Deep brain stimulation for refractory major depressive disorder: a comprehensive review.

Deep brain stimulation (DBS) has emerged as a promising treatment for select patients with refractory major depressive disorder (MDD). The clinical effectiveness of DBS for MDD has been demonstrated in meta-analyses, open-label studies, and a few controlled studies. However, randomized controlled trials have yielded mixed outcomes, highlighting challenges that must be addressed prior to widespread adoption of DBS for MDD. These challenges include tracking MDD symptoms objectively to evaluate the clinical effectiveness of DBS with sensitivity and specificity, identifying the patient population that is most likely to benefit from DBS, selecting the optimal patient-specific surgical target and stimulation parameters, and understanding the mechanisms underpinning the therapeutic benefits of DBS in the context of MDD pathophysiology. In this review, we provide an overview of the latest clinical evidence of MDD DBS effectiveness and the recent technological advancements that could transform our understanding of MDD pathophysiology, improve the clinical outcomes for MDD DBS, and establish a path forward to develop more effective neuromodulation therapies to alleviate depressive symptoms.

Motor network gamma oscillations in chronic home recordings predict dyskinesia in Parkinson's disease.

In Parkinson's disease, imbalances between 'antikinetic' and 'prokinetic' patterns of neuronal oscillatory activity are related to motor dysfunction. Invasive brain recordings from the motor network have suggested that medical or surgical therapy can promote a prokinetic state by inducing narrowband gamma rhythms (65-90 Hz). Excessive narrowband gamma in the motor cortex promotes dyskinesia in rodent models, but the relationship between narrowband gamma and dyskinesia in humans has not been well established. To assess this relationship, we used a sensing-enabled deep brain stimulator system, attached to both motor cortex and basal ganglia (subthalamic or pallidal) leads, paired with wearable devices that continuously tracked motor signs in the contralateral upper limbs. We recorded 984 h of multisite field potentials in 30 hemispheres of 16 subjects with Parkinson's disease (2/16 female, mean age 57 ± 12 years) while at home on usual antiparkinsonian medications. Recordings were done 2-4 weeks after implantation, prior to starting therapeutic stimulation. Narrowband gamma was detected in the precentral gyrus, subthalamic nucleus or both structures on at least one side of 92% of subjects with a clinical history of dyskinesia. Narrowband gamma was not detected in the globus pallidus. Narrowband gamma spectral power in both structures co-fluctuated similarly with contralateral wearable dyskinesia scores (mean correlation coefficient of ρ = 0.48 with a range of 0.12-0.82 for cortex, ρ = 0.53 with a range of 0.5-0.77 for subthalamic nucleus). Stratification analysis showed the correlations were not driven by outlier values, and narrowband gamma could distinguish 'on' periods with dyskinesia from 'on' periods without dyskinesia. Time lag comparisons confirmed that gamma oscillations herald dyskinesia onset without a time lag in either structure when using 2-min epochs. A linear model incorporating the three oscillatory bands (beta, theta/alpha and narrowband gamma) increased the predictive power of dyskinesia for several subject hemispheres. We further identified spectrally distinct oscillations in the low gamma range (40-60 Hz) in three subjects, but the relationship of low gamma oscillations to dyskinesia was variable. Our findings support the hypothesis that excessive oscillatory activity at 65-90 Hz in the motor network tracks with dyskinesia similarly across both structures, without a detectable time lag. This rhythm may serve as a promising control signal for closed-loop deep brain stimulation using either cortical or subthalamic detection.

Advances in Deep Brain Stimulation: From Mechanisms to Applications.

