Does the Use of Intraoperative Microelectrode Recording Influence the Final Location of Lead Implants in the Ventral Intermediate Nucleus for Deep Brain Stimulation?

To determine if the use of intraoperative microelectrode recording (MER) influences the final location of lead implant in deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM), and to evaluate the incidence of associated complications. The usefulness of intraoperative MER in DBS is debated, some centers suggesting it increases complications without additional benefit. We conducted a retrospective chart review of all patients who underwent VIM DBS with MER at the University of Texas Health Science Center in Houston from June 1, 2009 to October 1, 2013. Initial (MRI determined) and final (intraoperative MER determined) coordinates of implant were compared. To assess incidences of hemorrhagic and infectious complications, we reviewed postoperative CT scans and follow-up notes. Forty-five lead implants on 24 patients were reviewed. The mean age at implantation was 62.42 years (range 18–83). The average duration from diagnosis to surgery was 21.5 years (range 1–52). A statistically significant mean difference was observed in the superior-inferior plane (0.52 ± 0.80 mm inferiorly, p < 0.05) and the anterior-posterior plane (0.45 ± 0.86 mm posteriorly, p < 0.05). A non-statistically significant difference was also observed in the medial-lateral plane (0.02± 0.15 mm, p > 0.05). One patient developed an infectious complication (4.2 %) that required removal of leads; two patients had minimal asymptomatic intra-ventricular bleeding (8.3 %). In our DBS center, intraoperative MER in VIM DBS implant does not seem to have a higher rate of surgical complications compared to historical series not using MER, and might also be useful in determining the final lead location.     

Non-invasive Cerebellar Stimulation—a Consensus Paper

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.     

Ventral tegmental nucleus of Gudden: A pontine hippocampal theta generator?

It is well-established that rhythmically bursting (RB) activity in the medial septum is crucial for the generation of the hippocampal theta rhythm, but the contribution of other diencephalic-pontine structures is less documented. The ventral tegmental nucleus (VTn) of Gudden is related to the Papez's circuit via its interconnections with the medial mammillary nucleus, and therefore it may play a role in the generation of hippocampal theta. In the present study, extracellular activity from VTn neurons were recorded in unanesthetized restrained rats (n = 9). Hippocampal activity (EEG) and electromyograms were recorded simultaneously to identify sleep-waking states. RB activity was observed in VTn during wakefulness, with periods of hippocampal theta and during rapid eye movement (REM) sleep. Rhythmicity in VTn preceded theta activity in hippocampus. The frequency of RB neurons in VTn was 5.6 Hz during wakefulness and 6.8 Hz during REM sleep. It was similar to that of hippocampal theta. The rhythmicity was particularly stable and the firing rates were strikingly high during REM sleep. RB activity in VTn was also recorded from urethane-anesthetized rates (n = 3). Rhythmic firing (4.0 Hz) was slower than in unanesthetized rats and matched the urethane-related theta frequency. Our results show that neurons in VTn exhibit a marked RB activity during states of vigilance accompanied by hippocampal theta rhythm. They suggest that VTn may be a pontine hippocampal theta generator.     

Modulation of I-Wave Generating Pathways With Repetitive Paired-Pulse Transcranial Magnetic Stimulation: A Transcranial Magnetic Stimulation–Electroencephalography Study

ObjectivesRepetitive paired-pulse transcranial magnetic stimulation (iTMS) at indirect (I) wave intervals increases motor-evoked potentials (MEPs) produced by transcranial magnetic stimulation (TMS) to primary motor cortex (M1). However, the effects of iTMS at early and late intervals on the plasticity of specific I-wave circuits remain unclear. This study therefore aimed to assess how the timing of iTMS influences intracortical excitability within early and late I-wave circuits. To investigate the cortical effects of iTMS more directly, changes due to the intervention were also assessed using combined TMS-electroencephalography (EEG).Material and MethodsEighteen young adults (aged 24.6 ± 4.2 years) participated in four sessions in which iTMS targeting early (1.5-millisecond interval; iTMS_1.5) or late (4.0-millisecond interval; iTMS_4.0) I-waves was applied over M1. Neuroplasticity was assessed using both posterior-to-anterior (PA) and anterior-to-posterior (AP) stimulus directions to record MEPs and TMS-evoked EEG potentials (TEPs) before and after iTMS. Short-interval intracortical facilitation (SICF) at interstimulus intervals of 1.5 and 4.0 milliseconds was also used to index I-wave activity.ResultsMEP amplitude was increased after iTMS (p < 0.01), and this was greater for PA responses (p < 0.01) but not different between iTMS intervals (p = 0.9). Irrespective of iTMS interval and coil current, SICF was facilitated after the intervention (p < 0.01). Although the N45 produced by AP stimulation was decreased by iTMS_1.5 (p = 0.04), no other changes in TEP amplitude were observed.ConclusionsThe timing of iTMS failed to influence which I-wave circuits were potentiated by the intervention. In contrast, decreases in the N45 suggest that the neuroplastic effects of iTMS may include disinhibition of intracortical inhibitory processes.     

