Ahmad Alhourani

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.

Magnetoencephalography-based identification of functional connectivity network disruption following mild traumatic brain injury

Mild traumatic brain injury (mTBI) leads to long-term cognitive sequelae in a significant portion of patients. Disruption of normal neural communication across functional brain networks may explain the deficits in memory and attention observed after mTBI. In this study, we used magnetoencephalography (MEG) to examine functional connectivity during a resting state in a group of mTBI subjects (n = 9) compared with age-matched control subjects (n = 15). We adopted a data-driven, exploratory analysis in source space using phase locking value across different frequency bands. We observed a significant reduction in functional connectivity in band-specific networks in mTBI compared with control subjects. These networks spanned multiple cortical regions involved in the default mode network (DMN). The DMN is thought to subserve memory and attention during periods when an individual is not engaged in a specific task, and its disruption may lead to cognitive deficits after mTBI. We further applied graph theoretical analysis on the functional connectivity matrices. Our data suggest reduced local efficiency in different brain regions in mTBI patients. In conclusion, MEG can be a potential tool to investigate and detect network alterations in patients with mTBI. The value of MEG to reveal potential neurophysiological biomarkers for mTBI patients warrants further exploration.

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.

SUBTHALAMIC NUCLEUS NEURONS DIFFERENTIALLY ENCODE EARLY AND LATE ASPECTS OF SPEECH PRODUCTION

Basal ganglia-thalamocortical loops mediate all motor behavior, yet little detail is known about the role of basal ganglia nuclei in speech production. Using intracranial recording during deep brain stimulation surgery in humans with Parkinsons disease, we tested the hypothesis that the firing rate of subthalamic nucleus neurons is modulated in sync with motor execution aspects of speech. Nearly half of 79 unit recordings exhibited firing-rate modulation during a syllable reading task across 12 subjects (male and female). Trial-to-trial timing of changes in subthalamic neuronal activity, relative to cue onset versus production onset, revealed that locking to cue presentation was associated more with units that decreased firing rate, whereas locking to speech onset was associated more with units that increased firing rate. These unique data indicate that subthalamic activity is dynamic during the production of speech, reflecting temporally-dependent inhibition and excitation of separate populations of subthalamic neurons. SIGNIFICANCE STATEMENT The basal ganglia are widely assumed to participate in speech production, yet no prior studies have reported detailed examination of speech-related activity in basal ganglia nuclei. Using microelectrode recordings from the subthalamic nucleus during a single-syllable reading task, in awake humans undergoing deep brain stimulation implantation surgery, we show that the firing rate of subthalamic nucleus neurons is modulated in response to motor execution aspects of speech. These results are the first to establish a role for subthalamic nucleus neurons in encoding of aspects of speech production, and they lay the groundwork for launching a modern subfield to explore basal ganglia function in human speech.

207 Aberrant Preoperative Hippocampal Interconnectivity Predicts Verbal Memory Improvement Following Anterior Temporal Lobectomy.

INTRODUCTION Changes in connectivity have been found surrounding epileptic foci during resting state magnetoencephalography (MEG). One manifestation of these changes is disorganization manifested by increased interconnectivity within a region. This abnormal interconnectivity indicates a decrease in efficiency, because efficient function within a system requires communication across brain regions. Surgical resection of seizure foci may attenuate these aberrant patterns of connectivity. Thus far, the relationship between postoperative changes in cognitive function and aberrant connectivity has not been established. METHODS We obtained pre- and postoperative neuropsychological testing on 20 patients (10 right sided, 10 left) undergoing anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). In addition, we obtained preoperative resting MEG. We compared interconnectivity in the beta frequency band for the hippocampus to interconnectivity in other brain regions. In addition, we compared interconnectivity in the hippocampus to changes in cognitive function following surgery. RESULTS Patients undergoing ATL showed increased phase locking in the beta frequency band within the hippocampus on preoperative MEG, relative to other regions (eg, Broca and Wernicke areas, dorsolateral prefrontal cortex, and the superior parietal lobule). There was no significant change in most cognitive measures. However, patients showed significant improvement in immediate, F(1,19) = 8.51, P = .007, and long-term verbal memory, F(1,19) = 5.68, P = .03. The improvement in verbal memory following ATL was positively correlated to the degree of aberrant connectivity in the hippocampus, r = 0.68, P = .04. CONCLUSION MTLE was associated with aberrant interconnectivity within the hippocampus. This aberrant interconnectivity was positively correlated with the degree of postoperative improvement in verbal memory following ATL. This suggests that resection of aberrant temporal lobe resulted in removal of inefficient cortical networks, which may have led to improvement in cognitive performance.