Mark R. Witcher

Plasticity of perisynaptic astroglia during synaptogenesis in the mature rat hippocampus.

Astroglia are integral components of synapse formation and maturation during development. Less is known about how astroglia might influence synaptogenesis in the mature brain. Preparation of mature hippocampal slices results in synapse loss followed by recuperative synaptogenesis during subsequent maintenance in vitro. Hence, this model system was used to discern whether perisynaptic astroglial processes are similarly plastic, associating more or less with recently formed synapses in mature brain slices. Perisynaptic astroglia was quantified through serial section electron microscopy in perfusion‐fixed or sliced hippocampus from adult male Long‐Evans rats that were 65–75 days old. Fewer synapses had perisynaptic astroglia in the recovered hippocampal slices (42.4% ± 3.4%) than in the intact hippocampus (62.2% ± 2.6%), yet synapses were larger when perisynaptic astroglia was present (0.055 ± 0.003 μm2) than when it was absent (0.036 ± 0.004 μm2) in both conditions. Importantly, the length of the synaptic perimeter surrounded by perisynaptic astroglia and the distance between neighboring synapses was not proportional to synapse size. Instead, larger synapses had longer astroglia‐free perimeters where substances could escape from or enter into the synaptic clefts. Thus, smaller presumably newer synapses as well as established larger synapses have equal access to extracellular glutamate and secreted astroglial factors, which may facilitate recuperative synaptogenesis. These findings suggest that as synapses enlarge and release more neurotransmitter, they attract astroglial processes to a discrete portion of their perimeters, further enhancing synaptic efficacy without limiting the potential for cross talk with neighboring synapses in the mature rat hippocampus.

Three-Dimensional Relationships Between Perisynaptic Astroglia and Human Hippocampal Synapses

Perisynaptic astroglia are critical for normal synaptic development and function. Little is known, however, about perisynaptic astroglia in the human hippocampus. When mesial temporal lobe epilepsy (MTLE) is refractory to medication, surgical removal is required for seizure quiescence. To investigate perisynaptic astroglia in human hippocampus, we recovered slices for several hours in vitro from three surgical specimens and then quickly fixed them to achieve high‐quality ultrastructure. Histological samples from each case were found to have mesial temporal sclerosis with Blumcke Type 1a (mild, moderate) or 1b (severe) pathology. Quantitative analysis through serial section transmission electron microscopy in CA1 stratum radiatum revealed more synapses in the mild (10/10 μm3) than the moderate (5/10 μm3) or severe (1/10 μm3) cases. Normal spines occurred in mild and moderate cases, but a few multisynaptic spines were all that remained in the severe case. Like adult rat hippocampus, perisynaptic astroglial processes were preferentially associated with larger synapses in the mild and moderate cases, but rarely penetrated the cluster of axonal boutons surrounding multisynaptic spines. Synapse perimeters were only partially surrounded by astroglial processes such that all synapses had some access to substances in the extracellular space, similar to adult rat hippocampus. Junctions between astroglial processes were observed more frequently in moderate than mild case, but were obscured by densely packed intermediate filaments in astroglial processes of the severe case. These findings suggest that perisynaptic astroglial processes associate with synapses in human hippocampus in a manner similar to model systems and are disrupted by severe MTLE pathology.

Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

Significance There is an abundance of circumstantial evidence (primarily work in nonhuman animal models) suggesting that dopamine transients serve as experience-dependent learning signals. This report establishes, to our knowledge, the first direct demonstration that subsecond fluctuations in dopamine concentration in the human striatum combine two distinct prediction error signals: (i) an experience-dependent reward prediction error term and (ii) a counterfactual prediction error term. These data are surprising because there is no prior evidence that fluctuations in dopamine should superpose actual and counterfactual information in humans. The observed compositional encoding of “actual” and “possible” is consistent with how one should “feel” and may be one example of how the human brain translates computations over experience to embodied states of subjective feeling. In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.

