High-frequency Stimulation Research Articles

Deep brain stimulation for movement disorders after stroke: a systematic review of the literature.

Stroke remains the leading cause of disability in the United States. Even as acute care for strokes advances, there are limited options for improving function once the patient reaches the subacute and chronic stages. Identification of new therapeutic approaches is critical. Deep brain stimulation (DBS) holds promise for these patients. A number of case reports and small case series have reported improvement in movement disorders after strokes in patients treated with DBS. In this systematic review, the authors have summarized the patient characteristics, anatomical targets, stimulation parameters, and outcomes of patients who have undergone DBS treatment for poststroke movement disorders. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The PubMed, Scopus, and SpringerLink databases were searched for the keywords "DBS," "stroke," "movement," and "recovery" to identify patients treated with DBS for movement disorders after a stroke. The Joanna Briggs Institute Critical Appraisal checklists for case reports and case series were used to systematically analyze the quality of the included studies. Data collected from each study included patient demographic characteristics, stroke diagnosis, movement disorder, DBS target, stimulation parameters, complications, and outcomes. The authors included 29 studies that described 53 patients who underwent placement of 82 total electrodes. Movement disorders included tremor (n = 18), dystonia (n = 18), hemiballism (n = 6), spastic hemiparesis (n = 1), chorea (n = 1), and mixed disorders (n = 9). The most common DBS targets were the globus pallidus internus (n = 32), ventral intermediate nucleus of thalamus (n = 25), and subthalamic area/subthalamic nucleus (n = 7). Monopolar stimulation was reported in 43 leads and bipolar stimulation in 13. High-frequency stimulation was used in 57 leads and low-frequency stimulation in 6. All patients but 1 had improvement in their movement disorders. Two complications were reported: speech impairment in 1 patient and hardware infection in another. The median (interquartile range) duration between stroke and DBS treatment was 6.5 (2.1-15.8) years. This is the first systematic review of DBS for poststroke movement disorders. Overall, most studies to date have been case reports and small series reporting heterogeneous patients and surgical strategies. This review suggests that DBS for movement disorders after a stroke has the potential to be effective and safe for diverse patients, and DBS may be a feasible option to improve function even years after a stroke.

High-Frequency Transcranial Random Noise Stimulation Modulates Gamma-Band EEG Source-Based Large-Scale Functional Network Connectivity in Patients with Schizophrenia: A Randomized, Double-Blind, Sham-Controlled Clinical Trial.

Schizophrenia is associated with increased resting-state large-scale functional network connectivity in the gamma frequency. High-frequency transcranial random noise stimulation (hf-tRNS) modulates gamma-band endogenous neural oscillations in healthy individuals through the application of low-amplitude electrical noises. Yet, it is unclear if hf-tRNS can modulate gamma-band functional connectivity in patients with schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast hf-tRNS (N = 17) and sham stimulation (N = 18) for treating negative symptoms in 35 schizophrenia patients. Short continuous currents without neuromodulatory effects were applied in the sham group to mimic real-stimulation sensations. We used electroencephalography to investigate if a five-day, twice-daily hf-tRNS protocol modulates gamma-band (33–45 Hz) functional network connectivity in schizophrenia. Exact low resolution electromagnetic tomography (eLORETA) was used to compute intra-cortical activity from regions within the default mode network (DMN) and fronto-parietal network (FPN), and functional connectivity was computed using lagged phase synchronization. We found that hf-tRNS reduced gamma-band within-DMN and within-FPN connectivity at the end of stimulation relative to sham stimulation. A trend was obtained between the change in within-FPN functional connectivity from baseline to the end of stimulation and the improvement of negative symptoms at the one-month follow-up (r = −0.49, p = 0.055). Together, our findings suggest that hf-tRNS has potential as a network-level approach to modulate large-scale functional network connectivity pertaining to negative symptoms of schizophrenia.

