2017 International Conference on Intelligent Informatics and Biomedical Sciences (ICIIBMS)
Parkinson's disease is a neurodegenerative disorder with severe motor deficits such as bradyk... more Parkinson's disease is a neurodegenerative disorder with severe motor deficits such as bradykinesia, muscle rigidity, tremor at rest and abnormal posture. From neurophysiological perspective, the most prominent feature of Parkinsonian pathophysiology is enhanced beta-band power (1340 Hz beta oscillations) in the local field potentials (LFPs) in motor cortex and in several basal ganglia nuclei. Currently, the most effective treatment for advanced Parkinson's disease is the electrical deep brain stimulation (eDBS) targeting at the subthalamic nucleus or internal globus pallidus, in which electrical current at about 125 Hz is continuously injected in to the target area. Even though eDBS significantly alleviates motor symptoms of the disease, it does not provide a complete cure. Therefore, there have been ongoing efforts to develop more effective brain stimulation paradigms, e.g. exploration of alternative areas for stimulation, or employment of advanced stimulation paradigms. A major obstacle against these efforts has been the ambiguities associated with electrical stimulation. Due to nonspecific nature of electrical stimulation and its incompatibility with simultaneous electrophysiology, it has been challenging to fine tune stimulation parameters and target specific neuronal groups or circuits with eDBS. In this work, we demonstrate optogenetics-based brain stimulation as a potential alternative to electrical brain stimulation in the treatment of Parkinson's disease. Optogenetics, with its cellular specificity and compatibility with electrophysiology, offers unique opportunities to monitor the neural activity while modulating the activity of targeted neuronal populations. In our study, we address two important premises for assessment of an optogenetics-based therapeutic brain stimulation paradigm: (1) validation of therapeutic value of precisely targeted deep brain optogenetic modulation; (2) demonstration of potential benefits of spatiotemporally patterned optogenetic stimulation of the motor cortex by characterizing the spatiotemporal dynamics of pathological cortical beta-band activity. In 6-OHDA-induced hemi-Parkinsonian rat model, we used excitatory opsins (ChR2 and C1V1) or inhibitory opsins (iC1C2 and NpHR) to excite or inhibit the subthalamic nucleus. Neural activity across motor cortex was recorded with microelectrode arrays (MEAs, 400μm electrode pitch) implanted unilaterally (6×6 MEA) or bilaterally (two 5×5 MEAs) into the anterior forelimb area of motor cortices. Recording/stimulation sessions were performed during free behavior or during behavioral assays (e.g. amphetamine-induced rotation and mobility test) to quantify and compare therapeutic efficacies of optogenetic stimulation and eDBS. The spatiotemporal dynamics of LFPs were examined with spectral, correlation, and coherence analyses. Our data confirmed the motor deficits such as akinesia and rotational bias in h-P rats. eDBS of subthalamic nucleus improved these motor deficits to some extent, but not completely. In agreement with earlier findings (Gradinaru et al., Science, 2009), optogenetic excitation of subthalamic nucleus did not lead to behavioral improvements; by contrast we found that optogenetic inhibition of subthalamic did alleviate akinesia and rotational bias. Accompanying the motor deficits, elevated betaband power in LFPs was observed on the lesioned side of motor cortex. Interestingly, these beta oscillations appeared intermittently only at certain locations as distinct spatial activity patterns. A linear discriminant analysis showed that the beta band power at some recording sites was indistinguishable from control levels. However, further analysis indicated that these sites could be distinguished from control sites by their phase coherence. We found, within the lesioned motor cortex, excess phase coherence at the beta band between pairs of recording sites. The beta synchrony was not distributed uniformly; it was more pronounced between sites with higher beta power. Single-site optogenetic modulation of subthalamic nucleus led to behavioral improvements, but effects were limited as in eDBS. Our results show that optogenetics-based brain stimulation could be used as a therapeutic interference in Parkinson's disease. On the other hand, the variation of beta power and phase across motor cortex implied inhomogeneity in the extent of Parkinsonism, and hence, the potential therapeutic benefit of differential neuromodulation at different cortical sites. Therefore, given the anatomical and functional location of the motor cortex within motor circuitry and its large size, our results imply that spatiotemporally-specific optogenetic modulation of motor cortex might be a potential approach for therapeutic brain stimulation. Such modulation paradigm could allow more specific control of motor cortical activity, and thereby alleviate motor symptoms. Our next step is to investigate the therapeutic potential of spatiotemporally-specific…