Corpus Callosotomy for Treatment of Pediatric Epilepsy in the Modern Era

Objective: The purpose of this study was to evaluate seizure outcome in children with intractable secondary generalized epilepsy without a resectable focus who underwent complete corpus callosotomy and compare these results to those of anterior two-third callosotomy. Method: Data were obtained for all patients who underwent a corpus callosotomy from 2000 to 2005. The study involved 37 patients. Eleven patients had anterior two-third corpus callosotomy compared with 28patients who underwent complete corpus callosotomy. Two of these patients had completion of their callosotomy following initial partial callosotomy. Seizure type, seizure frequency, and family satisfaction were evaluated for all patients pre- and postoperatively. Results: A reduction of ≧75% in seizures occurred in 75% of the total-callosotomy patients compared to 55% of the partial-callosotomy patients. Family satisfaction for complete and partial callosotomy was 89 and 73%, respectively. No prolonged neurologic deficits were observed in either group. Conclusion: Complete corpus callosotomy is the most effective treatment for secondary generalized intractable seizures not amenable to focal resection in children.

Postoperative pain management with tramadol after craniotomy: evaluation and cost analysis

OBJECT Patients undergoing craniotomies have traditionally received opiates with acetaminophen for the management of their postoperative pain. The use of narcotic pain medications can be costly, decrease rates of early postoperative ambulation, lengthen hospital stays, and alter a patients neurological examination. The use of alternative pain medications such as tramadol may benefit patients by resolving many of these issues. METHODS The authors conducted a randomized, blinded prospective study to evaluate the efficacy of alternative pain management strategies for patients following craniotomies. Fifty patients were randomly assigned either to a control group who received narcotics and acetaminophen alone or an experimental group who received tramadol in addition to narcotic pain medications (25 patients assigned to each group). RESULTS The control group was noted to have statistically significant higher visual analog scale pain scores, an increased length of hospital stay, and increased narcotic use compared with the tramadol group. The narcotics and acetaminophen group also had increased hospitalization costs when compared with the tramadol group. CONCLUSIONS The use of scheduled atypical analgesics such as tramadol in addition to narcotics with acetaminophen for the management of postoperative pain after craniotomy may provide better pain control, decrease the side effects associated with narcotic pain medications, encourage earlier postoperative ambulation, and reduce total hospitalization costs.

Astroglial Networks and Implications for Therapeutic Neuromodulation of Epilepsy

Epilepsy is a common chronic neurologic disorder affecting approximately 1% of the world population. More than one-third of all epilepsy patients have incompletely controlled seizures or debilitating medication side effects in spite of optimal medical management. Medically refractory epilepsy is associated with excess injury and mortality, psychosocial dysfunction, and significant cognitive impairment. Effective treatment options for these patients can be limited. The cellular mechanisms underlying seizure activity are incompletely understood, though we here describe multiple lines of evidence supporting the likely contribution of astroglia to epilepsy, with focus on individual astrocytes and their network functions. Of the emerging therapeutic modalities for epilepsy, one of the most intriguing is the field of neuromodulation. Neuromodulatory treatment, which consists of administering electrical pulses to neural tissue to modulate its activity leading to a beneficial effect, may be an option for these patients. Current modalities consist of vagal nerve stimulation, open and closed-loop stimulation, and transcranial magnetic stimulation. Due to their unique properties, we here present astrocytes as likely important targets for the developing field of neuromodulation in the treatment of epilepsy.

Neuronal oscillations in Parkinson's disease

Parkinsons Disease (PD), characterized by tremor, rigidity, and bradykinesia, is one of the most prevalent neurodegenerative disorders in the world. The pathological hallmark of PD is the loss of dopaminergic cells in the substantia nigra and other brain regions. The pathophysiological mechanisms by which dopaminergic cell loss leads to the motor manifestations of PD are yet to be fully elucidated. A growing body of evidence has revealed abnormal neuronal oscillations within and between multiple brain regions in PD. Unique oscillatory patterns are associated with specific motor abnormalities in PD. Therapies, such as dopaminergic medication and deep brain stimulation that disrupt these abnormal neuronal oscillatory patterns produce symptomatic improvement in PD patients. These findings emphasize the importance of abnormal neuronal oscillations in the pathophysiology of PD, making the disruption of these oscillatory patterns a promising target in the development of effective PD treatments.