Torque and Discomfort During Electrically Evoked Muscle Contractions in Healthy Young Adults: Influence of Stimulation Current and Pulse Frequency

ObjectiveTo investigate (1) how current and pulse frequency of electrical stimulation (ES) as well as contraction mode (isometric, concentric, and eccentric) influence torque output and discomfort and (2) how familiarization by repeated ES sessions influences ratings of perceived discomfort. DesignAn experimental study, 3 sessions. SettingA university laboratory. ParticipantsEight healthy participants (5 men, 3 women; mean age 25.2 years; N=8). InterventionsParticipants completed 3 trial days, each including 17 electrically evoked thigh muscle contractions. On each trial day, the first 6 contractions consisted of 2 isometric, 2 concentric, and 2 eccentric muscle contractions randomly ordered with a fixed stimulation current and pulse frequency (200 mA, 20 Hz), while the remaining 11 muscle contractions were all isometric with randomly ordered combinations of current (100-250 mA) and pulse frequency (20-100 Hz). Main Outcome MeasuresTorque and perceived discomfort were measured for each ES-evoked contraction. ResultsOverall, the findings revealed that a higher stimulation frequency was associated with an increased torque without increased discomfort, while higher currents were associated with increases of both torque and discomfort. Contraction type did not influence level of discomfort, despite eccentric contractions eliciting higher torque compared with concentric and isometric contractions (P<.001). Finally, a significant familiarization to ES (P<.001) was observed after just 1 of 3 identical stimulation sessions. ConclusionsThe outlined data suggest that to elicit high torque levels while minimizing levels of discomfort in young subjects, eccentric muscle contractions evoked with a low stimulation current, and a high pulse frequency are preferable. Furthermore, a single familiarization session significantly lowers rating of perceived discomfort during ES.

The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome

Genetic alterations in autism spectrum disorders (ASD) frequently disrupt balance between synaptic excitation and inhibition and alter plasticity in the hippocampal CA1 region. Individuals with Timothy Syndrome (TS), a genetic disorder caused by CaV1.2 L-type Ca2+ channel (LTCC) gain-of function mutations, such as G406R, exhibit social deficits, repetitive behaviors, and cognitive impairments characteristic of ASD that are phenocopied in TS2-neo mice expressing G406R. Here, we characterized hippocampal CA1 synaptic function in male TS2-neo mice and found basal excitatory transmission was slightly increased and inhibitory transmission strongly decreased. We also found distinct impacts on two LTCC-dependent forms of long-term potentiation (LTP) synaptic plasticity that were not readily consistent with LTCC gain-of-function. LTP induced by high-frequency stimulation (HFS) was strongly impaired in TS2-neo mice, suggesting decreased LTCC function. Yet, CaV1.2 expression, basal phosphorylation, and current density were similar for WT and TS2-neo. However, this HFS-LTP also required GABAA receptor activity, and thus may be impaired in TS2-neo due to decreased inhibitory transmission. In contrast, LTP induced in WT mice by prolonged theta-train (PTT) stimulation in the presence of a β-adrenergic receptor agonist to increase CaV1.2 phosphorylation was partially induced in TS2-neo mice by PTT stimulation alone, consistent with increased LTCC function. Overall, our findings provide insights regarding how altered CaV1.2 channel function disrupts basal transmission and plasticity that could be relevant for neurobehavioral alterations in ASD.This article is part of the Special Issue on ‘L-type calcium channel mechanisms in neuropsychiatric disorders’.

Dorsal Column Stimulation for the Treatment of Refractory Thoracic Radiculopathy: A Case Report

Between 1996-2016, low back and neck pain expenditures amounted to $134.5 billion according to the Journal of the American Medical Association. Spinal Cord Stimulation (SCS) has been used with success in treatment of radiculopathy, peripheral nerve injury, diabetic neuropathy, failed back surgery syndrome, and complex regional pain syndrome. [1] Initially, low-frequency SCS was used and worked by activating large-diameter Ab fibers in the dorsal column, creating paresthesia stimulation at low frequency (120 Hz), high amplitude, and long duration. This was based on the Gate Control Theory so the low-rate pulsed energy applied at the certain vertebrae of the spine would activate A-beta fibers, which would gate out the nociceptive sensations carried by A-delta and C fibers. Then high-frequency stimulation was used with a frequency of 10,000 Hz, low amplitude, and short duration. This selectively activates inhibitory interneurons in the dorsal horn which suppresses wide dynamic range neurons, which are hyperactive in chronic pain. [2] High frequency stimulation has been found to be superior to low frequency in a RCT with 24 month data showing sustained relief [3].

