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Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.

Importance: Unilateral magnetic resonance-guided focused ultrasound ablation of ventralis intermedius nucleus of the thalamus for essential tremor reduces tremor on 1 side, but untreated contralateral or midline symptoms remain limiting for some patients. Historically, bilateral lesioning produced unacceptable risks and was supplanted by deep brain stimulation; increasing acceptance of unilateral focused ultrasound lesioning has led to interest in a bilateral option., Objective: To evaluate the safety and efficacy of staged, bilateral focused ultrasound thalamotomy., Design, Setting, and Participants: This prospective, open-label, multicenter trial treated patients with essential tremor from July 2020 to October 2021, with a 12-month follow-up, at 7 US academic medical centers. Of 62 enrolled patients who had undergone unilateral focused ultrasound thalamotomy at least 9 months prior to enrollment, 11 were excluded and 51 were treated. Eligibility criteria included patient age (22 years and older), medication refractory, tremor severity (Clinical Rating Scale for Tremor [CRST] part A score ≥2 for postural or kinetic tremor), and functional disability (CRST part C score ≥2 in any category)., Intervention: A focused ultrasound system interfaced with magnetic resonance imaging allowed real-time alignment of thermography maps with anatomy. Subthreshold sonications allowed target interrogation for efficacy and off-target effects before creating an ablation., Main Outcomes and Measures: Tremor/motor score (CRST parts A and B) at 3 months for the treated side after treatment was the primary outcome measure, and secondary assessments for efficacy and safety continued to 12 months., Results: The mean (SD) population age was 73 (13.9) years, and 44 participants (86.3%) were male. The mean (SD) tremor/motor score improved from 17.4 (5.4; 95% CI, 15.9-18.9) to 6.4 (5.3; 95% CI, 4.9 to 7.9) at 3 months (66% improvement in CRST parts A and B scores; 95% CI, 59.8-72.2; P < .001). There was significant improvement in mean (SD) postural tremor (from 2.5 [0.8]; 95% CI, 2.3 to 2.7 to 0.6 [0.9]; 95% CI, 0.3 to 0.8; P < .001) and mean (SD) disability score (from 10.3 [4.7]; 95% CI, 9.0-11.6 to 2.2 [2.8]; 95% CI, 1.4-2.9; P < .001). Twelve participants developed mild (study-defined) ataxia, which persisted in 6 participants at 12 months. Adverse events (159 of 188 [85%] mild, 25 of 188 [13%] moderate, and 1 severe urinary tract infection) reported most commonly included numbness/tingling (n = 17 total; n = 8 at 12 months), dysarthria (n = 15 total; n = 7 at 12 months), ataxia (n = 12 total; n = 6 at 12 months), unsteadiness/imbalance (n = 10 total; n = 0 at 12 months), and taste disturbance (n = 7 total; n = 3 at 12 months). Speech difficulty, including phonation, articulation, and dysphagia, were generally mild (rated as not clinically significant, no participants with worsening in all 3 measures) and transient., Conclusions and Relevance: Staged, bilateral focused ultrasound thalamotomy significantly reduced tremor severity and functional disability scores. Adverse events for speech, swallowing, and ataxia were mostly mild and transient., Trial Registration: ClinicalTrials.gov Identifier NCT04112381.

Although certain drivers of familial Parkinson's disease (PD) compromise mitochondrial integrity, whether metabolic deficits underly other idiopathic or genetic origins of PD is unclear. Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5'-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that this activity enhancement depends on the molecular chaperone PARK7/DJ-1, whose loss of function significantly disrupts axonal bioenergetics. In vivo, viral expression of PGK1 confers protection of striatal dopamine axons against metabolic lesions. These data support the notion that bioenergetic deficits may underpin PD-associated pathologies and point to improving neuronal adenosine 5'-triphosphate production kinetics as a promising path forward in PD therapeutics.

Cognitive impairments are a common feature of synucleinopathies such as Parkinson's Disease Dementia and Dementia with Lewy Bodies. These pathologies are characterized by accumulation of Lewy bodies and Lewy neurites as well as neuronal cell death. Alpha-synuclein is the main proteinaceous component of Lewy bodies and Lewy neurites. To model these pathologies in vivo , toxins that selectively target certain neuronal populations or different means of inducing alpha-synuclein aggregation can be used. Alpha-synuclein accumulation can be induced by genetic manipulation, viral vector overexpression or the use of preformed fibrils of alpha-synuclein. In this review, we summarize the cognitive impairments associated with different models of synucleinopathies and relevance to observations in human diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Haikal, Winston and Kaplitt.)

Background and Purpose: The purpose of this study is to evaluate the feasibility of using 3-dimensional (3D) ultra-short echo time (UTE) radial imaging method for measurement of the permeability of the blood-brain barrier (BBB) to gadolinium-based contrast agent. In this study, we propose to use the golden-angle radial sparse parallel (GRASP) method with 3D center-out trajectories for UTE, hence named as 3D UTE-GRASP. We first examined the feasibility of using 3D UTE-GRASP dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) for differentiating subtle BBB disruptions induced by focused ultrasound (FUS). Then, we examined the BBB permeability changes in Alzheimer's disease (AD) pathology using Alzheimer's disease transgenic mice (5xFAD) at different ages., Methods: For FUS experiments, we used four Sprague Dawley rats at similar ages where we compared BBB permeability of each rat receiving the FUS sonication with different acoustic power (0.4-1.0 MPa). For AD transgenic mice experiments, we included three 5xFAD mice (6, 12, and 16 months old) and three wild-type mice (4, 8, and 12 months old)., Results: The result from FUS experiments showed a progressive increase in BBB permeability with increase of acoustic power (p < .05), demonstrating the sensitivity of DCE-MRI method for detecting subtle changes in BBB disruption. Our AD transgenic mice experiments suggest an early BBB disruption in 5xFAD mice, which is further impaired with aging., Conclusion: The results in this study substantiate the feasibility of using the proposed 3D UTE-GRASP method for detecting subtle BBB permeability changes expected in neurodegenerative diseases, such as AD., (© 2024 American Society of Neuroimaging.)

