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Patient expectations, including both positive (placebo) and negative (nocebo) effects, influence treatment outcomes, yet their impact on acute repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) is unclear. In this single-center retrospective chart review, 208 TRD patients completed the Stanford Expectation of Treatment Scale (SETS) before starting open-label rTMS treatment. Patients were offered two excitatory rTMS protocols (deep TMS or intermittent theta-burst stimulation), which stimulated the left dorsolateral prefrontal cortex. A minimum of 20 once daily treatments were provided, delivered over 4–6 weeks. Primary outcomes were 1) remission, measured by a post-treatment score of <8 on the Hamilton Depression Rating Scale (HAMD-17), and 2) premature discontinuation. The change in HAMD-17 scores over time was used as a secondary outcome. Physicians were blinded to SETS scores. Logistic and linear regression, adjusting for covariates, assessed SETS and HAMD-17 relationships. Of 208 patients, 177 had baseline and covariate data available. The mean positivity bias score (positive expectancy minus negative expectancy subscale averages) was 0.48 ± 2.21, indicating the cohort was neutral regarding the expectations of their treatment on average. Higher positive expectancy scores were significantly associated with greater odds of remission (OR = 1.90, p = 0.003) and greater reduction in HAMD-17 scores (β = 1.30, p = 0.005) at the end of acute treatment, after adjusting for covariates. Negative expectancy was not associated with decreased odds of remission (p = 0.2) or treatment discontinuation (p = 0.8). Higher pre-treatment positive expectations were associated with greater remission rates with open-label rTMS in a naturalistic cohort of patients with TRD. • Positive pre-treatment expectancy boosts remission odds in Treatment-Resistant Depression (TRD) after acute rTMS. • Negative pre-treatment expectancy did not impact treatment discontinuation or lower remission odds following rTMS. • Understanding the impact of expectations on rTMS for TRD may help shape trial design and treatment outcomes. [ABSTRACT FROM AUTHOR]

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]

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. • The ASSFN convened a meeting of leaders in the field to discuss a path forward for psychiatric neurosurgery. • The participants were experts in the fields of neurology, neurosurgery, psychiatry, industry, government, ethics, and law. • We focused on interdisciplinary engagement, regulatory pathways, trial design, biomarkers, ethics, and resource allocation. • We present our strengths, weaknesses, opportunities, and threats analyses of the current state of psychiatric neurosurgery. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a prevalent and debilitating illness. While standard treatment with pharmacotherapy and psychotherapy may be effective, approximately 20 to 30% of patients remain symptomatic. These individuals experience depression, anxiety, and elevated rates of suicide. For treatment-resistant patients, there is a growing interest in the use of neuromodulation therapies, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). We conducted a systematic review on the use of neuromodulation strategies for PTSD and pooled 13 randomized clinical trials (RCTs), 11 case series, and 6 case reports for analysis. Overall, most studies reported favorable outcomes in alleviating both PTSD and depressive symptoms. Although several RCTs described significant differences when active and sham stimulations were compared, others found marginal or nonsignificant differences between groups. Also positive were studies comparing PTSD symptoms before and after treatment. The side effect profile with all 3 modalities was found to be low, with mostly mild adverse events being reported. Despite these encouraging data, several aspects remain unknown. Given that PTSD is a highly heterogeneous condition that can be accompanied by distinct psychiatric diagnoses, defining a unique treatment for this patient population can be quite challenging. There has also been considerable variation across trials regarding stimulation parameters, symptomatic response, and the role of adjunctive psychotherapy. Future studies are needed to address these issues. [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 Some of the antidepressant-like effects of ventromedial prefrontal cortex (vmPFC) deep brain stimulation (DBS) in rodents have been attributed to the modulation of prefrontal-raphe pathways. This is largely different from selective serotonin reuptake inhibitors (SSRIs), which increase serotonin (5-HT) levels by inhibiting the serotonin transporter (SERT). SSRIs have limited efficacy when given to SERT knockout (KO) mice, or patients with mutations in the serotonin transporter promoter gene (5-HTTLPR). Hypothesis vmPFC DBS will induce antidepressant-like effects and serotonin release in SERT KOs. Results DBS-treated wild-type and SERT KO mice had a significant 22-26% decrease in immobility in the forced swim test. DBS delivered to either group was associated with 33–55% increase in 5-HT levels. Conclusions DBS induced a significant antidepressant-like effect in KO mice. This suggests that it may be reasonable to consider DBS in states where SERT is not fully operational. [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 Medial forebrain bundle (MFB) deep brain stimulation (DBS) is currently being investigated in patients with treatment-resistant depression. Striking features of this therapy are the large number of patients who respond to treatment and the rapid nature of the antidepressant response. Objective To study antidepressant-like behavioral responses, changes in regional brain activity, and monoamine release in rats receiving MFB DBS. Methods Antidepressant-like effects of MFB stimulation at 100 μA, 90 μs and either 130 Hz or 20 Hz were characterized in the forced swim test (FST). Changes in the expression of the immediate early gene (IEG) zif268 were measured with in situ hybridization and used as an index of regional brain activity. Microdialysis was used to measure DBS-induced dopamine and serotonin release in the nucleus accumbens. Results Stimulation at parameters that approximated those used in clinical practice, but not at lower frequencies, induced a significant antidepressant-like response in the FST. In animals receiving MFB DBS at high frequency, increases in zif268 expression were observed in the piriform cortex, prelimbic cortex, nucleus accumbens shell, anterior regions of the caudate/putamen and the ventral tegmental area. These structures are involved in the neurocircuitry of reward and are also connected to other brain areas via the MFB. At settings used during behavioral tests, stimulation did not induce either dopamine or serotonin release in the nucleus accumbens. Conclusions These results suggest that MFB DBS induces an antidepressant-like effect in rats and recruits structures involved in the neurocircuitry of reward without affecting dopamine release in the nucleus accumbens. [ABSTRACT FROM AUTHOR]

