Wireless stimulation of the subthalamic nucleus with nanoparticles modulates key monoaminergic systems similar to contemporary deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is commonly used to alleviate motor symptoms in several movement disorders. However, the procedure is invasive, and the technology has remained largely stagnant since its inception decades ago. Recently, we have shown that wireless nanoelectrodes may offer an alternative approach to conventional DBS. However, this method is still in its infancy, and more research is required to characterize its potential before it can be considered as an alternative to conventional DBS. OBJECTIVES: Herein, we aimed to investigate the effect of stimulation via magnetoelectric nanoelectrodes on primary neurotransmitter systems that have implications for DBS in movement disorders. METHODS: Mice were injected with either magnetoelectric nanoparticles (MENPs) or magnetostrictive nanoparticles (MSNPs, as a control) in the subthalamic nucleus (STN). Mice then underwent magnetic stimulation, and their motor behavior was assessed in the open field test. In addition, magnetic stimulation was applied before sacrifice and post-mortem brains were processed for immunohistochemistry (IHC) to assess the co-expression of c-Fos with either tyrosine hydroxylase (TH), tryptophan hydroxylase-2 (TPH2) or choline acetyltransferase (ChAT). RESULTS: Stimulated animals covered longer distances in the open field test when compared to controls. Moreover, we found a significant increase in c-Fos expression in the motor cortex (MC) and paraventricular region of the thalamus (PV-thalamus) after magnetoelectric stimulation. Stimulated animals showed fewer TPH2/c-Fos double-labeled cells in the dorsal raphe nucleus (DRN), as well as TH/c-Fos double-labeled cells in the ventral tegmental area (VTA), but not in the substantia nigra pars compacta (SNc). There was no significant difference in the number of ChAT/ c-Fos double-labeled cells in the pedunculopontine nucleus (PPN). CONCLUSIONS: Magnetoelectric DBS in mice enables selective modulation of deep brain areas and animal behavior. The measured behavioral responses are associated with changes in relevant neurotransmitter systems. These changes are somewhat similar to those observed in conventional DBS, suggesting that magnetoelectric DBS might be a suitable alternative.

Magnetic nanomaterials for wireless thermal and mechanical neuromodulation.

Magnetic fields are very attractive for non-invasive neuromodulation because they easily penetrate trough the skull and tissue. Cell specific neuromodulation requires the magnetic field energy to be converted by an actuator to a biologically relevant signal. Miniaturized actuators available today range from small, isotropic magnetic nanoparticles to larger, submicron anisotropic magnetic nanomaterials. Depending on the parameters of external magnetic fields and the properties of the nanoactuators, they create either a thermal or a mechanical stimulus. Ferromagnetic nanomaterials generate heat in response to high frequency alternating magnetic fields associated with dissipative losses. Anisotropic nanomaterials with large magnetic moments are capable of exerting forces at stationary or slowly varying magnetic fields. These tools allow exploiting thermosensitive or mechanosensitive neurons in circuit or cell specific tetherless neuromodulation schemes. This review will address assortment of available magnetic nanomaterial-based neuromodulation techniques that rely on application of external magnetic fields.

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.

Deep brain stimulation of the nucleus basalis of Meynert in an experimental rat model of dementia: Stimulation parameters and mechanisms.

BACKGROUND/OBJECTIVE: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has gained interest as a potential therapy for treatment-resistant dementia. However, optimal stimulation parameters and mechanisms of action are yet to be elucidated. METHODS: First, we assessed NBM DBS at different stimulation parameters in a scopolamine-induced rat model of dementia. Rats were tested in the object location task with the following conditions: (i) low and high frequency (20 Hz or 120 Hz), (ii) monophasic or biphasic pulse shape (iii) continuous or intermittent DBS (20s on, 40s off) and 100 µA amplitude. Thereafter, rats were stimulated with the most effective parameter followed by 5-bromo-2'-deoxyuridine (BrdU) administration and perfused 4 weeks later. We then evaluated the effects of NBM DBS on hippocampal neurogenesis, synaptic plasticity, and on cholinergic fibres in the perirhinal and cingulate cortex using immunohistochemistry. We also performed in-vivo microdialysis to assess circuit-wide effects of NBM DBS on hippocampal acetylcholine levels during on and off stimulation. RESULTS: Biphasic, low frequency and intermittent NBM DBS reversed the memory impairing effects of scopolamine when compared to sham rats. We found that acute stimulation promoted proliferation in the dentate gyrus, increased synaptic plasticity in the CA1 and CA3 subregion of the hippocampus, and increased length of cholinergic fibres in the cingulate gyrus. There was no difference regarding hippocampal acetylcholine levels between the groups. CONCLUSION: These findings suggest that the potential mechanism of action of the induced memory enhancement through NBM DBS might be due to selective neuroplastic and neurochemical changes.

