Insertional effect following electrode implantation: an underreported but important phenomenon.

Deep brain stimulation has revolutionized the treatment of movement disorders and is gaining momentum in the treatment of several other neuropsychiatric disorders. In almost all applications of this therapy, the insertion of electrodes into the target has been shown to induce some degree of clinical improvement prior to stimulation onset. Disregarding this phenomenon, commonly referred to as 'insertional effect', can lead to biased results in clinical trials, as patients receiving sham stimulation may still experience some degree of symptom amelioration. Similar to the clinical scenario, an improvement in behavioural performance following electrode implantation has also been reported in preclinical models. From a neurohistopathologic perspective, the insertion of electrodes into the brain causes an initial trauma and inflammatory response, the activation of astrocytes, a focal release of gliotransmitters, the hyperexcitability of neurons in the vicinity of the implants, as well as neuroplastic and circuitry changes at a distance from the target. Taken together, it would appear that electrode insertion is not an inert process, but rather triggers a cascade of biological processes, and, as such, should be considered alongside the active delivery of stimulation as an active part of the deep brain stimulation therapy.

Fundamentals of deep brain stimulation for Parkinson's disease in clinical practice: part 1.

Deep brain stimulation (DBS) is recognized as an established therapy for Parkinson's disease (PD) and other movement disorders in the light of the developments seen over the past three decades. Long-term efficacy is established for PD with documented improvement in the cardinal motor symptoms of PD and levodopa-induced complications, such as motor fluctuations and dyskinesias. Timing of patient selection is crucial to obtain optimal benefits from DBS therapy, before PD complications become irreversible. The objective of this first part review is to examine the fundamental concepts of DBS for PD in clinical practice, discussing the historical aspects, patient selection, potential effects of DBS on motor and non-motor symptoms, and the practical management of patients after surgery.

Nas últimas três décadas, a estimulação cerebral profunda (ECP) se tornou um tratamento bem estabelecido para doença de Parkinson (DP) e outros transtornos do movimento. A eficácia a longo prazo na DP foi bem documentada para a melhora dos sintomas motores cardinais da DP e das complicações induzidas pelo uso do levodopa, como as flutuações motoras e as discinesias. O momento da seleção do paciente é crucial para se obter os benefícios ideais da ECP, antes que as complicações da DP se tornem irreversíveis. O objetivo desta primeira parte da revisão é examinar os conceitos fundamentais da ECP na prática clínica, discutindo os aspectos históricos, a seleção de pacientes, os potenciais efeitos da ECP nos sintomas motores e não motores da doença e o manejo prático dos pacientes após a cirurgia.

Fundamentals of deep brain stimulation for Parkinson's disease in clinical practice: part 2.

The field of neuromodulation has evolved significantly over the past decade. Developments include novel indications and innovations of hardware, software, and stimulation techniques leading to an expansion in scope and role of these techniques as powerful therapeutic interventions. In this review, which is the second part of an effort to document and integrate the basic fundamentals and recent successful developments in the field, we will focus on classic paradigms for electrode placement as well as new exploratory targets, mechanisms of neuromodulation using this technique and new developments, including focused ultrasound driven ablative procedures.

O campo da neuromodulação evoluiu significativamente na última década. Esse progresso inclui novas indicações e inovações de hardware, software e técnicas de estimulação, levando a uma expansão das áreas clínicas cobertas e no papel dessas técnicas como intervenções terapêuticas eficazes. Nesta revisão, que é a segunda parte de um esforço para documentar e integrar os fundamentos básicos e os desenvolvimentos recentes e bem-sucedidos no campo, vamos nos concentrar em paradigmas clássicos para colocação de eletrodos, bem como em novos alvos exploratórios, mecanismos de neuromodulação usados por esta técnica e novos desenvolvimentos, incluindo procedimentos ablativos orientados por ultrassom focalizado.

Adverse Effects of Deep Brain Stimulation for Treatment-Resistant Depression: A Scoping Review.

Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD). Although adverse effects have been reported in early-phase and a few randomized clinical trials, little is known about its overall safety profile, which has been assumed to be similar to that of DBS for movement disorders. The objective of this study was to pool existing safety data on DBS for TRD. Following PRISMA guidelines, PubMed was searched for English articles describing adverse outcomes after DBS for TRD. Studies were included if they reported at least 5 patients with a minimal follow-up of 6 months. After abstract (n = 607) and full-article review (n = 127), 28 articles reporting on 353 patients met criteria for final inclusion. Follow-up of the studies retrieved ranged from 12 to 96 months. Hemorrhages occurred in 0.8% of patients and infections in 10.2%. The rate of completed suicide was 2.5%. Development or worsening of depressive symptoms, anxiety, and mania occurred in 18.4%, 9.1%, and 5.1%, respectively. There were some differences between targets, but between-study heterogeneity precluded statistical comparisons. In conclusion, DBS for TRD is associated with surgical and psychiatric adverse events. Hemorrhage and infection occur at rates within an accepted range for other DBS applications. The risk of suicide after DBS for TRD is 2.5% but may not represent a significant deviation from the natural history of TRD. Finally, risks of worsening depression, anxiety, and the incidence of mania should be acknowledged when considering DBS for TRD.

Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo.

BACKGROUND: 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. OBJECTIVE: We examined the effects of high frequency electrical stimulation on α-Syn levels and oligomerization in cell and rodent models. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Seasonal pattern and depression outcomes from repetitive transcranial magnetic stimulation.

Individuals with major depressive disorder (MDD) may exhibit a seasonal pattern. The impact of a seasonal pattern in depressive symptoms on rTMS outcomes is unexplored. A retrospective analysis was performed on patients with MDD receiving open-label high frequency rTMS to the left dorsolateral prefrontal cortex. Having a seasonal pattern was defined as scoring ≥ 12 on the Personal Inventory for Depression and Seasonal Affective Disorder (PIDS). Primary outcomes included improvement in the Hamilton Depression Rating Scale (HAMD) and remission. Secondary analyses included the use of the self-rated Quick Inventory of Depressive Symptomatology (QIDS) to assess for changes in atypical neurovegetative symptoms. Multiple linear regression, multiple logistic regression, and linear mixed effects analyses were performed. 46 % (58/127) of the sample had a seasonal pattern. Seasonal pattern did not significantly influence improvement in HAMD (PIDS < 12, 7.8, SD 5.9; PIDS ≥ 12, 10.4, SD 4.9 or remission (PIDS < 12, 30 %; PIDS ≥ 12, 34 %). There were equivalent degrees of improvement in atypical neurovegetative symptoms over time as assessed using the QIDS. Depression with seasonal pattern was found to respond to rTMS treatment similarly to depression without seasonal pattern, suggesting that this may be a viable treatment for this group.

What do we know about astrocytes and the antidepressant effects of DBS?

Treatment-resistant depression (TRD) is a debilitating condition that affects millions of individuals worldwide. Deep brain stimulation (DBS) has been widely used with excellent outcomes in neurological disorders such as Parkinson's disease, tremor, and dystonia. More recently, DBS has been proposed as an adjuvant therapy for TRD. To date, the antidepressant efficacy of DBS is still controversial, and its mechanisms of action remain poorly understood. Astrocytes are the most abundant cells in the nervous system. Once believed to be a "supporting" element for neuronal function, astrocytes are now recognized to play a major role in brain homeostasis, neuroinflammation and neuroplasticity. Because of its many roles in complex multi-factorial disorders, including TRD, understanding the effect of DBS on astrocytes is pivotal to improve our knowledge about the antidepressant effects of this therapy. In depression, the number of astrocytes and the expression of astrocytic markers are decreased. One of the potential consequences of this reduced astrocytic function is the development of aberrant glutamatergic neurotransmission, which has been documented in several models of depression-like behavior. Evidence from preclinical work suggests that DBS may directly influence astrocytic activity, modulating the release of gliotransmitters, reducing neuroinflammation, and altering structural tissue organization. Compelling evidence for an involvement of astrocytes in potential mechanisms of DBS derive from studies suggesting that pharmacological lesions or the inhibition of these cells abolishes the antidepressant-like effect of DBS. In this review, we summarize preclinical data suggesting that the modulation of astrocytes may be an important mechanism for the antidepressant-like effects of DBS.

