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Deep brain stimulation (DBS) has been widely used to manage debilitating neurological symptoms in movement disorders such as Parkinson's disease (PD). Despite its well-established symptomatic benefits, our understanding of the mechanisms underlying DBS and its possible effect on the accumulation of pathological proteins in neurodegeneration remains limited. Accumulation and oligomerization of the protein alpha-synuclein ( α -Syn) are implicated in the loss of dopaminergic neurons in the substantia nigra in PD, making α -Syn a potential therapeutic target for disease modification. We examined the effects of high frequency electrical stimulation on α -Syn levels and oligomerization in cell and rodent models. High frequency stimulation, mimicking DBS parameters used for PD, was combined with viral-mediated overexpression of α -Syn in cultured rat primary cortical neurons or in substantia nigra of rats. Bimolecular protein complementation with split fluorescent protein reporters was used to detect and quantify α -Syn oligomers. High frequency electrical stimulation reduced the expression of PD-associated mutant α -Syn and mitigated α -Syn oligomerization in cultured neurons. Furthermore, DBS in the substantia nigra, but not the subthalamic nucleus, decreased overall levels of α -Syn, including oligomer levels, in the substantia nigra. Taken together, our results demonstrate that direct high frequency stimulation can reduce accumulation and pathological forms of α -Syn in cultured neurons in vitro and in substantia nigra in vivo. Thus, DBS therapy could have a role beyond symptomatic treatment, with potential disease-modifying properties that can be exploited to target pathological proteins in neurodegenerative diseases. • High frequency stimulation reduces α -synuclein accumulation in cultured neurons. • Deep brain stimulation of the substantia nigra reduces α -synuclein accumulation in rats. • Deep brain stimulation could have a role beyond symptomatic treatment, with potential disease-modifying properties. One sentence summary: Electrical stimulation reduces α -synuclein accumulation in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Information transmission into the human nervous system is the basis for a variety of prosthetic applications. Spinal cord stimulation (SCS) systems are widely available, have a well documented safety record, can be implanted minimally invasively, and are known to stimulate afferent pathways. Nonetheless, SCS devices are not yet used for computer-brain-interfacing applications. Here we aimed to establish computer-to-brain communication via medical SCS implants in a group of 20 individuals who had been operated for the treatment of chronic neuropathic pain. In the initial phase, we conducted interface calibration with the aim of determining personalized stimulation settings that yielded distinct and reproducible sensations. These settings were subsequently utilized to generate inputs for a range of behavioral tasks. We evaluated the required calibration time, task training duration, and the subsequent performance in each task. We could establish a stable spinal computer-brain interface in 18 of the 20 participants. Each of the 18 then performed one or more of the following tasks: A rhythm-discrimination task (n = 13), a Morse-decoding task (n = 3), and/or two different balance/body-posture tasks (n = 18; n = 5). The median calibration time was 79 min. The median training time for learning to use the interface in a subsequent task was 1:40 min. In each task, every participant demonstrated successful performance, surpassing chance levels. The results constitute the first proof-of-concept of a general purpose computer-brain interface paradigm that could be deployed on present-day medical SCS platforms. • We repurposed SCS implants to serve as computer-brain-interfaces (CBI). • The CBI could transmit rhythmic cues, morse code and postural information. • Individuals swiftly learned how to use the CBI effectively across various tasks. • SCS is widely available, positioning it strongly amongst other CBI platforms. • This proof-of-concept lays the foundation for future clinical applications. [ABSTRACT FROM AUTHOR]

Deep brain stimulation of the subcallosal cingulate area (SCC-DBS) is a promising neuromodulatory therapy for treatment-resistant depression (TRD). Biomarkers of optimal target engagement are needed to guide surgical targeting and stimulation parameter selection and to reduce variance in clinical outcome. We aimed to characterize the relationship between stimulation location, white matter tract engagement, and clinical outcome in a large (n = 60) TRD cohort treated with SCC-DBS. A smaller cohort (n = 22) of SCC-DBS patients with differing primary indications (bipolar disorder/anorexia nervosa) was utilized as an out-of-sample validation cohort. Volumes of tissue activated (VTAs) were constructed in standard space using high-resolution structural MRI and individual stimulation parameters. VTA-based probabilistic stimulation maps (PSMs) were generated to elucidate voxelwise spatial patterns of efficacious stimulation. A whole-brain tractogram derived from Human Connectome Project diffusion-weighted MRI data was seeded with VTA pairs, and white matter streamlines whose overlap with VTAs related to outcome ('discriminative' streamlines; P uncorrected < 0.05) were identified using t-tests. Linear modelling was used to interrogate the potential clinical relevance of VTA overlap with specific structures. PSMs varied by hemisphere: high-value left-sided voxels were located more anterosuperiorly and squarely in the lateral white matter, while the equivalent right-sided voxels fell more posteroinferiorly and involved a greater proportion of grey matter. Positive discriminative streamlines localized to the bilateral (but primarily left) cingulum bundle, forceps minor/rostrum of corpus callosum, and bilateral uncinate fasciculus. Conversely, negative discriminative streamlines mostly belonged to the right cingulum bundle and bilateral uncinate fasciculus. The best performing linear model, which utilized information about VTA volume overlap with each of the positive discriminative streamline bundles as well as the negative discriminative elements of the right cingulum bundle, explained significant variance in clinical improvement in the primary TRD cohort (R = 0.46, P < 0.001) and survived repeated 10-fold cross-validation (R = 0.50, P = 0.040). This model was also able to predict outcome in the out-of-sample validation cohort (R = 0.43, P = 0.047). These findings reinforce prior indications of the importance of white matter engagement to SCC-DBS treatment success while providing new insights that could inform surgical targeting and stimulation parameter selection decisions. • SCC-DBS locus-outcome relationship probed with probabilistic stimulation mapping. • Spatial pattern of SCC-DBS 'hotspots' differs by hemisphere. • Relevance of white matter tract engagement tested with normative connectomics. • Stimulating cingulum, uncinate, and forceps minor fibers relates to good outcome. • Linear model utilizing white matter engagement data robustly predicts outcome. [ABSTRACT FROM AUTHOR]

