The neurophysiology of selective attention in visual and auditory systems has been studied in animal models but not with single unit recordings in human. Here, we recorded neuronal activity in the ...ventral intermediate nucleus as well as the ventral oral anterior, and posterior nuclei of the motor thalamus in 25 patients with parkinsonian (n = 6) and non-parkinsonian tremors (n = 19) prior to insertion of deep brain stimulation electrodes while they performed an auditory oddball task. In this task, patients were requested to attend and count the randomly occurring odd or "deviant" tones, ignore the frequent standard tones and report the number of deviant tones at trial completion. The neuronal firing rate decreased compared to baseline during the oddball task. Inhibition was specific to auditory attention as incorrect counting or wrist flicking to the deviant tones did not produce such inhibition. Local field potential analysis showed beta (13-35 Hz) desynchronization in response to deviant tones. Parkinson's disease patients off medications had more beta power than the essential tremor group but less neuronal modulation of beta power to the attended tones, suggesting that dopamine modulates thalamic beta oscillations for selective attention. The current study demonstrated that ascending information to the motor thalamus can be suppressed during auditory attending tasks, providing indirect evidence for the searchlight hypothesis in humans. These results taken together implicate the ventral intermediate nucleus in non-motor cognitive functions, which has implications for the brain circuitry for attention and the pathophysiology of Parkinson's disease.
Neural communication across different spatial and temporal scales is a topic of great interest in clinical and basic science. Phase‐amplitude coupling (PAC) has attracted particular interest due to ...its functional role in a wide range of cognitive and motor functions. Here, we introduce a novel measure termed the direct modulation index (dMI). Based on the classical modulation index, dMI provides an estimate of PAC that is (1) bound to an absolute interval between 0 and +1, (2) resistant against noise, and (3) reliable even for small amounts of data. To highlight the properties of this newly‐proposed measure, we evaluated dMI by comparing it to the classical modulation index, mean vector length, and phase‐locking value using simulated data. We ascertained that dMI provides a more accurate estimate of PAC than the existing methods and that is resilient to varying noise levels and signal lengths. As such, dMI permits a reliable investigation of PAC, which may reveal insights crucial to our understanding of functional brain architecture in key contexts such as behaviour and cognition. A Python toolbox that implements dMI and other measures of PAC is freely available at https://github.com/neurophysiological-analysis/FiNN.
Neural coupling measures are sensitive to higher harmonics of the target oscillation. The direct modulation index is a novel measure that achieves frequency‐specificity by sine‐fitting the phase‐amplitude histogram. dMI allows for reliable estimation of phase‐amplitude coupling with increased robustness to noise and signal duration in comparison to other measures.
Abstract
Deep brain stimulation is a neuromodulatory treatment for managing the symptoms of Parkinson’s disease and other neurological and psychiatric disorders. Electrodes are chronically implanted ...in disease-relevant brain regions and pulsatile electrical stimulation delivery is intended to restore neurocircuit function. However, the widespread interest in the application and expansion of this clinical therapy has preceded an overarching understanding of the neurocircuit alterations invoked by deep brain stimulation. Over the years, various forms of neurophysiological evidence have emerged which demonstrate changes to brain activity across spatiotemporal resolutions; from single neuron, to local field potential, to brain-wide cortical network effects. Though fruitful, such studies have often led to debate about a singular putative mechanism.
In this Update we aim to produce an integrative account of complementary instead of mutually exclusive neurophysiological effects to derive a generalizable concept of the mechanisms of deep brain stimulation. In particular, we offer a critical review of the most common historical competing theories, an updated discussion on recent literature from animal and human neurophysiological studies, and a synthesis of synaptic and network effects of deep brain stimulation across scales of observation, including micro-, meso- and macroscale circuit alterations.
Neumann et al. provide a critical review of competing theories of the mechanisms of action of deep brain stimulation. By integrating findings from neurophysiological studies across different spatiotemporal resolutions, they derive a potential explanation for how deep brain stimulation exerts its effects.
