Methods for Isolating Extracellular Action Potentials and Removing Stimulus Artifacts from Microelectrode Recordings of Neurons Requiring Minimal Operator Intervention

Journal of Neuroscience Methods. May, 2005  |  Pubmed ID: 15848245

Recent successes in treating neurological disorders with electrical stimulation of the brain have spurred interest in studying the neuronal mechanisms by which such therapies work. However, microelectrode recordings can be confounded by stimulation artifact. Also, large microelectrode arrays now allow recording amounts of data that would otherwise overwhelm current analytic methods that depend heavily on human intervention and interpretation. A set of algorithms is described for automatically removing stimulus artifacts that minimize signal loss with minimum human involvement. Other algorithms automatically differentiate between the extracellular action potentials of individual neurons.

Pallidal Stimulation for Dystonia in Pantothenate Kinase-associated Neurodegeneration

Pediatric Neurology. Dec, 2007  |  Pubmed ID: 18021929

Patients with generalized dystonia secondary to pantothenate kinase-associated neurodegeneration are traditionally treated palliatively with medical therapy. Therapeutic advances include stereotactic basal ganglia ablative techniques and, more recently, pallidal deep-brain stimulation. We report the course of dystonia in a teenage male. Bilateral microelectrode-guided pallidal deep-brain stimulators were placed while the patient was awake. Three parasagittal microelectrodes were inserted simultaneously. Two anterior microelectrodes were relatively quiet. The posterior electrode demonstrated a pattern of frequent bursts with high-frequency activity. The stimulator was therefore placed in the posterior location, which resulted in symptomatic improvement. Pallidal deep-brain stimulation appears to create a functional correction that may alter globus pallidus internus inhibitory output to the motor thalamus. The prominent, noisy bursting patterns observed in the globus pallidus internus suggests that high-frequency stimulation may improve signs of dystonia by normalizing thalamic discharge patterns.

Microelectrode-guided Deep Brain Stimulation for Tourette Syndrome: Within-subject Comparison of Different Stimulation Sites

Stereotactic and Functional Neurosurgery. 2008  |  Pubmed ID: 18073521

As medical therapy for Tourette syndrome (TS) is ineffective in a small subset of patients, surgical interventions, including deep brain stimulation at various sites, have been developed in recent years.

From Symphony to Cacophony: Pathophysiology of the Human Basal Ganglia in Parkinson Disease

Neuroscience and Biobehavioral Reviews. 2008  |  Pubmed ID: 17466375

Despite remarkable advances, the relationship between abnormal neuronal activity and the clinical manifestations of Parkinson disease (PD) remains unclear. Numerous hypotheses have emerged to explain the relationship between neuronal activity and symptoms such as tremor, rigidity and akinesia. Among these are the antagonist balance hypothesis wherein increased firing rates in the indirect pathway inhibits movement; the selectivity hypothesis wherein loss of neuronal selectivity leads to an inability to select or initiate movements; the firing pattern hypothesis wherein increased oscillation and synchronization contribute to tremor and disrupt information flow; and the learning hypothesis, wherein the basal ganglia are conceived as playing an important role in learning sensory-motor associations which is disrupted by the loss of dopamine. Deep brain stimulation (DBS) surgery provides a unique opportunity to assess these different ideas since neuronal activity can be directly recorded from PD patients. The emerging data suggest that the pathophysiologic changes include derangements in the overall firing rates, decreased neuronal selectivity, and increased neuronal oscillation and synchronization. Thus, elements of all hypotheses are present, emphasizing that the loss of dopamine results in a profound and multifaceted disruption of normal information flow through the basal ganglia that ultimately leads to the signs and symptoms of PD.

Mechanisms of Action of Deep Brain Stimulation(DBS)

Neuroscience and Biobehavioral Reviews. 2008  |  Pubmed ID: 17706780

Deep brain stimulation (DBS) is remarkably effective for a range of neurological and psychiatric disorders that have failed pharmacological and cell transplant therapies. Clinical investigations are underway for a variety of other conditions. Yet, the therapeutic mechanisms of action are unknown. In addition, DBS research demonstrates the need to re-consider many hypotheses regarding basal ganglia physiology and pathophysiology such as the notion that increased activity in the globus pallidus internal segment is causal to Parkinson's disease symptoms. Studies reveal a variety of apparently discrepant results. At the least, it is unclear which DBS effects are therapeutically effective. This systematic review attempts to organize current DBS research into a series of unifying themes or issues such as whether the therapeutic effects are local or systems-wide or whether the effects are related to inhibition or excitation. A number of alternative hypotheses are offered for consideration including suppression of abnormal activity, striping basal ganglia output of misinformation, reduction of abnormal stochastic resonance effects due to increased noise in the disease state, and reinforcement of dynamic modulation of neuronal activity by resonance effects.

