Investigating Resistance to Antidepressants in Animal Models.

Major depressive disorder is one of the most prevalent psychiatric diseases, and up to 30-40% of patients remain symptomatic despite treatment. Novel therapies are sorely needed, and animal models may be used to elucidate fundamental neurobiological processes that contribute to human disease states. We conducted a systematic review of current preclinical approaches to investigating treatment resistance with the goal of describing a path forward for improving our understanding of treatment resistant depression. We conducted a broad literature search to identify studies relevant to the preclinical investigation of treatment resistant depression. We followed PRISMA (Preferred Reporting Items for Systemic Reviews and Meta-Analyses) guidelines and included all relevant studies. We identified 467 studies in our initial search. Of these studies, we included 69 in our systematic review after applying our inclusion/exclusion criteria. We identified 10 broad strategies for investigating treatment resistance in animal models. Stress hormone administration was the most commonly used model, and the most common behavioral test was the forced swim test. We systematically identified and reviewed current approaches for gaining insight into the neurobiology underlying treatment resistant depression using animal models. Each approach has its advantages and disadvantages, but all require careful consideration of their potential limitations regarding therapeutic translation. An enhanced understanding of treatment resistant depression is sorely needed given the burden of disease and lack of effective therapies.

Stress circuitry: mechanisms behind nervous and immune system communication that influence behavior.

Inflammatory processes are increased by stress and contribute to the pathology of mood disorders. Stress is thought to primarily induce inflammation through peripheral and central noradrenergic neurotransmission. In healthy individuals, these pro-inflammatory effects are countered by glucocorticoid signaling, which is also activated by stress. In chronically stressed individuals, the anti-inflammatory effects of glucocorticoids are impaired, allowing pro-inflammatory effects to go unchecked. Mechanisms underlying this glucocorticoid resistance are well understood, but the precise circuits and molecular mechanisms by which stress increases inflammation are not as well known. In this narrative review, we summarize the mechanisms by which chronic stress increases inflammation and contributes to the onset and development of stress-related mood disorders. We focus on the neural substrates and molecular mechanisms, especially those regulated by noradrenergic signaling, that increase inflammatory processes in stressed individuals. We also discuss key knowledge gaps in our understanding of the communication between nervous and immune systems during stress and considerations for future therapeutic strategies. Here we highlight the mechanisms by which noradrenergic signaling contributes to inflammatory processes during stress and how this inflammation can contribute to the pathology of stress-related mood disorders. Understanding the mechanisms underlying crosstalk between the nervous and immune systems may lead to novel therapeutic strategies for mood disorders and/or provide important considerations for treating immune-related diseases in individuals suffering from stress-related disorders.

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.

Silencing hippocampal CA2 reduces behavioral flexibility in spatial learning.

The hippocampus is a key structure involved in learning and remembering spatial information. However, the extent to which hippocampal region CA2 is involved in these processes remains unclear. Here, we show that chronically silencing dorsal CA2 impairs reversal learning in the Morris water maze. After platform relocation, CA2-silenced mice spent more time in the vicinity of the old platform location and less time in the new target quadrant. Accordingly, behavioral strategy analysis revealed increased perseverance in navigating to the old location during the first day and an increased use of non-spatial strategies during the second day of reversal learning. Confirming previous indirect indications, these results demonstrate that CA2 is recruited when mice must flexibly adapt their behavior as task contingencies change. We discuss how these findings can be explained by recent theories of CA2 function and outline testable predictions to understand the underlying neural mechanisms. Demonstrating a direct involvement of CA2 in spatial learning, this work lends further support to the notion that CA2 plays a fundamental role in hippocampal information processing.

Gamma Knife radiosurgery for trigeminal neuralgia provides greater pain relief at higher dose rates.