Objective: The ability to predict final lesion characteristics during magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for the treatment of essential tremor remains technically challenging, yet it is essential in order to avoid off-target ablation and to ensure adequate treatment. The authors sought to evaluate the technical feasibility and utility of intraprocedural diffusion-weighted imaging (DWI) in the prediction of final lesion size and location., Methods: Lesion diameter and distance from the midline were measured on both intraprocedural and immediate postprocedural diffusion and T2-weighted sequences. Bland-Altman analysis was utilized to determine differences in measurement between intraprocedural and immediate postprocedural images with both sequences., Results: Lesion size increased on both the postprocedural diffusion and T2-weighted sequences, although the difference was smaller on the T2-weighted sequence. There was only a small difference in intraprocedural and postprocedural lesion distance from the midline on both the diffusion and T2-weighted sequences., Conclusions: Intraprocedural DWI is both feasible and useful with regard to predicting final lesion size and providing an early indication of lesion location. Further research should determine the value of intraprocedural DWI in predicting delayed clinical outcomes.

A lack of comprehensive mapping of ganglionic inputs into the pancreas and of technology for the modulation of the activity of specific pancreatic nerves has hindered the study of how they regulate metabolic processes. Here we show that the pancreas-innervating neurons in sympathetic, parasympathetic and sensory ganglia can be mapped in detail by using tissue clearing and retrograde tracing (the tracing of neural connections from the synapse to the cell body), and that genetic payloads can be delivered via intrapancreatic injection to target sites in efferent pancreatic nerves in live mice through optimized adeno-associated viruses and neural-tissue-specific promoters. We also show that, in male mice, the targeted activation of parasympathetic cholinergic intrapancreatic ganglia and neurons doubled plasma-insulin levels and improved glucose tolerance, and that tolerance was impaired by stimulating pancreas-projecting sympathetic neurons. The ability to map the peripheral ganglia innervating the pancreas and to deliver transgenes to specific pancreas-projecting neurons will facilitate the examination of ganglionic inputs and the study of the roles of pancreatic efferent innervation in glucose metabolism., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Heightened aggressive behavior is considered as one of the central symptoms of many neuropsychiatric disorders including autism, schizophrenia, and dementia. The consequences of aggression pose a heavy burden on patients and their families and clinicians. Unfortunately, we have limited treatment options for aggression and lack mechanistic insight into the causes of aggression needed to inform new efforts in drug discovery and development. Levels of proinflammatory cytokines in the periphery or cerebrospinal fluid were previously reported to correlate with aggressive traits in humans. However, it is still unknown whether cytokines affect brain circuits to modulate aggression. Here, we examined the functional role of interleukin 1β (IL-1β) in mediating individual differences in aggression using a resident-intruder mouse model. We found that nonaggressive mice exhibit higher levels of IL-1β in the dorsal raphe nucleus (DRN), the major source of forebrain serotonin (5-HT), compared to aggressive mice. We then examined the effect of pharmacological antagonism and viral-mediated gene knockdown of the receptors for IL-1 within the DRN and found that both treatments consistently increased aggressive behavior of male mice. Aggressive mice also exhibited higher c-Fos expression in 5-HT neurons in the DRN compared to nonaggressive mice. In line with these findings, deletion of IL-1 receptor in the DRN enhanced c-Fos expression in 5-HT neurons during aggressive encounters, suggesting that modulation of 5-HT neuronal activity by IL-1β signaling in the DRN controls expression of aggressive behavior., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Although mammalian retinal ganglion cells (RGCs) normally cannot regenerate axons nor survive after optic nerve injury, this failure is partially reversed by inducing sterile inflammation in the eye. Infiltrative myeloid cells express the axogenic protein oncomodulin (Ocm) but additional, as-yet-unidentified, factors are also required. We show here that infiltrative macrophages express stromal cell–derived factor 1 (SDF1, CXCL12), which plays a central role in this regard. Among many growth factors tested in culture, only SDF1 enhances Ocm activity, an effect mediated through intracellular cyclic AMP (cAMP) elevation and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation. SDF1 deficiency in myeloid cells (CXCL12flx/flxLysM-Cre−/+ mice) or deletion of the SDF1 receptor CXCR4 in RGCs (intraocular AAV2-Cre in CXCR4flx/flx mice) or SDF1 antagonist AMD3100 greatly suppresses inflammation-induced regeneration and decreases RGC survival to baseline levels. Conversely, SDF1 induces optic nerve regeneration and RGC survival, and, when combined with Ocm/cAMP, SDF1 increases axon regeneration to levels similar to those induced by intraocular inflammation. In contrast to deletion of phosphatase and tensin homolog (Pten), which promotes regeneration selectively from αRGCs, SDF1 promotes regeneration from non-αRGCs and enables the latter cells to respond robustly to Pten deletion; however, SDF1 surprisingly diminishes the response of αRGCs to Pten deletion. When combined with inflammation and Pten deletion, SDF1 enables many RGCs to regenerate axons the entire length of the optic nerve. Thus, SDF1 complements the effects of Ocm in mediating inflammation-induced regeneration and enables different RGC subtypes to respond to Pten deletion.

