Emily Knight

Deep brain stimulation induces BOLD activation in motor and non-motor networks: an fMRI comparison study of STN and EN/GPi DBS in large animals.

The combination of deep brain stimulation (DBS) and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. The goal of this study was to trace DBS-induced global neuronal network activation in a large animal model by monitoring the blood oxygenation level-dependent (BOLD) response on fMRI. We conducted DBS in normal anesthetized pigs, targeting the subthalamic nucleus (STN) (n=7) and the entopeduncular nucleus (EN), the non-primate analog of the primate globus pallidus interna (n=4). Using a normalized functional activation map for group analysis and the application of general linear modeling across subjects, we found that both STN and EN/GPi DBS significantly increased BOLD activation in the ipsilateral sensorimotor network (FDR<0.001). In addition, we found differential, target-specific, non-motor network effects. In each group the activated brain areas showed a distinctive correlation pattern forming a group of network connections. Results suggest that the scope of DBS extends beyond an ablation-like effect and that it may have modulatory effects not only on circuits that facilitate motor function but also on those involved in higher cognitive and emotional processing. Taken together, our results show that the swine model for DBS fMRI, which conforms to human implanted DBS electrode configurations and human neuroanatomy, may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS.

Nucleus Accumbens Deep Brain Stimulation Results in Insula and Prefrontal Activation: A Large Animal fMRI Study

Background Deep Brain Stimulation (DBS) of the nucleus accumbens (NAc) has previously been investigated clinically for the treatment of several psychiatric conditions, including obsessive-compulsive disorder and treatment resistant depression. However, the mechanism underlying the therapeutic benefit of DBS, including the brain areas that are activated, remains largely unknown. Here, we utilized 3.0 T functional Magnetic Resonance Imaging (fMRI) changes in Blood Oxygenation Level-Dependent (BOLD) signal to test the hypothesis that NAc/internal capsule DBS results in global neural network activation in a large animal (porcine) model Methods Animals (n = 10) were implanted in the NAc/internal capsule with DBS electrodes and received stimulation (1, 3, and 5 V, 130 Hz, and pulse widths of 100 and 500 µsec). BOLD signal changes were evaluated using a gradient echo-echo planar imaging (GRE-EPI) sequence in 3.0 T MRI. We used a normalized functional activation map for group analysis and applied general linear modeling across subjects (FDR<0.001). The anatomical location of the implanted DBS lead was confirmed with a CT scan Results We observed stimulation-evoked activation in the ipsilateral prefrontal cortex, insula, cingulate and bilateral parahippocampal region along with decrease in BOLD signal in the ipsilateral dorsal region of the thalamus. Furthermore, as the stimulation voltage increased from 3 V to 5 V, the region of BOLD signal modulation increased in insula, thalamus, and parahippocampal cortex and decreased in the cingulate and prefrontal cortex. We also demonstrated that right and left NAc/internal capsule stimulation modulates identical areas ipsilateral to the side of the stimulation Conclusions Our results suggest that NAc/internal capsule DBS results in modulation of psychiatrically important brain areas notably the prefrontal cortex, cingulate, and insular cortex, which may underlie the therapeutic effect of NAc DBS in psychiatric disorders. Finally, our fMRI setup in the large animal may be a useful platform for translational studies investigating the global neuromodulatory effects of DBS