Abstract INTRODUCTION The COVID-19 pandemic has caused unprecedented social, geopolitical, and he... more Abstract INTRODUCTION The COVID-19 pandemic has caused unprecedented social, geopolitical, and health systems factors that may affect types of patients presenting for essential, non-ambulatory care. Social distancing and lockdowns may reduce the incidence of trauma; however, a significant decline in presentations of acute medical conditions such as stroke and ACS have been reported. Furthermore, health system capacities are substantially altered, with elective surgeries postponed to devote resources to COVID-related illness and high acuity non-COVID illness. METHODS We reviewed all emergency department and inpatient consultations to the neurosurgical service at a Level 1 Trauma Center during an 8-week post-lockdown period (3/15-5/4), quantifying overall volume, as well the distribution of problem types and management endpoints. RESULTS Pandemic period consult volumes were significantly lower than those of parallel periods in 2016–2019 (388 vs. a 4-year average of 576, P < .001, Pearson's chi-squared test). Compared to 2016–2019, 2020 consult volume was decreased by 37% during the first four weeks following lockdown (204 vs. 280, P = .01), and by 48% during the latter four weeks (184 vs. 296, P < .001). Pandemic period consults required acute surgery in 21% of cases, non-acute or non-surgical management in 75%, and palliative management (CMO, hospice, death) in 4%. During the prior year (2019), these proportions were 15%, 80% and 5%, respectively (P = .06). The distribution of consult problem types was not statistically different between periods. Among cranial consults, trauma comprised 45% during the pandemic compared to 41% in the analogous 2019 period; tumor 20% vs 18%; vascular 16%; and ICH/stroke 8%. Among spinal consults, trauma comprised 47% vs 43%, tumor 6% vs 3%, and degenerative disc disease 29% vs 36%. CONCLUSION Neurosurgical consult volume increasingly declined throughout the post-lockdown COVID-19 pandemic period, which was unprecedented over the 5 years studied. A higher proportion of consults resulted in acute care surgery, approaching statistical significance. Surprisingly, problem types did not differ in the pandemic period despite vastly different social circumstances. Further study will employ time series analysis to contextualize these changes within local COVID-19 surge data.
Laser Interstitial Thermal Therapy in Neurosurgery, 2020
Functional lesions for the treatment of intractable, debilitating psychiatric disease have been c... more Functional lesions for the treatment of intractable, debilitating psychiatric disease have been created using a variety of techniques over many decades. Here, we describe the relative advantages and disadvantages of laser thermal lesions and the application of this technique to one particular disease, refractory and severe obsessive-compulsive disorder (OCD). Early experience suggests this approach will enable the creation of reliable and morphologically consistent lesions while avoiding some of the pitfalls and complications of other lesion modalities.
Creating successful new neuromodulation therapies requires innovative trial design and the balanc... more Creating successful new neuromodulation therapies requires innovative trial design and the balancing of a wide variety of complex factors. The ultimate goal is to advance our ability to restore appropriate brain function through the targeted manipulation of neural circuits and, to this end, clinical trials should be just as informative in failure as they are in success. Some aspects of neuromodulation trials are common to all clinical studies, while other aspects are fairly specific to invasive neurosurgical interventions for complex neurological and psychiatric disease. This chapter examines the major factors to be considered in constructing clinical studies to investigate the various forms and applications of novel neuromodulation strategies.
Introduction: Parkinson's disease (PD) is a progressive movement disorder characterized by hetero... more Introduction: Parkinson's disease (PD) is a progressive movement disorder characterized by heterogenous motor dysfunction with fluctuations in severity. Objective, short-timescale characterization of this dysfunction is necessary as therapies become increasingly adaptive. Objectives: This study aims to characterize a novel, naturalistic, and goal-directed tablet-based task and complementary analysis protocol designed to characterize the motor features of PD. Methods: A total of 26 patients with PD and without deep brain stimulation (DBS), 20 control subjects, and eight patients with PD and with DBS completed the task. Eight metrics, each designed to capture an aspect of motor dysfunction in PD, were calculated from 1-second, non-overlapping epochs of the raw positional and pressure data captured during task completion. These metrics were used to generate a classifier using a support vector machine (SVM) model to produce a unifying, scalar "motor error score" (MES). The data generated from these patients with PD were compared to same-day standard clinical assessments. Additionally, these data were compared to analogous data generated from a separate group of 12 patients with essential tremor (ET) to assess the task's specificity for different movement disorders. Finally, an SVM model was generated for each of the eight patients with PD and with DBS to differentiate between their motor dysfunction in the "DBS On" and "DBS Off" stimulation states. Results: The eight metrics calculated from the raw positional and force data captured during task completion were non-redundant. MES generated by the SVM analysis protocol showed a strong correlation with MDS-UPDRS-III scores assigned by movement disorder specialists. Analysis of the relative contributions of each of the eight metrics showed a significant difference between the motor dysfunction of PD and ET. Much of this difference was attributable to the homogenous, tremor-dominant phenotype Sanderson et al. Quantifying Movement Disorders on a Tablet of ET motor dysfunction. Finally, in individual patients with PD with DBS, task performance and subsequent SVM classification effectively differentiated between the "DBS On" and "DBS Off" stimulation states. Conclusion: This tablet-based task and analysis protocol correlated strongly with expert clinical assessments of PD motor dysfunction. Additionally, the task showed specificity for PD when compared to ET, another common movement disorder. This specificity was driven by the relative heterogeneity of motor dysfunction of PD compared to ET. Finally, the task was able to distinguish between the "DBS On" and "DBS Off" states within single patients with PD. This task provides temporally-precise and specific information about motor dysfunction in at least two movement disorders that could feasibly correlate to neural activity.