There is currently a gap in accessibility to neuromodulation tools that can approximate the efficacy and spatial resolution of invasive methods. Low intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation (NIBS) that can penetrate cortical and deep brain structures with more focal stimulation compared to existing NIBS modalities. Theta burst TUS (tbTUS, TUS delivered in a theta burst pattern) is a novel repetitive TUS protocol that can induce durable changes in motor cortex excitability, thereby holding promise as a novel neuromodulation tool with durable effects. The aim of the present study was to elucidate the neurophysiologic effects of tbTUS motor cortical excitability, as well on local and global neural oscillations and network connectivity. An 80-s train of active or sham tbTUS was delivered to the left motor cortex in 15 healthy subjects. Motor cortical excitability was investigated through transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) using paired-pulse TMS. Magnetoencephalography (MEG) recordings during resting state and an index finger abduction-adduction task were used to assess oscillatory brain responses and network connectivity. The correlations between the changes in neural oscillations and motor cortical excitability were also evaluated. tbTUS to the motor cortex results in a sustained increase in MEP amplitude and decreased SICI, but no change in ICF. MEG spectral power analysis revealed TUS-mediated desynchronization in alpha and beta spectral power. Significant changes in alpha power were detected within the supplementary motor cortex (Right > Left) and changes in beta power within bilateral supplementary motor cortices, right basal ganglia and parietal regions. Coherence analysis revealed increased local connectivity in motor areas. MEP and SICI changes correlated with both local and inter-regional coherence. The findings from this study provide novel insights into the neurophysiologic basis of TUS-mediated neuroplasticity and point to the involvement of regions within the motor network in mediating this sustained response. Future studies may further characterize the durability of TUS-mediated neuroplasticity and its clinical applications as a neuromodulation strategy for neurological and psychiatric disorders. • tbTUS impacts motor cortex excitability and intracortical circuits. • Repetitive tbTUS induces durable alterations in the human motor cortex. • tbTUS affects connectivity at the whole brain level and at distinct motor centers. • Understanding the mechanisms of tbTUS can inform novel neuromodulation protocols. [ABSTRACT FROM AUTHOR]

Deep 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. The 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). Two 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. Inhibitory 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). Persistent 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. [Display omitted] •In the STN, extracellular stimulation elicits excitatory and inhibitory effects •STN evoked field responses are predictive of bidirectional effects on firing rates •Persistent synaptic inhibition at high stimulation frequencies in STN, but not SNr •Synaptic inhibition at DBS targets is frequency- and projection-source specific •Synaptic dynamics may justify DBS frequency selection [ABSTRACT FROM AUTHOR]

• Hypoxic-ischemic encephalopathy is the leading cause of neonatal encephalopathy. • Therapeutic hypothermia offers limited improvement in neurodevelopmental outcomes. • Transcranial ultrasound stimulation (TUS) can modulate specific brain regions. • TUS has drawn attention for its potential to modulate brain activity in adults. • TUS may induce neuroplasticity, potentially transforming HIE treatment in newborns. Perinatal hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy, accounting for over half of all cases and the consequences of HIE can be devastating, making it one of the most severe perinatal complications. Therapeutic hypothermia has been shown to offer neuroprotection by reducing metabolic demand and slowing the cascade of injury processes. However, despite its benefits, therapeutic hypothermia has only modestly improved neurodevelopmental outcomes, indicating a major need for additional therapeutic approaches. Low-intensity transcranial ultrasound stimulation (TUS) is an emerging non-invasive brain stimulation technique for focally modulating specific brain regions that has recently drawn attention for its potential to modulate brain activity and promote neuroplasticity. The capacity of TUS to induce neuroplasticity through specific sonication parameters has been demonstrated in adult patients. Leveraging TUS to enhance functional connectivity and inhibit GABAergic systems within the injured thalami holds promise for inducing neuroplasticity in neonates with HIE. We hypothesize that enhancing thalamocortical functional connectivity and reducing local GABA levels through the use of TUS could potentially improve neurodevelopmental outcomes in neonates with HIE who have sustained thalamic injury and aim to test this hypothesis. Testing of the hypothesis will be conducted with a comprehensive assessment of safety and feasibility in neonates through a Phase I study, followed by further clinical studies to evaluate efficacy. [ABSTRACT FROM AUTHOR]

Transcranial ultrasound stimulation (TUS) is gaining traction as a safe and non-invasive technique in human studies. There has been a rapid increase in TUS human studies in recent years, with more than half of studies to date published after 2020. This rapid growth in the relevant body of literature necessitates comprehensive reviews to update clinicians and researchers. The aim of this work is to review human studies with an emphasis on TUS devices, sonication parameters, outcome measures, results, and adverse effects, as well as highlight future directions of investigation. A systematic review was conducted by searching the Web of Science and PubMed databases on January 12, 2022. Human studies of TUS were included. A total of 35 studies were identified using focused/unfocused ultrasound devices. A total of 677 subjects belonging to diverse cohorts (i.e., healthy, chronic pain, dementia, epilepsy, traumatic brain injury, depression) were enrolled. The stimulation effects vary in a sonication parameter-dependant fashion. Clinical, neurophysiological, radiological and histological outcome measures were assessed. No severe adverse effects were reported in any of the studies surveyed. Mild symptoms were observed in 3.4% (14/425) of the subjects, including headache, mood deterioration, scalp heating, cognitive problems, neck pain, muscle twitches, anxiety, sleepiness and pruritis. Although increasingly being used, TUS is still in its early phases. TUS can change short-term brain excitability and connectivity, induce long-term plasticity, and modulate behavior. New techniques should be used to further elucidate its underlying mechanisms and identify its application in novel populations. • TUS was investigated in patients with depression, epilepsy, dementia, pain and TBI. • Both unfocused diagnostic and focused devices was safely used for neuromodulation. • The effects appear to be dose-dependent and varying with distinct parameters. • No severe adverse events (AEs) has been reported. • Mild/moderate AEs were reported in 3% of individuals. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is an established treatment for certain movement disorders and has additionally shown promise for various psychiatric, cognitive, and seizure disorders. However, the mechanisms through which stimulation exerts therapeutic effects are incompletely understood. A technique that may help to address this knowledge gap is functional magnetic resonance imaging (fMRI). This is a non-invasive imaging tool which permits the observation of DBS effects in vivo. The objective of this review was to provide a comprehensive overview of studies in which fMRI during active DBS was performed, including studied disorders, stimulated brain regions, experimental designs, and the insights gleaned from stimulation-evoked fMRI responses. We conducted a systematic review of published human studies in which fMRI was performed during active stimulation in DBS patients. The search was conducted using PubMED and MEDLINE. The rate of fMRI DBS studies is increasing over time, with 37 studies identified overall. The median number of DBS patients per study was 10 (range = 1–67, interquartile range = 11). Studies examined fMRI responses in various disease cohorts, including Parkinson's disease (24 studies), essential tremor (3 studies), epilepsy (3 studies), obsessive-compulsive disorder (2 studies), pain (2 studies), Tourette syndrome (1 study), major depressive disorder, anorexia, and bipolar disorder (1 study), and dementia with Lewy bodies (1 study). The most commonly stimulated brain region was the subthalamic nucleus (24 studies). Studies showed that DBS modulates large-scale brain networks, and that stimulation-evoked fMRI responses are related to the site of stimulation, stimulation parameters, patient characteristics, and therapeutic outcomes. Finally, a number of studies proposed fMRI-based biomarkers for DBS treatment, highlighting ways in which fMRI could be used to confirm circuit engagement and refine DBS therapy. A review of the literature reflects an exciting and expanding field, showing that the combination of DBS and fMRI represents a uniquely powerful tool for simultaneously manipulating and observing neural circuitry. Future work should focus on relatively understudied disease cohorts and stimulated regions, while focusing on the prospective validation of putative fMRI-based biomarkers. • fMRI is a powerful technique for observing the network-wide effects of DBS in vivo. • fMRI studies reveal that DBS modulates large-scale brain networks. • fMRI responses are related to stimulation site, stimulation parameters, patient characteristics, and clinical outcomes. • Recent studies have proposed fMRI-based biomarkers for confirming circuit engagement and determining treatment efficacy. • These findings highlight ways in which the technique could be used to refine DBS therapy. [ABSTRACT FROM AUTHOR]

