Efstathios Kondylis

Network Effects of Deep Brain Stimulation

The ability to differentially alter specific brain functions via deep brain stimulation (DBS) represents a monumental advance in clinical neuroscience, as well as within medicine as a whole. Despite the efficacy of DBS in the treatment of movement disorders, for which it is often the gold-standard therapy when medical management becomes inadequate, the mechanisms through which DBS in various brain targets produces therapeutic effects is still not well understood. This limited knowledge is a barrier to improving efficacy and reducing side effects in clinical brain stimulation. A field of study related to assessing the network effects of DBS is gradually emerging that promises to reveal aspects of the underlying pathophysiology of various brain disorders and their response to DBS that will be critical to advancing the field. This review summarizes the nascent literature related to network effects of DBS measured by cerebral blood flow and metabolic imaging, functional imaging, and electrophysiology (scalp and intracranial electroencephalography and magnetoencephalography) in order to establish a framework for future studies.

Movement-related dynamics of cortical oscillations in Parkinson’s disease and essential tremor

Recent electrocorticography data have demonstrated excessive coupling of beta-phase to gamma-amplitude in primary motor cortex and that deep brain stimulation facilitates motor improvement by decreasing baseline phase-amplitude coupling. However, both the dynamic modulation of phase-amplitude coupling during movement and the general cortical neurophysiology of other movement disorders, such as essential tremor, are relatively unexplored. To clarify the relationship of these interactions in cortical oscillatory activity to movement and disease state, we recorded local field potentials from hand sensorimotor cortex using subdural electrocorticography during a visually cued, incentivized handgrip task in subjects with Parkinsons disease (n = 11), with essential tremor (n = 9) and without a movement disorder (n = 6). We demonstrate that abnormal coupling of the phase of low frequency oscillations to the amplitude of gamma oscillations is not specific to Parkinsons disease, but also occurs in essential tremor, most prominently for the coupling of alpha to gamma oscillations. Movement kinematics were not significantly different between these groups, allowing us to show for the first time that robust alpha and beta desynchronization is a shared feature of sensorimotor cortical activity in Parkinsons disease and essential tremor, with the greatest high-beta desynchronization occurring in Parkinsons disease and the greatest alpha desynchronization occurring in essential tremor. We also show that the spatial extent of cortical phase-amplitude decoupling during movement is much greater in subjects with Parkinsons disease and essential tremor than in subjects without a movement disorder. These findings suggest that subjects with Parkinsons disease and essential tremor can produce movements that are kinematically similar to those of subjects without a movement disorder by reducing excess sensorimotor cortical phase-amplitude coupling that is characteristic of these diseases.

Three-dimensional localization of cortical electrodes in deep brain stimulation surgery from intraoperative fluoroscopy

Electrophysiological recordings from subdural electrocorticography (ECoG) electrodes implanted temporarily during deep brain stimulation (DBS) surgeries offer a unique opportunity to record cortical activity for research purposes. The optimal utilization of this important research method relies on accurate and robust localization of ECoG electrodes, and intraoperative fluoroscopy is often the only imaging modality available to visualize electrode locations. However, the localization of a three-dimensional electrode position using a two-dimensional fluoroscopic image is problematic due to the lost dimension orthogonal to the fluoroscopic image, a parallax distortion implicit to fluoroscopy, and variability of visible skull contour among fluoroscopic images. Here, we present a method to project electrodes visible on the fluoroscopic image onto a reconstructed cortical surface by leveraging numerous common landmarks to translate, rotate, and scale coregistered computed tomography (CT) and magnetic resonance imaging (MRI) reconstructed surfaces in order to recreate the coordinate framework in which the fluoroscopic image was acquired, while accounting for parallax distortion. Validation of this approach demonstrated high precision with an average total Euclidian distance between three independent reviewers of 1.65±0.68mm across 8 patients and 82 electrodes. Spatial accuracy was confirmed by correspondence between recorded neural activity over sensorimotor cortex during hand movement. This semi-automated interface reliably estimates the location of temporarily implanted subdural ECoG electrodes visible on intraoperative fluoroscopy to a cortical surface.

Detection of high-frequency oscillations by hybrid depth electrodes in standard clinical intracranial EEG recordings.

