Aperiodic components of local field potentials reflect inherent differences between cortical and subcortical activity.

Information flow in brain networks is reflected in local field potentials that have both periodic and aperiodic components. The 1/fχ aperiodic component of the power spectra tracks arousal and correlates with other physiological and pathophysiological states. Here we explored the aperiodic activity in the human thalamus and basal ganglia in relation to simultaneously recorded cortical activity. We elaborated on the parameterization of the aperiodic component implemented by specparam (formerly known as FOOOF) to avoid parameter unidentifiability and to obtain independent and more easily interpretable parameters. This allowed us to seamlessly fit spectra with and without an aperiodic knee, a parameter that captures a change in the slope of the aperiodic component. We found that the cortical aperiodic exponent χ, which reflects the decay of the aperiodic component with frequency, is correlated with Parkinson's disease symptom severity. Interestingly, no aperiodic knee was detected from the thalamus, the pallidum, or the subthalamic nucleus, which exhibited an aperiodic exponent significantly lower than in cortex. These differences were replicated in epilepsy patients undergoing intracranial monitoring that included thalamic recordings. The consistently lower aperiodic exponent and lack of an aperiodic knee from all subcortical recordings may reflect cytoarchitectonic and/or functional differences. SIGNIFICANCE STATEMENT: The aperiodic component of local field potentials can be modeled to produce useful and reproducible indices of neural activity. Here we refined a widely used phenomenological model for extracting aperiodic parameters (namely the exponent, offset and knee), with which we fit cortical, basal ganglia, and thalamic intracranial local field potentials, recorded from unique cohorts of movement disorders and epilepsy patients. We found that the aperiodic exponent in motor cortex is higher in Parkinson's disease patients with more severe motor symptoms, suggesting that aperiodic features may have potential as electrophysiological biomarkers for movement disorders symptoms. Remarkably, we found conspicuous differences in the aperiodic parameters of basal ganglia and thalamic signals compared to those from neocortex.

Lateralized and Region-Specific Thalamic Processing of Lexical Status during Reading Aloud.

To explore whether the thalamus participates in lexical status (word vs nonword) processing during spoken word production, we recorded local field potentials from the ventral lateral thalamus in 11 essential tremor patients (three females) undergoing thalamic deep-brain stimulation lead implantation during a visually cued word and nonword reading-aloud task. We observed task-related beta (12-30 Hz) activity decreases that were preferentially time locked to stimulus presentation, and broadband gamma (70-150 Hz) activity increases, which are thought to index increased multiunit spiking activity, occurring shortly before and predominantly time locked to speech onset. We further found that thalamic beta activity decreases bilaterally were greater when nonwords were read, demonstrating bilateral sensitivity to lexical status that likely reflects the tracking of task effort; in contrast, greater nonword-related increases in broadband gamma activity were observed only on the left, demonstrating lateralization of thalamic broadband gamma selectivity for lexical status. In addition, this lateralized lexicality effect on broadband gamma activity was strongest in more anterior thalamic locations, regions which are more likely to receive basal ganglia than cerebellar afferents and have extensive connections with prefrontal cortex including Brodmann's areas 44 and 45, regions consistently associated with grapheme-to-phoneme conversions. These results demonstrate active thalamic participation in reading aloud and provide direct evidence from intracranial thalamic recordings for the lateralization and topography of subcortical lexical status processing.SIGNIFICANCE STATEMENT Despite the corticocentric focus of most experimental work and accompanying models, there is increasing recognition of the role of subcortical structures in speech and language. Using local field potential recordings in neurosurgical patients, we demonstrated that the thalamus participates in lexical status (word vs nonword) processing during spoken word production, in a lateralized and region-specific manner. These results provide direct evidence from intracranial thalamic recordings for the lateralization and topography of subcortical lexical status processing.

Differentiation of speech-induced artifacts from physiological high gamma activity in intracranial recordings.