Numerous neuromodulatory therapies are currently under investigation or in clinical use for the treatment of psychiatric conditions. We sought to catalogue past and present human research studies on psychiatric neuromodulation and identify relevant trends in this field. ClinicalTrials.gov (https://www.clinicaltrials.gov/) and the International Clinical Trials Registry Platform (https://www.who.int/ictrp/en/) were queried in March 2020 for trials assessing the outcome of neuromodulation for psychiatric disorders. Relevant trials were categorized by variables such as neuromodulation modality, country, brain target, publication status, design, and funding source. From 72,086 initial search results, 1252 unique trials were identified. The number of trials registered annually has consistently increased. Half of all trials were active and a quarter have translated to publications. The largest proportion of trials involved depression (45%), schizophrenia (18%), and substance use disorders (14%). Trials spanned 37 countries; China, the second largest contributor (13%) after the United States (28%), has increased its output substantially in recent years. Over 75% of trials involved non-convulsive non-invasive modalities (e.g., transcranial magnetic stimulation), while convulsive (e.g., electroconvulsive therapy) and invasive modalities (e.g., deep brain stimulation) were less represented. 72% of trials featured approved or cleared interventions. Characteristic inter-modality differences were observed with respect to enrollment size, trial design/phase, and funding. Dorsolateral prefrontal cortex accounted for over half of focal neuromodulation trial targets. The proportion of trials examining biological correlates of neuromodulation has increased. These results provide a comprehensive overview of the state of psychiatric neuromodulation research, revealing the growing scope and internationalism of this field. • Clinical research involving psychiatric neuromodulation is a growing field. • Most trials focus on depression, schizophrenia, or substance use disorders. • ¾ of trials utilize non-convulsive non-invasive stimulation modalities like TMS. • Trials span 37 countries; the largest contributors are the United States and China. • Dorsolateral prefrontal cortex accounts for over ½ of focal neuromodulation trial targets. [ABSTRACT FROM AUTHOR]

The application of stimulators implanted directly over deep brain structures (i.e., deep brain stimulation, DBS) was developed in the late 1980s and has since become a mainstream option to treat several neurological conditions. Conventional DBS involves the continuous stimulation of the target structure, which is an approach that cannot adapt to patients' changing symptoms or functional status in real-time. At the beginning of 2000, a more sophisticated form of stimulation was conceived to overcome these limitations. Adaptive deep brain stimulation (aDBS) employs on-demand, contingency-based stimulation to stimulate only when needed. So far, aDBS has been tested in several pathological conditions in animal and human models. To review the current findings obtained from application of aDBS to animal and human models that highlights effects on motor, cognitive and psychiatric behaviors. while aDBS has shown promising results in the treatment of Parkinson's disease and essential tremor, the possibility of its use in less common DBS indications, such as cognitive and psychiatric disorders (Alzheimer's disease, obsessive-compulsive disorder, post-traumatic stress disorder) is still challenging. While aDBS seems to be effective to treat movement disorders (Parkinson's disease and essential tremor), its role in cognitive and psychiatric disorders is to be determined, although neurophysiological assumptions are promising. • Conventional Deep Brain Stimulation, despite its efficacy, presents limitations. • New strategies adapting real-time DBS parameters have been tested in patients. • aDBS is effective in treating Parkinson's disease and tremor. • The evolution of technology allows to include other less common DBS indications. • Implantable devices for aDBS will be available for patients soon. [ABSTRACT FROM AUTHOR]

Deep brain stimulation is an established therapy for several neurological disorders; however, its effects on neuronal activity vary across brain regions and depend on stimulation settings. Understanding these variable responses can aid in the development of physiologically-informed stimulation paradigms in existing or prospective indications. Provide experimental and computational insights into the brain-region-specific and frequency-dependent effects of extracellular stimulation on neuronal activity. In patients with movement disorders, single-neuron recordings were acquired from the subthalamic nucleus, substantia nigra pars reticulata, ventral intermediate nucleus, or reticular thalamus during microstimulation across various frequencies (1–100 Hz) to assess single-pulse and frequency-response functions. Moreover, a biophysically-realistic computational framework was developed which generated postsynaptic responses under the assumption that electrical stimuli simultaneously activated all convergent presynaptic inputs to stimulation target neurons. The framework took into consideration the relative distributions of excitatory/inhibitory afferent inputs to model site-specific responses, which were in turn embedded within a model of short-term synaptic plasticity to account for stimulation frequency-dependence. We demonstrated microstimulation-evoked excitatory neuronal responses in thalamic structures (which have predominantly excitatory inputs) and inhibitory responses in basal ganglia structures (predominantly inhibitory inputs); however, higher stimulation frequencies led to a loss of site-specificity and convergence towards neuronal suppression. The model confirmed that site-specific responses could be simulated by accounting for local neuroanatomical/microcircuit properties, while suppression of neuronal activity during high-frequency stimulation was mediated by short-term synaptic depression. Brain-region-specific and frequency-dependant neuronal responses could be simulated by considering neuroanatomical (local microcircuitry) and neurophysiological (short-term plasticity) properties. • Extracellular stimulation is brain-region-specific and frequency-dependent. • Neuronal stimulus responses were excitatory in thalamus & inhibitory in basal ganglia. • High-frequency stimulation led to neuronal suppression/a loss of site-specificity. • Responses to single stimuli could be predicted based on anatomy/local microcircuitry. • Frequency-dependant neuronal suppression could be modelled by synaptic depression. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5–12 Hz) are important in cognition. We tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients' peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation. Acute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions. Here, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes. • Verbal fluency was assessed in PD patients with externalized STN DBS electrodes. • Dorsal theta and gamma, ventral theta and gamma, and off were compared. • Dorsal theta stimulation improves episodic verbal fluency vs all other settings. • Stimulation did not affect nonepisodic verbal fluency. • Dorsal STN theta stimulation could be integrated into clinical DBS paradigms. [ABSTRACT FROM AUTHOR]

