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Parkinson's disease is characterized by exaggerated beta activity (13–35 Hz) in cortico‐basal ganglia motor loops. Beta activity includes both periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and excitation/inhibition balance (i.e. non‐oscillatory activity). However, the relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non‐oscillatory beta activity remain unclear. We recorded, modelled and analysed subthalamic local field potentials in parkinsonian patients at rest while off or on medication. Autoregressive modelling with additive 1/f noise clarified the relationships between measures of beta activity in the time domain (i.e. amplitude and duration of beta bursts) or in the frequency domain (i.e. power and sharpness of the spectral peak) and oscillatory vs. non‐oscillatory activity: burst duration and spectral sharpness are specifically sensitive to oscillatory activity, whereas burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non‐oscillatory activity. Our experimental data confirmed the model predictions and assumptions. We subsequently analysed the effect of levodopa, obtaining strong‐to‐extreme Bayesian evidence that oscillatory beta activity is reduced in patients on vs. off medication, with moderate evidence for absence of modulation of the non‐oscillatory component. Finally, specifically the oscillatory component of beta activity correlated with the rate of motor progression of the disease. Methodologically, these results provide an integrative understanding of beta‐based biomarkers relevant for adaptive deep brain stimulation. Biologically, they suggest that primarily the oscillatory component of subthalamic beta activity is dopamine dependent and may play a role not only in the pathophysiology but also in the progression of Parkinson's disease. Key points: Beta activity in Parkinson's disease includes both true periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and synaptic balance (i.e. non‐oscillatory activity).The relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non‐oscillatory beta activity remain unclear.Burst duration and spectral sharpness are specifically sensitive to oscillatory activity, while burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non‐oscillatory activity.Only the oscillatory component of subthalamic beta activity is dopamine‐dependent.Stronger beta oscillatory activity correlates with faster motor progression of the disease. [ABSTRACT FROM AUTHOR]

We describe a novel application of methodology for high‐density surface electromyography (HDsEMG) decomposition to identify motor unit (MU) firings in response to transcranial magnetic stimulation (TMS). The method is based on the MU filter estimation from HDsEMG decomposition with convolution kernel compensation during voluntary isometric contractions and its application to contractions elicited by TMS. First, we simulated synthetic HDsEMG signals during voluntary contractions followed by simulated motor evoked potentials (MEPs) recruiting an increasing proportion of the motor pool. The estimation of MU filters from voluntary contractions and their application to elicited contractions resulted in high (>90%) precision and sensitivity of MU firings during MEPs. Subsequently, we conducted three experiments in humans. From HDsEMG recordings in first dorsal interosseous and tibialis anterior muscles, we demonstrated an increase in the number of identified MUs during MEPs evoked with increasing stimulation intensity, low variability in the MU firing latency and a proportion of MEP energy accounted for by decomposition similar to voluntary contractions. A negative relationship between the MU recruitment threshold and the number of identified MU firings was exhibited during the MEP recruitment curve, suggesting orderly MU recruitment. During isometric dorsiflexion we also showed a negative association between voluntary MU firing rate and the number of firings of the identified MUs during MEPs, suggesting a decrease in the probability of MU firing during MEPs with increased background MU firing rate. We demonstrate accurate identification of a large population of MU firings in a broad recruitment range in response to TMS via non‐invasive HDsEMG recordings. Key points: Transcranial magnetic stimulation (TMS) of the scalp produces multiple descending volleys, exciting motor pools in a diffuse manner.The characteristics of a motor pool response to TMS have been previously investigated with intramuscular electromyography (EMG), but this is limited in its capacity to detect many motor units (MUs) that constitute a motor evoked potential (MEP) in response to TMS.By simulating synthetic signals with known MU firing patterns, and recording high‐density EMG signals from two human muscles, we show the feasibility of identifying firings of many MUs that comprise a MEP.We demonstrate the identification of firings of a large population of MUs in the broad recruitment range, up to maximal MEP amplitude, with fewer required stimuli compared to intramuscular EMG recordings.The methodology demonstrates an emerging possibility to study responses to TMS on a level of individual MUs in a non‐invasive manner. [ABSTRACT FROM AUTHOR]

Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans. [ABSTRACT FROM AUTHOR]

The SMA is fundamental in planning voluntary movements and execution of some cognitive control operations. Specifically, the SMA has been known to play a dominant role in controlling goal-directed actions as well as those that are highly predicted (i.e., automatic). Yet, the essential contribution of SMA in goal-directed or automatic control of behavior is scarce. Our objective was to test the possible direct role of SMA in automatic and voluntary response inhibition. We separately applied two noninvasive brain stimulation (NIBS) inhibitory techniques over SMA: either continuous theta-burst stimulation using repetitive transcranial magnetic stimulation or transcranial static magnetic field stimulation. Each NIBS technique was performed in a randomized, crossover, sham-controlled design. Before applying NIBS, participants practiced a go/no-go learning task where associations between stimulus and stopping behaviors were created (initiation and inhibition). After applying each NIBS, participants performed a go/no-go task with reversed associations (automatic control) and the stop signal task (voluntary control). Learning associations between stimuli and response initiation/inhibition was achieved by participants and therefore automatized during training. However, no significant differences between real and sham NIBS were found in either automatic (go/no-go learning task) or voluntary inhibition (stop signal task), with Bayesian statistics providing moderate evidence of absence. In conclusion, our results are compatible with a nondirect involvement of SMA in automatic control of behavior. Further studies are needed to prove a noncausal link between prior neuroimaging findings relative to SMA controlling functions and the observed behavior. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD.Objective: Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients.Methods: Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18 F-fluorodopa (FDOPA), and β-amyloid PET (positron emission tomography) images were determined.Results: The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in β-amyloid uptake in the targeted region and no change in FDOPA PET.Conclusions: These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

• tSMS is a portable, inhibitory, non-invasive brain stimulation technique. • Repeated sessions of home-based tSMS of the motor cortex are feasible and safe. • tSMS may provide subjective benefit for the treatment of levodopa-induced dyskinesias. [ABSTRACT FROM AUTHOR]

Directional subthalamic stimulation in Parkinson's disease can increase stimulation threshold for adverse effects and widen the therapeutic window. However, selection of programming settings is time consuming, requiring a thorough monopolar clinical review. To overcome this, programming may be guided by intraoperatively recording local field potential beta oscillations (13–35 Hz). 1) Evaluate whether the power of beta oscillations recorded intraoperatively can predict the clinically most effective directional contacts; and 2) assess long-term directional stimulation outcomes between patients programmed based on clinical monopolar review and patients programmed based on beta activity. We conducted a non-randomized, prospective study with 24 Parkinson's disease patients divided into two groups. In group A (14 patients, 2016–2018), we investigated whether beta activity in the directional contacts correlated with clinical efficacy. Stimulating parameters were selected according to clinical monopolar review and mean follow-up was 27 months. In group B (10 patients, 2018–2019), stimulating parameters were selected according to beta activity and mean follow-up was 13 months. Neurophysiological results showed a strong correlation between clinical efficacy and the low-beta sub-band. Contacts with highest beta peaks increased the therapeutic window by 25%. Selecting the two contacts with highest beta peaks provided an 82% probability of selecting the best clinical contact. Clinical results showed similar improvements in group A (motor score, 72% reduction; levodopa-equivalent daily dose, 65% reduction) and B (72% and 63% reduction, respectively), maintained at long-term follow-up. Our results validate the long-term efficacy of directional stimulation guided by intraoperative local field potential beta oscillations. • Intraoperative LFP beta activity predicts the most effective directional contact. • Intraoperative LFP can guide programming of long term directional stimulation. • Combination of physiological guidance with directionality individualize DBS therapy. • Directional stimulation maintains clinical efficacy at 3 years of follow up. [ABSTRACT FROM AUTHOR]