The Alteration of Neurogenesis and Pathological Markers in Alzheimer's Disease After Deep Brain Stimulation.

Alzheimer's disease (AD) is the most common type of dementia that causes disabilities in memory formation and activities of daily living. Unfortunately, pharmacologic treatments have minimal and short-lasting effects on AD. With the increasing aging population, investigations into therapeutic strategies for AD that lead to a delay in disease progression would significantly reduce the global burden of AD. Deep brain stimulation (DBS) is considered therapeutic for several conditions, such as movement disorders and some psychiatric diseases. Preclinical and clinical studies that used DBS as a treatment modality demonstrate the safety of DBS in AD and suggest potential memory improvements after surgery. Nevertheless, more studies are needed to understand the therapeutic mechanism of DBS. In this review, we summarize studies on DBS in various targets for AD and discuss DBS-induced changes in neurogenesis and pathological markers in AD.

Magnetothermal nanoparticle technology alleviates parkinsonian-like symptoms in mice.

Deep brain stimulation (DBS) has long been used to alleviate symptoms in patients suffering from psychiatric and neurological disorders through stereotactically implanted electrodes that deliver current to subcortical structures via wired pacemakers. The application of DBS to modulate neural circuits is, however, hampered by its mechanical invasiveness and the use of chronically implanted leads, which poses a risk for hardware failure, hemorrhage, and infection. Here, we demonstrate that a wireless magnetothermal approach to DBS (mDBS) can provide similar therapeutic benefits in two mouse models of Parkinson's disease, the bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in the unilateral 6-hydroxydopamine (6-OHDA) model. We show magnetothermal neuromodulation in untethered moving mice through the activation of the heat-sensitive capsaicin receptor (transient receptor potential cation channel subfamily V member 1, TRPV1) by synthetic magnetic nanoparticles. When exposed to an alternating magnetic field, the nanoparticles dissipate heat, which triggers reversible firing of TRPV1-expressing neurons. We found that mDBS in the subthalamic nucleus (STN) enables remote modulation of motor behavior in healthy mice. Moreover, mDBS of the STN reversed the motor deficits in a mild and severe parkinsonian model. Consequently, this approach is able to activate deep-brain circuits without the need for permanently implanted hardware and connectors.

Electrical stimulation of the fornix for the treatment of brain diseases.

Deep brain stimulation (DBS) has proven to be safe and effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin, while its application to other neural pathways such as the circuit of Papez is under investigation. In particular, the fornix has gained interest as potential DBS target to decrease rates of cognitive decline, enhance memory, aid visuospatial memorization, and improve verbal recollection. While the exact mechanisms of action of fornix DBS are not completely understood, studies found enhanced hippocampal acetylcholine release, synaptic plasticity, and decreased inflammatory responses in cortex and hippocampus. Nevertheless, it is still premature to conclude that fornix DBS can be used in the treatment of cognitive disorders, and the field needs sound, preclinically tested, and disease-specific a posteriori hypotheses.

Deep brain stimulation and cognition: Translational aspects.

Many neurological patients suffer from memory loss. To date, pharmacological treatments for memory disorders have limited and short-lasting effects. Therefore, researchers are investigating novel therapies such as deep brain stimulation (DBS) to alleviate memory impairments. Up to now stimulation of the fornix, nucleus basalis of Meynert and entorhinal cortex have been found to enhance memory performance. Here, we provide an overview of the different DBS targets and mechanisms within the memory circuit, which could be relevant for enhancing memory in patients. Future studies are warranted, accelerating the efforts to further unravel mechanisms of action of DBS in memory-related disorders and develop stimulation protocols based on these mechanisms.

Correction to: The effect of fornix deep brain stimulation in brain diseases.

After publication of the original article it came to the authors' attention that there was an error under the subheading Traumatic Brain Injury (TBI) as well as Table 1.