Deep brain stimulation (DBS) is an effective therapy for various neurologic and neuropsychiatric disorders, involving chronic implantation of electrodes into target brain regions for electrical stimulation delivery. Despite its safety and efficacy, DBS remains an underutilized therapy. Advances in the field of DBS, including in technology, mechanistic understanding, and applications have the potential to expand access and use of DBS, while also improving clinical outcomes. Developments in DBS technology, such as MRI compatibility and bidirectional DBS systems capable of sensing neural activity while providing therapeutic stimulation, have enabled advances in our understanding of DBS mechanisms and its application. In this review, we summarize recent work exploring DBS modulation of target networks. We also cover current work focusing on improved programming and the development of novel stimulation paradigms that go beyond current standards of DBS, many of which are enabled by sensing-enabled DBS systems and have the potential to expand access to DBS.

Responsive Versus Continuous Deep Brain Stimulation for Speech in Essential Tremor: A Pilot Study.

BACKGROUND: Responsive deep brain stimulation (rDBS) uses physiological signals to deliver stimulation when needed. rDBS is hypothesized to reduce stimulation-induced speech effects associated with continuous DBS (cDBS) in patients with essential tremor (ET). OBJECTIVE: To determine if rDBS reduces cDBS speech-related side effects while maintaining tremor suppression. METHODS: Eight ET participants with thalamic DBS underwent unilateral rDBS. Both speech evaluations and tremor severity were assessed across three conditions (DBS OFF, cDBS ON, and rDBS ON). Speech was analyzed using intelligibility ratings. Tremor severity was scored using the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: During unilateral cDBS, participants experienced reduced speech intelligibility (P = 0.025) compared to DBS OFF. rDBS was not associated with a deterioration of intelligibility. Both rDBS (P = 0.026) and cDBS (P = 0.038) improved the contralateral TRS score compared to DBS OFF. CONCLUSIONS: rDBS maintained speech intelligibility without loss of tremor suppression. A larger prospective chronic study of rDBS in ET is justified. © 2024 International Parkinson and Movement Disorder Society.

Optic Neuropathy Revealing Severe Superficial Siderosis in the Setting of Long-standing Low-grade Intracranial Neoplasm.

Two cases of optic neuropathy due to superficial siderosis (SS) are reported in two patients, aged 29 and 38 years, operated for intracranial neoplasms, the first one with a desmoplasic infantile ganglioglioma excised in 1991, and the other one with a pilocytic astrocytoma, operated on in 1997, 1998 and 2016. Both patients presented with progressive loss of visual acuity, as a result of bilateral optic nerve atrophy, as well as unsteadiness, ataxic gait and hearing loss. Magnetic resonance imaging (MRI) of the brain and spine, including gradient echo (GRE) T2-weighted acquisitions, revealed thin optic nerves and strong hypointensity with susceptibility artefacts corresponding to haemosiderin deposits within the meningeal layers of the spine, the infra- and supratentorial spaces of the brain and the peri-optic sheaths in both patients. The cerebrospinal fluid (CSF) was macroscopically haemorrhagic in one patient, who underwent a dynamic myelography, which failed to reveal any trans-dural CSF leakage. Neuro-ophthalmological symptoms due to SS, such as visual acuity loss, have been scarcely reported. MRI using GRE T2-weighted sequences highlighting the presence of haemosiderin deposits plays a key role in the diagnosis of this condition. Treatment should aim at preventing haemosiderin deposition by treating the cause of the subarachnoid bleeding.

Influence of prior and visual information on eye movements in amblyopic children.

This study analyzed the characteristics of pursuit and assessed the influence of prior and visual information on eye velocity and saccades in amblyopic and control children, in comparison to adults. Eye movements of 41 children (21 amblyopes and 20 controls) were compared to eye movements of 55 adults (18 amblyopes and 37 controls). Participants were asked to pursue a target moving at a constant velocity. The target was either a 'standard' target, with a uniform color intensity, or a 'noisy' target, with blurry edges, to mimic the blurriness of an amblyopic eye. Analysis of pursuit patterns showed that the onset was delayed, and the gain was decreased in control children with a noisy target in comparison to amblyopic or control children with a standard target. Furthermore, a significant effect of prior and visual information on pursuit velocity and saccades was found across all participants. Moreover, the modulation of the effect of visual information on the pursuit velocity by group, that is amblyopes or controls with a standard target, and controls with a noisy target, was more limited in children. In other words, the effect of visual information was higher in control adults with a standard target compared to control children with the same target. However, in the case of a blurry target, either in control participants with a noisy target or in amblyopic participants with a standard target, the effect of visual information was larger in children.