Converging evidence supports that co-stimulation of the subthalamic nucleus and the substantia nigra pars reticulata can be efficacious for the management of the resistant gait impairment in ...Parkinson's disease. In this Correspondence, we comment on a recent publication in Parkinsonism & Related Disorders regarding this novel intervention.
The widespread use of dicamba across the soybean growing regions of the United States resulted in increased off-target movement of this herbicide to susceptible vegetations. There are speculations ...that a drift of sublethal (ultra-low) doses of dicamba can enhance soybean growth and yield through a phenomenon called hormesis. Field studies were conducted during 2018 and 2019 to determine whether soybean growth and yield can be enhanced with ultra-low doses (0.0112–56 g ae ha−1) of dicamba, applied at three growth stages (V2, R1 and R2). There was no evidence that the ultra-low doses of dicamba (0.0112–56 g ae ha−1) increased any of the observed parameters, irrespective of the application timing. Doses of 0.56 g ae ha−1 and lower did not have a negative impact on plant dry matter, height and grain yield, even if causing visible symptomology. The estimated effective doses for 50% reduction in various growth parameters and yield (ED50) indicate that soybean is more sensitive at the R1 compared to the V2 or R2 stages. The estimated visual injury threshold that caused 5% yield loss were 53, 36 and 21% for V2, R1 and R2 stage of dicamba exposure, respectively. The proposed “No Observed Adverse Effect Level” (NOAEL), which is a safe exposure threshold, ranged from 0.0003 to 0.033 g ae ha−1. However, efforts should be made to avoid dicamba drift to susceptible soybean as there is no evidence of enhanced growth and yield with the ultra-low doses.
•Sublethal dicamba doses did not elicit hormesis response in soybean.•Soybean exhibited extreme sensitivity to dicamba, especially in R1 stage.•Visual injury threshold (5% yield loss) ranged from 28 to 53% depending on the soybean growth stage to dicamba exposure.•NOAEL of dicamba was determined and ranged from 0.0003 to 0.033 g ae ha−1.
The mechanisms underlying the therapeutic benefits of deep-brain stimulation (DBS) are complex and varied. Milosevic et al. examine frequency-dependent effects of DBS on cell firing and synaptic ...plasticity in the basal ganglia of patients with Parkinson's disease. Enhanced inhibitory synaptic plasticity, and frequency-dependent potentiation and depression may underlie the observed therapeutic effects.
Abstract
Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease symptoms. The therapeutic benefits of deep brain stimulation are frequency-dependent, but the underlying physiological mechanisms remain unclear. To advance deep brain stimulation therapy an understanding of fundamental mechanisms is critical. The objectives of this study were to (i) compare the frequency-dependent effects on cell firing in subthalamic nucleus and substantia nigra pars reticulata; (ii) quantify frequency-dependent effects on short-term plasticity in substantia nigra pars reticulata; and (iii) investigate effects of continuous long-train high frequency stimulation (comparable to conventional deep brain stimulation) on synaptic plasticity. Two closely spaced (600 µm) microelectrodes were advanced into the subthalamic nucleus (n = 27) and substantia nigra pars reticulata (n = 14) of 22 patients undergoing deep brain stimulation surgery for Parkinson's disease. Cell firing and evoked field potentials were recorded with one microelectrode during stimulation trains from the adjacent microelectrode across a range of frequencies (1-100 Hz, 100 µA, 0.3 ms, 50-60 pulses). Subthalamic firing attenuated with ≥20 Hz (P < 0.01) stimulation (silenced at 100 Hz), while substantia nigra pars reticulata decreased with ≥3 Hz (P < 0.05) (silenced at 50 Hz). Substantia nigra pars reticulata also exhibited a more prominent increase in transient silent period following stimulation. Patients with longer silent periods after 100 Hz stimulation in the subthalamic nucleus tended to have better clinical outcome after deep brain stimulation. At ≥30 Hz the first evoked field potential of the stimulation train in substantia nigra pars reticulata was potentiated (P < 0.05); however, the average amplitude of the subsequent potentials was rapidly attenuated (P < 0.01). This is suggestive of synaptic facilitation followed by rapid depression. Paired pulse ratios calculated at the beginning of the train revealed that 20 Hz (P < 0.05) was the minimum frequency required to induce synaptic depression. Lastly, the average amplitude of evoked field potentials during 1 Hz pulses showed significant inhibitory synaptic potentiation after long-train high frequency stimulation (P < 0.001) and these increases were coupled with increased durations of neuronal inhibition (P < 0.01). The subthalamic nucleus exhibited a higher frequency threshold for stimulation-induced inhibition than the substantia nigra pars reticulata likely due to differing ratios of GABA:glutamate terminals on the soma and/or the nature of their GABAergic inputs (pallidal versus striatal). We suggest that enhancement of inhibitory synaptic plasticity, and frequency-dependent potentiation and depression are putative mechanisms of deep brain stimulation. Furthermore, we foresee that future closed-loop deep brain stimulation systems (with more frequent off stimulation periods) may benefit from inhibitory synaptic potentiation that occurs after high frequency stimulation.