Subthalamic Nucleus Discharge Patterns During Movement in the Normal Monkey and Parkinsonian Patient

Brain Research. Mar, 2009  |  Pubmed ID: 19167367

The pathophysiology of Parkinson disease (PD) is characterized by derangements in the discharge rates, bursting patterns, and oscillatory activity of basal ganglia (BG) neurons. In this study, subthalamic nucleus (STN) neuronal activity patterns in humans with PD were compared with that in the normal monkey during performance of similar volitional movements. Single-unit STN recordings were collected while PD patients and animals moved a joystick in the direction of targets presented on a monitor. When discharge rates in all PD human and normal monkey neurons were compared, no significant differences were observed. However, when neurons were classified by peri-movement response type (i.e., excited, inhibited, or unresponsive to movement) statistical differences were demonstrated - most significantly among PD excited neurons. Analysis of burst activity demonstrated inter- and intra-burst activities were greater in the PD human compared to the monkey irrespective of neuronal response type. Moreover, simultaneously recorded neurons in the human demonstrated consistent oscillatory synchronization at restricted frequency bands, whereas synchronized oscillatory neurons in the monkey were not restricted to distinct frequencies. During movement, discharge and burst rates were positively correlated, independent of subject or neuronal response type; however, rates and oscillatory activity were more strongly correlated in the PD human than the normal monkey. Interestingly, across all domains of analysis, STN neurons in PD demonstrated reduced response variability when compared to STN neurons in the normal monkey brain. Thus, the net effect of PD may be a reduction in the physiological degrees of freedom of BG neurons with diminished information carrying capacity.

Risk Factors for Hemorrhage During Microelectrode-guided Deep Brain Stimulation and the Introduction of an Improved Microelectrode Design

Neurosurgery. Apr, 2009  |  Pubmed ID: 19349834

Hemorrhage is an infrequent but potentially devastating complication of deep brain stimulation (DBS) surgery. We examined the factors associated with hemorrhage after DBS surgery and evaluated a modified microelectrode design that may improve the safety of this procedure.

Heterogeneous Neuronal Firing Patterns During Interictal Epileptiform Discharges in the Human Cortex

Brain : a Journal of Neurology. Jun, 2010  |  Pubmed ID: 20511283

Epileptic cortex is characterized by paroxysmal electrical discharges. Analysis of these interictal discharges typically manifests as spike-wave complexes on electroencephalography, and plays a critical role in diagnosing and treating epilepsy. Despite their fundamental importance, little is known about the neurophysiological mechanisms generating these events in human focal epilepsy. Using three different systems of microelectrodes, we recorded local field potentials and single-unit action potentials during interictal discharges in patients with medically intractable focal epilepsy undergoing diagnostic workup for localization of seizure foci. We studied 336 single units in 20 patients. Ten different cortical areas and the hippocampus, including regions both inside and outside the seizure focus, were sampled. In three of these patients, high density microelectrode arrays simultaneously recorded between 43 and 166 single units from a small (4 mm x 4 mm) patch of cortex. We examined how the firing rates of individual neurons changed during interictal discharges by determining whether the firing rate during the event was the same, above or below a median baseline firing rate estimated from interictal discharge-free periods (Kruskal-Wallis one-way analysis, P<0.05). Only 48% of the recorded units showed such a modulation in firing rate within 500 ms of the discharge. Units modulated during the discharge exhibited significantly higher baseline firing and bursting rates than unmodulated units. As expected, many units (27% of the modulated population) showed an increase in firing rate during the fast segment of the discharge (+ or - 35 ms from the peak of the discharge), while 50% showed a decrease during the slow wave. Notably, in direct contrast to predictions based on models of a pure paroxysmal depolarizing shift, 7.7% of modulated units recorded in or near the seizure focus showed a decrease in activity well ahead (0-300 ms) of the discharge onset, while 12.2% of units increased in activity in this period. No such pre-discharge changes were seen in regions well outside the seizure focus. In many recordings there was also a decrease in broadband field potential activity during this same pre-discharge period. The different patterns of interictal discharge-modulated firing were classified into more than 15 different categories. This heterogeneity in single unit activity was present within small cortical regions as well as inside and outside the seizure onset zone, suggesting that interictal epileptiform activity in patients with epilepsy is not a simple paroxysm of hypersynchronous excitatory activity, but rather represents an interplay of multiple distinct neuronal types within complex neuronal networks.

System Identification of Local Field Potentials Under Deep Brain Stimulation in a Healthy Primate

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2010  |  Pubmed ID: 21096635

High frequency (HF) Deep Brain Stimulation (DBS) in the Sub-Thalamic Nucleus (STN) is a clinically recognized therapy for the treatment of motor disorders in Parkinson Disease (PD). The underlying mechanisms of DBS and how it impacts neighboring nuclei, however, are not yet completely understood. Electrophysiological data has been collected in PD patients and primates to better understand the impact of DBS on STN and the entire Basal Ganglia (BG) motor circuit. We use single unit recordings from Globus Pallidus, both pars interna and externa segments (GPi and GPe) in the BG, in a normal primate before and after DBS to reconstruct Local Field Potentials (LFPs) in the region. We then use system identification techniques to understand how GPe LFP activity and the DBS signal applied to STN influence GPi LFP activity. Our models suggest that when no stimulation is applied, the GPe LFPs have an inhibitory effect on GPi LFPs with a 2-3 ms delay, as is the case for single unit neuronal activity. On the other hand, when DBS is ON the models suggest that stimulation has a dominant effect on GPi LFPs which mask the inhibitory effects of GPe.