Magnetic resonance guided focused ultrasound (MRgFUS) is a non-invasive therapeutic modality for neurodegenerative diseases that employs real-time imaging and thermometry monitoring of targeted regions. MRI is used in guidance of ultrasound treatment; however, the MR image quality in current clinical applications is poor when using the vendor built-in body coil. We present an 8-channel, ultra-thin, flexible, and acoustically transparent receive-only head coil design (FUS-Flex) to improve the signal-to-noise ratio (SNR) and thus the quality of MR images during MRgFUS procedures. Acoustic simulations/experiments exhibit transparency of the FUS-Flex coil as high as 97% at 650 kHz. Electromagnetic simulations show a SNR increase of 13× over the body coil. In vivo results show an increase of the SNR over the body coil by a factor of 7.3 with 2× acceleration (equivalent to 11× without acceleration) in the brain of a healthy volunteer, which agrees well with simulation. These preliminary results show that the use of a FUS-Flex coil in MRgFUS surgery can increase MR image quality, which could yield improved focal precision, real-time intraprocedural anatomical imaging, and real-time 3D thermometry mapping.

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease 1 . Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear 2 . Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm 3,4 ., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Magnetic resonance-guided focused ultrasound is a powerful new technology that is enabling development of noninvasive applications for complex brain disorders. This is currently revolutionizing the treatment of tremor disorders, and a variety of experimental applications are under active investigation. To fully realize the potential of this disruptive technology, many challenges have been identified, some of which have been addressed and others remain to be solved. As an image-based technology, optimal intraoperative imaging can be difficult to achieve and several factors can influence the quality of these images. Technical issues with current devices can also limit the effective delivery of ultrasound technology to particular targets. While lesioning is the primary approved application of magnetic resonance-guided focused ultrasound at present, the ability to transient and precisely open the blood-brain barrier has the potential to clear brain pathologies and deliver restorative therapies, but this more experimental method presents unique difficulties to overcome. Finally, regulatory and reimbursement hurdles currently remain complex and continue to limit widespread application of even approved, effective applications. Here we review many of these challenges, discuss several solutions that have already been developed, and propose potential options for addressing some of these complexities in the future., (Copyright © 2020. Published by Elsevier Inc.)

Magnetic resonance-guided focused ultrasound (MRgFUS) is a cutting-edge technology that is changing the practice of movement disorders surgery. Given the noninvasive and innovative nature of this technology, there is great interest in expanding the use of MRgFUS to additional diseases and applications. Current approved applications target the motor thalamus to treat tremor, but clinical trials are exploring or plan to study noninvasive lesions with MRgFUS to ablate tumor cells in the brain as well as novel targets for movement disorders and brain regions associated with pain and epilepsy. Although there are additional potential indications for lesioning, the ability to improve function by destroying parts of the brain is still limited. However, MRgFUS can also be applied to a brain target after intravenous delivery of microbubbles to create cavitations and focally open the blood-brain barrier (BBB). This has already proven to be safe and technically feasible in human patients with Alzheimer's disease, and this action alone has potential to clear extracellular pathology associated with this and other neurodegenerative disorders. This also provides a foundation for noninvasive intravenous delivery of therapeutic molecules to precise brain targets after transient disruption of the BBB. Certain chemotherapies for brain tumors, immunotherapies, gene, and cell therapies are all examples of therapeutic or even restorative agents that normally will not enter the brain without direct infusion but which have been shown in preclinical studies to effectively traverse the BBB after transient disruption with MRgFUS. Here we will review these novel applications of MRgFUS to provide an overview of the extraordinary potential of this technology to expand future neurosurgical treatments of brain diseases., (Copyright © 2020. Published by Elsevier Inc.)

