Language impairments in patients with cerebellar damage or dysfunction strongly implicate the cerebellum in language processing but the nature, timing, and specificity of its contributions are unclear. A clinical trial of cerebellar stimulation for motor recovery after middle cerebral artery stroke provided a rare opportunity to record invasive, intracranial local field potential activity from the cerebellar dentate nucleus of eight patients during language processing. Patients performed semantic priming tasks that either discouraged or encouraged semantic predictions. We found evidence for communication between the dentate nucleus and frontal scalp EEG sites in the alpha band when semantic predictions were violated. This did not occur when semantic predictions were fulfilled or when prediction violations were nonlinguistic in nature. This language-specific activity occurred in the N400window where semantic processing of a visually presented word takes place. These data point to a linguistic feedback function that could help to account for the language deficits observed in diseases and disorders involving the cerebellum.

BACKGROUND:Maladaptive pain avoidance plays a critical role in chronic pain development and maintenance. Pain avoidance reinforced instrumentally through action-outcome contingencies remains poorly understood, specifically in complex regional pain syndrome (CRPS), a nociplastic condition. We aim to identify mechanisms underlying maladaptive avoidance to inform interventions and improve quality of life. METHODS:Twenty-eight lower extremity CRPS and twenty-seven healthy (HC) participants performed an instrumental pain avoidance task in which they chose between two options linked to different probabilities of receiving pain, enabling assessment of avoidance learning and decision-making. Pain was delivered to the affected or non-affected extremity in CRPS and to either hand in HC. A reinforcement learning model estimated threat and safety learning, choice stochasticity, and trial-wise pain expectancies based on task behaviour. Resting-state magnetoencephalography was used to quantify intrinsic alpha-band activity, a frequency linked to chronic pain experience, in relation to pain avoidance. RESULTS:Threat and safety learning did not differ between extremities in CRPS. CRPS exhibited significantly elevated threat and safety learning than HC, accompanied by increased choice stochasticity, despite similar pain exposure. Pain expectancies directly influenced avoidance decisions independent of perceived pain in both groups; however, this expectancy-decision relationship was significantly weaker in CRPS. Increased threat learning in CRPS was statistically accounted for by elevated anxiety, sentimental personality, and reduced resting-state alpha power in the prefrontal cortex. CONCLUSIONS:Collectively, compared to HC, CRPS exhibited higher learning from recent outcomes and diminished expectancy-guided control of behaviour. Prefrontal alpha partially mediated the effects of pain severity on threat learning. TRIAL REGISTRATION:The study was registered in Clinicaltrials.gov [NCT04603417]. SIGNIFICANCE STATEMENT:CRPS is a debilitating condition associated with disproportionate pain, sensorimotor abnormalities, and autonomic dysfunction, often arising without underlying structural or organic causes. Maladaptive pain avoidance, driven by fear of pain, severely hinders physical therapy and rehabilitation by creating a cycle of inactivity, physical deconditioning, and increased pain sensitivity. This work highlights specific behavioural and neural mechanisms underlying pain avoidance for the development of novel psychosocial and neuromodulatory interventions that can be incorporated in clinical practice to treat CRPS.

Chronic ocular surface pain (COSP) is a debilitating condition of the eye driven by nociceptive, nociplastic, and neuropathic mechanisms. While individual studies using functional neuroimaging techniques to investigate ocular pain exist, the full extent, methodologies, and cumulative findings of this body of literature have not been systematically synthesized. Using a systematic review approach, we identified 5 articles evaluating the use of functional neuroimaging in COSP patients from an initial pool of 643 unique studies. All studies used functional magnetic resonance imaging exclusively as their functional neuroimaging modality, and 4 included photophobia as a manifestation of COSP. Across the studies, there were a total of 107 adult patients enrolled, of whom 83 were cases (37.3% female) with active COSP/photophobia and 24 were controls (29.2% female). The results of the studies demonstrate that light robustly recruits trigeminocortical nociceptive networks (spinal trigeminal/brainstem, S1, insula, anterior midcingulate), with partial attenuation after interventions such as topical anesthesia, botulinum toxin, or FL-41 lenses. Mechanistically, photophobia may reflect convergence of melanopsin/intrinsically photosensitive retinal ganglion cells signaling with trigeminothalamic pathways, motivating brain-based biomarkers alongside surface metrics. The consistency in study design, imaging hardware, and analytical pipelines across the 5 primary articles facilitates direct comparison but also highlights current limitations in the broader generalizability and diversity of the field. Notably, the paucity of neurophysiological studies limits our mechanistic understanding of COSP in terms of neural oscillations that can be potential targets of neuromodulatory interventions.