ABSTRACTTremor, a common and often primary symptom of Parkinson’s disease, has been modeled with ... more ABSTRACTTremor, a common and often primary symptom of Parkinson’s disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic correlates of each state, we acquired intraoperative cortical and subthalamic nucleus recordings from ten patients performing a naturalistic visual-motor task. From this task we isolated short epochs of tremor onset and sustained tremor. Comparing these epochs, we found that the subthalamic nucleus was central to tremor onset, as it drove both motor cortical activity and tremor output. Once tremor became sustained, control of tremor shifted to cortex. At the same time, changes in directed functional connectivity across sensorimotor cortex further distinguished the sustained tremor state.SIGNIFICANCE STATEMENTTremor is a common symptom of Parkinson’s disease (PD). While tremor pathophysiology is thought to involve both basal ganglia and cerebello-thalamic-cortical circuits, it is unknown how these structures functio...
Identifying neural activity biomarkers of brain disease is essential to provide objective estimat... more Identifying neural activity biomarkers of brain disease is essential to provide objective estimates of disease burden, obtain reliable feedback regarding therapeutic efficacy, and potentially to serve as a source of control for closed-loop neuromodulation. In Parkinson's Disease (PD), microelectrode recordings (MER) are routinely performed in the basal ganglia to guide electrode implantation for deep brain stimulation (DBS). While pathologically-excessive oscillatory activity has been observed and linked to PD motor dysfunction broadly, the extent to which these signals provide quantitative information about disease expression and fluctuations, particularly at short timescales, is unknown. Furthermore, the degree to which informative signal features are similar or different across patients has not been rigorously investigated. Here, we recorded neural activity from the subthalamic nucleus (STN) of patients with PD undergoing awake DBS surgery while they performed an objective, c...
learning modelling in conjunction with robust multivariate analysis of neuroimaging data to assoc... more learning modelling in conjunction with robust multivariate analysis of neuroimaging data to associate different algorithmic components of avoidance generalization with regional brain circuitry (sample one) and self-reported psychological symptom scores (sample two). Results: We found that generalization of avoidance could be parsed into perceptual and value-based processes, and further, that value-based generalization could be subdivided into that relating to aversive and neutral feedback-with corresponding circuitry including primary sensory cortex, anterior insula, and ventromedial prefrontal cortex, respectively (p0.029 precision-weighted multiple linear regression models, testing association between individual estimates of relevant model parameters and the cross-validated multivariate representational distance between conditioned stimuli and generalization stimuli in each brain region). Further, generalization from aversive, but not neutral, feedback was selectively associated with greater self-reported anxiety and intrusive thoughts (p¼0.008 precision-weighted multiple linear regression model, testing association between individual parameter estimates and factor analysisderived psychological symptom scores, corrected for age and gender identity). Conclusions: These results reveal a set of distinct mechanisms that mediate generalization in avoidance learning, and show how specific individual differences within them can yield anxiety.
Background: Can a single-dose of a testosterone-containing nasal spray reduce anxiety? Although b... more Background: Can a single-dose of a testosterone-containing nasal spray reduce anxiety? Although both exogenous and endogenous testosterone have been associated with reductions in implicitly measured fear responses, it remains unknown whether exogenous testosterone can reduce the explicit, subjective experience of anxiety in humans. Methods: In the present study, participants (N ¼ 104, 48.1% female) were randomly assigned to receive either testosterone or placebo via intranasal spray before taking part in an acute psychosocial stressor. Participants used visual analogue scales to rate their subjective anxiety before, during, and after the stressor. Results: Results revealed a statistically significant drug by sex interaction, in which womendas expecteddexperienced significantly higher levels of subjective anxiety in the placebo condition compared to men; a sex difference that was eliminated in the drug condition. Further, women randomized to the testosterone condition experienced significantly lower levels of anxiety during recovery from the acute stressor relatively to women in the placebo condition. Conclusions: Taken together, these results have important implications for the etiology of anxiety and treatment.