Delayed improvements in visual memory task performance among chronic schizophrenia patients after high-frequency repetitive transcranial magnetic stimulation.

BACKGROUNDCognitive impairments are core characteristics of schizophrenia, but are largely resistant to current treatments. Several recent studies have shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dor-solateral prefrontal cortex (DLPFC) can reduce negative symptoms and improve certain cognitive deficits in schizophrenia patients. However, results are inconsistent across studies.AIMTo examine if high-frequency rTMS of the DLPFC can improve visual memory deficits in patients with schizophrenia.METHODSForty-seven chronic schizophrenia patients with severe negative symptoms on stable treatment regimens were randomly assigned to receive active rTMS to the DLPFC (n = 25) or sham stimulation (n = 22) on weekdays for four consecutive weeks. Patients performed the pattern recognition memory (PRM) task from the Cambridge Neuropsychological Test Automated Battery at baseline, at the end of rTMS treatment (week 4), and 4 wk after rTMS treatment (week 8). Clinical symptoms were also measured at these same time points using the Scale for the Assessment of Negative Symptoms (SANS) and the Positive and Negative Syndrome Scale (PANSS).RESULTSThere were no significant differences in PRM performance metrics, SANS total score, SANS subscores, PANSS total score, and PANSS subscores between active and sham rTMS groups at the end of the 4-wk treatment period, but PRM performance metrics (percent correct and number correct) and changes in these metrics from baseline were significantly greater in the active rTMS group at week 8 compared to the sham group (all P < 0.05). Active rTMS treatment also significantly reduced SANS score at week 8 compared to sham treatment. Moreover, the improvement in visual memory was correlated with the reduction in negative symptoms at week 8. In contrast, there were no between-group differences in PANSS total score and subscale scores at either week 4 or week 8 (all P > 0.05).CONCLUSIONHigh-frequency transcranial magnetic stimulation improves visual memory and reduces negative symptoms in schizophrenia, but these effects are delayed, potentially due to the requirement for extensive neuroplastic changes within DLPFC networks.

Donepezil inhibits neuromuscular junctional acetylcholinesterase and enhances synaptic transmission and function in isolated skeletal muscle.

Donepezil, a piperidine inhibitor of acetylcholinesterase (AChE) prescribed for treatment of Alzheimer's disease, has adverse neuromuscular effects in humans, including requirement for higher concentrations of non-depolarising neuromuscular blockers during surgery. Here, we examined the effects of donepezil on synaptic transmission at neuromuscular junctions (NMJs) in isolated nerve-muscle preparations from mice. We measured effects of therapeutic concentrations of donepezil (10 nM to 1 μM) on AChE enzymic activity, muscle force responses to repetitive stimulation, and spontaneous and evoked endplate potentials (EPPs) recorded intracellularly from flexor digitorum brevis muscles from CD01 or C57BlWldS mice. Donepezil inhibited muscle AChE with an approximate IC50 of 30 nM. Tetanic stimulation in sub-micromolar concentrations of donepezil prolonged post-tetanic muscle contractions. Preliminary Fluo4-imaging indicated an association of these contractions with an increase and slow decay of intracellular Ca2+ transients at motor endplates. Donepezil prolonged spontaneous miniature EPP (MEPP) decay time constants by about 65% and extended evoked EPP duration almost threefold. The mean frequency of spontaneous MEPPs was unaffected but the incidence of 'giant' MEPPs (gMEPPs), some exceeding 10 mV in amplitude, was increased. Neither mean MEPP amplitude (excluding gMEPPs), mean EPP amplitude, quantal content or synaptic depression during repetitive stimulation were significantly altered by concentrations of donepezil up to 1 μM. Adverse neuromuscular signs associated with donepezil therapy, including relative insensitivity to neuromuscular blockers, are probably due to inhibition of AChE at NMJs, prolonging the action of ACh on postsynaptic nicotinic acetylcholine receptors but without substantively impairing evoked ACh release.