Elevated Mood States in Patients With Parkinson's Disease Treated With Deep Brain Stimulation: Diagnosis and Management Strategies.

OBJECTIVE: Deep brain stimulation (DBS) is an effective surgical treatment for patients with Parkinson's disease (PD). DBS therapy, particularly with the subthalamic nucleus (STN) target, has been linked to rare psychiatric complications, including depression, impulsivity, irritability, and suicidality. Stimulation-induced elevated mood states can also occur. These episodes rarely meet DSM-5 criteria for mania or hypomania. METHODS: The investigators conducted a chart review of 82 patients with PD treated with DBS. RESULTS: Nine (11%) patients developed stimulation-induced elevated mood. Five illustrative cases are described (all males with STN DBS; mean age=62.2 years [SD=10.5], mean PD duration=8.6 years [SD=1.6]). Elevated mood states occurred during or shortly after programming changes, when more ventral contacts were used (typically in monopolar mode) and lasted minutes to months. Four patients experienced elevated mood at low amplitudes (1.0 V/1.0 mA); all had psychiatric risk factors (history of impulse-control disorder, dopamine dysregulation syndrome, substance use disorder, and/or bipolar diathesis) that likely contributed to mood destabilization. CONCLUSIONS: Preoperative DBS evaluations should include a thorough assessment of psychiatric risk factors. The term "stimulation-induced elevated mood states" is proposed to describe episodes of elevated, expansive, or irritable mood and psychomotor agitation that occur during or shortly after DBS programming changes and may be associated with increased goal-directed activity, impulsivity, grandiosity, pressured speech, flight of ideas, or decreased need for sleep and may persist beyond stimulation adjustments. This clinical phenomenon should be considered for inclusion in the bipolar disorder category in future DSM revisions, allowing for increased recognition and appropriate management.

Eight cylindrical contact lead recordings in the subthalamic region localize beta oscillations source to the dorsal STN.

BACKGROUND: In Parkinson's disease (PD) patients, the subthalamic nucleus (STN) has prominent oscillatory activity in the beta band, which may be related to the motor symptoms severity. Local field potential (LFP) studies using standard four-contact deep brain stimulation (DBS) leads indicate that the source of beta activity in the STN region is the dorsolateral segment of the nucleus. However, these leads have few contacts outside of the STN, making the source localization of beta activity around the STN region uncertain. OBJECTIVE: This study aimed to investigate the electrophysiological characteristics of the STN and the surrounding area in PD to better locate the source of these oscillations and their clinical relevance. METHODS: Eight PD patients were bilaterally implanted in the STN with the eight ring-contact DBS lead (Boston Scientific Corporation). LFPs were recorded intra-operatively from each DBS contact in the off medication state at rest. Each contact location was normalized relative to the STN borders based on microelectrode recordings. For each recording, power spectral density was computed, averaged over multiple frequency bands and phase reversal analysis was used to localize the source of oscillatory activity. Beta burst, high-frequency activity (HFA), and phase-amplitude coupling (PAC) were also computed. Neurophysiological signatures were correlated with hemibody symptoms severity and clinical outcomes. RESULTS: Beta band power and phase reversal localized the beta oscillator to the dorsal STN and correlated with pre-operative off medication hemibody bradykinesia and rigidity score. The contact along the electrode with the largest beta oscillatory power co-localized with the independently chosen optimized contact used for long-term chronic DBS. Lastly, beta bursting, HFA, and Beta-HFA PAC co-localized with the beta oscillator at the dorsal STN, and Beta-HFA PAC correlated with DBS effect. CONCLUSIONS: Our findings support the hypothesis that the primary source of beta oscillations is located in dorsal STN, and argue against the alternative hypothesis that beta activity in the STN region arises from volume conduction from other sources. We demonstrate intrinsic STN beta-HFA PAC as an independent marker of DBS effect.

