Phosphene perceptions and safety of chronic visual cortex stimulation in a blind subject.

Stimulation of primary visual cortices has the potential to restore some degree of vision to blind individuals. Developing safe and reliable visual cortical prostheses requires assessment of the long-term stability, feasibility, and safety of generating stimulation-evoked perceptions.A NeuroPace responsive neurostimulation system was implanted in a blind individual with an 8-year history of bare light perception, and stimulation-evoked phosphenes were evaluated over 19 months (41 test sessions). Electrical stimulation was delivered via two four-contact subdural electrode strips implanted over the right medial occipital cortex. Current and charge thresholds for eliciting visual perception (phosphenes) were measured, as were the shape, size, location, and intensity of the phosphenes. Adverse events were also assessed.Stimulation of all contacts resulted in phosphene perception. Phosphenes appeared completely or partially in the left hemifield. Stimulation of the electrodes below the calcarine sulcus elicited phosphenes in the superior hemifield and vice versa. Changing the stimulation parameters of frequency, pulse width, and burst duration affected current thresholds for eliciting phosphenes, and increasing the amplitude or frequency of stimulation resulted in brighter perceptions. While stimulation thresholds decreased between an average of 5% and 12% after 19 months, spatial mapping of phosphenes remained consistent over time. Although no serious adverse events were observed, the subject experienced mild headaches and dizziness in three instances, symptoms that did not persist for more than a few hours and for which no clinical intervention was required.Using an off-the-shelf neurostimulator, the authors were able to reliably generate phosphenes in different areas of the visual field over 19 months with no serious adverse events, providing preliminary proof of feasibility and safety to proceed with visual epicortical prosthetic clinical trials. Moreover, they systematically explored the relationship between stimulation parameters and phosphene thresholds and discovered the direct relation of perception thresholds based on primary visual cortex (V1) neuronal population excitation thresholds.

Neuronal activity and outcomes from thalamic surgery for spinocerebellar ataxia.

Objectives: We investigated the effects of deep brain stimulation (DBS) or lesions of the ventral intermediate nucleus (Vim) of the thalamus for spinocerebellar ataxia (SCA) and examined the pathophysiological role of neuronal activity of the Vim underlying ataxia. Methods: Five patients with SCA with cortical atrophy (ages 60-69 years; 2 sporadic and three familial SCA) and five patients with essential tremor (ET) (ages 57-71 years) were treated with Vim surgery. Intraoperatively, we recorded neuronal activity from single neurons in the Vim thalamus while patients were at rest and compared the physiological properties of those neurons between patients with SCA and those with ET. Results: Postsurgery mean scores for the Fahn-Tolosa-Marin Tremor Scale were improved from 78 to 44 in SCA patients and from 54 to 21 in ET patients. Stronger stimulation was necessary to optimize outcomes in SCA as compared to ET patients. We analyzed 68 Vim neurons in SCA and 60 Vim neurons in ET. Mean discharge rates, burst characteristics, and oscillatory activity were similar for both patient groups, however, we observed that the ratio of cells responding to passive manipulation was significantly smaller (P = 0.0001) in SCA (22%) than in ET (71%). Interpretation: Thalamic surgery led to a significant improvement in tremor in SCA patients. One potential mechanism underlying ataxia in SCA may be disruption of cerebellar sensory feedback, which modulates motor commands in the cerebello-thalamo-cortical network.

Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease.