BACKGROUND:Chronic refractory pain presents limited treatment options and diminished quality of life. While ketamine treatment shows promise, protocol variations and safety concerns have hindered widespread adoption. This study evaluated preliminary effectiveness and rate of treatment completion for a standardized low-dose ketamine infusion therapy (KIT) protocol. METHODS:This retrospective observational study examined adult patients with chronic refractory pain who received KIT between May 2021 and October 2024 at the Cleveland Clinic's outpatient multidisciplinary pain clinic. Patients received a standardized protocol of 0.5 mg/kg ketamine infused over 40 min for five consecutive days. We measured effectiveness using patient-reported outcomes (PROs) at baseline, last infusion, and 3-month and 6-month post-treatment, and rate of treatment completion. The primary outcome of interest was the proportion of patients achieving clinically meaningful improvement on validated measures. RESULTS:Among 1034 patients (mean age 50.4±15.2 years; 71.8% female; 83.3% of white ethnicity), treatment completion was high, with 890 (86.1%) patients completing 5+ infusions. No adverse events were reported. Baseline measures reflected moderate impairment in pain interference, global physical health, fatigue, physical function, and depression. Between 20.3% and 46.4% of patients achieved clinically meaningful improvement on PROs from baseline to last infusion, with similar proportions maintained at 3-month and 6-month follow-up. Statistically significant mean improvements were observed across multiple domains; however, the majority of individual outcomes did not reach clinically meaningful thresholds. Patients demonstrated significant mean improvements in fatigue, pain interference, and social role satisfaction (mean change -2.1±7.7, -2.0±5.8, and 2.0±7.7, respectively), with improvements in depression, social role satisfaction, pain interference, self-efficacy, global health, and pain catastrophizing sustained through 6 months post-treatment. DISCUSSION:This standardized low-dose ketamine protocol demonstrated therapeutic benefit and high completion rates within a multidisciplinary care model. Future randomized controlled trials are warranted to confirm findings and explore treatment response factors across pain conditions.

Chronic pain alters resting-state cerebral alpha rhythms (8-12 Hz), including whole-brain slowing of peak alpha frequency (PAF). Nevertheless, how the power of brain activity at PAF (PAF power) or across the entire alpha frequency range (alpha power) is decreased or increased compared to healthy controls (HC) varies greatly across pain phenotypes. The brain regions exhibiting such alterations and their association with the pain severity experienced by patients are also unclear. The study addressed this question in participants experiencing complex regional pain syndrome (CRPS; 19 females and 10 males) against pain-free HC (14 females and 15 males). Resting-state magnetoencephalography imaging was used to estimate the power spectral density of neurophysiological activity across the cortex to identify group differences in alpha activity. The study found decreased alpha power and slower PAF in patients with CRPS, especially over bilateral posteromedial regions including the precuneus, paracentral and superior parietal cortices. In CRPS, pain severity was associated with the suppression of PAF power in the medial and lateral prefrontal cortex (PFC) and orbitofrontal cortex (OFC). Furthermore, the same PFC and OFC areas showed increased interregional alpha-band functional connectivity in patients with CRPS. Although the greatest pain-related alpha alterations mapped to sensory-discriminative areas, including the posteromedial cortex, PFC alpha activity encoded subjective CRPS pain severity. Hyperconnectivity between medial PFC and OFC further emphasized the affective-motivational nature of CRPS pain. Overall, these findings highlight the multiple functional roles of alpha activity in nociplastic conditions such as CRPS and provide potential targets for neuromodulatory interventions. PERSPECTIVE: Complex regional pain syndrome (CRPS) is a debilitating disorder driven by altered brain processes. The authors characterize deviations in alpha brain activity in CRPS compared to healthy controls which could inform the development of novel neuromodulation therapies.