The Inhibitory Effects of Pudendal Nerve Stimulation on Bladder Overactivity in Spinal Cord Injury Dogs: Is Early Stimulation Necessary?

Objective: To determine the inhibitory effects of pudendal nerve stimulation (5 Hz) on bladder overactivity at early and late stages of spinal cord injury in dogs. Materials and Methods: The study was performed in eight dogs with chronic spinal cord transection at the T9‐T10 level. Group 1 (four dogs) underwent electrical stimulation of pudendal nerve one month after spinal cord transection. Group 2 (four dogs) underwent stimulation six months after spinal cord transection. The bladders were removed for histological examination of fibrosis after the stimulation. Results: The bladder capacity and the compliance were significantly increased (p < 0.05) by pudendal nerve stimulation in group 1, but not in group 2. The nonvoiding contractions were inhibited in both groups by electrical stimulation. Collagen fiber was increased, while elastic fiber was significantly decreased (p < 0.05) in group 2 when compared with group 1. Conclusion: Pudendal nerve stimulation can increase the bladder capacity and compliance only during the early period before the bladder wall becomes fibrosit and can inhibit the nonvoiding contraction during two stages.     

Optimizing Deep Brain Stimulation Parameters in Obsessive–Compulsive Disorder

ObjectivesDeep brain stimulation (DBS) is an innovative and effective treatment for patients with therapy-refractory obsessive–compulsive disorder (OCD). DBS offers unique opportunities for personalized care, but no guidelines on how to choose effective and safe stimulation parameters in patients with OCD are available. Our group gained relevant practical knowledge on DBS optimization by treating more than 80 OCD patients since 2005, the world’s largest cohort. The article’s objective is to share this experience.Materials and MethodsWe provide guiding principles for optimizing DBS stimulation parameters in OCD and discuss the neurobiological and clinical basis.ResultsAdjustments in stimulation parameters are performed in a fixed order. First, electrode contact activation is determined by the position of the electrodes on postoperative imaging. Second, voltage and pulse width are increased stepwise, enlarging both the chance of symptom reduction and of inducing side effects. Clinical evaluation of adjustments in stimulation parameters needs to take into account: 1) the particular temporal sequence in which the various OCD symptoms and DBS side-effects change; 2) the lack of robust response predictors; 3) the limited sensitivity of the Yale-Brown Obsessive–Compulsive Scale to assess DBS-induced changes in OCD symptoms; and 4) a patient’s fitness for additional cognitive-behavioral therapy (CBT).ConclusionsDecision-making in stimulation parameter optimization needs to be sensitive to the particular time-courses on which various symptoms and side effects change.     

Neural Sources of Vagus Nerve Stimulation–Induced Slow Cortical Potentials

ObjectivesThis study investigated neuronal sources of slow cortical potentials (SCPs) evoked during vagus nerve stimulation (VNS) in patients with epilepsy who underwent routine electroencephalography (EEG) after implantation of the device.Materials and MethodsWe analyzed routine clinical EEG from 24 patients. There were 5 to 26 trains of VNS during EEG. To extract SCPs from the EEG, a high-frequency filter of 0.2 Hz was applied. These EEG epochs were averaged and used for source analyses. The averaged waveforms for each patient and their grand average were subjected to multidipole analysis. Patients with at least 50% seizure frequency reduction were considered responders. Findings from EEG analysis dipole were compared with VNS responses.ResultsVNS-induced focal SCPs whose dipoles were estimated to be located in several cortical areas including the medial prefrontal cortex, postcentral gyrus, and insula, with a significantly higher frequency in patients with a good VNS response than in those with a poor response.ConclusionsThis study suggested that some VNS-induced SCPs originating from the so-called vagus afferent network are related to the suppression of epileptic seizures.     

Combined Ketogenic Diet and Vagus Nerve Stimulation: Rational Polytherapy?

OBJECTIVE: The concept of "rational polypharmacy" has been associated with anticonvulsant management for decades, but the term has not been applied to nonpharmacologic therapies. METHODS: We conducted a multicenter, retrospective study of children who received concurrent diet (ketogenic or modified Atkins) and vagus nerve stimulation (VNS) treatment for medically intractable epilepsy. RESULTS: Thirty children in total from six epilepsy centers were treated over a 6-yr period. The median age at the initiation of combination therapy was 10 yr (range, 4-24 yr). Sixteen (53%) received dietary therapy followed by VNS; no differences were noted between centers. After 3 months, 21 (70%) had seizure reduced by >50% over the previous single nonpharmacologic treatment, of whom 13 (62%) had improvement within the first month. A 5-min VNS off-time correlated with >90% seizure reduction (p = 0.02). The median duration of nonpharmacologic polytherapy was 12 months (range, 0.5-96 months); 17 (57%) remain on dual therapy at this time. No side effects were noted. Most patients who discontinued combination therapy did so because of a lack of efficacy rather than restrictiveness. CONCLUSIONS: In this small group, the combined use of diet and VNS appeared synergistic and yielded rapid benefits. It may be more effective with longer VNS off-times. Further prospective studies of this combination in refractory pediatric epilepsy are needed to help guide optimal use.     