Point Process Models Show Temporal Dependencies of Basal Ganglia Nuclei Under Deep Brain Stimulation

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2010  |  Pubmed ID: 21096637

Deep Brain Stimulation (DBS) is an effective treatment for patients with Parkinsons disease, but its impact on basal ganglia nuclei is not fully understood. DBS applied to the subthalamic nucleus (STN) affects neurons in the Globus Pallidus pars interna (GPi) through direct projections, as well as indirectly through the Globus Pallidus pars externa (GPe). Since traditional statistical analyses of electrophysiological data provide too coarse a view of circuit dynamics, and mesoscopic biophysical dynamic models contain an intractable number of state variables for small populations of neurons, we apply a modular approach and treat each region in the STN-GPe-GPi circuit as a multi-input multi-output point process system. We use microelectrode recordings of a normal primate with DBS applied to STN at 100 and 130 Hz to estimate point process models (PPMs) for recorded regions in GPi. Our PPMs uncovered distinct dependencies between regions of GPe and GPi neurons, separated by the position of the GPi neurons, and showed normal refractory periods, inhibition from projecting neurons in the GPe, and DBS-induced oscillatory effects. The PPMs also showed the relative impact of the above factors, which traditional statistics fail to capture. Our PPM framework suggests a useful approach for understanding dynamics of complex neural circuits.

Basal Ganglia Neurons Dynamically Facilitate Exploration During Associative Learning

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Mar, 2011  |  Pubmed ID: 21451026

The basal ganglia (BG) appear to play a prominent role in associative learning, the process of pairing external stimuli with rewarding responses. Accumulating evidence suggests that the contributions of various BG components may be described within a reinforcement learning model, in which a broad repertoire of possible responses to environmental stimuli are evaluated before the most profitable one is chosen. The striatum receives diverse cortical inputs, providing a rich source of contextual information about environmental cues. It also receives projections from midbrain dopaminergic neurons, whose phasic activity reflects a reward prediction error signal. These coincident information streams are well suited for evaluating responses and biasing future actions toward the most profitable response. Still lacking in this model is a mechanistic description of how initial response variability is generated. To investigate this question, we recorded the activity of single neurons in the globus pallidus internus (GPi), the primary BG output nucleus, in nonhuman primates (Macaca mulatta) performing a motor associative learning task. A subset (29%) of GPi neurons showed learning-related effects, decreasing firing during the early stages of learning, then returning to higher baseline rates as associations were mastered. On a trial-by-trial basis, lower firing rates predicted exploratory behavior, whereas higher rates predicted an exploitive response. These results suggest that, during associative learning, BG output is initially permissive, allowing exploration of a variety of responses. Once a profitable response is identified, increased GPi activity suppresses alternative responses, sharpening the response profile and encouraging exploitation of the profitable learned behavior.

The Need for a Multifactorial Approach to Raise the Standard in Deep Brain Stimulation Reporting

Neuromodulation : Journal of the International Neuromodulation Society. Mar-Apr, 2011  |  Pubmed ID: 21992209

Modulations in the Oscillatory Activity of the Globus Pallidus Internus Neurons During a Behavioral Task-A Point Process Analysis

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. Aug, 2011  |  Pubmed ID: 22255260

The behavioral state of a subject is hypothesized to be reflected in the oscillatory modulations of the spiking activity of certain groups of neurons. In particular, the beta- and gamma-bands have been experimentally shown to be related to movement in the motor cortex and parts of the basal ganglia. Here, we analyze the relationship between directional tuning and oscillations in the beta- and gamma-bands of the neurons in the Globus Pallidus internus (GPi) of two healthy nonhuman primates during a radial center-out motor task. We find that, during the planning stages of the movement, the percentage of directionally tuned neurons displaying gamma oscillations increases when compared to the percentage of directionally tuned neurons displaying beta oscillations. A similar trend is not seen in non-directionally tuned neurons. This suggests that the GPi neurons involved in the planning of movement communicate information using an emergence of oscillations in the gamma-band.

Recombinant Adeno-associated Virus Type 2 Pseudotypes: Comparing Safety, Specificity, and Transduction Efficiency in the Primate Striatum. Laboratory Investigation

Journal of Neurosurgery. Mar, 2011  |  Pubmed ID: 20950087

Although several clinical trials utilizing the adeno-associated virus (AAV) type 2 serotype 2 (2/2) are now underway, it is unclear whether this particular serotype offers any advantage over others in terms of safety or efficiency when delivered directly to the CNS.