Abstract: Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) has been routinely used for the treatment of some movement disorders. However, DBS may be associated with adverse psychiatric effects, such as depression, anxiety and impulsivity. Objective: To compare DBS applied to the entopeduncular nucleus (EPN; the rodent homolog of the GPi) and STN in terms of their effects on depressive- and anxiety-like behavior in rats. Methods: DBS was applied for 21 days (4 h a day) to either the STN or EPN. Rats then underwent behavioral testing on learned helplessness and elevated plus maze tasks before being sacrificed for brain analyses of zif268, BDNF and trkB mRNA as well as BDNF protein levels. Results: Repeated DBS of the STN, but not of the EPN, led to impaired performance in the learned helplessness task, suggesting that STN-DBS induces or potentiates depressive-like behavior. There was no effect of DBS on elevated plus maze or on open field behavior. Repeated STN-DBS, but not EPN-DBS, led to decreased levels of BDNF and trkB mRNA in hippocampus. Acute stimulation of the STN or EPN resulted in similar changes in zif268 levels in several brain areas, except for the raphe where decreases were seen only after STB-DBS. Conclusions: Together these results indicate that the effects of STN- and EPN-DBS differ in behavioral and neurochemical respects. Results further suggest that the EPN may be a preferable target for clinical DBS when psychiatric side effects are considered insofar as it may be associated with a lower incidence of depressive-like behavior than the STN. [Copyright &y& Elsevier]

Deep brain stimulation (DBS) is currently being investigated for the treatment of depression. Results of early clinical trials have been very promising, but the mechanisms responsible for the effects of DBS are still unknown. This article reviews behavioral findings of stimulation applied to different brain targets in rodents, with a particular focus on the ventromedial prefrontal cortex. Mechanisms and substrates involved in the antidepressant-like effects of DBS, including the role of local tissue inactivation, the modulation of fiber pathways in the vicinity of the electrodes, as well as the importance of the serotonergic system and brain derived neurotrophic factor are discussed. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) is being investigated as a treatment for major depression, but its mechanisms of action are still unknown. We have studied the effects of ventromedial prefrontal cortex (vmPFC) stimulation in a chronic model of depression and assessed the involvement of the serotonergic system and brain derived neurotrophic factor (BDNF) in a DBS response. Methods: Rats were subjected to chronic unpredictable mild stress during 4 weeks. Decline in preference for sucrose solutions over water, an index suggested to reflect anhedonic-like behavior, was monitored on a weekly basis. The outcome of chronic vmPFC stimulation alone (8 hours/day for 2 weeks) or combined with serotonin-depleting lesions was characterized. BDNF levels were measured in the hippocampus. Results: Stress induced a significant decrease in sucrose preference as well as hippocampal BDNF levels as compared with those recorded in control subjects. vmPFC stimulation completely reversed this behavioral deficit and partially increased BDNF levels. In contrast, DBS did not improve stress-induced anhedonic-like behavior in animals bearing serotonin-depleting raphe lesions with associated normal hippocampal BDNF levels. Conclusions: vmPFC stimulation was effective in a chronic model of depression. Our results suggest that the integrity of the serotonergic system is important for the anti-anhedonic-like effects of DBS but question a direct role of hippocampal BDNF. [Copyright &y& Elsevier]

