Robert A. McGovern

Divergence of Melanocortin Pathways in the Control of Food Intake and Energy Expenditure

Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can be reactivated by Cre-recombinase. Mice homozygous for the loxTB Mc4r allele do not express MC4Rs and are markedly obese. Restoration of MC4R expression in the paraventricular hypothalamus (PVH) and a subpopulation of amygdala neurons, using Sim1-Cre transgenic mice, prevented 60% of the obesity. Of note, increased food intake, typical of Mc4r null mice, was completely rescued while reduced energy expenditure was unaffected. These findings demonstrate that MC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure. Disassociation of food intake and energy expenditure reveals unexpected divergence in melanocortin pathways controlling energy balance.

Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis

Neuroanatomical and electrophysiological studies have shown that hypothalamic POMC neurons are targets of the adipostatic hormone leptin. However, the physiological relevance of leptin signaling in these neurons has not yet been directly tested. Here, using the Cre/loxP system, we critically test the functional importance of leptin action on POMC neurons by deleting leptin receptors specifically from these cells in mice. Mice lacking leptin signaling in POMC neurons are mildly obese, hyperleptinemic, and have altered expression of hypothalamic neuropeptides. In summary, leptin receptors on POMC neurons are required but not solely responsible for leptins regulation of body weight homeostasis.

The Hippocampus and Nucleus Accumbens as Potential Therapeutic Targets for Neurosurgical Intervention in Schizophrenia

Schizophrenia is a chronic and disabling psychiatric illness that is often refractory to treatment. Psychotic symptoms (e.g. hallucinations and delusions) in schizophrenia are reliably correlated with excess dopamine levels in the striatum, and have more recently been related to excess metabolic activity in the hippocampus. Multiple lines of evidence suggest that aberrantly high hippocampal activity may, via hippocampal connections with the limbic basal ganglia, drive excessive dopamine release into the striatum. In the present paper, we hypothesize that inhibition or stabilization of neural activity with high-frequency electrical stimulation of the hippocampus or nucleus accumbens, through different mechanisms, would treat the positive symptoms of schizophrenia. Thus, we suggest a direction for further experimentation aimed at developing neurosurgical therapeutic approaches for this devastating disease.

The mTOR pathway is activated in glial cells in mesial temporal sclerosis

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates basic cellular processes, including development and growth. Mutations in mTOR cause tuberous sclerosis complex (TSC), a condition that is characterized by developmental brain malformations (cortical tubers) and epilepsy. Although considerable insight has been gained recently into the pathologic dysfunction of mTOR in tubers in TSC‐related epilepsy, data on the mTOR cascade in mesial temporal lobe epilepsy (MTLE) are lacking. Immunohistochemical investigation with confocal microscopy was performed to evaluate mTOR cascade and to correlate its activity with cellular alterations observed in surgically resected samples of human neocortex and hippocampus in MTLE. We compared results in human tissue to findings in the rat pilocarpine model of sclerotic MTLE. In nonsclerotic and control hippocampus, many neurons in the CA1 subfield expressed high levels of phospho‐S6 (p‐S6), a reliable marker of mTOR activation. In nonsclerotic and control hippocampus, as well as in magnetic resonance imaging (MRI) normal human neocortex, protoplasmic astrocytes did not express p‐S6. In contrast, in sclerotic hippocampus, prominent p‐S6 immunostaining was observed mainly in astrocytes and microglia located in the areas of neuronal loss and astrogliosis, whereas neurons in preserved areas of CA1 expressed significantly lower levels of p‐S6 immunopositivity than neurons in nonsclerotic or control CA1 subfields. In surgically resected neocortex with chronic astroglial scar tissue, only microglia revealed moderate p‐S6 immunoreactivity. Different from human sclerotic epileptic hippocampus, astrogliosis in the chronic rat pilocarpine model of epilepsy was not characterized by glial cells with mTOR activation. The mTOR cascade is activated in astroglial cells in sclerotic MTLE, but not in astrocytes in chronic neocortical scarring or in the pilocarpine model of MTLE. These findings suggest that the astroglial “scar” in sclerotic MTLE has active, ongoing cellular changes. Targeting mTOR in MTLE may provide new pathways for the medical therapy of epilepsy.

