Faculty Bibliography

OBJECTIVE:Incomplete resection of neocortical epileptogenic foci correlates with failed epilepsy surgery in children. We often treat patients with neocortical epilepsy with a staged approach using invasive monitoring to localize the focus, resect the seizure onset zone, and, in select cases, post-resection invasive monitoring (PRM). We report the technique and the outcomes of children treated with staged surgery including PRM. METHODS:We retrospectively reviewed the charts of pediatric patients with neocortical epilepsy who underwent resective surgery with PRM. RESULTS:We identified 71 patients, 5 patients with MRI-negative epilepsy and 66 patients with MRI-identified neocortical lesions; 64/66 (97%) patients had complete lesionectomy. In 61/71 (86%) patients PRM was associated with positive outcomes. Those findings were: 1) clinical seizures with electrographic involvement at resection margins (47%); 2) subclinical seizures and interictal discharges at resection margins (29%); and 3) clinical and subclinical seizures revealing a new epileptogenic focus (20%). In 55/71 (77%) patients, PRM data led to additional resection (re-resection; RR). Six additional patients had no further resection due to overlap with eloquent cortex. Histopathology showed tuberous sclerosis complex (TSC; n = 46), focal cortical dysplasia (FCD; n = 16)), gliosis (n = 4), tumors (n = 4), and Sturge-Weber syndrome (n = 1). There were no major complications. Seizure-free outcome in children with TSC was 63% at 1-year follow-up and 56% at 2-year follow-up. In FCD, seizure freedom after 1 and 2 years was 85%. SIGNIFICANCE/CONCLUSIONS:Post-resection monitoring may provide additional information about the extent of the epileptogenic zone, such as residual epileptogenic activity at the margins of the resection cavity, and may unmask additional seizure foci. This method may be especially useful in achieving long-term stable seizure-free outcome.

The running-down phenomenon refers to 2 analogous but distinct entities that may be seen after epilepsy surgery. The first is clinical, and denotes a progressive diminution in seizures after epilepsy surgery in which the epileptogenic zone could not be completely removed (Modern Problems of Psychopharmacology 1970;4:306, Brain 1996:989). The second is electrographic, and refers to a progressive deactivation of a secondary seizure focus after removal of the primary epileptogenic zone. This progressive decrease in epileptiform activity may represent a reversal of secondary epileptogenesis, where a primary epileptogenic zone is postulated to activate epileptiform discharges at a second site and may become independent.³ The electrographic running-down phenomenon has been reported in only limited numbers of patients, using serial postoperative routine scalp electroencephalography (EEG) (Arch Neurol 1985;42:318). We present what is, to our knowledge, the most detailed demonstration of the electrographic running-down phenomenon in humans, made possible by chronic electrocorticography (ECoG). Our patient's left temporal seizure focus overlapped with language areas, limiting the resection to a portion of the epileptogenic zone, followed by implantation of a direct brain-responsive neurostimulator (RNS System, NeuroPace Inc.) to treat residual epileptogenic tissue. Despite the limited extent of the resection, the patient remains seizure-free more than 2 years after surgery, with the RNS System recording ECoG without delivering stimulation. We reviewed the chronic recordings with automated spike detection and inspection of electrographic episodes marked by the neurostimulator. These recordings demonstrate progressive diminution in spiking and rhythmic discharges, consistent with an electrographic running-down phenomenon.

Noninvasive brain stimulation techniques are used in experimental and clinical fields for their potential effects on brain network dynamics and behavior. Transcranial electrical stimulation (TES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), has gained popularity because of its convenience and potential as a chronic therapy. However, a mechanistic understanding of TES has lagged behind its widespread adoption. Here, we review data and modelling on the immediate neurophysiological effects of TES in vitro as well as in vivo in both humans and other animals. While it remains unclear how typical TES protocols affect neural activity, we propose that validated models of current flow should inform study design and artifacts should be carefully excluded during signal recording and analysis. Potential indirect effects of TES (e.g., peripheral stimulation) should be investigated in more detail and further explored in experimental designs. We also consider how novel technologies may stimulate the next generation of TES experiments and devices, thus enhancing validity, specificity, and reproducibility.