The effect of fornix deep brain stimulation in brain diseases.

Deep brain stimulation is used to alleviate symptoms of neurological and psychiatric disorders including Parkinson's disease, epilepsy, and obsessive-compulsive-disorder. Electrically stimulating limbic structures has been of great interest, and in particular, the region of the fornix. We conducted a systematic search for studies that reported clinical and preclinical outcomes of deep brain stimulation within the fornix up to July 2019. We identified 13 studies (7 clinical, 6 preclinical) that examined the effects of fornix stimulation in Alzheimer's disease (n = 9), traumatic brain injury (n = 2), Rett syndrome (n = 1), and temporal lobe epilepsy (n = 1). Overall, fornix stimulation can lead to decreased rates of cognitive decline (in humans), enhanced memory (in humans and animals), visuo-spatial memorization (in humans and animals), and improving verbal recollection (in humans). While the exact mechanisms of action are not completely understood, studies suggest fornix DBS to be involved with increased functional connectivity and neurotransmitter levels, as well as enhanced neuroplasticity.

Progress in neuromodulation of the brain: A role for magnetic nanoparticles?

The field of neuromodulation is developing rapidly. Current techniques, however, are still limited as they i) either depend on permanent implants, ii) require invasive procedures, iii) are not cell-type specific, iv) involve slow pharmacokinetics or v) have a restricted penetration depth making it difficult to stimulate regions deep within the brain. Refinements into the different fields of neuromodulation are thus needed. In this review, we will provide background information on the different techniques of neuromodulation discussing their latest refinements and future potentials including the implementation of nanoparticles (NPs). In particular we will highlight the usage of magnetic nanoparticles (MNPs) as transducers in advanced neuromodulation. When exposed to an alternating magnetic field (AMF), certain MNPs can generate heat through hysteresis. This MNP heating has been promising in the field of cancer therapy and has recently been introduced as a method for remote and wireless neuromodulation. This indicates that MNPs may aid in the exploration of brain functions via neuromodulation and may eventually be applied for treatment of neuropsychiatric disorders. We will address the materials chemistry of MNPs, their biomedical applications, their delivery into the brain, their mechanisms of stimulation with emphasis on MNP heating and their remote control in living tissue. The final section compares and discusses the parameters used for MNP heating in brain cancer treatment and neuromodulation. Concluding, using MNPs for nanomaterial-mediated neuromodulation seem promising in a variety of techniques and could be applied for different neuropsychiatric disorders when more extensively investigated.

Fornix deep brain stimulation induces reduction of hippocampal synaptophysin levels.

Fornix deep brain stimulation (DBS) has the ability to refurbish memory functions in animal models with experimental dementia. One of the possible underlying mechanisms is the acute increase of acetylcholine in the hippocampus. Another suggested hypothesis is neuroplasticity. Recent work in rats has shown that acute fornix DBS can modulate neurotrophic factors as well as synaptic plasticity markers on the short-term. Here, we want to test the hypothesis that acute fornix DBS can also lead to long-term effects on neuroplasticity. Rats received DBS at 100 Hz, 100 µA and 100 µs pulse width for 4 h with electrodes placed bilaterally in the fornix. Seven weeks after stimulation, rats were sacrificed. BDNF, p-CREB, SV2 and synaptophysin immunohistochemistry was performed for their brains. No differences were found in the number of BDNF, p-CREB or SV2 positive cells for fornix DBS rats when compared to sham. Surprisingly, the density of synaptophysin immunoreactive presynaptic boutons was significantly decreased in the CA1 and CA3 subregion of the hippocampus for DBS rats. Therefore, fornix DBS might induce long-term depression related mechanisms.

Deep brain stimulation for Alzheimer's Disease: An update.

BACKGROUND: Dementia is among the leading causes of severe and long-term disability worldwide, decreasing the quality of life of individuals and families. Moreover, it induces an enormous economic burden on societies. The most prevalent cause of dementia is Alzheimer's disease (AD). Because current treatment options for AD are limited, deep brain stimulation (DBS) has been considered. METHODS: The aim of this review is to survey the current understanding regarding the effects of DBS in AD and possibly shed light on the mechanisms of DBS in AD. We searched PubMed and Cochrane for various studies in English literature describing DBS in patients with AD and relevant preclinical studies. All related studies published from December 2013 to March 2017 were included in this review. RESULTS: Our understanding of the neural circuitry underlying learning and memory in both rodent models and human patients has grown over the past years and provided potential therapeutic targets for DBS such as the fornix and the nucleus basalis of Meynert. Clinical results indicate that DBS is most beneficial for patients who are in the early stages of AD. Potential mechanisms of action of DBS in AD comprise long-term structural plasticity, including hippocampal enlargement as well as enhanced neurotransmitter release. CONCLUSION: It is still premature to conclude that DBS can be used in the treatment of AD, and the field will wait for the results of ongoing and future clinical trials.