Parkinson's Disease patients undergo time-consuming programming to refine stimulation parameters after deep brain stimulation surgery. To assess whether the use of the advanced functions of a patient's programmer would facilitate programming of deep brain stimulation. Thirty patients were randomly allocated to the use of advanced versus simple mode of the patient programmer in this single-centre, prospective, randomized, controlled study. Primary outcome was the number of days required to optimize the stimulation settings. The number of days required to optimize stimulation was significantly lower in the simple mode (88.5 ± 33.1 vs. 142.1 ± 67.4, p = 0.01). In addition, the advanced mode group had a higher number of side effects (5.4 ± 3.1 vs. 2.6 ± 1.9, p = 0.0055). The use of the advanced functions of patient programmer delays programming optimization and it is associated with a higher number of side effects. These findings highlight the need for other methods for faster and safer stimulation programming. • Parkinson's patients undergo time-consuming programming after DBS. • Whether a patient's programmer facilitates programming is unknown. • The advanced functions of patient programmer delayed programming optimization. • The use of patient programmer was associated to a higher number of side effects. • Other methods for faster and safer stimulation programming are needed. [ABSTRACT FROM AUTHOR]

Electrical stimulation in the kilohertz-frequency range has gained interest in the field of neuroscience. The mechanisms underlying stimulation in this frequency range, however, are poorly characterized to date. To summarize the manifold biological effects elicited by kilohertz-frequency stimulation in the context of the currently existing literature and provide a mechanistic framework for the neural responses observed in this frequency range. A comprehensive search of the peer-reviewed literature was conducted across electronic databases. Relevant computational, clinical, and mechanistic studies were selected for review. The effects of kilohertz-frequency stimulation on neural tissue are diverse and yield effects that are distinct from conventional stimulation. Broadly, these can be divided into 1) subthreshold, 2) suprathreshold, 3) synaptic and 4) thermal effects. While facilitation is the dominating mechanism at the subthreshold level, desynchronization, spike-rate adaptation, conduction block, and non-monotonic activation can be observed during suprathreshold kilohertz-frequency stimulation. At the synaptic level, kilohertz-frequency stimulation has been associated with the transient depletion of the available neurotransmitter pool – also known as synaptic fatigue. Finally, thermal effects associated with extrinsic (environmental) and intrinsic (associated with kilohertz-frequency stimulation) temperature changes have been suggested to alter the neural response to stimulation paradigms. The diverse spectrum of neural responses to stimulation in the kilohertz-frequency range is distinct from that associated with conventional stimulation. This offers the potential for new therapeutic avenues across stimulation modalities. However, stimulation in the kilohertz-frequency range is associated with distinct challenges and caveats that need to be considered in experimental paradigms. • Despite growing interest, the mechanisms underlying kilohertz-frequency stimulation are poorly characterized to date. • We performed a comprehensive literature search to characterize the neural effects underlying kilohertz-frequency stimulation. • Kilohertz-frequency stimulation yields distinct sub- and suprathreshold effects that are unique to this frequency range. • Phenomena include: facilitation, desynchronization, non-monotonic activation, spike-rate adaptation, conduction block, and synaptic fatigue. • The spectrum of distinct neuronal responses may offer the potential for new therapeutic avenues. [ABSTRACT FROM AUTHOR]

Endovascular delivery of current using 'stentrodes' – electrode bearing stents – constitutes a potential alternative to conventional deep brain stimulation (DBS). The precise neuroanatomical relationships between DBS targets and the vascular system, however, are poorly characterized to date. To establish the relationships between cerebrovascular system and DBS targets and investigate the feasibility of endovascular stimulation as an alternative to DBS. Neuroanatomical targets as employed during deep brain stimulation (anterior limb of the internal capsule, dentatorubrothalamic tract, fornix, globus pallidus pars interna, medial forebrain bundle, nucleus accumbens, pedunculopontine nucleus, subcallosal cingulate cortex, subthalamic nucleus, and ventral intermediate nucleus) were superimposed onto probabilistic vascular atlases obtained from 42 healthy individuals. Euclidian distances between targets and associated vessels were measured. To determine the electrical currents necessary to encapsulate the predefined neurosurgical targets and identify potentially side-effect inducing substrates, a preliminary volume of tissue activated (VTA) analysis was performed. Six out of ten DBS targets were deemed suitable for endovascular stimulation: medial forebrain bundle (vascular site: P1 segment of posterior cerebral artery), nucleus accumbens (vascular site: A1 segment of anterior cerebral artery), dentatorubrothalamic tract (vascular site: s2 segment of superior cerebellar artery), fornix (vascular site: internal cerebral vein), pedunculopontine nucleus (vascular site: lateral mesencephalic vein), and subcallosal cingulate cortex (vascular site: A2 segment of anterior cerebral artery). While VTAs effectively encapsulated mfb and NA at current thresholds of 3.5 V and 4.5 V respectively, incremental amplitude increases were required to effectively cover fornix, PPN and SCC target (mean voltage: 8.2 ± 4.8 V, range: 3.0–17.0 V). The side-effect profile associated with endovascular stimulation seems to be comparable to conventional lead implantation. Tailoring of targets towards vascular sites, however, may allow to reduce adverse effects, while maintaining the efficacy of neural entrainment within the target tissue. While several challenges remain at present, endovascular stimulation of select DBS targets seems feasible offering novel and exciting opportunities in the neuromodulation armamentarium. • Endovascular brain stimulation using 'stentrodes' constitutes an appealing alternative to conventional deep brain stimulation. • Success of endovascular stimulation will greatly depend on accurate targeting. • The relationship between neurovascular structures and established surgical targets is poorly characterized to date. • We investigated the neuroanatomical relationships between conventional DBS targets and associated vascular sites. • Endovascular stimulation of select DBS targets using stentrodes seems feasible. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is a surgical neuromodulation procedure with a historically wide range of possible therapeutic indications, including movement disorders, neuropsychiatric conditions, and cognitive disorders. Ongoing research in this field is critical to gain further insights into the mechanisms of DBS, to discover novel brain targets for new and existing indications, and to refine targeting and post-operative programming techniques for the optimization of therapeutic outcomes. To update on the state of DBS-related clinical human research by cataloging and summarizing clinical trials that have been completed or are currently ongoing in this field worldwide. A search was conducted for clinical trials pertaining to DBS, currently listed on the ClinicalTrials.gov database. Trials were analyzed to generate a detailed overview of ongoing DBS-related research. Specifically, trials were categorized by trial start date, study completion status, clinical phase, projected subject enrollment, disorder, brain target, country of origin, device manufacturer, funding source, and study topic. In total, 384 relevant clinical trials were identified. The trials spanned 28 different disorders across 26 distinct brain targets, with almost 40% of trials being for conditions other than movement disorders. The majority of DBS trials have been US-based (41.9% of studies) but many countries are becoming increasingly active. The ratio of investigator-sponsored to industry-sponsored trials was 3:1. Emphasizing the need to better understand the mechanism of action of DBS, one-third of the studies predominantly focus on imaging or electrophysiological changes associated with DBS. This overview of current DBS-related clinical trials provides insight into the status of DBS research and what we can anticipate in the future concerning new brain targets, indications, techniques, and developing a better understanding of the mechanisms of action of DBS. • 384 clinical trials on deep brain stimulation span 28 disorders across 26 brain targets. • Most trials are US-based, pertain to movement disorders, and are non-industry-sponsored. • 1/3 of studies focus on imaging or electrophysiological changes associated with DBS. [ABSTRACT FROM AUTHOR]

