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Resting DLPFC local field potentials recorded from each subject. The 3D reconstruction of each subject’s cortical surface (except Subject 4), with localized subdural strip contacts (circles colored according to contact number) and DLPFC region colored red. All subjects displayed prominent peaks in theta (3–8 Hz) and/or alpha/beta (10–30 Hz) ranges. In some subjects, particularly Subject 1, theta and alpha/beta activity had clearly different distributions along the strip, possibly indicating separate neural sources.
Source publication
Introduction
Cognitive symptoms from Parkinson’s disease cause severe disability and significantly limit quality of life. Little is known about mechanisms of cognitive impairment in PD, although aberrant oscillatory activity in basal ganglia-thalamo-prefrontal cortical circuits likely plays an important role. While continuous high-frequency deep br...
Citations
... A 2018 study compared VFS to HFS in 4 PD patients with freezing of gait (Jia et al., 2018) and reported a 14% improvement in the Unified Parkinson's disease rating scale III (UPDRS-III) motor score using VFS over HFS. Burst cycling, including theta burst stimulation, is another example of a polyrhythmic stimulation pattern, which alternates between periods of ON and OFF stimulation (Fig. 3D) (Bentley et al., 2020;Sáenz-Farret et al., 2021;Wong et al., 2021). The effectiveness of burst cycling may depend on the movement disorder: eliciting variable PD symptom improvement (Montgomery, 2005;M. ...
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.
... theta-burst) stimulationwould provoke induced as opposed to evoked rhythmic activity. Prior work examining the cortical responses to patterned direct intracranial stimulation suggest this would be the case by demonstrating prolonged power increases or nontimelocked events 15,18,[59][60][61] , though this remains to be established with TMS. Second, as noted above, the statistical methods used here relied on aggregate effects, generally at the level of broad ROIs. ...
Transcranial magnetic stimulation (TMS) is increasingly deployed in the treatment of neuropsychiatric illness, under the presumption that stimulation of specific cortical targets can alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach is most useful for evaluating low-frequency neural activity at the cortical surface. As such, little is known about how TMS perturbs rhythmic activity among deeper structures -- such as the hippocampus and amygdala -- and whether stimulation can alter higher-frequency oscillations. Recent work has established that TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct neural recordings at sufficient spatiotemporal resolution to examine localized oscillatory responses across the frequency spectrum. To that end, we recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at several cortical sites. Stimulation to the dorsolateral prefrontal cortex (DLPFC) drove widespread low-frequency increases (3-8Hz) in frontolimbic cortices, as well as high-frequency decreases (30-110Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with brief evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. Taken together, we established that non-invasive stimulation can (1) provoke a mixture of low-frequency evoked power and induced theta oscillations and (2) suppress high-frequency activity in deeper brain structures not directly accessed by stimulation itself.
... Our literature search of TBS yielded 29 studies, six of which were included (Miller et al., 2015;Titiz et al., 2017;Kim et al., 2018;Bentley et al., 2020;Horn et al., 2020;Sáenz-Farret et al., 2021). Of the excluded studies, 11 were reviews, seven were nonhuman animal studies, three were TMS studies without DBS, and two were editorials or commentaries with no original clinical data. ...
... Since then, TBS has been applied successfully in several neurologic disorders and has been shown to modulate neuronal activity and associated cognitive functions. Our group found that subcortical iTBS can evoke theta oscillatory activity, known to be important in cognitive domains such as decision making and memory (Zavala et al., 2017;Jones et al., 2020;Vivekananda et al., 2021;Zeng et al., 2021;Chen et al., 2022), in connected dorsolateral prefrontal cortex (Bentley et al., 2020). Others expanded on this and found that cortical TBS evokes frequency-specific oscillations (Solomon et al., 2021), such that 5 Hz TBS maximally increases 5 Hz power. ...
Deep brain stimulation (DBS) is a widely used clinical therapy that modulates neuronal firing in subcortical structures, eliciting downstream network effects. Its effectiveness is determined by electrode geometry and location as well as adjustable stimulation parameters including pulse width, interstimulus interval, frequency, and amplitude. These parameters are often determined empirically during clinical or intraoperative programming and can be altered to an almost unlimited number of combinations. Conventional high-frequency stimulation uses a continuous high-frequency square-wave pulse (typically 130–160 Hz), but other stimulation patterns may prove efficacious, such as continuous or bursting theta-frequencies, variable frequencies, and coordinated reset stimulation. Here we summarize the current landscape and potential clinical applications for novel stimulation patterns.
