Deep brain stimulation is an established therapy for Parkinson's disease; however, its effectiveness is hindered by limited understanding of therapeutic mechanisms and the lack of a robust feedback ...signal for tailoring stimulation. We recently reported that subthalamic nucleus deep brain stimulation evokes a neural response resembling a decaying high-frequency (200-500 Hz) oscillation that typically has a duration of at least 10 ms and is localizable to the dorsal sub-region. As the morphology of this response suggests a propensity for the underlying neural circuitry to oscillate at a particular frequency, we have named it evoked resonant neural activity. Here, we determine whether this evoked activity is modulated by therapeutic stimulation – a critical attribute of a feedback signal. Furthermore, we investigated whether any related changes occurred in spontaneous local field potentials. Evoked and spontaneous neural activity was intraoperatively recorded from 19 subthalamic nuclei in patients with Parkinson's disease. Recordings were obtained before therapeutic stimulation and during 130 Hz stimulation at increasing amplitudes (0.67–3.38 mA), ‘washout’ of therapeutic effects, and non-therapeutic 20 Hz stimulation. Therapeutic efficacy was assessed using clinical bradykinesia and rigidity scores. The frequency and amplitude of evoked resonant neural activity varied with the level of 130 Hz stimulation (p < .001). This modulation coincided with improvement in bradykinesia and rigidity (p < .001), and correlated with spontaneous beta band suppression (p < .001). Evoked neural activity occupied a similar frequency band to spontaneous high-frequency oscillations (200-400 Hz), both of which decreased to around twice the 130 Hz stimulation rate. Non-therapeutic stimulation at 20 Hz evoked, but did not modulate, resonant activity. These results indicate that therapeutic deep brain stimulation alters the frequency of evoked and spontaneous oscillations recorded in the subthalamic nucleus that are likely generated by loops within the cortico-basal ganglia-thalamo-cortical network. Evoked resonant neural activity therefore has potential as a tool for providing insight into brain network function and has key attributes of a dynamic feedback signal for optimizing therapy.
•Subthalamic nucleus deep brain stimulation evokes resonant neural activity.•Increasing 130 Hz stimulation to therapeutic levels modulates the evoked response.•Evoked response modulation coincides with improvement in bradykinesia and rigidity.•Evoked response modulation coincides with spontaneous beta-band suppression.•Evoked response frequency correlates with spontaneous high frequency oscillations.
The efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on how closely electrodes are implanted relative to an individual's ideal stimulation ...location. Yet, previous studies have assessed how closely electrodes are implanted relative to the planned location, after homogenizing data to a reference. Thus here, we measured how accurately electrodes are implanted relative to an ideal, dorsal STN stimulation location, assessed on each individual's native imaging. This measure captures not only the technical error of stereotactic implantation but also constraints imposed by planning a suitable trajectory. This cross-sectional study assessed 226 electrodes in 113 consecutive PD patients implanted with bilateral STN-DBS by experienced clinicians utilizing awake, microelectrode guided, surgery. The error (Euclidean distance) between the actual electrode trajectory versus a nominated ideal, dorsal STN stimulation location was determined in each hemisphere on native imaging and predictive factors sought. The median electrode location error was 1.62 mm (IQR = 1.23 mm). This error exceeded 3 mm in 28/226 electrodes (12.4%). Location error did not differ between hemispheres implanted first or second, suggesting brain shift was minimised. Location error did not differ between electrodes positioned with (48/226), or without, a preceding microelectrode trajectory shift (suggesting such shifts were beneficial). There was no relationship between location error and case order, arguing against a learning effect. The proximity of STN-DBS electrodes to a nominated ideal, dorsal STN, stimulation location is highly variable, even when implanted by experienced clinicians with brain shift minimized, and without evidence of a learning effect. Using this measure, we found that assessments on awake patients (microelectrode recordings and clinical examination) likely yielded beneficial intraoperative decisions to improve positioning. In many patients the error is likely to have reduced therapeutic efficacy. More accurate methods to implant STN-DBS electrodes relative to the ideal stimulation location are needed.
Abstract
Background
Some people with Parkinson’s disease (PD) report poorer dynamic postural stability following high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS), which may ...contribute to an increased falls risk. However, some studies have shown low-frequency (60 Hz) STN-DBS improves clinical measures of postural stability, potentially providing support for this treatment. This double-blind randomised crossover study aimed to investigate the effects of low-frequency STN-DBS compared to high-frequency stimulation on objective measures of gait rhythmicity in people with PD.