Panic attacks affect a sizeable proportion of the population. The neurocircuitry of panic remains incompletely understood. To investigate the neuroanatomical underpinnings of panic attacks induced by deep brain stimulation (DBS) through (1) connectomic analysis of an obsessive-compulsive disorder patient who experienced panic attacks during inferior thalamic peduncle DBS; (2) appraisal of existing clinical reports on DBS-induced panic attacks. Panicogenic, ventral contact stimulation was compared with benign stimulation at other contacts using volume of tissue activated (VTA) modelling. Networks associated with the panicogenic zone were investigated using state-of-the-art normative connectivity mapping. In addition, a literature search for prior reports of DBS-induced panic attacks was conducted. Panicogenic VTAs impinged primarily on the tuberal hypothalamus. Compared to non-panicogenic VTAs, panicogenic loci were significantly functionally coupled to limbic and brainstem structures, including periaqueductal grey and amygdala. Previous studies found stimulation of these areas can also provoke panic attacks. DBS in the region of the tuberal hypothalamus elicited panic attacks in a single obsessive-compulsive disorder patient and recruited a network of structures previously implicated in panic pathophysiology, reinforcing the importance of the hypothalamus as a hub of panicogenic circuitry. [ABSTRACT FROM AUTHOR]

Abstract Background Several different surgical procedures targeting the limbic circuit have been utilized for severe, treatment resistant obsessive-compulsive disorder; however, there has only been limited exploration of the inferior thalamic peduncle (ITP). The aim of this study was to determine the safety and initial efficacy of ITP deep brain stimulation (DBS) in patients with severe obsessive-compulsive disorder. Methods Patients with severe, treatment-refractory obsessive-compulsive disorder were enrolled into this open-label phase 1 DBS pilot study. Bilateral ITP DBS devices were implanted between November 2010 and December 2015. The primary outcome was safety. The initial efficacy was determined by Yale-Brown Obsessive-Compulsive scale (YBOCs) scores. Component Y-BOCs scores, Hamilton Depression Severity Scale, Quality of Life Assessment (SF-36), Oxford Happiness Questionnaire, Warwick-Edinburgh Mental Well-Being Scale, and Sheehan Disability Scale were also analyzed for a minimum of 2 years after surgery. Additionally, preoperative and three-month postoperative FDG-PET studies were performed on two patients. Results Five patients (2 males, 3 females; age range 25–48 years) received ITP DBS. All five patients were considered responders at one year (52% improvement in YBOCs scores compared to baseline (range 39–73%, p < 0.01) and last follow-up (54% improvement; range 38–85%; p < 0.01). At two years follow-up, there were three adverse events that occurred in two patients. One patient had his DBS system removed after one year due to the device becoming the object of his obsession. The other two adverse events were not related to the device. Post-operative FDG-PET imaging in two patients demonstrated decreased glucose uptake within the right caudate, right putamen, right supplementary motor area, and right cingulum and increased glucose uptake in bilateral motor areas, left temporal pole, and left orbitfrontal cortex. Conclusions ITP DBS has a favorable safety profile and is potentially an efficacious treatment for severe obsessive-compulsive disorder. Larger clinical trials are necessary to determine efficacy. Highlights • Inferior thalamic peduncle deep brain stimulation for treatment refractory obsessive-compulsive disorder has a favorable safety profile. • ITP DBS is a potentially efficacious treatment, as all five patients in this study were considered treatment responders. • After three months of chronic ITP DBS, PET imaging was consistent with network engagement. [ABSTRACT FROM AUTHOR]

Essential tremor DBS targeting the ventral intermediate nucleus (Vim) of the thalamus and its input, the dentato-rubro-thalamic tract (DRTt), has proven to be an effective treatment strategy. We examined thalamo-cortical evoked potentials (TCEPs) and cortical dynamics during stimulation of the DRTt. We recorded TCEPs in primary motor cortex during clinical and supra-clinical stimulation of the DRTt in ten essential tremor patients. Stimulation was varied over pulse amplitude (2–10 ​mA) and pulse width (30–250 ​μs) to allow for strength-duration testing. Testing at clinical levels (3 ​mA, 60 ​μs) for stimulation frequencies of 1–160 ​Hz was performed and phase amplitude coupling (PAC) of beta phase and gamma power was calculated. Primary motor cortex TCEPs displayed two responses: early and all-or-none (<20 ​ms) or delayed and charge-dependent (>50 ​ms). Strength-duration curve approximation indicates that the chronaxie of the neural elements related to the TCEPs is <200 ​μs. At the range of clinical stimulation (amplitude 2–5 ​mA, pulse width 30–60 ​μs), TCEPs were not noted over primary motor cortex. Decreased pathophysiological phase-amplitude coupling was seen above 70 ​Hz stimulation without changes in power spectra and below the threshold of TCEPs. Our findings demonstrate that DRTt stimulation within normal clinical bounds does not excite fibers directly connected with primary motor cortex but that supra-clinical stimulation can excite a direct axonal tract. Both clinical efficacy and phase-amplitude coupling were frequency-dependent, favoring a synaptic filtering model as a possible mechanism of action. [ABSTRACT FROM AUTHOR]