BACKGROUND: The motor thalamus is a key nodal point in the pallidothalamocortical "motor" circuit, which has been implicated in the pathogenesis of Parkinson's disease (PD) and other movement disorders. Although a critical structure in the motor circuit, the role of the motor thalamus in mediating the therapeutic effects of deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) is not fully understood. OBJECTIVE: To characterize the changes in neuronal activity in the pallidal (ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)) and cerebellar (ventralis posterior lateralis pars oralis (VPLo)) receiving areas of the motor thalamus during therapeutic GPi DBS. METHODS: Neuronal activity from the VA/VLo (n = 134) and VPLo (n = 129) was recorded from two non-human primates made parkinsonian using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. For each isolated unit, one minute of data was recorded before, during and after DBS; a pulse width of 90 µs and a frequency of 135 Hz were used for DBS to replicate commonly used clinical settings. Stimulation amplitude was determined based on the parameters required to improve motor signs. Severity of motor signs was assessed using the UPDRS modified for nonhuman primates. Discharge rate, presence and characteristics of bursts, and oscillatory activity were computed and compared across conditions (pre-, during, and post-stimulation). RESULTS: Neurons in both the pallidal and cerebellar receiving areas demonstrated significant changes in their pattern of activity during therapeutic GPi DBS. A majority of the neurons in each nucleus were inhibited during DBS (VA/VLo: 47% and VPLo: 49%), while a smaller subset was excited (VA/VLo: 21% and VPLo: 17%). Bursts changed in structure, becoming longer in duration and both intra-burst and inter-spike intervals and variability were increased in both subnuclei. High frequency oscillatory activity was significantly increased during stimulation with 33% of VA/VLo (likelihood ratio: p < 0.0001) and 34% of VPLo (p < 0.0001) neurons entrained to the stimulation pulse train. CONCLUSIONS: Therapeutic GPi DBS produced a significant change in neuronal activity in both pallidal and cerebellar receiving areas of the motor thalamus. DBS suppressed activity in the majority of neurons, changed the structure of bursting activity and locked the neuronal response of one-third of cells to the stimulation pulse, leading to an increase in the power of gamma oscillations. These data support the hypothesis that stimulation activates output from the stimulated structure and that GPi DBS produces network-wide changes in neuronal activity that includes both the pallidal and cerebellar thalamo-cortical circuits.

Closed-Loop Deep Brain Stimulation Effects on Parkinsonian Motor Symptoms in a Non-Human Primate - Is Beta Enough?

BACKGROUND: Incorporating feedback controls based on real-time measures of pathological brain activity may improve deep brain stimulation (DBS) approaches for the treatment of Parkinson's disease (PD). Excessive beta oscillations in subthalamic nucleus (STN) local field potentials (LFP) have been proposed as a potential biomarker for closed-loop DBS (CL-DBS). OBJECTIVE: In a non-human primate PD model we compared CL-DBS, which delivered stimulation only when STN LFP beta activity was elevated, to traditional continuous DBS (tDBS). METHODS: Therapeutic effects of CL-DBS and tDBS relative to the Off-DBS condition were evaluated via a clinical rating scale and objective measures of movement speed during a cued reaching task. RESULTS: CL-DBS was comparable to tDBS at reducing rigidity, while reducing the amount of time DBS was on by ≈50%; however, only tDBS improved bradykinesia during the reaching behavior. This was likely due to reach-related reductions in beta amplitude that influence the timing and duration of stimulation in the CL-DBS condition. CONCLUSION: These results illustrate the potential utility of closed-loop DBS devices for PD based on STN beta LFP levels. They also point to possible consequences in behavioral tasks when restricting real-time sensing to a single LFP frequency that itself is modulated during performance of such tasks. The present study provides data that suggest alternate algorithms or more than one physiological biomarker may be required to optimize the performance of behavioral tasks and demonstrates the value of using multiple objective measures when evaluating the efficacy of closed-loop DBS systems.

Coordinated Reset Deep Brain Stimulation of Subthalamic Nucleus Produces Long-Lasting, Dose-Dependent Motor Improvements in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Non-Human Primate Model of Parkinsonism.

BACKGROUND: Novel deep brain stimulation (DBS) paradigms are being explored in an effort to further optimize therapeutic outcome for patients with Parkinson's disease (PD). One approach, termed 'Coordinated Reset' (CR) DBS, was developed to target pathological oscillatory network activity. with desynchronizing effects and associated therapeutic benefit hypothesized to endure beyond cessation of stimulus delivery. OBJECTIVE: To characterize the acute and carry-over effects of low-intensity CR DBS versus traditional DBS (tDBS) in the region of the subthalamic nucleus (STN). METHODS: A within-subject, block treatment design involving the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) non-human primate model of parkinsonism was used. Each treatment block consisted of five days of daily DBS delivery followed by a one week minimum post-treatment observation window. Motor behavior was quantified using a modified rating scale for both animals combined with an objective, upper-extremity reach task in one animal. RESULTS: Both animals demonstrated significant motor improvements during acute tDBS; however, within-session and post-treatment carry-over was limited. Acute motor improvements were also observed in response to low-intensity CR DBS; however, both within- and between-session therapeutic carry-over enhanced progressively following each daily treatment. Moreover, in contrast to tDBS, five consecutive days of CR DBS treatment yielded carry-over benefits that persisted for up to two weeks without additional intervention. Notably, the magnitude and time-course of CR DBS' effects on each animal varied with daily dose-duration, pointing to possible interaction effects involving baseline parkinsonian severity. CONCLUSION: Our results support the therapeutic promise of CR DBS for PD, including its potential to induce carryover while reducing both side effect risk and hardware power consumption.

Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator.

OBJECTIVE: Using the Medtronic Activa® PC + S system, this study investigated how passive joint manipulation, reaching behavior, and deep brain stimulation (DBS) modulate local field potential (LFP) activity in the subthalamic nucleus (STN) and globus pallidus (GP). APPROACH: Five non-human primates were implanted unilaterally with one or more DBS leads. LFPs were collected in montage recordings during resting state conditions and during motor tasks that facilitate the expression of parkinsonian motor signs. These recordings were made in the naïve state in one subject, in the parkinsonian state in two subjects, and in both naïve and parkinsonian states in two subjects. MAIN RESULTS: LFPs measured at rest were consistent over time for a given recording location and parkinsonian state in a given subject; however, LFPs were highly variable between subjects, between and within recording locations, and across parkinsonian states. LFPs in both naïve and parkinsonian states across all recorded nuclei contained a spectral peak in the beta band (10-30 Hz). Moreover, the spectral content of recorded LFPs was modulated by passive and active movement of the subjects' limbs. LFPs recorded during a cued-reaching task displayed task-related beta desynchronization in STN and GP. The bidirectional capabilities of the Activa® PC + S also allowed for recording LFPs while delivering DBS. The therapeutic effect of STN DBS on parkinsonian rigidity outlasted stimulation for 30-60 s, but there was no correlation with beta band power. SIGNIFICANCE: This study emphasizes (1) the variability in spontaneous LFPs amongst subjects and (2) the value of using the Activa® PC + S system to record neural data in the context of behavioral tasks that allow one to evaluate a subject's symptomatology.

Information in pallidal neurons increases with parkinsonian severity.

INTRODUCTION: The motor symptoms of Parkinson's disease (PD) present with pathological neuronal activity in the basal ganglia. Although neuronal firing rate changes in the globus pallidus internus (GPi) and externus (GPe) are reported to underlie the development of PD motor signs, firing rates change inconsistently, vary confoundingly with some therapies, and are poor indicators of symptom severity. METHODS: We explored the relationship between parkinsonian symptom severity and the effectiveness with which pallidal neurons transmit information. We quantify neuronal entropy and information - alternatives to firing rate and correlations respectively - in and between GPe and GPi neurons using a progressive, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, non-human primate model of PD. RESULTS: Neuronal entropy and symptom severity were not linearly correlated: in both pallidal segments, entropy increased from naive to moderate parkinsonism, but decreased with further progression to the severely parkinsonian condition. In contrast, information transmitted from GPe to GPi increased consistently with symptom severity. Furthermore, antidromic information from GPi to GPe increased substantially with symptom severity. Together, these findings suggest that as parkinsonian severity increases, more and more information enters GPe and GPi from common sources, diminishing the relative importance of the orthodromic GPe to GPi connection. CONCLUSIONS: With parkinsonian progression, the direct and indirect pathways lose their independence and start to convey redundant information. We hypothesize that a loss of parallel processing impairs the ability of the network to select and implement motor commands, thus promoting the hypokinetic symptoms of PD.

Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS.

High-frequency stimulation is known to entrain spike activity downstream and upstream of several clinical deep brain stimulation (DBS) targets, including the cerebellar-receiving area of thalamus (VPLo), subthalamic nucleus (STN), and globus pallidus (GP). Less understood are the fidelity of entrainment to each stimulus pulse, whether entrainment patterns are stationary over time, and how responses differ among DBS targets. In this study, three rhesus macaques were implanted with a single DBS lead in VPLo, STN, or GP. Single-unit spike activity was recorded in the resting state in motor cortex during VPLo DBS, in GP during STN DBS, and in STN and pallidal-receiving area of motor thalamus (VLo) during GP DBS. VPLo DBS induced time-locked spike activity in 25% (n = 15/61) of motor cortex cells, with entrained cells following 7.5 ± 7.4% of delivered pulses. STN DBS entrained spike activity in 26% (n = 8/27) of GP cells, which yielded time-locked spike activity for 8.7 ± 8.4% of stimulus pulses. GP DBS entrained 67% (n = 14/21) of STN cells and 32% (n = 19/59) of VLo cells, which showed a higher fraction of pulses effectively inhibiting spike activity (82.0 ± 9.6% and 86.1 ± 16.6%, respectively). Latency of phase-locked spike activity increased over time in motor cortex (58%, VPLo DBS) and to a lesser extent in GP (25%, STN DBS). In contrast, the initial inhibitory phase observed in VLo and STN during GP DBS remained stable following stimulation onset. Together, these data suggest that circuit-level entrainment is low-pass filtered during high-frequency stimulation, most notably for glutamatergic pathways. Moreover, phase entrainment is not stationary or consistent at the circuit level for all DBS targets.

