%) patients, all with focal epilepsy. Sleep state was related to presence of ICA [RR 1.33, CI 95% (1.08-1.64), p = 0.008] whereas extratemporal epilepsy was related to lower incidence of ICA [RR 0.58, CI 95% (0.37-0.90), p = 0.015]. ICA recurred in 45/60 (75%) patients. PCCA occurred in 41/228 (18%) of GCS in 30/134 (22.4%) patients, regardless of epilepsy type. Female sex [RR 11.30, CI 95% (4.50-28.34), p < 0.001] and ICA duration [RR 1.14 CI 95% (1.05-1.25), p = 0.001] were related to PCCA presence, whereas absence of PGES was related to absence of PCCA [0.27, CI 95% (0.16-0.47), p < 0.001]. PCCA duration was longer in males [HR 1.84, CI 95% (1.06-3.19), p = 0.003]. In 9/17 (52.9%) patients, PCCA was recurrent. Conclusion: ICA incidence is almost twice the incidence of PCCA and is only seen in focal epilepsies, as opposed to PCCA, suggesting different pathophysiologies. ICA is likely to be a recurrent semiological phenomenon of cortical seizure discharge, whereas PCCA may be a reflection of brainstem dysfunction after GCS. Prolonged ICA or PCCA may, respectively, contribute to SUDEP, as evidenced by two cases we report. Further prospective cohort studies are needed to validate these hypotheses.

Although a memory systems view of the medial temporal lobe (MTL) has been widely influential in understanding how memory processes are implemented, a large body of work across humans and animals has converged on the idea that the MTL can support various other decisions, beyond those involving memory. Specifically, recent work suggests that perception of and memory for visual representations may interact in order to support ongoing cognition. However, given considerations involving lesion profiles in neuropsychological investigations and the correlational nature of fMRI, the precise nature of representations supported by the MTL are not well understood in humans. In the present investigation, three patients with highly specific lesions to MTL were administered a task that taxed perceptual and mnemonic judgments with highly similar face stimuli. A striking double dissociation was observed such that I.R., a patient with a cyst localized to right posterior PRc, displayed a significant impairment in perceptual discriminations, whereas patient A.N., an individual with a lesion in right posterior parahippocampal cortex and the tail of the right hippocampus, and S.D., an individual with bilateral hippocampal damage, did not display impaired performance on the perceptual task. A.N. and S.D. did, however, show impairments in memory performance, whereas patient I.R. did not. These results causally implicate right PRc in successful perceptual oddity judgments, however they suggest that representations supported by PRc are not necessary for correct mnemonic judgments, even in situations of high featural overlap.