Derek G. Southwell

Cortical Plasticity Induced by Inhibitory Neuron Transplantation

Inflexible Timing for Flexibility During critical periods in early life, sensory experience molds circuits in the brain. In the visual cortex, blurring or occluding vision in one eye triggers a rapid reorganization of neuronal responses known as ocular dominance plasticity. The critical period for this plasticity depends on inhibitory neurotransmission. Southwell et al. (p. 1145) show that by transplanting embryonic precursors of inhibitory neurons into mice, a period of ocular dominance plasticity can be induced after the end of the normal critical period. These observations suggest that transplantation of inhibitory neurons has therapeutic potential for brain repair and for treating neurological disorders and inducing periods of brain plasticity. Plasticity in the mouse brain’s visual cortex can be re-induced by neurons embedded by an earlier transplantation. Critical periods are times of pronounced brain plasticity. During a critical period in the postnatal development of the visual cortex, the occlusion of one eye triggers a rapid reorganization of neuronal responses, a process known as ocular dominance plasticity. We have shown that the transplantation of inhibitory neurons induces ocular dominance plasticity after the critical period. Transplanted inhibitory neurons receive excitatory synapses, make inhibitory synapses onto host cortical neurons, and promote plasticity when they reach a cellular age equivalent to that of endogenous inhibitory neurons during the normal critical period. These findings suggest that ocular dominance plasticity is regulated by the execution of a maturational program intrinsic to inhibitory neurons. By inducing plasticity, inhibitory neuron transplantation may facilitate brain repair.

Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain.

Embryonic medial ganglionic eminence (MGE) cells transplanted into the adult brain can disperse, migrate, and differentiate to neurons expressing GABA, the primary inhibitory neurotransmitter. It has been hypothesized that grafted MGE precursors could have important therapeutic applications increasing local inhibition, but there is no evidence that MGE cells can modify neural circuits when grafted into the postnatal brain. Here we demonstrate that MGE cells grafted into one location of the neonatal rodent brain migrate widely into cortex. Grafted MGE-derived cells differentiate into mature cortical interneurons; the majority of these new interneurons express GABA. Based on their morphology and expression of somatostatin, neuropeptide Y, parvalbumin, or calretinin, we infer that graft-derived cells integrate into local circuits and function as GABA-producing inhibitory cells. Whole-cell current-clamp recordings obtained from MGE-derived cells indicate firing properties typical of mature interneurons. Moreover, patch-clamp recordings of IPSCs on pyramidal neurons in the host brain, 30 and 60 d after transplantation, indicated a significant increase in GABA-mediated synaptic inhibition in regions containing transplanted MGE cells. In contrast, synaptic excitation is not altered in the host brain. Grafted MGE cells, therefore, can be used to modify neural circuits and selectively increase local inhibition. These findings could have important implications for reparative cell therapies for brain disorders.

Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice

Epilepsy, a disease characterized by abnormal brain activity, is a disabling and potentially life-threatening condition for nearly 1% of the world population. Unfortunately, modulation of brain excitability using available antiepileptic drugs can have serious side effects, especially in the developing brain, and some patients can only be improved by surgical removal of brain regions containing the seizure focus. Here, we show that bilateral transplantation of precursor cells from the embryonic medial ganglionic eminence (MGE) into early postnatal neocortex generates mature GABAergic interneurons in the host brain. In mice receiving MGE cell grafts, GABA-mediated synaptic and extrasynaptic inhibition onto host brain pyramidal neurons is significantly increased. Bilateral MGE cell grafts in epileptic mice lacking a Shaker-like potassium channel (a gene mutated in one form of human epilepsy) resulted in significant reductions in the duration and frequency of spontaneous electrographic seizures. Our findings suggest that MGE-derived interneurons could be used to ameliorate abnormal excitability and possibly act as an effective strategy in the treatment of epilepsy.

