Stephen C. Harward

Diminished FoxP2 Levels Affect Dopaminergic Modulation of Corticostriatal Signaling Important to Song Variability

Mutations of the FOXP2 gene impair speech and language development in humans and shRNA-mediated suppression of the avian ortholog FoxP2 disrupts song learning in juvenile zebra finches. How diminished FoxP2 levels affect vocal control and alter the function of neural circuits important to learned vocalizations remains unclear. Here we show that FoxP2 knockdown in the songbird striatum disrupts developmental and social modulation of song variability. Recordings in anesthetized birds show that FoxP2 knockdown interferes with D1R-dependent modulation of activity propagation in a corticostriatal pathway important to song variability, an effect that may be partly attributable to reduced D1R and DARPP-32 protein levels. Furthermore, recordings in singing birds reveal that FoxP2 knockdown prevents social modulation of singing-related activity in this pathway. These findings show that reduced FoxP2 levels interfere with the dopaminergic modulation of vocal variability, which may impede song and speech development by disrupting reinforcement learning mechanisms.

Autocrine BDNF–TrkB signalling within a single dendritic spine

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for many forms of neuronal plasticity, including structural long-term potentiation (sLTP), which is a correlate of an animal’s learning. However, it is unknown whether BDNF release and TrkB activation occur during sLTP, and if so, when and where. Here, using a fluorescence resonance energy transfer-based sensor for TrkB and two-photon fluorescence lifetime imaging microscopy, we monitor TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured murine hippocampal slices. In response to sLTP induction, we find fast (onset < 1 min) and sustained (>20 min) activation of TrkB in the stimulated spine that depends on NMDAR (N-methyl-d-aspartate receptor) and CaMKII signalling and on postsynaptically synthesized BDNF. We confirm the presence of postsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines of hippocampal CA1 pyramidal neurons. Consistent with these findings, we also show rapid, glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines using BDNF fused to superecliptic pHluorin. We demonstrate that this postsynaptic BDNF–TrkB signalling pathway is necessary for both structural and functional LTP. Together, these findings reveal a spine-autonomous, autocrine signalling mechanism involving NMDAR–CaMKII-dependent BDNF release from stimulated dendritic spines and subsequent TrkB activation on these same spines that is crucial for structural and functional plasticity.

Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity

The Rho GTPase proteins Rac1, RhoA and Cdc42 have a central role in regulating the actin cytoskeleton in dendritic spines, thereby exerting control over the structural and functional plasticity of spines and, ultimately, learning and memory. Although previous work has shown that precise spatiotemporal coordination of these GTPases is crucial for some forms of cell morphogenesis, the nature of such coordination during structural spine plasticity is unclear. Here we describe a three-molecule model of structural long-term potentiation (sLTP) of murine dendritic spines, implicating the localized, coincident activation of Rac1, RhoA and Cdc42 as a causal signal of sLTP. This model posits that complete tripartite signal overlap in spines confers sLTP, but that partial overlap primes spines for structural plasticity. By monitoring the spatiotemporal activation patterns of these GTPases during sLTP, we find that such spatiotemporal signal complementation simultaneously explains three integral features of plasticity: the facilitation of plasticity by brain-derived neurotrophic factor (BDNF), the postsynaptic source of which activates Cdc42 and Rac1, but not RhoA; heterosynaptic facilitation of sLTP, which is conveyed by diffusive Rac1 and RhoA activity; and input specificity, which is afforded by spine-restricted Cdc42 activity. Thus, we present a form of biochemical computation in dendrites involving the controlled complementation of three molecules that simultaneously ensures signal specificity and primes the system for plasticity.

Quality-of-life metrics with vagus nerve stimulation for epilepsy from provider survey data

OBJECTIVE Drug-resistant epilepsy is a devastating disorder associated with diminished quality of life (QOL). Surgical resection leads to seizure freedom and improved QOL in many epilepsy patients, but not all individuals are candidates for resection. In these cases, neuromodulation-based therapies such as vagus nerve stimulation (VNS) are often used, but most VNS studies focus exclusively on reduction of seizure frequency. QOL changes and predictors with VNS remain poorly understood. METHOD Using the VNS Therapy Patient Outcome Registry, we examined 7 metrics related to QOL after VNS for epilepsy in over 5000 patients (including over 3000 with ≥12months follow-up), as subjectively assessed by treating physicians. Trends and predictors of QOL changes were examined and related to post-operative seizure outcome and likelihood of VNS generator replacement. RESULTS After VNS therapy, physicians reported patient improvement in alertness (58-63%, range over follow-up period), post-ictal state (55-62%), cluster seizures (48-56%), mood change (43-49%), verbal communication (38-45%), school/professional achievements (29-39%), and memory (29-38%). Predictors of net QOL improvement included shorter time to implant (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.1-1.6), generalized seizure type (OR, 1.2; 95% CI, 1.0-1.4), female gender (OR, 1.2; 95% CI, 1.0-1.4), and Caucasian ethnicity (OR, 1.3; 95% CI, 1.0-1.5). No significant trends were observed over time. Patients with net QOL improvement were more likely to have favorable seizure outcomes (chi square [χ2]=148.1, p<0.001) and more likely to undergo VNS generator replacement (χ2=68.9, p<0.001) than those with worsened/unchanged QOL. SIGNIFICANCE VNS for drug-resistant epilepsy is associated with improvement on various QOL metrics subjectively rated by physicians. QOL improvement is associated with favorable seizure outcome and a higher likelihood of generator replacement, suggesting satisfaction with therapy. It is important to consider QOL metrics in neuromodulation for epilepsy, given the deleterious effects of seizures on patient QOL.