The application of stimulators implanted directly over deep brain structures (i.e., deep brain stimulation, DBS) was developed in the late 1980s and has since become a mainstream option to treat several neurological conditions. Conventional DBS involves the continuous stimulation of the target structure, which is an approach that cannot adapt to patients' changing symptoms or functional status in real-time. At the beginning of 2000, a more sophisticated form of stimulation was conceived to overcome these limitations. Adaptive deep brain stimulation (aDBS) employs on-demand, contingency-based stimulation to stimulate only when needed. So far, aDBS has been tested in several pathological conditions in animal and human models. To review the current findings obtained from application of aDBS to animal and human models that highlights effects on motor, cognitive and psychiatric behaviors. while aDBS has shown promising results in the treatment of Parkinson's disease and essential tremor, the possibility of its use in less common DBS indications, such as cognitive and psychiatric disorders (Alzheimer's disease, obsessive-compulsive disorder, post-traumatic stress disorder) is still challenging. While aDBS seems to be effective to treat movement disorders (Parkinson's disease and essential tremor), its role in cognitive and psychiatric disorders is to be determined, although neurophysiological assumptions are promising. • Conventional Deep Brain Stimulation, despite its efficacy, presents limitations. • New strategies adapting real-time DBS parameters have been tested in patients. • aDBS is effective in treating Parkinson's disease and tremor. • The evolution of technology allows to include other less common DBS indications. • Implantable devices for aDBS will be available for patients soon. [ABSTRACT FROM AUTHOR]

In Parkinson's disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson's disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson's disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson's disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson's Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson's disease. [ABSTRACT FROM AUTHOR]

A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease-modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood-brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease-modifying therapy in very-early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood-brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies-subthalamotomy and putaminal blood-brain barrier opening-could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Essential tremor is the most common movement disorder in adults. In patients who are not responsive to medical treatment, functional neurosurgery and, more recently, transcranial MR‐guided focused ultrasound thalamotomy are considered effective therapeutic approaches. However, the structural brain changes following a thalamotomy that mediates the clinical improvement are still unclear. In here diffusion weighted images were acquired in a cohort of 24 essential tremor patients before and 3 months after unilateral transcranial MR‐guided focused ultrasound thalamotomy targeting at the posteroventral part of the VIM. Microstructural changes along the DRTT were quantified by means of probabilistic tractography, and later related to the clinical improvement of the patients at 3‐months and at 1‐year after the intervention. In addition the changes along two neighboring tracts, that is, the corticospinal tract and the medial lemniscus, were assessed, as well as the relation between these changes and the presence of side effects. Thalamic lesions produced local and distant alterations along the trajectory of the DRTT, and each correlated with clinical improvement. Regarding side effects, gait imbalance after thalamotomy was associated with greater impact on the DRTT, whereas the presence of paresthesias was significantly related to a higher overlap between the lesion and the medial lemniscus. This work represents the largest series describing the microstructural changes following transcranial MR‐guided focused ultrasound thalamotomy in essential tremor. These results suggest that clinical benefits are specific for the impact on the cerebello‐thalamo‐cortical pathway, thus reaffirming the potential of tractography to aid thalamotomy targeting. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a degenerative disorder of the brain characterized by the impairment of the nigrostriatal system. This impairment leads to specific motor manifestations (i.e., bradykinesia, tremor, and rigidity) that are assessed through clinical examination, scales, and patient-reported outcomes. New sensor-based and wearable technologies are progressively revolutionizing PD care by objectively measuring these manifestations and improving PD diagnosis and treatment monitoring. However, their use is still limited in clinical practice, perhaps because of the absence of external validation and standards for their continuous use at home. In the near future, these systems will progressively complement traditional tools and revolutionize the way we diagnose and monitor patients with PD. [ABSTRACT FROM AUTHOR]

