Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation.

The ability to optimize behavioural performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, is important in regulating cognitive control. Hypotheses about its function include guiding reward-based decision making, monitoring for conflict between competing responses and predicting task difficulty. Precise mechanisms of dACC function remain unknown, however, because of the limited number of human neurophysiological studies. Here we use functional imaging and human single-neuron recordings to show that the firing of individual dACC neurons encodes current and recent cognitive load. We demonstrate that the modulation of current dACC activity by previous activity produces a behavioural adaptation that accelerates reactions to cues of similar difficulty to previous ones, and retards reactions to cues of different difficulty. Furthermore, this conflict adaptation, or Gratton effect, is abolished after surgically targeted ablation of the dACC. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioural responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands it engenders accuracy by delaying responses.

Encoding of rules by neurons in the human dorsolateral prefrontal cortex.

We use rules to extend learned behavior beyond specific instances to general scenarios. The prefrontal cortex (PFC) is thought to play an important role in representing rules, as evidenced by subjects who have difficulty in following rules after PFC damage and by animal studies demonstrating rule sensitivity of individual PFC neurons. How rules are instantiated at the single-neuronal level in the human brain, however, remains unclear. Here, we recorded from individual neurons in the human dorsolateral prefrontal cortex (DLPFC) as subjects performed a task in which they evaluated pairs of images using either of 2 abstract rules. We find that DLPFC neurons selectively encoded these rules while carrying little information about the subjects' responses or the sensory cues used to guide their decisions.

Utility of foramen ovale electrodes in mesial temporal lobe epilepsy.

OBJECTIVES: To determine the ability of foramen ovale electrodes (FOEs) to localize epileptogenic foci after inconclusive noninvasive investigations in patients with suspected mesial temporal lobe epilepsy (MTLE). METHODS: We identified patients with medically intractable epilepsy who had undergone FOE investigation for initial invasive monitoring at our institution between 2005 and 2012. Indications for initiating FOE investigation were grouped into four categories: (1) bilateral anterior temporal ictal activity on scalp electroencephalography (EEG), (2) unclear laterality of scalp EEG onset due to muscle artifact or significant delay following clinical manifestation, (3) discordance between ictal and interictal discharges, and (4) investigation of a specific anatomic abnormality or competing putative focus. The FOE investigation was classified as informative if it provided sufficient evidence to make a treatment decision. RESULTS: Forty-two consecutive patients underwent FOE investigation, which was informative in 38 patients (90.5%). Of these 38 patients, 24 were determined to be appropriate candidates for resective surgery. Five were localized sufficiently for surgery, but were considered high risk for verbal memory deficit, and nine were deemed poor surgical candidates because of bilateral ictal origins. The remaining 4 of 42 patients had inconclusive FOE studies and were referred for further invasive investigation. Of the 18 patients who underwent resective surgery, 13 (72%) were seizure-free (Engel class I) at last follow-up (mean 22.5 months). SIGNIFICANCE: More than 90% of our 42 FOE studies provided sufficient evidence to render treatment decisions. When undertaken with an appropriate hypothesis, FOE investigations are a minimally invasive and efficacious means for evaluating patients with suspected MTLE after an inconclusive noninvasive investigation.

Single-neuron responses in the human nucleus accumbens during a financial decision-making task.

Linking values to actions and evaluating expectations relative to outcomes are both central to reinforcement learning and are thought to underlie financial decision-making. However, neurophysiology studies of these processes in humans remain limited. Here, we recorded the activity of single human nucleus accumbens neurons while subjects performed a gambling task. We show that the nucleus accumbens encodes two signals related to subject behavior. First, we find that under relatively predictable conditions, single neuronal activity predicts future financial decisions on a trial-by-trial basis. Interestingly, we show that this activity continues to predict decisions even under conditions of uncertainty (e.g., when the probability of winning or losing is 50/50 and no particular financial choice predicts a rewarding outcome). Furthermore, we find that this activity occurs, on average, 2 s before the subjects physically manifest their decision. Second, we find that the nucleus accumbens encodes the difference between expected and realized outcomes, consistent with a prediction error signal. We show this activity occurs immediately after the subject has realized the outcome of the trial and is present on both the individual and population neuron levels. These results provide human single neuronal evidence that the nucleus accumbens is integral in making financial decisions.