Intrinsically determined cell death of developing cortical interneurons

Cortical inhibitory circuits are formed by γ-aminobutyric acid (GABA)-secreting interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis, is that cortical interneurons are overproduced, and then after their migration into cortex the excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we characterize the developmental cell death of mouse cortical interneurons in vivo, in vitro and after transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax (Bcl-2-associated X)-dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by neurons of the central nervous system. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Taken together, our findings indicate that interneuron cell death is determined intrinsically, either cell-autonomously or through a population-autonomous competition for survival signals derived from other interneurons.

Interneurons from Embryonic Development to Cell-Based Therapy

Background Alterations in neural excitation and inhibition cause a number of neurologic and psychiatric disorders. In the cerebral cortex, excitation and inhibition are mediated by two cell types born in distinct areas of the embryo: excitatory projection neurons, which are generated in the developing cortex, and inhibitory interneurons, which are produced outside the cortex in the ventral forebrain. After migrating from their origins across the developing brain, young interneurons reach the cortex and differentiate into various inhibitory neuronal cell types. Roughly two-thirds of these young cells survive in the cortex to form the local inhibitory circuits that shape excitatory neuron activity. The embryologic programs that guide interneuron migration, survival, and circuit integration are also executed by these young neurons after their transplantation into the juvenile and adult nervous systems. These processes, realized in the developmentally and topographically distinct environment of the recipient, offer a unique opportunity for studying neurodevelopment and therapeutically modifying neural circuits. Transplanted interneurons for the study of neural development and the treatment of nervous system disorders. Precursors of inhibitory interneurons transplanted from the medial ganglionic eminence of the ventral embryonic forebrain into the juvenile or adult rodent cortex migrate from the graft site and become dispersed throughout the recipient tissue (shown as small red dots in the transplanted hemisphere in a cross section of the rodent brain, upper left). In the recipient, transplanted interneurons follow cell-intrinsic programs that normally regulate their survival and differentiation in the embryo. Interneurons in the host brain (small green dots) do not die as a result of the additional neurons; rather, transplantation increases the total interneuron population. Transplanted interneurons develop axonal and dendritic arbors (red cell magnified in foreground), synaptically integrate into neural circuits, and modify inhibitory signaling. Interneuron transplantation provides a method for studying neural circuit assembly and function and is a potential cell-based therapy for conditions such as epilepsy, Parkinson’s disease, schizophrenia, anxiety, and chronic pain. Advances In both neonatal and adult rodents, transplanted embryonic interneurons have been shown to migrate and survive in diverse neural structures, including the cerebral cortex and the spinal cord. Transplanted interneurons form elaborate processes in host tissues, receive synaptic inputs, and make inhibitory connections with host neurons, similar to what they do in their normal setting. Functionally, transplantation has been used to modify inhibitory signaling in the host brain and to induce reorganization of the cortex by creating new windows of neural circuit plasticity. Transplanted interneurons have been shown to modify disease phenotypes in several rodent models of neurologic and psychiatric disorders, including epilepsy, chronic pain, Parkinson’s disease, schizophrenia, and anxiety. Interneuron transplantation has also been used to explore how cell-intrinsic and environmental factors interact to govern cellular fate and circuit formation. To generate interneurons for possible clinical applications, researchers are developing in vitro culture systems for the derivation of interneurons from embryonic stem cells and induced pluripotent stem cells. These efforts have produced new interneurons that, like their endogenous counterparts, disperse and integrate in the recipient brain after transplantation. Outlook Cortical interneurons are a heterogeneous population, and little is known about how distinct subtypes of interneurons function in neural circuits. Thus far, transplantation studies have used donor pools containing large mixtures of interneurons. As the mechanisms underlying interneuron diversity become better understood, donor populations may be selected or produced to include only specific subtypes of cells. This will allow researchers to study the functional roles of different interneuron types and may permit the use of specific donor populations for different pathologies. It is unknown how transplanted interneurons modify disease phenotypes. While transplanted interneurons likely exert therapeutic effects by increasing neural inhibition, other mechanisms are also possible. By transplanting mutant cells, or cells engineered to respond to optogenetic or chemical stimulation, these mechanisms may be elucidated. Eventual clinical applications will require more subtle and detailed studies of the behavioral effects of interneuron transplantation. Interneurons Reach Far and Wide Interneurons in the brain have been garnering increasing attention. Southwell et al. (10.1126/science.1240622) review the development of this unique class of neurons. The cells migrate long distances during brain development. Transplantation of interneurons derived from embryonic stem cells is yielding insight into disease processes and may have therapeutic potential. For example, Parkinsons disease, epilepsy, certain psychiatric disorders, and even some sorts of chronic pain either involve interneurons or may respond to transplanted interneurons. Many neurologic and psychiatric disorders are marked by imbalances between neural excitation and inhibition. In the cerebral cortex, inhibition is mediated largely by GABAergic (γ-aminobutyric acid–secreting) interneurons, a cell type that originates in the embryonic ventral telencephalon and populates the cortex through long-distance tangential migration. Remarkably, when transplanted from embryos or in vitro culture preparations, immature interneurons disperse and integrate into host brain circuits, both in the cerebral cortex and in other regions of the central nervous system. These features make interneuron transplantation a powerful tool for the study of neurodevelopmental processes such as cell specification, cell death, and cortical plasticity. Moreover, interneuron transplantation provides a novel strategy for modifying neural circuits in rodent models of epilepsy, Parkinson’s disease, mood disorders, and chronic pain.