mortality in ECMO. Regional cerebral oxygen saturation (SrO 2) measured by near-infrared spectros... more mortality in ECMO. Regional cerebral oxygen saturation (SrO 2) measured by near-infrared spectroscopy could be a useful technology to identify those at risk for brain injury. We describe the interpretation of SrO 2 that best indicates brain injury. METHODS: We performed a single-institution, prospective, observational analysis of ECMO patients receiving near-infrared spectroscopy monitoring between June 2018 and January 2019. Near-infrared spectroscopy was analyzed for SrO 2 <40%, and SrO 2 drop 25% from baseline. Coma (defined as Glascow Coma Scale score <8) was used to determine presence of brain injury. RESULTS: Of the 24 patients (57 years old, 54% female) with median of 9 days of ECMO support (range 2 to 16 days); 17 (71%) were comatose. The median SrO 2 was 48.3 in coma vs 49.1 without coma (p ¼ 0.848). Those with a 25% drop in SrO 2 had higher APACHE II scores (30 vs 21; p ¼ 0.002), and incidence of coma (87% vs 20%; p ¼ 0.024) compared with those without. Demographics, medical history, Sequential Organ Failure Assessment, number of transfusions, and mortality were not significantly different. An SrO 2 <40 was not significantly associated with outcomes. Logistic models demonstrated that a 25% drop in SrO 2 was associated with a 57% increase in coma, and median SrO 2 , SrO 2 <40, and difference in left and right SrO 2 were not associated with increased outcomes (Figure).
The ability to link effects with their causes is fundamental to learning. If the causal feature d... more The ability to link effects with their causes is fundamental to learning. If the causal feature does not present when an outcome delivers or presents intermingled with distractors, then how neural learning process can link between the causal features and behavioral outcomes and how identify the causal feature among distractors? It is the credit assignments problem and it is a crucial factor to survive an organism successfully. We trained two monkeys to perform a credit assignment (CA) task in which they learned to attribute a choice outcome to one of several earlier options. The particular option, a visual cue, that deserved credit varied across different blocks of trials. Performance on this task was compared to a simple delayedmatch-to-sample (DMS) task in which no credit assignment was necessary to perform subsequent trials correctly. We implanted large arrays of independently-moveable electrodes over the lateral prefrontal cortex in each animal (96 electrodes in one, 128 in the other). We observed differences in neuronal population activity between early (initial learning) and late (well-learned) trials in the CA task, and these differences varied according to the region of the lateral prefrontal cortex. Furthermore, we observed differences between the CA and DMS tasks, particularly with respect to "ramping" activity at the end of the delay period prior to the choice. This ramping activity also varied topographically across the prefrontal cortex.
INTRODUCTION Recent research has demonstrated improved outcomes for trauma patients at higher vol... more INTRODUCTION Recent research has demonstrated improved outcomes for trauma patients at higher volume institutions. However, the volume-outcome relationship for severe pediatric traumatic brain injury (TBI) patients, specifically, has yet to be demonstrated. METHODS We isolated all severe pediatric TBI admissions (GCS admission score 3-8) to pediatric American College of Surgeons (ACS) level 1 and 2 trauma centers in the 2012 National Trauma Data Bank. Pediatric TBI volume was analyzed on a continuous scale as the primary independent variable. Our outcome variables were mortality, hospital discharge disposition (home, rehab/other care facility, died/hospice), presence of complications (deep vein thrombosis [DVT], cardiac arrest, cerebrovascular accident, acute respiratory distress syndrome [ARDS], urinary tract infection [UTI], pneumonia), length of stay (LOS), and intensive care unit (ICU) days. We utilized multivariate analyses to adjust for the following confounding variables: inj...
Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a pro... more Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4–10 Hz rhythmic movement. The presence of tremor frequency oscillations (TFOs) in the ventral intermediate nucleus of the thalamus (VIM) is well-established, but it is often assumed that it is driven by cerebellar tremor frequency activity, while the role of intrinsic oscillatory activity in VIM is not clear. An improved understanding of the mechanisms of tremor and non-tremor frequency activity in VIM is critical to the development of improved pharmacological and neuromodulatory therapies. Starting from a canonical model of thalamus, we developed a biophysically-principled computational model of tremor field activity in the VIM, coupled with the thalamic reticular nucleus (TRN). We simulated TFOs in the model generated either by extrinsic tremor-periodic drive or intrinsic VIM-TRN interaction to understand whether these networks exhibited distinct biophysical proper...