Aversive prediction error (PE) brain signals generated by unexpected pain or pain absence are crucial for learning to avoid future pain. Yet, the detailed neurophysiological origins of PE signaling remain unclear. In this study, we combined an instrumental pain avoidance task with computational modeling and magnetoencephalography to detect time-resolved activations underlying pain expectations and aversive PE signals in the human brain. The task entailed learning probabilistically changing cue-pain associations to avoid receiving a pain stimulus. We used an axiomatic approach to identify general aversive PE signals that encode the degree to which the outcome deviated from expectations. Our findings indicate that aversive PE signals are generated in the alpha band (8-12 Hz) by the midbrain/diencephalon, lateral orbitofrontal cortex, and ventrolateral prefrontal cortex approximately 150 milliseconds after outcome delivery. Moreover, alpha oscillations in these regions also encoded pain expectations before the outcome. We speculate that this may facilitate the rapid generation of PEs by allowing outcome-related nociceptive activity to be integrated with ongoing predictive signals. Finally, decisions to avoid pain recruited alpha oscillations in the anterior cingulate and dorsomedial prefrontal cortices, suggesting their active engagement in comparing predicted action values. Overall, our data reveal the rapid neurophysiological mechanisms underlying the generation of aversive PEs and subsequent decision-making.

The cerebellum acts as a forward internal model to predict motor outcomes, compare them with sensory feedback, and generate prediction errors that refine prediction accuracy. Our physiological understanding of cerebellar function during motor control derives predominantly from animal experiments and clinical observations in patients with disorders of the cerebellum or its connections with the cerebrum and spinal cord. Here, we report a human electrophysiology-based investigation of cerebello-thalamo-cortical pathway activity during motor error detection and correction. Participants performed a computerized motor oddball task while synchronized electrophysiological recordings were collected from cerebellar dentate (DN) using depth electrodes and scalp electroencephalography (EEG). The task involved moving a 2-D ball on a screen toward a predetermined target at 40% (standard trials) or 20% (oddball trials) of their maximum voluntary contraction. Six participants completed an average of 239 trials, with oddball trials randomly occurring with a 30% frequency. At the cortex, oddball trials exhibited significantly greater centro-parietal error positivity and fronto-centro-parietal desynchronization during error correction, predominantly in the alpha and low beta frequency bands. DN examination also revealed greater alpha and low beta desynchronization during error correction. Lastly, oddball trials showed significantly greater cortico-cerebellar coherence during error correction in the same frequency bands with bidirectional interaction between the cortex and DN. These findings expand on the cortico-cerebello-cortical physiology of human motor control and provide cues for designing interventions aimed at alleviating the functional burdens of acquired injuries of the central nervous system.

Resting-state peak alpha frequency (PAF) between 8–12 Hz has been found to be suppressed and slowed in chronic pain conditions suggesting its role as a potential biomarker. However, the cortical regions exhibiting PAF suppression and slowing, and their relationship with baseline pain levels are currently unknown. To address this question, we collected resting-state magnetoencephalography (MEG) from twenty-three complex regional pain syndrome (CRPS) patients (15F, 20-75 years) and pain-free controls (8F, 19-50 years). Min-norm source localization was performed on the preprocessed MEG data followed by power spectral density estimation at each source. To identify cortical sources exhibiting significant alpha power difference between patients and controls (P<0.05), we performed a nonparametric spatio-spectral cluster permutation t-test (cluster-defining threshold P<0.001). We parcellated the brain using a standard atlas to identify anatomical regions underlying significant clusters. Overall, both alpha power and PAF were significantly lower in CRPS patients compared to controls. The difference was most pronounced over bilateral paracentral, postcentral, precentral, precuneus, superior parietal and medial temporal areas. In CRPS patients, higher baseline pain level (measured using visual analog scale) was associated with 1. lower PAF power in frontal regions, 2. slower PAF in inferior frontal gyrus and 3. faster PAF in the temporal-parietal regions. Though greatest difference in alpha power between groups was observed over the sensorimotor areas, suppression and slowing of PAF in the frontal regions were associated with baseline pain level. These findings inform us about novel targets for neuromodulatory interventions that can alleviate pain in chronic pain populations. Funding: NIH K01DA050804.

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4–8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS.