The subcallosal cingulate gyrus (SCG), including Brodmann area 25 and parts of 24 and 32, is the portion of the cingulum that lies ventral to the corpus callosum. It constitutes an important node in a network that includes cortical structures, the limbic system, thalamus, hypothalamus, and brainstem nuclei. Imaging studies have shown abnormal SCG metabolic activity in patients with depression, a pattern that is reversed by various antidepressant therapies. The involvement of the SCG in mechanisms of depression and its emerging potential role as a surgical target for deep brain stimulation has focused recent interest in this area. We review anatomic and histologic attributes of the SCG and the morphologic and imaging changes observed in depression. Particular attention is given to the regional and downstream structures that could be influenced by the application of deep brain stimulation in this region. [ABSTRACT FROM AUTHOR]

Abstract: Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is currently being investigated as a treatment for major depression. Despite the encouraging findings of the initial clinical series, several questions remain unanswered, including the most effective stimulation parameters (i.e., current intensity and frequency) and whether unilateral stimulation is also beneficial. We have recently found that some of the effects of SCG DBS could be modeled by stimulating the ventromedial prefrontal cortex (vmPFC) of rats undergoing the forced swim test (FST). Here we investigate whether changes in a number of DBS parameters, including electrode placement, influence outcome in this paradigm. Overall, we found that the antidepressant-like effects of DBS varied as a function of stimulation settings and target. The strongest response was observed with a current intensity of 200μA, followed by 100μA, and 300μA. In contrast, 400μA produced no effect. Using 200μA, a frequency of 130Hz was more effective than 20Hz. An intriguing finding was that left unilateral stimulation was as effective as bilateral DBS. When different targets within the vmPFC were considered, a significant antidepressant-like response was observed after PL DBS, whereas IL stimulation was associated with a non-significant reduction in immobility scores. In summary, vmPFC DBS at high frequency and moderate intensity led to a maximal response in the FST. [Copyright &y& Elsevier]

Abstract: The anterior nucleus of the thalamus (AN) has been suggested as a potential target for seizure modulation in animal models and patients with refractory epilepsy. We investigate whether microinjections of GABAergic agonists into the AN were protective against pilocarpine-induced generalized seizures and status epilepticus (SE). Rats were treated with bilateral AN injections of muscimol (160 or 80nmol), bicuculline (15nmol), or saline (controls) 20min prior to pilocarpine administration (350mg/kg i.p.). Electrographic recordings were used to confirm seizure activity. We found that pretreatment with AN muscimol 160nmol increased the latency to seizures and SE by 2.5–3.0-fold. This dose however was associated with side effects, particularly hypotonia. AN bicuculline was proconvulsant, whereas no major effect was observed after muscimol 80nmol injections. The percentage of animals that developed SE was similar across groups. Overall, microinjection of high doses of muscimol into the AN delayed the occurrence of pilocarpine-induced seizures and SE but was not able to prevent these events. [Copyright &y& Elsevier]

Background: Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). Methods: The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. Results: Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. Conclusions: Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS. [Copyright &y& Elsevier]

Summary: The advancement of electrical stimulation of the central nervous system has been a story of fits and bursts with numerous setbacks. In many ways, this history has paralleled the history of medicine and physics. We have moved from anecdotal observation to double-blinded, prospective randomized trials. We have moved from faradic stimulation to systems that lie completely under the skin and can deliver complex electrical currents to discrete areas of the brain while controlled through a device that is not much bigger than a PDA. This review will discuss how deep brain stimulation has developed into its current form, where we see the field going and the potential pitfalls along the way. [Copyright &y& Elsevier]