2017 International Conference on Intelligent Informatics and Biomedical Sciences (ICIIBMS)
Parkinson's disease is a neurodegenerative disorder with severe motor deficits such as bradyk... more Parkinson's disease is a neurodegenerative disorder with severe motor deficits such as bradykinesia, muscle rigidity, tremor at rest and abnormal posture. From neurophysiological perspective, the most prominent feature of Parkinsonian pathophysiology is enhanced beta-band power (1340 Hz beta oscillations) in the local field potentials (LFPs) in motor cortex and in several basal ganglia nuclei. Currently, the most effective treatment for advanced Parkinson's disease is the electrical deep brain stimulation (eDBS) targeting at the subthalamic nucleus or internal globus pallidus, in which electrical current at about 125 Hz is continuously injected in to the target area. Even though eDBS significantly alleviates motor symptoms of the disease, it does not provide a complete cure. Therefore, there have been ongoing efforts to develop more effective brain stimulation paradigms, e.g. exploration of alternative areas for stimulation, or employment of advanced stimulation paradigms. A major obstacle against these efforts has been the ambiguities associated with electrical stimulation. Due to nonspecific nature of electrical stimulation and its incompatibility with simultaneous electrophysiology, it has been challenging to fine tune stimulation parameters and target specific neuronal groups or circuits with eDBS. In this work, we demonstrate optogenetics-based brain stimulation as a potential alternative to electrical brain stimulation in the treatment of Parkinson's disease. Optogenetics, with its cellular specificity and compatibility with electrophysiology, offers unique opportunities to monitor the neural activity while modulating the activity of targeted neuronal populations. In our study, we address two important premises for assessment of an optogenetics-based therapeutic brain stimulation paradigm: (1) validation of therapeutic value of precisely targeted deep brain optogenetic modulation; (2) demonstration of potential benefits of spatiotemporally patterned optogenetic stimulation of the motor cortex by characterizing the spatiotemporal dynamics of pathological cortical beta-band activity. In 6-OHDA-induced hemi-Parkinsonian rat model, we used excitatory opsins (ChR2 and C1V1) or inhibitory opsins (iC1C2 and NpHR) to excite or inhibit the subthalamic nucleus. Neural activity across motor cortex was recorded with microelectrode arrays (MEAs, 400μm electrode pitch) implanted unilaterally (6×6 MEA) or bilaterally (two 5×5 MEAs) into the anterior forelimb area of motor cortices. Recording/stimulation sessions were performed during free behavior or during behavioral assays (e.g. amphetamine-induced rotation and mobility test) to quantify and compare therapeutic efficacies of optogenetic stimulation and eDBS. The spatiotemporal dynamics of LFPs were examined with spectral, correlation, and coherence analyses. Our data confirmed the motor deficits such as akinesia and rotational bias in h-P rats. eDBS of subthalamic nucleus improved these motor deficits to some extent, but not completely. In agreement with earlier findings (Gradinaru et al., Science, 2009), optogenetic excitation of subthalamic nucleus did not lead to behavioral improvements; by contrast we found that optogenetic inhibition of subthalamic did alleviate akinesia and rotational bias. Accompanying the motor deficits, elevated betaband power in LFPs was observed on the lesioned side of motor cortex. Interestingly, these beta oscillations appeared intermittently only at certain locations as distinct spatial activity patterns. A linear discriminant analysis showed that the beta band power at some recording sites was indistinguishable from control levels. However, further analysis indicated that these sites could be distinguished from control sites by their phase coherence. We found, within the lesioned motor cortex, excess phase coherence at the beta band between pairs of recording sites. The beta synchrony was not distributed uniformly; it was more pronounced between sites with higher beta power. Single-site optogenetic modulation of subthalamic nucleus led to behavioral improvements, but effects were limited as in eDBS. Our results show that optogenetics-based brain stimulation could be used as a therapeutic interference in Parkinson's disease. On the other hand, the variation of beta power and phase across motor cortex implied inhomogeneity in the extent of Parkinsonism, and hence, the potential therapeutic benefit of differential neuromodulation at different cortical sites. Therefore, given the anatomical and functional location of the motor cortex within motor circuitry and its large size, our results imply that spatiotemporally-specific optogenetic modulation of motor cortex might be a potential approach for therapeutic brain stimulation. Such modulation paradigm could allow more specific control of motor cortical activity, and thereby alleviate motor symptoms. Our next step is to investigate the therapeutic potential of spatiotemporally-specific…