Methods
During high- and low-frequency STN-DBS and while off-medication, participants completed assessments of symptom severity and walking (e.g., Timed Up-and-Go). During comfortable walking, the harmonic ratio, an objective measures of gait rhythmicity, was derived from head- and trunk-mounted accelerometers to provide insight in dynamic postural stability. Lower harmonic ratios represent less rhythmic walking and have discriminated people with PD who experience falls. Linear mixed model analyses were performed on fourteen participants.
Results
Low-frequency STN-DBS significantly improved medial–lateral and vertical trunk rhythmicity compared to high-frequency. Improvements were independent of electrode location and total electrical energy delivered. No differences were noted between stimulation conditions for temporal gait measures, clinical mobility measures, motor symptom severity or the presence of gait retropulsion.
Conclusions
This study provides evidence for the acute benefits of low-frequency stimulation for gait outcomes in STN-DBS PD patients, independent of electrode location. However, the perceived benefits of this therapy may be diminished for people who experienced significant tremor pre-operatively, as lower frequencies may cause these symptoms to re-emerge.
Trial registration
: This study was prospectively registered with the Australian and New Zealand Clinical Trials Registry on 5 June 2018 (ACTRN12618000944235).
Phosphenes are the fundamental building blocks for presenting meaningful visual information to the visually impaired using a bionic eye device. The aim of this study was to characterize the size, ...shape, and location of phosphenes elicited using a suprachoroidal retinal prosthesis.
Three patients with profound vision loss due to retinitis pigmentosa were implanted with a suprachoroidal electrode array, which was used to deliver charge-balanced biphasic constant-current pulses at various rates, amplitudes, and durations to produce phosphenes. Tasks assessing phosphene appearance, location, overlap, and the patients' ability to recognize phosphenes were performed using a custom psychophysics setup.
Phosphenes were reliably elicited in all three patients, with marked differences in the reported appearances between patients and between electrodes. Phosphene shapes ranged from simple blobs to complex forms with multiple components in both space and time. Phosphene locations within the visual field generally corresponded to the retinotopic position of the stimulating electrodes. Overlap between phosphenes elicited from adjacent electrodes was observed with one patient, which reduced with increasing electrode separation. In a randomized recognition task, two patients correctly identified the electrode being stimulated for 57.2% and 23% of trials, respectively.
Phosphenes of varying complexity were successfully elicited in all three patients, indicating that the suprachoroidal space is an efficacious site for electrically stimulating the retina. The recognition scores obtained with two patients suggest that a suprachoroidal implant can elicit phosphenes containing unique information. This information may be useful when combining phosphenes into more complex and meaningful images that provide functional vision.
We present results from a multiwavelength study of 29 sources (false detection probabilities <5 per cent) from a survey of the Great Observatories Origins Deep Survey-North (GOODS-N) field at 1.1 mm ...using the Astronomical Thermal Emission Camera (AzTEC). Comparing with existing 850 μm Submillimetre Common-User Bolometer Array (SCUBA) studies in the field, we examine differences in the source populations selected at the two wavelengths. The AzTEC observations uniformly cover the entire survey field to a 1σ depth of ∼1 mJy. Searching deep 1.4 GHz Very Large Array (VLA) and Spitzer 3–24 μm catalogues, we identify robust counterparts for 21 1.1 mm sources, and tentative associations for the remaining objects. The redshift distribution of AzTEC sources is inferred from available spectroscopic and photometric redshifts. We find a median redshift of z= 2.7, somewhat higher than z= 2.0 for 850 μm selected sources in the same field, and our lowest redshift identification lies at a spectroscopic redshift z= 1.1460. We measure the 850 μm to 1.1 mm colour of our sources and do not find evidence for ‘850 μm dropouts’, which can be explained by the low signal-to-noise ratio of the observations. We also combine these observed colours with spectroscopic redshifts to derive the range of dust temperatures T, and dust emissivity indices β for the sample, concluding that existing estimates T∼ 30 K and β∼ 1.75 are consistent with these new data.
Speech production relies on motor control and cognitive processing and is linked to cerebellar function. In diseases where the cerebellum is impaired, such as multiple sclerosis (MS), speech ...abnormalities are common and can be detected by instrumental assessments. However, the potential of speech assessments to be used to monitor cerebellar impairment in MS remains unexplored. The aim of this study is to build an objectively measured speech score that reflects cerebellar function, pathology and quality of life in MS. Eighty-five people with MS and 21 controls participated in the study. Speech was independently assessed through objective acoustic analysis and blind expert listener ratings. Cerebellar function and overall disease disability were measured through validated clinical scores; cerebellar pathology was assessed via magnetic resonance imaging, and validated questionnaires informed quality of life. Selected speech variables were entered in a regression model to predict cerebellar function. The resulting model was condensed into one composite speech score and tested for prediction of abnormal 9-hole peg test (9HPT), and for correlations with the remaining cerebellar scores, imaging measurements and self-assessed quality of life. Slow rate of syllable repetition and increased free speech pause percentage were the strongest predictors of cerebellar impairment, complemented by phonatory instability. Those variables formed the acoustic composite score that accounted for 54% of variation in cerebellar function, correlated with cerebellar white matter volume (
r
= 0.3,
p =
0.017), quality of life (
r
= 0.5,
p
< 0.001) and predicted an abnormal 9HPT with 85% accuracy. An objective multi-feature speech metric was highly representative of motor cerebellar impairment in MS.