Rates and predictors of success and failure in repeat epilepsy surgery: A meta‐analysis and systematic review

Medically refractory epilepsy is a debilitating disorder that is particularly challenging to treat in patients who have already failed a surgical resection. Evidence regarding outcomes of further epilepsy surgery is limited to small case series and reviews. Therefore, our group performed the first quantitative meta‐analysis of the literature from the past 30 years to assess for rates and predictors of successful reoperations.

Seizure Outcomes in Occipital Lobe and Posterior Quadrant Epilepsy Surgery: A Systematic Review and Meta-Analysis

BACKGROUND Occipital lobe epilepsy (OLE) is an uncommon but debilitating focal epilepsy syndrome with seizures often refractory to medical management. While surgical resection has proven a viable treatment, previous studies examining postoperative seizure freedom rates are limited by small sample size and patient heterogeneity, thus exhibiting significant variability in their results. OBJECTIVE To review the medical literature on OLE so as to investigate rates and predictors of both seizure freedom and visual outcomes following surgery. METHODS We reviewed manuscripts exploring surgical resection for drug-resistant OLE published between January 1990 and June 2015 on PubMed. Seizure freedom rates were analyzed and potential predictors were evaluated with separate meta-analyses. Postoperative visual outcomes were also examined. RESULTS We identified 27 case series comprising 584 patients with greater than 1 yr of follow-up. Postoperative seizure freedom (Engel class I outcome) was observed in 65% of patients, and was significantly predicted by age less than 18 yr (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.13-2.18), focal lesion on pathological analysis (OR 2.08, 95% CI 1.58-2.89), and abnormal preoperative magnetic resonance imaging (OR 3.24, 95% 2.03-6.55). Of these patients, 175 also had visual outcomes reported with 57% demonstrating some degree of visual decline following surgery. We did not find any relationship between postoperative visual and seizure outcomes. CONCLUSION Surgical resection for OLE is associated with favorable outcomes with nearly two-thirds of patients achieving postoperative seizure freedom. However, patients must be counseled regarding the risk of visual decline following surgery.

In search of the ever-elusive positive endozepine.

In this issue of Neuron, Christian et al. (2013) provide functional evidence for positive endozepines (positive allosteric modulators of GABAARs) within the thalamic reticular nucleus. These molecules are encoded by the Dbi gene and modulate thalamocortical oscillations.

Integrating Molecular, Cellular, and Systems Approaches to Repairing the Brain After Stroke

A stroke implies a sudden and spontaneous onset of neurological symptoms due to a vascular insult. Despite the brain’s inherent capacity for plasticity and spontaneous improvement, strokes still leave many patients with devastating deficits that can permanently affect independence and quality of life. This chapter focuses on ways to help restore the functionality of the central nervous system (CNS) after this type of injury. Understanding how neurons interact on both individual (i.e. cellular and molecular) and population (i.e. synapses and circuits) levels is crucial to developing successful restorative strategies, as is appreciating how these interactions change over the injury-recovery timeline. The CNS has several characteristics that make its restitution exceptionally difficult; beyond even its incredible intricacy, its parenchymal cells, or neurons, do not regenerate well after injury, and this damaged neuronal substrate embodies a consciousness system that must be engaged in its own recovery. In fact, there is now data suggesting that conscious intention, often invoked through goal-oriented rehabilitation, plays a crucial role in facilitating functional plasticity and long-range axonal sprouting. To capitalize on this principle, neural interfaces and electrical stimulation strategies are being integrated into rehabilitation paradigms to provide critically-timed feedback that can reinvigorate injured circuits. Combining these approaches with interventions at the cellular and molecular level (e.g. immunological or genetic modulations aimed at promoting neuronal outgrowth, or stem cells that can replace damaged parenchyma) has the chance to improve neurological recovery to back toward baseline levels. Ultimately, because cells of the CNS do not regrow on their own, and because regrowth and synapse formation does not necessarily ensure restoration of function, harmonious application of synergistic approaches at both the micro- and macroscopic levels will be needed to establish long-lasting functional plasticity and meaningful recovery.

Toward Functional Restoration of the Central Nervous System: A Review of Translational Neuroscience Principles

Injury to the central nervous system (CNS) can leave patients with devastating neurological deficits that may permanently impair independence and diminish quality of life. Recent insights into how the CNS responds to injury and reacts to critically timed interventions are being translated into clinical applications that have the capacity to drastically improve outcomes for patients suffering from permanent neurological deficits due to spinal cord injury, stroke, or other CNS disorders. The translation of such knowledge into practical and impactful treatments involves the strategic collaboration between neurosurgeons, clinicians, therapists, scientists, and industry. Therefore, a common understanding of key neuroscientific principles is crucial. Conceptually, current approaches to CNS revitalization can be divided by scale into macroscopic (systems-circuitry) and microscopic (cellular-molecular). Here we review both emerging and well-established tenets that are being utilized to enhance CNS recovery on both levels, and we explore the role of neurosurgeons in developing therapies moving forward. Key principles include plasticity-driven functional recovery, cellular signaling mechanisms in axonal sprouting, critical timing for recovery after injury, and mechanisms of action underlying cellular replacement strategies. We then discuss integrative approaches aimed at synergizing interventions across scales, and we make recommendations for the basis of future clinical trial design. Ultimately, we argue that strategic modulation of microscopic cellular behavior within a macroscopic framework of functional circuitry re-establishment should provide the foundation for most neural restoration strategies, and the early involvement of neurosurgeons in the process will be crucial to successful clinical translation.