Glucocorticoid regulation of lactate release from spinal astrocytes contributes to the induction of spinal LTP of C-fiber-evoked field potentials and the development of mechanical allodynia

High-frequency stimulation (HFS) of the sciatic nerve leads to long-term potentiation (LTP) at C-fiber synapse and long-lasting pain hypersensitivity. The underlying mechanisms, however, are still unclear. In the present study, we investigated the involvement of astrocytes derived l-lactate in the spinal dorsal horn subsequent to glucocorticoid (GC) secretion into the plasma in this process using Sprague-Dawley rats and Aldh1L1-CreERT2 mice of either sex. We found that HFS increased l-lactate and monocarboxylate transporters 1/2 (MCT1/2) in the spinal dorsal horn. Inhibition of glycogenolysis or blocking lactate transport prevented the induction of spinal LTP following HFS. Furthermore, Chemogenetical inhibition of dorsal horn astrocytes, which were activated by HFS, prevented spinal LTP, alleviated the mechanical allodynia and the decreased the level l-lactate and GFAP expression in the dorsal horn following HFS. In contrast, Chemogenetics activation of dorsal horn astrocytes in naïve rats induced spinal LTP as well as mechanical allodynia, and increased GFAP expression and l-lactate. Application of l-lactate directly to the spinal cord of naïve rats induced spinal LTP, mechanical allodynia, and increased spinal expression of p-ERK. Importantly, HFS increased GC in the plasma and glucocorticoid receptor (GR) expression in spinal astrocytes, adrenalectomy or knocking down of GR in astrocytes by using Cre-Loxp system blocked the mechanical allodynia, prevented the spinal LTP and the enhancement of lactate after HFS. These results show that lactate released from spinal astrocytes following glucocorticoid release into the plasma enhance synaptic transmission at the C-fiber synapse and underlie pain chronicity.

Clinical Efficacy of Catheter Ablation in the Treatment of Vasovagal Syncope.

Catheter ablation of ganglionated plexi (GPs) performed as cardioneuroablation in the left atrium (LA) has been reported previously as a treatment for vasovagal syncope (VVS). However, the efficacy and safety of catheter ablation in the treatment of VVS remains unclear. The objective of this study is to explore the efficacy and safety of catheter ablation in the treatment of VVS and to compare the different ganglion-mapping methods for prognostic effects. A total of 108 patients with refractory VVS who underwent catheter ablation were retrospectively enrolled. Patients preferred to use high-frequency stimulation (HFS) (n = 66), and anatomic landmark (n = 42) targeting is used when HFS failed to induce a positive reaction. The efficacy of the treatment is evaluated by comparing the location and probability of the intraoperative vagal reflex, the remission rate of postoperative syncope symptoms, and the rate of negative head-up tilt (HUT) results. Adverse events are analyzed, and safety is evaluated. After follow-up for 8 (5, 15) months, both HFS mapping and anatomical ablation can effectively improve the syncope symptoms in VVS patients, and 83.7% of patients no longer experienced syncope (<0.001). Both approaches to catheter ablation in the treatment of VVS effectively inhibit the recurrence of VVS; they are safe and effective. Therefore, catheter ablation can be used as a treatment option for patients with symptomatic VVS.

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

BackgroundDeep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized. ObjectiveThe objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr). MethodsTwo microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. ResultsInhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation but not in SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). InterpretationPersistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.

Impact of high frequency stimulation to confirm a complete box isolation in catheter ablation of non-paroxysmal atrial fibrillation.