In Gamma Knife (GK) radiosurgery, dose rate decreases during the life cycle of its radiation source, extending treatment times. Prolonged treatments influence the amount of sublethal radiation injury that is repaired during exposure, and is associated with decreased biologically-equivalent dose (BED). We assessed the impact of treatment times on clinical outcomes following GK of the trigeminal nerve - a rare clinical model to isolate the effects of treatment times. This is a retrospective analysis of 192 patients with facial pain treated across three source exchanges. All patients were treated to 80 Gy with a single isocenter. Treatment time was analyzed in terms of patient anatomy-specific dose rate, as well as BED calculated from individual patient beam-on times. An outcome tool measuring pain in three distinct domains (pain intensity, interference with general and oro-facial activities of daily living), was administered before and after intervention. Multivariate linear regression was performed with dose rate/BED, brainstem dose, sex, age, diagnosis, and prior intervention as predictors. BED was an independent predictor of the degree of improvement in all three dimensions of pain severity. A decrease in dose rate by 1.5 Gy/min corresponded to 31.8% less improvement in the overall severity of pain. Post-radiosurgery incidence of facial numbness was increased for BEDs in the highest quartile. Treatment time is an independent predictor of pain outcomes, suggesting that prescription dose should be customized to ensure iso-effective treatments, while accounting for the possible increase in adverse effects at the highest BEDs.

Laterality and Sex Differences of Human Lateral Habenula Afferent and Efferent Fiber Tracts.

Introduction: The lateral habenula (LHb) is an epithalamic nucleus associated with negative valence and affective disorders. It receives input via the stria medullaris (SM) and sends output via the fasciculus retroflexus (FR). Here, we use tractography to reconstruct and characterize this pathway. Methods: Multi-shell human diffusion magnetic resonance imaging (dMRI) data was obtained from the human connectome project (HCP) (n = 20, 10 males) and from healthy controls (n = 10, 6 males) scanned at our institution. We generated LHb afferents and efferents using probabilistic tractography by selecting the pallidum as the seed region and the ventral tegmental area as the output target. Results: We were able to reconstruct the intended streamlines in all individuals from the HCP dataset and our dataset. Our technique also aided in identification of the LHb. In right-handed individuals, the streamlines were significantly more numerous in the left hemisphere (mean ratio 1.59 ± 0.09, p = 0.04). In left-handed individuals, there was no hemispheric asymmetry on average (mean ratio 1.00 ± 0.09, p = 1.0). Additionally, these streamlines were significantly more numerous in females than in males (619.9 ± 159.7 vs. 225.9 ± 66.03, p = 0.04). Conclusion: We developed a method to reconstruct the SM and FR without manual identification of the LHb. This technique enables targeting of these fiber tracts as well as the LHb. Furthermore, we have demonstrated that there are sex and hemispheric differences in streamline number. These findings may have therapeutic implications and warrant further investigation.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Essential Tremor Under General Anesthesia: Technical Note.

BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an incisionless therapy for the treatment of medication-resistant essential tremor. Although its safety and efficacy has been demonstrated, MRgFUS is typically performed with the patient awake, with intraprocedural neurological assessments to guide lesioning. OBJECTIVE: To report the first case of MRgFUS thalamotomy under general anesthesia in a patient whose medical comorbidities prohibit him from being in a supine position without a secured airway. METHODS: The dentatorubrothalamic tract was directly targeted. Two sonications reaching lesional temperatures (≥54°C) were delivered without any complications. RESULTS: Lesioning was confirmed on intraoperative magnetic resonance imaging, and the patient experienced 89% improvement in his tremor postoperatively. CONCLUSION: This demonstrates the safety and feasibility of MRgFUS thalamotomy under general anesthesia without the benefit of intraprocedural neurological assessments.

Feasibility of Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Essential Tremor in the Setting of Prior Craniotomy.

BACKGROUND: Magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy is a rapidly evolving therapy for the treatment of essential tremor. Although the skull is a major determinant of the delivery of acoustic energy to the target, how the presence of a prior craniotomy must be accounted for during lesioning is unclear. OBJECTIVE: To demonstrate novel application of this therapeutic option in a patient with a history of prior craniotomies for unrelated intracranial pathologies. METHODS: A 55-yr-old man with a history of right frontal craniotomy for resection of a colloid cyst underwent a left ventrointermedius nucleus thalamotomy through MRgFUS. The prior craniotomy flap was not excluded in the treatment plan; however, all bony defects and hardware were marked as "no-pass" regions. Clinical outcomes were collected at the 6-mo follow-up. RESULTS: Transducer elements whose acoustic paths would have been altered by the craniotomy defect were turned off. Sonications reaching lesional temperatures of up to 56°C were successfully delivered. The procedure was well-tolerated, without any persistent intra-ablation or postablation adverse effects. The presence of a lesion was confirmed on MRI, which was associated with a significant reduction in the patient's tremor that was sustained at the 6-mo follow-up. CONCLUSION: This case demonstrates the safety and efficacy of MRgFUS thalamotomy in a patient with prior craniotomies and highlights our strategy for acoustic lesioning in this setting.

Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Treatment-Resistant Depression: A Decade of Clinical Follow-Up.

Objective: Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD) that has shown variable efficacy. This report describes long-term outcomes of DBS for TRD.Methods: A consecutive series of 8 patients with TRD were implanted with ventral capsule/ventral striatum (VC/VS) DBS systems as part of the Reclaim clinical trial. Outcomes from 2009 to 2020 were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Demographic information, MADRS scores, and data on adverse events were collected via retrospective chart review. MADRS scores were integrated over time using an area-under-the-curve technique.Results: This cohort of patients had severe TRD-all had failed trials of ECT, and all had failed a minimum of 4 adequate medication trials. Mean ± SD follow-up for patients who continued to receive stimulation was 11.0 ± 0.4 years (7.8 ± 4.3 years for the entire cohort). At last follow-up, mean improvement in MADRS scores was 44.9% ± 42.7%. Response (≥ 50% improvement) and remission (MADRS score ≤ 10) rates at last follow-up were 50% and 25%, respectively. Two patients discontinued stimulation due to lack of efficacy, and another patient committed suicide after stimulation was discontinued due to recurrent mania. The majority of the cohort (63%) continued to receive stimulation through the end of the study.Conclusions: While enthusiasm for DBS treatment of TRD has been tempered by recent randomized trials, this small open-label study demonstrates that some patients achieve meaningful and sustained clinical benefit. Further trials are required to determine the optimal stimulation parameters and patient populations for which DBS would be effective. Particular attention to factors including patient selection, integrative outcome measures, and long-term observation is essential for future trial design.Trial Registration: ClinicalTrials.gov identifier: NCT00837486.

Patient-specific effects on sonication heating efficiency during magnetic resonance-guided focused ultrasound thalamotomy.

PURPOSE: During magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for refractory tremor, high temperatures must be achieved and sustained for tissue necrosis. We assessed the impact of both patient-specific as well as procedure-related factors on the efficiency of acoustic energy transfer, or heating efficiency (HE). METHODS: Retrospective analysis of 92 consecutive patients (857 sonications) with essential tremor or tremor-dominant Parkinson's disease treated at a single institution. Temperature elevations at the target were measured for each sonication with MR thermometry. HE of each sonication was defined as the ratio of peak temperature elevation and the delivered energy. HE was analyzed with respect to patient skull features (area, thickness, skull density ratio [SDR]), computed from CT scans, as well as demographic and clinical variables (age, sex, diagnosis, and duration of symptoms). RESULTS: Across the full range of sonication energies that can be delivered with current devices (up to 36 kJ), average sonication HE was diminished in patients with lower SDR. In individual subjects, there was a progressive loss in HE as sonication energy was titrated up throughout the course of treatment, with a more rapid decline in patients with higher SDR. This energy-dependent loss in HE was not related to procedural factors, namely, the number of previous sonications, or the cumulative energy deposited during previous sonications. In contrast to SDR, neither skull area nor thickness was an independent predictor of average HE or the rate of its decline with increasing energies. In 11% of patients, all of whom with SDR < 0.45, sonication HE fell below the threshold to reach 54°C even with delivery of maximum energy. In contrast, temperatures ≥ 50°C could be obtained in all but one patient. CONCLUSIONS: SDR is predictive of sonication HE, and determines patient-specific limits on the magnitude of temperature elevation that can be achieved with current devices. These data inform strategies for predictable lesioning in MRgFUS thalamotomy.

Deep Brain Stimulation Is Effective for Treatment-Resistant Depression: A Meta-Analysis and Meta-Regression.

Major depressive disorder (MDD) is a leading cause of disability and a significant cause of mortality worldwide. Approximately 30-40% of patients fail to achieve clinical remission with available pharmacological treatments, a clinical course termed treatment-resistant depression (TRD). Numerous studies have investigated deep brain stimulation (DBS) as a therapy for TRD. We performed a meta-analysis to determine efficacy and a meta-regression to compare stimulation targets. We identified and screened 1397 studies. We included 125 citations in the qualitative review and considered 26 for quantitative analysis. Only blinded studies that compared active DBS to sham stimulation (k = 12) were included in the meta-analysis. The random-effects model supported the efficacy of DBS for TRD (standardized mean difference = -0.75, <0 favors active stimulation; p = 0.0001). The meta-regression did not demonstrate a statistically significant difference between stimulation targets (p = 0.45). While enthusiasm for DBS treatment of TRD has been tempered by recent randomized trials, this meta-analysis reveals a significant effect of DBS for the treatment of TRD. Additionally, the majority of trials have demonstrated the safety and efficacy of DBS for this indication. Further trials are required to determine the optimal stimulation parameters and patient populations for which DBS would be effective. Particular attention to factors including electrode placement technique, patient selection, and long-term follow-up is essential for future trial design.