The suprachoroidal location for a retinal prosthesis provides advantages over other locations in terms of a simplified surgical procedure and a potentially more stable electrode-neural interface. The ...aim of this study was to assess the factors affecting perceptual thresholds, and to optimize stimulus parameters to achieve the lowest thresholds in patients implanted with a suprachoroidal retinal prosthesis.
Three patients with profound vision loss from retinitis pigmentosa were implanted with a suprachoroidal array. Perceptual thresholds measured on individual electrodes were analyzed as a function of stimulus (return configuration, pulse polarity, pulse width, interphase gap, and rate), electrode (area and number of ganged electrodes), and clinical (retinal thickness and electrode-retina distance) parameters.
A total of 92.8% of 904 measurements made up to 680 days post implantation yielded thresholds (range, 44-436 nanocoulombs nC) below the safe charge limit. Thresholds were found to vary between individuals and to depend significantly on electrode-retina distance, negligibly on retinal thickness, and not on electrode area or the number of ganged electrodes. Lowest thresholds were achieved when using a monopolar return, anodic-first polarity, short pulse widths (100 μs) combined with long interphase gaps (500 μs), and high stimulation rates (≥400 pulses per second pps).
With suprachoroidal stimulation, anodic-first pulses with a monopolar return are most efficacious. To enable high rates, an appropriate combination of pulse width and interphase gap must be chosen to ensure low thresholds and electrode voltages. Electrode-retina distance needs to be monitored carefully owing to its influence on thresholds. These results inform implantable stimulator specifications for a suprachoroidal retinal prosthesis. (ClinicalTrials.gov number, NCT01603576.).
Background:
Tremor is present in almost half of multiple sclerosis (MS) patients. The lack of understanding of its pathophysiology is hampering progress in development of treatments.
Objectives:
To ...clarify the structural and functional brain changes associated with the clinical phenotype of upper limb tremor in people with MS.
Methods:
Fifteen healthy controls (46.1 ± 15.4 years), 27 MS participants without tremor (46.7 ± 11.6 years) and 42 with tremor (46.6 ± 11.5 years) were included. Tremor was quantified using the Bain score (0–10) for overall severity, handwriting and Archimedes spiral drawing. Functional magnetic resonance imaging activations were compared between participants groups during performance of a joystick task designed to isolate tremulous movement. Inflammation and atrophy of cerebello-thalamo-cortical brain structures were quantified.
Results:
Tremor participants were found to have atrophy of the cerebellum and thalamus, and higher ipsilateral cerebellar lesion load compared to participants without tremor (p < 0.020). We found higher ipsilateral activation in the inferior parietal lobule, the premotor cortex and supplementary motor area in MS tremor participants compared to MS participants without tremor during the joystick task. Finally, stronger activation in those areas was associated with lower tremor severity.
Conclusion:
Subcortical neurodegeneration and inflammation along the cerebello-thalamo-cortical and cortical functional neuroplasticity contribute to the severity of tremor in MS.
Lyman-alpha emitters are thought to be young, low-mass galaxies with ages of approximately 10(8) yr (refs 1, 2). An overdensity of them in one region of the sky (the SSA 22 field) traces out a ...filamentary structure in the early Universe at a redshift of z approximately 3.1 (equivalent to 15 per cent of the age of the Universe) and is believed to mark a forming protocluster. Galaxies that are bright at (sub)millimetre wavelengths are undergoing violent episodes of star formation, and there is evidence that they are preferentially associated with high-redshift radio galaxies, so the question of whether they are also associated with the most significant large-scale structure growing at high redshift (as outlined by Lyman-alpha emitters) naturally arises. Here we report an imaging survey of 1,100-microm emission in the SSA 22 region. We find an enhancement of submillimetre galaxies near the core of the protocluster, and a large-scale correlation between the submillimetre galaxies and the low-mass Lyman-alpha emitters, suggesting synchronous formation of the two very different types of star-forming galaxy within the same structure at high redshift. These results are in general agreement with our understanding of the formation of cosmic structure.
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