The ability of ultrasonography to safely penetrate deeply into the brain has made it an attractive technology for neurological applications for almost 1 century. Having recognized that converging ultrasound waves could deliver high levels of energy to a target and spare the overlying and surrounding brain, early applications used craniotomies to allow transducers to contact the brain or dural surface. The development of transducer arrays that could permit the transit of sufficient numbers of ultrasound waves to deliver high energies to a target, even with the loss of energy from the skull, has now resulted in clinical systems that can permit noninvasive focused ultrasound procedures that leave the skull intact. Another major milestone in the field was the marriage of focused ultrasonography with magnetic resonance thermometry. This provides real-time feedback regarding the level and location of brain tissue heating, allowing for precise elevation of temperatures within a desired target to lead to focal therapeutic lesions. The major clinical use of this technology, at present, has been limited to treatment of refractory essential tremor and parkinsonian tremor, although the first study of this approach had targeted sensory thalamus for refractory pain, and new targets and disease indications are under study. Finally, focused ultrasonography can also be used at a lower frequency and energy level when combined with intravenous microbubbles to create cavitations, which will open the blood-brain barrier rather than ablate tissue. In the present review, we have discussed the historical and scientific foundations and current clinical applications of magnetic resonance-guided focused ultrasonography and the genesis and background that led to the use of this technique for focal blood-brain barrier disruption., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Magnetic resonance guided focused ultrasound (MRgFUS) of the globus pallidus interna (GPi) has shown promise in the treatment of drug-resistant Parkinson's disease, though direct visualization of the GPi remains challenging with MRI. The purpose of this study was to compare various preoperative MR imaging techniques and to evaluate the utility of quantitative susceptibility imaging (QSM) in the depiction of the GPi prior to MRgFUS ablation., Materials and Methods: Six patients with medication refractory advanced idiopathic Parkinson's disease were referred for preoperative MR imaging prior to MRgFUS pallidotomy. Axial T1WI and T2WI, Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR), and QSM sequences were acquired. DTI tractography was performed to delineate the corticospinal tracts. Qualitative visualization scores and contrast to noise ratios (CNR) were recorded and measured on all images., Results: QSM had significantly higher median qualitative visualization scores (3.00) compared with the T1WI (1.00), T2WI (1.50), and FGATIR sequences (1.50) (p < 0.05). QSM provided superior CNR for GPi depiction in each category (GPi-GPe and GPi-IC), respectively. For GPi-GPe, median CNR for T1WI, T2WI, FGATIR, and QSM was 1.13, 1.68, 0.79, and 10.78. For GPi-IC, median CNR for T1WI, T2WI, FGATIR, and QSM was 1.48, 4.63, 4.24, and 40.26, respectively (p < 0.05)., Conclusion: QSM offers improved visualization of the GPi compared with the traditional and currently recommended MR sequences prior to MRgFUS ablation in patients with Parkinson's disease. These results suggest that QSM should be considered as part of all preoperative imaging protocols prior to MRgFUS pallidotomy., (Copyright © 2020. Published by Elsevier Inc.)

There is a pressing need to increase the rigor of research in the life and biomedical sciences. To address this issue, we propose that communities of 'rigor champions' be established to campaign for reforms of the research culture that has led to shortcomings in rigor. These communities of rigor champions would also assist in the development and adoption of a comprehensive educational platform that would teach the principles of rigorous science to researchers at all career stages., Competing Interests: WK, SB, CB, JB, EB, EC, DD, JE, PG, KG, SH, MK, BK, AK, DL, MM, CM, MM, BO, JO, NP, IR, CR, AS, SU, DC, SS No competing interests declared

Purpose of Review: To summarize the current state of art of gene therapy for Parkinson's disease., Recent Findings: Introduction of the gene for glutamic acid decarboxylase (GAD) into the subthalamic nucleus was successful in a randomized, double-blind clinical trial and recent data from PET imaging identified novel brain networks underlying both sham surgery and therapeutic responses in treated participants. Two other approaches use viral vectors to increase dopamine transmission in the striatum. Both strategies are being studied in active trials and have recently reported promising responses in human participants. New strategies in Parkinson's disease are focused upon targeting the underlying pathogenesis in those with genetic defects thought to be the cause of disease. Finally, noninvasive focused ultrasound is currently being tested for lesioning in Parkinson's disease patients, but this same technology can be used to transiently open the blood-brain barrier, raising the potential for noninvasive delivery of gene therapy vectors to specific brain targets., Summary: Parkinson's disease gene therapy has moved from purely animal research three decades ago, to initial human studies two decades ago to many applications moving into late stage trials, currently. Recent successes and promising new technology should only accelerate the advance of gene therapy into active clinical practice.

Objective: The authors tested the feasibility of magnetic resonance-guided focused ultrasound (MRgFUS) ablation of mesial temporal lobe epilepsy (MTLE) seizure circuits. Up to one-third of patients with mesial temporal sclerosis (MTS) suffer from medically refractory epilepsy requiring surgery. Because current options such as open resection, laser ablation, and Gamma Knife radiosurgery pose potential risks, such as infection, hemorrhage, and ionizing radiation, and because they often produce visual or neuropsychological deficits, the authors developed a noninvasive MRgFUS ablation strategy for mesial temporal disconnection to mitigate these risks., Methods: The authors retrospectively reviewed 3-T MRI scans obtained with diffusion tensor imaging (DTI). The study group included 10 patients with essential tremor (ET) who underwent pretreatment CT and MRI prior to MRgFUS, and 2 patients with MTS who underwent MRI. Fiber tracking of the fornix-fimbria pathway and inferior optic radiations was performed, ablation sites mimicking targets of open posterior hippocampal disconnection were modeled, and theoretical MRgFUS surgical plans were devised. Distances between the targets and optic radiations were measured, helmet angulations were prescribed, and the numbers of available MRgFUS array elements were calculated., Results: Tractograms of fornix-fimbria and optic radiations were generated in all ET and MTS patients successfully. Of the 10 patients with both the CT and MRI data necessary for the analysis, 8 patients had adequate elements available to target the ablation site. A margin (mean 8.5 mm, range 6.5-9.8 mm) of separation was maintained between the target lesion and optic radiations., Conclusions: MRgFUS offers a noninvasive option for seizure tract disruption. DTI identifies fornix-fimbria and optic radiations to localize optimal ablation targets and critical surrounding structures, minimizing risk of postoperative visual field deficits. This theoretical modeling study provides the necessary groundwork for future clinical trials to apply this novel neurosurgical technique to patients with refractory MTLE and surgical contraindications, multiple prior surgeries, or other factors favoring noninvasive treatment.

Magnetic resonance guided focused ultrasound (MRgFUS) recently received FDA approval for treatment of medically refractory essential tremor and significant progress continues to be made in operational protocols. To that end, the goal of this technical article is to illustrate current optimization strategies for preprocedural, intraprocedural, and postprocedural imaging, with a particular focus on technically challenging intraprocedural MRI to assess satisfactory ablation.