High-frequency oscillations (HFOs) have been proposed as a novel marker for epileptogenic tissue, spurring tremendous research interest into the characterization of these transient events. A wealth of continuously recorded intracranial electroencephalographic (iEEG) data is currently available from patients undergoing invasive monitoring for the surgical treatment of epilepsy. In contrast to data recorded on research-customized recording systems, data from clinical acquisition systems remain an underutilized resource for HFO detection in most centers. The effective and reliable use of this clinically obtained data would be an important advance in the ongoing study of HFOs and their relationship to ictogenesis. The diagnostic utility of HFOs ultimately will be limited by the ability of clinicians to detect these brief, sporadic, and low amplitude events in an electrically noisy clinical environment. Indeed, one of the most significant factors limiting the use of such clinical recordings for research purposes is their low signal to noise ratio, especially in the higher frequency bands. In order to investigate the presence of HFOs in clinical data, we first obtained continuous intracranial recordings in a typical clinical environment using a commercially available, commonly utilized data acquisition system and “off the shelf” hybrid macro-/micro-depth electrodes. These data were then inspected for the presence of HFOs using semi-automated methods and expert manual review. With targeted removal of noise frequency content, HFOs were detected on both macro- and micro-contacts, and preferentially localized to seizure onset zones. HFOs detected by the offline, semi-automated method were also validated in the clinical viewer, demonstrating that (1) this clinical system allows for the visualization of HFOs and (2) with effective signal processing, clinical recordings can yield valuable information for offline analysis.

Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement

Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinsons disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate.NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also demonstrate, for the first time in humans, a mechanism through which the premotor and sensory cortices are functionally connected to the STN.

Effects of hippocampal low-frequency stimulation in idiopathic non-human primate epilepsy assessed via a remote-sensing-enabled neurostimulator.

&NA; Individuals with pharmacoresistant epilepsy remain a large and under‐treated patient population. Continued technologic advancements in implantable neurostimulators have spurred considerable research efforts directed towards the development of novel antiepileptic stimulation therapies. However, the lack of adequate preclinical experimental platforms has precluded a detailed understanding of the differential effects of stimulation parameters on neuronal activity within seizure networks. In order to chronically monitor seizures and the effects of stimulation in a freely‐behaving non‐human primate with idiopathic epilepsy, we employed a novel simultaneous video‐intracranial EEG recording platform using a state‐of‐the‐art sensing‐enabled, rechargeable clinical neurostimulator with real‐time seizure detection and wireless data streaming capabilities. Using this platform, we were able to characterize the electrographic and semiologic features of the focal‐onset, secondarily generalizing tonic‐clonic seizures stably expressed in this animal. A series of acute experiments exploring low‐frequency (2 Hz) hippocampal stimulation identified a pulse width (150 &mgr;s) and current amplitude (4 mA) combination which maximally suppressed local hippocampal activity. These optimized stimulation parameters were then delivered to the seizure onset‐side hippocampus in a series of chronic experiments. This long‐term testing revealed that the suppressive effects of low‐frequency hippocampal stimulation 1) diminish when delivered continuously but are maintained when stimulation is cycled on and off, 2) are dependent on circadian rhythms, and 3) do not necessarily confer seizure protective effects. HighlightsA novel video‐intracranial EEG implantable telemetry recording system is described.Spontaneous seizures in a primate with idiopathic epilepsy are characterized.Parameter dependent effects of low‐frequency hippocampal stimulation are explored.Factors affecting chronic stimulation effects are modeled using multiple regression.

High frequency activation data used to validate localization of cortical electrodes during surgery for deep brain stimulation

Movement related synchronization of high frequency activity (HFA, 76–100 Hz) is a somatotopic process with spectral power changes occurring during movement in the sensorimotor cortex (Miller et al., 2007) [1]. These features allowed movement-related changes in HFA to be used to functionally validate the estimations of subdural electrode locations, which may be placed temporarily for research in deep brain stimulation surgery, using the novel tool described in Randazzo et al. (2015) [2]. We recorded electrocorticography (ECoG) signals and localized electrodes in the region of the sensorimotor cortex during an externally cued hand grip task in 8 subjects. Movement related HFA was determined for each trial by comparing HFA spectral power during movement epochs to pre-movement baseline epochs. Significant movement related HFA was found to be focal in time and space, occurring only during movement and only in a subset of electrodes localized to the pre- and post-central gyri near the hand knob. To further demonstrate the use of movement related HFA to aid electrode localization, we provide a sample of the electrode localization tool, with data loaded to allow readers to map movement related HFA onto the cortical surface of a sample patient.