BACKGROUND:Understanding the neural mechanisms underlying migraine and other primary headache disorders is critical for the development of long-term cures. Magnetoencephalography (MEG), an imaging modality that measures neuronal currents and cortical excitability with high temporal and superior spatial resolution, has been increasingly used in neurological research. Initial MEG studies showed promise in directly recording cortical spreading depression-a cortical correlate of migraine with aura. However, lately MEG technology has highly evolved with greater potential to reveal underlying pathophysiology of migraine and primary headache disorders, and aid in the identification of biomarkers. OBJECTIVE:To systematically review the use of MEG in migraine and other primary headache disorders and summarize findings. METHODS:We conducted a systematic search and selection of MEG studies in migraine and primary headache disorders from inception until June 8, 2023, in Medline, Embase, Cochrane, and Scopus databases. Peer-reviewed English articles reporting the use of MEG for clinical or research purposes in migraine and primary headache disorders were selected. RESULTS:We found 560 articles and included 38 in this review after screening. Twelve studies investigated resting-state, while others investigated a sensory modality using an evoked or event-related paradigm with a total of 35 cohort and 3 case studies. Thirty-two studies focused exclusively on migraine, while the rest reported other primary headache disorders. CONCLUSION:The findings show an evolution of MEG from a 7- to a 306-channel system and analysis evolving from sensor-level evoked responses to more advanced source-level connectivity measures. A relatively few MEG studies portrayed migraine and primary headache disorders as a sensory abnormality, especially of the visual system. We found heterogeneity in the datasets, data reporting standards (due to constantly evolving MEG technology and analysis methods), and patient characteristics. Studies were inadequately powered and there was no evidence of blinding procedures to avoid selection bias in case-control studies, which could have led to false-positive findings. More studies are needed to investigate the affective-cognitive aspects that exacerbate pain and disability in migraine and primary headache disorders.

Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorganization of ipsilesional cortex in 12 individuals with persistent (1-3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: NCT02835443 .

The robust, reciprocal anatomic connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscore the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, poststroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in participants (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigated the excitability of ipsilesional cortex, DN, and their interaction as a function of motor impairment and performance. Our results indicate the following: (1) event-related oscillations in the ipsilesional cortex and DN were significantly correlated at movement onset in the low beta band, with moderately and severely impaired participants showing desynchronization and synchronization, respectively; and (2) significant CCC was observed during the isometric hold period in the low beta band, which was critical for maintaining task accuracy. Our findings support a strong coupling between ipsilesional cortex and DN in the low beta band during motor control across all impairment levels, which encourages the exploitation of the cerebello–thalamo–cortical pathway as a neuromodulation target to promote rehabilitation. SIGNIFICANCE STATEMENT Cerebral infarct because of stroke can lead to lasting reduction in cerebellar metabolism, resulting in poor rehabilitative outcomes. Thorough investigation of the cerebellar electrophysiology, as well as cortico-cerebellar connectivity in humans that could provide key insights to facilitate the development of novel neuromodulatory technologies, has been lacking. As a part of the first in-human phase I trial investigating deep brain stimulation of the cerebellar dentate nucleus (DN) for chronic, poststroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG while stroke survivors performed a motor task. Our data indicate strong coupling between ipsilesional sensorimotor cortex and DN in the low beta band across all impairment levels encouraging the exploration of electrical stimulation of the DN.

Cerebellar pathways are increasingly being targeted using both non-invasive and invasive neurostimulation-based approaches for the treatment of neurologic disease. Our recently-completed Phase I trial of deep brain stimulation (DBS) of the dentato-thalamo-cortical (DTC) pathway to enhance chronic, post-stroke motor rehabilitation has demonstrated promise for reducing impairment. As part of that study, we were able to characterize acute electrophysiological changes associated with cerebellar dentate nucleus (DN) DBS in relation to motor behavior and examined the spatiotemporal pattern of cerebral cortical changes using scalp electroencephalography (EEG).