Reduction of aggressive behaviour following hypothalamic deep brain stimulation: Involvement of 5-HT1A and testosterone.

BACKGROUND: Aggressive behaviour (AB) may occur in patients with different neuropsychiatric disorders. Although most patients respond to conventional treatments, a small percentage continue to experience AB despite optimized pharmacological management and are considered to be treatment-refractory. For these patients, hypothalamic deep brain stimulation (pHyp-DBS) has been investigated. The hypothalamus is a key structure in the neurocircuitry of AB. An imbalance between serotonin (5-HT) and steroid hormones seems to exacerbate AB. OBJECTIVES: To test whether pHyp-DBS reduces aggressive behaviour in mice through mechanisms involving testosterone and 5-HT. METHODS: Male mice were housed with females for two weeks. These resident animals become territorial and aggressive towards intruder mice placed in their cages. Residents had electrodes implanted in the pHyp. DBS was administered for 5 h/day for 8 consecutive encounters prior to the interaction with the intruder. After testing, blood and brains were recovered for measuring testosterone and 5-HT receptor density, respectively. In a second experiment, residents received WAY-100635 (5-HT1A antagonist) or saline injections prior to pHyp-DBS. After the first 4 encounters, the injection allocation was crossed, and animals received the alternative treatment during the next 4 encounters. RESULTS: DBS-treated mice showed reduced AB that was correlated with testosterone levels and an increase in 5-HT1A receptor density in the orbitofrontal cortex and amygdala. Pre-treatment with WAY-100635 blocked the anti-aggressive effect of pHyp-DBS. CONCLUSIONS: This study shows that pHyp-DBS reduces AB in mice via changes in testosterone and 5-HT1A mechanisms.

Multi-centre analysis of networks and genes modulated by hypothalamic stimulation in patients with aggressive behaviours.

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behavior, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fiber tracts and functionally connected with brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas - together with patient age - were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behavior, neuronal communication, plasticity and neuroinflammation might underlie this functional network.

Future directions in psychiatric neurosurgery: Proceedings of the 2022 American Society for Stereotactic and Functional Neurosurgery meeting on surgical neuromodulation for psychiatric disorders.

OBJECTIVE: Despite advances in the treatment of psychiatric diseases, currently available therapies do not provide sufficient and durable relief for as many as 30-40% of patients. Neuromodulation, including deep brain stimulation (DBS), has emerged as a potential therapy for persistent disabling disease, however it has not yet gained widespread adoption. In 2016, the American Society for Stereotactic and Functional Neurosurgery (ASSFN) convened a meeting with leaders in the field to discuss a roadmap for the path forward. A follow-up meeting in 2022 aimed to review the current state of the field and to identify critical barriers and milestones for progress. DESIGN: The ASSFN convened a meeting on June 3, 2022 in Atlanta, Georgia and included leaders from the fields of neurology, neurosurgery, and psychiatry along with colleagues from industry, government, ethics, and law. The goal was to review the current state of the field, assess for advances or setbacks in the interim six years, and suggest a future path forward. The participants focused on five areas of interest: interdisciplinary engagement, regulatory pathways and trial design, disease biomarkers, ethics of psychiatric surgery, and resource allocation/prioritization. The proceedings are summarized here. CONCLUSION: The field of surgical psychiatry has made significant progress since our last expert meeting. Although weakness and threats to the development of novel surgical therapies exist, the identified strengths and opportunities promise to move the field through methodically rigorous and biologically-based approaches. The experts agree that ethics, law, patient engagement, and multidisciplinary teams will be critical to any potential growth in this area.

Neurochemical mechanisms of deep brain stimulation for depression in animal models.