Long-term seizure control outcomes after resection of gangliogliomas.

BACKGROUND Gangliogliomas are rare glioneuronal tumors that typically cause refractory seizures during the first 3 decades of life. OBJECTIVE To determine the prognosticators of seizure outcome after surgery for ganglioglioma. METHODS We reviewed the cases of 66 patients who underwent resection of gangliogliomas at the University of California, San Francisco. Demographic, seizure history, and operative data were examined for statistical association with postoperative seizure outcomes. RESULTS Of the 66 patients who underwent surgical resection of ganglioglioma, 49 patients (74%) presented with a history of seizures. Of those 49 patients, 50% presented with intractable epilepsy. Temporal lobe gangliogliomas were present in 76% of the patients who presented with a history of seizures. Electrocorticography was performed on 35% of the patients, and of those patients, 82% underwent extended lesionectomy to remove abnormally epileptogenic extralesional tissue. The median follow-up duration was 6.9 years, during which tumor progression occurred in 38% of patients who underwent subtotal resection and in 8% of patients who underwent gross total resection (P = .02). Overall, 85% of patients were seizure free (International League Against Epilepsy class I or II) 5 years after surgery. Subtotal resection was associated with poor seizure outcomes 1 year after resection (odds ratio = 14.6; 95% confidence interval = 2.4-87.7): rates of seizure freedom were 54% after subtotal resection, 96% after gross total resection, and 93% after gross total resection with intraoperative electrocorticography-guided extended lesionectomy. CONCLUSION We report excellent long-term seizure control outcomes after surgery for gangliogliomas. Intraoperative electrocorticography may be a useful adjunct for guiding extended resection in certain pharmacoresistant epilepsy patients with gangliogliomas. Subtotal resection is associated with higher rates of tumor progression and nonoptimal seizure outcomes.

Comparison of Deep Brain Stimulation Lead Targeting Accuracy and Procedure Duration between 1.5-and 3-Tesla Interventional Magnetic Resonance Imaging Systems: An Initial 12-Month Experience