Cortical Potentials Evoked by Subthalamic Stimulation Demonstrate a Short Latency Hyperdirect Pathway in Humans.

A monosynaptic projection from the cortex to the subthalamic nucleus is thought to have an important role in basal ganglia function and in the mechanism of therapeutic subthalamic deep-brain stimulation, but in humans the evidence for its existence is limited. We sought physiological confirmation of the cortico-subthalamic hyperdirect pathway using invasive recording techniques in patients with Parkinson's disease (9 men, 1 woman). We measured sensorimotor cortical evoked potentials using a temporary subdural strip electrode in response to low-frequency deep-brain stimulation in patients undergoing awake subthalamic or pallidal lead implantations. Evoked potentials were grouped into very short latency (<2 ms), short latency (2-10 ms), and long latency (10-100 ms) from the onset of the stimulus pulse. Subthalamic and pallidal stimulation resulted in very short-latency evoked potentials at 1.5 ms in the primary motor cortex accompanied by EMG-evoked potentials consistent with corticospinal tract activation. Subthalamic, but not pallidal stimulation, resulted in three short-latency evoked potentials at 2.8, 5.8, and 7.7 ms in a widespread cortical distribution, consistent with antidromic activation of the hyperdirect pathway. Long-latency potentials were evoked by both targets, with subthalamic responses lagging pallidal responses by 10-20 ms, consistent with orthodromic activation of the thalamocortical pathway. The amplitude of the first short-latency evoked potential was predictive of the chronic therapeutic stimulation contact.SIGNIFICANCE STATEMENT This is the first physiological demonstration of the corticosubthalamic hyperdirect pathway and its topography at high spatial resolution in humans. We studied cortical potentials evoked by deep-brain stimulation in patients with Parkinson's disease undergoing awake lead implantation surgery. Subthalamic stimulation resulted in multiple short-latency responses consistent with activation of hyperdirect pathway, whereas no such response was present during pallidal stimulation. We contrast these findings with very short latency, direct corticospinal tract activations, and long-latency responses evoked through polysynaptic orthodromic projections. These findings underscore the importance of incorporating the hyperdirect pathway into models of human basal ganglia function.

Pallidal Deep-Brain Stimulation Disrupts Pallidal Beta Oscillations and Coherence with Primary Motor Cortex in Parkinson's Disease.

In Parkinson's disease (PD), subthalamic nucleus beta band oscillations are decreased by therapeutic deep-brain stimulation (DBS) and this has been proposed as important to the mechanism of therapy. The globus pallidus is a common alternative target for PD with similar motor benefits as subthalamic DBS, but effects of pallidal stimulation in PD are not well studied, and effects of pallidal DBS on cortical function in PD are unknown. Here, in 20 PD and 14 isolated dystonia human patients of both genders undergoing pallidal DBS lead implantation, we recorded local field potentials from the globus pallidus and in a subset of these, recorded simultaneous sensorimotor cortex ECoG potentials. PD patients had elevated resting pallidal low beta band (13-20 Hz) power compared with dystonia patients, whereas dystonia patients had elevated resting pallidal theta band (4-8 Hz) power compared with PD. We show that this results in disease-specific patterns of interaction between the pallidum and motor cortex: PD patients demonstrated relatively elevated phase coherence with the motor cortex in the beta band and this was reduced by therapeutic pallidal DBS. Dystonia patients had greater theta band phase coherence. Our results support the hypothesis that specific motor phenomenology observed in movement disorders are associated with elevated network oscillations in specific frequency bands, and that DBS in movement disorders acts in general by disrupting elevated synchronization between basal ganglia output and motor cortex.SIGNIFICANCE STATEMENT Perturbations in synchronized oscillatory activity in brain networks are increasingly recognized as important features in movement disorders. The globus pallidus is a commonly used target for deep-brain stimulation (DBS) in Parkinson's disease (PD), however, the effects of pallidal DBS on basal ganglia and cortical oscillations are unknown. Using invasive intraoperative recordings in patients with PD and isolated dystonia, we found disease-specific patterns of elevated oscillatory synchronization within the pallidum and in coherence between pallidum and motor cortex. Therapeutic pallidal DBS in PD suppresses these elevated synchronizations, reducing the influence of diseased basal ganglia on cortical physiology. We propose a general mechanism for DBS therapy in movement disorders: functional disconnection of basal ganglia output and motor cortex by coherence suppression.