Inequalities in Meningioma Survival: Results from the National Cancer Database.

Background Meningiomas are the second most common primary tumors of the central nervous system. However, there is a paucity of literature examining how healthcare, demographic, and socioeconomic factors impact patient outcomes. Methods We conducted a retrospective study of 65,812 patients from the National Cancer Database (NCDB; 2004-2012) who received treatment for their meningioma. Univariate and multivariate analyses were performed with the overall five-year survival as the primary outcome, and the following factors: facility type, geography, housing area, patient insurance, sex, ethnicity, race, income, and education. The multivariate model was adjusted for patient age, co-morbidity, tumor size, behavior, and treatment strategy. Results Diagnosis and treatment at an academic/research program, private insurance, female sex, Hispanic ethnicity, and high school diploma conferred a survival advantage on both univariate and multivariate analyses. Conclusions Disparities in survival outcomes in patients with meningiomas exist across multiple healthcare, demographic, and socioeconomic factors. Additional research is needed to elucidate the genetic and environmental factors driving these inequalities.

Thalamic Deep Brain Stimulation for Essential Tremor: Relation of the Dentatorubrothalamic Tract with Stimulation Parameters.

BACKGROUND: In deep brain stimulation (DBS) for essential tremor, the primary target ventrointermedius (VIM) nucleus cannot be clearly visualized with structural imaging. As such, there has been much interest in the dentatorubrothalamic tract (DRTT) for target localization, but evidence for the DRTT as a putative stimulation target in tremor suppression is lacking. We evaluated proximity of the DRTT in relation to DBS stimulation parameters. METHODS: This is a retrospective analysis of 26 consecutive patients who underwent DBS with microelectrode recordings (46 leads). Fiber tracking was performed with a published deterministic technique. Clinically optimized stimulation parameters were obtained in all patients at the time of most recent follow-up (6.2 months). Volume of tissue activated (VTA) around contacts was calculated from a published model. RESULTS: Tremor severity was reduced in all treated hemispheres, with 70% improvement in the treated hand score of the Clinical Rating Scale for Tremor. At the level of the active contact (2.9 ± 2.0 mm superior to the commissural plane), the center of the DRTT was lateral to the contacts (5.1 ± 2.1 mm). The nearest fibers of the DRTT were 2.4 ± 1.7 mm from the contacts, whereas the radius of the VTA was 2.9 ± 0.7 mm. The VTA overlapped with the DRTT in 77% of active contacts. The distance from active contact to the DRTT was positively correlated with stimulation voltage requirements (Kendall τ = 0.33, P = 0.006), whereas distance to the atlas-based VIM coordinates was not. CONCLUSIONS: Active contacts in proximity to the DRTT had lower voltage requirements. Data from a large cohort provide support for the DRTT as an effective stimulation target for tremor control.

Surgical Outcomes in Post-Traumatic Epilepsy: A Single Institutional Experience.

BACKGROUND: Post-traumatic epilepsy (PTE) is a debilitating sequela of traumatic brain injury (TBI), occurring in up to 20% of severe cases. This entity is generally thought to be more difficult to treat with surgical intervention. OBJECTIVE: To detail our experience with the surgical treatment of PTE. METHODS: Patients with a history of head injury undergoing surgical treatment for epilepsy were retrospectively enrolled. Engel classification at the last follow-up was used to assess outcome of patients that underwent surgical resection of an epileptic focus. Reduction in seizure frequency was assessed for patients who underwent vagal nerve stimulator (VNS) or responsive neurostimulator (RNS) implantation. RESULTS: A total of 23 patients met inclusion criteria. Nineteen (82.6%) had mesial temporal sclerosis, 3 had lesional neocortical epilepsy (13.0%), and 1 had nonlesional neocortical epilepsy (4.3%). Fourteen patients (60.9%) underwent temporal lobectomy (TL), 2 underwent resection of a cortical focus (8.7%), and 7 underwent VNS implantation (30.4%). Three patients underwent RNS implantation after VNS failed to reduce seizure frequency more than 50%. In the patients treated with resection, 11 (68.8%) were Engel I, 3 (18.8%) were Engel II, and 2 (12.5%) were Engel III at follow-up. Average seizure frequency reduction in the VNS group was 30.6% ± 25.6%. RNS patients had reduction of seizure severity but seizure frequency was only reduced 9.6% ± 13.6%. CONCLUSION: Surgical outcomes of PTE patients treated with TL were similar to reported surgical outcomes of patients with nontraumatic epilepsy treated with TL. Patients who were not candidates for resection demonstrated variable response rates to VNS or RNS implantation.