An Essential Role for Adenosine Signaling in Alcohol Abuse

In the central nervous system (CNS), adenosine plays an important role in regulating neuronal activity and modulates signaling by other neurotransmitters, including GABA, glutamate, and dopamine. Adenosine suppresses neurotransmitter release, reduces neuronal excitability, and regulates ion channel function through activation of four classes of G protein-coupled receptors, A(1), A(2A), A(2B), and A(3). Central adenosine are largely controlled by nucleoside transporters, which transport adenosine levels across the plasma membrane. Adenosine has been shown to modulate cortical glutamate signaling and ventral-tegmental dopaminergic signaling, which are involved in several aspects of alcohol use disorders. Acute ethanol elevates extracellular adenosine levels by selectively inhibiting the type 1 equilibrative nucleoside transporter, ENT1. Raised adenosine levels mediate the ataxic and sedative/hypnotic effects of ethanol through activation of A(1) receptors in the cerebellum, striatum, and cerebral cortex. Recently, we have shown that pharmacological inhibition or genetic deletion of ENT1 reduces the expression of excitatory amino acid transporter 2 (EAAT2), the primary regulator of extracellular glutamate, in astrocytes. These lines of evidence support a central role for adenosine-mediated glutamate signaling and the involvement of astrocytes in regulating ethanol intoxication and preference. In this paper, we discuss recent findings on the implication of adenosine signaling in alcohol use disorders.

Transitions between Central and Peripheral Vision Create Spatial/Temporal Distortions: A Hypothesis Concerning the Perceived Break of the Curveball

Background The human visual system does not treat all parts of an image equally: the central segments of an image, which fall on the fovea, are processed with a higher resolution than the segments that fall in the visual periphery. Even though the differences between foveal and peripheral resolution are large, these differences do not usually disrupt our perception of seamless visual space. Here we examine a motion stimulus in which the shift from foveal to peripheral viewing creates a dramatic spatial/temporal discontinuity. Methodology/Principal Findings The stimulus consists of a descending disk (global motion) with an internal moving grating (local motion). When observers view the disk centrally, they perceive both global and local motion (i.e., observers see the disks vertical descent and the internal spinning). When observers view the disk peripherally, the internal portion appears stationary, and the disk appears to descend at an angle. The angle of perceived descent increases as the observer views the stimulus from further in the periphery. We examine the first- and second-order information content in the display with the use of a three-dimensional Fourier analysis and show how our results can be used to describe perceived spatial/temporal discontinuities in real-world situations. Conclusions/Significance The perceived shift of the disks direction in the periphery is consistent with a model in which foveal processing separates first- and second-order motion information while peripheral processing integrates first- and second-order motion information. We argue that the perceived distortion may influence real-world visual observations. To this end, we present a hypothesis and analysis of the perception of the curveball and rising fastball in the sport of baseball. The curveball is a physically measurable phenomenon: the imbalance of forces created by the balls spin causes the ball to deviate from a straight line and to follow a smooth parabolic path. However, the curveball is also a perceptual puzzle because batters often report that the flight of the ball undergoes a dramatic and nearly discontinuous shift in position as the ball nears home plate. We suggest that the perception of a discontinuous shift in position results from differences between foveal and peripheral processing.

Centromedian-Parafascicular Deep Brain Stimulation Induces Differential Functional Inhibition of the Motor, Associative, and Limbic Circuits in Large Animals

BACKGROUND Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome. Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS. METHODS The combination of DBS and functional magnetic resonance imaging is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. With a within-subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n = 5). RESULTS Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS. CONCLUSIONS Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of Tourette syndrome as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms.

Frequency-dependent functional neuromodulatory effects on the motor network by ventral lateral thalamic deep brain stimulation in swine

Thalamic deep brain stimulation (DBS) is an FDA-approved neurosurgical treatment for medication-refractory essential tremor. Its therapeutic benefit is highly dependent upon stimulation frequency and voltage parameters. We investigated these stimulation parameter-dependent effects on neural network activation by performing functional magnetic resonance imaging (fMRI) during DBS of the ventral lateral (VL) thalamus and comparing the blood oxygenation level-dependent (BOLD) signals induced by multiple stimulation parameter combinations in a within-subject study of swine. Low (10 Hz) and high (130 Hz) frequency stimulation was applied at 3, 5, and 7 V in the VL thalamus of normal swine (n = 5). We found that stimulation frequency and voltage combinations differentially modulated the brain network activity in the sensorimotor cortex, the basal ganglia, and the cerebellum in a parameter-dependent manner. Notably, in the motor cortex, high frequency stimulation generated a negative BOLD response, while low frequency stimulation increased the positive BOLD response. These frequency-dependent differential effects suggest that the VL thalamus is an exemplary target for investigating functional network connectivity associated with therapeutic DBS.