Dear Editor Continuous, high-frequency isochronal (i.e., "traditional") deep brain stimulation (tDBS), is a standard treatment option for advanced-stage Parkinson's disease (PD). However, tDBS is limited by side effects [[1]van Nuenen B.F. Esselink R.A.J. Munneke M. Speelman J.D. Van Laar T. Bloem B.R. Postoperative gait deterioration after bilateral subthalamic nucleus stimulation in Parkinson's disease.Mov Disord. 2008; 23: 2404-2406https://doi.org/10.1002/mds.21986Crossref PubMed Scopus (70) Google Scholar] and its chronic nature can necessitate frequent battery replacement. To address these issues, a novel stimulation method, coordinated reset (CR)-DBS, was developed through computational modeling [[2]Tass P.A. A model of desynchronizing deep brain stimulation with a demand controlled coordinated reset of neural subpopulations.Biol Cybern. 2003; 89: 81-88Crossref PubMed Scopus (320) Google Scholar,[3]Adamchic I. Hauptmann C. Barnikol U.B. Pawelczyk N. Popovych O. Barnikol T.T. et al.Coordinated reset neuromodulation for Parkinson's disease: proof-of-concept study.Mov Disord. 2014; 29: 1679-1684https://doi.org/10.1002/mds.25923Crossref PubMed Scopus (133) Google Scholar]. To date, however, data addressing its underlying electrophysiological effects are limited [[3]Adamchic I. Hauptmann C. Barnikol U.B. Pawelczyk N. Popovych O. Barnikol T.T. et al.Coordinated reset neuromodulation for Parkinson's disease: proof-of-concept study.Mov Disord. 2014; 29: 1679-1684https://doi.org/10.1002/mds.25923Crossref PubMed Scopus (133) Google Scholar]. The goal of this study was to characterize the sub-acute and carryover motor and electrophysiological effects of CR-DBS in terms of both local field potential (LFP) power changes and brain connectivity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) non-human primate (NHP) model of parkinsonism. Animal care complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and a protocol approved by the Cleveland Clinic Institutional Animal Care and Use Committee (IACUC). A 14-year-old adult female NHP (Macaca mulatta) was instrumented with a DBS lead in the subthalamic nucleus (STN) and a pair of twelve-contact electrocorticography (ECoG) arrays spanning from medial somatosensory to prefrontal cortex (Fig. 1A) as described previously [[4]Campbell B. Cho H. Faulhammer R. Hogue O. Tsai J. Hussain M. Machado A. Baker K. Stability and effect of Parkinsonian state on Deep Brain Stimulation cortical evoked potentials.Neuromodulation: Technology at the Neural Interface. 2021; https://doi.org/10.1111/ner.13508Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar,[5]Bore J.C. Campbell B.A. Cho H. Gopalakrishnan R. Machado A.G. Baker K.B. Prediction of mild Parkinsonism revealed by neural oscillatory changes and machine learning.J Neurophysiol. 2020 Dec 1; 124 (Epub 2020 Oct 14. PMID: 33052766): 1698-1705https://doi.org/10.1152/jn.00534.2020Crossref PubMed Scopus (3) Google Scholar]. The M1 region was identified as the contacts showing the lowest threshold for corticospinal activation, with localization confirmed by 3D reconstruction of the co-registered preoperative MRI and postoperative CT (Fig. 1B) [[6]Fedorov A. Beichel R.R. Kalpathy-Cramer J. Finet J. Fillion-Robin J. Pujol S. Bauer C. Jennings D. Fennessy F. Sonka M. Buatti J.M. Aylward S.R. Miller J.V. Pieper S. Kikinis R. 3D slicer as an image computing platform for the quantitative imaging network.Magn Reson Imaging. 2012; 30: 1323-1341https://doi.org/10.1016/j.mri.2012.05.001Crossref PubMed Scopus (3160) Google Scholar]. The data presented in this work are novel and not derived from [[7]Wang J. Nebeck S. Muralidharan A. Johnson M.D. Vitek J.L. Baker K.B. Coordinated reset deep brain stimulation of subthalamic nucleus produces long-lasting, dose-dependent motor improvements in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine non-human primate model of parkinsonism.Brain Stimul. 2016; 9: 609-617https://doi.org/10.1016/j.brs.2016.03.014Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Each day, before stimulation, the animal was brought into the lab for measurement of behavioral and electrophysiological metrics, including 30 minutes performing a simple touchscreen-based reach task [[4]Campbell B. Cho H. Faulhammer R. Hogue O. Tsai J. Hussain M. Machado A. Baker K. Stability and effect of Parkinsonian state on Deep Brain Stimulation cortical evoked potentials.Neuromodulation: Technology at the Neural Interface. 2021; https://doi.org/10.1111/ner.13508Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar]. A custom stimulator was then mounted to the cranial implant, stimulation activated, and the animal returned to its home cage. After the four-hour stimulation period, the animal was returned to the lab, the stimulation device was removed, and data collection repeated. This process was repeated over five consecutive days [[7]Wang J. Nebeck S. Muralidharan A. Johnson M.D. Vitek J.L. Baker K.B. Coordinated reset deep brain stimulation of subthalamic nucleus produces long-lasting, dose-dependent motor improvements in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine non-human primate model of parkinsonism.Brain Stimul. 2016; 9: 609-617https://doi.org/10.1016/j.brs.2016.03.014Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Behavioral and electrophysiological data were collected once daily for an additional seven days after the stimulation period to characterize carry-over effects. This treatment block was replicated four times over a period of 12 months with periodic evaluation of behavioral and electrophysiological metrics between each session to ensure return to pre-treatment baseline. To characterize electrophysiological differences between CR-DBS vs tDBS effects, the animal received tDBS using the same schedule design. The animal also performed the behavioral task while tDBS was delivered to further establish the efficacy of tDBS [[7]Wang J. Nebeck S. Muralidharan A. Johnson M.D. Vitek J.L. Baker K.B. Coordinated reset deep brain stimulation of subthalamic nucleus produces long-lasting, dose-dependent motor improvements in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine non-human primate model of parkinsonism.Brain Stimul. 