Background: Interventional magnetic resonance imaging (iMRI) allows deep brain stimulator lead placement under general anesthesia. While the accuracy of lead targeting has been described for iMRI systems utilizing 1.5-tesla magnets, a similar assessment of 3-tesla iMRI procedures has not been performed. Objective: To compare targeting accuracy, the number of lead targeting attempts, and surgical duration between procedures performed on 1.5- and 3-tesla iMRI systems. Methods: Radial targeting error, the number of targeting attempts, and procedure duration were compared between surgeries performed on 1.5- and 3-tesla iMRI systems (SmartFrame and ClearPoint systems). Results: During the first year of operation of each system, 26 consecutive leads were implanted using the 1.5-tesla system, and 23 consecutive leads were implanted using the 3-tesla system. There was no significant difference in radial error (Mann-Whitney test, p = 0.26), number of lead placements that required multiple targeting attempts (Fishers exact test, p = 0.59), or bilateral procedure durations between surgeries performed with the two systems (p = 0.15). Conclusions: Accurate DBS lead targeting can be achieved with iMRI systems utilizing either 1.5- or 3-tesla magnets. The use of a 3-tesla magnet, however, offers improved visualization of the target structures and allows comparable accuracy and efficiency of placement at the selected targets.

Atypical pituitary adenoma: a clinicopathologic case series

OBJECTIVE In 2004, the WHO classified atypical pituitary adenoma as a distinct adenoma subtype. However, the clinical significance of this distinction remains undetermined. The authors sought to define patient characteristics, tumor features, and treatment outcomes associated with atypical pituitary adenoma. METHODS The authors reviewed records of patients who underwent resection of pituitary adenoma at the University of California, San Francisco, between 2007 and 2014. Per institutional protocol, adenomas exhibiting mitotic activity underwent evaluation for all 3 markers of atypicality (mitotic index, extensive p53 staining, and MIB-1 index ≥ 3%). Statistical analyses were performed using χ2, Fishers exact test, t-test, log-rank, and logistic regression. RESULTS Between 2007 and 2014, 701 patients underwent resection for pituitary adenoma. Among these patients, 122 adenomas exhibited mitotic activity and therefore were evaluated for all 3 markers of atypicality, with 36 tumors (5%) proving to be atypical. There were 21 female patients (58%) and 15 male patients (42%) in the atypical cohort, and 313 female patients (47%) and 352 male patients (53%) in the nonatypical cohort (p = 0.231). The mean age of patients in the atypical cohort was 37 years (range 10-65 years), which was significantly lower than the mean age of 49 years (range 10-93 years) for patients in the nonatypical cohort (p < 0.001). The most common presenting symptoms for patients with atypical adenomas were headaches (42%) and visual changes (33%). Atypical adenomas were more likely to be functional (78%) than nonatypical adenomas (42%; p < 0.001). Functional atypical adenomas were significantly larger than functional nonatypical adenomas (mean diameter 2.2 vs 1.4 cm; p = 0.009), as were nonfunctional atypical adenomas compared with nonfunctional nonatypical adenomas (mean diameter 3.3 vs 2.3 cm; p = 0.01). Among the entire adenoma cohort, larger presenting tumor size was associated with cavernous sinus invasion (p < 0.001), and subtotal resection was associated with cavernous sinus invasion (p < 0.001) and larger size (p < 0.001) on binomial multivariate regression. The median time until recurrence was 56 months for atypical adenomas, 129 months for functional nonatypical adenomas, and 204 months for nonfunctional nonatypical adenomas (p < 0.001). Functional atypical adenomas recurred more frequently and significantly earlier than functional nonatypical adenomas (p < 0.001). When accounting for extent of resection, cavernous sinus invasion, size, age, sex, and functional subtype, atypicality remained a significant predictor of earlier recurrence among functional adenomas (p = 0.002). CONCLUSIONS When compared with nonatypical pituitary adenomas, atypical adenomas are more likely to present in younger patients at a larger size, are more often hormonally hypersecretory, and are associated with earlier recurrence. These features lend credence to atypical pituitary adenomas being a distinct clinical entity in addition to a discrete pathological diagnosis.