Abstract INTRODUCTION The COVID-19 pandemic has caused unprecedented social, geopolitical, and he... more Abstract INTRODUCTION The COVID-19 pandemic has caused unprecedented social, geopolitical, and health systems factors that may affect types of patients presenting for essential, non-ambulatory care. Social distancing and lockdowns may reduce the incidence of trauma; however, a significant decline in presentations of acute medical conditions such as stroke and ACS have been reported. Furthermore, health system capacities are substantially altered, with elective surgeries postponed to devote resources to COVID-related illness and high acuity non-COVID illness. METHODS We reviewed all emergency department and inpatient consultations to the neurosurgical service at a Level 1 Trauma Center during an 8-week post-lockdown period (3/15-5/4), quantifying overall volume, as well the distribution of problem types and management endpoints. RESULTS Pandemic period consult volumes were significantly lower than those of parallel periods in 2016–2019 (388 vs. a 4-year average of 576, P < .001, Pearson's chi-squared test). Compared to 2016–2019, 2020 consult volume was decreased by 37% during the first four weeks following lockdown (204 vs. 280, P = .01), and by 48% during the latter four weeks (184 vs. 296, P < .001). Pandemic period consults required acute surgery in 21% of cases, non-acute or non-surgical management in 75%, and palliative management (CMO, hospice, death) in 4%. During the prior year (2019), these proportions were 15%, 80% and 5%, respectively (P = .06). The distribution of consult problem types was not statistically different between periods. Among cranial consults, trauma comprised 45% during the pandemic compared to 41% in the analogous 2019 period; tumor 20% vs 18%; vascular 16%; and ICH/stroke 8%. Among spinal consults, trauma comprised 47% vs 43%, tumor 6% vs 3%, and degenerative disc disease 29% vs 36%. CONCLUSION Neurosurgical consult volume increasingly declined throughout the post-lockdown COVID-19 pandemic period, which was unprecedented over the 5 years studied. A higher proportion of consults resulted in acute care surgery, approaching statistical significance. Surprisingly, problem types did not differ in the pandemic period despite vastly different social circumstances. Further study will employ time series analysis to contextualize these changes within local COVID-19 surge data.
Laser Interstitial Thermal Therapy in Neurosurgery, 2020
Functional lesions for the treatment of intractable, debilitating psychiatric disease have been c... more Functional lesions for the treatment of intractable, debilitating psychiatric disease have been created using a variety of techniques over many decades. Here, we describe the relative advantages and disadvantages of laser thermal lesions and the application of this technique to one particular disease, refractory and severe obsessive-compulsive disorder (OCD). Early experience suggests this approach will enable the creation of reliable and morphologically consistent lesions while avoiding some of the pitfalls and complications of other lesion modalities.
Creating successful new neuromodulation therapies requires innovative trial design and the balanc... more Creating successful new neuromodulation therapies requires innovative trial design and the balancing of a wide variety of complex factors. The ultimate goal is to advance our ability to restore appropriate brain function through the targeted manipulation of neural circuits and, to this end, clinical trials should be just as informative in failure as they are in success. Some aspects of neuromodulation trials are common to all clinical studies, while other aspects are fairly specific to invasive neurosurgical interventions for complex neurological and psychiatric disease. This chapter examines the major factors to be considered in constructing clinical studies to investigate the various forms and applications of novel neuromodulation strategies.
Introduction: Parkinson's disease (PD) is a progressive movement disorder characterized by hetero... more Introduction: Parkinson's disease (PD) is a progressive movement disorder characterized by heterogenous motor dysfunction with fluctuations in severity. Objective, short-timescale characterization of this dysfunction is necessary as therapies become increasingly adaptive. Objectives: This study aims to characterize a novel, naturalistic, and goal-directed tablet-based task and complementary analysis protocol designed to characterize the motor features of PD. Methods: A total of 26 patients with PD and without deep brain stimulation (DBS), 20 control subjects, and eight patients with PD and with DBS completed the task. Eight metrics, each designed to capture an aspect of motor dysfunction in PD, were calculated from 1-second, non-overlapping epochs of the raw positional and pressure data captured during task completion. These metrics were used to generate a classifier using a support vector machine (SVM) model to produce a unifying, scalar "motor error score" (MES). The data generated from these patients with PD were compared to same-day standard clinical assessments. Additionally, these data were compared to analogous data generated from a separate group of 12 patients with essential tremor (ET) to assess the task's specificity for different movement disorders. Finally, an SVM model was generated for each of the eight patients with PD and with DBS to differentiate between their motor dysfunction in the "DBS On" and "DBS Off" stimulation states. Results: The eight metrics calculated from the raw positional and force data captured during task completion were non-redundant. MES generated by the SVM analysis protocol showed a strong correlation with MDS-UPDRS-III scores assigned by movement disorder specialists. Analysis of the relative contributions of each of the eight metrics showed a significant difference between the motor dysfunction of PD and ET. Much of this difference was attributable to the homogenous, tremor-dominant phenotype Sanderson et al. Quantifying Movement Disorders on a Tablet of ET motor dysfunction. Finally, in individual patients with PD with DBS, task performance and subsequent SVM classification effectively differentiated between the "DBS On" and "DBS Off" stimulation states. Conclusion: This tablet-based task and analysis protocol correlated strongly with expert clinical assessments of PD motor dysfunction. Additionally, the task showed specificity for PD when compared to ET, another common movement disorder. This specificity was driven by the relative heterogeneity of motor dysfunction of PD compared to ET. Finally, the task was able to distinguish between the "DBS On" and "DBS Off" states within single patients with PD. This task provides temporally-precise and specific information about motor dysfunction in at least two movement disorders that could feasibly correlate to neural activity.