Abstract Background Deep brain stimulation (DBS) is currently used to treat addiction, with the nucleus accumbens (NAc) as one promising target. The anterior limb of the internal capsule (ALIC) is also a potential target, as it carries fiber tracts connecting the mesocorticolimbic circuits that are crucially involved in several psychiatric disorders, including addiction. Stimulating the NAc and ALIC simultaneously may have a synergistic effect against addiction. Methods Eight patients with a long history of heroin use and multiple relapses, despite optimal conventional treatments, were enrolled. Customized electrodes were implanted through the ALIC into the NAc, and deep brain stimulation (DBS) treatment began two weeks after surgery. The patients were followed for at least 24 months. The duration of drug-free time, severity of drug cravings, psychometric evaluations, and PET studies of glucose metabolism before and after DBS were conducted. All adverse events were recorded. Results With DBS, five patients were abstinent for more than three years, two relapsed after abstaining for six months, and one was lost of follow-up at three months. The degree of cravings for drug use after DBS was reduced if the patients remained abstinent (p < 0.001). Simultaneous DBS of the NAc and ALIC also improved the quality of life, alleviated psychiatric symptoms, and increased glucose metabolism in addiction-related brain regions. Moreover, stimulation-related adverse events were few and reversible. Conclusions Simultaneous DBS of the NAc and ALIC appears to be safe, with few side effects, and may prevent long-term heroin relapse after detoxification in certain patients. (This trial was registered at ClinicalTrials.gov , NCT01274988). Highlights • Bilateral NAc and ALIC were simultaneously stimulated in heroin addicts for preventing relapse after detoxification. • Five of eight patients have kept abstinent for more than 3 years, with few side effects. • Decreased cravings for drug use, improved quality of life and alleviated mental disorders were observed. • Simultaneous DBS of NAc and ALIC appears to be safe, and produces long-term effects for preventing heroin relapse. [ABSTRACT FROM AUTHOR]

Abstract Background There is an emerging need for noninvasive neuromodulation techniques to improve patient outcomes while minimizing adverse events and morbidity. Low-intensity focused ultrasound (LIFUS) is gaining traction as a non-surgical experimental approach of modulating brain activity. Several LIFUS sonication parameters have been found to potentiate neural firing, suppress cortical and epileptic discharges, and alter behavior when delivered to cortical and subcortical mammalian brain regions. Objective This review introduces the elements of an effective sonication protocol and summarizes key preclinical studies on LIFUS as a neuromodulation modality. The state of the art in human ultrasound neuromodulation is then comprehensively summarized, and current hypotheses regarding the underlying mechanism of action on neural activity are presented. Methods Peer-reviewed literature on human ultrasound neuromodulation was obtained by searching several electronic databases. The abstracts of all reports were read and publications which examined low-intensity transcranial ultrasound applied to human subjects were selected for review. Results LIFUS can noninvasively influence human brain activity by suppressing cortical evoked potentials, influencing cortical oscillatory dynamics, and altering outcomes of sensory/motor tasks compared to sham sonication. Proposed mechanisms include cavitation, direct effects on neural ion channels, and plasma membrane deformation. Conclusions Though optimal sonication paradigms and transcranial delivery methods are still being established, future applications may include non-invasive human brain mapping experiments, and nonsurgical treatments for functional neurological disorders. Highlights • Low-intensity ultrasound can noninvasively modulate mammalian brain activity. • Pulsing parameters and intensity determine excitatory or inhibitory neural effects. • Human US neuromodulation has been achieved in cortical and deep structures. • Ultrasound holds promise as a precise, nonsurgical and safe brain stimulation tool. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation (DBS) is an important form of neuromodulation that is being applied to patients with motor, mood, or cognitive circuit disorders. Despite the efficacy and widespread use of DBS, the precise mechanisms by which it works remain unknown. Over the last decade, magnetoencephalography (MEG) has become an important functional neuroimaging technique used to study DBS. Objective This review summarizes the literature related to the use of MEG to characterize the effects of DBS. Methods Peer reviewed literature on DBS-MEG was obtained by searching the publicly accessible literature databases available on PubMed. The abstracts of all reports were scanned and publications which combined DBS-MEG in human subjects were selected for review. Results A total of 32 publications met the selection criteria, and included studies which applied DBS for Parkinson's disease, dystonia, chronic pain, phantom limb pain, cluster headache, and epilepsy. DBS-MEG studies provided valuable insights into network connectivity, pathological coupling, and the modulatory effects of DBS. Conclusions As DBS-MEG research continues to develop, we can expect to gain a better understanding of diverse pathophysiological networks and their response to DBS. This knowledge will improve treatment efficacy, reduce side-effects, reveal optimal surgical targets, and advance the development of closed-loop neuromodulation. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation of the ventro-intermedius nucleus of the thalamus is an established treatment for tremor of differing etiologies but factors that may predict the short- and especially long-term outcome of surgery are still largely unknown. Methods We retrospectively investigated the clinical, pharmacological, electrophysiological and anatomical features that might predict the initial response and preservation of benefit in all patients who underwent deep brain stimulation for tremor. Data were collected at the following time points: baseline (preoperative), one-year post-surgery, and most recent visit. Tremor severity was recorded using the Fahn-Tolosa-Marin Tremor Rating Scale and/or the Unified Parkinson's Disease Rating Scale. Results A total of 52 patients were included in the final analysis: 31 with essential tremor, 15 with cerebellar tremor of different etiologies, and 6 with Parkinson's disease. Long-term success (mean follow-up duration 34.7 months, range 1.7–121.1 months) was reported in 63.5%. Predictors of long-term benefit were: underlying tremor etiology (best outcome in Parkinson's disease, worst outcome in cerebellar tremor); age at surgery (the older the better); baseline tremor severity (the greater the better); lack of response to benzodiazepines; a more anterior electrode placement and single-unit beta power (the greater the better). Conclusions Specific patients' features (including single unit beta activity) and electrode locations may predict the short- and long-term benefit of thalamic stimulation for tremor. Future prospective studies enrolling a much larger sample of patients are needed to substantiate the associations detected by this retrospective study. [ABSTRACT FROM AUTHOR]