Disparities in Access to Deep Brain Stimulation Surgery for Parkinson Disease Interaction Between African American Race and Medicaid Use

IMPORTANCE African American individuals experience barriers to accessing many types of health care in the United States, resulting in substantial health care disparities. To improve health care in this patient population, it is important to recognize and study the potential factors limiting access to care. OBJECTIVE To examine deep brain stimulation (DBS) use in Parkinson disease (PD) to determine which factors, among a variety of demographic, clinical, and socioeconomic variables, drive DBS use in the United States. DESIGN, SETTING, AND PARTICIPANTS We queried the Nationwide Inpatient Sample in combination with neurologist and neurological surgeon countywide density data from the Area Resource File. We used International Classification of Diseases, Ninth Revision codes to identify discharges of patients at multicenter, all-payer, nonfederal hospitals in the United States diagnosed with PD (code 332.0) who were admitted for implantation of intracranial neurostimulator lead(s) (code 02.39), DBS. MAIN OUTCOMES AND MEASURES We analyzed factors predicting DBS use in PD using a hierarchical logistic regression analysis including patient and hospital characteristics. Patient characteristics included age, sex, comorbidity score, race, income quartile of zip code, and insurance type. Hospital characteristics included teaching status, size, regional location, urban vs rural setting, experience with DBS discharges, year, and countywide density of neurologists and neurological surgeons. RESULTS Query of the Nationwide Inpatient Sample yielded 2,408,302 PD discharges from 2002 to 2009; 18,312 of these discharges were for DBS. Notably, 4.7% of all PD discharges were African American, while only 0.1% of DBS for PD discharges were African American. A number of factors in the hierarchical multivariate analysis predicted DBS use including younger age, male sex, increasing income quartile of patient zip code, large hospitals, teaching hospitals, urban setting, hospitals with higher number of annual discharges for PD, and increased countywide density of neurologists (P < .05). Predictors of nonuse included African American race (P < .001), Medicaid use (P < .001), and increasing comorbidity score (P < .001). Countywide density of neurological surgeons and Hispanic ethnicity were not significant predictors. CONCLUSIONS AND RELEVANCE: Despite the fact that African American patients are more often discharged from hospitals with characteristics predicting DBS use (ie, urban teaching hospitals in areas with a higher than average density of neurologists), these patients received disproportionately fewer DBS procedures compared with their non-African American counterparts. Increased reliance on Medicaid in the African American population may predispose to the DBS use disparity. Various other factors may be responsible, including disparities in access to care, cultural biases or beliefs, and/or socioeconomic status.

Deep brain stimulation for severe autism: from pathophysiology to procedure.

Autism is a heterogeneous neurodevelopmental disorder characterized by early-onset impairment in social interaction and communication and by repetitive, restricted behaviors and interests. Because the degree of impairment may vary, a spectrum of clinical manifestations exists. Severe autism is characterized by complete lack of language development and potentially life-threatening self-injurious behavior, the latter of which may be refractory to medical therapy and devastating for affected individuals and their caretakers. New treatment strategies are therefore needed. Here, the authors propose deep brain stimulation (DBS) of the basolateral nucleus of the amygdala (BLA) as a therapeutic intervention to treat severe autism. The authors review recent developments in the understanding of the pathophysiology of autism. Specifically, they describe the genetic and environmental alterations that affect neurodevelopment. The authors also highlight the resultant microstructural, macrostructural, and functional abnormalities that emerge during brain development, which create a pattern of dysfunctional neural networks involved in socioemotional processing. They then discuss how these findings implicate the BLA as a key node in the pathophysiology of autism and review a reported case of BLA DBS for treatment of severe autism. Much progress has been made in recent years in understanding the pathophysiology of autism. The BLA represents a logical neurosurgical target for treating severe autism. Further study is needed that considers mechanistic and operative challenges.

Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities

IntroductionRecent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers.ResultsIn every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic “microtubers”. A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells.ConclusionsMicrotubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC.

Unchanged safety outcomes in deep brain stimulation surgery for Parkinson disease despite a decentralization of care.