2016; 9: 609-617https://doi.org/10.1016/j.brs.2016.03.014Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. The animal was treated with tDBS while completing the touch screen task across five separate days at the same time during the day as the twelve-day schedule. (See Supplementary Fig. S1 for details on DBS conditions). Spontaneous LFP data were recorded with the awake animal seated in a commercial primate chair. Data from the four treatment blocks (5 stimulation days to 7 post-stimulation days each) yielded 45min recordings (split into 3min each for analysis, recorded pre- and post-stimulation, and once during post-stimulation days) collected from the baseline period for the separate tDBS and CR-DBS sessions recorded across the one year period. Recordings were grounded and referenced to the cranial head post, and digitized at 24,414.0625Hz (Tucker Davis Technologies, Alachua, FL). Bipolar referencing in M1 was achieved by medio-lateral subtraction of the pair of adjacent contacts situated over M1 of the cortical array ipsilateral to the implanted STN lead. Data were subsequently down-sampled (∼6 kHz) and pre-processed as reported previously [[5]Bore J.C. Campbell B.A. Cho H. Gopalakrishnan R. Machado A.G. Baker K.B. Prediction of mild Parkinsonism revealed by neural oscillatory changes and machine learning.J Neurophysiol. 2020 Dec 1; 124 (Epub 2020 Oct 14. PMID: 33052766): 1698-1705https://doi.org/10.1152/jn.00534.2020Crossref PubMed Scopus (3) Google Scholar]. (For more details on the preprocessing, see supplementary material, section 1.1). Fig. 1C and D reveal differences in M1 oscillatory power and cortico-cortical coherence (which is where we found significant network changes) between the untreated parkinsonian state and data acquired immediately following cessation of stimulation. The effects of DBS immediately following cessation of stimulation on each day of the treatment phase were compared to the pre-stimulation baseline using the nonparametric Mann-Whitney-Wilcoxon statistical inference testing (significance threshold: p < 0.05, and Bonferroni-corrected for multiple comparisons), and the results were averaged. Following both DBS conditions, therapeutic benefit was accompanied by a decrease (%change) in M1 power and cortico-cortical. As shown in Fig. 1E, CR-DBS produced overall sub-acute changes of PSD and coherence changes at the same level of those produced by tDBS (changes induced by both DBS therapies were not statistically significant as per the same Mann-Whitney-Wilcoxon test above with significance threshold: p < 0.05) with the effects of CR-DBS persisting into the long-term carry-over period. We analyzed the time course of pre-DBS changes in the theta and beta band PSD and coherence values by displaying the values from the electrophysiological recordings each morning over the 12-day experimental window. In both frequency bands, a clear, step-wise pattern of change in response to CR-DBS was observed across the 5-day treatment period. Persistent carry-over effects (%change in power) were observed in both bands for up to a week post-stimulation (Fig. 1F). (For more detailed individual plots, see Supplementary Fig. S2). Moreover, we observed that the %changes of PSD and coherence in the theta and beta bands persisted up to a week post-stimulation (Fig. 1G). The carry-over DBS effects on each day of the post-treatment phase were compared to the baseline before stimulation using the nonparametric Mann-Whitney-Wilcoxon statistical inference testing (significance threshold was set at p < 0.05). The similar trend of changes in the STN PSD and the M1-STN coherence are reported in the Supplementary Figs. S3 and S4. Fig. 1H (i) shows the sub-acute effect of traditional- and CR-DBS on mean movement time (MT) immediately after stimulation during the treatment period. Longer MT were observed in the OFF-therapy condition, whereas both tDBS and CR-DBS showed MT reductions. In addition to its sub-acute effect, CR-DBS further showed long-term carry-over motor benefits in terms of behavioral performance. Fig. 1H (ii) summarizes changes in MT during the reach phase of the motor task immediately after CR-DBS across both the stimulation and post-stimulation phases. Although some variability was observed, MT was significantly decreased on days 1, 2 and 4 during the treatment phase. Persistent carry over motor benefits were also observed that lasted up to about a week following cessation of DBS therapy. In this study, we observed that, despite its lower duty cycle and reduced pulse amplitude compared to tDBS, STN CR-DBS was associated with sub-acute motor effects similar to those observed during tDBS, but with the added advantage of providing carryover benefits following cessation of stimulation. CR-based approach has been previously shown, computationally, to shift networks from attractors with strong synaptic connectivity and strong neural synchrony to attractors with weak synaptic connectivity and weak synchrony [8Tass P.A. Majtanik M. Long-term anti-kindling effects of desynchronizing brain stimulation: a theoretical study.Biol Cybern. 2006; 94: 58-66https://doi.org/10.1007/s00422-005-0028-6Crossref PubMed Scopus (132) Google Scholar, 9Popovych O.V. Tass P.A. Desynchronizing electrical and sensory coordinated reset neuromodulation.Front Hum Neurosci. 2012; 6: 58https://doi.org/10.3389/fnhum.2012.00058Crossref PubMed Scopus (77) Google Scholar, 10Ebert M. Hauptmann C. Tass P. Coordinated reset stimulation in a large-scale model of the STN-GPe circuit.Front Comput Neurosci. 2014; 8: 154https://doi.org/10.3389/fncom.2014.00154Crossref PubMed Scopus (32) Google Scholar]. This indicates that CR-induced desynchronization lowers the rate of coincidences and, in turn, mediated by spike timing-dependent plasticity (STDP), an unlearning of abnormal synaptic connectivity and, in turn, of abnormal neuronal synchrony. Our findings in the parkinsonian MPTP provide further independent, in vivo evidence of that desynchronizing effect, with both sub-acute and long-lasting effects on both behavior and cortical physiology. Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number NS092730, the Farmer Family Foundation (Funding), and Abbott /St Jude (equipment and materials). Dr. Machado is a consultant to Abbott and Cleveland Clinic receives fellowship support from Medtronic. The Cleveland Clinic Conflict of Interest (COI) committee has approved a plan for managing these conflicts of interest. The authors have adhered to the management plan in the conduct and reporting of research findings. None of these entities had any role in the research or preparation of the manuscript. The other authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. The following is the Supplementary data to this article: Download .docx (.62 MB) Help with docx files Multimedia component 1