Ruxolitinib in clinical practice for therapy of myelofibrosis: Single USA center experience following Food and Drug Administration approval

Myelofi brosis is a myeloproliferative neoplasm (MPN) characterized by increased bone marrow fi brosis, abnormal blood counts with peripheral cytopenias, extramedullary hematopoiesis, splenomegaly and profound constitutional symptoms [1,2]. Presenting as a primary disease or arising from polycythemia vera or essential thrombocythemia, myelofi brosis incurs a signifi cant symptom burden for patients, and results in a reduced survival of 2 – 11 years [3 – 7]. Amongst MPNs, myelofi brosis has represented a unique challenge to eff orts aimed at palliating symptoms or impacting disease course. Th e 2005 discovery of the gain-of-function JAK2V617F mutation present in a signifi cant proportion of patients with polycythemia vera, essential thrombocythemia and myelofi brosis opened a new avenue of investigation into potential novel therapies [8,9]. Among the various JAK2 inhibitor agents that have been developed, ruxolitinib was the fi rst to receive Food and Drug Administration (FDA) approval in the USA for the treatment of intermediate- and high-risk myelofi brosis. Th e Controlled Myelofi brosis Study with Oral JAK Inhibitor Treatment Trials compared ruxolitinib therapy in patients with intermediate-2 or high-risk myelofi brosis with placebo (COMFORT-I) and with best available therapy (COMFORT-II) [10,11]. In both trials, patients in the ruxolitinib group experienced signifi cant clinical benefi ts, including reduction in spleen size and amelioration of debilitating symptoms coupled with a tolerable side-eff ect profi le. In this study, we report the initial clinical experience with ruxolitinib outside of the clinical trial setting at our high-volume MPN program. Approval for the analysis was obtained from the Mayo Clinic Institutional Review Board. Patients with myelofi brosis including primary myelofi brosis (PMF), post-polycythemia vera (post-PV MF) and post-essential thrombocythemia (post-ET MF) were included. All patients had a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1/2 risk or high risk at the start of therapy [12]. Clinical and hematopathological data, including bone marrow biopsy, were reviewed in all cases, and the diagnosis was made in accordance with the 2008 World Health Organization criteria. Baseline patient information, physical examination results, laboratory data, hematopathology reports and interim follow-up information were acquired via chart review, with baseline obtained within 1 month of initiating therapy. All patients were prescribed ruxolitinib within 6 months of FDA approval. Ruxolitinib was started at 20 mg twice daily for patients with platelet counts of 200 10 9 /L or hemoglobin concentrations 10 g/dL. Patients with values below these were started on lower doses at the discretion of the providing physician. Doses were adjusted for lack of effi cacy or excess toxicity. Complete blood counts were checked on a weekly basis for the fi rst 2 months, then monthly thereafter. Drug effi cacy and toxicity were determined at follow-up visits and through telephone conversations with patients. Symptoms were assessed through a verbal response during review of systems questioning. Spleen size was determined by physical examination. Descriptive statistics were determined using means, medians, ranges and standard deviations for continuous variables. Categorical variables were evaluated using frequencies and relative frequencies.

Motor and Nonmotor Circuitry Activation Induced by Subthalamic Nucleus Deep Brain Stimulation in Patients With Parkinson Disease: Intraoperative Functional Magnetic Resonance Imaging for Deep Brain Stimulation.