Abstract: Background: Magnetic resonance imaging (MRI) and microelectrode recording (MER) are commonly used to guide stereotactic procedures on the subthalamic nucleus (STN). Little is known about the correlation between the position of the STN as seen on MRI and that as determined by MER mapping. We compared these in 10 patients with Parkinson''s disease. Methods: The position of the STN was determined by intraoperative MER findings and stereotactic axial T2 magnetic resonance images with 2-mm slice thickness. Images were reconstructed in a 3-dimensional workstation. The anterior, posterior, medial, lateral, dorsal, and ventral borders of the STN defined with the MRI were measured relative to the midcommissural point. The location of STN activity during MER was reconstructed relative to the midcommissural point for comparison. Results: Twenty-nine tracks recorded with microelectrodes provided clear spans of STN-like activity in 18 STN nuclei. The coordinates of MER were, in general, within the borders of the STN defined with the MRI. However, when analyzed individually, some of the tracks had STN-like activity outside the borders of the MRI-defined nucleus (mostly <1 mm). Three tracks had STN-like activity recorded between 2 and 3 mm more anterior than the anterior border of the nucleus defined with the MRI. Conclusions: There was a good correlation between MER and the borders of the STN defined in the MRI, except for the anterior-posterior axis, in which MER indicated that the STN extended more anteriorly than as suggested by MRI. This should be taken into account in STN surgery. [Copyright &y& Elsevier]

Abstract: Background: Neuromodulation therapies are currently being investigated as potential treatments for depression. One of these treatments involves the stimulation of supraorbital branches of the trigeminal nerve. Objective: To show that supraorbital stimulation is effective in preclinical models. Methods: Rats were given supraorbital stimulation at different settings in the forced swim test (FST) and open field. Results: Supraorbital stimulation did not induce an antidepressant-like response in rats undergoing the FST. This is in contrast to other neuromodulation treatments, such as deep brain stimulation, vagus nerve stimulation and electroconvulsive therapy, which are all effective in this paradigm. Conclusions: Supraorbital stimulation was ineffective in rats undergoing the FST. Such findings do not invalidate results of recent clinical trials. [Copyright &y& Elsevier]

Abstract: The pedunculopontine nucleus (PPN) is a brainstem locomotive center that also processes sensory and behavioral information. Through its connections with basal ganglia structures and the spinal cord, the PPN may play a role in axial motor symptoms in Parkinson''s disease (PD). We review the anatomical features of the PPN, its role in motor control, and its potential role as a target for PD surgery, including the results of recently published clinical studies. [Copyright &y& Elsevier]

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a safe and effective intervention for the treatment of certain forms of epilepsy. In preclinical models, electrical stimulation of the ANT has antiepileptogenic effects but its underlying mechanisms remain unclear. In this review, we searched multiple databases for studies that described the effects and mechanisms of ANT low or high frequency stimulation (LFS or HFS) in models of epilepsy. Out of 289 articles identified, 83 were pooled for analysis and 34 were included. Overall, ANT DBS was most commonly delivered at high frequency to rodents injected with kainic acid, pilocarpine, or pentylenetetrazole. In most studies, this therapy increased the latency to the first spontaneous seizure and reduced the frequency of seizures by 20%–80%. Electrophysiology data suggested that DBS reduces the severity of electrographic seizures, decreases the duration and increases the threshold of afterdischarges, reduces the power of low-frequency and increase the power high-frequency bands. Mechanistic studies revealed that ANT DBS leads to a series of short- and long-term changes at multiple levels. Some of its anticonvulsant effects were proposed to occur via the modulation of serotonergic and adenosinergic transmission. The latter seems to be derived from the downregulation of adenosine kinase (ADK). ANT DBS was also shown to increase hippocampal levels of lactate, alter the expression of genes involved in calcium signaling, synaptic glutamate, and the NOD-like receptor signaling pathway. When delivered during status epilepticus or following the injection of convulsant agents, DBS was found to reduce the expression of proinflammatory cytokines and apoptosis. When administered chronically, ANT DBS increased the expression of proteins involved in axonal guidance, changed functional connectivity in limbic circuits, and increased the number of hippocampal cells in epileptic animals, suggesting a neuroprotective effect. [ABSTRACT FROM AUTHOR]