Sensorimotor cortical-subthalamic network dynamics during force generation

The subthalamic nucleus (STN) is proposed to participate in pausing, or alternately, in dynamic scaling of behavioral responses, roles that have conflicting implications for understanding STN function in the context of deep brain stimulation (DBS) therapy. To examine the nature of event-related STN activity and subthalamic-cortical dynamics, we performed primary motor and somatosensory electrocorticography while subjects (n=10) performed a grip force task during DBS implantation surgery. The results provide the first evidence from humans that STN gamma activity can predict activity in the cortex both prior to and during movement, consistent with the idea that the STN participates in both motor planning and execution. We observed that STN activity appeared to facilitate movement: while both movement onset and termination both coincided with STN-cortical phase-locking, narrow-band gamma power was positively correlated with grip force, and event-related causality measures demonstrated that STN gamma activity predicted cortical gamma activity during movement. STN participation in somatosensory integration also was demonstrated by casual analysis. Information flow from the STN to somatosensory cortex was observed for both beta and gamma range frequencies, specific to particular movement periods and kinematics. Interactions in beta activity between the STN and somatosensory cortex, rather than motor cortex, predicted PD symptom severity. Thus, the STN contributes to multiple aspects of sensorimotor behavior dynamically across time.

209 Movement-Related Dynamics of Beta Band Causal Interactions Between Subthalamic Nucleus and Sensorimotor Cortex Revealed Through Intraoperative Recordings in Parkinson's Disease.

INTRODUCTION Beta oscillations play an important role in gating movement. Because pathological oscillatory changes in the beta band represent a hallmark of Parkinson disease (PD), tracking oscillatory changes in this band has been proposed as a marker for closed-loop stimulation. However, the dynamics of casual influences across the motor circuit during movement remain unknown. Using intracranial local field potential (LFP) recordings, we used both standard functional connectivity and event-related causality (ERC) techniques to explore these interactions. METHODS LFPs were recorded simultaneously from subthalamic nucleus (STN) and sensorimotor cortex, while PD subjects (n = 8) undergoing the implantation of DBS leads performed an incentivized, bimanual handgrip task. Using the beta frequency band between 13 and 30 Hz, functional connectivity was estimated using wavelet-based phase locking values (PLV), and ERC was calculated by constructing a multivariate autoregressive model based on the signal of interest from M1, S1, and STN channels. A false discovery rate correction of 5% was applied. RESULTS All the patients showed significant causal interactions between STN and sensorimotor cortex that coincided with movement epochs showing significant PLV on the individual level. In the 200 ms before movement, precentral beta activity modulated beta activity in the STN, implying that cortical beta activity drives the STN beta activity in that epoch. Reciprocal modulations between the cortex and STN were apparent at the termination of movement. Causal influences from the precentral cortex to the STN in the beta band around 0.5 ms after movement onset correlated significantly with the time to peak force (rho = 0.86, corrected P < .0028). CONCLUSION The directionality of causal interactions across the basal ganglia-cortical motor loop are specific to the directionality of causal interactions across the basal ganglia-cortical motor loop are specific to different phases of motor planning and execution. These novel data highlight the value of intraoperative recordings for furthering our understanding of cortical-basal ganglia models.

High-frequency oscillations as discreet markers of cognitive processing.

During high-conflict trials, as coherence within the group of moving dots increased, a subpopulation of dots began to move in the opposite direction, creating conflict. This subpopulation was capped at 10% of the total number of dots and increased at the same rate as those moving in the correct direction. The conflict limit of 10% meant that maximum conflict occurred at around 0.8 seconds, which was typically 2 to 3 seconds before any response was given. This design feature provided separation between maximum conflict and response, allowing the removal of the confounding influence of response preparation. On analysis, the investigators identified an increase in theta power (4-8Hz) that was unique to high-conflict trials. Furthermore, they found that this change occurred approximately 2 seconds before response was recorded, correlating with the occurrence of maximum conflict. This increase in STN theta power was accompanied by an increase in low-frequency coherence between the STN local field potential and frontal electroencephalography that also occurred approximately 2 seconds before response during the period of highest conflict. Granger causality analysis revealed that flow of activity from the mPFC to the STN (and not the opposite) wasGranger causal, suggesting that the mPFC-STN coherence during high-conflict processing is cortically driven and that the STN responds to “top-down” cortical control during conflict processing. This study provides the first direct evidence of dynamic coupling and “top-down” mPFC control of STN during conflict processing. Furthermore, it confirms the important role that low-frequency oscillations play in this regulatory communication. This is significant because STN DBS has been associated with increased impulsivity by many investigators. STN DBS has additionally been shown to disrupt low-frequency mPFC activity. Taken together, these results support the hypothesis that lowfrequency coherence between the mPFC and STN underlies the ability to “hold your horses” and to process conflict before making a decision. Increased understanding of conflict-processing pathways may open the door to new management strategies for the treatment of impulse control disorders in both PD and non-PD patients.