Pulmonary vein (PV) isolation (PVI) including the left atrial posterior wall (LAPW) (Box-PVI) is proposed as an additional strategy for non-paroxysmal atrial fibrillation (NPAF), however, the efficacy remains controversial. The more reliable and durable the Box-PVI we can create, the better the rhythm outcomes might be than with a conventional PVI alone. This study focused on the potential exit conduction of the box lesion and investigated whether the conventional Box-PVI would be sufficient. We enrolled 350 consecutive patients with NPAF that underwent a conventional encircling Box-PVI and examined whether latent exit conduction and dormant "exit" conduction independently remained on the LAPW and in the PVs using high frequency stimulation (HFS) and an adenosine triphosphate (ATP) injection. All electrograms inside the box lesion were eliminated in all cases, however, HFS inside the box propagated outward in 23 cases (6.6%) without any exit conduction by conventional burst stimulation, and 24 cases (6.9%) exhibited only dormant "exit" conduction of the LAPW. Additional ablation where positive HFSs were observed created a complete bidirectional Box-PVI in 43 (41.3%) of the cases without a first pass Box-PVI. The recurrence rates depended on the groups classified according to the HFS response. HFS delivered with an ATP injection on the LAPW and in the PVs following a Box-PVI could not only elucidate true exit block but also identified possible incomplete lesions or connections outside the ablation line, whose elimination could achieve a complete Box-PVI leading to a better rhythm outcome.

Evaluation of the Analgesia Nociception Index and videopupillometry to predict post-tonsillectomy morphine requirements in children: a single-centre, prospective interventional study.

Tonsil surgery causes significant and challenging postoperative pain. The Analgesia Nociception Index (ANI) and videopupillometry are two techniques of interest to monitor nociception in adults and may predict postoperative morphine requirements. We hypothesised that these techniques could predict the need for morphine after tonsillectomy in children. The main objective was to assess the prognostic significance of ANI and videopupillometry, measured at the end of surgery, on morphine consumption determined by a Face, Legs, Activity, Cry, Consolability (FLACC) scale score >3 in the Post Anesthesia Care Unit (PACU). A single-centre, prospective, interventional study evaluating children between 2 and 7 yr old undergoing tonsil surgery was performed. ANI and videopupillometry with tetanic stimulation were measured under general anaesthesia 4 min after the end of the surgical procedure. Each child was evaluated every 10 min by a nurse using the FLACC scale in the PACU and blinded to the measurements performed in the operating theatre. Eighty-nine children were analysed and 39 (44%) received morphine in the PACU. Neither ANI values nor videopupillometry values were predictive of postoperative morphine consumption (areas under the receiver operating characteristic curve 0.54, 95% confidence interval [CI; 0.42-0.65], and P=0.57; and 0.52, 95% CI [0.41-0.63], and P=0.69, respectively). Neither ANI values nor videopupillometry values were correlated to the maximum FLACC scale score in the PACU with ρ=0.04 (P=0.71) and ρ=0.06 (P=0.57), respectively. Neither ANI nor videopupillometry performed at the end of surgery can predict morphine consumption in the PACU in children undergoing tonsillectomy.

WE-231. Application of tetanic stimulation to the pudendal nerve prior to transcranial stimulation for augmentation of motor-evoked potential

WE-231. Application of tetanic stimulation to the pudendal nerve prior to transcranial stimulation for augmentation of motor-evoked potential

Focal seizures producing loss of wakefulness without ictal asystole: Does temporal lobe syncope exist?

Focal seizures are frequently associated with alteration of consciousness, mainly of awareness, rather than with complete loss of wakefulness. We aimed to explore whether episodes of complete loss of wakefulness (LOW) could be attributed to focal seizures alone, out of the context of ictal asystole or secondary generalization. From a database of adult patients with refractory, focal epilepsy, evaluated for presurgical work-up we searched for patients having the following criteria: (1) focal epilepsy, and (2) transient loss of consciousness, documented in video EEG or/and video SEEG, characterized by an alteration in the level of wakefulness ("syncope like", LOW), with eye closure, hypotonia and non-reactivity state. Patients with motor signs of secondary generalization and patients with non-epileptic psychogenic seizures were excluded. Fifteen patients with transient ictal LOW during focal seizures were found. Among them, 12 patients had ictal asystole. We found 3 patients who had complete loss of wakefulness during focal seizures, without asystole or documented hypotension. In two patients the episodes were provoked by high frequency stimulation of hippocampus and amygdala. The third patient had LOW appearing during a spontaneous temporal lobe seizure. Syncope semiology without ictal asystole can be attributed to temporal lobe seizures but remains an exceptional phenomenon. A crucial clinical requirement is the exclusion of cardiac arrhythmias, especially asystole.

Differential microRNA profiles of intramuscular and secreted extracellular vesicles in human tissue-engineered muscle.