There is great interest in identifying the neurophysiological underpinnings of speech production. Deep brain stimulation (DBS) surgery is unique in that it allows intracranial recordings from both cortical and subcortical regions in patients who are awake and speaking. The quality of these recordings, however, may be affected to various degrees by mechanical forces resulting from speech itself. Here we describe the presence of speech-induced artifacts in local-field potential (LFP) recordings obtained from mapping electrodes, DBS leads, and cortical electrodes. In addition to expected physiological increases in high gamma (60-200 Hz) activity during speech production, time-frequency analysis in many channels revealed a narrowband gamma component that exhibited a pattern similar to that observed in the speech audio spectrogram. This component was present to different degrees in multiple types of neural recordings. We show that this component tracks the fundamental frequency of the participant's voice, correlates with the power spectrum of speech and has coherence with the produced speech audio. A vibration sensor attached to the stereotactic frame recorded speech-induced vibrations with the same pattern observed in the LFPs. No corresponding component was identified in any neural channel during the listening epoch of a syllable repetition task. These observations demonstrate how speech-induced vibrations can create artifacts in the primary frequency band of interest. Identifying and accounting for these artifacts is crucial for establishing the validity and reproducibility of speech-related data obtained from intracranial recordings during DBS surgery.

Lateralized Effect of Thalamic Deep Brain Stimulation Location on Verbal Abstraction.

BACKGROUND: Regionalized thalamic activity has been implicated in language function, and yet the effect of thalamic deep brain stimulation (DBS) on language-related clinical outcomes is underexplored. OBJECTIVE: The objective of this study was to determine if the location of stimulation within the thalamus correlates with changes in language-related neuropsychological outcomes following DBS for essential tremor. METHODS: Thirty patients with essential tremor underwent comprehensive neuropsychological evaluations before and after DBS surgery targeting the ventral intermediate nucleus of the thalamus. Changes in neuropsychological functions were evaluated. The relationships between language-related outcomes and stimulation location were assessed using both categorical and linear methods. Any significant results were further validated using linear discriminant analysis. RESULTS: Most neuropsychological functions remained unchanged at the group level. However, outcome on a measure of verbal abstraction was significantly dependent on stimulation location along the anterior-posterior axis within the left ventral lateral thalamus, with anterior stimulation associated with reduced verbal abstraction performance. This result was supported by linear discriminant analysis, which showed that stimulation locations with improved and reduced verbal abstraction function were best separated by a vector nearly parallel to the anterior-posterior axis. No stimulation location dependence was found for verbal abstraction outcome in the right thalamus or for outcomes of other language functions in either hemisphere. CONCLUSION: We demonstrate an effect of thalamic DBS on verbal abstraction as a function of left thalamic topography. This finding provides clinical evidence for the lateralization and regionalization of thalamic language function that may be relevant for understanding nonmotor effects of stimulation. © 2021 International Parkinson and Movement Disorder Society.

Subthalamic Nucleus Activity Influences Sensory and Motor Cortex during Force Transduction.

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. Phase-locking analyses demonstrated periods of STN-cortical coherence that bracketed force transduction, in both beta and gamma ranges. Event-related causality measures demonstrated that both STN beta and gamma activity predicted motor cortical beta and gamma activity not only during force generation but also prior to movement onset. These findings are consistent with the idea that the STN participates in motor planning, in addition to the modulation of ongoing movement. We also demonstrated bidirectional information flow between the STN and somatosensory cortex in both beta and gamma range frequencies, suggesting robust STN participation in somatosensory integration. In fact, interactions in beta activity between the STN and somatosensory cortex, and not between STN and motor cortex, predicted PD symptom severity. Thus, the STN contributes to multiple aspects of sensorimotor behavior dynamically across time.

Subthalamic Nucleus and Sensorimotor Cortex Activity During Speech Production.