Correction to:Clin Neuroradiol 2018 https://doi.org/10.1007/s00062-018-0709-x The original version of this article unfortunately contained a mistake. The tagging of the name J. Levi Chazen was incorrect. The correct information is given ….

Objective: Skull density ratio (SDR) assesses the transparency of the skull to ultrasound. Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in essential tremor (ET) patients with a lower SDR may be less effective, and the risk for complications may be increased. To address these questions, the authors analyzed clinical outcomes of MRgFUS thalamotomy based on SDRs., Methods: In 189 patients, 3 outcomes were correlated with SDRs. Efficacy was based on improvement in Clinical Rating Scale for Tremor (CRST) scores 1 year after MRgFUS. Procedural efficiency was determined by the ease of achieving a peak voxel temperature of 54°C. Safety was based on the rate of the most severe procedure-related adverse event. SDRs were categorized at thresholds of 0.45 and 0.40, selected based on published criteria., Results: Of 189 patients, 53 (28%) had an SDR < 0.45 and 20 (11%) had an SDR < 0.40. There was no significant difference in improvement in CRST scores between those with an SDR ≥ 0.45 (58% ± 24%), 0.40 ≤ SDR < 0.45 (i.e., SDR ≥ 0.40 but < 0.45) (63% ± 27%), and SDR < 0.40 (49% ± 28%; p = 0.0744). Target temperature was achieved more often in those with an SDR ≥ 0.45 (p < 0.001). Rates of adverse events were lower in the groups with an SDR < 0.45 (p = 0.013), with no severe adverse events in these groups., Conclusions: MRgFUS treatment of ET can be effectively and safely performed in patients with an SDR < 0.45 and an SDR < 0.40, although the procedure is more efficient when SDR ≥ 0.45.

Objective: Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain., Methods: Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses., Results: Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%-75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons., Conclusions: This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders.

Gene therapy is emerging as a promising approach for treating neurological disorders, including Parkinson's disease (PD). A phase 2 clinical trial showed that delivering glutamic acid decarboxylase ( GAD ) into the subthalamic nucleus (STN) of patients with PD had therapeutic effects. To determine the mechanism underlying this response, we analyzed metabolic imaging data from patients who received gene therapy and those randomized to sham surgery, all of whom had been scanned preoperatively and at 6 and 12 months after surgery. Those who received GAD gene therapy developed a unique treatment-dependent polysynaptic brain circuit that we termed as the GAD -related pattern (GADRP), which reflected the formation of new polysynaptic functional pathways linking the STN to motor cortical regions. Patients in both the treatment group and the sham group expressed the previously reported placebo network (the sham surgery-related pattern or SSRP) when blinded to the treatment received. However, only the appearance of the GADRP correlated with clinical improvement in the gene therapy-treated subjects. Treatment-induced brain circuits can thus be useful in clinical trials for isolating true treatment responses and providing insight into their underlying biological mechanisms., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

OBJECTIVE The objective of this study was to evaluate the utility of diffusion tensor imaging (DTI) tractography-based targeting of the dentatorubrothalamic tract (DRT) for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in patients with essential tremor (ET) and correlate postprocedural tract disruption with clinical outcomes. METHODS Four patients received preprocedural and immediate postprocedural DTI in addition to traditional anatomical MRI sequences for MRgFUS thalamotomy. Optimal ablation sites were selected based on the patient-specific location of the DRT as demonstrated by DTI (direct targeting) and correlated with traditional atlas-based measurements for thalamic ventral intermediate nucleus (Vim) lesioning (indirect targeting). Fiber tracts were displayed three-dimensionally during the procedure and used in conjunction with clinical signs of tremor control for fine correction of the ablation site. Immediately following the conclusion of the procedure, the MRgFUS head frame was removed and patients were placed in a 32-channel MRI head coil for follow-up DTI and anatomical MRI sequences. RESULTS All patients had excellent postoperative tremor control and successful pre- and postprocedural DTI fiber tracking of the corticospinal tract, medial lemniscus, and DRT. Immediate postprocedure DTI failed to track the DRT ipsilateral to the lesion site with a preserved contralateral DRT, coincident with substantial resolution of contralateral tremor. CONCLUSIONS DTI can reliably identify the optimal ablation target and demonstrates tract disruption on immediate postprocedural imaging. A clinical improvement of ET was observed immediately following the procedure, correlating with DRT disruption and suggesting that interruption of the DRT is a consequence of clinically successful MRgFUS thalamotomy. These findings may have utility for both MRgFUS procedure planning in surgically naive patients and retreatment of patients who have previously undergone unsuccessful thalamic Vim lesioning.

