Nader Pouratian

Linear and Nonlinear Relationships between Neuronal Activity, Oxygen Metabolism, and Hemodynamic Responses

We investigated the relationship between neuronal activity, oxygen metabolism, and hemodynamic responses in rat somatosensory cortex with simultaneous optical intrinsic signal imaging and spectroscopy, laser Doppler flowmetry, and local field potential recordings. Changes in cerebral oxygen consumption increased linearly with synaptic activity but with a threshold effect consistent with the existence of a tissue oxygen buffer. Modeling analysis demonstrated that the coupling between neuronal activity and hemodynamic response magnitude may appear linear over a narrow range but incorporates nonlinear effects that are better described by a threshold or power law relationship. These results indicate that caution is required in the interpretation of perfusion-based indicators of brain activity, such as functional magnetic resonance imaging (fMRI), and may help to refine quantitative models of neurovascular coupling.

Incidence of symptomatic hemorrhage after stereotactic electrode placement

OBJECT Intracranial hemorrhage (ICH) is the most significant complication associated with the placement of stereotactic intracerebral electrodes. Previous reports have suggested that hypertension and the use of microelectrode recording (MER) are risk factors for cerebral hemorrhage. The authors evaluated the incidence of symptomatic ICH in a large cohort of patients with various diseases treated with stereotactic electrode placement. They examined the effect of comorbidities on the risk of ICH and independently assessed the risks associated with age, sex, use of MER, diagnosis, target location, hypertension, and previous use of anticoagulant medications. The authors also evaluated the effect of hemorrhage on length of hospital stay and discharge disposition. METHODS Between 1991 and 2005, 567 electrodes were placed by two neurosurgeons during 337 procedures in 259 patients. Deep brain stimulation (DBS) was performed in 167 procedures, radiofrequency lesioning (RFL) of subcortical structures in 74, and depth electrodes were used in 96 procedures in patients with epilepsy. Electrodes were grouped according to target, patient diagnosis, use of MER, patient history of hypertension, and patient prior use of anticoagulant medication (stopped 10 days before surgery). The Charlson Comorbidity Index (CCI) was used to evaluate the effect of comorbidities. The CCI score, patient age, length of hospital stay, and discharge status were continuous variables. Symptomatic hemorrhages were grouped as transient or leading to permanent neurological deficits. RESULTS The risk of hemorrhage leading to permanent neurological deficits in this study was 0.7%, and the risk of symptomatic hemorrhage was 1.2%. A patient history of hypertension was the most significant factor associated with hemorrhage (p = 0.007). Older age, male sex, and a diagnosis of Parkinson disease (PD) were also significantly associated with hemorrhage (p = 0.01, 0.04, 0.007, respectively). High CCI scores, specific target locations, and prior use of anticoagulant therapy were not associated with an increased risk of hemorrhage. The use of MER was not found to be correlated with an increased hemorrhage rate (p = 0.34); however, the number of hemorrhages in the patients who underwent DBS was insufficient to draw definitive conclusions. The mean length of stay for the DBS, RFL, and depth electrode patient groups was 2.9, 2.6, and 11.0 days, respectively. For patients who received DBS and RFL, the mean duration of hospitalization in cases of symptomatic hemorrhage was 8.2 days compared with 2.7 days in those without hemorrhaging (p < 0.0001). Three of the seven patients with symptomatic hemorrhages were discharged home. CONCLUSIONS The placement of stereotactic electrodes is generally safe, with a symptomatic hemorrhage rate of 1.2%, and a 0.7% rate of permanent neurological deficit. Consistent with prior reports, this study confirms that hypertension is a significant risk factor for hemorrhage. Age, male sex, and diagnosis of PD were also significant risk factors. Patients with symptomatic hemorrhage had longer hospital stays and were less likely to be discharged home.

Evaluation of coupling between optical intrinsic signals and neuronal activity in rat somatosensory cortex.

We investigated the coupling between perfusion-related brain imaging signals and evoked neuronal activity using optical imaging of intrinsic signals (OIS) at 570 and 610 nm. OIS at 570 nm reflects changes in cerebral blood volume (CBV), and the 610 nm response is related to hemoglobin oxygenation changes. We assessed the degree to which these components of the hemodynamic response were coupled to neuronal activity in rat barrel, hindpaw, and forepaw somatosensory cortex by simultaneously recording extracellular evoked field potentials (EPs) and OIS while varying stimulation frequency. In all stimulation paradigms, 10 Hz stimulation evoked the largest optical and electrophysiological responses. Across all animals, the 610 late phase and 570 responses correlated linearly with sigmaEP (P < 0.05) during both whisker deflection and electrical hindpaw stimulation, but the 610 early phase did not (whisker P = 0.27, hindpaw P = 0.28). The signal-to-noise ratio (SNR) of the 610 early phase (whisker 3.1, hindpaw 5.3) was much less than that for the late phase (whisker 14, hindpaw 51) and 570 response (whisker 11, hindpaw 46). During forepaw stimulation, however, the 610 early phase had a SNR (17) higher than that during hindpaw stimulation and correlated well with neuronal activity (P < 0.05). We conclude that the early deoxygenation change does not correlate consistently with neuronal activity, possibly because of its low SNR. The robust CBV-related response, however, has a high SNR and correlates well with evoked cortical activity.