The sensorimotor cortex is somatotopically organized to represent the vocal tract articulators such as lips, tongue, larynx, and jaw. How speech and articulatory features are encoded at the subcortical level, however, remains largely unknown. We analyzed LFP recordings from the subthalamic nucleus (STN) and simultaneous electrocorticography recordings from the sensorimotor cortex of 11 human subjects (1 female) with Parkinson's disease during implantation of deep-brain stimulation (DBS) electrodes while they read aloud three-phoneme words. The initial phonemes involved either articulation primarily with the tongue (coronal consonants) or the lips (labial consonants). We observed significant increases in high-gamma (60-150 Hz) power in both the STN and the sensorimotor cortex that began before speech onset and persisted for the duration of speech articulation. As expected from previous reports, in the sensorimotor cortex, the primary articulators involved in the production of the initial consonants were topographically represented by high-gamma activity. We found that STN high-gamma activity also demonstrated specificity for the primary articulator, although no clear topography was observed. In general, subthalamic high-gamma activity varied along the ventral-dorsal trajectory of the electrodes, with greater high-gamma power recorded in the dorsal locations of the STN. Interestingly, the majority of significant articulator-discriminative activity in the STN occurred before that in sensorimotor cortex. These results demonstrate that articulator-specific speech information is contained within high-gamma activity of the STN, but with different spatial and temporal organization compared with similar information encoded in the sensorimotor cortex.SIGNIFICANCE STATEMENT Clinical and electrophysiological evidence suggest that the subthalamic nucleus (STN) is involved in speech; however, this important basal ganglia node is ignored in current models of speech production. We previously showed that STN neurons differentially encode early and late aspects of speech production, but no previous studies have examined subthalamic functional organization for speech articulators. Using simultaneous LFP recordings from the sensorimotor cortex and the STN in patients with Parkinson's disease undergoing deep-brain stimulation surgery, we discovered that STN high-gamma activity tracks speech production at the level of vocal tract articulators before the onset of vocalization and often before related cortical encoding.

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 Parkinson's 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.

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 Parkinson's 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.

Psychogenic Stress Activates C-Fos in Nucleus Accumbens-Projecting Neurons of the Hippocampal Ventral Subiculum.

Background: The ventral subiculum is known to be activated by the presentation of novel stressors. It has been hypothesized that neuronal ensembles at the ventral aspect of the hippocampal formation are involved in context-dependent processing and can guide the learning of appropriate action selections in response to threatening contexts. Artificial activation of the ventral subiculum can excite medium spiny neurons of the nucleus accumbens and can increase the excitability of mesolimbic dopamine neurons via a polysynaptic pathway through the basal ganglia. However, it remains unknown whether this circuit can be activated by aversive experience, and if so, whether ventral subiculum engages nucleus accumbens monosynaptically. Methods: To address this, the retrograde tracer fluorogold was used in rats to label neurons projecting to the caudomedial nucleus accumbens. One to 2 weeks later, the same rats were exposed to psychogenic stress (i.e., acute restraint in a novel test room) or served as nonhandled controls, followed by dual immunocytochemical localization of retrogradely transported tracer and nuclear Fos. Results: Compared with controls, rats exposed to psychogenic stress displayed more fluorogold-positive ventral subiculum neurons that were double-labeled for Fos. Conclusion: This study establishes that the direct pathway from ventral subiculum to the caudomedial nucleus accumbens is activated by stressful experience.

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 Parkinson's 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 Parkinson's 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 Parkinson's disease and essential tremor, with the greatest high-beta desynchronization occurring in Parkinson's 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 Parkinson's disease and essential tremor than in subjects without a movement disorder. These findings suggest that subjects with Parkinson's 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.

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.

Spatiotemporally-specific cortical-subthalamic coupling differentiates aspects of speech performance.