Deep brain stimulation (DBS) has emerged as a neuromodulation therapy for treatment-resistant depression, but its actual efficacy and mechanisms of action are still unclear. Changes in neurochemical transmission are important mechanisms of antidepressant therapies. Here, we review the preclinical DBS literature reporting behavioural and neurochemical data associated with its antidepressant-like effects. The most commonly studied target in preclinical models was the ventromedial prefrontal cortex (vmPFC). In rodents, DBS delivered to this target induced serotonin (5-HT) release and increased 5-HT1B receptor expression. The antidepressant-like effects of vmPFC DBS seemed to be independent of the serotonin transporter and potentially mediated by the direct modulation of prefrontal projections to the raphe. Adenosinergic and glutamatergic transmission might have also play a role. Medial forebrain bundle (MFB) DBS increased dopamine levels and reduced D2 receptor expression, whereas nucleus accumbens (NAcc), and lateral habenula (LHb) stimulation increased catecholamine levels in different brain regions. In rodents, subthalamic nucleus (STN) DBS induced robust depression-like responses associated with a reduction in serotonergic transmission, as revealed by a decrease in serotonin release. Some of these effects seemed to be mediated by 5HT1A receptors. In conclusion, the antidepressant-like effects of DBS in preclinical models have been well documented in multiple targets. Though variable mechanisms have been proposed, DBS-induced acute and long-term changes in neurochemical substrates seem to play an important role in the antidepressant-like effects of this therapy.

Anesthetic-loaded nanodroplets with focused ultrasound reduces agitation in Alzheimer's mice.

OBJECTIVE: Alzheimer's disease (AD) is often associated with neuropsychiatric symptoms, including agitation and aggressive behavior. These symptoms increase with disease severity, ranging from 10% in mild cognitive impairment to 50% in patients with moderate-to-severe AD, pose a great risk for self-injury and injury to caregivers, result in high rates of institutionalization and great suffering for patients and families. Current pharmacological therapies have limited efficacy and a high potential for severe side effects. Thus, there is a growing need to develop novel therapeutics tailored to safely and effectively reduce agitation and aggressive behavior in AD. Here, we investigate for the first time the use of focused ultrasound combined with anesthetic-loaded nanodroplets (nanoFUS) targeting the amygdala (key structure in the neurocircuitry of agitation) as a novel minimally invasive tool to modulate local neural activity and reduce agitation and aggressive behavior in the TgCRND8 AD transgenic mice. METHODS: Male and female animals were tested in the resident-intruder (i.e., aggressive behavior) and open-field tests (i.e., motor agitation) for baseline measures, followed by treatment with active- or sham-nanoFUS. Behavioral testing was then repeated after treatment. RESULTS: Active-nanoFUS neuromodulation reduced aggressive behavior and agitation in male mice, as compared to sham-treated controls. Treatment with active-nanoFUS increased the time male mice spent in social-non-aggressive behaviors. INTERPRETATION: Our results show that neuromodulation with active-nanoFUS may be a potential therapeutic tool for the treatment of neuropsychiatric symptoms, with special focus on agitation and aggressive behaviors. Further studies are necessary to establish cellular, molecular and long-term behavioral changes following treatment with nanoFUS.

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound.

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer's disease pathology (P-tau181, amyloid-ß42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Mapping the future of interventional psychiatry for the obsessive-compulsive related disorders: A scoping review.

Body dysmorphic disorder (BDD), hoarding disorder (HD), skin-picking disorder (SPD), and hair-pulling disorder (HPD) are characterized by compulsive behaviours leading to distress and impairment. Current treatments attain only partial or non-response. Interventional psychiatric approaches may target specific regions of the brain for treatment. This scoping review maps the current literature and synthesizes key findings. Databases were searched up to June 27, 2022 for studies examining interventional psychiatric treatments for BDD, HD, SPD, and HPD, producing 910 results. Twenty were included; 16 were case reports, two were case series, and two were randomized controlled trials. Studies reported on electroconvulsive therapy (ECT) (n=7), deep brain stimulation (DBS) (n=1), and intermittent theta-burst stimulation repetitive transcranial magnetic stimulation (rTMS) (n=1) for BDD; rTMS (n=1) and transcranial direct current stimulation (n=1) for HD; gamma knife capsulotomy (n=1) and rTMS (n=1) for SPD; and rTMS (n=2) and ECT (n=1) for HPD. Four studies reported on DBS for other indications complicated by SPD or HPD. The current literature consists mainly of case reports. Future studies should be randomized, controlled, adequately powered and blinded, examining rTMS localized to the anatomical targets for each disorder. Presently, the mainstay of treatment remains disorder-specific psychotherapy with limited evidence for medications.