Glutamatergic Ventral Pallidal Neurons Modulate Activity of the Habenula–Tegmental Circuitry and Constrain Reward Seeking

Background

The ability to appropriately integrate and respond to rewarding and aversive stimuli is essential for survival. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. However, the VP is a heterogeneous structure, and how VP subpopulations integrate into larger reward networks to ultimately modulate these behaviors is not known. We identify a noncanonical population of glutamatergic VP neurons that play a unique role in responding to aversive stimuli and constraining inappropriate reward seeking.

Non-invasive Cerebellar Stimulation: a Promising Approach for Stroke Recovery?

Non-invasive brain stimulation (NIBS) combined with behavioral training is a promising strategy to augment recovery after stroke. Current research efforts have been mainly focusing on primary motor cortex (M1) stimulation. However, the translation from proof-of-principle to clinical applications is not yet satisfactory. Possible reasons are the heterogeneous properties of stroke, generalization of the stimulation protocols, and hence the lack of patient stratification. One strategy to overcome these limitations could be the evaluation of alternative stimulation targets, like the cerebellum. In this regard, first studies provided evidence that non-invasive cerebellar stimulation can modulate cerebellar processing and linked behavior in healthy subjects. The cerebellum provides unique plasticity mechanisms and has vast connections to interact with neocortical areas. Moreover, the cerebellum could serve as a non-lesioned entry to the motor or cognitive system in supratentorial stroke. In the current article, we review mechanisms of plasticity in the cortico-cerebellar system after stroke, methods for non-invasive cerebellar stimulation, and possible target symptoms in stroke, like fine motor deficits, gait disturbance, or cognitive impairments, and discuss strategies for multi-focal stimulation.     

L-type Calcium Channels are Involved in Iron-induced Neurotoxicity in Primary Cultured Ventral Mesencephalon Neurons of Rats

In the present study,we investigated the mechanisms underlying the mediation of iron transport by Ltype Ca^2+ channels(LTCCs)in primary cultured ventral mesencephalon(VM)neurons from rats.We found that cotreatment with 100 lmol/L FeSO4 and MPP^+(1-methyl-4-phenylpyridinium)significantly increased the production of intracellular reactive oxygen species,decreased the mitochondrial transmembrane potential and increased the caspase-3 activation compared to MPP^+ treatment alone.Co-treatment with 500 lmol/L CaCl2 further aggravated the FeSO4-induced neurotoxicity in MPP^+-treated VM neurons.Co-treatment with 10 lmol/L isradipine,an LTCC blocker,alleviated the neurotoxicity induced by co-application of FeSO4 and FeSO4/CaCl2.Further studies indicated that MPP^+treatment accelerated the iron influx into VM neurons.In addition,FeSO4 treatment significantly increased the intracellular Ca^2+ concentration.These effects were blocked by isradipine.These results suggest that elevated extracellular Ca^2+ aggravates ironinduced neurotoxicity.LTCCs mediate iron transport in dopaminergic neurons and this,in turn,results in elevated intracellular Ca^2+ and further aggravates iron-induced neurotoxicity.     

Brain Stimulation for Epilepsy – Local and Remote Modulation of Network Excitability

BackgroundThe use of Deep Brain Stimulation (DBS) as a potential therapy for treatment resistant epilepsy remains an area of active clinical investigation. We recently reported the first chronic evaluation of an implantable, clinical-grade system that permits concurrent stimulation and recording, in a large animal (ovine) model developed to study DBS for epilepsy.ObjectiveIn this study we extended this work to compare the effects of remote (anterior thalamic) and direct (hippocampal) stimulation on local field potential (LFP) activity and network excitability, and to assess closed-loop stimulation within this neural network.MethodsFollowing anesthesia and 1.5T MRI acquisition, unilateral anterior thalamic and hippocampal DBS leads were implanted in three subjects using a frameless stereotactic system. Chronic, awake recordings of evoked potentials (EPs) and LFPs in response to thalamic and hippocampal stimulation were collected with the implanted device and analyzed off-line.ResultsConsistent with earlier reports, thalamic DBS and direct stimulation of the hippocampus produced parameter-dependent effects on hippocampal activity. LFP suppression could be reliably induced with specific stimulation parameters, and was shown to reflect a state of reduced network excitability, as measured by effects on hippocampal EP amplitudes and after-discharge thresholds. Real-time modulation of network excitability via the implanted device was demonstrated using hippocampal theta-band power level as a control signal for closed-loop stimulation.ConclusionsThe results presented provide evidence of network excitability changes induced by stimulation that could underlie the clinical effects that have been reported with both thalamic and direct cortical stimulation.