Deep Brain Stimulation (DBS) has become a pivotal therapeutic approach for Parkinson's Disease (PD) and various neuropsychiatric conditions, impacting over 200,000 patients. Despite its widespread ...application, the intricate mechanisms behind DBS remain a subject of ongoing investigation. This article provides an overview of the current knowledge surrounding the local, circuit, and neurobiochemical effects of DBS, focusing on the subthalamic nucleus (STN) as a key target in PD management.
The local effects of DBS, once thought to mimic a reversible lesion, now reveal a more nuanced interplay with myelinated axons, neurotransmitter release, and the surrounding microenvironment. Circuit effects illuminate the modulation of oscillatory activities within the basal ganglia and emphasize communication between the STN and the primary motor cortex. Neurobiochemical effects, encompassing changes in dopamine levels and epigenetic modifications, add further complexity to the DBS landscape.
Finally, within the context of understanding the mechanisms of DBS in PD, the article highlights the controversial question of whether DBS exerts disease-modifying effects in PD. While preclinical evidence suggests neuroprotective potential, clinical trials such as EARLYSTIM face challenges in assessing long-term disease modification due to enrollment timing and methodology limitations. The discussion underscores the need for robust biomarkers and large-scale prospective trials to conclusively determine DBS's potential as a disease-modifying therapy in PD.
Deep brain stimulation procedures offer an invaluable opportunity to study disease through intracranial recordings from awake patients. Here, we address the relationship between single-neuron and ...aggregate-level (local field potential; LFP) activities in the subthalamic nucleus (STN) and thalamic ventral intermediate nucleus (Vim) of patients with Parkinson's disease (
= 19) and essential tremor (
= 16), respectively. Both disorders have been characterized by pathologically elevated LFP oscillations, as well as an increased tendency for neuronal bursting. Our findings suggest that periodic single-neuron bursts encode both pathophysiological beta (13 to 33 Hz; STN) and tremor (4 to 10 Hz; Vim) LFP oscillations, evidenced by strong time-frequency and phase-coupling relationships between the bursting and LFP signals. Spiking activity occurring outside of bursts had no relationship to the LFP. In STN, bursting activity most commonly preceded the LFP oscillation, suggesting that neuronal bursting generated within STN may give rise to an aggregate-level LFP oscillation. In Vim, LFP oscillations most commonly preceded bursting activity, suggesting that neuronal firing may be entrained by periodic afferent inputs. In both STN and Vim, the phase-coupling relationship between LFP and high-frequency oscillation (HFO) signals closely resembled the relationships between the LFP and single-neuron bursting. This suggests that periodic single-neuron bursting is likely representative of a higher spatial and temporal resolution readout of periodic increases in the amplitude of HFOs, which themselves may be a higher resolution readout of aggregate-level LFP oscillations. Overall, our results may reconcile "rate" and "oscillation" models of Parkinson's disease and shed light on the single-neuron basis and origin of pathophysiological oscillations in movement disorders.
PDF