Adaptation of neural responses due to the history of sensory input has been observed across all sensory modalities. However, the computational role of adaptation is not fully understood, especially when one considers neural coding problems in which adaptation increases the ambiguity of the neural responses to simple stimuli. To address this, we quantified the impact of adaptation on the information conveyed by thalamic neurons about paired whisker stimuli in male rat. At the single neuron level, although paired-pulse adaptation reduces the information about the present stimulus, the information per spike increases. Moreover, the adapted response can convey significant amounts of information about whether, when and where a previous stimulus occurred. At the population level, ambiguity of the adapted responses about the present stimulus can be compensated for by large numbers of neurons. Therefore, paired-pulse adaptation does not reduce the discriminability of simple stimuli. It provides information about the spatiotemporal context of stimulus history. [ABSTRACT FROM AUTHOR]

Transcranial static magnetic field stimulation (tSMS) was recently introduced as a promising tool to modulate human cerebral excitability in a noninvasive and portable way. However, a demonstration that static magnetic fields can influence human brain activity and behavior is currently lacking, despite evidence that static magnetic fields interfere with neuronal function in animals. Here we show that transcranial application of a static magnetic field (120 -200 mT at 2-3 cm from the magnet surface) over the human occiput produces a focal increase in the power of alpha oscillations in underlying cortex. Critically, this neurophysiological effect of tSMS is paralleled by slowed performance in a visual search task, selectively for the most difficult target detection trials. The typical relationship between prestimulus alpha power over posterior cortical areas and reaction time (RT) to targets during tSMS is altered such that tSMS-dependent increases in alpha power are associated with longer RTs for difficult, but not easy, target detection trials. Our results directly demonstrate that a powerful magnet placed on the scalp modulates normal brain activity and induces behavioral changes in humans. [ABSTRACT FROM AUTHOR]

The field of invasive brain-machine interfaces (BMIs) is typically associated with neuroprosthetic applications aiming to recover loss of motor function. However, BMIs also represent a powerful tool to address fundamental questions in neuroscience. The observed subjects of BMI experiments can also be considered as indirect observers of their own neurophysiological activity, and the relationship between observed neurons and (artificial) behavior can be genuinely causal rather than indirectly correlative. These two characteristics defy the classical object-observer duality, making BMIs particularly appealing for investigating how information is encoded and decoded by neural circuits in real time, how this coding changes with physiological learning and plasticity, and how it is altered in pathological conditions. Within neuroengineering, BMI is like a tree that opens its branches into many traditional engineering fields, but also extends deep roots into basic neuroscience beyond neuroprosthetics. [ABSTRACT FROM AUTHOR]

Physical exercise promotes neural plasticity in the brain of healthy subjects and modulates pathophysiological neural plasticity after sensorimotor loss, but the mechanisms of this action are not fully understood. After spinal cord injury, cortical reorganization can be maximized by exercising the non-affected body or the residual functions of the affected body. However, exercise per se also produces systemic changes -- such as increased cardiovascular fitness, improved circulation and neuroendocrine changes -- that have a great impact on brain function and plasticity. It is therefore possible that passive exercise therapies typically applied below the level of the lesion in patients with spinal cord injury could put the brain in a more plastic state and promote cortical reorganization. To directly test this hypothesis, we applied passive hindlimb bike exercise after complete thoracic transection of the spinal cord in adult rats. Using western blot analysis, we found that the level of proteins associated with plasticity -- specifically ADCY1 and BDNF -- increased in the somatosensory cortex of transected animals that received passive bike exercise compared to transected animals that received sham exercise. Using electrophysiological techniques, we then verified that neurons in the deafferented hindlimb cortex increased their responsiveness to tactile stimuli delivered to the forelimb in transected animals that received passive bike exercise compared to transected animals that received sham exercise. Passive exercise below the level of the lesion, therefore, promotes cortical reorganization after spinal cord injury, uncovering a brain-body interaction that does not rely on intact sensorimotor pathways connecting the exercised body parts and the brain. [ABSTRACT FROM AUTHOR]

