Ashwin G. Ramayya

Theta and High-Frequency Activity Mark Spontaneous Recall of Episodic Memories

Humans possess the remarkable ability to search their memory, allowing specific past episodes to be re-experienced spontaneously. Here, we administered a free recall test to 114 neurosurgical patients and used intracranial theta and high-frequency activity (HFA) to identify the spatiotemporal pattern of neural activity underlying spontaneous episodic retrieval. We found that retrieval evolved in three electrophysiological stages composed of: (1) early theta oscillations in the right temporal cortex, (2) increased HFA in the left hemisphere including the medial temporal lobe (MTL), left inferior frontal gyrus, as well as the ventrolateral temporal cortex, and (3) motor/language activation during vocalization of the retrieved item. Of these responses, increased HFA in the left MTL predicted recall performance. These results suggest that spontaneous recall of verbal episodic memories involves a spatiotemporal pattern of spectral changes across the brain; however, high-frequency activity in the left MTL represents a final common pathway of episodic retrieval.

Human intracranial high-frequency activity during memory processing: neural oscillations or stochastic volatility?

Intracranial high-frequency activity (HFA), which refers to fast fluctuations in electrophysiological recordings, increases during memory processing. Two views have emerged to explain this effect: (1) HFA reflects a synchronous signal, related to underlying gamma oscillations, that plays a mechanistic role in human memory and (2) HFA reflects an asynchronous signal that is a non-specific marker of brain activation. We review recent data supporting each of these views and conclude that HFA during memory processing is more consistent with an asynchronous signal. Memory-related HFA is therefore best conceptualized as a biomarker of neural activation that can functionally map memory with high spatial and temporal precision.

Microstimulation of the Human Substantia Nigra Alters Reinforcement Learning

Animal studies have shown that substantia nigra (SN) dopaminergic (DA) neurons strengthen action–reward associations during reinforcement learning, but their role in human learning is not known. Here, we applied microstimulation in the SN of 11 patients undergoing deep brain stimulation surgery for the treatment of Parkinsons disease as they performed a two-alternative probability learning task in which rewards were contingent on stimuli, rather than actions. Subjects demonstrated decreased learning from reward trials that were accompanied by phasic SN microstimulation compared with reward trials without stimulation. Subjects who showed large decreases in learning also showed an increased bias toward repeating actions after stimulation trials; therefore, stimulation may have decreased learning by strengthening action–reward associations rather than stimulus–reward associations. Our findings build on previous studies implicating SN DA neurons in preferentially strengthening action–reward associations during reinforcement learning.

Electrophysiological evidence for functionally distinct neuronal populations in the human substantia nigra

The human substantia nigra (SN) is thought to consist of two functionally distinct neuronal populations—dopaminergic (DA) neurons in the pars compacta subregion and GABA-ergic neurons in the pars reticulata subregion. However, a functional dissociation between these neuronal populations has not previously been demonstrated in the awake human. Here we obtained microelectrode recordings from the SN of patients undergoing deep brain stimulation (DBS) surgery for Parkinsons disease as they performed a two-alternative reinforcement learning task. Following positive feedback presentation, we found that putative DA and GABA neurons demonstrated distinct temporal dynamics. DA neurons demonstrated phasic increases in activity (250–500 ms post-feedback) whereas putative GABA neurons demonstrated more delayed and sustained increases in activity (500–1000 ms post-feedback). These results provide the first electrophysiological evidence for a functional dissociation between DA and GABA neurons in the human SN. We discuss possible functions for these neuronal responses based on previous findings in human and animal studies.

Stimulation of the human medial temporal lobe between learning and recall selectively enhances forgetting

BACKGROUND Direct electrical stimulation applied to the human medial temporal lobe (MTL) typically disrupts performance on memory tasks, however, the mechanism underlying this effect is not known. OBJECTIVE To study the effects of MTL stimulation on memory performance. METHODS We studied the effects of MTL stimulation on memory in five patients undergoing invasive electrocorticographic monitoring during various phases of a memory task (encoding, distractor, recall). RESULTS We found that MTL stimulation disrupted memory performance in a timing-dependent manner; we observed greater forgetting when applying stimulation during the delay between encoding and recall, compared to when it was applied during encoding or recall. CONCLUSIONS The results suggest that recall is most dependent on the MTL between learning and retrieval.

Factors associated with increased survival after surgical resection of glioblastoma in octogenarians.

Elderly patients with glioblastoma represent a clinical challenge for neurosurgeons and oncologists. The data available on outcomes of patients greater than 80 undergoing resection is limited. In this study, factors linked to increased survival in patients over the age of 80 were analyzed. A retrospective chart review of all patients over the age of 80 with a new diagnosis of glioblastoma and who underwent surgical resection with intent for maximal resection were examined. Patients who had only stereotactic biopsies were excluded. Immunohistochemical expression of oncogenic drivers (p53, EGFR, IDH-1) and a marker of cell proliferation (Ki-67 index) performed upon routine neuropathological examination were recorded. Stepwise logistic regression and Kaplan Meier survival curves were plotted to determine correlations to overall survival. Fifty-eight patients fit inclusion criteria with a mean age of 83 (range 80–93 years). The overall median survival was 4.2 months. There was a statistically significant correlation between Karnofsky Performance Status (KPS) and overall survival (P < 0.05). There was a significantly longer survival among patients undergoing either radiation alone or radiation and chemotherapy compared to those who underwent no postoperative adjuvant therapy (p < 0.05). There was also an association between overall survival and lack of p53 expression (p < 0.001) and lack of EGFR expression (p <0.05). In this very elderly population, overall survival advantage was conferred to those with higher preoperative KPS, postoperative adjuvant therapy, and lack of protein expression of EGFR and p53. These findings may be useful in clinical decision analysis for management of patients with glioblastoma who are octogenarians, and also validate the critical role of EGFR and p53 expression in oncogenesis, particularly with advancing age.