OBJECT Early work on deep brain stimulation (DBS) surgery, when procedures were mostly carried out in a small number of high-volume centers, demonstrated a relationship between surgical volume and procedural safety. However, over the past decade, DBS has become more widely available in the community rather than solely at academic medical centers. The authors examined the Nationwide Inpatient Sample (NIS) to study the safety of DBS surgery for Parkinson disease (PD) in association with this change in practice patterns. METHODS The NIS is a stratified sample of 20% of all patient discharges from nonfederal hospitals in the United States. The authors identified patients with a primary diagnosis of PD (332.0) and a primary procedure code for implantation/replacement of intracranial neurostimulator leads (02.93) who underwent surgery between 2002 and 2009. They analyzed outcomes using univariate and hierarchical, logistic regression analyses. RESULTS The total number of DBS cases remained stable from 2002 through 2009. Despite older and sicker patients undergoing DBS, procedural safety (rates of non-home discharges, complications) remained stable. Patients at low-volume hospitals were virtually indistinguishable from those at high-volume hospitals, except that patients at low-volume hospitals had slightly higher comorbidity scores (0.90 vs 0.75, p < 0.01). Complications, non-home discharges, length of hospital stay, and mortality rates did not significantly differ between low- and high-volume hospitals when accounting for hospital-related variables (caseload, teaching status, location). CONCLUSIONS Prior investigations have demonstrated a robust volume-outcome relationship for a variety of surgical procedures. However, the present study supports safety of DBS at smaller-volume centers. Prospective studies are required to determine whether low-volume centers and higher-volume centers have similar DBS efficacy, a critical factor in determining whether DBS is comparable between centers.

Approaches to anterior and anterolateral foramen magnum lesions: A critical review

Foramen magnum (FM) lesions represent some of the most complex cases for the modern neurosurgeon because of their location near vital brainstem structures, the vertebral arteries, and lower cranial nerves. In particular, anterior or anterolaterally located FM tumors have traditionally been most difficult to resect with high morbidity and mortality resulting from approaches through the posterior midline or transorally. For many neurosurgeons, the far lateral, extreme lateral approach, and more recently, endoscopic endonasal approaches have become the preferred modern methods for the resection of anterior or anterolateral FM tumors. In this review, we examine both operative and non-operative approaches to FM tumors, including surgical anatomy, surgical technique, and indications for operative intervention in these complex cases. In addition, we compared outcomes from prior series.

Inferior short-term safety profile of endoscopic third ventriculostomy compared with ventriculoperitoneal shunt placement for idiopathic normal-pressure hydrocephalus: a population-based study.

BACKGROUND In small series, endoscopic third ventriculostomy (ETV) has been shown to potentially have efficacy similar to that of ventriculoperitoneal shunting (VPS) for idiopathic normal-pressure hydrocephalus (iNPH). Therefore, some clinicians have advocated for ETV to avoid the potential long-term complications associated with VPS. Complication rates for these procedures vary widely based on limited small series data. OBJECTIVE We used a nationwide database that provides a comprehensive investigation of the perioperative safety of ETV for iNPH compared with VPS. METHODS We identified discharges with the primary diagnosis of iNPH (International Classification of Diseases, Ninth Revision code 331.5 [ICD-9]) with ICD-9 primary procedure codes for VPS (02.34) and ETV (02.2) from 2007 to 2010. We analyzed short-term safety outcomes using univariate and hierarchical logistic regression analyses. RESULTS There were a total of 652 discharges for ETV for iNPH and 12,845 discharges for VPS for iNPH over the study period. ETV was associated with a significantly higher mortality (3.2% vs 0.5%) and short-term complication (17.9% vs 11.8%) rates than VPS despite similar mean modified comorbidity scores. On multivariate analysis, ETV alone predicted increased mortality and increased length of stay when adjusted for other patient and hospital factors. CONCLUSION This is the first study that robustly assesses the perioperative complications and safety outcomes of ETV for iNPH. Compared with VPS, ETV is associated with higher perioperative mortality and complication rates. This consideration is important to weigh against the potential benefit of ETV: avoiding long-term shunt dependence. Prospective, randomized studies are needed.