Background: Magnetic resonance imaging-guided focused ultrasound thalamotomy is approved by the U.S. Food and Drug Administration for treatment of essential tremor. Although this incisionless technology creates an ablative lesion, it potentially avoids serious complications of open stereotactic surgery., Objective: To determine the safety profile of magnetic resonance imaging-guided focused ultrasound unilateral thalamotomy for essential tremor, including frequency, and severity of adverse events, including serious adverse events., Methods: Analysis of safety data for magnetic resonance imaging-guided focused ultrasound thalamotomy (186 patients, five studies)., Results: Procedure-related serious adverse events were very infrequent (1.6%), without intracerebral hemorrhages or infections. Adverse events were usually transient and were commonly rated as mild (79%) and rarely severe (1%). As previously reported, abnormalities in sensation and balance were the commonest thalamotomy-related adverse events., Conclusion: The overall safety profile of magnetic resonance imaging-guided focused ultrasound thalamotomy supports its role as a new option for patients with medically refractory essential tremor. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage. To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of delivery to the CNS of nonhuman primates of AAVrh.10hAPOE2-HA, an AAVrh.10 serotype coding for an HA-tagged human APOE2 cDNA sequence, were evaluated. To evaluate the route of delivery that achieves the widest extent of APOE2 expression in the CNS, the expression of APOE2 in the CNS was evaluated 2 months following vector administration for APOE2 DNA, mRNA, and protein. Finally, using conventional toxicology assays, the safety of the best route of delivery was assessed. The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.

In Parkinson disease (PD), a complex neurodegenerative disorder that affects nearly 10 million people worldwide, motor skills are significantly impaired. However, onset and progression of motor deficits and the neural correlates of these deficits are poorly understood. We used a genetic mouse model of PD (Pink1-/-), with phenotypic similarities to human PD, to investigate the manifestation of early-onset sensorimotor deficits. We hypothesized this mouse model would show early vocalization and gross motor dysfunction that would be progressive in nature. Pink1-/- mice, compared to wild type (WT) controls, were evaluated at 2, 3, 4, 5, and 6 months of age. To quantify deficit progression, ultrasonic vocalizations and spontaneous locomotor activity (cylinder test and pole test) were analyzed. Although somewhat variable, in general, Pink1-/- mice produced significantly more simple calls with reduced intensity as well as a larger percentage of cycle calls compared to WT counterparts. However, there were no significant differences in duration, bandwidth, or peak frequency for any of the ultrasonic call types between genotypes. Pink1-/- mice showed a significant impairment in limb motor skills with fewer hindlimb steps, forelimb steps, and rears and lands in the cylinder test compared to WT. Additionally, Pink1-/- mice took significantly longer to turn and traverse during the pole test. Immunohistochemical staining showed no significant difference in the number of tyrosine hydroxylase (TH) positive cells in the substantia nigra or density of TH staining in the striatum between genotypes. These data suggest the Pink1-/- mouse model may be instrumental in defining early motor biomarkers of PD in the absence of nigrostriatal dopamine loss., (Published by Elsevier B.V.)

Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols., Level of Evidence: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951-971., (© 2017 International Society for Magnetic Resonance in Medicine.)

BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2- GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and 18 F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2- GAD group compared with the sham group continued at 12 months [time effect: F (4,138) = 11.55, P < 0.001; group effect: F (1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2- GAD group ( P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines ( P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2- GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2- GAD group ( P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2- GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc., Competing Interests: Conflict of interest: C.C. Tang, P.A. Le Witt, M.A. Leehey, S.G. Ojemann, A.W. Flaherty, S.K. Kostyk, M.S. Siddiqui, S.B. Tatter, J.M. Schwalb, K.L. Poston, I.H. Richard, M.J. During, and M.G. Kaplitt have received funding from funding from Neurologix Inc. M.J. During and M.G. Kaplitt are coinventors on the patent re: Glutamic acid decarboxylase (GAD) based delivery systems (United States Patent No. 7,695,959 B2). D. Eidelberg is a coinventor on the patents re: Markers for use in screening patients for nervous system dysfunction and a method and apparatus for using same (United States Patent No. 5,632,276 and No. 5,873,823). Additional COI information is reported in the supplemental materials.

The reduced movement repertoire of Parkinson's disease (PD) is mainly due to degeneration of nigrostriatal dopamine neurons. Restoration of dopamine transmission by levodopa (L-DOPA) relieves motor symptoms of PD but often causes disabling dyskinesias. Subchronic L-DOPA increases levels of adaptor protein p11 (S100A10) in dopaminoceptive neurons of the striatum. Using experimental mouse models of Parkinsonism, we report here that global p11 knockout (KO) mice develop fewer jaw tremors in response to tacrine. Following L-DOPA, global p11KO mice show reduced therapeutic responses on rotational motor sensitization, but also develop less dyskinetic side effects. Studies using conditional p11KO mice reveal that distinct cell populations mediate these therapeutic and side effects. Selective deletion of p11 in cholinergic acetyltransferase (ChAT) neurons reduces tacrine-induced tremor. Mice lacking p11 in dopamine D2R-containing neurons have a reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit tremor and rotational responses toward L-DOPA, but develop less dyskinesia. Moreover, coadministration of rapamycin with L-DOPA counteracts L-DOPA-induced dyskinesias in wild-type mice, but not in mice lacking p11 in D1R-containing neurons. 6-OHDA lesioning causes an increase of evoked striatal glutamate release in wild type, but not in global p11KO mice, indicating that altered glutamate neurotransmission could contribute to the reduced L-DOPA responsivity. These data demonstrate that p11 located in ChAT or D2R-containing neurons is involved in regulating therapeutic actions in experimental PD, whereas p11 in D1R-containing neurons underlies the development of L-DOPA-induced dyskinesias.