Deep brain stimulation for obsessive-compulsive disorder: past, present, and future.

Obsessive-compulsive disorder (OCD) is a psychiatric illness that can lead to chronic functional impairment. Some patients with severe, chronic OCD have been treated with ablative neurosurgical techniques over the past 4 decades. More recently, deep brain stimulation (DBS) has been investigated as a therapy for refractory OCD, and the procedure was granted a limited humanitarian device exemption by the FDA in 2009. In this article, the authors review the development of DBS for OCD, describe the current understanding of the pathophysiological mechanisms of the disorder and how the underlying neural circuits might be modulated by DBS, and discuss the clinical studies that provide evidence for the use of this evolving therapy. The authors conclude with suggestions for how a combined basic science and translational research approach could drive the understanding of the neural mechanisms underlying OCD as well as the clinical effectiveness of DBS in the setting of recalcitrant disease.

A microwell array system for stem cell culture.

Directed embryonic stem (ES) cell differentiation is a potentially powerful approach for generating a renewable source of cells for regenerative medicine. Typical in vitro ES cell differentiation protocols involve the formation of ES cell aggregate intermediates called embryoid bodies (EBs). Recently, we demonstrated the use of poly(ethylene glycol) (PEG) microwells as templates for directing the formation of these aggregates, offering control over parameters such as size, shape, and homogeneity. Despite these promising results, the previously developed technology was limited as it was difficult to reproducibly obtain cultures of homogeneous EBs with high efficiency and retrievability. In this study, we improve the platform by optimizing a number of features: material composition of the microwells, cell seeding procedures, and aggregate retrieval methods. Adopting these modifications, we demonstrate an improved degree of homogeneity of the resulting aggregate populations and establish a robust protocol for eliciting high EB formation efficiencies. The optimized microwell array system is a potentially versatile tool for ES cell differentiation studies and high-throughput stem cell experimentation.

Postoperative intensive care unit requirements after elective craniotomy.

OBJECTIVE: Commonly, patients undergoing craniotomy are admitted to an intensive care setting postoperatively to allow for close monitoring. We aim to determine the frequency with which patients who have undergone elective craniotomies require intensive care unit (ICU)-level interventions or experience significant complications during the postoperative period to identify a subset of patients for whom an alternative to ICU-level care may be appropriate. METHODS: Following Institutional Review Board approval, a prospective, consecutive cohort of adult patients undergoing elective craniotomy was established at the Massachusetts General Hospital between the dates of April 2010 and March 2011. Inclusion criteria were intradural operations requiring craniotomy performed on adults (18 years of age or older). Exclusion criteria were cases of an urgent or emergent nature, patients who remained intubated postoperatively, and patients who had a ventriculostomy drain in place at the conclusion of the case. RESULTS: Four hundred patients were analyzed. Univariate analysis revealed that patients with diabetes (P = 0.00047), those who required intraoperative blood product administration (P = 0.032), older patients (P < 0.0001), those with higher intraoperative blood losses (P = 0.041), and those who underwent longer surgical procedures (P = 0.021) were more likely to require ICU-level interventions or experience significant postoperative complications. Multivariate analysis only found diabetes (P = 0.0005) and age (P = 0.0091) to be predictive of a patient's need for postoperative ICU admission. CONCLUSIONS: Diabetes and older age predict the need for ICU-level intervention after elective craniotomy. Properly selected patients may not require postcraniotomy ICU monitoring. Further study of resource utilization is necessary to validate these preliminary findings, particularly in different hospital types.

Beneficial effect of subsequent lesion procedures after nonresponse to initial cingulotomy for severe, treatment-refractory obsessive-compulsive disorder.

