Robert Mark Richardson

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.

Sensing-enabled hippocampal deep brain stimulation in idiopathic nonhuman primate epilepsy

Epilepsy is a debilitating condition affecting 1% of the population worldwide. Medications fail to control seizures in at least 30% of patients, and deep brain stimulation (DBS) is a promising alternative treatment. A modified clinical DBS hardware platform was recently described (PC+S) allowing long-term recording of electrical brain activity such that effects of DBS on neural networks can be examined. This study reports the first use of this device to characterize idiopathic epilepsy and assess the effects of stimulation in a nonhuman primate (NHP). Clinical DBS electrodes were implanted in the hippocampus of an epileptic NHP bilaterally, and baseline local field potential (LFP) recordings were collected for seizure characterization with the PC+S. Real-time automatic detection of ictal events was demonstrated and validated by concurrent visual observation of seizure behavior. Seizures consisted of large-amplitude 8- to 25-Hz oscillations originating from the right hemisphere and quickly generalizing, with an average occurrence of 0.71 ± 0.15 seizures/day. Various stimulation parameters resulted in suppression of LFP activity or in seizure induction during stimulation under ketamine anesthesia. Chronic stimulation in the awake animal was studied to evaluate how seizure activity was affected by stimulation configurations that suppressed broadband LFPs in acute experiments. This is the first electrophysiological characterization of epilepsy using a next-generation clinical DBS system that offers the ability to record and analyze neural signals from a chronically implanted stimulating electrode. These results will direct further development of this technology and ultimately provide insight into therapeutic mechanisms of DBS for epilepsy.

Multi-Connection Pattern Analysis: Decoding the representational content of neural communication

&NA; The lack of multivariate methods for decoding the representational content of interregional neural communication has left it difficult to know what information is represented in distributed brain circuit interactions. Here we present Multi‐Connection Pattern Analysis (MCPA), which works by learning mappings between the activity patterns of the populations as a factor of the information being processed. These maps are used to predict the activity from one neural population based on the activity from the other population. Successful MCPA‐based decoding indicates the involvement of distributed computational processing and provides a framework for probing the representational structure of the interaction. Simulations demonstrate the efficacy of MCPA in realistic circumstances. In addition, we demonstrate that MCPA can be applied to different signal modalities to evaluate a variety of hypothesis associated with information coding in neural communications. We apply MCPA to fMRI and human intracranial electrophysiological data to provide a proof‐of‐concept of the utility of this method for decoding individual natural images and faces in functional connectivity data. We further use a MCPA‐based representational similarity analysis to illustrate how MCPA may be used to test computational models of information transfer among regions of the visual processing stream. Thus, MCPA can be used to assess the information represented in the coupled activity of interacting neural circuits and probe the underlying principles of information transformation between regions. HighlightsMCPA allows for multivariate single trial classification of functional connectivity.Decodes the representational content of interregional neural communication.Extracts the discriminant information in the shared activity between populations.A general framework that can be extended and applied to different signal modalities.

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.

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.

Cortico-basal-ganglia communication: Temporally structured activity for selective motor control

Despite the hard-wired structural connectivity of neural pathways, neural circuits allow context-dependent reactions to sensory cues by triggering the desired movement. Cortico-basal-ganglia circuits seem particularly important for flexible motor control as this is impaired in Parkinson’s disease (PD). We analysed subthalamic nucleus (STN) spike and cortical ECoG activity from PD patients performing a visually-cued hand grip task. Fast reaction times were preceded by enhanced STN spike-to-cortical gamma phase coupling irrespective of firing rate changes, suggesting a role of gamma coupling in motor preparation. STN spike timing was offset by half a cycle when comparing ipsilateral with contralateral movements. Additionally, cortical high-frequency activity increased more steeply within each gamma cycle at the sites that showed the strongest coupling with STN spikes. Cortico-basal-ganglia gamma coupling may thus help shape neural activity to facilitate selective motor control. The observation that this effect occurs independent of changes in mean firing rate has far-reaching implications. Highlights Fast RTs were preceded by enhanced STN spike-to-cortical gamma phase coupling STN spike probability was significantly modulated relative to the gamma cycle During ipsilateral movement, spikes were more likely at the opposite part of the cycle STN output may thus help shape cortical gamma for selective motor control

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.

Interventional MRI–Guided Deep Brain Stimulation Lead Implantation

Current knowledge of the functional anatomy of the subthalamic nucleus and globus pallidus, discovered through microelectrode recording and postoperative imaging, justifies purely anatomic targeting for deep brain stimulation (DBS). Interventional MRI (iMRI)-DBS is more anatomically accurate than traditional awake procedures and has similar clinical outcomes without increased risk or increased operative times. iMRI lead implantation allows patients to receive DBS therapy who cannot tolerate or do not agree to undergo an awake procedure. This article describes considerations for iMRI-DBS implantation in the subthalamic nucleus and globus pallidus, including patient selection, technique of electrode placement, expected outcomes, and potential complications.

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.