Exercise affects the expression of microRNAs (miR/s) and muscle-derived extracellular vesicles (EVs). To evaluate sarcoplasmic and secreted miR expression in human skeletal muscle in response to exercise-mimetic contractile activity, we utilized a three-dimensional tissue-engineered model of human skeletal muscle (“myobundles”). Myobundles were subjected to three culture conditions: no electrical stimulation (CTL), chronic low frequency stimulation (CLFS), or intermittent high frequency stimulation (IHFS) for 7 days. RNA was isolated from myobundles and from extracellular vesicles (EVs) secreted by myobundles into culture media; miR abundance was analyzed by miRNA-sequencing. We used edgeR and a within-sample design to evaluate differential miR expression and Pearson correlation to evaluate correlations between myobundle and EV populations within treatments with statistical significance set at p < 0.05. Numerous miRs were differentially expressed between myobundles and EVs; 116 miRs were differentially expressed within CTL, 3 within CLFS, and 2 within IHFS. Additionally, 25 miRs were significantly correlated (18 in CTL, 5 in CLFS, 2 in IHFS) between myobundles and EVs. Electrical stimulation resulted in differential expression of 8 miRs in myobundles and only 1 miR in EVs. Several KEGG pathways, known to play a role in regulation of skeletal muscle, were enriched, with differentially overrepresented miRs between myobundle and EV populations identified using miEAA. Together, these results demonstrate that in vitro exercise-mimetic contractile activity of human engineered muscle affects both their expression of miRs and number of secreted EVs. These results also identify novel miRs of interest for future studies of the role of exercise in organ-organ interactions in vivo.

The Effectiveness of High-Frequency Repetitive Transcranial Magnetic Stimulation on Patients with Neuropathic Orofacial Pain: A Systematic Review of Randomized Controlled Trials.

Background Repetitive transcranial magnetic stimulation (rTMS) has been widely used in the treatment of neuropathic orofacial pain (NOP). The consistency of its therapeutic efficacy with the optimal protocol is highly debatable. Objective To assess the effectiveness of rTMS on pain intensity, psychological conditions, and quality of life (QOL) in individuals with NOP based on randomized controlled trials (RCTs). Methods We carefully screened and browsed 5 medical databases from inception to January 1, 2022. The study will be included that use of rTMS as the intervention for patients with NOP. Two researchers independently completed record retrieval, data processing, and evaluation of methodological quality. Quality and evidence were assessed using the PEDro scores and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results Six RCTs with 214 participants were included in this systematic review: 2 studies were considered level 1 evidence, and 4 were considered level 2 evidence. Six studies found that high-frequency rTMS had a pain-relieving effect, while 4 studies found no improvement in psychological conditions and QOL. Quality of evidence (GRADE system) ranged from moderate to high. No significant side effects were found. Conclusions There is moderate-to-high evidence to prove that high-frequency rTMS is effective in reducing pain in individuals with NOP, but it has no significant positive effect on psychological conditions and QOL. High-frequency rTMS can be used as an alternative treatment for pain in individuals with NOP, but further studies will be conducted to unify treatment parameters, and the sample size will be expanded to explore its influence on psychological conditions and QOL.

In the back of your mind: Cortical mapping of paraspinal afferent inputs.

Topographic organisation is a hallmark of vertebrate cortex architecture, characterised by ordered projections of the body's sensory surfaces onto brain systems. High‐resolution functional magnetic resonance imaging (fMRI) has proven itself as a valuable tool to investigate the cortical landscape and its (mal‐)adaptive plasticity with respect to various body part representations, in particular extremities such as the hand and fingers. Less is known, however, about the cortical representation of the human back. We therefore validated a novel, MRI‐compatible method of mapping cortical representations of sensory afferents of the back, using vibrotactile stimulation at varying frequencies and paraspinal locations, in conjunction with fMRI. We expected high‐frequency stimulation to be associated with differential neuronal activity in the primary somatosensory cortex (S1) compared with low‐frequency stimulation and that somatosensory representations would differ across the thoracolumbar axis. We found significant differences between neural representations of high‐frequency and low‐frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral S1 sub‐regions, and in regions of the primary motor cortex (M1). High‐frequency stimulation preferentially activated Brodmann Area (BA) regions BA3a and BA4p, whereas low‐frequency stimulation was more encoded in BA3b and BA4a. Moreover, we found clear topographic differences in S1 for representations of the upper and lower back during high‐frequency stimulation. We present the first neurobiological validation of a method for establishing detailed cortical maps of the human back, which might serve as a novel tool to evaluate the pathological significance of neuroplastic changes in clinical conditions such as chronic low back pain.