... Despite these informative findings, a pertinent question is concerned with the more efficient strategy for determining the precise targets for TMS treatment or, alternatively, whether optimal targeting within a TMS target is a quick and plausible way for clinical populations, particularly those with neurodegenerative diseases. Based on the published TMS studies in PD patients, a figure-8 coil was positioned over the left DLPFC through scalp-based targeting, including Average 5 cm [38,39], EEG F3 [11], or neuronavigated targeting with the MNI coordinates close to BA46 centre [10,12]. However, when comes to senior adults or patients with dementia, there are several issues that need to be addressed in considering the TMS treatment targets. ...
Background
Transcranial magnetic stimulation (TMS) is increasingly used as a promising non-pharmacological treatment for Parkinson’s disease (PD). Scalp-to-cortex distance (SCD), as a key technical parameter of TMS, plays a critical role in determining the locations of treatment targets and corresponding dosage. Due to the discrepancies in TMS protocols, the optimal targets and head models have yet to be established in PD patients.
Objective
To investigate the SCDs of the most popular used targets in left dorsolateral prefrontal cortex (DLPFC) and quantify its impact on the TMS-induced electric fields (E-fields) in early-stage PD patients.
Methods
Structural magnetic resonance imaging scans from PD patients (n = 47) and normal controls (n = 36) were drawn from the NEUROCON and Tao Wu datasets. SCD of left DLPFC was measured by Euclidean Distance in TMS Navigation system. The intensity and focality of SCD-dependent E-fields were examined and quantified using Finite Element Method.
Results
Early-stage PD patients showed an increased SCDs, higher variances in the SCDs and SCD-dependent E-fields across the seven targets of left DLPFC than normal controls. The stimulation targets located on gyral crown had more focal and homogeneous E-fields. The SCD of left DLPFC had a better performance in differentiating early-stage PD patients than global cognition and other brain measures.
Conclusion
SCD and SCD-dependent E-fields could determine the optimal TMS treatment targets and may also be used as a novel marker to differentiate early-stage PD patients. Our findings have important implications for developing optimal TMS protocols and personalized dosimetry in real-world clinical practice.
... Theta burst stimulation of the right entorhinal cortex significantly increased performance on pattern separation and memory recall, suggesting utility for the treatment of Alzheimer's disease (Titiz et al., 2017). Moreover, intermittent theta-burst stimulation results in safe and reliable changes in dorsolateral prefrontal cortex electrophysiology (Bentley et al., 2020) and may improve treatment of neurological conditions with historically poor success rates. Emerging optogenetics-inspired DBS protocols consisting of 1 Hz electrical stimulation of the Nucleus Accumbens paired with a D1-Dopamine receptor antagonist reverse behavioral adaptations in a rodent model of addiction (Creed et al., 2015). ...
... Cortical thickness and surface area of the following regions were included: dlPFC, vlPFC, ACC, and OFC, as well as volume of the following regions: ventral striatum and amygdala. The average of the left and right hemisphere was used.The regions-of-interest were constructed by combining the following regions(8,(47)(48)(49):dlPFC: superior frontal, rostral middle frontal cortex and caudle middle frontal, vlPFC: pars opercularis, pars triangularis and pars orbitalis, ACC: rostral ACC and caudal ACC, OFC: lateral orbitofrontal cortex and middle orbitofrontal cortex and ventral striatum: caudate, putamen and nucleus accumbens. This resulted in a total of 6 ROIs, which consisted of 4 cortical thickness, 4 cortical surface area, and 2 subcortical volume measures. ...
Background: Mood swings, or mood variability, are associated with negative mental health outcomes. Since adolescence is a time when mood disorder onset peaks, mood variability during this time is of significant interest. Understanding biological factors that might affect mood variability, such as sleep and structural brain development, could elucidate the mechanisms underlying mood disorders.
Methods: Data from the longitudinal Leiden Self-Concept study (N=171) over 5 timepoints was used to study the association between sleep, brain structure, and mood variability in healthy adolescents aged 11-21 at baseline in this pre-registered study. Sleep was measured both objectively, using actigraphy, as well as subjectively, using a daily diary self-report. Negative mood variability was defined as day-to-day negative mood swings over a period of 5 days after an MRI scan.