ABSTRACTTremor, a common and often primary symptom of Parkinson’s disease, has been modeled with ... more ABSTRACTTremor, a common and often primary symptom of Parkinson’s disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic correlates of each state, we acquired intraoperative cortical and subthalamic nucleus recordings from ten patients performing a naturalistic visual-motor task. From this task we isolated short epochs of tremor onset and sustained tremor. Comparing these epochs, we found that the subthalamic nucleus was central to tremor onset, as it drove both motor cortical activity and tremor output. Once tremor became sustained, control of tremor shifted to cortex. At the same time, changes in directed functional connectivity across sensorimotor cortex further distinguished the sustained tremor state.SIGNIFICANCE STATEMENTTremor is a common symptom of Parkinson’s disease (PD). While tremor pathophysiology is thought to involve both basal ganglia and cerebello-thalamic-cortical circuits, it is unknown how these structures functio...
Identifying neural activity biomarkers of brain disease is essential to provide objective estimat... more Identifying neural activity biomarkers of brain disease is essential to provide objective estimates of disease burden, obtain reliable feedback regarding therapeutic efficacy, and potentially to serve as a source of control for closed-loop neuromodulation. In Parkinson's Disease (PD), microelectrode recordings (MER) are routinely performed in the basal ganglia to guide electrode implantation for deep brain stimulation (DBS). While pathologically-excessive oscillatory activity has been observed and linked to PD motor dysfunction broadly, the extent to which these signals provide quantitative information about disease expression and fluctuations, particularly at short timescales, is unknown. Furthermore, the degree to which informative signal features are similar or different across patients has not been rigorously investigated. Here, we recorded neural activity from the subthalamic nucleus (STN) of patients with PD undergoing awake DBS surgery while they performed an objective, c...
learning modelling in conjunction with robust multivariate analysis of neuroimaging data to assoc... more learning modelling in conjunction with robust multivariate analysis of neuroimaging data to associate different algorithmic components of avoidance generalization with regional brain circuitry (sample one) and self-reported psychological symptom scores (sample two). Results: We found that generalization of avoidance could be parsed into perceptual and value-based processes, and further, that value-based generalization could be subdivided into that relating to aversive and neutral feedback-with corresponding circuitry including primary sensory cortex, anterior insula, and ventromedial prefrontal cortex, respectively (p0.029 precision-weighted multiple linear regression models, testing association between individual estimates of relevant model parameters and the cross-validated multivariate representational distance between conditioned stimuli and generalization stimuli in each brain region). Further, generalization from aversive, but not neutral, feedback was selectively associated with greater self-reported anxiety and intrusive thoughts (p¼0.008 precision-weighted multiple linear regression model, testing association between individual parameter estimates and factor analysisderived psychological symptom scores, corrected for age and gender identity). Conclusions: These results reveal a set of distinct mechanisms that mediate generalization in avoidance learning, and show how specific individual differences within them can yield anxiety.
Background: Can a single-dose of a testosterone-containing nasal spray reduce anxiety? Although b... more Background: Can a single-dose of a testosterone-containing nasal spray reduce anxiety? Although both exogenous and endogenous testosterone have been associated with reductions in implicitly measured fear responses, it remains unknown whether exogenous testosterone can reduce the explicit, subjective experience of anxiety in humans. Methods: In the present study, participants (N ¼ 104, 48.1% female) were randomly assigned to receive either testosterone or placebo via intranasal spray before taking part in an acute psychosocial stressor. Participants used visual analogue scales to rate their subjective anxiety before, during, and after the stressor. Results: Results revealed a statistically significant drug by sex interaction, in which womendas expecteddexperienced significantly higher levels of subjective anxiety in the placebo condition compared to men; a sex difference that was eliminated in the drug condition. Further, women randomized to the testosterone condition experienced significantly lower levels of anxiety during recovery from the acute stressor relatively to women in the placebo condition. Conclusions: Taken together, these results have important implications for the etiology of anxiety and treatment.