Due to the lack of a specific diagnostic tool for neuropathic pain, a grading system to categorize pain as 'definite', 'probable', 'possible' and 'unlikely' neuropathic was proposed. Somatosensory abnormalities are common in neuropathic pain and it has been suggested that a greater number of abnormalities would be present in patients with 'probable' and 'definite' grades. To test this hypothesis, we investigated the presence of somatosensory abnormalities by means of Quantitative Sensory Testing (QST) in patients with a clinical diagnosis of neuropathic pain and correlated the number of sensory abnormalities and sensory profiles to the different grades. Of patients who were clinically diagnosed with neuropathic pain, only 60% were graded as 'definite' or 'probable', while 40% were graded as 'possible' or 'unlikely' neuropathic pain. Apparently, there is a mismatch between a clinical neuropathic pain diagnosis and neuropathic pain grading. Contrary to the expectation, patients with 'probable' and 'definite' grades did not have a greater number of abnormalities. Instead, similar numbers of somatosensory abnormalities were identified for each grade. The profiles of sensory signs in 'definite' and 'probable' neuropathic pain were not significantly different, but different from the 'unlikely' grade. This latter difference could be attributed to differences in the prevalence of patients with a mixture of sensory gain and loss and with sensory loss only. The grading system allows a separation of neuropathic and non-neuropathic pain based on profiles but not on the total number of sensory abnormalities. Our findings indicate that patient selection based on grading of neuropathic pain may provide advantages in selecting homogenous groups for clinical research. [ABSTRACT FROM AUTHOR]

Fast ripples are a type of transient high-frequency oscillations recorded from the epileptogenic regions of the hippocampus and the temporal cortex of epileptic humans and rodents. These events presumably reflect hypersynchronous bursting of pyramidal cells. However, the oscillatory spectral content of fast ripples varies from 250 to 800 Hz, well above the maximal firing frequency of most hippocampal pyramidal neurons. How such high-frequency oscillations are generated is therefore unclear. Here, we combine computational simulations of fast ripples with multisite and juxtacellular recordings in vivo to examine the underlying mechanisms in the hippocampus of epileptic rats. We show that populations of bursting cells firing individually at 100–400 Hz can create fast ripples according to two main firing regimes: (1) in-phase synchronous firing resulting in “pure” fast ripples characterized by single spectral peaks that reflect single-cell behavior and (2) out-of-phase firing that results in “emergent” fast ripples. Using simulations, we found that fast ripples generated under these two different regimes can be quantitatively separated by their spectral characteristics, and we took advantage of this separability to examine their dynamics in vivo. We found that in-phase firing can reach frequencies up to 300 Hz in the CA1 and up to 400 Hz in the dentate gyrus. The organization of out-of-phase firing is determined by firing delays between cells discharging at low frequencies. The two firing regimes compete dynamically, alternating randomly from one fast ripple event to the next, and they reflect the functional dynamic organization of the different regions of the hippocampus. [ABSTRACT FROM AUTHOR]

Spinal cord injury can produce extensive long-term reorganization of the cerebral cortex. Little is known, however, about the sequence of cortical events starting immediately after the lesion. Here we show that a complete thoracic transection of the spinal cord produces immediate functional reorganization in the primary somatosensory cortex of anesthetized rats. Besides the obvious loss of cortical responses to hindpaw stimuli (below the level of the lesion), cortical responses evoked by forepaw stimuli (above the level of the lesion) markedly increase. Importantly, these increased responses correlate with a slower and overall more silent cortical spontaneous activity, representing a switch to a network state of slow-wave activity similar to that observed during slow-wave sleep. The same immediate cortical changes are observed after reversible pharmacological block of spinal cord conduction, but not after sham. We conclude that the deafferentation due to spinal cord injury can immediately (within minutes) change the state of large cortical networks, and that this state change plays a critical role in the early cortical reorganization after spinal cord injury. [ABSTRACT FROM AUTHOR]