Resident simulation training in endoscopic endonasal surgery utilizing haptic feedback technology.

Simulated practice may improve resident performance in endoscopic endonasal surgery. Using the NeuroTouch haptic simulation platform, we evaluated resident performance and assessed the effect of simulation training on performance in the operating room. First- (N=3) and second- (N=3) year residents were assessed using six measures of proficiency. Using a visual analog scale, the senior author scored subjects. After the first session, subjects with lower scores were provided with simulation training. A second simulation served as a task-learning control. Residents were evaluated in the operating room over six months by the senior author-who was blinded to the trained/untrained identities-using the same parameters. A nonparametric bootstrap testing method was used for the analysis (Matlab v. 2014a). Simulation training was associated with an increase in performance scores in the operating room averaged over all measures (p=0.0045). This is the first study to evaluate the training utility of an endoscopic endonasal surgical task using a virtual reality haptic simulator. The data suggest that haptic simulation training in endoscopic neurosurgery may contribute to improvements in operative performance. Limitations include a small number of subjects and adjudication bias-although the trained/untrained identity of subjects was blinded. Further study using the proposed methods may better describe the relationship between simulated training and operative performance in endoscopic Neurosurgery.

Proximity of Substantia Nigra Microstimulation to Putative GABAergic Neurons Predicts Modulation of Human Reinforcement Learning

Neuronal firing in the substantia nigra (SN) immediately following reward is thought to play a crucial role in human reinforcement learning. As in Ramayya et al. (2014a) we applied microstimulation in the SN of patients undergoing deep brain stimulation (DBS) for the treatment of Parkinsons disease as they engaged in a two-alternative reinforcement learning task. We obtained microelectrode recordings to assess the proximity of the electrode tip to putative dopaminergic and GABAergic SN neurons and applied stimulation to assess the functional importance of these neuronal populations for learning. We found that the proximity of SN microstimulation to putative GABAergic neurons predicted the degree of stimulation-related changes in learning. These results extend previous work by supporting a specific role for SN GABA firing in reinforcement learning. Stimulation near these neurons appears to dampen the reinforcing effect of rewarding stimuli.

Thirty-Day Readmission Rates Following Deep Brain Stimulation Surgery

BACKGROUND Deep brain stimulation (DBS) has emerged as a safe and efficacious surgical intervention for several movement disorders; however, the 30-day all-cause readmission rate associated with this procedure has not previously been documented. OBJECT To perform a retrospective cohort study to estimate the 30-day all-cause readmission rate associated with DBS. METHODS We reviewed medical records of patients over the age of 18 who underwent DBS surgery at Pennsylvania Hospital of the University of Pennsylvania between 2009 and 2014. We identified patients who were readmitted to an inpatient medical facility within 30 days from their initial discharge. RESULTS Over the study period, 23 (6.6%) of 347 DBS procedures resulted in a readmission to the hospital within 30 days. Causes of readmission were broadly categorized into surgery-related (3.7%): intracranial lead infection (0.6%), battery-site infection (0.6%), intracranial hematoma along the electrode tract (0.6%), battery-site hematoma (0.9%), and seizures (1.2%); and nonsurgery-related (2.9%): altered mental status (1.8%), nonsurgical-site infections (0.6%), malnutrition and poor wound healing (0.3%), and a pulse generator malfunction requiring reprogramming (0.3%). Readmissions could be predicted by the presence of medical comorbidities ( P < .001), but not by age, gender, or length of stay ( P s > .15). CONCLUSION All-cause 30-day readmission for DBS is 6.6%. This compares favorably to previously studied neurosurgical procedures. Readmissions frequently resulted from surgery-related complications, particularly infection, seizures, and hematomas, and were significantly associated with the presence of medical comorbidities ( P < .001).

Operative Strategies to Minimize Complications Following Resection of Pituitary Macroadenomas

Introduction We sought to identify factors associated with increased length of stay (LOS) and morbidity in patients undergoing resection of pituitary macroadenomas. Methods We reviewed records of 203 consecutive patients who underwent endoscopic endonasal resection of a pituitary macroadenoma (mean age = 55.7 [16‐88]) years, volume = 11.3 (1.0‐134.3) cm3. Complete resection was possible in 60/29.6% patients. Mean follow‐up was 575 days. Multivariate logistic regression was performed using MATLAB. Results Mean LOS was 4.67 (1‐66) days and was associated with CSF leak (p = 0.025), lumbar drain placement (p = 0.041; n = 8/3.9% intraoperative, n = 20/9.9% postoperative), and any infection (p = 0.066). Age, diabetes insipidus (n = 17/8.37%), and syndrome of inappropriate antidiuretic hormone secretion (n = 12/5.9%) were not associated with increased LOS (p > 0.2). Postoperative CSF leak in the hospital (n = 21/10.3%) was associated with intraoperative CSF leak (p = 0.002; n = 82/40.4%) and complete resection (p = 0.012). There was no significant association (p > 0.1) between postoperative CSF leak in the hospital following surgery and the use of a fat graft (n = 61/30.1%), nasoseptal flap (155/76.4%), or perioperative lumbar drain placement (n = 8/3.94%). Conclusion Complete resection is associated with increased risk of CSF leak and LOS. Operative strategies including placement of fat graft, nasoseptal flap, or intraoperative lumbar drain placement may have limited value in reducing the risk of postoperative CSF leak.