Background Alzheimer's disease (AD) is a progressive degenerative disorder that currently remains extremely disabling. Recent work has shown that deep brain stimulation (DBS) has promising effects in AD patients. In parallel to the clinical trials, we investigated the impact of chronic DBS in 3xTg mice, a well-established animal model of AD. Methods AD mice were assigned to control (Cont), non-stimulation (NS) and stimulation (DBS) groups, along with age matched wild type controls (WT-Cont). Bilateral electrodes were implanted in the entorhinal cortex to deliver chronic high frequency stimulation for 25 days. Animals were tested in memory behavioral tasks, with post-mortem measurements of pathological markers. Results We found that chronic DBS in AD mice normalized their impaired performance in the Morris water maze task to that of the WT group in the probe test. In the novel object and novel place preference tasks, AD-DBS mice spent more time at the novel object and novice location compared to AD-NS mice. These cognitive improvements in AD-DBS mice were associated with DBS induced increased neurogenesis in the dentate gyrus, a significant reduction in β−amyloid plaques, a reduction in CA-1 cellular β−amyloid-42 levels, decreased cortical total-tau and phosphorylated-tau, along with decreased hippocampal total-tau. Conclusion Overall, we show that chronic DBS of the entorhinal cortex in AD mice improves both memory and AD specific pathological markers. These results support further testing of DBS as a potential treatment in AD patients. [ABSTRACT FROM AUTHOR]

Background Survivors of stroke often experience significant disability and impaired quality of life related to ongoing maladaptive responses and persistent neurologic deficits. Novel therapeutic options are urgently needed to augment current approaches. One way to promote recovery and ameliorate symptoms may be to electrically stimulate the surviving brain. Various forms of brain stimulation have been investigated for use in stroke, including deep brain stimulation (DBS). Objective/Methods We conducted a comprehensive literature review in order to 1) review the use of DBS to treat post-stroke maladaptive responses including pain, dystonia, dyskinesias, and tremor and 2) assess the use and potential utility of DBS for enhancing plasticity and recovery from post-stroke neurologic deficits. Results/Conclusions A large variety of brain structures have been targeted in post-stroke patients, including motor thalamus, sensory thalamus, basal ganglia nuclei, internal capsule, and periventricular/periaqueductal grey. Overall, the reviewed clinical literature suggests a role for DBS in the management of several post-stroke maladaptive responses. More limited evidence was identified regarding DBS for post-stroke motor deficits, although existing work tentatively suggests DBS—particularly DBS targeting the posterior limb of the internal capsule—may improve paresis in certain circumstances. Substantial future work is required both to establish optimal targets and parameters for treatment of maladapative responses and to further investigate the effectiveness of DBS for post-stroke paresis. [ABSTRACT FROM AUTHOR]

Introduction Deep Brain Stimulation (DBS) is an effective treatment extended broadly to many neurological and psychiatric disorders. Nevertheless, complications may arise during DBS procedures or following implantation due to implanted hardware. This may result in both minor and major adverse events that may necessitate hardware removal and/or compromise maximal therapeutic benefit for the patient. Objectives and methods To identify relevant literature on hardware-related complications from DBS procedures by performing a systematic review, and propose how to identify at-risk group and possible preventive approaches. Results Of 4592 abstract screened, 96 articles fulfilled the selection criteria and were reviewed. Overall, the most common hardware-related complications were infections (5.12% of patients), followed by lead migration (1.60%), fracture or failure of the lead or other parts of the implant (1.46% and 0.73%, respectively), IPG malfunctions (1.06% of patients), and skin erosions without infections (0.48% of patients). New indications for DBS, including Tourette's syndrome, cluster headache, and refractory partial epilepsy, were found to bear a higher incidence of hardware-related infections than established indications such as Parkinson's disease. The highest rate of lead fracture or failure was found in dystonia patients (4.22%). Ultimately, the highest rate of pain at the implantation sites was found in refractory partial epilepsy patients (16.55%). Conclusion Our analysis identified a variety of potential hardware-related complications among patients who underwent DBS procedures. Patients who were at risk of complications, such as patients with dystonia and off-label indications (e.g. Tourette's syndrome) should be informed prior to surgery and closely followed thereafter. [ABSTRACT FROM AUTHOR]

Background Parkinson's disease patients undergoing subthalamic nucleus deep brain stimulation (STN DBS) at standard frequency (>100 Hz) often develop gait impairment, postural instability and speech difficulties. Low frequency stimulation (<100 Hz, LFS) can improve such axial symptoms, but there are concerns that improvement may be transient. Objective To identify long-term outcome and predictors of low-frequency subthalamic stimulation in Parkinson's disease. Methods Through a chart review we identified 85 out of 324 STN DBS patients who received a trial of LFS and describe their characteristics and outcome predictors. Results Patients were switched to LFS (<100 Hz) 3.8 ± 3.3 years after surgery. Most patients (64%) attained a subjective improvement of gait, speech or balance for 2.0 ± 1.9 years. Motor scores improved within the first year after the stimulation change and showed a slower progression over time when compared to patients switched back to high frequency stimulation. UPDRS III axial score on medication before surgery and the y-axis coordinate of the active contact were independent predictors of LFS retention. Conclusions This report provides evidence that the use of LFS yields an enduring benefit in a considerable percentage of patients who develop axial motor symptoms during conventional stimulation. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation (DBS) is an established and effective treatment for Parkinson's disease (PD). After surgery, a number of extensive programming sessions are performed to define the most optimal stimulation parameters. Programming sessions mainly rely only on neurologist's experience. As a result, patients often undergo inconsistent and inefficient stimulation changes, as well as unnecessary visits. Objective/hypothesis We reviewed the literature on initial and follow-up DBS programming procedures and integrated our current practice at Toronto Western Hospital (TWH) to develop standardized DBS programming protocols. We propose four algorithms including the initial programming and specific algorithms tailored to symptoms experienced by patients following DBS: speech disturbances, stimulation-induced dyskinesia and gait impairment. Methods We conducted a literature search of PubMed from inception to July 2014 with the keywords “deep brain stimulation”, “festination”, “freezing”, “initial programming”, “Parkinson's disease”, “postural instability”, “speech disturbances”, and “stimulation induced dyskinesia”. Seventy papers were considered for this review. Results Based on the literature review and our experience at TWH, we refined four algorithms for: (1) the initial programming stage, and management of symptoms following DBS, particularly addressing (2) speech disturbances, (3) stimulation-induced dyskinesia, and (4) gait impairment. Conclusions We propose four algorithms tailored to an individualized approach to managing symptoms associated with DBS and disease progression in patients with PD. We encourage established as well as new DBS centers to test the clinical usefulness of these algorithms in supplementing the current standards of care. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation (DBS) is an effective treatment for essential tremor (ET) and dystonia. After surgery, a number of extensive programming sessions are performed, mainly relying on neurologist's personal experience as no programming guidelines have been provided so far, with the exception of recommendations provided by groups of experts. Finally, fewer information is available for the management of DBS in ET and dystonia compared with Parkinson's disease. Objective/hypothesis Our aim is to review the literature on initial and follow-up DBS programming procedures for ET and dystonia and integrate the results with our current practice at Toronto Western Hospital (TWH) to develop standardized DBS programming protocols. Methods We conducted a literature search of PubMed from inception to July 2014 with the keywords “balance”, “bradykinesia”, “deep brain stimulation”, “dysarthria”, “dystonia”, “gait disturbances”, “initial programming”, “loss of benefit”, “micrographia”, “speech”, “speech difficulties” and “tremor”. Seventy-six papers were considered for this review. Results Based on the literature review and our experience at TWH, we refined three algorithms for management of ET, including: (1) initial programming, (2) management of balance and speech issues and (3) loss of stimulation benefit. We also depicted algorithms for the management of dystonia, including: (1) initial programming and (2) management of stimulation-induced hypokinesia (shuffling gait, micrographia and speech impairment). Conclusions We propose five algorithms tailored to an individualized approach to managing ET and dystonia patients with DBS. We encourage the application of these algorithms to supplement current standards of care in established as well as new DBS centers to test the clinical usefulness of these algorithms in supplementing the current standards of care. [ABSTRACT FROM AUTHOR]