Complications of dopamine replacement for Parkinson's disease (PD) can limit therapeutic options, leading to interest in identifying novel pathways that can be exploited to improve treatment. p11 (S100A10) is a cellular scaffold protein that binds to and potentiates the activity of various ion channels and neurotransmitter receptors. We have previously reported that p11 can influence ventral striatal function in models of depression and drug addiction, and thus we hypothesized that dorsal striatal p11 might mediate motor function and drug responses in parkinsonian mice. To focally inhibit p11 expression in the dorsal striatum, we injected an adeno-associated virus (AAV) vector producing a short hairpin RNA (AAV.sh.p11). This intervention reduced the impairment in motor function on forced tasks, such as rotarod and treadmill tests, caused by substantia nigra lesioning in mice. Measures of spontaneous movement and gait in an open-field test declined as expected in control lesioned mice, whereas AAV.sh.p11 mice remained at or near normal baseline. Mice with unilateral lesions were then challenged with l-dopa (levodopa) and various dopamine receptor agonists, and resulting rotational behaviors were significantly reduced after ipsilateral inhibition of dorsal striatal p11 expression. Finally, p11 knockdown in the dorsal striatum dramatically reduced l-dopa-induced abnormal involuntary movements compared with control mice. These data indicate that focal inhibition of p11 action in the dorsal striatum could be a promising PD therapeutic target to improve motor function while reducing l-dopa-induced dyskinesias.

Little is known about the molecular similarities and differences between neurons in the ventral (vSt) and dorsal striatum (dSt) and their physiological implications. In the vSt, serotonin [5-Hydroxytryptamine (5-HT)] modulates mood control and pleasure response, whereas in the dSt, 5-HT regulates motor behavior. Here we show that, in mice, 5-HT depolarizes cholinergic interneurons (ChIs) of the dSt whereas hyperpolarizing ChIs from the vSt by acting on different 5-HT receptor isoforms. In the vSt, 5-HT1A (a postsynaptic receptor) and 5-HT1B (a presynaptic receptor) are highly expressed, and synergistically inhibit the excitability of ChIs. The inhibitory modulation by 5-HT1B, but not that by 5-HT1A, is mediated by p11, a protein associated with major depressive disorder. Specific deletion of 5-HT1B from cholinergic neurons results in impaired inhibition of ACh release in the vSt and in anhedonic-like behavior.

Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid-protein phosphatase known primarily as a growth preventing tumor suppressor. PTEN is also expressed in neurons, and pathways modulated by PTEN can influence neuronal function. Here we report a novel function of PTEN as a regulator of striatal dopamine signaling in a model of Parkinson's disease (PD). Blocking PTEN expression with an adeno-associated virus (AAV) vector expressing a small hairpin RNA (shRNA) resulted in reduced responses of cultured striatal neurons to dopamine, which appeared to be largely due to reduction in D2 receptor activation. Co-expression of shRNA-resistant wild-type and mutant forms of PTEN indicated that the lipid-phosphatase activity was essential for this effect. In both normal and Parkinsonian rats, inhibition of striatal PTEN in vivo resulted in motor dysfunction and impaired responses to dopamine, particularly D2 receptor agonists. Expression of PTEN mutants confirmed the lipid-phosphatase activity as critical, while co-expression of a dominant-negative form of Akt overcame the PTEN shRNA effect. These results identify PTEN as a key mediator of striatal responses to dopamine, and suggest that drugs designed to potentiate PTEN expression or activity, such as cancer chemotherapeutics, may also be useful for improving striatal responses to dopamine in conditions of dopamine depletion such as PD. This also suggests that strategies which increase Akt or decrease PTEN expression or function, such as growth factors to prevent neuronal death, may have a paradoxical effect on neurological functioning by inhibiting striatal responses to dopamine., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The comorbidity of depression and cocaine addiction suggests shared mechanisms and anatomical pathways. Specifically, the limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders. P11 (S100A10) is a promising target for manipulating depression and addiction in mice. We summarized the recent genetic and viral strategies used to determine how the titration of p11 levels within the NAc affects hedonic behavior and cocaine reward learning in mice. In particular, p11 in the ChAT+ cells or DRD1+ MSN of the NAc, controls depressive-like behavior or cocaine reward, respectively. Treatments to counter maladaptation of p11 levels in the NAc could provide novel therapeutic opportunities for depression and cocaine addiction in humans., (© 2015 médecine/sciences – Inserm.)

Malignant gliomas represent one of the most aggressive forms of cancer, displaying high mortality rates and limited treatment options. Specific subpopulations of cells residing in the tumor niche with stem-like characteristics have been postulated to initiate and maintain neoplasticity while resisting conventional therapies. The study presented here aims to define the role of glycogen synthase kinase 3 beta (GSK3b) in patient-derived glioblastoma (GBM) stem-like cell (GSC) proliferation, apoptosis and invasion. To evaluate the potential role of GSK3b in GBM, protein profiles from 68 GBM patients and 20 normal brain samples were analyzed for EGFR-mediated PI3kinase/Akt and GSK3b signaling molecules including protein phosphatase 2A (PP2A). To better understand the function of GSK3b in GBM, GSCs were isolated from GBM patient samples. Blocking GSK3b phosphorylation at Serine 9 attenuated cell proliferation while concomitantly stimulating apoptosis through activation of Caspase-3 in patient-derived GSCs. Increasing GSK3b protein content resulted in the inhibition of cell proliferation, colony formation and stimulated programmed cell death. Depleting GSK3b in GSCs down regulated PP2A. Furthermore, knocking down PP2A or blocking its activity by okadaic acid inactivated GSK3b by increasing GSK3b phosphorylation at Serine 9. Our data suggests that GSK3b may function as a regulator of apoptosis and tumorigenesis in GSCs. Therapeutic approaches targeting GSK3b in glioblastoma stem-like cells may be a useful addition to our current therapeutic armamentarium.

