Sarah K. Bick

Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.).

Why are people with focal epilepsy not continuously having seizures? Previous neuronal signalling work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is a high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure-onset zones have increased inward connectivity that could be associated with interictal suppression of seizure activity. Accordingly, we hypothesize that seizure-onset zones are actively suppressed by the rest of the brain network during interictal states. Full testing of this hypothesis would require collaboration across multiple domains of neuroscience. We focused on partially testing this hypothesis at the electrographic network level within 81 individuals with drug-resistant focal epilepsy undergoing presurgical evaluation. We used intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, early propagation and non-involved zones. We then used diffusion imaging to acquire estimates of white-matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, we generated a resting-state classification model to assist clinicians in detecting seizure-onset and propagation zones without the need for multiple ictal recordings. Our findings indicate that seizure onset and early propagation zones demonstrate markedly increased inwards connectivity and decreased outwards connectivity using both resting-state (one-way ANOVA, P-value = 3.13 × 10-13) and neurostimulation analyses to evaluate evoked responses (one-way ANOVA, P-value = 2.5 × 10-3). When controlling for the distance between regions, the difference between inwards and outwards connectivity remained stable up to 80 mm between brain connections (two-way repeated measures ANOVA, group effect P-value of 2.6 × 10-12). Structure-function coupling analyses revealed that seizure-onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue (two-way repeated measures ANOVA, interaction effect P-value of 9.76 × 10-21). Using these observations, our support vector classification models achieved a maximum held-out testing set accuracy of 92.0 ± 2.2% to classify early propagation and seizure-onset zones. These results suggest that seizure-onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure-onset zones. These findings have implications for the identification of seizure-onset zones using only brief electrographic recordings to reduce patient morbidity and augment the presurgical evaluation of drug-resistant epilepsy. Further testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative and neuromodulation approaches to improve surgical success rates in those suffering from drug-resistant focal epilepsy.

BACKGROUND: Trigeminal neuralgia (TN) increases in prevalence with age. Although microvascular decompression (MVD) is the most effective long-term operative treatment for TN, its use in older patient populations has been debated due to its invasive nature. Recent studies have demonstrated safety of MVD in older patients; however, efficacy data are more limited. OBJECTIVE: To determine the relationship between age and pain outcomes following MVD for TN. METHODS: Subjects underwent MVD for TN at our institution between 1/1/2004 and 12/31/2013, had typical TN, and demonstrated neurovascular compression on preoperative imaging. We performed a retrospective case series study by reviewing the electronic medical records and performing phone interviews to determine long-term outcomes. We divided patients into 2 groups for analysis, under 60 and 60 yr of age and older. RESULTS: One hundred twenty-four subjects were included in the study, 82 under 60, and 42 60 yr of age and older. The average length of follow-up was 42.4 mo. Patients in the older age group had average pain score of 1.57 at most recent follow-up, while for the younger age group it was 2.18 (P = .0084). Multiple regression analysis found that older age, male gender, and preoperative medication responsiveness were significantly correlated with lower long-term pain scores, while V2 dermatome involvement was correlated with higher long-term pain scores. CONCLUSION: Patients 60 yr of age and older have significantly better long-term pain outcomes following MVD than younger patients.

Cognitive impairment is the most frequent non-motor symptom in Parkinson's disease and is associated with deficits in a number of cognitive functions including working memory. However, the pathophysiology of Parkinson's disease cognitive impairment is poorly understood. Beta oscillations have previously been shown to play an important role in cognitive functions including working memory encoding. Decreased dopamine in motor cortico-striato-thalamo-cortical (CSTC) circuits increases the spectral power of beta oscillations and results in Parkinson's disease motor symptoms. Analogous changes in parallel cognitive CSTC circuits involving the caudate and dorsolateral prefrontal cortex (DLPFC) may contribute to Parkinson's disease cognitive impairment. The objective of our study is to evaluate whether changes in beta oscillations in the caudate and DLPFC contribute to cognitive impairment in Parkinson's disease patients. To investigate this, we used local field potential recordings during deep brain stimulation surgery in 15 patients with Parkinson's disease. Local field potentials were recorded from DLPFC and caudate at rest and during a working memory task. We examined changes in beta oscillatory power during the working memory task as well as the relationship of beta oscillatory activity to preoperative cognitive status, as determined from neuropsychological testing results. We additionally conducted exploratory analyses on the relationship between cognitive impairment and task-based changes in spectral power in additional frequency bands. Spectral power of beta oscillations decreased in both DLPFC and caudate during working memory encoding and increased in these structures during feedback. Subjects with cognitive impairment had smaller decreases in caudate and DLPFC beta oscillatory power during encoding. In our exploratory analysis, we found that similar differences occurred in alpha frequencies in caudate and theta and alpha in DLPFC. Our findings suggest that oscillatory power changes in cognitive CSTC circuits may contribute to cognitive symptoms in patients with Parkinson's disease. These findings may inform the future development of novel neuromodulatory treatments for cognitive impairment in Parkinson's disease.