Columnar Specificity of Microvascular Oxygenation and Volume Responses: Implications for Functional Brain Mapping

Cortical neurons with similar properties are grouped in columnar structures and supplied by matching vascular networks. The hemodynamic response to neuronal activation, however, is not well described on a fine spatial scale. We investigated the spatiotemporal characteristics of microvascular responses to neuronal activation in rat barrel cortex using optical intrinsic signal imaging and spectroscopy. Imaging was performed at 570 nm to provide functional maps of cerebral blood volume (CBV) changes and at 610 nm to estimate oxygenation changes. To emphasize parenchymal rather than large vessel contributions to the functional hemodynamic responses, we developed an ANOVA-based statistical analysis technique. Perfusion-based maps were compared with underlying neuroanatomy with cytochrome oxidase staining. Statistically determined CBV responses localized accurately to individually stimulated barrel columns and could resolve neighboring columns with a resolution better than 400 μm. Both CBV and early oxygenation responses extended beyond anatomical boundaries of single columns, but this vascular point spread did not preclude spatial specificity. These results indicate that microvascular flow control structures providing targeted flow increases to metabolically active neuronal columns also produce finely localized changes in CBV. This spatial specificity, along with the high contrast/noise ratio, makes the CBV response an attractive mapping signal. We also found that functional oxygenation changes can achieve submillimeter specificity not only during the transient deoxygenation (“initial dip”) but also during the early part of the hyperoxygenation. We, therefore, suggest that to optimize hemodynamic spatial specificity, appropriate response timing (using ≤2-3 sec changes) is more important than etiology (oxygenation or volume).

Impact of the Accreditation Council for Graduate Medical Education work-hour regulations on neurosurgical resident education and productivity.

OBJECT Recently, the Institute of Medicine examined resident duty hours and their impact on patient safety. Experts have suggested that reducing resident work hours to 56 hours per week would further decrease medical errors. Although some reports have indicated that cutbacks in resident duty hours reduce errors and make resident life safer, few authors have specifically analyzed the effect of the Accreditation Council for Graduate Medical Education (ACGME) duty-hour limits on neurosurgical resident education and the perceived quality of training. The authors have evaluated multiple objective surrogate markers of resident performance and quality of training to determine the impact of the 80-hour workweek. METHODS The United States Medical Licensing Examination (USMLE) Step 1 data on neurosurgical applicants entering ACGME-accredited programs between 1998 and 2007 (before and after the implementation of the work-hour rules) were obtained from the Society of Neurological Surgeons. The American Board of Neurological Surgery (ABNS) written examination scores for this group of residents were also acquired. Resident registration for and presentations at the American Association of Neurological Surgeons (AANS) annual meetings between 2002 and 2007 were examined as a measure of resident academic productivity. As a case example, the authors analyzed the distribution of resident training hours in the University of Virginia (UVA) neurosurgical training program before and after the institution of the 80-hour workweek. Finally, program directors and chief residents in ACGME-accredited programs were surveyed regarding the effects of the 80-hour workweek on patient care, resident training, surgical experience, patient safety, and patient access to quality care. Respondents were also queried about their perceptions of a 56-hour workweek. RESULTS Despite stable mean USMLE Step 1 scores for matched applicants to neurosurgery programs between 2000 and 2008, ABNS written examination scores for residents taking the exam for self-assessment decreased from 310 in 2002 to 259 in 2006 (16% decrease, p < 0.05). The mean scores for applicants completing the written examination for credit also did not change significantly during this period. Although there was an increase in the number of resident registrations to the AANS meetings, the number of abstracts presented by residents decreased from 345 in 2002 to 318 in 2007 (7% decrease, p < 0.05). An analysis of the UVA experience suggested that the 80-hour workweek leads to a notable increase in on-call duty hours with a profound decrease in the number of hours spent in conference and the operating room. Survey responses were obtained from 110 program directors (78% response rate) and 122 chief residents (76% response rate). Most chief residents and program directors believed the 80-hour workweek compromised resident training (96%) and decreased resident surgical experience (98%). Respondents also believed that the 80-hour workweek threatened patient safety (96% of program directors and 78% of chief residents) and access to quality care (82% of program directors and 87% of chief residents). When asked about the effects of a 56-hour workweek, all program directors and 98% of the chief residents indicated that resident training and surgical education would be further compromised. Most respondents (95% of program directors and 84% of chief residents) also believed that additional work-hour restrictions would jeopardize patient care. CONCLUSIONS Neurological surgery continues to attract top-quality resident applicants. Test scores and levels of participation in national conferences, however, indicate that the 80-hour workweek may adversely affect resident training. Subjectively, neurosurgical program directors and chief residents believe that the 80-hour workweek makes neurosurgical training and the care of patients more difficult. Based on experience with the 80-hour workweek, educators think that a 56-hour workweek would further compromise neurosurgical training and patient care in the US.