Structural and functional elements of biological systems are highly conserved across vertebrates. Many neurological and psychiatric conditions affect both humans and animals. A cross-species approach to the study of brain and behaviour can advance our understanding of human disorders via the identification of unrecognized natural models of spontaneous disorders, thus revealing novel factors that increase vulnerability or resilience, and via the assessment of potential therapies. Moreover, diagnostic and therapeutic advances in human neurology and psychiatry can often be adapted for veterinary patients. However, clinical and research collaborations between physicians and veterinarians remain limited, leaving this wealth of comparative information largely untapped. Here, we review pain, cognitive decline syndromes, epilepsy, anxiety and compulsions, autoimmune and infectious encephalitides and mismatch disorders across a range of animal species, looking for novel insights with translational potential. This comparative perspective can help generate novel hypotheses, expand and improve clinical trials and identify natural animal models of disease resistance and vulnerability.

OBJECTIVE:To evaluate the safety of mTOR inhibitors (sirolimus or everolimus) in infants and very young children with tuberous sclerosis complex (TSC) under two years of age. METHODS:Study design was retrospective to capture medical record data from 52 international TSC Centres who initiated treatment with sirolimus or everolimus in TSC children before the age of two years. Data collection included demographic and clinical information including reason(s) for initiating treatment with mTOR inhibitors, treatment duration, dosing, and corresponding serum trough levels, response to treatment, and adverse events (AE). RESULTS:19 of 52 (37%) TSC Centres reported treatment of at least one child with TSC under the age of two years with everolimus or sirolimus. Treatment-related data were provided for 45 patients meeting inclusion criteria. Everolimus was utilised 87% of the time, compared to 24% for sirolimus (5 subjects, 11%, were treated separately with both). Refractory epilepsy (45%) was the most common primary reason for initiating treatment and treatment was initiated on average at 11.6 ± 7.6 months of age. At least one AE, suspected or definitely treatment-related, occurred in 35 of 45 (78%) treated subjects. Most AEs were mild (Grade 1) or moderate (Grade 2) in severity and most commonly related to infections. Severe AE (Grade 3) was reported in 7 subjects (20%) and no life-threatening AE (Grade 4) or death/disability (Grade 5) was reported. Treatment was discontinued due to an AE in 9 of 45 (20%). CONCLUSIONS:Everolimus, and to a lesser extent sirolimus, are increasingly being used to treat TSC infants and very young children for multiple TSC-associated clinical indications. While AEs were common, most were not severe and did not prevent continued treatment in the majority of this younger population.

De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C-terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data-sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders.

Employing predictions based on environmental regularities is fundamental for adaptive behaviour. While it is widely accepted that predictions across different stimulus attributes (e.g., time and content) facilitate sensory processing, it is unknown whether predictions across these attributes rely on the same neural mechanism. Here, to elucidate the neural mechanisms of predictions, we combine invasive electrophysiological recordings (human electrocorticography in 4 females and 2 males) with computational modelling while manipulating predictions about content ('what') and time ('when'). We found that 'when' predictions increased evoked activity over motor and prefrontal regions both at early (∼180 ms) and late (430-450 ms) latencies. 'What' predictability, however, increased evoked activity only over prefrontal areas late in time (420-460 ms). Beyond these dissociable influences, we found that 'what' and 'when' predictability interactively modulated the amplitude of early (165 ms) evoked responses in the superior temporal gyrus. We modelled the observed neural responses using biophysically realistic neural mass models, to better understand whether 'what' and 'when' predictions tap into similar or different neurophysiological mechanisms. Our modelling results suggest that 'what' and 'when' predictability rely on complementary neural processes: 'what' predictions increased short-term plasticity in auditory areas, while 'when' predictability increased synaptic gain in motor areas. Thus, content and temporal predictions engage complementary neural mechanisms in different regions, suggesting domain-specific prediction signalling along the cortical hierarchy. Encoding predictions through different mechanisms may endow the brain with the flexibility to efficiently signal different sources of predictions, weight them by their reliability, and allow for their encoding without mutual interference.SIGNIFICANCE STATEMENTPredictions of different stimulus features facilitate sensory processing. However, it is unclear whether predictions of different attributes rely on similar or different neural mechanisms. By combining invasive electrophysiological recordings of cortical activity with experimental manipulations of participants' predictions about content and time of acoustic events, we found that the two types of predictions had dissociable influences on cortical activity, both in terms of the regions involved and the timing of the observed effects. Further, our biophysical modelling analysis suggests that predictability of content and time rely on complementary neural processes: short-term plasticity in auditory areas and synaptic gain in motor areas, respectively. This suggests that predictions of different features are encoded with complementary neural mechanisms in different brain regions.