Speech provides a rich context for exploring human cortical-basal ganglia circuit function, but direct intracranial recordings are rare. We recorded electrocorticographic signals in the cortex synchronously with single units in the subthalamic nucleus (STN), a basal ganglia node that receives direct input from widespread cortical regions, while participants performed a syllable repetition task during deep brain stimulation (DBS) surgery. We discovered that STN neurons exhibited spike-phase coupling (SPC) events with distinct combinations of frequency, location, and timing that indexed specific aspects of speech. The strength of SPC to posterior perisylvian cortex predicted phoneme production accuracy, while that of SPC to perirolandic cortex predicted time taken for articulation Thus, STN-cortical interactions are coordinated via transient bursts of behavior-specific synchronization that involves multiple neuronal populations and timescales. These results both suggest mechanisms that support auditory-sensorimotor integration during speech and explain why firing-rate based models are insufficient for explaining basal ganglia circuit behavior.

Broadband aperiodic components of local field potentials reflect inherent differences between cortical and subcortical activity.

Information flow in brain networks is reflected in intracerebral local field potential (LFP) measurements that have both periodic and aperiodic components. The 1/fχ broadband aperiodic component of the power spectra has been shown to track arousal level and to correlate with other physiological and pathophysiological states, with consistent patterns across cortical regions. Previous studies have focused almost exclusively on cortical neurophysiology. Here we explored the aperiodic activity of subcortical nuclei from the human thalamus and basal ganglia, in relation to simultaneously recorded cortical activity. We elaborated on the FOOOF (fitting of one over f) method by creating a new parameterization of the aperiodic component with independent and more easily interpretable parameters, which allows seamlessly fitting spectra with and without an aperiodic knee, a component of the signal that reflects the dominant timescale of aperiodic fluctuations. First, we found that the aperiodic exponent from sensorimotor cortex in Parkinson's disease (PD) patients correlated with disease severity. Second, although the aperiodic knee frequency changed across cortical regions as previously reported, no aperiodic knee was detected from subcortical regions across movement disorders patients, including the ventral thalamus (VIM), globus pallidus internus (GPi) and subthalamic nucleus (STN). All subcortical region studied exhibited a relatively low aperiodic exponent (χSTN=1.3±0.2, χVIM=1.4±0.1, χGPi =1.4±0.1) that differed markedly from cortical values (χCortex=3.2±0.4, fkCortex=17±5 Hz). These differences were replicated in a second dataset from epilepsy patients undergoing intracranial monitoring that included thalamic recordings. The consistently lower aperiodic exponent and lack of an aperiodic knee from all subcortical recordings may reflect cytoarchitectonic and/or functional differences between subcortical nuclei and the cortex.

Quantifying Phase-Amplitude Modulation in Neural Data.

Phase-amplitude modulation (the modulation of the amplitude of higher frequency oscillations by the phase of lower frequency oscillations) is a specific type of cross-frequency coupling that has been observed in neural recordings from multiple species in a range of behavioral contexts. Given its potential importance, care must be taken with how it is measured and quantified. Previous studies have quantified phase-amplitude modulation by measuring the distance of the amplitude distribution from a uniform distribution. While this method is of general applicability, it is not targeted to the specific modulation pattern frequently observed with low-frequency oscillations. Here we develop a new method that has increased specificity to detect modulation in the sinusoidal shape commonly observed in neural data.

Hyperdirect connectivity of opercular speech network to the subthalamic nucleus.

How the basal ganglia participate in the uniquely human behavior of speech is poorly understood, despite their known role in modulating critical aspects of cognitive and motor behavior. The subthalamic nucleus (STN) is well positioned to facilitate basal ganglia functions critical for speech. Using electrocorticography in patients undergoing awake deep brain stimulation (DBS) surgery, evidence is reported for a left opercular hyperdirect pathway in humans via stimulating the STN and examining antidromic-evoked activity in the left temporal, parietal, and frontal opercular cortex. These high-resolution cortical and subcortical mapping data provide evidence for hyperdirect connectivity between the inferior frontal gyrus and the STN. In addition, evoked potential data are consistent with the presence of monosynaptic projections from areas of the opercular speech cortex that are primarily sensory, including the auditory cortex, to the STN. These connections may be unique to humans, evolving alongside the ability for speech.

