Objective. Deep brain stimulation (DBS) is an established and valid therapy for a variety of pathological conditions ranging from motor to cognitive disorders. Still, much of the DBS-related ...mechanism of action is far from being understood, and there are several side effects of DBS whose origin is unclear. In the last years DBS limitations have been tackled by a variety of approaches, including adaptive deep brain stimulation (aDBS), a technique that relies on using chronically implanted electrodes on 'sensing mode' to detect the neural markers of specific motor symptoms and to deliver on-demand or modulate the stimulation parameters accordingly. Here we will review the state of the art of the several approaches to improve DBS and summarize the main challenges toward the development of an effective aDBS therapy. Approach. We discuss models of basal ganglia disorders pathogenesis, hardware and software improvements for conventional DBS, and candidate neural and non-neural features and related control strategies for aDBS. Main results. We identify then the main operative challenges toward optimal DBS such as (i) accurate target localization, (ii) increased spatial resolution of stimulation, (iii) development of in silico tests for DBS, (iv) identification of specific motor symptoms biomarkers, in particular (v) assessing how LFP oscillations relate to behavioral disfunctions, and (vi) clarify how stimulation affects the cortico-basal-ganglia-thalamic network to (vii) design optimal stimulation patterns. Significance. This roadmap will lead neural engineers novel to the field toward the most relevant open issues of DBS, while the in-depth readers might find a careful comparison of advantages and drawbacks of the most recent attempts to improve DBS-related neuromodulatory strategies.
Freezing of gait is a disabling symptom of Parkinson's disease that causes a paroxysmal inability to generate effective stepping. The underlying pathophysiology has recently migrated towards a ...dysfunctional supraspinal locomotor network, but the actual network derangements during ongoing gait freezing are unknown. We investigated the communication between the cortex and the subthalamic nucleus, two main nodes of the locomotor network, in seven freely-moving subjects with Parkinson's disease with a novel deep brain stimulation device, which allows on-demand recording of subthalamic neural activity from the chronically-implanted electrodes months after the surgical procedure. Multisite neurophysiological recordings during (effective) walking and ongoing gait freezing were combined with kinematic measurements and individual molecular brain imaging studies. Patients walked in a supervised environment closely resembling everyday life challenges. We found that during (effective) walking, the cortex and subthalamic nucleus were synchronized in a low frequency band (4-13 Hz). In contrast, gait freezing was characterized in every patient by low frequency cortical-subthalamic decoupling in the hemisphere with less striatal dopaminergic innervation. Of relevance, this decoupling was already evident at the transition from normal (effective) walking into gait freezing, was maintained during the freezing episode, and resolved with recovery of the effective walking pattern. This is the first evidence for a decoding of the networked processing of locomotion in Parkinson's disease and suggests that freezing of gait is a 'circuitopathy' related to a dysfunctional cortical-subcortical communication. A successful therapeutic approach for gait freezing in Parkinson's disease should aim at directly targeting derangements of neural network dynamics.
Abnormal beta band activity in the subthalamic nucleus (STN) is known to be exaggerated in patients with Parkinson’s disease, and the amplitude of such activity has been associated with akinetic ...rigid symptoms. New devices for deep brain stimulation (DBS) that operate by adapting the stimulation parameters generally rely on the detection of beta activity amplitude modulations in these patients. Movement-related frequency modulation of beta oscillatory activity has been poorly investigated, despite being an attractive variable for extracting information about basal ganglia activity.
We studied the STN oscillatory activity associated with locomotion and proposed a new approach to extract movement related information from beta band activity.
We recorded bilateral local field potential of the STN in eight parkinsonian patients implanted with DBS electrodes during upright quiet standing and unperturbed walking. Neurophysiological recordings were combined with kinematic measurements and individual molecular brain imaging studies. We then determined the information carried by the STN oscillatory activity about locomotion and we identified task-specific biomarkers.
We found a gait-related peak frequency modulation of the beta band of STN recordings of parkinsonian patients. This novel biomarker and the associated power modulations were highly informative to detect the walking state (with respect to standing) in each single patient.
Frequency modulation in the human STN represents a fundamental aspect of information processing of locomotion. Our information-driven approach could significantly enrich the spectrum of Parkinson’s neural markers, with input signals encoding ongoing tasks execution for an appropriate online tuning of DBS delivery.
•A peak frequency modulation of beta oscillatory activity of STN encodes gait in PD.•Information analysis can identify novel biomarkers for aDBS.•Most Informative Frequency power modulation is a promising input signal for aDBS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Speech impairment is commonly reported in Parkinson's disease and is not consistently improved by available therapies – including deep brain stimulation of the subthalamic nucleus (STN-DBS), which ...can worsen communication performance in some patients. Improving the outcome of STN-DBS on speech is difficult due to our incomplete understanding of the contribution of the STN to fluent speaking.