Transependymal Cerebrospinal Fluid Flow: Opportunity for Drug Delivery?

Drug delivery to the central nervous system (CNS) is complicated by the blood-brain barrier. As a result, many agents that are found to be potentially effective at their site of action cannot be sufficiently or effectively delivered to the CNS and therefore have been discarded and not developed further for clinical use, leaving many CNS diseases untreated. One way to overcome this obstacle is intracerebroventricular (ICV) delivery of the therapeutics directly to cerebrospinal fluid (CSF). Recent experimental and clinical findings reveal that CSF flows from the ventricles throughout the parenchyma towards the subarachnoid space also named minor CSF pathway, while earlier, it was suggested that only in pathological conditions such as hydrocephalus this form of CSF flow occurs. This transependymal flow of CSF provides a route to distribute ICV-infused drugs throughout the brain. More insight on transependymal CSF flow will direct more rational to ICV drug delivery and broaden its clinical indications in managing CNS diseases.

Infections in deep brain stimulation: Shaving versus not shaving.

BACKGROUND: To report our experience of infections in deep brain stimulation (DBS) surgeries comparing shaving versus no shaving of cranial hair. Nonshaving is strongly preferred by patients due to aesthetic and psychological factors. METHODS: This study is a prospective follow-up of the infection rate in 43 nonshaven DBS cases between April 2014 and December 2015 compared to our former infection rate with shaving in our center. Minimum follow-up was 6 months. All patients, except 7 epilepsy patients, received implantation of the electrodes together with the extension cables and internal pulse generator in one session. RESULTS: In 43 nonshaven patients, a total of 81 electrodes were implanted or revised with a mean follow-up of 16 months. One patient (2.32%) developed an infection of the implanted DBS-hardware and was treated with antibiotics. CONCLUSION: In our experience nonshaving of cranial hair in DBS surgery does not lead to more infections when compared to shaving. We have changed our protocol to nonshaving based on these findings.

Motor cortex stimulation does not lead to functional recovery after experimental cortical injury in rats.

BACKGROUND: Motor impairments are among the major complications that develop after cortical damage caused by either stroke or traumatic brain injury. Motor cortex stimulation (MCS) can improve motor functions in animal models of stroke by inducing neuroplasticity. OBJECTIVE: In the current study, the therapeutic effect of chronic MCS was assessed in a rat model of severe cortical damage. METHODS: A controlled cortical impact (CCI) was applied to the forelimb area of the motor cortex followed by implantation of a flat electrode covering the lesioned area. Forelimb function was assessed using the Montoya staircase test and the cylinder test before and after a period of chronic MCS. Furthermore, the effect of MCS on tissue metabolism and lesion size was measured using [18F]-fluorodesoxyglucose (FDG) µPET scanning. RESULTS: CCI caused a considerable lesion at the level of the motor cortex and dorsal striatum together with a long-lasting behavioral phenotype of forelimb impairment. However, MCS applied to the CCI lesion did not lead to any improvement in limb functioning when compared to non-stimulated control rats. Also, MCS neither changed lesion size nor distribution of FDG. CONCLUSION: The use of MCS as a standalone treatment did not improve motor impairments in a rat model of severe cortical damage using our specific treatment modalities.

Fornix deep brain stimulation induced long-term spatial memory independent of hippocampal neurogenesis.