Abstract: Intraoperative neuronal microrecordings can help in localizing the subthalamic nucleus (STN) during stereotactic neurosurgery for deep-brain stimulation (DBS) in Parkinson’s disease. To obtain quantitative information on neuronal spike descriptors, we systematically analysed neuronal spikes in the STN and substantia nigra pars reticulata (SNr) in 31 sides of the brain in awake patients undergoing stereotactic neurosurgery for DBS electrode implantation. In these two structures we evaluated spike amplitude, area, duration, rise time and mean total firing rate. The recording spike density was higher in the STN than in the SNr (94% vs. 28%). Microelectrode recordings showed a larger spike area and amplitude in the SNr than in the STN ([mean±SD] amplitude: 46.7±31.1 vs. 36.3±29.6 μV; area: 25.6±24.2 vs. 36.7±21.4 μVmsec), a higher total firing rate at rest in the SNr than in the STN (78.6±53.5 vs. 61.9±40.8 Hz), and a longer duration and rise time in the SNr than in the STN (duration: 2.0±1 vs. 1.3±0.6 ms; rise time: 0.95±0.6 vs. 0.67±0.3 ms). Our analysis also revealed sex-related differences in the studied spike descriptors, paralleling recent findings from deep electroencephalography recordings. In the STN, males had larger spike area and amplitude (amplitude: 41.97±32.57 vs. 26.2±19.7 μV; area: 31.8±26.4 vs. 13.0±10.6 μVmsec), whereas females had higher mean total firing rate (66.7±53.4 vs. 82.8±50.8 Hz). Our results have implications for clinical practice and the development of algorithms for the neurophysiological identification of the STN during stereotactic neurosurgery for Parkinson’s disease, based on the on-line automated computation of multiple spike-variables. [Copyright &y& Elsevier]

The application of deep brain stimulation (DBS) for the treatment of Parkinson's disease offered a direct "insight" into the human electrical activity in subcortical structures. The analysis of the oscillatory activity [local field potentials (LFPs)] disclosed the importance of rhythms and of interactions between rhythms in the human basal ganglia information processing. The aim of this study was to investigate the existence of possible nonlinear interactions between LFP rhythms characterizing the output structure of the basal ganglia, the globus pallidus internus, by means of bispectral analysis. The results of this study disclosed that the rhythms expressed in the globus pallidus internus of the untreated parkinsonian patient are not independent and, in particular, the low-beta (13-20 Hz) band generates harmonics that are included in the high-beta (20-35 Hz) band. Conversely, in the dystonic globus pallidus, as well as in the parkinsonian globus pallidus after dopaminergic medication (i.e., in the more "normal" condition), the rhythms are substantially independent and characterized by a strong activity in the low-frequency band that generates a second harmonic (4-14 Hz), mostly included in the same band. The interactions between rhythms in the human globus pallidus are therefore different in different pathologies and in different patient's states. The interpretation of these interactions is likely critical for fully understanding the role of LFP rhythms in the pathophysiology of human basal ganglia. [ABSTRACT FROM AUTHOR]

Summary: Ripples are sharp-wave-associated field oscillations (100–300 Hz) recorded in the hippocampus during behavioral immobility and slow-wave sleep. In epileptic rats and humans, a different and faster oscillation (200–600Hz), termed fast ripples, has been described. However, the basic mechanisms are unknown. Here, we propose that fast ripples emerge from a disorganized ripple pattern caused by unreliable firing in the epileptic hippocampus. Enhanced synaptic activity is responsible for the irregular bursting of CA3 pyramidal cells due to large membrane potential fluctuations. Lower field interactions and a reduced spike-timing reliability concur with decreased spatial synchronization and the emergence of fast ripples. Reducing synaptically driven membrane potential fluctuations improves both spike-timing reliability and spatial synchronization and restores ripples in the epileptic hippocampus. Conversely, a lower spike-timing reliability, with reduced potassium currents, is associated with ripple shuffling in normal hippocampus. Therefore, fast ripples may reflect a pathological desynchronization of the normal ripple pattern. [Copyright &y& Elsevier]