Growth of Lumbosacral Perineural (Tarlov) Cysts: A Natural History Analysis.

BACKGROUND: Tarlov cysts (TC) are commonly found spinal perineural cysts. Symptomatic TCs are rare, however, and there is no consensus on their pathogenesis and optimal management. OBJECTIVE: To characterize cyst growth in patients with symptomatic TCs. METHODS: This is a retrospective cohort study of 28 subjects, evaluated for symptomatic TCs (2011-2017). Each of the subjects had multiple magnetic resonance imaging (MRIs) across time and was included in a natural history analysis. RESULTS: A total of 42 TCs were identified across the 28 subjects, of which 7 cysts (17%) across 5 subjects demonstrated growth. Across a mean follow-up of 4.7 ± 1.8 years, TCs grew at a relative rate of 2.9 ± 2.6% in the anteroposterior, 4.3 ± 3.8% in the craniocaudal, and 1.4 ± 1.4% in the transverse dimensions per year. None of the cysts decreased in size between successive MRIs. Symptoms of cerebrospinal fluid (CSF) hypotension (positional headaches) were positive predictors of prior cyst growth on logistic regression (P = 0.02, odds ratio = 10). A total of 2 of the 5 subjects were initially asymptomatic from their TCs, and developed symptoms during the period of cyst growth, whereas 2 others experienced worsening of their symptoms during cyst growth. CONCLUSION: We report on the growth of TCs, which is consistent with a widely-held theory that hydrostatic and pulsatile forces of CSF along with a ball-valve phenomenon allow for continuous dilation of TCs.

Human gene therapy approaches for the treatment of Parkinson's disease: An overview of current and completed clinical trials.

Gene therapy has been employed in the human brain for a number of disorders in clinical trials and may serve as an avenue for the treatment of Parkinson's disease (PD). Several gene therapy treatment strategies have been developed and evaluated in patients with PD. Three main strategies have been used-enhancement of dopamine synthesis, expression of trophic factors, and neuromodulation. Typically, genes are delivered via viral vectors and expressed within neurons in PD-relevant areas of the brain such as the striatum. These methods of gene delivery have the potential for long-term expression and may only need to be delivered once. Notably, current gene therapy strategies do not address the non-motor symptoms of PD and do not curtail α-synuclein aggregation/spread. Furthermore, many of the completed trials were open-label trials and are subject to placebo effects and bias. Clinical trials have, however, demonstrated safety and studies are ongoing. Here, we review the current landscape of the development of gene therapy for PD and discuss the future of this novel treatment strategy.

Focused Ultrasound Thalamotomy for Essential Tremor in the Setting of a Ventricular Shunt: Technical Report.

BACKGROUND: A recent randomized controlled trial of magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) for essential tremor (ET) demonstrated safety and efficacy. Patients with ventricular shunts may be good candidates for FUS to minimize hardware-associated infections. OBJECTIVE: To demonstrate feasibility of FUS in this subset of patients. METHODS: A 74-yr-old male with medically refractory ET, and a right-sided ventricular shunt for normal pressure hydrocephalus, underwent FUS to the right ventro-intermedius (VIM) nucleus. The VIM nucleus was directly targeted using deterministic tractography. Clinical outcomes were measured using the Clinical Rating Scale for Tremor. RESULTS: Shunt components required 6% of the total ultrasound transducer elements to be shut off. Eight therapeutic sonications were delivered (maximum temperature, 64°), leading to a 90% improvement in hand tremor and a 100% improvement in functional disability at the 3-mo follow-up. No complications were noted. CONCLUSION: This is the first case of FUS thalamotomy in a patient with a shunt. Direct VIM targeting and achievement of therapeutic temperatures with acoustic energy is feasible in this subset of patients.