Altered Prefrontal Theta and Gamma Activity during an Emotional Face Processing Task in Parkinson Disease.

Patients with Parkinson disease (PD) often experience nonmotor symptoms including cognitive deficits, depression, and anxiety. Cognitive and affective processes are thought to be mediated by prefrontal cortico-basal ganglia circuitry. However, the topography and neurophysiology of prefrontal cortical activity during complex tasks are not well characterized. We used high-resolution electrocorticography in pFC of patients with PD and essential tremor, during implantation of deep brain stimulator leads in the awake state, to understand disease-specific changes in prefrontal activity during an emotional face processing task. We found that patients with PD had less task-related theta-alpha power and greater task-related gamma power in the dorsolateral pFC, inferior frontal cortex, and lateral OFC. These findings support a model of prefrontal neurophysiological changes in the dopamine-depleted state, in which focal areas of hyperactivity in prefrontal cortical regions may compensate for impaired long-range interactions mediated by low-frequency rhythms. These distinct neurophysiological changes suggest that nonmotor circuits undergo characteristic changes in PD.

Effect of levodopa on electroencephalographic biomarkers of the parkinsonian state.

The objective of this study was to evaluate proposed electroencephalographic (EEG) biomarkers of Parkinson's disease (PD) and test their correlation with motor impairment in a new, well-characterized cohort of PD patients and controls. Sixty-four-channel EEG was recorded from 14 patients with rigid-akinetic PD with minimal tremor and from 14 age-matched healthy controls at rest and during voluntary movement. Patients were tested off and on medication during a single session. Recordings were analyzed for phase-amplitude coupling over sensorimotor cortex and for pairwise coherence from all electrode pairs in the recording montage (distributed coherence). Phase-amplitude coupling and distributed coherence were found to be elevated Off compared with On levodopa, and their reduction was correlated with motor improvement. In the Off medication state, phase-amplitude coupling was greater in sensorimotor contacts contralateral to the most affected body part and reduced by voluntary movement. We conclude that phase-amplitude coupling and distributed coherence are cortical biomarkers of the parkinsonian state that are detectable noninvasively and may be useful as objective aids for management of dopaminergic therapy. Several analytic methods may be used for noninvasive measurement of abnormal brain synchronization in PD. Calculation of phase-amplitude coupling requires only a single electrode over motor cortex. NEW & NOTEWORTHY Several EEG biomarkers of the parkinsonian state have been proposed that are related to abnormal cortical synchronization. We report several new findings in this study: correlations of EEG markers of synchronization with specific motor signs of Parkinson's disease (PD), and demonstration that one of the EEG markers, phase-amplitude coupling, is more elevated over the more clinically affected brain hemisphere. These findings underscore the potential utility of scalp EEG for objective, noninvasive monitoring of medication state in PD.

Pallidal thermolesion unleashes gamma oscillations in the motor cortex in Parkinson's disease.