BACKGROUND: Anterior cingulotomy (AC) can be an effective therapy for patients with severe obsessive-compulsive disorder who are refractory to traditional medical therapy. For patients who do not respond to AC, the benefit of additional lesion procedures vs continued medical management remains unknown. OBJECTIVE: To determine whether a second lesion procedure is beneficial after unsuccessful initial AC. METHODS: In this retrospective cohort study, we reviewed the records of 31 patients who were nonresponders to initial AC. Full response was defined as at least a 35% decrease and partial response as a 25% to 34% decrease in Yale-Brown Obsessive-Compulsive Scale scores. Yale-Brown Obsessive-Compulsive Scale change was compared between patients who underwent additional surgery and those treated nonsurgically. In addition, for patients who underwent additional surgery, we compared the benefit of subcaudate tractotomy with repeat AC (extension of the initial lesion) as the second procedure. RESULTS: Nineteen patients underwent a second surgery and 12 patients continued nonsurgical therapy. Fifty-three percent of patients who received additional surgery were full responders and 21% were partial responders at the most recent follow-up compared with 17% full responders and 25% partial responders among those who continued conventional therapy (P = .02). Of the patients who underwent an additional surgery, there were 64% full and 9% partial responders in the subcaudate tractotomy group compared with 38% full and 38% partial responders in the repeat AC group (P = .04). CONCLUSION: Second lesion surgery can be a safe and effective therapy for patients who do not respond to initial AC. Subcaudate tractotomy may confer a higher response rate than repeat cingulotomy.

Limbic system surgery for treatment-refractory obsessive-compulsive disorder: a prospective long-term follow-up of 64 patients.

OBJECT: Obsessive-compulsive disorder (OCD) is a common and disabling psychiatric illness, and in a significant proportion of patients with OCD the disease is refractory to conventional pharmacotherapy and psychotherapy. For more than half a century, patients with severe, treatment-resistant OCD have been treated with stereotactic limbic system lesions, including dorsal anterior cingulotomy. The authors present their results describing the efficacy and durability of limbic system surgery for OCD, characterizing a large cohort of patients treated at a single institution with a mean follow-up of more than 5 years. METHODS: The authors identified 64 consecutive patients undergoing cingulotomy for refractory OCD at the Massachusetts General Hospital between 1989 and 2009. Changes in OCD and major depressive disorder symptom severity were assessed at both the initial and most recent postoperative follow-up by using the Yale-Brown Obsessive Compulsive Scale and the Beck Depression Inventory, respectively. Full and partial OCD symptom responses were defined as Yale-Brown Obsessive Compulsive Scale score reductions of ≥ 35% and 25%-34%, respectively. RESULTS: Regarding OCD symptom improvement, at the first postoperative follow-up (mean 10.7 months), 35% of patients demonstrated a full response and 7% were partial responders. Thirty patients had a subsequent procedure (repeat cingulotomy or subcaudate tractotomy). By the most recent follow-up (mean 63.8 months), rates climbed to 47% and 22% for full and partial responses, respectively. Of the 24 patients with at least a partial response at initial follow-up, 20 (83%) retained at least a partial response at final follow-up. Comorbid major depressive disorder severity decreased by 17% at the most recent follow-up. CONCLUSIONS: Limbic system surgery based on initial cingulotomy offers a durable and effective treatment option for appropriately selected patients with severe OCD who have not responded to conventional pharmacotherapy or psychotherapy.

Studying task-related activity of individual neurons in the human brain.

Single-neuronal studies remain the gold standard for studying brain function. Here we describe a protocol for studying task-related single-neuronal activity in human subjects during neurosurgical procedures involving microelectrode recordings. This protocol has two phases: a preoperative phase and an intraoperative phase. During the preoperative phase, we discuss informed consent, equipment setup and behavioral testing. During the intraoperative phase, we discuss the procedure for microelectrode recordings. Because patients are often awake during these procedures, this protocol can be performed in conjunction with behavioral tasks for studying a variety of cognitive functions. We describe the protocol in detail and provide two examples of expected results. In addition, we discuss the potential difficulties and pitfalls related to intraoperative studies. This protocol takes ∼1.5 h to complete.

Intraspinal migration of a clavicular Steinmann pin: case report and management strategy.

Spine injury resulting from migration of previously implanted appendicular skeleton fixation hardware is rare. We present a 41-year-old man who had Steinmann fixation pins placed for a left clavicular fracture 2 years prior. He presented with a burning sensation over his biceps bilaterally and numbness over the left anterior chest and abdomen following a significant blunt traumatic injury. A CT scan revealed migration of a fractured Steinmann pin entering the left C8 neural foramen, traversing anterior to the spinal cord. The patient underwent a left C7 hemilaminectomy, foraminal decompression, and first rib resection to identify the extraforaminal portion of the pin and remove it under direct vision. He recovered uneventfully. We conclude that a principle of safe surgical removal includes adequate exposure to allow for direct visualization of the pin and neural structures. We review the evaluation and management strategies of this unusual condition.