Neurophysiological biomarkers that correlate with motor symptoms or disease severity are vital to improve our understanding of the pathophysiology in Parkinson’s disease (PD) and for the development of more effective treatments, including deep brain stimulation (DBS). This work provides direct insight into the application of these biomarkers in training classifiers to discriminate between brain states, which is a first step toward developing closed-loop DBS systems.

Objective Deep brain stimulation (DBS) for pain has largely been implemented in an uncontrolled manner to target the somatosensory component of pain, with research leading to mixed results. We have previously shown that patients with poststroke pain syndrome who were treated with DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) demonstrated a significant improvement in measures related to the affective sphere of pain. In this study, we sought to determine how DBS targeting the VS/ALIC modifies brain activation in response to pain. Materials and Methods Five patients with poststroke pain syndrome who were blinded to DBS status (ON/OFF) and six age- and sex-matched healthy controls underwent functional magnetic resonance imaging (fMRI) measuring blood oxygen level-dependent activation in a block design. In this design, each participant received heat stimuli to the affected or unaffected wrist area. Statistical comparisons were performed using fMRI z-maps. Results In response to pain, patients in the DBS OFF state showed significant activation (p < 0.001) in the same regions as healthy controls (thalamus, insula, and operculum) and in additional regions (orbitofrontal and superior convexity cortical areas). DBS significantly reduced activation of these additional regions and introduced foci of significant inhibitory activation (p < 0.001) in the hippocampi when painful stimulation was applied to the affected side. Conclusions These findings suggest that DBS of the VS/ALIC modulates affective neural networks.