Neuromodulatory Treatment of Medically Refractory Epilepsy

Epilepsy is a common chronic neurologic disorder affecting 0.5 to 1 percent of the population. (Hauser, 1993 4131) More than one-third of all epilepsy patients have incompletely controlled seizures or debilitating medication side effects in spite of optimal medical management. (Kwan et al. 2000; Sillanpaa et al. 2006; Sander et al. 1993) Medically refractory epilepsy is associated with excess injury and mortality, psychosocial dysfunction, and significant cognitive impairment. (Brodie et al. 1996) Treatment options for these patients include new anti-epileptic drugs (AEDs), which may lead to seizure freedom in 7 percent of patients (Fisher et al. 1993) and resective surgery which is associated with longterm seizure freedom in 60-80% of patients.(Engel et al. 2003 ;Lee et al. 2005) Surgery for patients whose epilepsy has proven refractory to AEDs provides a high likelihood of reduction in seizure frequency, is generally safe, and is recommended for selected patients with refractory partial seizures. In spite of improvements in surgical technique, approximately 4 percent of patients will suffer death or permanent neurologic disability ( A global survey on epilepsy surgery, 1980-1990: a report by the Commission on Neurosurgery of Epilepsy, the International League Against Epilepsy 1997). Moreover, more than onethird of patients will not be candidates for surgical resection (Kwan et al. 2000). For patients who are not candidates for resective surgery, there are limited options. Neuromodulatory treatment, which consists of administering electrical pulses to neural tissue to modulate its activity leading to a beneficial effect, may be an option for these patients. The interest in neuromodulation for neurological disorders is driven by a desire to discover less invasive surgical treatments, as well as new treatments for patients whose medical conditions remain refractory to existing modalities. Vagal nerve stimulation (VNS) is one example of neuromodulation that was developed in the 1980s, and which is now routinely available. (Ben-Menachem et al. 2002) VNS, as an adjunct to medical management, may yield up to a 50 percent reduction in seizure frequency (A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. The Vagus Nerve Stimulation Study Group. 1995) although most of these patients will not be seizurefree. Deep brain stimulation (DBS) is another example of neuromodulation. Given the significant experience and success of DBS for movement disorders (Krack et al. 2003) combined with its reversibility, programmability, and low risk of morbidity, there has been

The Protective Action Encoding of Serotonin Transients in the Human Brain

The role of serotonin in human brain function remains elusive due, at least in part, to our inability to measure rapidly the local concentration of this neurotransmitter. We used fast-scan cyclic voltammetry to infer serotonergic signaling from the striatum of 14 brains of human patients with Parkinson’s disease. Here we report these novel measurements and show that they correlate with outcomes and decisions in a sequential investment game. We find that serotonergic concentrations transiently increase as a whole following negative reward prediction errors, while reversing when counterfactual losses predominate. This provides initial evidence that the serotonergic system acts as an opponent to dopamine signaling, as anticipated by theoretical models. Serotonin transients on one trial were also associated with actions on the next trial in a manner that correlated with decreased exposure to poor outcomes. Thus, the fluctuations observed for serotonin appear to correlate with the inhibition of over-reactions and promote persistence of ongoing strategies in the face of short-term environmental changes. Together these findings elucidate a role for serotonin in the striatum, suggesting it encodes a protective action strategy that mitigates risk and modulates choice selection particularly following negative environmental events.

Designing Patient-Specific Optimal Neurostimulation Patterns for Seizure Suppression

Neurostimulation is a promising therapy for abating epileptic seizures. However, it is extremely difficult to identify optimal stimulation patterns experimentally. In this study, human recordings are used to develop a functional 24 neuron network statistical model of hippocampal connectivity and dynamics. Spontaneous seizure-like activity is induced in silico in this reconstructed neuronal network. The network is then used as a testbed to design and validate a wide range of neurostimulation patterns. Commonly used periodic trains were not able to permanently abate seizures at any frequency. A simulated annealing global optimization algorithm was then used to identify an optimal stimulation pattern, which successfully abated 92% of seizures. Finally, in a fully responsive, or closed-loop, neurostimulation paradigm, the optimal stimulation successfully prevented the network from entering the seizure state. We propose that the framework presented here for algorithmically identifying patient-specific neurostimulation patterns can greatly increase the efficacy of neurostimulation devices for seizures.