To assess the relationship between subthalamic neural activity and speech production and intelligibility.
We investigated bilateral STN local field potentials (LFPs) in nine parkinsonian patients chronically implanted with DBS during overt reading. LFP spectral features were correlated with clinical scores and measures of speech intelligibility.
Overt reading was associated with increased beta-low (1220) Hz) power in the left STN, whereas speech intelligibility correlated positively with beta-high (2030) Hz) power in the right STN.
We identified separate contributions from frequency and brain lateralization of the STN in the execution of an overt reading motor task and its intelligibility. This subcortical organization could be exploited for new adaptive stimulation strategies capable of identifying the occurrence of speaking behavior and facilitating its functional execution.
•Speech impairment is common in Parkinson's disease (PD)•Deep brain stimulation of the subthalamic nucleus (STN) can worsen speech in PD•Left STN low-beta activity is increased during overt reading•Right STN high-beta power positively relates with speech intelligibility•Speech intelligibility can be measured with semi-automatized algorithms
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar ...syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.
Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin ...biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with 123I-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical work-up including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial 123I-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The 123I-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 ± 0.63 vs. 2.91 ± 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 ± 0.51 vs. 2.74 ± 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.
•p-alpha-syn in dermal autonomic structures is associated with cardiac denervation.•PD and MSA share pathophysiological mechanisms of the peripheral nervous system.•p-alpha-syn pathology in somatosensory fibers is not related to cardiac denervation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In addition to general considerations of locomotor network derangements in animal models and humans, specific aspects of locomotor control are discussed, such as the role of subpopulations of ...striatal neurons, the importance of low-frequency electromyographic activity of synergistic muscles and anticipatory postural adjustments during gait initiation. Particularly, the benefits of deep brain stimulation with trouble-shooting options for gait are reviewed and new stimulation paradigms, e.g., combined subthalamic and nigral stimulation and lead symmetry are presented to improve gait control in parkinsonian patients. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The diagnosis of Parkinson's disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are ...under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM's avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD.
Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the substantia nigra. Our main objective was to ...determine the correspondence between changes in the substantia nigra, evident in neuromelanin and iron sensitive magnetic resonance imaging (MRI), and dopaminergic striatal innervation loss in patients with PD. Eighteen patients and 18 healthy control subjects were included in the study. Using neuromelanin-MRI, we measured the volume of the substantia nigra and the contrast-to-noise-ratio between substantia nigra and a background region. The apparent transverse relaxation rate and magnetic susceptibility of the substantia nigra were calculated from dual-echo MRI. Striatal dopaminergic innervation was measured as density of dopamine transporter (DAT) by means of single-photon emission computed tomography and (123)I N-ω-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) tropane. Patients showed a reduced volume of the substantia nigra and contrast-to-noise-ratio and both positively correlated with the corresponding striatal DAT density. The apparent transverse relaxation rate and magnetic susceptibility values of the substantia nigra did not differ between patients and healthy controls. The best predictor of DAT reduction was the volume of the substantia nigra. Clinical and imaging correlations were also investigated for the locus coeruleus. Our results suggest that neuromelanin-MRI can be used for quantifying substantia nigra pathology in PD where it closely correlates with dopaminergic striatal innervation loss. Longitudinal studies should further explore the role of Neuromelanin-MRI as an imaging biomarker of PD, especially for subjects at risk of developing the disease.
Gait disturbances are common manifestations of Parkinson's disease (PD), with unmet therapeutic needs. Inertial measurement units (IMUs) are capable of monitoring gait, but they lack ...neurophysiological information that may be crucial for studying gait disturbances in these patients. Here, we present a machine learning approach to approximate IMU angular velocity profiles and subsequently gait events using electromyographic (EMG) channels during overground walking in patients with PD. We recorded six parkinsonian patients while they walked for at least three minutes. Patient-agnostic regression models were trained on temporally embedded EMG time series of different combinations of up to five leg muscles bilaterally (i.e., tibialis anterior, soleus, gastrocnemius medialis, gastrocnemius lateralis, and vastus lateralis). Gait events could be detected with high temporal precision (median displacement of <50 ms), low numbers of missed events (<2%), and next to no false-positive event detections (<0.1%). Swing and stance phases could thus be determined with high fidelity (median F1-score of ~0.9). Interestingly, the best performance was obtained using as few as two EMG probes placed on the left and right vastus lateralis. Our results demonstrate the practical utility of the proposed EMG-based system for gait event prediction, which allows the simultaneous acquisition of an electromyographic signal to be performed. This gait analysis approach has the potential to make additional measurement devices such as IMUs and force plates less essential, thereby reducing financial and preparation overheads and discomfort factors in gait studies.
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