There is increasing interest among functional neurosurgeons in the potential for novel therapies to impact upon diseases beyond movement disorders and pain. A target of increasing interest is the nucleus accumbens (NAc), which has long been studied as a key brain region mediating a variety of behaviors, including reward and satisfaction. As such, focal modulation of the biology of the NAc with deep brain stimulation or novel biological therapies such as gene therapy or cell transplantation could have a major impact upon disorders such as depression and drug addiction. In order to both develop appropriate therapies and then deliver them in an effective fashion, a thorough understanding of the biology, physiology, and anatomy of the NAc is critical. Here, we review the existing literature regarding several areas critical to the development of new therapies, including the known pharmacology, physiology, and connectivity of the NAc, as well as evidence supporting the potential for various NAc surgical therapies in animal models. We then review the relevant anatomy of the NAc, with particular attention to the surgical anatomy, imaging, and targeting necessary to facilitate a proper localization and delivery of new agents to this region. The NAc is a fascinating and potentially rich target for stereotactic neurosurgical intervention, and analysis of existing information regarding all aspects of this structure should help potentiate therapeutic advances and reduce complications from future studies of neurosurgical intervention in this region for a variety of disorders. © 2015 S. Karger AG, Basel.

Recurrent axon collaterals are a major means of communication between spiny projection neurons (SPNs) in the striatum and profoundly affect the function of the basal ganglia. However, little is known about the molecular and cellular mechanisms that underlie this communication. We show that intrastriatal nitric oxide (NO) signaling elevates the expression of the vesicular GABA transporter (VGAT) within recurrent collaterals of SPNs. Down-regulation of striatal NO signaling resulted in an attenuation of GABAergic signaling in SPN local collaterals, down-regulation of VGAT expression in local processes of SPNs, and impaired motor behavior. PKG1 and cAMP response element-binding protein are involved in the signal transduction that transcriptionally regulates VGAT by NO. These data suggest that transcriptional control of the vesicular GABA transporter by NO regulates GABA transmission and action selection.

Background: The high rate of comorbidity between depression and cocaine addiction suggests shared molecular mechanisms and anatomical pathways. Limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders, yet how different cell types within these structures contribute to the pathogenesis remains elusive. Downregulation of p11 (S100A10), specifically in the NAc, elicits depressive-like behaviors in mice, but its role in drug addiction is unknown., Methods: We combined mouse genetics and viral strategies to determine how the titration of p11 levels within the entire NAc affects the rewarding actions of cocaine on behavior (six to eight mice per group) and molecular correlates (three experiments, five to eight mice per group). Finally, the manipulation of p11 expression in distinct NAc dopaminoceptive neuronal subsets distinguished cell-type specific effects of p11 on cocaine reward (five to eight mice per group)., Results: We demonstrated that p11 knockout mice have enhanced cocaine conditioned place preference, which is reproduced by the focal downregulation of p11 in the NAc of wild-type mice. In wild-type mice, cocaine reduced p11 expression in the NAc, while p11 overexpression exclusively in the NAc reduced cocaine conditioned place preference. Finally, we identified dopamine receptor-1 expressing medium spiny neurons as key mediators of the effects of p11 on cocaine reward., Conclusions: Our data provide evidence that disruption of p11 homeostasis in the NAc, particularly in dopamine receptor-1 expressing medium spiny neurons, may underlie pathophysiological mechanisms of cocaine rewarding action. Treatments to counter maladaptation of p11 levels may provide novel therapeutic opportunities for cocaine addiction., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Patient responses to placebo and sham effects are a major obstacle to the development of therapies for brain disorders, including Parkinson's disease (PD). Here, we used functional brain imaging and network analysis to study the circuitry underlying placebo effects in PD subjects randomized to sham surgery as part of a double-blind gene therapy trial. Metabolic imaging was performed prior to randomization, then again at 6 and 12 months after sham surgery. In this cohort, the sham response was associated with the expression of a distinct cerebello-limbic circuit. The expression of this network increased consistently in patients blinded to treatment and correlated with independent clinical ratings. Once patients were unblinded, network expression declined toward baseline levels. Analogous network alterations were not seen with open-label levodopa treatment or during disease progression. Furthermore, sham outcomes in blinded patients correlated with baseline network expression, suggesting the potential use of this quantitative measure to identify "sham-susceptible" subjects before randomization. Indeed, Monte Carlo simulations revealed that a priori exclusion of such individuals substantially lowers the number of randomized participants needed to demonstrate treatment efficacy. Individualized subject selection based on a predetermined network criterion may therefore limit the need for sham interventions in future clinical trials.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The debilitating choreic movements that plague HD patients have been attributed to striatal degeneration induced by the loss of cortically supplied brain-derived neurotrophic factor (BDNF). Here, we show that in mouse models of early symptomatic HD, BDNF delivery to the striatum and its activation of tyrosine-related kinase B (TrkB) receptors were normal. However, in striatal neurons responsible for movement suppression, TrkB receptors failed to properly engage postsynaptic signaling mechanisms controlling the induction of potentiation at corticostriatal synapses. Plasticity was rescued by inhibiting p75 neurotrophin receptor (p75NTR) signaling or its downstream target phosphatase-and-tensin-homolog-deleted-on-chromosome-10 (PTEN). Thus, corticostriatal synaptic dysfunction early in HD is attributable to a correctable defect in the response to BDNF, not its delivery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.