Results: It was found that negative mood variability peaked in mid-adolescence, and average negative mood showed a similar pattern. Sleep duration (subjective and objective) generally decreased throughout adolescence. Mood variability was not associated with sleep, but average negative mood was associated with higher self-reported lower energy. In addition, higher thickness in the dorsolateral prefrontal cortex (dlPFC) compared to same-age peers, suggesting a delayed thinning process, was associated with higher negative mood variability in early and mid-adolescence. Lastly, higher mood variability preceded higher levels of anxiety and depression, as well as current anxiety and depression. Conclusions: Together, this study provides an insight into the development of mood variability and its association with brain structure.
... It is worth mentioning that Bentley et al. explored the neurophysiology changes of DLPFC after iTBS on different deep brain stimulation (DBS) targets, subthalamic nucleus (STN), or globus pallidus interna (GPi) in seven patients with PD and found that GPi stimulation results in significantly greater theta power vs. STN stimulation (71). It is the first study that suggested TBS can be safely transmitted to human subcortical by DBS. ...
Background: Theta burst stimulation (TBS), a type of patterned repetitive transcranial magnetic stimulation (rTMS), has several advantages, such as short time of single treatment and low stimulation intensity compared with traditional rTMS. Since the efficacy of TBS on the symptoms of Parkinson's disease (PD) was inconsistent among different studies, we systematically searched these studies and quantitatively analyzed the therapeutic effect of TBS for patients with PD.
Methods: We followed the recommended PRISMA guidelines for systematic reviews. Studies from PubMed, EMBASE, CENTRAL, and ClinicalTrials.gov from January 1, 2005 of each database to September 30, 2021 were analyzed. We also manually retrieved studies of reference.
Results: Eight eligible studies with 189 participants (received real TBS and/or sham TBS) were included. This metaanalysis found that TBS did not significantly improve Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score in the “on” medicine state (SMD = −0.06; 95% CI, −0.37 to 0.25; p = 0.69; I² = 0%), while, it brought significant improvement of UPDRS-III scores in the “off” medicine state (SMD = −0.37; 95% CI, −0.65 to −0.09; p < 0.01; I² = 19%). Subgroup analysis found that merely continuous TBS (cTBS) over the supplementary motor area (SMA) brought significant improvement of UPDRS-III score (SMD = −0.63; 95% CI, −1.02 to −0.25; p < 0.01). TBS had insignificant effectiveness for upper limb movement disorder both in the “on” and “off” medicine status (SMD = −0.07; 95% CI, −0.36 to 0.22; p = 0.64; I² = 0%; SMD = −0.21; 95% CI, −0.57 to 0.15; p = 0.26; I² = 0%; respectively). TBS significantly improved slowing of gait in the “off” medicine status (SMD = −0.37; 95% CI, −0.71 to −0.03; p = 0.03; I² = 0%). Subgroup analysis suggested that only intermittent TBS (iTBS) over the primary motor cortex (M1) + dorsolateral prefrontal cortex (DLPFC) had significant difference (SMD = −0.57; 95% CI, −1.13 to −0.01; p = 0.04). Additionally, iTBS over the M1+ DLPFC had a short-term (within 2 weeks) therapeutic effect on PD depression (MD = −2.93; 95% CI, −5.52 to −0.33; p = 0.03).
Conclusion: Our study demonstrated that cTBS over the SMA could significantly improve the UPDRS-III score for PD patients in the “off,” not in the “on,” medicine state. TBS could not bring significant improvement of upper limb movement dysfunction. ITBS over the M1+DLPFC could significantly improve the slowing of gait in the “off” medicine status. Additionally, iTBS over the M1+DLPFC has a short-term (within 2 weeks) therapeutic effect on PD depression. Further RCTs of a large sample, and excellent design are needed to confirm our conclusions.
... При этом виде стимуляции 3 импульса доставляются с частотой 50 Гц каждые 200 мс либо непрерывно (continuous TBS; cTBS), либо прерывистыми 2-секундными последовательностями каждые 10 с (intermittent TBS; iTBS). Предполагается, что различные протоколы стимуляции создают более продолжительное возбуждение (iTBS) или торможение (cTBS) [55,[62][63][64]. ...
Speech disorders have the leading position among cognitive disorders and represent the urgent medical problem. The modern approach to the treatment of cognitive and behavioral disorders in children consists of the integrity of pharmacotherapeutic, correctional and psychotherapeutic, as well as non-invasive instrumental methods of brain neurostimulation. This article provides the overview of the currently available data on transcranial magnetic stimulation method as noninvasive treatment of various neuropsychiatric disorders in children and its difference from physiotherapeutic methods used in traditional Russian practice.