Electrocorticography is superior to subthalamic local field potentials for movement decoding in Parkinson's disease.

Brain signal decoding promises significant advances in the development of clinical brain computer interfaces (BCI). In Parkinson's disease (PD), first bidirectional BCI implants for adaptive deep brain stimulation (DBS) are now available. Brain signal decoding can extend the clinical utility of adaptive DBS but the impact of neural source, computational methods and PD pathophysiology on decoding performance are unknown. This represents an unmet need for the development of future neurotechnology. To address this, we developed an invasive brain-signal decoding approach based on intraoperative sensorimotor electrocorticography (ECoG) and subthalamic LFP to predict grip-force, a representative movement decoding application, in 11 PD patients undergoing DBS. We demonstrate that ECoG is superior to subthalamic LFP for accurate grip-force decoding. Gradient boosted decision trees (XGBOOST) outperformed other model architectures. ECoG based decoding performance negatively correlated with motor impairment, which could be attributed to subthalamic beta bursts in the motor preparation and movement period. This highlights the impact of PD pathophysiology on the neural capacity to encode movement vigor. Finally, we developed a connectomic analysis that could predict grip-force decoding performance of individual ECoG channels across patients by using their connectomic fingerprints. Our study provides a neurophysiological and computational framework for invasive brain signal decoding to aid the development of an individualized precision-medicine approach to intelligent adaptive DBS.

Movement-related coupling of human subthalamic nucleus spikes to cortical gamma.

Cortico-basal ganglia interactions continuously shape the way we move. Ideas about how this circuit works are based largely on models those consider only firing rate as the mechanism of information transfer. A distinct feature of neural activity accompanying movement, however, is increased motor cortical and basal ganglia gamma synchrony. To investigate the relationship between neuronal firing in the basal ganglia and cortical gamma activity during movement, we analysed human ECoG and subthalamic nucleus (STN) unit activity during hand gripping. We found that fast reaction times were preceded by enhanced STN spike-to-cortical gamma phase coupling, indicating a role in motor preparation. Importantly, increased gamma phase coupling occurred independent of changes in mean STN firing rates, and the relative timing of STN spikes was offset by half a gamma cycle for ipsilateral vs. contralateral movements, indicating that relative spike timing is as relevant as firing rate for understanding cortico-basal ganglia information transfer.

Anterior Sensorimotor Subthalamic Nucleus Stimulation Is Associated With Improved Voice Function.

BACKGROUND: Despite the impact of Parkinson disease (PD) on speech communication, there is no consensus regarding the effect of lead location on voice-related outcomes in subthalamic nucleus (STN) deep brain stimulation (DBS). OBJECTIVE: To determine the relationship of stimulation location to changes in cepstral analyses of voice following STN DBS. METHODS: Speech pathology evaluations were obtained from 14 PD subjects, before and after STN DBS, including audio-perceptual voice ratings (overall severity, loudness, hoarseness changes), measured indices of dysphonia (cepstral peak prominence and cepstral spectral index of dysphonia), and phonatory aerodynamics. The contact locations used for active stimulation at the time of postoperative voice evaluations were determined and assessed in relation to voice outcomes. RESULTS: Voice outcomes remained relatively unchanged on average. Stimulation locations in the anterior portion of the sensorimotor region of the left STN, however, were associated with improvements in voice severity scores, cepstral spectral index of dysphonia, shortness of breath, and phonatory airflow during connected speech. Posterior locations were associated with worsening of these outcomes. Variation in the medial-lateral or dorsal-ventral position on the left, and in any direction on the right, did not correlate with any voice outcome. CONCLUSION: Active contact placement within the anterior sensorimotor STN was associated with improved perceptual and acoustic-aerodynamic voice-related outcomes. These findings suggest an STN topography for improving airflow for speech, in turn improving how PD patients' voices sound.

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

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 (2Hz) hippocampal stimulation identified a pulse width (150µs) and current amplitude (4mA) 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.