Gamma Knife radiosurgery to the surgical cavity following resection of brain metastases.

OBJECT This study evaluated the efficacy of postoperative Gamma Knife surgery (GKS) to the tumor cavity following gross-total resection of a brain metastasis. METHODS A retrospective review was conducted of 700 patients who were treated for brain metastases using GKS. Forty-seven patients with pathologically confirmed metastatic disease underwent GKS to the postoperative resection cavity following gross-total resection of the tumor. Patients who underwent subtotal resection or who had visible tumor in the resection cavity on the postresection neuroimaging study (either CT or MR imaging with and without contrast administration) were excluded. Radiographic and clinical follow-up was assessed using clinic visits and MR imaging. The radiographic end point was defined as tumor growth control (no tumor growth regarding the resection cavity, and stable or decreasing tumor size for the other metastatic targets). Clinical end points were defined as functional status (assessed prospectively using the Karnofsky Performance Scale) and survival. Primary tumor pathology was consistent with lung cancer in 19 cases (40%), melanoma in 10 cases (21%), renal cell carcinoma in 7 cases (15%), breast cancer in 7 cases (15%), and gastrointestinal malignancies in 4 cases (9%). The mean duration between resection and radiosurgery was 15 days (range 2-115 days). The mean volume of the treated cavity was 10.5 cm3 (range 1.75-35.45 cm3), and the mean dose to the cavity margin was 19 Gy. In addition to the resection cavity, 34 patients (72%) underwent GKS for 116 synchronous metastases observed at the time of the initial radiosurgery. RESULTS The mean radiographic follow-up duration was 14 months (median 10 months, range 4-37 months). Local tumor control at the site of the surgical cavity was achieved in 44 patients (94%), and tumor recurrence at the surgical site was statistically related to the volume of the surgical cavity (p=0.04). During follow-up, 34 patients (72%) underwent additional radiosurgery for 140 new (metachronous) metastases. At the most recent follow-up evaluation, 11 patients (23%) were alive, whereas 36 patients had died (mean duration until death 12 months, median 10 months). Patients who showed good systemic control of their primary tumor tended to have longer survival durations than those who did not (p=0.004). At the last clinical follow-up evaluation, the mean Karnofsky Performance Scale score for the overall group was 78 (median 80, range 40-100). CONCLUSION Radiosurgery appears to be effective in terms of providing local tumor control at the resection cavity following resection of a brain metastasis, and in the treatment of synchronous and metachronous tumors. These data suggest that radiosurgery can be used to prevent recurrence following gross-total resection of a brain metastasis.

Gamma knife radiosurgery for acromegaly: outcomes after failed transsphenoidal surgery.

OBJECTIVE This study evaluates the safety and efficacy of gamma knife radiosurgery (GKRS) in patients with a growth hormone-secreting adenoma. METHODS A retrospective review of data collected from a prospective database of GKRS patients between January 1988 and September 2006 was performed in patients with acromegaly. Successful endocrine outcome was defined as normalization of the insulin-like growth factor level. Tumor volume was also assessed. At least 18 months of follow-up was available in 95 patients who received radiosurgery during the study period. Mean endocrine follow-up was 57 months (range, 18-168 mo). RESULTS Normal insulin-like growth factor levels were achieved in 50 patients (53%) at an average time of 29.8 months after radiosurgery (median, 23.5 mo). A decrease in tumor volume control was achieved in 83 (92%) of 90 patients. Five patients (6%) had no change in tumor volume, and two patients (2%) had an increase in tumor volume. New endocrine deficiencies developed in 32 patients (34%). Four patients developed new-onset partial visual acuity deficits; three of these patients had received previous conventional fractionated radiation therapy. CONCLUSION GKRS is a complementary treatment for recurrent or residual growth hormone-secreting pituitary adenomas. Although infrequent, tumor growth, new-onset pituitary hormone deficiency, recurrence, and neurological dysfunction require careful clinical, radiological, and endocrinological follow-up.