BACKGROUND: In Parkinson's disease, the emergence of motor dysfunction is thought to be related to an imbalance between "antikinetic" and "prokinetic" patterns of oscillatory activity in the motor network. Invasive recordings from the basal ganglia and cortex in surgical patients have suggested that levodopa and therapeutic deep brain stimulation can suppress antikinetic beta band (13-30 Hz) rhythms while promoting prokinetic gamma band (60-90 Hz) rhythms. Surgical ablation of the globus pallidus internus is one of the oldest effective therapies for Parkinson's disease and produces remarkably immediate relief of rigidity and bradykinesia, but its effects on oscillatory activity in the motor network have not been studied. OBJECTIVES: We characterize the effects of pallidotomy on cortical oscillatory activity in Parkinson's patients. METHODS: Using a temporary 6-contact lead placed over the sensorimotor cortex in the subdural space, we recorded acute changes in cortical oscillatory activities in 3 Parkinson's disease patients undergoing pallidotomy and compared the results to that of 3 essential tremor patients undergoing thalamotomy. RESULTS: In all 3 Parkinson's disease patients, we observed the emergence of a ~70-80 Hz narrowband oscillation with effective thermolesion of the pallidum. This gamma oscillatory activity was spatially localized over the primary motor cortex, was minimally affected by voluntary movements, and was not found in the motor cortex of essential tremor patients undergoing thalamotomy. CONCLUSIONS: Our finding suggests that acute lesioning of the pallidum promotes cortical gamma band oscillations. This may represent an important mechanism for alleviating bradykinesia in Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

Nonsinusoidal Beta Oscillations Reflect Cortical Pathophysiology in Parkinson's Disease.

Oscillations in neural activity play a critical role in neural computation and communication. There is intriguing new evidence that the nonsinusoidal features of the oscillatory waveforms may inform underlying physiological and pathophysiological characteristics. Time-domain waveform analysis approaches stand in contrast to traditional Fourier-based methods, which alter or destroy subtle waveform features. Recently, it has been shown that the waveform features of oscillatory beta (13-30 Hz) events, a prominent motor cortical oscillation, may reflect near-synchronous excitatory synaptic inputs onto cortical pyramidal neurons. Here we analyze data from invasive human primary motor cortex (M1) recordings from patients with Parkinson's disease (PD) implanted with a deep brain stimulator (DBS) to test the hypothesis that the beta waveform becomes less sharp with DBS, suggesting that M1 input synchrony may be decreased. We find that, in PD, M1 beta oscillations have sharp, asymmetric, nonsinusoidal features, specifically asymmetries in the ratio between the sharpness of the beta peaks compared with the troughs. This waveform feature is nearly perfectly correlated with beta-high gamma phase-amplitude coupling (r = 0.94), a neural index previously shown to track PD-related motor deficit. Our results suggest that the pathophysiological beta generator is altered by DBS, smoothing out the beta waveform. This has implications not only for the interpretation of the physiological mechanism by which DBS reduces PD-related motor symptoms, but more broadly for our analytic toolkit in general. That is, the often-overlooked time-domain features of oscillatory waveforms may carry critical physiological information about neural processes and dynamics.SIGNIFICANCE STATEMENT To better understand the neural basis of cognition and disease, we need to understand how groups of neurons interact to communicate with one another. For example, there is evidence that parkinsonian bradykinesia and rigidity may arise from an oversynchronization of afferents to the motor cortex, and that these symptoms are treatable using deep brain stimulation. Here we show that the waveform shape of beta (13-30 Hz) oscillations, which may reflect input synchrony onto the cortex, is altered by deep brain stimulation. This suggests that mechanistic inferences regarding physiological and pathophysiological neural communication may be made from the temporal dynamics of oscillatory waveform shape.

Gamma Oscillations in the Hyperkinetic State Detected with Chronic Human Brain Recordings in Parkinson's Disease.