mortality in ECMO. Regional cerebral oxygen saturation (SrO 2) measured by near-infrared spectros... more mortality in ECMO. Regional cerebral oxygen saturation (SrO 2) measured by near-infrared spectroscopy could be a useful technology to identify those at risk for brain injury. We describe the interpretation of SrO 2 that best indicates brain injury. METHODS: We performed a single-institution, prospective, observational analysis of ECMO patients receiving near-infrared spectroscopy monitoring between June 2018 and January 2019. Near-infrared spectroscopy was analyzed for SrO 2 <40%, and SrO 2 drop 25% from baseline. Coma (defined as Glascow Coma Scale score <8) was used to determine presence of brain injury. RESULTS: Of the 24 patients (57 years old, 54% female) with median of 9 days of ECMO support (range 2 to 16 days); 17 (71%) were comatose. The median SrO 2 was 48.3 in coma vs 49.1 without coma (p ¼ 0.848). Those with a 25% drop in SrO 2 had higher APACHE II scores (30 vs 21; p ¼ 0.002), and incidence of coma (87% vs 20%; p ¼ 0.024) compared with those without. Demographics, medical history, Sequential Organ Failure Assessment, number of transfusions, and mortality were not significantly different. An SrO 2 <40 was not significantly associated with outcomes. Logistic models demonstrated that a 25% drop in SrO 2 was associated with a 57% increase in coma, and median SrO 2 , SrO 2 <40, and difference in left and right SrO 2 were not associated with increased outcomes (Figure).
The ability to link effects with their causes is fundamental to learning. If the causal feature d... more The ability to link effects with their causes is fundamental to learning. If the causal feature does not present when an outcome delivers or presents intermingled with distractors, then how neural learning process can link between the causal features and behavioral outcomes and how identify the causal feature among distractors? It is the credit assignments problem and it is a crucial factor to survive an organism successfully. We trained two monkeys to perform a credit assignment (CA) task in which they learned to attribute a choice outcome to one of several earlier options. The particular option, a visual cue, that deserved credit varied across different blocks of trials. Performance on this task was compared to a simple delayedmatch-to-sample (DMS) task in which no credit assignment was necessary to perform subsequent trials correctly. We implanted large arrays of independently-moveable electrodes over the lateral prefrontal cortex in each animal (96 electrodes in one, 128 in the other). We observed differences in neuronal population activity between early (initial learning) and late (well-learned) trials in the CA task, and these differences varied according to the region of the lateral prefrontal cortex. Furthermore, we observed differences between the CA and DMS tasks, particularly with respect to "ramping" activity at the end of the delay period prior to the choice. This ramping activity also varied topographically across the prefrontal cortex.
INTRODUCTION Recent research has demonstrated improved outcomes for trauma patients at higher vol... more INTRODUCTION Recent research has demonstrated improved outcomes for trauma patients at higher volume institutions. However, the volume-outcome relationship for severe pediatric traumatic brain injury (TBI) patients, specifically, has yet to be demonstrated. METHODS We isolated all severe pediatric TBI admissions (GCS admission score 3-8) to pediatric American College of Surgeons (ACS) level 1 and 2 trauma centers in the 2012 National Trauma Data Bank. Pediatric TBI volume was analyzed on a continuous scale as the primary independent variable. Our outcome variables were mortality, hospital discharge disposition (home, rehab/other care facility, died/hospice), presence of complications (deep vein thrombosis [DVT], cardiac arrest, cerebrovascular accident, acute respiratory distress syndrome [ARDS], urinary tract infection [UTI], pneumonia), length of stay (LOS), and intensive care unit (ICU) days. We utilized multivariate analyses to adjust for the following confounding variables: inj...
Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a pro... more Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4–10 Hz rhythmic movement. The presence of tremor frequency oscillations (TFOs) in the ventral intermediate nucleus of the thalamus (VIM) is well-established, but it is often assumed that it is driven by cerebellar tremor frequency activity, while the role of intrinsic oscillatory activity in VIM is not clear. An improved understanding of the mechanisms of tremor and non-tremor frequency activity in VIM is critical to the development of improved pharmacological and neuromodulatory therapies. Starting from a canonical model of thalamus, we developed a biophysically-principled computational model of tremor field activity in the VIM, coupled with the thalamic reticular nucleus (TRN). We simulated TFOs in the model generated either by extrinsic tremor-periodic drive or intrinsic VIM-TRN interaction to understand whether these networks exhibited distinct biophysical proper...
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Papers by Wael Asaad