Gamma Knife surgery for pituitary adenomas: factors related to radiological and endocrine outcomes

OBJECT Gamma Knife surgery (GKS) is a common treatment for recurrent or residual pituitary adenomas. This study evaluates a large cohort of patients with a pituitary adenoma to characterize factors related to endocrine remission, control of tumor growth, and development of pituitary deficiency. METHODS A total of 418 patients who underwent GKS with a minimum follow-up of 6 months (median 31 months) and for whom there was complete follow-up were evaluated. Statistical analysis was performed to evaluate for significant factors (p < 0.05) related to treatment outcomes. RESULTS In patients with a secretory pituitary adenoma, the median time to endocrine remission was 48.9 months. The tumor margin radiation dose was inversely correlated with time to endocrine remission. Smaller adenoma volume correlated with improved endocrine remission in those with secretory adenomas. Cessation of pituitary suppressive medications at the time of GKS had a trend toward statistical significance in regard to influencing endocrine remission. In 90.3% of patients there was tumor control. A higher margin radiation dose significantly affected control of adenoma growth. New onset of a pituitary hormone deficiency following GKS was seen in 24.4% of patients. Treatment with pituitary hormone suppressive medication at the time of GKS, a prior craniotomy, and larger adenoma volume at the time of radiosurgery were significantly related to loss of pituitary function. CONCLUSIONS Smaller adenoma volume improves the probability of endocrine remission and lowers the risk of new pituitary hormone deficiency with GKS. A higher margin dose offers a greater chance of endocrine remission and control of tumor growth.

Functional signal- and paradigm-dependent linear relationships between synaptic activity and hemodynamic responses in rat somatosensory cortex

Linear relationships between synaptic activity and hemodynamic responses are critically dependent on functional signal etiology and paradigm. To investigate these relationships, we simultaneously measured local field potentials (FPs) and optical intrinsic signals in rat somatosensory cortex while delivering a small number of electrical pulses to the hindpaw with varied stimulus intensity, number, and interstimulus interval. We used 570 and 610 nm optical signals to estimate cerebral blood volume (CBV) and oxygenation, respectively. The spatiotemporal evolution patterns and trial-by-trial correlation analyses revealed that CBV-related optical signals have higher fidelity to summed evoked FPs (ΣFPs) than oxygenation-derived signals. CBV-related signals even correlated with minute ΣFP fluctuations within trials of the same stimulus condition. Furthermore, hemodynamic signals (CBV and late oxygenation signals) increased linearly with ΣFP while varying stimulus number, but they exhibited a threshold and steeper gradient while varying stimulus intensity, suggesting insufficiency of the homogeneity property of linear systems and the importance of spatiotemporal coherence of neuronal population activity in hemodynamic response formation. These stimulus paradigm-dependent linear and nonlinear relationships demonstrate that simple subtraction-based analyses of hemodynamic signals produced by complex stimulus paradigms may not reflect a difference in ΣFPs between paradigms. Functional signal- and paradigm-dependent linearity have potentially profound implications for the interpretation of perfusion-based functional signals.

Gamma knife radiosurgery for medically and surgically refractory prolactinomas

OBJECTIVE:Experience with gamma knife radiosurgery (GKRS) for prolactinomas is limited because of the efficacy of medical and surgical intervention. Patients who are refractory to medical and/or surgical therapy may be treated with GKRS. We characterize the efficacy of GKRS for medically and surgically refractory prolactinomas. METHODS:We reviewed our series of patients with prolactinomas who were treated with GKRS after failing medical and surgical intervention who had at least 1 year of follow-up. RESULTS:Twenty-three patients were included in analysis of endocrine outcomes (median and average follow-up of 55 and 58 mo, respectively) and 28 patients were included in analysis of imaging outcomes (median and average follow-up of 48 and 52 mo, respectively). Twenty-six percent of patients achieved a normal serum prolactin (remission) with an average time of 24.5 months. Remission was significantly associated with being off of a dopamine agonist at the time of GKRS and a tumor volume less than 3.0 cm3 (P < 0.05 for both). Long-term image-based volumetric control was achieved in 89% of patients. Complications included new pituitary hormone deficiencies in 28% of patients and cranial nerve palsy in two patients (7%). CONCLUSION:Clinical remission in 26% of treated patients is a modest result. However, because the GKRS treated tumors were refractory to other therapies and because complication rates were low, GKRS should be part of the armamentarium for treating refractory prolactinomas. Patients with tumors smaller than 3.0 cm3 and who are not receiving dopamine agonist at the time of treatment will likely benefit most.