... Subcortical intervention, where fibers converge on smaller targets, may be more efficient for modulating mood networks. Theta burst stimulation of ventral STN, for example, has been used to modulate theta band activity in DLPFC (Bentley et al., 2020). STN stimulation paradigms that reduce lateral prefrontal beta activity merit investigation and could be facilitated by the enhanced spatial resolution offered by recently introduced "directional" DBS leads (Aman et al., 2020). ...
Objective: Anxiety and depression are prominent non-motor symptoms of Parkinson’s disease (PD), but their pathophysiology remains unclear. We sought to understand their neurophysiological correlates from chronic invasive recordings of the prefrontal cortex (PFC).
Methods: We studied four patients undergoing deep brain stimulation (DBS) for their motor signs, who had comorbid mild to moderate anxiety and/or depressive symptoms. In addition to their basal ganglia leads, we placed a permanent prefrontal subdural 4-contact lead. These electrodes were attached to an investigational pulse generator with the capability to sense and store field potential signals, as well as deliver therapeutic neurostimulation. At regular intervals over 3–5 months, participants paired brief invasive neural recordings with self-ratings of symptoms related to depression and anxiety.
Results: Mean age was 61 ± 7 years, mean disease duration was 11 ± 8 years and a mean Unified Parkinson’s Disease Rating Scale, with part III (UPDRS-III) off medication score of 37 ± 13. Mean Beck Depression Inventory (BDI) score was 14 ± 5 and Beck Anxiety Index was 16.5 ± 5. Prefrontal cortex spectral power in the beta band correlated with patient self-ratings of symptoms of depression and anxiety, with r-values between 0.31 and 0.48. Mood scores showed negative correlation with beta spectral power in lateral locations, and positive correlation with beta spectral power in a mesial recording location, consistent with the dichotomous organization of reward networks in PFC.
Interpretation: These findings suggest a physiological basis for anxiety and depression in PD, which may be useful in the development of neurostimulation paradigms for these non-motor disease features.
... A potential explanation of the heterogenous effects is that stimulation was applied across several different functional regions 4 across patients. Additionally, the authors used intermittent alpha burst stimulation while the most efficient protocol to induce increases in neural excitability uses intermittent theta burst stimulation (iTBS, brief bursts of 50-100Hz pulses repeated at 5 Hz) [18,[22][23][24][25][26][27][28]). ...
... The averaged power spectra for two example contacts that were functionally connected to the treatment site within motor areas is shown in Fig. 2b. These contacts exhibited prominent spectral and coherence peaks at the beta frequency (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). The dominant spectral power peaks and coherence peaks for the population of sensorimotor sites across the 7 patients is shown in figure 2c. ...
... Prior studies translating rTMS paradigms to intraparenchymal stimulation showed varying or weak results [21,23], or did not report neurophysiological changes [36]. For example, Keller et al. (2018) stimulated several different brain regions across patients and found mixed excitation at some treatment locations and inhibition at others. ...
The progress of therapeutic neuromodulation greatly depends on improving stimulation parameters to most efficiently induce neuroplasticity effects. Intermittent Theta Burst stimulation (iTBS), a form of electrical stimulation that mimics the natural brain activity patterns, has shown efficacy in inducing such effects in animal studies and rhythmic Transcranial Magnetic Stimulation (rTMS) studies in humans. However, little is known about the potential neuroplasticity effects of iTBS applied through intracranial electrodes in humans which could have implications for deep brain stimulation therapies. This study characterizes the physiological effects of cortical iTBS in the human cortex and compare them with single pulse alpha stimulation, another frequently used paradigm in rTMS research. We applied these stimulation paradigms to well-defined regions in the sensorimotor cortex which elicited contralateral hand or arm muscle contractions during electrical stimulation mapping in epilepsy patients implanted with intracranial electrodes. Treatment effects were evaluated using effective connectivity and beta oscillations coherence measures in areas connected to the treatment site as defined with cortico-cortical evoked potentials. Our results show that iTBS increases beta band synchronization within the sensorimotor network indicating a potential neuroplasticity effect. The effect is specific to the sensorimotor system, the beta frequency band and the stimulation pattern (no effect was found with single-pulse alpha stimulation). The effects outlasted the stimulation by three minutes. By characterizing the neurophysiological effects of iTBS within well-defined cortical networks, we hope to provide an electrophysiological framework that allows clinicians and researchers to optimize brain stimulation protocols which may have translational value.