With a high prevalence of posttraumatic stress disorder (PTSD) in females, studying sex differences in preclinical models is of substantial importance. We have previously employed behavioural criteria to identify and characterize a subpopulation of rats that presented impaired fear extinction and long-term fear and anxiety responses following fear conditioning. We now exposed male and female rats to fear conditioning and extinction and segregated the animals into weak- (WE) and strong-extinction (SE) groups based on behavioural scores during extinction. Animals were subsequently tested for tone and context recall, as well as anxiety-like responses in the marble burying and novelty suppression of feeding (NSF) tests. Vaginal lavages were collected to characterize the phase of the estrous cycle during fear extinction. We found that females had reduced freezing during tone recall and a lower latency to feed in the NSF test. No differences were found in females undergoing extinction during high and low estrogen phases of the cycle in any of the performed tests. Overall, the percentage of animals that presented WE and SE phenotypes was similar in males and females. Both, WE males and females had increased freezing during tone and context recall. Along with our previous reports, WE males presented anxiety-like responses, particularly in the NSF compared to SE animals. In contrast, WE females buried less marbles than their SE mates. Future investigation including a larger number of behavioural tests are certainly required to corroborate our findings and ascertain potential mechanisms to explain the differences observed in our study. • 25% of rats presented extinction deficits following fear conditioning. • At long-term, weak-extinction males showed anxiety-like behaviour, while females presented anxiolytic responses. • Sex differences could not be attributed to the estrous cycle. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate an ocular motor role for the STN in Parkinson’s disease (PD) patients. Methods: Potentials were recorded from deep brain stimulation (DBS) electrodes implanted in the vicinity of STN in five PD patients, while patients simultaneously performed visually cued saccades, self-paced saccades and in two patients self-paced wrist extensions. Results: Premovement potentials related to visually cued saccades were found in 4/5 patients and 56% (5/9) of potentials showed phase reversal indicating a local generator. Onsets of these potentials began closer to saccade initiation from STN contacts (0.88±0.30s) than thalamic ones (1.39±0.28s). Self-paced saccade-related potentials were found in 4/4 patients. Self-paced saccade potential onsets (1.82±0.88s) were not different from self-paced wrist extension onsets (1.27±0.98s), suggesting a non-specific mechanism could be responsible for both potentials. 50% (3/6) of potentials to self-paced saccades and 66% (2/3) of potentials to self-paced wrist extensions showed phase reversal. Potentials could be found either ipsilaterally or contralaterally with respect to saccade direction. Conclusions: These subcortical premovement potentials to saccades are similar to Bereitschaftspotentials and contingent negative variations to limb movements recorded in cortical and subcortical regions. Significance: These studies further support a role of STN in ocular motor control and suggest a common mechanism of motor preparation for both eye and limb movements in the basal ganglia. [Copyright &y& Elsevier]

Abstract: Objective: The study aims to compare 2-dimensional (2D) and 3-planar (3P) reconstruction magnetic resonance imaging (MRI) methods of targeting the optimal region of the subthalamic nucleus (STN) for chronic stimulation in patients with Parkinson disease. Methods: We studied 14 patients with Parkinson disease treated with bilateral STN deep brain stimulation (DBS) (28 STN targets). Electrode implantation was based on direct and indirect targeting based upon the position of the anterior and posterior commissures using 2D MRI, with selection of the final target based on microelectrode recording. Optimal settings, including the contacts used, were determined during the clinical follow-up. The position of the best contact was defined with postoperative MRI. Optimal contact position was compared to targets calculated by the direct method from the preoperative 2D MRI and 3P reconstruction. Optimal contact position was also compared to the indirect targets calculated from the preoperative 2D MRI and 3P reconstruction. The distance between the targets and the position of the best contact were calculated. Results: The mean improvement in OFF-period Unified Parkinson Disease Rating Scale III subscores with STN DBS was 52%. The mean distance between the optimal contact position and the direct target was 4.66 mm (SD = 1.33) using the 2D MRI and 3.49 mm (SD = 1.29) using the 3P reconstruction (t test, P < .001). The mean distance between the optimal contact and the indirect target was 3.42 mm (SD = 1.34) using the 2D MRI and 2.61 mm (SD = 0.97; t test, P = .001) using the 3P reconstruction. The variance of the direct target was less using the 3P reconstruction than using the 2D MRI (F test, P = .002), indicating greater precision. Similarly, the variance of the indirect target using the 3P reconstruction was less than using the 2D MRI (F test, P = .012). Conclusion: Indirect and direct targets chosen using 3P reconstruction more closely approximate the position of the clinically optimal contact than targets chosen using 2D MRI. [Copyright &y& Elsevier]