OBJECTIVE To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease would affect the activity of motor and nonmotor networks, we applied intraoperative functional magnetic resonance imaging (fMRI) to patients receiving DBS. PATIENTS AND METHODS Ten patients receiving STN DBS for Parkinson disease underwent intraoperative 1.5-T fMRI during high-frequency stimulation delivered via an external pulse generator. The study was conducted between January 1, 2013, and September 30, 2014. RESULTS We observed blood oxygen level-dependent (BOLD) signal changes (false discovery rate <0.001) in the motor circuitry (including the primary motor, premotor, and supplementary motor cortices; thalamus; pedunculopontine nucleus; and cerebellum) and in the limbic circuitry (including the cingulate and insular cortices). Activation of the motor network was observed also after applying a Bonferroni correction (P<.001) to the data set, suggesting that across patients, BOLD changes in the motor circuitry are more consistent compared with those occurring in the nonmotor network. CONCLUSION These findings support the modulatory role of STN DBS on the activity of motor and nonmotor networks and suggest complex mechanisms as the basis of the efficacy of this treatment modality. Furthermore, these results suggest that across patients, BOLD changes in the motor circuitry are more consistent than those in the nonmotor network. With further studies combining the use of real-time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01809613.

Stimulation-Induced Transient Nonmotor Psychiatric Symptoms following Subthalamic Deep Brain Stimulation in Patients with Parkinson's Disease: Association with Clinical Outcomes and Neuroanatomical Correlates.

Background: The clinical and neurobiological underpinnings of transient nonmotor (TNM) psychiatric symptoms during the optimization of stimulation parameters in the course of subthalamic nucleus deep brain stimulation (STN-DBS) remain under intense investigation. Methods: Forty-nine patients with refractory Parkinsons disease underwent bilateral STN-DBS implants and were enrolled in a 24-week prospective, naturalistic follow-up study. Patients who exhibited TNM psychiatric manifestations during DBS parameter optimization were evaluated for potential associations with clinical outcome measures. Results: Twenty-nine TNM+ episodes were reported by 15 patients. No differences between TNM+ and TNM- groups were found in motor outcome. However, unlike the TNM- group, TNM+ patients did not report improvement in subsyndromal depression or quality of life. TNM+ episodes were more likely to emerge during bilateral monopolar stimulation of the medial STN. Conclusions: The occurrence of TNM psychiatric symptoms during optimization of stimulation parameters was associated with the persistence of subsyndromal depression and with lower quality of life ratings at 6 months. The neurobiological underpinnings of TNM symptoms are investigated yet remain difficult to explain.

Implementation of a chronic unilateral intraparenchymal drug delivery system in a swine model

BACKGROUND Systemic delivery of pharmacologic agents has led to many significant advances in the treatment of neurologic and psychiatric conditions. However, this approach has several limitations, including difficulty penetrating the blood-brain barrier and enzymatic degradation prior to reaching its intended target. Here, we describe the testing of a system allowing intraparenchymal (IPa) infusion of therapeutic agents directly to the appropriate anatomical targets, in a swine model. NEW METHOD Five male pigs underwent 3.0T magnetic resonance (MR) guided placement of an IPa catheter into the dorso-medial putamen, using a combined system of the Leksell stereotactic arc, a Mayo-developed MRI-compatible pig head frame, and a custom-designed Fred Haer Company (FHC) delivery system. RESULTS Our results show hemi-lateral coverage of the pig putamen is achievable from a single infusion point and that the volume of the bolus detected in each animal is uniform (1544±420mm(3)). COMPARISON WITH EXISTING METHOD The IPa infusion system is designed to isolate the intracranial catheter from bodily-induced forces while delivering drugs and molecules into the brain tissue by convection-enhanced delivery, with minimal-to-no catheter track backflow. CONCLUSION This study presents an innovative IPa drug delivery system, which includes a sophisticated catheter and implantable pump designed to deliver drugs and various molecules in a precise and controlled manner with limited backflow. It also demonstrates the efficacy of the delivery system, which has the potential to radically impact the treatment of a wide range of neurologic conditions. Lastly, the swine model used here has certain advantages for translation into clinical applications.