UNLABELLED: Hyperkinetic states are common in human movement disorders, but their neural basis remains uncertain. One such condition is dyskinesia, a serious adverse effect of medical and surgical treatment for Parkinson's disease (PD). To study this, we used a novel, totally implanted, bidirectional neural interface to obtain multisite long-term recordings. We focus our analysis on two patients with PD who experienced frequent dyskinesia and studied them both at rest and during voluntary movement. We show that dyskinesia is associated with a narrowband gamma oscillation in motor cortex between 60 and 90 Hz, a similar, though weaker, oscillation in subthalamic nucleus, and strong phase coherence between the two. Dyskinesia-related oscillations are minimally affected by voluntary movement. When dyskinesia persists during therapeutic deep brain stimulation (DBS), the peak frequency of this signal shifts to half the stimulation frequency. These findings suggest a circuit-level mechanism for the generation of dyskinesia as well as a promising control signal for closed-loop DBS. SIGNIFICANCE STATEMENT: Oscillations in brain networks link functionally related brain areas to accomplish thought and action, but this mechanism may be altered or exaggerated by disease states. Invasive recording using implanted electrodes provides a degree of spatial and temporal resolution that is ideal for analysis of network oscillations. Here we used a novel, totally implanted, bidirectional neural interface for chronic multisite brain recordings in humans with Parkinson's disease. We characterized an oscillation between cortex and subcortical modulators that is associated with a serious adverse effect of therapy for Parkinson's disease: dyskinesia. The work shows how a perturbation in oscillatory dynamics might lead to a state of excessive movement and also suggests a possible biomarker for feedback-controlled neurostimulation to treat hyperkinetic disorders.

Motor System Interactions in the Beta Band Decrease during Loss of Consciousness.

Communication between brain areas and how they are influenced by changes in consciousness are not fully understood. One hypothesis is that brain areas communicate via oscillatory processes, utilizing network-specific frequency bands, that can be measured with metrics that reflect between-region interactions, such as coherence and phase amplitude coupling (PAC). To evaluate this hypothesis and understand how these interactions are modulated by state changes, we analyzed electrophysiological recordings in humans at different nodes of one well-studied brain network: the basal ganglia-thalamocortical loops of the motor system during loss of consciousness induced by anesthesia. We recorded simultaneous electrocorticography over primary motor cortex (M1) with local field potentials from subcortical motor regions (either basal ganglia or thalamus) in 15 movement disorder patients during anesthesia (propofol) induction as a part of their surgery for deep brain stimulation. We observed reduced coherence and PAC between M1 and the subcortical nuclei, which was specific to the beta band (∼18-24 Hz). The fact that this pattern occurs selectively in beta underscores the importance of this frequency band in the motor system and supports the idea that oscillatory interactions at specific frequencies are related to the capacity for normal brain function and behavior.

Electrocorticography reveals beta desynchronization in the basal ganglia-cortical loop during rest tremor in Parkinson's disease.

The pathophysiology of rest tremor in Parkinson's disease (PD) is not well understood, and its severity does not correlate with the severity of other cardinal signs of PD. We hypothesized that tremor-related oscillatory activity in the basal-ganglia-thalamocortical loop might serve as a compensatory mechanism for the excessive beta band synchronization associated with the parkinsonian state. We recorded electrocorticography (ECoG) from the sensorimotor cortex and local field potentials (LFP) from the subthalamic nucleus (STN) in patients undergoing lead implantation for deep brain stimulation (DBS). We analyzed differences in measures of network synchronization during epochs of spontaneous rest tremor, versus epochs without rest tremor, occurring in the same subjects. The presence of tremor was associated with reduced beta power in the cortex and STN. Cortico-cortical coherence and phase-amplitude coupling (PAC) decreased during rest tremor, as did basal ganglia-cortical coherence in the same frequency band. Cortical broadband gamma power was not increased by tremor onset, in contrast to the movement-related gamma increase typically observed at the onset of voluntary movement. These findings suggest that the cortical representation of rest tremor is distinct from that of voluntary movement, and support a model in which tremor acts to decrease beta band synchronization within the basal ganglia-cortical loop.

Subthalamic local field potentials in Parkinson's disease and isolated dystonia: An evaluation of potential biomarkers.