Background The forniceal area is currently being evaluated as a target for deep brain stimulation (DBS) to improve cognitive function in patients with Alzheimer's disease. The molecular changes at downstream targets within the stimulated circuit are unknown. Objective To analyze the modulation of hippocampal protein expression following 1 h of fornix DBS in the rat. Methods Animals underwent bilateral forniceal DBS for 1 h and sacrificed at different time-points after the initiation of the stimulation (1 h, 2.5 h, 5 h, 25 h). Bilateral hippocampi were isolated for western blot analyses. Results Forniceal DBS led to a dramatic elevation of cFos post-stimulation, suggesting that forniceal DBS activates the hippocampus. There was also a significant increase in candidate proteins including several trophic factors, such as brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) but not glial cell-derived neurotrophic factor (GDNF). There was in addition, increased expression of the synaptic markers growth associated protein 43 (GAP-43), synaptophysin and α-synuclein. No changes were observed at the studied time-points in Alzheimer's-related proteins including amyloid precursor protein (APP), tau, phosphorylated tau (ptau), or selected chaperone proteins (HSP40, HSP70 and CHIP). Conclusions Forniceal DBS triggers hippocampal activity and rapidly modulate the expression of neurotrophic factors and markers of synaptic plasticity known to play key roles in memory processing. The clinical effects of DBS of the fornix may, in part, be mediated by producing changes in the expression of these proteins. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG) is becoming an effective therapeutic option for treatment resistant depression (TRD). Objective/hypothesis Identifying the neurophysiological mechanisms altered by DBS may lead to more tailored treatment parameters and enhanced efficacy. Methods Twenty TRD patients with implanted DBS in the SCG were recruited. Patients participated in three EEG recording sessions, one with DBS ON, one with DBS randomized to ON or OFF, and one with DBS OFF. During each session, subjects performed N-back working memory tasks, namely the 0-back and 3-back. Fourteen subjects with valid EEG were included in the analysis. Changes in frontal gamma oscillations (30–50 Hz) and coupling between theta (4–7 Hz) and gamma oscillations as a result of DBS stimulation were quantified and correlated with depressive symptoms. Results DBS stimulation resulted in suppression of frontal oscillations in the ON state relative to the OFF state during the N-back tasks. Greatest suppression was demonstrated in beta and gamma oscillations and most pronounced during the 3-back. Suppression of gamma oscillations in the 3-back correlated with a reduction in depressive symptoms. DBS ON relative to OFF in the 3-back also resulted in an increase in theta-gamma coupling that correlated with a reduction in depressive symptoms. Conclusion Suppression of gamma oscillations and increased theta-gamma coupling through DBS is likely mediated by both SCG activation of inhibitory circuits and an enhancement of plasticity in the frontal cortex. Activation of both pathways may explain the therapeutic properties of DBS in TRD. [ABSTRACT FROM AUTHOR]

Background Anorexia nervosa is characterized by extreme low body weight and alterations in affective processing. The subcallosal cingulate regulates affect through wide-spread white matter connections and is implicated in the pathophysiology of anorexia nervosa. Objectives We examined whether those with treatment refractory anorexia nervosa undergoing deep brain stimulation (DBS) of the subcallosal white matter (SCC) show: 1) altered anatomical SCC connectivity compared to healthy controls, 2) white matter microstructural changes, and 3) microstructural changes associated with clinically-measured affect. Methods Diffusion magnetic resonance imaging (dMRI) and deterministic multi-tensor tractography were used to compare anatomical connectivity and microstructure in SCC-associated white matter tracts. Eight women with treatment-refractory anorexia nervosa were compared to 8 age- and sex-matched healthy controls. Anorexia nervosa patients also completed affect-related clinical assessments presurgically and 12 months post-surgery. Results 1) Higher (e.g. left parieto-occipital cortices) and lower (e.g. thalamus) connectivity in those with anorexia nervosa compared to controls. 2) Decreases in fractional anisotropy, and alterations in axial and radial diffusivities, in the left fornix crus, anterior limb of the internal capsule (ALIC), right anterior cingulum and left inferior fronto-occipital fasciculus. 3) Correlations between dMRI metrics and clinical assessments, such as low pre-surgical left fornix and right ALIC fractional anisotropy being related to post-DBS improvements in quality-of-life and depressive symptoms, respectively. Conclusions We identified widely-distributed differences in SCC connectivity in anorexia nervosa patients consistent with heterogenous clinical disruptions, although these results should be considered with caution given the low number of subjects. Future studies should further explore the use of affect-related connectivity and behavioral assessments to assist with DBS target selection and treatment outcome. [ABSTRACT FROM AUTHOR]