Introduction Deep brain stimulation (DBS) is a widely accepted therapy for Parkinson's disease. While outcome predictors such as levodopa-response are well established, there remains a need for objective and unbiased predictors in clinical practice. We performed an exploratory study to examine whether cortical thickness, derived from preoperative MRI, correlates with postoperative outcome. Methods Using freesurfer, we retrospectively measured cortical thickness on the preoperative MRI of 38 patients who underwent bilateral STN-DBS for PD during a 4-year period. The Unified Parkinson Disease Rating motor (UPDRS III) and experiences of daily living subscales (UPDRS II) were collected at baseline and six months after surgery. As an initial analysis, a series of partial correlations was conducted to evaluate the association between postoperative outcome scores and average cortical thickness from predefined regions of interest, adjusting for candidate confounders, without correcting for multiple comparisons. A confirmatory vertex-wise analysis was performed using a cluster-wise correction for multiple comparisons. Results Based on the ROI analysis, the strongest correlation with motor outcome was found to be with the left lateral-occipital cortex. Patients with greater cortical thickness in this area presented with greater improvements in motor scores. This relationship was also supported by the vertex-wise analysis. Greater cortical thickness in frontal and temporal regions may be correlated with greater post-operative improvements in UPDRS II, but this was not confirmed in the vertex-wise analysis. Conclusions Our data indicate that greater cortical thickness in visuo-motor areas is correlated with motor outcomes after DBS for PD. Further prospective investigations are needed to confirm our findings and better-investigate potential image biomarkers.

Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective-cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. DBS-induced changes in event-related fields could potentially serve as biomarkers for clinical outcomes.

Central poststroke pain (CPSP) is characterized by hemianesthesia associated with unrelenting chronic pain. The final pain experience stems from interactions between sensory, affective, and cognitive components of chronic pain. Hence, managing CPSP will require integrated approaches aimed not only at the sensory but also the affective-cognitive spheres. A better understanding of the brain's processing of pain anticipation is critical for the development of novel therapeutic approaches that target affective-cognitive networks and alleviate pain-related disability. We used magnetoencephalography (MEG) to characterize the neural substrates of pain anticipation in patients suffering from intractable CPSP. Simple visual cues evoked anticipation while patients awaited impending painful (PS), nonpainful (NPS), or no stimulus (NOS) to their nonaffected and affected extremities. MEG responses were studied at gradiometer level using event-related fields analysis and time-frequency oscillatory analysis upon source localization. On the nonaffected side, significantly greater responses were recorded during PS. PS (vs. NPS and NOS) exhibited significant parietal and frontal cortical activations in the beta and gamma bands, respectively, whereas NPS (vs. NOS) displayed greater activation in the orbito-frontal cortex. On the affected extremity, PS (vs. NPS) did not show significantly greater responses. These data suggest that anticipatory phenomena can modulate neural activity when painful stimuli are applied to the nonaffected extremity but not the affected extremity in CPSP patients. This dichotomy may stem from the chronic effects of pain on neural networks leading to habituation or saturation. Future clinically effective therapies will likely be associated with partial normalization of the neurophysiological correlates of pain anticipation.

Objective: Pain experience is not only a function of somatosensory inputs. Rather, it is strongly influenced by cognitive and affective pathways. Pain anticipatory phenomena, an important limitation to rehabilitative efforts in the chronic state, are processed by associative and limbic networks, along with primary sensory cortices. Characterization of neurophysiological correlates of pain anticipation, particularly during very early stages of neural processing is critical for development of therapeutic interventions.Methods: Here, we utilized magnetoencephalography to study early event-related fields (ERFs) in healthy subjects exposed to a 3 s visual countdown task that preceded a painful stimulus, a non-painful stimulus or no stimulus.Results: We found that the first countdown cue, but not the last cue, evoked critical ERFs signaling anticipation, attention and alertness to the noxious stimuli. Further, we found that P2 and N2 components were significantly different in response to first-cues that signaled incoming painful stimuli when compared to non-painful or no stimuli.Conclusions: The findings indicate that early ERFs are relevant neural substrates of pain anticipatory phenomena and could be potentially serve as biomarkers.Significance: These measures could assist in the development of neurostimulation approaches aimed at curbing the negative effects of pain anticipation during rehabilitation. (c) 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.