The Effect of Noise Trauma and Deep Brain Stimulation of the Medial Geniculate Body on Tissue Activity in the Auditory Pathway.

Tinnitus is defined as the phantom perception of sound. To date, there is no curative treatment, and contemporary treatments have failed to show beneficial outcomes. Deep brain stimulation has been suggested as a potential therapy for refractory tinnitus. However, the optimal target and stimulation regimens remain to be defined. Herein, we investigated metabolic and neuronal activity changes using cytochrome C oxidase histochemistry and c-Fos immunohistochemistry in a noise trauma-induced rat model of tinnitus. We also assessed changes in neuronal activity following medial geniculate body (MGB) high-frequency stimulation (HFS). Metabolic activity was reduced in the primary auditory cortex, MGB and CA1 region of the hippocampus in noise-exposed rats. Additionally, c-Fos expression was increased in the primary auditory cortex of those animals. Furthermore, MGB-HFS enhanced c-Fos expression in the thalamic reticular nucleus. We concluded that noise trauma alters tissue activity in multiple brain areas including the auditory and limbic regions. MGB-HFS resulted in higher neuronal activity in the thalamic reticular nucleus. Given the prominent role of the auditory thalamus in tinnitus, these data provide more rationales towards targeting the MGB with HFS as a symptom management tool in tinnitus.

Focal non-invasive deep-brain stimulation with temporal interference for the suppression of epileptic biomarkers.

IntroductionNeurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 and 165 Hz, to various deep-seated targets, such as the Mesio-temporal lobe (MTL), which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely an increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs).Materials and methodsIn the current study, we use Temporal Interference (TI) stimulation to provide a non-invasive DBS (130 Hz) of the MTL, specifically the hippocampus, in both mouse models of epilepsy, and scale the method using human cadavers to demonstrate the potential efficacy in human patients. Simulations for both mice and human heads were performed to calculate the best coordinates to reach the hippocampus.ResultsThis non-invasive DBS increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. We therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs. TCS in human cadavers. Results show a better penetration of TI fields into the human hippocampus as compared with TCS.SignificanceThese results constitute the first proof of the feasibility and efficiency of TI to stimulate at depth an area without impacting the surrounding tissue. The data tend to show the sufficiently focal character of the induced effects and suggest promising therapeutic applications in epilepsy.

High-frequency stimulation of the subthalamic nucleus induces a sustained inhibition of serotonergic system via loss of cell phenotype

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a standard treatment for Parkinson’s disease (PD). However, in a considerable number of patients debilitating psychiatric side-effects occur. Recent research has revealed that external stimuli can alter the neurotransmitters’ homeostasis in neurons, which is known as “neurotransmitter respecification”. Herein, we addressed if neurotransmitter respecification could be a mechanism by which DBS suppresses the serotonergic function in the dorsal raphe nucleus (DRN) leading to mood changes. We infused transgenic 5-HT-Cre (ePET-Cre) mice with AAV viruses to achieve targeted expression of eYFP and the genetically encoded calcium indicator GCaMP6s in the DRN prior to methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Mice received bilateral DBS electrodes in the STN and an optic fiber in the DRN for calcium photometry. MPTP-treated mice demonstrated behavioral and histological PD phenotype, whereas all STN-DBS animals exhibited an increased immobility time in the forced swim test, reduced calcium activity, and loss of tryptophan hydroxylase-2 expression in the DRN. Given the prominent role of calcium transients in mediating neurotransmitter respecification, these results suggest a loss of serotonergic phenotype in the DRN following STN-DBS. These findings indicate that loss of serotonergic cell phenotype may underlie the unwanted depressive symptoms following STN-DBS.