Resection of gliomas deemed inoperable by neurosurgeons based on preoperative imaging studies

OBJECTIVE Maximal safe resection is a primary objective in the management of gliomas. Despite this objective, surgeons and referring physicians may, on the basis of radiological studies alone, assume a glioma to be unresectable. Because imaging studies, including functional MRI, may not localize brain functions (such as language) with high fidelity, this simplistic approach may exclude some patients from what could be a safe resection. Intraoperative direct electrical stimulation (DES) allows for the accurate localization of functional areas, thereby enabling maximal resection of tumors, including those that may appear inoperable based solely on radiological studies. In this paper the authors describe the extent of resection (EOR) and functional outcomes following resections of tumors deemed inoperable by referring physicians and neurosurgeons. METHODS The authors retrospectively examined the cases of 58 adult patients who underwent glioma resection within 6 months of undergoing a brain biopsy of the same lesion at an outside hospital. All patients exhibited unifocal supratentorial disease and preoperative Karnofsky Performance Scale scores ≥ 70. The EOR and 6-month functional outcomes for this population were characterized. RESULTS Intraoperative DES mapping was performed on 96.6% (56 of 58) of patients. Nearly half of the patients (46.6%, 27 of 58) underwent an awake surgical procedure with DES. Overall, the mean EOR was 87.6% ± 13.6% (range 39.0%-100%). Gross-total resection (resection of more than 99% of the preoperative tumor volume) was achieved in 29.3% (17 of 58) of patients. Subtotal resection (95%-99% resection) and partial resection (PR; < 95% resection) were achieved in 12.1% (7 of 58) and 58.6% (34 of 58) of patients, respectively. Of the cases that involved PR, the mean EOR was 79.4% ± 12.2%. Six months after surgery, no patient was found to have a new postoperative neurological deficit. The majority of patients (89.7%, 52 of 58) were free of neurological deficits both pre- and postoperatively. The remainder of patients exhibited either residual but stable deficits (5.2%, 3 of 58) or complete correction of preoperative deficits (5.2%, 3 of 58). CONCLUSIONS The use of DES enabled maximal safe resections of gliomas deemed inoperable by referring neurosurgeons. With rare exceptions, tumor resectability cannot be determined solely by radiological studies.

Language outcomes after resection of dominant inferior parietal lobule gliomas

OBJECTIVE The dominant inferior parietal lobule (IPL) contains cortical and subcortical regions essential for language. Although resection of IPL tumors could result in language deficits, little is known about the likelihood of postoperative language morbidity or the risk factors predisposing to this outcome. METHODS The authors retrospectively examined a series of patients who underwent resections of gliomas from the dominant IPL. Postoperative language outcomes were characterized across the patient population. To identify factors associated with postoperative language morbidity, the authors then compared features between those patients who experienced postoperative deficits and those who experienced no postoperative language dysfunction. RESULTS Twenty-four patients were identified for analysis. Long-term language deficits occurred in 29.2% of patients (7 of 24): 3 of these patients had experienced preoperative language deficits, whereas new long-term language deficits occurred in 4 patients (16.7%; 4 of 24). Of those patients who exhibited preoperative language deficits, 62.5% (5 of 8) experienced long-term resolution of their language deficits with surgical treatment. All patients underwent intraoperative brain mapping by direct electrical stimulation. Awake, intraoperative cortical language mapping was performed on 17 patients (70.8%). Positive cortical language sites were identified in 23.5% of these patients (4 of 17). Awake, intraoperative subcortical language mapping was performed in 8 patients (33.3%). Positive subcortical language sites were identified in 62.5% of these patients (5 of 8). Patients with positive cortical language sites exhibited a higher rate of long-term language deficits (3 of 4, 75%), compared with those who did not (1 of 13, 7.7%; p = 0.02). Although patients with positive subcortical language sites exhibited a higher rate of long-term language deficits than those who exhibited only negative sites (40.0% vs 0.0%, respectively), this difference was not statistically significant (p = 0.46). Additionally, patients with long-term language deficits were older than those without deficits (p < 0.05). CONCLUSIONS In a small number of patients with preoperative language deficits, IPL glioma resection resulted in improved language function. However, in patients with intact preoperative language function, resection of IPL gliomas may result in new language deficits, especially if the tumors are diffuse, high-grade lesions. Thus, language-dominant IPL glioma resection is not risk-free, yet it is safe and its morbidity can be reduced by the use of cortical and subcortical stimulation mapping.