Local field potentials (LFP) recorded from the subthalamic nucleus in patients with Parkinson's disease (PD) demonstrate prominent oscillations in the beta (13-30 Hz) frequency range, and reduction of beta band spectral power by levodopa and deep brain stimulation (DBS) is correlated with motor symptom improvement. Several features of beta activity have been theorized to be specific biomarkers of the parkinsonian state, though these have rarely been studied in non-parkinsonian conditions. To compare resting state LFP features in PD and isolated dystonia and evaluate disease-specific biomarkers, we recorded subthalamic LFPs from 28 akinetic-rigid PD and 12 isolated dystonia patients during awake DBS implantation. Spectral power and phase-amplitude coupling characteristics were analyzed. In 26/28 PD and 11/12 isolated dystonia patients, the LFP power spectrum had a peak in the beta frequency range, with similar amplitudes between groups. Resting state power did not differ between groups in the theta (5-8 Hz), alpha (8-12 Hz), beta (13-30 Hz), broadband gamma (50-200 Hz), or high frequency oscillation (HFO, 250-350 Hz) bands. Analysis of phase-amplitude coupling between low frequency phase and HFO amplitude revealed significant interactions in 19/28 PD and 6/12 dystonia recordings without significant differences in maximal coupling or preferred phase. Two features of subthalamic LFPs that have been proposed as specific parkinsonian biomarkers, beta power and coupling of beta phase to HFO amplitude, were also present in isolated dystonia, including focal dystonias. This casts doubt on the utility of these metrics as disease-specific diagnostic biomarkers.

Elevated synchrony in Parkinson disease detected with electroencephalography.

OBJECTIVE: Parkinson disease (PD) can be difficult to diagnose and treat. Development of a biomarker for PD would reduce these challenges by providing an objective measure of disease. Emerging theories suggest PD is characterized by excessive synchronization in the beta frequency band (∼20Hz) throughout basal ganglia-thalamocortical loops. Recently we showed with invasive electrocorticography that one robust measure of this synchronization is the coupling of beta phase to broadband gamma amplitude (ie, phase-amplitude coupling [PAC]). Other recent work suggests that high-frequency activity is detectable at the scalp using electroencephalography (EEG). Motivated by these findings, we tested whether beta-gamma PAC over sensorimotor cortex, recorded noninvasively with EEG, differs between PD patients off and on medications, and healthy control subjects. METHODS: Resting EEG was compared from 15 PD patients and 16 healthy control subjects. PD patients were tested on and off medications on different days, in a counterbalanced order. For each data set we calculated PAC and compared results across groups. RESULTS: PAC was elevated in the patients off medications compared to on medications (p = 0.008) and for patients off medications compared to controls (p = 0.009). INTERPRETATION: Elevated PAC is detectable using scalp EEG in PD patients off medications compared to on medications, and compared to healthy controls. This suggests that EEG PAC may provide a noninvasive biomarker of the parkinsonian state. This biomarker could be used as a control signal for closed-loop control of deep brain stimulation devices, for adjustment of dopaminergic treatment, and also has the potential to aid in diagnosis.

Exaggerated phase-amplitude coupling in the primary motor cortex in Parkinson disease.

An important mechanism for large-scale interactions between cortical areas involves coupling between the phase and the amplitude of different brain rhythms. Could basal ganglia disease disrupt this mechanism? We answered this question by analysis of local field potentials recorded from the primary motor cortex (M1) arm area in patients undergoing neurosurgery. In Parkinson disease, coupling between ß-phase (13-30 Hz) and γ-amplitude (50-200 Hz) in M1 is exaggerated compared with patients with craniocervical dystonia and humans without a movement disorder. Excessive coupling may be reduced by therapeutic subthalamic nucleus stimulation. Peaks in M1 γ-amplitude are coupled to, and precede, the subthalamic nucleus ß-trough. The results prompt a model of the basal ganglia-cortical circuit in Parkinson disease incorporating phase-amplitude interactions and abnormal corticosubthalamic feedback and suggest that M1 local field potentials could be used as a control signal for automated programming of basal ganglia stimulators.