Extracting Attempted Hand Movements from EEGs in People with Complete Hand Paralysis Following Stroke.

This study examines the feasibility of using electroencephalograms (EEGs) to rapidly detect the intent to open one's hand in individuals with complete hand paralysis following a subcortical ischemic stroke. If detectable, this motor-planning activity could be used in real time to trigger a motorized hand exoskeleton or an electrical stimulation device that opens/closes the hand. While EEG-triggered movement-assist devices could restore function, they may also promote recovery by reinforcing the use of remaining cortical circuits. EEGs were recorded while participants were cued to either relax or attempt to extend their fingers. Linear-discriminant analysis was used to detect onset of finger-extension from the EEGs in a leave-one-trial-out cross-validation process. In each testing trial, the classifier was applied in pseudo-real-time starting from an initial hand-relaxed phase, through movement planning, and into the initial attempted-finger-extension phase (finger-extension phase estimated from typical time-to-movement-onset measured in the unaffected hand). The classifiers detected attempted-finger-extension at a significantly higher rate during both motor-planning and early attempted execution compared to rest. To reduce inappropriate triggering of a movement-assist device during rest, the classification threshold could be adjusted to require more certainty about one's intent to move before triggering a device. Additionally, a device could be set to activate only after multiple time samples in a row were classified as finger-extension events. These options resulted in some sessions with no false triggers while the person was resting, but moderate-to-high true trigger rates during attempted-movements.

Decoding of auditory cortex signals with a LAMSTAR neural network.

OBJECTIVES: Each neuron has a specific set of stimuli, which it preferentially responds to (the receptive field of the neuron). For implantable cortical prosthetic devices specific points of the cortex (or groups of neurons) have to be stimulated to create perceptions of sensory stimulus with specific attributes (such as frequency, temporal characteristics, etc). Such applications would need real time decoding of signals. Previously mathematical techniques, such as computing the receptive field (using electrophysiology data) and artificial neural networks (Kohonen network or SOM and back propagation network) have been used to decode neural signals. METHODS: A Large Adaptive Memory Storage and Retrieval (LAMSTAR) neural-network-based decoder was designed to decode responses recorded from neurons in the auditory cortex. It was designed to identify the frequency of the tonal stimuli that elicited a particular discharge rate pattern recorded on two channels of a tungsten wire electrode array. RESULTS: The network functioned efficiently as a decoder with 100% accuracy for the small sample of stimulus-response data used. DISCUSSION: The results show that the network is effective in studying the functional organization of the auditory cortex and other sensory systems. Depending on the input sub-word, information about the kind of stimuli that activates particular parts of the sensory cortex can be studied.

Modified spike-triggered averaging to assess rat auditory cortex time-frequency receptive fields.

Receptive fields have been used as a tool to study the functional organization of the auditory system in several animals. In this study, they have been used to characterize the primary auditory cortex of rats, specifically to address the differences in auditory processing at different depths of the cortex. The depths chosen; 500, 800 and 1300 microm correspond to layers IV, V and VI of the cortex. This study aims at quantifying the differences in the receptive field in terms of changes in latency, differences in tuning curves, spectral bandwidth and the complexity of the receptive fields. The following preliminary trends were observed: the mean peak latency changes from 10 +/- 4 ms at a depth of 500 microm to 46 +/- 13.08 ms at a depth of 1300 microm. Mean spectral bandwidth changes from 6.4 +/- 0.95 kHz at 500 microm to 8.9 +/- 1.73 KHz at 800 microm to 8 +/- 2.53 KHz at 1300 microm. The mean temporal width changes with increasing depth from 13.6 +/- 1.15 ms at 500 microm to 9.4 +/- 1.88 ms at 1300 microm. Quantitative characterization of the receptive field can be used to generate mathematical models of the auditory neurons, which could aid the computation of stimulation levels for implantable cortical prosthetics. Preliminary data from our experiment on three animals has been presented here.