Transsphenoidal surgery for cushing disease after nondiagnostic inferior petrosal sinus sampling.

BACKGROUND: Inferior petrosal sinus sampling (IPSS) is a useful technique for confirming a pituitary source of adrenocorticotropic hormone (ACTH) overproduction in Cushing disease. Uncertainty remains regarding the appropriate course of therapy when an ectopic tumor is predicted by IPSS but none can be found and in circumstances when the procedure cannot be successfully completed owing to technical or anatomic limitations. OBJECTIVE: To determine an appropriate course of action after nondiagnostic IPSS. METHODS: We reviewed 288 IPSS procedures in 283 patients between 1986 and 2010 at our center. An IPS:peripheral ACTH ratio ≥ 2 at baseline or ≥ 3 after corticotrophin-releasing hormone was considered predictive of a pituitary source of ACTH. A procedure was considered nondiagnostic if the procedure was successfully performed and the results predicted an ectopic source but none could be found despite extensive imaging or if the IPS could not be bilaterally cannulated because of technical difficulties or anatomic variants. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value of IPSS for detecting a pituitary source in Cushing disease were 94%, 50%, 98%, and 29%, respectively. We identified 3 categories of nondiagnostic IPSS comprising 44 of the total procedures. These patients underwent exploratory transsphenoidal surgery, and in 42 of these patients (95%), a pituitary source was surgically proven, with a remission rate of 83%. CONCLUSION: Transsphenoidal surgery should be considered in cases of ACTH-dependent Cushing disease and noncentralized or technically unsuccessful IPSS without evidence of ectopic tumor.

Glioblastoma multiforme and cerebral cavernous malformations: intersection of pathophysiologic pathways.

Cerebral cavernous malformations (CCM) are known to occur in both sporadic and familial forms. To date, there has been no identified association of CCM with glioblastoma multiforme. We present a 69-year-old woman with a 14 year history of multiple CCM who developed progressive aphasia. She had no radiation exposure and had only undergone a single computed tomography scan in her entire life. MRI demonstrated irregular gadolinium enhancement in the area of a prior stable CCM, suspicious for a high grade tumor. Stereotactic biopsy revealed a glioblastoma multiforme. This is a unique case of glioblastoma multiforme arising from the "site" of a known CCM. We review the literature on the genetics of cavernous malformations and propose a mechanism for the tumorigenic potential of these vascular malformations.

Interfacility helicopter ambulance transport of neurosurgical patients: observations, utilization, and outcomes from a quaternary level care hospital.

BACKGROUND: The clinical benefit of helicopter transport over ground transportation for interfacility transport is unproven. We sought to determine actual practice patterns, utilization, and outcomes of patients undergoing interfacility transport for neurosurgical conditions. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively examined all interfacility helicopter transfers to a single trauma center during 2008. We restricted our analysis to those transfers leading either to admission to the neurosurgical service or to formal consultation upon arrival. Major exclusion criteria included transport from the scene, death during transport, and transport to any area of the hospital other than the emergency department. The primary outcome was time interval to invasive intervention. Secondary outcomes were estimated ground transportation times from the referring hospital, admitting disposition, and discharge disposition. Of 526 candidate interfacility helicopter transfers to our emergency department in 2008, we identified 167 meeting study criteria. Seventy-five (45%) of these patients underwent neurosurgical intervention. The median time to neurosurgical intervention ranged from 1.0 to 117.8 hours, varying depending on the diagnosis. For 101 (60%) of the patients, estimated driving time from the referring institution was less than one hour. Four patients (2%) expired in the emergency department, and 34 patients (20%) were admitted to a non-ICU setting. Six patients were discharged home within 24 hours. For those admitted, in-hospital mortality was 28%. CONCLUSIONS/SIGNIFICANCE: Many patients undergoing interfacility transfer for neurosurgical evaluation are inappropriately triaged to helicopter transport, as evidenced by actual times to intervention at the accepting institution and estimated ground transportation times from the referring institution. In a time when there is growing interest in health care cost containment, practitioners must exercise discretion in the selection of patients for air ambulance transport--particularly when it may not bear influence on clinical outcome. Neurosurgical evaluation via telemedicine may be one strategy for improving air transport triage.