Deep brain stimulation (DBS) is an established symptomatic treatment modality for movement disorders and constitutes an emerging therapeutic approach for the treatment of memory impairment. In line with this, fornix DBS has shown to ameliorate cognitive decline associated with dementia. Nonetheless, mechanisms mediating clinical effects in demented patients or patients with other neurological disorders are largely unknown. There is evidence that DBS is able to modulate neurophysiological activity in targeted brain regions. We therefore hypothesized that DBS might be able to influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters, which were validated to restore memory loss in a previous behavioral study, we here assessed long-term effects of fornix DBS. To do so, we injected the thymidine analog, 5-bromo-2'-deoxyuridine (BrdU), after DBS and perfused the animals 6.5 weeks later. A week prior to perfusion, memory performance was assessed in the water maze. We found that acute stimulation of the fornix improved spatial memory performance in the water maze when the probe trial was performed 1 h after the last training session. However, no evidence for stimulation-induced neurogenesis was found in fornix DBS rats when compared to sham. Our results suggest that fornix DBS improves memory functions independent of hippocampal neurogenesis, possibly through other mechanisms such as synaptic plasticity and acute neurotransmitter release.

Fornix deep brain stimulation enhances acetylcholine levels in the hippocampus.

Deep brain stimulation (DBS) of the fornix has gained interest as a potential therapy for advanced treatment-resistant dementia, yet the mechanism of action remains widely unknown. Previously, we have reported beneficial memory effects of fornix DBS in a scopolamine-induced rat model of dementia, which is dependent on various brain structures including hippocampus. To elucidate mechanisms of action of fornix DBS with regard to memory restoration, we performed c-Fos immunohistochemistry in the hippocampus. We found that fornix DBS induced a selective activation of cells in the CA1 and CA3 subfields of the dorsal hippocampus. In addition, hippocampal neurotransmitter levels were measured using microdialysis before, during and after 60 min of fornix DBS in a next experiment. We observed a substantial increase in the levels of extracellular hippocampal acetylcholine, which peaked 20 min after stimulus onset. Interestingly, hippocampal glutamate levels did not change compared to baseline. Therefore, our findings provide first experimental evidence that fornix DBS activates the hippocampus and induces the release of acetylcholine in this region.

Deep Brain Stimulation of the Rat Subthalamic Nucleus Induced Inhibition of Median Raphe Serotonergic and Dopaminergic Neurotransmission.

AIM: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) relieves motor dysfunction in advanced Parkinson's disease (PD). However, STN DBS treated patients can experience unpleasant and debilitating psychiatric side effects such as depression and impulsivity. The neural basis of these psychiatric effects has been linked to a dysfunction of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission. STN DBS inhibited activity of 5-HT cell bodies in the dorsal raphe nucleus (DRN). Another important 5-HT source is located in the median raphe nucleus (MRN), which also contains a population of dopamine neurons. The effects of STN DBS on the MRN are unknown. Here, we test the hypothesis that STN DBS reduces 5-HT and dopaminergic function in the MRN, which may contribute to the psychiatric side effects of STN stimulation. MATERIAL AND METHODS: Bilateral STN DBS was applied in a freely moving rat model. Following STN DBS, rats were sacrificed and the brains were processed for c-Fos, 5-HT and tyrosine hydroxylase (TH) immunohistochemistry. RESULTS: We found that STN DBS significantly lowered c-Fos expression compared to non-stimulated controls indicating reduced neuronal activity. Moreover, the mean optical density values of 5-HT and TH cells in the MRN was significantly lower compared to controls. CONCLUSION: These results show that STN DBS inhibits 5-HT and dopamine neurotransmission in the MRN.

Behavioral effects of deep brain stimulation of different areas of the Papez circuit on memory- and anxiety-related functions.

Deep brain stimulation (DBS) has gained interest as a potential therapy for advanced treatment-resistant dementia. However, possible targets for DBS and the optimal stimulation parameters are not yet clear. Here, we compared the effects of DBS of the CA1 sub-region of the hippocampus, mammillothalamic tract, anterior thalamic nucleus, and entorhinal cortex in an experimental rat model of dementia. Rats with scopolamine-induced amnesia were assessed in the object location task with different DBS parameters. Moreover, anxiety-related side effects were evaluated in the elevated zero maze and open field. After sacrifice, we applied c-Fos immunohistochemistry to assess which memory-related regions were affected by DBS. When comparing all structures, DBS of the entorhinal cortex and CA1 sub-region was able to restore memory loss when a specific set of stimulation parameters was used. No anxiety-related side effects were found following DBS. The beneficial behavioral performance of CA1 DBS rats was accompanied with an activation of cells in the anterior cingulate gyrus. Therefore, we conclude that acute CA1 DBS restores memory loss possibly through improved attentional and cognitive processes in the limbic cortex.